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EDITORIAL
Prostate cancer
This issue of the Hamdan Medical Journal deals with
prostate cancer (PCa). Everybody in the medical
community today understands that PCa is driven by
testosterone; nevertheless, we gained a tremendous
new insight into molecular pathways in the last
decade, showing that even castration-resistant PCa
still depends on testosterone and the androgen
receptor. In the state-of-the-art review entitled
�Testosterone and prostate cancer – new insights to
help guide therapy’, by Kratzik, I have tried to report,
in an understandable manner, the mechanisms
involved, as knowledge of these interactions has led
to development of new medications with which to
treat patients suffering from advanced PCa. In the
future, this will gain even more importance.
In the last 25 years, there has been a remarkable
increase in the diagnosis of PCa owing to the
introduction of PSA testing. In addition, a significant
proportion of men harbouring PCa will never
die of the disease, which raises the question of
overdiagnosis and overtreatment. One must not
forget the implications for these patients, since any
form of treatment bears a certain risk of morbidity.
The state-of-the-art review entitled �Biomarkers for
screening and early detection of prostate cancer’,
by Rieken and Shariat, deals with this subject and
provides recommendations for future research to
avoid unnecessary diagnosis.
The state-of-the-art review entitled �Focal ablation
of prostate cancer�, by Schatzl, reports on minimally
invasive treatment options such as high-intensity
focused ultrasound (HIFU). HIFU is mentioned in the
European Association of Urology Guidelines as an
experimental therapeutic option in selected cases and
may gain further importance in the future. This article
describes the potential advantages and limitations of
HIFU; however, at present, only a limited knowledge
of the long-term results is available.
The gold standard for localized PCa still is radical
retropubic prostatectomy (RP), which can be
performed via open surgery, laparoscopically or a
robotic approach. The final state-of-the-art review,
entitled �The Martini-Clinic technique of open radical
retropubic prostatectomy’, by Haese et al., deals with
the experience of RP of the Martini-Clinic in Germany.
RP is still the most widely used approach for PCa
treatment throughout the world and has undergone
remarkable developments, since its invention, to
prevent the risk of incontinence and impotence
in patients. This article describes the technique of
nerve-sparing RP and the results of such surgery.
Christian Kratzik
Medical University of Vienna
Währinger Gürtel 18–20
1090 Vienna Austria
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В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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В­State-of-the-art review
Testosterone and prostate cancer – new insights to
help guide therapy
Christian Kratzik
Medical University of Vienna, Vienna, Austria, and Karl Landsteiner Institute of Andrology and
Prostate Research, Mistelbach, Austria
Abstract
Introduction
The role of androgen deprivation in slowing the effects of metastatic prostate
cancer (PCa) has been recognized and established for more than 60 years.
Nevertheless, the effect is only temporary, and virtually all cancers progress
to a castration-resistant state. The discovery that late-stage PCa is driven
by androgen receptor (AR) signalling led to it being described as �castration
resistant’ rather than �hormone refractory’. During the castration-resistant
stage, the PCa cell develops multiple cellular pathways to overcome
androgen deprivation, including AR gene amplification, AR gene mutation,
ligand-independent activation of the AR, involvement of coregulators and
tumour stem cells as well as androgen production via a �backdoor pathway’.
New therapeutic options have been created to work against these survival
abilities of the PCa cell. Abiraterone (ZytigeВ®, Jannsen-Cilag, Neuss, Germany)
inhibits the cytochrome P450 17 (CYP17) enzyme, which is essential for
synthesis of testosterone from cholesterol, therefore affecting the traditional,
as well as backdoor, pathways. Another promising drug, enzalutamide
(XtandiВ®, Astellas, Tokyo, Japan) (formerly known as MDV3100), is an AR
signalling inhibitor that may be able to overcome the increased transcription
of ARs. It has been well known for several years that, in a certain number
of PCa patients, the application of testosterone results in a decrease in
prostate-specific antigen (PSA). To maintain cellular genetic stability and
viability, chromosomal DNA must be precisely replicated once and only once
during each cell cycle. This is carried out through a process known as DNA
replication licensing, in which a licensing factor is bound at the origin of
replication. In PCa cells, the AR has a �gain of function’ and acts as a licensing
factor, which implies that the AR is degraded during mitosis because,
without such degradation, the androgen-sensitive PCa cell will come to a
subsequent S-phase arrest. This may be an explanation for the long-standing
experimental paradox that testosterone can have a deleterious effect on
PCa cells.
It is estimated that one in six men will be diagnosed
with prostate cancer (PCa) during their lifetime.
Despite the wide application of prostate-specific
antigen (PSA) screening, a significant number of
patients still present with an advanced form of the
disease, and up to 40% of patients treated with
primary therapy, with curative intent, will experience
disease progression. For a large proportion of these
patients, hormonal therapy in the form of medical or
surgical castration [i.e. androgen deprivation therapy
(ADT)] can improve survival.
Correspondence: Christian Kratzik, Medical University of Vienna,
Währinger Gürtel 18–20, 1090 Vienna, Austria, and Karl Landsteiner
Institute of Andrology and Prostate Research, Spreitzergasse 9,
2130 Mistelbach, Austria. Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Clinicians treating PCa should have a complete
understanding of the molecular background and
effects of androgens and ARs to optimize treatment of
their patients.
The first step in the history of testosterone and PCa
was the seminal discovery by Charles Huggins and
Clarence Hodges nearly three-quarters of a century
ago, in the 1940s, that surgical castration has a
beneficial effect on patients with advanced PCa.1
The next step was the discovery concerning peptide
hormone production of the brain by Roger Guillemin
and Andrew Schally, who jointly received the Nobel
Prize in 1977.2 This was a crucial step to enable the
development of chemical castration. Since then,
we have gained further insight into the intracellular
signalling of testosterone and its role as the primary
driver for the growth of PCa cells. We have learned
that, in addition to peptide hormone production,
the androgen receptor (AR) plays a crucial role in the
control of the PCa cell. Progress since the 1970s has
led to a large variety of ADTs; however, despite being
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treated with ADT, PCa can develop into a castrationresistant state. There are a number of mechanisms
that contribute to the development of castrationresistant prostate cancer (CRPC) including reactivation
of ARs despite castrate levels of circulating androgens,
neuroendocrine differentiation and transformation
of the disease to an AR-negative, and truly
hormone-refractory, disease. CRPC usually develops
approximately 1–3 years after the start of ADT and
patients with CRPC have an average survival of
approximately 30 months. The poor quality of life and
prognosis of these patients has invigorated research
with the goals of understanding the biology behind
PCa progression and identifying novel therapeutic
targets. Paradoxically, some patients with metastatic
PCa experience symptomatic improvement after
exogenous testosterone administration3 and some
patients with CRPC experience a PSA decline after
exogenous testosterone administration.4,5
Effect of androgens in the normal
prostate
The majority of testosterone is synthesized under
the control of the hypothalamus and the anterior
pituitary gland by the Leydig cells of the testis and a
minority of testosterone is produced by the adrenal
gland. Approximately 3% of the testosterone in blood
is bioavailable, while the rest is bound to a sexual
hormone that is also bound to globulin and albumin.6
Testosterone is necessary for the sexual differentiation
in the fetus and maturation in the adult as well as for
the development and growth of the prostate.7
Testosterone is converted intracellularly by the
enzyme 5a-reductase in the basal and secretory
epithelial cells to dihydrotestosterone (DHT),
which is the more potent ligand for the AR. After
ligand binding and transactivation, the DHT–AR
complex is translocated from the cytoplasm to the
nucleus, where the activation of transcription of the
relevant genes occurs. A sufficient amount of the
activated complex, DHT–AR, is required to keep the
homeostatic balance of proliferation and survival
signals in the prostate, which consists mainly of
two cell types – stromal and epithelial cells. The
epithelium consists of basal and luminal cells;
however, only the latter express ARs. These luminal
cells express the prostate-specific differentiation
markers, one of which is PSA. Expression of these
marker genes is enhanced by the binding of the
DHT–AR complex to the androgen-responsive
elements in the nuclei of these luminal cells. The AR
116
in the nuclei of the secretory epithelial cells does
not directly regulate the cell’s survival or directly
affect proliferation and survival of the basal cells;
instead, in the healthy prostate, the epithelial cells
depend on the paracrine signalling of andromedins,
which are growth and survival factors produced
by the stromal cells, for regulation of survival. The
activated AR within the nucleus of the stromal cells
triggers the production of andromedins. These
andromedins diffuse back across the basal membrane
and enter the epithelial cell to keep them alive.
Insufficiency of andromedins results in upregulation
of apoptotic signalling via thyroid growth factor
receptor in epithelial secretory cells, inducing
their degeneration.8
The AR is a protein complex consisting of three
domains: the N-terminal domain, the ligand-binding
domain and the DNA-binding domain. The ligandbinding domain is required for activation of the
AR by androgens and, after translocation to the
nucleus, it binds to specific DNA sequences called
androgen-responsive elements via the DNA-binding
domain, thus promoting protein synthesis. The
N-terminal domain is needed for the transcriptional
transactivation activity of AR.9
Androgens and androgen receptors in
prostate cancer
In PCa cells, certain molecular features of the basal
and epithelial cells seem to be highly correlated. In
certain circumstances, the previously mentioned
paracrine AR signalling mechanism is converted into
an autocrine mechanism; therefore, these cells are
less dependent on stromal cell-derived factors. The AR
acquires a �gain of function’ and, after stimulation by
androgens, is capable of direct production stimulation
of growth and survival factors.10 In other words, the
vital cell functions can be autonomously regulated
by these cells. Nevertheless, at that stage, the cell
depends on the homeostatic balance of androgens in
the surroundings.
Initiation of ADT results in a relatively rapid decline
in the available serum androgens and, owing to
apoptosis of androgen-sensitive cells, temporary
tumour remission. However, after 2–3 years, virtually
all patients will experience disease progression and
ADT will no longer be effective. This was previously
considered as a hormone-refractory disease state
but findings in the last decade have revealed that,
even in this disease state, PCa remains responsive
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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В­State-of-the-art revie
to AR signalling. This resulted in designation of a
new stage: CRPC.11 Furthermore, serum testosterone
levels do not reflect tissue androgen levels within
the prostate, where levels of testosterone and DHT
are still sufficient to activate the AR.12 This means
that AR signalling and, therefore, AR-related gene
and protein expression within the microenvironment
of the prostate remain functional.13 This is further
supported by the fact that recurrent tumours
frequently re-express AR target genes such as
PSA and nearly 30% of patients with progressive
disease after first-line ADT will respond to secondary
hormonal manipulations.14
After initiation of ADT, many, but not all, PCa cells
will die. This is evidenced by the eventual disease
progression after 2–3 years, showing that PCa cells
can develop the capacity to adapt to the altered
environment. The resumption of AR-dependent
transcriptional activity in CRPC is achieved by
AR aberrations, rendering them more sensitive
to androgens,15 or by producing the necessary
ligands autonomously.
If there is a shortage of testosterone after ADT, the
PCa cell is capable of producing testosterone itself
via the �backdoor pathway’. To achieve this, the cell
needs certain enzymes, the most important being
cytochrome P450 17 (CYP17).16 Another possibility is
to increase the conversion rate of testosterone to DHT
by increasing 5a-reductase activity.6
Apart from the ligand, the PCa cell can also influence
the AR itself and, if the AR is more sensitive, it can be
activated despite low available levels of androgens.
One of the first steps that PCa cells take is to simply
increase the number of ARs by amplification. In
addition, mechanisms of AR degradation can be
impaired, leading to an increased stability of the ARs.
Another form of modulation is to enhance nuclear
translocation of the AR. In addition to rendering the
AR more sensitive to its natural ligand, the protein
structure of the AR can be changed in such a way that
other ligands can activate it. This promiscuous AR
can then be activated by coactivators such as adrenal
androgens, metabolic products of DHT and even
by antagonists such as flutamide or bicalutamide.
This explains the clinical observations of the benefit
of the �withdrawal syndromes’. Overexpression
of coactivators can further create or enhance the
promiscuity of AR. The third possibility is that the AR
is activated in the absence of androgens by growth
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
factors such as insulin growth factor or epidermal
growth factor; an AR with these capabilities is termed
outlaw AR.17,18
In addition to the three mechanisms mentioned
above, there is also the possibility to bypass the
AR completely by alternative or parallel survival
pathways, thus rendering the PCa cell completely
androgen independent.
Another method of increasing the availability
of AR is to enhance activation of the receptor. A
certain proportion of the AR is bound to a nuclear
corepressor (NCOR1) and is therefore rendered
inactive. PCa cells can upregulate a protein called
SIAH2, which removes NCOR1 from the AR, thereby
making it sensitive to ligands.19
Finally, the epigenetic state of PCa cells can
also be altered so that the AR can be activated
without changing its DNA structure. Enhancer of
zeste homologue 2 (EZH2) is also known to be
overexpressed in CRPC. Usually, EZH2 silences genes,
but in CRPC, a switch in the function of EZH2 leads to
gene activation instead of transcriptional repression.
This is achieved by alterations in the methylation of
the AR.20
Taken together, there are a multitude of mechanisms
leading to AR-dependent and AR-independent
molecular growth promotion in the PCa cell.
Understanding these processes is essential for the
development of novel therapeutic strategies for
early-stage PCa, and especially late-stage PCa, such
as CRPC.
Paradox effects of androgens in
prostate cancer
It is well accepted that testosterone fuels PCa cell
growth; however, as previously mentioned, there
are clinical reports showing an inhibitory effect of
testosterone on PCa cells. For a long time this was
considered to be a paradox since there was a lack
of understanding of the molecular background
explaining this phenomenon. Through gain of AR
function and loss of AR function in epithelial–stromal
cell coculture and coimplantation experiments, it was
demonstrated in animals that the AR could function
in epithelial basal cells as a tumour suppressor, in
epithelial luminal cells as a survival factor and in
stromal cells as a proliferation promoter.21 This is
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В­State-of-the-art revie
explained not only by a change in function of AR but
also by the role of the different microenvironment.
In addition, it could, hypothetically, be that AR acts
as a sort of changeover switch whereby certain
coactivators influence the AR in different ways. Since
we know that PCa can develop at different sites in the
prostate, it may be that the stage of differentiation is
different and the action of the AR varies accordingly.
On the way from a paracrine to a cell-autonomous
autocrine mechanism, these changes may be not
uniform but overlapping so that testosterone and
the activated AR–ligand complex act differently at
different sites.
Another finding that may explain paradoxical
effects of testosterone is its role in DNA replication
licensing. In order to maintain cellular viability and
genome integrity, chromosomal DNA must be
precisely replicated once and only once before cell
division occurs.22 Since the genome is too long to
start replication from one end continuing to the
other end, DNA synthesis has to occur at one of
thousands of origins of replication simultaneously.10
The authorization for replication takes place in the
early G1 phase and must be cancelled at the end
of this phase to avoid rereplication, which could
lead to an S-phase arrest of the cell. In PCa cells,
the AR acquires a role as a licensing factor, which
means that it must be degraded in order to allow
relicensing in the subsequent cell cycle. In the early
G1 phase, anti-androgens such as bicalutamide
can block proliferation of androgen-sensitive PCa
cells by deactivating the AR licensing capabilities.
If AR licensing took place, degradation would be
mandatory at a later stage in G1 phase. Upregulation
of the AR protein and/or ligand-induced AR
stabilization during this critical time frame results
in growth inhibition. This time dependence for AR
stabilization provides a theoretical rationale for
intermittent androgen blockade.23
New agents targeting the androgen
axis in castration-resistant prostate
cancer
Traditionally, advanced PCa is treated by surgical
or chemical castration, which reduces testosterone
to castrate levels (≤ 0.5 ng/ml). This effect lasts for
a sustained period of time until CRPC emerges,
which emphasises that traditional therapies causing
surgical or chemical castration do not abrogate all
sources of testosterone as approximately 10% of
the body’s testosterone is produced by the adrenal
118
glands and by de novo synthesis of testosterone by
PCa cells. Therefore, inhibiting testosterone synthesis
in addition to blocking testicular function presents a
compelling rationale for treating PCa.24 Examples of
novel androgen-modulatory therapeutic modalities
that are already available to the clinician, as outlined
above, are the following.
Abiraterone acetate (ZytigeВ®, Jannsen-Cilag, Neuss,
Germany) is an inhibitor of CYP17, which is a key
enzyme in androgen synthesis. It is also required
in the cell-autonomous androgen production
(backdoor pathway). Two studies, each enrolling
more than 1000 patients who were given abiraterone
acetate and who either did25 or did not undergo
chemotherapy26 for metastatic CRPC, reported
improved overall survival. This is probably due
to a reduction in available androgen levels27 and
clearly indicates that CRPC clinically remains
androgen responsive.
A large phase 3 study (known as AFFIRM;
NCT00974311) was carried out in men with metastatic
CRPC who experienced disease progression
after previous treatment with docetaxel-based
chemotherapy and were subsequently given
enzalutamide (XtandiВ®, Astellas, Tokyo, Japan). The
trial was stopped in November 2011 after a planned
interim analysis showed a 35% reduction in the risk
of death in the enzalutamide group compared with
the placebo group (median survival 18.4 months
vs. 13.6 months respectively; hazard ratio 0.631;
P < 0.0001). The data of this study also confirm the
central role of AR-signalling throughout the disease
and emphasize that CRPC is neither androgen
independent nor hormone refractory.28
In the near future, studies should be conducted
combining abiraterone acetate and enzalutamide
to target testosterone and the AR with the aim
of increasing survival in CRPC patients. To our
knowledge, it is not currently possible to synchronize
cells so that they are in the same cell cycle and
testosterone administration is not effective in a
clinical setting. To date, all therapeutic modalities
target the ligand-binding domain of the AR; however,
if the N-terminal is blocked, interaction of the AR
and androgen-responsive elements is reduced,
resulting in impaired protein expression. A small
molecule called EPI-001 has the capacity to block the
N-terminal and may be a promising way to further
impair the androgen axis in PCa in the future.29
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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We are in a highly exciting era regarding the
management of PCa, especially CRPC. A plethora
of novel therapies based on our increasing
understanding of molecular networks underlying
cellular PCa activity are now available. Optimal use
of such therapies for patients requires familiarity
with the biological processes of both normal and
malignant prostate cells.
14
15
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CAN_10-3398
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Hamdan Medical Journal  2013; 6:121–128 (http://dx.doi.org/10.7707/hmj.v6i2.277)
 
State-of-the-art review
Biomarkers for screening and early detection of
prostate cancer
Malte Rieken1,2 and Shahrokh F Shariat1,3
Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New
York, USA, 2Department of Urology, University Hospital Basel, Switzerland, and 3Department of
Urology, Medical University of Vienna, Vienna, Austria
1
Abstract
Prostate cancer (PCa) represents a significant health burden and the high
prevalence and natural course of the untreated disease make PCa ideal for
screening and early detection. The aim of this review is to give an overview
of the recent evidence on biomarkers for screening and early detection of
PCa. A review of the current literature on prostate-specific antigen (PSA)
and novel biomarkers in PCa diagnosis and screening was conducted using
MEDLINE/PubMed to identify relevant publications. PSA is currently the
main biomarker for PCa screening and diagnosis, and two out of three recent
randomized controlled trials on PSA screening for PCa showed a 20–40% risk
reduction of PCa-specific mortality in the screened group. In contrast, one
study did not show any beneficial effect of PSA screening. Although each
study had flaws, the study that reported no benefit from PSA screening had
a high contamination rate in the control group and non-compliance in the
screening group. However, PCa screening was associated with overdiagnosis,
which led to overtreatment. Therefore, there is a need for novel biomarkers
that are more specifically associated with PCa and its biological and clinical
behaviour. Several such biomarkers are currently being investigated as an
adjunct to PSA; however, none can currently replace PSA. Among novel
biomarkers, PCa antigen 3 (PCA3) and TMPRSS2–ERG gene fusions appear
to be most promising and, currently, PCA3 is reported as the more efficient
diagnostic test in patients who have had a previous negative biopsy.
Introduction
Prostate cancer (PCa) represents a significant burden
to men’s health. It is the most common cause of
cancer in men and the second leading cause of cancer
death. In 2008, approximately 900 000 men were
diagnosed with PCa worldwide, with the highest
Correspondence: Shahrokh F Shariat, Department of Urology,
Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna,
Austria. Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
rates in Europe, North America, South America and
Oceania. An estimated one in six men in the USA will
be diagnosed with PCa in their lifetime; however, the
risk of dying from PCa is only 1 in 35.1
PCa lends itself to early detection as it has a slow
natural course if untreated, allowing for the cancer
to be diagnosed before it progresses to an advanced
and incurable stage. In addition, most tumours have a
long latency period and remain contained within one
organ, allowing for potentially life-saving therapeutic
interventions.2 Moreover, screening or early detection
can be performed with a simple test to determine the
levels of prostate-specific antigen (PSA) in the blood.
The benefits and disadvantages of PSA-based
screening have become the subject of intense
investigations and debate. First and foremost,
the high prevalence of PCa makes the disease a
socioeconomic, as well as personal, problem. Autopsy
series have, for example, shown PCa in a high
proportion of men dying from other causes, rising
from 27% in men aged 41–50 years to 65% in men
aged 71–80 years.3 Second, treatment of PCa can be
associated with serious and life-long side-effects such
as incontinence and erectile dysfunction;4 therefore,
screening should identify only men with clinically
significant PCa in its early stages. In recent years, there
has been debate concerning the utility and potential
harms of PSA-based PCa screening. This review
summarizes the latest evidence on this subject and
gives an overview of future candidate biomarkers.
121
121
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State-of-the-art review
Methods
A non-systematic literature search using the
MEDLINE/PubMed database was conducted to
identify original articles, review articles and editorials
regarding PSA and novel biomarkers in PCa diagnosis
and screening. Searches were limited to the English
language, humans and adults. All abstracts were
reviewed and the corresponding full-length articles
for those that were most relevant were analysed.
Prostate-specific antigen screening
Prostate-specific antigen is a glycoprotein secreted
by prostate epithelial cells. It was first studied in the
late 1970s and replaced prostatic acid phosphatase
as a PCa biomarker in the 1980s.5 In conjunction with
a digital rectal examination (DRE), PSA has become
a widely used tool for PCa screening.6,7 However, an
elevated blood level of PSA does not automatically
indicate PCa as the PSA level can be elevated in men
with benign prostatic hyperplasia or inflammation.
There is a large body of retrospective or case–control
prospective studies on PSA-based PCa screening.
However, owing to various methodological
limitations, conclusions based on these studies are
limited.8 Recently, three prospective randomized trials
assessed the impact of PSA-based screening on PCa
mortality. Each of these trials is discussed separately
below and the results are shown in Table 1.
Prostate, Lung, Colorectal and Ovarian
cancer screening trial
The Prostate, Lung, Colorectal and Ovarian (PLCO)
trial accrued close to 77 000 men aged 55–74 years
from1993 to 2001 at 10 different centres in the USA.9
The trial reported information on PCa incidence,
cancer-specific mortality (CSM), all-cause mortality
and cancer staging. Participants were randomly
assigned to 6 years of annual PSA tests and 4 years of
DRE. The PSA cut-off was 4 ng/ml, and patients with
a PSA above the cut-off, or suspicious DRE results,
were advised to seek further diagnostic evaluation.
Compliance rates were 85% for PSA testing and 86%
for DRE. The incidence of PCa per 10 000 person-years
after 7 years was 116 in the screened group compared
with 95 in the control group. The incidence of death
per 10 000 person-years was 2.0 in the screened group
and 1.7 in the control group. The authors concluded
that, after 7–10 years of follow-up, the rate of death
122
TABLE 1  Overview of randomized controlled trials of
prostate cancer screening
Study
details
Number of
participants
Age range
(years)
Ratio of
screening to
no screening
Primary
endpoint
Median
follow-up
(years)
Main results
Conclusion
PLCO9
ERSPC10
Göteborg11
77 000 men
182 000 men
20 000 men
55–74
50–74
50–64
1:1
1:1
1:1
CSM
CSM
CSM
7
9
14
Incidence of
death per
10 000 personyears: 2.0 in
the screening
group ; 1.7 in
the control
group
20% reduction
in relative risk of
death from PCa in
screened group
compared with
control group
To prevent one
death: number of
men that need to
be screened: 1410;
number of men
that need to be
treated: 48
Rate of death PSA-based
from PCa very screening reduced
low and not
the rate of death
significantly
from PCa by 20%
different
PSA-based
between the screening
screened group associated with
and control
high risk of
group
overdiagnosis
44% reduction in
relative risk of death
from PCa in screened
group compared
with control group
To prevent one
death: number of
men that need to
be screened: 293;
number of men
that need to be
treated: 12
PCa mortality
reduced almost by
half in the screened
group
Benefit of PCa
screening compares
favourably to other
cancer screening
programmes
from PCa was very low and did not differ significantly
between the two groups.
The PLCO trial has been criticized for various reasons,
the first of which was the high contamination rate
in the control group. Reflecting community practice
in the USA, approximately 44% of patients in the
control group had at least one PSA test prior to study
entry. Furthermore, in the first year of the trial, the
rate of PSA testing in the control group was 40% and
increased to 52% by the sixth year of study inclusion,
suggesting that the control group contained men
who were less likely to harbour PCa. In addition,
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:121–128 (http://dx.doi.org/10.7707/hmj.v6i2.277)
State-of-the-art review
some cancers that are detectable on initial screening
may have been already removed from the study
population. Second, the biopsy rate was only around
40% in men who had an elevated PSA.12 Third, a PSA
level of 4 ng/ml was used as cut-off and a low cut-off
level may lead to detection of low-stage cancers that
are associated with higher CSM. Fourth, the follow-up
time of 7 years was too short to detect a significant
effect of PCa screening, given the natural course of
untreated PCa.
An analysis of the PLCO data with a focus on
comorbidities showed a significant decrease
in the risk of CSM in men with no or minimal
comorbidities who were randomly assigned to PSA
screening versus usual care (22 vs. 38 deaths). It
was reported that treatment needed to be given
to an additional five men before one PCa death at
10 years could be prevented. These data suggest
that selective use of PSA screening for men in good
health appears to reduce the risk of PCa CSM with
minimal overtreatment.13
European Randomized Study of Prostate
Cancer
The European Randomized Study of Prostate Cancer
(ERSPC) trial was a European-based multi-institutional
trial that was initiated in 1991 for men between
the ages of 50 and 74 years. In total, 72 952 men
were randomly assigned to PSA screening at 2-year
or 4-year intervals in centres in Belgium, Finland,
France, Italy, the Netherlands, Spain, Sweden and
Switzerland.10 The control group consisted of
89 435 men who did not undergo screening for PCa.
Most centres used a PSA cut-off of 3.0 ng/ml as an
indication for biopsy, except in Finland, where a PSA
of 4.0 ng/ml was used.10 During a median follow-up of
9 years, the cumulative PCa incidence was 8.2% in the
screened group compared with 4.8% in the control
group. The rate ratio for CSM in the screened group
was 0.80, indicating a 20% relative risk reduction
in death from PCa in relation to the control group.
However, in order to prevent one death from PCa,
1410 men would need to be screened and 48 men
would need to be treated. The reduction in mortality
due to PSA screening in the ERSPC study was further
increased to 30% when adjusting for non-compliance
in the screened population and contamination in the
control group.14
An analysis of follow-up data regarding the
development of metastatic disease from the four
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
centres conducting the ERSPC study was published
in 2012. After a median follow-up of 12 years, 256
men in the PSA-screened group and 410 men in the
control group were diagnosed with metastatic PCa,
resulting in a cumulative PCa incidence of 0.67%
and 0.86% per 1000 men, respectively. This finding
translates into a 42% reduction for men who were
actually screened and an absolute risk reduction of
metastatic disease of 3.1 per 1000 randomized men.15
Despite several methodological strengths, the
results of the ERSPC trial should be interpreted with
caution. The risk of overdiagnosis was estimated to
be around 50% and the benefit of screening appears
to be restricted to men in the core age group of
55– 69 years.16 In addition, the results of the ERSPC
trial showed that PCa screening is associated with
a high risk of overtreatment. Moreover, a control
subject with high-risk PCa was more likely than
a subject in the PSA-screened group to receive
radiotherapy, expectant management or hormonal
treatment instead of radical prostatectomy. However,
the trial group (screened or control) had only a
minor role in treatment choice compared with other
variables, and the differences in treatment between
groups are unlikely to play a major role in the
interpretation of the results of the ERSPC trial.17
Göteborg trial
The Göteborg screening trial was originally an
independent trial and later joined the ERSPC.11 It
accrued 20 000 men aged 50–64 years who were
randomized in a 1:1 ratio to screening with PSA every
2 years versus no screening.11 The primary endpoint
of the study was CSM. During the median follow-up
of 14 years, 12.7% of men in the screening group and
8.2% of men in the control group were diagnosed
with PCa. The rate ratio for CSM was 0.56, which
translated into a 44% relative risk reduction of death
from PCa in the PSA-screened group of the study. In
order to prevent one death from PCa, 293 men would
need to be screened and 12 men would need to
be treated.
Interestingly, the Göteborg study reported better
outcomes of screening than the PLCO and the
ERSPC trial. This may be explained by differences
in trial design and cohort composition such as
younger patients, shorter intervals for screening,
lower rate of PSA testing prior to study entry, lower
rate of contamination in the control group and
longer follow-up.16
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Current debate on prostate-specific antigen
screening
Based on the results of the three major screening
trials, various health organizations published
recommendations on PSA screening. The United
States Preventive Services Task Force (USPSTF)
published the most widely debated statement. In
a 2012 update of a previous analysis, the USPSTF
recommended against PSA-based PCa screening
for all men in the general US population, regardless
of age.18 The American Urological Association
(AUA) clearly opposed this position and published
a response to the recommendation of the USPSTF,
which can be found online (http://www.auanet.
org/content/media/USPSTF_AUA_Response.
pdf ). The AUA currently promotes a baseline PSA
value in all men aged 40 years and screening is
discouraged in men with a life expectancy less than
10 years.19 The ongoing debate reflects the current
uncertainties and opposing positions regarding PCa
screening and emphasizes the necessity for novel
biomarkers that could help avoid the overdiagnosis
and overtreatment associated with PSA-based
PCa screening.
Novel biomarkers for prostate cancer
diagnosis
Currently, PSA remains the predominant tool in
PCa diagnosis and screening; however, PSA is a
poor predictor of disease. Approximately 65–70%
of men presenting with an elevated PSA between
4 and 10 ng/ml will have a negative biopsy result.20
In addition, prostate biopsies can be associated with
significant morbidity21 and the limitations of PSA
in screening and prognostication of PCa facilitated
the search for new blood-based or urine-based
biomarkers for PCa diagnosis and screening.22,23 A
large part of the limitation of serum PSA is the low
specificity because it is not a PCa-specific marker.
Methods to enhance PSA specificity have assisted
clinicians in deciding which patients should undergo
biopsy, but have not necessarily improved diagnostic
accuracy or facilitated optimal therapeutic decisionmaking (e.g. PSA density, complex PSA, free PSA,
etc).23 More accurate tests that can stratify patients
according to their risk of developing PCa and identify
men who require repeat prostate biopsy and those
at risk for aggressive disease are required. Since the
introduction of PSA, advances in DNA sequence
and RNA transcriptome profiling have broadened
our understanding of cancer biology24 and novel
124
assays are able to detect PCa-associated biomarkers
in various biological fluids including serum and
urine. The three most advanced urinary tests are
discussed below.
Prostate cancer antigen 3
Prostate cancer antigen 3 (PCA3) is the most
prominent, non-PSA-based biomarker for PCa.
PCA3 is a non-coding RNA that has been shown
to be elevated in > 90% of PCa tissues, but not in
normal or benign prostatic hyperplastic tissue.25,26
Owing to the high sensitivity and specificity of
PCA3 in PCa tissue, assays were further developed
to detect PCA3 in urine, which led to the currently
available transcription-mediated amplification-based
urine assay.27 The assay uses PSA transcripts as
internal controls for RNA quality and presence of
prostate-specific nuclear material. The PCA3 score
is generated by the PCA3 to PSA ratio.28 In several
studies, PCA3 appeared to be superior to PSA in
predicting PCa based on biopsy alone.28–32 A urine
PCA3 score of > 35 had an average specificity of 76%
and sensitivity of 66% for the prediction of PCa at
biopsy, whereas serum PSA had a specificity of only
47% at about the same sensitivity (65%).29 Urine PCA3
measurements provide additional information to
the PSA test with area under the curve (AUC) values
of 0.66–0.72, compared with 0.54–0.63 for serum
PSA alone.30 Combining PCA3 analysis with PSA
testing further improves both measures, resulting in
an AUC of 0.71–0.75.31 In a study of 495 men, PCA3
had a negative predictive value of 90% and was
independently associated with PCa.32
The PCA3 score is not influenced by age, prostatitis,
prostate volume or 5a-reductase inhibitors. In men
with elevated serum PSA levels and one or two
previous negative biopsy results, elevated PCA3
scores were associated with a higher risk of PCa. In
2012, the US Food and Drug Administration (FDA)
approved PCA3 as a diagnostic test for PCa in the
setting of a previous negative biopsy. PCA3 has
become the first basis for the molecular diagnostics in
clinical urological practice.
One limitation of the PCA3 test is the cut-off score
used to determine the test as positive. As expected,
while sensitivity increases, specificity of the assay
decreases with lower cut-offs. Furthermore, a low
PCA3 score does not exclude cancer and, therefore,
not reaching a satisfactory negative predictive value
in order to rule out PCa.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:121–128 (http://dx.doi.org/10.7707/hmj.v6i2.277)
State-of-the-art review
Studies on the predictive value of PCA3 for aggressive
disease have been contradictory. No significant
association between PCA3 score and any prognostic
parameter (including stage, Gleason score, tumour
volume or extraprostatic extension) was found in
independent studies;33,34 however, other studies
found an association between high PCA3 scores and a
Gleason score of ≥ 7, extracapsular extension and high
tumour volume.35,36 Recently, PCA3 score was found
to be a valuable predictor of low-volume, insignificant
cancer35,36 and, as such, PCA3 could be of use in
selecting patients for active surveillance. However, in
men with significant PCa, PCA3 may not differentiate
the aggressiveness of a tumour; therefore, a
biomarker indicative of tumour aggressiveness is still
an unmet need for patients suffering from PCa.
TMPRSS2–ERG
Gene rearrangements are known events in cancers
such as haematological malignancies and have also
been described in PCa. TMPRSS2-ERG gene fusions
are one of the most common genetic events in PCa,
are present in 50% of all cases and are specific for PCa
but can also be detected in prostate intraepithelial
neoplasia.24 It was shown that men with extremes of
TMPRSS2–ERG gene fusion and PCA3 have different
risks of cancer and different aggressiveness of the
cancer, as seen in the biopsy. In combination with
other clinical and pathological parameters (combined
using the multivariate prostate cancer prevention trial
risk calculator), urine TMPRSS2–ERG and PCA3 may
guide the urgency of biopsy after the detection of an
elevated serum PSA.37 The combined measurement of
PCA3 and TMPRSS2-ERG in urine outperformed serum
PSA for PCa diagnosis and may represent a promising
urine test for PCa.37 However, urine expression of
PCA3 and TMPRSS2–ERG is related to urine PSA
mRNA and thus the tests are not informative if the
PSA mRNA level is too low. Furthermore, it has to
be kept in mind that both PCA3 and TMPRSS2–ERG
are currently helpful only as adjuncts to PSA. There
is currently a need for studies determining the
performance of the tests in the absence of PSA.
Prostate-specific membrane antigen
Prostate-specific membrane antigen (PSMA) is a
transmembrane glycoprotein that is expressed on
the surface of prostate epithelial cells. It has been
reported that PSMA is upregulated in PCa tissue but
not in benign prostatic tissues and no overlap in
PSMA expression has been found between benign
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
prostatic hyperplasia and PCa, indicating that
PSMA is a very promising diagnostic marker.38 It
has been shown that high PSMA expression in PCa
cases is correlated with tumour grade, pathological
stage, aneuploidy and biochemical recurrence.39,40
In addition, increased PSMA mRNA expression in
primary PCas and metastasis has been reported to
correlate with PSMA protein overexpression.40 The
clinical utility of PSMA as a diagnostic or prognostic
marker for PCa has been hindered by the lack of a
sensitive immunoassay for this protein.
Reverse transcriptase polymerase chain reaction
studies have shown that PSMA, in combination
with its splice variant, could be used as a prognostic
marker for PCa.41 In the normal prostate, PSMA splice
variant expression is higher than that of PSMA,
whereas in PCa tissues the PSMA expression is more
dominant; therefore, the ratio of PSMA to its splice
variant is highly indicative of disease progression.
Designing a quantitative PCR analysis that
discriminates between the two PSMA forms could
yield another application for PSMA in diagnosis and
prognosis of PCa.42
In men with serum PSA values between 4 and
10 ng/ml with no previous biopsies, PSMA mRNA
measured in postprostate massage urinary sediments
was superior to PCA3 in predicting cancer upon
biopsy. At 70% specificity, the sensitivity for PSMA
and PCA3 was 64% and 46%, respectively.43 Because
of its specific expression on prostate epithelial cells
and its upregulation in PCa, PSMA has become a
target for therapies and the proposed strategies
range from targeted toxins and radionuclides to
immunotherapeutic agents.44 First-generation
products have entered clinical testing.
Conclusions
Prostate-specific antigen testing has dramatically
changed the diagnostic approach and clinical
presentation of PCa. While PSA is associated with PCa,
it has only moderate specificity. The benefits of PSA
screening have been established in different trials
and include earlier diagnosis of disease, reduction
in initial diagnosis of metastasis and improvement
in PCa-specific mortality. However, PSA screening is
also associated with substantial overdiagnosis and
overtreatment; therefore, the treatment decision
should be tailored to the risk of metastasis and
PCa-specific mortality. New biomarkers are currently
adjunctive to PSA and can guide further diagnostic
125
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State-of-the-art review
tests after initial negative biopsy. When used in the
proper context, future biomarkers may prevent
unnecessary biopsies and help identify patients
who are likely to benefit from early diagnosis and
treatment. Furthermore, they may be helpful in
risk stratification that can lead to an individualized
treatment decision.
To achieve this goal, there is an urgent need to
discover more accurate non-invasive tests for PCa
diagnosis and to allow the stratification of patients
with life-threatening PCa. Because of the ease of
collection, and the fact that prostate cells are directly
released into the urethra through prostatic ducts
after DRE or prostate massage, urine has become
the future of non-invasive biomarker testing. Many
studies26,27,29–34 have shown the feasibility of urine
for the non-invasive detection of PCa and biomarker
research is a focus at many laboratories, where several
biomarkers are promising owing to their specificity
for the disease in tissue. To our knowledge, only a
few of these biomarkers have shown to be useful
as urinary marker to date, and two PCa-specific
RNA-based biomarkers have been identified (PCA3
and TMPRSS2–ERG gene fusions). The recent FDA
approval of PCA3 has led to its introduction in clinical
practice and the combination of both markers has
been marketed for clinical use as well. Compared
with single biomarkers, the combination of several
biomarkers considerably improves the prediction of
PCa in urine samples and also reflects the biology of
the disease, which can be indolent or aggressive.
In the era of individualized therapy, the biomarker
combinations are necessary not only to predict PCa at
biopsy, but also to predict the aggressiveness of the
cancer. Preliminary results show that the PCa-specific
TMPRSS2–ERG gene fusion may be indicative of the
aggressiveness of cancer upon biopsy, although
further studies are warranted. As mentioned above,
in PCa biomarker development, the greatest unmet
need is a biomarker that stratifies men at risk of
aggressive PCa, eventually leading to a reduction of
unnecessary interventions.
Conflict of interest
Dr Shariat is on the advisory board for
Ferring Pharmaceuticals.
126
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importance of methods and context. J Natl Cancer Inst
2009; 101:374–83. http://dx.doi.org/10.1093/jnci/djp001
Nam RK, Saskin R, Lee Y, et al. Increasing hospital
admission rates for urological complications after
transrectal ultrasound guided prostate biopsy. J Urol
2013; 189:S12–7; discussion S7–8.
Shariat SF, Karam JA, Margulis V, Karakiewicz PI. New
blood-based biomarkers for the diagnosis, staging and
prognosis of prostate cancer. BJU Int 2008; 101:675–83.
http://dx.doi.org/10.1111/j.1464-410X.2007.07283.x
Shariat SF, Semjonow A, Lilja H, Savage C, Vickers AJ,
Bjartell A. Tumor markers in prostate cancer I: bloodbased markers. Acta Oncol 2011; 50:61–75. http://dx.doi.
org/10.3109/0284186X.2010.542174
Prensner JR, Rubin MA, Wei JT, Chinnaiyan AM. Beyond
PSA: the next generation of prostate cancer biomarkers.
Science translational medicine 2012; 4:127rv3.
Bussemakers MJ, van Bokhoven A, Verhaegh GW,
et al. DD3: a new prostate-specific gene, highly
overexpressed in prostate cancer. Cancer Res 1999;
59:5975–9.
de Kok JB, Verhaegh GW, Roelofs RW, et al. DD3(PCA3),
a very sensitive and specific marker to detect prostate
tumors. Cancer Res 2002; 62:2695–8.
Hessels D, Schalken JA. The use of PCA3 in the diagnosis
of prostate cancer. Nat Rev Urol 2009; 6:255–61.
Truong M, Yang B, Jarrard DF. Toward the detection of
prostate cancer in urine: a critical analysis. J Urol 2013;
189:422–9. http://dx.doi.org/10.1016/j.juro.2012.04.143
van Gils MP, Hessels D, van Hooij O, et al. The timeresolved fluorescence-based PCA3 test on urinary
sediments after digital rectal examination; a Dutch
multicenter validation of the diagnostic performance.
Clin Cancer Res 2007; 13:939–43.
Roobol MJ, Schroder FH, van Leenders GL, et al.
Performance of prostate cancer antigen 3 (PCA3)
and prostate-specific antigen in prescreened men:
reproducibility and detection characteristics for
prostate cancer patients with high PCA3 scores (≥ 100).
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Rational approach to implementation of prostate cancer
antigen 3 into clinical care. Cancer 2009; 115:3879–86.
http://dx.doi.org/10.1002/cncr.24447
Marks LS, Fradet Y, Deras IL, et al. PCA3 molecular
urine assay for prostate cancer in men undergoing
repeat biopsy. Urology 2007; 69:532–5. http://dx.doi.
org/10.1016/j.urology.2006.12.014
Hessels D, van Gils MP, van Hooij O, et al. Predictive value
of PCA3 in urinary sediments in determining clinicopathological characteristics of prostate cancer. Prostate
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Liss MA, Santos R, Osann K, Lau A, Ahlering TE, Ornstein
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association with pathologic features and impact of
collection protocols. World J Urol 2011; 29:683–8. http://
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Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3
molecular urine assay correlates with prostate cancer
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of preoperative urinary prostate cancer antigen
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eururo.2010.10.024
Tomlins SA, Aubin SM, Siddiqui J, et al. Urine
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expression is associated with early PSA recurrence
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BA. Expression of prostate specific membrane antigen
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urolonc.2007.07.016
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on urine increases PSA specificity in the detection of
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State-Of-the-art Review
Focal ablation of prostate cancer
Georg Schatzl
Department of Urology, Medical University Vienna, Vienna, Austria, and Karl Landsteiner Institute
of Andrology and Prostate Research, Vienna, Austria
Abstract
The aim of the article was to evaluate the treatment potential for focal
therapies of prostate cancer (PCa). A literature research was performed to
evaluate efficiency of the minimally invasive methods of PCa treatment.
The two treatment methods evaluated were high-intensity focused
ultrasonography (HIFU) and cryoablation. There are few studies with
sufficient long-term follow-up and follow-up criteria are very diverse. The
increasing number of cryoablation and HIFU treatments in the last 10 years
confirms the considerable demand for minimally invasive treatment for
localized PCa. Focal ablation of PCa is an interesting treatment option for
low-risk PCa, but there are not many opportunities for this treatment and the
patient experience is often negative.
Introduction
treatment but also in those who may be wary of
the potential side-effects of radical prostatectomy,
such as erectile dysfunction and incontinence.2,4
Potential alternative treatments include cryoablation,
three-dimensional conformal radiotherapy and
brachytherapy.2 Furthermore, active surveillance has
been accepted as an alternative to active treatment,
although Cooperberg et al.5 reported that only 10%
of patients who are considered appropriate for active
surveillance actually opt for this management.
Treatment options
In the last 15 years, these minimally invasive
treatment options for localized PCa have been
studied not only in men deemed unfit for surgical
There are few focal treatment options for PCa, with
only high-intensity focused ultrasonography (HIFU)
or cryoablation described in the literature; however,
research has been limited by the relatively small
number of patients.6–8 In comparison, treatment of
the whole prostate gland has been well documented.
Chapelon et al.9 reported that HIFU induced
coagulation necrosis and can destroy Dunning R3327
PCa cells in rats. In 1995, Madersbacher et al.10,11
described the effects of HIFU in 10 cases of localized
PCa and reported the effectiveness of coagulation
necrosis through histological examination. Moreover,
HIFU treatment of other tissues, such as benign
prostate tissue, testicular tumours and kidney
tumours, resulted in coagulation necrosis. Recently,
Uchida et al.12 examined 181 men suffering from
PCa who were treated by HIFU with the Sonoblate
500 deviceпЈЄ (Focus Surgery, Indianapolis, IN,
USA). However, long-term studies of focal ablation
are rare.6–8
Correspondence: Georg Schatzl, Department of Urology, Medical
University Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria.
Email: [email protected]
The European Association of Urology (EAU) Guidelines
describe HIFU of the prostate as an experimental
treatment.2 Critics of focal ablation argue that, since
80% of prostate tumours are multifocal,13 the utility of
Prostate cancer (PCa) is the second most common
form of cancer in men worldwide.1 With the
increasing incidence of localized disease, minimally
invasive treatment options for those deemed
unsuitable for open surgery have become a focus of
research and innovation. The current approaches to
treatment (surgery, external irradiation treatment
and brachytherapy) are the gold standard but are
associated with important side-effects.2 Schröder et
al.3 report that 1410 men have to be screened and
48 men have to be diagnosed to prevent one PCarelated death over an period of 9 years.2 The effects of
ovvertreatment are also not negligible, with a survival
benefit at 15 years of only 1% among a prostatespecific antigen (PSA)-screened population.3
В© 2013 The Author(s)
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State-Of-the-art Review
HIFU for diagnosis and treatment is limited. Ahmed
et al.8 reported that 23% of patients showed evidence
of cancer after focal ablation and 8% were found to
have clinically significant disease according to the
Epstein criteria. In contrast, we treated all patients
with a recurrent form of the disease with repeat HIFU
of the entire prostate gland. Bahn et al.14 reported
that, in a study of 70 men, 17% had a recurrent form
of the disease 1 year after focal cryoablation: 1.4%
at an ipsilateral site and 16% at a contralateral site.14
However, in that study, 31% of treated men refused a
rebiopsy, which limits the authors’ conclusions.14
Ahmed et al.8 suggest two different strategies for
HIFU: disease control and cancer cure. Whereas
the disease control strategies treat only clinically
significant lesions, cancer cures strategies treat
all cancerous lesions.13 The authors recommend
controlling the PSA levels for 3 months, obtaining a
biopsy of the untreated area after 2–3 years and using
multiparametric magnetic resonance imaging (MRI).15
However, these hypotheses are limited by the lack
of valid criteria for follow-up. The American Society
for Radiation Oncology (ASTRO) criteria are valid
for radiation therapy, but are not approved for HIFU
or cryoablation.
Many new HIFU devices have recently been
developed; however, there are few studies with
sufficient long-term follow-up. Thuroff et al.16 reported
1.47 HIFU sessions per patient, or a retreatment rate
of nearly 50%, in a European long-term multicentre
study employing the Ablatherm system (EDAP TMS,
Lyon, France). Blana et al.17 described 1.17 sessions
per patient in a study of 146 patients, with 21
patients receiving two treatments and two patients
receiving three treatments. Uchida et al.18 reported a
retreatment rate of 34% in men without neoadjuvant
androgen suppression and of 31% in men with
androgen suppression treated with the Sonoblate
500 system.18
The increasing number of cryoablation and
HIFU treatments in the last 10 years confirms
the considerable demand for minimally invasive
treatment for localized PCa.19 Data are available
for follow-up for an average of 5–7 years for
cryotherapy. The most recently developed devices are
associated with lower complication rates than earlier
technologies, with the exception of an observed
rise in erectile dysfunction. Aus et al.19 reported an
130
incontinence rate of 4.4% following cryoablation
using the most recent generation of cryomachines,
compared with 2–27% using older technology.19
However, the rate of erectile dysfunction is very
high, at 80–87%, using new technology compared
with using the older equipment, for which there are
limited data.
Following treatment of the whole gland, rates of
erectile dysfunction range from 25% to 61%12,17–19
and Poissonier et al.20 noted an impotence rate of
39% without the nerve-sparing procedure.20 Uchida
et al.18 observed an erectile dysfunction rate of 9%,12
whereas Ahmed et al.15 reported no changes in the
15-question International Index of Erectile Function
score at 6 and 12 months following hemiablation.8
Ahmed and Emberton15 found that the International
Prostate Symptom score decreased from 22 to 12
after 1 year. It has been reported that control biopsy
is preferable to MRI, after 6 or 12 months, since the
sensitivity of T2-weighted sequences for PCa ranges
from 37% to 96% and the sensitivity ranges from
21% to 67%. 21–23 Nogueira et al.23 reported that the
sensitivity of PCa detection with transrectal MRI was
between 2% and 20% and the sensitivity ranged from
91% to 95%, which suggested that transrectal MRI
is not sufficient to identify small tumours for local
treatment.23 Trivedi et al.24 detailed the limitations
for MRI, such as detection rate and costs, in a cost–
benefit analysis.24
Using the ASTRO criteria, in which three consecutive
rises of PSA above the PSA nadir suggests treatment
failure, nearly 90% of patients were disease free
7 years after treatment; however, using a fixed cut-off
level of > 0.5 ng/ml, the rate decreased to nearly
65%.12 Therefore, a definition for the biochemical
disease-free survival following minimally invasive
treatment is required.
Other focal ablations include focal laser ablation
and focal photodynamic therapy. The number of
treatments currently available is very low and the
follow-up period very short.25 Focal ablation of PCa is
a interesting treatment option for low-risk PCa, but
there are not many opportunities for focal ablation
and the patient experience is often negative. In
addition, a definition of biochemical disease-free
survival following minimally invasive treatment is
required for the future.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:129–132 (http://dx.doi.org/10.7707/hmj.v6i2.280)
State-Of-the-art Review
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EA, Whittemore AS, Schmid HP. Locallised
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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Hamdan Medical Journal  2013; 6:133–140 (http://dx.doi.org/10.7707/hmj.v6i2.281)
 
State-of-the-art review
The Martini-Clinic technique of open radical
retropubic prostatectomy
Alexander Haese, Markus Graefen, Thorsten Schlomm, Thomas Steuber, Georg
Salomon, Uwe Michl, Lars Budäus, Hans Heinzer and Hartwig Huland
The Martini-Clinic Prostate Cancer Center, University Clinic Eppendorf, Hamburg, Germany
Abstract
Despite the emergence of robotic approaches, the technique of open radical
retropubic prostatectomy (RP) is still the predominant approach for surgical
treatment of clinically localized prostate cancer in most clinics worldwide.
The principles of this technique and its oncological efficacy were published
decades ago; however, the surgery carried out today has undergone
continuous refinements, reducing the morbidity rate and significantly
improving postoperative functional outcomes such as urinary continence and
erectile function. We report on the current technique of open nerve-sparing
radical RP with data analysis to address the issues of urinary continence,
potency, cancer control rates and perioperative morbidity. The analyses are
based on 1875 patients who were treated with nerve-sparing RP in the
Martini-Clinic. The key elements of open radical RP are a selective ligation
of the dorsal vein complex and early release of the neurovascular bundles
using a high anterior tension-free and energy-free intrafascial technique,
intraoperative frozen section (NeuroSAFE technique) and full functional
length urethral sphincter preparation (FFLU technique). During dissection of
the urethra, the posterior insertion at Denonvilliers’ fascia is preserved and
remains in situ, and is selectively opened above the seminal vesicles. The
later seminal vesicles are completely removed inside Denonvilliers’ fascia and
six muscle-sparing interrupted sutures are used for anastomosis. Functional
and oncological outcome data were determined, which were prospectively
collected using validated questionnaires and intraoperative and perioperative
morbidity data were also evaluated. Patient age and the extent to which
the nerve-sparing approach was influenced by urinary continence and
potency. Overall, 97.4% of men less than 60 years of age, and 84.1% of men
over 70 years, had complete urinary continence 1 year after nerve-sparing
RP. In preoperative potent men, erections sufficient for intercourse were
seen in 84–92% of patients who underwent bilateral nerve sparing and
in 58.3–70% of men who underwent unilateral nerve sparing. Median
blood loss was 590 ml (range 130–1800 ml) and the transfusion rate was
4.5%. Median operative time was 175 minutes (range 95–215 minutes). In
organ-confined cancers, recurrence-free survival and cancer-specific survival
at 10 years after RP were 87% and 98.3%, respectively. Open intrafascial
nerve-sparing RP combines excellent long-term cancer control rates with
superior functional outcome and a low morbidity.
Introduction
Open retropubic prostatectomy (RP) is one of the
standard surgical approaches for treating clinically
localized prostate cancer.1 Recently, aside from the
established open retropubic or perineal approach,
conventional laparoscopic prostatectomy and robotassisted radical prostatectomy have experienced
increasing popularity.2,3 Today, most clinics have a
preferred surgical approach, based on their surgical
school, and favourable outcomes are reported with all
techniques.2–8 In a recent review article, no superiority,
in terms of functional and oncological outcome,
was reported for any particular technique except for
lower blood loss and transfusion rates associated with
robotic prostatectomy.9 However, all techniques are
under constant refinement and it is important that
updated results of existing techniques are published
to allow an ongoing and timely comparison of
the available approaches. Such studies aid the fair
judgement of developments in each technique and
help to better assess functional outcome, efficacy
and morbidity. We report our current technique of
open nerve-sparing RP, including cancer control rates,
functional outcome and perioperative morbidity.
Correspondence: Alexander Haese, The Martini-Clinic Prostate
Cancer Center, University Clinic Eppendorf, Maratinistrasse 52,
20246 Hamburg, Germany. Email: [email protected]
В© 2013 The Author(s)
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State-of-the-art review
Surgical methods
Equipment recommendations for open
nerve-sparing retropubic prostatectomy
We consider a self-retraining retractor system
(Bookwalter autoretractor,пЈЄ Codman, Le Locle,
Switzerland), which has 4- to 5-fold magnification
surgical loupes and a xenon headlamp for optimal
exposure and illumination of the operative field. No
specific positioning of the patient is necessary.
We recommend spinal anaesthesia and additional
total intravenous anaesthesia. Intravenous fluid
replacement should be limited to 500 ml until the
prostate is removed. Based on an individual fast-track
concept, discharge from hospital in a good physical
condition is possible 3–4 days after surgery and a
minimum hospital stay of 4 days postoperatively is
required in Germany for legal reasons.
FIGURE 1  The dorsal vein complex adjacent to the
prostate, starting on the superior half of the prostate at the
10 and 2 o’clock positions.
Open radical retropubic prostatectomy –
step-by-step
Incision of the endopelvic fascia and preparation
of the dorsal vein complex
After an 8–12 cm subumbilical vertical medial skin
incision, Retzius’ space is established. The endopelvic
fascia is incised and fibres of the levator ani muscle
are carefully pushed away. However, fibres from
the levator urethrae are preserved to maintain the
anterior position of the urethra. The attachments of
the detrusor apron, also called the puboprostatic
ligaments, are isolated and then removed.
Throughout the procedure, no coagulation enhancers
should be used in the vicinity of the neurovascular
bundle or the surface of the prostate to avoid damage
to the nerves.
A superficial stay suture (3-0 monofile suture using
a UR-6 needle) is created distally to the prostate
and will later be used for the selective ligation of
the dorsal vein complex. The lateral parts of the
fascia below the 10 and 2 o’clock positions of the
sphincter muscle, also called Mueller’s ligaments, are
not touched as they separate the sphincter from the
neurovascular bundle (Figures 1 and 2). To prevent
backflow bleeding, an additional 2-0 Vicryl suture is
placed in the midline of the prostate.
The trans-section of the exposed dorsal vein complex,
situated between the continuation of the endopelvic
134
FIGURE 2  Only the endopelvic fascia and the membrane
of the external sphincter are included within the oversewn
distal part of the dorsal vein complex. Mueller’s ligaments,
with the adjacent neurovascular bundles below the 10 and
2 o’clock positions, are marked with red arrows.
fascia superiorly and the fascia of circular striated
sphincter muscle inferiorly, is initiated near the apex
of the prostate. The dorsal vein complex is dissected
without any ligation until the fascia of the external
sphincter is visible. While the fascia of the external
sphincter is incised, care is taken that the muscle
fibres of the external sphincter that are directly
underneath are kept intact. The blood loss during
the trans-section is typically moderate, averaging
150–250 ml of blood loss per patient.
The selective suturing of the distal parts of the dorsal
vein complex between the 10 and 2 o’clock positions
involves two layers: the ventral part of the dorsal
vein complex, which consists of the continuation of
the endopelvic fascia; and the dorsal part, which is
covered by the fascia of the external sphincter. This
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:133–140 (http://dx.doi.org/10.7707/hmj.v6i2.281)
State-of-the-art review
approach ensures that functional tissue of either the
sphincter fibres or the urethra is not incorporated into
the ligation and that traction to the adjacent tissue is
avoided (Figure 3).
Intrafascial nerve-sparing procedure
The dissection of the neurovascular bundles starts
on the anterosuperior part of the prostate with an
incision to the parapelvic fascia, because the majority
of nerves run on the inferolateral part of the prostate.
The neurovascular bundles are mobilized and
lateralized before the urethra is dissected (Figure 3).
For careful dissection, the attached levator fascia and
periprostatic fascia are carefully lifted and incised at
the anterior aspect of the prostate above the 10 and
2 o’clock positions. The underlying space, including
the nerves, fatty tissue and small vessels supplying
the prostate, is identified. When the correct plane of
dissection is entered, the shiny, smooth and reflecting
surface of the prostatic capsule becomes visible.
The neurovascular bundles are gently pushed laterally
and inferiorly using the blunt tip of the scissors. The
dissected fascia and vessels are clipped with 5 mm
rectangular titanium clips and 3 or 5 mm 45° angle
titanium clips, or selective stitches [5-0 resorbable
polydioxanone (PDS) sutures], to control arterial
bleeding. The neurovascular bundle can be released
when the periurethral area is 3–5 cm proximal to the
base of the prostate and the bundle can be released
into the perivesical fat to avoid tension on the bundle
and to expose the prostatic pedicles.
FIGURE 3  Longitudinal section of the prostate. Most of the
fibres of the neurovascular bundles are running adjacent,
on the lateral and lower parts of the prostate; therefore,
dissection should begin on the superior part of the prostate.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Full functional length preparation of the urinary
sphincter
To preserve a maximum amount of functional tissue,
the preparation of the sphincter and urethra begins
at the apex. Fibres of the circular striated sphincter
muscle, covering the apex outside of the prostate, are
carefully pushed distally with blunt scissors until the
longitudinal smooth muscle fibres become visible.
Subsequently, the longitudinal smooth muscle fibres,
running inside the prostate, are incised. Transection
of the longitudinal fibres is performed approximately
3 mm within the prostate, superior to the apex of
the prostate. The remaining muscle fibres are gently
pushed distally for preservation. Subsequently, the
urethra is incised anteriorly and the preparation
is performed for two-thirds of its circumference.
By beginning the subtle dissection with the fibres
covering the apex of the prostate, the entire length of
the functional urethra is preserved (Figure 4).10
Anastomotic sutures and prostate removal
Six sutures are required for a complete anastomosis.
At the 3 o’clock, 1 o’clock, 11 o’clock and 9 o’clock
positions, a UR-6 needle with a 3-0 PDS suture is
passed through the ligated dorsal vein complex,
which is used as an anchor. The needle is then passed
through the mucosa of the urethra and only a small
part of the sphincter muscle is incorporated. At the
5 o’clock and the 7 o’clock positions, the last two
3-0 PDS sutures are generated with a UR-6 needle.
These also fix the dorsal part of the sphincter to
Denonvilliers’ fascia and the raphe of the sphincter
muscle for traction of the whole membranous urethra
(Figure 5), which is similar to the technique described
by Rocco et al.11 As mentioned above, perivesical fat
FIGURE 4  Preparation of the apex and sphincter, with the
circular and longitudinal muscle fibres dissected very close
to the apex of the prostate, ensuring the preservation of a
maximum amount of functional tissue.
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State-of-the-art review
Indication for nerve-sparing and lymph node
dissection
FIGURE 5  Principle of anastomotic sutures. The sutures are
placed through the everted bladder mucosa. Traction of
the whole membranous urethra is reached by including the
Denonvilliers’ fascia and the raphe of the sphincter muscle
within the 6 o’clock suture.
is mobilized during the nerve-sparing procedure to
release the bundles and avoid traction during the
surgery. In addition, the release of the fatty tissue up
to 3–5 cm proximal to the base of the prostate allows
an exact visualization of the prostatic pedicles, which
then are selectively ligated or clipped.
At the base of the prostate, the Denonvilliers’ fascia
is incised for preparation of the seminal vesicles. By
incising the Denonvilliers’ fascia, a ventral part of
this fascia is left on the specimen to prevent positive
margins. The part of the Denonvilliers’ fascia covering
the seminal vesicles is incised and is left in situ in
order to protect the underlying neurovascular bundle.
The tips of the seminal vesicles are identified and the
adjacent vessels are clipped and dissected with 5 mm
titanium clips. No thermal energy is used to protect
the integrity of the nerves running close to the tips of
the seminal vesicles. If required, the bladder outlet is
narrowed with a tennis-racket suture (3-0 Vicryl) and
eversion of the mucosa. The operating field is checked
and if bleeding close to the neurovascular bundle
occurs, 5-0 PDS sutures, or clips, are used to control
the bleeding.
End of the procedure
The needles of the six anastomotic sutures are placed
through the everted bladder mucosa and tied in a
single-knot technique to avoid compromising the
blood supply, which results in a stricture rate of
< 1%. The wound is closed using a self-resorbable
intracutaneous suture, which has good aesthetic
results. Whether a drain is carried out is left to the
discretion of the surgeon.
136
The indication that nerve-sparing surgery (bilateral
vs. unilateral vs. no nerve sparing) and lymph node
dissection is required is based on nomograms used to
predict the probability of side-specific extraprostatic
extension and lymph node invasion.12,13 To further
increase the oncological safety of a nerve-sparing
procedure, frozen sections (NeuroSAFE)14 of the lateral
surface of the prostate are taken from every patient.15
In the Martini-Clinic, preoperative nomography and
intraoperative sections are used to avoid positive
surgical margins in inadequately indicated nervesparing procedures (i.e. in patients with capsular
penetration) and to identify as many candidates for
nerve-sparing RP as possible. As the advantages
of nerve-sparing RP are obvious compared to
non-nerve-sparing RP, it seems necessary to identify
as many suitable cancers for nerve-sparing RP
as possible. Using nomography to estimate the
side-specific likelihood of organ confinement
in combination with NeuroSAFE intraoperative
frozen section analysis in the Martini-Clinic, the
rate of patients undergoing nerve-sparing RP for
pathologically organ-confined disease is as high as
98.3%. These results corroborate that we strive to
carry out nerve-sparing RP as much as possible using
frozen section analysis to minimize side-effects on
functional outcome.
NeuroSAFE frozen sections are cut from the apex
to the base of the complete dorsolateral part of
the prostate and the sides of the slice are inked
in different colours (Figures 6 and 7).15 If tumour
cells extend to the outer surface on microscopic
evaluation, we remove the corresponding
neurovascular bundle and its adjacent tissue.
Although NeuroSAFE frozen section analysis does
not completely eliminate the risk of positive surgical
margins, it does effectively minimize the risk.
Results
Perioperative parameters and morbidity
Preoperative parameters and morbidity were
based on the data from 1150 patients, whereas the
functional results reported below are based on 637
preoperative potent men. The median operating time
was 175 minutes (range 95–215 minutes), the median
blood loss was 590 ml (range 130–1800 ml) and the
transfusion rate was 4.5%. There was no rectal injury,
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:133–140 (http://dx.doi.org/10.7707/hmj.v6i2.281)
State-of-the-art review
NVB
(a)
Right side:
Intrafascial nerve sparing
NVB
(b)
Right side:
Intrafascial nerve sparing
FIGURE 6  (a) The right side of the prostate. (b) The right side of the prostate is inked green before removing the slice for
frozen section analyses and intraoperative evaluation of the surgical margin. NVB, neurovascular bundle.
(a)
(b)
FIGURE 7  (a) The different sides of the slice for frozen section analyses. (b) The different sides of the slice for frozen section
analysis are inked green on the outside of the prostate and towards the neurovascular bundle, and inked yellow on the
inside of the prostate. This technique enables the pathologist to differentiate between true- and false-positive surgical
margins.
ureteral injury or perioperative death. All patients
were routinely investigated by pelvic ultrasound
before discharge to detect a pelvic haematoma
(present in 5.3% of patients) or lymphocele (present
in 7.5% of patients). Surgical revision for pelvic
haematoma was necessary in 0.4% of patients and
lymphoceles were treated only when compression
of the external iliac vein was seen by Doppler
sonography; these cases (0.8% of patients) were
managed by puncture therapy. No patient had to
undergo laparoscopic fenestration for lymphoceles;
however, deep vein thrombosis was observed in 1.3%
of patients 14 days postoperatively.
Functional outcome
Urinary continence 1 year after surgery
The reported number of required pads for urine
leakage after nerve-sparing RP is commonly used
to assess postoperative urinary continence. In the
Martini-Clinic, validated questionnaires (International
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Continence Society and European Organization for
Research and Treatment of Cancer Quality of Life C30
questionnaires) are routinely conducted 1 year after
surgery. Continence results were stratified by age
and extent of nerve sparing (the unilateral vs. the
bilateral approach).
In men aged  70 years, urinary continence 1 year
after nerve-sparing RP was reported to be between
93.2% and 97.4% and did not seem to be influenced
by the extent of nerve sparing (Table 1). Among men
> 70 years of age, urinary continence was observed
in 94.5% after bilateral nerve-sparing RP; however,
after unilateral nerve-sparing RP, only 84.1% achieved
continence, suggesting a meaningful effect of the
extent of nerve sparing on urinary continence in
this patient group.16 Some 2.6–6.8% of patients
< 70 years of age reported needing two pads per
day, and this did not seem to be influenced by the
extent of nerve sparing. However, among men aged
> 70 years, 3.7% needed two pads after bilateral
nerve-sparing RP and 10.7% needed two pads after
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Hamdan Medical Journal  2013; 6:133–140 (http://dx.doi.org/10.7707/hmj.v6i2.281)
State-of-the-art review
TABLE 1  Continence levels 1 year after surgery
< 60 years
60–70 years
> 70 years
Number of pads
used in 24 hours
Bilateral nerve
sparing
Unilateral nerve
sparing
Bilateral nerve
sparing
Unilateral nerve
sparing
Bilateral nerve
sparing
Unilateral nerve
sparing
0–1
1–2
> 2
95.9%
3.3%
0.7%
97.4%
2.6%
0.0%
93.8%
5.5%
0.7%
93.2%
6.8%
1.8%
94.5%
3.7%
1.8%
84.1%
10.7%
5.2%
unilateral nerve-sparing RP. More than two pads
were used by 0.7% of men ≤ 70 years who underwent
bilateral nerve-sparing RP and up to 1.8% of men
who underwent unilateral nerve-sparing RP. Among
men > 70 years, more than two pads were used by
1.8% and 5.2% of patients after bilateral and unilateral
nerve-sparing RP, respectively. There was no complete
urinary incontinence.
Erectile function 1 year after surgery
Evaluation of postoperative potency was restricted
to men with documented good preoperative
erectile function who underwent a unilateral or
bilateral nerve-sparing RP and in whom information
on postoperative erectile function 1 year after
surgery was available. The five-item version of the
International Index of Erectile Function (IIEF-5) was
given before surgery and 12 months after RP for all
patients.17 There are several approaches to describe
postoperative erectile function and the IIEF-5 score
is one of the most commonly used questionnaires.
Many centres do not report postoperative IIEF scores
but report patients’ ability to perform intercourse
after RP instead. Such results strongly correlate;
nevertheless, the number of potent patients
substantially varies by the type of evaluation and
the definition of being potent. Question 2 of the
IIEF-5 questionnaire asks for erections sufficient for
penetration after sexual stimulation. By this definition,
potency rates varied from 84% to 92% in men who
underwent a bilateral nerve-sparing RP and from
58.3% to 70% following unilateral nerve-sparing RP
(Table 2). The use of proerectile medication, such as
phosphodiesterase type 5 (PDE-5) inhibitors, was left
to the patient’s discretion and 20% of men used such
medications. The potency rates of only 25–59% of
men returned to a normal score of > 19 (based on the
IIEF questionnaire).
Oncological results
In this article, we describe our current technique
of nerve-sparing RP and, therefore, cannot present
meaningful oncological long-term follow-up data
for this specific cohort. All prostatectomy specimens
were inked and underwent a 3 mm step-section
procedure for pathological work-up. Using margin
status as a surrogate parameter for cancer control,
the positive margin rate was 5.2% in pT2 cancers
and 27.1% in pT3 cancers. However, because our
surgical approach is based on previous reports from
the Martini-Clinic, we report on long-term data
addressing prostate-specific antigen recurrence-free
survival and, more importantly, cancer-specific
survival rates.4,18 At 10 years after RP, the biochemical
recurrence-free survival rates ranged from 5.9%
to 87%, depending on the pathological stage, and
cancer-specific survival rates ranged from 72.2%
to 98.3%.
Discussion
Retropubic prostatectomy has been performed for
several decades and the groundbreaking work on
anatomy and surgical technique was published by
Walsh and Donker more than 30 years ago.1 Several
studies have published results of this technique
TABLE 2  Ability to perform intercourse 1 year after surgery
< 60 years
Ability to have
intercourse
138
60–70 years
> 70 years
Bilateral nerve
sparing
Unilateral nerve
sparing
Bilateral nerve
sparing
Unilateral nerve
sparing
Bilateral nerve
sparing
Unilateral nerve
sparing
92.0%
58.3%
84.0%
70.0%
84.0%
63.6%
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:133–140 (http://dx.doi.org/10.7707/hmj.v6i2.281)
State-of-the-art review
and the ongoing modifications.4–8 The refinements
observed in this report are certainly no reinvention
of the technique, but nuances of the prescribed
approach have changed. One modification in the
current technique is a more precise dissection of the
posterior urethra. The continence rate 1 year after
surgery, defined as no pad used or one safety pad
used only, increased from 92% in 2006 to 95.5% in
our latest questionnaire series in 2011 on more recent
patients. The above-mentioned modification may
be responsible for that increase and the intrafascial
approach for the nerve-sparing procedure and the
increased number of NeuroSAFE intraoperative
frozen sections, including the complete capsule
corresponding to the neurovascular bundle, is
another alteration from previous studies. The current
positive surgical margin rate in pT2 cancers has fallen
in recent years from 9.4% to 5.2%.18 These data have
to be viewed in the context that 98.3% of patients
with organ-confined disease at final pathology are
undergoing a nerve-sparing procedure.
The intrafascial approach has also slightly increased
potency rates reported by patients in the present
study, with 58.3–92% of men reporting having
postoperative erections sufficient for intercourse.
Potency assessment based on whether an IIEF score
of > 19 was reached resulted in potency rates falling
to 25–59%, a phenomenon that has already been
described by Menon et al.3 In that study, 70% of
preoperative potent men had erections sufficient for
intercourse 1 year after surgery; however, only half
of these patients returned to a normal Sexual Health
Inventors for Men score, indicating the necessity of
using identical and validated assessment tools when
differences in potency rates of published studies
are considered.
Cancer control rates cannot be provided on
the present cohort as these are recent patients.
Nevertheless, the presented data based on the
patients who underwent surgery earlier showed
favourable recurrence-free and cancer-specific
survival rates. Although we cannot prove that such
data can be extrapolated to the present patient
cohort, we believe that long-term cancer control rates
will further improve in the present study. This is based
on the fact that positive margin rates are lower in the
present study than in previously studied patients.18
The importance of negative margins on outcome
has been discussed extensively and we believe that
intraoperative frozen sections are one of the keys to
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
achieving favourable functional outcomes without
compromising the procedure.19
Interestingly, the recurrence-free survival rate in
a previous report from the Martini-Clinic in pT2
cancers at 10 years was 80% and increased to 87%
in our recent analysis.18 This change may be due to
favourable cancers within defined cohorts, which is
often associated with the phenomenon that the year
of surgery may have prognostic impact.20
One of the aims of this report is to demonstrate that
the decrease in morbidity of RP is based not on the
methods used but on the experience of the surgical
team. Complication rates, and especially transfusion
rates, in the current study are in the range of a
high-volume endoscopic series, which highlights
our hypothesis.9 Prospective trials are needed to
show whether or not any method is advantageous
over another.
Conclusions
Open radical RP is still the most frequently performed
surgical approach for the treatment of localized
prostate cancer. Surgical refinements include a strict
intrafascial approach and subtle preservation of
the posterior urethra and its insertion. In the hands
of experienced surgeons, open radical RP provides
excellent long-term cancer control rates, favourable
functional outcome and low perioperative morbidity.
References
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7
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R. Tension and energy-free robotic-assisted laparoscopic
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Schlomm T, Tennstedt P, Huxhold C, et al. Neurovascular
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(NeuroSAFE) increases nerve-sparing frequency
and reduces positive surgical margins in open and
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Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:141–148 (http://dx.doi.org/10.7707/hmj.v6i2.200)
 
REVIEW
Hepatic stellate cell – vitamin A-rich cells
SF Bennaser and NC Bird
Liver Research Group, Department of Oncology, School of Medicine and Biomedical Sciences,
Royal Hallamshire Hospital, University of Sheffield, UK
Abstract
Quiescent hepatic stellate cells (HSCs) are characterized by their localization
of perisinusoidal cells and their long cytoplasmic processes, extending both
along and around the sinusoids as well as between the hepatocytes. These
long cytoplasmic processes, which have numerous vitamin A-containing lipid
droplets, are essential for the identification of HSCs in the quiescent phase.
Glial fibrillary acidic protein (GFAP) (Abcam, Cambridge, UK) is another crucial
marker for HSCs which may allow a distinction to be made between the HSCs
and other fibroblastic liver cells. However, induction of alpha-smooth muscle
actin (О±-SMA) is the most reliable marker of stellate cell activation because
it is absent from other resident hepatocytes in a normal or injured liver, with
the exception of the smooth muscle cells surrounding large vessels where it is
present. Desmin has been used as a typical marker for contractile stellate cells
in rodent livers; however, its expression is unreliable in humans. Furthermore,
HSCs’ transdifferentiation to the active phase has been proven to rely on
E-cadherin switching to N-cadherin during HSC activation. Significant
evidence now exists to consider HSCs as the main matrix-producing cells
in the process of the liver fibrosis. Liver injury, regardless of the aetiology,
tumour growth and metastases will ultimately lead to activation of HSCs.
Several studies have dissected the molecular mechanisms involved in liver
fibrosis, most of which are intimately connected to HSCs. As a result, a
number of key steps in the process of stellate cell activation and fibrogenesis
have been identified as potential therapeutic targets that may be clinically
useful in preventing, or treating, liver fibrosis.
Hepatic stellate cell
Hepatic stellate cells (HSCs) were described first
by Kupffer in the nineteenth century.1 He reported
the finding of stellate cells in 1876 by using a
gold chloride method that identified vitamin A
droplets.2 Recently, HSCs have been considered to
be mesenchymal cells with differing functions that
are critical to the state of the liver and the response
Correspondence: Dr Sirag Bennaser, Liver Research Group,
Department of Oncology, School of Medicine and Biomedical
Sciences, Royal Hallamshire Hospital, University of Sheffield, UK.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
to liver injury.1 Confusion arose during research and
reporting on HSCs owing to the different names in
use to refer to these cells; in 1996, investigators in the
field agreed to the standard name hepatic stellate cell
to refer to the quiescent phase of the cell type found
in a normal liver.1 This term is now widely accepted2 as
an alternative to the former litany of names including
perisinusoidal cell, Ito cell, lipocyte, parasinusoidal cell
and fat-storing cell (FSC).
Hepatic stellate cells are located in the subendothelial
space (space of Disse) between the basolateral
surface of the hepatocytes and the endothelial cells
that line the sinusoidal space. These cells represent
approximately one-third of the non-parenchymal
cell population and approximately 15% of the total
number of cells in a normal liver.3 Some researchers
have found a difference in the distribution of normal
liver HSCs between species. In humans, there is
a slight predominance of HSCs in the pericentral
zone,4 whereas in porcine liver there is a higher
concentration of HSCs in the periportal zone.5
The significance of these different patterns of cell
distribution between species is not understood.1
In a normal human liver, stellate cells have
spindle-shaped cell bodies with oval, or elongated,
nuclei, the cytoplasm of which extends into the
recesses between the neighbouring parenchymal
cells. Additionally, each cell has a moderately
developed rough endoplasmic reticulum, a
juxtanuclear small Golgi complex6 and dendritic
cytoplasmic processes.7 These dendritic cytoplasmic
processes have numerous microprojections
(spines) which wrap around the sinusoids between
the endothelial cells and parenchymal cells.8 The
significance of these spines was unclear until a
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recent study showed that they play a critical role as
the leading edge of the cell by sensing chemotactic
signals and mechanically transmitting the cell under a
contractile force.9
and a marker of contractile cells. It has been widely
used as a stellate cell marker in human and rodent
liver; however, in human liver, the expression of
desmin is inconsistent.17,18 This may be related to
the distribution of desmin, i.e. desmin-negative
cells may be concentrated in the pericentral zone
whereas desmin-positive cells may be typically
concentrated in the periportal zone.19 In the quiescent
phase, the HSCs can also be detected by vitamin
A contained within lipid droplets using vitamin A
autofluorescence, which creates a rapidly fading
blue-green fluorescence at 328 nm (Figure 1A).20 Lipid
droplets also represent a characteristic morphological
feature of these cells that can be detected in a
normal liver (Figure1B).21 Von Kupffer originally
described HSCs using a gold chloride method,
which is a technique that was later modified.2 Using
gold chloride staining on the human liver, a higher
number of cells were detected in the centrolobular
zone.22 Glial fibrillary acidic protein (GFAP) (Abcam,
Cambridge, UK) is an intermediate filament marker for
astrocytes which can be detected in normal stellate
cells only, and for a period of up to 2 days after their
isolation (Figure 2).23 Another stellate cell marker
is actin, which comprises six isoforms including
gamma (Оі) and beta (ОІ) non-muscle actin, known as
cytoplasmic actin. In contrast, alpha-smooth muscle
actin (О±-SMA), О±-cardiac, О±-skeletal and Оі-smooth
A single HSC usually surrounds more than two
sinusoids. On the anti-luminal surface of the cells,
multiple processes extend from the HSC through the
space of Disse to make contact with the hepatocytes.8
This close contact with the hepatocytes may facilitate
the intercellular transport of soluble mediators and
cytokines.1 HSCs also make direct contact with nerve
endings,10,11 a finding which has emerged from papers
identifying neurotrophin receptors.12 In addition,
functional studies have also confirmed that HSCs
display a neurohumoral response.13–15
Hepatic stellate cells identification
Many antibodies have been developed for the
different cytoskeletal and cell surface markers
that have facilitated the extensive features of the
stellate cell’s phenotype. These markers revealed
heterogeneity and plasticity in the adult liver,
depending on their lobular location, the type of
liver investigated (human or non-human) and
whether the tissue was normal or injured. Desmin
is an intermediate filament present in stellate cells16
(a)
(b)
FIGURE 1  (a) Vitamin A autofluorescence excited at 330 nm (the light blue regions). (b) Visualization of lipid droplets within
the HSCs obtained from a Wistar rat liver incubated with Oil red O to stain lipid vesicles red. Г—40 magnification. (These
photos are the unpublished results of a research project by Sirag Bennaser in 2010.)
142
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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REVIEW
FIGURE 2  Immunocytochemistry reveals GFAP in
quiescent HSCs at day 0. The regions that fluoresce green
due to fluorescein isothiocyanate (FITC) represent the
GFAP protein whereas the regions that are stained blue
by 4’, 6-diamidino-2-phenylindole (DAPI) are the nuclei of
the quiescent cells. x20 magnification. Scale bar = 100 µm.
(These photos are the unpublished results of a research
project by Sirag Bennaser in 2010.)
FIGURE 3  Immunocytochemistry technique expressed
actin filaments (Abcam, Cambridge, UK) in activated
HSCs at day 10. The regions that fluoresce green due
to FITC represent actin filaments whereas the regions
that are stained blue by DAPI are the nuclei of the
activated cells. x20 magnification. Scale bar = 100 µm.
(These photos are the unpublished results of a research
project by Sirag Bennaser in 2010.)
muscle actin (Оі-SMA) are considered tissue-specific
actin isoforms.24 The enhanced expression of О±-SMA is
the most consistent marker of stellate cell activation
as it is absent from other resident hepatocytes in
normal or injured liver, with the exception of the
smooth muscle cells surrounding large vessels, where
it is present (Figure 3).1
TABLE 1  A summary of the HSC markers in the quiescent
and activated phases
There are continuous changes in gene expression
during the fluctuating phenotype stages of a
stellate cell. For instance, the quiescent cell has a
pattern of gene expression that changes during
the activated phase and that continuously changes
during the myofibroblast-like phase. The pattern of
gene expression changes in an ageing stellate cell
to become more inflammatory and less fibrogenic.25
A study26 has reported the change from E-cadherin
to N-cadherin in activated stellate cells during
liver fibrosis, which suggests that HSC activation
represents transdifferentiation from an epithelial to a
mesenchymal phenotype (Table 1).26
Hepatic stellate cells function in normal
and injured liver
In a normal human liver under standard physiological
conditions, stellate cells store and transport
vitamin A compounds and 50–80% of the total
retinoid produced by the body is stored in these
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Marker
Quiescent HSCs Activated HSCs
Desmin
–
Vitamin A autofluorescence
Lipid droplets
GFAP
О±-SMA
E-cadherin
N-cadherin
+
+
+
–
+
-
+ in the periportal area of
the liver lobule. However,
outside this area, the
positivity of desmin is
approximately 50%
–
–
–
+
+
+, positive; –, negative.
cells.27,28 Stellate cells also exert immunoregulatory
activity by producing chemokines which promote
monomorphonuclear and polymorphonuclear
leucocyte infiltration, activate neutrophils and
regulate lymphocyte populations.2,29 They express
Toll-like receptors which cause HSC activation
when interacting with bacteria.30,31 HSCs also
act as antigen-presenting cells that activate
T-lymphocytes.30,32 Stellate cells secrete, and respond
to, a variety of cytokines (Table 2) and they modify
the activity of various growth factors. Stellate cells
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TABLE 2  Cytokines associated with HCS activity. The
expression and interaction of HSCs with a large variety
of biological molecules allow them to mediate multiple
activities and functions (adapted from reference 2)
Cytokines
Cytokine actin
Transforming growth factors: TGFОІ1, TGFО±
Proliferative or fibrogenic
Platelet-derived growth factors: PDGF-B
Hepatocyte growth factor
Stem cell factor
Fibroblast growth factors: aFGF, bFGF
Vascular endothelial growth factor
Insulin-like growth factors: IGF-I, II
Endothelin-1: ET-1, endothelin-converting
enzyme
Antifibrogenic
Apoptotic
Hepatic stellate cells and clinical liver
dysfunction
Plasminogen: urokinase plasminogen
activator, plasminogen activator
inhibitor-1
Fibrillar collagens: collagens I, II
Chemotactic or inflammatory
Regenerative
also express adhesion molecules such as intercellular
cell adhesion molecule-1, vascular cell adhesion
molecule-1 and neural cell adhesion molecule,
and they mediate detoxification of ethanol and
xenobiotics.2,33
Overall, stellate cells exhibit proliferation, chemotaxis,
fibrogenesis, contractility, matrix degradation activity
and retinoid loss when activated.1 They have roles
in inflammation,34 cell survival and apoptosis,35
fibrinogenesis, matrix metalloproteinase expression,
liver regeneration and monitoring of cellular pH.1
144
Fibrosis is an overgrowth, hardening and scarring
of connective tissue caused by excessive deposits
of extracellular matrix components, including
collagen. Myofibroblasts are a cellular source of
fibrosis, which, when activated, become the primary
collagen-producing cell. Myofibroblasts develop
from different kinds of cells, for instance resident
mesenchymal cells, developing epithelial and
endothelial cells (termed epithelial–mesenchymal and
endothelial–mesenchymal transition respectively)
and circulating fibroblast-like cells called fibrocytes
that are derived from bone marrow stem cells.36
Stellate cell activation refers to the alteration of a
resting vitamin A-rich cell to one that is proliferating,
fibrogenic and contractile, which is the main
pathway of hepatic fibrosis.1 The activation of
stellate cells consists of two major phases – initiation
and perpetuation – which is then followed by
the resolution of the fibrosis once the underlying
cause subsides. The initiation phase, known as the
preinflammatory stage, is associated with early
changes in gene and phenotype expression that
induce the cells to respond to cytokine stimulation.
It begins primarily from paracrine stimulation, which
is a result of changes in the surrounding extracellular
matrix and the exposure to lipid peroxides and the
products of damaged hepatocytes.1 In contrast,
perpetuation involves maintaining the activated
phenotype and fibrosis under the effects of these
stimuli. Nonetheless, the resolution of fibrosis is
related to pathways that lead the stellate cell to
apoptosis or reversion to the quiescent phase.37
Leptin
Renin, angiotensin II
Macrophage colony-stimulating factor
Platelet-activating factor
CD40
Tumour necrosis factor О±
Opioids
Toll-like receptor ligands: TLR4, CD14
Interleukin 6
Neurotrophins: NT-4, nerve growth factor,
brain-derived neurotrophic factor
Interleukin 10
Adiponectin
Follistatin
Fas signalling
Stellate cells and liver fibrosis
Extracellular matrix accumulation in the space
of Disse produces a disruption of the normal,
fenestrated microanatomy of the hepatic sinusoids.
This mechanism is identified as the capillarization of
the sinusoids38 that vitiate the normal bidirectional
exchange between the portal venous blood and
parenchymal cells. This causes toxic or nutrient
substances to be degraded, or metabolized, by the
hepatocytes and therefore to enter the bloodstream.
In addition, this mechanism leads to problems that
are mainly due to portal hypertension and declining
hepatocellular synthetic function, for instance
hyperbilirubinaemia, hepatic encephalopathy,
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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REVIEW
hypoalbuminaemia and a deficiency of coagulation
factors.39 An accumulation of data40 suggests
that stellate cells also play a role in the regulation
of portal venous blood and affect portal blood
resistance. Strong evidence supports the view that
portal hypertension may be partially created by
the modulation of the contractile activity of stellate
cells in the space of Disse under the effect of the
vasoactive components.38 In the experimental field,
portal hypertension can be reduced by 20–30% by
using pharmacological agents. Currently, stellate cells
are regarded as therapeutic targets to prevent and
treat the complications of chronic liver disease.40
Hepatic stellate cells and tumour
metastases
Hepatic stellate cells have a role in tumour growth
and metastatic processes. Experimental studies on
rats have reported that a conditioned medium from
cultures of hepatocellular carcinoma hepatocytes
could induce HSC activation.41 Injection of colon
carcinoma cells in nude mice provoked the formation
of hepatic metastatic foci and the activation of
HSCs.42 The latter produced hepatocyte growth factor
and transforming growth factor ОІ1 (TGF-ОІ1), which
induced tumour cell migration and proliferation.
Similarly, tumour cells secreted platelet-derived
growth factors (PDGF)-A and PDGF-B and enhanced
stellate cell locomotion and proliferation.42 In vitro
experiments on melanoma cells that cause liver
metastases concluded that tumour cells activate
HSCs, which in turn promote angiogenesis through
vascular endothelial growth factor expression.43
Experiments on rats44 showed that co-cultures of
sinusoidal endothelial cells (SECs) and HSCs presented
spontaneous differentiation, with HSCs forming the
core of the cell population and SECs forming the
surface. In vitro-activated stellate cells, cultured with
SECs, expressed a functional smooth muscle cell
phenotype and formed capillary-like structures in
angiogenesis assays. Tumours may activate HSCs and
therefore these studies44 implicated their mediation
in neoangiogenesis through interactions with SECs.
In hepatocellular carcinoma and colorectal liver
metastases, most investigations are concerned
with the activated HSCs that are responsible for the
formation of cancer stroma and fibrotic capsules.45,46
In addition, in biliary malignancy and hepatocellular
carcinoma, activated stellate cells contribute to
the accumulation of tumour stroma.47,48 These
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
results support those of the animal studies that
suggested that activated stellate cells play a role in
hepatic metastases,43,49 and cell culture studies have
demonstrated paracrine activation of stellate cells by
tumour cells.41
Conclusion
Hepatic stellate cells, also known as FSCs, reside
in the space of Disse between hepatocytes and
the hepatic sinusoids. In a normal human liver, the
main function of HSCs is to store vitamin A as well
as to produce extracellular matrix components.
After liver injury, cytokines are stimulated following
secretion from inflammatory cells, Kupffer cells
and dysplastic hepatocytes. HSCs then undergo
activation, which marks the transition from
quiescent vitamin A-rich cells into proliferative,
migrated, contractile and protein-synthesizing
myofibroblasts that are regarded as the major cell
type responsible for liver fibrosis.1 Myofibroblasts
were recently postulated to be a component of the
prometastatic liver microenvironment because they
can transdifferentiate into highly proliferative and
motile myofibroblasts that are implicated in the
desmoplastic reaction and tumour growth.50 The
activation of HSCs is a complex process regulated
by multiple factors, for example TGF-ОІ1 and
PDGF signalling pathways, which may present as
therapeutic targets in the prevention and treatment
of liver metastases. It would be worth investigating
whether targeting the HSCs/myofibroblasts with
a growth factor antagonist in coordination with
chemotherapy, radiotherapy and surgery would be
effective in reducing liver metastases and increasing
the survival rate of patients by targeting both tumour
cells and the tumour milieu.51
Acknowledgement
I thank Dr NC Bird (Liver Research Group, Floor
K, School of Medicine and Biomedical Sciences,
Royal Hallamshire Hospital, University of Sheffield)
for his guidance and advice in the preparation of
this manuscript.
Disclosure
No author has any potential conflict of interest.
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REVIEW
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Review
Literature review of small cell carcinoma of the
urinary bladder
Anthony Kodzo-Grey Venyo1 and Douglas John Lindsay Maloney2
Department of Urology, North Manchester General Hospital, Manchester, UK, and 2Department
of Pathology, Airedale District General Hospital, Steeton, Keighley, West Yorkshire, UK
1
Abstract
Small cell carcinoma of the urinary bladder is a rare tumour that resembles
small cell carcinoma in the lung and elsewhere. Because of its rarity,
practitioners may not be familiar with the biological behaviour of this
tumour. The aim of this article is to review the literature on small cell
carcinoma of the urinary bladder. Various internet search engines were
used to explore the literature on small cell carcinoma of the urinary
bladder including Google, Google Scholar, UpToDate, Pub Med and Educus.
About 42 references were selected as the basis for the literature review.
Small cell carcinoma of the urinary bladder is an aggressive tumour that
typically presents with advanced or disseminated disease. This is a rare
disease, accounting for only 0.5–1.0% of all bladder malignancies. Affected
individuals show no age, sex or clinical differences from those with the
typical type of urothelial carcinoma. Some cases of small cell carcinoma of
the urinary bladder arise from urothelial carcinoma in situ while others arise
from totipotent stem cells in the submucosa. The tumours are usually large
polypoid masses that can occur anywhere in the bladder. Microscopically,
the tumours appear as loosely cohesive sheets, or nests, of small to
intermediate-sized cells with minimal cytoplasm, hyperchromatic nuclei,
stippled or coarsely granular chromatin, indistinct nucleoli and no nuclear
overlapping. Mitotic activity and necrosis are common and the tumours
may co-exist with other forms of in situ, or invasive, carcinoma. Radical
cystectomy is the main treatment for small cell carcinoma of the urinary
bladder, unless metastatic disease is present, followed by systemic treatment.
Response to chemotherapy is good, similar to treatment for small cell
carcinoma of the lung, but the overall prognosis remains poor. There is no
consensus regarding treatment of small cell carcinoma of the urinary bladder
although general recommendations for the approach to treatment of this
aggressive disease have been suggested.
Introduction
Small cell carcinoma of the urinary bladder is an
uncommon, aggressive and poorly differentiated
Correspondence: Mr Anthony Kodzo-Grey Venyo, Department
of Urology, North Manchester General Hospital, Manchester, UK.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
neuroendocrine tumour that has similar behavioural
characteristics to small cell carcinoma of the lung.1
Gilligan et al.1 reported that although small cell
carcinoma has been classified as an isolated entity,
the results of a molecular study by Cheng et al.2
indicate that small cell carcinoma and urothelial
carcinoma are derived from the same clonal
population. Gilligan et al.1 reported that small cell
carcinoma of the urinary bladder has frequently been
found in association with other histological forms of
bladder cancer. Cheng et al.3 reported on a sample
of 66 cases of small cell carcinoma of the urinary
bladder, of which 44 (67%) were associated with other
types of tumours and 38 (58%) were associated with
elements of urothelial carcinoma.
This paper reviews the literature on small cell
carcinoma of the urinary bladder and provides a
discussion of the topic.
Epidemiology
Sved et al.4 and Koay et al.5 reported that between
1991 and 2005 the annual incidence of small cell
carcinoma of the urinary bladder increased from
0.05 to 0.14 cases per 100 000. Nevertheless, small
cell carcinoma accounts for less than 1% of all urinary
bladder malignancies worldwide.
Cheng et al.3 reported that a history of smoking
is associated with the development of small cell
carcinoma of the urinary bladder, and Koay et al.5
reported that the prevalence of small cell carcinoma
of urinary bladder is higher in whites than in nonwhites (91% vs. 9%). Koay et al.5 also found that
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men are more frequently affected than women
(76% vs. 24%), the median age at diagnosis is 73 years
and patient survival varies substantially depending
upon the presence or absence of distant metastases
at the time of initial diagnosis but the median overall
survival is 11 months.
Small cell carcinoma of the urinary bladder is
rare, accounting for only 0.5–1.0% of all bladder
malignancies, and affected individuals show no age,
sex or clinical differences from those with the usual
type of urothelial carcinoma.6
Aetiology
Gaisa et al.7 reported that at least some cases of
small cell carcinoma of the urinary bladder arise
from urothelial carcinoma in situ, whereas Shahab8
reported that small cell carcinoma of the urinary
bladder may arise from totipotent stem cells in
the submucosa.
Clinical features
It has been suggested that the clinical features of
small cell carcinoma of the urinary bladder are similar
to those of other bladder tumours, and reflect the
presence of a mass.1 It has also been suggested that
the tumour normally infiltrates the wall of the urinary
bladder, leading to either ulceration or bleeding, and
that most patients present with locally advanced
disease or metastatic disease.1
Koay et al.5 reported that, of a sample of 642 patients
presenting with small cell carcinoma of the urinary
bladder, 12% had stage I disease, 32% stage II disease,
14% stage III disease and 36% stage IV disease at
the time of presentation; the remaining 6% of the
tumours were unstaged.
It has been stated by Koay et al.5 that most patients
with small cell carcinoma of the urinary bladder in
the USA present with poorly differentiated (33% of
patients) or undifferentiated tumours (43%), and
the most common sites for tumours to form in the
urinary bladder are the lateral wall (16%) and the
the dome (10%), although they can occur anywhere.
Twenty-four per cent of patients in a study reported
by Koay et al.5 had distant metastases at the time
of initial diagnosis and a further 5% had multiple
lymph node metastases that were stage N2 or N3.
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Paraneoplastic syndromes can occur, but not as
commonly as with small cell carcinoma of the lung.1,9
It has also been stated that in the majority of
cases (65%) small cell carcinoma of the urinary
bladder is advanced by the time of diagnosis or
soon after.6 Occasionally, it may be associated
with hypercalcaemia and ectopic production of
adrenocorticotropic hormone (ACTH). A diagnosis of
small cell carcinoma of the urinary bladder should
be made whenever a tumour includes a significant
component of small cell because the prognosis
will be affected by this component.6 This disease is
aggressive and metastases of the regional lymph
nodes and the peritoneal cavity develop rapidly;
median survival is reported to be 11 months.5,6 Small
cell carcinoma of the urinary bladder rarely co-exists
with tumour cells that exhibit skeletal muscle
differentiation10 and in this case 5-year survival ranges
from 8% to 16%.3
Pathology
Gross findings
Jiang and Cheng11 reported that small cell carcinoma
of the urinary bladder has a polypoid, or nodular,
appearance and frequently has an ulcerated surface.
Gross examination reveals a solid tumour that
originates from the mucosa and often penetrates
deeply into the wall of the urinary bladder.
Microscopic findings
With regard to the microscopic findings, Cheng et al.3
reported that 68% are usually admixed with classic
urothelial carcinomas or adenocarcinomas of the
urinary bladder. The histological features of small
cell carcinoma of the urinary bladder are the same
as those of small cell carcinoma in other organs.11
Microscopic examination of small cell carcinoma
of the urinary bladder reveals sheets and nests of
loosely cohesive, small, round or oval cells with very
scant cytoplasm (Figure 1). The cell nuclei of the
tumour are typically hyperchromatic with coarsely
granular chromatin, and nuclei moulding can almost
invariably be seen. Figures 1 to 7 show haematoxylin
and eosin-stained sections of a muscle-invasive small
cell carcinoma of the urinary bladder at different
magnification. The tumour shown in these figures
consists of sheets of small dark pleomorphic cells
with scant cytoplasm and finely stippled nuclear
В© 2013 The Author(s)
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FIGURE 1  Haematoxylin and eosin staining at
× 100 magnification. The tumour consists of sheets of small
dark pleomorphic cells with scant cytoplasm and finely
stippled nuclear chromatin. There are some pink strands
of detrusor muscle confirming the tumour to be at least a
stage pT2.
FIGURE 2  Haematoxylin and eosin staining at
× 400 magnification.
FIGURE 3  An additional view of haematoxylin and eosin
staining of the tumour in Figure 1 at × 400 magnification.
FIGURE 4  Haematoxylin and eosin staining at
× 200 magnification.
chromatin. In Figure 1, some pink strands of detrusor
muscle are apparent, confirming the tumour had
invaded the muscle and was therefore at least stage
pT2. In addition, the tumour was solid and contained
no other elements (e.g. there were no elements of
transitional cell carcinoma, squamous cell carcinoma
or adenocarcinoma). Mitosis is present, the nucleoli
are absent or small and tumour necrosis is present.11
Cytological examination of the urine specimen of
patients suffering from small cell carcinoma of the
urinary bladder often reveals single and loosely
cohesive clusters of tumour cells with typical small
cell carcinoma morphology.
Cytology
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Cytological examination of urine specimens from
patients with small cell carcinoma of the urinary
bladder shows numerous tumour cells in loose
clusters. The cells tend to be larger than lymphocytes
and show scant cytoplasm. The nuclei tend to
be eccentric with evenly dispersed, but coarse,
chromatin and the nucleoli tend to be indistinct.6
Immunohistochemistry
Immunohistochemistry is a useful tool in the
diagnosis of small cell carcinoma of the urinary
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FIGURE 5  An additional view of haematoxylin and eosin
staining of the tumour in Figure 4 at × 400 magnification.
FIGURE 6  An additional view of haematoxylin and eosin
staining of the tumour in Figure 4 at × 400 magnification.
FIGURE 7  An additional view of haematoxylin and eosin
staining at of the tumour in Figure 4 × 400 magnification.
FIGURE 8  Immunohistochemistry for small cell
neuroendocrine marker CD56 at × 400 magnification.
bladder because neuroendocrine markers,
including chromogranin A, synaptophysin, CD56
and neuron-specific enolase, are quite often
focal or diffusely positive. Figure 8 shows positive
immunohistochemical staining of the muscle-invasive
small cell carcinoma of the urinary bladder for CD56.
Figures 9 and 10 show positive immunohistochemical
staining for synaptophysin at × 200 magnification
(Figure 9) and × 400 magnification (Figure 10).
however, a combination of low-molecular-weight
cytokeratin, CAM5.2 and epithelial membrane antigen
(EMA) is mostly positive.
Documented immunohistochemical positive stains in
small cell carcinoma of the urinary bladder include:
в– в– в– в– Some authors12,13 have stated that a definitive
diagnosis of small cell carcinoma of the urinary
bladder can be achieved based on morphology
alone as immunohistochemisty frequently fails to
identify the markers mentioned previously. A cocktail
of cytokeratin markers is quite often non-reactive;
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в– в– EMA and CAM5.2 (which result in a visible dot-like
perinuclear pattern);
neuron-specific enolase and synaptophysin,
both of which frequently express
neuroendocrine features;14
variable c-Kit (27% of small cell carcinomas of the
urinary bladder are positive for c-Kit expression),15
chromogranin (weak/focal if present),
cytokeratin 716 and thyroid transcription factor 1.17
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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FIGURE 9  Immunohistochemical staining of small cell
carcinoma showing positive staining for synaptophysin at
× 200 magnification.
FIGURE 10  Immunohistochemical staining of small cell
carcinoma showing positive staining for synaptophysin at
× 400 magnification.
Pernick6 stated that neuroendocrine stains are of
questionable value to many researchers for the
diagnosis of small cell carcinoma of the urinary
bladder as this is based on a morphological diagnosis.
It has been documented that immunohistochemical
stains for various markers such as carcinoembryonic
antigen marker, cytokeratin 20 marker and human
papillomavirus (HPV) marker are negative for small
cell carcinoma.8
to broad-spectrum HPV DNA amplification and
typing and were immunohistochemically examined
to test for the expression of p16, Rb and p53 proteins.
The results showed that HPV DNA was detected in
every case (100%) and 18 cases (82%) were found to
harbour HPV type 18. The tumour cells in 20 of the
cases (91%) exhibited strong nuclear staining for
p16, which was associated with a complete loss of
Rb nuclear staining in 16 cases (73%), and the p53
protein was essentially undetectable in all cases. HPV
DNA was not detected in nine colorectal and eight
urinary bladder small cell carcinoma samples that
were included in the study for comparison. While
similar p16 and Rb expression patterns were observed
in these HPV-negative colorectal and urinary
bladder small cell carcinoma samples, a different
expression pattern for p53 was noted, in which
strong nuclear staining was seen in 8 of the 17 cases
(47%, P = 0.0004 compared with cervical tumours).
Wang and Lu18 reported that these observations
indicate that different mechanisms are involved in the
pathogenesis of small cell carcinomas of the uterine
cervix compared with colorectal small cell carcinomas
or small cell carcinomas of the urinary bladder.
These observations also support the suggestion
that overexpression of nuclear p16 serves as an
indication of Rb malfunction in tumour cells, which
may or may not result from high-risk HPV infection.
The aforementioned results of protein expression
may relate only to carcinomas of the cervix; however,
the small sample size of small cell carcinomas of the
bladder does not allow for a definite conclusion to
be reached.
Electron microscopy
Electron microscopic examination of small cell
carcinoma of urinary bladder tissue may reveal only
few dense core granules.6
Detection of human papillomavirus
DNA and the expression of p16,
retinoblastoma protein and p53
proteins in small cell carcinoma
Human papillomavirus has been implicated as an
aetiological agent for the development of primary
small cell carcinoma of the uterine cervix.18 It
has been demonstrated that the HPV E6 and E7
oncoproteins are able to inactivate the tumoursuppressing functions of p53 and retinoblastoma
protein (Rb). With regard to squamous cell carcinoma
and adenocarcinoma of the cervix, HPV infection
is also associated with overexpression of p16, a
cyclin-dependent kinase inhibitor.18 Wang and
Lu18 reported on 22 cases of primary small cell
carcinoma of the uterine cervix that were subjected
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Genomic alterations
Terracciano et al.19 reported that small cell carcinoma
of the urinary bladder shows abundant genomic
abnormalities, typically more than 10, similar to small
cell carcinomas of other organs.19 Terracciano et al.19
also reported that the most frequent changes
occurring in small cell carcinoma of the urinary
bladder are deletions of 10q, 4q, 5q and 13q and
gains in 8q, 5p, 6p and 20q. They also showed that
small cell carcinoma has been caused by acquisitions
of genomic alterations in a typical invasive urothelial
carcinoma. In addition, genomic DNA amplifications
are identified in many loci where oncogenes
are located.19
Differential diagnosis
It has been suggested that the following tumours
should be considered in the differential diagnosis of
small cell carcinoma of the urinary bladder:6
в– в– в– в– в– в– High-grade urothelial carcinoma that, by
definition, should lack any appreciable small cell
component such as p63+ or synaptophysin. A
limited immunohistochemical panel including
pan-cytokeratin, synaptophysin and p63 can
discriminate high-grade neuroendocrine
carcinoma and small cell carcinoma from
high-grade urothelial carcinoma.20
Lymphoma, in which tumour cells are smaller and
positive for CD45 and B- or T-cell markers.6
Metastatic small cell carcinoma, in which there is
usually no associated urothelial carcinoma.6
Treatment
Gilligan et al.1 stated that there is currently no
consensus regarding the treatment of small
cell carcinoma of the urinary bladder because
there are no randomized clinical trials on which
definitive recommendations could be made for the
management of patients. However, the results of
several retrospective studies and one prospective
phase II study provide some insight into the
therapeutic approach to the management of small
cell carcinoma of the urinary bladder.1,21–24
Localized disease
Some authors3,4,25,26 have reported that patients
with small cell carcinoma of the urinary bladder
are likely to have a poor prognosis, even when it is
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evident that the disease is localized, as a result of
the potential development of disseminated disease.
However, some studies1,21 have shown that small
cell carcinoma of the bladder responds to the same
chemotherapy procedures that are used for the
management of small cell carcinoma of the lung and
that some patients can achieve lasting complete
remission. Some of these studies1,21 have also
reported that combination or aggressive systemic
chemotherapy, followed by local therapy (cystectomy
or radiotherapy), may increase the long-term
survival rate among who present with clinically
localized disease.1,21
Cystectomy may or may not be accompanied by
adjuvant chemotherapy, but cystectomy alone is
associated with a relatively poor prognosis.4,22,23
Siefker-Radtke et al.23 reported a retrospective series
of 25 patients with small cell carcinoma of the urinary
bladder who initially underwent cystectomy between
1985 and 2002. They reported that the 5-year cancerspecific survival was 36%, and 7 of these 25 patients
received postoperative adjuvant chemotherapy;
nevertheless, their outcome was not better than
the outcome of those patients who did not receive
postoperative adjuvant chemotherapy.
Choong et al.22 reported a series of 44 patients
with small cell carcinoma of the urinary bladder
who were treated between 1975 and 2003. They
reported that 7 out of 17 patients (41%) were
cured following radical cystectomy alone. They also
reported that the patients who received perioperative
chemotherapy, instead of surgery alone, were more
likely to be cured irrespective of whether they had
stage II (100% vs. 71%), stage III (50% versus 13%) or
stage IV (20% versus 0%) disease. In relation to the
Choong et al.22 study, Gilligan et al.1 commented that
the number of patients treated was too small to make
the conclusions valid.
Cheng et al.3 reported on 64 patients, of whom 59%
underwent cystectomy while the remainder did not.
The study found that there was no difference in the
survival outcome of the two groups in that the 1- and
5-year survival rates were 57% and 16%, respectively,
in the cystectomy group in comparison with 55% and
18%, respectively, in the group without cystectomy.
Sved et al.4 reported on the analysis of published
literature on a number of patients with small cell
carcinoma of the urinary bladder. Of 20 patients who
underwent cystectomy alone, 11 died as a result of
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Review
their carcinomas, four were in complete remission,
one was continuing to live with the disease and four
were lost to follow-up. The study also reported that,
of the 23 patients who underwent cystectomy with
chemotherapy and radiotherapy, six died as a result
of their carcinomas, 11 were in complete remission
and six were continuing to live with the disease. The
summary of the outcome of small cell carcinoma
of the urinary bladder treatment was detailed by
Sved et al.4 as follows:
в– в– в– в– в– в– в– в– в– в– в– в– в– в– в– в– в– в– Twenty patients underwent cystectomy alone and
their mean survival was 12.9 months.
Eighteen patients underwent cystectomy and
chemotherapy and their mean survival was
27 months.
Five patients underwent cystectomy and
radiotherapy and their mean survival was
29.2 months.
Two patients underwent cystectomy and
chemotherapy/radiotherapy and their mean
survival was 6 months.
Twelve patients underwent partial cystectomy
and/or chemotherapy/radiotherapy and their
mean survival was 34.9 months.
Thirteen patients underwent chemotherapy alone
and their mean survival was 6.5 months.
Fifteen patients underwent chemotherapy
plus radiotherapy and their mean survival was
32.9 months.
Forty patients underwent radiotherapy alone and
their mean survival was 7.8 months.
Twenty-eight patients underwent transurethral
resection of the bladder tumour alone and their
mean survival was 8.6 months.
A number of studies4,24,25,27–30 have reported on the
use of neoadjuvant chemotherapy followed by
cystectomy or radiotherapy in responders. However,
Gilligan et al.1 stated that there are no definitive
data which indicate whether cystectomy and
radiation therapy improves the outcome compared
with chemotherapy alone, or whether there is any
difference in the outcome with cystectomy alone
versus radiation therapy alone.
In relation to neoadjuvant chemotherapy plus
cystectomy, Siefker-Radtke et al.24 reported a phase
II study which included 18 patients with clinically
localized small cell carcinoma of the urinary bladder
who had either cT2 (stage II) or cT3b (stage III) disease.
The study reported that the patients were initially
treated with four cycles of chemotherapy, in which
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
a combination of ifosfamide and doxorubicin was
alternated with a combination of etoposide plus
cisplatin. During subsequent cystectomy, 14 out
of the 18 patients (78%) had either no evidence of
residual disease or only carcinoma in situ and the
median overall survival was 58 months; at the time of
reporting the study results, 13 out of the 18 patients
were alive and disease free.
In another study, Siefker-Radtke et al.23 reported that,
among patients who initially underwent cystectomy
for small cell carcinoma, the 5-year cancer-specific
survival was higher for those who also received
preoperative chemotherapy than for those who
did not (78% and 36%, respectively); in addition,
no cancer-related deaths were observed beyond
2 years in those who had also received preoperative
chemotheraphy. Likewise, Quek et al.25 reported
that 14 patients who received either preoperative or
postoperative chemotherapy alongside cystectomy
had significantly longer overall survival (P = 0.051) and
relapse-free survival (P = 0.003) than the 11 patients
who underwent cystectomy alone. Nevertheless,
there were only two long-term survivors among the
25 patients in this study.
With regard to neoadjuvant chemotherapy plus
radiotherapy, some authors27,29–32 have used
radiotherapy as an alternative to cystectomy.
Bex et al.29 reported on a sample of 17 patients
with small cell carcinoma of the urinary bladder
who underwent transurethral resection of the
tumour and were then treated with platinumbased chemotherapy followed by radiotherapy.
They reported that a complete local response was
achieved in 15 of the 17 patients (88%); the overall
survival was 33 months and seven patients remained
disease free; however, four patients developed local
recurrence. Lohrisch et al.32 reported on a sample
of 10 patients who underwent chemoradiation for
small cell carcinoma of the urinary bladder in which
they observed a 70% disease-free survival rate at the
2- and 5-year mark, and five patients were alive at the
time of publication of the article in 1999.
Metastatic disease
Siefker-Radtke et al.24 and Mukesh et al.27 reported
that metastatic small cell carcinoma of the urinary
bladder is highly responsive to chemotherapy
regimens similar to those used in the treatment of
small cell carcinoma of the lung. Siefker-Radtke et al.24
and Ismaili et al.33 reported a median survival of
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approximately 7–13 months for those presenting with
small cell carcinoma of the urinary bladder, which was
treated using chemotherapy. However, Gilligan et al.1
reported that these responses were generally
transient and most patients relapsed. Gilligan et al.1
stated that the most commonly reported treatment
is etoposide in combination with cisplatin or
carboplatin; however, numerous other treatments
have been reported, as listed by Kelly et al.21 including:
в– в– в– в– в– в– в– в– в– в– в– в– в– в– в– в– platinum compounds (cisplatin, carboplatin)
podophyllotoxins (etoposide, teniposide)
camptothecins (irinotecans, topotecan)
alkylating agents (ifosfamide, cyclophosphamide)
anthracyclines (doxorubicin, epirubicin,
amrubicin)
taxanes (paclitaxel, docetaxel)
vincristine
other less frequently used drugs with single-agent
activity (nitrosoureas, methotrexate, gemcitabine
and vinorelbine).
Siefker-Radtke et al.24 reported 12 patients who
presented with stage IV disease, five wth only lymph
node involvement and seven with involvement of
other sites, with or without lymph node disease.
They reported that the patients were treated with a
chemotherapy regimen in which cycles of ifosfamide
plus doxorubicin were alternated with cycles of
etoposide plus cisplatin. Three of the patients who
originally had lymph node metastases showed
complete remission following chemotherapy and
underwent surgical consolidation. The overall median
survival for this cohort of patients was 13 months.
One of the patients remained disease free 28 months
following the original treatment. Other studies22,33,34
have reported either very small numbers of patients
treated by chemotherapy and/or used different
chemotherapeutic treatments for different patients
and therefore it is difficult to estimate response rates
and comparative outcomes for different treatments.
Brain metastases
Accoording to Gilligan et al.,1 brain metastases are a
frequent complication of small cell carcinomas of the
lung but there are only limited data regarding the
frequency of brain metastases in patients with small
cell carcinoma of the urinary bladder.
Siefker-Radtke et al.24 reported brain metastases in
8 out of 16 patients (50%) with stage III or IV small cell
carcinoma of the bladder but none of the 14 patients
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with stage II disease. Ismaili et al.33 reported that
2 out of 12 relapsing patients (17%) who were treated
between 1996 and 2007 had central nervous system
involvement; however, a number of larger studies
observed a lower prevalence of brain metastases
in cases of small cell carcinoma of the urinary
bladder.23,27,35 Gilligan et al.,1 in a pooled analysis of
15 series in which the sites of the metastatic disease
were identified, found that 37 out of 342 patients had
developed brain metastases [11%; 95% confidence
interval (CI) 7.5–14.1%].
Gilligan et al.1 reported that prophylactic cranial
irradiation decreases the incidence of brain
metastases and prolongs survival in patients with
small cell carcinoma of the lung; thus, prophylactic
cranial irradiation is generally given to patients with
small cell lung cancer patients in whom spread of the
disease is limited and response to initial therapy is
good. Gilligan et al.1 also stated that there are no data
evaluating this approach for patients with small cell
carcinoma of the urinary bladder.
In conclusion, the treatment for small cell carcinoma
of the urinary bladder may be summarized generally
as follows:
в– в– в– в– Radical cystectomy should be performed except
in the presence of metastatic disease, in which
case systemic therapy would be required.36
There is a high response rate to chemotherapy,
which is similar to the treatment used for lung
tumours. However, the overall prognosis is
still poor.27
Discussion
Since the report of the first case of small cell
carcinoma of the urinary bladder in 1981,37 the
majority of patients diagnosed with this rare disease
have been male. The male to female ratio is 7.6:1 and
the disease typically presents between the ages of
60 and 80 years.37–39
Several studies40–43 have reported that most patients
who present with small cell carcinoma of the lung or
other extrapulmonary sites have a history of extensive
smoking. Nevertheless, most patients with small cell
carcinoma of the urinary bladder are non-smokers.
Kayler et al.44 stated that it is unclear whether tobacco
contributes to disease progression in view of the
paucity of information regarding small cell carcinoma
of the bladder.
В© 2013 The Author(s)
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Review
Mills et al.14 reported that the majority of small cell
carcinomas of the urinary bladder have histological
patterns consistent with transitional cell carcinoma,
squamous cell carcinoma or spindle cell carcinoma.
Atkin et al.45 conducted a cytogenetic study to
illustrate that small cell carcinomas of the urinary
bladder display rearrangement of the long arms of
chromosomes 6, 9, 11, 3 and 18, with hypertriploid
DNA and expression of p53.
Pearse46 reported that immunohistochemical studies
have revealed the existence of neurosecretory
granules in the majority of small cell carcinomas of
the urinary bladder, which led some researchers to
form the opinion that small cell carcinomas of the
urinary bladder are derived from neuroendocrine
precursor and decarboxylation cells. However,
other studies37,42,47 have suggested a multipotential
stem cell origin, which would account for the minor
component of admixed non-small cell carcinoma
which is commonly seen in these tumours.
Partanen et al.48 reported that small cell carcinoma
of the urinary bladder rarely demonstrated ectopic
hormone production. Grignon et al.49 reported
hyperphosphataemia without hypercalcaemia prior
to tumour resection, which suggested that humoral
production disturbed phosphate metabolism;
however, the phosphate level returned to normal
following resection. Reyes and Soneru41 reported that
the association between small cell carcinoma of the
urinary bladder and hypercalcaemia was attributed to
skeletal metastasis.
Gilligan et al.1 made the following recommendations
for the management of small cell carcinoma of the
urinary bladder.
Localized disease
In the case of patients with localized disease, when
the tumour has been assessed as stage II or stage
III and when the patient’s overall condition permits
aggressive therapy, Gilligan et al.1 recommend
a combined modality approach which includes
neoadjuvant chemotherapy using a platinum-based
combination, as is used for small cell lung cancer,
followed by specific treatment directed towards
the primary tumour (for example, cystectomy or
radiotherapy; grade 1B).
в– в– Gilligan et al.1 suggest the use of the combination
of cisplatin plus etoposide (grade 2C). They report
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
в– в– that this approach has been associated with
a higher incidence of long-term, disease-free
survival than in historical series treated with
cystectomy alone, or cystectomy followed by
adjuvant chemotherapy.
They also suggested that following neoadjuvant
chemotherapy, cystectomy rather than
radiotherapy should be performed to treat
grade 2C small cell bladder tumour. They further
recommend that in the case of patients who
are not surgical candidates (e.g. patients with
inoperable tumours), radiotherapy should be the
alternative method of treatment.
Disseminated disease
In the case of patients with disseminated disease,
Gilligan et al.1 recommend systemic chemotherapy
using a regimen that is also used to treat advanced
small cell carcinoma of the lung (grade 1B).
Brain metastasis
в– в– в– в– Gilligan et al.1 recommend that patients with stage
I or stage II disease and brain metastases who
achieve complete remission after neoadjuvant
chemotherapy plus either cystectomy or
radiotherapy should not undergo prophylactic
cranial irradiation (grade 2C).
For patients with stage III or IV disease who have
partial or complete response to the treatment,
Gilligan et al.1 recommend prophylactic
cranial irradiation as an additional treatment;
however, they also state that the advantages
and disadvantages should be discussed with
the patient.
Gilligan et al.1 also report that although there are
no data for patients with small cell carcinoma of the
urinary bladder, prophylactic irradiation decreases
the incidence of brain metastases and prolongs
survival in those with small cell carcinoma of the lung;
however, whole-brain irradiation can have substantial
neurological side-effects.
Future directions
Ismaili50 reported that:
1
Although the results of cisplatin-based
chemotherapy are promising, most patients die
as a result of metastatic disease.
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Review
2
Developments in molecular biology have
led to the investigation of new molecules in
a large number of tumours including small
cell carcinoma of the lung. Overexpression
of a number of receptors, including vascular
endothelial growth factor receptor (VEGFR)
on endothelial cells, epidermal growth factor
receptor (EGFR), c-KIT, platelet-derived growth
factor receptor (PDGFR) and fibroblast growth
factor receptor (FGFR) on tumour cells, has
prompted the scientific community to evaluate
the efficacy and safety of new molecules that
target signalling pathways controlled by proteins
such as bevacizumab, sunitinib, sorafenib,
pazopanib, Imatinib, cetuximab, erlotinib,
gefitinib, lapetinib, everolimus and bortezomib in
metastatic small cell cancer of lung.
Puglisi et al.51 based their report on preliminary
studies and suggested that targeting angiogenesis
would be the most promising strategy for the
treatment for small cell carcinoma of the lung.
Ismaili50 added that in analogy to small cell carcinoma
of the lung, the role of the aforementioned molecules
would be the most promising treatment for
metastatic small cell carcinoma of the urinary bladder.
A number of studies28,52–54 have recommended the
following strategies for the treatment of small cell
carcinoma of the urinary bladder.
Surgically resectable disease
Neoadjuvant chemotherapy followed by radical
resection should be considered the initial treatment
of choice in surgically resectable small cell carcinoma
of urinary bladder. Some authors23,24 have reported
that this can achieve a cure in 78–80% of patients.
Sequential chemoradiotherapy is the second
treatment option and is reported29,32 to have a cure
rate of 36–70%.
If surgery was performed first, some studies22,25
suggest that adjuvant chemotherapy or
adjuvant chemoradiotherapy should be
sought postoperatively.
Advanced disease
In advanced disease, cisplatin chemotherapy should
be considered the initial treatment of choice for
patients who have an acceptable performance
158
status (e.g. a score of 0–1 on the Zubrod scale) and
acceptable renal function (glomerular filtration rate
> 60 ml/min). The therapeutic treatment should be
centred on the chemotherapy regimen – etoposide
plus cisplatin or a sequential protocol of ifosfamide
plus doxorubicin on day 1 and etoposide plus
cisplatin at day 21. However, in patients who do
not have an acceptable performance status or renal
function, cisplatin should be replaced by carboplatin
with a target area under the concentration versus
time curve of 5–6 mg/ml/min.
Prognosis
A number of authors3,22 have reported that the
prognosis of small cell carcinoma of the urinary
bladder is poor and that the 5-year survival rate for all
stages is 19% (CI 16–25%).
Choong et al.22 reported that the 5-year survival
rate of patients with stage II, III and IV disease was
63.6%, 15.4% and 10.5%, respectively. Choong et al.22
also reported that the prognosis of patients with
advanced disease, stage III or IV, is significantly poorer
(P < 0.0001) than that of patients with stage II disease.
Other authors25,33,55 have reported that small cell
carcinoma of urinary bladder with pure small cell
histology had a poorer prognosis in comparison
with tumours which had mixed small cell histology.
Ismaili50 stated that, in view of the rarity of the disease,
no other prognostic factors had been identified.
Conclusions
Small cell carcinoma of the urinary bladder is
an aggressive tumour that typically presents
with advanced or disseminated disease. It is
rare, accounting for only 0.5–1.0% of all bladder
malignancies, and patients show no clinical,
age or sex differences from those with typical
urothelial carcinoma.
Some cases of small cell carcinoma of the urinary
bladder arise from urothelial carcinoma in situ
whereas some small cell carcinoma of the urinary
bladder may arise from totipotent stem cells in the
submucosa. Small cell carcinomas of the urinary
bladder are usually large polypoid masses and can
occur anywhere in the bladder.
Microscopically, small cell carcinomas of the urinary
bladder are seen as loosely cohesive sheets, or nests,
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:149–162 (http://dx.doi.org/10.7707/hmj.v6i2.225)
Review
of small to intermediate-sized cells with minimal
cytoplasm, hyperchromatic nuclei, stippled or
coarsely granular chromatin, indistinct nucleoli and
no nuclear overlapping. Mitotic activity and necrosis
are common and the tumours may co-exist with other
forms of in situ or invasive carcinoma.
Co-existence of small cell carcinoma of the urinary
bladder with other types of carcinoma is common
and immunohistochemistry plays a pivotal role in the
diagnosis of small cell carcinoma of urinary bladder
using the markers of neuroendocrine tumours.
The strategy to treat small cell carcinoma of the
urinary bladder was extrapolated from the strategy
used to treat small cell carcinoma of the lung. In cases
where the tumour may have to be surgically resected,
the treatment should include multimodal therapy
with chemotherapy being delivered initially, followed
by radical resection or radiotherapy.
Radical cystectomy is the main treatment for small cell
carcinoma of the urinary bladder, unless metastatic
disease is present, followed by systemic treatment.
Response to chemotherapy is good, similar to
response to treatment for small cell carcinoma of the
lung; however, the overall prognosis remains poor.
In cases where the disease is in the advanced stages,
chemotherapy with a platinum agent, such cisplatin
in suitable patients, is the mainstay of treatment.
There is currently no consensus regarding the
treatment of small cell carcinoma of the urinary
bladder; however, Gilligan et al.,1 among others, have
made general recommendations for the approach to
treatment of this aggressive disease.
Small cell carcinomas of the urinary bladder with pure
small cell histology have been shown to have a poorer
overall prognosis than small cell carcinomas of the
urinary bladder with mixed small cell histology.
There is a dire need for further investigations of small
cell carcinomas of the urinary bladder in order to
improve our knowledge regarding the diagnosis and
treatment of this rare disease.
2
3
4
5
6
7
8
9
10
11
12
13
14
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REVIEW
Asymptomatic bacteriuria and urinary tract
infections in pregnancy – a review of the literature
Anthony Kodzo-Grey Venyo
North Manchester General Hospital, Department of Urology, Manchester, UK
Abstract
The approach to the management of asymptomatic bacteriuria (AB)
and urinary tract infections (UTIs) in pregnancy, including the choice of
antibiotics, is not always straightforward. The aim of this article is to review
the literature on AB and UTI in pregnancy and to discuss the findings.
Various internet search engines were used to identify references regarding
pregnancy-associated AB and UTI, which formed a framework for the
literature review. Both conditions were found to be common in pregnancy.
Pregnancy-associated UTI is defined as either a lower urinary tract infection
(acute cystitis) or an upper urinary tract infection (acute pyelonephritis). The
approach to the management of pregnancy-associated AB and UTI presents
a complex issue, including the choice of antibiotics. UTIs occur when there
are at least 100 000 organisms present per ml of urine in an asymptomatic
patient, or more than 100 organisms per ml of urine with accompanying
pyuria (more than seven white blood cells per ml in a symptomatic patient).
A diagnosis of UTI requires a positive culture and identification of the
pathogen, especially in patients with vague symptoms. UTIs are associated
with risks to both the mother and the fetus, including pyelonephritis,
preterm birth, low birthweight and increased risk of perinatal mortality. AB
occurs when the bacterial count is greater than 100 000 organisms per ml in
two consecutive samples of urine and in the absence of declared symptoms.
If AB remains untreated during pregnancy, the risk of developing cystitis
is 40% and the risk of developing pyelonephritis is 25–30%. The tendency
for AB to progress to pyelonephritis is higher in pregnant women than in
non-pregnant women and is associated with an increased risk of preterm
birth, low birthweight and perinatal mortality. Appropriate antibiotics are
recommended for both pregnant and non-pregnant women. Short-term
courses have been recommended to minimize antimicrobial exposure to
the fetus. The prognosis of the majority of pregnant women with UTI or AB
during pregnancy is good. Most long-term sequelae are due to complications
associated with septic shock, respiratory failure or hypotensive hypoxia with
extreme gangrene. UTIs associated with pregnancy have few direct sequelae
in view of the fact that fetal bloodstream infection is rare; nevertheless,
uterine hypoperfusion due to maternal dehydration, maternal anaemia
Correspondence: Anthony Kodzo-Grey Venyo, North Manchester
General Hospital, Department of Urology, Manchester, UK.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
and direct bacterial endotoxin damage to the placental vasculature may
result in fetal cerebral hypoperfusion. Untreated upper UTIs in pregnant
women are associated with low birthweight, prematurity, premature
labour, hypertension, pre-eclampsia, maternal anaemia and amnionitis.
UTIs which occur during pregnancy are associated with intrauterine growth
retardation, pre-eclampsia, preterm delivery and caesarean delivery. In
order to avoid or minimize complications that may be associated with AB
and UTI during pregnancy, both should be appropriately treated. Several
antibiotic treatments are available and details of the antibiotic therapies are
discussed below.
Introduction
Pregnancy causes a number of changes to a woman’s
body, including mechanical and hormonal changes
that may increase the risk of urinary stasis and
vesicoureteric reflux. These changes, combined
with a short female urethra (approximately 3–4 cm)
and difficulty with hygiene as a result of distended
abdomen during pregnancy, are responsible
for the increase in frequency of urinary tract
infections (UTIs) in pregnant women. UTIs are one
of the most common bacterial infections occurring
during pregnancy.
In view of the physiological changes associated
with pregnancy, pregnant patients are regarded
as immunocompromised hosts for UTIs. These
physiological changes add to the risk of serious
infectious complications that may be associated
with asymptomatic and symptomatic UTIs, even in
pregnant women who are considered to be healthy.
This article provides a review of the literature on
asymptomatic bacteriuria (AB) and UTIs, including a
summary of the salient points and recommendations
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REVIEW
regarding the management of AB and UTIs
during pregnancy.
Literature review
Definitions of key terms
Conventionally, UTI has been categorised as upper
urinary tract infection (acute pyelonephritis) or lower
urinary tract infection (acute cystitis).
Asymptomatic bacteriuria can be diagnosed when
a positive urine culture is identified in a patient who
is asymptomatic.
Urinary tract infection
Urinary tract infection has been defined as the
presence of at least 100 000 organisms per ml of
urine in an asymptomatic patient, or more than100
organisms per ml of urine when accompanied by
pyuria (more than seven white blood cells per ml
in a symptomatic patient). It has been stated that a
diagnosis of UTI should be supported by a positive
culture for a uropathogen, especially in patients with
vague symptoms. It has also been reported that UTIs
are associated with risks to both the mother and the
fetus, including pyelonephritis, preterm delivery, low
birthweight and perinatal mortality.1
Asymptomatic bacteriuria
Asymptomatic bacteriuria is usually defined as the
presence of > 100 000 organisms per ml of urine in
two consecutive samples of urine in an asymptomatic
patient. It has been stated that the risk to pregnant
women of developing cystitis following untreated
AB is 40% and the risk of developing pyelonephritis
is 25–30%, and that these cases account for 70%
of all cases of symptomatic UTI in unscreened
pregnant women.1
Acute pyelonephritis
It has been reported that pyelonephritis is the most
common urinary tract complication in pregnant
women and occurs in approximately 2% of all
pregnancies.1 It has also been reported that acute
pyelonephritis characteristically presents alongside
nausea, vomiting, increased frequency of micturition,
urinary urgency and dysuria. Additionally, women
who have additional risk factors (for example,
164
diabetes, immunosuppression, neurogenic bladder,
sickle cell anaemia or recurrent persistent UTIs prior to
pregnancy) are at increased risk for the development
of a complicated UTI.1
Acute cystitis
Acute cystitis affects the lower urinary tract only;
inflammation of the urinary bladder may be a sequel
of bacterial or non-bacterial causes, for example
viral infection or radiation.1 It has been stated that
about 1% of pregnant patients develop acute cystitis
and 60% of these patients are found to have a
negative result on initial screening.1 Their symptoms
include dysuria, haematuria, suprapubic discomfort,
increased frequency of micturition, urinary urgency
and nocturia, which are symptoms that are often
difficult to distinguish from the symptoms related to
the pregnancy itself; in addition, upper urinary tract
disease (for example, pyelonephritis) complicates
acute cystitis in 15–50% of cases.1
Pathophysiology
Epidemiology of asymptomatic bacteriuria
Stenqvist et al.2 reported that bacteriuria occurs
in 2–7% of pregnancies, and is more common
in multiparous women. A similar prevalence of
bacteriuria is seen in non-pregnant women and
the causative species and their virulence factors are
similar in both pregnant and non-pregnant women. In
view of these facts, the basic mechanism of bacterial
entry into the urinary tract is likely to be the same for
both pregnant and non-pregnant women.2
Kaitz3 reported that bacteriuria often develops within
the first months of pregnancy and is frequently
associated with a reduction in the ability of the
kidney to concentrate urine, which would suggest
involvement of the kidney.3 A number of authors4–6
have suggested that the smooth muscle relaxation
and subsequent ureteral dilatation that is associated
with pregnancy facilitates the ascent of bacteria
from the urinary bladder to the kidney. As a result,
bacteriuria during pregnancy has a greater propensity
to progress to the kidneys and the risk of developing
pyelonephritis is 20- to 30-fold higher in pregnant
women with AB than in non-pregnant women
without AB.7
A number of authors5,8–11 have observed an
association between bacteriuria and an increased
В© 2013 The Author(s)
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risk of preterm birth, low birthweight and increased
risk of perinatal mortality. Naeye8 reviewed more
than 50 000 pregnancies between 1959 and 1966,
and found that the rate of perinatal mortality of any
cause was higher among women who developed
bacteriuria and/or pyuria (there was no comment
regarding absence or presence of symptoms in
this review paper) in the first 2 weeks of pregnancy
than in those who did not. Reports of various
studies5,12–16 have shown that treatment of bacteriuria
during pregnancy reduces the incidence of these
complications and lowers the long-term risk of
sequelae following AB.17
Diagnosis of asymptomatic bacteriuria
Nicolle et al.18 reported that the diagnosis of AB
should be based on the result of a urine specimen
culture that has been collected with minimal
contamination and that, in the case of asymptomatic
women, bacteriuria should be diagnosed based
on two consecutive voided urine specimens with
isolation of the same bacterial strain in quantitative
counts of ≥ 105 colony-forming units (cfu)/ml, or
a single catheterized urine specimen with one
bacterial species isolated with a quantitative count
of ≥ 102 cfu/ml. Hooton et al.19 stated that, despite
the aforementioned, in clinical practice, only one
voided urine specimen is usually obtained and
treatment is usually commenced in women with
asymptomatic bacterial counts of ≥ 105 cfu/ml without
a confirmatory repeat culture. Hooton et al.19 also
reported that, in order to avoid the risk of infection,
routine catheterization to screen for bacteriuria is
not warranted.19
Hooton et al.19 reported that in order to avoid falsepositive results, proper handling and processing
of the specimen is vital. Isolation of more than
one species, or the presence of Lactobacillus or
Propionibacterium, may suggest a contaminated
specimen, and isolation of Lactobacillus necessitates
treatment if it is the only organism that has been
isolated in consecutive urine cultures with high
colony counts, although the significance in pregnancy
is unknown.
A number of studies that have examined rapid
screening tests, for example reagent strip, enzymatic
screen or interleukin 8, have found that the sensitivity,
specificity and predictive value of these tests for the
detection of AB in pregnant women are nowhere near
those of urine culture and therefore should not be
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
used.20–22 Furthermore, urine cultures are beneficial
in guiding therapy and this can be pertinent in
pregnancy, when there is reduction in the number of
safe therapeutic alternatives.
Lin and Fajardo23 stipulated that screening for AB
should be undertaken either during the first prenatal
visit or between weeks 12 and 16 of pregnancy.
Hooton et al.19 reported that rescreening for
bacteriuria could be considered in women who are
at high risk, for example women with haemoglobin
S, women during preterm labour and women with
urinary tract abnormalities.
Infectious Diseases Society of America (ISDA) 2005
guidelines for the diagnosis and treatment of AB
in adults recommended screening urine during
pregnancy and treatment of a positive urine culture.18
A number of studies have found that early screening
and treatment for AB during pregnancy is associated
with benefits for both the mother and the fetus.6,13–15
It is widely accepted that penicillin and
cephalosporins are reasonably safe antibiotics to
prescribe to pregnant women. However, it may
be inappropriate to prescribe antibiotics with
high protein binding, for example ceftriaxone,
within 24 hours of parturition because of the
risk of displacement of bilirubin and subsequent
development of kernicterus.19
Some problems are reported to be associated with
some drugs during pregnancy:
в– в– в– в– в– в– Nitrofurantoin and sulphonamides: Crider et al.24
reported an association with birth defects. Hooton
et al.19 suggested that if there is an alternative
antibiotic which is safe and effective, then the
safest course would be to avoid nitrofurantoin
during the first trimester of pregnancy.
Nitrofurantoin: Ben David et al.25 reported
nitrofurantoin to be a cause of haemolytic
anaemia in both the mother and the fetus
with glucose-6-phosphate dehydrogenase
deficiency. Some studies26,27 estimated the risk
of haemolytic anaemia, in association with the
use of nitrofurantoin, to be 0.0004% of cases but
authors26,27 recommend that nitrofurantoin should
be avoided near term in order to avoid haemolytic
anaemia in both the mother and the fetus.
Sulphonamides: in view of the fact that
sulphonamides have the ability to increase
the level of unbound bilirubin in the neonate
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в– в– в– в– в– в– (despite the fact that kernicterus related to
in utero sulphonamide exposure has so far not
been reported), Hooton et al.19 advised that the
use of sulphonamides during pregnancy should
be avoided.
Trimethoprim: Crider et al.24 advised that
trimethoprim should be avoided during the
first trimester of pregnancy as it is a folic acid
antagonist and has caused abnormal embryo
development in experimental animals. Although
it is not a proven teratogen in human beings,
some studies28,29 have reported a possible
association between the use of trimethoprim and
birth defects. Hooton et al.19 suggested that as
pregnant women are routinely prescribed folic
acid supplements, the use of trimethoprim should
be avoided.
Fluoroquinolones and tetracyclines: Hooton et al.19
stated that fluoroquinolones and tetracyclines are
inadvisable during pregnancy.
Fosfomycin: Stein30 reported that the use of
fosfomycin is safe during pregnancy.
Some authors have stipulated that the use of shortcourse antibiotic therapy is most often effective in
eradicating AB during pregnancy.31–33
Hooton et al.19 recommended a short course of the
following therapeutic treatments to eradicate AB if
the bacteria are susceptible:
в– в– в– в– в– в– в– в– в– в– в– в– 166
amoxicillin: 500 mg orally every 12 hours for
3–7 days;
Augmentin: amoxicillin (500 mg) and clavulanate
(125 mg) orally every 12 hours for 3–7 days;
nitrofurantoin: 100 mg orally every 12 hours for
5 days;
cephalexin: 500 mg orally every 12 hours for
3–7 days;
fosfomycin: 3 g orally as a single dose.
Sulphonamides: Hooton et al.19 advised that
sulphonamides should not be given in the final
days preceding parturition because they easily
traverse the placenta and can displace bilirubin
from bilirubin binding sites in the newborn
and, therefore, there is a theoretical risk of
development of kernicterus in the newborn.
Hooton et al.19 also stated that sulphonamides
may be used in pregnancy; however, it should be
kept in mind that resistance among uropathogens
is high and sulphonamides offer no advantage
over the aforementioned antibiotics.
With regard to patient follow-up, Patterson and
Andriole10 stated that a follow-up urine culture
should be performed 1 week after the completion
of treatment but a short course of treatment fails to
eliminate AB in up to 30% of women. Hooton et al.19
recommend repeating the urine cultures at monthly
intervals until parturition in order to identify
persistent or recurrent bacteriuria.
Hooton et al.19 reported that suppressive or
prophylactic antibiotics may be prescribed in
women with persistent bacteriuria after two or more
courses of therapy. They suggested that 50–100 mg
of nitrofurantoin should be taken orally every day
(if the bacterium is susceptible to nitrofurantoin)
throughout the pregnancy and that monthly urine
cultures are not necessary if suppressive therapy
is being given. As breakthrough bacteriuria can
occur during suppressive therapy, Hooton et al.19
suggested that a urine culture should be performed
at the beginning of the third trimester to ensure the
suppression is effective.
Acute cystitis
Acute cystitis is defined as a symptomatic infection
of the urinary bladder that can occur alone or it
may be complicated by ascending infection and
pyelonephritis. When acute cystitis occurs during
pregnancy, it is considered complicated as it is
often associated with ascending infection or
pyelonephritis.19 Some authors34,35 report that acute
cystitis occurs in about 1–2% of pregnant women.
Stamm et al.36 stated that:
в– в– в– в– в– в– A urine culture should be performed in
pregnant women with symptoms suggestive of
acute cystitis.
Low colony counts in the urine culture specimens
have been noted to be significant in symptomatic
non-pregnant women, despite the fact that
studies to define thresholds representing
significant bacteriuria in pregnant women have
not been performed.
In women who have had uncomplicated
cystitis, coliform colony counts in voided urine
specimens as low as 102 cfu/ml were adjudged to
reflect infection.
Nevertheless, Hooton et al.19 reported that the
majority of clinical laboratories do not routinely
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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REVIEW
quantify urine isolates to the level of 102 cfu/ml and
thus they recommend that it would be reasonable
to adopt a quantitative count of ≥ 103 cfu/ml in a
symptomatic pregnant woman as an indicator of
symptomatic UTI.
With regard to treatment of cystitis during pregnancy,
some authors10,37 have suggested a 3–7-day course
of antibiotics, provided there are no symptoms
suggestive of pyelonephritis. Other studies38–40 stated
that short-term therapy is associated with decreased
costs and side-effects, with improved compliance,
and less fetal exposure to drugs.37
another urine culture should be conducted at the
beginning of the third trimester and, if a subsequent
urine culture is positive, then a different antibiotic
therapy should be used, based on the sensitivity
pattern of the bacteria and an assessment of the
suppressive therapy.19
With regard to recurrent UTIs (recurrent cystitis),
the use of prophylactic antibiotics has been
recommended for the duration of the pregnancy
in the following forms depending on the sensitivity
profile of the cystitis-causing strains.19
в– в– Hooton et al.19 suggested the use of one of the
following treatment options while awaiting the
results of urine culture and sensitivity:
■■■■■■■■■■■■■■Augmentin: amoxicillin (500 mg) and clavulanic
acid (125 mg) orally every 12 hours for 3–7 days;
nitrofurantoin: 100 mg orally every 12 hours for
5 days;
cefpodoxime: 100 mg twice daily for 3–7 days;
fosfomycin: 3 g orally as a single dose;
trimethoprim–sulphamethoxaxole: one doublestrength dose twice daily for 3 days in the second
trimester, but this should be avoided both in the
first trimester and near term;
amoxicillin: 500 mg twice daily every 12 hours for
7 days for the treatment of Enterococcus infection.
Hooton et al.19 additionally warned that
fluoroquinolones should be avoided in pregnancy.
With regard to follow-up, it has been recommended
that a urine specimen should be collected and
sent for culture and sensitivity 1 week after
completion of treatment to confirm the absence
of bacterial growth and resolution of cystitis.19 It
has also been recommended that the urine culture
should be repeated at monthly intervals until
the end of pregnancy to assess for persistent or
recurrent bacteriuria.19
It has been suggested that if bacteriuria persists
after two or three courses of antibiotic treatment,
suppressive therapy could be initiated and a daily
oral dose of 50 mg nitrofurantoin at bedtime for the
duration of the pregnancy could be prescribed, if
the organism is susceptible.19 Monthly urine culture
may not be necessary if suppressive therapy is used;
however, in order to detect a breakthrough infection,
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Postcoital prophylaxis: if the UTI or cystitis
is presumed to be coitus related, treat with
50–100 mg nitrofurantoin orally and postcoitally,
or 250–500 mg cephalexin orally and postcoitally.
Daily prophylaxis: to be prescribed in situations
of increased risk of urinary complications during
episodes of UTI or cystitis (for example, if the
patient suffers from diabetes mellitus or sickle
cell trait). In such situations, prophylaxis must be
considered following the first UTI (50–100 mg of
nitrofurantoin orally every evening or 250–500 mg
of cephalexin orally every evening).
With regard to recurrent cystitis or UTIs preceding
pregnancy, which is usually related to sexual
intercourse and treated with postcoital prophylaxis,
Pfau and Sacks41 carried out a prospective study
on 33 women with a history of recurrent UTIs and
who had a total of 39 pregnancies with a single
postcoital dose of either 250 mg cephalexin or
50 mg nitrofurantoin. Only one UTI occurred during
pregnancy in comparison with the 130 UTIs that
had occurred during a mean observation period of
7 months prior to the use of prophylaxis. Based upon
the experience of Pfau and Sacks,41 Hooton et al.19
made the following recommendations:
в– в– в– в– In pregnant women who have had recurrent UTIs
that are considered to be temporally related to
sexual intercourse, postcoital prophylaxis should
be used.
The preferred prophylactic treatment should be a
single postcoital dose of either 250 mg cephalexin
or 50 mg nitrofurantoin.
Acute pyelonephritis
Acute pyelonephritis is an infection of the kidney
that tends to present with flank pain, nausea and
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vomiting, pyrexia > 38°C and/or costovertebral angle
tenderness, which may occur in the absence or
presence of cystitis symptoms.
Some authors10,18 have reported that, although the
prevalence of AB in pregnant women is similar to
that in non-pregnant women, as many as 30–40% of
pregnant women with untreated AB may develop a
symptomatic UTI, including pyelonephritis, during
pregnancy. Other authors6,18 have reported that
the risk of pregnant women developing acute
pyelonephritis is reduced by 70–80% if bacteria
are eradicated.
The pregnancy-related anatomical changes in the
urinary tract that predispose pregnant women to
pyelonephritis include:
в– в– в– в– в– в– pressure on the urinary bladder from the
enlarging uterus;
an increase in the size of the ureters due to
smooth muscle relaxation;
the immune suppression of pregnancy; for
example, mucosal interleukin-6 levels and serum
antibody responses to Escherichia coli antigens are
reported to be lower in pregnant women.42
Organisms reported to be cultured in the general
obstetric population include:
в– в– в– в– в– в– в– в– E. coli, in 70% of cases;43
Klebsiella or Enterobacter, in 3% of cases;
Proteus, in 2% of cases;
Gram-negative organisms including group B
Streptococcus, in 10% of cases.
With regard to the clinical manifestations of acute
pyelonephritis in pregnancy, Hooton et al.19 reported
that the presentation is similar in pregnant and
non-pregnant women and that pregnant women may
become ill and are at risk of developing both medical
and obstetric complications from pyelonephritis.
Complications associated with pyelonephritis in
pregnancy which were reported by Hill et al.43 include:
в– в– в– в– в– в– в– в– 168
anaemia: 23%;
bacteraemia: 17% in the minority of the pregnant
patients who were tested;
respiratory insufficiency: 7%;
renal dysfunction: 2%.
Cox et al.44 reported that the mechanism of anaemia
associated with pyelonephritis in pregnancy is not
well understood; nevertheless, haemolysis mediated
by endotoxin may be of importance.
Some authors45,46 estimated that 20% of women with
severe pyelonephritis will develop complications
that include septic shock syndrome or its variants,
including acute respiratory distress syndrome.
Thompson et al.47 described acute renal failure with
microabscesses and suppurative pyelonephritis in
isolated cases, independent of sepsis.
A number of authors have reported a relationship
between maternal UTI, especially AB, and adverse
pregnancy outcomes including preterm birth and low
birthweight.6,10,48,49 They have suggested that acute
pyelonephritis has a similar association with adverse
pregnancy outcomes but the association is not
definitely known, in view of confounding variables
such as economic status and previous preterm
birth. It is worth noting that Hill et al.43 reported
that preterm birth occurred in 5% of women with
pyelonephritis, which is similar to the rate of preterm
birth in the general obstetric population.
Hooton et al.19 stated that pyelonephritis should not
be an indication for induction of labour or caesarean
section. If induction of labour or caesarean section
is planned for standard obstetric reasons in patient
receiving treatment for pyelonephritis, the authors
recommended delaying induction until the patient
is afebrile, as long as the delay in delivery is relatively
safe for both the mother and the fetus.
It has been stated that pregnant women with
pyelonephritis are traditionally admitted to hospital
and given intravenous antibiotics until the mother
has been afebrile for 24 hours and her symptoms
have improved.50
With regard to treatment of acute pyelonephritis in
pregnancy, Hooton et al.19 recommend that the initial
choice of antibiotics should be guided by the local
microbiology and sensitivity data; however, generally,
parenteral beta-lactams (ОІ-lactams) are the preferred
antibiotics which include:
1  In mild to moderate pyelonephritis
■■ceftriaxone: 1 g every 24 hours;
■■cefepime: 1 g every 12 hours;
В© 2013 The Author(s)
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REVIEW
■■■■■■aztreonam: 1 g every 8–12 hours (with a warning
of the possibility of ototoxicity which occurs with
aminoglycosides and that this treatment should
be used only if intolerance precludes the use of
less toxic agents);
ampicillin: 1–2 g every 6 hours;
gentamicin: 1.5 mg/kg every 8 hours (with a
warning of the possibility of ototoxicity which
occurs with aminoglycosides and that this
treatment should be used only if intolerance
precludes the use of less toxic agents).
2  In severe pyelonephritis with immune compromise
and/or incomplete urinary drainage
■■ticarcillin–clavulanate: 3.1 g every 6 hours;
■■piperacillin–tazobactam: 3.375 g every 6 hours;
■■meropenem: 500 mg every 8 hours;
■■ertapenem: 1 g every 24 hours;
■■doripenem: 500 mg every 8 hours.
According to Hooton et al.,19 fluoroquinolones should
be avoided in pregnancy.
With regard to duration of therapy, it has been stated
that both pregnant and non-pregnant patients with
complicated pyelonephritis should show definite
improvement within 24–48 hours of therapy. Once the
patient has been afebrile for 48 hours, oral antibiotic
therapy, guided by culture susceptibility results, can
be initiated and the patient can be discharged with a
10- to 14-day course of treatment.50 It has also been
advised that if the symptoms and fever persist beyond
24–48 hours of treatment, a repeat urine culture and
ultrasonography should be performed to rule out
persistent infection and urinary tract pathology.19
Some studies38,51,52 found recurrent pyelonephritis
during pregnancy in 6–8% of women and one
treatment plan for this is the use of low-dose
antimicrobial prophylaxis with an antibiotic to which
the bacteria are sensitive, taken by the patient for
the duration of the pregnancy.27,50 Some of the
recommended antibiotics include:
■■■■nitrofurantoin: 50–100 mg orally every day;
cephalexin: 250–500 mg orally every day.27,50
Hooton et al.19 stated that if preventative therapy is
given, then monthly urine cultures are not necessary;
nevertheless, in view of the fact that breakthrough
bacteriuria can occur during preventative therapy,
the authors recommend one later urine culture being
conducted at the beginning of the third trimester
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
in order to confirm that the preventative therapy
is working. Hooton et al.19 recommended that if a
follow-up urine culture is positive (≥ 105 cfu/ml), then
a course of antibiotics based upon the sensitivity data
should be given and, additionally, the preventative
treatment plan should be reassessed and adjusted
if required.
Discussion
Awonuga et al.53 conducted a cross-sectional
study to determine prevalence of AB in Ibadan,
Nigeria, and to evaluate the diagnostic accuracy
and relative cost-effectiveness of dipstick tests for
nitrite and leucocyte esterase in comparison with
laboratory culture. Urine samples obtained from
205 participants in the study were subjected to two
tests: reagent dipstick test for nitrite and leucocyte
esterase, and a routine laboratory culture. The main
outcome measures in the study included sensitivity,
specificity, positive and negative predictive values of
the reagent dipstick tests as well as likelihood ratios.
Awonuga et al.53 reported the following results:
в– в– в– в– в– в– The prevalence of AB in pregnancy with routine
laboratory culture and using combined leucocyte
esterase and nitrite strip tests was 10.7% and
11.7%, respectively.
In comparison with laboratory culture of urine
specimens, combined strip tests had sensitivity,
specificity and negative predictive values of 50%,
92.9%, and 93.9%, respectively, which indicated
a statistically significant lower level of accuracy
(P < 0.05).
The corresponding likelihood ratios for positive
and negative strip tests (LR+ and LR–) were 7 and
0.5, respectively.
Awonuga et al.53 concluded that combined leucocyte
esterase and nitrite dipstick test is not sufficiently
sensitive or specific to be used for routine screening
of bacteriuria in pregnancy in place of laboratory
culture, although it may be cost-effective in
low-resource settings.
In order to determine the epidemiological
profile of women who were admitted to a
university hospital in Brazil with a UTI, and to
verify the most prevalent agents and response
to antibiotic therapy, Calegari et al.54 undertook a
retrospective study of 106 pregnant women who
were admitted for the treatment of a UTI between
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January 2007 and December 2010. Calegari et al.54
based their evaluation on the analysis of medical
records of the pregnant women, observations during
the hospitalization period, pregnancy data and the
overall outcome. The authors54 performed statistical
analysis using Statistical Package for the Social
Sciences, version 15.0, and also used the bilateral
Fisher exact test and Student’s t-test for data analysis,
as well as descriptive statistical methods. Calegari et
al.54 reported the following results:
в– в– в– в– в– в– в– в– в– в– в– в– в– в– Positive urine cultures were obtained in 60.5%
of the pregnant women who were admitted
suffering from a UTI.
The most frequent infectious agent that
was cultured was E. coli and there was no
observed difference in resistance, recurrence
or complications between the most frequent
aetiological agents.
Pregnant women who had suffered from previous
UTIs had a higher recurrence risk [odds ratio
(OR) = 10.8; P < 0.05].
The antibiotics that were most frequently used
were ampicillin and cefazolin.
A necessary change of therapeutic agent as a
result of bacterial resistance occurred in 11.9% of
patients who took cefazolin and 20% of patients
who took ampicillin (OR = 5.5; P < 0.05).
The rate of gestational complications was the
same for both treatments.
There was no difference in mean hospitalization
duration between the treatments.
Calegari et al. concluded that, in their study
population, ampicillin showed a higher rate of
bacterial resistance than cefazolin, requiring a larger
number of treatment alterations; however, this
did not result in differences in clinical outcome or
duration of hospitalization.
54
Versi et al.55 reported a higher prevalence of
bacteriuria among pregnant white women (6.3%)
than in pregnant Bangladeshi women (2%). They
also reported that pregnancies that resulted in
preterm deliveries were strongly associated with
bacteriuria in white women but this association was
not observed in the Bangladeshi women. Versi et al.55
postulated that the difference between the white
and Bangladeshi pregnant women could be due to
variation in hygiene practices and clothing.
A large population-based study of nearly 200 000
pregnant Israeli women56 found a 2.5% rate of
170
AB and 2.3% rate of symptomatic UTI.56 It was
observed in this study population that AB had an
association with multiple pregnancy complications
which included hypertension, diabetes, intrauterine
growth retardation, prolonged hospitalization and
preterm labour.56
Mazor-Dray et al.56 reported that their findings
may be a marker for the intensity of prenatal care
received, rather than a specific causal effect of the UTI.
Furthermore, their follow-up study, which examined
women with symptomatic UTIs, demonstrated a clear
association between UTI and low birthweight and
preterm delivery, a finding similar to those of multiple
previous investigations.57–59
Whitehead et al.60 reported on a retrospective study
of 24 000 births and found the prevalence of UTI
during pregnancy to be 28.7% in whites and Asians
combined, 30.1% in blacks, and 41.1% in Hispanics.
Whitehead et al.60 also reported that:
в– в– в– в– в– в– When socioeconomic status was controlled for, no
significant inter-racial differences existed.
A survey-based analysis of self-reported UTI found
similar trends.60
Their study also looked at Native American
women and found the highest prevalence of UTIs
in this population (24.2%) in comparison with
Asian (10.3%), white (16.6%), Hispanic (18.3%) and
black (20.3%) women.60
Johnson and Kim61 reported that UTIs are associated
with preterm delivery in patients of all races and that
the adjusted OR in infants with very low birthweight
is 2.8 for blacks and 5.6 for whites, when adjusted
for parity, body mass index, maternal age, marital
status, cigarette smoking, education and prenatal
care. Johnson and Kim61 also reported that the overall
relative risk of bacteriuria in blacks or whites was
estimated at 1.5–5 and the relative risk of preterm
birth in women with bacteriuria was 1.8–2.3.
Giraldo et al.62 reported that urogenital infections
are extremely prevalent during pregnancy and they
are an important cause of premature labour in Brazil.
Nevertheless, the prevalence of urogenital infections
during childbirth is not well known. Giraldo et al.62
conducted a study to identify urogenital infections
which were present at the beginning of labour in both
full-term and preterm pregnancies. Giraldo et al.62
reported that, out of 94 women who were admitted
to their inpatient maternity clinic, 49 women were
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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REVIEW
in preterm labour and 45 were in full-term labour.
Samples of urinary, vaginal and perianal material
were collected for microbiological analysis. They
reported that:
в– в– в– в– The prevalence of general infections in the
preterm labour group and the full-term labour
group was 49.0% and 53.3%, respectively
(P = 0.8300).
The rates of urogenital infections in the preterm
and full-term labour groups were as follows: UTIs,
36.7% and 22.2% respectively; vaginal candidiasis,
20.4% and 28.9% respectively; bacterial vaginosis,
34.7% and 28.9% respectively; and group B
Streptococcus, 6.1% and 15.6% respectively.55
Giraldo et al.62 concluded that urogenital infections
were prevalent in women in preterm labour and
full-term labour but significant differences between
the groups were not observed.
Kladensky63 reported that UTIs in pregnant women
are a relatively frequent occurrence and the spectrum
of these infections ranges from lower urinary tract
infection (AB, acute cystitis) to upper urinary tract
infection (acute pyelonephritis). Kladensky63 reported
that anatomical and functional changes in the urinary
tract in pregnancy result in a significantly higher
susceptibility to progression of the infection from AB
to the stage of acute pyelonephritis. Kladensky63 also
reported the following regarding UTIs in pregnancy:
в– в– в– в– в– в– в– в– в– в– Untreated AB in pregnancy may lead to the
development of acute pyelonephritis in as many
as 40% of cases, which includes all the subsequent
negative effects not only for the pregnant woman
herself, but also, and particularly, for the fetus.
Bacteriuria in pregnancy accounts for a
significantly higher number of newborns with
low birthweight and low gestational age and is
associated with a higher neonatal mortality rate
than in pregnancy without bacteriuria.
In view of the points raised above, it is necessary
to perform screening for bacteriuria in pregnant
women and, when the finding is positive, treat
the bacteriuria.
The selection of an appropriate antimicrobial
agent for the treatment of a UTI during pregnancy
is limited by the safety of a given drug not only for
the pregnant woman, but also for the fetus.
The selection of an appropriate antibiotic
should always be determined by the result of
urine culture.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
The efficacy of ОІ-lactams in the treatment of
pyelonephritis was demonstrated in a randomized
trial of 179 pregnant women with acute
pyelonephritis before the 24th week of gestation.38
Wing et al.38 reported that intravenous cefazolin,
or intramuscular ceftriaxone, had the equivalent
efficacy to the use of intravenous ampicillin
in combination with gentamicin. Although a
number of authors64–67 reported that the rates of
resistance to first-generation cephalosporins had
generally been < 10% in their surveillance studies,
Warren et al.68 stated that ОІ-lactams, including
first-generation cephalosporins, have been generally
less effective than trimethoprim–sulphamethoxazole,
or fluoroquinolones, for the treatment of
cystitis. Warren et al.68 reported that given the
aforementioned data and the paucity of data
evaluating the narrow spectrum of cephalosporins
in the treatment of pyelonephritis, they favour
the third-generation cephalosporins over the first
and second generations, such as cefazolin, for the
empirical treatment of acute pyelonephritis.
Le et al.26 reported an association of fetal exposure
to aminoglycosides with ototoxicity and therefore,
in view of this, Hooton et al.19 recommended that
aminoglycosides should be avoided in pregnancy
associated with pyelonephritis unless intolerance or
resistance prohibits the use of less toxic agents.
Garau69 reported that carbapenems are usually
effective in the treatment of serious extendedspectrum ОІ-lactamase (ESBL)-producing strains that
cause infections. However, Hooton et al.19 reported
that some animal studies have exhibited adverse fetal
effects when exposed to imipenem–cilastatin, and,
in view of this, they recommended that meropenem,
ertapenem or doripenem should be the preferred
carbapenems for use during pregnancy.
Millar et al.39 randomly assigned 120 pregnant women
(less than 24 weeks’ gestation) with pyelonephritis
to an outpatient regimen consisting of ceftriaxone
(1 g intramuscularly daily for 2 days) followed by
500 mg cephalexin orally four times per day for
10 days, or an inpatient treatment consisting of
intravenous cefazolin, followed at discharge by
500 mg cephalexin orally four times per day for
10 days. Millar et al.39 reported that the clinical
responses to therapy and birth outcomes were similar
in both the outpatient and the inpatient groups.
They also reported that six patients who were initially
treated with ceftriaxone were eventually admitted
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REVIEW
to the hospital for intravenous therapy and that one
woman developed septic shock during observation in
the emergency department.
Wing et al.40 undertook a study in pregnant women
(more than 24 weeks’ gestation) with pyelonephritis
to establish whether or not early discharge and
outpatient management with cephalexin after initial
hospitalization and treatment with ceftriaxone
is as effective and safe as conventional inpatient
management. They reported that 51% of patients
either did not qualify for outpatient management
based upon their study criteria or developed
complications which precluded early discharge from
hospital. The studies of Millar et al.39 and Wing et al.40
suggest that outpatient therapy is less safe and
less effective than inpatient treatment for pregnant
women with pyelonephritis.
It has been stated that for the majority of UTIs and
AB during pregnancy, the prognosis is good. Most
of the long-term sequelae are due to complications
associated with septic shock, respiratory failure and
hypotensive hypoxia with extreme gangrene.61
Urinary tract infections in pregnant women have
few direct sequelae as fetal bloodstream infection
is rare; nevertheless, uterine hypoperfusion
as a result of maternal dehydration, maternal
anaemia and direct bacterial endotoxin damage
to the placental vasculature may result in fetal
cerebral hypoperfusion.61
Untreated upper UITs in pregnant women are
associated with low birthweight, prematurity,
premature labour, hypertension, pre-eclampsia,
maternal anaemia and amnionitis.56 UTIs during
pregnancy are associated with intrauterine growth
retardation, pre-eclampsia, preterm delivery and
caesarean delivery.56
Summary
Asymptomatic bacteriuria
Asymptomatic bacteriuria refers to the presence of
a positive urine culture in an asymptomatic person.
The risk of developing pyelonephritis is 20- to 30-fold
higher in pregnant women with AB than in nonpregnant women without AB7 and the progression
of AB to pyelonephritis is associated with an
172
increased risk of preterm birth, low birthweight and
perinatal mortality.
Asymptomatic bacteriuria is diagnosed following the
culture of a urine specimen that has been collected
with minimal contamination. Treatment of AB usually
commences if a colony urine culture has a count of
≥ 105 cfu/ml.
The 2005 Infectious Diseases Society of America
guidelines for the diagnosis and treatment of AB in
adults recommended screening all pregnant women
for AB and the instituting treatment in the event of a
positive culture.18
Hooton et al.19 recommended short courses of any
of the following therapeutic treatments to minimize
antimicrobial exposure to the fetus:
■■■■■■■■amoxicillin: 500 mg orally every 12 hours for
3–7 days;
Augmentin: amoxicillin (500 mg) and clavulanate
(125 mg)] every 12 hours for 3–7 days;
nitrofurantoin: 100 mg orally every 12 hours for
5 days;
cephalexin: 500 mg orally every 12 hours for
3–7 days.
In view of the fact that up to 30% of women are not
cleared of AB following a short course of therapy,
Hooton et al.19 recommend a repeat urine culture
1 week after completion of antibiotic therapy,
as well as repeat urine cultures on a monthly
basis until parturition to assess for persistent or
recurrent bacteriuria.
Acute cystitis
Cystitis refers to a symptomatic infection of the
urinary bladder which can occur either alone
or complicated by ascending infection and
pyelonephritis. Acute cystitis in pregnant women
is generally considered to be complicated as it
is often associated with an ascending infection
or pyelonephritis.
A urine culture must be performed for pregnant
women with symptoms of acute cystitis and a
resulting quantitative count of ≥ 103 cfu/ml in a
symptomatic pregnant woman should be taken as
an indicator of symptomatic UTI. Pregnant women
with acute cystitis should be treated with a 3- to 7-day
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:163–176 (http://dx.doi.org/10.7707/hmj.v6i2.209)
REVIEW
course of antibiotics as long as they do not have
symptoms suggestive of pyelonephritis.
Hooton et al.19 suggested one of the following
empirical treatments should be prescribed while
awaiting urine culture and sensitivity results.
■■■■■■■■■■■■■■nitrofurantoin: 100 mg orally every 12 hours for
5 days;
cefpodoxime: 100 mg twice daily for 3–7 days;
amoxicillin–clavulanate: 500 mg orally every
12 hours for 3–7 days;
fosfomycin: 3 g orally as a single dose;
trimethoprim–sulphamethoxazole: one doublestrength dose twice daily for 3 days in the second
trimester (this should be avoided in the first
trimester or near term);
amoxicillin (for treatment of Enterococcus): 500 mg
twice daily every 12 hours for 7 days;
fluroroquinolones: should be avoided
during pregnancy.
A repeat urine culture should be conducted 1 week
after completion of treatment and monthly thereafter
until parturition.
Pyelonephritis
Acute pyelonephritis tends to manifest with flank
pain, nausea and vomiting, pyrexia > 38°C and
costovertebral angle tenderness, which may occur in
the presence or absence of symptoms of cystitis.
Organisms responsible for acute pyelonephritis
in pregnancy include E. coli (approximately 70%),
Klebsiella, Enterobacter, Proteus and Gram-positive
organisms inclusive of group B Streptococcus.
In view of the high risk of complications associated
with pyelonephritis in pregnancy, pregnant women
with pyelonephritis are usually admitted to hospital
for intravenous antibiotics until they are afebrile
for 24 hours and their symptoms have improved.
Taking blood samples for a culture is recommended
in pregnant women with signs of sepsis or
serious underlying medical conditions such as
diabetes mellitus.19
The initial choice of antibiotics should depend
on the local microbiology and susceptibility
data. Parenteral ОІ-lactams are the antibiotics of
choice but fluoroquinolones should be avoided
during pregnancy.19
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
When the patient has been afebrile for 48 hours
on intravenous antibiotics, oral antibiotic therapy,
based upon the culture and sensitivity pattern of
the causative organism, can be initiated and the
patient discharged to complete 10–14 days of
antibiotic treatment.
Recurrent pyelonephritis occurs during pregnancy
in 6–8% of women; therefore, low-dose antibiotic
prophylaxis with an agent to which the bacteria
is sensitive is recommended for the duration of
the pregnancy. Some of the treatment options to
choose from include 50–100 mg nitrofurantoin orally
every evening, or 250–500 mg cephalexin orally
every evening.
Conclusions
For the majority of UTI and AB cases diagnosed
during in pregnancy, the prognosis is good. Most
of the long-term sequelae are due to complications
associated with septic shock, respiratory failure and
hypotensive hypoxia with extreme gangrene.
Urinary tract infections which develop in pregnant
women have few direct sequelae as fetal bloodstream
infection is rare; nevertheless, uterine hypoperfusion
as a result of maternal dehydration, maternal
anaemia and direct bacterial endotoxin damage
to the placental vasculature may result in fetal
cerebral hypoperfusion.
Untreated upper UTIs in pregnant women are
associated with low birthweight, prematurity,
premature labour, hypertension, pre-eclampsia,
maternal anaemia and amnionitis. UTIs that
develop during pregnancy are also associated with
intrauterine growth retardation, pre-eclampsia,
preterm delivery and caesarean delivery.
In order to avoid, or minimize, complications that
may be associated with AB and UTI, both should be
appropriately treated during pregnancy.
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MR, Goncalves AK. The prevalence, of urogenital
infections in pregnant women experiencing preterm
and full-term labour. Infect Dis Obstet Gynecol 2012;
2012:878241.
Kladensky J. Urinary tract infections in pregnancy: when
to treat, how to treat, and what to treat with. Ceska
Gynekol 2012; 77:167–71.
Kahlmeter G, ECO.SENS. An international survey of
the antimicrobial susceptibility of pathogens from
uncomplicated urinary tract infections: the ECO.SENS
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project. J Antimicrob Chemother 2003; 51:69–76.
http://dx.doi.org/10.1093/jac/dkg028
Kahlmeter G. Prevalence and antimicrobial susceptibility
of pathogens in uncomplicated cystitis in Europe:
the ECO.SENS study. Int J Antimicrob Agents 2003;
22(Suppl. 2):49–52.
http://dx.doi.org/10.1016/S0924-8579(03)00229-2
Naber KG, Schito G, Botto H, Palou J, Mezzei
T. Surveillance study in Europe and Brazil
on clinical aspects and Antimicrobial
Resistance Epidemiology in Females with Cystitis
(ARESC): implications for empiric therapy. Eur Urol
2008; 54:1164–75. http://dx.doi.org/10.1016/j.
eururo.2008.05.010
Zhannel GG, Hisanaga TL, Laing NM, Decorby KA, Nichol
LP. Antibiotic resistance in Escherichia coli outpatient
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urinary isolates: final results from the North American
Urinary Tract Infection Collaborative Alliance (NAUTICA).
Int J Antimicrob Agents 2006; 27:468–75.
http://dx.doi.org/10.1016/j.ijantimicag.2006.02.009
Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer
AJ, Stamm WE. Guidelines for antimicrobial treatment
of uncomplicated acute bacterial cystitis and acute
pyelonephritis in women. Infectious Diseases Society of
America (IDSA). Clin Infect Dis 1999; 29:745–58.
http://dx.doi.org/10.1086/520427
Garau J. Other antimicrobials of interest in the era
of extended-spectrum beta-lactamases: fosfomycin,
nitrofurantoin and tigecycline. Clin Microbiol Infect 2008;
14(Suppl. 5):21–4. http://dx.doi.org/10.1111/j.14690691.2007.01852.x
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Hamdan Medical Journal  2013; 6:177–184 (http://dx.doi.org/10.7707/hmj.v6i2.239)
 
Review
Chronic neuropathic pain management – a review article
Alhan S Khazaal
FICM A (Fellowship of Iraqi Commission for Medical Specializations/Anaesthesia and ICU), Dubai Hospital,
Dubai, United Arab Emirates
Abstract
Introduction
Chronic neuropathic pain (NEP) is commonly seen in clinical practice and
represents a challenge to patients as well as clinicians. Pain is a complex
sensory modality, resulting from the physiological activation of nociceptors
that trigger a behavioural process to protect the individual from any existing,
or further, tissue damage. Conditions that are frequently associated with NEP
can be classified into two main groups: first, conditions that cause damage
to the central nervous system (CNS), such as cortical and subcortical strokes;
and, secondly, conditions that cause damage to the peripheral nervous
system (PNS) such as ischaemic neuropathy, nerve root compression and
phantom pain. There are multiple theories and pathophysiological processes
underlying NEP; both basic and human research indicates that a lesion
of afferent pathways is necessary for development of NEP. Furthermore,
data clearly indicate that several mechanisms can lead to NEP and many
of these mechanisms do not depend on the cause of the disease. The main
mechanisms for the development NEP are ectopic nerve activity, upregulation
of receptor proteins, central sensitization, inflammatory mechanism and
disinhibition. The management of chronic NEP is challenging and the primary
goal is to treat the pain and associated comorbidities, such as anxiety and
depression. The secondary goals of treatment are to improve sleep, the ability
to function normally and the overall quality of life. Tricyclic antidepressants
(TCAs) are the most effective treatment in the management of NEP; however,
serotonin–noradrenaline reuptake inhibitors (SNRIs), gabapentin and
pregabalin, or lidocaine patches are also effective. Randomized controlled
trials have reported the efficacy of opioids for different peripheral and central
neuropathic disorders; however, using opioids for the treatment of NEP is
not necessarily associated with a significant improvement in quality of life,
psychological comorbidities or sleep disorders. In summary, management of
NEP should be tailored to the individual patient on the basis of pain type(s),
the causative disease, the relevant psychological factors and the interactions
between the biological and psychosocial processes.
The International Association for the Study of Pain
(IASP) has defined pain as �an unpleasant sensory
and emotional experience associated with actual or
potential tissue damage’.1 Pain is a complex sensory
modality, resulting from the physiological activation
of nociceptors that trigger a behavioural process to
protect the individual from any existing, or further,
tissue damage; therefore, it is an essential process
for survival.1
Correspondence: Dr Alhan S Khazaal, FICM A (Fellowship of Iraqi
Commission for Medical Specializations/Anaesthesia and ICU),
Dubai Hospital, Dubai, United Arab Emirates.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Chronic neuropathic pain (NEP) is commonly seen
in clinical practice and represents a challenge to
patients as well as clinicians. NEP is defined by the
IASP as �pains resulting from disease or damage of
the peripheral or central nervous system and from
dysfunction of the nervous system’. NEP can result
from damage anywhere along the neuraxis, such
as the central nervous system (CNS), peripheral
nervous system (PNS), spinal nervous system or
supraspinal nervous system, and, to the best of our
knowledge, does not serve any protective purpose for
the individual.1
Conditions that are frequently associated with
NEP can be classified into two main groups: first,
conditions that cause damage to the CNS, such as
cortical and subcortical strokes, traumatic spinal
cord injuries, syringomyelia, trigeminal neuralgia,
glossopharyngeal neuralgia and neoplastic as well
as other space-occupying lesions; and, secondly,
conditions that cause damage to the PNS such as
ischaemic neuropathy, peripheral polyneuropathies,
nerve root compression, post-amputation stump
and phantom pain, post-herpetic neuralgia and
cancer-related neuropathies.1
177
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Review
Clinically, NEP can be differentiated from other
types of pain by the notable persistence of pain
beyond the healing period. It is also characterized by
spontaneous shooting pains and evokes amplified
pain in response to noxious or non-noxious stimuli.
Symptoms consist of both �negative’ symptoms
such as sensory loss and numbness, and �positive’
symptoms such as paraesthesia, spontaneous pain
and increased sensation of pain.1
Psychological factors, which include emotional
and behavioural responses, are fundamental
components in the perception and expression of
pain and the patient should be considered in the
context of the interactions between biological and
psychosocial processes. Attempts to manage pain
without considering these interactions will inevitably
lead to patient frustration and treatment failure.
Management of pain should be tailored to the
individual patient on the basis of pain type(s), the
causative disease, the relevant psychological factors
and the interactions between the biological and
psychosocial processes.1
The aim of this article is to review the
pathophysiology and treatment modalities of NEP.
Pathophysiology
There are multiple theories and pathophysiological
processes underlying NEP; however, it is crucial
to review the physiology of normal pain before
exploring that of NEP. The term nociception (from the
Latin nocere, meaning �to hurt’) refers to the sensory
process that is triggered when pain occurs, whereas
the term pain refers to the perception of a feeling or
the actual sensation of pain.
Nociceptors are unspecialized and unmyelinated
nerve endings that transduce a variety of stimuli
into nerve impulses, which are interpreted by the
brain and lead to the sensation of pain . The nerve
cell bodies are located in the dorsal root ganglia, or,
in the case the trigeminal nerve, in the trigeminal
ganglia, and they send one nerve fibre branch to the
periphery of the trigeminal territory and another to
the spinal cord or brainstem. There are two types of
nociceptors: the C-fibre nociceptors, which respond
polymodally to thermal, mechanical and chemical
stimuli to produce the sensation of delayed and
dull pain, and the A delta (d)-fibre nociceptors,
which respond to mechanical and mechanothermal
stimuli to produce the sensation of immediate and
sharp pain.2
178
Normal pain pathways involve activation of
nociceptors in response to a painful stimulus. A
wave of depolarization is then sent to the first-order
neurons, which sodium enters and potassium
exits via the sodium–potassium pump. First-order
neurons terminate at the brainstem, in the trigeminal
nucleus or in the dorsal horn of the spinal cord,
and it is here that the electrochemical signals open
voltage-gated calcium channels in the presynaptic
terminal, allowing calcium to enter and glutamate
(an excitatory neurotransmitter) to be released into
the synaptic space. Glutamate binds to N-methyld-aspartate (NMDA) receptors on the second-order
neurons, causing depolarization. These neurons then
cross over in the spinal cord and ascend to enter the
thalamus, where they synapse with the third-order
neurons. These, in turn, connect to the limbic system
and the cerebral cortex.2
Antinociceptive neurons originate in the brainstem
and descend the spinal cord, where they synapse
with short interneurons in the dorsal horn, releasing
serotonin and noradrenaline. The interneurons
modulate the synapse between the first-order
neurons and the second-order neurons by releasing
gamma-aminobutyric acid (GABA), an inhibitory
neurotransmitter, which results in pain cessation.
Suppression of inhibitory synaptic connections can
enhance pain sensation.2
Both basic and human research indicates that a lesion
of afferent pathways is necessary for development of
NEP.2 Furthermore, data clearly indicate that several
mechanisms can lead to NEP and that many of these
mechanisms do not depend on the cause of the
disease, i.e. the same mechanism underlies different
diseases. The main mechanisms for the development
NEP are as follows.
Ectopic nerve activity
The sensation of ongoing spontaneous pain,
combined with paroxysmal shooting pain, in the
absence of an external stimulation, is caused by
ectopic impulse generation within nociceptive
pathways. After a peripheral nerve lesion,
spontaneous activity is evident in both the injured
and neighbouring uninjured nociceptive afferents.3–5
Increasing levels of messenger RNA in association
with voltage-gated sodium channels seem to
correlate with ectopic activity. In addition, increased
expression of sodium channels in injured and intact
fibres may lower the action potential threshold
until ectopic activity occurs. Similar changes in the
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:177–184 (http://dx.doi.org/10.7707/hmj.v6i2.239)
Review
second-order nociceptive neurons are thought
to occur after a central lesion, which leads to
central NEP.6
Upregulation of receptor proteins
Nerve injury can induce upregulation of various
receptor proteins located in undamaged peripheral
nociceptive endings and downregulation of receptor
proteins in damaged nerve endings, which may result
in spontaneous nerve activity. This spontaneous
nerve activity may be induced by normally innocuous
tactile stimuli that do not usually induce pain (known
as allodynia), or an abnormality such as hyperalgesia
(an increased response to normal painful stimuli).2,4,5,7
Central sensitization
Central sensitization may develop as a result of
ectopic activity in the primary nociceptive afferent
fibres without actual structural damage to the CNS.
Ongoing discharges of peripheral afferent fibres that
release excitatory amino acids and neuropeptides
within the dorsal horn of the spinal cord lead to
postsynaptic changes in second-order nociceptive
neurons, such as the expression of voltage-gated
sodium channels. These changes induce neuronal
hyperexcitability that enables low-threshold
mechanosensitive A beta (b) and Ad afferent fibres to
activate second-order nociceptive neurons, resulting
in allodynia. Similar mechanisms may take place at
the supraspinal levels.2,4,5,7
Inflammatory mechanism
Inflammation following a nerve lesion induces
activation of macrophages that migrate into the nerve
and dorsal root ganglion and release proinflammatory
cytokines, including tumour necrosis factor alpha (a),
which contributes to pain hypersensitivity. Following
peripheral and central nerve lesions, activated
microglia within the CNS release several immune
modulators that also play a role in NEP.7
Disinhibition
After a peripheral nerve lesion, inhibitory GABAergic
interneurons in the spinal horn are lost. Prevention
of interneuron cell death attenuates the mechanical
and thermal hyperalgesia and contributes to NEP.
Furthermore, lesions that affect the opioidergic
and monoaminergic systems (the inhibitory
descending pathways that originate in the brainstem
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
and block pain) contribute to pain exacerbation
through disinhibition.2,4,5,7
Pharmacological management of
neuropathic pain
The management of a patient with chronic NEP is
challenging and the primary goal is to treat the pain
and associated comorbidities, such as anxiety and
depression. The secondary goals of treatment are to
improve sleep, the ability to function normally and
the overall quality of life.
Tricyclic antidepressants
Tricyclic antidepressants (TCAs) are the most effective
treatment in the management of NEP. These drugs,
which were originally thought to block the reuptake
of noradrenaline and serotonin, actually block NMDA
agonist-induced hyperalgesia and also have sodium
channel-blocking properties.8 Although the analgesic
effect of TCAs is independent of the antidepressant
effect, the analgesic effect could be beneficial to
those suffering from depression as depression is
commonly associated with NEP.8–11
The anticholinergic effect of TCAs is associated
with several adverse effects, such as a dry mouth,
constipation, sweating, dizziness, blurred vision,
drowsiness, palpitation, orthostatic hypotension,
sedation and urinary retention. TCAs can also cause
cognitive disorders and disturbance to gait, which
may result in falls, particularly in elderly patients.8–11
These adverse effects mean that precautions need to
be taken while using TCAs and electrocardiography
needs to be conducted before the start of treatment,
especially in patients over 40 years of age and/or
with a history of ischaemic heart disease, as these
patients are at a higher risk of developing adverse
effects while taking TCAs. More selective TCAs, such
as nortriptyline, cause fewer anticholinergic and
sedation effects.8–11
Tricyclic antidepressants should be taken at low
dosages initially (10–25 mg in the evening) and then
slowly tailored on an individual basis depending on
how the patient tolerates the drug. The reported
effective dosage of amitriptyline, or its equivalent,
ranges from 25 to 150 mg, with the average dosage
being 75 mg per day. Owing to the substantial
pharmacokinetic variability of TCAs, the monitoring
of serum drug concentrations is helpful for
guiding treatment.8–11
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Review
Serotonin–noradrenaline reuptake inhibitors
Duloxetine and venlafaxine are
serotonin–noradrenaline reuptake inhibitors (SNRIs)
that are efficacious in the treatment of painful
polyneuropathies. The most common adverse effects
associated with duloxetine are nausea, somnolence,
a dry mouth, constipation, reduced appetite,
diarrhoea, hyperhidrosis and dizziness. Additional
rare adverse effects that have been reported are
the elevation of plasma glucose, hepatic enzymes
or blood pressure. The reported adequate dosage
of duloxetine ranges from 60 to 120 mg per day.
Treatment should be prescribed at 30 mg per day
initially to avoid nausea and increased to 60 mg per
day after 1 week. In comparison, only high doses
of venlafaxine (150–225 mg per day) are effective.
Patients have been reported to tolerate venlafaxine
better than duloxetine and the main side-effect is
gastrointestinal disturbance.8–11
Anticonvulsants
Gabapentin and pregabalin bind to presynaptic
voltage-gated calcium channels in the dorsal horn,
resulting in a decrease in the release of excitatory
neurotransmitters such as glutamate and substance
P. Studies reporting on diabetic neuropathy12 and
post-herpetic neuralgia13 concluded that gabapentin
treatment produced significant pain relief and
significant improvement in quality of life and patient
mood. Pregabalin is an analogue of gabapentin with
the same mechanism of action, but demonstrates
linear pharmacokinetics and has a higher affinity for
the presynaptic calcium channel. It has been shown
that pregabalin provides significant pain relief and
improved quality of sleep in post-herpetic neuralgia
and painful diabetic neuropathy. Pregabalin also
produces significant pain relief for chronic central NEP
following injury to the spinal cord.9–13
The most common side-effects of gabapentin and
pregabalin are dizziness, somnolence, peripheral
oedema, weight gain, asthenia, headache and
a dry mouth. The reported effective dosage
is 1800–3600 mg per day for gabapentin and
150–600 mg per day for pregabalin; however,
inconsistent effects have been reported with a dose
of 150 mg of pregabalin per day. Both drugs need to
be tailored to the individual patient, but the period
for tailoring is generally shorter for pregabalin (the
dose should be increased by 75 mg every 3 days)
than for gabapentin (the dose should be increased
180
by 600–900 mg over 3 days in three divided doses).
Gabapentin is generally administered three times
a day, with the exception of the extended-release
formulation, which releases drug over an extended
period of time; pregabalin is generally administered
twice a day.
Carbamazepine remains the treatment of choice for
cases of idiopathic trigeminal neuralgia; however,
this drug is not recommended for the management
of NEP.
Topical lidocaine
Lidocaine relieves pain through the non-specific block
of sodium channels on the ectopic peripheral afferent
fibres without causing numbness of the treated skin.
Lidocaine patches are generally safe and give low
systemic absorption, which offers the benefit of local
side-effects only, such as a mild skin reaction. Up to
four patches per day may be used to cover the painful
area and alteration of the dosage is not necessary.
Lidocaine patches are most appropriate for localized
peripheral NEP such as post-herpetic neuralgia.14
Tramadol
Tramadol shows direct agonist activity at both
presynaptic and postsynaptic opioid receptors.
Furthermore, it has additional analgesic properties
through the inhibition of serotonin and noradrenaline
reuptake. Tramadol can induce dizziness, a dry
mouth, nausea, constipation and somnolence
and can aggravate existing cognitive impairment,
particularly in elderly patients. Patients with history
of epilepsy, or who are receiving drugs to reduce
the seizure threshold, such as TCAs, are at an
increased risk of seizures while taking tramadol.
Serotonergic syndrome may occur if tramadol is
used in combination with serotonergic medication,
particularly SNRIs. The effective dose of tramadol
ranges from 200 to 400 mg per day, but it should be
prescribed at low dosage initially (50 mg per day),
and continuous low dosage is recommended for
elderly patients and patients with renal impairment
and cirrhosis.10,11,15
Strong opioids
Opioid analgesics such as oxycodone, methadone,
fentanyl and morphine are presynaptic and
postsynaptic opioid receptor agonists. Randomized
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:177–184 (http://dx.doi.org/10.7707/hmj.v6i2.239)
Review
controlled trials have reported the efficacy of opioids
for different peripheral and central neuropathic
disorders.10,11,15,16 Opioids have a comparable analgesic
efficacy to TCAs;17 however, concerns about long-term
side-effects, such as immunological changes, physical
dependency and drug abuse, may limit the use of
strong opioids in patients with chronic neuropathic
non-cancerous pain. Oxycodone is the most
commonly studied drug for the treatment of NEP and
the recommended dose ranges from 10 to 200 mg
per day.
Using opioids for the treatment of NEP is not
necessarily associated with a significant improvement
in quality of life, psychological comorbidities or
sleep disorders.15 The most common side-effects
are constipation, sedation, nausea, dizziness
and vomiting; however, these effects generally
decrease after long-term treatment. Opioid-induced
hyperalgesia, which consists of an increase in pain
sensitivity and potential aggravation of existing pain,
may also be observed in patients receiving long-term
opioid treatment.
Miscellaneous drugs
Mexiletine
Mexiletine is a class 1B local anaesthetic and
antiarrhythmic agent that functions by blocking
sodium channels. Mexiletine regulates an ectopic
neural pacemaker by slowing its conduction and
therefore may have a prolonged duration of action.
However, mexiletine has produced positive results in
only two of seven NEP trials.18
Clonidine
Clonidine is an a2-agonist sympathetic blocker which
has proved to have benefits for a subset of patients
with painful diabetic neuropathy in an enriched
enrolment trial.16
Capsaicin
Capsaicin is an agonist of the transient receptor
potential vanilloid receptors (TRPV1s) on nociceptive
fibres. After several days of capsaicin treatment,
TRPV1-containing sensory axons become
desensitized, thereby inhibiting the transmission of
pain. Standard capsaicin-containing creams have
been found to be moderately effective in postherpetic neuralgia; however, these creams need to
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
be applied several times a day and cause a burning
sensation before the analgesic effect begins. Recently,
a single highly concentrated (8%) capsaicin patch,
applied to the painful area for 30, 60 or 120 minutes,
has been demonstrated to be effective during
weeks 2–12 of post-herpetic neuropathy.15
Adverse effects while using capsaicin are primarily
due to local capsaicin-related reactions at the
application site (pain, erythema and sometimes
oedema and itching). Furthermore, the patient’s
blood pressure should be monitored because of the
risk of high blood pressure during treatment.15
Cannabinoids
The therapeutic potential of cannabinoids for
the remedy of chronic pain has been extensively
investigated. Oromucosal cannabinoids (2.7 mg
d-9-tetrahydrocannabinol plus 2.5 mg cannabidiol)
have been found to be effective for multiple
sclerosis-associated pain and allodynia associated
with refractory peripheral NEP.15 Adverse effects
include dizziness, a dry mouth, sedation, fatigue,
gastrointestinal problems and oral discomfort,
and cannabinoids may aggravate existing mental
conditions. Oromucosal cannabinoids are currently
available for the treatment of NEP only in Canada.
Botulinum toxin A
Several investigations have suggested that botulinum
toxin A (BTX-A), a potent neurotoxin commonly
used for the treatment of focal muscle hyperactivity,
may have analgesic effects that are independent
of its action on muscle tone, possibly by acting
on neurogenic inflammation.19 In patients with
mononeuropathy, 100–200 units of BTX-A is injected
into the painful area, which is usually the area
associated with mechanical allodynia; the onset of
action of BTX-A is about 1 week and duration of effect
3 months. BTX-A has an excellent safety profile with
no systemic side-effects.
Summary of current recommendations
for medical treatment of neuropathic
pain
Management of NEP should be tailored to the
individual patient on the basis of pain type(s), the
causative disease, the relevant psychological factors
and the interactions between the biological and
psychosocial processes. Classification of evidence
181
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Review
Table 1  Classification of evidence for drug treatment in commonly studied NEP conditions and recommendations for
their use. Treatments are presented in alphabetical order. Drugs marked with an asterisk were found effective in single class
II or III studies and are generally not recommended. Reprinted from Attal N, Cruccu G, Baron R, et al. EFNS guidelines on
pharmacological treatment of neuropathic pain, Eur J Neurol 2010 revision, vol. 17, pp. 1113-e88,15 with permission from
John Wiley & Sons Inc.
Aetiology
Diabetic
neuropathyd
Level Aa rating
for efficacy
Level Bb rating for
efficacy
Duloxetine
Gabapentin
Gabapentinmorphine
Oxycodone
Pregabalin
TCAse
Tramadol
alone or with
acetaminophen
Venlafaxine
extended release
Botulinum toxin*
Dextromethorphan
Gabapentinvenlafaxine*
Levadopa*
Post-herpetic Capsaicin 8% patch
neuralgia
Gabapentin
Lidocaine plasters
Opioid (morphine,
oxycodone,
methadone)
Pregabalin
TCAse
h
Central pain Cannabinoids
(oromucosal or
oral) (multiple
sclerosis)
Pregabalin (spinal
cord injury)
a
Level A/B rating for
Level Cc rating inefficacy or discrepant
for efficacy
results
Recommendations Recommendations
as first-line
as second- or thirdtreatment
line treatment
Carbamazepine
Phenytoin
Duloxetine
Gabapentin
Pregabalin
TCAs
Venlafaxine
extended release
Opioid
Tramadolf
Gabapentin
Pregabalin
TCAs
Lidocaine plasterg
Capsaicin
Opioid
Capsaicin cream
Lacosamide
Lamotrigine
Memantine
Mexiletine
Mianserin
Oxacarbazepine
Selective serotonin reuptake
inhibitors
Topical clonidine
Topiramate
Valproate
Zonisamide
Benzydamine (topical)
Dextromethorphan
Fluphenazine
Lorazepam
Memantine
Mexiletine
Tramadol
Capsaicin cream
Valproate*
Lamotrigine (central
post-stroke pain)
Opioid
TCAs (spinal cord
injury, central poststroke pain)
Tramadol (spinal cord
injury)*
Carbamazepine
Gabapentin
Gabapentin
Pregabalin
Duloxetine (found effective TCAs
in allodynia in one study)
Lamotrigine in spinal cord
injury (except in patient
with allodynia in one study)
Levetiracetam
Mexiletine
S-Ketamine iontophoresis
Valproate
Cannabinoids
(multiple sclerosis)
Lamotrigine
Opioid
Tramadol (spinal cord
injury)
Good scientific evidence suggests that the benefits of treatment substantially outweigh the potential risks.
Some scientific evidence suggests that the benefits of treatment outweigh the potential risks.
b
At least fair scientific evidence suggests that there are benefits provided by the clinical service, but the balance between benefits and risks are too close for making general recommendations.
Clinicians need not offer it unless there are individual considerations.
c
Only TCAs, tramadol and venlafaxine were studied in non-diabetic neuropathy.
d
TCAs include amitriptyline, clomipramine, nortriptyline, desipramine and imipramine.
e
Tramadol is recommended as a first-line treatment in patients with acute exacerbations of pain, in particular the tramadol–acetaminophen combination.
f
Lidocaine is recommended as a first-line treatment mainly in elderly patients.
g
Cannabinoids and lamotrigine are proposed for refractory cases.
h
182
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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Review
for drug treatments in commonly studied NEP
conditions, and recommendations for their use, can
be seen in Table 1.
Tricyclic antidepressants, gabapentin, pregabalin
and SNRI antidepressants are recommended as
first-line treatments for NEP by the Neuropathic
Pain Special Interest Group of the IASP10,11,15 and the
European Federation of the Neurological Society.10 It
is reasonable to initiate treatment with either TCAs
or anticonvulsants and, if TCAs fail, then switch to
anticonvulsants, or vice versa. If TCAs provide only
partial relief, then an anticonvulsant can be added to
the treatment plan.
Topical lidocaine is recommended as a first-line
treatment in for post-herpetic neuralgia, especially in
elderly patients. If first-line medications fail, tramadol
or conventional opioid analgesics may be useful
as second-line treatment; however, these are also
recommended as first-line treatments in patients with
episodic pain exacerbations10 and for breakthrough
pain during the first-line medication-tailoring period.
Third-line treatment for management of NEP includes
prescription of cannabinoids, mexiletine, clonidine,
methadone, lamotrigine, topramate and valproic acid.
These should be considered when other options have
failed or are not possible and they can be considered
as adjunctive therapies if there is no concern
regarding polypharmacy or drug interactions.
Intractable pain may require treatment with a
combination of antidepressants, anticonvulsants
and opioids.
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5
Baron R, Binder A, Wasner G. Neuropathic pain:
diagnosis, pathophysiological mechanisms and
treatment. Lancet Neurol 2010; 9:807–19. http://dx.doi.
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Baron R. Mechanisms of disease: neuropathic pain – a
clinical perspective. Nat Clin Pract Neurol 2006; 2:95–106.
http://dx.doi.org/10.1038/ncpneuro0113
Bostock H, Campero M, Serra J, Ochoa J. Temperaturedependent double spikes in C-nociceptors of
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Lai J, Hunter J, Porreca F. The role of voltage-gated
sodium channels in neuropathic pain. Curr Opin
Neurobiol 2003; 13:291–7. http://dx.doi.org/10.1016/
S0959-4388(03)00074-6
Wu G, Ringkamp M, Murinson B et al. Degeneration
of myelinated efferent fibres induces spontaneous
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Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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activity in uninjured C-fibre afferent. J Neurosci 2002;
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Hains B, Waxman S. Sodium channel expression and
the molecular pathophysiology of pain after SCI. Prog
Brain Res 2007; 161:195–203. http://dx.doi.org/10.1016/
S0079-6123(06)61013-3
Scholz J, Woolf C. The neuropathic pain triad: neurons,
immune cells and glia. Nat Neurosci 2007; 10:23–36.
http://dx.doi.org/10.1038/nn1992
Kingry W. A critical review of controlled clinical trials
for peripheral neuropathic pain and complex regional
pain syndromes. Pain 1997; 73:123–39. http://dx.doi.
org/10.1016/S0304-3959(97)00049-3
Moulin DE, Clark AJ, Gilron I, Ware MA. Pharmacological
management of chronic neuropathic pain – consensus
statement and guidelines from the Canadian Pain
Society. Pain Res Manag 2007; 12:13–21.
Dworkin RH, O’Connor AB, Audett J, et al.
Recommendations for the pharmacological
management of neuropathic pain: an overview and
literature update. Mayo Clin Proc 2010; 85:S3–14. http://
dx.doi.org/10.4065/mcp.2009.0649
O’Connor AB, Dworkin RH. Treatment of neuropathic
pain: an overview of recent guidelines. Am J Med
2009; 122:S22–32. http://dx.doi.org/10.1016/j.
amjmed.2009.04.007
Backonja M, Beydoun A, Edwards KR, et al. Gabapentin
for the symptomatic treatment of painful neuropathy in
patients with diabetes mellitus: a randomized controlled
trial. JAMA 1998; 280:1831–6. http://dx.doi.org/10.1001/
jama.280.21.1831
Rowbotham M, Harden N, Stacey B, Bernstein P,
Mangus-Miller L. Gabapentin for the treatment of
post-herpetic neuralgia: a randomized controlled trial.
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jama.280.21.1837
Baron R, Mayoral V, Leijion G, Binder A, Stergelwald
I, Serpell M. 5% Lidocaine medicated plaster versus
pregabalin in post-herpetic neuralgia and diabetic
polyneuropathy: an open label, non-inferiority twostage RCT study. Curr Med Res Opin 2009; 27:1663–76.
http://dx.doi.org/10.1185/03007990903047880
Attal N, Cruccu G, Baron R, et al. EFNS guidelines on
pharmacological treatment of neuropathic pain. Eur
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Byas-Smith G, Max B, Muir J, Kingman A. Transdermal
clonidine compared to placebo in painful diabetic
neuropathy using a two-stage �enriched enrollment’
design. Pain 1995; 60:267–74. http://dx.doi.
org/10.1016/0304-3959(94)00121-T
Raja SN, Haythornthwaite JA, Pappagallo M, et al.
Opioids versus antidepressants in post-herpetic
neuralgia: a randomized, placebo-controlled trial.
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WNL.59.7.1015
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based proposal. Pain 2005; 118:289–305. http://dx.doi.
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Aoki R. Review of a proposed mechanism for the
antinociceptive action of Botulinum toxin type A.
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org/10.1016/j.neuro.2005.01.017
183
Hamdan Medical Journal  2013; 6:185–190 (http://dx.doi.org/10.7707/hmj.v6i2.163)
 
Original research article
Improving the management of placenta
praevia accreta
Khalid Saleh,1 Nawal M Hubaishi,1 Hena Zaheer,2 Fatima Cherifi1 and Ibtihaj Alanizi1
Obstetrics and Gynaecology Department, Dubai Hospital, and 2Dubai Gynaecology and Fertility
Centre, Dubai Health Authority, Dubai, United Arab Emirates
1
Abstract
Objectives. The aims of this study were to assess the incidence of placenta
praevia accreta, to identify risk factors for this complication and to analyse
sonographic findings and the outcomes of interventions. This should improve
antenatal diagnosis and facilitate the introduction of a new protocol for
conservative management of this condition.
Materials and methods. This is a retrospective and descriptive study, over
a period of 30 months, of women who underwent a caesarean section (CS)
owing to placenta praevia accreta within the Obstetrics and Gynaecology
Department at Dubai Hospital, United Arab Emirates. During this time, all
files were reviewed and parameters collected, including patients’ profile, risk
factors, interventions, complications, blood loss, blood transfusion and length
of hospitalization.
Results. There were 11 cases of placenta praevia accreta (1 in 909 births).
Two major risk factors were identified: the presence of a pre-existing
uterine scar and previous occurrence of placenta praevia. Ultrasound
findings were of limited use in reaching a diagnosis, resulting in 7 of these
11 patients requiring emergency intrapartum hysterectomy. Two had bladder
injuries with blood loss of 2.9 l, and most of the patients required massive
transfusion. The mean hospital stay was 7.1 days. The results were compared
with those reported in the literature.
Conclusions. Previous placenta praevia and previous CS delivery are
associated with placenta accreta, and result in an increased risk of morbidity
and mortality. A key priority must be the introduction of a new protocol
to include leaving the placenta in situ, particularly in women who wish to
become pregnant again in the future.
Introduction
Placenta praevia and placenta accreta occur when
the placenta is located wholly or partly in the
Correspondence: Fatima Cherifi, Obstetrics and Gynaecology
Department, Dubai Hospital, Al Baraha, PO Box 7272, Dubai, United
Arab Emirates. Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
lower uterine segment and is morbidly adherent
to it. Placenta accreta is defined as an abnormally
deep attachment of the placenta, through the
endometrium and into the myometrium. There are
three forms of placenta accreta, distinguishable by
the depth of penetration: placenta accreta describes
the partial or complete absence of decidua, with
adherence of the placenta directly to the superficial
myometrium; placenta increta is an invasion into,
but not all the way through, the myometrium; and
placenta percreta describes penetration through the
full thickness of the myometrium and into the serosa.
This is relatively rare but potentially life-threatening,
as it often results in complications in the peripartum
period such as severe haemorrhage, a possible need
for caesarean hysterectomy and even severe injuries
to pelvic organs.
The aim nowadays is to manage placenta accreta
conservatively not only to avoid massive pelvic
bleeding and massive transfusions, but also to
preserve fertility. The improvement of imaging
investigations facilitates a diagnosis, allowing
management plans to be discussed with other clinical
professionals (e.g. interventional radiologists and
anaesthetists), as well as the patient and her family.
The association between placenta accreta, placenta
praevia and caesarean section (CS) has become more
striking in recent years, and the incidence of placenta
accreta (including increta and percreta) may have
risen 10-fold in the past 50 years.1 Recent reports
suggest that the incidence ranges from 1 in 110 to
1 in 2500 deliveries,2 and this incidence is expected to
rise as the number of CSs increases.
185
185
Hamdan Medical Journal  2013; 6:185–190 (http://dx.doi.org/10.7707/hmj.v6i2.163)
Original research article
The present study was conducted over a period of
30 months. The aims of the study were as follows:
to determine the incidence of confirmed placenta
accreta at Dubai Hospital, United Arab Emirates, and
to compare this with the literature; to examine the
influence of an antenatal diagnosis in determining
approaches to management; to assess the effect of
subsequent separation of the placenta during CS
on maternal outcomes; to discuss new challenges in
management; and to institute new guidelines in our
department for the management of future patients
with the same pathology, including undertaking
caesarean hysterectomy in patients who do not wish
to have further pregnancies, or leaving the placenta
in situ in those who wish to preserve their fertility.
Materials and methods
A retrospective and descriptive study was conducted
of all pregnant women at or beyond 24 weeks
of gestation who were diagnosed with placenta
praevia accreta, either antenatally or during CS,
between 1 June 2009 and 31 December 2011.
Patients were identified from medical files, record
books and electronic medical record databases at
Dubai Hospital.
The medical notes were examined and checked
against the database for the following: gestational
age at diagnosis and delivery; risk factors;
imaging findings; operative interventions and any
complications; estimated blood loss; blood unit
transfusion; and findings confirmed by the pathology
department in cases where hysterectomy was carried
out. Admission to the intensive care unit (ICU) and
the mean hospitalization period were analysed. The
literature was reviewed and our results compared
with those of international reports.
Results
During the study period of 30 months, there
were 9577 deliveries at Dubai Hospital, of which
2966 deliveries (31%) were by CS. Eleven cases
of placenta praevia accreta were diagnosed. The
estimated incidence of the condition, based on the
results of this study, is 1 in 909 deliveries. During this
study period, no vaginal deliveries were followed by
post-partum diagnosis of placenta accreta, nor were
there any cases of CS with placenta accreta only.
The mean maternal age was 33.5 years (range
25–37 years). The mean gestational age at delivery
186
was 35.7 weeks (range 24–37 weeks). Patients with
placenta praevia accreta were pauciparous, with an
average parity of three. This does not correspond to
the literature, with multiparity considered a risk factor
for this condition.
All patients with placenta praevia accreta had
undergone at least one prior CS (Table 1).
An ultrasound examination is performed routinely
in all pregnant women attending the hospital.
Screening for placenta accreta is carried out only once
an antenatal diagnosis of placenta praevia has been
made, in view of the association between placenta
praevia and the diagnosis of placenta accreta. In
most cases, the diagnosis of placenta praevia accreta
was made before 30 weeks of gestation. Table 2
shows the level of concordance between ultrasound
results and final diagnosis. Although the sample was
small, it is clear nonetheless that the sensitivity of
ultrasound was poor, compared with that reported
in the literature. Only 4 out of 11 patients with
placenta praevia accreta (36.4%) had corresponding
ultrasound findings.
Seven out of 11 patients were misdiagnosed by
ultrasound (63.6%), and hysterectomy was necessary
in six of these patients. In two cases, the pathology
indicated the presence of placenta accreta increta,
and in one case placenta accreta percreta. Magnetic
resonance imaging (MRI) was requested in five cases.
In one case this was cancelled as the patient did
not tolerate the examination. Diagnoses based on
TABLE 1  Risk factors for placenta praevia and placenta
accreta
Case
number Age Parity
Number of Number of
previous CSs miscarriages
Other risk
factors
1
2
3
4
5
6
7
8
9
10
11
2
3
1
2
3
2
4
4
1
3
3
–
–
ERPOC
–
–
ERPOC
–
–
–
–
ERPOC
35
37
34
25
38
35
35
33
32
36
31
2
3
1
2
3
7
4
7
1
3
3
–
–
2
–
–
3
2
–
–
–
3
ERPOC, evacuation of retained products of conception.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:185–190 (http://dx.doi.org/10.7707/hmj.v6i2.163)
Original research article
TABLE 2  Concordance between imaging and final diagnosis
Case number
Interpretation of abdominal ultrasound Interpretation of MRI
Hysterectomy (yes/no)
Final diagnosis
1
2
3
4
5
6
7
8
9
10
11
Suggestive of accreta
Suggestive of accreta
Suggestive of accreta
Placenta praevia posterior
Placenta praevia
Placenta praevia
Suggestive of partial localized accreta
Placenta praevia posterior
Placenta praevia
Placenta praevia
Placenta praevia
No
No
Yes
Yes
Yes
No
No
Yes
Yes
Yes
Yes
Placenta accreta
Placenta accreta
Placenta percreta
Placenta accreta
Placenta accreta
Placenta accreta
Placenta accreta
Placenta accreta/increta
Placenta accreta/increta
Placenta accreta
Placenta increta/percreta
Ultrasound result confirmed
Not tolerated
Not carried out
Negative
Not carried out
Not carried out
Ultrasound result confirmed
Not carried out
Not carried out
Negative
Not carried out
MRI, magnetic resonance imaging.
ultrasound were confirmed in two of the remaining
four patients; in the other two patients these
diagnoses were wrongly excluded. Both of these
patients underwent hysterectomy for placenta accreta
with intractable post-partum haemorrhage (PPH).
With regards to procedure, six patients had elective
CSs whereas five underwent emergency CSs.
All CSs were carried out in the presence of a
consultant. Four units of blood were cross-matched as
per protocol for any patient undergoing a CS. As the
diagnosis of placenta praevia accreta was not made
in 7 out of 11 cases, an attempt was made to separate
the placenta after delivery in all patients. In two
cases, part of the placenta was left in situ; however,
one of these patients subsequently returned to the
operating theatre for secondary PPH and required
a hysterectomy due to massive bleeding with
profound hypotension. Another patient underwent
a second laparotomy after collapsing, with 1 l of
haemoperitoneum resulting from intraperitoneal
bleeding. Ligation of the internal iliac artery was
performed to stop the bleeding.
Immediately after placenta removal, all patients
experienced severe bleeding with hypotension. In all
cases, every effort was made to arrest the bleeding
before resorting to emergency hysterectomy
[including the use of oxytocin (SyntocinonВ®, Sandoz,
Sandoz International GmbH, Holzkirchen, Germany),
prostaglandin, uterine sutures, bed stitches and
Bakriв„ў Balloon (Cook Medical, Limerick, Ireland)], and
this may account for the significantly larger volume
of blood lost and blood transfused in this group
(Table 3). There were two cases of bladder injury
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
during dissection (see Table 3). There were no bowel
injuries, despite adhesions and post-partum infection.
Blood loss leads to marked circulatory collapse,
vasoconstriction and oliguria, and may even be
life-threatening. Mean blood loss in the patients in
this study was estimated at 2.9 l (range 1.5–5.0 l).
An analysis of blood units received during and
after surgery suggests that this may be an
underestimate (Figure 1).
The mean number of blood units transfused
was 8.1 (range 5.0–15.0 units). An average of
8.5 units of other blood products were required
(range 2.0–15.0 units). All patients with placenta
accreta or placenta praevia with PPH were admitted
to the ICU for between 24 and 72 hours. The mean
length of hospital stay after delivery was 7.1 days.
Discussion
As numbers of CSs continue to rise, both within Dubai
Hospital and worldwide, the problem of placenta
praevia accreta will become more common. At Dubai
Hospital, 1 in 909 deliveries is affected. This is within
the range of figures reported internationally, which
varies from 1 in 1102 to 1 in 2510 deliveries affected.3
The association between placenta praevia and prior
CS delivery with placenta accreta and the risk of
requiring a hysterectomy is well documented.4 Miller
et al.3 found that the risk of placenta accreta ranged
from 2% in women < 35 years of age with no history
of CS to almost 39% in women who had undergone
two or more previous CSs and who had an anterior or
central placenta praevia.
187
Hamdan Medical Journal  2013; 6:185–190 (http://dx.doi.org/10.7707/hmj.v6i2.163)
Original research article
TABLE 3  Operation interventions to arrest bleeding
a
Case
number
CS
Bed
stitches
Bakri
Balloon
Lynch
technique
Uterine artery Internal iliac
ligation
artery ligation
Hysterectomy
Pathology
1
2
3
4
5
6
7
8
9
10
11
Elective
Emergency
Emergency
Elective
Elective
Elective
Elective
Emergency
В Elective
В Emergency
Emergency
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
Yes
No
No
No
No
No
No
No
No
Yes
No
Yes
No
No
No
No
No
No
No
No
Yes
Yes
Yes
No
No
Yesb
Yes
Yesc
Yesb
–
–
Placenta percreta
Placenta accreta
Placenta accreta
–
–
Placenta increta
Placenta increta
Placenta accreta
Placenta increta/percreta
В No
No
No
Yesa
No
No
No
No
No
No
No
Second laparotomy required because of haemoperitoneum.
Bladder injury sustained.
В b
Hysterectomy required due to late PPH.
c
Figure В 4: В blood В products В transfused
В Blood В products В 20
RBC
10
FFP
0
PLT
1
2
3
4
5
6
Cryo
7
FIGURE 1  Blood products transfused.
Greyscale ultrasonography is now an established
first-line investigation for suspected placental
invasion of the myometrium and has clear diagnostic
criteria: placental lacunae and loss of retroplacental
clear space.5 It has reduced the morbidity and
mortality from placenta accreta by helping to
establish the diagnosis and detect complications
antepartum. Comstock5 found that, at 15–20 weeks
of gestation, the presence of lacunae in the placenta
is the most predictive sonographic sign of placenta
accreta, with a sensitivity of 79% and a positive
predictive value of 92%. MRI has been shown
to be beneficial in some cases when ultrasound
findings are equivocal or not diagnostic.6 The use
of MRI has a variable sensitivity ranging from 38%
188
8
9
10
11
Case В n umber В В to 88%, and specificity of up to 100% when it is
applied as a secondary diagnostic tool. In this study,
errors were made on both ultrasound and MRI; the
direct consequences were a high rate of morbidity
(hysterectomies, bladder injuries and massive blood
transfusions). In future, antenatal diagnosis should be
improved by training obstetricians and radiologists
to approach the diagnosis according to clear,
established criteria, which will benefit those patients
who wish to avoid hysterectomy in order to preserve
their fertility.
Owing to a lack of antenatal diagnosis, all patients
experienced massive bleeding, leading to emergency
peripartum hysterectomy. Hsu et al.7 reported an
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:185–190 (http://dx.doi.org/10.7707/hmj.v6i2.163)
Original research article
estimated mean blood loss of 3.8 l, as compared with
2.9 l in this study. The mean quantity of whole blood
transfused in the study by Hsu et al. was 15 units,7
as compared with 8.1 units for our patients. Wong
et al.8 compared one group of patients who did
not receive an antenatal diagnosis with another
group given an antenatal diagnosis of placenta
accreta. They concluded that women without an
antenatal diagnosis of placenta accreta experienced
significantly more haemorrhaging (a mean total blood
loss of 3.6 l vs. 1.4 l in the group given an antenatal
diagnosis; P = 0.003).8 Despite the limitations
of studying a small number of conservatively
managed cases, these authors concluded that a clear
relationship had been shown between antenatal
diagnosis of placenta accreta and non-separation
of the placenta, with accompanying improved
maternal outcome. According to Chan et al.,9 by
leaving the morbidly adherent placenta in situ,
with or without pelvic arterial embolization, they
succeeded in preserving the uterus in three patients.
Kayem et al.10 reported on a much larger number
of patients with placenta accreta, managed using
a similar conservative approach. In this study, the
uterus was preserved in 80% of patients, and the
number of complications was low compared with
historical attempts to remove the placenta.10 In 2009,
at a 33 national days meeting of the French National
College of Gynaecologists and Obstetricians (CNGOF),
the findings of a large multicentre study comprising
167 patients from 25 university hospitals, who had
conservative management for placenta accreta, were
presented.11 The results showed that the uterus was
preserved in 78.4% of these patients, with maternal
morbidity reported in 6% of cases. Of the patients
who had conservative management for placenta
accreta, 28.2% later became pregnant without the aid
of medication. The main drawback of conservative
management of placenta accreta is that a long
period of follow-up is required for those patients who
experience a delay in the spontaneous resorption
of the placenta, which may take up to 17 weeks on
average (range 4–45 weeks). For this reason, patients
should be fully advised of the options available for the
management of placenta accreta during the antenatal
period. Our department at Dubai Hospital is working
towards this goal in order to decrease the rate of
morbidity, despite well-known risks of conservative
management, e.g. blood transfusion (required in 40%
of patients), infection (can affect 28% of patients) and
recurrence of placenta accreta in future pregnancies
(can affect 30% of patients).
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Conclusion
Placenta accreta is a relatively rare but potentially
catastrophic obstetric complication. It is likely that
its incidence will continue to increase because
of increasing numbers of repeat CS deliveries.
Antenatal diagnosis is an invaluable aid in perinatal
management, as it allows the clinician to anticipate
and recognize complications that might not
otherwise be expected. Conservative management is
one option that should be discussed with the patient,
with a view to decreasing massive maternal bleeding
and conserving fertility should the patient wish to
do so.
References
1
2
3
4
5
6
7
8
9
10
11
American College of Obstetricians and Gynecologists
(ACOG) Committee on Obstetric Practice. ACOG
Committee opinion. Number 266, January 2002:
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Wu S, Kocherginsky M, Hibbard JU. Abnormal
placentation: twenty-year analysis. Am J Obstet Gynecol
2005; 192:1458–61.
http://dx.doi.org/10.1016/j.ajog.2004.12.074
Miller DA, Chollet JA, Goodwin TM. Clinical risk factors
for placenta previa–placenta accreta. Am J Obstet
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http://dx.doi.org/10.1016/S0002-9378(97)70463-0
Nielsen T, Hagberg H, Ljungblad U. Placenta previa
and antepartum hemorrhage after previous cesarean
section. Gynecol Obstet Invest 1989; 27:88–90.
http://dx.doi.org/10.1159/000293625
Comstock CH. Antenatal diagnosis of placenta accreta:
a review. Ultrasound Obstet Gynecol 2005; 26:89–96.
http://dx.doi.org/10.1002/uog.1926
Stolpen AH, Abu-Yousef M, Hansen WF. Antepartum
evaluation of suspected placenta accreta: is there a role
for MRI? Proc Intl Soc Mag Reson Med 2001; pp. 2082.
Hsu YR, Kung FT, Roan CJ. Emergency peripartum
hysterectomy due to placenta previa/accreta: 10 years’
experience. Taiwanese J Obstet Gynecol 2004; 43:206–10.
http://dx.doi.org/10.1016/S1028-4559(09)60087-5
Wong HS, Hutton J, Zuccollo J, Tait J, Pringle JC. The
maternal outcome in placenta accreta: the significance
of antenatal diagnosis and non-separation of placenta
at delivery. N Z Med J 2008; 121:30–8.
Chan BC, Lam HS, Yuen JH, et al. Conservative
management of placenta praevia with accreta. Hong
Kong Med J 2008; 14;479–84.
Kayem G, Davy C, Goffinet F, Thomas C, Clement D,
Cabrol D. Conservative versus extirpative management
in cases of placenta accreta. Obstet Gynecol 2004;
104:531–6.
http://dx.doi.org/10.1097/01.AOG.0000136086.78099.0f
Sentilhes L, Ambroselli C, Kayem G, et al. Maternal
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189
Hamdan Medical Journal  2013; 6:191–196 (http://dx.doi.org/10.7707/hmj.v6i2.118)
 
OriginaL RESEARCH article
Quantitative analysis of mercury burden in the
wastewater released from dental clinics in the United
Arab Emirates
Sausan Al Kawas
Oral and Craniofacial Health Sciences Department, College of Dentistry, University of Sharjah,
Sharjah, United Arab Emirates
Abstract
Amalgam waste from dental clinics is a significant source of mercury
released into the environment when it is washed down a drain or disposed
of improperly. Mercury is of particular concern because of its potential
adverse effects on humans and the environment. As a consequence, several
measures have been adopted by dental clinics worldwide to reduce mercury
discharge into the environment. The aim of this study was to quantitatively
asses the mercury burden in the wastewater discharged from some dental
clinics in the United Arab Emirates using a cold-vapour atomic absorption
spectrometry technique. Wastewater samples were collected from 28 public
clinics at Sharjah and Abu Dhabi over a period of 10–14 days. The average
concentration of mercury in all samples was 317.7 µg/l, with a standard
deviation of 379.7 µg/l and a range from below the method detection
limit (MDL) to 1535.2 µg/l. The results show some variation in mercury
concentrations between samples, depending on the type and nature of
dental operations undertaken at the specific clinic from which each sample
originated. Most of the wastewater released from dental clinics in the study
area contains concentrations of mercury which, although lower than levels
reported elsewhere in the literature, are unacceptable according to local and
international environmental standards. This implies that such wastewater
should not be discharged without adequate pretreatment in order to reduce
mercury pollution in the environment.
Introduction
Amalgam is one of the most commonly used
materials in restorative dentistry. The amalgam alloy is
composed of many metals, including mercury, silver,
tin, copper and zinc.1,2 Amalgam waste from dental
practices and clinics is a significant source of mercury
Correspondence: Sausan Al Kawas, Oral and Craniofacial Health
Sciences Department, College of Dentistry, University of Sharjah,
Sharjah, PO Box 27272, United Arab Emirates.
Email: [email protected]
В© 2013 The Author
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
released into the environment when it is washed
down a drain or disposed of improperly. Mercury is
of particular concern owing to its potential adverse
effects on humans and the environment. Several
studies have shown that exposure to mercury may
lead to health complications such as impairment of
the developing central nervous system, pulmonary
and nephrotic damage and impairment of
osmoregulatory functions.3–5 Additionally, mercury
is very mobile in the environment and is known
to accumulate in fish and other marine organisms,
and therefore has the potential to contaminate the
entire food chain.5–8 It is also known that dentists and
their assistants and patients are directly exposed to
mercury, with significant increases in their plasma
mercury concentrations reported in comparison
with those of control groups.9–12 The public and
the environment are also indirectly exposed to this
element via mercury emissions from incinerators
and mercury in wastewater from dental clinics
and households.4,6,13,14
Globally, hundreds of tonnes of mercury are used
annually in dental amalgam15 and, according to many
investigations, dental clinics appear to be responsible
for most of the mercury found in the sludge
generated by sewage treatment plants. As a result,
dental clinics are considered an indubitable source of
environmental pollution with mercury.14,16–18
Increasing knowledge of the health risks associated
with exposure to mercury and its accumulation in
the food chain and in ecosystems has led to growing
191
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OriginaL RESEARCH article
pressure to reduce emissions of this metal into the
environment. Consequently, the mercury waste
generated by dental clinics has received increased
attention. Additionally, restrictions on the handling
and discharge of contaminated waste have been
established in several countries. For instance, the
United States Environmental Protection Agency
(USEPA) has set a maximum contaminant level of
inorganic mercury in drinking water of only 2 µg/l.19
Environmental standards set by Dubai Municipality
state that the maximum allowable discharge of
mercury-containing waste into the sewerage system
is 10 µg/l, with no more than 1 µg/l to be released
into the land for irrigation.20 In Saudi Arabia, the
maximum level of mercury permissible in source
water discharged into the public sewer is 50 μg/l,21
and the limit for treated wastewater intended for
use in agriculture is just 1 μg/l.22 As a consequence,
several measures have been adopted by dental
clinics worldwide to reduce quantities of mercury
discharged into the environment, including the use
of amalgam separators and filters, improvements in
the design of the waste discharge system, and the
use of high-pressure water cleaning.14,23,24 However,
implementation of such measures to reduce mercury
waste from dental clinics in the United Arab Emirates
(UAE) is still unregulated.
The aim of this study was to quantitatively assess the
mercury burden in the wastewater discharged from a
number of dental clinics in the UAE.
Materials and methods
Equipment
TABLE 1  Instrumental parameters for the cold-vapour
atomic absorption spectrometry (CVAAS)
Parameter
Unit
Wavelength
Slit width
Lamp current
Measurement time
Background correction
Vapour type
Pre-read delay
Sampling mode
Calibration mode
Measurement mode
Replicates standard
Replicates sample
Smoothing
Calibration algorithm
Flow rate of reducing agent
Flow rate of samples
253.7 nm
0.5R nm
4.0 mA
5.0 seconds
BC On
Cold vapour
70 seconds
AutoMix
Concentration
Peak area
3
3
5 point
Linear
1.0 ml/min
7.0 ml/min
The nitric acid (68–70%) and sodium chloride
(99.5%) used were purchased from Panreac Quimica
(Barcelona, Spain); the sulphuric acid (GPR),
hydrochloric acid (37%), hydroxyl ammonium
chloride (99%) and stannous chloride (98–103%)
from BDH (VWR International Ltd, UK); the potassium
permanganate (99.5%) from Surechem Products Ltd
(Suffolk, UK); the potassium persulphate (98%) from
Fluka (USA); mercury (for calibration, 1001 ± 5mg/l
solution in 2 mol/l HNO3) from BDH (England); and
CRM (20.0 µg/l ± 0.5% in 2% HNO3) from High Purity
Standards (Charleston, SC, USA).
An atomic absorption spectrometer (SpectraAA 220
FS, Varian) equipped with a cold vapour generation
accessory (VGA-77, Varian) and a T-shaped quartz
absorption cell was used for mercury determination.
The instrument has been used according to the
parameters listed in Table 1.
The stannous chloride (25% weight per volume)
reducing solution was prepared by adding 25 g
of stannous chloride to 20 ml of concentrated
hydrochloric acid. The mix was heated to dissolve
the stannous chloride then allowed to cool, before
diluting the solution to 100 ml with water and mixing.
Reagents and solutions
Sample collection, treatment and analysis
All chemicals used were of analytical reagent grade
unless otherwise stated. Water used was obtained
from a Milli-Q reagent system (resistivity 18.2 MW cm;
Millipore, Bedford, MA, USA). All plastic and glassware
used was soaked in 4 M nitric acid for a minimum
of 12 hours, washed with distilled water and finally
rinsed with Milli-Q water before use.
Wastewater samples were collected in acid-washed
plastic containers from the academic dental centre at
the University of Sharjah in Sharjah and Zayed Military
Hospital in Abu Dhabi. At Zayed Military Hospital, the
samples were collected from four different general
dental practitioners over a period of 10 days. All
the clinicians used dental units fitted with built-in
amalgam separators. The samples were collected
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Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:191–196 (http://dx.doi.org/10.7707/hmj.v6i2.118)
OriginaL RESEARCH article
directly from the final drain outlet of the dental unit
prior to its joining the central drainage duct of the
hospital sewage system. Clinical dental procedures
were not limited to the removal or placement
of dental amalgam restorations. The clinicians
routinely performed comprehensive dental care
which, to an appreciable extent, involved removal of
existing amalgam restorations and, less frequently,
placement of dental amalgam. The samples were
collected continuously from the beginning of the
clinical session at 0730 h until the end of the session
at 1330 h.
At the University of Sharjah academic dental
centre, the samples were collected from 24 clinics
in two different ways. The first of these was to
collect samples directly from the outlets of the
dental chairs into the collection containers. These
samples were collected from 12 clinics at the end
of the day (Table 2). The second method was to
take representative samples from 12 dental chairs
connected to a central suction unit. Here, the
wastewater generated during dental treatments
passes into the collection tank and then on through
an amalgam separator, and finally reaches the main
sewer with no further treatment. These representative
samples were collected over a period of 2 weeks (from
7 April to 21 April 2010), after passing through the
amalgam separator and before being drained into the
main sewer.
Collected samples were treated with nitric acid.
Concentrated acid was added to each sample
container to achieve a final acid concentration of 1%,
before storing at 4ВєC in a refrigerator until the time of
analysis. The wastewater samples were then digested
according to USEPA Method 245.1, by shaking the
samples’ containers before taking subsamples for
analysis. Subsamples were gravity filtered using
595 filter 45 papers (Schleicher & Schuell), and 50 ml
of filtered sample was placed in a 150-ml, clean plastic
bottle. This was followed by the addition of 5 ml of
concentrated sulphuric acid, 2.5 ml of concentrated
nitric acid, 5 ml of potassium persulphate (5%) and
5 ml of potassium permanganate (5%). Samples
treated in this way were then placed inside an oven
preset to 95ВєC for 2 hours. After cooling to room
temperature, hydroxyl amine hydrochloride (12% in
12% sodium chloride) was added dropwise to each
bottle until the colour of potassium permanganate
disappeared. More hydroxyl amine hydrochloride
was added if the potassium permanganate colour
reappeared before 15 minutes had elapsed since the
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
first addition. Approximately 1 ml of hydroxyl amine
hydrochloride was found to be enough to completely
reduce any excess potassium permanganate. Finally,
water was added to each bottle to obtain a final
volume of 100 ml. All calibration solutions, blanks and
CRM were treated in the same way. Concentrations
of mercury in the samples were determined using
cold-vapour atomic absorption spectrometry (CVAAS).
Results and discussion
The mercury concentrations in the wastewater
samples are listed in Table 2. This table also includes
the average, standard deviation and range of the
mercury concentrations in the samples.
The average concentration of mercury in all samples,
as shown in Table 2, was 317.7 µg/l, with a standard
deviation of 379.7 µg/l and a range from < MDL to
1535.2 µg/l. These results show some variation
in mercury concentrations between samples.
This variation is expected, and can be explained
by differences in the nature of dental operations
undertaken at each of the clinics from which samples
were collected (e.g. placement or extraction of
amalgam fillings, placement of non-amalgam fillings,
teeth extraction, and scaling and polishing). Similar
findings and explanations have been reported
by other investigators.1,16 It should be noted here
that the obtained mercury results represent only
the soluble fraction of the metal; the actual values
are certainly higher because much of the mercury
released from the clinics remains insoluble as solid
amalgam, which stays trapped inside the chair
filters, vaporizes to the air25,26 or settles on the
bottom of sample containers. It is also obvious from
Table 2 that most of the wastewater samples contain
unacceptable concentrations of mercury according
to Dubai Municipality standards.20 This means that
these samples are considered as hazardous waste
(in terms of metals contamination) and should
not be discharged into the main sewer without
proper treatment to reduce the mercury content to
acceptable levels.
The levels of mercury found in the study samples
are lower than those reported in the literature in
several parts of the world.1,14,27,28 The low average
level of mercury in these results can be attributed
to the use of new alternatives to mercury amalgam
(e.g. non-mercury composite), which are available
on the market and already employed by dentists in
the UAE and other countries. Other factors include
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OriginaL RESEARCH article
TABLE 2  Concentrations of mercury in the samples
Sample number
Mercury concentration (Вµg/l)
Collection date and time
Location
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
Average
Standard deviation
Range
528.1
< MDLa
674.7
284.0
98.2
153.9
177.0
245.7
435.2
498.9
131.5
86.6
58.3
84.3
82.3
119.7
1028.0
4.6
1148.0
1095.7
7.2
349.6
865.4
9.7
746.1
1535.2
59.8
406.5
74.8
332.3
93.4
80.7
34.6
136.4
206.3
75.1
68.6
55.9
317.7
379.7
< MDL–1535.2
7 April 2010 at 1300 h
7 April 2010 at 1310 h
8 April 2010 at 1420 h
8 April 2010 at 1620 h
10 April 2010 at 1330 h
10 April 2010 at 1400 h
10 April 2010 at 1620 h
13 April 2010 at 1130 h
13 April 2010 at 1340 h
13 April 2010 at 1630 h
14 April 2010 at 1320 h
14 April 2010 at 1000 h
14 April 2010 at 1600 h
15 April 2010 at 1300 h
15 April 2010 at 1420 h
15 April 2010 at 1620 h
18 April 2010 at 1200 h
18 April 2010 at 1400 h
18 April 2010 at 1615 h
19 April 2010 at 1330 h
19 April 2010 at 1430 h
19 April 2010 at 1645 h
20 April 2010 at 1320 h
20 April 2010 at 1420 h
20 April 2010 at 1600 h
21 April 2010 at 1320 h
21 April 2010 at 1430 h
21 April 2010 at 1620 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
0730–1330 h
UoS clinic A – unit 3
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic A – unit 1
UoS clinic D – unit 4
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 5
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 2
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 5
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 3
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 7
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 1
UoS clinic – central suction unit
UoS clinic – central suction unit
UoS clinic D – unit 3
UoS clinic – central suction unit
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
Zayed Military Hospital
UoS, University of Sharjah.
a
The MDL is 0.2 µg/l, calculated as three times the standard deviation of nine blank replicates.
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В© 2013 The Author
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Hamdan Medical Journal  2013; 6:191–196 (http://dx.doi.org/10.7707/hmj.v6i2.118)
OriginaL RESEARCH article
the use of amalgam separators in most of the clinics
investigated, and the large number of private
and public dental clinics in the UAE, which results
in fewer patients attending each clinic. A more
comprehensive investigation, covering more clinics,
should be conducted to build a clearer idea of the
total levels of mercury released from dental clinics in
their wastewater.
Conclusion
Most of the wastewater released from dental clinics in
this study contains concentrations of mercury which,
although lower than what has been reported in the
literature, are unacceptable according to local and
international environmental standards. This implies
that such wastewater should not be discharged
without adequate pretreatment. The authorities
concerned must monitor the mechanisms employed
by dental clinics for the disposal of mercury wastes,
and their efficiency in the sorting and handling of
amalgam, to reduce the levels of mercury in medical
wastes. A more comprehensive investigation,
involving a larger number of dental clinics studied
over a longer period of time, will certainly provide a
clear idea of the levels of mercury in the wastewater
from dental clinics, and the impact of mercury
pollution on the environment.
5
6
7
8
9
10
11
12
13
Acknowledgements
This study was supported by full funding from Sheikh
Hamdan Bin Rashid Al Maktoum Award for Medical
Sciences (Grant No. MRG-18/2007–2008). The author
would like to thank Dr Imad Abu-Yousef, Dr Amjad
Shraim, Dr Abu baker Siddique and Mr Naser Abdo for
their valuable assistance in this study.
14
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Hamdan Medical Journal  2013; 6:197–204 (http://dx.doi.org/10.7707/hmj.v6i2.119)
 
ORIGINAL RESEARCH article
The impact of child-rearing by maids on mother–child
attachment
Abdulrahman Al-Matary1 and Jaffar Ali2–4
Children’s Hospital, King Fahad Medical City, Riyadh, 2Research and Scientific Publications
Center, Riyadh, 3Stem Cell Unit, Anatomy Department, College of Medicine, King Saud University,
Riyadh, Saudi Arabia, and 4Department of Obstetrics and Gynaecology, Faculty of Medicine,
University of Malaya, Kuala Lumpur, Malaysia
1
Abstract
Introduction. The objective of this study was to assess the perceived
negative impact on mother–child attachment of raising children with the
help of foreign maids, as practised in Arab Gulf countries.
Materials and methods. A descriptive cross-sectional study was
conducted. A convenience sample was recruited from June 2010 to
December 2010 from three tertiary hospitals and shopping centres. Five
hundred questionnaires were distributed. Of these, 336 with complete data
sets were analysed. The study was approved by the Institutional Review
Board of the King Fahad Medical City. The analysed data were tabulated in
the form of descriptive statistics.
Results. Eighty per cent of households had a maid, but only 50% of mothers
had careers. The proportion of babies who were not bottle-fed was 31.6%,
with 15.7% exclusively breast-fed. Of the 52.8% of babies who were both
breast- and bottle-fed, most were usually bottle-fed. The proportions of
participants who reported high and low levels of mother–child attachment
were 61.9% and 15.6% respectively. Although 22.6% declined to comment
on this, questioning revealed a low level of mother–child attachment in
this group, and therefore low mother–child attachment totalled 38.2%
(15.6% + 22.6%). In 45.2% of cases, mothers stated that bonding was
not affected by the maid, whereas 30% stated that bonding was affected.
Although 24.2% declined to express their view, further questioning
confirmed their discomfort in answering this question; this suggested that
they did perceive a lack of bonding, and therefore that this affected a total of
54.2% (24.2% + 30%) of households.
Discussion. Although only half of the mothers had careers, a larger
proportion of households had maids, indicating an overdependence of
mothers on domestic aides. The very low proportion of babies who were
Correspondence: Abdulrahman Al-Matary, Children’s Hospital,
King Fahad Medical City, PO Box 59046, Riyadh 11525, Saudi Arabia.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
exclusively breast-fed would suggest that mother–child bonding was
affected in a large proportion of households that bottle-fed. However,
about two-thirds of the mothers claimed high levels of mother–child
bonding, whereas only one-sixth felt that bonding was adversely affected.
The remainder were reluctant to discuss this point, suggesting that the
problem of low levels of mother–child bonding exists. The study found that
almost half of mother–child bonding relationships could be impaired by the
presence of maids.
Conclusion. This study indicates that mother–child attachment is adversely
affected by the presence of maids, which could prove detrimental to the
psychosocial development of affected children and the population of the Gulf
Cooperation Council countries in the long term. Family-friendly work policies
for mothers and education on responsible parenting are recommended.
Introduction
One of the most important relationships in any
child’s life is that shared with his or her primary
caregiver, usually the child’s mother. This is changing
in contemporary Gulf Cooperation Council (GCC)
countries. With increasing national wealth leading
to changes in lifestyle, more families now hire maids,
often recruited from overseas, to assist in daily chores,
which may include child-rearing. This ability to
employ maids has provided a freedom not hitherto
experienced by these households. Consequently,
an increasing number of children are now raised
by maids, even where non-working mothers are at
home. Career responsibilities may also conflict with
maternal duties, by resulting in fewer hours of contact
between mother and child. Although statistics are not
available, the clinical impression perceived by one
of the authors of the present study during routine
paediatrician practice supports this assumption. The
197
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ORIGINAL RESEARCH article
present study examines the level of involvement that
maids have in day-to-day family life, and whether this
has any effect on the strength of the mother–child
attachment or bonding.
Attachment, as defined by the classic study by
Bowlby (reviewed by Bretherton1), is a basic
behavioural system whereby the child seeks the
sanctuary provided by his or her mother through
the establishment of an intimate mother–child
relationship. Previous studies have demonstrated
that the absence of this relationship has devastating
consequences for children’s emotional health.2
The goals of this research were (a) to conduct a pilot
study investigating the increasing dependence of
Saudi mothers on maids to assist them with the
upbringing of their children; (b) to investigate the
level of mother–child attachment in the presence
of a maid; and (c) to study the prevalence of
breastfeeding. The hypothesis being tested was that
the involvement of maids in child-rearing affects
levels of mother–child attachment. The roles that
maids play in society have not been documented
in Saudi Arabia, nor perhaps in the GCC countries
generally, and thus the findings of this study could
have relevance to the entire GCC Arab community.
Materials and methods
A descriptive cross-sectional study was designed
in consultation with an epidemiologist, and was
conducted in Riyadh, Saudi Arabia. A convenience
sample was recruited from three different tertiary
hospitals and shopping centres by health educators
and case managers not involved in the study. In total,
500 questionnaires were distributed, 336 of which
yielded complete data sets. The inclusion criteria of
the sample included living in Saudi Arabia and having
one or more children of at least 1 year of age.
Two measures were administered for the study. First,
the Demographic Data Sheet (DDS) was developed.
The DDS records information such as age, nationality
and education level, and addresses the maid’s
role within the household and the frequency of
breastfeeding. All answers submitted were subject to
statistical analysis. The questionnaires were translated
from English into Arabic and back by a panel of
bilingual experts. This instrument is valid and reliable,
and has a Cronbach’s alpha value of 0.84. Moreover,
the content validity of the revised version of the
DSS was established by national experts, and the
198
construct validity was established using exploratory
factor analysis.
The study was approved by the Institutional Review
Board of the King Fahad Medical City. Participants
were identified and provided with information
regarding the significance and the purpose of
the study. Verbal consent was then obtained. The
participants were assured that participation was
voluntary and that their responses would be treated
in confidence. They were also informed they were free
to withdraw at any time. Anonymity was advocated
in all aspects of data collection. The participants’
identities was neither requested nor required. The
questionnaire was designed to enable completion
within 5–10 minutes.
Completed questionnaires were collected by the
researcher and the data analysed and recorded as
descriptive statistics. The study investigated the
association between the number of maids in a
household (and their responsibilities) and a mother’s
choice of bottle-feeding over breastfeeding. The
study also analysed the relationship between levels of
mother–child attachment and the presence of a maid,
using a mother–child attachment scale. In addition,
any association between the duration, or exclusive
use, of breastfeeding and the employment of a maid
was analysed.
Results
The study recruited 336 mothers with at least one
child of least 1 year of age. The mean age of the
participants was 33 years; the average age at marriage
was 21 years. The majority of the mothers were
married, educated, had moderate to higher incomes
and lived in the capital city, Riyadh. In all, 91% were
married, 87% were educated to secondary school
level or higher, and 78% had a monthly income of
SAR5000 (US$1300) or more. Half of the mothers were
employed, working an average of 8 hours per day,
and 84% lived in Riyadh. The proportion of babies
that were exclusively bottle-fed was 31.5%, with
only 15.7% exclusively breast-fed, and 52.8% both
breast- and bottle-fed (Table 1).
It was determined that 79.9% of the mothers had
one or more maids. Thirty per cent of maids had
responsibility only for cleaning the house; 16% only
looked after the children; and 53% had responsibility
both for cleaning the house and nurturing the
children (Table 1). It was found that, although almost
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:197–204 (http://dx.doi.org/10.7707/hmj.v6i2.119)
ORIGINAL RESEARCH article
TABLE 1  Sociodemographic characteristics of the sample
80% of the households employed a maid, only 50% of
the mothers had careers.
Sample characteristics
n (% of sample)
Mean age
Mean age at marriage
Level of education
Less than secondary
Secondary
Diploma
Bachelor degree
Masters degree or above
Total tertiary
Total
Marital status
Married
Divorced
Widowed
Total
Residency
In Riyadh
Outside Riyadh
Total
Occupation
Employed
Unemployed
32.79
21.08
Total
Mean number of working hours per day
Monthly income (SAR)
< 3000
3000–4999
5000–9999
10 000–14 999
15 000–19 999
20 000 and over
Total
Feeding type
Breastfeeding
Bottle-feeding
Both
Total
Availability of domestic aid
Available
Unavailable
Total
Responsibilities of the maid
Clean home only
Nurture children only
Cleaning and nurturing
Total
334
7.99
About 16% of the mothers felt that their children did
not meet their expectations. Eleven per cent believed
that their children made their lives difficult, 18.2%
of the mothers had feelings of anger towards their
children and 70.6% (100 – 29.4 = 70.6%) believed that
their children were impatient. From these responses it
was calculated that the overall level of mother–child
bonding is high, in the order of 61.9%.
20 (6.1)
51 (15.6)
111 (33.6)
84 (25.5)
43 (13.0)
21 (6.4)
330
When questioned about the impact of hiring a maid
on their relationship or bonding with their children,
30.4% of mothers agreed that the relationship was
negatively affected, and a large proportion (24.2%)
declined to answer the question. The remaining
45.2% of mothers claimed that their relationship with
their children was not affected by the presence of a
maid (Table 3).
43 (13.0)
108 (32.5)
58 (17.5)
104 (31.3)
19 (5.7)
181 (54.5)
332
303 (90.7)
22 (6.6)
9 (2.7)
334
278 (84.0)
53 (16.0)
331
169 (50.6)
165 (49.4)
51 (15.7)
102 (31.5)
171 (52.8)
324
267 (79.9)
67 (20.1)
334
81 (30.5)
43 (16.2)
142 (53.4)
266
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
The results based on the mother–child attachment
scale can be seen in Table 2. The table shows the
phrases with which participants were asked to agree
or disagree, and the mothers’ responses. These results
show that 5.7% of the mothers believed that their
children did not love them, while 57% said that they
cannot bear to be separated from their children for
short periods of time. It was found that 20.7% of the
mothers have experienced difficulties in raising their
children; 22.1% became worried if their children
were not with them; and 14% felt annoyed by their
children. It can be seen that 70.7% of the mothers
were extremely proud of their children, even though
only 11.4% believed that their children have great
futures. About 12% of the mothers said that their
children did not obey them, and 16.1% found their
children troublesome.
Discussion
Increasing levels of education have enabled women
to enter the workforce, which results in less time
being available to devote to child-rearing (although
the additional income earned by most of these
mothers may not be essential for the well-being of the
family). Women have the right to an education and
subsequently to a career; however, the recruitment
of maids appears to have promoted a shift away
from traditional Arab family values, which have been
regarded as binding households together and leading
to the creation of well-balanced individuals with
strong family ties and interpersonal relationships.
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ORIGINAL RESEARCH article
TABLE 2  Mother–child attachment scale (English translation of the Arabic questionnaire)
Comment
Number reporting a high level of mother–
child attachment (% of sample)
Number declining to Number reporting a low level
respond (% of sample) of mother–child attachment
It seems that this child obeys me
This child has troubled me a lot
This child fulfils all of my expectations
This child has increased our difficulties
I am angry with this child
This child is very affectionate towards me
This child seems to be promising
This child has a lot of patience
Total scores
194 (57.9)
196 (58.5)
177 (52.8)
234 (69.8)
208 (62.1)
231 (69)
211 (63)
125 (37.3)
3108 (61.9)
101 (30.1)
85 (25.4)
105 (31.3)
64 (19.1)
66 (19.7)
69 (20.6)
100 (29.9)
111 (33.2)
1133 (22.6)
40 (12)
54 (16.1)
53 (15.8)
37 (11.0)
61 (18.2)
35 (10.5)
24 (7.2)
98 (29.4)
782 (15.6)
TABLE 3  The impact of hiring a maid on the mother–child relationship (English translation of the Arabic questionnaire)
Question
Disagree [n (%)] No response [n (%)] Agree [n (%)]
Do you think the relationship between you and your child is negatively affected by the
presence of a housemaid?
Does your child falls asleep quickly and easily with the housemaid?
After hurting him/herself, your child becomes quiet if the housemaid holds him/her.
Total scores
106 (44.1)
61 (25.42)
73 (30.42)
138 (47.75)
117 (43.82)
361 (45.35)
75 (25.95)
57 (21.35)
193 (24.25)
76 (26.3)
93 (34.83)
242 (30.40)
These strong family ties are perceived to have waned
over the last two decades. This could be attributed in
part to the hiring of maids, among other factors.
Mothers who choose to breastfeed have higher levels
of maternal–fetal attachment.3 The emotional state of
the mother during pregnancy, and the level of social
support received during that time, are related to the
mother’s ability to bond with her child both during
and after pregnancy.4 Some studies have found that
attachment begins in the womb, and women with
higher levels of maternal–fetal attachment are more
likely to breastfeed than those with lower levels of
maternal–fetal attachment.3
In the present study, a very high proportion of
babies (31.5%) were entirely bottle-fed. According
to Hawwas,5 Islamic law requires breastfeeding for
a minimum of 2 years. Only 15.7% of the babies in
this study were exclusively breastfed. It was found
that about 53% of mothers both breastfed and
bottle-fed their babies. If the last two figures are
combined, it could be assumed that around 69%
of mothers breastfed; however, it is not completely
certain that those who both bottle- and breastfeed
do not resort to bottle-feeding most of the time. The
investigator’s impression after questioning mothers
was that most babies in the �bottle- and breastfed’
200
group were usually bottle-fed, so that within this
group bottle-feeding is the norm. In any event, the
low proportion of mothers using breastfeeding alone
suggests a very low level of breastfeeding, which
does not satisfy the Saudi government’s call for levels
of breastfeeding to be in the order of > 60%. The
results of the present study showed that the absence
of the mother tends to affect breastfeeding, which
agrees with a recent study that reviewed mothers
suffering from asthma who were unable to breastfeed
during the course of their treatment.6 Several
respondents indicated that short maternal leave
prevented breastfeeding.
Interestingly, very few studies worldwide have
examined the impact of live-in domestic staff on
mother–child attachment. The findings of the present
study demonstrate the development of a unique and
disconcerting lack of firm mother–child attachment
in a select population of households employing
maids in Saudi Arabia; this is also relevant to all GCC
countries in which the employment of overseas maids
is widespread. The results indicate that the level of
attachment is lower when a maid is present. Even
though the majority of households have maids, only
about half the mothers in the study have a career. This
indicates that the low attachment between a mother
and her child is generally not caused by the absence
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:197–204 (http://dx.doi.org/10.7707/hmj.v6i2.119)
ORIGINAL RESEARCH article
of the mother due to career commitments, but rather
an overdependence on the maid to look after the
children even when the mother is at home. Indeed, it
is not uncommon to find the baby left almost totally
in the care of the maid in households where the
mother has no career commitments, a practice which
may negatively affect the psyche of the child.
This should not imply that refraining from employing
maids will be the correct course of action. Maids
undeniably perform a valuable service; however, their
presence appears to have the potential to undermine
mother–child bonding, with serious potential
long-term psychosocial implications for the GCC Arab
society. The negative implications for the child could
have far-reaching consequences, well beyond poor
mother–child bonding. The education of mothers in
parenting skills to foster mother–child attachment
is recommended, as opposed to abandoning the
employment of maids. As well as performing an
important role in assisting with household chores,
maids contribute significantly to the economy of their
own, usually less affluent, countries; in turn, this helps
foster strong relationships between the provider and
host countries. There are, therefore, positive aspects
of hiring domestic staff. However, mothers in GCC
countries must be more actively involved in raising
their children to ensure their healthy development.
Studies have shown that the strength of a child’s
attachment to his or her parent is related to anxiety
symptoms.7 The importance of the presence of an
attachment figure has been found to increase with
age,3 through mid-childhood and adolescence.
Therefore, the continued presence of an attachment
figure is important to the emotional security and
development of a child. Employment visas are valid
for 2 years in Saudi Arabia and, indeed, all GCC
countries provide only limited periods of residence
for maids. The visa is extendable; nevertheless,
most maids choose to move elsewhere or return
to their home countries at the end of the contract.
Following the departure of a maid, a replacement
is usually engaged. Based on current findings and
past, unmeasured, observations, it appears that
the child bonds with the maid more strongly than
with the mother, and with the departure of the
maid at the end of her contract the child is left
without this emotional support. With the arrival of
another maid, the child must establish a new bond,
which is again lost at the end of the replacement
maid’s contract, and so on. This situation results in
a disorganized pattern of attachment during early
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
childhood similar to that seen in challenged mothers8
(e.g. handicapped mothers, those with a poor
education, single mothers) and could have serious
consequences and implications.9
This lack of attachment could result in a sense of
insecurity in the child, and impair his or her normal
psychological development; as a consequence, a
pathological state of varying degrees of insecurity
could manifest in future generations in the GCC
countries. The major causes of insecurity in childhood
have been described.10,11 These include physical and
emotional neglect; physical or emotional abuse;
separation from the primary caregiver; changes in the
primary caregiver, that is, contact with a succession
of maids or staff at day-care centres; frequent moves
or placements, especially in orphanages or foster
homes; traumatic experiences; maternal depression
or withdrawal (caused by a number of factors); and
inexperience or a lack of parenting skills on the part
of the mother. Poor emotional attachment during
childhood may lead to difficulties in forming lasting
interpersonal relationships in adult life, which could
impair an individual’s ability to get on with others. It
may also contribute to high divorce rates as affected
individuals struggle to form lasting relationships, and
could even lead to increased crimes rates. Another
possible outcome of a lack of maternal care in
childhood is obesity,12,13 and possibly other diseases
not yet known to be associated with this problem.
In the present study, maternal employment does
not appear to be the cause of poor mother–child
attachment, but rather an overdependence on maids
to look after children.
Another interesting finding concerns the percentage
of mothers who chose not to respond to questions
about pride, love and anger in relation to their
children. This may suggest the mothers either did
not know how to respond or were afraid to agree
with negative statements about their children. Given
the prevailing cultural conditions, it is suspected
that these mothers do not wish to acknowledge any
negative impact on the mother–child relationship
caused by the presence of a maid, and therefore
did not answer the question. If this assumption is
correct, and the proportion of mothers declining to
answer is added to the proportion who agreed that
bonding between mother and child was adversely
affected, then around half the study population
(54.8%) can be said to be affected by impaired
mother–child bonding.
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ORIGINAL RESEARCH article
In addition, some maids may be very young girls
with no experience of working with children. No
reliable source of data can be obtained on the ages
of maids. Documents prepared by the International
Labour Organization and the Philippine Institute of
Development Studies suggest that the minimum age
of maids is around 18 years;14,15 however, newspaper
reports suggest that maids as young as 16 years of
age are employed in the United Arab Emirates.16
These maids are not trained childminders, but rather
housekeepers in charge of both the upkeep of the
home and the care of the children. Leaving babies in
the care of untrained workers could have negative
long-term consequences.
study should test specific factors that affect the
mother–child attachment in the context of the Saudi
Arabian and GCC culture and lifestyle.
It is common knowledge that, in some countries,
employers may provide childcare facilities within their
premises so that mothers can frequently interact with
their children. This enhances mother–infant bonding
and helps to ensure the healthy development of
the infant. It is suggested that employers in the GCC
countries and elsewhere should consider providing
such childcare facilities to allow regular visits to the
children by their mothers. This is supported by the
finding that mothers who work part-time appear to
raise their children better than mothers who work
full-time.17 Government family-friendly work policies,
providing longer maternity leave and education on
responsible parenting, may be required and could be
an important consideration for promoting healthy
family lifestyles and early childhood well-being. The
GCC employment system should consider allowing
working mothers to work part-time or flexible
hours while receiving full-time pay (as practised in
Australia), allowing them to devote more time to
child-rearing to ensure the mental and physical health
of future generations. The healthy development of
our children begins with the security that they feel in
their relationships with their primary caregivers.
Acknowledgements
To date, no comparable studies have been published
on the relationship between the presence of maids
and compromised maternal–child attachment in
Saudi Arabia, and perhaps throughout the GCC
countries. This study has shown a need for more
research examining mother–child attachment in
Saudi Arabia and elsewhere in the GCC, and for a
more in-depth look at the effect that the presence
of maids has on family dynamics and on the
psychological development and well-being of the
affected child, as well as the future ability of that child
to form lasting relationships. In addition, a follow-up
202
Conclusion
This study highlights that the attachment between
mother and child is affected by the employment of
maids for the purpose of child-rearing. This could
prove detrimental to the psychosocial development
of affected children and the population of the GCC
countries in the long term. Family-friendly work
policies for mothers and education on responsible
parenting are recommended.
The authors express gratitude to Mr Ahmed Shorman,
Pediatric Intensive Care Unit (PICU), for designing
the survey questionnaire, and to Mr Mohammad Riaz
of the Research and Scientific Publications Centre
and Ms Eman Al-Amodi, Department of Dietetics, for
their assistance with the statistical analyses and the
distribution of questionnaires respectively.
Disclosure
The authors have no conflicts of interest whatsoever
with regard to funding, commercial interests, etc.
Ethical approval
This work was performed with the informed consent
of the subjects and the approval of the King Fahad
Medical City Institutional Review Board (No. 10-037,
dated 19 May 2010).
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Hamdan Medical Journal  2013; 6:205–208 (http://dx.doi.org/10.7707/hmj.v6i2.208)
 
Original Research article
How many renal colic patients undergo the
recommended computed tomography? The Pennine
Acute Trust Audit
William Evans, Helen Pollitt and Anthony Kodzo-Grey Venyo
Urology Department, North Manchester General Hospital, Manchester, UK
Abstract
Non-contrast computed tomography (NCCT) is recommended by the
British Association of Urological Surgeons (BAUS) guidelines for suspected
renal calculi as this form of imaging offers kidney stone identification in
> 99% of cases. We used the picture archiving and communications system
(PACS) and automated letter systems to determine how many of the
144 patients admitted to the surgical triage unit (STU) at North Manchester
General Hospital over the course of 14 months did in fact have renal colic,
which radiological investigations were performed, how many patients
with suspected renal colic underwent NCCT within 24 hours or 48 hours
and how many underwent intervention. We found that only 19.8% of
patients underwent NCCT within 24 hours and 22.9% within 24–48 hours.
However, only three patients (3.12%) required an intervention related to
this presentation. These low rates of intervention support the conclusions of
other authors who believe that a combination of ultrasound and abdominal
radiography in cases of suspected renal colic may be preferable to NCCT,
which is costly and potentially harmful.
Introduction
Non-contrast computed tomography (NCCT) is the
gold standard investigation for suspected renal calculi
as it offers kidney stone identification in > 99% of
cases. The British Association of Urological Surgeons
(BAUS) guidelines1 recommend that NCCT should
be performed within 24 hours of first presentation
of suspected renal colic. However, critics maintain
that NCCT is overused as the condition is not
life-threatening and the majority of kidney stones less
than 5 mm pass spontaneously.2
Correspondence: Anthony Kodzo-Grey Venyo, Urology
Department, North Manchester General Hospital, Manchester, UK.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
The preferred imaging for this clinical presentation
has changed over the past two decades, with
intravenous urography (IVU) being the investigation
of choice in the 1990s. However, as computed
tomography (CT) imaging improved and became able
to detect renal calculi at an increased rate, IVU was
phased out. A study by Eikefjord et al.3 found that CT
was not only more cost-effective than IVU, but also
more effective at detecting renal calculi.3
Non-contrast computed tomography is also
expensive compared with imaging modalities such
as abdominal radiography and abdominal ultrasound
and an additional drawback is the potentially
harmful effects of the radiation dose involved. Even
if a kidney stone has been found, it is by no means
likely that urological intervention will be needed.4
It has been suggested that, in order to minimize
the exposure to radiation, a viable alternative
needs to be found. If a positive CT rarely changes
management, or results in any form of intervention,
is it strictly necessary? Indeed, studies have shown
that ultrasound combined with radiography is able
to identify clinically significant kidney stones and is
an effective predictor of the need for intervention.5,6
Studies suggest that, even in patients with known
nephrolithiasis, repeat CT changes the management
of only a small number of cases.7
This audit aimed to discover how many of the patients
admitted to the surgical triage unit (STU) at North
Manchester General Hospital had scans in keeping
with the current guidelines, but to also discover how a
positive scan changed overall management.
205
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Original Research article
Methods
Our audit group looked at 144 patients admitted to
the STU at North Manchester General Hospital with
suspected renal colic between November 2010 and
January 2012 (Figure 1). The picture archiving and
communications system (PACS) and automated letter
systems were used to find out how many of these
patients did in fact have renal colic, what radiological
investigations were performed, how many patients
with suspected renal colic underwent NCCT within
24 hours, 48 hours and 6 months and how many
underwent further intervention.
Results
Of the 96 patients who presented for the first time
with renal colic, only 19 patients (19.8%) underwent
NCCT within 24 hours (Table 1 and Figure 2).
Fifty-nine patients (61.5%) underwent NCCT within
6 months of presenting with renal colic and three
patients required surgical/radiological intervention
(two underwent NCCT within 24 hours of presenting
with renal colic and one did so 1 month after
presentation). The most popular investigations were
abdominal radiography, carried out in 86.5% of
patients, and abdominal ultrasound, performed in
31 patients (32.3%).
Discussion
From this audit, it appears that, despite the BAUS
guidelines, very few patients presenting with
suspected renal colic are receiving the advised
TABLE 1  Summary of investigations and interventions
performed on the patient group
Abdominal radiography
Abdominal ultrasound
Other (magnetic resonance
imaging, pelvic ultrasound, chest
radiography)
NCCT < 24 hours
NCCT within 24–48 hours
Outpatient NCCT
48 hours–6 months
Number of patients requiring
surgical/radiological intervention
206
Number of patients
having study/
intervention at first
presentation
Percentage
83
31
12
86.5%
32.3%
12.5%
19
22
18
19.8%
22.9%
18.8%
3
imaging within 24 hours as recommended. In fact,
only slightly over half had the scan within 6 months
of initial presentation. However, through this audit
we demonstrate that, for this group of patients, there
is a relatively low rate of urological or radiological
intervention following scanning. In this study, only
two patients who had underwent the recommended
CT imaging within 24 hours actually went on to
receive any sort of intervention. Of those patients
who did not undergo CT imaging within 24 hours, one
required subsequent intervention. These results beg
the question of whether this imaging is required.
Studies have shown that a combination of
radiography and ultrasound is effective in identifying
patients at high risk of requiring intervention.5,6 It is
important to consider the real need for CT scans if
there is a viable alternative that can reduce exposure
and be performed at a lower expense. In this audit,
86.5% of patients underwent abdominal radiography
but ultrasound of the abdomen was performed in
only 32.3% (Table 1 and Figure 2). It appears that
most patients who present with abdominal pain
with renal colic as one of the differential diagnoses
undergo abdominal radiography. It can be argued
that if patients automatically receive this imaging,
bearing in mind the studies mentioned above,
it would be more cost-effective to subsequently
order an ultrasound of the abdomen. From these
data, it appears that relatively few patients undergo
ultrasound at any point and it can be argued that
this is therefore an underused diagnostic tool
as, when used in combination with radiography,
ultrasound can effectively predict who is at low risk of
requiring intervention.
Henderson8 argues that the use of diagnostic
radiation has become excessive and draws attention
to the work of Katz et al.,9 who found that 4% of the
patient population studied underwent unenhanced
3.13%
FIGURE 1  Schematic of patients included in study.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:205–208 (http://dx.doi.org/10.7707/hmj.v6i2.208)
Original Research article
FIGURE 2  Bar chart showing percentage of group who received each investigation/intervention.
CT on three or more occasions and were exposed to
between 20 and 154 mSv of radiation.
However, it cannot be denied that CT is a highly
effective method of diagnosing renal calculi. Studies
comparing CT scanning with other imaging methods
have found it to be superior. A study conducted
by Mitterberger et al.10 found that CT identified
the calculus in 100% of patients with confirmed
renal calculi, with 100% specificity and sensitivity.
These patients also underwent radiography and
ultrasound, and this combination was 96% sensitive
and 91% specific. This shows that, although there are
alternatives that have high success rates, CT is still
superior in its ability to detect smaller kidney stones.10
Computed tomography also has a use in identifying
alternative diagnoses in patients who do not have
renal calculi. Owing to the nature of the scan, it
provides information about more than just the renal
tract. One study found that, of 1035 patients who
underwent CT for suspected renal colic, 14% had
non-kidney stone-related pathology necessitating
treatment and 68% had calculi coupled with a
second pathology.11
A study conducted in 2007 comparing the diagnostic
ability of standard-dose and low-dose CT in patients
with a body mass index (BMI) of under 30 kg/m2 and
kidney stones over 3 mm found that the sensitivity
and specificity of low-dose CT were very similar
to those of standard-dose CT.12 A second study
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
found similar results, reporting that there was no
significant difference in the results from low-dose and
standard-dose scanning for kidney stones over 2 mm
in size.13
One possible compromise seems to be the use of
radiography and ultrasound to risk stratify patients
to determine which are at high risk of requiring
intervention and then consider the need for CT. This
will undoubtedly increase the length of time between
presentation and the CT; however, it does seem
pertinent to have a concrete risk stratification system
before ordering potentially harmful scans.
A useful addition to this audit would be to include
a section reporting on the final diagnosis of these
patients and also the findings from CT. This audit
included data from all patients who presented to
the STU and in whom renal colic was legitimately
considered in the differential diagnoses at first
presentation. The final diagnosis (or lack thereof )
was not included in the audit pro forma. Thus,
CT of the kidneys, ureters and bladder (KUB) may
not have been considered necessary once further
investigation was undertaken. It may also be useful
to include further details of the patient’s presenting
complaint, and it would be valuable to know which
presenting symptoms were more likely to result in CT.
Some studies3,4,9 have found that women presenting
with flank pain are a particularly difficult diagnostic
group. One study which looked at the positive rate
in patients who underwent CT for suspected renal
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Original Research article
colic found that the positive rate was much lower
in women, who were therefore needlessly exposed
to radiation.3 It would be valuable to differentiate
between the sexes in this audit in order to see how
sex affects prognosis and therefore the value of CT.
5
6
Conclusion
This study showed that, within the Pennine Acute
Trust, a mere 19.8% received the recommended
imaging within the recommended time period.
However, with studies5,6 showing the efficacy of
a combination of abdominal radiography and
ultrasound, the question remains whether CT
imaging is necessary considering the efficacy of
other investigations and the small numbers requiring
intervention. Is it purely academic to subject the
patient to CT when there are effective, cheaper and
less harmful alternatives?
7
8
9
10
References
1
2
3
4
208
British Association of Urological Surgeons (BAUS)
guidelines for acute management of first presentation
of renal/ureteric lithiasis. December 2008 (reviewed
2012). URL: http://www.baus.org.uk/AboutBAUS/
publications/stones-guidelines (accessed 5 May 2013).
Parmar MS. Kidney stones. BMJ. 2004; 328:1420–4.
http://dx.doi.org/10.1136/bmj.328.7453.1420
Eikefjord E, Askildsen JE, RГёrvik J. Cost-effectiveness
analysis (CEA) of intravenous urography (IVU) and
unenhanced multidetector computed tomography
(MDCT) for initial investigation of suspected acute
ureterolithiasis. Acta Radiol 2008; 49:222–9.
http://dx.doi.org/10.1080/02841850701708304
Irving HC, Panditaratne N, Patatas K, Wah TM, Weston
MJ. Emergency department imaging protocol for
suspected acute renal colic: re‐evaluating our service.
Br J Radiol 2012; 85:1118–22.
http://dx.doi.org/10.1259/bjr/62994625
11
12
13
Ekicis S, Sinanoglu O. Comparison of conventional
radiography combined with ultrasonography versus
non-enhanced helical computed tomography in
evaluation of patients with renal colic. Urol Res 2012;
40:543–7.
http://dx.doi.org/10.1007/s00240-012-0460-8
Edmonds ML, Yan JW, Sedran RJ, McLeod SL, Theakston
KD. The utility of renal ultrasonography in the diagnosis
of renal colic in emergency department patients.
CJEM 2010; 12:201–6.
Goldstone A, Bushnell A. Does diagnosis change as a
result of repeat renal colic computed tomography scan
in patients with a history of kidney stones? Am J Emerg
Med 2010; 28:291–5.
http://dx.doi.org/10.1016/j.ajem.2008.11.024
Henderson S. Point: diagnostic radiation: why aren’t we
stopping (or at least slowing down)? West J Emerg Med
2008; 9:118–19.
Katz SI, Saluja S, Brink JA, Forman HP. Radiation dose
associated with unenhanced CT for suspected renal
colic: impact of repetitive studies. AJR Am J Roentgenol
2006; 186:1120–4.
http://dx.doi.org/10.2214/AJR.04.1838
Mitterberger M, Pinggera GM, Pallwein L, et al.
Plain abdominal radiography with transabdominal
native tissue harmonic imaging ultrasonography vs
unenhanced computed tomography in renal colic.
BJU Int 2007; 100:887–90.
http://dx.doi.org/10.1111/j.1464-410X.2007.07048.x
Hoppe H, Studer R, Kessler T, Vock P, Studer U, Thoeny
H. Alternate or additional findings to stone disease on
unenhanced computerized tomography for acute flank
pain can impact management. J Urol 2006; 175:1725–30.
http://dx.doi.org/10.1016/S0022-5347(05)00987-0
Poletti P, Platon A, Rutschmann O, Schmidlin F, Iselin C,
Becker C. Low-dose versus standard-dose CT protocol
in patients with clinically suspected renal colic. AJR Am J
Roentgenol 2007; 188:927–33
http://dx.doi.org/10.2214/AJR.06.0793
Kim BS, Hwang IK, Choi YW, et al. Low-dose and
standard-dose unenhanced helical computed
tomography for the assessment of acute renal colic:
prospective comparative study. Acta Radiol 2005;
76:756–63.
http://dx.doi.org/10.1080/02841850500216004
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:209–220 (http://dx.doi.org/10.7707/hmj.v6i2.224)
 
ORIGINAL RESEARCH ARTICLE
Prenatal screening for fetal aneuploidies during the
first and second trimester of pregnancy
Shiefa Sequeira and Shweta Uppal
SRL Diagnostics Private Limited, Fortis Healthcare Enterprise, Dubai Healthcare City,
Dubai, United Arab Emirates
Abstract
Prenatal screening for chromosomal defects during the first and second
trimesters of pregnancy has become an established part of obstetric
practice in many countries. The goal of current maternal serum screening
programmes is to identify women who are at an increased risk of having
a baby affected with Down syndrome (trisomy 21), Edwards syndrome
(trisomy 18) or neural tube defects and who will benefit from such diagnostic
tests. The most commonly used test for genetic diagnosis is amniocentesis;
however, the rate of spontaneous fetal loss caused by this test averages at
about 1 in every 200 procedures. Because of this risk, serum analyte testing
has become an important and non-invasive first step in detecting patients
at risk of carrying a child with congenital abnormalities. The non-invasive
screening options which are currently available to patients include combining
maternal age with one of the following: first-trimester serum screening
[nuchal translucency (NT) and maternal serum biochemistry markers];
second-trimester serum screening (maternal serum biochemistry markers
such as the triple test and the quadruple test); or the two-step integrated
screening, which comprises first- and second-trimester serum screening with
or without NT.
Introduction
Pregnancy screening for fetal aneuploidy began
during the 1960s,1 using maternal age as the
screening test. With the development of new
serum biochemistry markers in the 1980s,2 the
triple screening test (conducted during the second
trimester of pregnancy) became the most prominent
screening tool and demonstrated a substantial
improvement in detection rates of Down syndrome
compared with the previous method of screening
using maternal age alone. The detection rate
Correspondence: Shiefa Sequeira, SRL Diagnostics Private Limited,
Fortis Healthcare Enterprise, Number 64, Al Razi, Unit 1007, Block A,
Dubai Healthcare City, PO Box 505143, Dubai, United Arab Emirates.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
improved from 30% by screening using maternal age
alone to 65% by combining maternal age and the
triple test, with a false-positive rate (FPR) of 5%. In the
1990s, the emphasis shifted from second-trimester
to first-trimester screening when it was realized that
the majority of fetuses with aneuploidies could be
identified by screening based on a combination of
maternal age, fetal nuchal translucency (NT) and
maternal serum biochemistry [i.e. levels of free
beta-human chorionic gonadotropin (free ОІ-hCG) and
pregnancy-associated plasma protein A (PAPP-A)].
The risk of developing some of the fetal chromosomal
abnormalities increases with maternal age
(Table 1), and pregnant women who will be older
than 35 years at time of parturition are routinely
offered invasive prenatal diagnostic testing. The
most commonly used tests for genetic diagnosis
are chorionic villous sampling (CVS) in the first
trimester and amniocentesis in the second trimester;
however, the rate of spontaneous fetal loss related
to amniocentesis or CVS averages at about 1 in every
200 procedures.3 Because of this risk, serum analyte
testing has become an important and non-invasive
first step in detecting women at risk of having a
baby with congenital abnormalities. The goal of
prenatal screening is to identify women who are
at an increased risk of having a baby affected with
aneuploidy and who will benefit from diagnostic
testing. Maternal screening has the added benefit
of reducing the number of normal pregnancies lost
because of the complication of an invasive procedure.
Currently available non-invasive screening options
include maternal age combined with one of
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209
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ORIGINAL RESEARCH ARTICLE
TABLE 1  Estimated risk of a fetus developing Down syndrome, Edwards syndrome or Patau syndrome in relation to
maternal age and number of weeks’ gestation (adapted from references 4–7)
Maternal age (years)
Syndrome
20
25
Down syndrome
Number of weeks' gestation
1068 946
12a
1200 1062
16a
1295 1147
20a
1527 1352
40a
Edwards syndrome
Number of weeks' gestation
2484 2200
12a
a
3590 3179
16
4897 4336
20a
18 013 15 951
40a
Patau syndrome
Number of weeks' gestation
7826 6930
12a
a
11 042 9778
16
14 656 12 978
20a
42 423 37 567
40a
30
31
32
33
34
35
36
37
38
39
40
41
42
626
703
759
895
543
610
658
776
461
518
559
659
383
430
464
547
312
350
378
446
249
280
302
356
196
220
238
280
152
171
185
218
117
131
142
167
89
100
108
128
68
76
82
97
51
57
62
73
38
43
46
55
1456
2103
2869
10 554
1263
1825
2490
9160
1072
1549
2114
7775
891
1287
1755
6458
725
1047
1429
5256
580
837
1142
4202
456
659
899
3307
354
512
698
2569
272
393
537
1974
208
300
409
1505
157
227
310
1139
118
171
233
858
89
128
175
644
4585
6470
8587
24 856
3980
5615
7453
21 573
3378
4766
6326
18 311
2806
3959
5254
15 209
2284
3222
4277
12 380
1826
2576
3419
9876
1437
2027
2691
7788
1116
1575
2090
6050
858
1210
1606
4650
654
922
1224
3544
495
698
927
2683
373
526
698
2020
280
395
524
1516
Table numbers refer to 1 in every number presented e.g. at maternal age 20 and 12 weeks’ gestation, the risk of having a baby with Down syndrome is 1 in every 1068 pregnancies.
a
the following: first-trimester serum screening
(NT and maternal serum biochemistry markers);
second-trimester serum screening (maternal
serum biochemistry markers – triple test or the
quadruple test); or two-step integrated screening,
which comprises first- and second-trimester serum
screening with or without NT (Figure 1).
First-trimester screening test
First-trimester screening is performed at a gestation
of between 10 weeks and 13 weeks 6 days and was
first suggested by Brizot et al.8 in 1994. The markers
used to calculate the risk of the fetus developing
abnormalities are two serum markers: PAPP-A
and free ОІ-hCG. A third marker is fetal NT (a fluidcontaining area at the back of the fetal neck), which
is identified by ultrasonography. NT measurement
needs to be carried out by experienced sonographers
at a gestation of between 10 weeks and 13 weeks
6 days.
First-trimester screening allows early diagnosis of
chromosomal abnormalities such as Down syndrome
(trisomy 21), Edwards syndrome (trisomy 18) and
210
Patau syndrome (trisomy 13). The detection rate for
Down syndrome is 91% with an associated FPR of 5%.
For an equivalent FPR, the detection rate of screening
using maternal age alone is 30% and screening
using maternal age plus the serum biochemistry test
gives a detection rate of 65% for Down syndrome
(Table 2).9,10 This method also identifies 94% of
all major chromosomal defects, such as Edwards
syndrome, Patau syndrome, triploidy and Turner
syndrome, and 60% of other chromosomal defects
such as deletions, partial trisomies, unbalanced
translocations and sex chromosome aneuploidies
other than Turner syndrome.11 To assess the patientspecific risks, the a priori maternal age-related risk is
multiplied by a likelihood ratio, which is determined
from the deviation of the measured NT, free ОІ-hCG
and PAPP-A from their expected medians.
Biochemical markers during the first
trimester of pregnancy
A number of changes have been observed in the level
of hormones in the body during a normal human
pregnancy, from very early gestation to parturition,
and even beyond. Many hormonal proteins are
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:209–220 (http://dx.doi.org/10.7707/hmj.v6i2.224)
ORIGINAL RESEARCH ARTICLE
FIGURE 1  Maternal serum screening during first and second trimester of pregnancy.
TABLE 2  Detection rate of Down syndrome, Edwards syndrome and Patau syndrome during the first trimester of pregnancy
(adapted from reference 9)
Screening policy
Down syndrome (FPR 5%)
Maternal age and fetal NT
80
65
Maternal age and serum free ОІ-hCG and PAPP-A
Maternal age, NT and serum free ОІ-hCG and PAPP-A 91
created, or modified, by the placenta; however, the
level of these hormonal proteins differs in cases of
pathological pregnancies and may be monitored to
provide a diagnosis or a risk prediction for developing
gestational diseases, taking into account hormone
levels as well as any pre-existing maternal risk factors.
The excessive release of some placental hormones
in association with gestational diseases may be part
of an adaptive response from the placenta and fetal
membranes to adverse environmental conditions,
such as hypertension, hypoxia and infection, or to
malformations of the fetus and placenta. A high
concentration of these hormones in the maternal
peripheral blood, in the fetal (cord) blood and in
the amniotic fluid is a clinical sign of increased
placental hormone synthesis. The discovery of these
slight differences in protein levels in pathological
and non-pathological pregnancies forms the basis
for using these proteins as biochemical markers in
screening protocols. During biochemical testing,
each element being measured is first converted
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Edwards syndrome (FPR 0.5%) Patau syndrome (FPR 0.5%)
68
80
97
61
59
84
in to a multiple of the expected normal median
(MoM), which is specific to fetal gestational age,
maternal weight, ethnicity, smoking status, method
of conception and parity as well as the machine and
reagents used for the assay. In euploid pregnancies,
the average adjusted value for both free ОІ-hCG and
PAPP-A is 1.0 MoM at all gestational ages.12
Pregnancy-associated plasma protein A
Plasma-associated protein A is a large zinc-containing
glycoprotein that is produced by both the placental
syncytiotrophoblast13 and the decidua and is located
on human chromosome 9q33.1.14 It belongs to the
alpha-macroglobulin plasma protein group, which
was first identified in 1974 in the plasma of a pregnant
woman. The protein is secreted as a disulphide-bound
homodimer with a molecular weight of 400 kDa.
In the plasma, PAPP-A circulates either in the free
form or as a heterotetrameric complex of the
proform of eosinophil major basic protein (proMBP)
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ORIGINAL RESEARCH ARTICLE
forming PAPP-A/proMBP with a molecular weight of
approximately 500 kDa.14,15 During pregnancy, both
PAPP-A and proMBP are expressed in abundance
in the placenta but they are each expressed in
different cell types. Most of the PAPP-A is synthesized
in the placental syncytiotrophoblast whereas all
of the proMBP is synthesized in the extravillous
cytotrophoblasts, from where it is secreted
without propeptide cleavage. The processes of the
PAPP–A/proMBP complex occur in the extracellular
environment and, to the best of our knowledge, at
the surface of syncytiotrophoblast. During a normal
pregnancy, the concentration of PAPP-A in the
maternal circulation increases with increasing fetal
gestational age. PAPP-A becomes detectable soon
after zygote implantation and increases throughout
the pregnancy, doubling every 3–4 days during the
first trimester. As a result of the rapid increase in
PAPP-A during the first trimester, the level of this
protein is closely related to gestational age and it is
common practice to express PAPP-A concentration
in terms of MoM. In addition to gestational age,
a number of maternal and pregnancy-associated
characteristics such as smoking, multiple parity,
diabetes mellitus and maternal weight also affect the
maternal serum concentration of PAPP-A.
The most important clinical use of PAPP-A is
the first-trimester screening for chromosomal
abnormalities that are characterized by a low
concentration of PAPP-A. Decreased levels of PAPP-A
are found in association with abnormal placental
function, which has formed the basis for the
first-trimester screening for fetal Down syndrome. The
purpose of these programmes is to identify pregnant
woman who should be offered diagnostic CVS or
amniocentesis. PAPP-A concentrations are 100-fold
and 1000-fold lower in fetal blood and amniotic fluid,
respectively, than in maternal blood and the amniotic
fluid of a non-Down syndrome fetus. Low PAPP-A
values during the first trimester have been observed
and are typically 0.15 MoM for Down syndrome,
0.18 MoM for Edwards syndrome, 0.25 MoM for Patau
syndrome and 0.49 for Turner syndrome.16 Low levels
of PAPP-A have also been associated with preterm
delivery, intrauterine growth retardation, miscarriage,
stillbirth, small for gestational age infants and ectopic
gravidity.17,18
212
Free beta-human chorionic gonadotropin
In 1990, Macri et al. reported that maternal serum
ОІ-hCG is elevated in Down syndrome pregnancies.19
In 1995, Eldar-Geva et al. reported that, although the
production of each subunit’s hCG messenger RNA
(mRNA) is increased in Down syndrome pregnancies,
ОІ-subunit production is more markedly increased.20
These findings suggests that the free ОІ-hCG subunit
might be superior to hCG for detection of Down
syndrome. Various authors have reported that
screening for elevated levels of free ОІ-hCG is more
effective than screening for increased hCG in the
maternal serum;21,22 therefore, ОІ-hCG has been
introduced in first-trimester screening.
Human chorionic gonadotropin hormone
is composed of two non-covalently linked
subunits, alpha (О±) and ОІ, and is produced by the
syncytiotrophoblast cells of the placenta. hCG has
a single ОІ-subunit that contains 145 amino acids
linked by six disulphide bridges and an О±-subunit
that contains 92 amino acids linked by five disulphide
bridges. Five hCG-related molecules are present in the
maternal serum: non-nicked hCG (which represents
the active form), nicked hCG, a free О±-subunit, a free
ОІ-subunit and the nicked free ОІ-subunit.23 The free
ОІ-subunit can be derived from three sources: direct
trophoblast cell production, dissociation of hCG into a
free О±-subunit and a free ОІ-subunit or by macrophage
or neutrophil enzymes nicking the hCG molecule.12
The free ОІ-hCG circulating in the maternal serum
accounts for only about 0.3–4% of the total hCG.12
Maternal serum hCG peaks at 8–10 weeks’ gestation
and then declines to reach a plateau at 18–20 weeks’
gestation and remains relatively constant until term.
Molecular biology studies12,20 have demonstrated
that Down syndrome trophoblasts show a marked
increase in the production of ОІ-hCG mRNA and a
smaller increase in О±-hCG mRNA, suggesting that one
of the causes of high hCG levels in the maternal serum
is the increased hCG production and secretion by the
placenta. hCG is also used to predict complications,
especially in early pregnancy, such as miscarriage
and ectopic pregnancy. A failing pregnancy is usually
associated with a slower than normal increase in the
maternal serum hCG, which gradually turns into a
decrease. In a successful pregnancy, the increase in
the maternal serum hCG level is exponential, i.e. the
concentration doubles in approximately 1.5–2 days.
In ectopic pregnancies resulting from in vitro
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:209–220 (http://dx.doi.org/10.7707/hmj.v6i2.224)
ORIGINAL RESEARCH ARTICLE
fertilization, the increase in maternal serum hCG is
delayed by an average of 1.5 days, but the rate of
increase usually normalizes during the first 4 weeks
after embryo transfer.
Nuchal translucency
In 1992, Schulte-Valentin and Schindler24 first reported
on non-echogenic nuchal oedema, which is currently
known as NT (Figure 2). It is the most important
marker on an ultrasound scan during first-trimester
screening for chromosomal abnormalities and is
measured between 10 and 14 weeks’ gestation.
NT measures the subcutaneous fluid-filled space
between the back of the spine and the skin on
the back of the neck of the fetus. Increased NT is
associated with Down syndrome, Turner syndrome
and other chromosomal abnormalities as well as
many fetal malformations and genetic syndromes.
The prevalence of these abnormalities is related to
the thickness, rather than the appearance, of NT.
Fetal NT increases with crown–rump length (CRL) and
increases at about 17% a week; hence, it is important
to take gestational age into account when analysing
NT. The translucent area disappears after 14 weeks’
gestation, when the subcutaneous tissue becomes
more echogenic, and NT is therefore a transient
phenomenon.25 The NT measurement is converted
into MoM for the relevant gestational age, based on
CRL, for risk calculation. Using the NT measurement
plus maternal age, 73% of affected pregnancies can
be identified with a 5% FPR.26 The NT measurement
needs to be performed by experienced sonographers
and should be obtained at a gestation of between
10 weeks and 13 weeks 6 days, which is equivalent to
a CRL of between 38 and 84 mm. NT can be detected
in 99% of fetuses at the end of the first trimester. The
50th percentile NT increases from 1.2 mm in week 11
(CRL of 45 mm) to 1.5 mm in week 13, day 6 (CRL of
82 mm). The 95th percentile ranges from 2 mm in
week 11 to 2.6 mm in week 13, day 6.
In the majority of fetuses with Down syndrome, NT is
increased compared with normal fetuses of the same
gestational age. Increased NT measurement may
also be associated with miscarriage and an abnormal
karyotype. In addition to Down syndrome, the NT
measurement can also indicate the risk of triploidies,
Edwards syndrome, Patau syndrome and monosomy
X. Special attention should be given to those cases
in which the NT is increased and the karyotype is
normal. When NT levels increase above the 95th
percentile, the chance that a healthy baby will be
born decreases; however, when the NT level is above
the 95th percentile and the karyotype is normal,
this may be indicative of different malformations
and genetic syndromes, the most frequent of
which are defects of the heart and great arteries
and a wide range of structural defects and genetic
conditions. Increased NT has also been associated
with other anomalies, including diaphragmatic
hernia, omphalocele, neural tube defects, body stalk
anomalies, a number of rare genetic syndromes
and skeletal dysplasias. These include rare genetic
syndromes such as Smith–Lemli–Opitz syndrome,
Noonan syndrome, arthrogryposis, Pena–Shokeir
syndrome, multiple pterygium syndrome, spinal
muscular atrophy, Jarcho–Levin syndrome,
thanatophoric dysplasia and thalassaemia.
Patient-specific risk for
chromosomal abnormalities
FIGURE 2  An ultrasound scan at 11–14 weeks’ gestation for
measurement of fetal NT thickness.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
All pregnancies are associated with some risk that
the fetus has a chromosomal defect. To calculate the
individual risk, it is necessary to take into account
the a priori risk, which depends on maternal age
and gestational age, and to multiply this by a
likelihood ratio, which depends on the results of the
ultrasonography and/or maternal serum biochemical
tests that may have been performed during the
course of the pregnancy to determine the patientspecific risk. Every time a test is carried out, the a
priori risk is multiplied by the likelihood ratio derived
213
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ORIGINAL RESEARCH ARTICLE
from that test to calculate a new risk, which then
becomes the a priori risk for the next test.
Fetal nuchal translucency and maternal
serum testing in the first trimester
In Down syndrome pregnancies, the maternal
serum concentration of free ОІ-hCG is about twice as
high as in euploid pregnancies whereas PAPP-A is
reduced to half compared with euploid pregnancies
(approximately 1 MoM and 0.5 MoM, respectively)10
(Table 3). There is no significant association between
fetal NT and maternal serum free ОІ-hCG or PAPP-A
in either Down syndrome or chromosomally normal
pregnancies; therefore, the ultrasonography results
and the biochemical markers can be combined
to provide more effective screening than either
method individually. One option for first-trimester
combined screening for Down syndrome is to
perform biochemical and ultrasonography testing
at 12 weeks’ gestation. The detection rate of Down
syndrome at 12 weeks’ gestation is about 90% with an
FPR of 5%.10 An alternative strategy for first-trimester
combined screening is for biochemical testing and
ultrasonography scanning to be carried out in two
separate patient visits, with the biochemical testing
conducted at 9 to 10 weeks’ gestation and the
ultrasonography scanning at 12 weeks’ gestation. It
has been estimated that this approach would improve
the detection rate from 90% to 93–94%.10 The tests
are better at 9–10 weeks’ gestation rather than at
13 weeks’ gestation because the difference in PAPP-A
between trisomic and euploid pregnancies is greater
during the earlier gestational period. Although
the difference in free ОІ-hCG between trisomic and
euploid pregnancies increases with gestation length,
the magnitude of the difference is smaller than that
of the difference in PAPP-A levels between trisomic
and euploid pregnancies. A third option would be to
perform the scan at 12 weeks’ gestation and optimize
the performance of biochemical testing by measuring
PAPP-A at 9 weeks’ gestation and free β-hCG at the
time of the first ultrasonography scanning session
at 12 weeks’ gestation, or even later, which gives an
estimated detection rate of 95% with an FPR of 5%.12
All three syndromes are associated with increased
maternal age, increased fetal NT and decreased
maternal serum PAPP-A, but whereas maternal
serum free ОІ-hCG is increased in a Down syndrome
pregnancy it is decreased in in pregnancies affected
by Edwards and Patau syndromes. In cases of sex
214
TABLE 3  Ultrasonography and biochemical characteristics
of fetuses with normal chromosomes and of those with
Down syndrome, Edwards syndrome and Patau syndrome.
Reproduced from Kagan KO, Wright D, Valencia C, Maiz
N, Nicolaides KH. Screening for trisomy 21, 18 and 13 by
maternal age, fetal nuchal translucency, fetal heart rate,
free beta hCG and pregnancy-associated plasma protein-A.
Hum Reprod 2008; 23:1968–759 by permission of Oxford
University Press
Normal karyotype
Down syndrome
Edwards syndrome
Patau syndrome
Fetal NT (mm) PAPP-A MoM
Free ОІ-hCG
MoM
2.0
3.4
5.5
4.0
1.0
2.0
0.2
0.5
1.0
0.5
0.2
0.3
chromosomal anomalies, the level of maternal serum
free ОІ-hCG is normal whereas the level of PAPP-A
is low. In diandric triploidy, the level of maternal
serum free ОІ-hCG is greatly increased, whereas
the level of PAPP-A is mildly decreased. Digynic
triploidy is associated with markedly decreased
levels of maternal serum free ОІ-hCG and PAPP-A.
Screening for chromosomal defects in the first,
rather than the second, trimester provides earlier
reassurance for those with normal results and a
less traumatic termination for those choosing this
option. A potential disadvantage of early detection
of chromosomal anomalies is that an earlier
assessment of risk and prenatal diagnosis identifies
the pregnancies that are more likely to miscarry.
Approximately 30% of Down syndrome fetuses
miscarry between 12 weeks’ gestation and full term.
This issue of intrauterine lethality for chromosomally
defected fetuses is a potential criticism of all methods
of antenatal screening, including second-trimester
maternal serum biochemistry.
Second-trimester screening
Two screening tests are performed during the second
trimester: the triple and the quadruple screening
test. The triple screening test has been available since
the late 1980s as a cost-effective serum pregnancy
screening test for Down syndrome, neural tube
defects and Edwards syndrome.27 A combination
of maternal age with serum О±-fetoprotein (AFP),
total hCG and unconjugated estriol (uE3) can
identify approximately 60–65% of affected
pregnancies with a 5% FPR28 (Table 4). Although the
triple screening test can be performed between
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:209–220 (http://dx.doi.org/10.7707/hmj.v6i2.224)
ORIGINAL RESEARCH ARTICLE
TABLE 4  Screening strategies for Down syndrome
Method of screening
Detection
rate (%)
Maternal age
30
First-trimester screening (10–14 weeks)
Maternal age plus NT measurement (by ultrasound)
75–80
Maternal age plus first-trimester double test (PAPP-A,
60–70
ОІ-hCG)
Maternal age plus first-trimester combined test (NT, PAPP-A, 85–96
ОІ-hCG)
Second-trimester screening (14–22 weeks)
Maternal age plus second-trimester double test (AFP, hCG)
Maternal age plus triple test (AFP, hCG, uE3)
Maternal age plus quadruple test (AFP, hCG, uE3, inhibin A)
Integrated test (first trimester: NT, PAPP-A and ОІ-hCG;
second trimester: quadruple test)
Prenatal diagnosis
Amniocentesis (14–16 weeks’ gestation)
CVS (10–12 weeks’ gestation)
Fluorescence in situ hybridization
55–60
60–65
65–80
90–95
100
100
100
15 and 22 weeks’ gestation, it is most effective when
conducted at 15–16 weeks’ gestation as this allows
simultaneous assessment of AFP as an additional
screen for neural tube defects. This method of risk
calculation was devised by Wald et al.28 and involves
multiplying the age-specific risk, as an odds ratio,
by the likelihood ratio which was derived from
the approximate trivariate Gaussian frequency
distribution of the serum markers. Maternal weight,
twin pregnancy and the presence of insulindependent diabetes mellitus also affect the serum
markers for the triple test. Increasing maternal weight
is associated with a lowering of maternal serum
AFP (MSAFP), uE3 and hCG levels. Wald et al.28 have
reported that routine maternal weight adjustments
for the serum marker levels can increase the detection
rate by approximately 0.5% for a given FPR, or can
reduce the FPR by 0.1% for a given detection rate.
In comparison with singleton pregnancies, in twin
pregnancies a median MSAFP is 2.1 times higher,
median uE3 level is 1.7 times higher and median
hCG level is 1.8 times higher. In women with insulindependent diabetes mellitus, the MSAFP, uE3 and hCG
levels are 0.7, 0.92 and 0.95 times higher, respectively,
than in women who do not suffer from insulindependent diabetes mellitus. Several studies27,28 have
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
shown a significant correlation between the results of
the triple screening test showing abnormal markers
and preterm labour, pre-eclampsia, intrauterine
growth restriction and premature rupture of the
membranes. Recently, the maternal serum quadruple
screen has been replacing the triple screen as it
provides greater sensitivity (80% detection rate with
an FPR of 5% for Down syndrome).29 The quadruple
test can be performed on antenatal patients between
15 and 22 weeks’ gestation and includes the triplescreen serum markers with an additional marker,
inhibin A, which is initially produced by the corpus
luteum and later by the placenta.
Alpha-fetoprotein
Alpha-fetoprotein is a glycoprotein with a molecular
weight of 68 kDa produced by the fetal yolk sac,
liver and gastrointestinal tract. This protein was first
discovered by Bergstrand and Czar in 195630 and
subsequently named by Gitlan31 as О±-fetoprotein.
AFP has approximately 4% carbohydrate moiety
represented by one oligosaccharide residue.32 The
protein moiety has been completely determined and
consists of one polypeptide chain of 590 amino acids
arranged in three well-defined domains.33
Alpha-fetoprotein is produced by the fetal yolk sac
in small quantities and by the fetal liver in large
quantities as the yolk sac degenerates. The fetal liver
produces AFP until 30 weeks’ gestation and then
stops abruptly. Fetal serum levels peak at about
9 weeks’ gestation (at approximately 3 million µg/l)
and decline progressively until term, when the final
level of fetal serum is approximately 20 000 µg/l. AFP
is initially detectable at a level of approximately 5 Вµg/l
in the maternal serum at about 10 weeks’ gestation.34
The concentration increases at an approximate rate
of 15% per week to peak at approximately 180 Вµg/l at
about 25 weeks’ gestation.34 The concentration of AFP
in the maternal serum subsequently declines slowly
until term. After birth, the MSAFP rapidly decreases
to < 2 µg/l and the levels of serum AFP in the baby
decline exponentially to reach adult concentration by
the 10th month of life.34
Laboratory measurements of AFP levels are reported
as MoM. Maternal AFP is said to be elevated when the
value is ≥ 2.5 MoM for a single fetus and ≥ 4.5MoM for
a pregnancy with two or more fetuses. The MSAFP
is elevated in 85–95%35 of cases in which the fetus
has open neural tube defects whereas the MSAFP
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ORIGINAL RESEARCH ARTICLE
is lowered in approximately 30%36,37 of cases where
the fetus has Down syndrome. In addition to neural
tube defects, such as spina bifida and anencephaly
(failure of brain and skull development), the causes
of elevated MSAFP to a level of > 2.5 MoM include
fetal death, misdated pregnancies, other anatomical
abnormalities (such as abdominal wall defects),
placental abnormalities (such as chorioangiomas,
placental lakes and placental oedemas), fetal
growth restriction, pre-eclampsia, preterm delivery,
stillbirth, infection and hypoxia.38,39 In fetuses with
open neural tube defects (such as spina bifida) the
normal integumentary covering at the site of the
lesion is absent, which allows abnormally large
quantities of AFP to leak into the amniotic fluid
and subsequently into the maternal serum. As this
phenomenon also occurs in other non-neural tube
lesions, other morphological abnormalities, such as
abdominal wall defects and cystic hygromas, also
demonstrate an elevated level of AFP in the amniotic
fluid and the maternal serum that can be detected
during screening.
In 1984, Merkatz et al. reported that the MSAFP in
the second trimester of pregnancies affected by
fetal Down syndrome was lower (< 0.7 MoM) than
that of normal pregnancies.37 Lower levels of AFP
(< 0.25 MoM) may be seen not only in patients who
are not pregnant, but also in those affected by fetal
death, spontaneous abortion, preterm birth, stillbirth
or macrosomia or have a misdated pregnancy, a
hydatidiform mole or trisomic fetus or who are going
through a normal pregnancy.
Human chorionic gonadotropin
Bogart et al.40 reported an elevation of maternal
serum hCG levels in Down syndrome pregnancies,
and since then the levels of hCG have been
measured in most screening programmes. hCG is a
complex glycoprotein produced exclusively by the
syncytiotrophoblast shortly after zygote implantation
into the uterine wall. The level of hCG increases
rapidly in the first 8 weeks of gestation and then
decreases steadily until 20 weeks’ gestation, when
it plateaus. Maternal weight and parity have an
effect on hCG levels and high maternal serum levels
of hCG accompanied by low levels of MSAFP have
been associated with an increased risk of carrying
a fetus with Down syndrome. The geometric mean
MoM for Down syndrome pregnancies determined
from the results of 18 studies, comprising a total of
216
559 Down syndrome cases, was 2.03 MoM.41 Although
the precise explanation for this finding is unknown, it
may be due to fetuses with Down syndrome showing
delayed development. Since maternal serum levels
of hCG decline between 12 and 20 weeks’ gestation,
an immature fetus with Down syndrome will be
associated with a higher concentration of hCG than an
unaffected pregnancy. A low hCG level is associated
with Edwards syndrome and normal hCG levels are
associated with neural tube defects. Increased hCG
levels are found in placental anomalies (such as molar
pregnancies), multiple pregnancy or fetal demise.
Unexplained elevation of second-trimester hCG has
been seen in hypoxic cytotrophoblasts; however, the
exact cause is not known.21
Unconjugated estriol
Estriol is produced in very large quantities during
the final trimester of pregnancy. The biosynthesis
pathway requires three organs to be fully functioning:
the fetal adrenal glands, the fetal liver and the
placenta. uE3 is produced by the placenta from
precursors that are created in the fetal adrenal glands
and the fetal liver. Estriol diffuses from the placenta
into the maternal blood, where it can be measured
as uE3. The levels of maternal serum uE3 rise above
non-pregnancy levels by 7–9 weeks’ gestation
and continue to increase throughout pregnancy.
The level of maternal serum uE3 is approximately
4 nmol/l at 15 weeks’ gestation and increases to
approximately 40 nmol/l by parturition.38,42 Any
disruption in the biosynthesis pathway will lead to
very low level of maternal serum uE3. Conditions
that cause such disruption include fetal anencephaly,
molar pregnancy, placental steroid sulphatase
deficiency, fetal death, and chromosomal or
congenital anomalies such as Down syndrome,
Smith–Lemli–Opitz syndrome and Edwards
syndrome.43,44
Low levels of maternal uE3 in the third trimester have
also been reported in newborns with low birthweight
and have been found to indicate fetal distress.
Decreased uE3 levels (< 0.5 MoM) have been found to
be significantly associated with pregnancy-induced
hypertension, miscarriage, intrauterine growth
restriction and intrauterine fetal death.45 Maternal
serum uE3 levels are significantly lower in Down
syndrome pregnancies than non-Down syndrome
pregnancies, ranging from 0.6546 to 0.79 MoM.47,48
Amniotic fluid and placental tissue uE3 levels are
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:209–220 (http://dx.doi.org/10.7707/hmj.v6i2.224)
ORIGINAL RESEARCH ARTICLE
also significantly lower in a Down syndrome-related
pregnancy. uE3 is a variable that is independent of
maternal age and therefore can be used alone or in
combination with maternal age for the determination
of the relative risk of Down syndrome.
Dimeric inhibin A
Inhibins are circulating dimeric glycoprotein
hormones synthesized by the gonads and the
placenta. These glycoproteins were first isolated
from the ovarian follicular fluid and named after
their ability to inhibit the pituitary secretion of
follicle-stimulating hormone. The О±-subunit can
combine with one of the two ОІ-subunits (ОІA or
ОІB) to form inhibin A or inhibin B. Dimeric inhibin
A (DIA) concentrations exhibit a complex pattern
during the course of pregnancy, rising to a peak
at 8–10 weeks’ gestation and then declining to a
minimum at 17 weeks’ gestation, before beginning
to slowly increase towards term. The average inhibin
levels do not change greatly from 15 to 20 weeks’
gestation and a typical value of DIA at 17 weeks’
gestation is 175 ng/l.34
The maternal serum levels of inhibin A in the
second trimester of pregnancy are twice as high
in pregnancies affected by Down syndrome as
in those that are not affected. Studies49,50 have
reported DIA values ranging from 1.53 to 2.60 MoM
in Down syndrome pregnancies. Inhibin A is as
effective a marker for Down syndrome as hCG, and
yet it also provides information that hCG and the
other markers do not.51–54 The level of inhibin is
significantly decreased in the presence of primary
antiphospholipid antibodies syndrome (median
MoM 0.6) and it has also been described as extremely
elevated in pregnancies complicated by triploidy,
HELLP syndrome (where the patient suffers from
haemolysis, elevated liver enzymes and a low platelet
count) and following the loss of one twin in the
first trimester.17
Clinical application of the triple and
quadruple analyte-screening test
Many biochemical markers have been studied during
the second trimester of pregnancy, but the triple test,
which analyses serum AFP, hCG, uE3 and maternal
age, is the most popular combination. The triple test
has a sensitivity of approximately 65% for Down
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
TABLE 5  The second-trimester biochemical markers
Neural tube defects
Down syndrome
Edwards syndrome
AFP
uE3
Total hCG Inhibin A
↑
↓
↓
NA
↓
↓
NA
↑
↓
NA
↑
NA
NA, not applicable.
syndrome and 70% for Edwards syndrome.28 In Down
syndrome pregnancies, the levels of hCG increase
whereas levels of AFP and uE3 decrease (Table 5).
In the case of Edwards syndrome, the levels of all
three analytes are low. In twin pregnancies, secondtrimester serum screening detects approximately 50%
of affected fetuses and can be difficult to interpret
because a normal twin may mask the results of an
affected twin.55 Recently, a quadruple-screening test
has been developed, so named because it uses four
biochemical markers (AFP, hCG, uE3 and DIA).56 The
combination of maternal age and the quadruple
screening test detects approximately 75% of Down
syndrome fetuses in women who are younger than
35 years with an FPR of 5%, and it detects > 80% of
the Down syndrome fetuses in women who are over
the age of 35 years with an FPR of 5%.29 In most cases
of Down syndrome, the AFP and uE3 levels are low,
whereas hCG and DIA levels are high compared with a
non-Down syndrome pregnancy.
Screening in the second trimester using multiple
markers does not reliably detect the other forms
of aneuploidy that can occur as result of increasing
maternal age, such as Patau syndrome (1 in 20 000 live
births) and Klinefelter syndrome (47,XXY; 1 in 1000
live births). These forms of aneuploidy would be
detected by amniocentesis and CVS.
The laboratory conducting the tests must be
informed of the gestational age of the fetus at the
time the sample was taken to ensure an accurate
interpretation. Gestational age is usually calculated
from the first day of the last menstrual period;
however, ultrasonographic measurement of the CRL
in the first trimester, or measuring the biparietal
diameter of the fetus in the second trimester,
provides a more reliable estimate of gestational
age, accurate to within 7 and 10 days, respectively.
If ultrasonography results in a change in gestational
age of more than10 days, then the test results
must be reinterpreted. If the sample was taken at
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ORIGINAL RESEARCH ARTICLE
< 15 weeks’ gestation then a new sample should be
obtained and analysed in accordance with the correct
gestational age.
First- and second-trimester screening
for aneuploidy
There have been several different approaches
proposed to improve screening detection rates,
many of which take advantage of both first- and
second-trimester screening tests: first, the integrated
screening test, which combines maternal age with
NT measurement, PAPP-A and free ОІ-hCG in the
first trimester; and, secondly, triple and quadruple
screening in the second trimester. These tests are
reported to be more effective and accurate than all
other tests, yielding very good results, with detection
rates of 94% for the first-trimester tests and 85%
for the second-trimester tests, with an FPR of 5%
and 1%, respectively.57 The disadvantage of these
screening methods is that a portion of woman may
fail to attend the second-trimester test. Additionally,
the results of these tests are not obtained until
after 16 weeks’ gestation and a termination of the
pregnancy at this stage can be traumatic since it
usually requires a medical abortion rather than
surgical and the mother may have already felt the
fetal movements. Another screening method is
stepwise sequential screening, in which all patients
have a first-trimester NT test, serum PAPP-A and
free ОІ-hCG tests and the resulting high-risk patients
are offered CVS whereas low- or intermediate-risk
patients have a second-trimester AFP test, a uE3
test, free ОІ-hCG and inhibin tests. If the combined
risk from first- and second-trimester testing is high,
patients are offered second-trimester amniocentesis.
An alternative option is the contingent screening
method, which is similar to stepwise sequential
screening except that second-trimester biochemical
testing is performed only in women in whom firsttrimester screening suggests an intermediate risk of
fetal anomalies.10 The estimated performance of the
three approaches is similar, with an overall detection
rate of 90–94% and an FPR of 5%. The advantages of
the contingent screening method are twofold: first,
second-trimester testing can be avoided in 75–80%
of patients; and, secondly, approximately 60% of
fetuses with aneuploidies can be identified during the
first trimester.10
218
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Hamdan Medical Journal  2013; 6:221–226 (http://dx.doi.org/10.7707/hmj.v6i2.233)
 
Original Research Article
Respiratory distress syndrome in preterm neonates
of Lahore
Iftikhar Ejaz,1 Mumtaz Ali Bharo1 and Mehwish Anwer2,3
Department of Pediatrics, Children’s Hospital, Lahore, Pakistan, 2Centre for Research
in Molecular Medicine, The University of Lahore, Lahore, Pakistan, and 3Department of
Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain,
United Arab Emirates
1
Abstract
Compromised health facilities in developing countries often result in
inadequate care for both mothers and their newborns. Consequently, a large
number of neonates who are born prematurely with serious prepartum
difficulties develop additional postpartum complications. Respiratory
distress syndrome (RDS) in infants is a complex pulmonary state in which
the lungs are not properly developed and therefore produce very little
surfactant, resulting in morbidity of many preterm newborns. The present
study investigated the frequency of RDS in neonates born at various
gestational ages and of various birthweights. Out of 180 subjects, 50 (27.8%)
developed RDS, the diagnosis of which was based on radiological findings
and symptoms such as tachypnoea, nasal flaring and central cyanosis.
The frequency of RDS is inversely, and significantly, associated with both
gestational age and birthweight, which were found to be good predictors
of the likelihood of a newborn developing RDS. Preterm newborns of low
birthweight have a higher risk of developing RDS than full-term newborns
of heavier birthweight. In light of these observations, proper management
strategies should be devised for the assessment and treatment of preterm
neonates with, or without, RDS.
Introduction
Approximately 1.5% of total child deaths are caused
by neonatal infections and complications. According
to the Centers for Disease Control and Prevention1
the prevalence of respiratory distress syndrome
(RDS) in a US study population is 3.9 in every 1000
infants, which poses a great threat to the survival rate
of preterm neonates.1 RDS is caused by insufficient
production of surfactant in the lungs, which results in
Correspondence: M Anwer, Department of Anatomy, Faculty of
Medicine and Health Sciences, United Arab Emirates University,
Al-Ain, 17666, United Arab Emirates.
E-mail: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
the respiratory organs being unable to develop and
operate fully.2 Clinical symptomatic presentations
include central cyanosis, tachypnoea and nasal flaring,
and a pulmonary radiograph showing the lungs to
have a ground-glass appearance is generally regarded
as a confirmatory diagnostic test for RDS.3 Acute RDS
may cause the lungs to collapse, resulting in death,4
but antenatal administration of corticosteroids,
postnatal surfactant replacement therapy5 and
ventilation support with continuous positive airway
pressure (CPAP) may be used as therapeutic options
for RDS.6–8
Most of the public medical centres in developing
countries cannot cope with the requirements of all
patients and, as a result, maternal health and neonatal
care is often compromised. Consequently, a large
number of neonates who are born with, or develop,
serious difficulties and complications may not survive
and the mortality rate for infants is increasing.
Additionally, preterm neonates are at a greater risk
of developing postpartum disorders, including RDS.
Only a small number of studies in Pakistan have
addressed the frequency of various prenatal and
postnatal diseases. Bhutta et al.9 and Ghafoor et al.10
comprehensively discuss the prevalence of RDS in
a Karachi and Rawalpindi population, respectively.
However, to the best of our knowledge, no study in a
Lahore population has been reported.
In view of this, the present study offers an assessment
of RDS prevalence in preterm neonates residing in
Lahore. The relationship between the presence of
221
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Hamdan Medical Journal  2013; 6:221–226 (http://dx.doi.org/10.7707/hmj.v6i2.233)
Original Research Article
RDS and either gestational age or weight at the time
of birth is also examined. Both of these parameters,
along with other considerations, may serve as useful
predictive markers of RDS in preterm neonates.
using Pearson’s correlation coefficients with a 95%
confidence interval.
Results
Materials and methods
General characteristics of observed neonates
Patients from the neonatal ward of the Children’s
Hospital in Lahore, Pakistan, were included in
the study after approval from the hospital’s
ethical committee. This descriptive study
was conducted over a period of 6 months
(September 2011–February 2012). There were
180 non-probability based and purposive preterm
neonates who were included in the study, with a
confidence interval of 95%.
A total of 180 neonates with a mean gestational age
of 30 ± 0.91 weeks (range 26–34 weeks) were studied.
The relative proportions of male and female neonates
were 62.8% (n = 113) and 37.2% (n = 67) respectively,
giving a male to female ratio of 1.68:1.
Preterm neonates who were born between 26 and
34 weeks’ gestation were selected for the study and
gestational age was calculated using the Ballard
scoring system. The subjects with clinical presentation
of respiratory distress, tachypnoea, cyanosis and
radiological findings of a ground-glass appearance in
the lungs were categorized as having RDS.
Preterm neonates suffering from congenital defects
such as cleft palate, Pierre Robin syndrome, Down
syndrome, Turner syndrome, hydrocephalus and
cyanotic heart disease were not included in the study.
Infants whose mothers suffered from chronic diseases
such as diabetes mellitus, renal failure and congenital
pneumonia were also excluded from the study.
Informed consent was requested from the parents of
the participants and participant age, sex and weight
were recorded and all the information was collected
on a specifically designed questionnaire. A physical
examination provided information regarding nasal
flaring, tachypnoea (with subcostal and intercostal
recession) and cyanosis, whereas chest radiography
was carried out to assess the appearance of the lungs.
A combination of nasal flaring, tachypnoea, cyanosis
and a ground-glass appearance of the lungs on chest
radiography confirmed the diagnosis of RDS.
The collected data were entered into SPSS (SPSS v.17,
SPSS Inc., Chicago, IL, USA) for analysis. Qualitative
data such as sex (male or female) and RDS (present
or absent) were presented as frequency distributions
and percentages. The association of RDS with
gestational age and birthweight was evaluated
222
Gestational age varied: 14 neonates (7.8%) were born
during week 26 of gestation, 26 (14.4%) in week 27,
15 (8.3%) in week 28, 19 (10.6%) in week 29, 27 (15%)
in week 30, 16 (8.9%) in week 31, 20 (11.1%) in week
33, 26 (14.4%) in week 33 and 17 (9.4%) in week 34.
Thus, the greatest number of neonates were born in
week 30 (n = 27). The variable presentation provided
the opportunity to compare respiratory outcome at
different gestational ages.
Among the 180 neonates observed in this study,
42 (23.3%) had a birthweight of < 1000 g, 39 (21.7%)
of 1001–1500 g, 44 (24.4%) of 1501–2000 g, 32 (17.8%)
of 2001–2500 g and 23 (12.8%) of > 2500 g.
Symptoms associated with pulmonary infections
were considered but exclusion criteria were strictly
applied. Nasal flaring was seen in 89 neonates
(49.4%), tachypnoea in 78 (43.3%) and central
cyanosis in 63 (35%) (Figure 1). In view of these
clinical presentations, radiography was performed
in all participants and a ground-glass appearance in
the lungs clearly indicated the presence of RDS in a
subset of the neonates.
Frequency of respiratory distress syndrome
Respiratory distress syndrome was present
in 50 participants (27.8%) and not present in
130 (72.2%), as confirmed by radiological examination
(Figure 1). These values indicated a high frequency of
RDS in this population.
Gestational age at birth versus frequency of
respiratory distress syndrome
Among the 50 neonates diagnosed with RDS,
14 (28%) were born at 26 weeks’ gestation, seven
(14%) at 27 weeks, five (10%) at 28 weeks, seven
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:221–226 (http://dx.doi.org/10.7707/hmj.v6i2.233)
Original Research Article
(a)
(b)
(c)
Figure 1  (a) Distribution of the neonates in the study according to birthweight. (b) Frequency of RDS among the neonates.
(c) The symptomatic presentation of the neonates in the study.
(14%) at 29 weeks, five (10%) at 30 weeks, six (12%)
at 31 weeks, three (6%) at 32 weeks, two (4%) at
33 weeks and one (2%) at 34 weeks. The number of
patients with RDS showed a negative correlation
with gestational age. The association of RDS with
gestational age was statistically significant (P < 0.005)
with a correlation co-efficient (r) of –0.86 (Figure 2).
Birthweight and respiratory distress syndrome
Among the infants with RDS, birthweight was
< 1000 g in 11 (22%), 1001–1500 g in 15 (30%),
1501–2000 g in 12 (24%), 2001–2500 g in nine (18%)
and > 2500 3g in three (6%). Increasing birthweight
was found to be inversely correlated with RDS
frequency, indicating a higher risk for RDS in early
preterm infants. The correlation was statistically
significant (P < 0.05; r = – 0.98) (Figure 2).
Discussion
Neonatal morbidity is an issue of prime importance
in the underdeveloped and developing countries.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Many infant deaths may be attributed to pulmonary
diseases such as pneumonia and asphyxia, or other
congenital anomalies.11 A few studies in Pakistani
populations9,10 have reported the high incidence of
RDS, but it is necessary to look to studies conducted
in other populations for a guide to the management
of this disorder.12
The present study attempted to quantify the recent
RDS frequency in preterm neonates presenting at a
local hospital with access to basic paediatric intensive
care facilities. A total of 180 preterm neonates were
assessed with a mean birth age of 30 ± 0.91 weeks’
gestation, birthweight ranging from 500 to 3000 g
and clinical presentation of nasal flaring, tachypnoea,
cyanosis and a ground-glass appearance of the lungs
after radiological examination.
Sex-based differences in the frequency of preterm
neonates were observed. Almost twice as many boys
(n = 113) as girls were affected (n = 67) and the male
to female ratio was 1.68:1. Previous studies have
observed a tendency for more males to be born
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Hamdan Medical Journal  2013; 6:221–226 (http://dx.doi.org/10.7707/hmj.v6i2.233)
Original Research Article
(a)
(b)
(c)
(d)
Figure 2  (a and b) Association of RDS with gestational age. (c and d) Association of RDS with birthweight.
prematurely, which may be due to various sex-specific
biochemical processes during the later trimesters.13,14
The gestational age of our neonates ranged from
26 to 34 weeks; most were born in week 27, 30 or
33 (14.4%, 15% and 14.4%, respectively). The lowest
number were born at 26 weeks’ gestation. The study
group included neonates with a range of birthweights
and with those weighing 1501–2000 g forming the
largest group (24.4%).
Infants in the study group presented symptoms
of pulmonary discomfort. Some of the notable
presentations included nasal flaring (49.4%),
tachypnoea (43.3%) and central cyanosis (35%). In
50 infants (27.8%), RDS was confirmed by a groundglass appearance of the lungs on radiography and
a bell-shaped chest due to decreased lung volume.
The remaining 130 patients (72.2%) also had signs
of respiratory distress but chest radiographs were
notably different and indicated absence of RDS. The
incidence of RDS was therefore found to be 27.8%
over a period of 6 months. It is very important to
address this alarming number of affected infants
224
as this high incidence of RDS in preterm neonates
may contribute dramatically to decreased neonatal
survival rate. RDS serves as an additional threat to
neonates born at an early gestational age as they
have a compromised state of health. However,
this number of neonates with RDS could be an
overestimate because of the small sample size in this
study, which could be evaluated by further studies
over a longer time period.
The prevalence of RDS among preterm newborns in
our study decreased with increasing gestational age,
a correlation that that was found to be statistically
significant (r = –0.86, P < 0.005). The risk of preterm
neonates developing RDS can be predicted from the
gestational age, as reported in previous studies.15 This
may be useful for risk assessment of RDS in preterm
neonates, which may enable physicians to prepare
for treatment. In addition, the frequency of RDS
was found to increase with decreasing birthweight,
highlighting the importance of birthweight
for risk assessment of RDS in both preterm and
full-term neonates.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:221–226 (http://dx.doi.org/10.7707/hmj.v6i2.233)
Original Research Article
The observations of the study were limited because
of its limited scope and small sample size. A
larger number of neonates with a larger variety of
gestational ages and a more precise diagnosis of RDS
is required to derive more accurate conclusions. A
larger-scale study may be useful in devising a numeric
score for the health of a fetus to estimate the chance
of preterm parturition and, ultimately, the probability
of developing RDS. Additionally, as indicated by some
studies,16,17 the health status of the mother should
also be utilized as an indicator for the subsequent
risk of neonatal RDS. An account of the survival and
mortality rates of the affected neonates may also be
helpful for postnatal management of the infants.
6
Our observations highlight the significance of
gestational age and birthweight in prediction of the
incidence of RDS. Infants born prematurely should
receive particular attention and an appropriate
intensive care and therapeutic protocol should be
instituted. The appearance of any of the symptoms of
pulmonary discomfort should assist the physician in
making the correct diagnosis. If the symptoms are not
noted, or the wrong diagnosis is given, the life of the
neonate may not be secured.
10
7
8
9
11
12
13
14
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Original Research Article
Respiratory diseases burden in the United
Arab Emirates
Bassam H Mahboub,1,2 Seemin Afshan Shiraz,3 Amna Hassan,4 Arif Noor Mohammad,3
Muzaffar Iqbal,5 Mayank Vats,6 Jamal Abdul Razak,6 Bassel Safareni,6 Ashraf al Zaabi7
and Mohamad Al Sairi7
Department of Pulmonary Medicine, University of Sharjah, United Arab Emirates, 2Department of
Respiratory, Sleep and Allergy, Rashid Hospital, Dubai, United Arab Emirates, 3Department of Internal
Medicine, University Hospital Sharjah, United Arab Emirates, 4Medicine, Dubai Health Authority, Dubai,
United Arab Emirates, 5Lahore, Pakistan, 6Department of Pulmonary Medicine, Rashid Hospital, Dubai,
United Arab Emirates, and 7Respiratory Division, Zayed Military Hospital, Abu Dhabi, United Arab Emirates
1
Abstract
Respiratory diseases affect individuals worldwide and United Arab Emirates
(UAE) is no exception. The burden of respiratory diseases is varied, and over
the past two decades several studies have been carried out across UAE to
estimate the load of respiratory diseases in the area and compare this with
the international respiratory disease burden. The purpose of the present
study was to compile the results of studies conducted in UAE in order to
obtain an overview of the situation in this area. Comparison of the respiratory
disease status in UAE and internationally will improve our knowledge about
the situation, which will help us to implement strategies for improved
respiratory care and respiratory disease outcome at a reasonable cost.
Introduction
Respiratory diseases affect millions of individuals
worldwide and the United Arab Emirates (UAE)
is no exception to this global phenomenon. The
spectrum and the burden of respiratory diseases vary
throughout the UAE. Asthma, respiratory infections,
sleep disorders and chronic obstructive pulmonary
disease (COPD), in decreasing order of prevalence, are
all underdiagnosed but remain the most important
respiratory problems.
In a recent study1 that investigated the prevalence
of asthma and its determinants in the UAE [based on
the European Community Respiratory Health Survey1
Correspondence: Dr Seemin Afshan Shiraz, Department of Internal
Medicine, University Hospital Sharjah, United Arab Emirates.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
(ECRHS)], it was found that 15.4% of participants
[95% confidence interval (CI) 13.5–17.5%] fulfilled
the UAE screening criteria for asthma, while 12.1% of
participants (95% CI 10.4–14.1%) fulfilled the ECRHS
asthma definition criteria. Of these patients, 9.8%
(95% CI 7.8–12.2%) overall (8.6% of male and 11.8%
of female patients) were aged 20–44 years. Certain
specific persistent environmental factors, along
with non-adherence to the controller medicines,
lead to uncontrolled asthma with consequential
exacerbations, morbidity and increased healthcare
costs in the UAE.2
In a large, randomized, age-stratified cohort study
of adolescent school children and their caretakers,
allergic rhinitis and asthma comorbidity was
monitored and multinomial regression was used
to determine independent risk factors.3 A total of
6543 subjects were included in the study [median
age 30 years (range 8–93 years) 52% males]. The
standardized prevalence of concomitant asthma
and allergic rhinitis was 7.3%. Subjects with allergic
rhinitis had a 3-fold increased risk of also suffering
from asthma compared with subjects without allergic
rhinitis (23.8% and 7.5%, respectively). Subjects who
had immigrated to the UAE had a significantly lower
prevalence of asthma and allergic rhinitis comorbidity
[adjusted odds ratio (OR) 0.53; 95% CI 0.33–0.85] than
UAE nationals whereas higher age was associated
with a lower risk (adjusted OR 0.58; 95% CI 0.44–0.78).
227
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Original Research Article
A family history of both allergic rhinitis (adjusted OR
3.03; 95% CI 2.31–3.98) and asthma (adjusted OR
4.65; 95% CI 3.53–6.12) was strongly associated with
the co-occurrence of these two conditions, whereas
gender and education were not. Patients with both
asthma and allergic rhinitis displayed more severe
symptoms than patients with asthma alone: 65% of
patients with both conditions complained of a dry
cough at night as opposed to only 36% with asthma
alone; beta-mimetics were used by 42% of patients
with both conditions compared with 30% of asthma
suffers; and steroids were used by 25% of patients
with both conditions compared with 13% of patients
with asthma only.
In another community-based face-to-face survey4
of asthma control carried out in 2009, 64% of
200 asthmatic subjects experienced sudden and
severe asthma attacks in the course of a year.
Day-time symptoms and night-time symptoms were
reported by 57.5% and 35.5%, respectively, over a
1-week period. Overall, 52.8% of children missed
school and 17.1% of adults missed work during 2009,
27.5% had visited the emergency room and 4% were
hospitalized. Only 5.5% used inhaled corticosteroids
during the year, and 47.5% had been prescribed
short-acting b2-agonists. Only 17.8% had ever owned
a peak flowmeter and only 30% had ever undergone
a lung function test. Only 17% were given scheduled
follow-up sessions and 66% of these patients were
followed up by general practitioners.4 This survey
shows that the level of asthma control in the UAE is far
from optimal and it is therefore necessary to increase
the awareness among patients and update doctors
about asthma control guidelines, thus reducing the
burden of the disease.
To estimate the prevalence of allergic rhinitis in Al-Ain
city, a validated and self-administered questionnaire,
modified from the International Study of Asthma
and Allergies in Childhood study, was used to collect
data from a two-stage randomly selected sample
of 10 000 school children.5 Overall, 7550 subjects
(all aged 13 years and above and the participants
included siblings and parents) responded. The crude
and standardized prevalence of allergic rhinitis over
the previous 12 months was assessed, as was the
independent relationship of allergic rhinitis with age,
gender, education, nationality and family history, by
means of logistic regression. The response rate was
76% and a total of 6543 subjects (with a median age
of 30 years) were included in the final analysis. Allergic
rhinitis (defined as having suffered symptoms in the
228
past 12 months) was self-reported by 36% of subjects,
while adjustments for gender and age yielded a
prevalence of 32%. Regression analysis revealed that
allergic rhinitis was independently associated with
family history, Arab origin, younger age, being female
and higher education. The relatively high prevalence
of allergic rhinitis found in this study was attributed
to modernization (e.g. adoption of a sterile, urban
lifestyle and less exposure to infectious agents) and
genetic factors.
The Asthma Insights and Reality in the Gulf
and Near-East survey was carried out in five
countries – Jordan, Kuwait, Lebanon, Oman and the
UAE – involving a total of 1000 patients with asthma.6
The authors reported several striking findings; for
example, 68% of respondents had experienced
daytime asthma symptoms and 51% had been woken
by asthma in the preceding 4 weeks. Use of health
services in the previous 12 months was high, with
52% having attended the emergency department
and 23% having been hospitalized. Overall, 52% of
children and 30% of adults missed school or work
because of asthma; the highest rate of school absence
was observed in Jordan and Lebanon (both 69%), and
the highest rate of absence from work among adults
was also in Jordan (46%). The use of peak flowmeters
was very low, with only 17% of participants owning
a device. Overall, 66% of participants had never
undergone a lung function test.
Another study determined a prevalence of
self-reported asthma of 13% in the UAE.7 Direct
standardization of this result with the UAE population
as a reference yielded an asthma prevalence of
12% in the UAE. Logistic regression revealed the
main risk factors for asthma to be a family history
of the condition and UAE nationality (about 50% of
UAE nationals were of Bedouin origin). In addition,
a significant (P = 0.001) interaction was observed
between gender and age: in the group aged
13–19 years, asthma prevalence was significantly
higher in males than in females (17% and 14%,
respectively; adjusted OR 1.45; 95% CI 1.10–1.90)
whereas, among those > 19 years, prevalence was
significantly lower in males than in females (11%
and 13%, respectively; adjusted OR 0.77; 95% CI
0.60–0.95).
A recent study8 revealed COPD prevalence to be
approximately 3.7% among 40- to 80-year-old Emirati
nationals, which makes the UAE as a low-prevalence
country for COPD; however, one of the limitations
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:227–232 (http://dx.doi.org/10.7707/hmj.v6i2.251)
Original Research Article
of the study was that it was carried out in an Emirati
population only, who make up just 20% of the total
UAE population of 6 million people. The prevalence
of smoking in the UAE is approximately 24%,9 which
will increase the prevalence of COPD in the future.
If patients of all nationalities were to be included
in the evaluation of COPD prevalence, then the
values for smoking and COPD prevalence would be
relatively high.
Smoking
A 2009 federal law on tobacco control in the UAE
forbids smoking (including using a Midwakh and
shisha) in public places; however, despite this,
smoking continues to represent a significant health
hazard to the UAE society in general, as there are a
large number of active or passive smokers, which
reflects the failure to properly implement the law.
It is important to note that prevalence of tobacco
smoking in the UAE is lower than in many other
countries in the Middle East;10 however, it is common
among young Emiratis, which will inevitably lead
to an increase in smoking-related comorbidities in
the decades to come. Smoking is still uncommon
among Arab women,11 with only 1.72% of adult
females smoking, compared with 18.7% of adult
males in 2009 (according to the World Bank report
published in 2010).12 According to the Dubai
Household Health Survey (DHHS),13 which reported
on a sample size of 5000 households, making this
the largest and most comprehensive survey ever
carried out on health and healthcare issues in the
Emirate of Dubai, the prevalence of smoking among
Dubai residents is 17.2%, and men are five times
more likely to smoke than women. The survey also
showed that one-third of the Dubai population is
exposed to the risk of smoking, either directly or as
passive smokers. The DHHS showed that people in the
lowest income quintile and the lowest educational
level are approximately twice as likely to smoke as
people in the highest income quintile and the highest
educational level.
Some men start to smoke as young as 10 years and
women at the age of 13, with 13% of smokers in
Dubai having started before they complete secondary
school. Amongst Emirati men in Dubai who smoke,
one in every five had started smoking by the time
they completed secondary school. The prevalence
of smoking in the 18–24 years age group is 16.2%
although overall smoking prevalence among UAE
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
nationals is only 8.6%, which is significantly lower
than any other nationality.13
Most male smokers in Dubai smoke on a daily basis
(18.1%), and only 3% smoke occasionally. Only 3%
of female smokers in Dubai smoke on a daily basis
and 1% smoke occasionally. Approximately 17% of
non-smoking Dubai residents are exposed to passive
smoking in their own homes and men are as twice
as likely to be exposed (19.8%) as women (9.1%).
Approximately 62% of non-smoking Dubai residents
are exposed to passive smoking at work and men are
reported to be three times more likely to be exposed
to passive smoking than women.13
The Weqaya population-based screening programme
in Abu Dhabi9 screened 170 430 UAE nationals
between 2008 and 2010 and found that the
prevalence of smoking was over 24% among males
and only 1% among females. The prevalence varied
considerably by age and was highest in males aged
20–29 years (27.4%) and 30–39 years (28.2%). This
screening programme showed that cigarettes remain
the preferred method of smoking: 78% of smokers
use cigarettes while 15% use a Midwakh and 6.8%
prefer to use a shisha, although shisha smoking has
increased over the past 30 years.14 Furthermore,
smoking a Midwakh is cheaper than cigarettes as a
week’s supply of Dokha for an average smoker costs
US$3 compared with US$21 for the average cigarette
tobacco. Although shops are required to check the
buyer’s age before selling cigarettes, this is not always
practised for the sale of Dokha.15 Despite this, the
prevalence of smoking in the UAE is still lower than in
many other countries.10
A study conducted by the Health Authority Abu Dhabi
(HAAD) in government and private schools suggested
that 25% of students had tried smoking before the
age of 10 years.16 The study concluded that the home
environment, i.e. exposure to smoke and the smoking
habits of their parental role models, contributes to
youngsters taking up smoking early in life.16
Another study carried out by HAAD in 194 schools in
2005 and in 52 schools in 2010 revealed that 48.3%
of smoking students were Emiratis and 51.7% were
expatriates; 15.7% of the students started smoking
before the age of 12 years and 67% between 13 and
15 years of age. Approximately 21% of the students
had parents who smoked at home.16
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Original Research Article
Tuberculosis
Tuberculosis (TB) is another challenging public health
concern and is the most prevalent infectious disease,
with over one-third of the world’s population infected
with latent TB. According to WHO, the incidence of TB
in the UAE was 3.1% per 100 000 people in 2010.17,18
Fortunately, the rates of TB in the UAE are low
compared with other countries; however, the main
challenge is to monitor the majority of workers
coming from countries with a high prevalence of TB,
such as in Asia and Africa. Health Authority Abu Dhabi
statistics show that newcomers to the country have a
20-fold higher TB rate than UAE nationals, which is a
huge risk to the resident and national population.
There has been a sharp increase in the number of
would-be migrants who are suffering from TB. Studies
conducted by HAAD16 suggested the increase was
consistent with findings from WHO in which an
increase in the number of drug-resistant TB cases in
Asia was reported.
According to the Dubai Health Authority, and
supported by findings form HAAD, a sharp increase in
the prevalence of TB has been reported over the past
4 years among those applying for work and residency
visas within the UAE. There were 122 cases of TB
detected in 2008, which increased during 2009 and
increased further during 2010 to 722 cases. During
the initial 3 months of 2011, there were 606 reported
TB cases.19
According to HAAD statistics,16,20 there were 450 cases
of pulmonary TB and 175 cases of extrapulmonary TB
registered in the Emirate of Abu Dhabi during 2010.
A study carried out in Al-Qasimi Hospital between
2004 and 2008 found a high level of resistance to
anti-TB drugs, with 21% of patients being resistant to
isoniazid and 14% to streptomycin.21 Another study
on all pulmonary and extrapulmonary TB patients
with positive culture results was conducted between
January 2001 and December 2008 in Abu Dhabi and
reported that resistance to anti-TB drugs, such as
isoniazid and pyrazinamide, was as high as 27.7%.22
A 2010 study conducted by HAAD23 summarized the
risk of TB among 948 504 Abu Dhabi residents: 14%
of the 1558 people who had TB were found to have
a positive interferon-gamma release assay result,
indicating that they carry a latent form of TB that may
230
reactivate at any time. In addition, 9% had a positive
response to the tuberculin skin test. These results
showed that there is a potential risk of activation of TB
in some individuals, with consequent spread of TB to
the community.
Pneumonia
Pneumonia is a health problem that mainly affects
children under the age of 5 years and adults over
65 years. Figures from WHO show that 5% of deaths
among children under the age of 5 years in the UAE
are caused by pneumonia.
A study carried out at Sheikh Khalifa Medical City
found that the prevalence of pneumococcal disease
among children was far higher in the UAE than in the
West before the introduction of a vaccine against
seven strains of the pneumococcal bacteria in the
UAE that can lead to pneumonia.24
The incidence of invasive pneumococcal disease and
non-invasive pneumococcal disease is 13.6/100 000
per year (95% CI 6.5–24.9) and 172.5/100 000 per
year (95% CI 143.8–205.2), respectively. The total
incidence of pneumonia in the UAE is 186.0/100 000
per year (95% CI 156.2–219.9). For comparison, in
North America, the reported annual incidence of
pneumonia is 72 per 100 000 in southern California
and 11.8–16.1 in Canada.25,26 In Europe, the annual
incidence per 100 000 is 42.1 in Great Britain, 24.2 in
Finland and 10.1 in Germany,27–29 while the incidence
in Australia is 12.7/100 000.30 In Saudi Arabia, the
reported incidence of pneumonia is 3.4–53.5 per
100 000 per year.31
Obesity
Obesity is becoming a major medical concern in
several parts of the world, with huge economic
impacts on healthcare system, mainly as a result
of the associate in increased cardiovascular risks.
In addition, obesity leads to a number of sleep
disorders and interrupted breathing patterns such as
obstructive sleep apnoea and obesity hypoventilation
syndrome, which leads to increased morbidity and, as
a result, reduced quality of life.
A study carried out at Rashid Hospital, UAE, using the
Berlin Questionnaire, found that 15% of the residents
in Dubai experience sleep disorders, which is lower
than the average number of residents in the USA and
the UK where a quarter of the population typically
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:227–232 (http://dx.doi.org/10.7707/hmj.v6i2.251)
Original Research Article
experience such problems.32 In a country such as the
UAE, where nearly two in five women, and more than
a quarter of men, are obese, this is a major problem.
11
12
Conclusion
Respiratory diseases are a major health concern
in the UAE. Demographic data suggest that social
and cultural norms will play an important role in
formulating strategies for patient education, creating
appropriate country-wide health facilities and gaining
governmental support in order to improve the health
of UAE residents and decrease the future financial
burden on healthcare organizations.
13
14
15
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Hamdan Medical Journal  2013; 6:233–240 (http://dx.doi.org/10.7707/hmj.v6i2.248)
 
Original Research Article
A study in pleiotropy – Jalili syndrome
Pratibha Nair,1 Tasneem Obeid,1 Ghazi Omar Tadmouri,1,2 Najib Al-Khaja1 and
Ismail K Jalili3
Centre for Arab Genomic Studies, Dubai, United Arab Emirates, 2Faculty of Public Health,
Jinan University of Lebanon, Tripoli, Lebanon, and 3Stamford, UK
1
Abstract
Jalili syndrome, first described 25 years ago in a Palestinian family, is a rare
autosomal recessive genetic disorder that is characterized by the comorbid
appearance of cone–rod dystrophy (CRD) and amelogenesis imperfecta.
To date, 71 patients with this condition belonging to 17 different families
have been reported worldwide. Studies into the molecular aetiology of
Jalili syndrome have identified mutations in the CNNM4 gene, located
on chromosome 2q11. Other members of this protein family have been
shown to be involved in mineral transport. We postulate a role for the
CNNM4 protein in metal ion transport and homeostasis and especially in
the transport of magnesium ions. Mutations in the gene could interfere
with the depolarization process of retinal cells, as well as in the dental
biomineralization process. We also show that mutations localized to the
transmembrane domain of this protein result in more severe phenotypes of
the syndrome, indicating an important function for this domain, probably
as a transmembrane channel for metal transport. Jalili syndrome offers
an example of how a single mutation in a gene is capable of affecting
two independent traits by causing a defect in a single protein that carries
out essentially the same function in two different tissue types. Given that
274 inherited disorders, almost exclusively reported in Arab families, have
no defined genetic aetiologies as yet, and with the increasing trend of
genome-wide association studies in the region, it is highly plausible that
more conditions will be assumed to be manifestations of pleiotropy.
Introduction
Cone–rod dystrophy (CRD) refers to a clinically and
genetically heterogeneous group of retinal disorders
in which the cone photoreceptors are initially, and
primarily, affected by a progressive and degenerative
process. This is followed by the degeneration of
the rod photoreceptors; however, simultaneous
Correspondence: Ghazi Omar Tadmouri, Centre for Arab Genomic
Studies, 22252 Dubai, United Arab Emirates and Faculty of Public
Health, Jinan University of Lebanon, Tripoli, Lebanon.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
degeneration of both types of photoreceptors can
occur. Clinically, CRD is characterized by a progressive
loss of vision, photoaversion (photophobia) and
achromatopsia, but it can also present as nystagmus
and visual impairment. Cone dysfunction is
followed by the loss of photopic function during
electrodiagnostic tests and various degrees of
abnormalities in the scotopic responses, which
is commonly known as night blindness. The loss
of central vision in those suffering from CRD is
progressive, with an eventual loss of peripheral visual
fields and total blindness. The severity and rapidity of
the loss of vision with CRD is worse than in rod–cone
dystrophy (RCD) and is commonly referred to as
retinitis pigmentosa (RP).1
CRD occurs in both non-syndromic and syndromic
forms. At least 15 subtypes of non-syndromic CRD
are currently recognized, each with a distinct genetic
locus. X-linked forms of CRD include CORDX1
[Online Mendelian Inheritance in Man (OMIM):
304020], CORDX2 (OMIM: 300085) and CORDX3
(OMIM: 300476). Autosomal forms of CRD are more
common and include dominant forms such as
CORD2 (OMIM: 120970), CORD6 (OMIM: 601777),
CORD7 (OMIM: 603649) and CORD14 (OMIM: 602093),
and recessive forms such as CORD3 (OMIM: 604116),
CORD5 (OMIM: 600977), CORD8 (OMIM: 605549) and
CORD9 (OMIM: 612775). These loci contain genes
that code for a diverse range of proteins that play an
important role either in the visual cycle, including
forming structural components of photoreceptors
and acting as photoreceptor-specific transcription
factors, or in ocular neuronal development. Many
of these genes are also involved in RCD, macular
233
233
Hamdan Medical Journal  2013; 6:233–240 (http://dx.doi.org/10.7707/hmj.v6i2.248)
Original Research Article
dystrophies and cone dystrophies.1 Syndromic CRD
has been increasingly reported.2
Amelogenesis imperfecta (AI) is another group of
heterogeneous disorders; however, this relates to
dental development. All AI cases are characterized
by abnormal structure and/or clinical appearance
of the tooth enamel, which is seen in both primary
and secondary dentitions. Neglect results in various
degrees of decay with the eventual loss of teeth.
Based on the histological and morphological changes
in enamel, two forms of AI exist, a hypoplastic form
and a hypomineralized form; however, these types
may overlap.3 Genetically, all except one form of
non-syndromic AI are transmitted autosomally;
the one exception, AI1E (OMIM: 301200), is an
X-linked form. Autosomal dominant forms of AI
are predominantly hypoplastic and include AI1B
(OMIM: 104500), AI3 (OMIM: 130900) and AI4
(OMIM: 104510). The autosomal recessive forms of
AI are seen predominantly in countries with high
rates of consanguinity or with a high frequency of
the mutated gene within the population.4,5 These
include AI1C (OMIM: 204650), AI2A1 (OMIM: 204700)
and AI2A2 (OMIM: 612529). The genes at the abovementioned loci are all involved in the process of
highly mineralized dental enamel formation.6 AI can
also present alongside other syndromes, such as
enamel renal syndrome, Kohlschutter–Tonz syndrome
and trichodento-osseous syndrome.
This article reviews the rare Jalili syndrome
(OMIM: 217080), which is characterized by the
co-occurrence of CRD with AI, and highlights the
contribution of Arab scientists in the identification of
rare and novel genetic disorders.
Historical background
The appearance of CRD and AI as comorbidities in
the same individual was named Jalili syndrome in
honour of Ismail Jalili, an ophthalmologist of Iraqi
origin who first reported the condition in 29 members
of an extended Arab family from the Gaza Strip (the
Jalili A subjects).7 These patients, identified during
blind school surveys, presented with photophobia,
nystagmus and achromatopsia, and all dentate
members showed abnormal teeth, with either a
complete absence of enamel or gross hypoplasticity.
The affected family had a very high rate of
consanguinity, with 91% of marriages being between
cousins.8 This high level of consanguinity pointed
towards an autosomal recessive mode of inheritance.
In the 20 years since the identification of Jalili
syndrome, families affected with this rare syndrome
have been found in several ethnically diverse
populations. Jalili reported on another affected
family from Gaza City (the Jalili B subjects) as well
as a singleton from another family in the Gaza Strip
(the Jalili C subject).9 Interestingly, several other
cases from the Jalili A family are known to reside
in some oil-producing countries. In addition to the
published cases, a further six patients with Jalili
syndrome have been identified from four families.
One is a Caucasian child, while all of the others are
of Middle Eastern or North African origin (Professor
Chris Inglehearn, St. James's University Hospital, 2012,
personal communication). Over 71 patients, including
the unreported cases, have been recognized to be
suffering from Jalili syndrome to date and these
patients belong to approximately 38 sibships
(Figure 1 and Table 1). In most cases of Jalili syndrome,
it is the ocular phenotype that is most prominent
and is the first anomaly observed. In a recent study
of a family with achromatopsia, the presence of Jalili
syndrome was initially suggested by the results of
molecular analysis testing, prompting the researchers
to look for a corresponding dental phenotype, which
they then found.10
Figure 1  Graphical representation of the cyclin M4 (CNNM4) protein domains (coloured boxes), polymorphisms (labelled
in blue) and disease-causing mutations (labelled in red) that were discovered in those members of a family suffering from
Jalili syndrome. The mutation data are adapted from Table 1. Polymorphism and protein domain data are from Swiss-Prot
(www.uniprot.org), PhosphoSitePlus (www.phosphosite.org), and InterPro (www.ebi.ac.uk/interpro/) databases. CBS,
cystathionine beta-synthase domain; cNMP, cyclic nucleotide monophosphate domain; DUF21, domain of unknown
function; TM, transmembrane helix.
234
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Original Research Article
Clinical heterogeneity
Wide intrafamilial and interfamilial phenotypic
variability is noted in the families affected by Jalili
syndrome. On the basis of retinal morphology, Jalili
distinguished two phenotypes: one with early-onset
macular dystrophy (type A) and a second with no
morphological evidence of macular involvement
(type B).9 Macular lesions ranged from an early
bull’s eye and/or chorioretinal excavation to
large-scale excavation of the macula and posterior
staphyloma (coloboma). As the disease advances,
the peripheral retina becomes more involved
with eventual contraction of the peripheral fields
and ultimately total blindness. This creates a very
similar presentation to classical RP, including the
development of cataracts in some patients. The
tendency for wide heterogeneity in the retinal
phenotype has been explained by the embryological
origin of the retina, which develops from the part of
the brain that exhibits variable expression, as well as
variable levels of disease susceptibility, second site
modifiers and epigenetics. This may also explain the
absence of such phenotypical variability of dental
forms of the disease.9
Molecular genetics
Cone–rod dystrophy and AI seem to be distinct
entities that affect two entirely different tissues, and
their co-occurrence could be due either to chance
alone or to a tight linkage between the individual
genes concerned. However, the fact that this
comorbidity has been observed in a large number
of individuals in the present study, and within
several different families, shifts the balance from a
random association, or strong linkage, to a single
underlying factor.
The first clue in identifying the molecular pathology
of Jalili syndrome was reported by Downey et al.,11
who studied the two main families previously
mentioned (Jalili A subjects and Jalili B subjects).7,9
This study utilized linkage analysis to pinpoint
the locus to a 5-Mb region on chromosome 2q11.
However, the strongest contender for a putative gene
at this location, the CNGA3 gene, which codes for a
part of the ion channels in photoreceptor cells, was
found to not contain any pathogenic mutations in
these families;11 similar results were obtained from
an affected Kosovan family.12 The gene responsible
for Jalili syndrome was discovered simultaneously by
two groups working independently on families with
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
both CRD and AI. In one of these studies, six patients
belonging to three different families were screened
for putative genes in the identified locus at 2q11.
Sequencing of these genes led to the identification
of mutations in the cyclin M4 (CNNM4) gene, which
appeared to be the cause of the disorder.13 The other
study utilized a much larger patient population,
including the previously described families from
Palestine (Jalili A subjects and Jalili B subjects) and
Kosovo as well as other newly identified families from
Guatemala, Turkey, Iran and Scotland, and arrived at
the same conclusion.14
The CNNM4 gene codes for a protein that belongs
to the ancient conserved domain protein (ACDP)
family. This family of proteins is characterized by
the presence of a highly conserved region found
in evolutionarily divergent species from bacteria
to mammals. Additionally, all four proteins in this
family contain a 31-residue cyclin box motif, a cyclic
nucleotide monophosphate (cNMP)-binding domain
and two cystathionine beta-synthase domains.15
In addition, the CNNM4 protein contains four
transmembrane helices, which suggests plasma
membrane localization, and a domain of unknown
function 21.14 At least two other members of this
family have been shown to be involved in mineral
transport: cyclin M1, which functions as a cytosolic
copper chaperone,16 and cyclin M2, which has a role in
the transport of magnesium.17 It is, therefore, possible
to visualize a role for CNNM4 in metal ion transport
and homeostasis, especially in the transport of
magnesium ions. Further support for this hypothesis
comes from the known interaction of CNNM4 with
COX11, an intracellular metal ion chaperone.18
So far, 12 different mutations have been identified in
the CNNM4 gene in 13 families worldwide (Table 1).
As expected, in all affected individuals with a history
of parental consanguinity, the mutations were
homozygous, whereas patients belonging to the
non-consanguineous families (the Guatemalan and
Scottish cases) carried heterozygous mutations
(Table 1).13,14 More recently, Zobor et al.19 identified
the same mutation in all patients with Jalili syndrome
from Kosovo, indicating the possibility of a founder
mutation in this population.
The families from the Gaza Strip carried two
different mutations, each in homozygous form.
Interestingly, these two mutations were found to
exhibit considerably variant phenotypic effects. The
c.599C > A (p.Ser200Tyr) mutation, in the homozygous
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Original Research Article
Table 1  Clinical and genetic features of patients reported with Jalili syndrome
a
Origin (family code)
Number of
patients Sibships Age/age range
Male–
female ratio Consanguinity Mutation 1/mutation 2 Protein change
Gaza (Jalili A)c
36
20
3 months–
50 years
20:16
Gaza (Jalili B)
3
1
Gaza (Jalili C)
1
Lebanon (Polok B)
Yes
c.599C > A/c.599C > A
p.Ser200Tyr
5, 6 and 10 years 1:2
Yes
c.1813C > T/c.1813C > T
p.Arg605X
1
17 years
1:0
Yes
Was not tested
–
3
2
2 years
1:0
Yes
c.707G > A/c.707G > A
p.R236Q
Kosovo (Michaleides UK)
2
1
7 and 14 years
2:0
No
c.1312dupC/c.1312dupC
p.Leu438ProfsX9
Kosovo (Polok A)
2
1
7 and 14 years
0:2
No
c.1312dupC/c.1312dupC
p.Leu438ProfsX9
Kosovof
1
1
9 years
1:0
No
c.1312dupC/c.1312dupC
p.Leu438ProfsX9
Unknown (Polok C)
1
1
38 years
0:1
No
c.971T > C/c.971T > C
p.Leu324Pro
Turkey
2
1
5 and 6 years
0:2
Yes
c.586T > C/c.586T > C
p.Ser196Pro
Iran
4
2
NA
2:2
Yes
Guatemala
5
1
NA
5:0
No
Scotland
1
1
NA
1: 0
No
Newfoundland
4
1
47–54 years
1:3
Yes
c.1?_1403+?del/
NA
c.1?_1403+?del
c.2149C > T/c.62_145 del p.Gln717X/p.
Leu21HisfsX185
c.971T > C/c.1690C > T
p.Leu324Pro/p.
Gln564X
c.1555C > T
p.R519X
Unpublished
6
4
–
–
–
One compound heterozygous for a new
mutations, the remainder are homozygous for
new/known mutations
Clinical presentation at onset as described by either the family or medical personnel.
Based on the World Health Organization (WHO) categorization.21
b
c
Probable Saudi Arabian origin. Includes 30 examined patients, one screened but declined full examination and five cases lived abroad: two in Saudi Arabia, two in Algeria and one in Libya
(correct in September 1987).
Visual impairment was present but visual acuity was unreported.
d
Based on comment by the author of close resemblance to family Kosova A.
e
f
These patients were associated with neurofibromatosis of two separate alleles and Lisch nodules were present on both irises.
CBS, cystathionine beta-synthase domain; cNMP, cyclic nucleotide monophosphate; DUF21, domain of unknown function; NA, not available; TM1, transmembrane domain 1; TM2,
transmembrane domain 2.
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Hamdan Medical Journal  2013; 6:233–240 (http://dx.doi.org/10.7707/hmj.v6i2.248)
Original Research Article
Visual
acuityb
Night
Macular
Refraction blindness Photophobia phenotype
Macular
degeneration
Photophobia,
nystagmus and visual
impairment
cNMP-binding Teeth anomalies and
domain
visual impairment
NA
NA
1–5
Low myopia No
to high
hyperopia
+5.00
No
Yes
Maculopathy
Bull’s eye to
excavation
Yes
+3.00
average
No
Yes
DUF21
Visual
High
impairmentd hyperopiae
Yes
Yes
3
Yes
Yes
Yes
Yes
Low myopia No
Yes
Low myopia Yes
Yes
Maculopathy
TM2
Photophobia,
4
nystagmus and visual
impairment
Photophobia and night 4
blindness at 2 years
and nystagmus at
2 months
NA
NA
Normal macular Normal
morphology
morphology
Maculopathy
Posterior
staphyloma
(coloboma)
Maculopathy e Atrophic macular
degeneration with
pigment mottling
Maculopathy
Yes, macular
pigment mottling
and atrophy
Maculopathy
Atrophic macular
degeneration with
pigment mottling
Maculopathy
Bull’s eye
NA
NA
NA
14
–
NA
NA
NA
NA
NA
Normal macular Normal
morphology
morphology
NA
NA
–/TM1
NA
NA
NA
NA
NA
NA
14
DUF21/-
NA
NA
NA
NA
NA
14
Myopia
NA
NA
Normal macular Normal
morphology
morphology
Maculopathy
NA
–
–
–
Professor Chris
Inglehearn, St.
James's University
Hospital,
2012, personal
communication
Affected
domain
Presentationa
TM2
CBS domain
CBS domain
CBS domain
DUF21
Photophobia, night
blindness and
nystagmus at 2 years.
Photophobia,
nystagmus and teeth
anomalies
Photophobia and
nystagmus
2–3
4
3–4
Between CBS Nystagmus and severe 2–3
and cyclin box enamel dysplasia
domains
Moderate
to high
hyperopia
High
hyperopia
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Bull’s eye
NA
–
References
7, 9, 14
9, 14
9, 20
13
12, 14
13
19
13
14
10
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Hamdan Medical Journal  2013; 6:233–240 (http://dx.doi.org/10.7707/hmj.v6i2.248)
Original Research Article
form, was found to be associated with a severe
infancy-onset form of the syndrome with progressive
macular lesions, while the c.1813C > T (p.Arg605X)
mutation was associated with a relatively less severe
form of childhood onset with normal fundi.9 The
former mutation has been found to affect one of
the transmembrane domains in the ACDP family,
while the latter inserted a stop mutation in the
cNMP-binding domain.14 These observations prompt
us to suggest that the transmembrane helix domains
within the protein have an important functional role
to play, which may be associated with the formation
of transmembrane ion channels facilitating transport
of metal ions. This hypothesis is strengthened by the
observation that other patients with mutations in the
transmembrane domains also show a more severe
form of the syndrome (Table 1).
Jalili9 suggested the possibility that high fluoride
levels in the groundwater of the Gaza Strip, as
well as in the regions where the reported cases
of Jalili syndrome originated, may have a role to
play in establishing the original mutation. There
is some evidence to suggest genotoxic effects
from long-term exposure to fluoride in drinking
water.22 It is possible that this high fluoride level in
the groundwater, together with increased water
intake in hot climates and low calcium intake due to
malnutrition, could have triggered the mutagenesis
in the index cases. Spread of this mutation resulted
in a proportionally higher number of patients in an
extended family suffering from Jalili syndrome and
can be attributed to the high level of consanguinity
and the high fertility rate in the population. The rate
of consanguinity in the extended Jalili A family was
91% and is very similar to the consanguinity rate of
92% among parents of Palestinian Arabs suffering
from autosomal recessive genetic disorders.23 The
remainder of families reported with Jalili syndrome
can also be traced back to regions recognized for
their high fluoride levels in groundwater or from
neighbouring regions.24,25 This hypothesis calls for
further investigations including analysing the effects
of other water contaminants.
One protein, many functions
Pleiotropy, a term coined by the German geneticist
Ludwig Plate,26 is the phenomenon whereby a single
gene affects two or more apparently unrelated
phenotypic traits. A stricter definition involves a
mutation in the gene affecting two or more wild-type
traits. The phenomenon has been discussed in genetic
238
circles since Mendelian times; however, support for
the importance of this phenomenon was dealt a
blow by the popularity of the one gene–one enzyme
hypothesis during the previous century. It was only
with the advent of the �molecular age’ that pleiotropic
effects were understood more clearly, resulting in the
current recognition of pleiotropy in higher organisms
as the rule, rather than the exception.27
Jalili syndrome offers an example of how a single
mutation in a gene is capable of affecting two
independent traits by causing a defect in a single
protein that carries out essentially the same function
in two different tissue types. The importance of
metal ions in the depolarization of the retinal cells
is well understood. The CNNM4 protein may be
playing a key role in the maintenance of this state
through transport of magnesium ions, which act as
cofactors for several enzymes involved in the retinal
transduction process; however, during development
of the dentition, the enamel begins with a relatively
high concentration of magnesium deposit, which
is progressively removed, in order to aid the dental
biomineralization process. A failure of removal of
these ions could lead to hypomineralized teeth.28
The possible role of CNNM4 in magnesium transport
could also explain how mutations in the gene
may lead to dental abnormalities. The functional
significance of the CNNM4 protein is further
supported by histological studies that show the
localization of the protein within the retina in the
ganglion cell layers, inner and outer plexiform layers,
the outer segments of the photoreceptors and in the
ameloblasts as well as the odontoblasts of the teeth.13
Interestingly, Zobor et al.19 recently described a
Kosovan girl who presented with Jalili syndrome in
association with type 1 neurofibromatosis. This can
be considered a random association, with mutations
in two different genes causing two unrelated
conditions; however, although Jalili syndrome
is a rare condition, the relatively high frequency
of the mutant allele in the Kosovan population
could explain this comorbidity. Cases such as this
are more likely in populations with high rates of
consanguinity, e.g. in Arab countries. Reproductive
choices in such populations are biased towards the
amplification of rare genetic disorders and there is a
heightened tendency for more than one autosomal
recessive gene disorder to simultaneously manifest
itself. Comorbid conditions are therefore common
in this region.29 In fact, the third Palestinian family
with the affected singleton (the Jalili C subject),
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:233–240 (http://dx.doi.org/10.7707/hmj.v6i2.248)
Original Research Article
described by Jalili9, is also a highly inbred family and
has multiple members affected with other genetic
conditions, including subnormal intelligence, ptosis
and buphthalmos.
Jalili syndrome is just one of nearly 1000 genetic
conditions that are known to cause various forms of
inherited disorders in Arab populations.30 This is in
addition to several other new syndromes described
among the Palestinian population.31,32 Of these
conditions, a large majority of the 735 known genetic
disorders are associated with well-documented gene
pathologies, and include 71 disorders that have been
clinically and genetically characterized in the last
12 years for the first time in Arab families.33 Several
clinical conditions, other than Jalili syndrome, have
been described in Arab populations in the last two
decades under the influence of genetic pleiotropic
events, including achalasia–addisonianism–alacrimia
syndrome (triple-A or Allgrove syndrome);
Bartter syndrome with sensorineural deafness;
branchiogenic–deafness syndrome; chorioretinal
dystrophy, spinocerebellar ataxia and
hypogonadotropic hypogonadism; dysmyelinating
leucodystrophy with oligodontia, El-Shanti syndrome;
Rambam–Hasharon syndrome, which causes
psychomotor retardation with short stature, defective
neutrophil motility and Bombay phenotype; and
Waardenburg–Hirschsprung disease.34–38
Given that 27439 inherited disorders, almost
exclusively reported in Arab families, have no defined
genetic aetiologies as yet, and with genome-wide
association studies being increasingly carried out in
the region, it is highly plausible that more conditions
will be assumed to be manifestations of pleiotropy.
The benefits that will be gained from such studies are
twofold: the confirmation of the role of pleiotropy
in the molecular aetiology of clinically complex
disorders; therefore, facilitating correct diagnosis, and
the perception that pleiotropy has possibly been an
important evolutionary component that shaped the
extreme variety of genetic conditions observed in
the region.
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В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:241–246 (http://dx.doi.org/10.7707/hmj.v6i2.193)
 
Case report
Birth of a healthy boy after fertilization of a
cryopreserved oocyte and testicular spermatozoon
followed by preimplantation genetic screening
Hena Zaheer, Mohammed Elkalyoubi, Wael Ismail Madkour, Maise Al Adham and
Awatif Albahar
Dubai Gynaecology and Fertility Centre, Dubai, United Arab Emirates
Introduction
We report the birth of a healthy male infant from
a pregnancy resulting from a thawed from frozen
oocyte on which intracytoplasmic sperm injection
(ICSI) was performed using a thawed from frozen
spermatozoon obtained from testicular aspiration.
Preimplantation genetic screening (PGS) was
performed on the embryo at the cleavage stage
(day 3) to determine the sex.
Expressing a preference for a child of a particular
sex has existed for years. Greek philosophers and
medical workers offered detailed advice on the
means to ensure the production of a child of a
chosen sex. Aristotle gave advice on positions for
sexual intercourse and a desirable diet for the mother
whereas Anaxagoras believed that each testicle
determined one sex and advocated tying off one
testicle before coitus, and Hippocrates deduced that
male and female children developed in different parts
of the uterus.1
Preimplantation genetic screening for sex selection
is an extremely sensitive issue. The application of
techniques for sex selection, including the use of
preimplantation genetic diagnosis (PGD), creates
moral and ethical concerns in the opinion of some,
Correspondence: Hena Zaheer, Dubai Gynaecology and Fertility
Centre, PO Box 8729, Dubai, United Arab Emirates.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
while the advantages of sensible use of selected
technologies is favoured by others.
Since PGS is rarely performed in many in vitro
fertilization (IVF) centres, no standard treatment
protocol has been established, although a number
of births have been recorded. Cryopreservation
of oocytes combined with ICSI could offer young
women undergoing chemotherapy or radiotherapy
a reasonable option to preserve and balance
their family.2
Although the cryopreservation of oocytes is ethically
more acceptable than the freezing of embryos,
variable oocyte survival and pregnancy rates have
precluded the application of oocyte cryopreservation
in assisted reproductive technology. Cytotoxicity of
the cryoprotectants, poor survival, low fertilization
rates and high rates of polyploidy3–7 have prevented
the widespread use of oocyte cryopreservation,
despite reports of healthy and normal babies.3,4,5,8
Resurgence of interest in human oocyte
cryopreservation shows that it may be safe in
appropriate circumstances and its clinical application
has resulted in a number of live births. Development
of oocyte cryopreservation is being pursued
because embryo cryopreservation is prohibited in
some countries, such as Italy and the United Arab
Emirates (UAE).
More than 1000 babies have been born as a result
of preimplantation genetic testing, attesting to the
241
241
Hamdan Medical Journal  2013; 6:241–246 (http://dx.doi.org/10.7707/hmj.v6i2.193)
Case report
accuracy and safety of the procedure, which as a
result has gained a place as a good alterative among
the choices offered to couples at risk of transmitting
serious and incurable genetic diseases.
We report the first case of sex selection of an
embryo resulting from a frozen oocyte and a frozen
spermatozoon obtained from a testicular sperm
aspiration (TESA). PGS was then performed for
non-genetic social reasons (sex selection).
Case Report
A couple visited Dubai Gynaecology and Fertility
Centre for their second complaint of infertility over
a 5-year period. Mrs X is a 31-year-old woman in
whom four natural pregnancies had resulted in three
normal deliveries at full term and one, the last, in
a spontaneous miscarriage at 6 weeks’ gestation
(i.e. P3+1). Over time, Mrs X’s husband developed
non-obstructive azoospermia and he has suffered
from diabetes for the past 9 years. His hormonal
profile was normal and a TESA was performed and
the sperm cryopreserved. Testicular sperm freezing
was carried out with the use of a HEPES-buffered
freezing medium (SpermFreeze Solutionв„ў; Origio
MediCult, Jyllinge, Denmark) containing 0.4% (v/v)
human serum albumin. After centrifugation of partly
disintegrated testicular tissue (2500 g for 10 minutes),
the pellet was rinsed with 0.4 ml of universal IVF
culture medium, CE marked (Origio MediCult, Jyllinge,
Denmark), mixed with SpermFreeze Solutionв„ў in
a 1:1 ratio, equilibrated at room temperature for
10 minutes and loaded into vials. The vials were
first placed vertically in liquid nitrogen vapour for
15 minutes and then plunged into liquid nitrogen.
Mrs X has regular menstrual periods but also a
strong family history of diabetes mellitus. Her
hormonal profile was within normal limits; however,
a scan showed that she had polycystic ovaries. She
had a controlled ovarian hyperstimulation on a
long down-regulation protocol with recombinant
follicle-stimulating hormone (rFSH) when 35 eggs,
20 metaphase II (MII) mature oocytes, were collected
and frozen to prevent ovarian hyperstimulation.
Oocyte cryopreservation was conducted by
vitrification. The oocytes were vitrified according to
the Cryotop method.9,10 Basic solution (BS) was used
as a buffer and equilibration solution (ES) was made
up of 7.5% (v/v) ethylene glycolВ© (EGВ©) (Kitazato
BioPharma Co., Ltd, Fuji, Shizuoka, Japan) and
242
7.5% (v/v) dimethylsulphoxideВ© (DMSOВ©) (Kitazato
BioPharma Co., Ltd, Fuji, Shizuoka, Japan). Vitrification
solution (VS) was prepared with 15% (v/v) EGВ©, 15%
(v/v) DMSOВ© and 0.5 mol/l sucrose. One drop of BS
was aligned with three drops of ES and two drops of
VS in a small Petri dish and these solutions were then
allowed to equilibrate to room temperature (25В°C) for
15 minutes.
Oocytes were then placed briefly in the BS drops and
a channel was opened with first drop of ES to allow a
gradual increase in the cryoprotective concentration
and keep the oocytes on the edge of the BS drop for
3 minutes at room temperature. A new channel was
then made with next ES drop to transfer the oocytes
to the edge of the first ES drop and keep them there
for another 3 minutes at room temperature. These
oocytes were then transferred to the third ES drop
for 9 minutes at room temperature. Oocytes were
then transferred to the first drop of VS for 1 minute
and then the second VS drop for 30 seconds and
subsequently loaded on the flattened tip of the
Cryotop with approximately 2 μl of VS. The Cryotop
was then immersed directly in liquid nitrogen and
stored in the freezing tanks.
Two months later, Mrs X had a trial of ICSI of frozen
oocytes by spermatozoa obtained from a frozen
TESA conducted earlier. At the time of thawing, the
vials were removed from liquid nitrogen and rapidly
placed in warm water (30В°C). After expulsion from
the vials, the thawed samples were washed with
universal IVF culture medium, centrifuged at 2500 g
twice for 10 minutes each time and the pellet was
then resuspended in a small volume of the same
universal IVF culture medium, and incubated at 37В°C
for 30 minutes before being used for ICSI.
Nine oocytes were thawed and the vitrified oocytes
were warmed by swiftly immersing the Cryotop in
the thawing solutionВ© (Kitazato BioPharma Co., Ltd,
Fuji, Shizuoka, Japan) containing 1 mol/l sucrose for
1 minute at 37В°C. The oocytes were then equilibrated
in a diluent solutionВ© (Kitazato BioPharma Co., Ltd,
Fuji, Shizuoka, Japan) containing 0.5 mol/l sucrose
for 3 minutes followed by two 5-minute consecutive
flushes in washing solutionВ© (Kitazato BioPharma Co.,
Ltd, Fuji, Shizuoka, Japan). These oocytes were then
placed in the fertilization medium (William A. Cook
Australia Pty Ltd, Brisbane, Australia) and incubated at
37°C in 6% CO2 air for 2 hours prior to ICSI.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:241–246 (http://dx.doi.org/10.7707/hmj.v6i2.193)
Case report
Eight oocytes survived thawing and were injected. All
were fertilized and cleaved and PGS was performed
for all embryos on day 3.
Biopsy medium (William A. Cook Australia Pty
Ltd, Brisbane, Australia) was warmed to 37В°C and
supplemented with human albumin solution.
Numbered drops of biopsy medium were layered in
a Petri dish under oil (William A. Cook Australia Pty.
Ltd, Brisbane, Australia) and embryos were loaded in
to the numbered drops. A hole was made in the zona
pellucida of 20 Ојm using laser-assisted hatching. The
location of the embryo was such that a nucleated
blastomere occurred at the 3 o’clock position. The
blastomere was slowly aspirated using aspiration
pipettes of 42 Ојm (William A. Cook Australia Pty
Ltd, Brisbane, Australia) and then released in to
the medium.
The biopsied embryos were then washed thoroughly
from the biopsy medium and incubated in culture
media (William A. Cook Australia Pty Ltd, Brisbane,
Australia) until transfer to the uterus. The blastomere
was then spread on frosted slides until it burst and the
nucleus became exposed. Fixation of the blastomere
was conducted using acetic acid and methanol in a
1:3 ratio. The slides then underwent genetic analysis
for sex selection and a single embryo of XY karyotype
was transferred in to the uterus. Endometrial
preparation was conducted on a down-regulated
cycle and Triptorelinв„ў (IPSEN, Boulogne-Billancourt,
France) 3.75 mg was given by deep intramuscular
injection on the second day of a spontaneous
menstrual period. A scan was conducted and a serum
estradiol (14 pg/ml) was obtained to confirm downregulation. Hormone replacement therapy (HRT)
was carried out using oral estradiol valerate (2 mg)
three times a day for 9 days, after which a scan was
performed to assess endometrial thickness, which
was found to be 9.5 mm. Progesterone suppositories
of 400 mg twice daily were prescribed as a luteal
support that was started on the first day of oocyte
thawing. Luteal support and HRT was continued until
the 12th week of gestation.
Mrs X became pregnant, which was confirmed by
ascertaining a single intrauterine gestational sac
containing a live fetus, and the pregnancy progressed
uneventfully until 35 weeks, when preterm rupture
of membranes induced the vaginal delivery of a
live healthy baby boy weighing 1.9 kg and with no
congenital abnormalities.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Discussion
Reproductive specialists who provide non-medical
sex selection services argue that this technology
was initiated and pursued by women and is an
expression of reproductive rights as well as a sign
of female empowerment. In addition providing
for family balancing and fulfilment of culture and
religious practice,11 non-medical sex selection allows
couples to make informed family planning decisions,
prevents unintended pregnancy and abortion, and
minimizes intimate partner violence and/or child
abuse.12 Opponents question whether women can
truly express free choice under family and community
pressures,13 and contend that sex selection is
incompatible with unconditional parental acceptance
of offspring and results in potential distortion of sex
ratios11 and sex discrimination.14 In addition, PGD
used only for sex selection involves preferential use
of embryos and termination of those embryos not
chosen, which raises ethical questions regarding
abortion. In the Dubai Gynaecology and Fertility
Centre, we consider social sex selection only for
family balancing and we have not noticed a persistent
preference for a particular sex, or social disagreement
or religious conflict.
The present study indicates that freezing of either
oocytes or spermatozoa can be efficient and can
avoid repetitive surgical procedures for future
attempts. PGS for sex selection of embryos can be
an option for couples, if the law permits. Although
Chen8 achieved the first frozen egg pregnancy
in 1986, this application was not adopted widely
for clinical assistance because survival of oocytes
and pregnancy rates were comparatively low. This
freezing method was based on a slow cooling and
rapid thawing procedure using propanediol and
sucrose as cryoprotectants, in line with the conditions
originally developed for embryo freezing. Alteration
of the ooplasm organelles, owing to the formation of
intracellular ice crystals, is one of the main changes
inflicted on the oocytes by the freezing process.15
Vitrification was first introduced in order to avoid
crystallization damage. Another advantage of this
freezing method is that it is very simple and based
on direct contact between the vitrification solution
containing cryoprotectants and liquid nitrogen.16
Vitrification is an ultra rapid freezing method using
high concentration of cryoprotectants (ethylene,
glycol and DMSO©) and rapid cooling at –1500°C/
minute, which helps to solidify without crystal
formation, which reduces the thermal stress of
243
Hamdan Medical Journal  2013; 6:241–246 (http://dx.doi.org/10.7707/hmj.v6i2.193)
Case report
oocytes and decreases injury. Borini et al.17 reported
pregnancies and births after oocyte cryopreservation
in 68 patients. Since then, several other pregnancies
have been reported worldwide.18 Cryopreservation
of human oocytes is still considered an experimental
technique despite improvements achieved over
the past few years;19 however, the cryopreservation
of spermatozoa is a widely used and efficient
technique that can avoid repetition of surgical
procedures for future ICSI attempts.20 The safety of
cryopreservation has now been established in the
human reproductive field.
Reports on the survival rates of cryopreserved human
oocytes using the PROH–sucrose freezing method
are highly variable, ranging from 25% to 95%,21
depending on the individual study. The establishment
of successful pregnancies from frozen oocytes is
highly dependent on the efficacy in preserving the
meiotic spindle or microtubule structures within
the oocytes after cryopreservation. There has been
a consensus that the microtubules within the
mammalian oocyte will depolymerize during freezing
and therefore early insemination of thawed from
frozen oocytes, before full restoration of meiotic
spindle, may compromise fertilization outcome and
subsequent embryonic development. An incubation
of 4 hours before insemination by ICSI may seem
to be an appropriate time to allow for the full
recovery of normal spindles in cryopreserved human
oocytes.22,23 Furthermore, hardening of zona pellucida
due to vitrification can be overcome by ICSI24 and
applying ICSI to the thawed human oocytes results
in reasonable fertilization and blastocyst rates of
50% and 43% respectively.18 More studies should
be carried out to explore the optimal conditions for
enhancing the developmental potential of thawed
from frozen human oocytes. Also, cryopreservation
of human oocytes has a role to play in preserving the
fertility of young women undergoing chemotherapy
or radiotherapy and in cases of IVF when a sperm
sample cannot be produced. In such cases, the
oocytes can be frozen and then thawed at a later
date when a sperm sample has been produced.
Additionally, cryopreservation of human oocytes
may play a role in circumventing ethical and legal
issues associated with the established practice of
cryopreservation of embryos.8 A number of babies
born in the past few years can be attributed to the
changes in the IVF laws, such as occurred in Italy and
the UAE in 2010.
244
The first birth from human oocyte cryopreservation
was reported in 1986.22,23 By 2004, approximately
100 children had been born from human oocyte
cryopreservation. Pregnancy rate was low at
1–5% due to low oocyte survival at 25–40%, poor
fertilization rate after IVF, the high incidence of
polyploidy and poor developmental capacity. The
incidence of chromosomal abnormalities was not
different from that associated with fresh oocytes.24
The European Society of Human Reproduction
and Embryology (ESHRE) PGD consortium was set
up in 1997 and has been collecting data on PGD
and PGS. Since 1997, the consortium has analysed
32 838 PGD and PGS cycles for various indications, of
which 786 cycles were conducted for social reasons.
Kuleshova et al.25 reported the birth of the first child
conceived using oocytes stored by vitrification, and
this was successfully followed by other studies and
reports of a further 10 pregnancies.26,27 Studies on
pregnancies from frozen oocytes inseminated with
epididymal and testicular28 spermatozoa have been
published, and the birth of a child conceived from
frozen oocytes and spermatozoa has been reported.29
Larger studies are needed to quote a realistic figure
of live birth rates from frozen oocytes. In addition,
it is crucial to follow up children conceived from
frozen oocytes.
In conclusion, this case is the first one of its kind in
the Gulf region, even, to our knowledge, in the world
where PGS was performed on an embryo obtained
from a cryopreserved oocyte and a cryopreserved
spermatozoon obtained from testicular aspiration
on which PGS was conducted for sex selection. This
was conducted for social reasons, balancing the
family, which was allowed under UAE law at that
time. This case also supports the concept that the
developmental competence of the oocyte is not
affected by vitrification of the oocyte and its biopsy.
Acknowledgement
I am extremely grateful to the staff of Dubai
Gynaecology and Fertility Centre for their
co-operation.
Disclosure
No author has any potential conflict of interest.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:241–246 (http://dx.doi.org/10.7707/hmj.v6i2.193)
Case report
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http://dx.doi.org/10.1111/j.1467-9566.2007.01021.x
Tucker M, Wright G, Morton P, Shanguo L, Massey J,
Kort H. Fertilization and early embryology: preliminary
experience with human oocyte cryopreservation
using 1, 2-propanediol and sucrose. Hum Reprod 1996;
11:1513–15.
Kuleshova L, Gianaroli L, Magli C, Ferraretti A, Trounson.
Birth following vitrification of a small number of human
oocytes: case report. Hum Reprod 1999; 14:3077–9.
http://dx.doi.org/10.1093/humrep/14.12.3077
Yoon TK, Kim TJ, Park SE, et al. Live births after
vitrification of oocytes in a stimulated in vitro
fertilization-embryo transfer program. Fertil Steril 2003;
79:1323–6.
http://dx.doi.org/10.1016/S0015-0282(03)00258-9
Katayama KP, Stehlik J, Kuwayama M, Kato O, Stehlik E.
High survival rate of vitrified human oocytes results in
clinical pregnancy. Fertil Steril 2003; 80:223–4.
http://dx.doi.org/10.1016/S0015-0282(03)00551-X
Porcu E, Fabbri R, Ciotti PM, Petracchi S, Seracchioli
R, Flamigni C. Ongoing pregnancy after
intracytoplasmic sperm injection of epididymal
spermatozoa into cryopreserved human oocytes.
J Assist Reprod Genet 1999; 16:283–5. http://dx.doi.
org/10.1023/A:1020375714978
Porcu E, Fabbri R, Damiano G, et al. Clinical experience
and applications of oocyte cryopreservation. Mol Cell
Endocrinol 2000 27; 169:33–7.
http://dx.doi.org/10.1016/S0303-7207(00)00348-8
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Case Report
Obesity surgery can be life saving
Sangram Jadhav1 and Sanjay Borude2
Dr DY Patil Medical College, Hospital and Research Centre, Pimpri, Pune, India, and 2Obesity
Surgery Clinic, Mumbai, India
1
Abstract
An 11-month-old female, who was born to consanguineous parents,
weighed 19 kg at the time of referral from the Endocrine Department of
Topiwala National Medical College and Nair Hospital to the Obesity Surgery
Clinic for consideration for bariatric surgery. The patient had been admitted
to the Endocrine Department of Topiwala National Medical College and Nair
Hospital by her parents at the age of 2 months. The parents had lost their
elder child at the age of 18 months and weighing 22 kg. The only chance of
survival for the patient was to perform laparoscopic sleeve gastrectomy.
Introduction
The prevalence of morbid obesity has risen sharply
in recent years, even among paediatric patients.1
Bariatric surgery is becoming an increasingly common
method of weight loss, with resulting improvement in
quality of life and increased survival.1
The weight gain pattern, as recorded, is shown in
Table 1.
The patient’s parents were able to provide a history
of breastfeeding, the frequency of which had been
about 12 or 13 times per day since the child had been
6 weeks old. Family history indicated that there had
been an elder child who suffered from morbid obesity
and respiratory complications and died at the age of
18 months, weighing 22 kg. There was no history of
obesity in either parent nor any history of seizures
or hearing or visual imparments. The patient was
referred from the Endocrine Department of Topiwala
National Medical College and Nair Hospital for
surgical management at the Obesity Surgery Clinic.
Following investigations, the patient showed normal
Laparoscopic sleeve gastrectomy is a recognized
surgical treatment for morbidly obese adults, and
such surgery is also performed in children between
10 and 12 years of age.2 However, this is the first time,
to our knowledge, that such surgery has been carried
out in a morbidly obese infant.
Case study
An 11-month-old girl was referred to the Obesity
Surgery Clinic on 19 November 2011 with a history of
excessive weight gain due to hyperphagia and a lower
respiratory tract infection which had been recurring
for over 2 months (Figure 1).
Correspondence: Dr Sangram Jadhav, Dr DY Patil Medical College,
Hospital and Research Centre, Pimpri, Pune 400703 India. Email:
[email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
247
FIGURE 1  The patient before the operation.
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Hamdan Medical Journal  2013; 6:247–250 (http://dx.doi.org/10.7707/hmj.v6i2.228)
Case Report
TABLE 1  Weight gain pattern
Date
3 December 2010
8 February 2011
29 March 2011
3 May 2011
8 November 2011
19 November 2011
Weight (kg)
Height (cm)
3
50
7.2
57
10.3
63
12.5
67.5
18
81
19
81
TABLE 2  Haemotology results
Blood component
Level
Free thyroxine
Thyroid-stimulating hormone
Serum insulin
Fasting blood sugar
Glycosylated haemoglobin type A1c
25-Hydroxyvitamin D
Serum vitamin B12
Serum calcium
Serum phosphorus
Serum magnesium
Serum iron
Leptin
1.2 nmol/l (0.82–1.8)
2.5 µU/l (0.35–5.5)
18.2 µU/ml
82 mg/dl
6.6%
14.0 nmol/l (30–74)
306 pg/ml (200–800)
9.82 mg/dl (8.4–10.2)
5.1 mg/dl (2.5–4.5)
2.27 mg/dl (1.6–2.3)
14.0 µg/dl (37–170)
95.0 ng/ml (n = 0.1–13.0 ng/ml)
U, unit.
FIGURE 2  The patient before the operation.
cognitive milestones and genitals and there was no
evidence of hypotonia. At the time of admittance to
the Obesity Surgery Clinic, the patient weighed 19 kg
and was 81 cm in height (Figure 2).
Haemography of the patient returned normal results,
which can be seen in Table 2.
In addition, ultrasonography revealed grade I fatty
liver whereas two-dimensional echocardiography
was normal.
An overnight dexamethasone suppression test
generated a result of 0.71 ng, which is less than the
value of 0.8 ng expected in a patient with Cushing’s
syndrome. A cortisol test conducted at 0800 hours
revealed cortisol levels of 22.8 mg/dl, which was within
the normal cortisol level range of 3–23 mg/dl.
The coding regions for leptin, leptin receptor,
melanocortin receptor 4 and the ShB1 gene were
sequenced by Cambridge University, UK (Dr P Pawal,
Topiwala National Medical College, 2011, personal
communication), and all were found to be normal,
with the exception of the gene mutation which
248
results in leptin deficiency, which is to date the only
treatable genetic form of obesity.
The parents of the patient were able to give a history
which detailed their consanguineous marriage and
their elder child, who weighed 2.75 kg at birth and
excessesively gained weight from 6 weeks of age
until reaching 22 kg in weight at 18 months of age,
when he died from a lower respiratory tract infection.
As a result, the parents were aware of these issues
with their second child and that the patient’s only
option for survival was to undergo a laparoscopic
sleeve gastrectomy.
During the course of the surgery, it was clear that
the patient had a large stomach for her age and she
displayed retrogastric and splenic adhesions which
contributed to the inflammation of fat cells that is
normally found in those with morbid obesity. The
surgery was uneventful and the patient responded
positively to the procedure.
At a 1-month follow-up, the patient had lost 2 kg in
weight (Figure 3), and after 3 months the patient
weighed 14 kg, which represented 5 kg weight loss
(Figure 4).
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:247–250 (http://dx.doi.org/10.7707/hmj.v6i2.228)
Case Report
The results of the biochemistry tests 1 month after the
surgery showed that the patient’s blood urea nitrogen
level was 10 mg/dl, creatinine 0.4 mg/dl, sodium
138 mEq/l, potassium 5.0 mEq/l, total protein 6.8 g%,
albumin 4.0 g%, total bilirubin 0.3 mg/dl, alkaline
phosphatase 264 units (U)/l and fasting insulin
18.4 µU/ml. The histopathology report indicated
that the laparoscopic sleeve gastrectomy had been
successful with no evidence of neoplasia.
FIGURE 3  The patient post operation.
The patient’s appetite and food intake have reduced
substantially since the surgery, and the level of
physical activity has improved. At 15 months of age,
the patient could not stand on her own but walked
with the aid of a walker and crawled on the floor.
At 2 years of age, the patient walks independently,
weighs 16 kg and is about 88 cm in height. In addition,
the developmental milestones of the patient
appear normal.
Discussion
Although bariatric surgery for infants is still a new
and developing technique, it may be in the best
interests of a patient who has been referred from the
endocrine department. One such case is described
here, of a child whose elder sibling died from the
complications associated with morbid obesity
and in whom laparoscopic sleeve gastrectomy
was performed with the aim of increasing the
patient’s survival.
Bariatric surgery has been advocated as an
intervention for those with extreme obesity and is
most effective for those with early childhood-onset
obesity to reduce weight and serious obesity
related medical conditions, and also to improve
psychosocial status.3
FIGURE 4  The patient post operation.
The results of the haematology tests 1 month after
the surgery showed that the patient’s haemoglobin
concentration was 11 g%, total cholesterol was
16 000 cells/mm3, the mean corpuscular volume
was 67.93 fl, mean corpuscular haemoglobin level
was 20.60 pg, mean corpuscular haemoglobin
concentration was 30.32 g/dl and the platelet count
was 2.11 × 105/mm3.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Non-operative approaches to weight loss have
shown less than optimal results; therefore,
paediatric patients are increasingly seeking bariatric
surgical interventions if respiratory complications
are involved.4
A genetic syndrome works pathologically on the
patient’s hormones, specifically ghrelin and leptin.
Ghrelin is a circulating hormone that is mainly
produced by the body and fundus of the stomach
and acts as an appetite stimulant, encouraging
food intake, and is responsible for weight gain in
children.5,6 Endogenous ghrelin is a potentially
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Hamdan Medical Journal  2013; 6:247–250 (http://dx.doi.org/10.7707/hmj.v6i2.228)
Case Report
important regulator of the complex systems which
control food intake and body weight.6 Leptin acts on
the receptors in the hypothalamus of the brain to
inhibit the activity of peptides, therefore producing a
feeling of satiety and signalling that the body has had
enough to eat, especially of high-calorie foods.7
surgery has been a pioneering attempt with mixed
reactions from fraternity colleagues, we conducted
this procedure in a charitable, sincere and honest
manner with the patient’s best interests in mind,
owing to the family income of Rs.100 per day.
Laparoscopic sleeve gastrectomy removes the excess
part of the body and fundus of the stomach, along
with the ghrelin-secreting portion, thereby reducing
appetite and subsequent food intake. Laparoscopic
sleeve gastrectomy also enhances formation of
peptides such as glucagon-like peptide 1 and peptide
YY from the small intestine, both of which play a role
in weight loss.5 This surgery reduces the stomach
size to a more normal size for the patient’s age and
weight. The remainder of the stomach continues to
grow, but not at the same rate as before the surgery.
Laparoscopic gastric band and gastric bypass
surgeries play a role in weight loss but demand
lifelong tolerance of, respectively, an artificial device
or significant malabsorption.2
Disclosure
No author has any potential conflict of interest and no
external source of funding.
References
1
2
3
Conclusion
Although no appropriate weight loss technique
for infants has been identified thus far,8,9 judicious
use of surgical procedures after the failure of
conservative treatments in a life-threatening medical
condition can sometimes benefit the patient. Both
laparoscopic adjustable gastric band surgery and
laparoscopic sleeve gastrectomy reduce excess
body weight and fat mass in children. Plasma
ghrelin levels are down-regulated by laparoscopic
sleeve gastrectomy whereas hypothalamic growth
hormone secretagogue receptor type 1a protein
expression level is elevated following sleeve
gastrectomy. Laparoscopic sleeve gastrectomy results
in complicated feedback between the hypothalamus
and the digestive tract.10
With the instigation of a well-developed department
of bariatric and metabolic surgery hosting trained
surgeons, anaesthetists and equipped postoperative
intensive care units for children, patients such as
those described here could be offered the best
chance of survival through surgery. Although this
250
4
5
6
7
8
9
10
Treadwell JR, Sun F, Schoelles K. Systematic review and
meta-analysis of bariatric surgery for paediatric obesity.
Ann Surgery 2008; 248:763–76.
http://dx.doi.org/10.1097/SLA.0b013e31818702f4
Till HK, Muensterer O, Keller A, et al. Laparoscopic sleeve
gastrectomy achieves substantial weight loss in an
adolescent girl with morbid obesity. Eur J Pediatr Surg
2008; 18:47–9.
http://dx.doi.org/10.1055/s-2008-1038356
Inge TH, Xanthakos SA, Zeller MH. Bariatric surgery of
paediatric extreme obesity: now or later? Int J Obesity
(Lond) 2007; 31:1–14.
http://dx.doi.org/10.1038/sj.ijo.0803525
Kalra M, Inge T. Effect of bariatric surgery on obstructive
sleep apnoea in adolescents. Paediatr Respir Rev 2006;
7:260–7. http://dx.doi.org/10.1016/j.prrv.2006.08.004
Steinert RE, Meyer-Gerspach AC, Beglinger C. Role of
stomach in control of appetite and secretion of satiation
peptides. Am J Physiol Endocrinol Metab. In press 2013.
Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances
appetite and Increases food intake in humans. J Clin
Endocrinol Metab 2001; 86;5992–5.
http://dx.doi.org/10.1210/jc.86.12.5992
Klok MD, Jakobsdottir S, Drent ML. The role of leptin
and grelin in the regulation of food intake and body
weight in humans. Obes Rev 2007; 8:21–34. http://dx.doi.
org/10.1111/j.1467-789X.2006.00270.x
Pratt Janey SA, Lenders CM, Dionne EA, et al. Best
practice updates for paediatric/adolescent weight loss
surgery. Obesity 2009; 175:901–10.
http://dx.doi.org/10.1038/oby.2008.577
Alqahtani AR, Antoniswamy B, Alamri H, et al.
Laparoscopic sleeve gastrectomy in 108 obese children
and adolescents aged 5–21 years. Ann Surg 2012;
256:266–73.
Yong Wang, Jingang Liu. Plasma ghrelin modulation
in gastric band operation and sleeve gastrectomy.
Obes Surg 2009; 19:357–62.
http://dx.doi.org/10.1007/s11695-008-9688-3
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:251–254 (http://dx.doi.org/10.7707/hmj.v6i2.142)
 
CASE REPORT
Partial molar pregnancy resulting in a
healthy newborn
Nawal M Hubaishi,1 Fatima Cherifi,1 Wafa F Mohsen,1 Amina Karami Binashoor,1
Saba Yehya Al Sayari1 and Nargis Mehdipour2
1
Department of Obstetric Gynecology, Dubai Hospital, Dubai, United Arab Emirates, and 2Dubai
Health Authority, Dubai Hospital, Dubai, United Arab Emirates
Abstract
This article reviews a rare case of partial placental molar pregnancy resulting
in a healthy newborn. A woman was admitted to the Department of
Obstetric Gynecology at Dubai Hospital in the United Arab Emirates (UAE),
where she subsequently gave birth to a healthy baby. In this multiparous
patient, recurrent partial molar pregnancy was identified at 13 weeks by
ultrasonography, which showed focal placental changes. However, the
patient refused medical intervention and was kept under observation until
36 weeks, when a baby girl with a normal karyotype was born by normal
vaginal delivery. There were no maternal complications. Partial molar
pregnancy resulting in a live and healthy baby is rare and usually associated
with numerous maternal complications, which were not present in this case.
Complete evaluation of the placental tissue is important in cases where a
live and healthy baby is delivered because molar changes may be focal and,
therefore, cause unpredicted antenatal problems for the mother.
Introduction
Partial molar pregnancy is a trophoblastic disease
caused by a genetic disorder, such as an additional
haploid set of chromosomes, which results in a total
of 69 chromosomes.
Excluding molar pregnancy cases resulting from
multiple conceptions and therefore co-existing
fetuses, partial molar pregnancy in which a living
fetus is carried to term is very rare. When molar
changes exist alongside the living fetus, the patient
can be offered close observation.1
Correspondence: Nawal M Hubaishi, Department of Obstetric
Gynecology, Dubai Hospital, Al Baraha area, PO Box 7272, Dubai,
United Arab Emirates. Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
We describe a case of partial molar pregnancy that
was managed throughout at Dubai Hospital in the
United Arab Emirates (UAE) and resulted in a live and
healthy baby delivered at 36 weeks.
Case report
A 32-year-old Emirati woman, gravida 3, para 1,
with no family history of genetic abnormalities,
was initially assessed at 9 weeks’ gestation in the
gynaecology clinic at Dubai Hospital for management
of early threatened miscarriage. Clinical examination
was normal and ultrasonography revealed a live
embryo consistent with 9 weeks’ gestation.
The patient’s obstetric history detailed that her first
pregnancy, during 2007, was complicated by partial
molar pregnancy and resulted in miscarriage; her
second pregnancy, during 2009, resulted in the
delivery of a live newborn by emergency caesarean
section at full term.
Serum beta-human chorionic gonadotropin (ОІ-HCG)
was given to the patient at 9 weeks’ gestation in view
of her previous history of molar pregnancy. It was
suggested to the patient that she should attend an
antenatal clinic follow-up at 13 weeks’ gestation and
at regular intervals thereafter. At these follow-up
sessions, the patient complained of vaginal spotting.
The patient’s clinical and gynaecological examination
was normal and ultrasonography showed a single live
fetus corresponding to the 13 weeks’ gestation stage.
However, multiple cystic changes, of differing sizes,
251
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Hamdan Medical Journal  2013; 6:251–254 (http://dx.doi.org/10.7707/hmj.v6i2.142)
CASE REPORT
of the umbilical artery Doppler assessment can
be seen in Figure 3 where the colour shows the
hypervascularized nature of the placenta.
FIGURE 1  Ultrasound image of the fetus at 13 weeks’
gestation.
suggestive of partial molar degeneration, were noted
in the placenta (Figure 1).
The result of the β-HCG test was > 200 000 iu/l and the
results of renal, liver and thyroid function tests were
all normal.
The bleeding caused by the antepartum
haemorrhage lessened 2 days after admission and
as a result the patient was discharged and and asked
to return for weekly follow-up appointments at the
antenatal clinic. As the pregnancy continued, the rate
of growth of the fetus decreased and a symmetrical
intrauterine gestational retardation was identified.
However, the results of the umbilical artery Doppler
assessment remained normal; thus, the observation
continued and cardiotocography and biophysical
profiling were carried out twice a week.
The patient was readmitted with spontaneous labour
pain at 36 weeks’ gestation, which resulted in a
The patient was advised to undergo karyotyping
to analyse the chromosomes in a sample of the
fetal cells at 13 weeks’ gestation and again at
20 weeks’ gestation; however, she refused any
medical intervention.
The patient was kept under observation at regular
antenatal clinic sessions and growth of the fetus,
placental size and the placental mass were monitored
every 2 weeks. The patient did not develop preeclampsia, thyrotoxicosis or anaemia; however,
vaginal spotting persisted throughout the pregnancy.
FIGURE 2  Changes in the resulting ultrasound image at
32 weeks’ gestation.
At 32 weeks’ gestation, the patient presented with
antepartum haemorrhage and was admitted to
the Department of Obstetric Gynecology at Dubai
Hospital for assessment. Following an examination,
the patient’s vital signs were normal. Fundal height of
the uterus corresponded to the gestational age of the
fetus and the cervix was closed; however, bleeding
was detected at the cervical os.
Ultrasonography revealed a single and viable fetus
in cephalic presentation whose measurements were
consistent with gestational age and there were no
obvious gross anomalies. An umbilical artery Doppler
assessment was conducted and the results were
normal. The placenta was positioned posterior to the
fundus of the uterus and was 50 mm in thickness,
with hyperechoic and cystic changes visible but no
signs of placental separation (Figure 2). The result
252
FIGURE 3  The result of the placenta hypervascularization
assessment.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:251–254 (http://dx.doi.org/10.7707/hmj.v6i2.142)
CASE REPORT
normal vaginal delivery of a live and healthy baby girl
who weighed 1710 g. Despite this low birthweight,
the baby had a good Apgar score of 9 and 10 at
1 and 5 minutes, respectively, and was admitted to
the neonatal intensive care unit for close observation.
The subsequent pathological analysis of the placental
tissue was consistent with the diagnosis of partial
molar placenta.
The patient was discharged in fit and healthy
condition and was followed up in the gynaecology
clinic. The patient’s β-HCG concentration levels were
repeatedly checked until three negative results were
obtained (Figure 4). Oral contraceptive pills were
offered for family planning.
Discussion
Partial hydatidiform mole is a histopathological entity
characterized by a focal trophoblastic hyperplasia that
is associated with hydropic villi along with identifiable
fetal tissue.2 This usually results in a fetus displaying a
triploid karyotype, resulting from the fertilization of a
normal ovum with two sperm.
Partial molar pregnancy resulting in a live and healthy
child is rare and estimated to occur in 1 in 20 000
to 1 in 100 000 pregnancies.2 It is even rarer for the
resulting child to be born with a normal karyotype.
There are few cases reported in the literature;
however, some studies do report on this rare
condition.1,3–6
Several studies5,7 have reported cases of a single
normal fetus associated with partial molar placenta
and stated that the fetus must have a normal
karyotype to survive in utero, although the placenta
can show some variation, from diploidy of the amnion
to triploidy of the chorionic villi,7 which is similar to
the patient in the case discussed above. From this
clinical perspective, there are two different types of
gross pathology that can affect the placenta: focal
degeneration and diffuse partial degeneration.5,8–10
Previously, most partial molar pregnancies identified
early were terminated8,11,12 with or without medical
complications, but especially when pre-eclampsia was
also present.13 However, termination of the pregnancy
is not always the only option as the pregnancy can
be managed conservatively if the fetus appears
normal and healthy on ultrasound, and if there are
no maternal complications. Patients who develop
partial molar placenta may find the pregnancy
complicated by intrauterine growth restriction and
oligohydramnios, which were both observed in the
case discussed above.14
Some studies11,15,16 have questioned whether
patients with partial hydatidiform mole require
follow-up observation and assessment of serum
ОІ-HCG concentration. However, patients can develop
choriocarcinoma if not followed up correctly, and
250000  200000  150000  100000  50000  0  during  pregnancy  a1er  delivery  a1er  2weeks  PP  a1er  4weeks  PP  a1er  6  weeks  PP   FIGURE 4  β-HCG level during pregnancy and after delivery.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
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CASE REPORT
one study by Seckl et al.16 reported the death of one
such patient.
Szulman and Surti17 reviewed 86 cases of partial
hydatidiform mole and reported that the overall
prevalence of the disease was 4%; however,
Berkowitz et al.15 reported a higher prevalence (9.9%)
among patients who had developed persistent
gestational trophoblastic disease.6
The patient in the case discussed above did not show
any persistent trophoblastic disease after the birth
and her serum ОІ-HCG concentration returned to
normal within 4 weeks.
A single assessment of a patient’s serum β-HCG
concentration after the termination of pregnancy is
sufficient to confirm remission in these patients.18
4
5
6
7
8
9
10
Conclusion
Partial molar pregnancy resulting in a live and healthy
baby is rare and is usually associated with numerous
maternal complications, including persistent
gestational trophoblastic disease, which is diagnosed
by histopathological examination. It is important that
a diagnosis of partial molar placenta, which may be
only suspected during pregnancy, is confirmed after
delivery as the result may affect the future of both the
mother and her baby.
References
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2
3
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Berkowitz RS, Goldstein DP, Bernstein MR. Natural
history of partial molar pregnancy. Obstet Gynecol
1985; 66:677–81.
Seckl MJ, Fisher RA, Saermo G, et al. Choriocarcinoma
and partial hydatiform moles. Lancet 2000; 356:36–9.
http://dx.doi.org/10.1016/S0140-6736(00)02432-6
Szulman AE, Surti U. The clinicopathologic profile
of the partial hydatiform mole. Obstet Gynecol
1982; 159:597–602.
Felmate CM, Bartorfi J, Fulop V, Goldstein DP, Doszpod
J, Berkovitz RS. Human chorionic gonadotropin follow
up in patients with molar pregnancy: a time for
reevaluation. Obstet Gynecol 2003; 101:732–6.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:255–258 (http://dx.doi.org/10.7707/hmj.v6i2.240)
 
Case Report
Familial haemophagocytic lymphohistiocytosis
Ammar MH Shehadeh
Department of Pediatrics, Hatta Hospital, Hatta, United Arab Emirates
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a rare, but potentially fatal,
disease that occurs when normal histiocytes and lymphocytes become
overactive and commonly occurs in infancy. Two forms of the disease have
been described: primary and secondary. This article reports twins who
were less than 2 years old at the time of presentation and who had clinical
symptoms of primary (familial) HLH, which was diagnosed by a contributory
pathological bone marrow test.
which can occur because of systemic infection,
immunodeficiency or underlying malignancy.
Both forms of HLH are characterized by the
overwhelming activation of normal T lymphocytes
and macrophages, invariably leading to clinical and
haematological alterations and, if untreated, death of
the patient.4
Introduction
Case report
Haemophagocytic lymphohistiocytosis (HLH) is a rare,
but potentially fatal, disease that occurs when normal
histiocytes and lymphocytes become overactive and
commonly occurs in infancy, although it has been
reported in all age groups.1,2 The initial presentation
of HLH is often comprises fever, hepatosplenomegaly,
pancytopenia, lymphadenopathy and a rash.
We report on Kuwaiti twins who were less than
2 years old at the time of the presentation. The first
twin, a female, presented at 20 months of age with
fever, neck swelling, abdominal distension and a skin
rash that had been present for 1 week. In addition,
she also showed a poor intake of food, resulting in
weight loss, lethargy and pallor.
Cutaneous involvement of HLH occurs in as many
as 65% of patients, with various skin manifestations
having been reported, including erythroderma,
generalized purpuric macules and papules, and
morbilliform eruptions.3 Detection of cutaneous
involvement can assist in the initial diagnosis of HLH
and potentially signify recurrences.
The patient’s history showed that she was a born to
consanguineous parents and her mother was diabetic
and also suffered from hypothyroidism, but was being
treated for both. The patient was born prematurely at
36 weeks’ gestation but the delivery was normal. The
patient’s birthweight was 2.3 kg and she had a history
of seborrhoeic dermatitis since birth. The patient’s
twin and younger sister displayed almost the same
clinical presentation.
Primary HLH [i.e. familial erythrophagocytic
lymphohistiocytosis (FEL)] is defined as an inherited
form of HLH and is a heterogeneous autosomal
recessive disorder that has been found to be more
prevalent in cases of parental consanguinity.
Secondary HLH (i.e. acquired HLH) occurs as a result
of strong immunological activation, such as that
Correspondence: Dr Ammar Shehadeh, Department of Pediatrics,
Hatta Hospital, Hatta, United Arab Emirates.
Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
On examination, the patient was febrile, irritable,
pallid and emaciated with poor activity. Bilateral
cervical lymphadenopathy was present as defined
by large, tender and palpable cervical lymph nodes.
The small inguinal lymph nodes were also bilaterally
palpable. Hepatosplenomegaly, ascites and a purpuric
rash were present all over the patient’s body and
a follicular erythematous rash was present all over
the scalp.
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Hamdan Medical Journal  2013; 6:255–258 (http://dx.doi.org/10.7707/hmj.v6i2.240)
Case Report
Investigations revealed leucocytosis,
thrombocytopenia, anaemia and high serum
triglyceride and ferritin levels. The C-reactive protein
test was positive, which, in combination with the
clinical presentation and the leucocytosis, indicated
an acute infection. This was expected as HLH can
compromise the immune system. The patient was
also found to have elevated liver enzymes.
The second twin presented 1 month after the first
with an intermittent fever which had been present
for 6 days, a maculopapular skin rash, a small
purpuric skin rash on the trunk and thighs as well as
congestion of the throat and swelling of the lips.
The patient had a history of bilateral otitis media
with bleeding from the right ear. On examination,
the patient was febrile, irritable, thin and her height
and weight were both below the fifth centile for age.
The right eardrum was perforated with purulent
bloody discharge and the abdomen was distended
with hepatosplenomegaly. The skin rash present on
the trunk and thighs did not fade when pressure was
applied, which is characteristic of a purpuric rash.
Like her twin, the results of various tests revealed
thrombocytopenia, anaemia and high serum
triglyceride and ferritin levels. The C-reactive protein
test was positive, which, in combination with the
clinical presentation and the leucocytosis, indicated
an acute infection. This was expected as HLH can
compromise the immune system. The patient
was also found to have elevated liver enzymes.
An ear-swab culture showed a heavy growth of
Morganella morganii.
Bone marrow aspiration was performed in both twins
and in both cases showed infiltration of the bone
marrow with histiocyte-like cells that were S-100 and
CD68 positive.
In view of the clinical presentation and the bone
marrow pathological results in both twins, the
patients were diagnosed as having HLH and
treated accordingly. In addition to prescribing
antibiotics for the bacterial infection present in both
patients, they were kept under close observation
and requested to attend follow-up sessions in the
outpatient department of Hatta Hospital until clinical
improvement could be detected.
256
Discussion
Primary HLH (i.e. FEL) is defined as an inherited
form of HLH and is a heterogeneous autosomal
recessive disorder that has been found to be
more prevalent in the children of consanguineous
parents. Secondary HLH (i.e. acquired HLH) is the
result of strong immunological activation, such as
that which can occur alongside systemic infection,
immunodeficiency or underlying malignancy.
Both forms of HLH are characterized by the
overwhelming activation of normal T lymphocytes
and macrophages, invariably leading to clinical and
haematological alterations and, if not treated, death
of the patient.4
The pathological hallmark of this disease is the
aggressive proliferation of activated macrophages
and histiocytes, which phagocytose other cells
(namely red blood cells, white blood cells and
platelets), leading to the clinical symptoms of
HLH. The uncontrolled proliferation of activated
macrophages and histiocytes is not malignant
and does not appear clonal, in contrast to the
lineage of cells in Langerhans’ cell histiocytosis. The
spleen, lymph nodes, bone marrow, liver, skin and
membranes that surround the brain and spinal cord
are preferential sites for HLH involvement.5
A currently accepted in theory is that an inappropriate
immune reaction caused by the proliferating and
activated T cells results in macrophage activation and
inadequate apoptosis of immunogenic cells, leading
to HLH.6 Although the precise mechanism behind the
occurrence of HLH remains unclear, many researchers
have offered convincing reports for the role of
perforin and natural killer cells in the manifestation of
both primary and secondary HLH.7
The incidence of HLH in a Swedish population was
reported to be 1.2 cases per million people each
year.8–10
The age at onset of primary HLH is usually before
1 year; however, the onset of secondary HLH can be
later and usually occurs after 6 years of age. Although
the primary form of the disease frequently affects
infants from birth to 18 months of age,6 it has been
reported in individuals as old as 8 years, and adult
onset has been also reported.1,2
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:255–258 (http://dx.doi.org/10.7707/hmj.v6i2.240)
Case Report
The diagnostic criteria enforced by the International
Registry for HLH11 are given below; all five criteria
must be met to establish a diagnosis of HLH:
1
2
3
4
5
fever – ≥ 7 days of a temperature as high as 38.5°C
(101.3В°F);
splenomegaly – a palpable spleen greater than
3 cm below the costal margin;
cytopenia – counts below the specified range for
at least two of the following:
a absolute neutrophils < 1000/µl;
b platelets < 100 000/µl;
c haemoglobin < 9.0 g/dl;
hypofibrinogenaemia or hypertriglyceridaemia –
fibrinogen at a level of < 1.5 g/l or more than 3 SD
below the age-adjusted reference range value,
or fasting triglycerides at a level of > 2 mmol/l or
more than 3 SD above the age-adjusted reference
range value;
haemophagocytosis – tissue from the lymph
nodes, spleen or bone marrow that does not
show evidence of malignancy.
Other symptoms found in patients suffering from HLH
are swollen or haemorrhagic gums, which can result
in tooth loss, feeding problems (especially prominent
in infants), abdominal pain, vomiting, diarrhoea,
weight loss and a skin rash. A rash is found in more
than half of patients and can present in a several
ways, such as scaly and waxy lesions or rashes on the
scalp and behind the ear. The skin can be involved
in HLH in various ways and this is best characterized
clinically as erythroderma, generalized purpuric
macules and papules, or morbilliform eruptions.
One Swedish study reported that nearly 75% of
patients suffering from HLH had some form of
CNS involvement, with half showing neurological
symptoms including seizures, ataxia, hemiplegia,
mental status changes or simply irritability.10 Because
of the predilection of the disease for certain tissues,
such as the lymph nodes, lymphadenopathy is
commonly found during physical examination.
Other common findings, such as malaise, anorexia
(with or without weight loss) and failure to thrive,
have been reported.11 Findings in up to two-thirds of
initial bone marrow aspirates may be non-diagnostic;
therefore, a negative examination may not rule out
HLH. Additional tests, including a lymph node biopsy,
should be performed and treatment should not be
delayed if all other criteria have been met.12 Although
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
problematic in a patient with a coagulopathy, a liver
biopsy providing results that would be expected in a
case of chronic persistent hepatitis can support the
diagnosis of HLH, as can the presence of mononuclear
cells in the cerebrospinal fluid (CSF).
The initial therapy for patients with HLH consists
of etoposide plus dexamethasone for 8 weeks. In
the HLH-2004 protocol,13 it was recommended that
cyclosporine be added at the start of treatment.
Intrathecal methotrexate is used only as a treatment
for cases with persistently abnormal CSF or
progressive neurological symptoms. Resolved
non-familial HLH does not require continuation
of the therapy regime unless disease reactivation
occurs after completion of the initial therapy, or
unless patients are undergoing bone marrow
transplantation. The remaining patients with either
persistent non-familial HLH or the familial form of the
disease should continue with therapy of intravenous
etoposide infusions and dexamethasone pulses,
and oral cyclosporine should be initiated at week 9
of treatment.14 HLH associated with malignancies
demands prompt therapy directed at the neoplasm.
Bone marrow transplantation is performed if a
suitable donor can be found and the patient is stable.
A recent study reported on a group of patients given
reduced-intensity conditioned treatment before stem
cell transplantation from a matched family, unrelated
or haploidentical donor.15 A total of 84% of patients
with HLH were in remission at a median of 36 months
following stem cell transplantation.15 In another
study, reduced-intensity conditioned treatment was
successful for 96% of patients.16 Reduced-intensity
conditioned treatment compares favourably with
conventional stem cell transplantation and provides
long-term disease control in surviving patients with
HLH.15 If the patient is experiencing life-threatening
respiratory difficulties or uncontrolled hypersplenism,
then splenectomy is an option.
Although the prognosis varies between studies and
with different approaches to the treatment, HLH is
invariably fatal if not treated. Patients suffering from
HLH are at a high risk of early death and the median
survival rate has been reported to be 2–6 months
without treatment. However, steroids or intravenous
immunoglobulin, or both, can be prescribed
as a first-line therapy and may be sufficient to
preserve life.17
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Case Report
Conclusion
Familial HLH is a rare disease that can affect several
members of the same family, as seen with the twins
in the case report discussed above. The diagnosis
of HLH can be very difficult if it is not suspected
from the beginning. Familial HLH can present in
various non-specific forms and all paediatricians
should consider rare diseases such as HLH if the
clinical presentation does not fit a familiar and
common disease.
References
1
2
3
4
5
6
7
258
Reiner AP, Spivak JL. Hematophagic histiocytosis. A
report of 23 new patients and a review of the literature.
Medicine (Baltimore) 1988; 67:369–88.
Clementi R, Emmi L, Maccario R, et al. Adult onset
and atypical presentation of hemophagocytic
lymphohistiocytosis in siblings carrying PRF1 mutations.
Blood 2002; 100:2266–7. http://dx.doi.org/10.1182/
blood-2002-04-1030
Morrell DS, Pepping MA, Scott JP, et al. Cutaneous
manifestations of hemophagocytic lymphohistiocytosis.
Arch Dermatol 2002; 138:1208–12. http://dx.doi.
org/10.1001/archderm.138.9.1208
Feldmann J, Le Deist F, Ouachee-Chardin M, et al.
Functional consequences of perforin gene mutations
in 22 patients with familial haemophagocytic
lymphohistiocytosis. Br J Haematol 2002; 117:965–72.
http://dx.doi.org/10.1046/j.1365-2141.2002.03534.x
Arico M, Allen M, Brusa S, et al. Haemophagocytic
lymphohistiocytosis: proposal of a diagnostic algorithm
based on perforin expression. Br J Haematol 2002;
119:180–8.
Imashuku S, Ueda I, Teramura T, et al. Occurrence of
haemophagocytic lymphohistiocytosis at less than
1 year of age: analysis of 96 patients. Eur J Pediatr
2005;164:315–19. http://dx.doi.org/10.1007/s00431005-1636-9
Katano H, Cohen JI. Perforin and lymphohistiocytic
proliferative disorders. Br J Haematol 2005; 128:739–50.
http://dx.doi.org/10.1111/j.1365-2141.2004.05305.x
8
9
10
11
12
13
14
15
16
17
Malloy CA, Polinski C, Alkan S, Manera R, Challapalli M.
Hemophagocytic lymphohistiocytosis presenting with
nonimmune hydrops fetalis. J Perinatol 2004; 24:458–60.
http://dx.doi.org/10.1038/sj.jp.7211121
Sung L, King SM, Carcao M, Trebo M, Weitzman SS.
Adverse outcomes in primary hemophagocytic
lymphohistiocytosis. J Pediatr Hematol Oncol 2002;
24:550–4. http://dx.doi.org/10.1097/00043426200210000-00011
Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden
and clinical features of familial hemophagocytic
lymphohistiocytosis. Acta Paediatr Scand 1991;
80:428–35. http://dx.doi.org/10.1111/j.1651-2227.1991.
tb11878.x
Henter JI, Elinder G, Ost A. Diagnostic guidelines for
hemophagocytic lymphohistiocytosis. The FHL Study
Group of the Histiocyte Society. Semin Oncol 1991;
18:29–33.
Macheta M, Will AM, Houghton JB, Wynn RF. Prominent
dyserythropoiesis in four cases of haemophagocytic
lymphohistiocytosis. J Clin Pathol 2001; 54:961–3.
http://dx.doi.org/10.1136/jcp.54.12.961
Henter JI, Horne A, AricГі M, et al. HLH-2004: Diagnostic
and therapeutic guidelines for hemophagocytic
lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:
124–31. http://dx.doi.org/10.1002/pbc.21039
Henter JI, Samuelsson-Horne A, Arico M, et al.
Treatment of hemophagocytic lymphohistiocytosis
with HLH-94 immunochemotherapy and bone marrow
transplantation. Blood 2002; 100:2367–73. http://dx.doi.
org/10.1182/blood-2002-01-0172
Cooper N, Rao K, Gilmour K, et al. Stem cell
transplantation with reduced-intensity conditioning
for hemophagocytic lymphohistiocytosis. Blood
2006; 107:1233–6. http://dx.doi.org/10.1182/
blood-2005-05-1819
Marsh RA, Jordan MB, Filipovich AH. Reduced-intensity
conditioning haematopoietic cell transplantation for
haemophagocytic lymphohistiocytosis: an important
step forward. Br J Haematol 2011; 154:556–63. http://
dx.doi.org/10.1111/j.1365-2141.2011.08785.x
Gupta AA, Tyrrell P, Valani R, Benseler S, Abdelhaleem
M, Weitzman S. Experience with hemophagocytic
lymphohistiocytosis/macrophage activation
syndrome at a single institution. J Pediatr Hematol
Oncol 2009; 31:81–4. http://dx.doi.org/10.1097/
MPH.0b013e3181923cb4
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:259–262 (http://dx.doi.org/10.7707/hmj.v6i2.260)
 
Case report
Pleomorphic lipoleiomyoma of uterus
Farhana Zakaria
Yenepoya Medical College, Mangalore, India
Abstract
Scattered adipocytes in an otherwise typical leiomyoma are a relatively
common finding. A leiomyoma that contain a large number of adipocytes
is called a lipoleiomyoma. We report a unique case of leiomyoma that
presented with the following morphological features: mature spindled
smooth muscle cells with and without nuclear atypia, epithelioid smooth
muscle cells, mature adipose tissue, benign clear cells, coagulation
necrosis. Only a few mitotic figures were noted. The rare occurrence of
lipoleiomyomatous features in an otherwise pleomorphic leiomyoma
prompted the report of the case below.
Introduction
Lipoleiomyoma is a very rare lesion of the uterus
occurring primarily in obese perimenopausal or
postmenopausal women. The tumour consists of
long intersecting bundles of bland, smooth muscle
cells admixed with nests of mature adipocytes and
fibrous tissue. We report a patient who presented
with suspected leiomyoma who was subsequently
found to have lipoleiomyoma showing pleomorphic
changes without any increased mitotic activity.
Case report
A 63-year-old postmenopausal woman presented
with uterine bleeding that had been ongoing for
3 months, with each episode lasting for approximately
3 days. She had begun menopause 13 years ago
and had undergone modified radical mastectomy
for breast carcinoma 1 year previously, followed
by six cycles of chemotherapy and a prescription
of tamoxifen for 6 months. Clinically, there was no
evidence of recurrence in the breast or axilla. On
abdominal examination, a mass corresponding in
size to a uterus of 22 weeks’ gestation was palpable,
Correspondence: Farhana Zakaria, Yenepoya Medical College,
Mangalore, India. Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
occupying the suprapubic area and the right and left
iliac fossae.
Several tests were conducted and a gynaecological
examination revealed a polyp arising from the
cervix; a chest radiograph returned normal results
and ultrasonography of the abdomen showed a
bulky uterus with multiple fibroids and a bilateral
ovarian mass.
All the standard serological and haematological
parameters were within the normal range and the
patient underwent an abdominal hysterectomy with
bilateral salpingo-oophorectomy.
Gross examination of the uterus showed that it
measured 13 × 8 × 4 cm and the outer surface of
the cervix showed a polypoid growth with a stalk
measuring 1.3 × 0.4 cm. On the cut surface of the
uterus, the endometrial cavity could not be seen
owing to three large intramural fibroids, the largest
of which measured 6 × 5 cm; the second measured
4 × 4 cm and the smallest measured 2 × 1 cm (Figure 1).
The cut surface of the fibroids showed a whorled
pattern and the lower part of largest mass was brown
in colour. The left ovary measured 3 × 1.5 × 0.5 cm,
the right ovary was much larger and measured
16 × 10 × 5 cm; however, the fallopian tubes were of
normal size.
Histological examination of the uterus showed
non-secretory endometrium and adenomyosis,
and the endometrial stroma displayed foamy
cytoplasmic changes.
Histological sections from the largest fibroid showed
a mixture of bland, spindle-shaped smooth muscle
cells with nuclear atypia in a whorled pattern admixed
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Case report
Figure 1  The uterus and visible leiomyomata.
with mature adipocytes (Figure 2). The adipose tissue
component was entirely mature and did not display
any lipoblasts.
Sections from the brownish area of the fibroid
showed smooth muscle cells of varying sizes
with pale pink vacuolated cytoplasm containing
hyperchromatic bizarre nuclei and some areas of clear
cytoplasm (Figures 3 and 4). Areas of coagulation
necrosis (red degeneration) and congested blood
vessels with haemorrhagic zones could be seen, as
could epithelioid smooth muscle cells with clear
cytoplasm; however, mitosis was not significantly
advanced. Following examination of the ovaries, it
was concluded that both ovaries showed features of
mucinous cystadenoma.
Discussion
Adipose tissue is the most common heterologous
component in leiomyomata, and uterine leiomyomata
containing a large number of adipocytes are
classified as lipoleiomyomas. Lipoleiomyomas
also occur in the cervix and ovaries1 and generally
occur in asymptomatic and obese perimenopausal
or postmenopausal women.2–4 Lin et al.2 analysed
2878 cases of leiomyomata and 2071 hysterectomy
specimens and reported that approximately 0.28% of
all leiomyomata and 0.39% of all hysterectomies were
harbouring a lipoleiomyoma.
260
Figure 2  Histological section of the largest fibroid
displaying leiomyoma, characterized by pleomorphic
smooth muscle cells and mature adipocytes.
The pathogenesis of lipoleiomyomas remains
obscure; however, immunohistochemical studies
confirm the complex histogenesis of these tumours,
which may arise from immature mesenchymal cells
or from direct transformation of smooth muscle cells
into adipocytes.2,4 A number of lipid metabolism
disorders and related conditions which are associated
with oestrogen deficiency, such as that which occurs
in perimenopausal or postmenopausal women,
possibly promote abnormal intracellular storage
of lipids.2
Leiomyomata that are not associated with a mitotic
index of over 10 mitotic figures (mfs) per 10 highpower fields (hpfs), even if they are associated with
severe cytologic atypia, are unreliable for identifying
clinically malignant uterine smooth muscle tumours.
The defining features of atypical leiomyomata include
symplastic growth, bizarre cells and the presence
of cells with atypical pleomorphic nuclei, which can
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:259–262 (http://dx.doi.org/10.7707/hmj.v6i2.260)
Case report
Figure 3  Marked nuclear pleomorphism and intranuclear
inclusions. In addition, bizarre cells with multilobulated
nuclei could be seen.
be multinucleated or mononucleated large cells
associated with abundant eosinophilic cytoplasm.
There are spindled cells with variable degrees of
nuclear atypia interspersed between the cells with
bizarre nuclei; however, in areas of the tumour that
are not involved with bizarre cells, the spindled cells
have uniform and bland cytological features. It has
been shown that an excess of global DNA methylation
associated with DNA inactivation may be one of
the molecular mechanisms underlying the benign
nature of this leiomyoma variant. This striking atypia
most likely represents the presence of abundant
heterochromatin, which is known to be associated
with inactivated DNA.
Bizarre leiomyoma has been diagnosed in sites other
then uterus, such as the vagina, nasal cavity and
the scrotum.5
The characteristics of lipoleiomyomas, such as
average age of patient at presentation and maximum
tumour size, are identical to those of common
leiomyomata but the clinical behaviour and prognosis
of these rare tumours depends on the number of
mf/hpf.6
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Figure 4  A section from the brownish area of the fibroid
showing the pleomorphic smooth cells.
References
1
2
3
4
5
6
Rollasson TP, Wilkinson N. Non neoplastic conditions
of myometrium and pure mesenchymal tumours of
the uterus. In Fox H, Wells M (eds.) Haines and Taylor
Obstetrical and Gynaecological Pathology, 5th edn.
Edinburgh: Churchill Livingstone; 2003. pp. 531–5.
Lin KC, Sheu BC, Huang SC. Lipoleiomyoma of the
uterus. Int J Gynaecol Obstet 1999; 67:47–9. http://dx.doi.
org/10.1016/S0020-7292(99)00094-6
Willen R, Gad A, Willen H. Lipomatous lesions of
the uterus. Virchows Arch A Pathol Anat Histol 1978;
377:351–61. http://dx.doi.org/10.1007/BF00507135
Resta L, Maiorano E, Piscitelli D, Botticella MA.
Lipomatous tumors of the uterus. Clinico-pathological
features of 10 cases with immunocytochemical study of
histogenesis. Pathol Res Pract 1994; 190:378–83. http://
dx.doi.org/10.1016/S0344-0338(11)80410-3
Kim NR, Saug CO, Han J. Bizarre leiomyoma of the
scrotum. J Korean Med Sci 2003; 18:452–4.
Rammeh-Rommani S, Mokni M, Stita W, et al. Uterine
smooth muscle tumors: retrospective epidemiological
and pathological study of 2760 cases. J Gynecol Obstet
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org/10.1016/S0368-2315(05)82881-9
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Case Report
Uterine rupture in a nulliparous woman at 26 weeks’
gestation after laparoscopic myomectomy
Tasneem Rangwala, Abeer Ammar and Nadia Sawalhi
Department of Obstetrics and Gynecology, Latifa Hospital, Dubai, United Arab Emirates
Abstract
Uterine scar dehiscence following laparoscopic myomectomy is very rare.
We present a case of a nulliparous woman who was pregnant with twins
and who had undergone laparoscopic excision of a small subserous myoma
2 years previously. The patient had subsequently developed a uterine rupture
at 26 weeks’ gestation; however, this was not initially suspected as the cause
of the patient’s abdominal pain owing to the rarity of this event. All pregnant
patients who have a history of laparoscopic myomectomy, superficial or deep,
should be closely monitored throughout pregnancy and uterine dehiscence or
rupture should be suspected if they present with abdominal pain.
Introduction
Myomectomy is increasingly used as an elective
procedure in selected patients to preserve or enhance
fertility. The laparoscopic route reduces length
of hospital stay and avoids adhesion formation.
Complication rates in the short term are low, provided
the surgeon is suitably trained. Cases of uterine
rupture following laparoscopic myomectomy to
remove subserous and even pedunculated myomas
have been reported long before term, which raises
concern regarding the integrity of a uterine scar
following laparoscopic myomectomy.В№ The case
below highlights the importance of suspecting
this rare complication in patients presenting with
abdominal pain.
Case report
Mrs DA, 31 years old, gravida 3, para 0+2, was
admitted to delivery suite of Latifa Hospital, via the
emergency room, complaining of sudden-onset
Correspondence: Tasneem Rangwala, Department of Obstetrics
and Gynecology, Latifa Hospital, PO Box 9115, Dubai, United Arab
Emirates. Email: [email protected]
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
generalized abdominal pain. She was at 24 weeks’
gestation, with a dichorionic diamniotic twin
pregnancy conceived using in vitro fertilization (IVF)
and there was no history of vaginal loss.
Her first pregnancy, a tubal ectopic pregnancy, was
terminated at 6 weeks’ gestation in another hospital
by laparoscopic right salpingectomy, during which
an incidental subserous myoma of 1.2 cm was found
and excised. No details of myoma site, or method of
removal, were mentioned in the operative report. The
patient’s second pregnancy resulted in miscarriage
at 8 weeks’ gestation and an evacuation of uterus
was carried out. Seven months later, the patient
underwent diagnostic laparoscopy to investigate the
reason for her inability to conceive and it was found
that her left fallopian tube was patent and there were
no other abnormal findings. The patient had regular
menstrual cycles, no prior medical illness or drug
allergy and therefore underwent IVF.
On admission, the patient’s vital signs were normal,
but abdominal examination revealed her uterus to
be enlarged, corresponding to a fetus of 28 weeks’
gestation, and she was experiencing palpable
contractions. A vaginal examination revealed a
short soft cervix with os closed. Ultrasonography
showed viable twin fetuses, of which the first was
cephalic but the second was in the breech position.
Cardiotocography (CTG) revealed regular uterine
contractions and a diagnosis of threatened preterm
labour was made; therefore, tocolytics were given
alongside an intravenous infusion with Tractocile
(Ferring, West Drayton, UK) and two doses of
betamethasone steroid were given.
263
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Hamdan Medical Journal  2013; 6:263–266 (http://dx.doi.org/10.7707/hmj.v6i2.253)
Case Report
Investigations
The patient�s blood group was O Rh positive, her
haemoglobin concentration was 11 g%, her white
blood cell count was 18 000/mm3, her C–reactive
protein level was 14.6 mg/l and her coagulation
profile was normal. Tests that were used to look for
hepatitis markers, human immunodeficiency virus
and venereal disease were all negative. A mid-stream
urine sample and a high vaginal swab both confirmed
that no pathogens were present and detailed
obstetric ultrasonography showed viable dichorionic
diamniotic twins. The first twin was estimated to
weigh 953 g and the second twin 1820 g. The liquor
was found to be adequate around both twins
and two placentae were seen, one anteriorly and
one posteriorly.
After completion of the 48-hour cycle of Tractocile,
the patient began to experience contractions again;
therefore, oral nifedipine was given as second-line
tocolytic in view of extreme fetal prematurity.
She remained pain free for 24 hours before the
contractions began again. The patient was suffering
from dyspnoea, cough and palpitations but on
vaginal examination, the os was still closed. Vital
signs remained stable and a blood culture showed no
growth, with tests for Mycoplasma giving a negative
result. Chest radiography revealed bilateral haziness
in the lower lung zones and Doppler study of lower
limbs showed no signs of deep vein thrombosis.
Medical consultation resulted in diagnosis of atypical
pneumonia. Antibiotics were given intravenously
and the patient’s condition improved over the next
10 hours of observation in the high-dependency unit
of Latifa Hospital.
following this examination, it was decided that an
emergency lower segment caesarean section should
be performed as intraperitoneal haemorrhage
was suspected.
The lower uterine segment was incised and first
baby was in the correct position for delivery, with the
vertex at the front of the mother’s pelvis. The baby
was female and weighed 850 g with Apgar scores
of 8 at 1 minute and 8 at 5 minutes. The second
baby was delivered from the breech position, was
also female, weighed 865 g and had Apgar scores of
6 at 1 minute and 8 at 5 minutes. Both babies were
attended by a neonatologist and transferred to the
special care baby unit (SBCU).
During investigation, a defect of 6 × 6 cm was noted at
the left uterine cornua and posterior wall that resulted
in placental tissue and the amniotic sac of the second
twin protruding through the defect (Figure 1). No
active bleeding was noted at that site (Figure 2) and
both placentae, with complete membranes, were
delivered and blood clots removed. The defective
area was repaired in two layers and checked for
integrity through the cavity (Figure 3). The lower
segment incision was closed in two layers and
haemostasis ensured. The patient suffered 1.5 litres of
blood loss and her haemoglobin concentration was
8.6 g%. She was monitored in the intensive care unit
postoperatively and received a blood transfusion. She
was stable postnatally and discharged after 3 days
with a haemoglobin concentration of 12.5 g%.
The first twin died after 20 days in SBCU; however, the
second twin was doing well at the time of reporting.
During her stay, the patient continued to experience
irregular abdominal pain. CTG was reassuring as
regards the condition of both twins; however, on
palpation, there was tenderness mainly on left side
of uterus. It was decided that the babies should be
delivered if signs of chorioamnionitis developed.
A week after her admission, the patient was
experiencing stronger abdominal pain in association
with shivering and dizziness; however, her vital
signs were normal. Strong uterine contractions
were palpable and there was tenderness in left
upper quadrant of the uterus. CTG showed regular
uterine contractions but the cervical os was still not
sufficiently dilated for vaginal delivery. One hour
264
Figure 1  Placenta and amniotic sac of the second twin
protruding through the uterine defect.
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
Hamdan Medical Journal  2013; 6:263–266 (http://dx.doi.org/10.7707/hmj.v6i2.253)
Case Report
commonly resulting in a weak scar include difficulty
in suturing the defect, the use of electrocautery,
single-layer closure, presence of haematoma,
use of radiofrequencies for fusion of the tissues
and the wound healing characteristics of the
individual patient.
The first case of obstetric uterine rupture subsequent
to removal of a superficial myoma via laparoscopic
myomectomy was reported in 1997 in a primigravid
woman at 33 weeks’ gestation who presented with
acute abdomen.2
Figure 2  The uterine defect at the left cornua and
posterior wall.
Figure 3  The uterine defect after closure.
The mother was reviewed at 6 weeks in the postnatal
clinic and she was asymptomatic and the caesarean
wound was well healed.
Discussion
Laparoscopic myomectomy allows removal of
small numbers of subserous and intramural
myomas of less than 9 cm. Uterine rupture during
pregnancy following laparoscopic myomectomy
is a rare occurrence. The rate of uterine rupture
after abdominal myomectomy is 5.3%, and after
a previous caesarean ranges from 0.3% to 3.8%.
In a large study reporting on pregnancies after
laparoscopic myomectomy,В№ the rate of uterine
rupture was 1% and, to date, only 19 cases of uterine
rupture have been reported in the literature, which
raises concern regarding the integrity of the scar
created by laparoscopic myomectomy. Factors
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences
In 2002, Hasbargen et al.3 reported a case of uterine
rupture in a nulliparous woman at 29 weeks’ gestation
who had been diagnosed preoperatively via
magnetic resonance imaging (MRI) and underwent
laparoscopic subserosal myomectomy that used
unipolar electrocautery to seal the wound. However,
inflammation and necrosis are often associated with
electrocautery and can lead to delayed healing of the
wound and a weak scar.
Asakura et al.4 reported a case in 2004 of a multigravid
woman at a gestation of 34 weeks and 1 day who
was admitted because of threatened preterm labour
with frequent uterine contractions and a normal fetal
heart pattern. On examination, the internal os was
closed; therefore, the tocolytic drug ritodrine was
given and the patient was observed in hospital. At
35 weeks and 4 days of gestation, the patient had
severe uterine tenderness. The fetal heart rate was
initially reassuring but variable decelerations occurred
after 7 hours and there was no reduction in the
uterine tenderness, even after analgesia. Caesarean
section revealed haemoperitoneum of 50 ml and a
defect of 5 cm in the anterior fundus of the uterus.
There was no fresh bleeding at site of rupture;
therefore, the uterine dehiscence had occurred at
admission (at 34 weeks and 1 day of gestation) and
an overt rupture had occurred by the time of uterine
tenderness (at 35 weeks and 4 days of gestation). In
the case discussed previously, uterine dehiscence
had occurred at 24 weeks and 4 days of gestation and
overt rupture occurred a week later.
Uterine rupture has also been reported to occur
without signs of fetal distress. Banas et al.5 reported
such a case of spontaneous uterine rupture at
35 weeks’ gestation, which was 3 years after the
patient had undergone laparoscopic myomectomy,
without signs of fetal distress.5
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Hamdan Medical Journal  2013; 6:263–266 (http://dx.doi.org/10.7707/hmj.v6i2.253)
Case Report
Principles to follow during laparoscopic
myomectomy include:
1
2
3
4
Use microsurgical techniques with fine,
atraumatic sutures.
Be sure to dissect along cleavage planes.
Use electrocoagulation sparingly while
controlling bleeding to avoid excess thermal
damage and haematoma formation, especially
during subserous myomectomy.
Accurately approximate the hysterotomy incision
by taking into account the full thickness of the
edges of the uterus and ensure that the sutures
are evenly spaced, irrespective of the number of
suture layers.6
The mode of fetal delivery after laparoscopic
myomectomy is elective caesarean section if
the uterine wall was deeply penetrated during
myomectomy, or vaginal delivery if subserous or
pedunculated myomas were removed.
our case, uterine rupture occurred early, at 24 weeks’
gestation, as the uterus was already overdistended
by twins. MRI was not used as a diagnostic modality
in this case, but may be the only method for
preoperative diagnosis of uterine rupture,3 especially
in women with posterior uterine scars.
References
1
2
3
4
Conclusions
Laparoscopic myomectomy is an effective technique
and is associated with a low rate of patient morbidity.
As the aim of the intervention is to preserve the
uterus for future pregnancy, it is important to
maintain the integrity of uterine wall. Because of
the increasing number of cases of uterine rupture
after laparoscopic myomectomy, stringent selection
of patients suitable for the surgical procedure7 and
awareness that this complication may occur long
before term is essential. Uterine rupture can occur
after removal of superficial myomas and even in the
presence of a reassuring fetal heart pattern; therefore,
careful review of surgical records is warranted. In
266
5
6
7
Dubuisson JB, Fauconnier A, Deffarges J-V, Norgaard C,
Kreiker G, Chapron C. Pregnancy outcome and deliveries
following laparoscopic myomectomy. Hum Reprod 2000;
15:869–73. http://dx.doi.org/10.1093/humrep/15.4.869
Pelosi MA, Pelsi MA. Spontaneous uterine rupture at 33
weeks subsequent to previous superficial laparoscopic
myomectomy. Am J Obstet Gynecol 1997; 177:1547–9.
http://dx.doi.org/10.1016/S0002-9378(97)70110-8
Hasbargen U, Summerer-Monstaki M, Hillemanns P,
Scheidler J, Kimmig R, Hepp H. Uterine dehiscence in a
nullipara; diagnosed by MRI, following use of unipolar
electrocautery during laparoscopic myomectomy. Hum
Reprod 2002; 17:2180–2.
http://dx.doi.org/10.1093/humrep/17.8.2180
Asakura H, Oda T, Tsunoda Y, Matsushima T, Kaseki
H, Takeshita T. Change in fetal heart rate pattern on
spontaneous uterine rupture at 35 weeks gestation after
lapraroscopically assisted myomectomy. J Nippon Med
Sch 2004; 71:69–72.
http://dx.doi.org/10.1272/jnms.71.69
Banas T, Klimek M, Fugiel A, Skotniczny K. Spontaneous
uterine rupture at 35 weeks gestation, 3 years after
laparoscopic myomectomy, without signs of fetal
distress. J Obstet Gynaecol Res 2005; 31:527–30.
http://dx.doi.org/10.1111/j.1447-0756.2005.00331.x
Paul PG, Koshy AK, Thomas T. Pregnancy outcomes
following laparoscopic myomectomy and single layer
closure. Hum Reprod 2006; 21:3278–81.
http://dx.doi.org/10.1093/humrep/del296
Nkemayim DC, Hammadeh ME, Hippach M, Mink D,
Schmidt W. Uterine Rupture in pregnancy subsequent to
previous Laparoscopic Electromyolysis. Archiv Gynaecol
Obstet 2000; 264:154–6.
http://dx.doi.org/10.1007/s004040000075
В© 2013 The Author(s)
Journal Compilation В© 2013 Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences

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