Part Two
What is Down’s syndrome?
The classification of Down’s syndrome was made
in 1866 by Dr John Langdon Down who made
‘Observations on an ethnic classification of idiots’. In 1956 46 chromosomes were described and in
1959 Professor Jerome Lejeune described the
extra copy of chromosome 21
Regular Down’s syndrome
Recurrence risk
Following a regular trisomy 21, the recurrence risk
is 0.75% at 12 weeks (Nicolaides et al 1999)
0.42% mid trimester and 0.34% at term (Noble
1998) plus the background age chance
• Following a trisomy due to a translocation
the recurrence chance is dependent on type
of tranlocation and which partner carries the
translocation
• Affected persons rarely reproduce and there is
no evidence of paternal offspring. Of maternal
offspring less than half are affected
Clinical features
•
Aetiology
•
•
•
•
•
•
Incidence of 1 in 600 – 800 births
95% are regular Trisomy 21 due to nondysjunction
85% maternally derived
15% paternally derived
4% due to translocation usually Robertsonian
1% mosaicism
•
•
•
•
•
•
•
•
•
•
Brachycephaly excess neck folds, small nose,
flattened broad bridge of nose, flat facial profile
Low set simple ears
Epicanthic folds
Upslanting palpebral fissures
Small carp-shaped mouth, protruding tongue
Brushfield spots
Single palmar crease
Clinodactyly
Sandal gap toes
Hypotonia and poor feeding
Developmental delay
1
Part Two
What is Down’s syndrome?
Gastrointestinal Tract
Cardiac Anomalies
•
•
40 – 50% have Congenital Heart Defect
- 30 – 40% have complete AVSD
- Common others include VSD and PDA
All babies should have a clinical examination
and an echocardiogram
•
•
•
10 – 12% have abnormalities of the
gastrointestinal tract. Most prevalent are TOF
(Tracheo-oesophageal fistula), duodenal
obstruction with or without pyloric stenosis,
imperforate anus and Hirschsprungs disease
Constipation is very common at all ages
Coeliac Disease
Atrial septal defect
Other Associated Problems
Ventricular septal defect
Epilepsy 10% in late fifties, 1 -2% in children
Leukaemia 1% in first 2 -3 years
Alzheimer’s disease is common affecting 45%
from age 45
Dentition hypoplasia – less caries, more gum
disease
Skin is dry, some hyperkeratotic areas, less
elastic, prone to chapping. Fine and sparse hair
with some balding
Hearing and Opthalmic
•
•
•
•
•
Over 50% have significant impairment,
sensorineural and/or conductive loss
Need lifelong audiological surveillance
High incidence of visual problems, 5 times more
likely to wear glasses
Cataracts and/or glaucoma may occur in infancy
Neonatal testing for cataracts and continued
opthalmological screening is required
Thyroid Disorder
•
•
•
At all ages more frequent than in general
population, usually hypothyroidism. Around
10% of school age children with Down’s
have uncompensated hypothyroidism, but
prevalence increases with age
Biochemical screening essential throughout life
Hyperthyroidism rare
Musculoskeletal
•
•
•
2
Joint laxity – knee problems, patella-femoral
instability, genu valgus, pes planus
High BMI – feet problems, vertical talus, spinal
problems, genu valgum
Cervical spine instability – atlantoaxial joint.
There is a small chance for acute or chronic
neurological problems
Down’s syndrome
•
•
•
One of the most common cause of learning
difficulties – some will cope with extra help in
mainstream schools, others will need to attend
special schools
Some adults will live semi-independent lives,
others will always be dependent
Life expectancy is 50 -55 years with 44% of
live births surviving to age 60
It is therefore difficult to generalise since there
are more difference between people with Down’s
syndrome than there are similarities...
Most children with Down’s syndrome will walk and
talk. Many will read and write. Many go to ordinary
schools, and look forward to a semi-independent
life, away from the family home...
Just as there is a wide spread of abilities in the
general population, the ability range of people with
Down’s syndrome is very wide.
Extracts from leaflet by the DSA
See Down’s syndrome Scotland for further
information: http://www.dsscotland.org.uk/
Part Two
First Trimester Screening for Down’s Syndrome
Screening Tests
Diagnostic Tests
Screening tests identify individuals as broadly ‘high’
or ‘low’ chance. High chance results do not indicate
that the baby definitely has Down’s syndrome, but
should prompt the health care professional to offer
further screening or diagnostic tests.
Diagnostic tests for Down’s syndrome give definite
information on fetal chromosomes by confirming
the presence of a third copy of chromosome 21.
Historical Milestones
1933
Association
between
maternal age
and Down’s
syndrome
reported
1959
Trisomy 21
identified
as cause
of Down’s
syndrome
1966
First
chromosome
analysis from
amniotic fluid
1968
Prenatal
diagnosis
of Down’s
syndrome
1974
1983-8
1988
Raised AFP
associated
with open
neural tube
defects
Maternal
serum
markers
for Down’s
syndrome
Triple test
introduced
1990
Nuchal
translucency
test
introduced
3
Part Two
First Trimester Screening for Down’s Syndrome
Terminology
Detection Rate (DR)
The proportion of women who will be identified by
the screening test with an affected pregnancy
False Negative Rate (FNR)
The proportion of women who are given a lower
chance result but have an affected pregnancy
False Positive Rate (FPR)
The proportion of women with a higher chance/
screen positive result but have an unaffected
pregnancy
Multiples of the median
The serum marker concentration for a pregnant
woman, divided by the median concentration value for
unaffected pregnancies of the same gestational age.
Communicating Chance
Reframing Chance
Chances of an affected pregnancy
Chances of an unaffected pregnancy
1 in 4
25%
3 in 4
75%
1 in 5
20%
4 in 5
80%
1 in 10
10%
9 in 10
90%
1 in 20
5%
19 in 20
95%
1 in 30
3%
29 in 30
97%
1 in 50
2%
49 in 50
98%
1 in 100
1%
99 in 100
99%
1 in 200
0.5%
199 in 200
99.5%
First Trimester Serum Markers
Pregnancy Associated Plasma Protein – A
(PAPP – A)
Free beta Human Chorionic Gonadotrophin
(FßhCG)
•
•
•
•
•
•
•
•
•
•
4
Originates mainly from placental
syncytiotrophoblast
Concentration increases with gestation
Screening sensitivity decreases with gestation
Optimal sensitivity at 8 – 9 weeks gestation
Levels reduced in pregnancies affected by
Down’s syndrome
Beta subunit of hCG/intact hCG
Produced by the syncytiotrophoblast cells
Decreases with gestational age
Sensitivity maintained in second trimester
Raised levels in pregnancies affected by
Down’s syndrome
Part Two
First Trimester Screening for Down’s Syndrome
Nuchal Translucency
Chitty describes nuchal tranlucency (NT) the
‘swelling’ just under the skin at the back of the
fetal neck’, recognised to be a collection of
lymphatic fluid under the skin. The measurement is
defined as a saggital (front to back) measurement
between the muscles of the cervical spine
and the inner layer of echogenic skin. An
increased NT measurement is associated with
chromosomal abnormalities, an increasing risk of
structural anomalies (including cardiac defects),
neuromuscular problems and a wide range
of syndromic problems. The risk of all these
increases as the NT increases from about 2.5mm
upwards.
Screening for Down’s syndrome
Women should have a pre-test discussion
regarding the screening programme available in
Scotland and its benefits. A copy of the national
information leaflet to support the pregnancy
screening programmes should be given at least 48
hrs prior to collection of the blood sample, unless
precluded by late presentation however these
women still need to give informed choice and
appropriate support to facilitate this should be given.
The woman should be asked to sign the consent
section in their Scottish Woman Held Maternity
Record (SWHMR) accepting or declining
screening stating that they have received sufficient
information to understand the reasons for
testing, the consequences of the results and the
significance of not having these tests performed. The form should be countersigned by the midwife/
health professional taking the blood sample
or ultrasound examination. It should be noted
and parents should be made aware that other
conditions such as Edwards’s syndrome may also
be identified through either the screening test or
any subsequent diagnostic procedure.
First trimester combined screen for Down’s
syndrome consists of an ultrasound scan to
measure the nuchal fold of the fetus and the
result of this will be combined with the results
of a blood test and also the woman’s age to
calculate the woman’s individual chance of their
baby having Down’s syndrome. The first trimester
markers free beta subunit of hCG (FßhCG) and
pregnancy associated plasma protein A (PAPP-A)
are measured in serum by specific immunoassay.
Results are converted to MoM and corrected for
co-variables including maternal weight, smoking
status, and if applicable, previous affected
pregnancy and assisted conception.
NT measurements (in mm) are averaged and
converted to MoM. This test is carried out between
11 – 13+ 6 weeks gestation and the blood samples
should be collected on the same day that the NT
measurement is performed. The first trimester
screening test should give a detection rate of 90%
at a 5% false positive rate (Stenhouse et al 2004).
It should be noted that this test no longer screens
for neural tube defects and the 18 – 21 week fetal
anomaly scan is now the screening test of choice
for these conditions.
Median MoMs in Down’s syndrome pregnancies:
AFP
0.75
hCG
2.07
UE3
0.72
Inhibin-A
1.99
Second trimester screening for Down’s
syndrome
There will always be a percentage of women who
will present too late to be offered a first trimester
combined screen for Down’s syndrome (estimated
to be around 15-20%) and the new policy is for
these women to be offered a second trimester
screen using four serum markers [alphafetoprotein
(aFP); total human chorionic gonadotrophin
5
Part Two
Screening for Down’s Syndrome
(HCG); unconjugated eostriol (UE3) and Inhibin-A
(Inhibin)] to make it closer to the sensitivity and
specificity of the first trimester combined screen. The quadruple test should give a detection rate of
75%.
Second Trimester Screening Markers
Alpha-fetoprotein (AFP)
• Produced by fetal yolk sac and liver
• Increases with gestational age
• Levels reduced in pregnancies affected by
Down’s syndrome
• Levels increased in pregnancies affected by
open spina bifida or abdominal wall defects
e.g. gastroschisis
Human Chorionic Gonadotrophin (Intact hCG)
• Produced by the syncytiotrophoblast cells
• Decreases with gestational age
Unconjugated estriol (uE3)
• Produced by placenta, fetal liver and fetal
adrenals
• Increases with gestation
• Levels reduced in pregnancies affected by
Down’s syndrome
Inhibin-A
• Produced by placenta
• Decreases with gestational age between 14
and 17 weeks whereupon it begins to increase
again
• Levels increased in pregnancies affected by
Down’s syndrome
It should be noted that women who have second
trimester screening will have AFP measured as
part of the screening test and an interpretation of
the result for neural tube defects will be provided.
Clinical Follow-up
If the screening test result indicates the woman
is in the “higher chance” group she will be offered
counselling and a diagnostic test. If the pregnancy
is beyond 15 weeks’ gestation, the follow-on
diagnostic procedure for Down’s syndrome is
amniocentesis. If the pregnancy is of less than
13 weeks’ gestation, the follow-on diagnostic
procedure is chorionic villus sampling (CVS).
6
Amniocentesis
This test is performed usually between 15 and
20 weeks of pregnancy, although this may vary.
Amniocentesis is quite a common procedure and
is undertaken for many reasons. Normally it is
performed to establish the structure and number
of the chromosomes or to establish any genetic
problems that may affect the baby. A needle is
inserted through the abdomen. It is recommended
that this is performed under the guidance of
ultrasound. A small amount of fluid is removed and
sent to the genetic laboratory for investigation.
Chorionic villus sampling (CVS)
This is normally performed between 11 and 13
weeks of pregnancy. It is known that performing
this test before 9 weeks will increase the possibility
of limb abnormalities. Again it is recommended
that this procedure is performed under ultrasound
guidance. A needle is inserted through the
abdomen or, rarely, through the cervix. The aim is
to remove a small piece of placenta. The placenta
originates alongside the same cells as the baby
and consequently should have the same type of
chromosomal and genetic makeup.
Both of these diagnostic procedures carry a risk
of miscarriage, quoted as 2% for CVS and 1%
for amniocentesis by most hospitals.
Information
Information needs to be given in a way that
helps make it clear to the parents that the health
professional recognises the impact the diagnosis
will have on the parents.
The diagnosis of abnormalities which are perceived
by health professionals as ‘less severe’ than others
still cause significant distress for parents.
(Statham, Solomou & Green, 2003)
For parents, the quality of the care they receive is
crucial. Few forget their experience of loss. Most
have vivid memories of what happened, what was
done and what was said and these memories
may stay with them for months, years and often a
lifetime to come.
For further information go to:
www.fetalanomaly.screening.nhs.uk/
fetalanomalyfolder
Part Two
Laboratory Perspectives
Screening for Down’s syndrome
Drivers for change in Scotland
• CUBS screening for Down’s Syndrome in the
1st trimester: a Scottish multicentre study. JA
Crossley et al 2002 BJOG 109 p 667
• Health Technology Assessment Report 5
March 2004
Routine ultrasound scanning before 24 weeks of
pregnancy
• Quality Improvement Scotland ‘Clinical
Standards’ October 2005
Pregnancy and Newborn Screening
• CEL 31(2008)
Changes to Pregnancy and Newborn Screening
Programmes
UK Screening Committee Benchmarks
• >75% detection rate for a <3% false positive
rate by April 2007
• >90% detection rate for a <2% false positive
rate by April 2010
Changes being made to meet new targets and
standards
The laboratory service is on course for central
funding from 1st April 2010
Laboratory service to be provided from 2
laboratories:
Glasgow (Yorkhill) and Edinburgh ( Western
General Hospital)
First trimester screen will be offered for the
majority of women (85%)
Introduction of an enhanced second trimester
service (quadruple test) (15%)
The action limit is changing to a higher chance
value eg 1:200 or 1:150
report AFP MOM and indication of chance with 2nd
trimester results
Request Information
•
•
•
•
•
•
•
•
•
Demographics including DOB and CHI
Measure of gestation eg CRL/HC and date or
EDD
Current smoker
Ethnic origin
Previous affected pregnancy, parental history
Nuchal translucency and ‘sonographer’ ID
Singleton/multiple pregnancy
Maternal weight
Assisted conception
Laboratory Standards
•
•
•
•
•
•
•
•
•
Daily internal quality control
Monthly internal assessment
Monthly external quality assessment
CPA Accreditation
6 monthly data submission to DQASS
Minimum annual work load
Licensed chance calculation software
Target 3 day turn around time
Consultant grade staff heading the service
Nuchal Translucency
•
•
•
•
Measurement performed between 11 weeks 0
days and 13 weeks 6 days
Nuchal translucency measured in mm
performed routinely on the same day as the
blood sample
Unique ‘sonographer’ ID number
Regular review of operator bias eg DQASS
Twin pregnancy will be NT only but this may
change
Team work is essential at all stages of the
screening process
Screening for Neural Tube Defect using
maternal serum AFP
Maternal serum AFP measurement will cease to
be used to provide the screening service for neural
tube defects but the laboratory will continue to
7
Part Two
Mid Trimester Fetal Anomaly Scan
Every woman has the right to make an informed
choice about each pregnancy screening event.
The 18+0–20+6 weeks fetal anomaly scan is an
important clinical examination and each woman
should be given full information to enable her to
consent to or decline the scan and if a serious
abnormality is found, information that will help
parents make complex and emotional decisions
about whether or not to continue with the
pregnancy.
At the time of the scan the sonographer should
establish that the woman has received and
understood the information about the scan in
order to accept or decline the offer of the scan.
This means the woman should understand that
the primary objectives of the scan are to identify
abnormalities either incompatible with life or
associated with morbidity at a time when she
still has a choice about whether to continue with
or terminate her pregnancy. The challenges are
even greater when helping parents, who are often
in a state of shock, to make decisions after an
abnormality is identified.
8
Key Points for Midwives
Preparation for the scan starts at the point of ‘first
contact’ and should be revisited at subsequent
appointments with the midwife, GP and/or
obstetrician.
Discussions between the health professional and
each woman should incorporate
•
•
Clear, consistent and accessible information
about the purpose, limitations and potential
consequences of the scan. This information
should be given verbally and every woman
should also be given the Information booklet
‘Your guide to screening tests during
pregnancy’
Practical information about how to prepare
for the scan and what will happen during the
scanning appointment.
Explaining the purpose and limitations of the
18+0-20+6 weeks scan
Information giving is a critical aspect of 18+0-20+6
scan –this is central to enabling each woman
to make an informed choice about accepting or
declining the offer of the scan.
Part Two
Mid Trimester Fetal Anomaly Scan
Each woman needs to understand that the scan is
an ‘option’ and that the main purpose of the scan
is to
• check her baby’s growth and development
• identify serious fetal abnormalities which
are incompatible with life or associated with
morbidity
• identify certain abnormalities which may
benefit from intervention in the pregnancy
period or soon after the birth of the baby.
Eleven auditable conditions to be screened for as
a minimum:
Conditions
Detection
rate%
Anencephaly
98
Open spina bifida
90
Cleft lip
75
Diaphragmatic hernia
60
Each woman also needs to understand the
limitations of the scan:
Gastroschisis
98
Exomphalos
80
•
•
Serious cardiac abnormalities
50
Bilateral renal agenesis
84
Lethal skeletal dysplasia
60
Edward’s syndrome (Trisomy 18)
95
Patau’s syndrome (Trisomy 13)
95
it is not possible to detect all abnormalities
the image quality may be compromised by a
number of factors, such as:
- increased maternal body mass index
- the presence of uterine fibroids/abdominal
scar tissue
- abnormal levels of amniotic fluid
- the fetus lying in a sub-optimal position.
If the scan cannot be completed to the required
standard at the first appointment, the woman will
be offered one further appointment only and this
should be scheduled before 23 completed weeks
of pregnancy.
Other points to incorporate into the explanation
and discussion are:
•
•
•
•
•
whilst all women are offered the scan, each
woman has the right to make an informed
choice to accept or decline the offer. If the offer
is declined that decision will be respected and
recorded
reassurance that the majority of scans indicate
that the baby has no obvious abnormalities
(but not guaranteed)
scanning is not considered harmful to the baby
or the woman
the NHS standard scan is two-dimensional
black and white imaging (not 3D or colour)
the scan is a clinical examination and is
therefore much more than determining the sex
of the baby and getting a picture
whilst all women are offered the
scan, each woman has the right
to make an informed choice to
accept or decline the offer.
9
Part Two
Mid Trimester Fetal Anomaly Scan
18+0 - 20+6 Fetal Anomaly Screening Base Menu
No.
1.
Area
Head and neck
Structure
Skull
Neck:
- skin fold (NF)
Brain:
-Cavum septum pellucidum
-Ventricular atrium
-Cerebellum
2.
Face
Lips
3.
Chest
Heart:
-Four-chamber view
-Outflow tracts
Lungs
4.
Abdomen
Stomach:
-Stomach and short intra-hepatic section of
umbilical vein
Abdominal wall
Bowel
Renal pelvis
Bladder
5.
Spine
Vertebrae
Skin covering
6.
Limbs (a)
Femur
Limbs (b)
Hands:
-Metacarpals (right and left)
Feet:
-Metatarsals (right and left)
7.
Uterine cavity
Amniotic fluid
Placenta
10
For further information go to: http://fetalanomaly.screening.nhs.uk/fetalanomalyresource/
Part Two
Haemoglobinopathies
The Haemoglobinopathies are common inherited
blood conditions which mainly affect people who
have originated from Africa, the Caribbean, the
Middle East, Asia and the Mediterranean, but are
also found in the northern European population.
The many people who ‘carry’ a gene for one of
these conditions are healthy but they can have an
ill child affected by one of these conditions if their
partner is also a carrier of the same condition.
Key Points
•
•
•
•
•
•
•
As part of pregnancy screening in Scotland,
all pregnant women are screened for
thalassaemias (using routine blood indices).
Screening for Sickle cell disorders will be
offered according to ancestry (using a standard
family origin questionnaire).
When a pregnant woman is found to be a
carrier, the baby’s father should be offered
testing as soon as possible
Early is best. The earlier in pregnancy an ‘at
risk’ couple (where both parents are carriers
and so at risk of having an affected child)
are identified - preferably well within the
first trimester - the more time they have to
be referred and to make choices about the
pregnancy, and whether or not they want
prenatal diagnosis.
Carrier screening before pregnancy, or at first
notification of pregnancy, allows choices to be
made even earlier.
Professionals should be sensitive to diversity
in patients’ attitudes to screening and making
choices in relation to the results. It is important
to communicate effectively; assess and
respond to all patients as individuals (avoid
assumptions about people’s views).
Newborn screening for sickle cell disorders will
be offered for all babies as part of the newborn
bloodspot test in Scotland. Although this is for
the early identification of children affected with
this disorder, many babies who are healthy
carriers will also be identified.
•
•
•
Each pregnancy is an opportunity. Do not
assume that patients have been screened or
adequately counselled previously.
Low mean cell haemoglobin (MCH) detected
on a full blood count may mean iron deficiency
or thalassaemia carrier status or both.
Ferritin assay and high performance liquid
chromatography is required to distinguish
these conditions, and provide appropriate
information and care.
Never accept a diagnosis (e.g. carrier or not
a carrier) on hearsay. All decisions should be
based on evidence from seeing the test result,
or a card previously issued to the patient.
What are haemoglobinopathies
Haemoglobinopathies are inherited disorders of
haemoglobin and are genetic conditions that are
autosomal recessive.
There are more than 1000 disorders, categorised
into two main groups:
1. Quantitative Disorders (Quantity)
Αlpha & Beta Thalassaemia
Thalassaemia blood film
2. Qualitative Disorders (Quality)
Sickle Cell Disease
Pitfalls to avoid
•
Do not assume that a genetic disorder (such
as sickle cell, thalassaemia or cystic fibrosis) is
confined to a particular ethnic group. They may
occur in any ethnic group.
11
Part Two
What are Haemoglobinopathies?
Sickle cell and thalassaemia disorders:
Are potentially life-threatening conditions causing
anaemia and other problems
Due to inheritance of haemoglobin gene variants
that alter the structure or amount of haemoglobin
– e.g. haemoglobin S, beta thalassaemia
• Not all combinations of haemoglobin gene
variants cause a disorder
• Increased population mixing have led to these
conditions being found in most populations
Sickle cell disorders
Sickle cell disorders refer to a group of disorders
caused by inheritance of a pair of abnormal
haemoglobin genes, including the sickle cell
gene. It is characterised by chronic haemolytic
anaemia, dactylitis (Inflammation of a digit), and
acute episodic clinical events called “crises”. Vasoocclusive (painful) crises are the most common,
and occur when abnormal red cells clog small
vessels, causing tissue ischaemia. A common
variant of sickle cell disorders, also characterised
by haemolytic anaemia, occurs in people with one
sickle and one thalassaemia gene. Sickle cell trait
occurs in people with one sickle gene and one
normal gene. People with sickle cell trait do not
have any clinical manifestation of illness.
12
Aetiology
Sickle cell disease is inherited as an autosomal
recessive disorder. For a baby to be affected,
both parents must have the sickle cell gene. In
parents with sickle cell trait, the risk of having an
affected baby is one in four for each pregnancy.
The genetic mutation for sickle occurs on the 6th
point of the beta globin chain; glutamic acid is
replaced by another amino acid called valine.
This amino acid substitution causes a change in
the beta globin chain resulting in the production
of sickle haemoglobin. A red blood cell which
contains only sickle haemoglobin and no normal
haemoglobin A is insoluble: under the right
conditions the haemoglobin molecules crystallise
when deoxygenated. These crystals are sticky
and stack up to form long stiff rods which distort
the membranes of the RBC. These rods exert
pressure against the wall of the RBC causing
it to change into the classic half moon shape
associated with sickle red blood cells. When these
RBCs are re-oxygenated they regain their original
round shape but with repeated oxygenation and
deoxygenation the RBC become increasingly
hard, brittle, break easily and eventually
become irreversibly sickled. This process takes
approximately 5 - 30 days depending on the
severity of the sickle cell disease. Once they are
irreversibly sickled these RBCs are destroyed by
the reticulo endothelial system. Because of this,
Part Two
Sickle Cell Disorders
erythrocytes in SCD have a grossly reduced life
span of only 17 days to the expected 120 days
in the unaffected population resulting in chronic
anaemia in these patients.
Factors that precipitate or modulate the
occurrence of sickle cell crisis are not fully
understood, but infections, hypoxia, dehydration,
acidosis, stress (such as major surgery or
childbirth), and cold are believed to play some
role. In tropical Africa, malaria is the most common
cause of anaemic and vaso-occlusive crisis.
Prevalence and Risk
Prevention and Treatment
Prevention
Care of a woman with sickle cell disorder in
pregnancy should be via a team approach
involving a haematologist and obstetrician working
closely together. Counselling should be made
available prenatally about the risks associated
with pregnancy. If the sickle status of the partner
is unknown, he can be offered testing in order to
predict the risk of the baby. If he should then test
positive, prenatal diagnosis is an option. Folic acid
is advised throughout the pregnancy but, because
of the risk of iron overload, ferrous sulphate should
not be routinely prescribed.
In the UK, it is estimated that 240,000 people are
healthy carriers of the sickle cell gene variant and
over 12,500 people have a sickle cell disorder. The
highest prevalence of sickle cell disorders is found
amongst Black Caribbeans, Black Africans and
Black British. Sickle cell disorders presently affects
more than 1 in every 2400 births in the UK. It is
vital to identify babies with the condition as soon
as possible. There is a high risk of sudden death
in the early years of life and prophylactic treatment
must be administered early.
Treatment
Patients with sickle cell disorders need continuous
treatment, even when they are not having a painful
crisis. The purpose of treatment is to manage
and control symptoms, and to try to limit the
frequency of crises. Supplementation with folic
acid, an essential element in producing red blood
cells, is required because of the rapid red blood
cell turnover. Testing of at-risk family members
ensures that early diagnosis and intervention are
possible before symptoms are present.
There are different variations of this disorder but
the 3 more severe types are:
• Homozygous Sickle Cell disease (HbSS)
• Sickle Cell/HbC (HbSC)
• Sickle-cell Thalassemia
Treatment for sickle cell disorders can include
oral hydration and oral analgesics including
opiates, acetaminophen, and ibuprofen for
uncomplicated episodes of vaso-occlusive pain.
People with sickle cell anemia need to keep their
immunisations up to date, including influenza,
pneumococcal, meningococcal, hepatitis B, and
influenza. Some patients may receive prophylactic
antibiotics to prevent infections.
Clinical Features
Sickle cell disorder has an unpredictable
clinical course therefore some of the following
complications may or may not occur, however the
symptoms of sickle cell disorder can include:
• Severe anaemia
• Intense pain
• Damage to major organs
• Infections
• Acute chest syndrome
• Bone marrow fat embolus
• Stroke
• Renal medullary infarction, hyposthenuria and
papillary necrosis
• Retinopathy
• Splenic sequestration
• Leg ulcers
• Aseptic necrosis of bone
Severe episodes of pain require administration
of parenteral analgesics. Oxygen, analgesics,
antibiotics, and transfusions are used to treat
acute chest syndrome. Affected individuals with
fever are given broad-spectrum antibiotics.
Because of the recognised association of sickle
cell disorders with Intra-uterine growth restriction
(IUGR), pre-eclampsia and premature labour, early
signs of these should be screened for throughout
the pregnancy of affected women. A caesarean
section is only indicated for obstetric reasons.
This is because it provides a higher risk for
thromboembolism in an already at-risk population.
Good pain relief in labour and adequate hydration
13
Part Two
What are Thalassaemia Disorders?
is very important to reduce stress and sickling. As
these infants are considered higher risk, especially
if small for gestational age (SGA), continual
monitoring is also suggested, as well as taking
steps not to prolong the labour. For some units,
assisted deliveries with an epidural are part of their
standard protocol for these women.
Postpartum care:
•
•
•
•
•
Early ambulation
Anti-embolic stockings
Appropriate hydration
Aggressive treatment of suspected infection
Neonatal testing (electrophoresis)
Thalassaemias
The thalassaemias are genetic defects affecting
globin (protein) chain synthesis (production). The
type of chain which is affected is dependent on
the gene defect inherited. The two most common
types affect the adult haemoglobin chains, i.e.
alpha or beta globin chain. If the alpha chain is
affected this gives rise to alpha thalassaemia. If
the beta chain is affected this gives rise to beta
thalassaemia. This can occur for a whole variety
of reasons as there are over 1000 thalassaemia
mutations.
Aetiology and Prevalence
Where a person has inherited haemoglobin A
from both parents they will have TWO usual beta
genes (b^b^), one from each parent, and FOUR
alpha genes (aa/aa), one pair from each parent.
They would, therefore, produce normal amounts of
BETA and ALPHA to make healthy red blood cells.
Some people inherit one usual and one unusual
Beta gene, in which case they have a condition
known as Beta Thalassaemia minor, (Hb AbThal),
sometimes referred to as a trait. Some people do
not inherit the usual number of Alpha genes in
which case they would have a condition known
as Alpha thalassaemia minor (trait). The terms
“minor” and “trait” refer to the same thing. It is not
clinically significant, does not cause this individual
or any of their children any health related problems
but does reduce the MCV & MCH as there is
reduced genetic material in the red blood cell.
14
There are two types of alpha thalassaemia trait.
The most common is Alpha Plus Thalassaemia
Trait. The less common is Alpha Zero
Thalassaemia Trait.
Alpha Plus Thalassaemia Trait is very common
in people whose families come from any of the
following parts of the world: Africa, the Caribbean,
the Mediterranean islands, India, Pakistan,
Bangladesh, the Middle East, and South East Asia.
Having this trait does NOT affect their health but
it is important that this carrier status is known as it
may be mistaken for iron deficiency anaemia, and
then be treated with iron medicines unnecessarily.
Alpha Zero Thalassaemia Trait is less common
but can be inherited by people whose families
come from any of the following parts of the world:
the Middle East, South East Asia, China, and the
Mediterranean islands. In this instance, no alpha
genes are inherited from one parent, but two
normal alpha genes are inherited from the other. It
does not affect the health of the affected individual,
however, if they have a child with a partner who
also has an alpha zero thalassaemia trait there
will be a 1 in 4 chance in EACH pregnancy that
the baby could inherit a severe anaemia called
Alpha Thalassaemia Major. In this instance
the child has not inherited any alpha genes at all
and, therefore, he or she will not be able to make
haemoglobin.
Alpha thalassaemia major is a serious blood
disorder because it affects the baby whilst it is
growing in its mother’s womb. If a baby inherits
this condition, the mother will also be at risk of
serious complications during pregnancy. This
condition is life threatening: babies who have
alpha thalassaemia major are unlikely to survive
pregnancy.
Part Two
Family Origin Questionnaire
Family Origin Questionnaire (FOQ)
The FOQ identifies the women and the baby’s
father from groups with higher carrier frequencies
for Hb disorders (non-North European origins)
ies
opath )
Q
globin
aemo nnaire (FO
H
r
fo
o
ning
uesti
Scree Origin Q
y
Famil e
ALL women are offered screening for
Thalassaemia
the
py of
nd co etion of
A seco
mpl
ples. le). The co
m
sa
blood if applicab
natal
s
e ante
record
with th e hospital
t form
th
reques added to
ry
to
be
ra
y labo copy can
og
ol
ird
at
(Ath
haem
to the nityrecord. s.
es
er
curely
ed se tient’smat ening proc
attach
re
pa
ust be edtothe rt of the sc
m
rm
dd
pa
This fo houldbea SENTIAL
an ES
forms
rm is
this fo
The screening programme recommends the use
of the Family Origin Questionnaire (FOQ) as part
of the pregnancy risk assessment, to determine
which women should be offered screening for
haemoglobin variants.
This will also include offering screening to low
risk women based on baby’s father being in a
high risk group.
Remember...
• ALL women will be offered screening for
Thalassaemia regardless of risk.
• In addition screening for sickle cell will be
offered if there is a “tick in the shaded box” for
her or the baby’s father
•
•
•
•
•
Provide written information as soon as possible
following confirmation of pregnancy (8-10
weeks)
Assess risk using the Family Origin
Questionnaire (FOQ) for each woman
Send top copy to lab with blood sample for
every woman
Obtain and document consent to take blood
sample for screening test
Identify at-risk couples by 12 weeks of
pregnancy
Inform the women of how and when she will
receive her results
an
woman
to the
Baby’
s fath
er
Pleas
Family origins are important for other inherited
conditions e.g. Tay sachs disease
•
father
baby’s
an
Wom
d the
s?
y
originns that appl
mily
io
our fas in ALL sect
are y
Whate tick all boxe
Screening for Sickle Cell is performed based on
FOQ risk group
Pregnancy screening
lined
st dec
ning te
Scree
m
ital Na
Hosp
.
te
ery Da
CHI No
Deliv
ated
Estim
e
Surnam
me
na
re
Fo
of Birth
Date
s1
Addres
s2
Addres
de
Postco
ing to
OFFER
n
oglobi
haem
en
t scre
varian
d
Signe
le
Job Tit
ple
l com
essiona
re Prof
alth Ca
(By He
oman
all w
if they
eir ba
or th
ve an
er ha
fath
by's
Name
Print
swer
s in a
shad
x
ed bo
Date
No
t Tel
Contac
)
e form
ting th
Couples at risk
Identified through:
1. Family Origin Questionnaire
(Sickle cell & Thalassaemia)
1. Laboratory algorithm using blood indices
results (Thalassaemia)
Completion of FOQ
•
•
•
•
Explore women’s and baby’s father family
origins for as many generations as possible
If woman declines, explore reason why and
document on FOQ
Send a copy to the lab with the request form. A
second copy should be added to the woman’s
maternity record. (A third copy can be added to
the hospital records if applicable)
Form determines whether lab screens for
Sickle Cell
ALL women screened for thalassaemia (unless
declined)
15
Part Two
Benefits of FOQ
Conditions screened for
Pregnancy (carrier)
Consider follow up procedures
Newborn (Conditions)
Hb-AS
HbSS
Hb-AC
HbSC
Hb-ADPunjab
HbSD
Hb-AE
Hb-AD
HbS/ß thalassaemia
Arab
Hb-A Lepore
HbS OArab
HbS/HPFH
•
•
δß-thalassaemia trait
•
αo thalassaemia trait
HPFH
•
•
Benefits of using FOQ
Women and their
partners
•
Who do the laboratory contact with the result?
Who, where and by what method is the women
informed?
What information is given, written & verbal?
Who counsels the couple and screens
the father of the baby and where is this
undertaken?
How is the father given the results?
Who and where are an ‘at risk’ couple referred
to?
Who and where undertakes diagnostic and
DNA testing?
Who follows up diagnostic results and
counsels the woman/couple?
Vital for newborn laboratory to know parents
carrier status – therefore record on bloodspot
card
Testing babies born to at-risk couples
Important to know parents’ carrier status when
dealing with newborn results
Important to remember that Beta Thalassaemia
may not be detected from newborn bloodspot
Hb-AS
HbSS
Remember
Hb-AC
HbSC
No haemoglobinopathy is exclusive to any single
ethnic group.
Hb-AD
Punjab
Hb-AE
HbSD
HbS/ß thalassaemia
Hb-ADArab
HbS OArab
Hb-A Lepore
HbS/HPFH
ß thalassaemia trait
δß-thalassaemia trait
αo thalassaemia trait
16
•
•
•
•
ß thalassaemia trait
Health Professionals
•
•
All persons are theoretically at chance of
carrying a haemoglobin mutation
Part Two
Laboratory Perspectives
Prevalence in the UK
Sickle Cell
1:2400 births
240,000 people are
healty carriers
12,500 people have
sickle cell disorder
Laboratory Practice
Thalassaemia
214,000 healthy
carriers
700 people are
affected with
Thalassamia
Affected groups
are Cypriots,
Italians, Greeks,
Indians, Pakistanis,
Bangladeshis,
Chinese and other
South Asian groups.
•
•
•
•
•
Receipt of samples at booking FBC
Unique Laboratory number attached
FOQ analysed, sample prioritised
Sample information entered into Laboratory
Information Management System (LIMS)
All samples with MCH < 27 are highlighted and
processed according to UK Guidelines
Thalassaemia Screening
MCH<27
From any Ante Natal
Location
Affected groups are
Black Africans, Black
Caribbean’s and
Black British
(Source: Handbook, September 2006)
Previous
Normal
MCH
No Previous
MCH >27
Delete Hbopathy
Request
Perform HPLC
And Ferritin
MCH <25
Guidelines
•
•
•
•
1998 BCSH Guideline Laboratory Diagnosis of
Haemoglobinopathies
All women with MCH < 27 screen for
β thalassemia trait, Hb Lepore and δβ
Thalassaemia
MCH < 25 screen for α thalassaemia trait.
Screening for Hb variants on all ethnic groups
except Northern European.
Prevalence in the UK
Sickle Cell
Thalassaemia
βthal
Hb S
δβthal
Hb E
Hb Lepore
α Thalassaemia
Hereditary
Persistance of Fetal
Haemoglobin (HPFH)
Perform HPLC
Ferritin and HbH
inclusions
Post Analysis
•
•
•
•
•
•
Interpretation of results
Standardised format for reporting
Communication with lead midwife
Follow up with the baby’s father’s samples
Perform Ferritin analysis on all MCH <27pg
Refer unknown variants and unusual results to
Reference laboratory
Hb O Arab
Hb C
Hb D Punjab
17
Part Two
Laboratory Perspectives
Thalassaemia Screening
Result Reporting
•
•
•
HPLC Analysis
•
•
Normal HbA2
HbF
ßThal/HPFH
/Hb Lepore etc
+/-
HbA2
HbF
ß Thal trait
Normal HbA2
& HbF
•
For further information refer to: NHS Sickle
Cell and Thalassaemia Screening Programme,
Handbook for Laboratories, 2nd edition; NSC,
September 2009
HbH inclusions/ http://sct.screening.nhs.uk/cms.php?folder=2493
PCR
Iron Deficiency
•
Standard Reporting Format
1. No Significant Haemoglobinopathy identified
2. Results indicate patient is a carrier for HbS/
Beta. Thalassaemia. Testing of baby’s father is
indicated
3. Confirmed Alpha Thalassaemia Trait.
4. Possible Alpha Thalassaemia Trait/Iron
Deficiency
Patterns of Genetic Inheritance
Screening for haemoglobin variants should
proceed without regard to iron deficiency,
suspected or proven, Hb A2 should be
measured and father testing requested to
prevent delay in identification of a couple ‘at
risk’.
Women can be simultaneously checked using
ferritin or Zinc protoporhyrin (ZPP).
Laboratory may require an additional sample
which may be taken at booking.
Partner Testing
•
•
•
•
•
Indicated if Mother is a carrier of any of the
significant Haemoglobinopathies.
Timely processing of samples
Clear information on baby’s father’s family
origin
Mechanism to link Mother and baby’s father
Links to Genetic Counselling and Prenatal
Diagnosis
Reproduced by kind permission of
UK National Screening Programme
18
Part Two
Laboratory Perspectives
Table of parental carrier state combinations that
give rise to the risk of a fetus with significant sickle
cell disease or ß-thalassaemia
(Table based on work of Prof. B. Modell)
Referral guidelines for antenatal screening specimens
Taken from NHS Sickle Cell and
Thalassaemia Screening Programme Handbook for Laborotories, 2nd edition,
NSC, September 2009.
19
20