PERINATAL AND LONG-TERM OUTCOME IN FETUSES DIAGNOSED WITH
UNILATERAL VENTRICULOMEGALY: SYSTEMATIC REVIEW AND METAANALYSIS
Scala C, Familiari A, Pinas A, Papageorghiou AT, Bhide A, Thilaganathan B, Khalil
A
Fetal Medicine Unit, St George’s Hospital, St George’s University of London, UK.
Corresponding author:
Dr Asma Khalil
Fetal Medicine Unit
St George’s University of London
Cranmer Terrace,
London SW17 0RE
Telephone: +442032998256
Fax: +442077339534
E-mail: [email protected]
ABSTRACT
Objectives: Ventriculomegaly is a common sonographic feature diagnosed in fetal life
that has been associated with poor outcome. The majority of the studies have focused
on the perinatal and long-term outcomes in fetuses with antenatal diagnosis of bilateral
ventriculomegaly. The aim of this study was to undertake a systematic review and metaanalysis to quantify the perinatal and long-term outcome of fetuses diagnosed with
unilateral ventriculomegaly during the second- or third- trimester of pregnancy.
Methods: Medline, and Embase and The Cochrane Library were searched
electronically. The outcomes investigated included incidence of aneuploidy, congenital
infections, progression, associated brain and extra-brain abnormalities and
neurodevelopmental delay. Reference lists of relevant articles and reviews were handsearched for additional reports. Cohort and case-control studies were included. Metaanalyses of proportions were used. Between-study heterogeneity was assessed using
the I2 test.
Results: The search yielded 2053 citations. Full text was retrieved for 202 and the 16
studies were included in the systematic review. In fetuses with unilateral
ventriculomegaly, the rates of chromosomal abnormalities and congenital infections were
1.7% (95% CI, 0.3-4.1) and 3.0% (95% CI, 1.3-5.4), respectively. The prevalence of
MRI-detected additional brain abnormalities prenatally and postnatally was 6.7% (95%
CI, 1.1-16.3) and 20.2%, (95% CI, 4.1-44.3), respectively. The incidence of abnormal
neurodevelopmental status overall was 10.8% (95% CI, 5.9-16.8), while it was 5.8%
(95% CI, 2.6 -10.2) in fetuses with isolated mild unilateral ventriculomegaly.
Conclusions: The prevalence of aneuploidy, congenital infections and
neurodevelopmental delay in fetuses with a prenatal diagnosis of unilateral
ventriculomegaly is low. Parents should be reassured that the incidence of
neurodevelopmental delay is similar to the rate seen in the general population when the
ventriculomegaly is isolated, unilateral and measures less than 15mm.
INTRODUCTION
Ventriculomegaly is a common sonographic feature diagnosed in fetal life that has been
associated with poor outcome1. The prevalence of ventriculomegaly varies between 0.3
and 1.5 per 1000 births, depending on the gestational age at examination, the technique
of measurement and whether one or both ventricles are evaluated2. Fetal
ventriculomegaly is defined as an atrial width, measured in the axial plane of the fetal
head at the level of the frontal horns and cavum septi pellucidi, greater than 10 mm1,3.
The etiology of fetal ventriculomegaly is diverse, including normal variation, aneuploidy,
genetic syndromes, primary brain abnormalities, congenital infection, cerebral vascular
accidents and intracranial hemorrhage. However, even when fetal VM is isolated, there
may be an associated risk of abnormal neurodevelopmental outcome4-7.
Fetal ventriculomegaly can be symmetrical, affecting both lateral ventricles (bilateral) or
may be unilateral, but the majority of the studies reporting perinatal and long-term
outcomes in fetuses with antenatal diagnosis of fetal ventriculomegaly have assessed
bilateral ventriculomegaly6.
The aim of this study was to undertake a systematic review and meta-analysis to
quantify the perinatal and long-term outcome of fetuses diagnosed with unilateral VM
during the second- or third- trimester ultrasound examination.
METHODS
Protocol, eligibility criteria, information sources and search
This review was performed according to a-priori designed protocol and recommended for
systematic reviews and meta-analysis8-10. The study was registered with the
PROSPERO
database
(registration
number:
CRD42015025602,
http://www.crd.york.ac.uk/PROSPERO). Medline, Embase, the Cochrane Library
including The Cochrane Database of Systematic Reviews (CDSR), Database of
Abstracts of Reviews of Effects (DARE) and The Cochrane Central Register of
Controlled Trials (CENTRAL) were searched electronically on the 19th February 2015,
utilizing combinations of the relevant medical subject heading (MeSH) terms, key words,
and word variants for “ventriculomegaly” and “outcome” (Supplementary Material 1). The
search and selection criteria were restricted to English language. Reference lists of
relevant articles and reviews were hand searched for additional reports. The Moose
guidelines were followed11.
Study selection, data collection and data items
The inclusion criteria were studies reporting data on the perinatal outcome of fetuses
with unilateral ventriculomegaly. Unilateral ventriculomegaly was defined as an atrial
measurement greater than 10 mm affecting only one side detected during the second- or
third trimester of pregnancy. Ventriculomegaly was further classified into mild/moderate
when the measurement was between 10 and <15 mm, and severe when it was 15 mm
or more. The outcomes assessed were the incidence of aneuploidy, congenital
infections, associated brain and extra-brain abnormalities, progression and
neurodevelopmental delay. Two authors (CS, AF) reviewed all the abstracts
independently. Agreement about potential relevance was reached by consensus, and full
text copies of those papers were obtained. Two reviewers (CS, AF) independently
extracted relevant data regarding study characteristics and pregnancy outcome.
Inconsistencies were discussed by the reviewers and consensus reached. If more than
one study was identified for the same cohort with identical endpoints, the report
containing the most comprehensive information and with the longer follow-up evaluation
interval was included to avoid overlapping populations. For those articles in which the
relevant information was not reported but the methodology was such that this information
would have been recorded initially, the authors were contacted. Only full text articles
were considered eligible for the inclusion. Case reports, and conference abstracts were
also excluded.
Risk of bias, summary measures and synthesis of the results
Quality assessment of the included studies was performed using the Newcastle-Ottawa
Scale (NOS). According to the NOS, each study is judged on three broad perspectives:
the selection of the study groups; the comparability of the groups; and the ascertainment
of the outcome of interest12. Assessment of the selection of a study includes the
evaluation of the representativeness of the exposed cohort, selection of the nonexposed cohort, ascertainment of exposure and the demonstration that the outcome of
interest was not present at the start of the study. Assessment of the comparability of the
study includes the evaluation of the comparability of cohorts based on the design or
analysis. Finally, the ascertainment of the outcome of interest includes the evaluation of
the type of the assessment of the outcome of interest, length and adequacy of followup12. According to NOS, a study can be awarded a maximum of one star for each
numbered item within the selection and outcome categories. A maximum of two stars
can be given for comparability.
We used meta-analyses of proportions to combine data13, 14. Funnel plots displaying the
outcome rate from individual studies versus their precision (1/standard error) were
carried out with an exploratory aim. Tests for funnel plot asymmetry were not used when
the total number of publications included for each outcome was less than ten. In this
case, the power of the tests is too low to distinguish chance from real asymmetry15.
Between-study heterogeneity was explored using the I2 statistic, which represents the
percentage of between-study variation that is due to heterogeneity rather than chance. A
value of 0% indicates no observed heterogeneity, whereas I2 values of ≥ 50% indicate a
substantial level of heterogeneity. A fixed effects model was used if substantial statistical
heterogeneity was not present. On the contrary, if there was evidence of significant
heterogeneity among the included studies, a random effect model was used. Sensitivity
analysis was attempted when possible according to whether the unilateral
ventriculomegaly was mild/moderate or severe. All proportion meta-analyses were
carried out using StatsDirect 2.7.9 (StatsDirect Ltd, Altrincham UK, 2012).
RESULTS
The database search yielded 2053 possible citations. From reviewing the title or
abstract, 1851 were excluded, as they did not meet the selection criteria. The remaining
202 full-text manuscripts were retrieved and a total of 16 eligible studies were included in
the meta-analysis. The 16 included studies reported on 1149 fetuses with
ventriculomegaly, and of these 397 (34.5%) were fetuses with unilateral
ventriculomegaly during the second or third- trimester ultrasound evaluation; these were
included in the analysis (Figure 1 and Table 1). Quality assessment according to NOS
was conducted on all 16 studies included in the systematic review and this showed
moderate heterogeneity, in particular for the comparability tool, (Table 2). Publication
bias assessed using the Egger test showed no significant bias for the studies reporting
associated aneuploidy (P=0.300), while there was significant bias for the studies
reporting neurodevelopmental outcomes (P=0.005) (Supplementary material 2). Most of
the studies were small case series and many of them did not report on all of outcomes
included in this systematic review.
Among the 169 fetuses with unilateral ventriculomegaly assessed for aneuploidy, there
was only one case of abnormal karyotype (Trisomy 21), giving an overall prevalence of
1.7% (95% CI, 0.3-4.1) (Figure 2). In this case it was not possible to define if the
ventriculomegaly was mild/moderate or severe. The prevalence of congenital infection
(n=8), as a possible cause of ventriculomegaly, was 3.0% (95% CI, 1.3-5.4) (Figure 3).
We identified 5 CMV cases, 1 toxoplasmosis case and 2 parvovirus cases. In only 3
cases (37.5%) the congenital infection was an isolated finding.
Additional fetal imaging with MRI was performed systematically in 6 (37.5%) out of 16
studies Figure 5 shows the prevalence of MRI-detected associated brain abnormalities.
These included cortical malformations, partial and complete agenesis of the corpus
callosum and intracranial hemorrhages (Table 3). There was significant heterogeneity
among these studies (I² = 73.3%), with an overall prevalence of 6.7% (95% CI, 1.1-16.3)
of MRI-detected lesions, (Figure 4). Postnatal follow up with MRI was undertaken in 6
studies (37.5%). Postnatal fetal brain imaging provided additional information in two
cases, in which brain abnormalities were already detected by prenatal ultrasound and/or
MRI evaluation, and 15 new information in cases with no previous brain abnormalities
(20.2%, 95% CI, 4.1-44.3; I² = 86%, Figure 5), (Table 4).
The incidence of progression during the pregnancy showed a significant heterogeneity
among the different studies (I² = 68.3%), ranging between 12.9% and 83.1%. The overall
incidence was 9.5% (95% CI, 2.5-20.1) (Figure 6).
Among the 397 fetuses with unilateral ventriculomegaly, 349 (92.1%) had postnatal
neurodevelopmental assessment. The median age at neurological follow-up assessment
was 35 (range 22.5-48.5) months. Out of the 349 infants that had follow up, 32 (10.8%,
95% CI, 5.9-16.8) received a diagnosis of neurodevelopmental delay (Figure 7); the
prevalence of mild and severe neurodevelopmental delay was 2.8% (95% CI, 1.2-4.9)
and 5.7% (95% CI, 3.4-8.7), respectively (Figure 8a and 8b), while in the remaining 10
cases the degree of neurodevelopmental delay was not reported. Out of 199 patients
where the ventriculomegaly was noted to be isolated, 17 (11.2%, 95% CI, 5.3-18.9) had
a diagnosis of neurodevelopmental delay (Figure 9).
Fetuses with unilateral ventriculomegaly less than 15mm:
Of the 397 fetuses with unilateral VM, this was <15mm in 218 cases (54.9%). In this
subgroup, the prevalence of congenital infection was 4.9% (95% CI, 0.74 -12.4), while
the incidence of progression was 4.7% (95% CI, 2.1 – 8.4) (Supplementary material 3).
The prevalence of associated brain and extra-brain abnormalities detected on ultrasound
were 4.7% (95% CI, 1.3 – 9.8%) and 6.4% (95% CI, 0.2 – 20.2), respectively. The rate of
MRI-detected lesions was 2.7% (95% CI, 0.6 – 6.4). Postnatal fetal MRI imaging
provided new information in 9.7% of the cases (95% CI, 1.2- 24.9, I² =74.4%),
(Supplementary material 4). Out of 140 cases of isolated mild/moderate unilateral
ventriculomegaly, only 8 had a diagnosis of neurodevelopmental delay, with an overall
prevalence of 5.8% (95% CI, 2.6 -10.2, I² = 48%), (Figure 10), (Table 5).
DISCUSSION
Summary of the main findings
The results of this systematic review show that in fetuses with unilateral
ventriculomegaly the prevalence of chromosomal abnormalities is about 2%; of
congenital infections 3%; and that in about 10% of fetuses there is progression during
the course of the pregnancy. Fetal MRI diagnosed additional brain abnormalities in 7%
and 20% of the cases prenatally and postnatally, respectively. The overall incidence of
neurodevelopmental delay in cases of unilateral ventriculomegaly was 10.8%.
In those fetuses with isolated unilateral ventriculomegaly less than 15mm, the
progression (5%) MRI detected lesions antenatally (3%) and postnatally (9%) were all
about half of the respective figures for the overall group. The incidence of any degree of
neurodevelopmental delay was also almost half (5.8%).
Although the quality assessment of the studies was generally adequate, the
heterogeneity was significant for the majority of the outcomes when we analyzed all the
ventriculomegaly cases, but became much lower when the analysis was limited to those
with mild ventriculomegaly.
Interpretation of the findings
Recent studies have reported slightly different results on the neurodevelopmental impact
of ventriculomegaly6, 7. Of note, no differentiation was made between unilateral and
bilateral ventriculomegaly cases in the majority of these studies32, 33. The incidence of
neurodevelopmental delay in mild to moderate (<15mm atrial width) bilateral
ventriculomegaly varies between 8% and 12%6,7,34 Our results suggest that the
observed overall incidence of neurodevelopmental delay was 11% in fetuses with
isolated unilateral ventriculomegaly, and 5.8% in those with isolated unilateral
ventriculomegaly less than 15mm atrial width. The latter seems similar to the rate
reported in the general population35.
In unilateral ventriculomegaly <15mm the prevalence of congenital infections is similar to
that in fetuses with bilateral ventriculomegaly36. However, the observed prevalence of
chromosomal abnormalities (1.7%), risk of progression (4.9%), associated brain
abnormalities detected on fetal brain MRI (2.7%) and neurodevelopmental delay (5.8%)
seems to be lower than that for fetuses with bilateral ventriculomegaly6,7,34,
(Supplementary Table 1).
Strengths and weaknesses
The main strengths of this review are the comprehensive search strategy and the
inclusion of a number of key outcomes in unilateral ventriculomegaly cases only. The
paucity of data on the perinatal and long-term outcomes in fetuses with antenatal
diagnosis of unilateral ventriculomegaly limits the evidence to guide our prenatal
management. Therefore, the findings of this meta-analysis could be valuable in parental
counseling.
The main limitations of this review are in the constituent studies: there is publication bias
and evidence of heterogeneity of included studies. The publication bias reflects the small
number of fetuses with unilateral ventriculomegaly extracted from the current literature.
Study heterogeneity is mainly due to the different accuracies of prenatal and postnatal
imaging, the gestational age at the time of the diagnosis, the different tests undertaken
to assess the neurodevelopmental outcome and the different lengths of postnatal followup. Although many studies have demonstrated the importance and superiority of MRI
over ultrasound examination as part of assessment of ventriculomegaly, it is important to
bear in mind that the diagnostic interpretation of both ultrasound and MRI images is
difficult to standardize and is influenced by the examiner and center experience. Our
study demonstrates the importance of undertaking MRI in fetuses with ventriculomegaly
as it offers important additional information in about 7% of cases. Another bias is the
method and the length of follow-up used in assessing the neurolodevelopmental
outcome. Although the majority of the methods were standardized screening tools, they
vary in their sensitivity and specificity. Moreover, the median follow-up assessment in
this review was 35 months and it can be argued that some neurodevelopmental delay
may not be apparent until later in life. However, extending the length of the follow-up, it
will increase the number of confounding variables, such as environmental factors,
making it difficult to ascertain the real cause of the neurodevelopmental delay39.
Conclusion
The prevalence of aneuploidy, congenital infections and neurodevelopmental delay in
fetuses with a prenatal diagnosis of unilateral ventriculomegaly is low. The incidence of
neurodevelopmental delay in cases of isolated unilateral ventriculomegaly <15 mm is
lower than that reported in isolated bilateral ventriculomegaly <15 mm and is similar to
the rate in the general population. Large multicentre prospective studies are needed in
order to ascertain the risk of neurodevelopmental delay in fetuses with unilateral
ventriculomegaly and the possible risk factors that might influence the postnatal
prognosis.
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Table 1. General characteristics of the 16 studies reporting prenatal detection of unilateral ventriculomegaly included in the
systematic review
First author
Country
Study design
VM cases
Unilateral VM
Mean Gestational
Method of
(n)
(n)
Age at diagnosis
neurodevelopmental
(weeks)
assessment
-pediatrician, medical
Pasquini et al. (2014)16
Italy
Retrospective
141
71
26.4
records and from the
parents
Gezer et al. (2014)17
Turkey
Retrospective
140
5
20.0
NR
-WISC-IV
-CCTT-1 and -2
Atad-Rapoport et al.
(2014)18
Israel
Prospective
33
18
NR
-RAVLT;
-the parents filled out
the BRIEF and
CBCL/6-18
Kutuk e al. (2013)19
Turkey
Retrospective
25
9
23.8
NR
Miguelote et al. (2012)20
Portugal
Prospective
24
10
25.7
NR
Spain
Retrospective
18
5
22.0
Weichert et al. (2010)22
Germany
Retrospective
109
42
24.3
Leitner et al. (2009)23
Israel
Retrospective
28
16
NR
Gomez-Arriaga et al.
(2012)21
- BDIST
- neuropediatric
assessment
-Physical and
neurological
evaluation
-K-ABC test
Nomura et al. (2009)24
Brazil
Retrospective
287
14
27.0
NR
-Brunet- Lezine
psychomotor scale
-MacCarthy scales of
children's abilities
Falip et al. (2007)25
France
Retrospective
101
51
27.6
(MSCA)
-Wechsler preschool
and primary scale of
Intelligence III (WPPSI
III)
-Brunet- Lezine
Ouahba et al. (2006)26
France
Retrospective
167
80
26.5
psychomotor scale
- MSCA
- WPPSI III
-Denver II
Kinzler et al. (2001)27
USA
Retrospective
15
15
26.5
developmental
screening test
Durfee et al. (2000)28
USA
Retrospective
14
14
29.2
NR
Senat et al. (1999)29
UK
Retrospective
14
14
26.0
-pediatrician
Lipitz et al. (1998)30
Israel
Retrospective
27
27
23.6
Patten et al. (1990)31
USA
Retrospective
6
6
32.8
1149
397
26.2 (23.9-26.8)
Total
NR
-neurodevelopmental
milestones chart
VM:Ventriculomegaly, WISC-IVHEB: Wechsler Intelligence Scale for Children, Fourth Edition, CCTT-1 and CCTT-2: Children’s Color
Trails Test 1 and 2, RAVLT : Rey’s Auditory Verbal Learning Test, BRIEF : Behavior Rating Inventory of executive Function,
CBCL/6–18: Child Behavior Checklist for Ages 6–18, BDIST : Battelle Developmental Inventory Screening Test, K-ABC: Kaufman
Assessment Battery for Children, BSID-II: Bayley Scale of Infant Development II, MSCA: MacCarthy scales of children's abilities,
WPPSI III :Wechsler preschool and primary scala of Intelligence III, NR: not reported
Table 2. Quality assessment of the included studies according to the Newcastle–Ottawa scale (NOS)
First author
Study type
Selection
Comparability
Outcome
Pasquini et al. (2014)16
Retrospective
****
**
***
Retrospective
***
**
***
Prospective
****
*
***
Kutuk e al. (2013) 19
Retrospective
****
**
***
Miguelote et al. (2012)20
Prospective
***
**
***
Gomez-Arriaga et al. (2012)21
Retrospective
****
**
***
Weichert et al. (2010)22
Retrospective
****
**
***
Leitner et al. (2009)23
Retrospective
****
***
***
Nomura et al. (2009)24
Retrospective
****
*
**
Falip et al. (2007)25
Retrospective
***
*
***
Retrospective
****
**
***
Kinzler et al. (2001)27
Retrospective
****
**
***
Durfee et al. (2000)28
Retrospective
****
**
***
Senat et al. (1999)29
Retrospective
****
**
***
Lipitz et al. (1998)30
Retrospective
****
**
***
Patten et al. (1990)31
Retrospective
**
*
**
Gezer et al. (2014)17
Atad-Rapoport et al. (2014)
Ouahba et al. (2006)
26
18
Table 3. Associated abnormalities detected prenatally with fetal MRI in fetuses with unilateral ventriculomegaly.
First author
Study design
Unilateral VM (n)
Associated
Details
abnormalities
detected with MRI (n)
Pasquini et al. (2014)16
Retrospective
71
1
Hypotrophy of
periventricular white
matter
Ouahba et al. (2006)26
Retrospective
80
15
-6 cases of third
ventricle enlargement
-4 cases of heterotopia
-2 cases of septum
pellucidum destruction
-2 cases of partial ACC
-1 case of complete
ACC
Senat et al. (1999)29
Retrospective
14
2
-1 cases of
schizencephaly
-1 cases of
porencephaly
VM= Ventriculomegaly, ACC= Agenesis of the corpus callosum
Table 4. Associated abnormalities detected postnatally with fetal MRI in fetuses with unilateral ventriculomegaly
First author
Study design
Unilateral VM (n)
Associated
Details
abnormalities
detected with MRI (n)
Gomez-Arriaga et al.
Retrospective
5
1
-Progressive VM
Kinzler et al. (2001)27
Retrospective
15
2
-1 case of arachnoid
cyst and brain stem
compression
-1 case of dysmorphic
frontal horn
Durfee et al. (2000)28
Retrospective
14
8
-2 cases of intracranial
hemorrage
-1 case of Joubert's
syndrome
-1 case of Warburg
syndrome
-1 case of tuberous
sclerosis
-1 case of cerebral
palsy due to
imperforate foramen of
Monroe
-2 case of complete
ACC
(2012)21
Senat et al. (1999)29
Retrospective
14
1
Patten et al. (1990)31
Retrospective
6
5
VM: Ventriculomegaly; ACC: Agenesis of the corpus callosum
-Agenesis of Monroe
foramen with
porencephaly
-1 case of brain
dysplasia
-1 case of
poroencephaly
-1 case of agenesis of
Monroe foramen
-1 case of obstruction
of Monroe foramen
-1 case of
intraventricular
thrombus
Table 5: Comparison of the perinatal and neurodevelopmental outcomes between all the unilateral VM cases and the unilateral VM
cases measuring <15 mm.
Overall unilateral VM
N=417
(Prevalence %)
Unilateral VM < 15 mm
N=218
(Prevalence %)
Chromosomal
abnormalities
Congenital infection
1.7%
NR
3.0%
4.9%
Prenatal MRI findings
6.7%
2.7%
Postnatal MRI findings
20.2%
9.7%
Progression
9.5%
4.7%
NDD
10.8%
5.8%
VM: Ventriculomegaly, NDD: neurodevelopmental delay, NR: not reported
Figure 2 Forest plot (fixed-effects model) showing the prevalence of associated aneuploidy in fetuses with unilateral
ventriculomegaly, individually for each of 11 studies and pooled for all studies. The pooled prevalence was 1.7% (95% CI, 0.334.1%). The size of boxes is proportional to the study sample size.
Figure 3 Forest plot (fixed-effects model) showing the prevalence of congenital infections in fetuses with unilateral ventriculomegaly,
individually for each of 9 studies and pooled for all studies. The pooled prevalence was 3% (95% CI, 1.3-5.4%). The size of boxes is
proportional to the study sample size.
Proportion meta-analysis plot [fixed effects]
Lipits et al 1998
0.000 (0.000, 0.128)
Senat et al 1999
0.071 (0.002, 0.339)
Kinzler et al 2001
0.067 (0.002, 0.319)
Falip et al 2007
0.000 (0.000, 0.070)
Leitner et al 2009
0.000 (0.000, 0.206)
Miguelote et al 2012
0.000 (0.000, 0.142)
Gomez-Arriaga et al 2012
0.000 (0.000, 0.185)
Kutuk e al 2013
0.000 (0.000, 0.137)
Pasquini et al 2014
0.085 (0.032, 0.175)
combined
0.030 (0.013, 0.054)
0.0
0.1
0.2
0.3
proportion (95% confidence interval)
0.4
Figure 4 Forest plot (random-effects model) showing the prevalence of associated brain abnormalities detect by MRI prenatally in
fetuses with unilateral ventriculomegaly, individually for each of five studies and pooled for all studies. The pooled incidence
prevalence was 6.7% (95% CI, 1.1-16.3%). The size of boxes is proportional to the study sample size.
Proportion meta-analysis plot [random effects]
Senat et al 1999
0.1429 (0.0178, 0.4281)
Ouahba et al 2006
0.1875 (0.1089, 0.2903)
Leitner et al 2009
0.0000 (0.0000, 0.2059)
Miguelote et al 2012
0.0000 (0.0000, 0.3085)
Gomez-Arriaga et al 2012
0.0000 (0.0000, 0.5218)
Pasquini et al 2014
0.0141 (0.0004, 0.0760)
combined
0.0665 (0.0110, 0.1636)
0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
Figure 5 Forest plot (random-effects model) showing the prevalence of associated brain abnormalities detect by MRI postnatally in
fetuses with unilateral ventriculomegaly, individually for each of 7 studies and pooled for all studies. The pooled prevalence was
20.3% (95% CI, 4.1-44.3%). The size of boxes is proportional to the study sample size.
Proportion meta-analysis plot [random effects]
Lipits et al 1998
0.000 (0.000, 0.128)
Patten et al 1990
0.833 (0.359, 0.996)
Senat et al 1999
0.071 (0.002, 0.339)
Durfee et al 2000
0.571 (0.289, 0.823)
Kinzler et al 2001
0.133 (0.017, 0.405)
Gomez-Arriaga et al 2012
0.200 (0.005, 0.716)
Atad-Rapoport et al 2014
0.000 (0.000, 0.185)
combined
0.203 (0.041, 0.444)
0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
1.0
Figure 6 Forest plot (random-effects model) showing the incidence of progression in fetuses with unilateral ventriculomegaly,
individually for each of 8 studies and pooled for all studies. The pooled incidence was 9.5% (95% CI, 2.5-20.1%). The size of boxes
is proportional to the study sample size.
Proportion meta-analysis plot [random effects]
Patten et al 1990
0.1667 (0.0042, 0.6412)
Lipits et al 1998
0.0370 (0.0009, 0.1897)
Senat et al 1999
0.2143 (0.0466, 0.5080)
Kinzler et al 2001
0.2000 (0.0433, 0.4809)
Miguelote et al 2012
0.2000 (0.0252, 0.5561)
Gomez-Arriaga et al 2012
0.0000 (0.0000, 0.5218)
Kutuk e al 2013
0.0000 (0.0000, 0.3363)
Pasquini et al 2014
0.0000 (0.0000, 0.0506)
combined
0.0945 (0.0252, 0.2015)
0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
Figure 7 Forest plot (random-effects model) showing the incidence of associated neurodevelopmental delay in fetuses with unilateral
ventriculomegaly, individually for each of 11 studies and pooled for all studies. The pooled incidence was 10.8% (95% CI, 5.916.8%). The size of boxes is proportional to the study sample size.
Proportion meta-analysis plot [random effects]
Patten et al 1990
0.5000 (0.1181, 0.8819)
Lipits et al 1998
0.0370 (0.0009, 0.1897)
Senat et al 1999
0.0714 (0.0018, 0.3387)
Kinzler et al 2001
0.0000 (0.0000, 0.2180)
Ouahba et al 2006
0.0500 (0.0138, 0.1231)
Falip et al 2007
0.0784 (0.0218, 0.1888)
Leitner et al 2009
0.1875 (0.0405, 0.4565)
Weichert et al 2010
0.2143 (0.1030, 0.3681)
Kutuk e al 2013
0.3333 (0.0749, 0.7007)
Pasquini et al 2014
0.0423 (0.0088, 0.1186)
Atad-Rapoport et al 2014
0.0556 (0.0014, 0.2729)
combined
0.1078 (0.0595, 0.1683)
0.0
0.3
0.6
proportion (95% confidence interval)
0.9
Figure 8a Forest plot (fixed-effect model) showing the incidence of associated mild neurodevelopmental delay in fetuses with
unilateral ventriculomegaly, individually for each of 9 studies and pooled for all studies. The pooled incidence was 2.8% (95% CI, 1.24.9%). The size of boxes is proportional to the study sample size.
Proportion meta-analysis plot [fixed effects]
Patten et al 1990
0.0000 (0.0000, 0.4593)
Senat et al 1999
0.0000 (0.0000, 0.2316)
Kinzler et al 2001
0.0000 (0.0000, 0.2180)
Ouahba et al 2006
0.0000 (0.0000, 0.0451)
Falip et al 2007
0.0392 (0.0048, 0.1346)
Leitner et al 2009
0.0625 (0.0016, 0.3023)
Kutuk e al 2013
0.3333 (0.0749, 0.7007)
Pasquini et al 2014
0.0141 (0.0004, 0.0760)
Atad-Rapoport et al 2014
0.0556 (0.0014, 0.2729)
combined
0.0277 (0.0119, 0.0497)
0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
Figure 8b Forest plot (fixed-effects model) showing the incidence of severe neurodevelopmental delay in fetuses with unilateral
ventriculomegaly, individually for each of 9 studies and pooled for all studies. The pooled incidence was 5.7% (95% CI, 3.4-8.7%).
The size of boxes is proportional to the study sample size.
Proportion meta-analysis plot [fixed effects]
Patten et al 1990
0.500 (0.118, 0.882)
Senat et al 1999
0.071 (0.002, 0.339)
Kinzler et al 2001
0.000 (0.000, 0.218)
Ouahba et al 2006
0.050 (0.014, 0.123)
Falip et al 2007
0.039 (0.005, 0.135)
Leitner et al 2009
0.125 (0.016, 0.383)
Kutuk e al 2013
0.000 (0.000, 0.336)
Pasquini et al 2014
0.028 (0.003, 0.098)
Atad-Rapoport et al 2014
0.056 (0.001, 0.273)
combined
0.058 (0.034, 0.087)
0.0
0.3
0.6
proportion (95% confidence interval)
0.9
Figure 9 Forest plot (random-effects model) showing the incidence of associated neurodevelopmental delay in fetuses with isolated
unilateral ventriculomegaly, individually for each of 9 studies and pooled for all studies. The pooled incidence was 11.2% (95% CI,
5.3-18.9%). The size of boxes is proportional to the study sample size.
Proportion meta-analysis plot [random effects]
Pasquini 2014
0.0159 (0.0004, 0.0853)
Atad-Rapoport 2014
0.0556 (0.0014, 0.2729)
Kutuk et al. 2013
0.3333 (0.0749, 0.7007)
Weichert et al. 2010
0.1667 (0.0358, 0.4142)
Falip et al 2007
0.0784 (0.0218, 0.1888)
Kinzler et al 2001
0.0000 (0.0000, 0.3694)
Senat et al 1999
0.0909 (0.0023, 0.4128)
Patten et al 1990
0.4000 (0.0527, 0.8534)
Leitner et al 2009
0.1250 (0.0155, 0.3835)
combined
0.1125 (0.0535, 0.1897)
0.0
0.3
0.6
proportion (95% confidence interval)
0.9
Figure 10 Forest plot (fixed-effects model) showing the incidence of neurodevelopmental delay in fetuses with isolated
mild/moderate unilateral ventriculomegaly (<15mm), individually for each of 7 studies and pooled for all studies, and the funnel plot
showing the heterogeneity between the included studies. The total prevalence was 5.8% (95% CI, 2.6-10.2%). Size of boxes is
proportional to study sample size.
Proportion meta-analysis plot [fixed effects]
Lipits et al 1998
0.0370 (0.0009, 0.1897)
Senat et al 1999
0.0000 (0.0000, 0.3085)
Kinzler et al 2001
0.0000 (0.0000, 0.3363)
Leitner et al 2009
0.1250 (0.0155, 0.3835)
Weichert et al 2010
0.1429 (0.0036, 0.5787)
Kutuk e al 2013
0.3333 (0.0749, 0.7007)
Pasquini et al 2014
0.0161 (0.0004, 0.0866)
combined
0.0584 (0.0264, 0.1019)
0.0
0.2
0.4
0.6
proportion (95% confidence interval)
0.8
Bias assessment plot
Standard error
0.00
0.04
0.08
0.12
0.16
-0.4
-0.2
0.0
0.2
0.4
Proportion
Supplementary Table 1: Comparison of the perinatal and neurodevelopmental outcomes between bilateral and unilateral
ventriculomegaly <15 mm.
Bilateral ventriculomegaly <15mm
Unilateral ventriculomegaly <15 mm
Congenital infection
1.5%-5%7,34
3%-4.7% (95% CI, 2.1-8.4%)
Progression
15.7%7
4.7% (95% CI, 0.74 -12.4%)
Associated brain abnormalities
7.4%7
detected on prenatal MRI
Neurodevelopmental delay
Non isolated: 14%34
Isolated: 8%7
VM: Ventriculomegaly, NDD: Neurodevelopmental delay
2.7% (95% CI, 0.6 – 6.4)
10.8% (95% CI, 5.9-16.8%)
5.8% (95% CI, 2.6-10.2%)