Keywords
fetal neurology - lateral ventricles - developmental outcome - asymmetry
Introduction
Human brain development results in distinct anatomical and volumetric variations across
cerebral hemispheres and lateral ventricles, thereby shaping functional differences
and behavioral nuances between genders. The asymmetry of the human brain is a remarkable
natural feature observed from fetal development through adulthood and is influenced
by genetic and endocrinological factors [1].
In routine fetal sonographic evaluations, the assessment of lateral ventricle size
is pivotal, with particular attention being given to measuring the distal cerebral
atria width. Typically, only one ventricle, the distal one, is visualized and measured
during routine fetal anomaly scans. The lack of formal guidelines advocating for the
systematic visualization or measurement of both ventricles may result in variability
in identifying lateral ventricular asymmetry. This variability underscores the importance
of exploring the outcomes of this condition. Ventriculomegaly, defined as a distal
lateral ventricle measurement of 10mm or greater at any gestational age, requires
further investigation – due to its potential indication of brain pathology [2]. Lateral ventricular asymmetry is generally defined as a difference of more than
2mm in width between the 2 ventricles, though some studies use alternative thresholds,
such as 2.4mm or 2 standard deviations above the mean, thus highlighting the variability
in the literature [1]. While postnatal ventricular asymmetry without dilatation is observed in 5–12% of
healthy individuals [3], it is inconclusive whether it signifies a normal variant or potential brain pathology
[4].
As ultrasound technology advances, prenatal evaluations increasingly detect subtle
brain anomalies, which complicate prenatal counseling on infant outcomes. Unlike major
fetal brain anomalies, subtle conditions pose challenges with respect to deciding
which prenatal investigations should be performed. Additionally, in this context,
the optimal approach regarding postnatal assessments, including neurocognitive status
in childhood, is yet to be clarified. In this systematic review, we investigated the
outcomes of pregnancies with cerebral lateral ventricle asymmetry without dilation.
We searched for reported fetal and neonatal outcomes, and also later neurodevelopmental
and neuropsychological outcomes. As this condition is occasionally encountered antenatally,
our systematic review may provide insight into its clinical implications and management
in prenatal care.
Methods
For this systematic review, we followed the guidelines outlined in the Meta-analysis
of Observational Studies in Epidemiology (MOOSE) statement and adhered to the Preferred
Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist [5]
[6]. The study was preregistered with the International Prospective Register of Systematic
Reviews (PROSPERO identifier CRD42024537299) prior to data extraction and analysis.
We included observational cohort studies that reported on prenatal investigation results,
neonatal outcomes, and neurodevelopmental and neuropsychological outcomes of pregnancies
with fetal ventricular asymmetry without dilation, regardless of whether detected
on ultrasound or magnetic resonance imaging (MRI). Studies that did not report on
the specific outcomes of interest were excluded from those subsections of the review
to maintain focus on the relevant data. Review articles, comments, guidelines, and
case reports were excluded. Only studies published in English up to April 2024 were
considered. A comprehensive literature search was conducted across Embase, Medline,
and Web of Science databases from inception to April 29, 2024. Collaborating with
information specialists from the Tel Aviv University Library, we developed a structured
search strategy focused on pregnancies with cerebral lateral ventricle asymmetry without
dilation. The detailed search strategies tailored to each database can be found in
supplementary Table 1.
Two independent researchers (I.S. and M.O.) conducted the entire selection process.
After removing duplicates, they reviewed the titles and abstracts of identified studies
for relevance, and then thoroughly examined the full texts. References from selected
papers were screened for additional relevant studies. Any disagreements in study selection
were resolved through consultation with a senior researcher (L.L.). The methodological
quality of included studies was evaluated using the Newcastle-Ottawa Quality Assessment
Scale NOS) for observational studies [7].
We presented a descriptive synthesis and conducted a pooled analysis to summarize
outcomes across studies. Notably, the substantial heterogeneity in study designs,
imaging modalities, and reported outcomes precluded the use of advanced meta-analytic
techniques.
Results
Identification and characteristics of the included studies
The initial systematic search process generated 150 results through database querying.
Upon reviewing the titles and abstracts, 137 references were identified as ineligible
based on the inclusion criteria. The full texts of the 13 remaining references were
reviewed. A detailed breakdown of the reasons for excluding full-text articles is
provided in supplementary Table 2. Ultimately, 6 studies met the criteria for inclusion in this systematic review,
as depicted in the flow diagram [8]
[9]
[10]
[11]
[12]
[13] ([Fig. 1]). Notably, all of the included studies were deemed to be of high quality. They were
all published during 1997 and 2023. One study defined non-dilated ventricular asymmetry
as a difference exceeding 2.4mm between the fetal lateral cerebral ventricles [8], while the remaining studies defined it as a difference greater than 2mm [9]
[10]
[11]
[12]
[13]. Among the included studies, 3 reported fetal neurosonogram results [8]
[12]
[13], 2 compared fetal neurosonograms and MRI findings [12]
[13], and 3 reported prenatal genetic test outcomes [8]
[12]
[13]. Five studies assessed neuropsychological and neurodevelopmental outcomes of children
with in-utero isolated non-dilated ventricular asymmetry at various ages: 6 weeks
[13], 6 months [8], 13–74 months [11], 24–42 months [9], and 9–11 years [10]. The mean gestational age at the time of the neurosonogram was 28.7 ± 3.8 weeks.
Males comprised 66.7% of the cohort. [Table 1] provides a comprehensive overview of the characteristics and quality assessment
of the included studies.
Fig. 1 PRISMA flowchart of the literature search.
Table 1 Characteristics and Quality Assessment of Studies Included in the Systematic Review.
|
Authors
|
Study location and period
|
Study design
|
Number of fetuses/children with non-dilated ventricular asymmetry included
|
Studies performed
|
Maternal age (years)
|
Gestational age/child age
|
Criteria for defining ventricular asymmetry
|
Mean right ventricular width
|
Mean left lateral ventricular width
|
Fetal/child gender
|
Quality assessment
|
|
‡ BSID-II – Bayley Scale of Infant Development II [15], # WISC-IVHEB – Wechsler Intelligence Scale for Children, 4th edition (Hebrew) [16], ^ CCTT-1 – Children’s Color Trails
Test 1 [16], *CCTT-2 – Children’s Color Trails Test 2 [17], ƪ RAVLT – Rey’s Auditory Verbal Learning Test [18], ** BRIEF – Behavior Rating Inventory of Executive Function [19], *** CBCL/6–18 – Child Behavior Checklist for Ages 6–18 [20]
[21], ^^VABS-II – Vineland-II Adaptive Behavior Scales [22]
MRI: magnetic resonance imaging; IQR: interquartile range
|
|
Achiron et al. (1997) [8]
|
Israel (January 1994–Jauary 1996)
|
Retrospective cohort
|
21
|
Serial neurosonogram, prenatal karyotype, infant development at 6 months of age
|
Mean 28 (range 21–35)
|
Mean 20.8±1.6 weeks of gestation (GA at diagnosis and at the time of the examination)
|
>2.4mm difference in ventricular width, and both ventricles <10 mm
|
7.14±1.79
|
8.74±1.78
|
Male – 12 (57.1%)
Female – 9 (42.9%)
|
9
|
|
Sadan et al. (2007) [9]
|
Israel (October 2001 to April 2003)
|
Case-control study
|
21 (compared to 20 with unilateral ventriculomegaly and 20 healthy controls)
|
Neuropsychological evaluation using the BSID-II‡
|
Not reported
|
Mean 32.4 ± 5.2 (range 24–42) months (study group) vs. 32.8 ± 5.9 months (control
group) (child age at the time of the examination)
|
>2.0mm difference in ventricular width, and both ventricles < 10mm
|
Not reported
|
Not reported
|
Male – 13 (61.9%)
Female – 8 (38.1%)
|
7
|
|
Atad-Rapaport et al. (2015) [10]
|
Israel (October 2001 to April 2003)
|
Case-control study
|
15 (compared to 18 with unilateral ventriculomegaly)
Both groups were compared with age-related
norms validated for the Israeli population
|
Parents’ reports on behavioral questionnaires and neuropsychological
tests:
WISC-IVHEB#, CCTT-1^ and CCTT-2*, RAVLTƪ, phonemic and semantic fluency tests [14].
The parents filled out the BRIEF 15** and the CBCL/6–18***
|
Not reported
|
9–11 years (child age at examination)
|
>2.0mm difference in ventricular width, and both ventricles <10mm
|
Not reported
|
Not reported
|
Not reported
|
7
|
|
Meyer et al. (2018) [11]
|
Israel (July 2011 and January 2015)
|
Case control
|
43 (compared to 94 controls)
|
VABS-II^^
|
Mean 30.8±4.4
|
Mean 36.35±13.3 months (range 13–74 months) (child age at the time of the examination)
|
>2.0mm difference in ventricular width, and both ventricles <10mm
|
Not reported
|
Not reported
|
Male – 33 (76.7%)
Female – 10 (23.3%)
|
7
|
|
Meyer et al. (2021) [12]
|
Israel (January 2011 and September 2018.)
|
Retrospective cohort
|
145
|
Neurosonogram, fetal brain MRI, prenatal karyotype, chromosomal microarray
|
Median 32.0 (IQR 9.0–36.0)
|
Mean 29.9 ± 2.4 weeks of gestation at the time of the neurosonogram and 32.6 ± 1.6
weeks of gestation at the time of the fetal brain MRI
|
>2.0mm difference in ventricular width, and both ventricles <10mm
|
Not reported
|
Not reported
|
Male – 102 (70.3%)
Female – 43 (29.7%)
|
8
|
|
Petpichetchian (2023) [13]
|
Canada (January 2012 and January 2020)
|
Retrospective cohort
|
17
|
Neurosonogram, fetal brain MRI
|
Mean 32.4±5.5
|
23.4 ± 2.9 at diagnosis, GA at the time of the MRI examination is not reported
|
>2.0mm difference in ventricular width, and both ventricles <10mm
|
Not reported
|
Not reported
|
Male – 9 (52.9%)
Female – 8 (47.1%)
|
8
|
Natural history of fetal non-dilated lateral ventricle asymmetry
In the study by Achiron et al. [8], isolated non-dilated ventricular asymmetry was identified during routine fetal
anomaly scans conducted at 18–24 weeks of gestation. These women were monitored with
ultrasound examinations every 3 weeks until delivery. Excluded were those with obstructive
hydrocephalus, other associated central nervous system (CNS) anomalies, or ventriculomegaly.
Among the 21 fetuses studied, 20% showed resolution of asymmetry, 5% progressed, and
75% remained stable. The sequential ultrasound examinations revealed one fetus with
periventricular leukomalacia and one with a subacute cytomegalovirus infection, the
latter was discovered due to an intraventricular adhesion.
Meyer et al. investigated 145 fetuses with asymmetric ventricles without dilation
[12]. Initially, these were referred for neurosonography and subsequently underwent fetal
MRI scans. Excluded were those with major CNS anomalies suspected on ultrasound. However,
pregnancies with minor brain or other minor body ultrasound findings were included.
MRI revealed a ventricular width of over 10mm in 46.2% of the fetuses and the resolution
of ventricular asymmetry in 11.7%. Major CNS findings were not discovered on MRI.
In 17.9% of the fetuses, additional minor findings in either the fetal brain or body
were also reported. The MRI study did not contribute significantly to the neurosonogram
findings, as rates of minor CNS findings did not differ significantly between neurosonogram
and MRI results. Reported brain findings included mega cisterna magna, arachnoid cyst,
choroid plexus cyst, narrow cavum septum pellucidum, periventricular pseudocyst, and
a white matter hyperintense signal. Minor body findings included pyelectasis, single
umbilical artery, a small ventricular septal defect, hypospadias, and undescended
testis.
Petpichetchian et al. investigated 17 fetuses characterized by non-dilated ventricular
asymmetry, all of which underwent fetal brain MRI at a later stage [13]. During a serial neurosonogram follow-up, 13 fetuses showed progression to mild
ventriculomegaly (76%). However, 12 of these resolved before childbirth, as was evident
in the subsequent ultrasound examinations. MRI scans revealed evidence of intraventricular
hemorrhage (IVH) in 13 of 17 fetuses. Among these, 12 showed minor bleeding confined
to the subependymal germinal matrix (grade I), while one exhibited grade II IVH with
subtle fluid sediment in the ventricle. One woman was found to have autoantibodies
targeting the platelet antigenic determinant glycoprotein IIb/IIIa, with no evidence
of thrombocytopenia observed in either the mother or the newborn.
Genetic findings in fetal non-dilated lateral ventricle asymmetry
Achiron et al. described 11 women who underwent karyotype analysis, with trisomy 21
being revealed in 1 case (1/11, 9.1%) [8]. Notably, this genetic study was prompted by the progression of asymmetry to ventriculomegaly.
Amniocentesis for karyotyping was conducted in 56 of the 145 women described by Meyer
et al., while 30 of them underwent chromosomal micro-array (CMA) [12]. The rate of abnormal karyotype was 1.8% (1/56), while abnormal CMA was detected
in 10% (3/30). In one woman, a chromosome 11 inversion was identified via karyotyping.
However, CMA and whole exome sequencing yielded normal results, leading to the conclusion
of a variant of unknown significance. The abnormal CMA findings included chromosomal
22q11.23 and 22q11 duplications and segmental X chromosome duplication. Two of these
findings were interpreted as likely pathogenic. Petpichetchian et al. reported that
2 of 17 women underwent amniocentesis with normal results, but it is unclear whether
they underwent CMA or karyotype testing [13].
Neurodevelopmental outcomes of fetal non-dilated lateral ventricle asymmetry
The earliest postnatal neurological evaluation was reported by Petpichetchian et al.
[13]. In this study, all newborns were evaluated by a neonatologist after birth, and
none exhibited dysmorphic features or macrocephaly. Two infants showed evidence of
germinal matrix hemorrhage on cranial ultrasound. Only one of them received a cranial
ultrasound follow-up at 1 month, which showed normal results. At 6 weeks, the infant’s
neurological evaluation was unremarkable. Achiron et al. followed 17 infants up to
the age of 6 months; all of them exhibited normal development at this stage [8].
Meyer et al. compared 43 children with non-dilated ventricular asymmetry to a control
group of 94 normal fetuses [11]. The children were assessed at ages 13–74 months using the Vineland-II Adaptive
Behavior Scales (VABS-II) [22], which is a structured parent interview that assesses 4 scales of performance: communication,
daily living skills, socialization, and motor skills. Social skill scores were lower
for the children with ventricular asymmetry than for the control group. Nonetheless,
the overall VABS-II scores remained within the normal range for both groups, and the
composite scores did not differ significantly between the groups.
Sadan et al. studied the neuropsychological outcomes of 21 children diagnosed with
isolated non-dilated ventricular asymmetry in utero, and 20 children with isolated
unilateral ventriculomegaly [9]. They compared them to a control group of children with normal ultrasound during
pregnancy. The mean infant age at the time of the examination was 32.1 months (range
24–42 months). For the asymmetrical ventricles group compared to the control group,
the psychomotor and mental developmental indices were similar. However, behavior scale
subtests (orientation, engagement, and emotional regulation) differed notably. Three
children (15%) in the asymmetric ventricles group, 4 children (20%) in the unilateral
ventriculomegaly group, and 1 child (5%) in the control group exhibited a Bayley developmental
score below 85, indicating developmental delay [15]. However, in a subsequent follow-up study, one of the children with asymmetric ventricles
was diagnosed with mucopolysaccharidosis type III and was consequently excluded from
the study [10].
The neurodevelopmental outcomes of 17 infants, originally studied by Sadan et al.
[8], were later reported by Atad-Rapaport et al. [9], when the children were aged 9–11 years. This study compared parameters of children
with asymmetric ventricles or unilateral ventriculomegaly to age-related norms that
were validated for the Israeli population. Most parameters showed no significant differences
between the children diagnosed with either of the conditions and the controls. Mean
full-scale IQ scores averaged 103.13 for the asymmetric ventricles group and 103.56
for the unilateral ventriculomegaly group. Minor differences were observed, including
slower performance in writing speed tasks among the asymmetric ventricles group. In
contrast, this group demonstrated unexpectedly higher scores in verbal fluency tests
compared with the general population. The outcomes of the fetuses and the children
with non-dilated ventricular asymmetry are presented in [Table 2].
Table 2 Outcomes of fetuses/children with in-utero non-dilated ventricular asymmetry.
|
US: ultrasound; MRI: magnetic resonance imaging; CNS: central nervous system
|
|
Antenatal follow-up
|
|
Characteristics
|
N (%)
|
|
Progression to ventriculomegaly (on follow-up ultrasound) (n=38)
|
14 (36.8)
|
|
Progression to ventriculomegaly (on follow-up MRI) (n=145)
|
67 (46.2)
|
|
Additional CNS findings during follow-up on US (n=183)
|
10 (5.5)
|
|
Additional CNS findings during follow-up on MRI (n=162)
|
17 (10.5)
|
|
Additional fetal body findings during follow-up on US or MRI (n=145)
|
11 (7.6)
|
|
Abnormal genetic findings (n=99)
|
5 (5.1)
|
|
Postnatal findings
|
|
Characteristics
|
Main findings
|
|
Abnormal developmental findings until 1 year of age (n=18)
|
No abnormal findings reported
|
|
Abnormal developmental findings at an age of 1–6 years (n=54)
|
-
Lower social score
-
Lower behavioral score (including orientation, engagement and emotional regulation)
-
Developmental delay in 2 of 20 children (10%), compared to 1 of 20 children (5%) in
the control group
|
|
Abnormal developmental findings at 9–11 years of age (n=17)
|
Lower writing speed
|
Discussion
The main finding of this systematic review is that 36.8–46.2% of fetuses with non-dilated
ventricular asymmetry progressed to ventriculomegaly during antenatal follow-up, either
on follow-up neurosonography or subsequent MRI. Abnormal genetic results were seen
in 5.1% of the fetuses. Postnatally, no abnormal developmental findings were reported
until 1 year of age. However, at an age of 1–6 years, lower social and behavioral
scores were noted, and a minority exhibited developmental delays. At an age of 9–11
years, a lower writing speed was observed, while unexpectedly higher scores in verbal
fluency tests were noted compared with the general population. Full-scale IQ scores
were comparable to the general population.
Human brain asymmetry, observed in fetal cerebral hemispheres and ventricles, has
been extensively documented in the medical literature [1]
[23]. Notably, this asymmetry tends to be more prominent on the left side and is often
observed to a greater extent in males [24]. In clinical practice, ventricular asymmetry within the normal width is generally
considered a benign finding, as emphasized by guidelines that recommend against further
investigations [4]. However, the studies included in this review reported rates of progression from
ventricular asymmetry to ventriculomegaly ranging from 5% to 76.4% [8]
[12]
[13]. These rates varied considerably depending on the modality of assessment. For instance,
one study found only a 5% progression rate when using neurosonography [8], while another study utilizing fetal brain MRI reported much higher rates, up to
76.4% [12]. This finding aligns with reports that ventricle measurements obtained via MRI are
often larger than those obtained by ultrasound [25]. Additionally, the time gap between ultrasound and MRI examinations may have contributed
to the higher proportion of ventricular dilation observed on MRI. This difference
suggests that the higher rates reported in MRI-based studies may not directly correspond
to the progression seen on neurosonography, making it important to interpret these
findings in the context of the imaging technique used. Nonetheless, these findings
suggest that as ventricular asymmetry has the potential to evolve into ventriculomegaly
– careful monitoring could be important to better understand the natural course of
this condition.
Notably, in fetuses in which ventriculomegaly developed, ventricular dilation never
exceeded 15mm and resolved before birth [13]. This transient ventriculomegaly was attributed to a temporary obstruction at the
foramina of Monro, likely induced by IVH [26]. However, Meyer et al. did not report a similarly high rate of IVH nor a considerable
rate of additional brain findings despite observing ventriculomegaly on fetal brain
MRI. This led them to conclude that MRI did not contribute substantially to the findings
obtained through neurosonography [12]. These discrepancies may arise from differences in the interpretation of MRI studies.
Nonetheless, the findings emphasize the importance of closely monitoring ventricular
width in fetuses with asymmetric ventricles. Based on our results, we suggest measuring
ventricular width during the standard second-trimester anomaly scan (18–24 weeks)
and recommend bilateral measurements to improve the detection of asymmetry. While
most cases resolve before birth and none progress to ventriculomegaly >15mm [13], the potential for progression in a subset of cases suggests that monitoring may
still be advisable. When non-dilated ventricular asymmetry is detected during anomaly
scans, a follow-up neurosonography examination within 3–4 weeks is generally sufficient.
This interval balances the need for timely detection of significant changes with the
avoidance of unnecessary interventions, considering the relatively low likelihood
of severe progression. However, serial follow-ups should be considered when progression
is evident or when additional findings raise concern. It is to be noted that bi-hemispheric
visibility may decrease in advanced gestational weeks due to factors such as skull
ossification, fetal positioning, and increased head size. These factors could complicate
accurate assessment of ventricular asymmetry during later scans.
Our research suggests a notable rate of abnormal karyotype and CMA in fetuses displaying
non-dilated ventricular asymmetry. However, it is important to note that only a subset
of women underwent invasive genetic exams, so our findings may reflect a higher likelihood
of abnormal results among those already suspected of having additional risk factors.
The majority of fetuses who underwent genetic counseling were from the study by Meyer
et al. [12], in which 86 out of 145 fetuses had either karyotype or CMA testing. In this study,
progression to ventriculomegaly on MRI was noted in 46.2% of fetuses. Moreover, 3.4%
had additional minor CNS findings, and 7.6% had additional body findings. However,
it is not explicitly clear from the article whether the fetuses that experienced progression
to ventriculomegaly or had additional findings were the same ones who underwent genetic
studies. Meyer et al. [12] mentioned that minor CNS findings included arachnoid cysts, cavum verge, megacisterna
magna, periventricular pseudocyst, and white matter hyperintense signals on MRI. In
terms of body findings, pyelectasis, cardiac ventriculoseptal defect, a single umbilical
artery, undescended testis, and hypospadias were reported. Given that only a subset
of fetuses underwent genetic testing, and some of these had additional CNS or anatomical
findings, the rate of abnormal genetic results observed in this review may not be
representative of all cases of non-dilated ventricular asymmetry. Nonetheless, further
research with larger sample sizes is needed to better understand the role of genetic
testing in this context, particularly for cases that show progression or additional
findings.
During earlier stages, children with asymmetric ventricles displayed lower social
and behavioral scores, and a minority exhibited a developmental delay [9]. Yet, subsequent findings indicated notable improvement in their behavioral patterns
over time [10]. Parents no longer reported persistent issues and noted enhanced executive functioning
compared to typical norms. These observations suggest that children with fetal ventricular
asymmetry might undergo a transient phase of developmental challenges that tend to
resolve by school age. This implies that developmental abnormalities detected early
may not have a lasting impact on mental development in individuals with non-dilated
ventricular asymmetry. It is important to acknowledge that these results should be
interpreted with caution. The studies included relatively small sample sizes, and
some patients were lost to follow-up or declined participation. Therefore, it is difficult
to determine whether these findings represent a true difference. Further larger prospective
studies are needed to better understand the long-term outcomes of these fetuses and
to determine whether these early findings have any lasting developmental implications.
Limitations of this study include the potential publication bias due to the identification
of a limited number of studies, despite extensive search efforts. Additionally, all
the included studies were retrospective and all but one were conducted in Israel,
which could introduce a selection bias. The lack of formal guidelines advocating for
the systematic visualization and measurement of both lateral ventricles during routine
anomaly scans contributes to the variability in the detection and reporting of ventricular
asymmetry. This variability may have influenced the inclusion criteria and reporting
standards of the studies, thus reducing the comparability of their findings. The small
sample size hinders the ability to draw conclusions regarding the utility of prenatal
MRI imaging or long-term developmental outcomes. We suggest that MRI be reserved for
situations in which neurosonography findings are inconclusive or when additional brain
abnormalities are suspected. The strengths of the study include a thorough literature
search and examination of outcomes related to non-dilated ventricular asymmetry, from
prenatal to postnatal stages, covering data up to an age of 11 years. The presented
evidence raises questions regarding the classification of non-dilated ventricular
asymmetry as a normal variant. Larger prospective studies are warranted to elucidate
the natural history of non-dilated ventricular asymmetry and its clinical implications.
Moreover, the efficacy of serial neurosonogram follow-up and prenatal fetal brain
MRI in this context should be examined. Additionally, given the relatively high rate
of abnormal genetic results, further exploration of this aspect in larger cohorts
is warranted.
