Assessment of the fetal cerebral lateral ventricle is a standard requirement during the mid-trimester morphology ultrasound performed between 18 and 22 weeks of gestation.1 The International Society of Ultrasound in Obstetrics and Gynecology has recommended a standard method to measure the size of the lateral ventricle, which should be in an axial transventricular plane at the atrium of the posterior horn with calibres placed over the inner edges.2 The reference ranges of lateral ventricle width were established by Cardoza et al3 in 1988; they are consistent across gestations. The diameter (mean ± standard deviation) of the lateral ventricle is 7.6 ± 0.6 mm (range, 6-9). Therefore, fetal cerebral ventriculomegaly is defined as dilation of the lateral ventricle atrium to a width of >10 mm (>4 standard deviations from the mean).3

The degree of lateral ventricle dilation is classically categorised as mild (10-11.9 mm), moderate (12-14.9 mm), or severe (≥15 mm) for clinical and research purposes. Mild fetal ventriculomegaly can be isolated and may represent a normal variant if other pathologies are excluded.4 Therefore, the identification of cerebral ventriculomegaly on prenatal ultrasound does not represent a conclusive diagnosis; it signifies a need to identify various underlying pathologies, including structural abnormalities of the central nervous system (CNS), from hypoxic, haemorrhagic, infective, and genetic causes. Fetal ventriculomegaly is considered a marker of abnormal karyotype; it can be associated with pathogenic copy number variations (CNVs) identified by chromosomal microarray analysis (CMA). The Society for Maternal Fetal Medicine recommends antenatal diagnostic testing (amniocentesis) with CMA when ventriculomegaly is detected.4 In this study, we examined the incidences of abnormal karyotype and CMA results in fetuses with cerebral ventriculomegaly in Hong Kong; we also evaluated their correlations with different degrees of ventriculomegaly. We aimed to determine whether amniocentesis with CMA should be offered to all fetuses with cerebral ventriculomegaly, regardless of the degree of ventriculomegaly. We also reviewed the neurodevelopmental outcomes of all live births with fetal ventriculomegaly to identify factors associated with developmental delay.

This retrospective cohort study included all pregnant women with antenatal ultrasound diagnosis of fetal cerebral ventriculomegaly from two maternal-fetal-medicine units in tertiary referral public obstetric centres in Hong Kong, United Christian Hospital and Prince of Wales Hospital, from January 2014 to December 2018. Cases of fetal ventriculomegaly were identified from the registries of prenatal ultrasound structural abnormalities, as well as the antenatal ultrasound and invasive procedures databases of the respective departments; they were also identified from the laboratory genetic diagnosis database of the Chinese University of Hong Kong (CUHK). All cases of fetal ventriculomegaly in the two units were carefully analysed by the maternal fetal medicine specialists, in accordance with standard departmental protocols. Fetal cerebral ventriculomegaly was classified as mild (10-11.9 mm), moderate (12-14.9 mm), or severe (≥15 mm), according to the greatest atrial width observed during ultrasound examinations in that pregnancy. Based on assessments of any associated ultrasound abnormalities, fetal cerebral ventriculomegaly was classified as isolated (if cerebral ventriculomegaly was the only abnormality identified) or non-isolated (if other structural abnormalities were detected, including CNS abnormalities of the brain or spine and abnormalities in other organ systems).

Pregnant women who chose amniocentesis underwent karyotyping as the standard primary genetic investigation. Chromosomal microarray analysis was offered as an additional self-financed test. The genetic samples of patients from United Christian Hospital were sent to the Prenatal Diagnostic Laboratory of Tsan Yuk Hospital; the genetic samples of patients from Prince of Wales Hospital were sent to the Prenatal Diagnostic Genetic Diagnosis Centre of the CUHK. The microarray platform Perkin Elmer CGX V2.0 (60K oligonucleotide array) and Affymetrix CytoScan 750K single nucleotide polymorphism array were used for CMA studies in Tsan Yuk Hospital from January 2014 to September 2018 and from October to December 2018, respectively; the Agilent Fetal DNA chip version 2.0 (8×60k) array comparative genomic hybridisation and single nucleotide polymorphism analysis methods were used in the CUHK throughout the study period. The neurodevelopmental outcomes of live births were reviewed using the hospital’s computerised clinical management system. Each child’s development was assessed by a paediatrician during follow-up; assessments determined the presence of cognitive impairment, speech delay, fine and gross motor skills, epilepsy, or developmental delay.

The study protocol was approved by the research ethics committees of the respective hospitals. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement was used as a reporting guideline for this study. SPSS software (Windows version 20.0; IBM Corp, Armonk [NY], United States) was used for data entry and analysis. Comparisons of categorical variables were performed using the Chi squared test or Fisher’s exact test, as appropriate. A P value of <0.05 was considered statistically significant.

From January 2014 to December 2018, there were 55 565 total deliveries in the study centres; 91 fetuses (0.16%) had antenatal ultrasound diagnosis of cerebral ventriculomegaly. After the exclusion of cases (ie, pregnant women and their fetuses) with incomplete information (eg, incomplete ultrasound details) and cases that had not delivered in the study units, 84 cases were included for final analysis. The maternal and fetal characteristics are shown in Table 1. Overall, 65.5% (55/84) of fetuses exhibited mildly dilated lateral ventricles and 54.8% (46/84) of fetuses exhibited isolated ventriculomegaly. More male fetuses had cerebral ventriculomegaly than did female fetuses (63.1% vs 36.9%). Screening for congenital fetal infections (eg, cytomegalovirus in amniotic fluid, maternal blood, or urine; toxoplasmosis in maternal blood) was conducted in 66.7% of all cases (73.9% of isolated ventriculomegaly cases); all had negative results. Infection screening was often not performed in cases of non-isolated fetal ventriculomegaly associated with other structural abnormalities; abnormalities in those cases were often presumed to be associated with genetic causes, rather than infection. Fetal magnetic resonance imaging (MRI) was performed in 16 cases (19.0%) to detect additional CNS abnormalities. The most common CNS abnormalities associated with ventriculomegaly were Dandy–Walker malformation (7 cases), corpus callosum disorders (5 cases), and spina bifida (3 cases). Other CNS abnormalities identified included brain tumour, occipital encephalocele, aqueductal stenosis, lissencephaly, and schizencephaly. The pregnancy outcomes are shown in the Figure. In total, 53 live births were delivered in our cohort at a mean gestational age of 38.1 ± 1.9 weeks. The mean birth weight was 3043 ± 614 g. The mean age at neurodevelopmental outcome assessment of the children was 33 months (range, 14-72); ultrasound, computed tomography, or MRI scanning was performed after delivery in 56.6% (30/53) of the cases.

Amniocentesis was performed in 77.4% (65/84) of cases. Among the 22.6% (19/84) of cases that did not involve amniocentesis, an invasive test was declined in 10; in the remaining nine cases, fetal ventriculomegaly was detected after 24 weeks of gestation, which exceeded the legal limit for termination of pregnancy in Hong Kong. The karyotype and CMA results in four cases were obtained from placental tissue after termination of pregnancy; in one case, the results were obtained from the baby’s peripheral blood after delivery. Altogether, karyotype results were available in 70 cases; CMAs were conducted in 53 of those cases. Fourteen cases (20%) had abnormal karyotype or CMA results (Table 2). In total, 11.4% (8/70) of cases had chromosomal abnormalities that could be detected by conventional karyotyping alone, while six cases (shown in Table 2) had chromosomal abnormalities that could only be detected by CMA testing. Therefore, CMA provided an incremental diagnostic yield of 8.6% (6/70) compared with conventional karyotyping; three cases exhibited pathogenic CNVs (4.3%, 3/70) and three cases exhibited variants of uncertain significance (VOUS) [4.3%, 3/70]. The three pathogenic CNVs included two cases of 17p13.3 deletion: one involved the lissencephaly 1 (LIS1) gene and one involved the YWHAE gene. Deletion of the LIS1 gene has been associated with classic lissencephaly, microcephaly, and mental insufficiency; YWHAE may be a susceptibility gene for schizophrenia.5 The third case of terminal 6p25 deletion involved the FOXC1 gene, which is reportedly associated with CNS anomalies (eg, hydrocephalus and hypoplasia of the cerebellum, brainstem, and corpus callosum) that cause mild to moderate developmental delay.6

Subgroup analysis showed that in the isolated cerebral ventriculomegaly group, 15.2% (5/33) of cases had abnormal karyotype or CMA results; the incidences of abnormal karyotype or CMA results did not significantly differ according to the degree of isolated cerebral ventriculomegaly (P=0.31) [Table 3]. In the mild isolated ventriculomegaly group, 12.0% (3/25) of cases had abnormal karyotype or CMA results, among which two cases could be detected by conventional karyotyping and one case (VOUS) could only be detected by CMA.

Concerning the evolution of isolated ventriculomegaly with live births, 8.3% (3/36) with mild isolated ventriculomegaly and 20% (1/5) with moderate isolated ventriculomegaly at diagnosis showed progression during pregnancy. Fewer cases of mild cerebral ventriculomegaly (10-11.9 mm) were associated with developmental delay than non-mild (≥12 mm) ventriculomegaly in the isolated ventriculomegaly group (9.7% vs 41.7%; P=0.03). Developmental delay tended to be more common in the isolated cerebral ventriculomegaly group with abnormal karyotype or CMA results (66.7% vs 14.8%), compared with isolated ventriculomegaly with normal karyotype or CMA; however, this difference was not statistically significant. The risk of developmental delay was not significantly different according to fetal sex in cases of isolated ventriculomegaly (Table 4). The clinical details of the 12 cases with developmental delay are summarised in Table 5.

The incidence of fetal ventriculomegaly in our cohort was 0.16%, reflecting the incidence of fetal ventriculomegaly detectable antenatally with mid-trimester morphology ultrasound examinations in a large cohort in Hong Kong. Our findings were compatible with previous reports of fetal ventriculomegaly incidence, which has ranged from 0.3 to 3.8 per 1000 pregnancies.7 8 While congenital infection screening was conducted in only 66.7% of our cases, no cases of intrauterine cytomegalovirus or toxoplasmosis infection were identified in our cohort. This is potentially because Chinese pregnant women have a high cytomegalovirus seroprevalence9 but a low prevalence of toxoplasmosis, compared with Caucasian pregnant women.10 Because even mild isolated ventriculomegaly <12 mm carried a 12.0% risk of chromosomal abnormalities, the findings of amniocentesis with CMA appeared to be clinically meaningful, regardless of the degree of fetal ventriculomegaly. In this study, isolated mild ventriculomegaly was associated with a normal outcome in approximately 90% of children, but the risk of developmental delay increased with increasing degree of ventriculomegaly.

Cerebral ventriculomegaly was more prevalent in male fetuses than in female fetuses in our cohort; the male to female ratio was 1.7. This finding is consistent with the results of previous studies, which demonstrated a male predominance regarding isolated cerebral ventriculomegaly (male to female ratio of 1.7).11 A study of isolated fetal ventriculomegaly in China showed no differences in chromosomal abnormalities between male and female fetuses (7.6% vs 8.0%, P=0.924).12 Our cohort demonstrated no significant difference in the risk of developmental delay according to fetal sex in cases of isolated ventriculomegaly. Previous studies also showed no significant differences in neurological outcomes between male and female infants with isolated ventriculomegaly and normal karyotype.11 Further studies are needed to explore the reason for a higher incidence of cerebral ventriculomegaly in male fetuses than in female fetuses.

The incidence of an abnormal karyotype (11.4% overall vs 8.0% in the mild isolated group) in our cohort was similar to the results of previous studies. Previous studies with differences in the proportions of cases with each degree of ventriculomegaly, as well as the proportions of associated abnormalities, demonstrated that the incidence of an abnormal karyotype in cases of fetal ventriculomegaly was between 5% and 11.3%.13 14 15 In a systematic review of isolated ventriculomegaly (10-15 mm), 4.7% (57/1213) of fetuses had abnormal karyotype results.16 Another prospective study, which included 355 cases of mild to moderate ventriculomegaly, showed a higher rate of abnormal karyotype results when other structural abnormalities were present (18.0%), compared with the isolated ventriculomegaly group (10.2%).

Chromosomal microarray analysis testing provided an incremental diagnostic yield of 8.6%, compared with conventional karyotyping in our cohort; 4.3% of cases exhibited pathogenic CNVs, while 4.3% of cases exhibited VOUS. Chromosomal microarray analysis can identify aneuploidies (ie, large structural chromosomal changes); it can also identify submicroscopic (<5 Mb) CNVs that cannot be detected by conventional karyotyping.17 Recent studies have focused on the application of CMA for detecting chromosomal aberrations in cases of fetal cerebral ventriculomegaly. The incremental diagnostic yields of CMA over karyotyping for diagnosing pathogenic CNVs and VOUS in previous studies of fetal cerebral ventriculomegaly conducted in China were 3.0% to 12.8% and 2.0% to 4.5%, respectively.18 19 20 21 A limitation of CMA testing is the reporting of VOUS, which poses counselling difficulties during subsequent management. In a recent cohort in Hong Kong, the rate of VOUS was 2.1% in prenatal samples obtained for various indications (eg, abnormal ultrasound, positive Down syndrome screening, abnormal non-invasive prenatal testing, advanced maternal age, and family history of chromosomal/genetic disorders).22 Our cohort detected 4.3% of VOUS, which is high but generally comparable with the findings of previous studies.

Consistent with our findings, the incidences of abnormal karyotype or CMA results in previous studies did not significantly differ according to the degree of cerebral ventriculomegaly.23 24 Therefore, invasive diagnostic tests are warranted for any degree of cerebral ventriculomegaly identified in prenatal ultrasound, including mild isolated ventriculomegaly. Chromosomal microarray analysis should be performed because of its higher diagnostic yield, compared with conventional karyotyping. The Hospital Authority of Hong Kong has replaced conventional karyotyping with CMA as the primary test for chromosomal studies of structural abnormalities detected in prenatal ultrasound since June 2019. Therefore, the incidences of chromosomal abnormalities detected in fetal cerebral ventriculomegaly are expected to increase in the future. Non-invasive prenatal testing for chromosomal abnormalities by maternal blood DNA testing is a trend among pregnant women because of its non-invasiveness. However, non-invasive prenatal testing for CNVs <5 Mb yielded a detection rate of only 14.3%.25 The above findings suggest that non-invasive prenatal testing should not be offered as an alternative for women with fetal cerebral ventriculomegaly, regardless of the degree of ventriculomegaly, because small pathogenic CNVs can be present in cases that involve any degree of ventriculomegaly.

One of the fetuses in our cohort had mild cerebral ventriculomegaly; MRI of the brain revealed ischaemic changes (Table 5 Case 10). Amniocentesis was performed and showed normal karyotype and CMA results. The baby had progressive hypertrophic cardiomyopathy with global developmental delay after delivery. Trio whole-exome sequencing (WES) was done after delivery, and the baby was diagnosed with autosomal recessive mitochondrial disease caused by SCO2 mutations; both parents were heterozygous carriers. In prenatal fetal structural abnormalities, WES can reveal a high proportion of diagnostic genetic variants, including up to 22% in CNS abnormalities including cerebral ventriculomegaly.26 Mutations in two X-linked genes (L1CAM and AP1S2) and two autosomal recessive genes (CCDC88C and MPDZ) have been described to cause congenital hydrocephalus or aqueductal stenosis, which can cause severe isolated ventriculomegaly.27 There is a potential role for WES in facilitating the genetic diagnosis in cerebral ventriculomegaly with negative karyotype and CMA results, particularly for those fetuses with severe ventriculomegaly suggestive of aqueductal stenosis and in couples with recurrent fetal abnormalities.

Fetal cerebral ventriculomegaly was associated with an increased risk of developmental delay in the child after delivery. The neurodevelopmental prognosis worsened as the degree of ventriculomegaly increased in our cohort (9.7% in cases of mild ventriculomegaly vs 41.7% in cases of moderate or severe ventriculomegaly) and in other studies. In a systematic review and meta-analysis of neurodevelopmental outcomes in cases of isolated ventriculomegaly (10-15 mm), the overall prevalence of developmental delay was 7.9%.16 In a meta-analysis of the neurological outcomes of fetal ventriculomegaly in China, the neurological prognosis was good in 88%, 57%, and 36% of mild, moderate, and severe ventriculomegaly cases, respectively.13 In another systematic review and meta-analysis of severe isolated ventriculomegaly, developmental delay was mild or moderate in 18.6% of children and severe in 39.6% of children.28 More than half (58.3%, 7/12) of the children diagnosed with developmental delay in our study exhibited only mild delay, although there was a background risk of mild developmental delay during counselling. The high incidence of developmental delay in cases of non-mild isolated ventriculomegaly was probably also associated with the presence of chromosomal abnormalities. Nevertheless, our data did not show associations of abnormal karyotype or CMA results with developmental delay among the 43 live births. This finding was presumably biased because pregnancies were terminated in many of the cases with abnormal karyotype or CMA results; the neurological outcomes could not be assessed in those cases.

This study had some limitations. First, it used a retrospective cohort design; thus, congenital infection screening and fetal MRI assessment were not performed in all cases. Second, there was no protocol for routine postnatal imaging evaluation, and the assessment of neurodevelopmental outcomes among the children was not standardised. However, our study provided data regarding the incidences of chromosomal and genetic abnormalities in cases of antenatally detected fetal ventriculomegaly in Hong Kong, as well as a general picture of neurological outcomes of affected children. The findings will allow prenatal counselling in Hong Kong to be performed on the basis of more relevant epidemiological and genomic data, rather than findings from other populations.

All degrees of cerebral ventriculomegaly may be associated with chromosomal abnormalities. Chromosomal microarray analysis has an increased diagnostic yield, compared with conventional karyotyping. Amniocentesis with CMA testing should be offered to all women with fetal cerebral ventriculomegaly. Non-invasive prenatal testing should not be offered as an alternative method of chromosomal analysis. The neurological outcomes of the children are associated with the degree of fetal ventriculomegaly. Whole-exome sequencing may be indicated for selected cases of fetal ventriculomegaly with normal CMA, but further studies are needed to support this recommendation.

Concept or design: WY Lok, CW Kong, WK To.
Acquisition of data: WY Lok, MM Shi, SYA Hui.
Analysis or interpretation of data: WY Lok, CW Kong, WK To.
Drafting of the manuscript: WY Lok, CW Kong.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval was obtained from the Kowloon Central/ Kowloon East Research Ethics Committees (Ref: KC/KE-19-0172/ER-4) and The Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (CREC Ref No.: 2019.468).

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