Asymmetric cortical development and prognosis in fetuses with isolated mild fetal ventriculomegaly: an observational prospective study

The present study was a prospective observational study involving singleton pregnant women who visited Peking University First Hospital from January 2016 to December 2019. The study was conducted in accordance with the Declaration of Helsinki. Our study was approved by the Peking University First Hospital Human Research Ethics Committee, and informed consent was obtained from all participants. The inclusion and exclusion criteria are shown in Fig. 1. We included fetuses between 21 weeks and 28 weeks of gestational age (GA) for two reasons. First, pregnant women undergo a second trimester ultrasound scan between 21 weeks and 23 weeks in our hospital; therefore, a fetus could be first diagnosed with mild ventriculomegaly at 21 weeks. Second, based on a previous study [7] and our experience, some sulci and gyri, such as the calcarine sulcus, might develop to grade 4 or 5 (maximum development) after 28 weeks, and thus an assessment of the cortical development process in fetuses who are diagnosed with IMVM after 28 weeks is of little value. We included 40 singleton pregnant women. The clinical information of each participant, including name, age, reproductive history and family history of nervous system disease, was recorded after inclusion. The gestational (postmenstrual) age was determined as the time from the first day of the last menstruation and was confirmed by a crown–rump length (CRL) measurement in the first trimester.

Transabdominal and transvaginal ultrasound examinations were conducted at an interval of 2–3 weeks using a Voluson E8 or Voluson E10 ultrasound device (GE Healthcare Ultrasound, Milwaukee, WI, USA) after the initial detection of ventriculomegaly. Regular ultrasound, including biometric measurements, was carried out, followed by neurosonography. Neurosonography was performed with a multiplanar assessment according to the International Society of Ultrasound in Obstetrics and Gynecology guidelines (ISUOG 2007) [10] Transabdominal neurosonography was performed with 3–5-MHz probes. Transvaginal neurosonography was performed with 5–9-MHz probes.

As a general neurosonographic assessment, the distal lateral ventricle atrial width was obtained in the transventricular plane, and the proximal lateral ventricle was assessed in coronal planes [10‐12]. Progression of ventriculomegaly was defined as ventricular enlargement greater than 2 mm compared with the initial measurement. Stable ventriculomegaly was defined as an enlargement of less than 2 mm, and regressive ventriculomegaly was defined as a decrease of 2 mm or more or as a ventricular diameter of less than 10 mm [8, 13].

We also assessed the maturation of the parieto-occipital, calcarine and cingulate sulci of both hemispheres in IMVM fetuses at specific planes using the scoring method described by L. R. Pistorius [7]. The sulci we chose to examine were close to the midline, which would not be shaded by the fetal skull and enabled their continuous assessment throughout pregnancy using transabdominal and transvaginal neurosonography. The parieto-occipital sulcus was evaluated in the axial cephalic plane, the calcarine sulcus was evaluated in the coronal transcerebellar plane, and the cingulate sulcus was evaluated in the coronal transcaudate and transthalamic planes. A subjective score ranging from grade 0 to grade 5 was used to assess cortical development, where 0 is no development and 5 is the highest grade of maturation. More specifically, a grade 0 sulcus is not visible, a grade 1 sulcus displays a shallow indentation or echogenic dot shape, a grade 2 sulcus exhibits a broad V (width ≥ depth) shape, a grade 3 sulcus has a Y or narrow V (depth > width) shape, a grade 4 sulcus has an I- or J-shape, and a grade 5 sulcus shows branches from the grade 4 shape. Asymmetric sulcal maturation in the two hemispheres was defined as a difference of at least one grade between any sulci in both hemispheres. Furthermore, the fetuses were divided into the symmetric maturation group and the asymmetric maturation group.

All participants in this study underwent fetal MRI. Fetal MRI was performed using a 1.5-T MRI System (Multiva 1.5 T, Philips Healthcare, Best, The Netherlands) with a 32-channel cardiac-phased array surface placed over the gravid uterus for signal reception. The fetal head was scanned at the scanning center in the coronal, transverse, and sagittal planes using Half-Fourier acquisition single-shot turbo spin-echo (HASTE) sequences (repetition time of 1500 ms, echo time of 107–160 ms, slice thickness of 3 mm, slice gap of 0 mm, matrix of 280 × 205). Additionally, the fetal head was scanned in the transverse plane using T1 fast field echo (T1-FFE) sequences (repetition time of 15 ms, echo time of 7.5 ms, slice thickness of 3 mm, slice gap of 0 mm, matrix of 160 × 151) and diffusion weighted imaging (DWI) sequences (repetition time of 3249 ms, echo time of 90 ms, slice thickness of 3 mm, slice gap of 0 mm, matrix of 92 × 72). A 24 cm to 30 cm field of view (FOV) was used.

Genetic examinations of all fetuses were performed to exclude common genetic abnormalities, including a karyotype analysis, array-based comparative genome hybridization (aCGH) and single nucleotide polymorphism (SNP) array analysis, referring to the Database of Genomic Variants, Decipher Database, Online Mendelian Inheritance in Man (OMIM) database, PubMed, and other databases. Additionally, a TORCH (toxoplasmosis, other, rubella, cytomegalovirus and herpes simplex virus) examination was performed in all fetuses to exclude common infections.

Data on pregnancy outcomes (gender, Apgar score and perinatal and neonatal morbidity and mortality) were recorded for all cases. Pediatricians from the Department of Pediatrics in our hospital with professional training evaluated the neonatal behavioral neurological assessment (NBNA) scores for each included infant, including the general condition, action behavior, muscular tension, and primitive reflex, within 7 days of birth. Each parameter was assigned 0–2 points, with a total score of 40 and a score of greater than 36 defined as normal. The peripheral environment was kept quiet, and the temperature was maintained at a suitable level. The room temperature was maintained at approximately 26 °C. All evaluation parameters were assessed in sleeping children 1 h after being fed.

Cranial ultrasound examinations of infants were performed by an experienced sonographer using an ATL 5000 Unit (Philips, Best, The Netherlands) within 6 months after birth. Abnormalities of the neonatal brain were recorded.

At 6, 12 and 18 months after birth, all included infants were assessed using the Ages and Stages Questionnaire, Third Edition (ASQ-3). Parents answered 30 questions covering 5 domains of development, including communication, gross motor, fine motor, problem-solving, and adaptive skills. Parents were instructed to try activities with their child to facilitate an accurate assessment. A pass/fail score was assigned for each area of development. The presence of a problem in any domain screened, defined as 2 standard deviations below the mean area score, was considered to indicate delayed development. Moreover, some of the included children were assessed with Bayley Scales of Infant Development, First Edition (BSID-I) at 6, 12 and 18 months. Experienced physicians in our hospital used the BSID-I to assess neurodevelopment, including the mental developmental index (MDI) and psychomotor developmental index (PDI). Scores of less than 79 on the MDI or PDI were considered to indicate a low level of development. Other infants were unable to undergo this assessment due to the COVID-19 outbreak or because they lived far from our hospital.

Data were analyzed using SPSS version 21 for Mac (SPSS Inc., Chicago, IL). Categorical variables are reported as percentages and continuous variables are presented as means or median values. Student’s t-test for independent samples and Pearson’s chi-square tests were used to compare quantitative and qualitative data between the symmetric maturation and asymmetric maturation groups.

Forty fetuses were included in this study: 20 (50.0%) of them showed symmetric cortical maturation and the other 20 (50.0%) exhibited asymmetric maturation. The demographic characteristics of the two groups are presented in Table 1. The mean maternal age of the symmetric maturation group was 32.20 years (range 27–38 years), the mean gestational age at birth was 38.95 weeks (range 37–41 weeks), and the mean birthweight was 3574.00 g (range 3005–4190 g). The mean maternal age of the asymmetric maturation group was 31.10 years (range 27–37 years), the mean gestational age at birth was 38.56 weeks (range 37–40 weeks), and the mean birthweight was 3464.94 g (range 2950–3835 g). Apgar scores at 1 and 5 min were 10 in all cases. Statistically significant differences in the aforementioned parameters were not observed between the symmetric and asymmetric maturation groups. (p values were 0.29, 0.30, 0.29, 1.00 and 1.00, respectively).

The mean GA at the first diagnosis of mild ventriculomegaly was 23.50 weeks (range 21–28 weeks) in the symmetric maturation group and 24.00 weeks (range 22–27 weeks) in the asymmetric maturation group. In the symmetric maturation group, 15 (75.0%) fetuses presented bilateral ventriculomegaly, and 5 (25.0%) fetuses presented unilateral ventriculomegaly. In the asymmetric maturation group, 19 (95.0%) fetuses presented unilateral ventriculomegaly, and 1 (5.0%) fetus presented bilateral ventriculomegaly. The incidence of unilateral ventriculomegaly was significantly different between the symmetric and asymmetric maturation groups (p = 0.00). The prenatal assessment of the lateral ventricle of IMVM fetuses is presented in Table 2. Notably, all developmental delays occurred in the hemisphere with ventriculomegaly compared with the other side in fetuses presenting unilateral ventriculomegaly. Only one fetus in the asymmetric group presented bilateral ventriculomegaly. In this fetus, the right ventriculomegaly was regressive, and the lateral width returned to normal at 32 weeks. The lateral width of the left side was stable throughout pregnancy. As expected, relatively delayed development occurred on the stable side. The sulcal development of the asymmetric maturation group is presented in Table 3. Eight (40.0%) fetuses showed asymmetric development of one sulcus, 10 (50.0%) fetuses showed asymmetric development of two sulci, 2 (10.0%) fetuses showed asymmetric development of three sulci, and 34 sulci with relatively delayed development were observed compared with sulci in the other hemisphere. The mean GA at the first diagnosis of relatively delayed development was 24.23 weeks (range 22–27 weeks) for the parieto-occipital sulcus, 24.71 weeks (range 22–28 weeks) for the calcarine sulcus, and 26.43 weeks (range 25–29 weeks) for the cingulate sulcus. According to our assessment, all sulci with delayed development underwent ‘catch-up growth’ and developed to the same grade as the sulci in the other hemisphere. The mean GA at which the two sides developed to the same grade was 29.40 weeks (range 24–32 weeks) for the parieto-occipital sulcus, 29.30 weeks (range 24–31 weeks) for the calcarine sulcus and 31.27 weeks (range 27–34 weeks) for the cingulate sulcus. Figures 2, 3 and 4 show the ‘catch-up growth’ patterns of the parieto-occipital sulcus, calcarine sulcus and calcarine sulcus, respectively. The relatively delayed sulci showed one or two grades of delay compared with the other side, but none showed three or more grades of delay. The change in the width of the lateral ventricle and development of the included sulci are shown in Figs. 5, 6 and 7 at two-week intervals during pregnancy. For statistical analyses, we used the width of the more dilated side in fetuses with bilateral ventriculomegaly. As shown in Figs. 5, 6 and 7, the parieto-occipital, calcarine and cingulate sulci of all IMVM fetuses presenting symmetric or asymmetric cortical maturation in our study developed to grade 5 before birth. Figures 5, 6 and 7 and Table 2 also show a regression of ventriculomegaly in only some fetuses with IMVM, while ventriculomegaly remained stable or even progressed in other fetuses during the course of cortical maturation. The median value of the lateral ventricle remained stable in both the asymmetric and symmetric groups. The change in the width of the lateral ventricle was not significantly different between the two groups (p = 0.51).

The NBNA scores of all included infants were greater than 36 within the seventh day after birth. The cranial ultrasounds of all infants showed no abnormalities other than mild ventriculomegaly.

The follow-up results are shown in Table 4. At the end of our study, the included children were of different ages. In the symmetric group, 6 children were between 6 and 12 months old, 3 children were between 12 and 18 months old, and 11 children were over 18 months old. In the asymmetric group, 7 children were between 6 and 12 months old, 7 children were between 12 and 18 months old, and 6 children were over 18 months old. We assessed the neurodevelopment of all the included children at 6, 12 and 18 months of age using the ASQ-3. Some of the included children were also assessed using the BSID-I at 6, 12 and 18 months of age. Scores in the normal range were recorded for all included infants, including those who underwent the ASQ-3 assessment and both the ASQ-3 and BSID-I assessments. None of the included children were defined as having delayed development according to the results of the assessments at 6, 12 or 18 months of age, and no statistically significant differences in the results were observed between the children in the two groups. Furthermore, at the end of our study, none of the included children showed neurological diseases other than mild fetal ventriculomegaly.