Introduction
Congenital malformations are the leading factor of perinatal death and childhood morbidity [
1‐
6]. Ultrasound screening has been a routine for all pregnant patients to detect structural anomalies [
7‐
13], and it is recommended to perform this scan at 18-22 weeks of gestation [
14‐
17].
Most of the time ultrasound (USG) screening provides reassurance to the couples, however, less than 5% of the scans revealed otherwise [
4,
5,
17‐
19] CNS anomalies accounts for the highest percentage of prenatally detected deformities among all organ systems [
3,
4,
11,
13,
20,
21], with an incidence of 2-10 per 1000 live births [
22‐
25]. With the advancement in imaging technologies offering a better resolution of the fetal cerebral structures and enhancement in the skill of sonographers, the detection rate was expected to rise [
14,
16,
26,
27].
Prenatal ultrasound and karyotyping findings often serve as the main guide for the prediction of prognostic outcomes and the establishment of management plans for fetuses with CNS anomalies. However, counseling on the prognosis is often difficult as most of the fetuses with these conditions ended up with abortion and neonatal death. There is also limited studies on long-term follow-up in children born with prenatally diagnosed CNS anomalies [
7,
20]. Therefore, we intend to address the outcome of those fetuses and outline the systematic approach once CNS anomaly is suspected.
Methodology
This was a retrospective cohort study that was performed at the Department of Obstetrics and Gynaecology, University of Malaya Medical Centre (UMMC) between January 2010 and December 2019. Pregnancies that were detected to have any CNS anomaly on ultrasonography at our institution within this ten-year duration were included.
UMMC was established as a tertiary referral center to receive referrals of pregnant patients with suspected congenital anomalies from all over Malaysia. All the prenatal ultrasound examinations were performed by sonographers or obstetricians and the prenatal diagnosis of CNS anomalies were confirmed by Maternal-Fetal Medicine specialists. All ultrasound examinations were performed using Voluson S8 (Buckinghamshire, United Kingdom) with 2- 5 MHz transabdominal transducer or 4-7 MHz transvaginal transducer. The obstetric USG assessment included a complete assessment of all morphological structures of the entire fetus. Any deformity noted from the scan was recorded according to respective organ systems. The fetus was considered to have multiple CNS anomalies if two or more CNS anomalies were revealed from prenatal scans. Fetus with both CNS and extra-CNS anomalies are classified to have multiple system deformities. Data collected also included gestational age (GA) at prenatal ultrasound diagnosis, maternal age, gravidity, parity, past obstetric and family history, sonographic findings on amniotic fluid volume and fetal parameters.
In our institution, cavum septi pellucidi (CSP) was considered wide when the transverse diameter was more than 10mm in thalamic view of the fetal head. Those fetuses with absent CSP without any other features suggestive of agenesis of corpus callosum were classified to have absent CSP. Cerebellar disorder in this study included cerebellar hypoplasia and/or dysplasia.
The abnormal sonographic findings were discussed among multidisciplinary teams to outline the management plan and establish the prognosis before parental counseling was carried out. Fetal karyotyping was recommended in all cases to determine any associated syndromic condition. Karyotype confirmation would be part of postnatal investigations.
After the multidisciplinary team meeting, TOP was an option offered to the couples if the anomaly potentially led to fetal or neonatal mortality and/or severe morbidity. TOP after 24 weeks was only offered for lethal and severely disabling abnormality, i.e. anencephaly. Post-mortem examination following elective and spontaneous abortions was recommended but rejected by all parents.
The maternal and infant records were traced to obtain the pregnancy outcomes. Fetuses with congenital CNS anomalies resulted in either termination of pregnancy (TOP), spontaneous abortion, stillbirth, or live birth. Live births were further grouped according to their survival durations.
Survivors in our study that were followed-up in our institution were evaluated via continuous neurodevelopmental assessments by pediatric neurologists and developmental pediatricians. Vision and hearing tests were done by ophthalmologists and Ear, Nose and Throat (ENT) physicians respectively. We reviewed their postnatal reports up to 2 years old or until they passed away, depending on which was earlier. Then, their neurocognitive functions were classified into normal development, motor delay, mental impairment, or motor and mental delay based on serial neurodevelopmental assessments performed by pediatricians. The neurodevelopmental assessment tool used in this study was created by Malaysian Paediatric Association and was used in all hospitals in Malaysia to detect and evaluate any developmental delay in gross motor, fine motor, social, speech and language. The child will be considered to have normal neurodevelopment if he/she passed the serial assessments as appropriate to the age and had not received any rehabilitative or neurotherapeutic treatment. Children with any significant motor or intellectual delay that was detected before they defaulted follow-up or passed away before 2 years old were classified as having abnormal development. Those with no neurological delay but defaulted follow-up or passed away before two years old were classified under the “lost to 2-year follow-up” category as we do not assume no abnormality until the age of two years.
Statistics analysis
The data were analysed using SPSS, Version 12.0 (Statistical Package for Social Sciences, SPSS Inc., Chicago, IL, USA). The data were presented as percentages where appropriate. Pearson’s Chi-square test and t-test were used to test the differences between groups. The level of significance was set at p < 0.05.
Result
We reported on 365 fetuses with abnormal central nervous system detected from prenatal ultrasound. There were two set of twins among them. The average maternal age was 31.26±5.13 years at the time of prenatal diagnosis. The diagnostic gestational age of fetuses ranged from 10 weeks to 39 weeks, with a mean of 24.65±7.37 weeks.
114 (31.40%) women were primigravida; whereas among the remaining 249 women, 90 (36.14%) of them experienced previous pregnancy loss and 226 (90.71%) women had at least one surviving child. There was a positive family history of CNS or chromosomal anomaly in eight women.
The prenatal ultrasonography represented 27 different anomalies that occurred 488 times in 365 fetuses and their distributions were described in Table
1. Overall, the commonest CNS anomaly detected on prenatal ultrasound was ventriculomegaly, which comprised 28 mild, 13 moderate, and 38 severe cases while the severity of the rest of 35 cases was unclassified. Based on the prenatal ultrasonographic findings, 198 (54.2%) had CNS anomalies that were associated with other systems’ anomalies, predominantly with cardiovascular system (20.37%), extremities (16.44%), and facial (15.51%) defects (Table
2). In the remaining 167 fetuses with isolated CNS anomalies, 33 (19.7%) of them were complicated with more than a single type of CNS anomalies. Anencephaly (87.80%) and cystic hygroma (53.33%) often occurred in isolation while microcephaly (85.71%), holoprosencephaly (82.85%), spinal malformations (82.76%), and agenesis of corpus callosum (81.25%) were predominantly associated with other systems’ anomalies (Table
1). Other anomalies were negligible due to insufficient data to make an inference.
Table 1
Distributions of 488 CNS anomalies in 365 fetuses
Neural tube defect |
- Anencephaly | 36 (7.38) | 1 (0.20) | 4 (0.82) | 41 (8.40) |
- Encephalocele | 9 (1.84) | 6 (1.23) | 9 (1.84) | 24 (4.92) |
-Meningocele | 1 (0.20) | - | - | 1 (0.20) |
-Myelomeningocele | 1 (0.20) | 9 (1.84) | 8 (1.64) | 18 (3.69) |
-Spina bifida occulta | - | - | 1 (0.20) | 1 (0.20) |
-Unclassified closed spina bifida | 1 (0.20) | - | - | 1 (0.20) |
-Unclassified NTD | 1 (0.20) | 6 (1.23) | 5 (1.02) | 12 (2.46) |
Ventriculomegaly | 29 (5.94) | 24 (4.92) | 61 (12.50) | 114 (23.36) |
Holoprosencephaly | 5 (1.02) | 1 (0.20) | 29 (5.94) | 35 (7.17) |
Microcephaly | - | 2 (0.41) | 12 (2.46) | 14 (2.87) |
Cysts |
- arachnoid cyst | 4 (0.82) | - | 3 (0.61) | 7 (1.43) |
- choroid plexus cyst | 1 (0.20) | - | 10 (2.05) | 11 (2.25) |
Cystic hygroma | - | 8 (1.64) | 10 (2.05) | 60 (12.30) |
Chiari Type II malformation | - | - | 2 (0.41) | 18 (3.69) |
Dandy Walker malformation | 4 (0.82) | 1 (0.20) | 17 (3.48) | 22 (4.51) |
Cerebellar disorder | - | 5 (1.02) | 14 (2.87) | 19 (3.89) |
Megacisterna magna | 1 (0.20) | 4 (0.82) | 18 (3.69) | 23 (4.71) |
Agenesis of corpus callosum | - | 3 (0.61) | 13 (2.66) | 16 (3.28) |
Other spinal malformations | 4 (0.82) | 1 (0.20) | 24 (4.92) | 29 (5.94) |
Miscellaneous |
-sacrococcygeal teratoma | 4 (0.82) | - | 1 (0.20) | 5 (1.02) |
-cerebral atrophy | - | - | 2 (0.41) | 2 (0.41) |
-wide CSP | - | - | 3 (0.61) | 3 (0.61) |
-absent CSP | - | 3 (0.61) | 5 (1.02) | 8 (1.64) |
-megalencephaly | - | - | 1 (0.20) | 1 (0.20) |
-hydranencephaly | - | - | 1 (0.20) | 1 (0.20) |
-intracranial haemorrhage | - | 1 (0.20) | - | 1 (0.20) |
- intracranial tumour | 1 (0.20) | - | - | 1 (0.20) |
Table 2
Distributions of 432 extra-central nervous system anomalies in 198 fetuses
Cardiovascular | 88 (20.37) |
Extremities | 71 (16.44) |
Facial | 67 (15.51) |
Skull | 55 (12.73) |
Gastrointestinal | 36 (8.33) |
Musculoskeletal | 33 (7.64) |
Respiratory | 33 (7.64) |
Renal | 27 (6.25) |
Umbilicus | 11 (2.55) |
Placenta | 4 (0.93) |
Hepatobiliary | 4 (0.93) |
Genitourinary | 3 (0.69) |
Total | 432 (100) |
CNS central nervous system, CSP cavum septi pellucidi
Of the pregnancies, 67 of them were thought to have abnormal amount of amniotic fluid at the time of ultrasonography; polyhydramnios (n=41, 11.29%) appeared more frequently than oligohydramnios (n=26, 7.16%). Smaller than gestational age (growth parameters less than 10th centile with normal and abnormal Doppler) occurred in 28 (7.67%) fetuses while 2 (0.55%) of anomalous fetuses were found to be larger than gestational age on prenatal ultrasonography.
Chromosomal analysis was attempted in 111 (30.41%) fetuses (Table
3). Of the karyotype analysis, 87 (78.38%) cases were performed prenatally via amniocentesis (98.20%)) and chorionic villous sampling (1.80%), whereas 24 (21.62%) cases were analyzed cytogenetically from neonatal tissue or blood samples. Ruling out three culture failures, abnormal karyotypes were recognized in 53 (49.07%) of 108 cases karyotyped. Edward syndrome (
n=23, 43.40%) and Patau syndrome (
n=14, 26.42%) were the commonest chromosomal aberrations in fetuses with CNS anomalies. Specific CNS anomaly shed light on the possibility of certain chromosomal abnormalities. Our study revealed a close relationship between holoprosencephaly with Patau syndrome, choroid plexus cyst with Edward syndrome, cystic hygroma with Turner syndrome, and megacisterna magna with Edward syndrome.
Table 3
Chromosomal abnormalities in 87 cases
Neural tube defect |
- Anencephaly | - | - | - | - | - | - |
- Encephalocele | 4 (4.60) | - | 1 (1.15) | - | - | - |
-Meningocele | 1 (1.15) | - | - | - | - | - |
-Myelomeningocele | 2 (2.30) | 1 (1.15) | - | - | - | - |
-Spina bifida occulta | - | - | - | - | - | - |
- Unclassified closed spina bifida | 3 (3.45) | - | - | - | - | - |
-Unclassified NTD | - | - | - | - | - | - |
Ventriculomegaly | 24 (27.59) | 4 (4.60) | 5 (5.75) | 5 (5.75) | - | 3 (3.45) |
Holoprosencephaly | 7 (8.05) | 7 (8.05) | 3 (3.45) | - | - | 1 (1.15) |
Microcephaly | 2 (2.30) | 2 (2.30) | - | 1 (1.15) | - | - |
Cysts |
- arachnoid cyst | 1 (1.15) | 1 (1.15) | - | - | - | - |
- choroid plexus cyst | - | - | 6 (6.90) | 1 (1.15) | - | - |
Cystic hygroma | 7 (8.05) | 1 (1.15) | - | - | 5 (5.75) | - |
Chiari Type II malformation | 2 (2.30) | - | 1 (1.15) | - | - | - |
Dandy Walker malformation | 5 (5.75) | 4 (4.60) | 4 (4.60) | - | - | - |
Cerebellar disorder | 5 (5.75) | 1 (1.15) | - | 1 (1.15) | - | - |
Megacisterna magna | 3 (3.45) | - | 6 (6.90) | - | - | 1 (1.15) |
Agenesis of corpus callosum (ACC) | 2 (2.30) | 1 (1.15) | - | 1 (1.15) | - | - |
Other spinal malformations | 7 (8.05) | 1 (1.15) | - | - | - | - |
Miscellaneous |
-sacrococcygeal teratoma | - | - | - | - | - | - |
-cerebral atrophy | - | - | - | - | - | - |
-wide CSP | - | - | 1 (1.15) | - | - | - |
-absent CSP | 1 (1.15) | - | 2 (2.30) | - | - | - |
-megalencephaly | - | - | - | - | - | - |
-hydranencephaly | - | - | - | - | - | - |
-intracranial haemorrhage | - | - | - | - | - | - |
-intracranial tumour | - | - | - | - | - | - |
CNS central nervous system, CSP cavum septi pellucidi
We identified 279 fetuses for whom the obstetric outcomes could be found from retrospective tracing (Table
4). The survival of anomalous fetuses was only achieved in 139 (49.82%) due to the high rate of induced TOP (
n=105, 37.63%) with additional 35 (12.54%) spontaneous fetal demise (8 intrauterine fetal death; 27 stillbirths). Moreover, 36 (25.90%) of the neonates died in the first month after birth, 3 (2.16%) of them survived till less than 6 months in life and 4 (2.88%) infants were alive for more than 6 months but less than a year. Only 75 (53.96%) live births remained alive after 2 years since birth. 21 (15.11%) live births were lost to follow-up, thus their survival durations remained undetermined.
Table 4
Obstetric outcomes in 279 fetuses
Neural tube defect |
- Anencephaly | 22 | 9 | - | 2 | - | 3 | - | - | - | - |
- Encephalocele | 10 | 3 | - | 2 | - | - | - | - | 3 | 1 |
-Meningocele | - | - | - | - | - | - | - | - | 1 | - |
-Myelomeningocele | 3 | - | - | 1 | 3 | - | - | - | 6 | 3 |
-Spina bifida occulta | - | - | - | - | - | - | - | - | 1 | - |
- Unclassified closed spina bifida | - | - | - | - | - | - | - | - | 1 | - |
-Unclassified NTD | 2 | 2 | - | 1 | 1 | - | - | - | 6 | - |
Ventriculomegaly | 4 | 8 | - | 7 | 14 | 3 | 4 | - | 45 | 11 |
Holoprosencephaly | 6 | 4 | 1 | 2 | 8 | - | - | - | 3 | 1 |
Microcephaly | 2 | 1 | - | 1 | 4 | - | - | - | - | 1 |
Cysts |
- arachnoid cyst | - | - | - | 2 | 1 | - | - | - | 2 | - |
- choroid plexus cyst | 2 | 1 | - | 1 | 1 | - | - | - | 2 | - |
Cystic hygroma | 18 | 1 | 6 | 3 | 1 | - | - | - | 8 | 3 |
Chiari Type II malformation | 3 | 3 | - | 2 | 1 | - | - | - | 7 | 1 |
Dandy Walker malformation | - | 3 | - | 5 | 4 | - | - | - | 4 | 1 |
Cerebellar disorder | - | 2 | 1 | 2 | 3 | 2 | 1 | - | 3 | - |
Megacisterna magna | - | 2 | - | 2 | 2 | 1 | - | - | 4 | 1 |
Agenesis of corpus callosum | 3 | 4 | - | - | 2 | - | 1 | - | 3 | 1 |
Other spinal malformations | 8 | 4 | - | 3 | 5 | - | - | - | 1 | 2 |
Miscellaneous |
-sacrococcygeal teratoma | 1 | - | - | - | - | - | - | - | 2 | 1 |
-cerebral atrophy | - | - | - | - | - | 1 | - | - | 1 | - |
-wide CSP | - | - | - | 1 | - | - | - | - | 1 | - |
-absent CSP | 1 | - | - | - | 1 | - | - | - | 3 | - |
-megalencephaly | - | - | - | - | - | - | - | - | 1 | - |
-hydranencephaly | - | - | - | - | 1 | - | - | - | - | - |
-intracranial haemorrhage | - | - | - | - | 1 | - | - | - | - | - |
-intracranial tumour | - | - | - | - | - | - | - | - | - | - |
CNS central nervous system, CSP cavum septi pellucidi, SB stillbirth, LB live birth, wks weeks, mths months
Follow-up data on delivery methods were available for 257 fetuses involved in the study. The fetuses were delivered at the average GA of 30.90±8.49 weeks. In specific, the mean GA for elective TOP, intra-uterine fetal loss, and live births were 21.93±5.99 weeks, 30.71±7.32 weeks, and 37.15±2.71 weeks respectively. In 124 cases of elective and spontaneous termination of pregnancy, 115 (92.74%) cases were performed vaginally via medical induction and 9 (7.26%) cases required surgical evacuation on the conception. On the other hand, live births were delivered more frequently through Caesarean section (n=78, 58.65%) than vaginal delivery (n=55, 41.35%).
139 surviving infants were classified according to their respective functional status based on two-year neurodevelopmental assessments (Table
5). Normal neurologic development was achieved in 32 (23.02%) children. Functionally abnormal children included 14 (10.07%) cases with pure motor disability, 9 (6.47%) cases with pure mental disability as well as 31 (22.30%) children with both motor and intellectual impairments. The remaining 53 (38.13%) children did not have any significant abnormality detected before they defaulted neurodevelopmental follow-up or passed away before 2 years old, therefore classified as “lost to follow-up” in Table
5. Among those children with neurological deficit, 17 (31.48%) of them had complete paralyzation, 11 (20.37%) of them experienced bladder and/or bowel incontinence, 7 (12.96%) of them had concomitant psychiatric disorder, 7 (12.96%) of them suffered from epilepsy, 6 (11.11%) of them had hearing loss, and 12 (22.22%) of them were reported to have vision problems.
Table 5
Two-year neurodevelopmental outcomes of 139 surviving infants
Neural tube defect |
- Anencephaly | - | - | - | - | 3 |
- Encephalocele | - | 1 | 1 | 2 | - |
-Meningocele | - | - | - | 1 | - |
-Myelomeningocele | 1 | 3 | - | 3 | 5 |
-Spina bifida occulta | 1 | - | - | - | - |
- Unclassified closed spina bifida | - | 1 | - | - | - |
-Unclassified NTD | 2 | 3 | - | 1 | 1 |
Ventriculomegaly | 16 | 9 | 7 | 19 | 26 |
Holoprosencephaly | - | 2 | - | 2 | 8 |
Microcephaly | - | - | - | 1 | 4 |
Cysts |
- arachnoid cyst | 2 | - | - | - | 1 |
- choroid plexus cyst | 1 | - | - | 1 | 1 |
Cystic hygroma | 8 | - | - | 2 | 2 |
Chiari Type II malformation | 1 | 3 | - | 3 | 2 |
Dandy Walker malformation | 2 | - | 1 | 1 | 5 |
Cerebellar disorder | - | - | - | 3 | 6 |
Megacisterna magna | 1 | 1 | - | 3 | 3 |
Agenesis of corpus callosum | - | 2 | - | 3 | 2 |
Other spinal malformations | 1 | - | - | 1 | 6 |
Miscellaneous |
-sacrococcygeal teratoma | 1 | 1 | - | - | 1 |
-cerebral atrophy | - | - | - | 1 | 1 |
-wide CSP | - | - | - | 1 | - |
-absent CSP | - | - | - | 3 | 1 |
-megalencephaly | - | - | - | 1 | - |
-hydranencephaly | - | - | - | - | 1 |
-intracranial haemorrhage | - | - | - | - | 1 |
-intracranial tumour | - | - | - | - | - |
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