Spectrum of prenatally detected central nervous system malformations: Neural tube defects continue to be the leading foetal malformation.

BACKGROUND &
OBJECTIVES: Prenatal diagnosis of malformations is an important method of prevention and control of congenital anomalies with poor prognosis. Central nervous system (CNS) malformations amongst these are the most common. The information about the prevalence and spectrum of prenatally detected malformations is crucial for genetic counselling and policymaking for population-based preventive programmes. The objective of this study was to study the spectrum of prenatally detected CNS malformations and their association with chromosomal abnormalities and autopsy findings.
METHODS: This retrospective study was conducted in a tertiary care hospital in north India from January 2007 to December 2013. The details of cases with prenatally detected CNS malformations were collected and were related with the foetal chromosomal analysis and autopsy findings.
RESULTS: Amongst 6044 prenatal ultrasonographic examinations performed; 768 (12.7%) had structural malformations and 243 (31.6%) had CNS malformations. Neural tube defects (NTDs) accounted for 52.3 per cent of CNS malformations and 16.5 per cent of all malformations. The other major groups of prenatally detected CNS malformations were ventriculomegaly and midline anomalies. Chromosomal abnormalities were detected in 8.2 per cent of the 73 cases studied. Foetal autopsy findings were available for 48 foetuses. Foetal autopsy identified additional findings in eight foetuses and the aetiological diagnosis changed in two of them (4.2%). INTERPRETATION &
CONCLUSIONS: Amongst prenatally detected malformations, CNS malformations were common. NTD, which largely is a preventable anomaly, continued to be the most common group. Moreover, 60 per cent of malformations were diagnosed after 20 weeks, posing legal issues. Chromosomal analysis and foetal autopsy are essential for genetic counselling based on aetiological diagnosis.

Foetal brain can be and has been prenatally imaged for a long time and prenatal diagnosis of brain anomalies is common1. The foetal central nervous system (CNS) develops during first trimester and the anatomy evolves over next two trimesters. Neural tube defects (NTDs) and other CNS malformations form the most common group of malformations detected prenatally and account for substantial proportion of all congenital abnormalities123456789. Primary prevention for spina bifida and other types of NTDs is possible by periconceptional folic acid intake10. Secondary prevention is possible by prenatal diagnosis. The purpose of this study was to analyze the spectrum of CNS malformations during a seven-year period at a tertiary care centre in north India and to relate these with chromosomal and autopsy findings. Other objective was to see the relative occurrence of NTD in prenatally detected malformations in view of the definite evidence of the efficacy of periconceptional folic acid therapy in primary prevention of NTD.

Material & Methods

The data of all pregnant women referred for ultrasonographic evaluation to the prenatal diagnostic facility of the department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, from January 2007 to December 2013 were included in the study. This study was approved by the Ethics Committee of the Institute. The cases with ultrasonographically detected major malformations were included in the study. The cases with ultrasonographically detected soft markers such as choroid plexus cyst, increased nuchal thickening and prominent cisterna magna were not included in the study. The detailed antenatal and family history including three-generation pedigree was obtained. The antenatal history, including a history of fever with rash, diabetes mellitus and exposure to teratogenic drugs, family history of miscarriages and congenital abnormalities was recorded. The ultrasonography (USG) machines used were Philips HD 11 (Philips, Netherlands) initially and Voluson E8 version (GE Healthcare, UK) from 2012 onwards. A detailed evaluation of foetal CNS and other organs was done for foetuses with CNS malformations to determine the type of CNS anomaly, associated other CNS abnormalities and other systemic malformations. Amniocentesis and foetal karyotyping were offered to all cases with anomalies. The CNS anomalies were grouped into categories, namely- NTDs, ventriculomegaly (lateral ventricle atrial width >10 mm), midline abnormalities [holoprosencephaly, agenesis of corpus callosum and Dandy-Walker malformation (DWM)], disorders of neuronal proliferation (microcephaly and macrocephaly), destructive cerebral lesions (intracranial haemorrhage and infection) and intracranial cysts. Informed consent was obtained from couple before amniocentesis. Foetal chromosomal analysis was done by traditional karyotyping after cell culture of amniotic fluid cells or postnatal cord blood cells. Foetal autopsy was performed after taking informed written consent of parents and according to the protocol which included photographs, foetal radiographs, external and internal examination and histopathological examination of foetal organs and tissues when indicated. Details of all the findings were noted from autopsy records.

Statistical analysis: The statistical analysis was done using the Statistical Package for Social Sciences software, version 15.0 (SPSS Inc., Chicago, IL, USA). Frequencies were calculated by using descriptive statistics and independent sample t test was done.

Results

During the study period, 6044 pregnancies were referred for ultrasonographic evaluation. A total of 768 (12.7%) were found to have malformations involving various systems, and of these cases, 243 (31.64%) had CNS malformations. A total of 158 foetuses were diagnosed in the second trimester and 82 in the third trimester. The most common indication for referral was suspicion or diagnosis of foetal CNS malformation (196 of 243, 80.6%). The mean age of women at the time of prenatal diagnosis was 28 yr (range 18-45 yr). In 70 cases (28.8%), prenatal diagnosis was made before 20 weeks, and in 173 cases (71.8%), the diagnosis was established after 20 wk of gestation. Fifty per cent of foetuses with anencephaly were also diagnosed after 20 wk of gestation. Diagnosis of foetal malformation was done in the first trimester in only three cases. Repeat ultrasonographic evaluation done at 15 to 16 wk confirmed the diagnosis. In 41 (16.9%) cases, there was a risk factor for foetal anomaly. Information about history of recurrent spontaneous miscarriages and factors for increased risk of malformation are given in Table I. Previous pregnancies with NTDs, and recurrent miscarriages had significant differences in a group with NTD in the current pregnancy as against non-NTD-CNS malformation group. The other risk factors observed in a significant number of cases were previous child with CNS malformation and multiple pregnancies. The rest of the risk factors were observed in a very small number of cases. Only 1.5 per cent cases with NTD were detected due to high maternal serum alpha-fetoprotein (MS-AFP), which is a biochemical marker for NTDs.

Table I

Risk factor assessment for central nervous system malformations in the study groups

The types of CNS malformations diagnosed at the time of USG are described in Table II. The most common group of anomalies were NTDs (127/243, 52.2%) followed by ventriculomegaly (63/243, 25.9%). Most of the cases with spina bifida had associated findings such as lemon sign, banana sign, ventriculomegaly, Arnold–Chiari malformation and talipes equinovarus. One case with iniencephaly and two cases with encephalocele were diagnosed in the first trimester. Fig. 1 shows various types of NTDs. The details of NTDs which were associated with other malformations are described in Table III.

Table II

Distribution of central nervous system malformations into groups and the gestational age at the time of detection

Fig. 1

Various types of neural tube defects in foetuses (A and B) anencephaly, (C and D) meningomyelocele, (E) open spina bifida without sac, (F) craniospinal rachischisis, (G and H) acrania with complete spinal rachischisis, (I and J) closed spina bifida, (K) encephalocele, (L) iniencephaly, (M) iniencephaly with spina bifida, (N) iniencephaly with encephalocele.

Table III

Details of cases with neural tube defects associated with non-central nervous system (CNS) abnormalities

Isolated ventriculomegaly was noted in 46 foetuses. Cases of ventriculomegaly associated with other CNS and non-CNS malformations are described in Tables IV and V, respectively. Malformations associated with ventriculomegaly other than NTDs and DWM were- cerebellar hypoplasia (5), periventricular calcification (2), cyst in frontoparietal region (1) and intraventricular haemorrhage (1). Other anomalies were cystic hygroma, single umbilical artery and mega cisterna magna, pyelectasis, hydrops fetalis and severe micromelia seen in one case each. Midline abnormalities such as holoprosencephaly, agenesis of corpus callosum and DWM were grouped together. There were 23 cases with DWM; 12 of them being isolated. Only five of them were referred before 20 wk of gestation. DWM was associated with mild ventriculomegaly in 10 cases. DWM associated with other CNS malformations was observed in five cases. Eleven cases of DWM had associated malformations in other systems. Chromosomal analysis was available in 10 of them and all were normal. There were four cases of aplasia of corpus callosum with associated malformations. Two of them had posterior urethral valves. One of them was from a twin pregnancy with the other twin having hydrops fetalis. In one case, with trisomy 18 there was absent stomach bubble and talipes equinovarus.

Table IV

Details of cases with ventriculomegaly associated with other central nervous system (CNS) malformations

Table V

Details of cases with ventriculomegaly associated with non-central nervous system (CNS) malformations

In 73 cases with CNS malformations, foetal karyotyping was done and of these six foetuses had chromosomal anomalies. Table VI lists details of foetuses with chromosomal abnormalities and CNS malformations. The chromosomal anomalies detected were- trisomy 21 (2), trisomy 18 (1) and chromosome 13 structural anomaly in three cases (2- chromosome 13 long arm-13q deletion and 1- balanced translocation between chromosome 2 and 13). Foetal autopsy findings were available for 48 foetuses. Foetal autopsy identified additional findings in eight of the 43 foetuses, by providing additional information about malformations or dysmorphic features. Six of them had chromosomal anomalies. Autopsy alone changed aetiological diagnosis in two cases. In one of them, USG detected DWM and polydactyly, but foetal examination after delivery showed facial dysmorphism consistent with the diagnosis of Cornelia de Lange syndrome (Fig. 2). In another case, prenatal USG detected lumbar meningocele with oligohydramnios and foetal autopsy showed sirenomelia, absent kidneys and unilateral radial ray defect. Foetal dysmorphism in first case was not detectable on prenatal ultrasound, and in the second case, the poor visibility due to oligohydramnios was the reason for missing associated limb and renal malformations.

Table VI

Details of foetuses with chromosomal abnormalities and central nervous system (CNS) malformation

Fig. 2

(A) Prenatal ultrasonography showing thickened subcutaneous space in frontal region. (B) Prenatal ultrasonography showing postaxial extra digit. (C and D) Foetus showing polydactyly and facial dysmorphism consistent with the diagnosis of Cornelia de Lange syndrome.

Discussion

Prenatal diagnosis, especially during the first half of pregnancy, provides a way of prevention of birth of an infant with major malformation with poor prognosis for survival. Here, we reviewed the data of a tertiary care centre in India regarding prenatal detection of CNS malformations. The limitations of this study were small sample size and involving a, single tertiary centre, which was not representative of general population-based data at primary or obstetric care facilities. Also, the study did not look at the sensitivity of USG-based diagnosis.

In this study, 12.7 per cent of total USG cases showed malformations and 243 of them (31.64% of total malformation) involved CNS. NTDs (52.2%), ventriculomegaly (25.9%) and midline abnormalities (18.1%) accounted for most of the CNS malformations. A study by Babu and Pasula1 had a small number of foetuses with anomalies but 45 per cent of them (17 out of 38) had CNS malformations.

The importance of accurate aetiological diagnosis for prognostication and genetic counselling and utility of chromosomal analysis and foetal autopsy has been stressed in the literature23. Foetal karyotyping and postnatal evaluation (foetal autopsy) could be done only in 28.9 and 18.9 per cent cases, respectively. Chromosomal anomalies in foetuses with CNS malformation was found in 8.2 per cent cases. It should be noted that in three of the six cases with chromosomal abnormalities had other ultrasonographically detected abnormalities whereas three cases had a single malformation on ultrasonographic evaluation. In a large study on 62,111 patients referred for ultrasound evaluation, there were 587 cases with major CNS malformations4. Holoprosencephaly had the highest prevalence of aneuploidies (2 out of 8) whereas aneuploidy was detected in 2 per cent of cases with isolated NTDs. A study on 75 cases with NTDs identified chromosomal abnormalities in nine cases3. Ultrasonographic detection of associated anomalies usually suggests poor prognosis. This is important in counselling, especially for surgically treatable malformations such as ventriculomegaly and meningocele. In this study 9.4 per cent cases with NTDs and 42.8 per cent cases of ventriculomegaly had prenatally detected other anomalies. The change in aetiological diagnosis by foetal autopsy has been evaluated in our centre previously. Autopsy-based diagnosis changed risk of recurrence significantly in 11.7 per cent of cases2. In the present study, the change in risk of recurrence by postnatal diagnosis was 4.2 per cent. This may be due to inclusion of cases with only CNS malformation and also due to actively looking for the abnormality in foetuses with risk factors and better quality USG machine.

NTDs are the most common major malformation accounting for 5 per 1000 neonates reported in 19945. High prevalence of NTDs has been reported from the various parts of India6789. The utility of periconceptional folic acid in prevention of NTDs has been documented long ago1112. Implementation of food fortification with folic acid has shown a reduction in the incidence of NTDs1314. However, in India, still NTDs continue to be the most common foetal malformation, and this preventable malformation accounts for 16.5 per cent of all malformations and 52 per cent of CNS malformations as per our findings. The risk factors for NTD such as diabetes mellitus in mother and use of teratogenic drugs were observed only in one case each. In this study, history of previous child with NTD was present in eight per cent cases of NTD, and none of them had taken periconceptional folic acid therapy. This indicates a lack of availability of genetic counselling after birth of a child with NTD. Twelve of the NTDs were associated with other malformations. Excluding these and the NTDs with other known risk factor such as teratogenic drug or maternal diabetes mellitus, 88.2 per cent cases of NTDs were isolated NTDs, which could have been perhaps prevented by periconceptional folic acid therapy. World Health Organization has advised South East Asian countries including India to take up the nationwide prevention programme of NTDs15. These data support strong and urgent need to take the food fortification with folic acid by the policymakers of India16.

The gestational age at diagnosis is important for decision about termination. Malformations such as ventriculomegaly are known to manifest after 20 wk. However, it is disturbing that 62.2 per cent NTDs were detected after 20 wk. This included 50 per cent cases of anencephaly which can be detected as early as 12-14 wk with the sensitivity of 100 per cent. This may be due to lack of expertise of ultrasonographers as well as lack of guidelines for MS-AFP and at least one ultrasonographic examination between 16 and 20 wk. There is a need of creating awareness amongst obstetricians, so that at least one detailed USG examination is performed during 16 to 20 wk of pregnancy, to rule out major malformations. However, more than 70 per cent of malformations were detected after 20 wk of gestation. The reasons included the first USG after 20 wk, but one other reason might be late manifestations of malformations such as ventriculomegaly. This stresses the urgency to look at the current medical termination of pregnancy Act 1971 (and MTP Amendment ACT 2002) of India in view of prenatal diagnostic facilities17.

In conclusion, our study highlighted the need of initiation of primary prevention of NTDs by food fortification with folic acid, better early prenatal diagnosis of malformations by adapting guideline of MS-AFP and one USG at 16-20 wk of gestation.