Meningomyelocele on Exposure to Clozapine During Perinatal Period.

Use of antipsychotics in pregnancy is based on a risk-benefit analysis. Clozapine is generally used in treatment-resistant schizophrenia, and it is often less used in pregnancy. Safety of clozapine is not well studied in pregnant women. We report a case where a woman on clozapine along with folic acid supplementation gave birth to an infant with neural tube defect (NTD).

Clozapine readily crosses the placenta and is found in amniotic fluid and fetal blood.[1] A few case reports and case series have reported macrocephaly, floppy infant syndrome, cardiac arrhythmias, and neonatal seizure as teratogenic effects of clozapine.[23] We report a rare case where an NTD was detected in a new-born exposed to clozapine during the antenatal period.

CASE HISTORY

A 30-year-old woman, who had a weight of 60 kg and height of 160 cm (BMI 23), was on clozapine 225 mg for more than 2 years for treatment of schizophrenia. She was found to be pregnant after four months of amenorrhea while on clozapine 225 mg, haloperidol 2.5 mg, and multivitamin tablets (containing vitamin A 2500 IU, vitamin D3 200 IU, vitamin B1 2 mg, vitamin B2 2 mg, vitamin B6 0.5 mg, niacinamide 25 mg, calcium pantothenate 10 mg, vitamin C 50 mg and 0.2 mg of folic acid). She was symptomatic even on the regime.

Following the detection of pregnancy, clozapine was stopped, and she was on haloperidol 10 mg/day for 15 days. As the schizophrenia symptoms were worsening, within a month, clozapine was restarted and maintained at 150 mg/day.

On ultrasonography in the fifth month and at term, fetal ventriculomegaly was noticed. As her symptoms were manageable on clozapine 150 mg/day, it was continued until delivery. At the 36th week, she developed gestational diabetes and was treated with insulin.

At term, she delivered a male baby. During labor, the baby had shoulder dystocia and had a low Apgar score at one and nine minutes. At birth, the baby weighed 3.49 kg, the height was 46 cm, and the head circumference was 34.5 cm. The baby had a lumbar swelling and was diagnosed to have lumbar meningomyelocele, an open NTD [Figure 1]. The baby was admitted in the intensive care unit for further care.

Figure 1

Swelling over the lumbosacral region

DISCUSSION

This case is one where an NTD is detected on in-utero exposure to clozapine. NTD on exposure to olanzapine, another atypical antipsychotic, has been reported.[4]

In our case, the mother was on 225 mg/d of clozapine and 2.5 mg/d of haloperidol throughout her first trimester, a critical period of organogenesis. Neural tube formation occurs between the third and fourth weeks of embryogenesis.[5] Failure of closure within this period results in NTD. In a study of 11 cases who were on clozapine, two babies had congenital anomalies: one had craniosynostosis and gastroschisis, and the other baby had horseshoe kidney.[6] Macrocephaly has been reported with clozapine and olanzapine.[2]

According to the National Birth Defect Prevention Study, risk factors for NTDs include family history of NTD, obesity, pregestational diabetes, low folate, and anticonvulsant use: Together, these factors account for less than 50% of NTD.[7] Folic acid has been observed to be critical in neural tube development. Our patient, the mother, was on multivitamin supplementation containing 0.2 mg of folic acid, for about two years until her pregnancy was detected. Hence, a deficiency of folate is less likely. There are studies which have shown that vitamin supplementation during the periconceptional period reduces the risk of NTD (OR >=1.7), while folic acid supplementation was slightly more protective against spina bifida.[8]

Overweight is a risk factor for NTD. It is known that atypical antipsychotics cause weight gain, and low serum folate levels, along with overweight, may put infants of women with clozapine at high risk for NTD.[9] Amount of overall weight gain during pregnancy and serum folate levels are not available for this patient. Maternal diabetes is also a risk factor for NTD. This case had no diabetes before conception and was diagnosed to have gestational diabetes at the third trimester.

Clozapine is less studied in pregnancy or animal studies. NTD may be an effect of clozapine interfering in organogenesis. Clinicians must be vigilant about such cases. Further prospective studies are warranted to determine the safety of clozapine in pregnancy. Clozapine should be used only in difficult cases and in such situations, monitoring should be ensured.

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Conflicts of interest

There are no conflicts of interest.