Children exposed to antiepileptic drugs in utero : clinical and epidemiological aspects on growth, development and occurrence of malformations

Antiepileptic drugs (AED) are known teratogenic substances. Major congenital malformations, minor anomalies, retarded intrauterine growth and delayed psychomotor development have been reported after exposure to AED in utero. Results from previous studies are inconclusive due to different study designs, therapeutic traditions, genetic and environmental factors. Aims of the study: A) To investigate the incidence of minor anomalies and psychomotor development in children born to women with epilepsy on AED treatment during pregnancy. B) To investigate foetal growth and the incidence of major congenital malformations in children exposed to AED in utero in Sweden between 1973 and 1997 by using the Swedish health registries.

One hundred prospectively collected infants, born to 136 women with carefully monitored epilepsy during pregnancy were included in the study of minor anomalies. Based on gestational age, sex and mode of delivery, each infant was matched with infants not exposed to AED in utero. The infants were examined at birth for the occurrence of minor anomalies according to a special protocol. The investigator was unaware of the exposure status of the child. The results showed a significant increase in the incidence of minor anomalies but no special dysmorphic syndromes were observed. The tests from the routinely performed neonatal screening for hypothyreosis and congenital adrenal hyperplasia were re-analysed for 34 of the matched pairs of exposed and unexposed infants. The results showed no differences between the groups. The psychomotor development was assessed with the Griffiths' test at 9 months and at 4.5-5 years of age in the children born to the women on strict treatment strategy during pregnancy (data set II). The test psychologist performed the evaluation without prior knowledge of the history of exposure status. Between the groups there was no difference in psychomotor development at 9 months of age. A subtle but significant difference in locomotor development in the children exposed to phenytoin (PHT) was observed at the 4.5-5 years follow-up. The influence on body dimensions was investigated in three different data sets collected 1973-1997.

Data set I (1973-1980) consisted of 354 children exposed to AED in utero identified retrospectively by record linkage between the Medical Birth Registry and the Hospital Discharge Registry in Sweden. Data set II (1985-1995) is the above-described data set, but here 123 of the eligible infants are included. Data set III (1995-1997) consists of 500 infants exposed to AED in utero, identified prospectively in the Medical Birth Registry. A total of 963 singleton deliveries was included. The mean values for birth weight, body length, head circumference, and pregnancy duration for the infants in the three data sets were compared with the general population (2.5 million births) after stratification for year of birth, maternal age, parity, and maternal educational level or smoking habits. The number of women with monotherapy treatment increased from 40 to 90 % over the study period. A reduction in body dimensions was observed, more marked after exposure to polytherapy. This reduction decreased over the 25-year study period. The incidence of major congenital malformations was investigated using the same three cohorts. In addition, data from the Swedish Registry of Congenital Malformations, the Child Cardiology Registry and the Hospital Discharge Registry were added. A total of 977 infants was included. There was a significant increase in the number of major congenital malformations (OR: 1.5 95% CI: 1.1-2.0).

Conclusions: There may be an association between exposure to AED in utero and a) impaired foetal growth, b) a subtle delay in motor development, c) an increased risk of major congenital malformations and d) minor anomalies in the children. Maternal treatment with monotherapy in low doses seems to have the least negative influence on the infants. The methods used in the present study do not distinguish between the effects of maternal AED treatment and genetic or environmental factors. Further follow-up studies are warranted to study subtle influences on growth and psychomotor development.

List of scientific papers

I. Wide K, Winbladh B, Guthenberg C, von Döbeln U (1996). Antiepileptic drug treatment during pregnancy and neonatal screening results. Acta Paediatr. 85(7):870-871.
https://pubmed.ncbi.nlm.nih.gov/8819557

II. Wide K, Winbladh B, Tomson T, Sars-Zimmer K, Berggren E (2000). Psychomotor development and minor anomalies in children exposed to antiepileptic drugs in utero: a prospective population-based study. Dev Med Child Neurol. 42(2):87-92.
https://pubmed.ncbi.nlm.nih.gov/10698324

III. Wide K, Winbladh B, Tomson T, Källén B (2000). Body dimensions of infants exposed to antiepileptic drugs in utero: observations spanning 25 years. Epilepsia. 41(7):854-861.
https://pubmed.ncbi.nlm.nih.gov/10897157

IV. Wide K, Henning E, Tomson T, Winbladh B (2000). Psychomotor development in preschool children exposed to antiepileptic drugs in utero. [Submitted]

V. Wide K, Winbladh B, Tomson T (2000). Major malformations in infants exposed to antiepileptic drugs during pregnancy. A nationwide registry study over 25 years. [Manuscript]