Population-based study of antiepileptic drug exposure in utero—Influence on head circumference in newborns

PURPOSE To study the effect of AED exposure on head circumference in the newborn. METHODS Data on all Swedish singletons births between 1995 and 2005, over 900,000 births, were obtained from the Swedish Medical Birth Registry. The effects of AEDs on birth-weight-adjusted mean head circumference (bw-adj-HC) were estimated by comparison with data from all births in an analysis which was adjusted for year of birth, maternal age, parity, maternal smoking, and maternal body mass index. RESULTS A significant reduction of mean bw-adj-HC was seen after both carbamazepine (CBZ) (standard deviation scores (SDS)=0.15, p<0.001) and valproic acid (VPA) (SDS=0.10, p=0.04) in monotherapy. No effect on mean bw-adj-HC was seen for phenytoin, clonazepam, lamotrigine and gabapentin. There was a significant increase in the occurrence of microcephaly (bw-adj-HC smaller than 2 SD below the mean) after any AED polytherapy (OR=2.85, 95% CI: 1.74-4.78) but not after AED monotherapy or monotherapy with CBZ or VPA. CBZ or VPA was taken by 71% of the pregnant mothers on AED, and the usage increased over time. CONCLUSIONS CBZ and VPA in monotherapy during pregnancy reduce mean bw-adj-HC. AED polytherapy increases the rate of microcephaly but no significant effect is seen of AED monotherapy. The possible significance for the further development of the child is uncertain but should be explored.