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Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate

From the Department of Obstetrics and Gynecology (Drs. R. Kaaja, Matila, and Hiilesmaa, and E. Kaaja), Helsinki University Central Hospital, and Division of Pharmacology and Toxicology (E. Kaaja), Department of Pharmacy, University of Helsinki, Finland.

Address correspondence and reprint requests to Dr. V. Hiilesmaa, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Box 140, 00029 HYKS, Finland; e-mail: ville.hiilesmaa{at}hus.fi

Background: Case reports suggest that maternal hepatic enzyme-inducing antiepileptic drugs (AED) increase the risk for neonatal bleeding. Antenatal administration of vitamin K₁ to mothers using these drugs therefore is widely recommended. There are, however, no studies on the incidence of this complication.

Objective: To assess the occurrence of bleeding complications in newborns exposed to maternal enzyme-inducing AED in utero.

Methods: The authors prospectively followed 662 pregnancies in women with epilepsy who used enzyme-inducing AED. Of the 667 neonates, 463 were exposed to carbamazepine, 212 to phenytoin, 44 to phenobarbital, 11 to primidone, and 7 to oxcarbazepine. The control subjects were 1,324 nonepileptic pregnancies (1,334 neonates) matched for maternal age, parity, number of fetuses, and delivery date. None of the mothers received vitamin K₁ during pregnancy, but all infants received 1 mg vitamin K₁ intramuscularly at birth.

Results: A bleeding complication was observed in five (0.7%) of the offspring exposed to maternal enzyme-inducing AED and in five (0.4%) control subjects (p = 0.3). After logistic regression analysis was performed, bleeding was associated with birth at <32 weeks of gestation (adjusted OR = 13; 95% CI = 2.7 to 64) and alcohol abuse (adjusted OR = 17; 95% CI = 1.8 to 162) but not with exposure to enzyme-inducing AED (adjusted OR = 1.1; 95% CI = 0.3 to 4.6; p = 0.8).

Conclusions: These data do not support the hypothesis that maternal enzyme-inducing AED increase the risk for bleeding in the offspring. Antenatal administration of vitamin K to these mothers may still be needed in selected cases.

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