Antiepileptic drugs in pregnancy and hemorrhagic disease of the newborn

Studies

In the 1970s and early 1980s, several studies described a possible association between maternal use of AEDs and hemorrhagic disease of newborns.7,8 These small studies suggested that the use of enzyme-inducing AEDs (eg, carbamazepine, phenobarbitone, topiramate) might induce fetal hepatic enzymes, resulting in vitamin K deficiency, and thus increase the risk of neonatal bleeding.9 In 1982, a small study recommended routine vitamin K prophylaxis for all epileptic mothers near term.8 A daily oral dose of 20 mg of vitamin K has been suggested but has not been proven to be effective.

After summarizing all available data, the American Academy of Neurology concluded in 1998 that “the prenatal administration of oral vitamin K to pregnant WWE [women with epilepsy] taking AEDs to prevent early first 24 hours of life hemorrhagic disease of the newborn is theoretically useful.”10 Prenatal vitamin K supplementation of 10 mg per day from the 36th week of gestation until delivery was suggested. Although this recommended dose of oral vitamin K was not supported by any specific study, it has been a widely accepted recommendation.

In 2002, Kaaja et al conducted the first evidence-based study of enzyme-inducing AEDs in pregnancy, analyzing 667 offspring of 452 women with epilepsy taking enzyme-inducing AEDs.11 None of the mothers received vitamin K during pregnancy, but all infants received 1 mg of vitamin K₁ intramuscularly at birth. The control subjects were 1324 nonepileptic mothers (1334 neonates) matched for maternal age, parity, number of fetuses, and delivery date. Bleeding complications were observed in 5 (0.7%) of the offspring exposed to maternal enzyme-inducing AEDs and in 5 (0.4%) control subjects (P = 0.3). After logistic regression, bleeding disorders were associated with birth at less than 32 weeks of gestation (adjusted odds ratio [AOR] 13, 95% confidence interval [CI] 2.7 to 64) and maternal alcohol abuse (AOR 17, 95% CI 1.8 to 162) but not with exposure to enzyme-inducing AEDs (AOR 1.1, 95% CI 0.3 to 4.6). This study did not support the hypothesis that maternal enzyme-inducing AEDs increased the risk of bleeding in the offspring.

In 2004, Choulika et al conducted a retrospective cohort study, analyzing 169 infants exposed to AEDs and 77 unexposed control infants.12 Only one woman had received vitamin K supplementation in the last weeks of pregnancy. Despite the lack of vitamin K supplementation in all but one woman with epilepsy at the end of the pregnancy, this study did not confirm bleeding tendencies in the infants exposed to anticonvulsant drugs: 12 (7.1%) infants in the group exposed to anticonvulsant drugs and 10 (12.9%) infants in the unexposed control group.

Conclusion

The American Academy of Neurology updated its recommendations in April 2009.13 Harden et al evaluated “the available evidence based on a structured literature review and classification of relevant articles published between 1985 and October 2007.” In their conclusion, they stated “there is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications.”13 Additionally, there is no adequate evidence that oral prenatal vitamin K supplementation in women with epilepsy diminished neonatal bleeding complications. In the clinical context, this analysis strengthens the practice of giving vitamin K at delivery to newborns exposed to enzyme-inducing AEDs in utero as is the routine practice for all newborns.