Effects of Antimanic Mood-Stabilizing Drugs on Fetuses, Neonates, and Nursing Infants

Mohammad Masud Iqbal, MD, MPH, MSPH, DTM; Sai Prakash Gundlapalli, MD, William G. Ryan, MD, Thad Ryals, MD, Birmingham, Ala; Terry E. Passman, MD, Department of Psychiatry and Behavioral Neurobiology, the Regional Neonatal Intensive Care Unit, and the Department of Epidemiology and International Health, University of Alabama at Birmingham School of Medicine; and the Harbor Unit, Thomas Hospital, Fairhope, Ala

South Med J. 2001;94(3) 

In This Article

Lamotrigine

Risk to Fetus

In animals. Studies in rats and rabbits indicate that lamotrigine crosses the placenta, yielding placental and fetal levels comparable with those in maternal plasma. No teratogenic effects were seen in animal studies using increasing doses, up to 1.2 times an equivalent human dose of 500 mg/day. However, rats receiving up to 0.5 times an equivalent human dose of 500 mg/day produced offspring with decreased fetal folate concentrations, an effect known to be associated with teratogenicity in humans and animals. In addition, an increase in stillbirths and postnatal deaths was noted among offspring of rats receiving lamotrigine at doses less than half the equivalent human dose of 500 mg/day and was attributed to in utero exposure to lamotrigine. The clinical significance of these effects is unknown.[136,138]

In humans. Evidence indicates that lamotrigine crosses the placenta. One report noted a decrease in plasma level of lamotrigine as pregnancy progressed.[139] The ratio of dose to plasma concentration was 5.8 times higher at delivery and 3.6 times higher in late pregnancy as compared with 5 months postpartum, suggesting clearance of lamotrigine during pregnancy. The ratio of umbilical cord to maternal plasma level was 1.2, indicating extensive placental passage of lamotrigine.[139] In another report,[140] maternal plasma lamotrigine concentrations were similar to those in the umbilical cord, and the lamotrigine plasma concentration in the newborn slowly declined. There are still no well-controlled studies of lamotrigine therapy in pregnant women to determine fetal risk.[136,141] Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lamotrigine is a dihydrofolate reductase inhibitor, and it decreases fetal folate levels in rats. Therefore, folic acid supplementation should be considered for all women of child-bearing potential who are taking lamotrigine.[141] To facilitate monitoring outcomes of pregnant women exposed to lamotrigine, physicians are encouraged to register them in the Antiepileptic Drug Pregnancy Registry.[135,136]

Risk to Infant During Breast-Feeding

Considerable amounts of lamotrigine are excreted in breast milk.[135,136,139,140,141,142,143] In the four reports dealing with breast-feeding infants exposed to lamotrigine and the amount of lamotrigine in breast milk, the milk to maternal serum ratio was approximately 0.6 in all of the cases, with a range of 0.3 to 0.6 in the first case.[139,142,143] The first infant, followed up for 5 months postpartum, had an estimated daily intake of 2 to 5 mg of lamotrigine, with serum levels ranging from 2.8 µmol/L (at 2 days after birth and exclusively breast-fed) to less than 0.2 µmol/L (when feeding was supplemented with formula in a 3:1 ratio).[142] The second report noted that plasma lamotrigine concentration in the newborn at 48 hours after birth was similar to the plasma levels of the mother at delivery and in the umbilical cord. The ratio of milk to plasma concentration was 0.6 2 weeks after delivery and the plasma concentration was 25% of the mother's plasma level.[139] The third report showed that the serum levels of three infants were 23% to 33% of the maternal serum levels.[143] The fourth report showed slow decline in the lamotrigine plasma concentration in 10 newborns of nine pregnant women.[140] At 72 hours postpartum, median lamotrigine plasma levels in the infants were 75% of the cord plasma levels (range, 50% to 100%). The median milk/plasma concentration ratio was 0.61 (range, 0.47 to 0.77) 2 to 3 weeks after delivery, and nursed infants maintained lamotrigine plasma concentrations of 30% (median, range, 23% to 50%) of the mother's plasma levels. None showed any adverse effects. Nonetheless, exposure of breast-feeding infants to lamotrigine is of some potential concern because of the increased risk of severe life-threatening rashes in children receiving the drug for mood disorder. Therefore, physicians should be alert for lamotrigine's possible side effects, and if they are observed, breast-feeding should be discontinued.

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