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

Carbamazepine

Risk to Fetus

In animals. Evidence indicates that carbamazepine crosses the placenta and its concentration in cord blood equals that in maternal serum.[104] In several animal reproductive studies, the use of carbamazepine at doses higher than the recommended dose in humans has been associated with teratogenic effects in rats and mice. These include cleft palate and clubfoot[97,105,106]; fetotoxic effects in mice, such as reduced fetal body weight and brain weight[105,107]; embryotoxic effects, such as cardiovascular anomalies in chick embryos[108]; neural tube defects in rat and mouse embryos[109,110]; and retardation of growth and development in rat embryos.[109]

In humans. Adequate studies have not yet been done to determine the risk of teratogenicity during pregnancy. However, many authors describe a twofold to threefold increase in the frequency of malformations in offspring exposed to carbamazepine during the first trimester when compared with the general population.[76,111,112,113]

An association between spina bifida and monotherapy or combination therapy with carbemazepine during gestation has been noted.[80,114,115,116] Rosa[116] studied a cohort of 1,490 pregnant women treated with antiepileptic drugs. Of the four infants with spina bifida, three had been exposed to carbamazepine. In one case, the mother was taking valproate in addition to carbamazepine. Rosa's review of all known maternal antiepileptic cohorts receiving carbamazepine revealed a tenfold increase in spina bifida compared with the general population and an absolute risk of spina bifida of 1% without the confounding effect of valproate.[116]

Combination therapy with carbamazepine during gestation, particularly along with valproate, has been associated with a higher frequency of congenital anomalies than treatment with carbamazepine alone.[97,117,118] In one report, 10 of 21 infants exposed to carbamazepine alone (n = 15) or in combination with other medication (n = 6) showed phenotypic abnormalities, such as round facies, hypertelorism, upslanting palpebral fissures, hypoplastic nasal bridge, nevus flammeus, large anterior fontanelle, and hypoplasia of nails.[117] Two infants had microcephaly manifested postnatally. Kaneko et al[118] reported seven malformations among 45 patients treated with carbamazepine and another drug during gestation. Sutcliffe et al[119] described 4 neonates born to mothers taking carbamazepine during pregnancy; 2 had bilateral severe microphthalmos, 1 had bilateral anophthalmos, and 1 had unilateral optic disk coloboma.

Hiilesmaa et al[120] reported a study of 133 epileptic pregnant women with matched controls, which showed that gestational carbamazepine was associated with a 10 mm decrease in fetal head circumference when compared with controls and that catch-up growth of the head was not observed by the age of 18 months. Bertollini et al[121] found an association between prenatal exposure to carbamazepine and reduction in head circumference, body length, and overall birth weight.

Kuhnz et al[122] reported that among 11 infants of mothers taking carbamazepine, 1 had major anomalies while the rest had minor anomalies, which were much less severe than those associated with other antiepileptics. Jones et al[123] observed craniofacial defects, fingernail hypoplasia, and developmental delay in the eight children retrospectively ascertained to have been exposed to carbamazepine in utero. This was confirmed by similar findings in a study of 35 children of women exposed to carbamazepine monotherapy during gestation. This prospective study showed facial abnormalities in 11%, developmental delay in 20%, and hypoplastic nails in 26%.

Gaily et al[124] observed that the prevalence of mental delay is the same or slightly increased among infants of epileptic mothers compared with the general population. The frequency of specific cognitive dysfunction was not higher than that expected in a group of 30 of these children who were tested.[125] In another study, the frequencies of neurologic dysfunction and school problems were no higher for 23 children between 6 and 13 years exposed in utero to carbamazepine.[126] However, most of the literature suggests increased developmental delay[123,127,128] and lower intelligent quotient scores[125,129] among children exposed in utero to carbamazepine. These findings were attributed to an epoxide intermediate of carbamazepine.[129]

Carbamazepine, like valproate, may cause deficiency of vitamin K during the latter half of gestation, leading to an abnormal coagulation profile that may result in uncontrolled bleeding. Bleeding in the central nervous system may cause permanent neurologic damage. Therefore, maternal vitamin K supplementation is necessary.[89]

To summarize, carbamazepine should be considered as a suspected human teratogen.[123] Monotherapy is less teratogenic than combination therapy.[96,97] Carbamazepine exposure in utero causes major and minor congenital anomalies and other adverse effects such as developmental problems, growth retardation, subnormal IQ, and bleeding disorders in the fetus and newborn. Hence, carbamazepine should not be used by pregnant women especially during the sensitive phase of organogenesis in the first trimester.

Risk to Infant During Breast-Feeding

Carbamazepine is detected in breast milk[104,130] but is not found in quantifiable amounts. There have been two clinical reports of transient hepatic toxicity such as cholestasis and jaundice in breast-feeding infants associated with the maternal use of VPA.[131,132] Also, seizure-like activity,[133] drowsiness, irritability, refusal to feed, and a high-pitched cry[134] have been reported in breast-fed 3-week-old and 10-week-old infants whose mothers were taking carbamazepine along with other drugs, though a causal relationship could not be established. In contrast, one study revealed no adverse outcomes in 94 infants exposed to carbamazepine while nursing.[104]

Therefore, if a woman wishes to continue breast-feeding while taking carbamazepine, concentrations of drug and its metabolite 10,11-epoxide in her plasma and breast milk and in the infant's plasma should be monitored. If the infant has adverse reactions such as hepatic and central nervous system dysfunction, nursing should be discontinued, at least temporarily. Neonatal acquisition via nursing does not seem to be harmful for the neonate, and weighing the benefits of breast-feeding against the potential risk, breast-feeding during maternal carbamazepine therapy is considered safe.

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