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

Clonazepam

Risk to Fetus

In animals. Ample evidence shows that clonazepam, a benzodiazepine, readily crosses the placental barrier. The reproductive toxicity of clonazepam has not been adequately evaluated in animals. However, several reproductive studies in mice, rats, and rabbits have shown no teratogenic, fetotoxic, or embryotoxic effects at usual therapeutic doses.[73,197,198] A study in rats at oral doses of 100 mg/kg of clonazepam has shown teratogenic, fetotoxic, and embryotoxic effects when administered during the period of organogenesis.[199] There is a report of long lasting immune suppression due to altered T-lymphocyte responsiveness in the offspring of rats treated with a low dose of clonazepam (1.25 mg/kg) during the third week of gestation.[200]

In humans. Adequate and well-controlled studies on teratogenicity of clonazepam have not been conducted. Clonazepam is primarily metabolized by hydroxylation, which is impaired in the newborn. The half-life of clonazepam in neonates is not known, but other benzodiazepine derivatives have half-lives two to four times longer in neonates than in adults.[201] There are a few clinical reports of teratogenic and nonteratogenic adverse effects among the children of epileptic mothers who took clonazepam during pregnancy.[201,202,203,204,205] A study conducted in Turkey observed that among 104 offspring exposed to antiepileptic drugs in utero, 12 (11.53%) showed major congenital malformations.[205] Of these 12 infants, 3 (25%) were exposed to combination therapy with clonazepam. It was coupled with phenobarbitol in two of them, while the third was exposed to primidone, phenytoin, and clonazepam. A significantly increased risk of congenital heart disease and hip dislocation was only found for clonazepam (doses of 1 to 6 mg/day) and phenobarbitol combination therapy. This was attributed to the combination therapy[206] or increased maternal mean plasma antiepileptic drug concentrations.[207] However, contrasting results were found in a study of 10,698 infants with congenital anomalies in which there was a lack of significant association between clonazepam and the anomalies.[202]

Johnson et al[208,209] described 6 cases of major malformations: 1 infant had a ureteropelvic junction obstruction, 2 infants had bilateral inguinal hernias, 1 infant had undescended testicle that required orchidopexy at 4 years of age, and 1 had both a ventricular septal defect and bilateral inguinal hernias. Haeusler et al[203] described a case of paralytic ileus of the small bowel diagnosed prenatally at 32 weeks' gestation after referral for polyhydramnios in a woman taking clonazepam and carbamazepine. All known causes for the ileus were ruled out, and it was concluded that these drugs were the most likely cause of the ileus.

There are reports of flaccidity, lethargy, respiratory difficulties, feeding difficulties, and subnormal temperature in offspring of mothers taking benzodiazepines during late pregnancy.[201,204] Fisher et al[201] described a case of neonatal apnea (with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively) in an infant born at 36 weeks to a 40-year-old multiparous myoclonic mother who took clonazepam throughout pregnancy. Six hours after birth, the infant had several episodes of apnea with cyanosis, lethargy, and hypotonia, which resolved in 10 days. The mother's serum clonazepam level at delivery was 32 ng/mL, and the cord blood level was 19 ng/mL. Follow-up at 5 months of age by neurodevelopmental examination revealed no neurologic abnormalities. Therefore, if a woman becomes pregnant during clonazepam therapy, she should be apprised of the potential hazard to the fetus, and serum clonazepam levels should be monitored during pregnancy and lactation. These infants should also be monitored for signs of central nervous system depression and apnea. Another case of respiratory depression has been reported in the newborn of a woman taking 5.5 mg of clonazepam daily during pregnancy and lactation.[204] Children born to mothers taking benzodiazepines in late gestation may be at risk of having withdrawal symptoms during the neonatal period. Consequently, clonazepam should be used during pregnancy only if the clinical benefit to the mother justifies the potential risk to the fetus.

Risk to Infant During Breast-Feeding

Like other benzodiazepines, clonazepam may be excreted in human milk in low concentrations.[201,210] A case of apnea, cyanosis, hypotonia, and excessive periodic breathing was seen in an infant fed breast milk from a clonazepam-treated mother.[201] This case prompted the authors to suggest that infants exposed to clonazepam in utero or during nursing should be monitored for central nervous system depression or apnea. Therefore, caution is advised when clonazepam is administered to nursing mothers, and it should be avoided especially when nursing premature infants.

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