CHLORDIAZEPOXIDE

Fetal Risk Summary

Chlordiazepoxide is a benzodiazepine (see also Diazepam). The drug has antianxiety, sedative, appetite-stimulating, and weak analgesic actions (1).

No teratogenic effects were observed in rats given doses of 10–80 mg/kg/day through one or two matings (1). At 100 mg/kg/day, maternal toxicity (decreased interest in mating and nursing) and marked decreases in offspring viability and body weight were attributed to sedative effects of the drug (1). Moreover, at this dose, one newborn in each of two matings had major skeletal abnormalities.

In a study evaluating 19,044 live births, the use of chlordiazepoxide was associated with a greater than 4-fold increase in severe congenital anomalies (2). In 172 patients exposed to the drug during the first 42 days of gestation, the following defects were observed: mental deficiency, spastic diplegia and deafness, microcephaly and retardation, duodenal atresia, and Meckel's diverticulum (2). Although not statistically significant, an increased fetal death rate was also found with maternal chlordiazepoxide ingestion (2). A survey of 390 infants with congenital heart disease matched with 1,254 normal infants found a higher rate of exposure to several drugs, including chlordiazepoxide, in the offspring with defects (3).

In contrast, other studies have not confirmed a relationship with increased defects or mortality (4,5,6,7 and 8). The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 257 of which were exposed in the 1st trimester to chlordiazepoxide (5,8). No association with large classes of malformations or to individual defects was found.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 788 newborns had been exposed to chlordiazepoxide during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 44 (5.6%) major birth defects were observed (34 expected). Specific data were available for six defect categories, including (observed/expected) 10/7 cardiovascular defects, 2/1 oral clefts, 0/0.5 spina bifida, 3/2 polydactyly, 1/1 limb reduction defects, and 2/2 hypospadias. These data do not support an association between the drug and congenital defects.

A 1992 study reported on heavy benzodiazepine exposure during pregnancy from Michigan Medicaid data collected during 1980 to 1983 (9). Of the 2,048 women, from a total sample of 104,339, who had received benzodiazepines, 80 had received 10 or more prescriptions for these agents. The records of these 80 women indicated frequent alcohol and substance abuse. Their pregnancy outcomes were 3 intrauterine deaths, 2 neonatal deaths in infants with congenital malformations, and 64 survivors. The outcome for 11 infants was unknown. Six of the surviving infants had diagnoses consistent with congenital defects (9). The investigators concluded that the high rate of congenital anomalies was suggestive of multiple alcohol and substance abuse and may not have been related to benzodiazepine exposure (9).

Neonatal withdrawal consisting of severe tremulousness and irritability has been attributed to maternal use of chlordiazepoxide (10). The onset of withdrawal symptoms occurred on the 26th day of life. Chlordiazepoxide readily crosses the placenta at term in an approximate 1:1 ratio (11,12 and 13). The drug has been used to reduce pain during labor, but the maternal benefit was not significant (14,15). Marked depression was observed in three infants whose mothers received chlordiazepoxide within a few hours of delivery (13). The infants were unresponsive, hypotonic, hypothermic, and fed poorly. Hypotonicity persisted for up to a week. Other studies have not seen depression (11,12).

Breast Feeding Summary

No reports describing the use of chlordiazepoxide during human lactation or measuring the amount, if any, excreted into breast milk have been located. The molecular weight (about 300) is low enough, however, that passage into milk should be expected. Moreover, other benzodiazepines are excreted into milk and have produced adverse effects in nursing infants (see Diazepam). Because of the potential for drug accumulation and toxicity in nursing infants, chlordiazepoxide should be avoided during breast feeding.

References

1. Product information. Librium. ICN Pharmaceuticals, 2000.
2. Milkovich L, van den Berg BJ. Effects of prenatal meprobamate and chlordiazepoxide hydrochloride on human embryonic and fetal development. N Engl J Med 1974;291:1268–71.
3. Rothman KJ, Fyler DC, Golblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109:433–9.
4. Crombie DL, Pinsent RJ, Fleming DM, Rumeau-Rouguette C, Goujard J, Huel G. Fetal effects of tranquilizers in pregnancy. N Engl J Med 1975;293:198–9.
5. Hartz SC, Heinonen OP, Shapiro S, Siskind V, Slone D. Antenatal exposure to meprobamate and chlordiazepoxide in relation to malformations, mental development, and childhood mortality. N Engl J Med 1975;292:726–8.
6. Bracken MB, Holford TR. Exposure to prescribed drugs in pregnancy and association with congenital malformations. Obstet Gynecol 1981;58:336–44.
7. Committee on Drugs, American Academy of Pediatrics. Psychotropic drugs in pregnancy and lactation. Pediatrics 1982;69:241–4.
8. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:336–7.
9. Bergman U, Rosa FW, Baum C, Wiholm B-E, Faich GA. Effects of exposure to benzodiazepine during fetal life. Lancet 1992;340:694–6.
10. Athinarayanan P, Pierog SH, Nigam SK, Glass L. Chlordiazepoxide withdrawal in the neonate. Am J Obstet Gynecol 1976;124:212–3.
11. Decancq HG Jr, Bosco JR, Townsend EH Jr. Chlordiazepoxide in labour: its effect on the newborn infant. J Pediatr 1965;67:836–40.
12. Mark PM, Hamel J. Librium for patients in labor. Obstet Gynecol 1968;32:188–94.
13. Stirrat GM, Edington PT, Berry DJ. Transplacental passage of chlordiazepoxide. Br Med J 1974;2:729.
14. Duckman S, Spina T, Attardi M, Meyer A. Double-blind study of chlordiazepoxide in obstetrics. Obstet Gynecol 1964;24:601–5.
15. Kanto JH. Use of benzodiazepines during pregnancy, labour and lactation, with particular Reference to pharmacokinetic considerations. Drugs 1982;23:354–80.