Sedative
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The effects of benzodiazepines, including chlordiazepoxide, on the human embryo and fetus are controversial. Although some studies have reported an association with various types of congenital defects, other studies have not found such associations. Maternal denial of exposure and concurrent exposure to other toxic drugs and substances (e.g., alcohol and smoking) may be confounding factors. If the drug does cause birth defects, the risk appears to be low. Continuous use during gestation has resulted in neonatal withdrawal, and depression of the newborn may occur if chlordiazepoxide is used close to birth. Consequently, if the maternal condition requires the use of the drug during pregnancy, the lowest possible dose should be taken. Moreover, abrupt discontinuance of chlordiazepoxide should be avoided. Severe withdrawal symptoms (physical and psychological) may occur in the mother and could result in the substitution of other substances (e.g., alcohol) to treat the symptoms. Fetal withdrawal, such as that observed with narcotics, has not been reported, but should be considered.
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 fourfold 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 1254 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 (4–8). The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 257 of whom 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 2048 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 (11–13). 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).
BREASTFEEDING SUMMARY
No reports describing the use of chlordiazepoxide during human lactation 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 breastfeeding.
References
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14.Duckman S, Spina T, Attardi M, Meyer A. Double-blind study of chlordiazepoxide in obstetrics. Obstet Gynecol 1964;24:601–5.
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