Risk Factor: DM
Class: Central nervous system drugs/ Sedatives and hypnotics
Fetal Risk Summary
Alprazolam, a member of the benzodiazepine class of agents, is used for the treatment of anxiety. Although no congenital anomalies have been attributed to the use of alprazolam during human pregnancies, other benzodiazepines (e.g., see Diazepam) have been suspected of producing fetal malformations after 1st trimester exposure. In pregnant rats, the drug produced thoracic vertebral anomalies and increased fetal death only at the highest dose (50 mg/kg) tested (1).
Researchers described the effects of alprazolam exposure on gestational day 18 (i.e., near term) on the neurodevelopment of mice in a series of reports (2,3 and 4). In one strain of mice, exposure induced persistent imbalance in the newborn and hind limb impairment in the adult offspring suggesting a defect in cerebellar development (2). In the second part of this study, in utero exposure to the drug (0.32 mg/kg orally) did not increase anxiety in adult offspring but did reduce motivation (3). A decrease in the tendency to engage in group activity and an increase in male aggression was observed in the third part of the study (4).
No data have been located on the placental passage of alprazolam. However, other benzodiazepines, such as diazepam, freely cross the placenta and accumulate in the fetus (see Diazepam). A similar distribution pattern should be expected for alprazolam.
One manufacturer has received 441 reports of in utero exposure to alprazolam or triazolam, two short-acting benzodiazepines, almost all of which occurred in the 1st trimester (5,6). Although most of the women discontinued the drugs when pregnancy was diagnosed, 24 continued to use alprazolam throughout their gestations (5). At the time of publication, about one-fifth of the 441 cases were still pregnant; one sixth had been lost to follow-up and one sixth had been terminated by elective abortion for various reasons (5). Spontaneous abortion or miscarriage (no congenital anomalies were observed in the abortuses) occurred in 16 women; two pregnancies ended in stillbirths; and one newborn infant died within 24 hours of birth. Most of the remainder of the reported exposures ended with the delivery of a normal infant. The manufacturer also received two retrospective reports of congenital defects after alprazolam exposure (5). One of the cases involved an infant with Down’s syndrome after maternal consumption of a single 5.5-mg dose of alprazolam and an unknown amount of doxepin during pregnancy (5). The second report involved a mother who ingested 0.5 mg/day of alprazolam during the first 2 months of gestation and was delivered of an infant with cat’s eye with Pierre Robin syndrome. Neither of these outcomes can be attributed to alprazolam.
A 1992 Reference reported the prospective evaluation of 542 pregnancies involving 1st trimester exposure to alprazolam gathered by a manufacturer from worldwide surveillance (7). These data were an extension of the data provided immediately above. Of the total, 131 (24.2%) were lost to follow-up. The outcome of the remaining 411 pregnancies was 42 (10.2%) spontaneous abortions, 5 (1.2%) stillbirths, 88 (21.4%) induced abortions, and 263 (64.0%) infants without and 13 (3.2%) infants with congenital anomalies. A total of 276 live births occurred, but two of these infants, both born prematurely, died shortly after birth. One, included in the group with congenital anomalies, had bilateral hydroceles and ascites, whereas the other died after intraventricular hemorrhage. The type and incidence of defects were comparable to those observed in the Collaborative Perinatal Project with no pattern of defects or excess of defects or spontaneous abortions apparent (7).
A second 1992 study reported on heavy benzodiazepine exposure during pregnancy from Michigan Medicaid data collected during 1980 to 1983 (8). 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 three intrauterine deaths, two 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. 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 (8).
Single case reports of pyloric stenosis, moderate tongue-tie, umbilical hernia and ankle inversion, and clubfoot have been received by the manufacturer after in utero exposure to either alprazolam or triazolam (5). In addition, the manufacturer has received five reports of paternal use of alprazolam with pregnancy outcomes of two normal births, one elective abortion, one unknown outcome, and one stillbirth with multiple malformations (5). There is no evidence that the drug affected any of these outcomes.
Neonatal withdrawal after in utero exposure to alprazolam throughout gestation has been reported in three infants (5, 9). In two cases involving maternal ingestion of 3 mg/day and 78 mg/day, mild withdrawal symptoms occurred at 2 days of age in the infant exposed to 3 mg/day (5). No details were provided on the onset or severity of the symptoms in the infant exposed to the higher dose. The third neonate was exposed to 1.01.5 mg/day (9). The mother continued this dosage in the postpartum interval while breast feeding. Restlessness and irritability were noted in the infant during the 1st week. The symptoms worsened 23 days after the breast feeding was stopped on the 7th day because of concerns over drug excretion into the milk. Short, episodic screams and bursts of crying were observed frequently. Treatment with phenobarbital was partially successful, allowing the infant to sleep for longer periods. However, on awakening, jerking movements of the extremities and crying continued to occur. The infant was lost to follow-up at approximately 3 weeks of age.
Breast Feeding Summary
Alprazolam is excreted into human breast milk (9). Eight lactating women, who stopped breast feeding their infants during the study, received a single 0.5-mg oral dose and multiple milk and serum samples were collected up to 36 hours after the dose. Transfer into milk was consistent with passive diffusion. The mean milk:serum concentrations ratio (using area under the drug concentration-time curve) was 0.36, indicating that a nursing infant would have received 0.35 g/kg/day, or about 3% (body weight adjusted) of the maternal dose (9).
A brief 1989 report, citing information obtained from the manufacturer, described a breast-fed infant whose mother took alprazolam (dose not specified) for 9 months after delivery but not during pregnancy (10). The mother tapered herself off of the drug over a 3-week period. The nursing infant exhibited withdrawal symptoms consisting of irritability, crying, and sleep disturbances that resolved without treatment after 2 weeks.
Because of the potent effects the drug may have on a nursing infant’s neurodevelopment, the case of probable alprazolam withdrawal, and the lethargy and loss of body weight observed with the chronic use of other benzodiazepines (see Diazepam), alprazolam should be avoided during lactation.
- Esaki K, Oshio K, Yanagita J. Effects of oral administration of alprazolam (TUS-1) on the rat fetus: experiment on drug administration during the organogenesis period. Preclin Rep Cent Inst Exp Anim 1981;7:6577. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:32.
- Gonzalez C, Smith R, Christensen HD, Rayburn WF. Prenatal alprazolam induces subtle impairment in hind limb balance and dexterity in C57BL/6 mice (abstract). Teratology 1994;49:390.
- Christensen HD, Pearce K, Gonzalez C, Rayburn WF. Does prenatal alprazolam exposure increase anxiety in adult mice offspring (abstract)? Teratology 1994;49:390.
- Rayburn W, Gonzalez C, Christensen D. Social interactions of C57BL/6 mice offspring exposed prenatally to alprazolam (Xanax) (abstract). Am J Obstet Gynecol 1995;172:389.
- Barry WS, St Clair SM. Exposure to benzodiazepines in utero. Lancet 1987;1:14367.
- Ayd FJ Jr, ed. Exposure to benzodiazepines in utero. Int Drug Ther Newslett 1987;22:378.
- St. Clair SM, Schirmer RG. First-trimester exposure to alprazolam. Obstet Gynecol 1992;80:8436.
- Bergman U, Rosa FW, Baum C, Wiholm B-E, Faich GA. Effects of exposure to benzodiazepine during fetal life. Lancet 1992;340:6946.
- Oo CY, Kuhn RJ, Desai N, Wright CE, McNamara PJ. Pharmacokinetics in lactating women: prediction of alprazolam transfer into milk. Br J Clin Pharmacol 1995;40:2316.
- Anderson PO, McGuire GG. Neonatal alprazolam withdrawalpossible effects of breast feeding. DICP Ann Pharmacother 1989;23:614.