Hypnotic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
A 1990 report evaluated the available published data to determine the fetal risk that occurs from exposure to various drugs (1). The risk for triazolam, based on poor data, was determined to be “none minimal.” This risk assignment was defined as “…a magnitude that patients and physicians would generally consider to be too small to influence the management of an exposed pregnancy” (1).
FETAL RISK SUMMARY
Triazolam, a short-acting benzodiazepine, is used as a hypnotic for the treatment of insomnia. Although no congenital anomalies have been attributed to the use of triazolam during human pregnancies, other benzodiazepines (e.g., see Chlordiazepoxide and Diazepam) have been suspected of producing fetal malformations after 1st trimester exposure. Because of this association, the manufacturer classifies the drug as contraindicated in pregnancy (2). In one report, the drug was not teratogenic in pregnant animals when administered in large oral doses (3).
It is not known if triazolam crosses the human placenta. 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 triazolam.
By the middle of 1988, the manufacturer had received >100 reports of in utero exposure to triazolam (J.H. Markillie, personal communication, Upjohn, 1989). Approximately one-seventh of these women were either lost to follow-up or further information was not available. Of the cases in which the outcome was known, more than one-half of the completed pregnancies ended with the delivery of a normal infant. Some of these exposures were reported in a 1987 correspondence that also included experience with alprazolam, another short-acting benzodiazepine (4). From these two sources, a total of five infants with congenital malformations have been described after in utero exposure to triazolam: extra digit on left foot and cleft uvula; incomplete closure of the foramen ovale (resolved spontaneously); small-for-gestational-age infant with left pelvic ectopic kidney; ventricular septal defect and possible coarctation of aorta (exposed to multiple drugs including triazolam); and premature, low-birth-weight infant with ventricular septal defect, pulmonary stenosis, intraventricular hemorrhage, hydrocephalus, apnea, bradycardia, anemia, jaundice, and seizure disorder (exposed to single 0.125-mg tablet at 1–2 weeks’ gestation).
Single reports received by the manufacturer of defects in infants exposed in utero to either triazolam or alprazolam include pyloric stenosis, moderate tongue-tie, umbilical hernia and ankle inversion, and clubfoot (4).
Three cases of nonmalformation toxicities have been observed in infants exposed during gestation to triazolam: tachycardia, bradycardia, respiratory pauses, hypotonia and axial hypotony, impaired arachnoid reflexes, hypothermia, sleepiness and lifeless (symptoms resolved after infant received supportive care for several days; mother took multiple medications during pregnancy); fetal distress requiring emergency cesarean section and infant resuscitation, umbilical cord wrapped around neck, seizure activity, and generalized cortical atrophy (exposed to triazolam and a second [not identified] benzodiazepine early in pregnancy and during the last week of gestation; apparent recovery with no permanent disability by 6 months of age); bradycardia, malaise, cyanosis, leukopenia, and chewing movements at 4 days of age (exposed during 3rd trimester; symptoms resolved by 1 week of age) (4).
Based on the available information, a causal relationship between triazolam and the various infant outcomes does not appear to exist. Moreover, these cases cannot be used to derive rate or incidence data, because of the probable bias involved in the reporting of pregnancy exposures to the manufacturer (4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 138 newborns were exposed to triazolam during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of seven (5.1%) major birth defects were observed (six expected). One cardiovascular defect (one expected) and one case of polydactyly (0.5 expected) were observed, but specific information on the other defects was not available. No anomalies were observed in four other categories of defects (oral clefts, spina bifida, limb reduction defects, and hypospadias) for which specific data were available. These data do not support an association between the drug and congenital defects.
BREASTFEEDING SUMMARY
No reports describing the use of triazolam during human lactation or measuring the amount excreted into milk have been located. The molecular weight (about 343) is low enough that passage into human milk should be expected. The effect of this exposure on a nursing infant is unknown, but closely related drugs are classified by the American Academy of Pediatrics as agents that may be of concern during breastfeeding (e.g., see Diazepam).
References
1.Friedman JM, Little BB, Brent RL, Cordero JF, Hanson JW, Shepard TH. Potential human teratogenicity of frequently prescribed drugs. Obstet Gynecol 1990;75:594–9.
2.Product information. Halcion. Pharmacia & Upjohn, 2008.
3.Matsuo A, Kast A, Tsunenari Y. Reproduction studies of triazolam in rats and rabbits. Iyakuhin Kenkyu 1979;10:52–67. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: The Johns Hopkins University Press, 1989:630.
4.Barry WS, St. Clair SM. Exposure to benzodiazepines in utero. Lancet 1987;1:1436–7.