Sedative
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Few indications exist for meprobamate in the pregnant woman. If therapy is required, avoiding the 1st trimester is the safest course, but inadvertent exposure does not appear to represent a major risk. Two large surveillance studies did not support the associations with defects reported in earlier studies. In those studies, the defects may have occurred by chance or have been caused by unidentified factors. Moreover, meprobamate is the active metabolite of the central acting muscle relaxant, carisoprodol. That agent has been used in pregnancy without causing birth defects (see Carisoprodol). Nevertheless, until additional data are available, avoiding meprobamate in the 1st trimester is best.
FETAL RISK SUMMARY
Meprobamate is used in the treatment of anxiety disorders or for the short-term treatment of the symptoms of anxiety. It has hypnotic, sedative, and sedative-related muscle-relaxant properties (1). It is partially metabolized to inactive metabolites before excretion in the urine. Meprobamate also is the active metabolite of carisoprodol (see Carisoprodol). The elimination half-life is in the range of 6–17 hours, but may be prolonged after chronic administration (1).
Schardein (2) reviewed seven reproduction studies in mice, rats, and rabbits. Meprobamate caused digital defects in mice and neurobehavior toxicity in rats. However, because most of the studies involved parenteral administration, the findings cannot be used to assess the degree of human risk (2).
Meprobamate crosses the placenta to the fetus and has been measured in umbilical cord blood at or near maternal plasma levels (3). The low molecular weight (about 218) and long elimination half-life are in agreement with that finding.
Four reports have associated the use of meprobamate in pregnancy with an increased risk of congenital anomalies (4–7). In a study of 395 patients (402 live births) who took meprobamate during pregnancy, 115 infants had been exposed during the 1st trimester (4). Ten of the 115 infants had birth defects, but only 5 of the defects, all involving different defects of the heart, could be potentially related to drugs or other unidentified factors. The other non-meprobamate-related defects were Down’s syndrome, partial deafness (a toxicity not known to be associated with meprobamate), deformed elbows and joints (a probable deformation), and two unspecified defects. A second report described multiple anomalies, including congenital heart defects, in a newborn exposed to meprobamate (5). The mother of this patient was treated very early in the 1st trimester with meprobamate and propoxyphene. Malformations observed were omphalocele, defective anterior abdominal wall, defect in diaphragm, congenital heart disease with partial ectopic cordis secondary to sternal cleft, and dysplastic hips. Multiple defects of the eye and central nervous system were observed in a newborn exposed to multiple drugs, including meprobamate and lysergic acid diethylamide (LSD) (6). A brief 1975 report summarized the findings of a combined England–France study on the fetal effects of tranquilizers (7). Of the 84 women that took meprobamate during the 1st trimester, 4 delivered infants with congenital malformations. None of the defects were cardiac malformations. In addition, three of the four mothers had experienced a previous pregnancy with a poor outcome (abortion, stillbirth, or malformation) (7).
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 356 of whom were exposed in the 1st trimester to meprobamate (8). No association of meprobamate with large classes of malformations or to individual defects was found. In a follow-up to this study, there was no evidence that exposure to meprobamate in the 1st trimester was related to congenital malformations (20 of 356 infants; expected 17.4; ns), deaths (stillbirth to the fourth birthday), adverse effects on mental and motor scores at the age of 8 months, or intelligence quotient scores at 4 years of age (9). Others also have failed to find a relationship between the use of meprobamate and congenital malformations (10).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 75 newborns had been exposed to meprobamate during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (4.0%) major birth defects were observed (three expected), including (observed/expected) 1/0 oral cleft and 2/0 polydactyly. No anomalies were observed in four other defect categories (cardiovascular defects, spina bifida, limb reduction defects, and hypospadias) for which specific data were available. Only with the cases of polydactyly is there a suggestion of a possible association, but other factors, such as the mother’s disease, concurrent drug use, and chance, may be involved.
A 1997 report described the pregnancy outcomes of 12 women who had taken large doses of various medications during the first postconception month and who had delivered live infants (11). Four of the cases involved the ingestion of meprobamate either alone or with other drugs. No birth defects were observed in three cases (dose and other drugs in parentheses): meprobamate (1400 mg), meprobamate (5000 mg), and meprobamate (2000 mg, plus chlordiazepoxide 25 mg). A nondrug-induced defect (bilateral undescended testis) was observed in one case in which the mother took meprobamate 1000 mg, promethazine 250 mg, diazepam 120 mg, and metoprolol 1000 mg (11).
BREASTFEEDING SUMMARY
Meprobamate is excreted into breast milk with concentrations 2–4 times that of maternal plasma (1,12). Two case reports described mothers who took carisoprodol throughout gestation and during breastfeeding. Both carisoprodol and meprobamate, the active metabolites, were found in milk. Meprobamate had the highest concentration (see Carisoprodol). The lack of detectable adverse effects in both infants suggested that the risk of toxicity is low, at least in infants that also were exposed during pregnancy. Starting meprobamate during breastfeeding may have different results in a nursing infant. Women taking meprobamate and who elect to nurse should closely monitor their infants for sedation and other changes in behavior or functions.
References
1.Sweetman SC, Editor. Martindale. The Complete Drug Reference. 34th ed. London: Pharmaceutical Press, 2005:706.
2.Schardein JL. Chemically Induced Birth Defects. 3rd ed. New York, NY: Marcel Dekker, 2000:243.
3.Product information. Miltown. Wallace Laboratories, 2000.
4.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.
5.Ringrose CAD. The hazard of neurotropic drugs in the fertile years. CMAJ 1972;106:1058.
6.Bogdanoff B, Rorke LB, Yanoff M, Warren WS. Brain and eye abnormalities: possible sequelae to prenatal use of multiple drugs including LSD. Am J Dis Child 1972;123:145–8.
7.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.
8.Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977:336–7.
9.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.
10.Belafsky HA, Breslow S, Hirsch LM, Shangold JE, Stahl MB. Meprobamate during pregnancy. Obstet Gynecol 1969;34:378–86.
11.Czeizel AE, Mosonyi A. Monitoring of early human fetal development in women exposed to large doses of chemicals. Environ Mol Mutagen 1997;30:240–4.
12.Wilson JT, Brown RD, Cherek DR, Dailey JW, Hilman B, Jobe PC, Manno BR, Manno JE, Redetzki HM, Stewart JJ. Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences. Clin Pharmacokinet 1980;5:1–66.