Risk Factor: CM
Class: Anti-infectives/ Antituberculosis
Fetal Risk Summary
Reproduction studies with rifampin in mice and rats at doses greater than 150 mg/kg produced spina bifida in both species and cleft palates in the mouse fetuses (1). Teratogenicity in rodents has been reported with oral doses 15 to 25 times the human dose (2). Studies with pregnant rabbits revealed no evidence of teratogenicity (1).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 20 newborns had been exposed to rifampin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (one expected).
No controlled studies have linked the use of rifampin with congenital defects (3,4). One report described nine malformations in 204 pregnancies that went to term (5). This incidence, 4.4%, is similar to the expected frequency of defects in a healthy nonexposed population but higher than the 1.8% rate noted in other tuberculosis patients (5): Anencephaly (1 case) Hydrocephalus (2 cases) Limb malformations (4 cases) Renal tract defects (1 case) Congenital hip dislocation (1 case) Several reviews have evaluated the available treatment of tuberculosis during pregnancy (6,7 and 8). All concluded that rifampin was not a proven teratogen and recommended use of the drug with isoniazid and ethambutol if necessary. Other reports on the use of the agent in pregnancy have observed no fetal harm (9,10).
Rifampin crosses the placenta to the fetus (11,12 and 13). At term, the cord:maternal serum ratio ranged from 0.120.33 (12). In a second case involving pregnancy termination at 13 weeks’ gestation, the fetal:maternal ratio 4 hours after a 300-mg dose was 0.23 (11).
Rifampin has been implicated as one of the agents responsible for hemorrhagic disease of the newborn (14). In one of the three infants affected, only laboratory evidence of hemorrhagic disease of the newborn was present, but in the other two, clinically evident bleeding was observed. Prophylactic vitamin K1 is recommended to prevent this serious complication (see Phytonadione).
Rifampin may interfere with oral contraceptives, resulting in unplanned pregnancies (see Oral Contraceptives) (15).
Breast Feeding Summary
Rifampin is excreted into human milk. In one report, the concentrations were 13 g/mL with about 0.05% of the daily dose appearing in the milk (16). In another study, milk levels were 3.44.9 g/mL, 12 hours after a single 450-mg oral dose (17). Maternal plasma samples averaged 21.3 g/mL, indicating a milk:plasma ratio of about 0.20. These amounts were thought to represent a very low risk to the nursing infant (18). No reports describing adverse effects in nursing infants have been located. The American Academy of Pediatrics considers rifampin to be compatible with breast feeding (19).
- Tuchmann-Duplessis H, Mercier-Parot L. Influence d’un antibiotique, la rifampicine, sur le developpement prenatal des ronguers. C R Acad Sci (d) (Paris) 1969;269:21479. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:5589.
- Product information. Rifadin. Hoechst Marion Roussel, 2000.
- Reimers D. Missbildungen durch Rifampicin. Bericht ueber 2 faelle von normaler fetaler entwicklung nach rifampicin-therapie in der fruehsch wangerschaft. Munchen Med Wochenschr 1971;113:1690.
- Warkany J. Antituberculous drugs. Teratology 1979;20:1338.
- Steen JSM, Stainton-Ellis DM. Rifampicin in pregnancy. Lancet 1977;2:6045.
- Snider DE, Layde PM, Johnson MW, Lyle MA. Treatment of tuberculosis during pregnancy. Am Rev Respir Dis 1980;122:6579.
- American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis 1986;134:35563.
- Medchill MT, Gillum M. Diagnosis and management of tuberculosis during pregnancy. Obstet Gynecol Surv 1989;44:814.
- Shneerson JM, Frances RS. Ethambutol in pregnancy: foetal exposure. Tubercle 1979;60:1679.
- Kingdon JCP, Kennedy DH. Tuberculosis meningitis in pregnancy. Br J Obstet Gynaecol 1989;96:2335.
- Rocker I. Rifampicin in early pregnancy. Lancet 1977;2:48.
- Kenny MT, Strates B. Metabolism and pharmacokinetics of the antibiotic rifampin. Drug Metab Rev 1981;12:159218.
- Holdiness MR. Transplacental pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1987;13:1259.
- Eggermont E, Logghe N, Van De Casseye W, Casteels-Van Daele M, Jaeken J, Cosemans J, Verstraete M, Renaer M. Haemorrhagic disease of the newborn in the offspring of rifampicin and isoniazid treated mothers. Acta Paediatr Belg 1976;29:8790.
- Gupta KC, Ali MY. Failure of oral contraceptives with rifampicin. Med J Zambia 1980;15:23.
- Vorherr H. Drug excretion in breast milk. Postgrad Med J 1974;56:97104.
- Lenzi E, Santuari S. Preliminary observations on the use of a new semi-synthetic rifamycin derivative in gynecology and obstetrics. Atti Accad Lancisiana Roma 1969;13(Suppl 1):8794. As cited in Snider DE Jr, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984;144:58990.
- Snider DE Jr, Powell KE. Should women taking antituberculosis drugs breast-feed? Arch Intern Med 1984;144:58990.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.