Risk Factor: C
Class: Anti-infectives/ Antituberculosis

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary

Fetal Risk Summary

Isoniazid is used in the prevention and treatment of pulmonary tuberculosis. Reproduction studies in mice, rats, and rabbits have not revealed teratogenic effects, but embryocidal effects were observed in rats and rabbits (1).

An official statement of the American Thoracic Society, published in 1986, recommends isoniazid as part of the treatment regimen for women who have tuberculosis during pregnancy (2). Other reviewers also consider isoniazid as part of the treatment of choice for tuberculosis occurring during pregnancy (3).

Isoniazid crosses the placenta to the fetus (4,5 and 6). In a 1955 study, 19 women in labor were given a single 100-mg dose of isoniazid 0.254.25 hours before delivery (4). The mean maternal serum concentration at birth was 0.32 g/mL compared with a cord blood level of 0.22 g/mL. The mean cord:maternal ratio was 0.73, but in 7 of the patients, cord blood concentrations exceeded those in the maternal plasma. Another study examined the placental transfer of isoniazid in two women who had been treated with 300 mg/day during the 3rd trimester (5). One hour before delivery, the women were given a single 300-mg IM dose. Mean cord blood and maternal serum concentrations were 4 and 6.5 g/mL, respectively, a ratio of 0.62. These studies and the elimination kinetics of intrauterine acquired isoniazid in the newborn were reviewed in 1987 (6).

Reports discussing fetal effects of isoniazid during pregnancy reflect multiple drug therapies. Early reports identified retarded psychomotor activity, psychic retardation, convulsions, myoclonia, myelomeningocele with spina bifida and talipes, and hypospadias as possible effects related to isoniazid therapy during pregnancy (7,8). The Collaborative Perinatal Project monitored 85 patients who received isoniazid during the 1st trimester (9, pp. 299, 313). They observed 10 malformations, an incidence almost twice the expected rate, but they cautioned that their findings required independent confirmation. For use anytime during pregnancy, 146 mother-child pairs were exposed to isoniazid, with malformations that may have been produced after the 1st trimester observed in 4 infants (9, p. 435). This was close to the expected frequency. Adverse outcomes in the fetus and newborn after intrauterine exposure to isoniazid have not been confirmed by other studies (10,11,12,13,14 and 15). Retrospective analysis of more than 4,900 pregnancies in which isoniazid was administered demonstrated rates of malformations similar to those in control populations (0.7%2.3%). A 1980 review also found no association between isoniazid and fetal anomalies (16).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 11 newborns had been exposed to isoniazid during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (9.1%) major birth defect was observed (0.5 expected), a case of polydactyly.

A case report of a malignant mesothelioma in a 9-year-old child who was exposed to isoniazid in utero was published in 1980 (17). The authors suggested a possible carcinogenic effect of isoniazid because of the rarity of malignant mesotheliomas during the first decade and supportive animal data. However, an earlier study examined 660 children up to 16 years of age and found no association with carcinogenic effects (18).

An association between isoniazid and hemorrhagic disease of the newborn has been suspected in two infants (19). The mothers were also treated with rifampin and ethambutol and in a third case, only with these latter two drugs. Although other reports of this potentially serious reaction have not been found, prophylactic vitamin K1 is recommended at birth (see Phytonadione).

In summary, isoniazid does not appear to be a human teratogen. The American Thoracic Society recommends use of the drug for tuberculosis occurring during pregnancy because, Untreated tuberculosis represents a far greater hazard to a pregnant woman and her fetus than does treatment of the disease. (2)

Breast Feeding Summary

No reports of isoniazid-induced effects in the nursing infant have been located, but the potential for interference with nucleic acid function and for hepatotoxicity may exist (20,21). Both isoniazid and its metabolite, acetylisoniazid, are excreted in breast milk (21,22 and 23). A woman was given a single oral dose of 300 mg after complete weaning of her infant (21). Both isoniazid and the metabolite were present in her milk within 1 hour with peak levels of isoniazid (16.6 g/mL) occurring at 3 hours and those of the metabolite (3.76 g/mL) at 5 hours. At 5 and 12 hours after the dose, isoniazid levels in the milk were twice the levels in simultaneously obtained plasma. Levels of acetylisoniazid were similar in plasma and milk at 5 and 12 hours. The elimination half-life for milk isoniazid was calculated to be 5.9 hours, whereas that of the metabolite was 13.5 hours. Both were detectable in milk 24 hours after the dose. The 24-hour excretion of isoniazid was estimated to be 7 mg. Two other studies also reported substantial excretion of isoniazid into human milk (22,23). A milk:plasma ratio of 1.0 was reported in one of these studies (22). In another, milk levels 3 hours after a maternal dose of 5 mg/kg were 6 g/mL (23). Doubling the maternal dose doubled the milk concentration.

Based on the above information, at least one review concluded that women can safely breast-feed their infants while taking isoniazid if, among other precautions, the infant is periodically examined for signs and symptoms of peripheral neuritis or hepatitis (20). Moreover, the American Academy of Pediatrics considers isoniazid to be compatible with breast feeding (24).



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