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NITROFURANTOIN

Fetal Risk Summary

The antiinfective agent nitrofurantoin is commonly used in pregnancy for the treatment and prophylaxis of urinary tract infections. No reports linking the use of nitrofurantoin with congenital defects have been located.

Neither impaired fertility, teratogenicity, nor other fetal adverse effects were observed in rats and rabbits treated with nitrofurantoin before and during gestation (1,2). Doses used were up to 6 times the human dose (1). In mice, a dose 68 times the human dose (on a mg/kg basis) was associated with fetal growth retardation and a low incidence of minor and common malformations (1). When a dose 25 times the human dose was administered, fetal malformations were not observed (1). A dose 19 times the human dose (on a mg/kg basis) induced lung papillary adenomas in mice offspring, but the relationship of this to potential human carcinogenesis is unknown (1).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,292 newborns had been exposed to nitrofurantoin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 52 (4.0%) major birth defects were observed (55 expected). Specific data were available for six defect categories, including (observed/expected) 15/12 cardiovascular defects, 1/2 oral clefts, 0/2 spina bifida, 4/4 polydactyly, 3/2 limb reduction defects, and 5/3 hypospadias. These data do not support an association between the drug and congenital defects.

One manufacturer (Norwich-Eaton Laboratories) has collected more than 1,700 case histories describing the use of this drug during various stages of pregnancy (95 References) (personal communication, 1981). None of the reports observed deleterious effects on the fetus. In a published study, a retrospective analysis of 91 pregnancies in which nitrofurantoin was used yielded no evidence of fetal toxicity (3). Other studies have also supported the safety of this drug in pregnancy (4).

Nitrofurantoin is capable of inducing hemolytic anemia in glucose-6-phosphate dehydrogenase (G-6-PD)–deficient patients and in patients whose red blood cells are deficient in reduced glutathione (5). One manufacturer considers nitrofurantoin to be contraindicated in pregnant women at term (38–42 weeks' gestation), when the onset of labor is imminent, or during labor and delivery, because of the risk of hemolytic anemia in the newborn secondary to immature erythrocyte enzyme systems (glutathione instability) (1). A 1990 Reference, citing data from a manufacturer's database, mentioned nine cases of hemolytic anemia in newborns whose mothers had taken the drug late in pregnancy (6). None of the mothers or infants were tested for G-6-PD deficiency and there was no information available as to whether the mothers were also affected. A 2000 case report published in France described hemolytic anemia in a full-term newborn whose mother had taken nitrofurantoin during the last month of pregnancy (7). The authors attributed the toxicity to the drug.

Nitrofurantoin has been reported to cause discoloration of the primary teeth when given to an infant; by implication, this could occur from in utero exposure (8). However, the fact that the baby was also given a 14-day course of tetracycline, an antibiotic known to cause this adverse effect, and the lack of other confirming reports make the likelihood of a causal relationship remote (9).

In a 1995 report, 22 studies of nitrofurantoin use in pregnancy were evaluated for a meta-analysis (10). Only four of the studies met the inclusion criteria of the investigators. The pooled odds ratio for malformations after use of the drug in the 1st trimester was 1.29 (95% confidence interval 0.25–6.57). These results demonstrated no significant correlation between nitrofurantoin use in early gestation and congenital malformations (10).

When given orally in high doses of 10 mg/kg/day to young males, nitrofurantoin may produce slight-to-moderate transient spermatogenic arrest (11). The lower doses used clinically do not seem to have this effect.

In summary, nitrofurantoin is not an animal teratogen with doses close to those used in humans, and there are no data suggesting that it is a human teratogen. However, there appears to be risk of hemolytic anemia in newborns, including those who are not G-6-PD deficient, who are exposed in utero to nitrofurantoin close to delivery. Although the incidence is unknown, the rare reports of this toxicity combined with the popularity of the drug for urinary tract infections in pregnant women suggests that the risk is rare. The safest course, however, would be to avoid nitrofurantoin close to delivery.

Breast Feeding Summary

Nitrofurantoin is excreted into breast milk. In one study, the drug could not be detected in 20 samples from mothers receiving 100 mg 4 times daily (12). In a second study, nine mothers were given 100 mg every 6 hours for 1 day, then either 100 mg or 200 mg the next morning (13). Only two of the four patients receiving the 200-mg dose excreted measurable amounts of nitrofurantoin, 0.3–0.5 µg/mL. Although these amounts are negligible, the authors cautioned that infants with G-6-PD deficiency may develop hemolytic anemia from this exposure (13).

A 2001 study concluded that nitrofurantoin is actively transported into milk by an unknown mechanism, resulting in a milk:plasma (M:P) ratio of 6.21 ± 2.71 (14). The observed M:P ratio was about 22-fold greater then the predicted ratio (0.28) that was determined in the study. Four lactating women, who did not breast feed during the study, were given a single 100-mg capsule of nitrofurantoin macrocrystals with a standardized high-fat breakfast. Nine serum and milk samples were drawn after the dose over a 12-hour interval. The mean milk drug concentration in each patient during the 12-hour interval was approximately 1.3 µg/mL. Based on this, the investigators estimated that, if a 60-kg woman was taking 100 mg twice daily, the infant dose would be 0.2 mg/kg, or about 6% of the mother's weight-adjusted dose. Although this exposure was thought to be low, the authors concluded that nursing infants younger than 1 month of age and those with a high frequency of G-6-PD deficiency or sensitivity to nitrofurantoin may be at risk for toxicity (14).

The above studies suggest that there is a potential for nitrofurantoin-induced toxicity from exposure to the drug in breast milk. Determining the magnitude of the risk is not possible because of the absence of published reports describing toxicity in breast-fed infants, but the risk appears to be rare. The American Academy of Pediatrics considers nitrofurantoin to be compatible with breast feeding (15).

References

1. Product information. Macrodantin. Procter & Gamble Pharmaceuticals, 2001.
2. Prytherch JP, Sutton ML, Denine EP. General reproduction, perinatal-postnatal and teratology studies of nitrofurantoin macrocrystals in rats and rabbits. J Toxicol Environ Health 1984;13:811–23. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:454.
3. Hailey FJ, Fort H, Williams JC, Hammers B. Foetal safety of nitrofurantoin macrocrystals therapy during pregnancy: a retrospective analysis. J Int Med Res 1983;11:364–9.
4. Lenke RR, VanDorsten JP, Schifrin BS. Pyelonephritis in pregnancy: a prospective randomized trial to prevent recurrent disease evaluating suppressive therapy with nitrofurantoin and close surveillance. Am J Obstet Gynecol 1983;146:953–7.
5. Powell RD, DeGowin RL, Alving AS. Nitrofurantoin-induced hemolysis. J Lab Clin Med 1963;62:1002–3.
6. Gait JE. Hemolytic reactions to nitrofurantoin in patients with glucose-6-phosphate dehydrogenase deficiency: theory and practice. DICP Ann Pharmacother 1990;24:1210–3.
7. Bruel H, Guillemant V, Saladin-Thiron C, Chabrolle JP, Lahary A, Poinsot J. Hemolytic anemia in a newborn after maternal treatment with nitrofurantoin at the end of pregnancy. Arch Pediatr 2000;7:745–7.
8. Ball JS, Ferguson AN. Permanent discoloration of primary dentition by nitrofurantoin. Br Med J 1962;2:1103.
9. Duckworth R, Swallow JN. Nitrofurantoin and teeth. Br Med J 1962;2:1617.
10. Ben David S, Einarson T, Ben David Y, Nulman I, Pastuszak A, Koren G. The safety of nitrofurantoin during the first trimester of pregnancy: meta-analysis. Fundam Clin Pharmacol 1995;9:503–7.
11. Nelson WO, Bunge RG. The effect of therapeutic dosages of nitrofurantoin (Furadantin) upon spermatogenesis in man. J Urol 1957;77:275–81.
12. Hosbach RE, Foster RB. Absence of nitrofurantoin from human milk. JAMA 1967;202:1057.
13. Varsano I, Fischl J, Shochet SB. The excretion of orally ingested nitrofurantoin in human milk. J Pediatr 1973;82:886–7.
14. Gerk PM, Kuhn RJ, Desai NS, McNamara PJ. Active transport of nitrofurantoin into human milk. Pharmacotherapy 2001;21:669–75.
15. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
    
    

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