Urinary Germicide
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 3rd Trimester
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Nitrofurantoin is not an animal teratogen with doses close to those used in humans and, although two retrospective studies reported associations with congenital anomalies, there are no confirmed data suggesting that it is a human teratogen. The two studies require confirmation. However, there appears to be risk of hemolytic anemia in newborns, including those who are not glucose-6-phosphate dehydrogenase (G6PD) 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 suggest that the risk is rare. The safest course, however, is to avoid nitrofurantoin close to delivery.
FETAL RISK SUMMARY
The anti-infective agent nitrofurantoin is commonly used in pregnancy for the treatment and prophylaxis of urinary tract infections.
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 six times the human dose based on body weight (HD) (1). In mice, a dose 68 times the HD was associated with fetal growth restriction and a low incidence of minor and common malformations (1). When a dose 25 times the HD was administered, fetal malformations were not observed (1). A dose 19 times the HD 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, 1292 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 1700 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).
In a 1995 report, 22 studies of nitrofurantoin use in pregnancy were evaluated for a meta-analysis (5). Only four of the studies met the inclusion criteria of the investigators. The pooled odds ratio (OR) for malformations after use of the drug in the 1st trimester was 1.29 (95% confidence interval [CI] 0.25–6.57). These results demonstrated no significant correlation between nitrofurantoin use in early gestation and congenital malformations (5).
In contrast to the above reports, a 2003 case–control study, using data from three Swedish health registers, was conducted to identify drug use in early pregnancy that was associated with cardiac defects (6). Cases (cardiovascular defects without known chromosome anomalies) (N = 5015) were compared with controls consisting of all infants born in Sweden from 1995 to 2001 (N = 577,730). Associations were identified for several drugs, some of which were probably due to confounding from the underlying disease or complaint or multiple testing, but some were thought to be true drug effects. For nitrofurantoin, there were 30 cases in 2060 exposures (OR 1.68, 95% CI 1.17–2.40) (6).
A 2009 report from the National Birth Defects Prevention Study estimated the association between antibacterial agents and more than 30 selected birth defects (7). The authors conducted a population-based, multiple site, case–control study of women who gave birth to an infant with one of >30 selected defects. The outcomes were identified in a 10-state birth defect surveillance program and involved 13,155 cases and 4941 controls selected from the same geographical regions. Exposure to an antibacterial was determined by a detailed telephone interview conducted within 24 months after the estimated date of delivery. Women were considered exposed if they had used an antibacterial drug during the month before the estimated date of conception through the end of the 1st trimester (defined as the end of the 3rd month of pregnancy). Significant associations with multiple selected birth defects were found (total number of exposed cases/controls) with sulfonamides (145/42) (probably combined with trimethoprim) and nitrofurantoin (150/42). The adjusted ORs and 95% CIs (in parentheses) for nitrofurantoin were anophthalmia or microphthalmos 3.7 (1.1–12.2), hypoplastic left heart syndrome 4.2 (1.9–9.1), atrial septal defects 1.9 (1.1–3.4), and cleft lip with cleft palate 2.1 (1.2–3.9). Significant associations (total number of exposed cases–controls; number of associations) also were found for penicillins (716–293; 1), erythromycins (202–78; 2), cephalosporins (128–47; 1), quinolones (42–14; 1) and tetracyclines (36–6; 1). The results for quinolones and tetracyclines, however, were based on small numbers of exposed cases and controls (7).
As with all retrospective case–control studies, the data can determine associations, but not causative associations (7). Moreover, several limitations were identified by the authors, including spurious associations caused by the large number of analyses, interviews were conducted 6 weeks to 2 years after the pregnancy making recall difficult for cases and controls, recall bias, and inability to distinguish between drug-induced defects and defects resulting from the infection (7).
Nitrofurantoin may induce hemolytic anemia in G6PD-deficient patients and in patients whose red blood cells are deficient in reduced glutathione (8). 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 (9). 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 (10). 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 (11). 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 (12).
The effect of postcoital prophylaxis with a single oral dose of either cephalexin (250 mg) or nitrofurantoin macrocrystals (50 mg) starting before or during pregnancy in 33 women (39 pregnancies) with a history of recurrent urinary tract infections was described in a 1992 reference (13). A significant decrease in the number of infections was documented without fetal toxicity.
Long-term, low-dose (50 mg at bedtime) nitrofurantoin for prophylaxis after acute pyelonephritis was shown to be effective in pregnant women (14). Nitrofurantoin was started after treatment of the infection and continued until 1 month after delivery. There were no additional cases of pyelonephritis (14). No mention was made on the fetal outcomes.
When given orally in high doses of 10 mg/kg/day to young males, nitrofurantoin may produce slight-to-moderate transient spermatogenic arrest (15). The lower doses used clinically do not seem to have this effect.
BREASTFEEDING 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 (16). 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 (17). Only two of the four patients receiving the 200-mg dose excreted measurable amounts of nitrofurantoin, 0.3–0.5 mcg/mL. Although these amounts are negligible, infants with G6PD deficiency may develop hemolytic anemia from this exposure (17).
A 2001 study concluded that nitrofurantoin is actively transported into milk, by an unknown mechanism, resulting in a milk:plasma ratio of 6.21 (18). The observed milk:plasma ratio was about 22-fold greater than the predicted ratio (0.28) that was determined in the study. Four lactating women, who did not breastfeed 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 mcg/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, nursing infants younger than 1 month of age and those with a high frequency of G6PD deficiency or sensitivity to nitrofurantoin may be at risk for toxicity (18).
In a 1993 cohort study, diarrhea was reported in 32 (19.3%) nursing infants of 166 breastfeeding mothers who were taking antibiotics (19). For the six women taking nitrofurantoin, decreased milk volume was observed in one woman and diarrhea was observed in two (33%) infants. Both effects were considered minor because they did not require medical attention (19).
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 will require more data, but the risk appears to be rare. The American Academy of Pediatrics classifies nitrofurantoin as compatible with breastfeeding (20).
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: The 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.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.
6.Kallen BAJ, Olausson PO. Maternal drug use in early pregnancy and infant cardiovascular defect. Reprod Toxicol 2003;17:255–61.
7.Crider KS, Cleves MA, Reefhuis J, Berry RJ, Hobbs CA, Hu DJ. Antibacterial medication use during pregnancy and risk of birth defects. Arch Pediatr Adolesc Med 2009;163:978–85.
8.Powell RD, DeGowin RL, Alving AS. Nitrofurantoin-induced hemolysis. J Lab Clin Med 1963;62:1002–3.
9.Gait JE. Hemolytic reactions to nitrofurantoin in patients with glucose-6-phosphate dehydrogenase deficiency: theory and practice. DICP Ann Pharmacother 1990;24:1210–3.
10.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.
11.Ball JS, Ferguson AN. Permanent discoloration of primary dentition by nitrofurantoin. Br Med J 1962;2:1103.
12.Duckworth R, Swallow JN. Nitrofurantoin and teeth. Br Med J 1962;2:1617.
13.Pfau A, Sacks TG. Effective prophylaxis for recurrent urinary tract infections during pregnancy. Clin Infect Dis 1992;14:810–4.
14.Sandberg T, Brorson JE. Efficacy of long-term antimicrobial prophylaxis after acute pyelonephritis in pregnancy. Scan J Infect Dis 1991;23:221–3.
15.Nelson WO, Bunge RG. The effect of therapeutic dosages of nitrofurantoin (Furadantin) upon spermatogenesis in man. J Urol 1957;77:275–81.
16.Hosbach RE, Foster RB. Absence of nitrofurantoin from human milk. JAMA 1967;202:1057.
17.Varsano I, Fischl J, Shochet SB. The excretion of orally ingested nitrofurantoin in human milk. J Pediatr 1973;82:886–7.
18.Gerk PM, Kuhn RJ, Desai NS, McNamara PJ. Active transport of nitrofurantoin into human milk. Pharmacotherapy 2001;21:669–75.
19.Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol 1993;168:1393–9.
20.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.