SULFONAMIDES

Fetal Risk Summary

Sulfonamides are a large class of antibacterial agents. Although there are differences in their bioavailability, all share similar actions in the fetal and newborn periods, and they will be considered as a single group.

Sulfamethoxazole was teratogenic (primarily cleft palates) in rats given oral doses of 533 mg/kg (1). The highest dose that did not produce cleft palates was 512 mg/kg.

The sulfonamides readily cross the placenta to the fetus during all stages of gestation (2,3,4,5,6,7,8,9 and 10). Equilibrium with maternal blood is usually established after 2–3 hours, with fetal levels averaging 70%–90% of maternal. Significant levels may persist in the newborn for several days after birth when given near term. The primary danger of sulfonamide administration during pregnancy is manifested when these agents are given close to delivery. Toxicities that may be observed in the newborn include jaundice, hemolytic anemia, and, theoretically, kernicterus. Severe jaundice in the newborn has been related to maternal sulfonamide ingestion at term by several authors (11,12,13,14,15 and 16). Premature infants seem especially prone to development of hyperbilirubinemia (15). However, a study of 94 infants exposed to sulfadiazine in utero for maternal prophylaxis of rheumatic fever failed to show an increase in prematurity, hyperbilirubinemia, or kernicterus (17). Hemolytic anemia has been reported in two newborns and in a fetus following in utero exposure to sulfonamides (11,12,16). Both newborns survived. In the case involving the fetus, the mother had homozygous glucose-6-phosphate dehydrogenase deficiency (16). She was treated with sulfisoxazole for a urinary tract infection 2 weeks before delivery of a stillborn male infant. Autopsy revealed a 36-week-gestation infant with maceration, severe anemia, and hydrops fetalis.

Sulfonamides compete with bilirubin for binding to plasma albumin. In utero, the fetus clears free bilirubin by the placental circulation, but after birth, this mechanism is no longer available. Unbound bilirubin is free to cross the blood-brain barrier and may result in kernicterus. Although this toxicity is well known when sulfonamides are administered directly to the neonate, kernicterus in the newborn following in utero exposure has not been reported. Most reports of sulfonamide exposure during gestation have failed to demonstrate an association with congenital malformations (10,11,18,19,20,21,22,23 and 24). Offspring of patients treated throughout pregnancy with sulfasalazine (sulfapyridine plus 5-aminosalicylic acid) for ulcerative colitis or Crohn's disease have not shown an increase in adverse effects (see also Sulfasalazine) (10,21,23). In contrast, a retrospective study of 1,369 patients found that significantly more mothers of 458 infants with congenital malformations took sulfonamides than did mothers in the control group (25). A 1975 study examined the in utero drug exposures of 599 children born with oral clefts (26). A significant difference (p<0.05), as compared with matched controls, was found with 1st- and 2nd-trimester sulfonamide use only when other defects, in addition to the clefts, were present.

As noted above, some sulfonamides are animal teratogens. Because of this, warnings of human teratogenicity have been published (27,28). In two reports, investigators associated in utero sulfonamide exposure with tracheoesophageal fistula and cataracts, but additional descriptions of these effects have not appeared (29,30). A mother treated for food poisoning with sulfaguanidine in early pregnancy delivered a child with multiple anomalies (31). The author attributed the defects to use of the drug, but a relationship is doubtful.

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 1,455 of whom had 1st-trimester exposure to sulfonamides (32, pp. 296–313). For use anytime during pregnancy, 5,689 exposures were reported (32, p. 435). In neither group was evidence found to suggest a relationship to large categories of major or minor malformations. Several possible associations were found with individual defects after anytime use, but the statistical significance of these are unknown (32, pp. 485–6). Independent confirmation is required.

Ductus arteriosus persistens (8 cases) Coloboma (4 cases) Hypoplasia of limb or part thereof (7 cases) Miscellaneous foot defects (4 cases) Urethral obstruction (13 cases) Hypoplasia or atrophy of adrenals (6 cases) Benign tumors (12 cases) In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 131 newborns had been exposed to sulfisoxazole, 1,138 to sulfabenzamide vaginal cream, and 2,296 to the combination of sulfamethoxazole-trimethoprim during the 1st trimester (F. Rosa, personal communication, FDA, 1993). For sulfisoxazole, eight (6.1%) major birth defects were observed (six expected), two cardiovascular defects (one expected) and one oral cleft (none expected). No anomalies were observed in four other categories of defects (spina bifida, polydactyly, limb-reduction defects, and hypospadias) for which data were available. For sulfabenzamide, 43 (3.8%) major birth defects were found (44 expected), including 11/10 cardiovascular defects, 0/2 oral clefts, 0/0.5 spina bifida, 2/3 polydactyly, 1/2 limb-reduction defects, and 1/3 hypospadias. The data for sulfisoxazole and sulfabenzamide do not support an association between the drug and congenital defects. In contrast, a possible association was found between sulfamethoxazole-trimethoprim and congenital defects (126 observed/98 expected; 5.5%) in general and for cardiovascular defects (37/23) in particular (see Trimethoprim for details).

Taken in sum, sulfonamides, as single agents, do not appear to pose a significant teratogenic risk. Because of the potential toxicity to the newborn, these agents should be avoided near term.

[*Risk Factor D if administered near term.]

Breast Feeding Summary

Sulfonamides are excreted into breast milk in low concentrations. Milk levels of sulfanilamide (free and conjugated) are reported to range from 6 to 94 µg/mL (4,33,34,35,36,37 and 38). Up to 1.6% of the total dose could be recovered from the milk (33,36). Milk levels often exceeded serum levels and persisted for several days after maternal consumption of the drug was stopped. Milk:plasma ratios during therapy with sulfanilamide were 0.5–0.6 (37). Reports of adverse effects in nursing infants are rare. One author found reports of diarrhea and rash in breast-fed infants whose mothers were receiving sulfapyridine or sulfathiazole (7). (See Sulfasalazine for another report of bloody diarrhea.) Milk levels of sulfapyridine, the active metabolite of sulfasalazine, were 10.3 µg/mL, a milk:plasma ratio of 0.5 (10). Based on these data, the nursing infant would receive approximately 3–4 mg/kg/day of sulfapyridine, an apparently nontoxic amount for a healthy neonate (17). Sulfisoxazole, a very water-soluble drug, was reported to produce a low milk:plasma ratio of 0.06 (39). The conjugated form achieved a ratio of 0.22. The total amount of sulfisoxazole recovered in milk during 48 hours after a 4-g divided dose was only 0.45%. Although controversial, breast feeding during maternal administration of sulfisoxazole seems to present a very low risk for the healthy neonate (40,41).

In summary, sulfonamide excretion into breast milk apparently does not pose a significant risk for the healthy, full-term neonate. Exposure to sulfonamides via breast milk should be avoided in ill, stressed, or premature infants and in infants with hyperbilirubinemia or glucose-6-phosphate dehydrogenase deficiency. With these latter precautions, the American Academy of Pediatrics considers sulfapyridine, sulfisoxazole, and sulfamethoxazole (when combined with trimethoprim) to be compatible with breast feeding (42).

References

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