Like all sulfonamides, sulfadiazine crosses the placenta, reaching equilibrium with maternal serum within two to three hours after administration. Because sulfonamides compete with bilirubin for binding to serum albumin, free bilirubin levels rise in the presence of sulfonamides. Neonates are, therefore, at risk for hyperbilirubinemia, jaundice, and kernicterus when sulfonamides are administered to the mother near term (prior to birth, the fetus is able to dispose of bilirubin via the placental circulation).

While there are no definitive data to demonstrate an association between sulfonamides and congenital defects, four significant sources of information are worthy of mention.

First, a retrospective study of 1,369 patients revealed that significantly more mothers of 458 offspring with congenital malformations had taken sulfonamides than did mothers of normal offspring.

Second, a retrospective study of 599 offspring with oral clefts revealed a significantly greater exposure to sulfonamides during the first and second trimesters compared with matched controls. Significance was found only when other defects were present.

Third, the Michigan Medicaid surveillance study showed a possible association between the combination drug, trimethoprim-sulfamethoxazole (TMP-SMX), and congenital defects. This report is a summary of information from two studies, one in which 1,116 of 104,000 pregnant women from 1980 to 1983, and one in which 2,296 of 229,000 pregnant women from 1985 to 1992 received TMP-SMX. In the first study, 83 total defects (13 cardiovascular defects) were observed (14 and 2 were expected, respectively). In the second study, 126 total defects (37 cardiovascular defects) were observed (98 and 27 were expected, respectively). Cleft palate was observed in three cases in the latter study. These data support an association between TMP-SMX and congenital defects, although other causes, such as the underlying disease(s) of the mother, the contribution of trimethoprim, and concomitant drug therapy are unaccounted for.

Fourth, and finally, the Collaborative Perinatal Project monitored 50,282 mother-child pairs, 1,455 of which had first trimester exposure to sulfonamides. In addition, a total of 5,689 exposures to sulfonamides at any time during pregnancy were retrospectively analyzed. There was no evidence to suggest a relationship of sulfonamides to large categories of major or minor malformations.

In summary, some experts agree that in general sulfonamides as single agents do not appear to pose a significant teratogenic risk, but due to the potential toxicity to the neonate, they should be avoided near term.

Sulfadiazine has been assigned to pregnancy category C by the FDA. Sulfonamides cross the placenta. Animal studies with high oral doses of some sulfonamides have revealed an increased incidence of cleft palate and other bony abnormalities. There are no controlled data in human pregnancy. Because of the potential for neonatal jaundice and kernicterus, sulfadiazine use near term is considered contraindicated.

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Sulfonamides are excreted into human milk. The manufacturer considers the use of sulfadiazine to be contraindicated in breast-feeding women. However, other sulfonamides are considered compatible with breast-feeding by the American Academy of Pediatrics if the infant is healthy and full-term. Breast-feeding during sulfonamide use should be avoided if the infant is premature, ill, hyperbilirubinemic, or glucose-6-phosphate dehydrogenase (G6PD) deficient.

See references