SULFASALAZINE

Fetal Risk Summary

Sulfasalazine is a compound composed of 5-aminosalicylic acid (5-ASA) joined to sulfapyridine by an azo-linkage (refer to Sulfonamides for a complete review of this class of agents). Sulfasalazine is used for the treatment of ulcerative colitis and Crohn's disease. Reproduction studies in rats and rabbits at doses up to 6 times the human dose revealed no impairment of fertility or fetal harm (1).

No increase in human congenital defects or newborn toxicity has been observed from its use in pregnancy (2,3,4,5,6,7,8,9,10,11 and 12). However, three reports, involving five infants (two stillborn), have described congenital malformations after exposure to this drug (13,14 and 15). It cannot be determined whether the observed defects were related to the therapy, the disease, or a combination of these or other factors: Bilateral cleft lip/palate, severe hydrocephalus, death (13) Ventricular septal defect, coarctation of aorta (14) Potter-type IIa polycystic kidney, rudimentary left uterine cornu, stillborn (first twin) (14) Potter's facies, hypoplastic lungs, absent kidneys and ureters, talipes equinovarus, stillborn (second twin) (14) Ventricular septal defect, coarctation of aorta, macrocephaly; gingival hyperplasia, small ears (both thought to be inherited) (15) Sulfasalazine and its metabolite, sulfapyridine, readily cross the placenta to the fetal circulation (6,7). Fetal concentrations are approximately the same as maternal concentrations. Placental transfer of 5-ASA is limited because only negligible amounts are absorbed from the cecum and colon, and these are rapidly excreted in the urine (16).

At birth, concentrations of sulfasalazine and sulfapyridine in 11 infants were 4.6 and 18.2 µg/mL, respectively (7). Neither of these levels was sufficient to cause significant displacement of bilirubin from albumin (7). Kernicterus and severe neonatal jaundice have not been reported following maternal use of sulfasalazine, even when the drug was given up to the time of delivery (7,8). Caution is advised, however, because other sulfonamides have caused jaundice in the newborn when given near term (see Sulfonamides).

Sulfasalazine may adversely affect spermatogenesis in male patients with inflammatory bowel disease (17,18). Sperm counts and motility are both reduced and require 2 months or longer after the drug is stopped to return to normal levels (17).

[*Risk Factor D if administered near term.]

Breast Feeding Summary

Sulfapyridine is excreted into breast milk (see also Sulfonamides) (6,16,19). Milk concentrations were approximately 40%–60% of maternal serum levels. One infant's urine contained 3–4 µg/mL of the drug (1.2–1.6 mg/24 hours), representing about 30%–40% of the total dose excreted in the milk. Unmetabolized sulfasalazine was detected in only one of the studies (milk:plasma ratio of 0.3) (6). Levels of 5-ASA were undetectable. No adverse effects were observed in the 16 nursing infants exposed in these reports (6,16,19). However, bloody diarrhea in an infant exclusively breast-fed, occurring first at 2 months of age, and then recurring 2 weeks later and persisting until 3 months of age, was attributed to the mother's sulfasalazine therapy (3 g/day) (20). The mother was a slow acetylator with a blood concentration of sulfapyridine of 42.4 µg/mL (therapeutic range 20–50 µg/mL) (20). The acetylation phenotype of the infant was not determined, but his blood level of sulfapyridine was 5.3 µg/mL. A diagnostic workup of the infant was negative. The bloody diarrhea did stop, however, 48–72 hours after discontinuance of the mother's therapy. A repeat colonoscopy of the infant 1.5 months later was normal. Based on this report, the American Academy of Pediatrics classifies sulfasalazine as a drug that should be given to nursing women with caution because significant adverse effects may occur in some nursing infants (21).

References

1. Product information. Azulfidine EN-tabs. Pharmacia & Upjohn, 2000.
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21. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.