This drug should be used during pregnancy only if clearly needed.

AU TGA pregnancy category: A
US FDA pregnancy category: B

Comments: This drug inhibits folic acid absorption and metabolism.

Animal studies have failed to reveal evidence of fetal harm. During animal studies using doses up to 6 times the human maintenance dose (2 g/day based on body surface area), no adverse fetal effects were revealed. There are no controlled data in human pregnancy.

Sulfasalazine and its metabolite, sulfapyridine, pass through the placenta. In one infant, umbilical cord serum levels of sulfasalazine and sulfapyridine were equal to maternal serum levels. Sulfonamides compete with bilirubin for plasma protein binding sites and may cause kernicterus in newborns. Although sulfapyridine has poor bilirubin-displacing capacity, newborns should be monitored for kernicterus.

Cases of neural tube defects have been reported in infants born to mothers exposed to this drug during pregnancy; causality has not been established. Oral sulfasalazine inhibits absorption and metabolism of folic acid which may interfere with folic acid supplementation and reduce its periconceptional effect. Periconceptional folic acid supplementation has been shown to decrease risk of neural tube defects.

A national survey evaluated outcomes of pregnancies associated with inflammatory bowel disease (IBD). In 186 pregnancies in women treated with sulfasalazine alone or with concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to 245 untreated IBD pregnancies and to pregnancies in the general population. A study of 1455 pregnancies with exposure to sulfonamides showed that these drugs did not appear to be associated with fetal malformations. A medical literature review of 1155 pregnancies in women with ulcerative colitis suggested outcomes were similar to those expected in the general population.

Use during pregnancy appears to be safe. A review compared 287 pregnancies in women with ulcerative colitis or Crohn's disease treated with sulfasalazine and/or steroids to 244 pregnancies in women who were not treated. Abnormalities reported in infants whose mothers received sulfasalazine and steroids included cleft palate, microglossia, and congenital deafness. The incidence of abnormalities was not significantly different between the treated and untreated patients. The incidence of spontaneous abortion, premature birth, and low birth weight in the treated infants was less than the predicted values based on the general population.

In a review of 229,101 deliveries to Michigan Medicaid patients, 72 first-trimester exposures and 72 exposures any time during pregnancy were recorded. A total of 2 birth defects were reported with first trimester exposure and 1 with exposure during pregnancy. These data do not support an association to birth defects. (written communication, Franz Rosa, MD, US FDA, 1994)

Agranulocytosis has been reported in a newborn whose mother took sulfasalazine and prednisone throughout pregnancy. Another infant whose mother was treated with sulfasalazine throughout pregnancy was born with microcephaly, ventricular septal defect, and coarctation of the aorta. Cleft palate and severe hydrocephalus has also been reported in an infant.

AU TGA pregnancy category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

US FDA pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

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Sulfonamides, including sulfasalazine, are present in human milk. Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid (5-ASA). Insignificant amounts of sulfasalazine and 5-ASA (but rather high levels of N-acetyl-5-ASA [the 5-ASA metabolite]) are found in breast milk; some experts consider 5-ASA derivatives safe during breastfeeding. The effects of N-acetyl-5-ASA on the nursing infant are not known. Sulfapyridine has levels in milk about 30% to 60% of those in maternal serum. Sulfonamides compete with bilirubin for plasma protein binding sites and may cause kernicterus in newborns. Although sulfapyridine has poor bilirubin-displacing capacity, newborns should be monitored for kernicterus.

One breastfed infant developed bloody diarrhea while the mother ingested sulfasalazine. The mother was determined to be a slow acetylator of sulfonamides. The diarrhea resolved 48 to 72 hours after the mother discontinued sulfasalazine. According to the authors, the reaction was likely due to an allergic reaction to sulfapyridine. The reaction was probably caused by sulfasalazine or one of its metabolites in breast milk; diarrhea has been reported in breastfed infants with both sulfapyridine and 5-ASA.

Cases (with limited data) of bloody stools or diarrhea have been reported in infants fed breast milk from mothers taking sulfasalazine. In cases where outcome was reported, the infant's bloody stools or diarrhea resolved after the mother discontinued sulfasalazine or breastfeeding was discontinued. Due to limited data, a causal relationship has not been established, but cannot be ruled out. Monitoring for signs and symptoms of diarrhea and/or bloody stools in infants receiving breast milk from mothers taking sulfasalazine is recommended.

LactMed/WHO: Use of sulfasalazine should be avoided if possible, especially if the nursing infant is premature or younger than 1 month; however, use of sulfasalazine is not a reason to discontinue breastfeeding if the drug is required by the mother. If the nursing infant is glucose-6-phosphate dehydrogenase (G6PD) deficient, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.
-AU: Sulfasalazine should not be used unless the benefit to the mother outweighs the risk to the infant; caution is recommended, especially if the nursing infant is premature or G6PD deficient.
-UK: Breastfeeding is not recommended during use of sulfasalazine.
-US: Caution is recommended.

Excreted into human milk: Yes

Comments:
-Use of drugs that do not contain a sulfonamide is preferred.
-Nursing infants should be monitored closely for side effects (e.g., bloody diarrhea, jaundice, hemolysis).

See references