Animal studies have revealed evidence of teratogenicity and fetolethality. In 1 of 3 rat studies, cleft palate was observed at doses about 5 times the recommended human dose (on a body surface area [BSA] basis); in studies in pregnant rabbits, increased fetal loss (dead and resorbed conceptuses) was observed at about 6 times the human dose (on a BSA basis). Both components cross the placenta in humans. There are no controlled data in human pregnancy.

Some retrospective epidemiologic studies suggest an association between first trimester exposure to this drug with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. Such studies were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders; they were further limited by recall, selection, and information biases, and by limited generalizability of findings. Outcome measures varied between studies, limiting cross-study comparisons.

Other epidemiologic studies did not detect statistically significant associations between exposure to this drug and specific malformations. In 1 retrospective study of mothers given this drug orally or given placebo, the outcome of 186 pregnancies showed congenital abnormalities in 3 of 66 patients using placebo and in 4 of 120 patients using this drug; no abnormalities reported in 10 children whose mothers used this drug during the first trimester. In a separate survey, the same authors found no congenital abnormalities in 35 children whose mother used this drug orally at time of conception or shortly thereafter.

Clinical considerations: Urinary tract infection during pregnancy is associated with adverse perinatal outcomes (e.g., preterm birth, low birth weight, preeclampsia, increased mortality to pregnant woman). Pneumocystis jirovecii pneumonia during pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman.

Sulfonamides may cause jaundice and hemolytic anemia in the newborn. Sulfonamides may cause kernicterus in babies during the first month of life by displacing bilirubin from plasma albumin; therefore, according to some authorities, they should be avoided as far as possible during the last month of pregnancy. Trimethoprim may interfere with folic acid metabolism and animal trials have shown that administration of very high doses during organ development may cause birth defects typical of folic acid antagonism; if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, folic acid supplementation may be required.

AU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.
-According to some authorities: Safety has not been established during pregnancy; use is not recommended during pregnancy, especially during the first trimester, unless clearly needed.
-According to some authorities: Use should be avoided in late pregnancy.

AU TGA pregnancy category: C
US FDA pregnancy category: Not assigned.

Risk summary: This drug may cause fetal harm if used during pregnancy.

Comments:
-Maternal and embryo/fetal risk due to the mother's underlying condition should be considered.
-If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
-According to some authorities: Because this drug may interfere with folic acid metabolism, a folate supplement should be considered.

See references

Levels of this combination drug in breast milk are about 2% to 5% of the recommended daily dose for infants over 2 months of age. Although the quantity ingested by a breastfed infant is small, it is recommended that the infant's age be considered and the benefits outweigh the risks.

This drug combination (equivalent to sulfamethoxazole 800 mg and trimethoprim 320 mg) was administered twice daily to 40 women who were up to 5 days postpartum; another 10 women were administered this dose 3 times a day. Milk levels were measured several times daily for 5 days. Sulfamethoxazole milk levels averaged 4.5 and 5.3 mg/L, respectively, with the 2 dosing regimens. After 320 mg/day of trimethoprim, milk levels averaged about 2 mg/L in both groups; milk levels increased to about 3 mg/L by day 5 of therapy. With the usual daily dose of sulfamethoxazole 800 mg and trimethoprim 320 mg, an exclusively breastfed infant would be expected to receive 0.68 mg/kg/day of sulfamethoxazole and 0.45 mg/kg/day of trimethoprim; this is very low compared to established treatment doses of 40 mg/kg/day (sulfamethoxazole) and 8 mg/kg/day (trimethoprim) for infants older than 2 months.

In the immediate postpartum period, 20 mothers were given oral trimethoprim; peak milk levels occurred 3 hours after dosing. A daily dose of 320 mg was administered to 14 of these women; peak and trough milk level averaged 2.4 and 1 mg/L, respectively. A daily dose of 480 mg was administered to the other 6 women; peak and trough milk level averaged 4 and 1.5 mg/L, respectively. According to author calculation, a breastfed infant would receive 0.75 and 1.7 mg/day with maternal doses of 320 and 480 mg/day, respectively.

An extensive systematic review of sulfonamide usage near term and during breastfeeding found no side effects in infants; the authors concluded that use of this combination drug during breastfeeding presents no risk of neonatal kernicterus.

In a prospective controlled study, mothers who called an information service were questioned about side effects experienced by their breastfed infants. Of 12 women who took this combination drug during breastfeeding (time postpartum and dose not provided), none reported diarrhea, drowsiness, or irritability in her infant; 2 mothers reported poor feeding in their infants.

LactMed: Use is considered acceptable when breastfeeding healthy, full-term infants after the newborn period; alternate agents are recommended in jaundiced, ill, stressed, or premature infants. Use should be avoided while breastfeeding glucose-6-phosphate dehydrogenase (G6PD)-deficient infants.
-According to some authorities: Use should be avoided.
-According to some authorities: Use is not recommended in premature neonates or in infants younger than 2 months; taking the infant's age into consideration, benefit should outweigh risk.
-According to some authorities: Caution is recommended, especially when breastfeeding jaundiced, ill, stressed, or premature infants.

Excreted into human milk: Yes (sulfamethoxazole, trimethoprim)

Comments:
-Premature, ill, jaundiced, or stressed infants are at risk of bilirubin displacement and kernicterus.
-This drug combination is considered compatible with breastfeeding by the American Academy of Pediatrics if the infant is healthy and full-term.

See references