Animal studies have failed to reveal evidence of fetotoxicity or teratogenicity at moderately maternotoxic oral doses; animal studies have not been reported with the IV formulation. After administration during organogenesis, this drug did not cause fetal malformations in rats and mice at oral doses up to 200 mg/kg/day (moderately maternotoxic); based on body surface area (BSA), this dose is about 4 (rats) and 2 (mice) times an adult human dose of 500 mg. After rabbits were administered oral doses of 10, 20, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food intake were seen in all groups; no evidence of fetotoxicity or teratogenicity was seen at these doses (highest dose estimated to be 2 times an adult human daily dose of 500 mg based on BSA). Studies in animals have shown that this drug crosses the placenta. There are no controlled data in human pregnancy.

Available data from published observational studies, case series, and case reports over several decades do not indicate an increased risk for major birth defects, miscarriage, or adverse maternal/fetal outcomes with use of this drug during pregnancy; limitations of these data include the lack of randomization and inability to control for confounders (e.g., underlying maternal disease, maternal use of concomitant drugs).

A large amount of data from observational studies performed in several countries are available on exposure to this drug during pregnancy; while most studies do not indicate an association with adverse fetal effects (e.g., major congenital malformations, cardiovascular malformations), there is limited epidemiological evidence of an increased risk of miscarriage after exposure to this drug in early pregnancy.

AU TGA pregnancy category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.

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 clearly needed and the benefit outweighs the risk.
-According to some authorities: The IV formulation is only recommended for use during pregnancy when there are no alternatives and the benefit outweighs the risk.

AU TGA pregnancy category: B1
US FDA pregnancy category: Not assigned.

Risk summary: Available data on use of this drug in pregnant women have not identified any drug-related risks for major birth defects, miscarriage, or adverse maternal/fetal outcomes.

See references

According to some authorities: A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother and the benefit of breastfeeding for the child.

Excreted into human milk: Yes

Comments:
-Developmental and health benefits of breastfeeding should be considered as well as the mother's clinical need for this drug; potential side effects in the breastfed child due to this drug or the mother's underlying condition should be considered.
-Nonserious adverse reactions have been reported in breastfed infants after maternal intake of this drug; women should be advised to monitor breastfed infants for diarrhea, vomiting, or rash.
---Mucous membrane fungal infections and sensitization are possible in nursing infants.
-According to some authorities: Nursing should be discontinued during therapy and milk should be discarded during and up until 2 days after discontinuation of therapy; nursing may resume thereafter.

Because of the low levels of this drug in breast milk and use in infants at higher doses, it would not be expected to cause harmful effects in nursing infants. Infants should be monitored for possible effects on the gastrointestinal flora (e.g., diarrhea, candidiasis [thrush, diaper rash]). According to unconfirmed epidemiologic evidence, maternal macrolide use during the first 2 weeks of breastfeeding may increase the risk of hypertrophic pyloric stenosis in infants, but others have questioned this relationship; 2 meta-analyses failed to demonstrate a relationship between maternal macrolide use during breastfeeding and infantile hypertrophic pyloric stenosis.

Due to the long half-life, accumulation in milk is possible; information available from published literature suggests this does not lead to clinically relevant quantities in milk with short-term use.

Limited information from published literature suggests this drug is in human milk at the highest median daily dose of 0.1 to 0.7 mg/kg/day (estimated).

Breast milk drug levels were measured In 20 women after a single 2 g oral dose during labor; breast milk samples collected on days 3 and 6 postpartum and 2 and 4 weeks postpartum showed this drug in breast milk up to 4 weeks after dosing.

In another study, a single 500 mg IV dose was administered to 8 women before incision for cesarean section; breast milk (colostrum) samples were collected between 12 and 48 hours after dosing. This drug persisted in breast milk up to 48 hours after a dose with a breast milk level of 1713 mcg/L (median) at 30.7 hours (median) after dosing; no adverse reactions were noted in their infants. A computer model calculated a half-life of 15.6 hours (median), which was longer than the maternal serum half-life of 6.7 hours; according to author calculation using the model, steady state would occur in 3 days with continuous administration of 500 mg every 12 hours and exclusively breastfed infants would receive 0.1 mg/kg/day.

A cohort study of infants diagnosed with infantile hypertrophic pyloric stenosis found that affected infants were 2.3 to 3 times more likely to have a mother taking a macrolide antibiotic during the 90 days after delivery; all of the affected infants were breastfed. Most of the macrolide prescriptions were for erythromycin, and only 7% were for azithromycin; however, authors did not state which macrolide was taken by the mothers of the affected infants.

A retrospective database study in Denmark of 15 years of data found a 3.5-fold increased risk of infantile hypertrophic pyloric stenosis in the infants of mothers who took a macrolide during the first 13 days postpartum, but not with later exposure. The proportion of breastfed infants was not known, but probably high; the proportion of women who took each macrolide was also not reported.

A study comparing breastfed infants of mothers taking amoxicillin to those taking a macrolide antibiotic found no cases of pyloric stenosis; however, only 10 of the 55 infants exposed to a macrolide were exposed to this drug. Adverse reactions occurred in 12.7% of the infants exposed to macrolides, which was similar to the rate in amoxicillin-exposed infants; reactions included rash, diarrhea, loss of appetite, and somnolence.

See references