Antibiotic
PREGNANCY RECOMMENDATION: Compatible (Excludes Estolate Salt)
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Most reports, including one animal study, have found no evidence of developmental toxicity with erythromycin. Although one report found an association with cardiovascular defects (see reference 17), the investigators could not determine if it was a true drug effect. There also is no evidence that maternal erythromycin treatment late in pregnancy causes infantile hypertrophic pyloric stenosis (IHPS). Because most studies do not indicate a risk, erythromycin can be used in pregnancy if indicated.
FETAL RISK SUMMARY
Erythromycin is a macrolide anti-infective that is in the same class as azithromycin, clarithromycin, dirithromycin, and troleadomycin.
The drug was not teratogenic in female rats fed erythromycin (up to 0.25% of the diet) before and during mating, and throughout gestation and weaning (1).
Erythromycin crosses the placenta but in concentrations too low to treat most pathogens (2–4). Fetal tissue levels increase after multiple doses (4). However, a case has been described in which erythromycin was used successfully to treat maternal syphilis but failed to treat the fetus adequately (5). During pregnancy, erythromycin serum concentrations vary greatly as compared with those in normal men and nonpregnant women, which might account for the low levels observed in the fetus (6).
The estolate salt of erythromycin has been observed to induce hepatotoxicity in pregnant patients (7). Approximately 10% of 161 women treated with the estolate form in the 2nd trimester had abnormally elevated levels of serum glutamic-oxaloacetic transaminase, which returned to normal after therapy was discontinued.
The use of erythromycin in the 1st trimester was reported in a mother who delivered an infant with left absence-of-tibia syndrome (8). The mother was also exposed to other drugs, which makes a relationship to the antibiotic unlikely.
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 79 of whom had 1st trimester exposure to erythromycin (9, pp. 297–313). For use anytime during pregnancy, 230 exposures were recorded (9, p. 435). No evidence was found to suggest a relationship to large categories of major and minor malformations or to individual defects. Erythromycin, like many other antibiotics, lowers urine estriol concentrations (see also Ampicillin for mechanism and significance) (10). The antibiotic has been used during the 3rd trimester to reduce maternal and infant colonization with group B β-hemolytic streptococcus (11,12). Erythromycin has also been used during pregnancy for the treatment of genital mycoplasma (13,14). A reduction in the rates of pregnancy loss and low-birth-weight infants was seen in patients with mycoplasma infection after treatment with erythromycin.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 6972 newborns had been exposed to erythromycin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 320 (4.6%) major birth defects were observed (297 expected). Specific data were available for six defect categories, including (observed/expected) 77/70 cardiovascular defects, 14/11 oral clefts, 1/3 spina bifida, 22/20 polydactyly, 14/12 limb reduction defects, and 11/17 hypospadias. These data do not support an association between the drug and congenital malformations.
Data from the Hungarian Case–Control Surveillance of Congenital Abnormalities, 1980–1996, regarding exposure to erythromycin during organogenesis were published in 1999 (15). Cases (N = 22,865) were fetuses or infants with congenital abnormalities, 113 (0.5%) of whom had been exposed to erythromycin. Among controls (N = 38,151), newborns without any congenital anomalies, 172 (0.5%) had been exposed to erythromycin. There were 20 cases and 43 controls exposed during the 2nd–3rd months (i.e., organogenesis), odds ratio (OR) 0.8, 95% confidence interval (CI) 0.5–1.4. For exposures during months 4–9, there were 78 cases and 112 controls, OR 1.2, 95% CI 0.9–1.6, and for the entire pregnancy, OR 1.1, 95% CI 0.9–1.5. The study found no detectable teratogenic risk from erythromycin (15).
A 2001 randomized study (ORACLE 1) was conducted in patients with preterm, prelabor rupture of fetal membranes to determine neonatal health benefits of three antibiotic regimens (16). The regimens, compared with a placebo group (N = 1225), were erythromycin (250 mg) (N = 1197), amoxicillin (250 mg)–clavulanic acid (125 mg) (N = 1212), or both (N = 1192) four times daily for 10 days or until delivery. The primary outcome measures were specific outcomes or a composite of neonatal death, chronic lung disease, or major cerebral abnormality. For these neonatal outcomes, the two groups with ACA had no benefit over placebo, whereas erythromycin use resulted in significantly better outcomes (both composite and specific). When any-ACA exposure was compared with no-ACA for outcomes with suspected or proven NEC, the results were 92 (3.8%) and 58 (2.4%) (p = 0.004). The authors thought that a possible mechanism for this outcome was that the ACA combination selected for Clostridium difficile and that abnormal colonization of the neonatal intestinal tract was one possible mechanism for NEC (16).
A 2003 case–control study, using data from three Swedish health registers, was conducted to identify drug use in early pregnancy that was associated with cardiac defects (17). Cases (cardiovascular defects without known chromosome anomalies) (N = 5015) were compared with controls consisting of all infants born in Sweden (1995–2001) (N = 577,730). Associations were identified for several drugs, some of which were probably due to confounding from the underlying disease or complaint or multiple testing, but some were thought to be true drug effects. For erythromycin, there were 27 cases in 1588 exposures (OR 1.91, 95% CI 1.30–2.80). The study could not determine if the association was due to confounding, multiple testing, or a true drug effect (17).
Three reports have examined the association between maternal treatment with erythromycin during pregnancy and IHPS in their infants (18–20). The first report evaluated the presence of IHPS in the infants (not treated with erythromycin) of mothers who were prescribed a macrolide antibiotic within three pregnancy time periods (18). The antibiotics were primarily erythromycin, but included azithromycin and clarithromycin and the infants were not treated with erythromycin. For the three time periods, the relative risk for subsequent infant IHPS and 95% CI were: anytime in pregnancy, 1.15, 0.5–2.4; within 10 weeks of delivery, including delivery date 1.76, 0.7–4.2; and within 10 weeks of delivery, excluding delivery date 1.84, 0.8–4.4 (18).
The second report used data collected between 1976 and 1998 as part of an ongoing case–control surveillance program (19). Cases, 1044 infants with IHPS, were compared with two control groups, normal and malformed. Erythromycin exposure in case subjects were identified in three pregnancy time periods: 1–24 weeks, 25–40 weeks, and 33–40 weeks. The number of cases, OR, 95% CI for each time period with normal controls were: 26, 1.0, 0.6–1.6; 10, 0.6, 0.3–1.1; and 6, 0.7, 0.3–1.8, respectively. For malformed controls, the OR and 95% CI for each period was: 1.1, 0.8–1.7; 0.6, 0.3–1.1; and 0.6, 0.3–1.3, respectively. The results indicated no evidence of an increased risk of pyloric stenosis with erythromycin (19).
The third study, published in 2002, used the Tennessee Medicaid/Tenn Care 1985–1997 database (20). Among the 260,799 mother–infant pairs, 13,146 mothers filled prescriptions for erythromycin and 621 filled prescriptions for nonerythromycin macrolides (azithromycin, clarithromycin, clindamycin, dirithromycin) or lincomycin from 32 weeks’ gestation through delivery. The number of infant IHPS cases, OR, and 95% CI, in the erythromycin group was 38, 1.17, 0.84–1.64 after 32 weeks’ gestation. There were 22,418 mother–infant pairs with erythromycin exposure anytime in pregnancy with 53 cases, 1.15, 0.84–1.56. For nonerythromycin macrolides, the data for the two pregnancy periods were 3 cases, 2.45, 0.78–7.68 and, for anytime in pregnancy, 1287 exposures, 6 cases, 2.77, 1.22–6.30. Although the latter data reached statistical significance, the authors concluded that a causal inference was limited by the small number of infants and for other reasons (20).
In a 2003 Danish study, 188 women received a macrolide (see Breastfeeding Summary) within 30 days of birth and none of their infants had IHPS (21).
Several reports have described the use of erythromycin for the successful treatment of Chlamydia infection in the second half of pregnancy (22–27). Although such use is effective, fewer maternal gastrointestinal adverse effects have been observed with amoxicillin (see Amoxicillin) (25–27).
BREASTFEEDING SUMMARY
Erythromycin is excreted into breast milk (28). Following oral doses of 400 mg every 8 hours, milk levels ranged from 0.4 to 1.6 mcg/mL. Oral doses of 2 g/day produced milk concentrations of 1.6–3.2 mcg/mL. The milk:plasma ratio in both groups was 0.5 (28).
In a 1993 cohort study, diarrhea was reported in 32 (19.3%) nursing infants of 166 breastfeeding mothers who were taking antibiotics (29). For the 17 women taking erythromycin, diarrhea was observed in 2 (12%) infants. The diarrhea was considered minor because it did not require medical attention (29).
A 2003 study investigated the association between maternal use of macrolides and infantile hypertrophic pyloric stenosis (21). The Danish population–based cohort study comprised 1166 women who had a prescribed macrolide (azithromycin, clarithromycin, erythromycin, spiramycin, or roxithromycin) from birth to 90 days postnatally compared with up to 41,778 controls. The ORs for stenosis was 2.3–3.0, depending on the postnatal period of exposure (42, 56, 70, or 90 days), but none were significant. When stratified by gender, the ORs for males were 1.8–3.1 and again were not statistically significant. For females, the OR at 70 and 90 days postbirth were 10.3 and 7.5, respectively, but only the former was significant (95% CI 1.2–92.3) (21).
Investigators from Israel examined the possible association between macrolide (azithromycin, clarithromycin, erythromycin, or roxithromycin) exposure in milk and infantile hypertrophic pyloric stenosis in a 2009 study (30). They compared 55 infants exposed to a macrolide antibiotic to 36 infants exposed to amoxicillin. In the macrolide group, 7 (12.7%) had an adverse reaction (rash, diarrhea, loss of appetite, somnolence), whereas 3 infants (8.3%) in the amoxicillin group had an adverse reaction (rashes, somnolence). The rates of adverse reactions were comparable. No cases of infantile hypertrophic pyloric stenosis were observed (30).
The American Academy of Pediatrics classified erythromycin as compatible with breastfeeding in 2001 (31).
References
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