Associations between use of macrolide antibiotics during pregnancy and adverse child outcomes: A systematic review and meta-analysis

Abstract

Background: Evidence on adverse effects of maternal macrolide use during pregnancy is inconsistent. We conducted a systematic review and meta-analysis to investigate the association between macrolide use during pregnancy and adverse fetal and child outcomes.

Methods and findings: We included observational studies and randomised controlled trials (RCTs) that recorded macrolide use during pregnancy and child outcomes. We prioritized comparisons of macrolides with alternative antibiotics (mainly penicillins or cephalosporins) for comparability of indication and effect. Random effects meta-analysis was used to derive pooled odds ratios (OR) for each outcome. Subgroup analyses were performed according to specific types (generic forms) of macrolide. Of 11,186 citations identified, 19 (10 observational, 9 RCTs) studies were included (21 articles including 228,556 participants). Macrolide prescribing during pregnancy was associated with an increased risk of miscarriage (pooled ORobs 1·82, 95% CI 1·57-2·11, three studies, I2 = 0%), cerebral palsy and/or epilepsy (ORobs 1·78, 1·18-2·69; one study), epilepsy alone (ORobs 2·02, 1·30-3·14, one study; ORRCT 1.03, 0.79-1.35, two studies), and gastrointestinal malformations (ORobs 1·56, 1·05-2·32, two studies) compared with alternative antibiotics. We found no evidence of an adverse effect on 12 other malformations, stillbirth, or neonatal death. Results were robust to excluding studies with high risk of bias.

Conclusions: Consistent evidence of an increased risk of miscarriage in observational studies and uncertain risks of cerebral palsy and epilepsy warrant cautious use of macrolide in pregnancy with warnings in drug safety leaflets and use of alternative antibiotics where appropriate. As macrolides are the third most commonly used class of antibiotics, it is important to confirm these results with high quality studies.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Study selection.

Fig 2. Assessment of bias.

a: Evaluated as moderate risk in secondary analysis (low risk in primary analysis) due to incomparable treatment effect. b: Studies only eligible for secondary analysis. c: In the study of Andersen (2013), the OR was adjusted by maternal age, number of previous miscarriages, income and education. d: In the study of Le guyen, the OR was adjusted by maternal age, long-term illnesses, parity and multiple pregnancy. e: In the study of Meeraus (2015), the Hazard Ratio was adjusted by maternal age, Townsend quintile, year of delivery, smoking, alcohol problems, obesity, illicit drug use, treatment of chronic medical conditions and potentially neurologically-damaging infection during pregnancy. f: In the study of Muanda (2017), cases and controls were matched by gestational age and year of pregnancy; in the analysis of specific macrolides, the ORs were adjusted by 11 covariates, e.g. maternal age, education level, chronic comorbidities, maternal infections (urinary tract infection, respiratory tract infection, bacterial vaginosis and sexually transmitted infections) and prior exposure to antibiotics.

Fig 3. Primary and secondary analysis for the association between prenatal use of macrolides and adverse child outcomes.