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

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

We searched PubMed, Embase, the Cochrane Library, Conference Proceeding Citation Index-Science, and ClinicalTrials.gov from inception to Feb 15, 2018, with no language restrictions. We included observational studies and randomised controlled trials (RCTs) that recorded macrolide use during pregnancy and fetal and child outcomes. We prioritised comparisons of macrolides with alternative antibiotics (mainly penicillins or cephalosporins) for indication and effect. Secondary analysis included RCTs that compared macrolide use with placebo and macrolide use plus alternative antibiotics with the same alternatives. Random effects meta-analysis was used to derive pooled odds ratios (OR) for each outcome. We described heterogeneity according to comparators (other antibiotics or placebo) and type of macrolide.

Findings

Of 11?186 citations identified, 19 studies (ten observational, nine RCTs) were included (21 articles with 228?556 participants). Macrolide prescribing during pregnancy was associated with an increased risk of miscarriage (pooled OR 1·82, 95% CI 1·57–2·11; I²=0% [three observational studies]), cerebral palsy or epilepsy (1·78, 1·18–2·69; one observational study), epilepsy alone (2·02, 1·30–3·14 [one observational study]; 1·03, 0·79–1·35 [two RCTs]), and gastrointestinal malformations (1·56, 1·05-2·32; two observational studies) compared with alternative antibiotics. We found no evidence of an adverse effect on 12 other malformations, stillbirth, or neonatal death. Secondary analyses showed similar results to those from the primary analysis. Results were robust to excluding studies with high risk of bias.

Interpretation

Our findings of an increased risk of miscarriage cannot be explained by indication bias. 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. Since macrolides are the third most commonly used class of antibiotics, it is important to confirm these results with high-quality studies.

Funding

Economic and Social Research Council (grant ES/L007517/1). Child Health Research CIO (CHR CIO) Trust and China Scholarship Council (grant 201606100058) (for HF).