Prenatal Exposure to Macrolides and Risk of Congenital Malformations: A Meta-Analysis

Introduction: Macrolides are widely used during pregnancy; however, their fetal safety remains uncertain. We performed a meta-analysis to assess the relation between prenatal exposure to macrolides and occurrence of congenital malformations. Methods: We searched MEDLINE, EMBASE, and other databases until June 12, 2019. We assessed the quality of the studies and checked for heterogeneity and publication bias. We performed three different analyses and compared the effect of macrolides with each of the following unexposed populations: Group 1: babies unexposed to any medicine before birth, Group 2: babies exposed to non-macrolide antibiotics/non-teratogens, and Group 3: mixed population of the first and second comparators. Results: A weak association between macrolides and congenital malformation of any type was observed when macrolides were compared with the mixed population (OR_{group 3} 1.06 [95% CI 1.01–1.10]). Subgroup analysis showed that this weak association is restricted to fetus exposure in the first trimester of pregnancy (OR 1.06 [95% CI 1.01–1.11]) and to cohort studies (OR 1.07 [95% CI 1.02–1.13]). Digestive system malformations were found to be slightly associated with prenatal exposure to macrolides (OR_group 3 1.14 [95% CI 1.02–1.26]). The musculoskeletal system was also found to be potentially affected (OR_group 2 1.21 [95% CI 1.08–1.35] and OR_group 3 1.15 [95% CI 1.05–1.26]). European studies showed a slightly stronger association than American studies in these two comparisons. Conclusions: Our study suggests a weak association between prenatal use of macrolides and congenital malformations, limited to exposure in early pregnancy, and musculoskeletal and digestive systems. In addition to studies with a larger control of confounding, risk–benefit research is needed to determine the usefulness of macrolides during pregnancy.