Systematic review with meta-analysis: the risks of proton pump inhibitors during pregnancy.

BACKGROUND: There have been safety concerns considering long-term proton pump inhibitor (PPI) use, also during pregnancy.

AIMS: To assess the risk of adverse neonatal outcomes associated with maternal intake of PPIs by means of systematic review and meta-analysis.

METHODS: The systematic search included PubMed, Web of Science, Cochrane Database and Embase (inception until June 2019). All studies reporting ≥1 adverse pregnancy outcome comparing PPI users to non-users. Histamine-2 receptor antagonists (H2RA) were also compared to both non-users and PPI users. Outcomes included congenital malformations, abortion, stillbirth, neonatal death, preterm birth, small for gestational age and low birth weight. Pooled odds ratios (OR) and 95% confidence intervals (CI) were obtained by random-effects modelling. PROSPERO study-protocol: CRD42018103320.

RESULTS: In total, 26 observational studies (20 cohort, 6 case-control studies) were identified, of which 19 assessed PPIs and 12 H2RA. PPI use was associated with an increased risk of congenital malformations (OR 1.28, 95% CI 1.09-1.52), especially in case-control studies (OR 2.04, 1.46-2.86). No associations were found between H2RA and congenital malformations. No significant associations were found between PPI use and abortions, stillbirth, neonatal death, preterm birth and low-birth weight, although H2RA use may be associated with an increased risk of preterm birth (OR 1.25, 95% CI 1.02-1.56). Although statistical heterogeneity and the risk of bias were overall low, clinical heterogeneity, information and selection bias may be present in the individual studies.

CONCLUSIONS: This meta-analysis suggests an association between maternal PPI use and congenital malformations in humans, yet power was insufficient to assess specific malformations and drugs.