Systematic Review With Meta-analysis

The Risks of Proton Pump Inhibitors During Pregnancy

Cheng Mei Li; Alexandra Zhernakova; Lars Engstrand; Cisca Wijmenga; Nele Brusselaers


Aliment Pharmacol Ther. 2020;51(4):410-420. 

In This Article

Abstract and Introduction


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.


Proton pump inhibitors (PPI) are among the most commonly and increasingly used drugs worldwide, with up to one-third using prescribed PPI annually.[1–4] PPIs are also accessible because of the over-the-counter availability in many countries. Yet, the safety of PPIs is more and more questioned in particular considering cancer, mortality, chronic kidney disease and other potential long-term effects.[1,5–7] PPIs have also been described as the drug group with the largest effect on the gastro-intestinal microbiome, in terms of decreasing diversity, based on population-based studies, larger than antibiotics and any other drug.[8–10] Safety during pregnancy has also been questioned repeatedly,[11–13] including a recent meta-analysis showing a 45% increased risk of childhood asthma in offspring,[14] and another study showing an increased risk of cholestasis.[15] The two previous meta-analyses assessing pregnancy outcomes after PPI use, published more than 10 years ago, showed an increased risk of congenital malformations in women using PPI during pregnancy, yet the results did not reach statistical significance (RR = 1.18, 95% CI 0.72–1.94, 5 studies;[11] RR = 1.12, 95% CI 0.86–1.45, 7 studies[12]). Two meta-analyses assessing H2-receptor antagonists (H2RA), the most popular alternative for PPIs, showed no associations with congenital malformations (pooled OR = 1.14, 95% CI 0.89–1.45, 4 studies),[16] and a significant increased risk of asthma (pooled RR = 1.57; 95% CI 1.46–1.69, 5 studies).[14]

Omeprazole, the most commonly used PPI was initially categorised as category C by the Food and Drug Administration, implying some teratogenic effects have been described in animal studies, and safety is not absolutely guaranteed for human use during pregnancy.[17,18] Other PPIs were categorised as category B, which also warrants some prudence in use during pregnancy.[17,18] Current recommendations (not using these categories anymore) for Omeprazole are that "this drug should be used during pregnancy only if the benefit outweighs the risk to the foetus", and that it is not recommended during breastfeeding.[19] Therefore, it may not be surprising that we have not identified any randomised clinical trials on PPI use during pregnancy assessing neonatal adverse events.[20,21] Yet, although not recommended for nausea and vomiting during pregnancy nor hyperemesis gravidarum,[21] a small studies reported effective treatment of reflux.[22] Global statistics on how many women use PPIs during pregnancy are scarce, but it's use is estimated to be below 1.5% in Sweden.[23] Yet, their use may also be underestimated if based on prescription-use,[24] and potentially increasing in the many countries with over-the-counter availability. Reported PPIs are also used for gastro-oesophageal reflux and heartburn during pregnancy, usually arising during the 2nd and 3rd trimester due to hormonal changes and mechanistic pressure.[25,26] Although outside the critical embryogenic period for congenital malformations, drug exposure during later pregnancy may affect other less-studied outcomes such as preterm birth and low-birth weight, and childhood asthma (although timing of exposure could not be assessed in this meta-analysis).[14]

Since several new studies have been published on PPI use during pregnancy during the last decade, the aim of this systematic review and meta-analysis is to assess the current evidence of PPI use (and H2RA as most popular alternative treatment) during pregnancy and the risk of adverse events, including congenital malformations but also preterm birth and other neonatal adverse events.