The Safety of Proton Pump Inhibitors (PPIs) in Pregnancy: A Meta-Analysis

The Motherisk Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada.
The American Journal of Gastroenterology (Impact Factor: 10.76). 07/2009; 104(6):1541-5; quiz 1540, 1546. DOI: 10.1038/ajg.2009.122
Source: PubMed


Heartburn and acid reflux are common medical disorders in pregnancy and can result in serious discomfort and complications. Furthermore, some pregnant women also experience more severe gastrointestinal conditions, such as Helicobacter pylori infections, peptic ulcers, and Zollinger-Ellison syndrome. To allow the use of proton pump inhibitors (PPIs) in pregnancy, the fetal safety of this drug class must be established. The aim of this study is to determine the fetal safety of PPIs during early pregnancy through systematic literature review.
All original research assessing the safety of PPIs in pregnancy was sought from inception to July 2008. Two independent reviewers identified articles, compared results, and settled differences through consensus. The Downs-Black scale was used to assess quality. Data assessed included congenital malformations, spontaneous abortions, and preterm delivery. A random effects meta-analysis combined the results from included studies.
Of the 60 articles identified, 7 met our inclusion criteria. Using data from 134,940 patients, including 1,530 exposed and 133,410 not exposed to PPIs, the overall odds ratio (OR) for major malformations was 1.12 (95% confidence interval, CI: 0.86-1.45). Further analysis revealed no increased risk for spontaneous abortions (OR=1.29, 95% CI: 0.84-1.97); similarly, there was no increased risk for preterm delivery (OR=1.13, 95% CI: 0.96-1.33). In the secondary analysis of 1,341 exposed and 120,137 not exposed to omeprazole alone, the OR and 95% CI for major malformations were 1.17 and 0.90-1.53, respectively.
On the basis of these results, PPIs are not associated with an increased risk for major congenital birth defects, spontaneous abortions, or preterm delivery. The narrow range of 95% CIs is further reassuring, suggesting that PPIs can be safely used in pregnancy.

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Available from: Lisa O'Brien, May 06, 2015
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    • "Furthermore, the regulation of ion flux has increasingly been identified as a critical player in diseases including cancer. Moreover, there have recently been concerns raised about the safety of proton pump inhibitors taken during pregnancy and their links to resulting birth defects (Gill et al., 2009; Pasternak and Hviid, 2010). Our application of optogenetics to the control of complex developmental and regenerative bioelectrical events, and the regulation of known transcriptional cascades by brief optical stimulation of cells demonstrates the enormous potential for expanding the use of light-controlled ion flux beyond regulating action potentials in nerve and muscle tissues. "
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    ABSTRACT: Optogenetics, the regulation of proteins by light, has revolutionized the study of excitable cells, and generated strong interest in the therapeutic potential of this technology for regulating action potentials in neural and muscle cells. However, it is currently unknown whether light-activated channels and pumps will allow control of resting potential in embryonic or regenerating cells in vivo. Abnormalities in ion currents of non-excitable cells are known to play key roles in the etiology of birth defects and cancer. Moreover, changes in transmembrane resting potential initiate Xenopus tadpole tail regeneration, including regrowth of a functioning spinal cord, in tails that have been inhibited by natural inactivity of the endogenous H(+)-V-ATPase pump. However, existing pharmacological and genetic methods allow neither non-invasive control of bioelectric parameters in vivo nor the ability to abrogate signaling at defined time points. Here, we show that light activation of a H(+)-pump can prevent developmental defects and induce regeneration by hyperpolarizing transmembrane potentials. Specifically, light-dependent, Archaerhodopsin-based, H(+)-flux hyperpolarized cells in vivo and thus rescued Xenopus embryos from the craniofacial and patterning abnormalities caused by molecular blockade of endogenous H(+)-flux. Furthermore, light stimulation of Arch for only 2 days after amputation restored regenerative capacity to inhibited tails, inducing cell proliferation, tissue innervation, and upregulation of notch1 and msx1, essential genes in two well-known endogenous regenerative pathways. Electroneutral pH change, induced by expression of the sodium proton exchanger, NHE3, did not rescue regeneration, implicating the hyperpolarizing activity of Archaerhodopsin as the causal factor. The data reveal that hyperpolarization is required only during the first 48 hours post-injury, and that expression in the spinal cord is not necessary for the effect to occur. Our study shows that complex, coordinated sets of stable bioelectric events that alter body patterning-prevention of birth defects and induction of regeneration-can be elicited by the temporal modulation of a single ion current. Furthermore, as optogenetic reagents can be used to achieve that manipulation, the potential for this technology to impact clinical approaches for preventive, therapeutic, and regenerative medicine is extraordinary. We expect this first critical step will lead to an unprecedented expansion of optogenetics in biomedical research and in the probing of novel and fundamental biophysical determinants of growth and form.
    Biology Open 03/2013; 2(3):306-13. DOI:10.1242/bio.20133665 · 2.42 Impact Factor
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    • "There is prospective data on PPIs taken during the first trimester of pregnancy, that showed no increased risk of major birth defects [20]. PPIs can be considered as safe drugs during pregnancy [21,22]. In most pregnant women reflux symptoms can be managed by lifestyle modifications and intermittent use of antacids. "
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    ABSTRACT: Background: Symptoms of gastro-esophageal reflux disease (GERD) in pregnancy are reported with a prevalence of 30-80%. The aim of this study was to assess the prevalence and severity of GERD symptoms during the course of pregnancy. Furthermore current practice in medical care for GERD during pregnancy was assessed. Methods: We performed a prospective longitudinal cohort study on 510 pregnant women (mean age 28.12, SD 5.3). Investigations for reflux symptoms where based on the use of validated reflux-disease questionnaire (RDQ). Additional information was collected about the therapy. A group of non-pregnant women (mean age 24.56, SD 5.7) was included as controls. Frequency and severity of reflux symptoms were recorded in each trimester of pregnancy. Results: The prevalence of GERD symptoms in pregnant women increased from the first trimester with 26.1 to 36.1% in the second trimester and to 51.2% in the third trimester of pregnancy. The prevalence of GERD symptoms in the control group was 9.3%.Pregnant women received medication for their GERD symptoms in 12.8% during the first, 9.1% during the second and 15.7% during the third trimester. Medications used >90% antacids, 0% PPI. Conclusion: GERD symptoms occur more often in pregnant women than in non-pregnant and the frequency rises in the course of pregnancy. Medical therapy is used in a minority of cases and often with no adequate symptom relief.
    BMC Gastroenterology 09/2012; 12(1). DOI:10.1186/1471-230X-12-131 · 2.37 Impact Factor
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    • "A meta-analysis examining 1530 pregnant women exposed to PPI therapy (predominantly omeprazole) during the first trimester of pregnancy failed to reveal any statistically significant increase in risk of teratogenicity [Gill et al. 2009]. A large registry-based cohort study of over 5000 live infants born to mothers who took PPIs during pregnancy (predominantly omeprazole) also failed to yield viable results linking PPI therapy to an increased risk of birth defects [Pasternak and Hviid, 2010]. "
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    ABSTRACT: Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.
    Therapeutic Advances in Gastroenterology 07/2012; 5(4):219-32. DOI:10.1177/1756283X12437358 · 3.93 Impact Factor
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