Acid-suppressive medications during pregnancy and risk of asthma and allergy in children: A systematic review and meta-analysis
2017; Elsevier BV; Volume: 139; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2016.09.046
ISSN1097-6825
AutoresRebecca E Devine, Nicola McCleary, Aziz Sheikh, Bright I. Nwaru,
Tópico(s)Pregnancy and Medication Impact
ResumoDiscuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. To the Editor: Acid-suppressive medications, such as H2-receptor antagonists (H2RA) and proton pump inhibitors (PPI), are the main treatment options for dyspepsia and gastroesophageal reflux disease. These are common problems in pregnancy.1Schöll I. Ackermann U. Blumer N. Özdemir C. Dicke T. Sel S. et al.Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2 bias in their offspring.FASEB J. 2007; 21: 1264-1270Crossref PubMed Scopus (60) Google Scholar Recently, concerns have been raised that prenatal exposure to these medications may increase the risk of allergic disease in the offspring, which was first reported by Schöll and colleagues.1Schöll I. Ackermann U. Blumer N. Özdemir C. Dicke T. Sel S. et al.Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2 bias in their offspring.FASEB J. 2007; 21: 1264-1270Crossref PubMed Scopus (60) Google Scholar This was followed by the study by Dehlink and colleagues2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar who reported the first findings in humans, proposing that use of acid-suppressive medications in pregnancy may increase the risk of allergic disease in the offspring through interference with maternal digestion of labile antigens, thereby increasing the amount of allergen to which the fetus is exposed. PPI use has also been linked to changes in the intestinal microbiota composition,3Theisen J. Nehra D. Citron D. Johansson J. Hagen J.A. Crookes P.F. et al.Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids.J Gastrointest Surg. 2000; 4: 50-54Crossref PubMed Scopus (198) Google Scholar which may also increase the risk of Th2-mediated conditions, such as asthma and allergy. Supporting the findings from the study by Schöll and colleagues,1Schöll I. Ackermann U. Blumer N. Özdemir C. Dicke T. Sel S. et al.Anti-ulcer treatment during pregnancy induces food allergy in mouse mothers and a Th2 bias in their offspring.FASEB J. 2007; 21: 1264-1270Crossref PubMed Scopus (60) Google Scholar Dehlink et al2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar therefore proposed that acid-suppressive medications could operate through 1 or both of these mechanisms, inducing a Th2 cytokine pattern in mothers that could then cross the fetal membrane and induce sensitization of fetal immune cells to food and airborne allergens prior to birth. An increasing number of studies have now investigated the impact of prenatal exposure to acid-suppressive medications on the risk of allergic disease in the offspring but with inconsistent results.2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar, 4Andersen A.B. Erichsen R. Farkas D.K. Mehnert F. Ehrenstein V. Sørensen H.T. Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study.Aliment Pharmacol Ther. 2012; 35: 1190-1198Crossref PubMed Scopus (20) Google Scholar, 5Källén B. Finnström O. Nygren K.G. Otterblad Olausson P. Maternal drug use during pregnancy and asthma risk among children.Pediatr Allergy Immunol. 2013; 24: 28-32Crossref PubMed Scopus (36) Google Scholar, 6Mulder B. Schuiling-Veninga C.C. Bos J.H. de Vries T.W. Hak E. Acid-suppressive drug use in pregnancy and the toddler's asthma risk: a crossover, case-control study.J Allergy Clin Immunol. 2013; 132: 1438-1440Abstract Full Text Full Text PDF PubMed Google Scholar, 7Hak E. Mulder B. Schuiling-Veninga C.C. De Vries T.W. Jick S.S. Use of acid-suppressive drugs in pregnancy and the risk of childhood asthma: bidirectional crossover study using the general practice research database.Drug Saf. 2013; 36: 1097-1104Crossref PubMed Scopus (10) Google Scholar, 8Mulder B. Schuiling-Veninga C.C. Bos H.J. De Vries T.W. Jick S.S. Hak E. Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.Clin Exp Allergy. 2014; 44: 261-269Crossref PubMed Scopus (13) Google Scholar, 9Cea Soriano L. Hernandez-Diaz S. Johansson S. Nagy P. Garcia-Rodriguez L.A. Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood: an observational cohort study.Aliment Pharmacol Ther. 2016; 43: 427-437Crossref PubMed Scopus (8) Google Scholar, 10Yitshak-Sade M. Gorodischer R. Aviram M. Novack L. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.J Clin Pharmacol. 2016; 56: 116-123Crossref PubMed Google Scholar To obtain a clearer appreciation of the evidence base, we undertook a systematic review and meta-analysis of these studies. We were also interested in clarifying whether use of the subtypes of acid-suppressive medications, namely H2RA and PPIs, was associated with asthma/allergy and whether any associations uncovered varied by time (trimester), dose, and frequency of exposure. We included analytical epidemiological studies (ie, cohort, case-control, and cross-sectional studies). We excluded reviews, case studies and case series, and animal studies. All women during preconception and pregnancy and their offspring who were ≤17 years were eligible for inclusion. Our primary outcomes were (1) objectively defined asthma, atopic dermatitis/eczema, allergic rhinitis or hay fever, food allergy, urticaria, and anaphylaxis and (2) atopic sensitization as defined either by skin prick test or raised antigen-specific IgE (see description of secondary outcomes in Study outcomes of this article's Online Repository at www.jacionline.org). To identify relevant studies, we searched 11 electronic databases and searched databases of ongoing studies and conference abstracts (see details in the Information sources, search strategy, and study selection section of this article's Online Repository). We also contacted experts in the field to identify additional studies and any ongoing studies. We developed a detailed search strategy in MEDLINE, which was then adapted for searching other databases (Table E1 in this article's Online Repository at www.jacionline.org). All databases were searched from inception to the end of 2015, with no language restrictions. Two reviewers (R.E.D. and B.I.N.) independently screened all titles and/or abstracts, screened full texts of potentially eligible studies, extracted study data onto a customized data extraction form, and quality appraised all studies using the Effective Public Health Practice Project tool (Hamilton, Ontario, Canada). Any discrepancies in the process were resolved by discussion or a third reviewer (N.M.) arbitrated. We graded key components from which we derived an overall grading for each study as strong, moderate, or weak (see Tables E2 and E3 in this article's Online Repository at www.jacionline.org). We employed random-effects meta-analysis to quantify the pooled effect estimates for reasonably homogeneous studies. Meta-analysis was possible with studies on risk of asthma but not for other outcomes due to insufficient number of studies. Dosage, trimester, and frequency of exposure to acid-suppressive medications were differentially reported across studies; hence we were unable to pool studies on these exposures. We quantified the level of heterogeneity between studies using the I2 statistic (values near 0 indicate good homogeneity across studies). Meta-analyses were undertaken using Stata 14 (StataCorp LP, College Station, Tex). See this article's Online Repository (www.jacionline.org) for a fuller description of our approach to data synthesis and application of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Of the 3282 records identified from our searches, 8 studies2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar, 4Andersen A.B. Erichsen R. Farkas D.K. Mehnert F. Ehrenstein V. Sørensen H.T. Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study.Aliment Pharmacol Ther. 2012; 35: 1190-1198Crossref PubMed Scopus (20) Google Scholar, 5Källén B. Finnström O. Nygren K.G. Otterblad Olausson P. Maternal drug use during pregnancy and asthma risk among children.Pediatr Allergy Immunol. 2013; 24: 28-32Crossref PubMed Scopus (36) Google Scholar, 6Mulder B. Schuiling-Veninga C.C. Bos J.H. de Vries T.W. Hak E. Acid-suppressive drug use in pregnancy and the toddler's asthma risk: a crossover, case-control study.J Allergy Clin Immunol. 2013; 132: 1438-1440Abstract Full Text Full Text PDF PubMed Google Scholar, 7Hak E. Mulder B. Schuiling-Veninga C.C. De Vries T.W. Jick S.S. Use of acid-suppressive drugs in pregnancy and the risk of childhood asthma: bidirectional crossover study using the general practice research database.Drug Saf. 2013; 36: 1097-1104Crossref PubMed Scopus (10) Google Scholar, 8Mulder B. Schuiling-Veninga C.C. Bos H.J. De Vries T.W. Jick S.S. Hak E. Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.Clin Exp Allergy. 2014; 44: 261-269Crossref PubMed Scopus (13) Google Scholar, 9Cea Soriano L. Hernandez-Diaz S. Johansson S. Nagy P. Garcia-Rodriguez L.A. Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood: an observational cohort study.Aliment Pharmacol Ther. 2016; 43: 427-437Crossref PubMed Scopus (8) Google Scholar, 10Yitshak-Sade M. Gorodischer R. Aviram M. Novack L. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.J Clin Pharmacol. 2016; 56: 116-123Crossref PubMed Google Scholar met our inclusion criteria (see Fig E1 in this article's Online Repository at www.jacionline.org). Key characteristics of the studies are presented in Table E2 (in this article's Online Repository at www.jacionline.org). Six studies were graded as strong and 2 as moderate. In pooled analysis, use of any acid-suppressive medications (risk ratio, 1.36; 95% CI, 1.16-1.61; I2 = 87.6%), H2RA (hazard ratio, 1.46; 95% CI, 1.29-1.65; I2 = 15.3%), and PPI (hazard ratio, 1.30; 95% CI, 1.07-1.56; I2 = 45.2%) were associated with an increased risk of asthma (Figs 1 and 2). Results of sensitivity analyses are given in this article's Online Repository. Two studies that considered other allergic disorders both reported an increased risk among offspring of mothers using any acid-suppressive medications, H2RA, and PPIs compared with the offspring of nonusing mothers2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar, 8Mulder B. Schuiling-Veninga C.C. Bos H.J. De Vries T.W. Jick S.S. Hak E. Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.Clin Exp Allergy. 2014; 44: 261-269Crossref PubMed Scopus (13) Google Scholar (see Table E2 in this article's Online Repository). By applying the GRADE approach, we graded the evidence regarding the risk of asthma as moderate, but evidence regarding other allergic outcomes as very low (see Table E4 in this article's Online Repository at www.jacionline.org). The Egger test (to evaluate publication bias and small-study effect) for the association between use of any acid-suppressive medications and risk of asthma showed P = .415.Fig 2A and B, Meta-analysis of studies investigating the association between maternal use of H2-receptor antagonists (H2RA) and proton pump inhibitors (PPI) during pregnancy and the risk of asthma in the offspring. HR represents the hazard ratio of association. Population represents the number of participants recruited into the study.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our literature search was comprehensive. We had no language restriction, used reproducible search strategies, and applied rigorous review processes, which were enhanced by publishing and registering a detailed protocol prior to undertaking the review.11Devine R.E. Sheikh A. Nwaru B.I. Acid-suppressive medications during pregnancy and risk of asthma and allergy in the offspring: protocol for a systematic review.NPJ Prim Care Respir Med. 2016; 26: 16001Crossref PubMed Google Scholar The degree of heterogeneity among studies was low; the only case of high heterogeneity was due to differences in the definition of the exposure. In the course of our literature search, we found a recent systematic review from Google Scholar, published in Chinese in a local journal.12Wang Y. Han F. Liu L. A meta-analysis of relationship between acid-suppressive drugs ingested by pregnant women and their descendent asthma.J Clin Med Pract. 2014; 18: 88-90Google Scholar Five studies were included in that review and were meta-analyzed. On translation to English, we found that the systematic review process was deficient in many aspects, including the following: lack of information about quality assessment, data extraction, or the number of reviewers involved; unclear decisions regarding meta-analysis decisions (whether fixed-effect or random-effects meta-analysis was used) or the approach employed to evaluate heterogeneity between studies. Animal models and studies undertaken in adults suggest that acid-suppressive medications may interfere with peptide digestion, thereby inducing a Th2 cytokine dominance, which may result in subsequent sensitization of the immune system.2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar Such interference may increase the amount of allergen the fetus is exposed to via the placenta, thereby resulting in sensitization and subsequent development of allergic disorders and asthma.2Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (0) Google Scholar Our findings of increased risk may reflect a true risk or may be explained by residual confounding and/or confounding by indication. Of note is that none of the studies adjusted for the full panel of known confounders in these associations. Although we cannot recommend any changes to the use of acid-suppressive medications by expectant mothers, further research is needed, particularly through mounting pharmacovigilance studies, which may prove more ethically acceptable and feasible than initiating randomized controlled clinical trials. We are grateful to Marshall Dozier and Angela Nicholson, the Academic Librarians at The University of Edinburgh, for their advice on the construction of search strategies. We are grateful to Io Hui for her help in translating 1 paper from Chinese. Finally, we wish to express our sincere gratitude to the experts contacted who responded, including Eelko Hak, Edda Fiebiger, Lucia Soriano, Rafael Gorodischer, and in particular to Maaya Yitshak-Sade who provided additional data. We completed the University of Edinburgh's Usher Institute of Informatics and Population Health Sciences Level 1 Ethics Clearance, which revealed that no further ethics clearance is required because the study is based on published literature. Prior to commencement of the review, we developed a detailed protocol, which was publishedE1Devine R.E. Sheikh A. Nwaru B.I. Acid-suppressive medications during pregnancy and risk of asthma and allergy in the offspring: protocol for a systematic review.NPJ Prim Care Respir Med. 2016; 26: 16001Crossref PubMed Scopus (2) Google Scholar and registered with the International Prospective Register of Systematic Reviews (PROSPERO; www.crd.york.ac.uk/prospero/, reference CRD42015029584). We included analytical epidemiological studies: cohort, case-control, and cross-sectional studies. We excluded reviews, case studies and case series, and animal studies. All women during preconception and pregnancy and their offspring who were ≤17 years were eligible for inclusion. We considered all studies that investigated the association between maternal use of any type of acid-suppressive medications ([ASMs], ie, H2-receptor antagonists [H2RA], proton pump inhibitors [PPIs], and antacids) during pregnancy and the risk of asthma and allergy in the offspring. We also considered the dose, frequency, and timing (trimester) of use of these medications. Our primary outcomes were objectively defined asthma, atopic dermatitis/eczema, allergic rhinitis or hay fever, anaphylaxis, food allergy, urticaria, and anaphylaxis by physician or hospital record or self-reported. Atopic sensitization as defined either by skin prick test or raised antigen-specific IgE. Secondary outcomes included objective and subjective measures of disease severity and impact on quality of life, including asthma exacerbations, use of asthma medications, hospitalization for asthma, wheeze as defined by self-report or objective diagnosis; indicators of airway function including (peak expiratory flow, forced expiratory volume in 1 second, forced vital capacity, forced expiratory flow rate or alternative age appropriate pulmonary function tests [oscillometry or exhaled nitric oxide analysis]); and measures of health-related quality of life. We searched the following international electronic databases: MEDLINE, EMBASE, Web of Science CORE, BIOSIS, CINAHL, Cochrane Library, Global Health CABI, Global Health Library, Scopus, Popline, and Google Scholar. Additional studies were retrieved by manual search of the references of eligible papers and by contacting a panel of international experts on the topic. Conference abstracts were retrieved by searching ISI Conference Proceedings Citation Index via Web of Knowledge and ZETOC (British Library). Unpublished and in-progress studies were identified by searching Current Controlled Trials, ClinicalTrials.gov, Australian and New Zealand Clinical Trials Registry. We developed a detailed search strategy in MEDLINE, which was then adapted in searching other databases (Table E1). All databases were searched from inception to the end of 2015, with no language restrictions. Identified records were exported to Endnote Library for screening. After removal of duplicate records, 2 reviewers (R.E.D. and B.I.N.) independently screened all titles and/or abstracts. Full texts of potentially eligible studies were obtained and independently screened for inclusion by the 2 reviewers. Studies that did not fulfill the inclusion criteria were excluded. Any discrepancies in the screening process were resolved by discussion. Two reviewers (R.E.D. and B.I.N.) independently extracted study data onto a customized data extraction form. The data extraction form was piloted and revised prior to use in collecting data from all studies. Discrepancies in data extraction were resolved by discussion and arbitration by a third reviewer (N.M.). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist guided reporting.E2Moher D. Liberati A. Tetzlaff J. Altman D.G. for the PRISMA GroupPreferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.BMJ. 2009; 339: b2535Crossref PubMed Scopus (15071) Google Scholar Two reviewers (R.E.D. and B.I.N.) independently undertook the risk of bias analysis in the study using the Effective Public Health Practice Project tool (Hamilton, Ontario, Canada), which was adapted for use in this review. We graded key components of each study as strong, moderate, or weak: suitability of the study design for the research question, validity of exposure and outcome assessments, potential for selection bias, and appropriate adjustment for confounding factors. From these component-specific assessments, we derived an overall grading for each study as strong, moderate, or weak. Any discrepancies were resolved by discussion or a third reviewer (N.M.) arbitrated. Eligible studies reported 1 of the following effect measures: hazard ratio (HR), risk ratio (RR), or odds ratio (OR). Although Andersen et alE3Andersen A.B. Erichsen R. Farkas D.K. Mehnert F. Ehrenstein V. Sørensen H.T. Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study.Aliment Pharmacol Ther. 2012; 35: 1190-1198Crossref PubMed Scopus (35) Google Scholar stated that they estimated incidence rate ratios using Cox proportional hazard regression, we took these estimates as HR in the pooled analysis because the Cox model estimates the hazard function. Mulder et alE4Mulder B. Schuiling-Veninga C. Bos H.J. De Vries T.W. Jick S.S. Hak E. Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.Clin Exp Allergy. 2014; 44: 261-269Crossref PubMed Scopus (28) Google Scholar and Soriano et alE5Cea Soriano L. Hernandez-Diaz S. Johansson S. Nagy P. Garcia Rodriguez L.A. Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood.Gastroenterology. 2015; : S135Abstract Full Text PDF PubMed Google Scholar also reported HR. Yitshak-Sade et alE6Yitshak-Sade M. Gorodischer R. Aviram M. Novack L. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.J Clin Pharmacol. 2016; 56: 116-123Crossref PubMed Scopus (8) Google Scholar reported RR; estimates of studies reporting ORE7Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (63) Google Scholar, E8Källén B. Finnstr€om O. Nygren K.G. Otterblad Olausson P. Maternal drug use during pregnancy and asthma risk among children.Pediatr Allergy Immunol. 2013; 24: 28-32Crossref PubMed Scopus (53) Google Scholar, E9Mulder B. Schuiling-Veninga C.C. Bos J.H. de Vries T.W. Hak E. Acid-suppressive drug use in pregnancy and the toddler's asthma risk: a crossover, case-control study.J Allergy Clin Immunol. 2013; 132: 1438-1440Abstract Full Text Full Text PDF PubMed Google Scholar, E10Hak E. Mulder B. Schuiling-Veninga C.C. de Vries T.W. Jick S.S. Use of acid-suppressive drugs in pregnancy and the risk of childhood asthma: bidirectional crossover study using the general practice research database.Drug Saf. 2013; 36: 1097-1104Crossref PubMed Scopus (19) Google Scholar were converted to RR using the formulae by GrantE11Grant R.L. Converting an odds ratio to a range of plausible relative risks for better communication of research findings.BMJ. 2014; 348: f7450Crossref PubMed Scopus (244) Google Scholar and then pooled with the Yitshak-Sade et alE6Yitshak-Sade M. Gorodischer R. Aviram M. Novack L. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.J Clin Pharmacol. 2016; 56: 116-123Crossref PubMed Scopus (8) Google Scholar study. The formula for conversion is given as follows: RR = OR/[1 − p0 + (p0 × OR)], where p0 is the baseline risk. The baseline risks for Dehlink et alE7Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (63) Google Scholar and Källén et alE8Källén B. Finnstr€om O. Nygren K.G. Otterblad Olausson P. Maternal drug use during pregnancy and asthma risk among children.Pediatr Allergy Immunol. 2013; 24: 28-32Crossref PubMed Scopus (53) Google Scholar were taken from the respective papers. The baseline risk for Mulder et al (2013)E9Mulder B. Schuiling-Veninga C.C. Bos J.H. de Vries T.W. Hak E. Acid-suppressive drug use in pregnancy and the toddler's asthma risk: a crossover, case-control study.J Allergy Clin Immunol. 2013; 132: 1438-1440Abstract Full Text Full Text PDF PubMed Google Scholar was taken from Mulder et al (2014),E4Mulder B. Schuiling-Veninga C. Bos H.J. De Vries T.W. Jick S.S. Hak E. Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.Clin Exp Allergy. 2014; 44: 261-269Crossref PubMed Scopus (28) Google Scholar which was based on the same study population. For Hak et al,E10Hak E. Mulder B. Schuiling-Veninga C.C. de Vries T.W. Jick S.S. Use of acid-suppressive drugs in pregnancy and the risk of childhood asthma: bidirectional crossover study using the general practice research database.Drug Saf. 2013; 36: 1097-1104Crossref PubMed Scopus (19) Google Scholar we used the prevalence estimate (4.2%) reported elsewhere but based on a similar primary care database.E12Simpson C.R. Sheikh A. Trends in the epidemiology of asthma in England: a national study of 333,294 patients.J R Soc Med. 2010; 103: 98-106Crossref PubMed Scopus (93) Google Scholar The RR derived from these calculations are presented in Table E5. Of the 8 studies, 6 were retrospective cohort studies,E3Andersen A.B. Erichsen R. Farkas D.K. Mehnert F. Ehrenstein V. Sørensen H.T. Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study.Aliment Pharmacol Ther. 2012; 35: 1190-1198Crossref PubMed Scopus (35) Google Scholar, E4Mulder B. Schuiling-Veninga C. Bos H.J. De Vries T.W. Jick S.S. Hak E. Prenatal exposure to acid-suppressive drugs and the risk of allergic diseases in the offspring: a cohort study.Clin Exp Allergy. 2014; 44: 261-269Crossref PubMed Scopus (28) Google Scholar, E5Cea Soriano L. Hernandez-Diaz S. Johansson S. Nagy P. Garcia Rodriguez L.A. Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood.Gastroenterology. 2015; : S135Abstract Full Text PDF PubMed Google Scholar, E6Yitshak-Sade M. Gorodischer R. Aviram M. Novack L. Prenatal exposure to H2 blockers and to proton pump inhibitors and asthma development in offspring.J Clin Pharmacol. 2016; 56: 116-123Crossref PubMed Scopus (8) Google Scholar, E7Dehlink E. Yen E. Leichtner A.M. Hait E.J. Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study.Clin Exp Allergy. 2009; 39: 246-253Crossref PubMed Scopus (63) Google Scholar, E8Källén B. Finnstr€om O. Nygren K.G. Otterblad Olausson P. Maternal drug use during pregnancy and asthma risk among children.Pediatr Allergy Immunol. 2013; 24: 28-32Crossref PubMed Scopus (53) Google Scholar and 2 were case-control studies.E9Mulder B. Schuiling-Veninga C.C. Bos J.H. de Vries T.W. Hak E. Acid-suppressive drug use in pregnancy and the toddler's asthma risk: a crossover, case-control study.J Allergy Clin Immunol. 2013; 132: 1438-1440Abstract Full Text Full Text PDF PubMed Google Scholar, E10Hak E. Mulder B. Schuiling-Veninga C.C. de Vries T.W. Jick S.S. Use of acid-suppressive drugs in pregnancy and the risk of childhood asthma: bidirectional crossover study using the general practice research database.Drug Saf. 2013; 36: 1097-1104Crossref PubMed Scopus (19) Google Scholar, E13Guddat C. Grouven U. Bender R. Skipka G. A note on the graphical presentation of prediction intervals in random-effects meta-analyses.Syst Rev. 2012; 1: 34Crossref PubMed Scopus (34) Google Scholar, E14Begg C.B. Mazumdar M. Operating characteristics of a rank correlation test for publication bias.Biometrics. 1994; 50: 1088-1101Crossref PubMed Scopus (11923) Google Scholar We summarized the overall evidence both narratively and quantitatively. For the quantitative synthesis, we employed random-effects meta-analysis to quantify the pooled effect estimates for sufficiently clinically, methodologically, and statistically homogeneous studies. Mulder et al (2013)E9Mulder B. Schuiling-Veninga C.C. Bos J.H. de Vries T.W. Hak E. Acid-suppressive drug use in pregnancy and the toddler's asthma risk: a crossover, case-control study.J Allergy Clin Immunol. 2013; 132: 1438-1440Abstract Full Text Full Text PDF PubMed Google Scholar analyzed 2 sets of control populations that were compared with the same asthma cases: sibling-based controls and non-sibling-based controls. In the analysis, we treated these sets of case-control populations independently. This was applicable for use of any ASMs, H2RA only, and PPIs only; there were no data on use of antacids. Dosage of ASMs and trimester of exposure were differentially reported across studies; hence we were unable to pool studies on these exposures. Meta-analys
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