Proton Pump Inhibitors updated on 08-08-2023

Major congenital malformations

R analysis
id Study   Lib. in paper Exposition period    Study type 
 Control type 
 
Tags OR 95%CI x1/n1 x0/n0 no cases no exposed ROB Ref.
S18808
R80033		 Broe (Controls unexposed, general pop), 2025 Major congenital malformations (exclusion of chromosomal abnormalities (ICD-10 codes Q90– Q99)) 1st trimester population based cohort retrospective unexposed (general population or NOS) excluded Adjustment: Yes 1.20 [1.09;1.31]
excluded (control group) 		540/12,129   16,811/468,490 17,351 12,129
ref
S18809
R80036		 Broe (Controls unexposed, sick), 2025 Major congenital malformations (exclusion of chromosomal abnormalities (ICD-10 codes Q90– Q99)) 1st trimester population based cohort retrospective unexposed, sick Adjustment: Yes 1.07 [0.95;1.21] 540/12,129   802/19,272 1,342 12,129
ref
S18819
R80061		 Hongoh - Lansoprazole, 2025 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: Yes 0.51 [0.07;3.79] 1/96   31/1,669 32 96
ref
S18406
R77680		 Choi a (Controls unexposed, sibling), 2023 Major congenital malformations 1st trimester retrospective cohort (claims database) sibling excluded Adjustment: Yes 1.05 [0.91;1.22]
excluded (control group) 		600/16,787   604/18,567 1,204 16,787
ref
S14453
R57351		 Choi a (Controls unexposed, sick), 2023 Major congenital malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes 1.07 [1.02;1.13] 1,608/40,540   85,900/2,655,676 87,508 40,540
ref
S4446
R10559		 Matok, 2012 Major malformations (according to CDC definitions) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes 1.06 [0.84;1.33] 80/1,186   6,425/109,597 6,505 1,186
ref
S4442
R10696		 Bànhidy - Omeprazole, 2011 Congenital abnormalities during pregnancy (anytime or not specified) excluded case control unexposed (general population or NOS) Adjustment: No Matched 1.23 [1.02;1.47] C
excluded (exposition period) 		206/487   22,637/60,507 22,843 487
ref
S4881
R12842		 Colvin, 2011 Major birth defects 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: No 1.20 [0.80;2.00] 18/360   3,953/98,825 3,971 360
ref
S4275
R10431		 Pasternak, 2010 Major birth defects (Exposure during First Trimester) 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes 1.10 [0.91;1.34] 118/3,651   21,867/837,317 21,985 3,651
ref
S4428
R10466		 Diav-Citrin, 2005 Major anomalies 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 1.04 [0.51;2.10] C 11/280   30/792 41 280
ref
S4883
R13158		 Moretti, 2002 Major malformations at least 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No 1.19 [0.17;8.21] 2/63   2/75 4 63
ref
S4293
R10017		 Lalkin - Omeprazole (Controls exposed to other treatment, sick), 1998 Major malformations 1st trimester prospective cohort exposed to other treatment, sick excluded Adjustment: No Matched 1.71 [0.37;7.89] C
excluded (control group) 		4/78   3/98 7 78
ref
S4407
R10425		 Lalkin - Omeprazole (Controls unexposed NOS), 1998 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Matched 1.73 [0.31;9.76] C 4/78   2/66 6 78
ref
Total 9 studies 1.07 [1.03;1.12] 121,394 58,383
x1: number of endpoints among exposed, n1: number of exposed; x0: number of endpoints among non exposed, n0: number of non exposed; C: calculated odds ratio from numbers of events and effectives

Forest plot

StudyTE95% CIn casesn exposedweightROBABCDEF Broe (Controls unexposed, sick), 2025Broe, 2025 1 1.07[0.95; 1.21]1,34212,12914%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Hongoh - Lansoprazole, 2025Hongoh - Lansoprazole, 2025 0.51[0.07; 3.79]32960%ROB confusion: seriousROB selection: criticalROB classification: moderateROB missing: unclearROB mesure: criticalROB reporting: critical Choi a (Controls unexposed, sick), 2023Choi a, 2023 2 1.07[1.02; 1.13]87,50840,54076%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: unclearROB mesure: NAROB reporting: NA Matok, 2012Matok, 2012 1.06[0.84; 1.33]6,5051,1864%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Colvin, 2011Colvin, 2011 1.20[0.80; 2.00]3,9713601%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Pasternak, 2010Pasternak, 2010 1.10[0.91; 1.34]21,9853,6515%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Diav-Citrin, 2005Diav-Citrin, 2005 1.04[0.51; 2.10]412800%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Moretti, 2002Moretti, 2002 1.19[0.17; 8.21]4630%ROB confusion: unclearROB selection: unclearROB classification: unclearROB missing: unclearROB mesure: unclearROB reporting: unclear Lalkin - Omeprazole (Controls unexposed NOS), 1998Lalkin - Omeprazole, 1998 3 1.73[0.31; 9.76]6780%ROB confusion: criticalROB selection: criticalROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Total (9 studies) I2 = 0% 1.07[1.03; 1.12]121,39458,3830.25.01.0ROB: A: confounding, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: Controls unexposed, sick; 3: Controls unexposed NOS;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.07[1.03; 1.12]121,39458,3830%NABroe (Controls unexposed, sick), 2025 Hongoh - Lansoprazole, 2025 Choi a (Controls unexposed, sick), 2023 Matok, 2012 Colvin, 2011 Pasternak, 2010 Diav-Citrin, 2005 Moretti, 2002 Lalkin - Omeprazole (Controls unexposed NOS), 1998 9 case control studiescase control studies 0 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 1.09[0.95; 1.25]32,5445,7140%NAHongoh - Lansoprazole, 2025 Matok, 2012 Colvin, 2011 Pasternak, 2010 Diav-Citrin, 2005 Moretti, 2002 Lalkin - Omeprazole (Controls unexposed NOS), 1998 7 unexposed, sickunexposed, sick 1.07[1.02; 1.12]88,85052,6690%NABroe (Controls unexposed, sick), 2025 Choi a (Controls unexposed, sick), 2023 2 Tags Adjustment   - No  - No 1.17[0.81; 1.69]4,0227810%NAColvin, 2011 Diav-Citrin, 2005 Moretti, 2002 Lalkin - Omeprazole (Controls unexposed NOS), 1998 4   - Yes  - Yes 1.07[1.02; 1.12]117,37257,6020%NABroe (Controls unexposed, sick), 2025 Hongoh - Lansoprazole, 2025 Choi a (Controls unexposed, sick), 2023 Matok, 2012 Pasternak, 2010 5 MatchedMatched 1.73[0.31; 9.76]678 -NALalkin - Omeprazole (Controls unexposed NOS), 1998 1 All studiesAll studies 1.07[1.03; 1.12]121,39458,3830%NABroe (Controls unexposed, sick), 2025 Hongoh - Lansoprazole, 2025 Choi a (Controls unexposed, sick), 2023 Matok, 2012 Colvin, 2011 Pasternak, 2010 Diav-Citrin, 2005 Moretti, 2002 Lalkin - Omeprazole (Controls unexposed NOS), 1998 90.25.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.42.51.2220.000Broe (Controls unexposed, sick), 2025Hongoh - Lansoprazole, 2025Choi a (Controls unexposed, sick), 2023Matok, 2012Colvin, 2011Pasternak, 2010Diav-Citrin, 2005Moretti, 2002Lalkin - Omeprazole (Controls unexposed NOS), 1998

Asymetry test p-value = 0.7140 (by Egger's regression)

slope=0.0669 (0.0118); intercept=0.0662 (0.1734); t=0.3818; p=0.7140

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 4293, 18406, 18808

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.17[1.08; 1.26]49,89517,8430%NABroe (Controls unexposed, general pop), 2025 Hongoh - Lansoprazole, 2025 Matok, 2012 Colvin, 2011 Pasternak, 2010 Diav-Citrin, 2005 Moretti, 2002 Lalkin - Omeprazole (Controls unexposed NOS), 1998 8 unexposed, sick controlsunexposed, sick controls 1.07[1.02; 1.12]88,85052,6690%NABroe (Controls unexposed, sick), 2025 Choi a (Controls unexposed, sick), 2023 2 exposed to other treatment, sick controlsexposed to other treatment, sick controls 1.71[0.37; 7.89]778 -NALalkin - Omeprazole (Controls exposed to other treatment, sick), 1998 1 siblingssiblings 1.05[0.91; 1.22]1,20416,787 -NAChoi a (Controls unexposed, sibling), 2023 10.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Li (Congenital malformations overall includin ...Li (Congenital malformations overall including continuity correction) 1.28[1.09; 1.52]26-Anyduring pregnancy (anytime or not specified)studies TTT18 Gill (Major congenital malformations)Gill (Major congenital malformations) 1.12[0.86; 1.45]0-T11st trimesterstudies TTT7 Nikfar (Major malformations)Nikfar (Major malformations) 1.18[0.72; 1.94]-T11st trimesterstudies TTT5 Samji (Major malformations)Samji (Major malformations) 1.20[1.00; 1.39]-Wwhatever (meta-analysis)T11st trimesterstudies TTT-9 Peron (metaPreg) (Overall major congenital ma ...Peron (metaPreg) (Overall major congenital malformations) 1.10[0.95; 1.26]0%-Wwhatever (meta-analysis)T11st trimesterstudies TTT6 metaPregmetaPreg 1.07[1.03; 1.12]0%58,383----Broe (Controls unexposed, sick), 2025 Hongoh - Lansoprazole, 2025 Choi a (Controls unexposed, sick), 2023 Matok, 2012 Colvin, 2011 Pasternak, 2010 Diav-Citrin, 2005 Moretti, 2002 Lalkin - Omeprazole (Controls unexposed NOS), 1998 90.510.01.0