Renin-angiotensin system (ACEIs and/or ARBs) (versus unexposed) updated on 03-11-2025

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.
S17123
R71707		 Van der Zande - ACE-Is and/or ARBs, 2024 Total congenital anomalies (fetal anomalies and congenital disease in the infant, that correspond to major malformations according to the table) 1st trimester prospective cohort unexposed, sick Adjustment: Yes Indications Antihypertensive: Only cardiac indications other than hypertension (long QT syndrome, structural heart disease, ...) Renin angiotensin: ARBs and/or ACEIs (Angiotensin II receptor blockers and/or Angiotensin-converting enzyme inhibitors) 3.15 [1.04;9.56] 4/34   294/5,697 298 34
ref
S14147
R55486		 Hoeltzenbein a - ARBs, 2018 Major birth defects early pregnancy prospective cohort unexposed, disease free Adjustment: Yes Indications Antihypertensive: Only chronic hypertension indication Matched Renin angiotensin: ARBs (Angiotensin II receptor blockers) 1.85 [0.70;4.90] 9/168   17/570 26 168
ref
S14149
R55513		 Hoeltzenbein b - ACEi, 2018 Major birth defects early pregnancy prospective cohort unexposed, disease free Adjustment: Yes Indications Antihypertensive: Only chronic hypertension indication Matched Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 2.41 [1.07;5.43] 14/255   19/567 33 255
ref
S13793
R54096		 Bateman - ACE inhibitor (Controls unexposed, NOS), 2017 Overall major malformations 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) excluded Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 1.82 [1.61;2.06]
excluded (control group) 		244/4,107   43,323/1,329,517 43,567 4,107
ref
S13794
R54099		 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Overall major malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indications Antihypertensive: Only chronic hypertension indication Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 0.89 [0.75;1.06] 142/2,631   634/15,884 776 2,631
ref
S13803
R54114		 Van Gelder - ACE inhibitors, 2015 Selected major birth defects (heart defects, CNS malformations, cleft lip with or without cleft palate, small intestinal atresia/stenosis, hypospadias, ...) 1st trimester case control unexposed (general population or NOS) Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 2.00 [0.70;5.50] 9/15   5,559/12,806 5,568 15
ref
S14211
R55717		 Colvin - ACEi, 2014 Any major birth defect 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 2.58 [1.27;5.24] 10/84   3,950/97,533 3,960 84
ref
S13936
R54561		 Vasilakis-Scaramozza - ACE inhibitors, 2013 Any anomaly, excluding minor and chromosomal anomalies 1st trimester retrospective cohort unexposed (general population or NOS) Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 2.50 [0.50;13.50] 2/40   16/682 18 40
ref
S14145
R55548		 Diav-Citrin - ACEi/ARB, 2011 Major anomalies without chromosomal, genetic, or related to other known teratogens (including ETOPs (elective termination of pregnancy) due to prenatally diagnosed anomalies) early pregnancy prospective cohort unexposed (general population or NOS) Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ARBs and/or ACEIs (Angiotensin II receptor blockers and/or Angiotensin-converting enzyme inhibitors) 1.11 [0.47;2.59] C 8/190   18/471 26 190
ref
S13783
R53935		 Li - ACE inhibitors (Controls unexposed, disease free), 2011 Major birth defects at least 1st trimester retrospective cohort (claims database) unexposed, disease free excluded Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 1.15 [0.87;1.52]
excluded (control group) 		58/704   22,429/416,218 22,487 704
ref
S13782
R53929		 Li - ACE inhibitors (Controls unexposed, sick), 2011 Major birth defects at least 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 0.97 [0.73;1.30] 58/704   2,247/31,274 2,305 704
ref
S13472
R51967		 Nakhai-Pour - ACE inhibitors, 2010 Major malformations 1st trimester nested case control unexposed (general population or NOS) Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 1.02 [0.13;7.77] C 1/14   4,154/59,019 4,155 14
ref
S14212
R55709		 Malm - ACEi, 2008 Major congenital malformations 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 2.20 [1.19;4.08] 11/137   11,767/348,852 11,778 137
ref
S14144
R55533		 Cooper - ACEi, 2006 Major congenital malformation (not related to a chromosomal defect or a clinical genetic syndrome) 1st trimester retrospective cohort (claims database) unexposed (general population or NOS) Adjustment: Yes Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 2.71 [1.72;4.27] 18/209   834/29,096 852 209
ref
S14146
R55480		 Cournot - ACEi, 2006 Major malformations 1st trimester prospective cohort unexposed (general population or NOS) Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified Matched Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 1.50 [0.30;6.50] 4/137   3/148 7 137
ref
Total 13 studies 1.68 [1.21;2.34] 29,802 4,618
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 Van der Zande - ACE-Is and/or ARBs, 2024Van der Zande - ACE-Is and/or ARBs, 2024 3.15[1.04; 9.56]298346%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Hoeltzenbein a - ARBs, 2018Hoeltzenbein a - ARBs, 2018 1.85[0.70; 4.90]261686%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Hoeltzenbein b - ACEi, 2018Hoeltzenbein b - ACEi, 2018 2.41[1.07; 5.43]332558%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Bateman - ACE inhibitor (Controls unexposed, sick), 2017Bateman - ACE inhibitor, 2017 1 0.89[0.75; 1.06]7762,63114%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Van Gelder - ACE inhibitors, 2015Van Gelder - ACE inhibitors, 2015 2.00[0.70; 5.50]5,568156%ROB confusion: criticalROB selection: criticalROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Colvin - ACEi, 2014Colvin - ACEi, 2014 2.58[1.27; 5.24]3,960849%ROB confusion: seriousROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: moderateROB reporting: critical Vasilakis-Scaramozza - ACE inhibitors, 2013Vasilakis-Scaramozza - ACE inhibitors, 2013 2.50[0.50; 13.50]18403%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Diav-Citrin - ACEi/ARB, 2011Diav-Citrin - ACEi/ARB, 2011 1.11[0.47; 2.59]261907%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Li - ACE inhibitors (Controls unexposed, sick), 2011Li - ACE inhibitors, 2011 2 0.97[0.73; 1.30]2,30570413%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: moderateROB reporting: moderate Nakhai-Pour - ACE inhibitors, 2010Nakhai-Pour - ACE inhibitors, 2010 1.02[0.13; 7.77]4,155142%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: moderate Malm - ACEi, 2008Malm - ACEi, 2008 2.20[1.19; 4.08]11,77813710%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Cooper - ACEi, 2006Cooper - ACEi, 2006 2.71[1.72; 4.27]85220912%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Cournot - ACEi, 2006Cournot - ACEi, 2006 1.50[0.30; 6.50]71374%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Total (13 studies) I2 = 71% 1.68[1.21; 2.34]29,8024,6180.210.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

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

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 1.69[1.19; 2.41]20,0794,58976%NAVan der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Diav-Citrin - ACEi/ARB, 2011 Li - ACE inhibitors (Controls unexposed, sick), 2011 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 11 case control studiescase control studies 1.74[0.69; 4.37]9,723290%NAVan Gelder - ACE inhibitors, 2015 Nakhai-Pour - ACE inhibitors, 2010 2 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 2.19[1.70; 2.83]26,4231,2490%NAHoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Van Gelder - ACE inhibitors, 2015 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Diav-Citrin - ACEi/ARB, 2011 Nakhai-Pour - ACE inhibitors, 2010 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 10 unexposed, sickunexposed, sick 1.01[0.74; 1.38]3,3793,36960%NAVan der Zande - ACE-Is and/or ARBs, 2024 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Li - ACE inhibitors (Controls unexposed, sick), 2011 3 Tags Adjustment   - No  - No 1.38[0.78; 2.46]9,7563560%NAVan Gelder - ACE inhibitors, 2015 Diav-Citrin - ACEi/ARB, 2011 Nakhai-Pour - ACE inhibitors, 2010 Cournot - ACEi, 2006 4   - Yes  - Yes 1.79[1.20; 2.65]20,0464,26280%NAVan der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Li - ACE inhibitors (Controls unexposed, sick), 2011 Malm - ACEi, 2008 Cooper - ACEi, 2006 9 Indications Antihypertensive   - All hypertensions, any indications ...  - All hypertensions, any indications or not specified 1.74[1.16; 2.60]28,6691,53061%NAVan Gelder - ACE inhibitors, 2015 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Diav-Citrin - ACEi/ARB, 2011 Li - ACE inhibitors (Controls unexposed, sick), 2011 Nakhai-Pour - ACE inhibitors, 2010 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 9   - Only cardiac indications other than ...  - Only cardiac indications other than hypertension (long QT syndrome, structural heart disease, ...) 3.15[1.04; 9.55]29834 -NAVan der Zande - ACE-Is and/or ARBs, 2024 1   - Only chronic hypertension indication  - Only chronic hypertension indication 1.43[0.70; 2.94]8353,05473%NAHoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 3 MatchedMatched 2.05[1.15; 3.66]665600%NAHoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Cournot - ACEi, 2006 3 Renin angiotensin   - ACEIs (Angiotensin-converting enzym ...  - ACEIs (Angiotensin-converting enzyme inhibitors) 1.67[1.14; 2.44]29,4524,22676%NAHoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Van Gelder - ACE inhibitors, 2015 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Li - ACE inhibitors (Controls unexposed, sick), 2011 Nakhai-Pour - ACE inhibitors, 2010 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 10   - ARBs (Angiotensin II receptor blockers)  - ARBs (Angiotensin II receptor blockers) 1.85[0.70; 4.89]26168 -NAHoeltzenbein a - ARBs, 2018 1   - ARBs and/or ACEIs (Angiotensin II r ...  - ARBs and/or ACEIs (Angiotensin II receptor blockers and/or Angiotensin-converting enzyme inhibitors) 1.75[0.63; 4.85]32422454%NAVan der Zande - ACE-Is and/or ARBs, 2024 Diav-Citrin - ACEi/ARB, 2011 2 All studiesAll studies 1.68[1.21; 2.34]29,8024,61871%NAVan der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Van Gelder - ACE inhibitors, 2015 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Diav-Citrin - ACEi/ARB, 2011 Li - ACE inhibitors (Controls unexposed, sick), 2011 Nakhai-Pour - ACE inhibitors, 2010 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 130.210.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.43.01.2450.000Van der Zande - ACE-Is and/or ARBs, 2024Hoeltzenbein a - ARBs, 2018Hoeltzenbein b - ACEi, 2018Bateman - ACE inhibitor (Controls unexposed, sick), 2017Van Gelder - ACE inhibitors, 2015Colvin - ACEi, 2014Vasilakis-Scaramozza - ACE inhibitors, 2013Diav-Citrin - ACEi/ARB, 2011Li - ACE inhibitors (Controls unexposed, sick), 2011Nakhai-Pour - ACE inhibitors, 2010Malm - ACEi, 2008Cooper - ACEi, 2006Cournot - ACEi, 2006

Asymetry test p-value = 0.0090 (by Egger's regression)

slope=-0.1990 (0.1417); intercept=1.9125 (0.6047); t=3.1627; p=0.0090

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 13783, 13793

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 1.79[1.46; 2.20]92,4776,06034%NAHoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, NOS), 2017 Van Gelder - ACE inhibitors, 2015 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Diav-Citrin - ACEi/ARB, 2011 Li - ACE inhibitors (Controls unexposed, disease free), 2011 Nakhai-Pour - ACE inhibitors, 2010 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 12 unexposed, sick controlsunexposed, sick controls 1.01[0.74; 1.38]3,3793,36960%NAVan der Zande - ACE-Is and/or ARBs, 2024 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Li - ACE inhibitors (Controls unexposed, sick), 2011 30.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Vial (ACEi) (Major congenital malformations)Vial (ACEi) (Major congenital malformations) 1.80[1.41; 2.31]53%-U,DFunexposed, disease freeT11st trimesterstudies TTT10 Walfisch (ARA/ACEi) (Major congenital malform ...Walfisch (ARA/ACEi) (Major congenital malformations) 1.78[1.07; 2.94]41%-U,DFunexposed, disease freeT11st trimesterstudies TTT5 Walfisch (ARA/ACEi) (Major congenital malform ...Walfisch (ARA/ACEi) (Major congenital malformations) 1.41[0.66; 3.04]52%-Eexposed to other treatment, sickT11st trimesterstudies TTT4 Fu (ACEi/ARBs) (Major congenital malformation ...Fu (ACEi/ARBs) (Major congenital malformations (versus exposed to other oral antihypertensives) - Fixed effects) 1.48[1.08; 2.02]8%-Eexposed to other treatment, sickT1+at least 1st trimesterstudies TTT6 Fu (ACEi/ARBs) (Major congenital malformation ...Fu (ACEi/ARBs) (Major congenital malformations (versus exposed to other oral antihypertensives) - Random effects) 1.64[0.97; 2.78]8%-Eexposed to other treatment, sickT1+at least 1st trimesterstudies TTT6 Fu (ACEi/ARBs) (Major congenital malformation ...Fu (ACEi/ARBs) (Major congenital malformations (versus non‐exposed controls)) 1.82[1.42; 2.34]26%-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT9 Vial (ACEi) (Major congenital malformations ( ...Vial (ACEi) (Major congenital malformations (versus treated or untreated hypertension)) 1.07[0.82; 1.40]38%-Eexposed to other treatment, sickT11st trimesterstudies TTT7 metaPregmetaPreg 1.68[1.21; 2.34]71%4,618----Van der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein a - ARBs, 2018 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Van Gelder - ACE inhibitors, 2015 Colvin - ACEi, 2014 Vasilakis-Scaramozza - ACE inhibitors, 2013 Diav-Citrin - ACEi/ARB, 2011 Li - ACE inhibitors (Controls unexposed, sick), 2011 Nakhai-Pour - ACE inhibitors, 2010 Malm - ACEi, 2008 Cooper - ACEi, 2006 Cournot - ACEi, 2006 130.510.01.0