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

Congenital heart defects

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
R71705		 Van der Zande - ACE-Is and/or ARBs, 2024 Neonatal congenital heart disease (malformations according to the table) 1st trimester prospective cohort unexposed, sick Adjustment: No 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) 3.20 [0.97;10.59] C 3/34   167/5,697 170 34
ref
S14118
R55461		 Chintamaneni - ACE inhibitors, 2018 Congenital cardiac malformation during pregnancy (anytime or not specified) excluded 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) 1.80 [1.10;3.00]
excluded (exposition period) 		17/404   5,304/378,834 5,321 404
ref
S14149
R55515		 Hoeltzenbein b - ACEi, 2018 Cardiac malformations early pregnancy prospective cohort unexposed, disease free Adjustment: No Indications Antihypertensive: Only chronic hypertension indication Matched Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 3.03 [1.04;8.82] C 8/255   6/567 14 255
ref
S13793
R54097		 Bateman - ACE inhibitor (Controls unexposed, NOS), 2017 Cardiovascular 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) 2.95 [2.50;3.47]
excluded (control group) 		139/4,107   15,272/1,329,517 15,411 4,107
ref
S13794
R54100		 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Cardiovascular malformations 1st trimester retrospective cohort (claims database) unexposed, sick Adjustment: Yes Indications Antihypertensive: Only chronic hypertension indication Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 0.95 [0.75;1.21] 77/2,631   260/15,884 337 2,631
ref
S14251
R56021		 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, disease free), 2017 Any Congenital Heart Defects early pregnancy case control unexposed, disease free excluded Adjustment: Yes 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) 2.89 [1.41;5.91]
excluded (control group) 		32/43   10,593/21,719 10,625 43
ref
S14246
R55977		 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Any Congenital Heart Defects early pregnancy case control unexposed, sick Adjustment: Yes 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) 2.43 [1.16;5.06] 32/43   -/- - 43
ref
S14211
R55719		 Colvin - ACEi, 2014 Cardiovascular defects (ICD-9: 745-747) 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) 0.82 [0.11;6.33] -/84   691/97,533 - 84
ref
S13783
R53936		 Li - ACE inhibitors (Controls unexposed, disease free), 2011 Congenital heart 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) 1.39 [0.91;2.13]
excluded (control group) 		24/670   6,232/400,021 6,256 670
ref
S13782
R53930		 Li - ACE inhibitors (Controls unexposed, sick), 2011 Congenital heart 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) 1.10 [0.70;1.71] 24/670   708/29,735 732 670
ref
S13438
R51776		 Lennestal - ACE inhibitors, 2009 Any cardiovascular defect early pregnancy 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) 1.68 [0.20;6.08] 2/91   12,660/1,046,843 12,662 91
ref
S14212
R55711		 Malm - ACEi, 2008 Cardiovascular malformations 1st trimester population based cohort retrospective unexposed (general population or NOS) Adjustment: No Indications Antihypertensive: All hypertensions, any indications or not specified Renin angiotensin: ACEIs (Angiotensin-converting enzyme inhibitors) 7.30 [3.17;16.83] -/-   -/- - -
ref
S14144
R55534		 Cooper - ACEi, 2006 Cardiovascular system malformations 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) 3.72 [1.89;7.30] 9/209   294/29,096 303 209
ref
Total 9 studies 2.17 [1.27;3.72] 14,218 4,017
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 3.20[0.97; 10.59]170349%ROB confusion: criticalROB selection: lowROB classification: criticalROB missing: unclearROB mesure: unclearROB reporting: moderate Hoeltzenbein b - ACEi, 2018Hoeltzenbein b - ACEi, 2018 3.03[1.04; 8.82]1425510%ROB confusion: criticalROB selection: moderateROB classification: moderateROB missing: lowROB mesure: criticalROB reporting: moderate Bateman - ACE inhibitor (Controls unexposed, sick), 2017Bateman - ACE inhibitor, 2017 1 0.95[0.75; 1.21]3372,63116%ROB confusion: moderateROB selection: lowROB classification: moderateROB missing: lowROB mesure: unclearROB reporting: moderate Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017Fisher - Renin inhibitors, 2017 2 2.43[1.16; 5.06]-4313%ROB confusion: seriousROB selection: criticalROB classification: criticalROB missing: lowROB mesure: moderateROB reporting: moderate Colvin - ACEi, 2014Colvin - ACEi, 2014 0.82[0.11; 6.33]-845%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: unclearROB mesure: moderateROB reporting: critical Li - ACE inhibitors (Controls unexposed, sick), 2011Li - ACE inhibitors, 2011 3 1.10[0.70; 1.71]73267015%ROB confusion: seriousROB selection: moderateROB classification: criticalROB missing: moderateROB mesure: moderateROB reporting: moderate Lennestal - ACE inhibitors, 2009Lennestal - ACE inhibitors, 2009 1.68[0.20; 6.08]12,662916%ROB confusion: criticalROB selection: moderateROB classification: criticalROB missing: lowROB mesure: criticalROB reporting: moderate Malm - ACEi, 2008Malm - ACEi, 2008 7.30[3.17; 16.83]--12%ROB confusion: criticalROB selection: lowROB classification: moderateROB missing: unclearROB mesure: unclearROB reporting: moderate Cooper - ACEi, 2006Cooper - ACEi, 2006 3.72[1.89; 7.30]30320913%ROB confusion: seriousROB selection: lowROB classification: moderateROB missing: lowROB mesure: moderateROB reporting: moderate Total (9 studies) I2 = 80% 2.17[1.27; 3.72]14,2184,0170.220.01.0ROB: A: confusion, B: selection, C: classification, D: missing, E: measurement, F: reportinglow,moderate,serious,critical,unclear,

1: Controls unexposed, sick; 2: ACE/ARBs) (Controls unexposed, sick; 3: Controls unexposed, sick;

Sensitivity analysis

SubsetTE95% CIn casesn exposedkI2 Type of studies cohort studiescohort studies 2.14[1.18; 3.88]14,2183,97481%NAVan der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, sick), 2011 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 8 case control studiescase control studies 2.43[1.16; 5.08]-43 -NAFisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 1 Type of controls unexposed (disease free or unspecified)unexposed (disease free or unspecified) 3.59[2.04; 6.33]12,97963929%NAHoeltzenbein b - ACEi, 2018 Colvin - ACEi, 2014 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 5 unexposed, sickunexposed, sick 1.38[0.87; 2.19]1,2393,37866%NAVan der Zande - ACE-Is and/or ARBs, 2024 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Li - ACE inhibitors (Controls unexposed, sick), 2011 4 Tags Adjustment   - No  - No 4.63[2.56; 8.40]1842895%NAVan der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein b - ACEi, 2018 Malm - ACEi, 2008 3   - Yes  - Yes 1.56[0.94; 2.61]14,0343,72873%NABateman - ACE inhibitor (Controls unexposed, sick), 2017 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, sick), 2011 Lennestal - ACE inhibitors, 2009 Cooper - ACEi, 2006 6 Indications Antihypertensive   - All hypertensions, any indications ...  - All hypertensions, any indications or not specified 2.39[1.18; 4.83]13,6971,09775%NAFisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, sick), 2011 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 6   - Only cardiac indications other than ...  - Only cardiac indications other than hypertension (long QT syndrome, structural heart disease, ...) 3.20[0.97; 10.59]17034 -NAVan der Zande - ACE-Is and/or ARBs, 2024 1   - Only chronic hypertension indication  - Only chronic hypertension indication 1.50[0.49; 4.56]3512,88677%NAHoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 2 MatchedMatched 3.03[1.04; 8.82]14255 -NAHoeltzenbein b - ACEi, 2018 1 Renin angiotensin   - ACEIs (Angiotensin-converting enzym ...  - ACEIs (Angiotensin-converting enzyme inhibitors) 2.04[1.08; 3.85]14,0483,94083%NAHoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, sick), 2011 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 7   - ARBs and/or ACEIs (Angiotensin II r ...  - ARBs and/or ACEIs (Angiotensin II receptor blockers and/or Angiotensin-converting enzyme inhibitors) 2.62[1.40; 4.91]170770%NAVan der Zande - ACE-Is and/or ARBs, 2024 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 2 All studiesAll studies 2.17[1.27; 3.72]14,2184,01780%NAVan der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, sick), 2011 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 90.220.01.0

Publication bias and p-hacking diagnosis

funnel plot
0.0-2.43.21.2410.000Van der Zande - ACE-Is and/or ARBs, 2024Hoeltzenbein b - ACEi, 2018Bateman - ACE inhibitor (Controls unexposed, sick), 2017Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017Colvin - ACEi, 2014Li - ACE inhibitors (Controls unexposed, sick), 2011Lennestal - ACE inhibitors, 2009Malm - ACEi, 2008Cooper - ACEi, 2006

Asymetry test p-value = 0.0488 (by Egger's regression)

slope=-0.2480 (0.2818); intercept=2.4060 (1.0107); t=2.3805; p=0.0488

p values plot
0.01.00.01.0

Sub-groups analysis using all included studies

excluded 13783, 13793, 14251

Sub-groupsTE95% CIn casesn exposedkI2ROB type of controls unexposed controls (disease free or unspecified)unexposed controls (disease free or unspecified) 2.74[1.88; 3.99]45,9535,45962%NAHoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, NOS), 2017 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, disease free), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, disease free), 2011 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 8 unexposed, sick controlsunexposed, sick controls 1.38[0.87; 2.19]1,2393,37866%NAVan der Zande - ACE-Is and/or ARBs, 2024 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Li - ACE inhibitors (Controls unexposed, sick), 2011 40.510.01.0

Umbrella review (other published meta-analyses)

Published MAControlPeriodTE95% CIn exposedkI2 Vial (ACEi) (Cardiac malformations)Vial (ACEi) (Cardiac malformations) 2.41[1.59; 3.65]61%-U,DFunexposed, disease freeT11st trimesterstudies TTT5 Vial (ACEi) (Cardiac malformations (versus tr ...Vial (ACEi) (Cardiac malformations (versus treated or untreated hypertension)) 1.17[0.82; 1.67]43%-Eexposed to other treatment, sickT11st trimesterstudies TTT4 Fu (ACEi/ARBs) (Cardiovascular malformations ...Fu (ACEi/ARBs) (Cardiovascular malformations (versus exposed to other oral antihypertensives)) 2.00[0.54; 7.37]0%-Eexposed to other treatment, sickT1+at least 1st trimesterstudies TTT3 Fu (ACEi/ARBs) (Cardiovascular malformations ...Fu (ACEi/ARBs) (Cardiovascular malformations (versus non‐exposed controls)) 2.50[1.62; 3.87]30%-Wwhatever (meta-analysis)T1+at least 1st trimesterstudies TTT7 Buawangpong (ACEi/ARBs) (Cardiovascular syste ...Buawangpong (ACEi/ARBs) (Cardiovascular system malformations) 3.02[2.60; 3.51]0%-Wwhatever (meta-analysis)T11st trimesterstudies TTT7 Buawangpong (ACEi/ARBs) (Cardiovascular syste ...Buawangpong (ACEi/ARBs) (Cardiovascular system malformations) 2.96[2.57; 3.39]0%-Wwhatever (meta-analysis)Anyduring pregnancy (anytime or not specified)studies TTT9 Buawangpong (ACEi/ARBs) (Cardiovascular syste ...Buawangpong (ACEi/ARBs) (Cardiovascular system malformations (versus other antihypertensive)) 1.68[1.13; 2.49]0%-Eexposed to other treatment, sickT11st trimesterstudies TTT5 Buawangpong (ACEi/ARBs) (Cardiovascular syste ...Buawangpong (ACEi/ARBs) (Cardiovascular system malformations (versus unexposed, sick or not)) 3.02[2.60; 3.51]0%-U,GPunexposed (general population or NOS)T11st trimesterstudies TTT7 Ramakrishnan (ACE inhibitors) (Congenital hea ...Ramakrishnan (ACE inhibitors) (Congenital heart defects) 2.12[0.76; 5.93]NA-Wwhatever (meta-analysis)T11st trimesterstudies TTT4 metaPregmetaPreg 2.17[1.27; 3.72]80%4,017----Van der Zande - ACE-Is and/or ARBs, 2024 Hoeltzenbein b - ACEi, 2018 Bateman - ACE inhibitor (Controls unexposed, sick), 2017 Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017 Colvin - ACEi, 2014 Li - ACE inhibitors (Controls unexposed, sick), 2011 Lennestal - ACE inhibitors, 2009 Malm - ACEi, 2008 Cooper - ACEi, 2006 90.510.01.0