Renin-angiotensin system (ACEIs and/or ARBs) (versus unexposed)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Bane - ACEs/ARB (Controls unexposed sick), 2024	USA 2007 - 2017	Pregnancies in women with chronic hypertension (at least one hypertension diagnosis at any point from 6 months before conception to 20 weeks of gestation) resulting in live births or stillbirths (i.e., delivery at ≥20 weeks of gestation of a fetus that died in utero).	Birth in pregnant women with chronic hypertension who have dispensation of angiotensin converting enzyme inhibitors (ACEs) or angiotensin receptor II blockers (ARBs) in prepregnancy and during pregnancy.	unexposed, sick Birth in pregnant women with chronic hypertension who have dispensation of angiotensin converting enzyme inhibitors (ACEs) or angiotensin receptor II blockers (ARBs) in prepregnancy but not use of antihypertensive drugs during pregnancy.	2520 / 791	ARBs: includes azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, valsartan, telmisartan. ACEs: includes benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril
Bateman - ACE inhibitor (Controls unexposed, NOS), 2017	USA 2000 - 2010	Women aged 12 to 55 who delivered liveborn infants and then linked these women with their offspring using a Medicaid identifier that is shared by families.	Pregnant women with a claim for a dispensed outpatient angiotensin-converting enzyme (ACE) inhibitor from the last menstrual period to day 90 of pregnancy, corresponding to the end of the first trimester.	unexposed (general population or NOS) Pregnant women not dispensed antihypertensive medications (angiotensin-converting enzyme (ACE) inhibitors or others) during the first trimester.	4107 / 1329517	The ACE inhibitors considered in the analysis included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. This study totally included data published in the Abstract of Bateman 2015.
Bateman - ACE inhibitor (Controls unexposed, sick), 2017	USA 2000 - 2010	Women aged 12 to 55 who delivered liveborn infants and then linked these women with their offspring using a Medicaid identifier that is shared by families.	Pregnant women with a diagnosis of chronic hypertension and a claim for a dispensed outpatient angiotensin-converting enzyme (ACE) inhibitor from the last menstrual period to day 90 of pregnancy, corresponding to the end of the first trimester.	unexposed, sick Pregnant women with a diagnosis of chronic hypertension and no dispensation of antihypertensive medications (angiotensin-converting enzyme (ACE) inhibitors or others) during the first trimester.	2631 / 15884	The ACE inhibitors considered in the analysis included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.
Chintamaneni - ACE inhibitors, 2018	USA 2003 - 2014	Singleton births in the Kaiser Permanente Southern California Region during the study period.	Pregnant women exposed to angiotensin-converting enzyme inhibitors (Ace-i) during pregnancy.	unexposed (general population or NOS) Pregnant women not exposed to angiotensin-converting enzyme inhibitors (Ace-i) during pregnancy.	404 / 378834	Ace-I used were lisinopril (n=398, 98%), captopril (n=3, 1%) and benazepril (n=3, 1%).
Colvin - ACEi, 2014	Australia 2002 - 2005	All births in Western Australia during the study period.	Births in women who were dispensed an angiotensin converting enzyme inhibitor (ACEI) medication during their pregnancy.	unexposed (general population or NOS) All other births in women who were not dispensed an antihypertensive under the Pharmaceutical Benefits Scheme.	95 / 95926	This study assessed 2 groups of Renin angiotensin system that cannot be added (monotherapy ?). Thus, in order to avoid redundancy of cases and controls, only the group with the higher number of exposure was used in the meta-analysis (i.e ACE inhibitors).
Cooper - ACEi, 2006	USA 1985 - 2000	Infants (including live births and fetal deaths) with maternal enrollment in Medicaid throughout pregnancy, with complete birth-certificate information for key variables.	Infants with exposure to angiotensin-converting–enzyme (ACE) inhibitors in the first trimester of pregnancy alone (the first day of the last menstrual period and the subsequent 90 days).	unexposed (general population or NOS) Infants with no exposure to antihypertensive drugs at any time during gestation.	209 / 29096	Exclusion of 2 infants whose mothers were prescribed angiotensin-receptor antagonists. Overlapping: no overlapping Bateman 2017 and Cooper 2006 (not the same study periods).
Cournot - ACEi, 2006	France Not specified.	Pregnant women counselled by one of the teratology information services for exposure during pregnancy.	Pregnant women with confirmed first-trimester exposure to Angiotensin-Converting Enzyme (ACE) Inhibitors.	unexposed (general population or NOS) Pregnant women counselled after exposure to a non teratogenic agent.	159 / 159	Children with documented chromosomal defects were excluded in both groups.
Diav-Citrin - ACEi/ARB, 2011	Israel and Italy 1990 - 2008	Pregnant women who contacted who contacted one of the two participating Teratology Information Service (TIS) during the study period.	Women who contacted one of the two participating centers in regard to gestational exposure to angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensin-receptor-blockers (ARBs).	unexposed (general population or NOS) Women who contacted one of the two participating centers during pregnancy in regard to exposures known not to be teratogenic in similar time frame.	252 / 495	The majority of the women were exposed to ACEIs (224/252, 88.9%), while 11.1% (28/252) were exposed to ARBs. The median gestational week of ACEI/ARB discontinuation was 6 (interquartile range, 5–9).
Fisher b - ACE inhibitors (Controls unexposed, disease free), 2018	USA 1997 - 2011	Non-malformed singleton live births randomly selected from birth certificates or hospital discharge records in 10 study sites participating in the National Birth Defects Prevention Study (NBDPS).	Mother with hypertension (chronic or pregnancy-related) that reported use of angiotensin-converting enzyme inhibitors at any time during the month before pregnancy until delivery.	unexposed, disease free Normotensive mothers who did not report taking an antihypertensive medication during pregnancy.	10 / 10050	This study assessed 2 groups of Renin angiotensin system that cannot be added (monotherapy ?). Thus, in order to avoid redundancy of cases and controls, only the group with the higher number of exposure was used in the meta-analysis (i.e ACE inhibitors).
Fisher b - ACE inhibitors (Controls unexposed, sick), 2018	USA 1997 - 2011	Non-malformed singleton live births randomly selected from birth certificates or hospital discharge records in 10 study sites participating in the National Birth Defects Prevention Study (NBDPS).	Mother with hypertension (chronic or pregnancy-related) that reported use of angiotensin-converting enzyme inhibitors at any time during the month before pregnancy until delivery.	unexposed, sick Mother with untreated hypertension (chronic or pregnancy-related).	10 / 839	This study assessed 2 groups of Renin angiotensin system that cannot be added (monotherapy ?). Thus, in order to avoid redundancy of cases and controls, only the group with the higher number of exposure was used in the meta-analysis (i.e ACE inhibitors).
Hoeltzenbein a - ARBs, 2018	Germany 2000 - 2014	Pregnancies ascertained through risk consultation by the German Embryotox pharmacovigilance institute.	Pregnancies with Angiotensin AT1 receptor blockers (ARBs) exposure in the first trimester of pregnancy.	unexposed, disease free Pregnant women randomly selected among those ascertained through risk consultation without a diagnosis of hypertension or treatment of hypertension during pregnancy.	215 / 642	The most frequently used ARBs were candesartan (n = 76, median daily dose 16 mg) and valsartan (n = 41, median daily dose 80 mg). Treatment indication was hypertension in 97% of patients. ARBs were discontinued at the median GW 6.29 (IQR 5.0–8.14).
Hoeltzenbein b - ACEi, 2018	Germany 2000 - 2014	Pregnancies ascertained through risk consultation by the German Embryotox pharmacovigilance institute.	Pregnancies with Angiotensin converting enzyme inhibitors (ACEIs) exposure at least during the first trimester, but no longer than gestational week (GW) 20 0 days.	unexposed, disease free Pregnancies randomly selected among those ascertained through risk consultation without a diagnosis of hypertension or treatment of hypertension during pregnancy.	329 / 654	Indication of ACEI: hypertension (91%). Ramipril (n=175, median 5 mg/d), enalapril (n=68, median 10 mg/d) and lisinopril (n = 41, median 5 mg/d). ACEIs discontinued at the median GW 7 (IQR 5–9.29). Use of other antihypertensives possible except ARBs.
Lennestal - ACE inhibitors, 2009	Sweden 1995 - 2006	Nearly all infants born in Sweden.	Infants born of women who reported the use of Angiotensin-converting enzyme (ACE) inhibitors only in early pregnancy, irrespective of the presence of a delivery diagnosis code of chronic hypertension.	unexposed (general population or NOS) Infants born of all women giving birth during the study period.	91 / 1046843	Overlapping: for beta-blockers, ARAII, ICE and calcium inhibitors, results of Kallen 2003 were totally overlapped by Lennestal 2009 a larger study: 1995 - 2006 with better adjustments) => Lennestal used rather than Kallen 2003.
Li - ACE inhibitors (Controls unexposed, disease free), 2011	USA 1995 - 2008	All live births in women members of the Kaiser Permanente Northern California during the study period.	Pregnant women who used angiotensin converting enzyme (ACE) inhibitors in isolation or in combination with other drugs.	unexposed, disease free Pregnant women who had neither a diagnosis of hypertension nor use of any antihypertensive drug.	755 / 416218	Analyses for use of ACE inhibitors during the 1st trimester, regardless of use in other trimesters, are reported here rather than 1st trimester only, because there are more exposures (it showed a largely similar pattern of association).
Li - ACE inhibitors (Controls unexposed, sick), 2011	USA 1995 - 2008	All live births in women members of the Kaiser Permanente Northern California during the study period.	Pregnant women who used angiotensin converting enzyme (ACE) inhibitors in isolation or in combination with other drugs.	unexposed, sick Pregnant women who had a diagnosis of hypertension at any time from one year before their last menstrual period to the end of their pregnancy but who were not prescribed any antihypertensive drugs.	755 / 31274	Analyses for use of ACE inhibitors during the 1st trimester, regardless of use in other trimesters, are reported here rather than 1st trimester only, because there are more exposures (it showed a largely similar pattern of association).
Malm - ACEi, 2008	Finland 1996 - 2001	All infants/fetuses from all pregnancies ending either in delivery or selective termination of pregnancy due to fetal malformation.	Infants/fetuses exposed to Angiotensin-converting enzyme (ACE)-inhibitors during the first trimester.	unexposed (general population or NOS) Infants/fetuses with no recorded purchases of Angiotensin-converting enzyme (ACE)-inhibitors in early pregnancy.	137 / 348852	The adjusted OR was preferentially reported here, when available.
Moretti - ACEi/ARBs, 2012	Canada Not specified.	Callers to the Motherisk Program at the Hospital for Sick Children, a counseling service for women, their families, and health professionals.	Pregnant women exposed to Angiotensin Converting Enzyme Inhibitors (ACE) or Angiotensin II Receptor Blockers (ARBs) during the first trimester.	unexposed, disease free Healthy pregnant women, without chronic medical conditions, not exposed to any known teratogen or medications for chronic conditions.	138 / 138	ACE/ARB: ramipril (38; 27.5%), lisinopril (25; 18.1%), enalapril (15; 10.9%). Malformations (n=6) not considered as majors because it includes '1 unspecified heart murmur', '1 undescended testicle' and 1 inguinal hernia', considered as minor in EUROCAT.
Vaclavik - ACEs/ARBs, 2024	The Czech Republic 2012 - 2022	All births and abortions in the period 2012 - 2022 in the Czech Republic.	Births whose mothers were prescribed Angiotensin-converting enzyme (ACE) -inhibitors and angiotensin receptor blockers (ARBs) during pregnancy (for pre-existing hypertension or pregnancy-induced hypertension).	unexposed, disease free Births whose mothers had no hypertension.	-9 / -9
Van der Zande - ACE-Is and/or ARBs, 2024	Worldwide (53 countries) 2007 - 2018	Pregnant patients with structural heart disease, included in the Registry from 2007 up to 2018.	Pregnant women who used angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) at any point during pregnancy, excluding use only during delivery or only prior to pregnancy.	unexposed, sick Pregnant women who did not use angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) during pregnancy.	42 / 5697	Enalapril 49% and valsartan 38% were the most frequently used types of ACE-I and ARB, respectively.
Vasilakis-Scaramozza - ACE inhibitors, 2013	United Kingdom (UK) 1991 - 2002	Offspring (including included livebirths, stillbirths, and therapeutic abortions) of singleton pregnancies (that lasted more than 20 weeks of gestation) among women 15– 45 years of age that occurred during the study period.	Offspring of women with one or more prescriptions for an angiotensin-converting enzyme inhibitor during early pregnancy, with a diagnosis of hypertension at any time prior to, or during, the pregnancy.	unexposed (general population or NOS) Offspring of women without exposure to antihypertensive drugs during pregnancy.	46 / 682

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Caton - Renin inhibitors (ACE/ARBs), 2009	USA 1997 - 2003	Cases of cardiovascular malformations in live births, fetal deaths occurring after 20 weeks, and elective pregnancy terminations.	Live births without birth defects randomly selected from birth certificates or hospital discharge listings in the same geographic areas as the cases.	5021 / 4796	Overlapping: Fisher 2017 included all data published by Caton 2009 based on a longer period study (1997-2011 versus 1977-2003), more cases, more outcomes and 2 control groups. Thus Fisher 2017 was used rather than Caton 2009 (except for Ebstein anomaly).
Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, disease free), 2017	USA 1997 - 2011	Cases of cardiovascular malformations in live births, fetal deaths occurring after 20 weeks, and elective pregnancy terminations. (According to Caton 2009)	Nonmalformed live births randomly selected from birth certificates or hospital discharge records in each study site.	10625 / 11137	Overlapping: Fisher 2017 included all data published by Caton 2009 based on a longer period study (1997-2011 versus 1977-2003), more cases, more outcomes and 2 control groups. Thus Fisher 2017 was used rather than Caton 2009 (except for Ebstein anomaly).
Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017	USA 1997 - 2011	Cases of cardiovascular malformations in live births, fetal deaths occurring after 20 weeks, and elective pregnancy terminations. (According to Caton 2009)	Nonmalformed live births randomly selected from birth certificates or hospital discharge records in each study site.	10625 / 11137	Overlapping: Fisher 2017 included all data published by Caton 2009 based on a longer period study (1997-2011 versus 1977-2003), more cases, more outcomes and 2 control groups. Thus Fisher 2017 was used rather than Caton 2009 (except for Ebstein anomaly).
Fisher a - Renin-angiotensin system blockers, 2018	USA 1997 - 2011	All cases (liveborn, stillborn after 20 weeks gestation, or induced abortions) with an eligible defect within the study time period and geographic areas.	Live births not affected by a birth defect randomly selected from birth certificates or hospital discharge records to represent the base population from which cases were selected in each study site.	17038 / 11477	Only OR provided by authors were reported (raw data not reported) because of discrepancies between crude OR provided by authors and raw data. Outcomes without OR provided by authors not reported here.
Nakhai-Pour - ACE inhibitors, 2010	Canada 1998 - 2003	Mothers who gave birth to a baby with a major congenital malformation (1st study). Newborns small for gestational age (a birth weight less than the 10th percentile for that gestational age and gender according to the Canadian gender-specific references) (2nd study).	Mothers who gave birth to babies without any major or minor congenital malformation diagnosed during the same time period (1st study). Newborns not small for gestational age (2nd study).	4155 / 54878	This study assessed 2 groups of Renin angiotensin system. In order to avoid redundancy of cases and controls, only the group with the higher number of exposure was used in the meta-analysis (i.e ACE inhibitors).
Van Gelder - ACE inhibitors, 2015	USA and Canada 1998 - 2010	Liveborn or stillborn infants with one of the selected birth defects without chromosomal abnormalities or associated syndromes.	Liveborn infants without birth defects randomly selected from state-wide birth records or from study hospitals covering the geographic catchment areas where the cases were identified.	5568 / 7253	This study assessed 2 groups of Renin angiotensin system that cannot be added (case control). Thus, in order to avoid redundancy of control, only the group with the higher number of exposure was used in the meta-analysis (i.e ACE inhibitors).
Van Zutphen - Renin–angiotensin system-acting, 2014	USA 1997 - 2009	All cases (liveborn, stillborn after 20 weeks gestation, or induced abortions) with severe hypospadias (ie, subcoronal or penile, scrotal, or perineal meatal opening) diagnosed at the time of physical examination, surgery, or autopsy.	Male live births without birth defects randomly selected from birth certificates or hospital discharge listings in the same population as the case neonates.	2131 / 5129	Mothers reporting antihypertensive medications for the treatment of other indications (eg, b-blockers for migraine headaches) were excluded from the analyses. Overlapping: Caton 2008 (1997-2002) totally included in Van Zutphen 2014 (1997-2009).

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