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

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Bane - ACEs/ARB (Controls unexposed sick)
2024 		USA
2007 - 2017
retrospective cohort (claims database) 		The Optum deidentified Clinformatics Data Mart Database (Optum), a large administrative claims database of individuals covered by employer-sponsored health insurance, USA. 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. 		during pregnancy (anytime or not specified) 2520 / 791 ARBs: includes azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, valsartan, telmisartan. ACEs: includes benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril
Optum is a large administrative claims database of individuals covered by employer-sponsored health insurance. Antihypertensive medication dispensation before and during pregnancy were examined and considered as a proxy for medication use.
Bateman - ACE inhibitor (Controls unexposed, NOS)
2017 		USA
2000 - 2010
retrospective cohort (claims database) 		The US Medicaid Analytic eXtract (MAX). 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. 		1st 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.
Claims database for all dispensed outpatient prescription medications.
Bateman - ACE inhibitor (Controls unexposed, sick)
2017 		USA
2000 - 2010
retrospective cohort (claims database) 		The US Medicaid Analytic eXtract (MAX). 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. 		1st trimester 2631 / 15884 The ACE inhibitors considered in the analysis included benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril.
Claims database for all dispensed outpatient prescription medications.
Chintamaneni - ACE inhibitors
2018 		USA
2003 - 2014
retrospective cohort (claims database) 		The Kaiser Permanente Southern California Region, USA. 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. 		during pregnancy (anytime or not specified) 404 / 378834 Ace-I used were lisinopril (n=398, 98%), captopril (n=3, 1%) and benazepril (n=3, 1%).
Pregnant women exposed to angiotensin-converting enzyme inhibitors (Ace-i) during pregnancy were identified using pharmacy dispensing records.
Colvin - ACEi
2014 		Australia
2002 - 2005
retrospective cohort (claims database) 		A population-based data linkage study investigating pregnancy events in Western Australia (WA). 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. 		1st trimester 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).
The national Pharmaceutical Benefits Scheme (PBS).
Cooper - ACEi
2006 		USA
1985 - 2000
retrospective cohort (claims database) 		The Tennessee Medicaid data. 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. 		1st trimester 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).
Maternal use of prescribed medications was determined from Medicaid pharmacy files, which included the date when the prescription was filled and the number of days for which the medication was supplied.
Cournot - ACEi
2006 		France
Not specified.
prospective cohort 		The French pharmacovigilance centres and the Centre de Renseignements sur les Agents Tératogènes (CRAT). 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. 		1st trimester 159 / 159 Children with documented chromosomal defects were excluded in both groups.
Details on the maternal history and treatments were collected during the first contact.
Diav-Citrin - ACEi/ARB
2011 		Israel and Italy
1990 - 2008
prospective cohort 		The Israeli Teratology Information Service (TIS), (Jerusalem, Israel) or the Servizio di Informazione Teratologica (Padova, Italy). 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. 		early pregnancy 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).
Details of exposure were collected at the initial contact to the service and before pregnancy outcome was known using a structured questionnaire. Exposure details were recorded: dose, duration, and timing in pregnancy, additional exposure.
Fisher b - ACE inhibitors (Controls unexposed, disease free)
2018 		USA
1997 - 2011
retrospective cohort 		A retrospective cohort study using data on National Birth Defects Prevention Study (NBDPS) singleton controls, USA. 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. 		during pregnancy (anytime or not specified) 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).
Trained interviewers collected data via telephone interview within 24 months of the infant’s birth. The interview included questions on medication use during the 3 months before pregnancy until delivery.
Fisher b - ACE inhibitors (Controls unexposed, sick)
2018 		USA
1997 - 2011
retrospective cohort 		A retrospective cohort study using data on National Birth Defects Prevention Study (NBDPS) singleton controls, USA. 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). 		during pregnancy (anytime or not specified) 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).
Trained interviewers collected data via telephone interview within 24 months of the infant’s birth. The interview included questions on medication use during the 3 months before pregnancy until delivery.
Hoeltzenbein a - ARBs
2018 		Germany
2000 - 2014
prospective cohort 		The German Embryotox pharmacovigilance institute in Berlin, Germany. 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. 		early 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).
Prospective observational cohort study, i.e., the outcome of the evaluated pregnancies was not known at the time of case enrollment. => Exposure collected at the time of enrollment when health care professionals and patients called the service.
Hoeltzenbein b - ACEi
2018 		Germany
2000 - 2014
prospective cohort 		The German Embryotox pharmacovigilance institute in Berlin, Germany. 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. 		early 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.
Prospective observational cohort study, i.e., the outcome of the evaluated pregnancies was not known at the time of case enrollment. => Exposure collected at the time of enrollment when health care professionals and patients called the service.
Lennestal - ACE inhibitors
2009 		Sweden
1995 - 2006
population based cohort retrospective 		The Swedish Medical Birth Register, the Congenital Malformation Register, and the Hospital Discharge Register. 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. 		early pregnancy 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.
Maternal use of drugs during pregnancy based on the midwife interview at the first antenatal visit (90% of women attend before week 12) and therefore mainly refers to first trimester exposure.
Li - ACE inhibitors (Controls unexposed, disease free)
2011 		USA
1995 - 2008
retrospective cohort (claims database) 		The Kaiser Permanente Northern California region, USA 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. 		2nd and/or 3rd trimester, at least 1st trimester 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).
The Pharmacy Information Management System, a computerised pharmacy prescription and dispensation database in Kaiser Permanente Northern California. This captures all prescription drugs dispensed, with information on date dispensed, dose, and days of supply.
Li - ACE inhibitors (Controls unexposed, sick)
2011 		USA
1995 - 2008
retrospective cohort (claims database) 		The Kaiser Permanente Northern California region, USA 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. 		2nd and/or 3rd trimester, at least 1st trimester 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).
The Pharmacy Information Management System, a computerised pharmacy prescription and dispensation database in Kaiser Permanente Northern California. This captures all prescription drugs dispensed, with information on date dispensed, dose, and days of supply.
Malm - ACEi
2008 		Finland
1996 - 2001
population based cohort retrospective 		Four national health registers have been linked: The Medical Birth Register, the National Register of Congenital Malformations, the National Register on Induced Abortions (STAKES), and the Drug Reimbursement Register (KELA). 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. 		1st trimester 137 / 348852 The adjusted OR was preferentially reported here, when available.
The Drug Reimbursement Register (KELA).
Moretti - ACEi/ARBs
2012 		Canada
Not specified.
prospective cohort 		The Motherisk Program at the Hospital for Sick Children in Toronto, Canada. 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. 		1st trimester 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.
At initial contact with the patient before or during the early weeks of pregnancy, standardized questionnaires were used to document maternal exposures. After delivery, the information collected at intake was complimented with additional details on exposures occurring since the initial contact.
Vaclavik - ACEs/ARBs
2024 		The Czech Republic
2012 - 2022
population based cohort retrospective 		The National Registry of Reproductive Health (NRRZ) and the National Registry of Reimbursable Health Services (NRHZS). 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. 		during pregnancy (anytime or not specified) -9 / -9
The National Registry of Reimbursable Health Services (NRHZS).
Van der Zande - ACE-Is and/or ARBs
2024 		Worldwide (53 countries)
2007 - 2018
prospective cohort 		The Registry Of Pregnancy And Cardiac disease (ROPAC), a prospective, worldwide, registry of pregnancies in women with heart disease. 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. 		1st trimester, during pregnancy (anytime or not specified) 42 / 5697 Enalapril 49% and valsartan 38% were the most frequently used types of ACE-I and ARB, respectively.
Data regarding medication use was collected. Medication use was reported by the local investigators and defined as prescribed.
Vasilakis-Scaramozza - ACE inhibitors
2013 		United Kingdom (UK)
1991 - 2002
retrospective cohort 		The United Kingdom’s General Practice Research Database, from 368 general medical practices from throughout the United Kingdom. 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. 		1st trimester 46 / 682
Data were extracted from standardized clinical records for every patient within a general medical practice. These records describe notably prescribed drugs from each clinical visit.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Caton - Renin inhibitors (ACE/ARBs)
2009 		USA
1997 - 2003
case control 		The National Birth Defects Prevention Study (NBDPS). 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. Data were collected via a computer-assisted telephone interview of infant's mothers within 24 months of the expected delivery date. Interviewers asked detailed questions about the diagnosis, timing, and treatment of high blood pressure. 1st trimester 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).
Case infants were identified from the population-based birth defects surveillance systems of the participating centers. Control infants were randomly selected from birth certificates or hospital discharge listings in the same geographic areas as the cases.
Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, disease free)
2017 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS). 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. Trained interviewers collected data via telephone interviews between 6 weeks and 24 months after the estimated delivery date. The interview included notably questions on medication use during the three months before pregnancy until delivery. early pregnancy 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).
Case infants were identified from the population-based birth defects surveillance systems of the participating centers. Control infants were randomly selected from birth certificates or hospital discharge listings in the same geographic areas as the cases. (According to Caton 2009)
Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick)
2017 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS). 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. Trained interviewers collected data via telephone interviews between 6 weeks and 24 months after the estimated delivery date. The interview included notably questions on medication use during the three months before pregnancy until delivery. early pregnancy 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).
Case infants were identified from the population-based birth defects surveillance systems of the participating centers. Control infants were randomly selected from birth certificates or hospital discharge listings in the same geographic areas as the cases. (According to Caton 2009)
Fisher a - Renin-angiotensin system blockers
2018 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study, USA. 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. Exposure information was collected via maternal self-report during a computer-assisted telephone interview administered between 6 weeks and 24 months after her estimated delivery date. Trained interviewers asked about medication use during the 3 months before pregnancy until delivery. 1st trimester 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.
Data were abstracted from medical record, birth certificates or hospital discharge records.
Nakhai-Pour - ACE inhibitors
2010 		Canada
1998 - 2003
nested case control 		The Quebec Pregnancy Registry, built with the linkage of three administrative databases: Regie de l’Assurance Maladie du Quebec (RAMQ); the hospital discharge database Med-Echo; and the Institut de la Statistique du Quebec (ISQ). 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). The Régie de l’Assurance Maladie du Québec (RAMQ) provides prospectively collected data on filled prescriptions. 1st trimester, 2nd and/or 3rd trimester 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).
The three administrative databases provided data on physician-based diagnosis (according to ICD-9), physician and emergency department visits and admissions, procedures and hospitalizations, health care providers, birth weight and gestational age for live births and stillbirths.
Van Gelder - ACE inhibitors
2015 		USA and Canada
1998 - 2010
case control 		The Slone Birth Defects Study, also known as the Pregnancy Health Interview Study, a multisite case–control. 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. Within 6 months after delivery, trained research nurses interviewed the mothers of case and control infants by telephone, in English or Spanish, about details of medication use in the 2 months before pregnancy until the end of pregnancy. 1st trimester, 2nd and/or 3rd trimester 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).
Cases and controls identified through birth defects registries (Massachusetts and parts of New York State) or from participating hospitals in the areas surrounding Boston (MA), Philadelphia (PA), San Diego (CA), and Toronto (Canada).
Van Zutphen - Renin–angiotensin system-acting
2014 		USA
1997 - 2009
case control 		The National Birth Defects Prevention Study, USA. 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. Antihypertensive medication use were collected by trained interviewers who conducted maternal telephone interviews within 24 months of delivery. early pregnancy 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).
Data were abstracted from medical record, birth certificates or hospital discharge records. To confirm cases, clinical geneticists reviewed data, including consultations (urology, endocrinology, and genetic), reports (operative, pathology, and autopsy), and radiographic results.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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