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

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Bane - ACEs/ARB (Controls unexposed sick), 2024	retrospective cohort (claims database)	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.	Cases with Severe Maternal Morbidity were identified using ICD-9-CM and ICD-10-CM diagnosis and procedure codes corresponding to a list of 21 indicators identified by the Centers for Disease Control and Prevention.	No adjustment for this group of comparison.
Bateman - ACE inhibitor (Controls unexposed, NOS), 2017	retrospective cohort (claims database)	Claims database for all dispensed outpatient prescription medications.	Malformations were defined based on the presence of diagnostic codes from ICD-9 recorded on two or more days in the infant inpatient or outpatient records or on one or more days if the infant died or underwent a corrective surgical procedure.	No adjustment. Pregnancies exposed to known teratogens during the first trimester were excluded.
Bateman - ACE inhibitor (Controls unexposed, sick), 2017	retrospective cohort (claims database)	Claims database for all dispensed outpatient prescription medications.	Malformations were defined based on the presence of diagnostic codes from ICD-9 recorded on two or more days in the infant inpatient or outpatient records or on one or more days if the infant died or underwent a corrective surgical procedure.	Maternal age, Maternal medical conditions (included chronic hypertension, diabetes, dyslipidemia, heart disease, renal disease, overweight or obesity, illicit drug or alcohol abuse, tobacco use, and multiple gestations), number of measures of healthcare utilization, the number of non-ACE-inhibitor prescriptions... Pregnancies exposed to known teratogens during the first trimester were excluded.
Caton - Renin inhibitors (ACE/ARBs), 2009	case control	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.	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.	ORs were adjusted for study center, maternal age at delivery, prepregnancy body mass index, and gestational diabetes.
Chintamaneni - ACE inhibitors, 2018	retrospective cohort (claims database)	Pregnant women exposed to angiotensin-converting enzyme inhibitors (Ace-i) during pregnancy were identified using pharmacy dispensing records.	Maternal co-morbidities and fetal congenital cardiac anomalies were identified by searching electronic medical records using ICD9-CM codes.	Malformations: adjusted for maternal age, ethnicity, and maternal comorbidities (certainly hypertension, heart failure, diabetes, and chronic renal insufficiency). No adjustment for other outcomes. Singletons only.
Colvin - ACEi, 2014	retrospective cohort (claims database)	The national Pharmaceutical Benefits Scheme (PBS).	The Western Australia Data Linkage System (WADLS), which linked the records of women with each pregnancy event to any related records in the Midwives’ Notification System (MNS), the Western Australian Register of Developmental Anomalies (WARDA) and the Registry of Births and Deaths.	For all (except fetal distress): Adjusted for gestational age, smoked during pregnancy, SEIFA, multiple birth, maternal age. For preterm also adjusted for previous preterm, parity and co-morbidities (obesity, diabetes. For malformations: also adjusted for parity, ethnicity, marital status, pre-existing diabetes, preeclampsia, essential hypertension, obesity, gestational diabetes.
Cooper - ACEi, 2006	retrospective cohort (claims database)	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.	Malformations were identified from: the birth certificate checkbox, infant hospitalization records (birth to day 365 of life), fetal death certificates (> 20 weeks of gestation) or infant death certificates (< the 1st birthday), and maternal hospitalization records (for delivery or fetal death).	Adjusted for the child’s birth year, maternal race, age, residence, neighborhood income and chronic illness (epilepsy, cardiovascular disease, autoimmune diseases, mental illness, obesity, migraine headaches, ... ). Controlling for other potential confounders (maternal education and smoking) did not affect results. Mothers with diabetes or exposed to other potential teratogens excluded.
Cournot - ACEi, 2006	prospective cohort	Details on the maternal history and treatments were collected during the first contact.	Pregnancy outcomes were prospectively ascertained in both groups (NOS).	Controls matched according to maternal and gestational age at the time of request. Patients with pre-existing diabetes or exposed to known teratogens were excluded.
Diav-Citrin - ACEi/ARB, 2011	prospective cohort	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.	After the expected date of delivery, pregnancy outcomes were actively sought. Follow-up was conducted by a telephone interview or mailed questionnaire to the woman or the child’s pediatrician.	No adjustment. Major anomalies analysed after exclusion of anomalies related to other known teratogens.
Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, disease free), 2017	case control	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.	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)	For 5 and more exposed cases: adjusted for maternal race/ethnicity, body mass index, age, early pregnancy smoking, and study site. Otherwise, not adjusted. Exclusion of mothers who reported preexisting type 1 or type 2 diabetes mellitus, and mothers with a multiple birth. Cases with a known pathogenesis (eg, recognized single gene disorder or chromosomal abnormality) were excluded.
Fisher - Renin inhibitors (ACE/ARBs) (Controls unexposed, sick), 2017	case control	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.	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)	For 5 and more exposed cases: adjusted for maternal race/ethnicity, body mass index, age, early pregnancy smoking, and study site. Otherwise, not adjusted. Exclusion of mothers who reported preexisting type 1 or type 2 diabetes mellitus, and mothers with a multiple birth. Cases with a known pathogenesis (eg, recognized single gene disorder or chromosomal abnormality) were excluded.
Fisher a - Renin-angiotensin system blockers, 2018	case control	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.	Data were abstracted from medical record, birth certificates or hospital discharge records.	For case groups with at least 5 exposed cases, estimates are adjusted for maternal age, race/ethnicity, body mass index, parity, pregestational type 1 or type 2 diabetes, and study site.
Fisher b - ACE inhibitors (Controls unexposed, disease free), 2018	retrospective cohort	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.	Infant sex and gestational age were obtained from the infant’s birth record.	No adjustment for this group of exposure. Singletons only. Exclusion of mothers who reported preexisting diabetes.
Fisher b - ACE inhibitors (Controls unexposed, sick), 2018	retrospective cohort	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.	Infant sex and gestational age were obtained from the infant’s birth record.	No adjustment for this group of comparison. Exclusion of mothers who reported preexisting diabetes.
Hoeltzenbein a - ARBs, 2018	prospective cohort	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.	Outcome of pregnancy is collected via mailed questionnaires about 8 weeks after the estimated date of birth. Additional medical records are requested in cases of anomalies or implausible information	Covariate adjustment or inverse probability of treatment weighting (IPTW) based on propensity scores, for: maternal age, body mass index, pre-gestational diabetes, alcohol consumption, smoking status, and numbers of previous parities, previous miscarriages, and previous children with birth defects. Matched by year of enrollment. Exclusion of pregnancies exposed to established teratogens.
Hoeltzenbein b - ACEi, 2018	prospective cohort	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.	Outcome of pregnancy is collected via mailed questionnaires about 8 weeks after the estimated date of birth. This questionnaire covers the results of the third pediatric examination at age of 4–5 weeks offered to all children in Germany.	Covariate adjustment or inverse probability of treatment weighting (IPTW) based on propensity scores, for: maternal age, body mass index, pre-gestational diabetes, alcohol consumption, smoking status, and numbers of previous deliveries, previous spontaneous abortions and previous children with birth defects. Matched by year of enrollment. Exclusion of pregnancies exposed to known teratogens.
Lennestal - ACE inhibitors, 2009	population based cohort retrospective	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.	The Swedish Medical Birth Register, the Congenital Malformation Register, and the Hospital Discharge Register.	Adjusted for year of birth, maternal age, parity, smoking, and body mass index (BMI). Women with a diagnosis of diabetes were removed from the analysis. For neonatal outcomes: analysis also performed for 'Only term infants'.
Li - ACE inhibitors (Controls unexposed, disease free), 2011	retrospective cohort (claims database)	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.	Clinical databases (both inpatient and outpatient data) including electronic medical records to identify diagnoses of major malformations (ICD-9 CM (international classification of diseases, ninth revision) codes 740.0–759.9).	Adjusted for pre-existing diabetes, maternal age, ethnicity, parity, and maternal weight, and with different reference categories (normal controls or hypertension controls).
Li - ACE inhibitors (Controls unexposed, sick), 2011	retrospective cohort (claims database)	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.	Clinical databases (both inpatient and outpatient data) including electronic medical records to identify diagnoses of major malformations (ICD-9 CM (international classification of diseases, ninth revision) codes 740.0–759.9).	Adjusted for pre-existing diabetes, maternal age, ethnicity, parity, and maternal weight, and with different reference categories (normal controls or hypertension controls).
Malm - ACEi, 2008	population based cohort retrospective	The Drug Reimbursement Register (KELA).	The Medical Birth Register, the National Register of Congenital Malformations, the National Register on Induced Abortions (STAKES).	Adjustment was made to maternal age, parity, smoking and purchases of other medicines.
Moretti - ACEi/ARBs, 2012	prospective cohort	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.	After the expected date of delivery, patients were followed up. Details about delivery and infant outcomes were recorded.	The comparator groups were matched to the study groups by gestational age at recruitment, maternal age, and alcohol and cigarette use. No significant differences among the three groups in terms of gravidity, parity, previous miscarriage or elective abortions. Possible confounding factors, such as the presence of diabetes, were also considered in the analysis.
Nakhai-Pour - ACE inhibitors, 2010	nested case control	The Régie de l’Assurance Maladie du Québec (RAMQ) provides prospectively collected data on filled prescriptions.	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.	No adjustment for this group of exposure. Singleton only. Exclusion of pregnant women who were exposed to known teratogens.
Vaclavik - ACEs/ARBs, 2024	population based cohort retrospective	The National Registry of Reimbursable Health Services (NRHZS).	Nationwide data on all births and abortions in the Czech Republic were obtained from the National Registry of Reproductive Health (NRRZ).	None.
Van der Zande - ACE-Is and/or ARBs, 2024	prospective cohort	Data regarding medication use was collected. Medication use was reported by the local investigators and defined as prescribed.	Obstetric and perinatal complications, pregnancy duration, and mode of delivery were collected (no other details).	For foetal or neonatal congenital anomalies: maternal age, nulliparity, low-or-middle-income country, twin pregnancy, other cardiac medication use, smoking, diabetes mellitus and maternal cardiac diagnosis. Other outcomes: no adjustment.
Van Gelder - ACE inhibitors, 2015	case control	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.	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).	No adjustment. Exclusion of multiple births. Sensitivity analysis excluding infants who had a first-degree relative with the birth defects of interest.
Van Zutphen - Renin–angiotensin system-acting, 2014	case control	Antihypertensive medication use were collected by trained interviewers who conducted maternal telephone interviews within 24 months of delivery.	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.	Adjusted for site, maternal age, race and ethnicity, parity, fertility treatment, prepregnancy diabetes, gestational diabetes, and multiple birth.
Vasilakis-Scaramozza - ACE inhibitors, 2013	retrospective cohort	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.	Data were extracted from standardized clinical records for every patient within a general medical practice, including notably medical diagnoses, using ICD 9. Previous studies determined that all congenital anomalies noted in the clinical records were recorded in the computerized medical record.	Each exposed woman was matched on age, year of pregnancy outcome, and general practice with two unexposed women. Potential confounders evaluated: prepregnancy body mass index (BMI), maternal age, smoking status, history of diabetes, insulin use, exposure to a known teratogen during the first trimester, history of infertility (including use of infertility drugs), and premature delivery.

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