Centrally acting antiadrenergic (versus unexposed)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Al Khalaf - Methyldopa (Controls unexposed, disease free), 2022	retrospective cohort (claims database)	Data on antihypertensive medication were identified from the Clinical Practice Research Datalink (CPRD) provides information about prescription details.	Outcomes were measured based on read or ICD-10 codes of diagnoses available in the Hospital Episodes Statistics (HES) data base.	No match/adjustment for this group of comparison.
Al Khalaf - Methyldopa (Controls unexposed, sick), 2022	retrospective cohort (claims database)	Data on antihypertensive medication were identified from the Clinical Practice Research Datalink (CPRD) provides information about prescription details.	Outcomes were measured based on read or ICD-10 codes of diagnoses available in the Hospital Episodes Statistics (HES) data base.	No match/adjustment for this group of comparison.
Chan - Methyldopa, 2010	prospective cohort	Prospectively collected database with participants contacting the Motherisk Program for counseling in case of use of medication during pregnancy.	Medical and psychological examinations (notably neurocognitive assessment) were performed on children by psychometrist and physician, both blinded to the participant’s group membership.	Controls were matched for age at delivery, children's gender and age at testing. Exclusion of mothers exposed to a known teratogen, on account of substance abuse and co-morbid illnesses which may have affected the child’s neurodevelopment (e.g., renal failure, diabetes, severe anemia, and psychiatric illness). No differences of alcohol use and maternal IQ (except performance IQ).
De Jonge - Methyldopa, 2013	case control	For controls: from the IADB (InterAction Database), a population-based prescription database. For cases: the pharmacy records for 3 months before conception until delivery were obtained and verified in a telephone interview and only the actually used medication is registered.	Information on congenital malformations is obtained from the medical files, including pathology reports, and coded afterwards, according to the International Classification of Diseases (ICD) coding system by trained registry staff.	No adjustment.
Fidler - Methyldopa, 1983	prospective cohort	The patients were allocated at random to receive either methyldopa or oxprenolol.	All out patients were seen every two weeks until 36 weeks' gestation and thereafter every week until delivery.	Matched for parity and gestational age at delivery. Exclusion of patients that were taking other hypertensive medication, had diabetes, expecting twins, had renal disease, and had congenital adrenal hyperplasia. No difference in smoking.
Fisher - Centrally acting antiadrenergics (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 - Centrally acting antiadrenergics (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 - Centrally acting, 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 - Centrally acting (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.	Adjusted for: maternal race/ethnicity; maternal age at delivery; maternal prepregnancy body mass index (BMI); folic acid-containing supplement use during the first trimester; maternal cigarette smoking after the first trimester; and study site. Singletons only. Exclusion of mothers who reported preexisting diabetes.
Fisher b - Centrally acting (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.
Fitton - Centrally acting, 2021	retrospective cohort (claims database)	The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.	The Scottish Morbidity Record databases: data on maternal, obstetric, child outcomes and all admissions to acute hospitals; and the Child Health Systems Programme Pre-School, which includes data on special needs and developmental outcomes, routinely collected at 10 days, 6–8 weeks and 27–30 months.	Regressions were adjusted for relevant confounders as identified by directed acyclic graphs (DAG) process. All models were adjusted for: maternal BMI, Scottish Index of Multiple Deprivation (SIMD), smoking, diabetes, previous stillbirths, parity, illicit drug use, recorded diagnosis of preeclampsia during the current pregnancy and maternal age. Only singleton live birth.
Fitton - Centrally acting (Controls unexposed, disease free), 2020	retrospective cohort (claims database)	The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.	The Scottish Morbidity Record 02 database, which collects data on maternal, obstetric, and child outcomes.	Adjusted for: Maternal body mass index, maternal diabetes, parity, smoking status, maternal age, preeclampsia, Scottish Index of Multiple Deprivation (SIMD) quintile, drug misuse, alcohol intake, previous stillbirths and interactions. Only singleton live birth.
Fitton - Centrally acting (Controls unexposed, sick), 2020	retrospective cohort (claims database)	The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.	The Scottish Morbidity Record 02 database, which collects data on maternal, obstetric, and child outcomes.	No adjustment for this group of comparison. Only singleton live birth.
Hoeltzenbein - Methyldopa (Controls unexposed, disease free), 2017	prospective cohort	Data on maternal medication are collected via structured telephone interview and mailed questionnaires. The outcome of pregnancy was not known at the time of enrollment.	Follow-up of pregnancy outcome is requested at week 8 after the estimated date of delivery and includes the third German pediatric examination due at the age of 4 to 6 weeks.	Propensity score estimation included maternal age, body mass index (BMI), alcohol consumption, smoking status, numbers of previous parities, miscarriages, and previous children with anomalies. Pregnancies exposed to established teratogens and fetotoxicants (including angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers) were excluded from both cohorts.
Huisjes - Clonidine, 1986	retrospective cohort	Not specified.	All children were examined neurologically according to the standardized and age-specific technique described by Touwen at ages varying from 3 to 9.5 years. A comprehensive questionnaire on sleeping behaviour, derived from a study by Cohen-Matthijsen, was sent to all parents.	Control group matched for diastolic blood pressure during pregnancy, and sex, birthweight and gestational age of the children.
Ishikawa - Methyldopa (Controls unexposed, disease free), 2023	retrospective cohort (claims database)	A large administrative claims database from JMDC Inc. (Tokyo, Japan), which contained all the inpatient, outpatient, and pharmacy claims received from insurers. These claims include prescribed medications.	A large administrative claims database which contained all the inpatient and outpatient received from insurers (including diagnoses, surgical and medical procedures). The major malformations in claims were validated against patient medical records: the overall predictive positive value was 91.5%	No adjustment for this group of comparison. Exclusion of multiple deliveries and infants who had chromosomal abnormalities.
Ishikawa - Methyldopa (Controls unexposed, sick), 2023	retrospective cohort (claims database)	A large administrative claims database from JMDC Inc. (Tokyo, Japan), which contained all the inpatient, outpatient, and pharmacy claims received from insurers. These claims include prescribed medications.	A large administrative claims database which contained all the inpatient and outpatient received from insurers (including diagnoses, surgical and medical procedures). The major malformations in claims were validated against patient medical records: the overall predictive positive value was 91.5%	No adjustment for this group of comparison. Exclusion of multiple deliveries and infants who had chromosomal abnormalities.
Kayser - Methyldopa, 2020	prospective cohort	Using a structured questionnaire at the first contact, all relevant data with respect to medication (including duration, time, dosage) are documented. In the majority of cases, neither pregnancy outcome nor prenatal abnormalities are known when the institute is contacted.	Follow-up data are obtained with a second questionnaire administered to the mother. If necessary, hospital discharge letters and additional medical reports are requested. The diagnosis of bradycardia and postnatal respiratory disorder was retrieved from medical reports.	No adjustment for this group of comparison. Exclusion of pregnancies with maternal concomitant medications considered as potent teratogens or fetotoxins (angiotensin system, ...), women with acute malignancies, preeclamp- sia or HELLP-syndrome.
Leather - Methyldopa, 1968	randomized controlled trial	On entry to the trial patients were allocated at random to control or treatment groups.	The clinical management in control and treated groups was the same. The patients were cared for by the obstetricians and given bed-rest and sedation as required. The decision to terminate pregnancy was taken by the obstetricians.	No adjustment. Randomisation. Exclusion of twin pregnancies.
Mabie - Methyldopa, 1986	prospective cohort	Not specified (study conducted in a department of obstetrics and gynecology but the source of exposure data, not clearly specified).	Not specified (study conducted in a department of obstetrics and gynecology but the source of outcome data, not clearly specified).	None.
Medveczky - Methyldopa, 2004	case control	Exposure data collected from 3 sources: a post-paid structured questionnaire sent to the parents requesting drugs taken during pregnancy, according to gestational months; maternal prenatal care logbook (in which obstetricians must record all prescribed drugs); nurses visited non-responding families.	The Hungarian Congenital Abnormality Registry (HCAR), in which notification by physicians of cases with Congenital anomalies is mandatory (including infant deaths and usual stillborn fetuses). Controls were selected from the National Birth Registry of the Central Statistical Office.	Controls matched according to sex, birth week, and district of parents' residence. Multivariable unconditional logistic regression model for maternal age, birth order, and employment status.
Nakhai-Pour - Centrally acting, 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.
Orbach - Methyldopa, 2013	retrospective cohort (claims database)	The medication data of Clalit members are stored in the Clalit data warehouse. This database contains information about dispensing date, the ATC code of the drug (including the commercial and generic names), dose schedule of drugs administration, and dose dispensed in defined daily dose.	Two computerized databases: the database of the Obstetrics and Gynecology Department which includes information on maternal medical conditions during pregnancy and delivery; and the Demog-ICD9 which includes medical diagnoses during hospitalization, drawn directly from the medical records.	The models were controlled for maternal age, ethnicity, smoking, diabetes mellitus, twin pregnancies, lack of prenatal care and parity.
Redman - Methyldopa, 1976	randomized controlled trial	Treatment was allocated randomly at the end of the baseline inpatient assessments to early and late entries separately. Placebo tablets were not used.	All fetal losses at or after 24 weeks were further investigated at necropsy. At delivery the condition of the baby was recorded in detail and the neonate was later examined for possible congenital malformation and assessment of gestational maturity.	No adjustment. Randomisation. Patients with major independent obstetric risk factors (diabetes, multiple pregnancy, rhesus immunisation) were excluded from random allocation of treatment. Treated and control patients were similar with respect to social and obstetric characteristics.
Sibai - Methyldopa (Controls unexposed, sick), 1990	randomized controlled trial	Eligible patients were randomly allocated to one of the 3 groups based on a computer-generated list of random numbers. The random allocation allowed patients who were already taking antihypertensive medication to be changed to a new type of management.	Maternal and perinatal outcomes reported.	No adjustment. Randomisation. Patients with associated medical complications (other than chronic hypertension) were excluded.
Su - Centrally acting (Controls unexposed, disease free), 2013	population based cohort retrospective	Data on anti-hypertensive drugs use come from the National Health Insurance Research Dataset (NHIRD), which consisted of all claims data during pregnancy.	The birth certificate registry, obtained from the Department of Health in Taiwan, that contains birthdates, as well as details on gestational weeks at birth and birth weight.	No adjustment for this group of comparison. Singletons only.
Su - Centrally acting (Controls unexposed, sick), 2013	population based cohort retrospective	Data on anti-hypertensive drugs use come from the National Health Insurance Research Dataset (NHIRD), which consisted of all claims data during pregnancy.	The birth certificate registry, obtained from the Department of Health in Taiwan, that contains birthdates, as well as details on gestational weeks at birth and birth weight.	Adjusted for the mother’s parity, maternal age, education level, diabetes, anemia, coronary heart disease, and hyperlipidemia. Singletons only.
Vaclavik - Methyldopa, 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 Zutphen - Centrally 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.
Weitz - Methyldopa, 1987	randomized controlled trial	Pregnancies randomly allocated into two groups: treatment with methyldopa (13 patients) or placebo (12 patients). At each clinic visit, the patients were asked to count their remaining tablets of assigned medication, to assess compliance in self medication.	All patients were followed in the high risk obstetrical clinic every 2 weeks until their 32nd week, and then weekly until delivery.	No adjustment but patients randomly allocated into two groups. Singletons only.
Welt - Methyldopa, 1981	randomized controlled trial	Pregnant women were randomly and blindly assigned to 1 of 3 drug groups.	Patients were seen intensively (twice monthly then weekly from the 30th week of gestation) during pregnancy, until delivery.	No adjustment. Randomisation. Exclusion of patients with insulin-requring diabetes or multiple pregnancies.

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