Methyldopa (versus unexposed)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Al Khalaf (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 (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, 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, 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, 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 (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 (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.
Hoeltzenbein, 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.
Ishikawa (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 (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, 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, 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, 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, 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.
Orbach, 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, 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, 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.
Vaclavik, 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, 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, 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, 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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