Labetalol (versus unexposed)

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Bateman, 2016	retrospective cohort (claims database)	Claims database of dispensed prescriptions for outpatient medications.	The outcomes were obtained in the infant records (at least 1 diagnostic code from the ICD-9 indicating the presence of neonatal hypoglycemia or bradycardia). Recordings of the diagnostic codes were identified for 1 month after delivery to allow for potential lags in the posting of claims.	Propensity score for maternal age, maternal ethnicity, maternal heart disease, gestational and preexisting hypertension, gestational and preexisting diabetes, preterm, multiple gestation, alcohol abuse, illicit drug use, tobacco use, chronic renal disease, essential tremor, overall burden of comorbidity, maternal exposure to insulin or oral hypogylcemics in the final month of pregnancy...
Bergman, 2018	case control	Medication exposure was obtained from the mother’s medical files (mostly these are only files relating to the pregnancy) and from the child’s, except for the Tuscany registry, which only collects data on medication use via a questionnaire sent to the mother after birth of the malformed child.	EUROCAT registries collect data on all pregnancy outcomes: live births, foetal deaths >= 20 weeks of gestational age (including stillbirths) and terminations of pregnancy for foetal anomalies (TOPFAs) with a major congenital anomaly.	Adjusted for registry, maternal age, use of other anti-hypertensive medications, birth year and pregnancy outcome (live births, stillbirths or terminations of pregnancy). Exclusion of registrations with maternal diabetes and/or insulin use during pregnancy, maternal epilepsy and/or anti-epileptic medication use during pregnancy and registrations with the use of highly teratogenic medication.
Caton, 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.
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.
Cruickshank, 1990	randomized controlled trial	The study women were randomly allocated using numbered sealed envelopes to receive either oral labetalol or no specific antihypertensive therapy (according Cruickshank et al. 1992).	Antenatally, pregnant women were all seen at least weekly as out-patients (according Cruickshank et al. 1992).	No adjustment. Randomisation. Singleton pregnancies only. Additional exclusion criteria were asthma, diabetes mellitus, psychosis, several psychoneuroses or any cardiac abnormality precluding the use of beta-blockers.
Cruickshank, 1991	randomized controlled trial	Pregnant women were randomly allocated using numbered sealed envelopes to receive either oral labetalol or no antihypertensive drug therapy.	Obstetric management decisions for both groups were based on current practice and independent of group allocation. Delivery was expedited when the clinican felt the risk to the fetus or mother was greater if the pregnancy continued.	No adjustment. Randomisation. Singleton pregnancies only. Additional exclusion criteria were asthma, diabetes mellitus, psychosis, several psychoneuroses or any cardiac abnormality precluding the use of beta-blockers.
Delteil, 2024	retrospective cohort (claims database)	Women's drug exposure during pregnancy was estimated on the basis of dispensed prescription drugs recorded by the French Assurance Maladie.	Pregnancy outcomes were obtained from compulsory health certificates at 8 days, 9 months and 2 years for children recorded by the Protection Maternelle et Infantile (PMI) for births, and from data from the Primary Health Insurance Fund and the Toulouse University Hospital.	For malformations: adjusted for folic acid intake, the number of other medications during pregnancy, exposure to at least one teratogenic drug, diabetes and maternal age. SGA adjusted for maternal age, the number of other medications during pregnancy, diabetes and child sex.
Duan, 2018	retrospective cohort (claims database)	Pregnant women exposed to beta‐blockers during their pregnancy were identified using pharmacy dispensing records.	This study utilized computerized electronic health system databases which includes inpatient and outpatient diagnoses, patient vital statistics,... Fetal birth weights were obtained from California birth certificates.	For SGA: multivariable logistic regression models were constructed to adjust for maternal age, gestational age, maternal race and ethnicity, body mass index, and maternal comorbidities (including hypertension, hyperlipidemia, diabetes, heart failure, stroke, arrhythmia, and renal insufficiency). Only singleton pregnancies.
Fisher, 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.
Fitton (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 (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.
Petersen, 2012	population based cohort retrospective	Information on redeemed prescriptions was retrieved from the National Prescription Register, which holds information on date of redemption, quantity, strength and form. Exposure to b-blockers by identifying redeemed prescriptions with ATC code C07.	The Danish National Hospital Register contains information on diagnoses of somatic admissions and outpatients at all Danish hospitals, inaccordance with the ICD-10 system.	Adjusted for maternal age, year of conception, annual household income, parity and educational level (model 1). Model 2: additional confounding variables: smoking status, comedication (yes/no) with statins, antiobesity drugs, insulin and insulin analogues, and diagnoses of pre-eclampsia/eclampsia. Post hoc propensity score-matched regression analysis was carried out.
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.
Thewissen (Controls unexposed, disease free), 2017	prospective cohort	Obstetrical data were collected from the hospital record. Prenatal maternal exposure and maximum dose and route of labetalol were noted.	Neonatal data were collected prospectively (no more details).	Matched for sex, gestational age and birthweight. Exclusion criteria were neonates with known or strongly suspected congenital abnormalities.
Thewissen (Controls unexposed, sick), 2017	prospective cohort	Obstetrical data were collected from the hospital record. Prenatal maternal exposure and maximum dose and route of labetalol were noted.	Neonatal data were collected prospectively (no more details).	Matched for sex, gestational age and birthweight. Exclusion criteria were neonates with known or strongly suspected congenital abnormalities.
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.
Xiang, 2020	randomized controlled trial	A simple random table was used for randomization after selection. In a 1:1:1 ratio patient was divided randomly into three groups.	Regular prenatal and postnatal visits continue, and the obstetric outcomes of the participants are registered.	No adjustment. Randomisation. Women with multiple embryos, prior proteinuria, and other conditions such as diabetes and asthma) as well as fetal defects during pregnancy were removed from the research. In terms of age, delivery numbers and body mass index, and systolic and diastolic blood pressure at the registration date, there were no major variations in demographic variables.

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