Centrally acting antiadrenergic (versus unexposed)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Al Khalaf - Methyldopa (Controls unexposed, disease free), 2022	United Kingdom 1997 - 2016	Women with complete pregnancies, with a minimum length of 20 weeks’ gestation, that consented to linkage with Hospital Episodes Statistics (HES).	Women with at least 1 prescription of Methyldopa for chronic hypertension (diagnosis of hypertension recorded during a consultation in primary care or hospitalization, or inferred hypertension if they received repeat prescriptions of Blood pressure (BP) lowering-medication or based on BP readings).	unexposed, disease free Untreated women without chronic hypertension.	1952 / 1739944
Al Khalaf - Methyldopa (Controls unexposed, sick), 2022	United Kingdom 1997 - 2016	Women with complete pregnancies, with a minimum length of 20 weeks’ gestation, that consented to linkage with Hospital Episodes Statistics (HES).	Women with at least 1 prescription of Methyldopa for chronic hypertension (diagnosis of hypertension recorded during a consultation in primary care or hospitalization, or inferred hypertension if they received repeat prescriptions of Blood pressure (BP) lowering-medication or based on BP readings).	unexposed, sick Women with chronic hypertension, not treated.	1952 / 7809	Pregnant women who had prescriptions for multiple antihypertensive medications or switched to other agent(s) at any stage of pregnancy were excluded when comparing agent versus agent.
Chan - Methyldopa, 2010	Canada 1997 - 2002	Pregnant women who had contacted the Motherisk Program for counseling of medication safety during pregnancy.	Children of women treated with Methyldopa for hypertension during pregnancy.	unexposed, disease free Children of normotensive women exposed to non-teratogenic substance during pregnancy.	25 / 42	Mothers were excluded if they used the medications of interest for less than three weeks, or were exposed to a second anti-hypertensive agent or to a known teratogen (e.g., isotretinoin, phenytoin).
Fidler - Methyldopa, 1983	United Kingdom (UK) Not specified.	All the women booked for delivery at Queen Charlotte's Maternity Hospital who had diastolic blood pressure of at least 95mm Hg on two separate occasions at least 24 hours apart or greater than105mm Hg on one occasion.	Hypertensive pregnant patients allocated at random to receive methyldopa (250mg 3 times a day and increased until 3g a day if necessary).	unexposed, disease free Normotensive pregnant women with the nearest hospital reference number after that of the index patient, matched for parity and gestational age at delivery.	50 / 96	Considered as a prospective cohort rather than a randomized control because patients were randomly allocated to methyldopa or oxprenolol but the Normotensive control group not randomly selected.
Fisher b - Centrally acting (Controls unexposed, disease free), 2018	USA 1997 - 2011	Non-malformed singleton live births randomly selected from birth certificates or hospital discharge records in 10 study sites participating in the National Birth Defects Prevention Study (NBDPS).	Mother with hypertension (chronic or pregnancy-related) that reported use of Centrally-acting antiadrenergics 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.	67 / 10050	Most (83.0%) mothers who began using an antihypertensive medication before or during the first trimester continued use in the second trimester or later (data not shown).
Fisher b - Centrally acting (Controls unexposed, sick), 2018	USA 1997 - 2011	Non-malformed singleton live births randomly selected from birth certificates or hospital discharge records in 10 study sites participating in the National Birth Defects Prevention Study (NBDPS).	Mother with hypertension (chronic or pregnancy-related) that reported use of Centrally-acting antiadrenergics any time during the month before pregnancy until delivery.	unexposed, sick Mother with untreated hypertension (chronic or pregnancy-related).	67 / 839	Most (83.0%) mothers who began using an antihypertensive medication before or during the first trimester continued use in the second trimester or later (data not shown).
Fitton - Centrally acting, 2021	Scotland 2010 - 2014	All women who had a singleton live birth in Scotland during the study period.	Pregnant women who were dispensed at least one prescription for a Centrally acting medication only during the 300 days before birth (whatever the indication).	unexposed, disease free All women who had a singleton birth during the same study period who were not dispensed antihypertensive medication during or 60 days following pregnancy, and who did not have an ICD-10 code for hypertension (chronic, gestational, or unspecified hypertension).	196 / 6066	The majority of offspring were exposed to a beta-blocker only (58.66%, 4003 children), calcium channel blockers only (8.18%, 558 children), or a combination of more than one antihypertensive medication (20.53%, 1403 children).
Fitton - Centrally acting (Controls unexposed, disease free), 2020	Scotland 2010 - 2014	All women who had a singleton live birth in Scotland during the study period.	All women who had a singleton birth and who were dispensed at least one prescription for a Centrally acting antihypertensive medication during the 300 days before birth (whatever the indication).	unexposed, disease free All women who had a singleton birth during the same study period who were not dispensed antihypertensive medication during or 60 days following pregnancy, and who did not have an ICD-10 code for hypertension (chronic, gestational, or unspecified hypertension).	136 / 250693	The majority of offspring were exposed to a β-blocker only (58.66%, 4003 children), calcium channel blockers only (8.18%, 558 children), or a combination of >1 antihypertensive medication (20.53%, 1403 children).
Fitton - Centrally acting (Controls unexposed, sick), 2020	Scotland 2010 - 2014	All women who had a singleton live birth in Scotland during the study period.	All women who had a singleton birth and who were dispensed at least one prescription for a Centrally acting antihypertensive medication during the 300 days before birth (whatever the indication).	unexposed, sick All women who had a singleton birth during the same study period, who had an ICD-10 code for hypertension (chronic, gestational, or unspecified hypertension) and who were not dispensed antihypertensive medication at any stage during or 60 days after pregnancy.	136 / 7971	The majority of offspring were exposed to a β-blocker only (58.66%, 4003 children), calcium channel blockers only (8.18%, 558 children), or a combination of >1 antihypertensive medication (20.53%, 1403 children).
Hoeltzenbein - Methyldopa (Controls unexposed, disease free), 2017	Germany 2000 - 2014	Pregnancies that called the German Embryotox institute for risk assessment on drug use during pregnancy.	Pregnancies with chronic hypertension, exposed to methyldopa in the first trimester (gestational week 12 plus 6 days after last menstrual period).	unexposed, disease free Pregnancies without a diagnosis of chronic hypertension and without antihypertensive therapy, randomly selected in the database.	261 / 526	Overlapping between Kayser 2020 and Hoeltzenbein 2017 for 2 outcomes (preterm/stillbirth) => about the same number of pregnancies, thus use of data with the most relevant period of exposure (2nd/3rd trimester of exposure), i.e Kayser 2020.
Huisjes - Clonidine, 1986	The Netherlands 1974 - 1981	Women who had been delivered of a surviving infant at the Groningen University Hospital during the years 1974-1981.	Pregnant women who had been treated for hypertension or superimposed preeclampsia with clonidine only.	unexposed, sick Non-treated hypertensive gravidae matched for diastolic blood pressure during pregnancy, and sex, birthweight and gestational age of the children.	22 / 22	The start of the clonidine medication varied from before conception to 35 weeks gestational age and it was continued until delivery in all cases, dosages ranged from twice 75 microg to three times 150 microg.
Ishikawa - Methyldopa (Controls unexposed, disease free), 2023	Japan 2010 - 2019	Pregnant women with chronic hypertension	Pregnant women with chronic hypertension and prescribed Methyldopa in the first trimester.	unexposed, disease free Pregnant women without hypertensive disorders in the first trimester.	93 / 74213
Ishikawa - Methyldopa (Controls unexposed, sick), 2023	Japan 2010 - 2019	Pregnant women with chronic hypertension	Pregnant women with chronic hypertension and prescribed Methyldopa in the first trimester.	unexposed, sick Pregnant women chronic hypertension but no first-trimester antihypertensive prescriptions.	93 / 1007
Kayser - Methyldopa, 2020	Germany 2001 - 2015	Pregnancies for which Embryotox service was contacted for risk assessment on drug use in pregnancy.	Pregnancies in hypertensive women treated with methyldopa after the first trimester, but not on beta-blockers at any time during pregnancy. Methyldopa exposure may have started before the second trimester.	unexposed, disease free Pregnancies in women without hypertension and without any antihypertensive therapy at any time during pregnancy.	221 / 580	Overlapping between Kayser 2020 and Hoeltzenbein 2017 for 2 outcomes (preterm/stillbirth) => about the same number of pregnancies, thus use of data with the most relevant period of exposure (2nd/3rd trimester of exposure), i.e Kayser 2020.
Leather - Methyldopa, 1968	United Kingdom Not specified.	Patients that were referred from the antenatal clinics and from obstetric wards, diagnosed with early (before 20 weeks of gestation) or late (normontensive before 20 weeks) hypertension.	Pregnant patients with early hypertension (before 20 gestational weeks) randomly allocated to treatment group, i.e bendrofluazide 5-10 mg daily with potassium supplements and methyldopa 0-5-2g daily in divided doses.	unexposed, sick Pregnant patients with early hypertension (before 20 gestational weeks) randomly allocated to control group.	23 / 24	Data related to chronic hypertension were reported here.
Mabie - Methyldopa, 1986	USA 1980 - 1984	Pregnant women with chronic hypertension (>= 140/90 mmHg before pregnancy or at less than 20 week's gestation) who delivered at this hospital during the study period.	Pregnant women with chronic hypertension treated with Methylopa only.	unexposed, sick Pregnant women with chronic hypertension without treatment.	54 / 82	Data on Methyldopa only reported rather than co-administration Methyldopa and hydrochlorothiazide.
Orbach - Methyldopa, 2013	Israel 1998 - 2008	Women from 15-49 years old who were registered with Clalit and who lived in the southern district of Israel who gave birth at Soroka Medical Center (SMC).	Pregnant women with Methyldopa dispensed during the third trimester of pregnancy.	unexposed, disease free All pregnant women without diagnosis of chronic hypertension and who were not exposed to antihypertensive drugs through the first or the third trimester during the study period.	340 / 97820	Chromosomal diseases were excluded. Five hundred fifteen infants who were exposed to antihypertensive drugs in utero for maternal indications other than hypertension were excluded from the cohort.
Redman - Methyldopa, 1976	United Kingdom Not specified.	Pregnant women with moderate hypertension detected before 28 gestational weeks in the routine antenatal clinics.	Pregnant women with moderate hypertension detected before 28 gestational weeks randomly allocated to the Methyldopa group.	unexposed, sick Pregnant women with moderate hypertension detected before 28 gestational weeks randomly allocated to no treatment group.	107 / 101	Patients separated into early or late group, if hypertension was detected before or after 28 weeks => After 28 weeks probably mainly pregnancy-induced hypertension => Thus, here use of data of 'early' groups.
Sibai - Methyldopa (Controls unexposed, sick), 1990	USA Not specified	Pregnant patients with mild to moderate chronic hypertension ascertained at 6 to 13 weeks' gestation at the E.H. Crump Women's Hospital.	Pregnant patients with mild to moderate chronic hypertension randomly allocated to methyldopa (start at 750 mg/day and maximum of 4 g/day).	unexposed, sick Pregnant patients with mild to moderate chronic hypertension randomly allocated to no medications.	88 / 90	Because pregnancies were exposed to anti-hypertensives before randomisation => outcomes potentially impacted by exposure during first trimester (superimposed pre-eclampsia, SGA, preterm, LBW, abruptio placentae and perinatal death) are not reported here.
Su - Centrally acting (Controls unexposed, disease free), 2013	Taiwan Jan 2005 - Dec 2005	All pregnant women in Taiwan, resulting in singletons.	Pregnant women with chronic hypertension (HTN) that have received a prescription of a Central alpha agonist for a period of at least 30 days during any time of their pregnancy.	unexposed, disease free Pregnant women with no diagnosis of chronic hypertension (HTN), randomly selected from the same cohort.	181 / 8181	Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Su - Centrally acting (Controls unexposed, sick), 2013	Taiwan Jan 2005 - Dec 2005	All pregnant women in Taiwan, resulting in singletons.	Pregnant women with chronic hypertension (HTN) that have received a prescription of a Central alpha agonist for a period of at least 30 days during any time of their pregnancy.	unexposed, sick Pregnant women with chronic hypertension (HTN) who had not used any anti-hypertensive drugs.	181 / 1006	Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Vaclavik - Methyldopa, 2024	The Czech Republic 2012 - 2022	All births and abortions in the period 2012 - 2022 in the Czech Republic.	Births whose mothers were prescribed Methyldopa during pregnancy (for pre-existing hypertension or pregnancy-induced hypertension).	unexposed, disease free Births whose mothers had no hypertension.	-9 / -9
Weitz - Methyldopa, 1987	USA Not specified	Singleton pregnancy (< 34 gestational age) in women with presumed chronic hypertension (140/90 mmHg).	Pregnant women allocated into the treatment group: methyldopa one tablet (250 mg) per os twice in day (tid). These doses were increased every 48 h as needed to a maximum of 2 tablets qid.	unexposed, sick Pregnant women allocated into the placebo group: one tablet per os twice in day (tid). These doses were increased every 48 h as needed to a maximum of 2 tablets qid.	13 / 12	Other antihypertensive medications were utilized only if severe superimposed pre--eclampsia developed. In that case, hydralazine and magnesium sulfate were administered, and the patient delivered.
Welt - Methyldopa, 1981	USA Not specified.	Pregnant women with underlying hypertensive disease elected to join a protocol of intensified prenatal care and prophylactic drug therapy.	Pregnant women with underlying hypertensive disease randomly and blindly assigned to methyldopa group (250 mg 3 times per day).	unexposed, sick Pregnant women with underlying hypertensive disease randomly and blindly assigned to placebo group (3 times per day).	6 / 6	The main results were provided for non randomized group versus randomized group (whatever treatment in the group). The only reported results are those of randomized group, with distinction between treatment (provided in the text, not in the tables).

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
De Jonge - Methyldopa, 2013	The Netherlands 1998 - 2008	All malformed foetuses and children (live births, stillbirths, spontaneous abortions and terminations of pregnancy) excluding chromosomal and genetic disorders.	From the InterAction Database (IADB), a population-based prescription database that contains prescription data from approximately 55 community pharmacies in The Netherlands, we selected the population controls. The IADB covers an estimated population of 500,000 individuals, which is considered representative of the general population.	3212 / 29223
Fisher - Centrally acting antiadrenergics (Controls unexposed, disease free), 2017	USA 1997 - 2011	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.	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.
Fisher - Centrally acting antiadrenergics (Controls unexposed, sick), 2017	USA 1997 - 2011	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.	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.
Fisher a - Centrally acting, 2018	USA 1997 - 2011	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.	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.
Medveczky - Methyldopa, 2004	Hungary 1980 - 1996	Newborn infants (including infant deaths and usual stillborn fetuses) with Neural tube defects with non-syndromic (i.e. isolated anencephaly, spina bifida aperta/cystica, encephalocele).	Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities.	1202 / 38151	Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).
Nakhai-Pour - Centrally acting, 2010	Canada 1998 - 2003	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).	4155 / 54878	Major congenital malformations: number of cases: 4,155; number of controls: 54,878.Small-for-gestational-age: number of cases: 7,445; number of controls: 48,889.
Van Zutphen - Centrally acting, 2014	USA 1997 - 2009	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.	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).

master protocol