Beta-blockers (All routes except ocular) (versus unexposed)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Al Khalaf - Beta-blockers (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 B-Blockers 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 - Beta-blockers (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 B-Blockers 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.
Albertini - Beta-blockers, 2023	Canada 2012 - 2021	Pregnant women with long QT syndrome (LQTS), followed during pregnancy in the tertiary Pregnancy and Heart Disease Program at the University of Toronto.	Babies born to mothers with long QT syndrome who had taken beta-blockers during pregnancy.	unexposed, sick Babies born to mothers with long QT syndrome who had not taken beta-blockers during pregnancy.	44 / 7
Baard - Beta-blockers, 2020	South Africa 2010 - 2016	Consecutive pregnant women with pre-existing structural heart disease (SHD) recruited from a tertiary hospital in South Africa.	Beta-blockers exposure during pregnancy with pre-existing structural heart disease (SHD).	unexposed, sick No beta-blockers exposure during pregnancy with pre-existing structural heart disease (SHD).	43 / 135	The median (range) dose used was 12.5 mg (6.25–50) for carvedilol and 50 mg (25–100) for atenolol. Of the 178 patients, 64 (36%) presented with congenital heart disease (CHD), valvular heart disease (33.1%), cardiomyopathy (20.2%) and ‘other’ (10.7%)
Bateman - Beta-blockers, 2016	USA 2003 - 2007	Women who were continuously eligible for Medicaid from 5 months after the Last menstrual period through 1 month postpartum.	Maternal consumption of β blockers at the time of delivery, i.e prescriptions that were filled between 5 months after the last menstrual period and the day of delivery.	unexposed, sick Pregnant patients without β blocker exposure at the time of delivery, notably matched on the preexisting hypertension.	10561 / 31683	The primary analysis included all β blockers, including combined α–β blockers, and combination medications that included a β blocker.
Bateman_Nordic - Beta-blockers, 2018	Denmark, Finland, Iceland, Norway and Sweden 1996 - 2010	All hypertensive women with singleton pregnancies resulting in a live-born infant.	Pregnant hypertensive women who filled a prescription for a β-blocker only (exclusion of antihypertensive medication other than a β-blocker) during the first trimester of pregnancy.	unexposed, sick Pregnant hypertensive women who did not fill a prescription for any antihypertensive medication during the first trimester.	682 / 2895	Periods of contribution: Denmark, 1997 to 2010; Finland, 1996 to 2006; Iceland, 2003 to 2007; Norway, 2005 to 2010; Sweden, 2006 to 2010; and USA, 2000 to 2010.
Bateman_USMAX - Beta-blockers, 2018	USA 2000 - 2010	Hypertensive pregnant women aged 12 to 55 years who were continuously enrolled in Medicaid from 3 months before the date of their last menstrual period (LMP) to 1 month after delivery.	Pregnant hypertensive women who filled a prescription for a β-blocker only (exclusion of antihypertensive medication other than a β-blocker) during the first trimester of pregnancy.	unexposed, sick Pregnant hypertensive women who did not fill a prescription for any antihypertensive medication during the first trimester.	1668 / 13232
Bayliss - Atenolol, 2002	United Kingdom (UK) 1980 - 1999	Consecutive chronic hypertensive pregnancies collected prospectively from the 2 included clinics.	Pregnancies in patient who had been taking atenolol from either conception or during the first trimester of pregnancy (i.e., before 15 weeks) until delivery.	unexposed, sick Pregnancies in women with hypertension who took no anti-hypertensive medication at all throughout their pregnancy.	50 / 189	Patients who suffered a miscarriage or intra-uterine death were excluded from the analysis. Also patients who started their pregnancies on one drug and later had a second added were excluded from the main analysis.
Chan - Labetalol, 2010	Canada 1997 - 2002	Pregnant women who had contacted the Motherisk Program for counseling of medication safety during pregnancy.	Children of women treated with labetalol for hypertension during pregnancy.	unexposed, disease free Children of normotensive women exposed to non-teratogenic substance during pregnancy.	32 / 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).
Cruickshank - Labetalol, 1990	Scotland A 2-year period	Singleton pregnancies with non-proteinuric hypertension (blood pressure greater than 90 mmHg), recruited between 24 and 39 weeks' gestation.	Pregnant women treated with Labetalol for hypertension in primigravid pregnancy (100 mg twice per day with a facility for dose escalation at 48-h intervals to a maximum of 400 mg X 3 per day).	unexposed, sick Pregnant women with no antihypertensive treatment for hypertension in primigravid pregnancy. None of the controls received antihypertensive agents antenatally.	31 / 45	Author's mistake for multigravid in the article for the last figure: 'Intrauterine growth retardation was more common in women treated with labetalol when compared with primigravid (7/45) and multigravid (22/18) controls. => Use of primigravid data.
Cruickshank - Labetalol, 1991	Scotland A 2-year period	Singleton pregnancies with non-proteinuric hypertension (blood pressure greater than 90 mmHg), recruited between 24 and 39 weeks' gestation.	Pregnant women treated with Labetalol for hypertension in pregnancy (100 mg twice per day with a facility for dose escalation at 48-h intervals to a maximum of 400 mg X 3 per day).	unexposed, sick Pregnant women with no antihypertensive treatment for hypertension in pregnancy. None of the controls received antihypertensive agents antenatally.	51 / 63
Darcie - Atenolol, 2004	Brazil 1994 - 1997	Singleton newborns of mothers with arterial hypertension (specific hypertensive disease of pregnancy (SHDP) or chronic arterial hypertension (CAH) and super-imposed SHDP).	Newborns of hypertensive mothers treated with atenolol (50 mg twice a day) for at least 2 weeks before the delivery.	unexposed, sick Newborns of hypertensive mothers whose hypertension was controlled with diet only (without antihypertensive medication), for a minimum period of 2 weeks.	40 / 14	Study considered as a prospective cohort because no precision indicating that a randomization was carried out.
Delteil - Beta-blockers, 2024	France 2004 - 2021	Pregnancies with a known outcome between July 2004 and December 2021 in Haute-Garonne, included in the EFEMERIS database.	Pregnancies with at least one dispensed prescription of beta-blockers (ATC code CO7) during pregnancy (between last menstrual period and delivery).	unexposed (general population or NOS) Pregnancies without dispensed prescription of beta-blockers and other anti-hypertensive agents during pregnancy.	1813 / 172284	When available, data in women with chronic pathology (hypertension or cardiac), treated at least during the 1st trimester were preferred to all indications (including gestational hypertension, ...). Exposure at least T1 considered as chronic indications.
Duan - Beta-blockers, 2017	USA 2003 - 2014	Singleton pregnancies with births during the study period.	Pregnant women exposed to β-blockers during pregnancy (with additional analysis for exposure during the first trimester of pregnancy).	unexposed (general population or NOS) Pregnant women unexposed to β-blockers during pregnancy.	4847 / 374391	The 4 most commonly prescribed β-blockers were labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324).
Duan - Beta-blockers, 2018	USA 2003 - 2014	All singleton births in the Kaiser Permanente Southern California (KPSC) Region during the study period, with at least 1‐year enrollment of the Kaiser Permanente Health Plan within the year prior to the estimated date of delivery.	Pregnant patients that filled a prescription for a beta‐blocker between their estimated conception date and the date of delivery.	unexposed (general population or NOS) Pregnant women who were not exposed to beta‐blockers at any time during their pregnancy.	4847 / 374391	The 4 most prescribed beta‐blockers: labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324). For preeclampsia and SGA: partial overlapping between Duan 2018 and Dublin 2022 => Use of Duan because more pregnancies.
Ersboll - Beta-blockers (Controls unexposed, disease free), 2014	Denmark 2003 - 2009	Singleton pregnancies with pre-existing heart disease attending the Centre for Pregnant Women with Heart Disease (CPWHD) and from the Danish Medical.	Pregnant women with pre-existing heart disease treated with oral beta-blockers for at least 2 weeks.	unexposed, disease free Pregnant women without pre-existing heart disease matched with exposed women.	51 / 627	The most commonly prescribed beta-blocker was metoprolol (72.5% of women). Mean duration of treatment: 163.0 days (range 23–284 days). Pregnancies with only chronic hypertension, pregnancy-induced hypertension, or pre-eclampsia/eclampsia were excluded.
Ersboll - Beta-blockers (Controls unexposed, sick), 2014	Denmark 2003 - 2009	Singleton pregnancies with pre-existing heart disease attending the Centre for Pregnant Women with Heart Disease (CPWHD).	Pregnant women with pre-existing heart disease treated with oral beta-blockers for at least 2 weeks.	unexposed, sick Pregnant women with pre-existing heart disease but no exposure to beta-blockers collected immediately before and immediately after each index case (11.3% receiving antihypertensive drugs other than beta-blockers during pregnancy).	51 / 124	The most commonly prescribed beta-blocker was metoprolol (72.5% of women). Mean duration of treatment: 163.0 days (range 23–284 days). Pregnancies with only chronic hypertension, pregnancy-induced hypertension, or pre-eclampsia/eclampsia were excluded.
Fidler - Oxprenolol, 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 oxprenolol (80mg twice a day and increased until 640 mg 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 - Beta-blockers (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 β-blockers any time during the month before pregnancy until delivery.	unexposed, disease free Normotensive mothers who did not report taking an antihypertensive medication during pregnancy.	54 / 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 - Beta-blockers (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 β-blockers any time during the month before pregnancy until delivery.	unexposed, sick Mother with untreated hypertension (chronic or pregnancy-related).	54 / 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 - Beta-blockers (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 Beta blocker 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).	985 / 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 - Beta-blockers (Controls unexposed, disease free), 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 Beta-blocker 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).	985 / 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 - Beta-blockers (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 Beta blocker 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 antihy- pertensive medication at any stage during or 60 days after pregnancy.	985 / 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).
Fitton - Beta-blockers (Controls unexposed, sick), 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 Beta-blocker medication during the 300 days before birth (whatever the indication).	unexposed, sick Pregnant women who had a code for hypertension (chronic, gestational, preeclampsia, eclampsia, unspecified) and who were not dispensed antihypertensive medication at any stage during or 60 days after pregnancy (untreated hypertension).	985 / 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).
Gandjbakhch - Beta-blockers, 2018	France 1968 - 2016	All women followed-up in the tertiary care center with an Arrhythmogenic Right Ventricular Cardiomyopathy/ dysplasia (ARVC/D) diagnosis and with a history of pregnancy.	Pregnancies in women with Arrhythmogenic Right Ventricular Cardiomyopathy/ dysplasia (ARVC/D) diagnosis treated with beta-blockers alone or in association with flecainide.	unexposed, sick Pregnancies in women with Arrhythmogenic Right Ventricular Cardiomyopathy/ dysplasia (ARVC/D) diagnosis not treated with beta-blockers.	15 / 45	Beta-blockers used were bisoprolol (n = 6), acebutolol (n = 1), propranolol (n = 1), nadolol (n = 1), betaxolol (n = 3), sotalol (n = 1) and undocumented in two cases.
Hoeltzenbein c - Bisoprolol, 2018	Germany 2000 - 2015	Pregnancies for which Embryotox service was contacted for risk assessment on drug use in pregnancy.	Pregnancies with bisoprolol exposure at least during the first trimester. Concomitant therapy with other antihypertensive drugs except angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) was possible.	unexposed, disease free Nonhypertensive pregnancies, without use of beta-blockers and other antihypertensives during pregnancy, randomly selected.	339 / 678	Overlapping between Kayser 2020 and Hoeltzenbein 2018 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.
Ishibashi - Beta-blockers, 2017	Japan 2000 - 2016	Congenital long QT syndrome (LQTS)	Pregnancies in long QT patients with β-blocker therapy.	unexposed, sick Pregnancies in long QT patients without β-blocker therapy.	42 / 94	Beta-blockers: 29 receiving propranolol (20–60mg, average: 40±14mg/day, 0.80±0.28mg/kg/day), 1 atenolol (50mg/day, 0.89mg/kg/day), 10 bisoprolol (5mg/day, 0.072±0.028mg/kg/day) and 1 carteolol (15mg/day, 0.25mg/ kg/day).
Kayser - Metoprolol/bisoprolol, 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 metoprolol and/or bisoprolol after the first trimester, but not with methyldopa at any time during pregnancy. Metoprolol/bisoprolol 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.	291 / 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.
Kubota - Beta-blockers, 2023	Japan 2014 - 2020	All consecutive pregnancies in women with heart disease admitted to the participating hospital.	Pregnancies in women with heart disease who were prescribed β-blocker (bisoprolol, propranolol, atenolol, metoprolol, or nadolol).	unexposed, sick Pregnancies in women with heart disease who did not take any of the α/β- blockers and β-blockers.	11 / 263	For SGA: in exposed group: the number of cases and the % did not correspond =>the nb of cases was used. Author confirmed that there are 5 cases of SGA (45.5%) in the βblocker group (e-mail).
Kumar - Beta-blockers, 2020	USA 2015 - 2018	All infants born at >=34 weeks who had point of care (POC) glucose level documented.	Beta-blocker exposure during the current pregnancy.	unexposed, disease free No disease (both prepregnancy and pregnancy complications) during the current pregnancy.	228 / 4104	Infants were excluded if they were out born, length of stay was less than 24 hours, and had congenital malformations or chromosomal abnormalities. Large for gestational age: not entered because of a mistake in the table (for group N).
Lennestal - Beta-blockers, 2009	Sweden 1995 - 2006	Nearly all infants born in Sweden.	Infants born of women who reported the use of Beta-blocking agent (only) in early pregnancy, and had a delivery diagnosis of chronic hypertension.	unexposed (general population or NOS) Infants born of all women giving birth during the study period.	798 / 1046843	Overlapping: for beta-blockers, ARAII, ICE and calcium inhibitors, results of Kallen 2003 were totally overlapped by Lennestal 2009 a larger study: 1995 - 2006 with better adjustments) => Lennestal used rather than Kallen 2003.
Lieberman - Propranolol, 1978	United Kingdom 1970 - 1973	Pregnancies complicated by maternal hypertension (diastolic blood pressure of 105 mm Hg or more at some point during pregnancy).	Pregnancies in hypertensive patients treated with propranolol and other hypotensive agents.	unexposed, sick Pregnancies in hypertensive patients treated with similar drugs excluding propranolol.	9 / 15	Pentolinium, clonidine and hydrallazine had been prescribed for so few patients (one, one and three respectively) that they were excluded from the analysis.
Lydakis - Atenolol, 1999	United Kingdom 1980 - 1997	Pregnant women referred to this clinic either due to previous chronic hypertension, increased blood pressure (BP), or preeclampsia during a previous pregnancy, or because of high BP readings in the first weeks of pregnancy measured by the general practitioner or the obstetrician.	Pregnant women with chronic hypertension receiving atenolol (as monotherapy).	unexposed, sick Pregnant women with chronic hypertension receiving no antihypertensive drugs.	78 / 91	Mean blood pressures did not differ between the three groups in the early (<20 weeks), mid- (between 20 and 30 weeks), and late (>30 weeks) stages of pregnancy.
Mazkereth - Beta-blockers, 2019	Israel 2011 - 2015	Term and late preterm infants born at the Sheba Medical Center during the study period.	Infants born to mothers who were treated with beta blockers during pregnancy and until delivery.	unexposed, sick Infants born to mothers with hypertension at the same gestational age, who where not treated with beta blockers.	153 / 153	Treatment indications included hypertension 76 mothers (49.7%), cardiac arrhythmias 48 (31.4%), rheumatic heart disease 14 (9.1%), cardiomyopathy 11 (7.2%) and migraine 4 (2.6%).
Orbach - Atenolol, 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 Atenolol 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.	107 / 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.
Petersen - Beta-blockers, 2012	Denmark 1995 - 2008	All pregnancies in Denmark during the study period.	Pregnancies with at least one prescription of b-blockers between conception and the 20th week of gestation (and at least 2 prescriptions between 6 monts before conception and 20 gestational weeks).	unexposed (general population or NOS) Pregnancies unexposed to b-blockers.	2459 / 909228	Ninety-eight pregnancies were exposed to more than one b-blocker.
Ray - Beta-blockers, 2001	Canada 1986 - 1995	All pregnant women whose sitting systolic blood pressure was ≥ 140 mm Hg or whose diastolic pressure was ≥ 90 mm Hg.	Hypertensive pregnant women with at least one dose of β-blocker drug (only), regardless of the route of administration, dose or duration of use, gestational age at initiation, or type or degree of hypertension.	unexposed, sick Hypertensive pregnant women with no anti-hypertensive drug.	428 / 980	When available, data obtained for CHRONIC hypertension (neonatal composite outcome, SGA, preterm) were used rather than those for any form of hypertension, because it seems to be a more homogeneous group.
Rosenfeld - Pindolol, 1986	Israel Not specified.	Consecutive pregnant hypertensive (a systolic blood pressure of 150 mmHg or more or a diastolic pressure of 90 mmHg or more) patients of 36 wk or less, who were routinely referred to the High-Risk Clinics for Hypertensive Pregnant Women.	Hypertensive pregnant patients randomly allocated to the group treated with hydralazine (25 mg b.i.d.) combined with pindolol (5 mg b.i.d).	unexposed, sick Hypertensive pregnant patients randomly allocated to the group treated with hydralazine only (25 mg b.i.d. in the monotherapy).	23 / 21	Chronic hypertension in 11/23 pregnancies exposed to Pindolol and in 10/21 of other pregnancies.
Sibai - Labetalol, 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 labetalol (start at 300 mg/day and maximum of 2400 mg/day).	unexposed, sick Pregnant patients with mild to moderate chronic hypertension randomly allocated to no medications.	86 / 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 - Beta-blockers (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 Beta-blocker 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.	414 / 8181	Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Su - Beta-blockers (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 Beta-blocker 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.	414 / 1006	Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Tanaka - Beta-blockers, 2016	Japan 2000 - 2010	Women with singleton pregnancies and with cardiovascular disease who delivered infants at the National Cerebral and Cardiovascular Center in Osaka, Japan.	Pregnant women with cardiovascular disease treated with an oral β-adrenergic blocker for at least 2 weeks before delivery.	unexposed, sick Pregnant women with cardiovascular disease who were not treated with an oral α/β- or β-adrenergic blocker randomly identified over the same period.	45 / 100	Maternal cardiovascular diseases: congenital heart disease and pulmonary hypertension; aortic disease; valvular heart disease; coronary artery disease and acute coronary syndrome; cardiomyopathy and heart failure; and arrhythmia.
Thewissen - Labetalol (Controls unexposed, disease free), 2017	The Netherlands 2009 - 2010	Neonates of mothers admitted in the Hospital in Utrecht (HDPlab), a tertiary referral center in the Netherlands.	Neonates of mothers treated with labetalol for hypertensive disorders of pregnancy (HDP) with a gestational age < 32 weeks.	unexposed, disease free Neonates of mothers without hypertensive disorders of pregnancy (HDP).	22 / 22	The median dose [range] of labetalol was 480 [100– 2400] mg/24h.
Thewissen - Labetalol (Controls unexposed, sick), 2017	The Netherlands 2009 - 2010	Neonates of mothers admitted in the Hospital in Utrecht (HDPlab), a tertiary referral center in the Netherlands.	Neonates of mothers treated with labetalol for hypertensive disorders of pregnancy (HDP) with a gestational age < 32 weeks.	unexposed, sick Neonates of mothers with hypertensive disorders of pregnancy (HDP) without labetalol treatment.	22 / 22	Both groups of pregnancies (exposed and non-exposed) were co-exposed to other anti-hypertensive treatments (methyldopa, dihydralazine, ...) => Control group considered as 'unexposed sick'. The median dose [range] of labetalol was 480 [100– 2400] mg/24h.
Vaclavik - Beta-blockers, 2024	The Czech Republic 2012 - 2022	All births and abortions in the period 2012 - 2022 in the Czech Republic.	Births whose mothers were prescribed Beta-blockers during pregnancy (for pre-existing hypertension or pregnancy-induced hypertension).	unexposed, disease free Births whose mothers had no hypertension.	-9 / -9
Vasilakis-Scaramozza - Beta-blockers, 2013	United Kingdom (UK) 1991 - 2002	Offspring (including included livebirths, stillbirths, and therapeutic abortions) of singleton pregnancies (that lasted more than 20 weeks of gestation) among women 15– 45 years of age that occurred during the study period.	Offspring of women with one or more prescriptions for a Beta-blocker during early pregnancy, with a diagnosis of hypertension at any time prior to, or during, the pregnancy.	unexposed (general population or NOS) Offspring of women without exposure to antihypertensive drugs during pregnancy.	215 / 682
Xiang - Labetalol, 2020	China 2018 - 2019	Pregnant women with mild to moderate chronic hypertension in the first trimester (6 to 10 weeks) and systemic blood pressure between 140 and 159 mmHg or diastolic blood pressure between 90 and 109 mmHg without medication and disease in the target organ.	Pregnant women with mild to moderate chronic hypertension randomly allocated to the labetalol group.	unexposed, sick Pregnant women with mild to moderate chronic hypertension randomly allocated to the placebo group.	131 / 131	Treatment administration not accurately reported by authors: Eligibility: from 6 to 10 gestational weeks => Considered as 'During pregnancy'.
Yassen - Acebutolol, 1992	France Not specified.	Neonates (>= 35 gestational weeks) hospitalized in the investigator Neonatal Medicine Service.	Neonates whose mothers were treated with Acebutolol for hypertension during pregnancy for at least 3 days.	unexposed, disease free Neonates born to normotensive mothers.	11 / 11	Acebutolol doses: 100-600 mg/d, for 4 days - 4 months.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Bergman - Beta-blockers, 2018	13 European countries (BE, CR, DE, DK, FR, IT, NO, SP, SW, UK) 1995 - 2013	Registrations with a specific congenital anomaly or anomaly subgroups (reported in the literature or not).	All other EURO-mediCAT registrations with a non-chromosomal non-signal anomaly group.	49243 / 50709	This is a case-malformed control study. 2 available controls: non-chromosomal non-signal anomaly group and a chromosomal anomaly group => use of the 1st one (more pregnancies; same control group for signal and exploratory analysis).
Caton - Beta-blockers, 2009	USA 1997 - 2003	Cases of cardiovascular malformations in live births, fetal deaths occurring after 20 weeks, and elective pregnancy terminations.	Live births without birth defects randomly selected from birth certificates or hospital discharge listings in the same geographic areas as the cases.	5021 / 4796	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 (except for Ebstein anomaly).
Cedergren - Beta-blockers, 2002	Sweden 1982 - 1996	Infants with a cardiovascular malformation, excluding persistent ductus arteriosus (PDA) and single umbilical artery (SUA).	Infants born in the region the same year as the case and with maternal age as close as possible to that of the case.	269 / 524
Fisher - Beta-blockers (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 (except for Ebstein anomaly).
Fisher - Beta-blockers (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 (except for Ebstein anomaly).
Fisher a - Beta-blockers, 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 - Pindolol, 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	This register is used to study several beta-blockers. Exposure cannot be added => To avoid redundancy of case and controls, only the substances with the higher number of exposed cases was used in the meta-analysis of the class (i.e. pindolol).
Nakhai-Pour - Beta-blockers, 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	Sum of Selective Beta-blockers and Non-selective Beta-blockers (possible because monotherapy). Major 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.
Puho - Metoprolol, 2007	Hungary 1980–1996	Cases with isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP).	Newborn infants without congenital abnormalities	1975 / 38151	For cleft palate: this register is used to study several beta-blockers. => To avoid redundancy of case and controls, only the substance with the highest number of exposed cases was used in the class meta-analysis (i.e . metoprolol).
Puho - Oxprenolol, 2007	Hungary 1980 - 1996	Cases with isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP).	Newborn infants without congenital abnormalities	1975 / 38151	For cleft palate: this register is used to study several beta-blockers. => To avoid redundancy of case and controls, only the substance with the highest number of exposed cases was used in the class meta-analysis (i.e . metoprolol).
Queisser-Luft - Beta-blockers, 1996	Germany 1990 - 1994	All neonates with at least one major malformation.	All healthy newborns without any major or minor malformation.	1472 / 9682	Continuous exposure reported rather than acute in order to maximize exposure period of exposure and because more outcomes are reported for this exposure (digestive malformations reported only for continuous exposure).
Syvanen - Beta-blockers, 2021	Finland 1996 - 2008	Foetus or neonates with congenital limb deficiencies associated with amniotic bands born ((ICD-9) codes 75XX and 65XX)..	Foetus or neonates without limb deficiencies matched for residency and time of conception were randomly selected from the Medical Birth Register for each case.	106 / 530
Van Zutphen - Beta-blockers, 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