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

Exposed non-exposed, cohort studies

Study Country
Study period
Study design		 Data source Exposure definition Non-exposure definition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Al Khalaf - Beta-blockers (Controls unexposed, disease free)
2022 		United Kingdom
1997 - 2016
retrospective cohort (claims database) 		The CALIBER study that linked the Clinical Practice Research Datalink (CPRD), Hospital Episodes Statistics (HES), Office for National Statistics cause-specific mortality records. 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. 		during pregnancy (anytime or not specified) 1952 / 1739944
Data on antihypertensive medication were identified from the Clinical Practice Research Datalink (CPRD) provides information about prescription details.
Al Khalaf - Beta-blockers (Controls unexposed, sick)
2022 		United Kingdom
1997 - 2016
retrospective cohort (claims database) 		The CALIBER study that linked the Clinical Practice Research Datalink (CPRD), Hospital Episodes Statistics (HES), Office for National Statistics cause-specific mortality records. 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. 		during pregnancy (anytime or not specified) 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.
Data on antihypertensive medication were identified from the Clinical Practice Research Datalink (CPRD) provides information about prescription details.
Albertini - Beta-blockers
2023 		Canada
2012 - 2021
retrospective cohort 		The tertiary Pregnancy and Heart Disease Program at the University of Toronto, Canada. 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. 		during pregnancy (anytime or not specified) 44 / 7
Maternal clinical history including medications was collected (no other details).
Baard - Beta-blockers
2020 		South Africa
2010 - 2016
prospective cohort 		A tertiary multidisciplinary maternal care facility, University of Cape Town, 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). 		during pregnancy (anytime or not specified) 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%)
Data were manually extracted from both cardiology and obstetric clinical records, after screening for eligibility, and captured in a modified database. Data on type of beta-blockers (BB) used, treatment dosage, treatment duration in weeks and trimester of BB initiation were recorded.
Bateman - Beta-blockers
2016 		USA
2003 - 2007
retrospective cohort (claims database) 		The US Medicaid Analytic eXtract (MAX). 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. 		late pregnancy 10561 / 31683 The primary analysis included all β blockers, including combined α–β blockers, and combination medications that included a β blocker.
Claims database of dispensed prescriptions for outpatient medications.
Bateman_Nordic - Beta-blockers
2018 		Denmark, Finland, Iceland, Norway and Sweden
1996 - 2010
population based cohort retrospective 		National health registries in the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden), collaborating for the InPreSS consortium. 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. 		1st 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.
Exposure was determined through the nationwide prescription drug registries in the Nordic cohort.
Bateman_USMAX - Beta-blockers
2018 		USA
2000 - 2010
retrospective cohort (claims database) 		The Medicaid Analytic eXtract (MAX) database in the United States, collaborating for the InPreSS consortium. 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. 		1st trimester 1668 / 13232
Exposure was determined by review of pharmacy dispensing records in the US MAX cohort.
Bayliss - Atenolol
2002 		United Kingdom (UK)
1980 - 1999
retrospective cohort 		The antenatal hypertension clinics in two district general hospitals (Birmingham and Sutton Coldfield), United Kingdom 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. 		2nd trimester, throughout 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.
Clinical data are collected on drug treatment used before and during pregnancy. Data is collected prospectively from the clinics (patient’s hospital records) onto a proforma and entered into a computer database by a research associate (MB).
Chan - Labetalol
2010 		Canada
1997 - 2002
prospective cohort 		The Motherisk Program at The Hospital for Sick Children, and The Obstetrical-Medicine clinic at Sunnybrook Health Sciences Centre, Toronto. Children of women treated with labetalol for hypertension during pregnancy. unexposed, disease free
Children of normotensive women exposed to non-teratogenic substance during pregnancy. 		during pregnancy (anytime or not specified) 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).
Prospectively collected database with participants contacting the Motherisk Program for counseling in case of use of medication during pregnancy.
Cruickshank - Labetalol
1990 		Scotland
A 2-year period
randomized controlled trial 		A randomised controlled study, Aberdeen Maternity Hospital, Aberdeen, Scotland, UK. 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. 		3rd trimester 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.
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).
Cruickshank - Labetalol
1991 		Scotland
A 2-year period
randomized controlled trial 		A randomised controlled study, Aberdeen Maternity Hospital, Aberdeen, Scotland, UK. 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. 		3rd trimester 51 / 63
Pregnant women were randomly allocated using numbered sealed envelopes to receive either oral labetalol or no antihypertensive drug therapy.
Darcie - Atenolol
2004 		Brazil
1994 - 1997
prospective cohort 		A randomized, longitudinal, prospective study conducting at the Neonatal Pediatrics Service, Faculty of Medicine, University of São Paulo. 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. 		late pregnancy 40 / 14 Study considered as a prospective cohort because no precision indicating that a randomization was carried out.
This was a randomized, longitudinal, prospective study comparing 3 groups of patients according to the type of maternal treatment. => Not otherwise specified => Considered as a prospective cohort because no precision indicating that a randomization was carried out.
Delteil - Beta-blockers
2024 		France
2004 - 2021
retrospective cohort (claims database) 		EFEMERIS (Évaluation chez la Femme Enceinte des MÉdicaments et de leurs RISques) database, and the Registre des Handicaps de l'Enfant en Haute-Garonne (RHE31), Haute-Garonne, France. 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. 		1st trimester, at least 1st trimester, during pregnancy (anytime or not specified) 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.
Women's drug exposure during pregnancy was estimated on the basis of dispensed prescription drugs recorded by the French Assurance Maladie.
Duan - Beta-blockers
2017 		USA
2003 - 2014
retrospective cohort (claims database) 		The Kaiser Permanente Southern California (KPSC) Region, USA. 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. 		1st trimester, during pregnancy (anytime or not specified) 4847 / 374391 The 4 most commonly prescribed β-blockers were labetalol (n = 3357), atenolol (n = 638), propranolol (n = 489), and metoprolol (n = 324).
Pregnant women exposed to β-blockers during pregnancy were identified using pharmacy dispensing records.
Duan - Beta-blockers
2018 		USA
2003 - 2014
retrospective cohort (claims database) 		The Kaiser Permanente Southern California (KPSC) Region. 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. 		during pregnancy (anytime or not specified) 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.
Pregnant women exposed to beta‐blockers during their pregnancy were identified using pharmacy dispensing records.
Ersboll - Beta-blockers (Controls unexposed, disease free)
2014 		Denmark
2003 - 2009
retrospective cohort 		The Centre for Pregnant Women with Heart Disease (CPWHD) and the Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Denmark. 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. 		during pregnancy (anytime or not specified) 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.
Electronic summary charts for all women attending the Centre for Pregnant Women with Heart Disease (CPWHD) during the study period were screened. Data on any medical treatment taken at the time of conception and/or during pregnancy were collected from obstetrical and cardiological charts.
Ersboll - Beta-blockers (Controls unexposed, sick)
2014 		Denmark
2003 - 2009
retrospective cohort 		The Centre for Pregnant Women with Heart Disease (CPWHD) and the Department of Obstetrics, Copenhagen University Hospital, Rigshospitalet, Denmark. 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). 		during pregnancy (anytime or not specified) 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.
Electronic summary charts for all women attending the Centre for Pregnant Women with Heart Disease (CPWHD) during the study period were screened. Data on any medical treatment taken at the time of conception and/or during pregnancy were collected from obstetrical and cardiological charts.
Fidler - Oxprenolol
1983 		United Kingdom (UK)
Not specified.
prospective cohort 		The Queen Charlotte's Maternity Hospital, London, England. 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. 		during pregnancy (anytime or not specified) 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.
The patients were allocated at random to receive either methyldopa or oxprenolol.
Fisher b - Beta-blockers (Controls unexposed, disease free)
2018 		USA
1997 - 2011
retrospective cohort 		A retrospective cohort study using data on National Birth Defects Prevention Study (NBDPS) singleton controls, USA. 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. 		during pregnancy (anytime or not specified) 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).
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.
Fisher b - Beta-blockers (Controls unexposed, sick)
2018 		USA
1997 - 2011
retrospective cohort 		A retrospective cohort study using data on National Birth Defects Prevention Study (NBDPS) singleton controls, USA. 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). 		during pregnancy (anytime or not specified) 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).
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.
Fitton - Beta-blockers (Controls unexposed, disease free)
2020 		Scotland
2010 - 2014
retrospective cohort (claims database) 		Linkage of 4 Scottish healthcare databases, held by the Information Statistics Division. 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). 		during pregnancy (anytime or not specified) 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).
The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.
Fitton - Beta-blockers (Controls unexposed, disease free)
2021 		Scotland
2010 - 2014
retrospective cohort (claims database) 		Linkage of 4 Scottish healthcare databases, held by the Information Statistics Division. 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). 		during pregnancy (anytime or not specified) 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).
The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.
Fitton - Beta-blockers (Controls unexposed, sick)
2021 		Scotland
2010 - 2014
retrospective cohort (claims database) 		Linkage of 4 Scottish healthcare databases, held by the Information Statistics Division. 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). 		during pregnancy (anytime or not specified) 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).
The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.
Fitton - Beta-blockers (Controls unexposed, sick)
2020 		Scotland
2010 - 2014
retrospective cohort (claims database) 		Linkage of 4 Scottish healthcare databases, held by the Information Statistics Division. 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. 		during pregnancy (anytime or not specified) 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).
The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents.
Gandjbakhch - Beta-blockers
2018 		France
1968 - 2016
retrospective cohort 		A single tertiary care center (Pitié-Salpêtrière University Hospital, France). 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. 		during pregnancy (anytime or not specified) 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.
Medications characteristics were obtained from medical records.
Hoeltzenbein c - Bisoprolol
2018 		Germany
2000 - 2015
prospective cohort 		The German Embryotox pharmacovigilance institute. 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. 		at least 1st trimester 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.
At the initial contact (during pregnancy) maternal characteristics and detailed exposure assessment are asked for after informed consent. The outcome of pregnancy was not known at the time of enrollment.
Ishibashi - Beta-blockers
2017 		Japan
2000 - 2016
retrospective cohort 		15 Japanese institutions. Pregnancies in long QT patients with β-blocker therapy. unexposed, sick
Pregnancies in long QT patients without β-blocker therapy. 		during pregnancy (anytime or not specified) 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).
All data were collected with checking their maternity record book.
Kayser - Metoprolol/bisoprolol
2020 		Germany
2001 - 2015
prospective cohort 		The German Embryotox Pharmacovigilance Centre in Berlin, Germany. 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. 		2nd and/or 3rd trimester, days before delivery 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.
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.
Kubota - Beta-blockers
2023 		Japan
2014 - 2020
retrospective cohort 		Not specified. 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. 		during pregnancy (anytime or not specified) 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).
This was a retrospective analysis of data collected for routine clinical care. The patients were identified based on their prescription histories, and their hospital records were examined.
Kumar - Beta-blockers
2020 		USA
2015 - 2018
retrospective cohort 		The neonatal unit at Hurley medical center, Michigan, USA. Beta-blocker exposure during the current pregnancy. unexposed, disease free
No disease (both prepregnancy and pregnancy complications) during the current pregnancy. 		during pregnancy (anytime or not specified) 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).
Data were collected retrospectively from the electronic medical record notably for medications including beta blocker use during current pregnancy.
Lennestal - Beta-blockers
2009 		Sweden
1995 - 2006
population based cohort retrospective 		The Swedish Medical Birth Register, the Congenital Malformation Register, and the Hospital Discharge Register. 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. 		early pregnancy 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.
Maternal use of drugs during pregnancy based on the midwife interview at the first antenatal visit (90% of women attend before week 12) and therefore mainly refers to first trimester exposure.
Lieberman - Propranolol
1978 		United Kingdom
1970 - 1973
retrospective cohort 		Not specified. Pregnancies in hypertensive patients treated with propranolol and other hypotensive agents. unexposed, sick
Pregnancies in hypertensive patients treated with similar drugs excluding propranolol. 		during pregnancy (anytime or not specified) 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.
Not specified.
Lydakis - Atenolol
1999 		United Kingdom
1980 - 1997
retrospective cohort 		The Antenatal Hypertension Clinic at City Hospital, Birmingham, United Kingdom. Pregnant women with chronic hypertension receiving atenolol (as monotherapy). unexposed, sick
Pregnant women with chronic hypertension receiving no antihypertensive drugs. 		during pregnancy (anytime or not specified) 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.
A retrospective cohort study from a computerized database of a clinic => medical records.
Mazkereth - Beta-blockers
2019 		Israel
2011 - 2015
retrospective cohort 		The Sheba Medical Center, Safra Children's Hospital, Tel Hashomer, Israel. 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. 		during pregnancy (anytime or not specified) 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%).
Medical files of infants.
Orbach - Atenolol
2013 		Israel
1998 - 2008
retrospective cohort (claims database) 		A retrospective cohort study that involved members of 'Clalit Health services' in southern Israel that gave birth at the Soroka Medical Center. 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. 		3rd trimester 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.
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.
Petersen - Beta-blockers
2012 		Denmark
1995 - 2008
population based cohort retrospective 		Three nationwide registries: the Danish Fertility Database, the Danish National Hospital Register and the National Prescription Register. 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. 		1st and 2nd trimester 2459 / 909228 Ninety-eight pregnancies were exposed to more than one b-blocker.
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.
Ray - Beta-blockers
2001 		Canada
1986 - 1995
prospective cohort 		The Obstetrics Service at the McMaster University Medical Center, Hamilton, Canada. 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. 		during pregnancy (anytime or not specified) 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.
Mother data were abstracted from their hospital charts by two authors three months after the patient's date of confinement.
Rosenfeld - Pindolol
1986 		Israel
Not specified.
randomized controlled trial 		The High-Risk Clinics for Hypertensive Pregnant Women, Tel Aviv University and Ben Gurion University of the Negev, Beer Sheva, Israel. 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). 		during pregnancy (anytime or not specified) 23 / 21 Chronic hypertension in 11/23 pregnancies exposed to Pindolol and in 10/21 of other pregnancies.
Patients were randomly allocated to one of two groups, who were treated with either hydralazine alone, or with hydralazine combined with pindolol.
Sibai - Labetalol
1990 		USA
Not specified
randomized controlled trial 		Randomized clinical trial conducted at the E.H. Crump Women's Hospital, Memphis, Tennessee, USA. 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. 		2nd and/or 3rd trimester 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.
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.
Su - Beta-blockers (Controls unexposed, disease free)
2013 		Taiwan
Jan 2005 - Dec 2005
population based cohort retrospective 		The National Health Insurance Research Dataset (NHIRD) and the birth certificate registry. 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. 		during pregnancy (anytime or not specified) 414 / 8181 Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Data on anti-hypertensive drugs use come from the National Health Insurance Research Dataset (NHIRD), which consisted of all claims data during pregnancy.
Su - Beta-blockers (Controls unexposed, sick)
2013 		Taiwan
Jan 2005 - Dec 2005
population based cohort retrospective 		The National Health Insurance Research Dataset (NHIRD) and the birth certificate registry. 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. 		during pregnancy (anytime or not specified) 414 / 1006 Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Data on anti-hypertensive drugs use come from the National Health Insurance Research Dataset (NHIRD), which consisted of all claims data during pregnancy.
Tanaka - Beta-blockers
2016 		Japan
2000 - 2010
retrospective cohort 		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. 		during pregnancy (anytime or not specified) 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.
Patient data were collected from their medical records and included medication(s) used (β-blockers and other ones).
Thewissen - Labetalol (Controls unexposed, disease free)
2017 		The Netherlands
2009 - 2010
prospective cohort 		The neonatal intensive care unit of the Wilhelmina Children’s 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). 		during pregnancy (anytime or not specified) 22 / 22 The median dose [range] of labetalol was 480 [100– 2400] mg/24h.
Obstetrical data were collected from the hospital record. Prenatal maternal exposure and maximum dose and route of labetalol were noted.
Thewissen - Labetalol (Controls unexposed, sick)
2017 		The Netherlands
2009 - 2010
prospective cohort 		The neonatal intensive care unit of the Wilhelmina Children’s 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. 		during pregnancy (anytime or not specified) 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.
Obstetrical data were collected from the hospital record. Prenatal maternal exposure and maximum dose and route of labetalol were noted.
Vaclavik - Beta-blockers
2024 		The Czech Republic
2012 - 2022
population based cohort retrospective 		The National Registry of Reproductive Health (NRRZ) and the National Registry of Reimbursable Health Services (NRHZS). 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. 		during pregnancy (anytime or not specified) -9 / -9
The National Registry of Reimbursable Health Services (NRHZS).
Vasilakis-Scaramozza - Beta-blockers
2013 		United Kingdom (UK)
1991 - 2002
retrospective cohort 		The United Kingdom’s General Practice Research Database, from 368 general medical practices from throughout the United Kingdom. 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. 		1st trimester 215 / 682
Data were extracted from standardized clinical records for every patient within a general medical practice. These records describe notably prescribed drugs from each clinical visit.
Xiang - Labetalol
2020 		China
2018 - 2019
randomized controlled trial 		A randomized multi-center clinical trial conducted in obstetrics and gynecology departments in university hospitals, Qingdao, China. 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. 		during pregnancy (anytime or not specified) 131 / 131 Treatment administration not accurately reported by authors: Eligibility: from 6 to 10 gestational weeks => Considered as 'During pregnancy'.
A simple random table was used for randomization after selection. In a 1:1:1 ratio patient was divided randomly into three groups.
Yassen - Acebutolol
1992 		France
Not specified.
prospective cohort 		Neonatal Medicine Service, Regional University Maternity Hospital, Nancy, France. Neonates whose mothers were treated with Acebutolol for hypertension during pregnancy for at least 3 days. unexposed, disease free
Neonates born to normotensive mothers. 		during pregnancy (anytime or not specified) 11 / 11 Acebutolol doses: 100-600 mg/d, for 4 days - 4 months.
Not specified.

Case-control studies

Study Country
Study period
Study design		 Data source Case Control Exposition Exposition period Sample size
(exposed/unexposed) Or (case / control)		 Remarks Risk of bias
Bergman - Beta-blockers
2018 		13 European countries (BE, CR, DE, DK, FR, IT, NO, SP, SW, UK)
1995 - 2013
case control 		EUROmediCAT network of 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT. 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. 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. 1st trimester, during pregnancy (anytime or not specified) 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).
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.
Caton - Beta-blockers
2009 		USA
1997 - 2003
case control 		The National Birth Defects Prevention Study (NBDPS). 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. 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. 1st trimester 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).
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.
Cedergren - Beta-blockers
2002 		Sweden
1982 - 1996
nested case control 		The Medical Birth Register and the Child Cardiology Register of the southeast region of Sweden. 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. For the register study, the exposure information was extracted from the Medical Birth Register, recorded at the mother’s first visit to the antenatal care center (usually week 10–12 of pregnancy), prior to knowledge of the outcome. early pregnancy 269 / 524
Outcome data were identified from various medical health registers: the Medical Birth Register and the Child Cardiology Register.
Fisher - Beta-blockers (Controls unexposed, disease free)
2017 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS). 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. 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. early pregnancy 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).
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)
Fisher - Beta-blockers (Controls unexposed, sick)
2017 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study (NBDPS). 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. 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. early pregnancy 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).
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)
Fisher a - Beta-blockers
2018 		USA
1997 - 2011
case control 		The National Birth Defects Prevention Study, USA. 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. 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. 1st trimester 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.
Data were abstracted from medical record, birth certificates or hospital discharge records.
Medveczky - Pindolol
2004 		Hungary
1980 - 1996
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). 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. 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. 1st trimester 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).
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.
Nakhai-Pour - Beta-blockers
2010 		Canada
1998 - 2003
nested case control 		The Quebec Pregnancy Registry, built with the linkage of three administrative databases: Regie de l’Assurance Maladie du Quebec (RAMQ); the hospital discharge database Med-Echo; and the Institut de la Statistique du Quebec (ISQ). 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). The Régie de l’Assurance Maladie du Québec (RAMQ) provides prospectively collected data on filled prescriptions. 1st trimester, 2nd and/or 3rd trimester 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.
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.
Puho - Metoprolol
2007 		Hungary
1980–1996
case control 		Hungarian Case-Control Surveillance of Congenital Abnormalities Cases with isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP). Newborn infants without congenital abnormalities Mothers were asked to send their prenatal maternity logbook and other medical records and they were mailed a questionnaire. Regional nurses were asked to visit and question the non-respondent. 1st trimester 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).
Notification by physicians to the Hungarian Congenital Abnormality Registry. Pathologists sent a copy of each autopsy report to the registry for stillborn fetuses or infant deaths and defect diagnosed in prenatal diagnostic centers with or without termination of pregnancy were included.
Puho - Oxprenolol
2007 		Hungary
1980 - 1996
case control 		Hungarian Case-ControlSurveillance of Congenital Abnormalities Cases with isolated cleft lip with or without cleft palate (CL/P) and posterior cleft palate (PCP). Newborn infants without congenital abnormalities Mothers were asked to send their prenatal maternity logbook and other medical records and they were mailed a questionnaire. Regional nurses were asked to visit and question the non-respondent. 1st trimester 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).
Notification by physicians to the Hungarian Congenital Abnormality Registry. Pathologists sent a copy of each autopsy report to the registry for stillborn fetuses or infant deaths and defect diagnosed in prenatal diagnostic centers with or without termination of pregnancy were included.
Queisser-Luft - Beta-blockers
1996 		Germany
1990 - 1994
nested case control 		The Mainz birth defect monitoring system, the 'Mainzer Model', Germany. All neonates with at least one major malformation. All healthy newborns without any major or minor malformation. Two sources of information: the health report of the gynecologist, and anamnestic data recorded by the delivery-hospital staff approximately 6 weeks prior to birth. 1st trimester, throughout pregnancy 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).
All examinations were performed in the first week of life of livebirths by four pediatricians trained in clinical genetics. For stillbirths and abortions, pathological findings were used.
Syvanen - Beta-blockers
2021 		Finland
1996 - 2008
nested case control 		The National Register of Congenital Malformations, the Medical Birth Register, the Register on Induced Abortions, and the Register on Reimbursed Drug Purchases. 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. Information on maternal prescription medicine use was obtained from the Register on Reimbursed Drug Purchases and the Register on Medical Special Reimbursements (Social Insurance Institution of Finland). 1st trimester 106 / 530
Cases and controls were identified from the National Register of Congenital Malformations, the Medical Birth Register and the Register on Induced Abortions.
Van Zutphen - Beta-blockers
2014 		USA
1997 - 2009
case control 		The National Birth Defects Prevention Study, USA. 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. Antihypertensive medication use were collected by trained interviewers who conducted maternal telephone interviews within 24 months of delivery. early pregnancy 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).
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.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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