Labetalol (versus unexposed) - Medication and Pregnancy KB

Labetalol (versus unexposed)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Bateman, 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 Labetalol 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 any β blocker exposure at the time of delivery, notably matched on the preexisting hypertension.	6730 / 20190
Chan, 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, 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, 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
Delteil, 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 Labetalol 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.	901 / 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, 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 Labetalol 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.	3357 / 374391	Partial overlapping for preeclampsia and SGA): Duan 2018 (South California; 2003-2014; n=3357 exposed pregnancies) and Dublin 2022 (4 USA regions ; 2005-2014; n=2550 exposed pregnancies) => Duan 2018 was used because it included more pregnancies.
Fitton (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 Labetalol 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).	680 / 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 (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 Labetalol during the 300 days before birth (whatever the indication).	unexposed, sick All women who had a singleton birth during the same study period, who had an ICD-10 code for hypertension (chronic, gestational, or unspecified hypertension) and who were not dispensed antihypertensive medication at any stage during or 60 days after pregnancy.	680 / 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).
Petersen, 2012	Denmark 1995 - 2008	All pregnancies in Denmark during the study period.	Pregnancies with at least one prescription of Labetalol only 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.	1452 / 909228
Sibai, 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.
Thewissen (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 (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.
Xiang, 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'.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Bergman, 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	Combined alpha- and beta-blockers: mainly Labetalol (101/103). 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, 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).
Fisher, 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).
Van Zutphen, 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.

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