| 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 |
|---|---|---|---|---|---|---|---|---|
|
Bateman 2016 |
USA 2003 - 2007 retrospective cohort (claims database) |
The US Medicaid Analytic eXtract (MAX). | 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. |
late pregnancy | 6730 / 20190 | ||
| Claims database of dispensed prescriptions for outpatient medications. | ||||||||
|
Chan 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 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 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. | ||||||||
|
Delteil 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 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. |
at least 1st trimester, during pregnancy (anytime or not specified) | 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. | |
| Women's drug exposure during pregnancy was estimated on the basis of dispensed prescription drugs recorded by the French Assurance Maladie. | ||||||||
|
Duan 2018 |
USA 2003 - 2014 retrospective cohort (claims database) |
The Kaiser Permanente Southern California (KPSC) Region. | 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. |
during pregnancy (anytime or not specified) | 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. | |
| Pregnant women exposed to beta‐blockers during their pregnancy were identified using pharmacy dispensing records. | ||||||||
|
Fitton (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 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). |
during pregnancy (anytime or not specified) | 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). | |
| The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents. | ||||||||
|
Fitton (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 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. |
during pregnancy (anytime or not specified) | 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). | |
| The Prescribing Information System which collects information on encashed prescriptions issued by primary care and dispensed from community pharmacies for all Scottish residents. | ||||||||
|
Petersen 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 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. |
1st and 2nd trimester | 1452 / 909228 | ||
| 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. | ||||||||
|
Sibai 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. | ||||||||
|
Thewissen (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 (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. | ||||||||
|
Xiang 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. | ||||||||
| 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 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 | 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). | |
| 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 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. | |||||||||
|
Fisher 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) | |||||||||
|
Van Zutphen 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. | |
| 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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