Calcium channel blockers (versus unexposed)

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Bateman - Calcium blockers, 2015	USA 2000 - 2007	Pregnant women with term deliveries, who were continuously eligible for Medicaid from 5 months after the LMP through one month postpartum.	Maternal consumption of a calcium channel blocker during the final 30 days of pregnancy (exposure that occurred between 33 and 40 weeks gestation).	unexposed (general population or NOS) Parturients without a calcium channel blocker dispensing whose days supply overlaps the final 30 days of pregnancy.	22908 / 2506728	The most commonly used calcium channel blocker was nifedipine (n = 21449), other calcium channel blockers used included amlodipine besylate (n = 523), verapamil hydrochloride (n = 424), and diltiazem hydrochloride (n = 339).
Bayliss - Calcium blockers, 2002	United Kingdom (UK) 1980 - 1999	Consecutive chronic hypertensive pregnancies collected prospectively from the 2 included clinics.	Pregnancies in patient who had been taking calcium channel blockers 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.	40 / 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.
Bortolus - Nifedipine, 2000	Italy 1992 - 1994	Children born to women recruited between 12 and 34 weeks of gestation, with chronic or gestational or unclassified hypertension (diastolic pressure between 90 and 110mmHg).	Children born to women with hypertension randomly assigned to slow-release nifedipine, starting from 10 mg twice daily (increased up to 80 mg daily, if necessary).	unexposed, sick Children born to women with hypertension randomly assigned to no treatment.	130 / 130	Methods completed with the 1st publication of this clinical trial: Parazziniet al., 1998. For all malformations: overlapping between Parazzini et al., 1998 and Bortolus 2000 => use of the 1st one because it is based on a higher number of babies.
Darcie - Isradipine, 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 isradipine (5 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.	39 / 14	Study considered as a prospective cohort because no precision indicating that a randomization was carried out.
Fisher b - Calcium inhibitors (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 Calcium channel blocker at any time during the month before pregnancy until delivery.	unexposed, disease free Normotensive mothers who did not report taking an antihypertensive medication during pregnancy.	18 / 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 - Calcium inhibitors (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 Calcium channel blocker at any time during the month before pregnancy until delivery.	unexposed, sick Mother with untreated hypertension (chronic or pregnancy-related).	18 / 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). Data extracted as a cohort.
Fitton - Calcium Blockers, 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 Calcium channel 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).	558 / 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 - Calcium 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 Calcium channel 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).	167 / 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 - Calcium 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 Calcium channel 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 antihypertensive medication at any stage during or 60 days after pregnancy.	167 / 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).
Ishikawa - Amlodipine (Controls unexposed, disease free), 2023	Japan 2010 - 2019	Pregnant women with chronic hypertension	Pregnant women with chronic hypertension and prescribed Amlodipine in the first trimester.	unexposed, disease free Pregnant women without hypertensive disorders in the first trimester.	44 / 74213
Ishikawa - Amlodipine (Controls unexposed, sick), 2023	Japan 2010 - 2019	Pregnant women with chronic hypertension	Pregnant women with chronic hypertension and prescribed Amlodipine in the first trimester.	unexposed, sick Pregnant women chronic hypertension but no first-trimester antihypertensive prescriptions.	44 / 1007
Lennestal - Calcium inhibitors, 2009	Sweden 1995 - 2006	Nearly all infants born in Sweden.	Infants born of women who reported the use of calcium-channel blockers (only) in early pregnancy, irrespective of the presence of a delivery diagnosis code of chronic hypertension.	unexposed (general population or NOS) Infants born of all women giving birth during the study period.	217 / 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.
Magee - Calcium blockers, 1996	Canada, United Kingdom and USA 1984 - 1994	Pregnant women who contacted these teratogen information services about first-trimester exposure to any calcium channel blockers or non teratogenic agents.	Pregnant women with first-trimester exposure to any calcium channel blockers.	unexposed (general population or NOS) Pregnant women with had been counseled about drugs or exposures not known or suspected of being teratogenic or fetotoxic (such as acetaminophenor dental x-rays), randomly selectedfrom the Motherisk database.	78 / 78	Indications: hypertension (57%, only 78% of which was essential hypertension), cardiac dysrhythmias (19%), migraine (16%), Raynaud's or systemic sclerosis (6%), and transient ischemic attack (3%).
Mito - Amlodipine, 2019	Japan 2008 - 2016	Pregnant women with chronic hypertension (systolic blood pressure ≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg before pregnancy or before 20 weeks' gestation) whose deliveries resulted in live births.	Chronic hypertensive pregnant women who received Amlodipine, a calcium channel blocker during the first trimester (from estimated conception to 11 weeks and 6 days’ gestation).	unexposed, sick Chronic hypertensive pregnant women who did not receive any antihypertensive drugs.	48 / 129	Data versus Group O (pregnancies exposed to antihypertensives other than amlodipine (including other calcium channel blockers)) cannot be used, because calcium channel blockers in both groups.
Parazzini - Nifedipine, 1998	Italy 1992 - 1994	Pregnant women, between 12 and 34 weeks of gestation, with chronic or gestational or unclassified hypertension (diastolic pressure between 90 and 110mmHg).	Pregnant women with hypertension randomly assigned to slow-release nifedipine, starting from 10 mg twice daily (increased up to 80 mg daily, if necessary).	unexposed, sick Pregnant women with hypertension randomly assigned to no treatment.	145 / 138	For all malformations: overlapping between Parazzini et al., 1998 and Bortolus 2000 => use of the 1st one because it is based on a higher number of babies.
Su - Calcium 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 calcium channels 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.	303 / 8181	Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Su - Calcium 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 Calcium channels 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.	303 / 1006	Women who used more than one type of anti-hypertensive drugs were excluded (n = 722).
Vasilakis-Scaramozza - Calcium 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 calcium channel 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.	55 / 682
Weber-Schoendorfer - Calcium blockers, 2008	Finland, France, Germany, Israel, Italy, the Netherlands. 1986 - 2003	Pregnant women who or whose physician contacted a Teratology Information Service (TIS) in regard to exposure to chemicals or drugs during pregnancy.	Pregnant women with first- trimester exposure to calcium channel blockers.	unexposed (general population or NOS) Pregnant women who had been counseled during pregnancy about exposures known to be non-teratogenic.	299 / 806	Nifedipine (n=76), verapamil (n=62), diltiazem (n = 41) and amlodipine (n = 38). Indications (n = 272): hypertension (64.0%), cardiac arrhythmia (8.8%), migraine (8.8%), other cardiac diseases (7.7%), autoimmune diseases (6.6%), others (4.0%).
Wide-Swensson - Isradipine, 1995	Denmark and Sweden Not specified.	Women with hypertension in pregnancy (diastolic blood pressure between >= 95 and <110 mm Hg), singleton pregnancy, gestational age > 25 weeks (<37) without other medication, and otherwise healthy.	Women with hypertension in pregnancy randomized to capsules of oral slow-release isradipine 5 mg twice daily.	unexposed, sick Women with hypertension in pregnancy randomized to capsules of placebo given twice daily.	54 / 57	Data related to Apgar scores not reported because the number of available data for the 2 groups not provided by authors.

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Caton - Calcium 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 data published by Caton 2009 based on a longer period study (1997-2011 versus 1977-2003), more cases and 2 control groups. Fisher 2017 was used rather than Caton 2009 (except for Ebstein anomaly and aorta coarctation).
Fisher - Calcium 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 data published by Caton 2009 based on a longer period study (1997-2011 versus 1977-2003), more cases and 2 control groups. Fisher 2017 was used rather than Caton 2009 (except for Ebstein anomaly and aorta coarctation).
Fisher - Calcium 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 data published by Caton 2009 based on a longer period study (1997-2011 versus 1977-2003), more cases and 2 control groups. Fisher 2017 was used rather than Caton 2009 (except for Ebstein anomaly and aorta coarctation).
Fisher a - Calcium 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	For this study, authors analyzed birth defect case groups with at least 100 participants; and excluded congenital heart defects and hypospadias, as those case groups have been studied previously.
Nakhai-Pour - Calcium 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	Major congenital malformations: number of cases: 4,155; number of controls: 54,878.Small-for-gestational-age: number of cases: 7,445; number of controls: 48,889.
Sorensen - Calcium blockers, 2001	Hungary 1980 - 1996	Cases with isolated and multiple congenital abnormalities.	Matched newborn infants without congenital abnormalities selected from the National Birth Registry of the Central Statistical Office.	22865 / 38151	Three less well-defined mild defects were excluded: congenital dislocation of the hip based on the Ortolani click, congenital inguinal hernia and hemangiomas. Syndromes of known origin were also excluded (e.g. Down Syndrome or rubella).
Van Gelder - Calcium blockers, 2015	USA and Canada 1998 - 2010	Liveborn or stillborn infants with one of the selected birth defects without chromosomal abnormalities or associated syndromes.	Liveborn infants without birth defects randomly selected from state-wide birth records or from study hospitals covering the geographic catchment areas where the cases were identified.	5568 / 7253	Any use of antiadrenergic agents, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, or direct vasodilators at any time from the month before pregnancy to the end of pregnancy.
Van Zutphen - Calcium 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).
Zarante - Nifedipine, 2009	Colombia 2001- 2006	All newborns and stillborns of weight >500 g that presented only one craniofacial malformation, not associated with any other congenital condition.	The next non-malformed same sex child born in the same hospital.	374 / 728	Exclusion of patients with Down syndrome, Potter sequence, VACTERL association, and other unspecified multiple malformations.

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