Centrally acting antiadrenergic (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 - Methyldopa (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 Methyldopa 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 - Methyldopa (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 Methyldopa 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.
Chan - Methyldopa
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 Methyldopa for hypertension during pregnancy. unexposed, disease free
Children of normotensive women exposed to non-teratogenic substance during pregnancy. 		during pregnancy (anytime or not specified) 25 / 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.
Fidler - Methyldopa
1983 		United Kingdom (UK)
Not specified.
prospective cohort 		The Queen Charlotte's Maternity Hospital, London, England. Hypertensive pregnant patients allocated at random to receive methyldopa (250mg 3 times a day and increased until 3g 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 - Centrally acting (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 Centrally-acting antiadrenergics 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. 		during pregnancy (anytime or not specified) 67 / 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 - Centrally acting (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 Centrally-acting antiadrenergics 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) 67 / 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 - Centrally acting
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 Centrally acting 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) 196 / 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 - Centrally acting (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 Centrally acting antihypertensive 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) 136 / 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 - Centrally acting (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 Centrally acting antihypertensive 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. 		during pregnancy (anytime or not specified) 136 / 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.
Hoeltzenbein - Methyldopa (Controls unexposed, disease free)
2017 		Germany
2000 - 2014
prospective cohort 		The German Embryotox pharmacovigilance institute in Berlin, Germany. Pregnancies with chronic hypertension, exposed to methyldopa in the first trimester (gestational week 12 plus 6 days after last menstrual period). unexposed, disease free
Pregnancies without a diagnosis of chronic hypertension and without antihypertensive therapy, randomly selected in the database. 		at least 1st trimester 261 / 526 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.
Data on maternal medication are collected via structured telephone interview and mailed questionnaires. The outcome of pregnancy was not known at the time of enrollment.
Huisjes - Clonidine
1986 		The Netherlands
1974 - 1981
retrospective cohort 		The database of the Obstetrical Department of the Groningen University Hospital, The Netherlands. Pregnant women who had been treated for hypertension or superimposed preeclampsia with clonidine only. unexposed, sick
Non-treated hypertensive gravidae matched for diastolic blood pressure during pregnancy, and sex, birthweight and gestational age of the children. 		during pregnancy (anytime or not specified) 22 / 22 The start of the clonidine medication varied from before conception to 35 weeks gestational age and it was continued until delivery in all cases, dosages ranged from twice 75 microg to three times 150 microg.
Not specified.
Ishikawa - Methyldopa (Controls unexposed, disease free)
2023 		Japan
2010 - 2019
retrospective cohort (claims database) 		A large administrative claims database from JMDC Inc. (Tokyo, Japan), which contained all the inpatient, outpatient, and pharmacy claims received from insurers. Pregnant women with chronic hypertension and prescribed Methyldopa in the first trimester. unexposed, disease free
Pregnant women without hypertensive disorders in the first trimester. 		1st trimester 93 / 74213
A large administrative claims database from JMDC Inc. (Tokyo, Japan), which contained all the inpatient, outpatient, and pharmacy claims received from insurers. These claims include prescribed medications.
Ishikawa - Methyldopa (Controls unexposed, sick)
2023 		Japan
2010 - 2019
retrospective cohort (claims database) 		A large administrative claims database from JMDC Inc. (Tokyo, Japan), which contained all the inpatient, outpatient, and pharmacy claims received from insurers. Pregnant women with chronic hypertension and prescribed Methyldopa in the first trimester. unexposed, sick
Pregnant women chronic hypertension but no first-trimester antihypertensive prescriptions. 		1st trimester 93 / 1007
A large administrative claims database from JMDC Inc. (Tokyo, Japan), which contained all the inpatient, outpatient, and pharmacy claims received from insurers. These claims include prescribed medications.
Kayser - Methyldopa
2020 		Germany
2001 - 2015
prospective cohort 		The German Embryotox Pharmacovigilance Centre in Berlin, Germany. Pregnancies in hypertensive women treated with methyldopa after the first trimester, but not on beta-blockers at any time during pregnancy. Methyldopa 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 221 / 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.
Leather - Methyldopa
1968 		United Kingdom
Not specified.
randomized controlled trial 		Department of Clinical research, Plymouth general hospital, United Kingdom. Pregnant patients with early hypertension (before 20 gestational weeks) randomly allocated to treatment group, i.e bendrofluazide 5-10 mg daily with potassium supplements and methyldopa 0-5-2g daily in divided doses. unexposed, sick
Pregnant patients with early hypertension (before 20 gestational weeks) randomly allocated to control group. 		during pregnancy (anytime or not specified) 23 / 24 Data related to chronic hypertension were reported here.
On entry to the trial patients were allocated at random to control or treatment groups.
Mabie - Methyldopa
1986 		USA
1980 - 1984
prospective cohort 		The Tulane Obstetrical Service of Charity Hospital at New Orleans, Louisiana, USA. Pregnant women with chronic hypertension treated with Methylopa only. unexposed, sick
Pregnant women with chronic hypertension without treatment. 		during pregnancy (anytime or not specified) 54 / 82 Data on Methyldopa only reported rather than co-administration Methyldopa and hydrochlorothiazide.
Not specified (study conducted in a department of obstetrics and gynecology but the source of exposure data, not clearly specified).
Orbach - Methyldopa
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 Methyldopa 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 340 / 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.
Redman - Methyldopa
1976 		United Kingdom
Not specified.
randomized controlled trial 		A randomized clinical trial conducted at the John Radcliffe Hospital, Oxford, England, United Kingdom. Pregnant women with moderate hypertension detected before 28 gestational weeks randomly allocated to the Methyldopa group. unexposed, sick
Pregnant women with moderate hypertension detected before 28 gestational weeks randomly allocated to no treatment group. 		during pregnancy (anytime or not specified) 107 / 101 Patients separated into early or late group, if hypertension was detected before or after 28 weeks => After 28 weeks probably mainly pregnancy-induced hypertension => Thus, here use of data of 'early' groups.
Treatment was allocated randomly at the end of the baseline inpatient assessments to early and late entries separately. Placebo tablets were not used.
Sibai - Methyldopa (Controls unexposed, sick)
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 methyldopa (start at 750 mg/day and maximum of 4 g/day). unexposed, sick
Pregnant patients with mild to moderate chronic hypertension randomly allocated to no medications. 		2nd and/or 3rd trimester 88 / 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 - Centrally acting (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 Central alpha agonist 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) 181 / 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 - Centrally acting (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 Central alpha agonist 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) 181 / 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.
Vaclavik - Methyldopa
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 Methyldopa 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).
Weitz - Methyldopa
1987 		USA
Not specified
randomized controlled trial 		A double-blind, controlled study in Divisions of Maternal and Fetal Medicine, The Johns Hopkins Hospital, Greater Baltimore Medical Center, The University of Florida College of Medicine, Florida (USA) Pregnant women allocated into the treatment group: methyldopa one tablet (250 mg) per os twice in day (tid). These doses were increased every 48 h as needed to a maximum of 2 tablets qid. unexposed, sick
Pregnant women allocated into the placebo group: one tablet per os twice in day (tid). These doses were increased every 48 h as needed to a maximum of 2 tablets qid. 		during pregnancy (anytime or not specified) 13 / 12 Other antihypertensive medications were utilized only if severe superimposed pre--eclampsia developed. In that case, hydralazine and magnesium sulfate were administered, and the patient delivered.
Pregnancies randomly allocated into two groups: treatment with methyldopa (13 patients) or placebo (12 patients). At each clinic visit, the patients were asked to count their remaining tablets of assigned medication, to assess compliance in self medication.
Welt - Methyldopa
1981 		USA
Not specified.
randomized controlled trial 		Duke university medical center, Durham, North Carolina, USA. Pregnant women with underlying hypertensive disease randomly and blindly assigned to methyldopa group (250 mg 3 times per day). unexposed, sick
Pregnant women with underlying hypertensive disease randomly and blindly assigned to placebo group (3 times per day). 		2nd and/or 3rd trimester 6 / 6 The main results were provided for non randomized group versus randomized group (whatever treatment in the group). The only reported results are those of randomized group, with distinction between treatment (provided in the text, not in the tables).
Pregnant women were randomly and blindly assigned to 1 of 3 drug groups.

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
De Jonge - Methyldopa
2013 		The Netherlands
1998 - 2008
case control 		EUROCAT NNL, a population-based birth defect registry in the northern part of the Netherlands and the InterAction Database (IADB) pregnancy database. All malformed foetuses and children (live births, stillbirths, spontaneous abortions and terminations of pregnancy) excluding chromosomal and genetic disorders. From the InterAction Database (IADB), a population-based prescription database that contains prescription data from approximately 55 community pharmacies in The Netherlands, we selected the population controls. The IADB covers an estimated population of 500,000 individuals, which is considered representative of the general population. For controls: from the IADB (InterAction Database), a population-based prescription database. For cases: the pharmacy records for 3 months before conception until delivery were obtained and verified in a telephone interview and only the actually used medication is registered. 1st trimester 3212 / 29223
Information on congenital malformations is obtained from the medical files, including pathology reports, and coded afterwards, according to the International Classification of Diseases (ICD) coding system by trained registry staff.
Fisher - Centrally acting antiadrenergics (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.
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 - Centrally acting antiadrenergics (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.
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 - Centrally acting
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 - Methyldopa
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 Study design completed with other studies published on the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA).
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 - Centrally acting
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 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.
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.
Van Zutphen - Centrally acting
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;  

master protocol

- About - Master protocol - Browse exposition - RSS - Made with in Lyon - Contact us - Privacy policy - Licence Creative Commons