| 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 (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 (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 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 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. | ||||||||
|
Hoeltzenbein 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. | ||||||||
|
Ishikawa (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 (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 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 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 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 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 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 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. | ||||||||
|
Vaclavik 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 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 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. | ||||||||
| 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 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 (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 (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) | |||||||||
|
Medveczky 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. | |||||||||
|
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. 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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