Diuretics (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
Fisher b - Diuretics (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 Diuretics 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) 15 / 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 - Diuretics (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 Diuretic at 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) 15 / 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.
Leather - Bendrofluazide
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 - Hydrochlorothiazide
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 Hydrochlorothiazide only. unexposed, sick
Pregnant women with chronic hypertension without treatment. 		during pregnancy (anytime or not specified) 10 / 82 Data on Hydrochlorothiazide 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).
Olesen_Denmark - Diuretics
2001 		Denmark
1991 - 1998
retrospective cohort (claims database) 		A population-based follow-up study based on the Northern Jutland Prescription Database (NJPD), the Danish Birth Registry, and the Danish Hospital Discharge Registry. Pregnant women who purchased prescription diuretics (1) any time during their pregnancy and (2) during their third trimester. unexposed (general population or NOS)
Pregnant women who did not purchase prescription diuretics during their pregnancy. 		1st trimester, during pregnancy (anytime or not specified) 315 / 46998
The Northern Jutland Prescription Database (NJPD) that provided data concerning purchased prescription drugs for the Danish study was used to identify all prescription drugs for diuretics (ATC C03) during pregnancy.
Olesen_Scotland - Diuretics
2001 		Scotland
1993 - 1995
retrospective cohort (claims database) 		A population-based follow-up study based on the Medicines Monitoring Unit's Database (MEMO) and the Scottish Tayside Neonatal Database. Pregnant women who purchased prescription diuretics (1) any time during their pregnancy and (2) during their third trimester. unexposed (general population or NOS)
Pregnant women who did not purchase prescription diuretics during their pregnancy. 		during pregnancy (anytime or not specified) 73 / 35798
The Medicines Monitoring Unit's Database (MEMO) that contains information on dispensed prescriptions for all drugs was used to identify all prescriptions for diuretics (ATC C03) used by pregnant women.
Sibai - Diuretics
1984 		USA
Not specified.
randomized controlled trial 		University of Tennessee College of Medicine, Memphis, Tennessee, USA. Pregnant women receiving diuretics in their first trimester and then randomly assigned to the group allowed to continue their diuretic medication throughout the course of pregnancy. unexposed, sick
Pregnant women receiving diuretics in their first trimester and then randomly assigned to the group that discontinued their diuretic medication immediately. 		throughout pregnancy 10 / 10 All women received diuretics at the entry into the study (1st trimester) and were then randomly to continue or discontinue => outcomes potentially impacted by exposure during first trimester (superimposed pre-eclampsia, SGA, preterm) not reported here.
Each patient was randomly assigned to one of two groups.
Su - Diuretics (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 diuretic drug 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) 371 / 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 - Diuretics (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 diuretics 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) 371 / 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 - Diuretics
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 Diuretics 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).
Van der Zande - Diuretics
2024 		Worldwide
2007 - 2018
prospective cohort 		The Registry Of Pregnancy And Cardiac disease (ROPAC), a prospective, worldwide, registry of pregnancies in women with heart disease. Pregnant women who used diuretics at any point during pregnancy, excluding use only during delivery or only prior to pregnancy. unexposed, sick
Pregnant women who did not use diuretics during pregnancy. 		1st trimester, during pregnancy (anytime or not specified) 382 / 5357 Structural heart disease: including congenital and valvular heartdisease, prosthetic heart valves, cardiomyopathy, ischaemic heart disease, aortopathy and pulmonary arterial hypertension. Furosemide was by far the most frequently used diuretic (86%).
From January 2008, patients were included prospectively. The following data relating directly to the pregnancy were collected: medication use (no other details).

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
Caton - Diuretics
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 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).
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.
Czeizel - Furosemide
1999 		Hungary
1980 - 1996
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA). Newborn infants (including infant deaths and usual stillborn fetuses) with congenital abnormalities. Newborn infants (including infant deaths and usual stillborn fetuses) without congenital abnormalities, matched according to gender, birth week and district of parents’ residence. 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, during pregnancy (anytime or not specified) 22865 / 38151 This register is used to study several diuretics. To avoid redundancy of case and controls, only 1 of these substances was used in the class meta-analysis: this one with more exposed cases in T1 or higher OR if equal nbs => NTD not reported here.
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.
Fisher - Diuretics (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 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).
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 - Diuretics (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 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).
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 - Diuretics
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.
Kramer - Diuretics
1987 		USA
1970 - 1979
case control 		The Children's Hospital Cancer Research Center, that maintains a registry covering the entire Greater Delaware Valley Region, Philadelphia, USA. Infants diagnosed with neuroblastoma, histologically confirmed. Randomly selected sibling without neuroblastoma within the cases family. Interviews, conducted over the telephone by trained interviewers, were identical for cases and controls. The mother was questioned about exposure to medical treatments and other exposures, during each pregnancy. during pregnancy (anytime or not specified) 86 / -9 Authors provided 90% confidence intervals and 2 control groups: 1 selected by telephone random digit dialing and 1 among sibling of cases's family => Sibling control preferred because more potential confounders (genetic, environ.) took into consideration.
Interviews, conducted over the telephone by trained interviewers, were identical for cases and controls. The mother was questioned about major health problem experienced by each of her children.
McCredie - Diuretics
1994 		Australia
1985 - 1989
case control 		A population-based case-control study of malignant brain tumours diagnosed in New South Wales children, Australia. All children aged 0 to 14 years, who were newly diagnosed with a primary malignant tumour of the brain (ICD-9 191) or cranial nerves (ICD-9 192.0) reported to the NSW Central Cancer Registry. Children matched by age and sex randomly selected in a random sample of children of women aged 20 to 55 years and living in the designated area. The biological mothers were interviewed in their homes by one of 3 trained interviewers. Using the standard SEARCH questionnaire, medication (a previously postulated risk factors for brain cancer) was sought. Reported medications were not validated through medical records or attending doctors. during pregnancy (anytime or not specified) 82 / 164
All cases of primary malignant tumour of the brain (ICD-9 191) or cranial nerves (ICD-9 192.0) reported to the New South Wales Central Cancer Registry. No details for controls.
Medveczky - Hydrochlorothiazide
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 This register is used to study several diuretics. To avoid redundancy of case and controls, only 1 of these substances was used in the class meta-analysis: this one with more exposed cases in T1 or higher OR if equal nbs (i.e. Hydrochlorothiazide).
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 - Diuretics
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 Sum of Diuretics thiazide and K sparing diuretics (possible because monotherapy). 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.
Orimoloye - Diuretics
2024 		Taiwan
2004 - 2015
nested case control 		The Maternal and Child Health Database linked with the National Health Insurance Database and Cancer Registry. Infants with cancer (all types) diagnosed before age 13. Infants without cancer (all types) at the age 13. The National Health Insurance Database holds information on every prescription filled at a pharmacy in Taiwan. during pregnancy (anytime or not specified) 2780 / 2291512
The National Health Insurance Database and Cancer Registry get the records of children with cancer diagnosed before 13 years.
Schwartzbaum - Diuretics
1992 		USA
1979 - 1986
case control 		The St. Jude Children's Research Hospital, a tertiary care childhood cancer hospital located in Memphis, Tennessee, USA. Children under age 9 years, newly diagnosed with neuroblastoma. Children under age 9 years, newly diagnosed with acute lymphocytic leukemia, Wilms' tumor, acute nonlymphocytic leukemia, non-Hodgkin's lymphoma, rhabdomyosarcoma, Hodgkin's disease, Ewing's sarcoma, soft tissue sarcoma, and osteosarcoma. Shortly after diagnosis, mothers of patients were contacted to be interviewed. Each mother who was interviewed was questioned for approximately 1 hour by a trained interviewer using a standardized questionnaire, containing notably questions about prenatal maternal drug. 3 months (or more) before pregnancy or during pregnancy 101 / 690
Database of the St. Jude Children's Research Hospital, a tertiary care childhood cancer hospital. All diagnoses were histologically confirmed.
Sorensen - Diuretics
2003 		Denmark
1959 - 1961
nested case control 		The Copenhagen Perinatal Cohort, at the maternity department of the Copenhagen University Hospital, Rigshospitalet, Denmark. Schizophrenia in the offspring. Cohort comparison subjects (NOS). Treatment with diuretics and other drugs was recorded by trimester on the basis of a face-to-face interview a few days after the women had given birth. 2nd trimester, 3rd trimester 84 / 7782 'The definition used here most likely included both cases of chronic hypertension and cases of gestational hypertension.'
Schizophrenia identified on the basis of Danish Psychiatric Central Register records of hospitalizations with a diagnosis of schizophrenia (ICD-8 code 295) before 1994.
Van Gelder - Diuretics
2015 		USA and Canada
1998 - 2010
case control 		The Slone Birth Defects Study, also known as the Pregnancy Health Interview Study, a multisite case–control. 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. Within 6 months after delivery, trained research nurses interviewed the mothers of case and control infants by telephone, in English or Spanish, about details of medication use in the 2 months before pregnancy until the end of pregnancy. 1st trimester, 2nd and/or 3rd trimester 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.
Cases and controls identified through birth defects registries (Massachusetts and parts of New York State) or from participating hospitals in the areas surrounding Boston (MA), Philadelphia (PA), San Diego (CA), and Toronto (Canada).
Van Zutphen - Diuretics
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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