Proton Pump Inhibitors

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
Andersen (Controls exposed to clarithromycin)
2013 		Denmark
1997 - 2007
population based cohort retrospective 		Danish Fertility Database, National Hospital Register and National Prescription Register. Pregnancy exposed to Proton Pump Inhibitors in first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Pregnancy exposed to clarithromycin. 		1st trimester 3577 / 401
From the National Prescription Register, exposure was defined as redemption of a prescription of a Proton Pump Inhibitor.
Andersen (Controls exposed to other treatment, sick)
2012 		Denmark
1996 - 2008
retrospective cohort (claims database) 		Danish Medical Birth Registry and Aarhus University Prescription Database (AUPD) At least one maternal PPI prescription from 30 days preceding the giving first day of the last menstrual period and until giving birth. exposed to other treatment, sick
At least one maternal H2RAs prescription from 30 days preceding the giving first day of the last menstrual period and until giving birth. 		during pregnancy (anytime or not specified) 2238 / 1605 In Denmark, all PPIs, except omeprazole and lanzoprazole, which became over-the-counter drugs in December 2006 and May 2007 are dispensed only by prescription.
Aarhus University Prescription Database.
Andersen (Controls unexposed NOS)
2012 		Denmark
1996 - 2008
retrospective cohort (claims database) 		Danish Medical Birth Registry and Aarhus University Prescription Database (AUPD) At least one maternal PPI prescription from 30 days preceding the giving first day of the last menstrual period and until giving birth. unexposed (general population or NOS)
Children unexposed to PPIs at any time during gestation as evidence by absence of maternal PPI prescriptions. 		1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) 2238 / 194822 In Denmark, all PPIs, except omeprazole and lanzoprazole, which became over-the-counter drugs in December 2006 and May 2007 are dispensed only by prescription.
Aarhus University Prescription Database.
Andersen (Controls unexposed, NOS)
2013 		Denmark
1997 - 2007
population based cohort retrospective 		Danish Fertility Database, National Hospital Register and National Prescription Register. Pregnancy exposed to Proton Pump Inhibitors in first trimester. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Pregnancy non-exposed to Proton Pump Inhibitors. 		1st trimester 3577 / 927927
From the National Prescription Register, exposure was defined as redemption of a prescription of a Proton Pump Inhibitor.
Breddels
2022 		Sweden
2006 - 2016
population based cohort retrospective 		A Swedish cohort created by linking data from four nationwide Swedish health data registries: the Medical Birth Registry, the Prescribed Drug Registry, the Patient Registry (in- and outpatient care) and the Causes Pregnant women filling at least two prescriptions of Proton pump inhibitors (PPI; ATC-code: A02BC) in the period ranging from 3 months before the last menstrual period (LMP) up to the delivery date. unexposed (general population or NOS)
Pregnant women without prescriptions of Proton pump inhibitors. 		1st trimester, 2nd trimester, 3 months (or more) before pregnancy or during pregnancy, 3rd trimester 14787 / 1074728
Drug exposure was extracted from the Prescribed Drug Registry are classified according to the Anatomical Therapeutic Chemical (ATC) Classification System (ATC-code: A02BC).
Cea Soriano
2016 		United Kingdom
1996 - 2010
retrospective cohort (registry) 		The Health Improvement Network (THIN) database Infants from women with at least one prescription of PPIs any time between the LMP (Last Menstrual Period) and delivery date. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants from women without prescription of any PPIs or H2RA during pregnancy. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified), throughout pregnancy 816 / 7745 For asthma: the index outcome was defined for the result with the exposition period ‘during pregnancy’.
Prescriptions issued by PCPs are recorded automatically in the database THIN.
Choi (Controls exposed to other treatment, sick)
2021 		South Korea
2011 - 2017
population based cohort propective 		The Health Insurance Review and Assessment database of South Korea Pregnant women with at least 1 prescription for proton pump inhibitors during 4 windows: any time during pregnancy or during the first, second, or third trimesters of pregnancy. exposed to other treatment, sick
Pregnant women exposed to an active comparator, histamine 2 receptor antagonist (H2RA) during 4 windows: any time during pregnancy or during the first, second, or third trimesters of pregnancy. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 43717 / 331795 When comparing with H2RA-exposed group, women who received both PPI and H2RA during pregnancy were excluded from both comparator groups.
the Health Insurance Review and Assessment database of South Korea.
Choi (Controls unexposed NOS)
2021 		South Korea
2011 - 2017
population based cohort propective 		The Health Insurance Review and Assessment database of South Korea. Pregnant women with at least 1 prescription for proton pump inhibitors during 4 windows: any time during pregnancy or during the first, second, or third trimesters of pregnancy. unexposed (general population or NOS)
Pregnant women unexposed to proton pump inhibitors from 90 days before the start of pregnancy to delivery. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 43717 / 1919973
The Health Insurance Review and Assessment database of South Korea.
Choi a
2023 		South Korea
2011 - 2020
retrospective cohort (claims database) 		The National Health Insurance Service–National Health Information Database of South Korea, longitudinal health care records of more than 50 million inhabitants (approximately 99% of the South Korean population). Pregnant women with one or more prescriptions for Proton Pump Inhibitors during the first trimester (defined as the start of pregnancy to the 90th day of gestation). unexposed, sick
Pregnant women with no filled Proton Pump Inhibitor prescriptions from 90 days before pregnancy through the end of the first trimester (with a propensity-score, made by stratification notably concerning the indications => unexposed sick). 		1st trimester 40540 / 2655676 Unexposed group adjusted with propensity-score, made by stratification, notably concerning the indications => considered as unexposed sick (mathematical deformation of total population). In South Korea, PPIs only available with a prescription.
Prescription database.
Choi b
2023 		South Korea
2008 - 2019
retrospective cohort (claims database) 		The National Health Insurance Service–National Health Information Database of South Korea, longitudinal health care records of more than 50 million inhabitants (approximately 99% of the South Korean population). Pregnant women that filled a prescription for proton pump inhibitors (PPIs) between the start of pregnancy and the 245th day of gestation. unexposed, sick
Pregnant women without exposure to proton pump inhibitors (PPIs) from 90 days before pregnancy to the delivery date. 		during pregnancy (anytime or not specified) 41664 / 2121323 Unexposed group adjusted with propensity-score, made by stratification, notably concerning the indications => considered as unexposed sick (mathematical deformation of total population). In South Korea, PPIs only available with a prescription.
Prescription database.
Cluver - Esomeprazole
2018 		South Africa
2016 - 2017
randomized controlled trial 		Pan African Clinical Trials Registry Women with early onset pre-eclampsia between 26 and 31 weeks exposed with a 40 mg daily dose of esomeprazole. unexposed, sick
Women with early onset pre-eclampsia between 26 and 31 weeks exposed to placebo. 		late pregnancy 59 / 60
Randomized controlled trial with appropriate exposition.
Colvin
2011 		Australia
2002 - 2005
retrospective cohort (claims database) 		Australian Pharmaceutical Benefits Scheme All births where the mother was dispensed a PPI during the fisrt trimester of pregnancy. unexposed (general population or NOS)
All other pregnancies. 		1st trimester 360 / 98825 The exposed and unexposed numbers were deducted from the percentage presented in the abstract.
Australian Pharmaceutical Benefits Scheme contain data on dispensation of PPIs and is the only source of PPIs in Australia during that period.
Dehlink (Controls exposed to other treatment, sick)
2009 		Swedish
1995 - 2004
population based cohort retrospective 		The Swedish Medical Birth Register, the Swedish Hospital Discharge Register, the Cause of Death Register of Statistics Sweden and the Swedish Prescribed Drug Register. Children whose mothers took PPIs during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Children whose mothers took H2-receptor antagonists during pregnancy. 		during pregnancy (anytime or not specified) 2916 / 1613 For the population exclusion criteria included pre-term birth (< 37 weeks of gestation), infertility, caesarean section, single mothers and stillborn or deceased children.
The Swedish Prescribed Drug Register was used to detect dispensed prescribed drugs during pregnancy. IPPs therapy in pregnant women were identified using the validated ATC code.
Dehlink (Controls unexposed NOS)
2009 		Swedish
1995 - 2004
population based cohort retrospective 		The Swedish Medical Birth Register, the Swedish Hospital Discharge Register, the Cause of Death Register of Statistics Sweden and the Swedish Prescribed Drug Register. Children whose mothers took PPIs during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children whose mothers didn't take PPIs during pregnancy. 		during pregnancy (anytime or not specified) 2916 / 582800 For the population exclusion criteria included pre-term birth (< 37 weeks of gestation), infertility, caesarean section, single mothers and stillborn or deceased children.
The Swedish Prescribed Drug Register was used to detect dispensed prescribed drugs during pregnancy. PPI therapy in pregnant women were identified using the validated ATC code.
Diav-Citrin
2005 		Israel, Germany, Netherlands, Italy, France, Greece and Finland.
1992 - 2001
prospective cohort 		The European Network of Teratology Information Services (ENTIS) Pregnancies with exposure to OPZ, LPZ and PPZ (This is a subgroup of exposure among the whole exposed group considered in the study ). unexposed (general population or NOS)
Group of women who had been counselled during pregnancy in regard to exposures known to be nonteratogenic from seven of the eight participating centres. 		1st trimester, during pregnancy (anytime or not specified) 410 / 868
Details of exposure were collected during pregnancy before pregnancy outcome was known, using a structured questionnaire.
Hastie
2019 		Sweden
2013 - 2017
population based cohort retrospective 		Swedish Pregnancy Register (combines data from the Swedish Maternal Health Care Register, the Swedish National Quality Register for Prenatal Diagnosis and obstetric data from electronic birth records). Women reporting the use of any Proton pump inhibitors (PPIs) at any point across gestation. unexposed (general population or NOS)
Women non-Proton pump inhibitors (PPIs) user. 		1st trimester, 2nd trimester, 3rd trimester, during pregnancy (anytime or not specified) 6051 / 151669
Maternal medication use is routinely collected from the time of registration for antenatal care (which occurs before 15 weeks in 95% of the pregnancies). Information on ongoing medication is collected by midwives, with women reporting the use of both prescribed and over the counter PPI.
Källèn
1998 		Sweden
1995 - 1997
population based cohort retrospective 		Swedish Medical Birth Registry, the Registry of Congenital Malformation and the Child Cardiology Register Infants were identified from the register whose mothers had used any PPIs after becoming pregnant and before the first antenatal visit (approximately first trimester exposure). (This is a subgroup of exposure among the whole exposed group considered in the study). exposed to other treatment, sick
Infants exposed to H2 receptor antagonists during pregnancy. 		1st trimester 275 / 255 The outcome 'all congenital malformations' isn't listed because a more relevant result (longer period, largest exposed population) is available (even if the control group is more relevant here) in a publication of Källén et al. 2001.
At the first visit to the antenatal clinic (usually during weeks 10-12), the pregnant woman is interviewed by a midwife on drugs taken after the time the woman became pregnant and before the antenatal visit.
Källén
2003 		Sweden
1995 - 2001
population based cohort retrospective 		The Swedish Medical Birth Registry, the Swedish Registry of Congenital Malformations and the Swedish Child Cardiology Registry. Infants exposed to PPIs during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Infants non-exposed to PPIs during pregnancy. 		early pregnancy 1863 / 575867 No result presented for any cardiovascular defect with chromosome anomaly.
At the first antenatal visit (usually week 10–12), a midwife interviewed the woman on the use of drugs during the pregnancy before the antenatal care visit. Throughout the subsequent antenatal care, additional prescriptions for drugs are recorded and also computerized.
Källén - Omeprazole
2001 		Sweden
1995 - 1999
population based cohort retrospective 		The Swedish Medical Birth Registry, the Registry of Congenital Malformations and the Child Cardiology Register Infants of women who had reported the use of omeprazole during pregnancy. unexposed (general population or NOS)
Infants of women who didn't used omeprazole during pregnancy. 		2nd and/or 3rd trimester, at least 1st trimester 955 / -9 The hospital discharge register isn't ready for 1998 - 1999, so the study had to be limited up to 1997. The outcome 'any cardiovascular defect' isn't listed because a more relevant result is available in a publication of Källén et al. 2003.
The pregnant women are interviewed by a midwife during the first visit to the antenatal clinic. During the continued antenatal care, further drug use is recorded at the attendance of the woman to the antenatal care centers.
Lalkin - Omeprazole (Controls exposed to other treatment, sick)
1998 		Canada, Italy and France
Not specified.
prospective cohort 		Motherisk, Telefono Rosso, Service De PharmacoToxicovigilance and Centro Regionale d’Informazione sul Farmaco. Women exposed to omeprazole during pregnancy. exposed to other treatment, sick
Women with similar conditions for which omeprazole was taken but who took histamine blockers. 		1st trimester, during pregnancy (anytime or not specified) 113 / 113
Standardized data collection forms were used to obtain information by telephone or clinic interview. The controls were selected from the Motherisk database.
Lalkin - Omeprazole (Controls unexposed NOS)
1998 		Canada, Italy and France.
Not specified.
prospective cohort 		Motherisk, Telefono Rosso, Service De PharmacoToxicovigilance and Centro Regionale d’Informazione sul Farmaco. Women exposed to omeprazole during pregnancy. unexposed (general population or NOS)
A nonteratogenic control, which included women who contacted Motherisk in a similar manner but who were exposed to a nonteratogenic agent. 		1st trimester, during pregnancy (anytime or not specified) 113 / 113
Standardized data collection forms were used to obtain information by telephone or clinic interview. Controls were selected from the Motherisk database.
Matok
2012 		Southern Israel
1998 - 2009
retrospective cohort (claims database) 		‘‘Clalit’’ pharmacies dispensation database, Soroka Medical Center database, The Obstetrics and Gynecology Department database and medical pregnancy termination SMC registry. Infants of women to whom PPIs were dispensed during pregnancy. unexposed (general population or NOS)
Fetuses of all women who did not take PPIs in pregnancy. 		1st trimester, 3rd trimester, preconception-only 1186 / 109597
Electronic database of medications dispensed by ‘‘Clalit’’ pharmacies.
Moretti
2002 		Canada
Not specified.
prospective cohort 		The Motherisk Program Exposed to PPIs at least in first trimester. unexposed (general population or NOS)
Unexposed to PPIs. 		at least 1st trimester 63 / 75 Unpublished study mentioned in the publication of 'Nikfar et al., 2002 Digestive Diseases and Sciences' as a personnal communication.
Not specified.
Mulder
2014 		Northern Netherlands
1995 - 2011
retrospective cohort (claims database) 		A pregnancy database that is part of the University of Groningen IADB.nl pharmacy prescription database. Exposure was defined as one or more maternal prescriptions for a PPI dispensed during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Children non-exposed to PPIs and H2RA during the entire pregnancy. 		during pregnancy (anytime or not specified) 319 / 33047
From the Pharmacy prescription database : medications are recorded for each patient for dispensed prescriptions, except for over the counter drugs and medication dispensed during hospitalization.
Nielsen
1999 		Denmark
1991 - 1996
retrospective cohort (claims database) 		Pharmaco-Epidemiological Prescription Database of North Jutland and the Danish Hospital Discharge Registry Pregnant women prescribed for proton pump inhibitors from 30 days before conception to the end of first trimester or to the end of pregnancy. unexposed (general population or NOS)
All pregnancies in which the mothers had obtained no prescriptions for any kind of reimbursed medicine. 		1st trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) 51 / 13327
Pharmaco-Epidemiological Prescription Database of North Jutland.
Noh
2023 		South Korea
2007 - 2020
population based cohort retrospective 		The National Health Insurance Service (NHIS) database (which represents the entire Korean population (>50 million)) of South Korea. Pregnant women with one or more prescriptions for a Proton Pump Inhibitor (PPI; Anatomical Therapeutic Chemical classification system code A02BC) at any time during pregnancy. unexposed, sick
Pregnant women who had no acid-suppressive medication (histamine 2 receptor antagonists [H2RAs] and proton pump inhibitors [PPIs]) prescription from 30 days before pregnancy to the delivery date, and propensity score matched for maternal conditions (considered as 'unexposed, sick').. 		during pregnancy (anytime or not specified) 36529 / 146116 Dose-response: eTable 8. Subgroup Analyses on the Risk of Allergic Disease in Children Following Prenatal Exposure to PPI only. Control group matched for maternal conditions (asthma, gastroesophageal reflux disease, ...).
The National Health Insurance Service (NHIS) database including comprehensive information on prescriptions.
Pasternak
2010 		Denmark
1996 - 2008
population based cohort retrospective 		The Medical Birth Register, the Prescription Drug Register, the National Patient Register, The Central Person Register and Statistics Denmark Infants born to women exposed to PPIs (any filling of a PPI prescription at any time during the period from 4 weeks before conception through the end of the first trimester). unexposed (general population or NOS)
Infants born to women not exposed to PPIs (all the women who were not exposed at any time during their pregnancy). 		1st trimester, 2nd and/or 3rd trimester, 3 months or more before pregnancy or1st trimester, preconception-only 5082 / 832031
The Prescription Drug Register provided information on all PPI prescriptions filled by women in the cohort between 4 weeks before conception and delivery. (Omeprazole and Lansoprazole became OTC in 2006 and 2007 respectively).
Ruigomez - Omeprazole (Controls exposed to other treatment, sick)
1999 		United Kingdom and Italy
1991 - 1996
retrospective cohort 		United Kingdom General Practice Research Database and the Italian Friuli-Venezia Giulia Health Database Offspring whose mothers had prescription of omeprazole any time from 180 days before the first recorded date of a pregnancy code until 180 days afterward (This is a subgroup of exposure among the whole exposed group considered in the study). Addition of UK and Italy cohort. exposed to other treatment, sick
Offspring whose mothers had prescription of ranitidine or cimetidine (H2 blockers) any time from 180 days before the first recorded date of a pregnancy code until 180 days afterward. 		1st trimester 139 / 567
Italy: Computer files registered in the output registration database. UK: Prescriptions issued by the general practitioner are directly generated by the computer system.
Ruigomez - Omeprazole (Controls unexposed NOS)
1999 		United Kingdom and Italy
1991 - 1996
retrospective cohort 		United Kingdom General Practice Research Database and the Italian Friuli-Venezia Giulia Health Database Offspring whose mothers had prescription of omeprazole any time from 180 days before the first recorded date of a pregnancy code until 180 days afterward (This is a subgroup of exposure among the whole exposed group considered in the study). Addition of UK and Italy cohort. unexposed (general population or NOS)
Offspring whose mothers were nonexposed during pregnancy. 		1st trimester 139 / 1575
Italy: Computer files registered in the output registration database. UK: Prescriptions issued by the general practitioner are directly generated by the computer system.
Saleh
2017 		Netherlands
2013 - 2016
prospective cohort 		The Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, The Netherlands. Women with confirmed preeclampsia or suspicion of preeclampsia and exposed to PPIs during pregnancy. unexposed, sick
Women with confirmed preeclampsia or suspicion of preeclampsia and non-exposed to PPIs during pregnancy. 		during pregnancy (anytime or not specified) 40 / 80 Women with multiple pregnancy or chromosomal/fetal anomalies were excluded from the study. Women were also exposed to α-Methyldopa, corticosteroids, ferrous fumarate, macrogol and nifedipine during pregnancy.
Medication use and preexisting conditions (such as hypertension and proteinuria) were collected at the time of study entry and recorded in a database.
Van Gelder
2022 		The Netherlands
2012 - 2019
prospective cohort 		The PRegnancy and Infant DEvelopment (PRIDE) Study and the Dutch Pregnancy Drug Register, two prospective ongoing cohorts, the Netherlands. Report of Proton Pump Inhibitor (ATC group A02BC) exposure during pregnancy. unexposed (general population or NOS)
No report of Proton Pump Inhibitor (ATC group A02BC) exposure during pregnancy. 		1st and 2nd trimester, 2nd and/or 3rd trimester, during pregnancy (anytime or not specified) 332 / 8502 Among PPIs: omeprazole was most commonly reported (92.5%), followed by pantoprazole (6.6%) and esomeprazole (6.0%).
Data on medication exposures were obtained from the three prenatal Web-based questionnaires (at baseline and in gestational weeks 17 and 34) and the first postpartum questionnaire. Proton Pump Inhibitor exposure was defined as report of medication belonging to ATC group A02BC.
Wolfe (Controls exposed to other treatment, sick)
2019 		USA
2006 - 2008
retrospective cohort (claims database) 		The Military Health System Data Repository (TRICARE) Maternal proton pump inhibitor use during pregnancy for gastroesophageal reflux disease. exposed to other treatment, sick
Maternal histamine type 2 receptor antagonist use for gastroesophageal reflux disease. 		during pregnancy (anytime or not specified) 10547 / 1932 Specific medications identified from these class included dexlansoprazole, esomeprazole, lansoprazole, omeprazole, and pantoprazole (no distinction can be made).
Pharmaceutical data were used to screen all women in the cohort for antireflux medication prescriptions during gestation.
Wolfe (Controls unexposed NOS)
2019 		USA
2006 - 2008
retrospective cohort (claims database) 		The Military Health System Data Repository (TRICARE) Maternal proton pump inhibitor use during pregnancy for gastroesophageal reflux disease. unexposed (general population or NOS)
No maternal antireflux medication use during pregnancy. 		during pregnancy (anytime or not specified) 10547 / 365671 Specific medications identified from these class included dexlansoprazole, esomeprazole, lansoprazole, omeprazole, and pantoprazole (no distinction can be made).
Pharmaceutical data were used to screen all women in the cohort for antireflux medication prescriptions during gestation.
Yitshak-Sade
2016 		Israel
1999 - 2008
retrospective cohort (claims database) 		Clalit Health Services and The Soroka Medical Center Admission-Transfer-Discharge database. Children whose mothers purchased PPIs 2 months prior to conception and during pregnancy. (This is a subgroup of exposure among the whole exposed group considered in the study). unexposed (general population or NOS)
Not exposed during pregnancy to H2Bs/PPIs. 		during pregnancy (anytime or not specified) 2336 / 86403 PPIs (ie, omeprazole, pantoprazole, and lansoprazole)
“Clalit” and Soroka Medical Center databases were encoded and linked to create a single registry of medications dispensed to children, and to their mothers before and during pregnancy.

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
Anderka
2012 		USA
1997 - 2004
case control 		The National Birth Defects Prevention Study (NBDPS) Infants with any of more than 30 selected birth defects. Infants without birth defect. Histories of NVP and treatments obtained from a standardized computer- assisted telephone interview with the mother. Data were collected by month for the first trimester and by trimester for the second and third trimesters. 1st trimester 4524 / 5859
Case infants (over 30 different birth defects) are identified prenatally, at birth or during the first year of life from the surveillance systems (10 participating sites). 9 sites also collected fetal deaths at 20 GW or greater and 8 sites collected diagnosed and electively terminated.
Bànhidy - Omeprazole
2011 		Hungary
1980 - 1996
case control 		The Hungarian Case-Control Surveillance of Congenital Abnormalities, The Hungarian Congenital Abnormality Registry and the National Birth Registry of the Central Statistical Office. Babies delivered with different CA (congenital abnormalities). Newborns delivered without CA (congenital abnormalities). Mothers were mailed a questionnaire (after the selection of cases and controls) requested information on medicinal products taken during pregnancy and to send their prenatal maternity logbook which related drug prescriptions. Regional nurses were asked to visit and question the non-respondent. during pregnancy (anytime or not specified) 22843 / 38151
Mothers were asked to send their prenatal maternity logbook and other medical records concerning their diseases during the pregnancy and their child’s CA. A questionnaire was also mailed requesting the same informations. Regional nurses were asked to question the non-respondent.
Fejzo - Lansoprazole
2015 		USA
2007 - 2011
case control 		the Hyperemesis Education and Research Foundation Web site Children exposed to hyperemesis gravidarum (HG) with neurodevelopmental delay. Children exposed to hyperemesis gravidarum (HG) with a good outcome. Participants were asked to submit their medical records and complete an online survey regarding treatment. during pregnancy (anytime or not specified) 138 / 174 Main analysis: case control related to the impact of the HG illness (treated or not) on child outcomes. Then impact of 37 medications/treatments (1st and/or 2nd trimester) on child outcome was investigated (none was significantly associated with delay).
Participants were asked to submit their medical records and complete an online survey regarding outcomes. A follow-up survey was administered on the diagnosis of childhood emotional, behavioral, and learning disorders.
Fejzo - Lansoprazole
2013 		USA
2007 - 2011
case control 		The Hyperemesis Education and Research Foundation Web site Pregnant women with hyperemesis gravidarum (HG) who have negative outcomes (birth weight less than 10%, perinatal mortality, and/or preterm birth (<37 weeks)). Pregnant women with hyperemesis gravidarum (HG) who have positive outcomes. Participants were asked to submit their medical records and complete an online survey regarding treatment. The majority of participants, both cases and controls, joined the study and began the survey during their pregnancies. during pregnancy (anytime or not specified) 43 / 211 Comparison of use of various medications/treatments in the two groups (43 HG participants with an adverse outcome compared to 211 HG participants with a good outcome).
Participants were asked to submit their medical records and complete an online surveyregarding outcomes. The majority of participants, both cases and controls, were automatically prompted to complete the survey on outcome following their due date.
Hak
2013 		United Kingdom
1996 - 2010
nested case control 		UK General Practice Research Database (GPRD) Children who received a first diagnosis of asthma any time between birth and 14 years of age and who were prescribed any asthma drug at least three times within 12 months after first asthma diagnosis date. Children from the mother–infant subset who were born to the same mother as a case child (before or after) were used as controls if they had neither a history of childhood asthma nor any prescription for asthma in their medical history. The UK General Practice Research Database (GPRD) who contained a prescription database. during pregnancy (anytime or not specified) 1874 / 1874 Sibling from the same mother.
The UK General Practice Research Database (GPRD) who contained electronic medical records for a nationally representative group of British residents.
Kerr
2018 		USA and Canada
1993 - 2015
case control 		Slone Birth Defects Study (BDS) Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”). Nonmalformed live-born infants. Within 6 months, nurse interviewers contacted mothers to complete a computer-assisted telephone interview to collect a detailed history of the pregnancy including illnesses and medications. 1st trimester, 2nd trimester, 3rd trimester 166 / 12059 Authors analyzed separately “isolated” microcephaly and “non-isolated” microcephaly. Only isolated microcephaly is indexed in MetaPreg. Cases with chromosomal or syndrome diagnosis and potential congenital infections were excluded.
Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas.
Lind
2013 		USA
1997 - 2007
case control 		National Birth Defects Prevention Study (NBDPS) Male infants with isolated second- or third-degree hypospadias, defined as the urethral opening at the penile shaft, scrotum, or perineum. Male infants with no major birth defects selected randomly from vital records or birth logs. The National Birth Defects Prevention Study uses computer-assisted telephone interviews to collect information from women 6 weeks to 24 months after their estimated date of delivery. 3 months or more before pregnancy or1st trimester 1537 / 4314 Hypospadias are already assessed in the publication of Anderka et al. 2012 (same database but with a more relevant period of exposure and calculated OR with adjustment). Result obtain by addition of lansoprazole and omeprazole results.
Cases are identified through population-based birth defects surveillance from each states. A clinical geneticist classifies eligible cases of hypospadias as isolated.
Malaeb
2021 		Lebanon
Jan - Sep 2017
case control 		Schools were randomly selected based on the list of the Lebanese Ministry of Higher Education. Children diagnosed asthma with symptoms (chronic wheezing, cough, and dyspnea), and an affirmative answer to the question 'did your doctor ever tell you that your child has asthma?' . Children with neither a physician-diagnosed respiratory illness nor respiratory symptoms (wheezing, coughing, and dyspnea). The questionnaire used was self-administered, anonymous, in Arabic and assessing behaviors during pregnancy like OTC medication use. during pregnancy (anytime or not specified) 107 / 893 Children were excluded from the analysis if they had respiratory symptoms without a physician’s diagnosis of asthma.
A standardized questionnaire fill out by parents to document asthma status and evaluate respiratory symptoms using validated International Study of Asthma and Allergies in Childhood (ISAAC) items.
Munch
2014 		Denmark
1995 - 2008
case control 		The Civil Registration System, the Danish National Patient Register, the Danish National Medical Birth Registry and the National Prescription Drug Register. Live-born children with isolated congenital hydrocephalus (CHC) defined as congenital cases without a known, likely causative aetiology or syndrome diagnosis. Live-born children without isolated congenital hydrocephalus (CHC). From the National Prescription Drug Register which contain all prescriptions filled at any pharmacy in Denmark with the ATC codes A02BC. 1st trimester 475 / 852008 The study period is 1978-2008 but exposition data are only available since 1995. Authors analyzed separately isolated and syndromic CHC. Only isolated CHC is indexed in MetaPreg.
The information on isolated and syndromic congenital hydrocephalus was obtained by linkage to the Danish National Patient Register. Diagnostic codes according to ICD8 and 10 were used to extract the cases from it.
Rhim
2010 		United Kingdom
2000 - 2008
nested case control 		The Health Improvement Network (THIN) database. All babies with a diagnosis of cardiac birth defect were identified. Babies without a diagnosis of cardiac birth defect. Data from the Health Improvement Network database, The Health Improvement Network (THIN) database, a UK general practitioner (GP) electronic medical record system. during pregnancy (anytime or not specified) 2445 / 19530
Cardiac birth defect coded in the Health Improvement Network database.
Werler
2014 		USA
2007 - 2011
case control 		The Slone Epidemiology Center Birth defect study - A population-based case-control study of medical record–confirmed clubfoot. All infants less than 11 months of age with a diagnosis of talipes equinovarus or clubfoot (without a known chromosomal anomaly, inherited syndrome, bilateral renal agenesis, Potter syndrome, or neural tube defect). Random samples of children born in the same years as cases but without known malformations. Mothers were interviewed by telephone within 12 months after delivery about medication use, including indication, product, timing, and frequency. early pregnancy 646 / 2037 'On the basis of the timing of clubfoot development, the exposure window of interest is lunar months (LMs) 2–4, which is 29–112 days after the first day of the last menstrual period.'
Study subjects were ascertained from birth defect registries in Massachusetts, New York, and North Carolina. Mothers were then interviewed and an orthopedist reviewed the children’s pediatric and orthopedic records (77% agreed). Controls identified from birth certificates or hospital records.

Risk of bias: : NA;   : low;   : moderate;   : serious;   : critical;   : unclear;  

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