Proton Pump Inhibitors

Exposed non-exposed studies (cohort)

Study	Country Study period	Population source	Exposure definition	Non-exposure definition	Sample size	Rmk
Andersen (Controls exposed to clarithromycin), 2013	Denmark 1997 - 2007	All live births with a conception date in the study period were identified.	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.	3577 / 401
Andersen (Controls exposed to other treatment, sick), 2012	Denmark 1996 - 2008	All singletons born alive for the period in northern Denmark (33% of the Danish population).	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.	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.
Andersen (Controls unexposed NOS), 2012	Denmark 1996 - 2008	All singletons born alive for the period in northern Denmark (33% of the Danish population).	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.	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.
Andersen (Controls unexposed, NOS), 2013	Denmark 1997 - 2007	All live births with a conception date in the study period were identified.	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.	3577 / 927927
Breddels, 2022	Sweden 2006 - 2016	All live singleton births delivered during the study period.	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.	14787 / 1074728
Cea Soriano, 2016	United Kingdom 1996 - 2010	Women aged 18–45 years between the study period, who had been registered with their PCP (primary care physicians) for at least 1 year.	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.	816 / 7745	For asthma: the index outcome was defined for the result with the exposition period ‘during pregnancy’.
Choi (Controls exposed to other treatment, sick), 2021	South Korea 2011 - 2017	All pregnant women aged 19 to 44 years who gave birth between the study period.	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.	43717 / 331795	When comparing with H2RA-exposed group, women who received both PPI and H2RA during pregnancy were excluded from both comparator groups.
Choi (Controls unexposed NOS), 2021	South Korea 2011 - 2017	All pregnant women aged 19 to 44 years who gave birth between the study period.	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.	43717 / 1919973
Choi a, 2023	South Korea 2011 - 2020	All pregnancies (in women aged 19-44 years) resulting in live births during the study period.	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).	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.
Choi b, 2023	South Korea 2008 - 2019	All pregnancies in women < 44 years old resulting in live births during the study period.	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.	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.
Cluver - Esomeprazole, 2018	South Africa 2016 - 2017	Pregnant women with singleton pregnancies diagnosed with preterm preeclampsia between 26 and 31 weeks.	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.	59 / 60
Colvin, 2011	Australia 2002 - 2005	All births in Western Australia during the study period.	All births where the mother was dispensed a PPI during the fisrt trimester of pregnancy.	unexposed (general population or NOS) All other pregnancies.	360 / 98825	The exposed and unexposed numbers were deducted from the percentage presented in the abstract.
Dehlink (Controls exposed to other treatment, sick), 2009	Swedish 1995 - 2004	A total of 860215 children were born in Sweden between the study period.	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.	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.
Dehlink (Controls unexposed NOS), 2009	Swedish 1995 - 2004	A total of 860215 children born in Sweden between the study period.	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.	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.
Diav-Citrin, 2005	Israel, Germany, Netherlands, Italy, France, Greece and Finland. 1992 - 2001	Pregnant women who or whose physician/midwife contacted one of eight Teratology Information Services (TISes).	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.	410 / 868
Hastie, 2019	Sweden 2013 - 2017	Delivries (including multiple pregnancies) during the study period from nulliparous women. This register covers over 90% of all deliveries within Sweden.	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.	6051 / 151669
Källèn, 1998	Sweden 1995 - 1997	The approximate number of births from which the cohort was identified is 200000.	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.	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.
Källén, 2003	Sweden 1995 - 2001	All infants born in Sweden during the study period. Stillbirths were included both among cases and in the population controls.	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.	1863 / 575867	No result presented for any cardiovascular defect with chromosome anomaly.
Källén - Omeprazole, 2001	Sweden 1995 - 1999	All birth registered in the Swedish Medical Birth Registry during the study period.	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.	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.
Lalkin - Omeprazole (Controls exposed to other treatment, sick), 1998	Canada, Italy and France Not specified.	All women exposed to omeprazole during pregnancy and counseled by the participating centers were included.	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.	113 / 113
Lalkin - Omeprazole (Controls unexposed NOS), 1998	Canada, Italy and France. Not specified.	All women exposed to omeprazole during pregnancy and counseled by the participating centers were included.	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.	113 / 113
Matok, 2012	Southern Israel 1998 - 2009	All girls and women 15–49 years of age registered in ‘‘Clalit’’ and living in the southern district who gave birth to singletons at ‘Soroka’’ Medical Center and all medical pregnancy terminations performed between the study period.	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.	1186 / 109597
Moretti, 2002	Canada Not specified.	Not specified.	Exposed to PPIs at least in first trimester.	unexposed (general population or NOS) Unexposed to PPIs.	63 / 75	Unpublished study mentioned in the publication of 'Nikfar et al., 2002 Digestive Diseases and Sciences' as a personnal communication.
Mulder, 2014	Northern Netherlands 1995 - 2011	All singleton children born between the study period whose mothers had at least 12 months of maternal data present prior to the birth date in the Northern Netherlands.	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.	319 / 33047
Nielsen, 1999	Denmark 1991 - 1996	All pregnant women who gave birth in the county (9% of the total Danish population) during the study period.	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.	51 / 13327
Noh, 2023	South Korea 2007 - 2020	All pregnancy episodes in women (19-44 years old) that resulted in live births between April 1, 2008, and December 31, 2019.	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')..	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, ...).
Pasternak, 2010	Denmark 1996 - 2008	A cohort of all live-born infants in Denmark for the study period.	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).	5082 / 832031
Ruigomez - Omeprazole (Controls exposed to other treatment, sick), 1999	United Kingdom and Italy 1991 - 1996	Italy : all women younger than 45 years with a hospital delivery between the study period. UK : women younger than 45 years with a code of pregnancy between the study period.	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.	139 / 567
Ruigomez - Omeprazole (Controls unexposed NOS), 1999	United Kingdom and Italy 1991 - 1996	Italy : all women younger than 45 years with a hospital delivery between the study period. UK : women younger than 45 years with a code of pregnancy between the study period.	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.	139 / 1575
Saleh, 2017	Netherlands 2013 - 2016	Women with singleton pregnancies from gestation age of ≥20 weeks who had to have preeclampsia or preeclampsia symptoms (hypertension, proteinuria, right upper quadrant abdominal pain, severe headaches, changes in vision, decreased levels of platelets, or elevated liver enzymes).	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.	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.
Van Gelder, 2022	The Netherlands 2012 - 2019	Women aged >= 18 years invited to participate to study cohort as early in pregnancy as possible.	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.	332 / 8502	Among PPIs: omeprazole was most commonly reported (92.5%), followed by pantoprazole (6.6%) and esomeprazole (6.0%).
Wolfe (Controls exposed to other treatment, sick), 2019	USA 2006 - 2008	All deliveries at civilian or military hospitals covered by TRICARE between the study period were identified. Only women who were able to be matched to dependent children and had at least 5 years of continuous health care coverage were included in this cohort.	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.	10547 / 1932	Specific medications identified from these class included dexlansoprazole, esomeprazole, lansoprazole, omeprazole, and pantoprazole (no distinction can be made).
Wolfe (Controls unexposed NOS), 2019	USA 2006 - 2008	All deliveries at civilian or military hospitals covered by TRICARE between the study period were identified. Only women who were able to be matched to dependent children and had at least 5 years of continuous health care coverage were included in this cohort.	Maternal proton pump inhibitor use during pregnancy for gastroesophageal reflux disease.	unexposed (general population or NOS) No maternal antireflux medication use during pregnancy.	10547 / 365671	Specific medications identified from these class included dexlansoprazole, esomeprazole, lansoprazole, omeprazole, and pantoprazole (no distinction can be made).
Yitshak-Sade, 2016	Israel 1999 - 2008	All children living in the Southern District of Israel (70% of the district population), born at Soroka Medical Center during the study period were included in this study.	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.	2336 / 86403	PPIs (ie, omeprazole, pantoprazole, and lansoprazole)

Case-control studies (cohort)

Study	Country Study period	Case	Control	Sample size	Rmk
Anderka, 2012	USA 1997 - 2004	Infants with any of more than 30 selected birth defects.	Infants without birth defect.	4524 / 5859
Bànhidy - Omeprazole, 2011	Hungary 1980 - 1996	Babies delivered with different CA (congenital abnormalities).	Newborns delivered without CA (congenital abnormalities).	22843 / 38151
Fejzo - Lansoprazole, 2015	USA 2007 - 2011	Children exposed to hyperemesis gravidarum (HG) with neurodevelopmental delay.	Children exposed to hyperemesis gravidarum (HG) with a good outcome.	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).
Fejzo - Lansoprazole, 2013	USA 2007 - 2011	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.	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).
Hak, 2013	United Kingdom 1996 - 2010	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.	1874 / 1874	Sibling from the same mother.
Kerr, 2018	USA and Canada 1993 - 2015	Infants with microcephaly alone (“isolated”) and microcephaly that included other major birth defects (“non-isolated”).	Nonmalformed live-born infants.	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.
Lind, 2013	USA 1997 - 2007	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.	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.
Malaeb, 2021	Lebanon Jan - Sep 2017	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).	107 / 893	Children were excluded from the analysis if they had respiratory symptoms without a physician’s diagnosis of asthma.
Munch, 2014	Denmark 1995 - 2008	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).	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.
Rhim, 2010	United Kingdom 2000 - 2008	All babies with a diagnosis of cardiac birth defect were identified.	Babies without a diagnosis of cardiac birth defect.	2445 / 19530
Werler, 2014	USA 2007 - 2011	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.	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.'

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