Proton Pump Inhibitors

Study	Type of data	Exposure measurement	Outcome assessment	Adjustment
Anderka, 2012	case control	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.	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.	Maternal age, race or ethnicity, education, parity, smoking in the month before conception, plurality, previous miscarriage, infant sex, use of multivitamin with folic acid anytime between the month before conception through the first trimester, body mass index, study site, and year of expected date of delivery.
Andersen (Controls exposed to clarithromycin), 2013	population based cohort retrospective	From the National Prescription Register, exposure was defined as redemption of a prescription of a Proton Pump Inhibitor.	Using the National Hospital Register all registered cases of miscarriages and provoked abortions were identified (O02, O03, O04, O05 or O06 according to the International Classification of Diseases 10th Danish revision).	Adjusted for age, parity, educational level, and income.
Andersen (Controls exposed to other treatment, sick), 2012	retrospective cohort (claims database)	Aarhus University Prescription Database.	At least two prescriptions of both an anti-asthma medication and/or a hospital diagnosis of asthma during the follow-up.	None for this group of comparison.
Andersen (Controls unexposed NOS), 2012	retrospective cohort (claims database)	Aarhus University Prescription Database.	At least two prescriptions of both an anti-asthma medication and/or a hospital diagnosis of asthma during the follow-up.	Adjusted for year of birth, county of residence, gender of child, gestational age, birth order, mode of delivery, mother’s age at delivery, maternal smoking in pregnancy, maternal use of systemic antibiotics during pregnancy and maternal history of asthma recorded at any time prior to delivery.
Andersen (Controls unexposed, NOS), 2013	population based cohort retrospective	From the National Prescription Register, exposure was defined as redemption of a prescription of a Proton Pump Inhibitor.	Using the National Hospital Register all registered cases of miscarriages and provoked abortions were identified (O02, O03, O04, O05 or O06 according to the International Classification of Diseases 10th Danish revision).	Adjusted for age, parity, educational level, and income.
Bànhidy - Omeprazole, 2011	case control	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.	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.	In general, two controls were matched to every case according to sex, birth week, and district of parents’ residence. Potential confounders were maternal age (<25 years, 25–29 years, and 30 years or more), birth order (ﬁrst delivery or one or more previous deliveries), employment status, PUD-related drugs (yes/no), and use of folic acid supplement (yes/no).
Breddels, 2022	population based cohort retrospective	Drug exposure was extracted from the Prescribed Drug Registry are classified according to the Anatomical Therapeutic Chemical (ATC) Classification System (ATC-code: A02BC).	Three high-quality nationwide Swedish health data registries: the Medical Birth Registry, the Patient Registry (in- and outpatient care) and the Causes of Death Registry.	Adjusted for maternal characteristics (age at delivery, body mass index (BMI), tobacco consumption, other prescribed drug use, hypertension, (gestational) diabetes mellitus (type 1 and type 2), hypo- and hyperthyroidism, obstetric characteristics (preeclampsia, mode of delivery, preterm, SGA, LGA, parity and time interval between pregnancies. Singleton deliveries).
Cea Soriano, 2016	retrospective cohort (registry)	Prescriptions issued by PCPs are recorded automatically in the database THIN.	Potential asthma cases in the study cohorts were identiﬁed from THIN records using an automated computer search and were confirmed by manual review of electronic medical records. And a secondary validation of cases for a random sample was obtained thanks to questionnaires to PCPs.	Number of maternal PCP visits and referrals during the year prior to the LMP date and year of delivery, maternal comorbidities (asthma, allergies,GERD, peptic ulcer), maternal use of NSAIDs, antacids, antibiotics and antihistamine medications during pregnancy,and sex of infant. Match by calendar time (within the same calendar quarter of LMP) and maternal age at LMP.
Choi (Controls exposed to other treatment, sick), 2021	population based cohort propective	the Health Insurance Review and Assessment database of South Korea.	the Health Insurance Review and Assessment database of South Korea.	Age, insurance type, nulliparity, multiple gestation, Charlson comorbidity index, indications for acid suppressive medications, maternal medical conditions (eg, asthma, anxiety, diabetes, depression, and chronic hypertension), inflammatory diseases, migraine/headache, renal disease, thyroid disorder, concurrent medications, and proxies of health care utilization.
Choi (Controls unexposed NOS), 2021	population based cohort propective	The Health Insurance Review and Assessment database of South Korea.	The Health Insurance Review and Assessment database of South Korea.	Age, insurance type, nulliparity, multiple gestation, Charlson comorbidity index, indications for acid suppressive medications, maternal medical conditions (eg, asthma, anxiety, diabetes, depression, and chronic hypertension), inflammatory diseases, migraine/headache, renal disease, thyroid disorder, concurrent medications, and proxies of health care utilization.
Choi a, 2023	retrospective cohort (claims database)	Prescription database.	The presence of congenital malformations was identified via infants’ records and major malformations and their subtypes were defined based on the European Surveillance of Congenital Anomalies (EUROCAT) classification system (minor defects were excluded according to the EUROCAT exclusion list).	Propensity score: maternal age, income level, parity, multiple gestations, indications for PPIs (GERD, duodenitis...), maternal conditions (eg, anxiety, diabetes, and epilepsy), medication use (eg, opioid, NSAIDs), obstetric comorbidity index, and measures of health care use. Exclusion of exposures with known or potential teratogens. Sensitivity analyses: indications, singleton only, BMI, smoking.
Choi b, 2023	retrospective cohort (claims database)	Prescription database.	The National Health Insurance Service (NHIS) database.	Propensity score: maternal age, medical aid, income level, parity, multiple gestations, indications for PPIs (GERD, duodenitis...), maternal conditions (eg, anxiety, diabetes, and epilepsy), other medication prescription, obstetric comorbidity index, and measures of health care use. Sensitivity analyses: indications, singleton only, body mass index, smoking, sibling design, first-time pregnancy.
Cluver - Esomeprazole, 2018	randomized controlled trial	Randomized controlled trial with appropriate exposition.	Plasma samples were collected to measures circulation preeclampsia and angiogenic biomarkers twice weekly until delivery. Placental tissue and umbilical artery cord blood were collected at delivery when possible. And surveillance of the other outcome.	Gestational age strata and treatment group. Randomisation.
Colvin, 2011	retrospective cohort (claims database)	Australian Pharmaceutical Benefits Scheme contain data on dispensation of PPIs and is the only source of PPIs in Australia during that period.	Not specified.	None.
Dehlink (Controls exposed to other treatment, sick), 2009	population based cohort retrospective	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.	Discharge and prescribed registers were used to detect children hospitalized for an allergic disease or who received two or more prescriptions for allergy medication. The allergic diseases were asthma, food allergy, atopic dermatitis, unspecified allergic reaction/anaphylaxis and allergic rhinitis.	No adjustment for this group of comparison.
Dehlink (Controls unexposed NOS), 2009	population based cohort retrospective	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.	Discharge and prescribed registers were used to detect children hospitalized for an allergic disease or who received two or more prescriptions for allergy medication. The allergic diseases were asthma, food allergy, atopic dermatitis, unspecified allergic reaction/anaphylaxis and allergic rhinitis.	Adjusted for year of birth, parity, maternal age, maternal smoking, and maternal body mass index (BMI).
Diav-Citrin, 2005	prospective cohort	Details of exposure were collected during pregnancy before pregnancy outcome was known, using a structured questionnaire.	After the expected date of delivery, follow-up was conducted with the woman, her physician or midwife by a telephone interview and/or mailed questionnaire to obtain details on the pregnancy outcome.	None.
Fejzo - Lansoprazole, 2015	case control	Participants were asked to submit their medical records and complete an online survey regarding treatment.	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.	Cases and controls were well-matched for mean maternal age, spontaneous labor, delivery method, and use of assisted reproduction. Children of cases and controls were well-matched for gender and age, with the average age between 8 and 9 years old.
Fejzo - Lansoprazole, 2013	case control	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.	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.	None.
Hak, 2013	nested case control	The UK General Practice Research Database (GPRD) who contained a prescription database.	The UK General Practice Research Database (GPRD) who contained electronic medical records for a nationally representative group of British residents.	Adjusted for gender, birth order, age of the mother at birth and number of GP visits during pregnancy. Matched sibling.
Hastie, 2019	population based cohort retrospective	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.	The Swedish National Quality Register for Prenatal Diagnosis and obstetric data from electronic birth records. Preeclampsia was identified by the diagnosis codes O14 or O15 (ICD-10).	A propensity score including maternal age, body mass index, year of delivery, country of birth, smoking status, educational level, occupation, use of assisted reproduction, and the presence of pregestational disorders (hypertension, diabetes mellitus, and inflammatory diseases; inflammatory bowel disease and systemic lupus erythematosus) along with multiple births as covariates.
Källèn, 1998	population based cohort retrospective	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.	Malformations which has been reported to the Medical Birth Registry completed by the data of the Registry of Congenital Malformation and the Child Cardiology Register.	Stratification was made for year of birth (1997 births were compared with 1996 population as no final population data for 1997 were available), maternal age, parity and smoking habits in early pregnancy.
Källén, 2003	population based cohort retrospective	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.	Infants with cardiovascular defects were identiﬁed from three sources: The Swedish Medical Birth Registry, the Swedish Registry of Congenital Malformations and the Swedish Child Cardiology Registry. Pregnancy outcome information was obtained from the delivery and pediatric records.	Stratiﬁcation for year of birth and possible confounders: maternal age, parity, smoking habits in early pregnancy, and years of involuntary childlessness.
Källén - Omeprazole, 2001	population based cohort retrospective	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.	Outcome of the deliveries were studied in the Medical Birth Registry and compared with data from all births in the register.	Year of birth, maternal age, parity, and maternal smoking habits.
Kerr, 2018	case control	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.	Cases and controls were ascertained at participating hospitals or birth defect registries in the same areas.	Study center, time period, maternal race/ethnicity, age and education (aORs were calculated when there were five or more exposed cases).
Lalkin - Omeprazole (Controls exposed to other treatment, sick), 1998	prospective cohort	Standardized data collection forms were used to obtain information by telephone or clinic interview. The controls were selected from the Motherisk database.	Each woman was recontacted regarding pregnancy outcome.	Each woman exposed was subsequently matched to 2 controls. All cases were match for maternal age, smoking pattern and alcohol consumption.
Lalkin - Omeprazole (Controls unexposed NOS), 1998	prospective cohort	Standardized data collection forms were used to obtain information by telephone or clinic interview. Controls were selected from the Motherisk database.	Each woman was recontacted regarding pregnancy outcome.	Each woman exposed was subsequently matched. All cases were match for maternal age, smoking pattern and alcohol consumption.
Lind, 2013	case control	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.	Cases are identified through population-based birth defects surveillance from each states. A clinical geneticist classifies eligible cases of hypospadias as isolated.	No adjustment for this group of exposure.
Malaeb, 2021	case control	The questionnaire used was self-administered, anonymous, in Arabic and assessing behaviors during pregnancy like OTC medication use.	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.	Variables entered in the model: paracetamol, ibuprofen, propranolol, acetylsalicylic acid, amoxicillin/clavulanic acid, vitamin C, fish oil, gender, school type, method of baby delivery, breastfeeding, mother’s and father’s level of education, and positive family history.
Matok, 2012	retrospective cohort (claims database)	Electronic database of medications dispensed by ‘‘Clalit’’ pharmacies.	Two electronic databases of SMC (Soroka Medical Center) comprising one with clinical information from the Department of Obstetrics and Gynecology, and one with demographic and hospitalization data, and an SMC registry of medical pregnancy terminations with information collected manually.	Maternal age, parity, self-reported smoking status during pregnancy, maternal diabetes mellitus, year of birth, and population group (i.e., Jewish or Bedouin Muslim). Peripartum fever (deﬁned as a temperature of 38°C or higher) and pregnancy duration in days were added to the covariates for pregnancy outcomes other than congenital malformations.
Moretti, 2002	prospective cohort	Not specified.	Ascertaining pregnancy outcome with direct interview with the mother.	Not specified.
Mulder, 2014	retrospective cohort (claims database)	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.	Identifying drugs received to treat allergic diseases according to Dutch General Practitioner Guidelines (atopic dermatitis, asthma or allergic rhinitis) with at least two prescriptions within a 12-month period. Except for asthma it's 2 prescriptions of inhaled corticosteroid after the age of 5.	Adjusted for birth year, gender, use of acid-suppressive drugs by the child, age of the mother at giving birth, maternal use of systemic antibiotics during pregnancy and allergic disease in the mother.
Munch, 2014	case control	From the National Prescription Drug Register which contain all prescriptions ﬁlled at any pharmacy in Denmark with the ATC codes A02BC.	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.	Adjusted for year of birth, maternal age, parity, child’s gender and multiples.
Nielsen, 1999	retrospective cohort (claims database)	Pharmaco-Epidemiological Prescription Database of North Jutland.	The Danish Hospital Discharge Registry and The Danish Medical Birth Registry.	Adjusted for maternal age, birth order, gestational age and smoking.
Noh, 2023	population based cohort retrospective	The National Health Insurance Service (NHIS) database including comprehensive information on prescriptions.	The National Health Insurance Service (NHIS) database including data on inpatient and outpatient health care utilization (diagnoses, procedures), using International Statistical Classification of Diseases, Tenth Revision (ICD-10) codes, recorded by a physician including primary and specialist care.	Propensity score matched: maternal age, income level, urban living, maternal conditions (eg, asthma, Gastroesophageal reflux disease, ...), co-medication use in fetal life (eg, antibiotics, antidepressants), health care utilization (eg, obstetric comorbidity index, number of outpatient visits), parity, plurality, and birth season. Smoking and Body mass index considered in sensitivity analysis.
Pasternak, 2010	population based cohort retrospective	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).	Cases of birth defects were identified with the use of the National Patient Register and a random sample had a medical records review. Major birth defects were defined according to the EUROCAT classification.	No potential confounder stood out as an important one, therefore, as an alternative all potential confounders and their effect were sum up into one variable: the propensity score.
Rhim, 2010	nested case control	Data from the Health Improvement Network database, The Health Improvement Network (THIN) database, a UK general practitioner (GP) electronic medical record system.	Cardiac birth defect coded in the Health Improvement Network database.	Up to 10 controls were identified per case matching for maternal age, GP location, delivery site, date of birth, and sex. Ajusted on BMI, cardiac malformation in the mother, smoking status, number of pregnancy GP visits, alcohol use, and use of medications associated with cardiac defects in published reports
Ruigomez - Omeprazole (Controls exposed to other treatment, sick), 1999	retrospective cohort	Italy: Computer files registered in the output registration database. UK: Prescriptions issued by the general practitioner are directly generated by the computer system.	UK and Italy: medical records (and hospital discharge letters in UK and birth certificate in Italy).	Adjustment was made for the mothers's age and prematurity.
Ruigomez - Omeprazole (Controls unexposed NOS), 1999	retrospective cohort	Italy: Computer files registered in the output registration database. UK: Prescriptions issued by the general practitioner are directly generated by the computer system.	UK and Italy: medical records (and hospital discharge letters in UK and birth certificate in Italy).	Adjustment was made for the mothers's age and prematurity.
Saleh, 2017	prospective cohort	Medication use and preexisting conditions (such as hypertension and proteinuria) were collected at the time of study entry and recorded in a database.	Maternal/neonatal complications (diagnosed by the treating physicians) and pre- and post-partum data were obtained from patient’s electronic medical records and ascertained by 2 independent researchers.	Match for gestational age at study entry.
Van Gelder, 2022	prospective cohort	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.	Participating women were asked to complete Web-based questionnaires at multiple time points postpartum, notably to gather data on pregnancy complications and infant health. Participants were asked consent for obtaining records from prenatal care providers.	Adjustment for a minimally sufficient set of confounders identified using directed acyclic graphs: maternal age, parity, pre-pregnancy Body Mass Index (BMI), maternal asthma, maternal depression, and smoking, alcohol consumption, and any use of calcium-containing supplements during pregnancy. In a sensitivity analysis, women with chronic hypertension (N=85) were excluded from the analyses.
Werler, 2014	case control	Mothers were interviewed by telephone within 12 months after delivery about medication use, including indication, product, timing, and frequency.	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.	Odds ratios were adjusted for study site, first born, sex, body mass index, and maternal smoking through Lunar Months 4. Confounding by the use of multiple medications was assessed. Analysis with exclusion of first-degree history of clubfoot.
Wolfe (Controls exposed to other treatment, sick), 2019	retrospective cohort (claims database)	Pharmaceutical data were used to screen all women in the cohort for antireflux medication prescriptions during gestation.	The claims database was then queried for International Classification of Diseases, Ninth Revision, diagnosis codes (ICD‐9: 810-829) for extremity fractures and long bone fractures.	No adjustment for this group of comparison.
Wolfe (Controls unexposed NOS), 2019	retrospective cohort (claims database)	Pharmaceutical data were used to screen all women in the cohort for antireflux medication prescriptions during gestation.	The claims database was then queried for International Classification of Diseases, Ninth Revision, diagnosis codes (ICD‐9: 810-829) for extremity fractures and long bone fractures.	Adjusted by region, rank, and service of the active‐duty sponsor or the active‐duty mother.
Yitshak-Sade, 2016	retrospective cohort (claims database)	“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.	The Soroka Medical Center Admission-Transfer-Discharge computerized database includes medical diagnoses from the hospital medical records. Children were deﬁned as asthmatic if they were hospitalized with asthma or recurrent wheezing between the ages of 2 and 13 years and with asthma medications.	Maternal allergies and asthma, maternal age, infertility treatment, lack of prenatal care, gestational age at delivery, cesarean section delivery, birth weight and sex, birth year, dispensing PPIs for children aged 0 to 2 years of age, and maternal use of the following medications during the exposure period: antibiotics, NSAI drugs, metoclopramide, and insulin.

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