Table 1.

Acid suppressant medications and allergic diseases: observational study design

A. Prenatal exposure to ASM
Author (year), Location	Study Design	Sample Size	Excluded	Exposure	Outcome- Asthma	Outcome- Atopic Dermatitis (AD)	Outcome – Food Allergy (FA)	Outcome- - Allergic Rhinitis (AR)	Outcome- Other Allergic Disease
Dehlink (2009), Sweden [24]	Cohort	585,716	<37 weeks GA, infertility, C-section, single parent household	Use of H2RA, prostaglandins, PPI, H. pylori treatment, or sucralfate during pregnancy identified by medication code in birth registry	Ever hospitalized for asthma (over age 2 or multiple hospitalizations) or received 2 or more prescriptions for asthma medication	AD by discharge diagnosis or 2 or more prescriptions to treat an allergic condition*	FA by discharge diagnosis or 2 or more prescriptions to treat an allergic condition*	AR by discharge diagnosis or 2 or more prescriptions to treat an allergic condition*	Unspecified allergic reaction or anaphylaxis: by a discharge diagnosis or 2 or more prescriptions to treat an allergic condition Allergic disease: if ever hospitalized for an allergic disease (asthma, FA, AD or unspecified allergic reaction/anaphylaxis) or if received 2 or more prescription allergy medications*
Hak (2013), United Kingdom [25]	Nested cross-over	1874 cases 1874 controls	Congenital birth defects, chromosomal anomaly, known teratogen exposure, <12 months of pre-pregnancy follow up or < 3 years follow up after birth	Prescription of any acid suppressive therapy during pregnancy	Diagnosis from birth to age 14 years and prescription for 3 asthma medications in the 12 months after diagnosis	-	-	-	-
Andersen (2012), Denmark [26]	Cohort	197,060	Twins or other multiple births	Prescription for H2RA or PPI during pregnancy	Diagnosis at hospitalization, outpatient visit, or ED visit or dispended anti-asthma medications†	-	-	-	-
Kallen (2013), Sweden [27]	Cohort	685,015	Not born in Sweden, twins or other multiple births, additional analysis excluding women with history of asthma	Prescription or recommendation for use of GERD medications and other medications during pregnancy	5 or more prescriptions for asthma medications in child > 2 years of age	-	-	-	-
Mulder (2013), Netherlands [28]	Case-Control	1253 cases 1253 controls	< 5.5 years of follow up after birth	1 or more prescription(s) for H2RA, PPI, prostaglandin, H. pylori therapy or GERD medication during pregnancy	2 or more prescriptions for asthma medications in a 6-month period prior to age 5	-	-	-	-
Mulder (2014), Netherlands [29]	Cohort	33,536	Twins or other multiple births, mothers with <12 months of follow up prior to pregnancy	1 or more prescription(s) for H2RA or PPI during pregnancy	Receiving two prescriptions for an inhaled corticosteroid within a 12 month period after age 5	2 or more prescriptions for steroid or calcineurin inhibitor ointment in 12 months	-	2 or more prescriptions for nasal steroids within a 12 month period	Allergic disease: combined outcome of asthma, AD, or AR as defined
Cea Soriano (2016), United Kingdom [30]	Case Control	2371 exposed 7745 un-exposed	< 12 months follow up prior to pregnancy or < 1 year of follow up after birth	1 or more prescription(s) for PPI or H2RA during pregnancy	Diagnosis codes for asthma then confirmed by manual chart review	-	-	-	-
Yitshak-Sade (2016), Israel [31]	Cohort	91,428	Unknown personal information for follow up, childhood diagnoses of cystic fibrosis, bronchiolitis, bronchitis, heart failure, chronic airway obstruction, other pulmonary disease, GERD or heart defects	Purchase of H2RA or PPI during pregnancy	Hospitalization with diagnosis of asthma or recurrent wheeze between the ages of 2-13 years or dispensed at least 2 or a combination of asthma medications‡	-	-	-	-

B. Childhood exposure to ASM
Author (year), Location	Study Design	Sample Size	Excluded	Exposure	Outcome- Asthma	Outcome – AD	Outcome- FA	Outcome- AR	Outcome- Other Allergic Disease
DeMuth (2013), United States [37]	Cross-sectional	104	Chronic conditions other than atopic disease	Parent report by questionnaire of use of any ASM during childhood	-	-	Food Allergy: By parent report with a reaction consistent with anaphylaxis and elevated food specific IgE or positive skin prick test	-	-
Jensen (2018), United States [38]	Case Control	136 cases 125 controls	Age > 18, symptoms of EOE started prior to age 3 years	Parental report by survey of ASM use during infancy	-	-	-	-	EOE: ≥15 eosinophils per high power field on endoscopy
Mitre (2018), United States [39]	Cohort	792,130	Initial birth hospital stay > 7 days, diagnosed with any allergic outcome by 6 months of age	Prescription for H2RA or PPI	Diagnosis code for asthma	Diagnosis code for atopic dermatitis	Diagnosis code for food allergy	Diagnosis code for allergic rhinitis	Allergic conjunctivitis: Diagnosis code Anaphylaxis: Diagnosis code Medication allergy: Diagnosis code Urticaria: Diagnosis code Contact dermatitis: Diagnosis code Other allergy: Diagnosis code

C. Adult exposure to ASM
Author (year), Location	Study Design	Sample Size	Excluded	Exposure	Outcome- Asthma	Outcome- AD	Outcome- FA	Outcome- AR	Outcome- Allergic Disease
Ramirez (2012), Spain [40]	Case Control	161 cases 318 controls	Allergic contact dermatitis, receipt of less than 1 systemic drug during admission	Receipt of PPI during admission	-	-	-	-	Drug Hypersensitivity: Cases identified by consultations to the allergy department and verified as drug hypersensitivity reaction based on record review

Abbreviations: AD: atopic dermatitis, ASM: acid suppressant medication, C-section: cesarean section, ED: emergency department, EOE: eosinophilic esophagitis, FA: food allergy, GA: gestational age, GERD: gastroesophageal reflux disease, H2RA: histamine-2 receptor antagonist, PPI: proton pump inhibitor, AR: allergic rhinitis.

^*Medications included asthma medications, antihistamines, steroid ointments or epinephrine auto injector.

^†Anti-asthmatic medications: Beta–agonist or inhaled glucocorticoid.

^‡6 categories of medications including inhaled beta agonists, oral corticosteroids, inhaled corticosteroids, combined inhalers, montelukast, ipratropium bromide or cromoglycate.