Prenatal Exposure to PPIs and the Risk of Childhood Asthma
Prenatal Exposure to PPIs and the Risk of Childhood Asthma
The study cohort and data collection have been previously described. This population-based cohort study included all singletons born alive from 1 January 1996 to 31 December 2008 in northern Denmark, a region representing approximately 33% of the Danish population. The study population was identified through the Danish Medical Birth Registry, which has recorded all births in Denmark since 1973. The Danish National Health Service provides tax-supported health care to all residents of the country and refunds a portion of patient expenditures for a wide range of prescribed drugs.
Data on maternal prescriptions dispensed during relevant pregnancy were extracted from the Aarhus University Prescription Database (AUPD), which tracks outpatient dispensations of reimbursed prescribed medicines in the northern Denmark region. Recorded data include personal identifiers, type of medication, coded according to the Anatomical Therapeutic Chemical classification, and the date of dispensation. From 1996 on, children's prescriptions have been recorded under their own, rather than their parents', identifiers. For this reason we restricted the study to births beginning in 1996. In Denmark, all PPIs, except omeprazole and lanzoprazole, which became over-the-counter drugs in December 2006 and May 2007, respectively, are dispensed only by prescription. Their cost is partially reimbursed by the National Health Service.
We searched AUPD for maternal prescriptions for PPIs and histamine 2-receptor antagonists (H2RAs). H2RAs were used to examine whether or not the putative association between prenatal exposure to PPIs and asthma is related to acid-suppressing drugs as a class (or their indication).
Presence of asthma among the children in the study population was defined based on an algorithm combining data on anti-asthma medication dispensations and a hospital diagnosis of asthma. A child was considered to have asthma if the child had a record of a hospitalisation, outpatient visit, or an emergency-room visit with a diagnosis of asthma or if the child had a dispensation record for an anti-asthma medication. For the medication-base criterion, we required prescriptions of both a β-agonist and an inhaled glucocorticoid. In patients aged 5–45 years, this algorithm has a positive predictive value (PPV) of 100% for 'any asthma' (including definitive asthma, wheezing, chronic obstructive pulmonary disease or allergy), and a PPV of 80% for a definitive asthma diagnosis. To ensure ongoing use of anti-asthma medication and to avoid possible misclassification of small children with wheezing, we additionally required that a given medication regimen be dispensed twice for a child to be counted as having asthma.
Asthma diagnoses were ascertained from records of inpatient, outpatient, and emergency-room visits, as recorded in the Danish National Registry of Patients (DNRP). The diagnoses were coded using the Eighth Revision of the International Classification of Diseases (ICD-10) before 1994 and ICD-10 thereafter. The DNRP has tracked all discharges from nonpsychiatric acute care hospitals since 1977; reporting of emergency-room and outpatient clinic contacts started in 1995. Prescription dispensations were ascertained from the AUPD.
We included the following covariates, selected a priori, as risk factors for asthma identified in previous studies and measureable using, as appropriate, DNRP, Birth Registry or AUPD: 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, maternal history of asthma recorded at any time prior to delivery, and maternal pregravid body mass index (BMI). BMI has been recorded in the Birth Registry from 2004 onwards. We identified maternal history of asthma using the same hospitalisation- and prescription-based algorithm as the one used for children but also included ICD-8 codes. Data from all sources were linked on an individual level using the Civil Registration number, a 10-digit unique number assigned to all Danish residents at birth or immigration and used in all Danish healthcare registries. All relevant diagnostic and medication codes are listed in the Appendix S1.
We defined prenatal exposure to PPIs as at least one maternal PPI prescription from 30 days preceding the giving first day of the last menstrual period (LMP) and until giving birth. We subsequently examined trimester-specific exposure: the first trimester was defined as the first 12 weeks of pregnancy counted from the first day of LMP; the second and third trimesters (examined together) were defined as the remainder of the pregnancy. According to this exposure classification, children exposed during the first trimester could also be exposed during second and/or third trimester, but not vice versa. To examine whether the cumulative dose of PPIs had any impact on subsequent asthma risk, we stratified PPI exposure according to the number of pills dispensed: ≤28 pills vs. >28 pills. We defined the reference group as children unexposed to PPIs at any time during gestation, as evidenced by absence of maternal PPI prescriptions.
The children were followed up from their date of birth until the date of asthma diagnosis, death, emigration, or the end of follow-up on 31 December 2009, whichever came first. We calculated incidence rates of asthma as the number of children with asthma divided by total follow-up time. We used the Kaplan–Meier method to estimate 2-year and 10-year risk of asthma according to PPI exposure. We used Cox proportional-hazards regression to compute crude and adjusted incidence rate ratios (IRRs and aIRRs) with 95% confidence intervals (95% CI). The assumption of proportional-hazards was assessed graphically and found appropriate. GERD in children may be related to asthma development. Additional adjustment for the children's postnatal use of PPIs and/or H2RAs as a proxy for GERD did not change the estimates; therefore reported estimates do not include this adjustment but are available from the authors on request.
In addition to the primary analyses described above, we performed a number of secondary analyses. Since a definitive diagnosis of asthma cannot be made before the age of 5–6 years, we performed an analysis restricted to children diagnosed with asthma from age 5 years or older. To examine whether or not the putative association varied by severity of asthma, we also performed an analysis restricted to children with a hospital diagnosis of asthma (excluding the definition of asthma requirement of outpatient prescriptions). We also conducted the following separate sub-analyses: (i) adjusting for maternal BMI for children born in 2004 or later; and changing the earliest PPI exposure period from 30 days to 0 days and 60 days before the first day of the last menstrual period, to examine sensitivity of results to modifications of definition of the exposure. Furthermore, we examined the association between prenatal exposure to maternal use of H2RAs and asthma (with the number of pills dispensed categorised as ≤20 vs. >20); and association with offspring's asthma of maternal PPI use in the year after giving birth, but not during pregnancy; children whose mothers did not use PPI in either of those periods were the reference group for this latter analysis. The latter analysis was also performed with H2RAs.
All analyses were carried out using sas version 9.2 (SAS Institute Inc., Cary, NC, USA). The study was approved by the Danish Data Protection Agency.
Methods
Study Population
The study cohort and data collection have been previously described. This population-based cohort study included all singletons born alive from 1 January 1996 to 31 December 2008 in northern Denmark, a region representing approximately 33% of the Danish population. The study population was identified through the Danish Medical Birth Registry, which has recorded all births in Denmark since 1973. The Danish National Health Service provides tax-supported health care to all residents of the country and refunds a portion of patient expenditures for a wide range of prescribed drugs.
Data on PPIs and Other Drugs
Data on maternal prescriptions dispensed during relevant pregnancy were extracted from the Aarhus University Prescription Database (AUPD), which tracks outpatient dispensations of reimbursed prescribed medicines in the northern Denmark region. Recorded data include personal identifiers, type of medication, coded according to the Anatomical Therapeutic Chemical classification, and the date of dispensation. From 1996 on, children's prescriptions have been recorded under their own, rather than their parents', identifiers. For this reason we restricted the study to births beginning in 1996. In Denmark, all PPIs, except omeprazole and lanzoprazole, which became over-the-counter drugs in December 2006 and May 2007, respectively, are dispensed only by prescription. Their cost is partially reimbursed by the National Health Service.
We searched AUPD for maternal prescriptions for PPIs and histamine 2-receptor antagonists (H2RAs). H2RAs were used to examine whether or not the putative association between prenatal exposure to PPIs and asthma is related to acid-suppressing drugs as a class (or their indication).
Data on Asthma
Presence of asthma among the children in the study population was defined based on an algorithm combining data on anti-asthma medication dispensations and a hospital diagnosis of asthma. A child was considered to have asthma if the child had a record of a hospitalisation, outpatient visit, or an emergency-room visit with a diagnosis of asthma or if the child had a dispensation record for an anti-asthma medication. For the medication-base criterion, we required prescriptions of both a β-agonist and an inhaled glucocorticoid. In patients aged 5–45 years, this algorithm has a positive predictive value (PPV) of 100% for 'any asthma' (including definitive asthma, wheezing, chronic obstructive pulmonary disease or allergy), and a PPV of 80% for a definitive asthma diagnosis. To ensure ongoing use of anti-asthma medication and to avoid possible misclassification of small children with wheezing, we additionally required that a given medication regimen be dispensed twice for a child to be counted as having asthma.
Asthma diagnoses were ascertained from records of inpatient, outpatient, and emergency-room visits, as recorded in the Danish National Registry of Patients (DNRP). The diagnoses were coded using the Eighth Revision of the International Classification of Diseases (ICD-10) before 1994 and ICD-10 thereafter. The DNRP has tracked all discharges from nonpsychiatric acute care hospitals since 1977; reporting of emergency-room and outpatient clinic contacts started in 1995. Prescription dispensations were ascertained from the AUPD.
Data on Covariates
We included the following covariates, selected a priori, as risk factors for asthma identified in previous studies and measureable using, as appropriate, DNRP, Birth Registry or AUPD: 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, maternal history of asthma recorded at any time prior to delivery, and maternal pregravid body mass index (BMI). BMI has been recorded in the Birth Registry from 2004 onwards. We identified maternal history of asthma using the same hospitalisation- and prescription-based algorithm as the one used for children but also included ICD-8 codes. Data from all sources were linked on an individual level using the Civil Registration number, a 10-digit unique number assigned to all Danish residents at birth or immigration and used in all Danish healthcare registries. All relevant diagnostic and medication codes are listed in the Appendix S1.
Statistical Analysis
We defined prenatal exposure to PPIs as at least one maternal PPI prescription from 30 days preceding the giving first day of the last menstrual period (LMP) and until giving birth. We subsequently examined trimester-specific exposure: the first trimester was defined as the first 12 weeks of pregnancy counted from the first day of LMP; the second and third trimesters (examined together) were defined as the remainder of the pregnancy. According to this exposure classification, children exposed during the first trimester could also be exposed during second and/or third trimester, but not vice versa. To examine whether the cumulative dose of PPIs had any impact on subsequent asthma risk, we stratified PPI exposure according to the number of pills dispensed: ≤28 pills vs. >28 pills. We defined the reference group as children unexposed to PPIs at any time during gestation, as evidenced by absence of maternal PPI prescriptions.
The children were followed up from their date of birth until the date of asthma diagnosis, death, emigration, or the end of follow-up on 31 December 2009, whichever came first. We calculated incidence rates of asthma as the number of children with asthma divided by total follow-up time. We used the Kaplan–Meier method to estimate 2-year and 10-year risk of asthma according to PPI exposure. We used Cox proportional-hazards regression to compute crude and adjusted incidence rate ratios (IRRs and aIRRs) with 95% confidence intervals (95% CI). The assumption of proportional-hazards was assessed graphically and found appropriate. GERD in children may be related to asthma development. Additional adjustment for the children's postnatal use of PPIs and/or H2RAs as a proxy for GERD did not change the estimates; therefore reported estimates do not include this adjustment but are available from the authors on request.
In addition to the primary analyses described above, we performed a number of secondary analyses. Since a definitive diagnosis of asthma cannot be made before the age of 5–6 years, we performed an analysis restricted to children diagnosed with asthma from age 5 years or older. To examine whether or not the putative association varied by severity of asthma, we also performed an analysis restricted to children with a hospital diagnosis of asthma (excluding the definition of asthma requirement of outpatient prescriptions). We also conducted the following separate sub-analyses: (i) adjusting for maternal BMI for children born in 2004 or later; and changing the earliest PPI exposure period from 30 days to 0 days and 60 days before the first day of the last menstrual period, to examine sensitivity of results to modifications of definition of the exposure. Furthermore, we examined the association between prenatal exposure to maternal use of H2RAs and asthma (with the number of pills dispensed categorised as ≤20 vs. >20); and association with offspring's asthma of maternal PPI use in the year after giving birth, but not during pregnancy; children whose mothers did not use PPI in either of those periods were the reference group for this latter analysis. The latter analysis was also performed with H2RAs.
All analyses were carried out using sas version 9.2 (SAS Institute Inc., Cary, NC, USA). The study was approved by the Danish Data Protection Agency.
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