Acetaminophen or Antibiotic Use and Childhood Allergic Diseases
Acetaminophen or Antibiotic Use and Childhood Allergic Diseases
Taiwan launched a single-payer National Health Insurance Programme (NHIP) in March 1995. Since 2000, the National Health Insurance reimbursement claims data have been managed by the National Health Research Institutes (NHRI) in Taiwan. The National Health Insurance Research Database (NHIRD), a medical claims database (including inpatient and outpatient services), was established and has been released for research purposes. Specifically, the NHIRD, derived from the original medical claims data of the NHI programme, contains all inpatient and outpatient medical claims data (including prescription claims data) from the enrollees, who represent over 98% of the total population in Taiwan, and has provided a valuable resource, a unique opportunity and sufficient sample size to pursue the objectives addressed in this study. To ensure the accuracy of disease diagnosis, the National Health Insurance Bureau of Taiwan has randomly reviewed medical charts of 1/100 ambulatory and 1/20 inpatient claims. The high validity of the diagnostic data from the NHIRD has been reported previously.
In detail, two independent birth cohorts were used in this study. (i) The 1998 birth cohort: a total of 263 620 children born in 1998 were identified, based on birth date in the enrolment data files from the total population in the NHIRD. (ii) The 2003 birth cohort: a total of 9910 children born in 2003 were identified, based on birth date in the enrolment data files from the Longitudinal Health Insurance Database 2005 (LHID 2005). Of note, the 1998 birth cohort included children who were born in 1998 and enrolled in the NHIRD from Taiwan's total population; and the 2003 birth cohort identified children who were born in 2003 from the LHID 2005, a subset of the NHIRD that includes an approximately 1:23 ratio of Taiwan's total population. Detailed information regarding the LHID 2005 and also the corresponding sampling method are provided at the following link: http://w3.nhri.org.tw/nhird/date_cohort.htm#1
The study protocol was approved by the Institutional Review Board of the NHRI in Taiwan.
Information from prescription records regarding acetaminophen and antibiotic use occurring within the windows 1998–99 and 2003–04, respectively, were extracted according to Anatomic Therapeutic Chemical Classification System (ATC) codes. In particular, the list of the examined prescriptions included acetaminophen (ATC code: N02BE01) and antibiotics (ATC code: J01). From the prescription claims data (including acetaminophen and antibiotics), types of medication, dosage, time of prescription and duration of drug supply were recorded from each prescription claim. The detailed list of examined antibiotics consisted of: tetracyclines (ATC code: J01A); amphenicols (ATC code: J01B); penicillins (ATC code: J01C); other beta-lactam antibacterials (ATC code: J01D); sulfonamides and trimethoprim (ATC code: J01E); macrolides, lincosamides and streptogramins (ATC code: J01F); aminoglycosides (ATC code: J01G); quinolones (ATC code: J01M); and other antibiotics (ATC code: J01X). We then documented the status of acetaminophen and antibiotics use based on the date of prescription plus the duration of the drug supply within the windows 1998–99 and 2003–04, respectively, which would coincide with the 1st year of life.
Three allergic diseases, atopic dermatitis, allergic rhinitis and asthma, were examined in this study. Notably, the disease diagnoses for the NHIP were coded using A-codes, a simplified disease diagnostic coding system that was mainly used for ambulatory care before 2000. Since 2000, the NHIP has switched the disease coding to the International Classification of Diseases [ICD]-9-CM codes. Therefore, for the 1998 birth cohort, diagnoses of the examined allergic diseases were provided as follows
Different from the 1998 birth cohort, diagnoses of the examined allergic diseases in the 2003 birth cohort were described as follows:
Of note, we used the date of the second ambulatory claim record or the date of one inpatient claim record for time to diagnosis for these three examined allergic diseases. Moreover, to ensure the reliability of disease diagnosis, we used the ICD-9 code, which has been used previously for identifying subjects with atopic dermatitis, asthma and allergic rhinitis, respectively, and only included children who had at least one inpatient claim record or two ambulatory claims records for the three examined allergic diseases.
We computed and compared the distribution of demographic and healthcare characteristics across different medication-use groups in both birth cohorts, separ ately. Specifically, the demographic and healthcare characteristics included: gender, enrollee category (I–IV), geographical area at birth (northern, central, southern and eastern) and healthcare utilization (including cumulative number of ambulatory visits and inpatient visits during the 1st year of life). Since most study subjects were dependants of the insured beneficiaries (those paying the insurance fee, such as a child's parents, grandparents or social welfare institution), this study used enrollee category (EC) as a proxy measure to represent the study subjects' socio-economic status (SES). A detailed description of EC classification can be obtained elsewhere. Briefly, the insurance fee for the NHIP was determined according to enrollees' wages; therefore we classified enrollees into four ECs (EC I–EC IV), with EC I indicating those with the highest wages compared with those in the subsequent EC groups (EC II–EC IV).
Next, we excluded children who were in the first 2 years of life, that is 1–2 years of age, and calculated among the remaining children the incidence rates atopic dermatitis, asthma and allergic rhinitis, separately in the 1998 and 2003 birth cohorts, respectively. Specifically, the incidence rates of atopic dermatitis, asthma and allergic rhinitis, separately, were calculated in children aged 2 to 6 years.
Furthermore, we examined the temporal relationship between exposure to acetaminophen/antibiotics and the risk of developing allergic diseases using the Cox proportional hazards model for both birth cohorts, separately, with and without covariates adjustment. In detail, exposure to acetaminophen/antibiotics was classified into four groups: (i) no use of acetaminophen or antibiotics; (ii) only antibiotic use; (iii) only acetaminophen use; and (iv) both acetaminophen and antibiotic use. Of note, only the data related to exposure to acetaminophen/antibiotics during the 1st year of life were included.
The outcomes of interest were atopic dermatitis (yes/no), asthma (yes/no) and allergic rhinitis (yes/no); and the adjusted covariates included: gender, EC at birth, geographical area at birth and healthcare utilization (including numbers of ambulatory visits, inpatient visits, otitis media diagnoses and bronchitis diagnoses), separately. Children who developed allergic diseases during the first 2 years of life were excluded in the subsequent analyses. We followed the development of examined outcomes among the study children untill they were 6 years old. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated using the 'no use of acetaminophen or antibiotics' group as the reference group. All of the analyses were performed using SAS version 8.2 (SAS institute, Cary, NC).
Methods
Study Population
Taiwan launched a single-payer National Health Insurance Programme (NHIP) in March 1995. Since 2000, the National Health Insurance reimbursement claims data have been managed by the National Health Research Institutes (NHRI) in Taiwan. The National Health Insurance Research Database (NHIRD), a medical claims database (including inpatient and outpatient services), was established and has been released for research purposes. Specifically, the NHIRD, derived from the original medical claims data of the NHI programme, contains all inpatient and outpatient medical claims data (including prescription claims data) from the enrollees, who represent over 98% of the total population in Taiwan, and has provided a valuable resource, a unique opportunity and sufficient sample size to pursue the objectives addressed in this study. To ensure the accuracy of disease diagnosis, the National Health Insurance Bureau of Taiwan has randomly reviewed medical charts of 1/100 ambulatory and 1/20 inpatient claims. The high validity of the diagnostic data from the NHIRD has been reported previously.
In detail, two independent birth cohorts were used in this study. (i) The 1998 birth cohort: a total of 263 620 children born in 1998 were identified, based on birth date in the enrolment data files from the total population in the NHIRD. (ii) The 2003 birth cohort: a total of 9910 children born in 2003 were identified, based on birth date in the enrolment data files from the Longitudinal Health Insurance Database 2005 (LHID 2005). Of note, the 1998 birth cohort included children who were born in 1998 and enrolled in the NHIRD from Taiwan's total population; and the 2003 birth cohort identified children who were born in 2003 from the LHID 2005, a subset of the NHIRD that includes an approximately 1:23 ratio of Taiwan's total population. Detailed information regarding the LHID 2005 and also the corresponding sampling method are provided at the following link: http://w3.nhri.org.tw/nhird/date_cohort.htm#1
The study protocol was approved by the Institutional Review Board of the NHRI in Taiwan.
Definition of Acetaminophen and Antibiotic Uses
Information from prescription records regarding acetaminophen and antibiotic use occurring within the windows 1998–99 and 2003–04, respectively, were extracted according to Anatomic Therapeutic Chemical Classification System (ATC) codes. In particular, the list of the examined prescriptions included acetaminophen (ATC code: N02BE01) and antibiotics (ATC code: J01). From the prescription claims data (including acetaminophen and antibiotics), types of medication, dosage, time of prescription and duration of drug supply were recorded from each prescription claim. The detailed list of examined antibiotics consisted of: tetracyclines (ATC code: J01A); amphenicols (ATC code: J01B); penicillins (ATC code: J01C); other beta-lactam antibacterials (ATC code: J01D); sulfonamides and trimethoprim (ATC code: J01E); macrolides, lincosamides and streptogramins (ATC code: J01F); aminoglycosides (ATC code: J01G); quinolones (ATC code: J01M); and other antibiotics (ATC code: J01X). We then documented the status of acetaminophen and antibiotics use based on the date of prescription plus the duration of the drug supply within the windows 1998–99 and 2003–04, respectively, which would coincide with the 1st year of life.
Definition of Examined Allergic Diseases
Three allergic diseases, atopic dermatitis, allergic rhinitis and asthma, were examined in this study. Notably, the disease diagnoses for the NHIP were coded using A-codes, a simplified disease diagnostic coding system that was mainly used for ambulatory care before 2000. Since 2000, the NHIP has switched the disease coding to the International Classification of Diseases [ICD]-9-CM codes. Therefore, for the 1998 birth cohort, diagnoses of the examined allergic diseases were provided as follows
atopic dermatitis: defined as at least one inpatient claim record for atopic dermatitis (A code: A429 or ICD-9 code = 691.8), or two ambulatory claims coded as A code = A429 or ICD-9 code = 493;
asthma: defined as at least one inpatient claim record for asthma (A code: A323 or ICD-9 code = 493), or two ambulatory claims coded as A code = A323 or ICD-9 code = 493;
allergic rhinitis: defined as at least one inpatient claim record for allergic rhinitis (A code: A319 or ICD-9 code = 477), or two ambulatory claims coded as A code = A319 or ICD-9 code = 477.
Different from the 1998 birth cohort, diagnoses of the examined allergic diseases in the 2003 birth cohort were described as follows:
atopic dermatitis: defined as at least one inpatient claim record for atopic dermatitis (ICD-9 code = 691.8), or two ambulatory claims coded ICD-9 = 691.8;
asthma: defined as at least one inpatient claim record for asthma (ICD-9 code = 493), or two ambulatory claims coded ICD-9 = 493;
allergic rhinitis: defined as at least one inpatient claim record for allergic rhinitis (ICD-9 code = 477), or two ambulatory claims coded ICD-9 = 477.
Of note, we used the date of the second ambulatory claim record or the date of one inpatient claim record for time to diagnosis for these three examined allergic diseases. Moreover, to ensure the reliability of disease diagnosis, we used the ICD-9 code, which has been used previously for identifying subjects with atopic dermatitis, asthma and allergic rhinitis, respectively, and only included children who had at least one inpatient claim record or two ambulatory claims records for the three examined allergic diseases.
Statistical Analyses
We computed and compared the distribution of demographic and healthcare characteristics across different medication-use groups in both birth cohorts, separ ately. Specifically, the demographic and healthcare characteristics included: gender, enrollee category (I–IV), geographical area at birth (northern, central, southern and eastern) and healthcare utilization (including cumulative number of ambulatory visits and inpatient visits during the 1st year of life). Since most study subjects were dependants of the insured beneficiaries (those paying the insurance fee, such as a child's parents, grandparents or social welfare institution), this study used enrollee category (EC) as a proxy measure to represent the study subjects' socio-economic status (SES). A detailed description of EC classification can be obtained elsewhere. Briefly, the insurance fee for the NHIP was determined according to enrollees' wages; therefore we classified enrollees into four ECs (EC I–EC IV), with EC I indicating those with the highest wages compared with those in the subsequent EC groups (EC II–EC IV).
Next, we excluded children who were in the first 2 years of life, that is 1–2 years of age, and calculated among the remaining children the incidence rates atopic dermatitis, asthma and allergic rhinitis, separately in the 1998 and 2003 birth cohorts, respectively. Specifically, the incidence rates of atopic dermatitis, asthma and allergic rhinitis, separately, were calculated in children aged 2 to 6 years.
Furthermore, we examined the temporal relationship between exposure to acetaminophen/antibiotics and the risk of developing allergic diseases using the Cox proportional hazards model for both birth cohorts, separately, with and without covariates adjustment. In detail, exposure to acetaminophen/antibiotics was classified into four groups: (i) no use of acetaminophen or antibiotics; (ii) only antibiotic use; (iii) only acetaminophen use; and (iv) both acetaminophen and antibiotic use. Of note, only the data related to exposure to acetaminophen/antibiotics during the 1st year of life were included.
The outcomes of interest were atopic dermatitis (yes/no), asthma (yes/no) and allergic rhinitis (yes/no); and the adjusted covariates included: gender, EC at birth, geographical area at birth and healthcare utilization (including numbers of ambulatory visits, inpatient visits, otitis media diagnoses and bronchitis diagnoses), separately. Children who developed allergic diseases during the first 2 years of life were excluded in the subsequent analyses. We followed the development of examined outcomes among the study children untill they were 6 years old. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were calculated using the 'no use of acetaminophen or antibiotics' group as the reference group. All of the analyses were performed using SAS version 8.2 (SAS institute, Cary, NC).
