Page 26 of 36 Online Data Supplement Low birthweight and respiratory disease in adulthood: A population-based casecontrol study Eric C. Walter, MD; William J. Ehlenbach, MD; David L. Hotchkin, MD, Jason W. Chien, MD; Thomas D. Koepsell, MD
Page 27 of 36 Methods Patient selection We conducted a population based case-control study. Potential cases were identified from the Washington State Comprehensive Hospital Abstract Reporting System (CHARS) discharge database, and defined as individuals hospitalized from January 1, 1998 to December 31, 2007, who were 18 years or older at the time of hospitalization, and who received a discharge diagnosis of a respiratory illness. Respiratory illnesses were defined using specific International Classification of Diseases, Ninth Revision (ICD-9) diagnosis and procedure codes representing acute and chronic respiratory disease, respiratory infections, respiratory symptoms, and non-operative mechanical ventilation (Table E1). Selection was limited to those individuals with a respiratory diagnosis code present among the first four listed discharge diagnoses. For those individuals with multiple hospital discharges during this period, information from only the first hospitalization was used. Controls were randomly selected from the WA State birth certificate database (excluding cases), and frequency matched to cases by birth year. Four times as many controls as cases were selected. The decision to choose four controls per case was made a priori. This provided 80% power to detect an odds ratio of at least 1.5, assuming an exposure prevalence of 1% and two-tailed significance testing at the.05 level. Controls were filtered through the WA State Department of Health death file to exclude individuals who were known to have died prior to the age of 18. 1
Page 28 of 36 Outcomes and exposures The primary outcome was hospitalization for a respiratory disease between the ages of 18 to 27. The primary exposure was LBW. LBW was classified as: VLBW (birthweight less than 1500 grams) and MLBW (birthweight 1500 to 2499 grams). Normal birthweight (NBW, birthweight 2500 to 4000 grams) individuals were considered unexposed. Individuals with macrosomia (birthweight > 4000 grams) were excluded as the primary research question related to the comparisons between low birthweight and normal birthweight survivors. Furthermore, infants born with macrosomia have specific complications related to their birthweight, distinct from those of low birthweight infants. Exploratory analyses were performed for 3 a priori identified subgroups of respiratory illness hospitalizations: asthma, respiratory infection, and respiratory failure requiring mechanical ventilation. Respiratory illness subgroups were defined as follows: Asthma was defined as those cases with ICD codes of 493 (and subsets). Respiratory infection was defined using ICD codes (including all subsets) 466, 480-487, 490, 491, 510, and 513. Respiratory failure requiring mechanical ventilation was defined as having nonoperative mechanical ventilation greater than 96 hours (ICD 9 procedure code 96.72) or requiring nonoperative mechanical ventilation of either unspecified duration or for less than 96 hours (ICD 9 procedure codes 96.70 or 96.71) in addition to any of the respiratory related ICD codes listed in Table E1. Clinical variables Maternal race/ethnicity was self-reported and categorized on birth certificates as White, Black, Native American, Chinese, Japanese, Filipino, Hawaiian, other Asian, Hispanic, 2
Page 29 of 36 and other Non-White. For data analysis, race/ethnicity was categorized as White, Black, and Other. Race/ethnicity was assessed as it is known to be associated with low birthweight (1). Additional variables included maternal smoking status (smoker or nonsmoker), maternal marital status (married or unmarried), induction of labor (yes or no), delivery type (vaginal or cesarean), and maternal residence. Maternal residence was classified as urban or rural using 1983 United States Department of Agriculture, Economic Research Service Rural-Urban Continuum Codes which classify each county as either metropolitan or non-metropolitan (2). To assess the stability of classifications in this database, changes in county designation were compared between 1983 and 1993. Only one county code was noted to have changed. 3
Page 30 of 36 Results Demographics Maternal and infant characteristics of included and excluded individuals are available in Table E3. The vast majority of excluded individuals were excluded for macrosomia (97%). Excluded individuals were less likely to be hospitalized for respiratory illness as an adult. They were also less likely to have mother s who were young, African American, and unmarried. These factors are all associated with low socioeconomic status, a known risk factor for LBW. Since all LBW births were included it is reasonable there would be differences between included and excluded individuals. Excluded individuals were also less likely to have mother s who smoked during pregnancy, another known risk factor for LBW. Finally, excluded individuals were less likely to have hyaline membrane disease and more likely to have been born via cesarean section. The vast majority of included cases (98.3%) and controls (97.6%) were singleton births. Twins accounted for 1.7% and 2.4% of cases and controls respectively. Primary outcome As respiratory symptoms (ICD-9 code 786 with all 4 and 5 digit breakouts), hypoxemia (799 with all 4 and 5 digit breakouts), respiratory arrest (799.1), and mechanical ventilation (ICD-9 procedure code 96.7 with all 4 and 5 digit breakouts) may occur in settings unrelated to clinically significant respiratory disease a sensitivity analysis was conducted after eliminating these diagnoses. VLBW and MLBW remained significantly associated with increased odds of adult respiratory disease (Table E4). 4
Page 31 of 36 Tables: TABLE E1: ICD-9 CODES FOR CASES Acute bronchitis and bronchiolitis 466 with all 4 & 5 digit breakouts Pneumonia and influenza 480-487 with all 4 & 5 digit breakouts Bronchitis 490 Chronic bronchitis 491 with all 4 & 5 digit breakouts Asthma 493 with all 4 & 5 digit breakouts Bronchiectasis 494 with all 4 & 5 digit breakouts Chronic airway obstruction 496 Empyema 510 with all 4 & 5 digit breakouts Pneumothorax 512 with all 4 & 5 digit breakouts Lung abscess 513 with all 4 & 5 digit breakouts Postinflammatory pulmonary fibrosis 515 Other diseases of the lung 518 with all 4 & 5 digit breakouts Respiratory symptoms 786.00, 786.05, 786.07, 786.09, 786.1, 786.2, 786.3, 786.4 Hypoxemia 799.02 Respiratory arrest 799.1 Mechanical ventilation 96.7 with all 4 & 5 digit breakouts 5
Page 32 of 36 TABLE E2: SUBGROUP CLASSIFICATIONS BY ICD-9 CODE Asthma Asthma 493 with all 4 & 5 digit breakouts Respiratory infections Acute bronchitis and bronchiolitis 466 with all 4 & 5 digit breakouts Pneumonia and influenza 480-487 with all 4 & 5 digit breakouts Bronchitis 490 Chronic bronchitis 491 with all 4 & 5 digit breakouts Empyema 510 with all 4 & 5 digit breakouts Lung abscess 513 with all 4 & 5 digit breakouts Respiratory failure Mechanical ventilation for > 72 hours 96.72 Mechanical ventilation for unspecified 96.70 or 96.71 + Any respiratory related duration or for < 72 hours in addition to code listed in Table E1 any respiratory related code above 6
Page 33 of 36 TABLE E3: MATERNAL AND INFANT CHARACTERISTICS OF INCLUDED AND EXCLUDED INDIVIDUALS Included individuals Excluded individuals (n=23,119) (n=3959) P-value Birthweight Median (Range) 3374 (227-3997) 4111 (4026-7257)* Hospitalized as adults 0.042 Yes (cases) 4674 (20.2) 745 (18.8) No (controls) 18,445 (79.8) 3214 (81.2) Sex Male 11,287 (48.8) 2505 (63.3) Female 11,832 (51.2) 1454 (36.7) Mother s age, y < 20 2940 (12.7) 327 (8.3) 20-34 18,957 (82.0) 3323 (83.9) > 35 1212 (5.2) 308 (7.8) Unknown 10 (<1) 1 (<1) Mother s ethnicity Caucasian 19,956 (86.3) 3550 (89.7) African-American 933 (4.0) 66 (1.7) Other 2128 (9.2) 257 (6.5) Unknown 102 (<1) 86 (2.2) Mother s marital status Married 18,683 (80.8) 3421 (86.4) Unmarried 4372 (18.9) 462 (11.7) Unknown 64 (<1) 76 (1.9) Maternal residence 0.057 Urban 18,494 (80.0) 3118 (78.8) Rural 4274 (18.5) 790 (20.0) Unknown 351 (1.5) 51 (1.3) Maternal smoking Yes 2513 (10.9) 217 (5.5) No 6314 (27.3) 1309 (33.1) Unknown 14,292 (61.8) 2433 (61.5) Induction of labor 0.165 Yes 480 (2.1) 100 (2.5) No 22,637 (97.9) 3859 (97.5) Unknown 2 (<1) 0 Delivery type Cesarean section 3516 (15.2) 705 (17.8) Vaginal 19,601 (84.8) 3254 (82.2) Unknown 2 (<1) 0 Hyaline membrane disease Yes 124 (0.5) 2 (0.1) No 21,665 (93.7) 3588 (94.1) Unknown 1330 (5.8) 281 (7.1) *Birthweight excludes 108 subjects with missing birthweight and 1 subject with an implausible birthweight Smoking data only available from 1984 1988 Percentages may not sum to 100 due to rounding 7
Page 34 of 36 TABLE E4: ODDS RATIOS FOR HOSPITALIZATION FOR RESPIRATORY ILLNESS FROM AGES 18 TO 26 EXCLUDING CASES WITH HOSPITALIZATIONS FOR RESPIRATORY SYMPTOMS OR MECHANICAL VENTILATION Exposure n (%) Unadjusted estimated association Test for trend Odds Ratio 95% CI P Value P Value NBW 20590 (93.9) Referent -- -- MLBW 1194 (5.5) 1.37 1.19 1.58 VLBW 135 (0.6) 1.91 1.31 2.78 0.001 Adjusted estimated association* Odds Ratio 95% CI P Value P Value NBW 20590 (93.9) Referent -- -- MLBW 1194 (5.5) 1.30 1.13 1.49 VLBW 135 (0.6) 1.75 1.19 2.57 0.004 * Adjusted for birth year, sex, maternal age, race, residence and marital status 8
Page 35 of 36 TABLE E5: ESTIMATED ASSOCIATIONS BETWEEN BIRTHWEIGHT AND THE RISK OF HOSPITALIZATION FOR RESPIRATORY SUBGROUPS AS A YOUNG ADULT, RESTRICTED TO BIRTHS FROM 1984 TO 1988 Exposure n (%) Unadjusted estimated effect Adjusted estimated effect * Asthma Odds ratio 95% CI P Value Odds ratio 95% CI P Value NBW 7151 (94.3) Referent -- -- Referent -- -- MLBW 399 (5.3) 1.25 0.91 1.72 0.17 1.05 0.75 1.47 0.76 VLBW 37 (0.5) 1.19 0.42 3.38 0.74 0.90 0.29 2.75 0.85 Trend 1.20 0.92 1.57 0.18 1.02 0.77 1.36 0.88 Respiratory infection Odds ratio 95% CI P Value Odds ratio 95% CI P Value NBW 6878 (94.1) Referent -- -- Referent -- -- MLBW 394 (5.4) 1.90 1.35 2.67 <0.001 1.77 1.26 2.50 0.001 VLBW 36 (0.5) 1.52 0.47 4.99 0.49 1.39 0.42 4.60 0.59 Trend 1.66 1.26 2.20 <0.001 1.57 1.18 2.09 0.002 Respiratory failure Odds ratio 95% CI P Value Odds ratio 95% CI P Value NBW 6705 (94.2) Referent -- -- Referent -- -- MLBW 374 (5.3) 1.71 1.07 2.74 0.023 1.65 1.04 2.64 0.04 VLBW 38 (0.5) 4.60 1.78 11.89 0.002 4.56 1.74 11.96 0.002 Trend 1.90 1.33 2.71 <0.001 1.86 1.30 2.65 0.001 *Adjusted for birth year, sex, maternal age, race, residence, marital status and smoking status 9
Page 36 of 36 References E1. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F, Kirmeyer S, Munson ML. Births: Final data for 2005. Natl Vital Stat Rep 2007;56:1-103. E2. Rural-urban continuum codes. In: United States Department of Agriculture ERS, editor; 1983. 10