Associations between Family History of Asthma, Bronchopulmonary Dysplasia, and Childhood Asthma in Very Low Birth Weight Children

Transcription

1 American Journal of Epidemiology Copyright 1998 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 148, No. 5 Printed in U.S.A. Associations between Family History of Asthma, Bronchopulmonary Dysplasia, and Childhood Asthma in Very Low Birth Weight Children Michael Evans 1 Mari Palta, 1 Mona Sadek, 1 Marie R. Weinstein, 2 and Mary Ellen Peters 3 Very low birth weight (VLBW) infants are at risk for childhood wheezing and asthma, as are children with a family history of asthma. Family history of asthma may also be associated with premature labor and, among VLBW infants, with bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD) of prematurity. This study targeted all neonates with birth weight < 1,501 g who were admitted to seven perinatal centers in Wisconsin and Iowa between August 1, 1988 and June 30, Comprehensive information was collected for 723 of the 1, day survivors, and for 106 full-term controls. A representative subgroup of 257 VLBW children was contacted at age 5 years to ascertain bronchodilator and/or steroid use and diagnosis of asthma. Some evidence of an association between family history of asthma and premature birth was found, but it was not associated with neonatal BPD/CLD or BPD/CLD severity. Among BPD/CLD indicators, radiographic evidence of BPD at age days was most strongly associated with bronchodilator use up to age 2 years (odds ratio (OR) = 10.1, 95% confidence interval (Cl) ) and with asthma between ages 2 years and 5 years (OR = 4.83, 95% Cl ). Among children without radiographic evidence of BPD, family history of asthma was associated with childhood asthma and bronchodilator use. Am J Epidemiol 1998; 148: asthma; family health; bronchopulmonary dysplasia; infant, very low birth weight In their 1980 article "Family History of Asthma in Infants with Bronchopulmonary Dysplasia," Nickerson and Taussig (1) were the first to report that family history of asthma may be associated with bronchopulmonary dysplasia (BPD) in neonates. Their article is extensively cited in the neonatal field, and other investigators (2-5) have recently carried out research to examine this hypothesized association, von Mutius et al. (2), who studied children born between 1977 and 1980, found an association between family history of asthma and history of neonatal ventilatory support among premature infants. A study of low birth weight infants by Chan et al. (3) and another of preterm infants by de Winter et al. (4), however, both failed to confirm an association between family his- Received for publication March 24, 1997, and accepted for publication February 19, Abbreviations: BPD, bronchopulmonary dysplasia; Cl, confidence interval; CLD, chronic lung disease of prematurity; OR, odds ratio; RDS, respiratory distress syndrome; VLBW, very low birth weight (s 1,500 g). 1 Department of Preventive Medicine, University of Wisconsin, Madison, Wl. 2 St. Mary's Hospital and Department of Pediatrics, University of Wisconsin, Madison, Wl. 3 Department of Radiology, University of Wisconsin, Madison, Wl. Reprint requests to Dr. Mari Palta, Department of Preventive Medicine, University of Wisconsin, 504 N. Walnut Street, Madison, Wl tory of asthma and BPD. Hagan et al. (5), whose study included preterm infants born between 1987 and 1988, did not find family history of asthma to be associated with commonly used markers for BPD or chronic lung disease (CLD) of prematurity. They did, however, find an association between family history of asthma and more severe respiratory disease, as defined by receiving supplemental oxygen at 40 weeks post-conceptional age (5). Among 90 children born prematurely (28 with asthma and 72 without), Giffin et al. (6) reported both family history of asthma and early respiratory support to be associated with childhood asthma, and they found that early respiratory support showed the stronger association. In 1985, Bertrand et al. (7) found that premature children and their full-term siblings had increased airway hyperreactivity. They postulated that hyperreactivity in both bronchial and uterine smooth muscle might account for an association between asthma and premature birth. While Chan et al. (3) did not find an association between family history of asthma and low birth weight, Kramer et al. (8) more recently found evidence of an association between spontaneous preterm labor and maternal asthma. Data presented by von Mutius et al. (2) also support an association. Our ongoing cohort study of very low birth weight (VLBW) children, the Newborn Lung Project, explored each of these previously described relations by 460

2 Very Low Birth Weight Children and Asthma 461 evaluating the associations between family history of asthma and respiratory disease at birth, in infancy, and in early childhood. Our investigation falls into three stages: 1) a case-control study of the association between family history of asthma and spontaneous preterm labor; 2) an analysis of family history of asthma as a predictor of early respiratory disease characteristics within our VLBW cohort; and 3) a study of early evidence of respiratory disease and family history of asthma as predictors of childhood asthma among VLBW children with long-term follow-up. MATERIALS AND METHODS Baseline population The Newborn Lung Project is a multicenter study of all neonates with birth weight < 1,501 g who were admitted to seven neonatal intensive care units in Wisconsin and Iowa. Institutional review boards of the participating centers approved the study protocol. Of the 1,291 VLBW neonates born between August 1, 1988 and June 30, 1991, 1,042 survived at least 30 days and had no congenital anomalies relevant to respiratory disease. Data on neonates who were transferred out of the neonatal intensive care unit before day 25 of life (n = 35) were considered incomplete for assessment of 30-day morbidity, leaving 1,007 assessed survivors. During the initial hospitalization, parents were approached for informed consent to perform a baseline interview and to abstract medical records. A total of 723 infants had maternal interviews, and their baseline data are consistent with all 30-day survivors (table 1). To investigate associations between maternal and family characteristics and VLBW delivery, a control group of full-term infants was enrolled for a baseline maternal interview. Dates and times of birth were selected at random for each month of the study, and a total of 183 infants from the seven neonatal centers born closest to those times were invited to participate. The enrolled control group consisted of 106 infants, which represents a 58 percent participation rate. Nonenrollment was predominantly due to the inability of interviewers to make contact with mothers before discharge. Follow-up population A follow-up study was implemented at six of the seven perinatal centers, and parents of children born during the first 2 years of the study (before August 1, 1990) were contacted. Of the 387 infants in the baseline group who fulfilled these criteria, 369 survived the initial hospitalization and seven are known to have died after discharge. Among the 362 children presumed alive at age 5 years, parents of 257 children were located and interviewed. These 257 children form a subgroup for whom data on childhood respiratory medication use and/or asthma diagnosis were collected. Their baseline characteristics were similar to those of all 5-year survivors (table 2). Neonatal data collection Birth characteristics analyzed included birth weight, sex, race, gestational age, and baseline respiratory distress severity. Data abstracted on maternal complications at delivery included presence of spontaneous preterm labor. Gestational age was determined by the method of Ballard et al. (9). From respiratory records, the respiratory distress severity in the first 72 hours was scored on a scale of by the method of Palta et al. (10). A score &25 was considered evidence of respiratory distress syndrome (RDS). All radiographs taken between days 25 and 35 of life were obtained. Because criteria for BPD and CLD are not standardized, five outcomes were considered: 1. Use of supplemental oxygen at 30 days of life. This outcome was ascertained from respiratory records. 2. Radiographic evidence of BPD. Each radiograph taken between 25 and 35 days was indepen- TABLE 1. Characteristics of very low birth weight (VLBW) neonates in Wisconsin and Iowa neonatal intensive care units, , at each stage of study selection Subject group All VLBW infants 30-day survivors Maternal interviews Alive at age 5 years, from participating centers Followed No. 1,291 1, Birth weight (g) Mean (SD«) 1,068(286),115(257),109 (257),124 (253),126 (247) MaJe minute Apgar Mean (SD) 6.6 (2.3) 7.0 (2.0) 7.1 (1.9) 7.2(1.8) 7.3(1.8) 24-hour O2«^ ^ Mean (SD) 0.42 (0.26) 0.39 (0.23) 0.39 (0.23) 0.40 (0.23) 0.40 (0.23) Full-term controls 106 3,507(465) (0.8) 0.22(0.08) NA* * SO, standard deviation; O 2, oxygen; NA, not available

3 462 Evans et al. TABLE 2. Characteristics of very low birth weight (VLBW) children from Wisconsin and Iowa neonatal intensive care units, Characteristic GestationaJ age (weeks), mean (SD*) RDS* score (scale 0-100), mean (SD) Radiographic score (scale 0-5), mean (SD) Radiographic evidence ot BPD' (%) Diagnosed with BPD (%) Supplemental O 2* at 30 days ol life Supplemental O 2 at 36 weeks postconceptional age Family history ol asthma Maternal history of asthma Bronchodilators up to age 2 years Asthma diagnosis after age 2 years Interviewed (n = 723) 29.1 (2.6) 30.1 (28.3) 1.14(1.54) NA* NA Followed (n = 257) 29.6 (2.6) 31.2 (27.8) 1.16(1.39) SD, standard deviation; RDS, respiratory distress syndrome; BPD, bronchopulmonary dysplasla; O 2, oxygen; NA, not available. dently scored on the scale of Weinstein et al. (11) by a radiologist and a neonatologist who were masked to infant identity and clinical characteristics. The overall score for each infant is the average of the readings across all radiographs, averaged over the two readers. Average scores of ^2 (presence of interstitial changes) were considered evidence of BPD. Previous analyses show that this level corresponds to an Edwards radiographic score of 3, employed as an indicator of BPD in several clinical trials (12). Infants with no radiographs taken were assigned a score of 0, because they had very low prevalence and incidence of other signs of respiratory disease. Imputed scores were also calculated for infants with no radiographs, based on the BPD score (see item 5 below) as a predictor (R 2 = 0.64). 3. Presence of the above radiographic evidence combined with use of supplemental oxygen at 30 days of life (termed "BPD diagnosis"). Positive diagnoses were assigned to infants with the radiographic changes described above who also received supplemental oxygen. 4. Use of supplemental oxygen at 36 weeks postconceptional age. This outcome was ascertained from respiratory records. 5. BPD severity. Two measures of BPD severity were used. One was the radiographic score (range 0-5) introduced in item 2 above (11). The second was a previously developed respiratory support-based score (11) scaled to the same increments as the radiographic score. This score is obtained by the following formula: Score = X (FIO 2 ) X (PIP) X (FIO 2 ) 2, where FIO 2 indicates mean fraction of inspired oxygen and PIP indicates mean peak inspiratory pressure. The means are taken over days 25, 30, and 35 of life, and the peak inspiratory pressure is 0 if the infant is not receiving mechanical ventilation. Outcomes based on the use of supplemental oxygen at different time points (30 days of life or 36 weeks post-conceptional age) are often labeled CLD, while the term BPD is reserved for criteria which include radiographic findings. Because we investigated both types of criteria, we refer to respiratory disease in infancy beyond the immediate postnatal period generically as BPD/CLD. Maternal baseline interview Parents who gave informed consent were interviewed by a trained neonatal nurse. Mothers were questioned on the history of physician-diagnosed asthma in the following relatives of the infant: parents and siblings, aunts and uncles, and grandparents. The information was summarized as family history of asthma in any first- or second-degree relative. Other ways of summarizing the family history, such as parental asthma or asthma in first-degree relatives yielded results that were similar, but that lacked in statistical power because of the smaller number with family history of asthma. Asthma in the mother was considered in the analysis of premature labor and delivery. Follow-up data collection After written consent was obtained, telephone interviews were conducted with parents when each child was approximately 5 years old (mean age 5.4 years). The interviewers were neonatal care nurses who were trained and monitored for between-interviewer consistency. Data collected on the children included physician diagnosis of asthma and the use of bronchodilators and steroids for each year of life. The presence of either physician diagnosis of asthma or use of respiratory medications for at least 2 weeks between ages 3 and 5 years was used as the criterion for childhood asthma. Statistical methods Statistical analyses were done with the SAS package (13) on a Sun SPARC station 10 (Sun Microsystems, Palo Alto, California). Descriptive statistics were produced as means, standard deviations, and percents, as appropriate. Logistic regression was used for investigation of the association between family history of asthma and neonatal and childhood outcomes. In stage 1, the association between maternal history of asthma

4 Very Low Birth Weight Children and Asthma 463 and incidence of VLBW and spontaneous preterm labor was investigated. Case/control status was the outcome in this stage, where cases were the VLBW infants and controls were the 106 full-term infants. This analysis was adjusted for neonatal center of admission. In stage 2, the association between family history of asthma and each of the five BPD/CLD indicators was examined. Each regression in this stage was adjusted for neonatal center of admission and race, along with the continuous variables respiratory distress severity, birth weight, and gestational age. To examine measures of BPD/CLD severity, analyses were performed both overall and within the subgroup with radiographic evidence of BPD. Finally, in stage 3, the outcomes bronchodilator use in the first 2 years and diagnosis of asthma after age 2 years were regressed on family history of asthma for each BPD/ CLD indicator. All two-way interactions with family history of asthma were investigated. ratios and confidence intervals were obtained by the SAS (13) logistic procedure with the risk limits option. RESULTS Associations of maternal and family history of asthma with preterm labor Associations of preterm labor and VLBW delivery with family history of asthma and maternal history of asthma are shown in table 3. The association between family history of asthma and spontaneous preterm labor fell just short of significance (odds ratio (OR) = 1.86, 95 percent confidence interval (CI) , adjusted for neonatal center), while no association between maternal history of asthma and preterm labor was evident (OR = 1.23, 95 percent CI , adjusted for neonatal center). We also found an association between family history of asthma and VLBW that was just short of significance (OR = 1.55, 95 percent CI , adjusted for neonatal center). Association between family history of asthma and BPD/CLD characteristics For the VLBW group, the association between family history of asthma and each BPD/CLD indicator was estimated among the 723 baseline infants and among the 257 follow-up children for comparison (table 4). We found no significant association between family history of asthma and BPD/CLD. The strongest association was between family history of asthma and use of supplemental oxygen at 36 weeks postconceptional age (OR = 1.52, 95 percent CI ). It has been hypothesized that family history of asthma may be predictive of more severe BPD/CLD among infants with BPD/CLD diagnosis (5). To explore this hypothesis, we examined the association between family history of asthma and BPD/CLD among infants who had radiographic evidence of BPD. Limiting analysis to these infants resulted in no evidence of an association between family history of asthma and use of supplemental oxygen at 36 weeks (OR = 1.33, 95 percent CI ). Two other measures of BPD/CLD severity, the radiographic severity score and the respiratory support based severity score, were not significantly associated with family history of asthma overall, or in the subgroup with radiographic evidence of BPD. Among the infants with radiographic evidence of BPD, the difference in radiographic score between infants with and without family history of asthma was very small (difference = -0.06, 95 percent CI to 0.26), which implies that infants with family history of asthma had virtually indistinguishable radiographic scores from those without family history of asthma. The respiratory supportbased severity score, where higher scores again indicate more severe BPD/CLD, also showed no evidence of a difference between those with and without family history of asthma (difference = 0.21, 95 percent CI to 0.75). Associations of family history of asthma and BPD/CLD with childhood asthma Infants with radiographic evidence of BPD or who received supplemental oxygen at 36 weeks postconceptional age were significantly more likely to use bronchodilators in the first 2 years of life and to have asthma after the first 2 years (table 5). Infants who TABLE 3. Association of family history of asthma with preterm labor and very low birth weight (VLBW) in 723 VLBW infants and 106 controls from Wisconsin and Iowa neonatal intensive care units, Characteristic Family history of asthma Spontaneous preterm labor 1.86 Birth weights 1,500 g 1.55 * Adjusted for neonatal center, t CI, confidence interval. 95% Clf Maternal history of asthma ratio' % CI

5 464 Evans et al. TABLE 4. Association between family history of asthma and bronchopulmonary dysplasia/chronic lung disease of prematurity (BPD/CLD) for 723 neonates and 257 follow-up children from Wisconsin and Iowa neonatal intensive care units, BPD/CLD characteristic Supplemental O 2 t at 30 days of life Diagnosed with BPD Radiographic evidence of BPD Radiographic evidence of BPD (imputed) Supplemental O 2 at 36 weeks postconceptional age Baseline (n = 723) 95% Clt Follow-up (n = 257) 95% Cl * Adjusted for respiratory distress severity, birth weight, gestationaj age, sex, race, and neonatal center, f Cl, confidence interval; O 2, oxygen. TABLE 5. Association between bronchopulmonary dysplasia/chronic lung disease of prematurity (BPD/CLD) and childhood bronchodilator use and asthma in 257 follow-up children from Wisconsin and Iowa neonatal intensive care units, BPD/CLD characteristic Supplemental O 2 t at 30 days of life Diagnosed with BPD Radiographic evidence of BPD Radiographic evidence of BPD (imputed) Supplemental O 2 at 36 weeks postconceptional age Bronchodilator use up to age 2 years 2E 95%c t * Adjusted for birth weight, gestational age, sex, race, and neonatal center, t Cl, confidence interval; O 2, oxygen. received supplemental oxygen at 30 days and those with BPD diagnosis were significantly more likely to use bronchodilators in the first 2 years of life. An interaction effect was found with radiographic evidence of BPD in the association between family history of asthma and childhood asthma (p < 0.01). Among infants with radiographic evidence of BPD, there was no significant association between family history of asthma and bronchodilator use (OR = 0.63, 95 percent Cl , table 6) or diagnosis of asthma (OR = 0.44, 95 percent Cl ). Among infants without radiographic evidence of BPD, there was a significant association between family history of Asthma after age 2 years 95% Cl ^».55 asthma and diagnosis of asthma (OR = 8.33, 95 percent Cl ) and a trend toward an association with bronchodilator use up to age 2 years (OR = 3.01, 95 percent Cl ). When we used imputed radiographic scores to determine the classification of infants with no radiographs, the results were very similar (table 6). DISCUSSION In this comprehensive three-stage study, we examined the association between family history of asthma (FHA) and premature delivery, the association be- TABLE 6. Association of family history of asthma (FHA) with childhood bronchodilator use and asthma in 257 follow-up children from Wisconsin and Iowa neonatal intensive care units, FHA by radiographic diagnosis Bronchodilator use up to age 2 years 95% Clt Asthma after age 2 years 95% Cl Radiographic evidence of BPDt No radiographic evidence of BPD or no radiographic taken No radiographic or imputed evidence of BPD * Adjusted for birth weight, gestational age, sex, race, and neonatal center, t Cl, confidence interval; BPD, bronchopulmonary dysplasia.

6 Very Low Birth Weight Children and Asthma 465 tween FHA and BPD/CLD, and the associations between childhood respiratory outcome and both FHA and BPD/CLD. In the case-control study of VLBW and full-term births in the first stage of our study, we found a positive association between family history of asthma and spontaneous preterm labor that fell just short of significance (OR = 1.86, 95 percent CI ). This is well within the confidence interval of Kramer et al. (8), who found a significant association between maternal history of asthma and incidence of preterm labor (OR = 2.3, 95 percent CI ). Furthermore, our result for the odds ratio between family history of asthma and premature birth is almost identical to that of von Mutius et al. (2), who found odds ratios of Considering all the information that is presently available, we conclude that parents with family history of asthma are more likely to give birth to a VLBW infant. In the second stage, we explored associations between family history of asthma and BPD/CLD. We examined five definitions of BPD/CLD based on supplemental oxygen use, ventilatory support, and radiographic changes. The criteria we examined include those most commonly used to diagnose BPD/CLD. We found that none of our BPD/CLD definitions was significantly associated with family history of asthma. This is consistent with the finding of de Winter et al. (4) but inconsistent with findings of Nickerson and Taussig (1) and von Mutius et al. (2). The current applicability of the results of Nickerson and Taussig (1), as well as those of von Mutius et al. (2), may be questionable. Enormous changes have recently taken place in neonatal intensive care (14), with greatly increased survival of the smallest neonates. The infants in the study by Nickerson and Taussig (1) were of greater gestational age than the infants in our study, and the factors that affected respiratory disease may have been quite different. Currently, BPD/CLD is very rare among infants above 1,500 g birth weight (15). We conclude from our results, together with the results from other studies of more recent VLBW births, that family history of asthma is not associated with BPD/CLD. Hagan et al. (5) also addressed the above issue and reported an association between family history of asthma and severe CLD, as defined by use of supplemental oxygen at term. However, we did not find family history of asthma to be associated with BPD/ CLD severity as defined by several validated criteria. Hagan et. al. (5) also examined the association between family history of asthma and use of supplemental oxygen at 36 weeks, and found that it did not reach statistical significance. We investigated this association and found very similar results. In the third stage of analysis, we explored associations between family history of asthma, BPD/CLD, and childhood respiratory outcome. To examine these associations, we recorded bronchodilator use up to age 2 years and diagnosis of asthma after age 2 years. Three of the five definitions of BPD/CLD showed significant associations with both childhood bronchodilator use and childhood diagnosis of asthma. Radiographic evidence of BPD was most strongly associated with both childhood respiratory disease indicators. We conclude that BPD/CLD is associated with childhood asthma, a finding also reported by Giffin et al. (6) and de Winter et al. (4). Finally, we explored possible associations between family history of asthma and childhood respiratory outcome. There was a significant interaction effect that indicated differing associations of family history of asthma with childhood asthma among infants with and without radiographic evidence of BPD. When we analyzed these subgroups separately, we observed an association between family history of asthma and childhood asthma among the group without radiographic evidence of BPD. Our findings imply that family history of asthma plays a role in both premature birth and childhood asthma among VLBW children. However, the incidence of BPD/CLD does not appear to be associated with family history of asthma. Further research concerning the associations between family history of asthma, premature labor, and prolonged use of supplemental oxygen should address questions of mechanism. The associations we found are weak, but significant results have been found in several other observational studies. ACKNOWLEDGMENTS This research was supported by grant nos. R01 HL38149 from the National Heart, Lung and Blood Institute and M01 RR03186 from the National Center for Research Resources. The authors thank the following collaborators: Debra Gabbert (University of Wisconsin); Dr. Christina Iyama, Nan Peterson, Deb Kessel, Dare Desnoyers (Meriter Hospital, Madison, WI); Dr. Margie Boyles, Suzann Wong, Sharon Nelson, Tamela Kloehn, Sally Sobel (Sinai-Samaritan Medical Center, Milwaukee, WI); Dr. Paul Myers, Cindy Wierichs, Pamela Verhagen (Theda Clark Hospital, Neenah, WI); Dr. Gail McGuinness, Irma Kromer (University of Iowa, Iowa City, IA); Dr. James Opitz, Joan Filbin (St. Joseph's Hospital, Marshfield, WI); Dr. David Samuels, Sue Volmer, Lana Reinke, Linda Pratt, Marsha Dvorak, Mary Anne Holmes, Susan Coppernoll (St. Vincent Hospital, Green Bay, WI); and Laura Ziebarth, Diane Buss,

7 466 Evans et al. Marsha Miller (St. Mary's Hospital, Madison, WI). They also thank Dr. Raul Mercer for his contributions to this research project. REFERENCES 1. Nickerson BJ, Taussig LM. Family history of asthma in infants with bronchopulmonary dysplasia. Pediatrics 1980;65: von Mutius E, Nicolai T, Martinez FD. Prematurity as a risk factor for asthma in preadolescent children. J Pediatr 1993; 123: Chan KN, Noble-Jamieson CM, Elliman A, et al. Airway responsiveness in low birthweight children and their mothers. Arch Dis Child 1988,63: de Winter JP, van Sonderen L, van den Anker JN, et al. Respiratory illness in families of preterm infants with chronic lung disease. Arch Dis Child 1995;73:F147-F Hagan R, Minutillo C, French N, et al. Neonatal chronic lung disease, oxygen dependency and a family history of asthma. Pediatr Pulmonol 1995,20: Giffin F, Greenough A, Yuksel B. Prediction of respiratory morbidity in the third year of life in children born prematurely. Acta Paediatr 1994;83: Bertrand J-M, Riley SP, Popkin J, et al. The long-term pulmonary sequelae of prematurity: the role of familial airway hyperreactivity and the respiratory distress syndrome. N Engl J Med 1985;312: Kramer MS, Coates AL, Michoud M-C, et al. Maternal asthma and idiopathic preterm labor. Am J Epidemiol 1995; 142: Ballard JL, Novak KK, Driver M. A simplified score for assessment of fetal maturation of newly born infants. J Pediatr 1979;95: Palta M, Gabbert D, Fryback D, et al. Development and validation of an index for scoring baseline respiratory disease in the very low birth weight neonate. Pediatrics 1990;86: Weinstein MR, Peters ME, Sadek M, et al. A new radiographic scoring system for bronchopulmonary dysplasia. Pediatr Pulmonol 1994;18: Edwards DK. Radiology of hyaline membrane disease, transient tachypnea of the newborn and bronchopulmonary dysplasia. In: Farrell PM, ed. Lung development: biological and clinical perspectives. New York: Academic Press, 1982: SAS Institute Inc. SAS/STAT user's guide, Version 6, 4th ed, vol 1. Cary, NC: SAS Institute Inc, Horbar JD, Wright EC, Onstad L, et al. Decreasing mortality associated with the introduction of surfactant therapy: an observational study of neonates weighing 601 to 1300 grams at birth. Pediatrics 1993;92: Hodgman JE. Chronic lung disease. In: Avery GB, ed. Neonatology: pathophysiology and management of the newborn. Philadelphia, PA: JB Lippincott Co, 1987: