In a prospective, multicenter cohort of infants hospitalized with bronchiolitis, we found infants born late pre-term (ie, gestational age 34-36.9 weeks) had 35% higher odds of having asthma by age 5 years as compared with infants born at full-term.
Late pre-term births (i.e., gestational age 34-36 weeks) have increased over the past 5 years and, in 2019, represented 7.5% of all U.S. births.(1) Compared with term infants, pre-term infants are at higher risk of both severe bronchiolitis (requiring hospitalization) and childhood asthma.(2) Although infants with severe bronchiolitis have a 3-4 times higher risk of childhood asthma than healthy controls, (3) it remains unclear if late-preterm infants with severe bronchiolitis have a higher risk of developing childhood asthma than term infants. (4) Also unclear is if late pre-term infants’ increased risk for higher severity of illness (i.e., intensive care use) than term infants mediates the relationship between late pre-term birth and asthma.(5) In a prospective, multicenter, U.S.-based, severe bronchiolitis cohort, we addressed these knowledge gaps by examining the association between late pre-term birth and the risk of developing asthma by age 5 years and if intensive care use mediates this association.
Methods
We used data from the 35th Multicenter Airway Research Collaboration (MARC-35) study of infants hospitalized for bronchiolitis. The study design has been described previously.(6–8) In the present analysis, we used gestational age data from medical record review by physicians. We dichotomized the gestational age exposure into late pre-term birth (gestational age of 34-36 weeks) versus early full-term to post-term birth (gestational age ≥37 weeks). Using data reported from biannual parent interviews, we defined the outcome, asthma by age 5 years, as a clinician diagnosis of asthma by age 5 years with either asthma medication use (e.g., bronchodilators, corticosteroids) or asthma-related symptoms between 4.0-4.9 years of age. (6)
Statistical Analyses
Analyses were performed using Stata 14.1 (Stata Corp). Descriptive statistics and bivariate comparisons between participant characteristics and gestational age were analyzed using chi-square and Fisher exact tests, as appropriate. Unadjusted and adjusted associations between gestational age and asthma by age 5 years were assessed using logistic regression modeling. We also evaluated the potential effect of intensive care treatment as a mediator in the association pathway between late pre-term and asthma using generalized structural equation modeling. Intensive care treatment was defined as intensive care unit (ICU) admission and/or receipt of mechanical ventilation (i.e., continuous positive airway pressure [CPAP] or intubation). A sensitivity analysis categorized gestational age into 4 groups: late pre-term (34-36.9 weeks), early full-term (37-38.9 weeks), full-term (39-41.9 weeks), and post-term (≥42 weeks). All adjusted multivariable models accounted for potential site clustering using a clustered sandwich estimator for standard error. Model covariates were selected a priori for inclusion in the model without regard for statistical significance (e.g., age at enrollment, sex, viral etiology). Participant age at enrollment was calculated as age since birth (no correction applied). Statistical significance was defined by two-sided P < .05.
Results
Among 921 infants enrolled in the longitudinal MARC-35 cohort, 853 (93%) had gestational age data. We excluded 17 early pre-term births (<34 weeks) from the analyses. Among the remaining 836 participants, 130/836 (16%) were late pre-term and 706/836 (84%) were early full-term to post term (Table I). Moreover, late pre-term infants were more likely to require intensive care treatment than full-term infants (22% vs 14%; P=0.04). The prevalence of asthma by age 5 years was 40/130 (31%) among late pre-term and 173/706 (25%) among early full-term to post term birth infants (P=0.11).
Table 1.
Baseline characteristics of infants, by gestational age of late pre-term birth and early full-term to post-term birth, n=836
| Characteristics | Overall, n=836 | Gestational age | ||
|---|---|---|---|---|
| Late pre-term (34-36.9 weeks), n=130 |
Full-term (≥37 weeks), n=706 |
P-value* | ||
| Child demographics | ||||
| Age at enrollment | 0.04 | |||
| <2 months | 249 (30) | 29 (22) | 220 (31) | |
| ≥2 months | 587 (70) | 101 (78) | 486 (69) | |
| Sex | 0.13 | |||
| Female | 346 (41) | 46 (35) | 300 (42) | |
| Male | 490 (59) | 84 (65) | 406 (58) | |
| Race/ethnicity | 0.32 | |||
| Non-Hispanic white | 369 (44) | 48 (37) | 321 (45) | |
| Non-Hispanic black | 188 (22) | 31 (24) | 157 (22) | |
| Hispanic | 246 (30) | 45 (35) | 201 (29) | |
| Other | 33 (4) | 6 (5) | 27 (4) | |
| Health insurance | 0.10 | |||
| Public or none | 490 (59) | 85 (65) | 405 (58) | |
| Private | 344 (41) | 45 (35) | 299 (42) | |
| Estimated median household income by ZIP code at enrollment | 0.11 | |||
| <$40,000 | 282 (34) | 54 (42) | 228 (32) | |
| $40,000-79,999 | 455 (54) | 64 (49) | 391 (56) | |
| ≥80,000 | 99 (12) | 12 (9) | 87 (12) | |
| Parental Characteristics | ||||
| Maternal age when child was born | 0.06 | |||
| <25 | 250 (30) | 35 (27) | 215 (30) | |
| 25-29 | 248 (30) | 31 (24) | 217 (31) | |
| 30-34 | 199 (24) | 33 (25) | 166 (24) | |
| ≥35 | 137 (16) | 31 (24) | 106 (15) | |
| Maternal history of asthma | 0.39 | |||
| Yes | 180 (22) | 32 (25) | 148 (21) | |
| No | 648 (78) | 98 (75) | 550 (79) | |
| Maternal history of eczema | 0.26 | |||
| Yes | 108 (13) | 13 (10) | 95 (14) | |
| No | 720 (87) | 117 (90) | 603 (86) | |
| Child Characteristics | ||||
| Maternal smoking during pregnancy | 0.23 | |||
| Yes | 119 (14) | 96 (14) | 23 (18) | |
| No | 706 (86) | 600 (86) | 106 (82) | |
| Palivizumab administration | <0.001 | |||
| Yes | 23 (3) | 10 (8) | 13 (2) | |
| No | 707 (85) | 97 (75) | 610 (86) | |
| Unknown | 106 (13) | 23 (18) | 83 (12) | |
| Breastfeed from birth to 3mo | 0.37 | |||
| Yes | 375 (45) | 324 (46) | 51 (39) | |
| No | 403 (48) | 334 (47) | 69 (53) | |
| Respiratory syncytial virus | 0.55 | |||
| Yes | 692 (83) | 582 (82) | 110 (85) | |
| No | 144 (17) | 124 (18) | 20 (15) | |
| Rhinovirus | 0.34 | |||
| Yes | 161 (19) | 132 (19) | 29 (22) | |
| No | 675 (81) | 574 (81) | 101 (78) | |
| Intensive care treatment† | 0.04 | |||
| Yes | 130 (16) | 28 (22) | 102 (14) | |
| No | 706 (84) | 102 (78) | 604 (86) | |
| Asthma by age 5 years | 0.11 | |||
| Yes | 213 (25) | 40 (31) | 173 (25) | |
| No | 572 (68) | 81 (62) | 491 (70) | |
| Unknown | 51 (6) | 9 (7) | 42 (6) | |
Results reported as n (%).
All of the P-values obtained by excluding participants with any missing data using chi-2 and Fischer’s exact test, as appropriate.
Intensive care treatment defined as ICU admission and/or receipt of mechanical ventilation (i.e., continuous positive airway pressure [CPAP] or intubation).
In unadjusted analyses, late pre-term birth was associated with a higher risk of developing asthma by age 5 years (OR 1.40, 95%CI 1.01-1.94, P=0.04; Table 2). Though intensive care treatment temporally occurred between the exposure, pre-term birth and the outcome, asthma by 5 years, ICU treatment was not found to mediate their association (OR: 1.11, 95%CI 0.88-1.39). After adjusting for 13 covariates including parental asthma and intensive care use, participants born late pre-term had 35% higher odds of developing asthma by age 5 years (OR 1.35, 95%CI 1.04-1.75, P=0.02; Table 2). Furthermore, in a sensitivity analysis adjusting for more granular gestational age categories, the association of late pre-term birth with asthma by age 5 years remained significant (OR 1.33, 95%CI 1.02-1.74, P=0.04; Table 2).
Table 2.
Unadjusted and adjusted logistic regression models for asthma by age 5 years
| Gestational age exposure | Unadjusted models | Adjusted models* | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95% CI | P-value | |
| Gestational age | ||||||
| Late pre-term birth (34-36 weeks) | 1.40 | 1.01-1.94 | 0.04 | 1.35 | 1.04-1.75 | 0.02 |
| Full-term (≥37 weeks) | 1.0 (ref) | 1.0 (ref) | ||||
| Gestational age - granular categories | ||||||
| Late pre-term (34-36 weeks) | 1.43 | 1.08-1.90 | 0.01 | 1.33 | 1.02-1.74 | 0.04 |
| Early full-term (37-38 weeks) | 1.05 | 0.74-1.47 | 0.80 | 0.96 | 0.67-1.39 | 0.84 |
| Full-term (39-41 weeks) | 1.0 (ref) | 1.0 (ref) | ||||
| Post-term (42+ weeks) | 1.93 | 0.46-8.11 | 0.37 | 1.41 | 0.39-5.11 | 0.60 |
Abbreviations: OR, odds ratio, CI, confidence interval.
Adjusted models are adjusted for: age at enrollment, sex, race/ethnicity, health insurance, median household income estimated by ZIP code at enrollment, maternal smoking during pregnancy, maternal age when child was born, maternal history of asthma, maternal history of eczema, breastfeed from birth to 3 age months, respiratory syncytial virus, rhinovirus, intensive care treatment, and clustering by site.
Discussion
In this severe cohort of subjects with bronchiolitis, late pre-term infants had a 35% higher odds of developing asthma by age 5 years than term infants, even after adjustment for 13 patient covariates and clustering by site. Furthermore, intensive care treatment did not mediate the relationship between late pre-term birth and asthma.
Late pre-term infants are a growing population and at birth they may not have completed alveolarization.(9) This lack of complete lung development places these infants at risk for dysfunctional gas exchange and difficulty breathing during viral respiratory infections due to high chest wall compliance.(9) In a birth cohort (n=232), infants born at 32-35 weeks gestational age were more likely than term infants to develop not only bronchiolitis, but also asthma.(10) Thus, the association between late pre-term birth and asthma may be independent of severe bronchiolitis. Indeed, even healthy infants who had tidal breathing flow-volume loops lower than the median had a higher risk of asthma by age 10 years.(11) Moreover, compared with controls, late pre-term infants given palivizumab had reduced wheezing in the first year of life, but not reduced asthma at age 6 years. (12, 13)Nonetheless, the present results demonstrate that among infants with severe bronchiolitis, those born late pre-term have an even higher risk of asthma than term infants. This finding adds to multiple other clinical and molecular factors associated with acute and chronic respiratory morbidity during and after severe bronchiolitis, including viral etiology of bronchiolitis. (5, 14, 15) One difference between this historical factor and others is late pre-term birth provides an easily identified, growing target group for further research to prevent both severe bronchiolitis and asthma.
This analysis has limitations. There is no standard for making an asthma diagnosis in children under 5 years of age, but results support the use of the epidemiologic definition utilized in this analysis. (6) In future work including not only gestational age, but also accounting for events during a neonatal intensive care unit course (e.g., ventilation) will provide a more comprehensive picture of the association between late pre-term birth and asthma. This study was unable to account for any extant pulmonary mechanical problems prior to severe bronchiolitis. Nonetheless, bronchiolitis is the leading cause of infant hospitalization and these infants are at high-risk for asthma.
We have demonstrated that late pre-term birth is independently associated with asthma by age 5 years among infants hospitalized for bronchiolitis. This finding should encourage clinicians caring for these children to be vigilant about future wheezing and asthma. For researchers, these findings should encourage further investigation of pulmonary function testing in this infant population to understand how the mechanical features of premature lungs contribute to both the severity of bronchiolitis and childhood asthma.
Acknowledgments:
We thank the MARC-35 hospitals and research personnel for their dedication to bronchiolitis and asthma research (Appendix; available at www.jpeds.com). We also thank Alkis Togias, MD for his ongoing support.
Supported by the National Institute of Allergy and Infectious Diseases (U01 AI-087881, R01 AI-114552, R01 AI-108588, and R01 AI-127507) and the Office of the Director at the National Institutes of Health (Bethesda, MD) (UG3/UH3 OD-023253). The authors declare no conflicts of interest.
Appendix. Additional Principal Investigators at the 17 participating sites in MARC-35
| Amy D. Thompson, MD | Alfred I. duPont Hospital for Children, Wilmington, DE |
| Federico R. Laham, MD, MS | Arnold Palmer Hospital for Children, Orlando, FL |
| Vincent J. Wang, MD, MHA and Susan Wu, MD | Children’s Hospital of Los Angeles, Los Angeles, CA |
| Michelle B. Dunn, MD and Jonathan M. Spergel, MD, PhD | Children’s Hospital of Philadelphia, Philadelphia, PA |
| Juan C. Celedón, MD, DrPH | Children’s Hospital of Pittsburgh, Pittsburgh, PA |
| Michael R. Gomez, MD, MS-HCA and Nancy R. Inhofe, MD | Children’s Hospital at St. Francis, Tulsa, OK |
| Brian M. Pate, MD | Children’s Mercy Hospital & Clinics, Kansas City, MO |
| Stephen J. Teach, MD, MPH | Children’s National Medical Center, Washington, DC |
| Stephen C. Porter, MD, MSc, MPH and Richard T. Strait, MD | Cincinnati Children’s Hospital and Medical Center, Cincinnati, OH |
| Ilana Y. Waynik, MD | Connecticut Children’s Medical Center, Hartford, CT |
| Sujit S. Iyer, MD | Dell Children’s Medical Center of Central Texas, Austin, TX |
| Ari R. Cohen, MD, Margaret Samuels-Kalow, MD, MPhil, MSHP and Wayne G. Shreffler, MD, PhD | Massachusetts General Hospital, Boston, MA |
| Michelle D. Stevenson, MD, MS | Norton Children’s Hospital and the University of Louisville, Louisville, KY |
| Cindy S. Bauer, MD and Anne K. Beasley, MD | Phoenix Children’s Hospital, Phoenix, AZ |
| Markus Boos, MD, PhD and Thida Ong, MD | Seattle Children’s Hospital, Seattle, WA |
| Charles G. Macias, MD, MPH and Sarah Meskill, MD | Texas Children’s Hospital, Houston, TX |
Footnotes
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