Abstract
Background
Asthma and obesity are frequent outcomes among individuals born extremely preterm and are associated with decreased lifespan. Neonatal inflammation is associated with chronic neurodevelopmental disorders; however, it is less studied in association with other later childhood chronic disorders in this population.
Methods
Fourteen hospitals in 5 U.S. states enrolled 1506 infants born before 28 weeks of gestation in the Extremely Low Gestational Age Newborn cohort in 2004–2014. Neonatal blood spots were collected on postnatal days 1, 7, 14, 21, and 28, and used to measure 14 inflammation-related proteins. Associations were evaluated between high (top quartile) levels of proteins and two chronic health disorders at ages 10 and 15 years: physician-diagnosed asthma and obesity (body mass index ≥95th percentile).
Results
Few associations were found between high levels of 14 inflammation-related proteins, either on a single day or on multiple days, and either asthma or obesity. Similarly, few associations were found in analyses stratified by sex or presence/absence of prenatal inflammation.
Conclusions
In extremely preterm newborns, systemic elevations of inflammation-related proteins during the neonatal period were not associated with childhood asthma and obesity outcomes at 10 or 15 years of age.
Impact
-
In the large multi-center Extremely Low Gestational Age Newborn (ELGAN) cohort, sustained elevation of neonatal levels of inflammation-related proteins was not consistently associated with asthma or obesity outcomes at 10 or 15 years of age.
-
This finding contrasts with reported associations of perinatal inflammation with obesity at 2 years and neurodevelopmental disorders at 2–15 years in the ELGANs, suggesting that unlike neurodevelopment, peripubertal obesity and asthma may be driven by later childhood exposures.
-
Future research on perinatal mechanisms of childhood asthma and obesity should account for both fetal and later exposures and pathways in addition to inflammation at birth.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 14 print issues and online access
$259.00 per year
only $18.50 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
Data for all variables except 15 year outcomes can be obtained from Archived Clinical Research Datasets | National Institute of Neurological Disorders and Stroke (nih.gov).
Data on 15 year outcomes can be obtained from the public use data set available on the NICDH DASH website.
References
Taylor, G. L. & O’Shea, T. M. Extreme prematurity: risk and resiliency. Curr. Probl. Pediatr. Adolesc. Health Care 52, 101132 (2022).
Korzeniewski, S. J. et al. Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation. Transl. Psychiatry 8, 115 (2018).
Kuban, K. C. et al. Circulating inflammatory-associated proteins in the first month of life and cognitive impairment at age 10 years in children born extremely preterm. J. Pediatr. 180, 116–123.e111 (2017).
Kuban, K. C. et al. The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns. Pediatr. Neurol. 52, 42–48 (2015).
Kuban, K. C. et al. Systemic inflammation and cerebral palsy risk in extremely preterm infants. J. Child Neurol. 29, 1692–1698 (2014).
Kuban, K. C. K. et al. Association of circulating proinflammatory and anti-inflammatory protein biomarkers in extremely preterm born children with subsequent brain magnetic resonance imaging volumes and cognitive function at age 10 years. J. Pediatr. 210, 81–90.e83 (2019).
Leviton, A. et al. Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage. Eur. J. Paediatr. Neurol. 22, 440–450 (2018).
Leviton, A. et al. Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm. Int. J. Dev. Neurosci. 66, 45–53 (2018).
Leviton, A. et al. Executive dysfunction early postnatal biomarkers among children born extremely preterm. J. Neuroimmune Pharmacol. 14, 188–199 (2019).
Leviton, A. et al. Early postnatal blood concentrations of inflammation-related proteins and microcephaly two years later in infants born before the 28th post-menstrual week. Early Hum. Dev. 87, 325–330 (2011).
Leviton, A. J. et al. The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm. Cytokine 110, 181–188 (2018).
O’Shea, T. M. et al. Elevated concentrations of inflammation-related proteins in postnatal blood predict severe developmental delay at 2 years of age in extremely preterm infants. J. Pediatr. 160, 395–401 (2012).
O’Shea, T. M. et al. Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants. Brain Behav. Immun. 29, 104–112 (2013).
Perrin, E. M. et al. Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature. Pediatr. Res. 83, 1110–1119 (2018).
van der Burg, J. W. et al. Is maternal obesity associated with sustained inflammation in extremely low gestational age newborns? Early Hum. Dev. 89, 949–955 (2013).
Hecht, J. et al. Relationship between neonatal blood protein profiles and placenta histologic characteristics in ELGANs. Pediatr. Res. 69, 68–73 (2010).
Wood, C. T. et al. Antecedents of obesity among children born extremely preterm. Pediatrics 142, e20180519 (2018).
O’Shea, T. M. et al. Growth during infancy after extremely preterm birth: Associations with later neurodevelopmental and health outcomes. J. Pediatr. 252, 40–47 (2023).
Fleiss, B. et al. Inflammation-induced sensitization of the brain in term infants. Dev. Med. Child Neurol. 57, 17–28 (2015).
Hagberg, H., Dammann, O., Mallard, C. & Leviton, A. Preconditioning and the developing brain. Semin. Perinatol. 28, 389–395 (2004).
Martin, E. et al. Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period. Epigenomics 9, 267–278 (2017).
Lertxundi, A. et al. Prenatal exposure to PM2.5 and NO2 and sex-dependent infant cognitive and motor development. Environ. Res. 174, 114–121 (2019).
Sutherland, S. & Brunwasser, S. M. Sex differences in vulnerability to prenatal stress: a review of the recent literature. Curr. Psychiatry Rep. 20, 102 (2018).
Bruce, M. et al. Acute peripheral immune activation alters cytokine expression and glial activation in the early postnatal rat brain. J. Neuroinflammation 16, 200 (2019).
Clifton, V. L. Review: sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 31, S33–S39 (2010).
Desrochers-Couture, M. et al. Prenatal, concurrent, and sex-specific associations between blood lead concentrations and IQ in preschool Canadian children. Environ. Int. 121, 1235–1242 (2018).
O’Shea, T. M. et al. The ELGAN study of the brain and related disorders in extremely low gestational age newborns. Early Hum. Dev. 85, 719–725 (2009).
McElrath, T. F. et al. Pregnancy disorders that lead to delivery before the 28th week of gestation: an epidemiologic approach to classification. Am. J. Epidemiol. 168, 980–989 (2008).
Hecht, J. L. et al. Histological characteristics of singleton placentas delivered before the 28th week of gestation. Pathology 40, 372–376 (2008).
Onderdonk, A. B., Delaney, M. L., Dubois, A. M., Allred, E. N. & Leviton, A. Detection of bacteria in placental tissues obtained from extremely low gestational age neonates. Am. J. Obstet. Gynecol. 198, e1–e7 (2008).
Yudkin, P. L., Aboualfa, M., Eyre, J. A., Redman, C. W. G. & Wilkinson, A. R. New birth-weight and head circumference centiles for gestational ages 24 to 42 weeks. Early Hum. Dev. 15, 45–52 (1987).
Fichorova, R. N. et al. Maternal microbe-specific modulation of inflammatory response in extremely low-gestational-age newborns. Mbio 2, e00280–00210 (2011).
Fichorova, R. N. et al. Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: a multicenter study. Anal. Chem. 80, 4741–4751 (2008).
Leviton, A. et al. Inflammation-related proteins in the blood of extremely low gestational age newborns. The contribution of inflammation to the appearance of developmental regulation. Cytokine 53, 66–73 (2011).
Kuczmarski, R. J. et al. 2000 CDC growth charts for the United States: methods and development. Vital-. Health Stat. 11, 1–190 (2002).
Allred, E. N. et al. Systemic inflammation during the first postnatal month and the risk of attention deficit hyperactivity disorder characteristics among 10 year-old children born extremely preterm. J. Neuroimmune Pharm. 12, 531–543 (2017).
Kuban, K. C. K. et al. Among children born extremely preterm a higher level of circulating neurotrophins is associated with lower risk of cognitive impairment at school age. J. Pediatr. 201, 40–48.e44 (2018).
Leviton, A. et al. Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation. Pediatr. Res. 73, 362–370 (2013).
O’Shea, T. M. et al. Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 mo in extremely preterm infants. Pediatr. Res. 75, 781–787 (2014).
Carlo, W. A. et al. Cytokines and neurodevelopmental outcomes in extremely low birth weight infants. J. Pediatr. 159, 919–U977 (2011).
Hansen-Pupp, I. et al. Inflammation at birth is associated with subnormal development in very preterm infants. Pediatr. Res. 64, 183–188 (2008).
Hansen-Pupp, I. et al. Circulating interferon-gamma and white matter brain damage in preterm infants. Pediatr. Res. 58, 946–952 (2005).
Bangma, J. T., Hartwell, H., Santos, H. P. Jr., O’Shea, T. M. & Fry, R. C. Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm. Pediatr. Res. 89, 326–335 (2021).
Eklind, S., Mallard, C., Arvidsson, P. & Hagberg, H. Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain. Pediatr. Res. 58, 112–116 (2005).
Mallard, C. & Hagberg, H. Inflammation-induced preconditioning in the immature brain. Semin. Fetal Neonatal Med. 12, 280–286 (2007).
Yanni, D. et al. Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns. Pediatr. Res. 82, 691–696 (2017).
Korzeniewski, S. J. et al. A “multi-hit” model of neonatal white matter injury: cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events. J. Perinat. Med. 42, 731–743 (2014).
Kuban, K. C. et al. Girls and boys born before 28 weeks gestation: risks of cognitive, behavioral, and neurologic outcomes at age 10 years. J. Pediatr. 173, 69–75 e61 (2016).
Leviton, A. et al. Socioeconomic status and early blood concentrations of inflammation-related and neurotrophic proteins among extremely preterm newborns. PLoS One 14, e0214154 (2019).
Bose, C. et al. Systemic inflammation associated with mechanical ventilation among extremely preterm infants. Cytokine 61, 315–322 (2013).
Leviton, A. et al. Systemic responses of preterm newborns with presumed or documented bacteraemia. Acta Paediatr. 101, 355–359 (2012).
Leviton, A. et al. Systemic inflammation, intraventricular hemorrhage, and white matter injury. J. Child Neurol. 28, 1637–1645 (2013).
Jackson, W. M. et al. Risk factors for chronic lung disease and asthma differ among children born extremely preterm. Pediatr. Pulmonol. 53, 1533–1540 (2018).
Miller, G. E., Chen, E. & Parker, K. J. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol. Bull. 137, 959–997 (2011).
Dankhara, N., Holla, I., Ramarao, S. & Kalikkot Thekkeveedu, R. Bronchopulmonary dysplasia: pathogenesis and pathophysiology. J. Clin. Med. 12, 4207 (2023).
Visness, C. M. et al. Asthma as an outcome: exploring multiple definitions of asthma across birth cohorts in the Environmental Influences on Child Health Outcomes Children’s Respiratory and Environmental Workgroup. J. Allergy Clin. Immunol. 144, 866–869.e864 (2019).
Van Wonderen, K. E. et al. Different definitions in childhood asthma: how dependable is the dependent variable? Eur. Respir. J. 36, 48–56 (2010).
Canova, C. et al. Epidemiological measures of childhood asthma: cross-sectional and longitudinal consistency. Respir. Med. 106, 1226–1235 (2012).
Funding
This study was supported by grants from the National Institute of Neurological Disorders and Stroke (5U01NS040069-05 to Alan Leviton; 2R01NS040069-06A2 to K.C.K.), the Office of the NIH Director (1UG3OD023348-01 to T.M.O.), National Heart Lung and Blood Institute (K23HL148394 to A.M. South; L40HL148910 to A.M. South; R01HL146818 to L. Washburn; R01HL164434 to S. Cilvik). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Author information
Authors and Affiliations
Consortia
Contributions
Crisma Emmanuel made substantial contributions to analysis and interpretation of data, drafting and revising the article critically for important intellectual content, and approved the version submitted for publication. Ali Oran, made substantial contributions to analysis and interpretation of data, revising the article critically for important intellectual content, and approved the version submitted for publication. Elizabeth T. Jensen made substantial contributions to conception and design, analysis and interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Raina N. Fichorova made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. William A. Gower made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Eliana M. Perrin made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Keia Sanderson made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Andrew M. South made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Semsa Gogcu made substantial contributions to conception and design, acquisition of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Jeffrey Shenberger made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Rachana Singh made substantial contributions to conception and design, acquisition of data, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Kartikeya Makker made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Amanda L. Thompson made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Hudson Santos made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. Rebecca C. Fry made substantial contributions to conception and design, interpretation of data, and revising the article critically for important intellectual content, and approved the version submitted for publication. T. Michael O’Shea made substantial contributions to conception and design, acquisition of data, analysis, and interpretation of data, drafting and revising the article critically for important intellectual content, and approved the version submitted for publication.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Content to participate
For collection of obstetrical and neonatal data for study participants, mothers provided signed informed consent. For collection of outcome data at 10 and 15 years, a parent or legal guardian provided signed informed consent and children provided assent. Consent and assent procedures were approved by institutional review board at each of 14 enrollment sites (maternal and neonatal data) and 12 follow up sites (10 and 15 year data).
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Emmanuel, C., Oran, A., Jensen, E.T. et al. Neonatal inflammation and its association with asthma and obesity in late childhood among individuals born extremely preterm. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03325-x
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41390-024-03325-x
