Inflammation induces stunting by lowering bone mass via GH/IGF-1 inhibition in very preterm infants | Pediatric Research – Nature.com

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Pediatric Research volume 94, pages 1136–1144 (2023)Cite this article
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Sustained systemic inflammatory response (SIR) was associated with poor postnatal growth in very preterm infants (VPI). We hypothesize that VPI with sustained SIR will exhibit linear growth retardation related to lower bone mass accrual mediated by GH/IGF-1 axis inhibition at term corrected age (CA).
C-reactive protein (CRP), procalcitonin (PCT), growth hormone (GH), insulin-like growth factor 1 (IGF-1), calcium, phosphorus, alkaline phosphatase, anthropometric, nutritional, neonatal and maternal data were collected prospectively in 23 infants <32 weeks gestational age. Body composition using dual-energy X-ray absorptiometry was performed at term CA. Analysis was undertaken with multiple linear regression models.
At term CA 11 infants with sustained SIR compared with 12 infants without sustained SIR present significantly lower IGF-1, length z-score (LZS), bone mineral content (BMC) and lean mass (LM), and higher GH and fat mass (FM). LZS was associated significantly with PCT, BMC with IGF-1, FM and LM with CRP, GH with bronchopulmonary dysplasia and CRP, and IGF-1 with invasive mechanical ventilation, CRP and PCT.
In addition to the known effect on linear growth failure, sustained SIR induces lower bone mass accrual related to higher GH and lower IGF-1 levels in VPI.
Very preterm infants (VPI) with sustained systemic inflammatory response (SIR) compared with VPI without SIR present stunting, lower bone mass, higher GH and lower IGF-1 levels at term corrected age.
SIR may help to explain the influence of non-nutritional factors on growth and body composition in VPI.
SIR induces postnatal stunting related to lower bone mass accrual via GH/IGF-1 axis inhibition in VPI.
VPI with SIR need special attention to minimize inflammatory stress, which could result in improved postnatal growth.
Research on inflammatory-endocrine interactions involved in the pathophysiology of postnatal stunting is needed as a basis for new interventional approaches.
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The datasets generated during the present study are available to others upon reasonable request via email to the corresponding author.
Johnson, L., Llewellyn, C. H., van Jaarsveld, C. H. M., Cole, T. J. & Wardle, J. Genetic and environmental influences on infant growth: prospective analysis of the gemini twin birth cohort. PLoS One 6, e19918 (2011).
CAS  PubMed  PubMed Central  Google Scholar 
Young, A., Beattie, R. M. & Johnson, M. J. Optimising growth in very preterm infants: reviewing the evidence. Arch. Dis. Child. Fetal Neonatal Ed. 108, 2–9. https://doi.org/10.1136/archdischild-2021-322892 (2023).
Möllers, L. S. et al. Metabolic-endocrine disruption due to preterm birth impacts growth, body composition, and neonatal outcome. Pediatr. Res. 91, 1350–1360 (2022).
PubMed  Google Scholar 
Maitre, L. et al. Human Early Life Exposome (HELIX) study: a European population-based exposome cohort. BMJ Open 8, e021311 (2018).
PubMed  PubMed Central  Google Scholar 
Cuestas, E. et al. Socioeconomic inequalities in low birth weight risk before and during the COVID-19 pandemic in Argentina: a cross-sectional study. Lancet Reg. Health Am. 2, 100049 (2021).
PubMed  PubMed Central  Google Scholar 
Manzar, S. Poor postnatal growth in preterm infants. Acta Paediatr. 111, 1458 (2022).
Ramel, S. E. et al. The relationship of poor linear growth velocity with neonatal illness and two-year neurodevelopment in preterm infants. Neonatology 102, 19–24 (2012).
PubMed  Google Scholar 
Morgan, A. S., Mendonça, M., Thiele, N. & David, A. L. Management and outcomes of extreme preterm birth. BMJ 376, e055924 (2022).
PubMed  PubMed Central  Google Scholar 
Lucaccioni, L., Iughetti, L., Berardi, A. & Predieri, B. Challenges in the growth and development of newborns with extra-uterine growth restriction. Expert Rev. Endocrinol. Metab. 17, 415–423 (2022).
CAS  PubMed  Google Scholar 
Cuestas, E., Aguilera, B., Cerutti, M. & Rizzotti, A. Sustained neonatal inflammation is associated with poor growth in infants born very preterm during the first year of life. J. Pediatr. 205, 91–97 (2019).
PubMed  Google Scholar 
Synnes, A. & Hicks, M. Neurodevelopmental outcomes of preterm children at school age and beyond. Clin. Perinatol. 45, 393–408 (2018).
PubMed  Google Scholar 
Bavineni, M. et al. Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood. Eur. Heart J. 40, 1107–1112 (2019).
CAS  PubMed  PubMed Central  Google Scholar 
Forbes, G. B. Relation of lean body mass to height in children and adolescents. Pediatr. Res. 6, 32–37 (1972).
CAS  PubMed  Google Scholar 
Belfort, M. B. et al. Systemic inflammation in the first 2 weeks after birth as a determinant of physical growth outcomes in hospitalized infants with extremely low gestational age. J. Pediatr. 240, 37–43.e1 (2022).
CAS  PubMed  Google Scholar 
Pfister, K. M. & Ramel, S. E. Linear growth and neurodevelopmental outcomes. Clin. Perinatol. 41, 309–321 (2014).
PubMed  Google Scholar 
Bell, K. A. et al. Body composition measurement for the preterm neonate: using a clinical utility framework to translate research tools into clinical care. J. Perinatol. 42, 1550–1555 https://doi.org/10.1038/s41372-022-01529-9 (2022).
DeBoer, M. D. et al. Mice with infectious colitis exhibit linear growth failure and subsequent catch-up growth related to systemic inflammation and IGF-1. Nutr. Res. 39, 34–42 (2017).
CAS  PubMed  PubMed Central  Google Scholar 
Cirillo, F., Lazzeroni, P., Sartori, C. & Street, M. E. Inflammatory diseases and growth: effects on the GH–IGF axis and on growth plate. Int. J. Mol. Sci. 18, 1878 (2017).
PubMed  PubMed Central  Google Scholar 
DeBoer, M. D. et al. Systemic inflammation, growth factors, and linear growth in the setting of infection and malnutrition. Nutrition 33, 248–253 (2017).
CAS  PubMed  PubMed Central  Google Scholar 
Villar, J. et al. INTERGROWTH-21st very preterm size at birth reference charts. Lancet 387, 844–845 (2016).
PubMed  Google Scholar 
Villar, J. et al. Postnatal growth standards for preterm infants: the Preterm Postnatal Follow-up Study of the INTERGROWTH-21(st) Project. Lancet Glob. Health 3, e681–e691 (2015).
PubMed  Google Scholar 
Mazess, R. B., Barden, H. S., Bisek, J. P. & Hanson, J. Dual-energy x-ray absorptiometry for total-body and regional bone-mineral and soft-tissue composition. Am. J. Clin. Nutr. 51, 1106–1112 (1990).
CAS  PubMed  Google Scholar 
Godang, K. et al. Assessing body composition in healthy newborn infants: reliability of dual-energy x-ray absorptiometry. J. Clin. Densitom. 13, 151–160 (2010).
PubMed  Google Scholar 
ICD-10 Version. https://icd.who.int/browse10/2016/en#/ (2016).
Bell, M. J. et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann. Surg. 187, 1–7 (1978).
CAS  PubMed  PubMed Central  Google Scholar 
Ehrenkranz, R. A. et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 117, 1253–1261 (2006).
PubMed  Google Scholar 
Papile, L. A., Burstein, J., Burstein, R. & Koffler, H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J. Pediatr. 92, 529–534 (1978).
CAS  PubMed  Google Scholar 
Chiang, M. F. et al. International Classification of Retinopathy of Prematurity, Third Edition. Ophthalmology 128, e51–e68 (2021).
PubMed  Google Scholar 
American Academy of Pediatrics. Committee on Nutrition. Nutritional needs of the preterm infant. In Pediatric Nutrition 8th edn (eds Kleinman, R. E. & Greer, F. R.) 113–162 (American Academy of Pediatrics, 2019).
Champely, S. et al. pwr: Basic Functions for Power Analysis (2020).
Kim, S. ppcor: an R package for a fast calculation to semi-partial correlation coefficients. Commun. Stat. Appl. Methods 22, 665–674 (2015).
PubMed  PubMed Central  Google Scholar 
Jafari, M. & Ansari-Pour, N. Why, when and how to adjust your P values?. Cell J. 20, 604–607 (2019).
PubMed  Google Scholar 
Kumar, P. & Seshadri, R. Neonatal morbidity and growth in very low birth-weight infants after multiple courses of antenatal steroids. J. Perinatol. 25, 698–702 (2005).
PubMed  Google Scholar 
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).
CAS  PubMed  PubMed Central  Google Scholar 
Chisholm, K. M., Norton, M. E., Penn, A. A. & Heerema-McKenney, A. Classification of preterm birth with placental correlates. Pediatr. Dev. Pathol. 21, 548–560 (2018).
PubMed  Google Scholar 
Mestan, K. et al. Placental inflammatory response is associated with poor neonatal growth: preterm birth cohort study. Pediatrics 125, e891–898 (2010).
PubMed  Google Scholar 
Scharf, R. J., Stroustrup, A., Conaway, M. R. & DeBoer, M. D. Growth and development in children born very low birthweight. Arch. Dis. Child. Fetal Neonatal Ed. 101, F433–F438 (2016).
PubMed  Google Scholar 
Ballinger, A. B., Azooz, O., El-Haj, T., Poole, S. & Farthing, M. J. Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis. Gut 46, 694–700 (2000).
CAS  PubMed  PubMed Central  Google Scholar 
Zemel, B. S. et al. Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children. J. Clin. Endocrinol. Metab. 95, 1265–1273 (2010).
CAS  PubMed  PubMed Central  Google Scholar 
Heaney, R. P. Bone mineral content, not bone mineral density, is the correct bone measure for growth studies. Am. J. Clin. Nutr. 78, 350–351 (2003).
CAS  PubMed  Google Scholar 
Mølgaard, C., Thomsen, B. L., Prentice, A., Cole, T. J. & Michaelsen, K. F. Whole body bone mineral content in healthy children and adolescents. Arch. Dis. Child. 76, 9–15 (1997).
PubMed  PubMed Central  Google Scholar 
Magnusson, A., Swolin-Eide, D. & Elfvin, A. Body composition and bone mass among 5-year-old survivors of necrotizing enterocolitis. Pediatr. Res. https://doi.org/10.1038/s41390-022-02236-z (2022).
Vohlen, C. et al. Dynamic regulation of GH-IGF1 signaling in injury and recovery in hyperoxia-induced neonatal lung injury. Cells 10, 2947 (2021).
CAS  PubMed  PubMed Central  Google Scholar 
Blair, C. et al. Liver IGF-1 mRNA expression is decreased by mechanical ventilation of preterm lambs. J. Investig. Med. 58, 105–105 (2010).
Google Scholar 
Löfqvist, C. et al. Low postnatal serum IGF-I levels are associated with bronchopulmonary dysplasia (BPD). Acta Paediatr. 101, 1211–1216 (2012).
PubMed  PubMed Central  Google Scholar 
DeBoer, M. D. & Denson, L. A. Delays in puberty, growth, and accrual of bone mineral density in pediatric Crohn’s disease: despite temporal changes in disease severity, the need for monitoring remains. J. Pediatr. 163, 17–22 (2013).
PubMed  PubMed Central  Google Scholar 
Wong, S. C. et al. Growth and the growth hormone-insulin like growth factor 1 axis in children with chronic inflammation: current evidence, gaps in knowledge, and future directions. Endocr. Rev. 37, 62–110 (2016).
CAS  PubMed  Google Scholar 
Kubicky, R. A., Wu, S., Kharitonenkov, A. & De Luca, F. Role of fibroblast growth factor 21 (FGF21) in undernutrition-related attenuation of growth in mice. Endocrinology 153, 2287–2295 (2012).
CAS  PubMed  Google Scholar 
Misra, M. et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J. Clin. Endocrinol. Metab. 88, 5615–5623 (2003).
CAS  PubMed  Google Scholar 
Yumani, D. F. J., Calor, A. K. & van Weissenbruch, M. M. The course of IGF-1 levels and nutrient intake in extremely and very preterm infants during hospitalisation. Nutrients 12, 675 (2020).
CAS  PubMed  PubMed Central  Google Scholar 
Cooke, R. J. & Griffin, I. Altered body composition in preterm infants at hospital discharge. Acta Paediatr. 1992 98, 1269–1273 (2009).
Google Scholar 
Tremblay, G. et al. Body composition in very preterm infants: role of neonatal characteristics and nutrition in achieving growth similar to term infants. Neonatology 111, 214–221 (2017).
CAS  PubMed  Google Scholar 
Moldawer, L. L. & Copeland, E. M. Proinflammatory cytokines, nutritional support, and the cachexia syndrome: interactions and therapeutic options. Cancer 79, 1828–1839 (1997).
CAS  PubMed  Google Scholar 
Roubenoff, R. Inflammatory and hormonal mediators of cachexia. J. Nutr. 127, 1014S–1016S (1997).
CAS  PubMed  Google Scholar 
Giannì, M. L. et al. Adiposity in small for gestational age preterm infants assessed at term equivalent age. Arch. Dis. Child Fetal Neonatal Ed. 94, F368–F372 (2009).
PubMed  Google Scholar 
Sauer, P. J. J. Can extrauterine growth approximate intrauterine growth? Should it? Am. J. Clin. Nutr. 85, 608S–613S (2007).
CAS  PubMed  Google Scholar 
Sethi, J. K. & Vidal-Puig, A. J. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J. Lipid Res. 48, 1253–1262 (2007).
CAS  PubMed  Google Scholar 
Ramel, S. E. et al. Body composition changes in preterm infants following hospital discharge: comparison with term infants. J. Pediatr. Gastroenterol. Nutr. 53, 333–338 (2011).
PubMed  PubMed Central  Google Scholar 
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The authors thank Nicholas Basily for editing the English language of this manuscript.
This study was supported by the Agencia Nacional de Promoción Científica y Tecnológica (FONCYT) grant PICT 2019-3062.
Department of Pediatrics and Neonatology, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
Eduardo Cuestas, Macarena Hillman, Silvia Galetto & Alina Rizzotti
Department of Clinical Biochemistry, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
María Isabel Gaido
Department of Radiology, Instituto Conci–Carpinella, Córdoba, Argentina
Viviana Sobh & Lucrecia Torres Damico
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E.C. conceptualized and designed the study, coordinated and supervised data collection, carried out the final data analyses, drafted the manuscript, and reviewed and revised the final manuscript. M.H., S.G., M.I.G., V.S. and A.R. designed the data collection instruments, manually collected data, carried out the initial analyses, and reviewed and revised the manuscript for important intellectual content. All authors have approved the final manuscript as submitted.
Correspondence to Eduardo Cuestas.
The authors declare no competing interests.
The study was approved by the Institutional Review Board at Hospital Privado Universitario de Córdoba, and the infants’ parents gave written informed consent (HP 4-308). This study used anonymized and deidentified data, fulfilling local data protection regulations.
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Cuestas, E., Hillman, M., Galetto, S. et al. Inflammation induces stunting by lowering bone mass via GH/IGF-1 inhibition in very preterm infants. Pediatr Res 94, 1136–1144 (2023). https://doi.org/10.1038/s41390-023-02559-5
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Received: 31 October 2022
Revised: 13 January 2023
Accepted: 22 February 2023
Published: 20 March 2023
Issue Date: September 2023
DOI: https://doi.org/10.1038/s41390-023-02559-5
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