Insulin-Like Growth Factor-1 Levels in Term Newborns with Hypoxic–Ischemic Encephalopathy

Abstract

Objective This study aims to evaluate the correlation of changes in serum insulin-like growth factor-1 (IGF-1) levels with the clinical staging of hypoxic–ischemic encephalopathy (HIE) in term newborns.

Study Design A prospective study of 29 newborns with HIE (stage I = 15, stage II + III = 14) and 28 healthy term newborns as the control group was performed in the neonatal intensive care unit. IGF-1 levels were obtained within 6 hours after birth from HIE and control groups and again on day 3 from HIE group. HIE was classified using the Sarnat staging I to III.

Results IGF-1 levels were significantly lower in the HIE group than in the control group (p = 0.024). It was lower in the HIE stage II to III group compared with HIE stage I group at birth (p < 0.0001) and on day 3 (p = 0.009). The mean IGF-1 levels were significantly higher on day 3 than on day 1 among stage II to III HIE (p = 0.006) and it was inversely correlated with staging (R =  − 0.475, p = 0.009). There was a significant correlation between IGF-1 levels and Apgar score at 5 (R = 0.39, p = 0.042) and 10 minutes (R = 0.38, p = 0.035).

Conclusions IGF-1 was lower in HIE and inversely correlated with clinical staging. It was increased with clinical improvement in the subsequent days.

Keywords

insulin-like growth factor-1 - IGF-1 - hypoxic–ischemic encephalopathy - HIE - birth asphyxia

• References

• 1 Herrera-Marschitz M, Neira-Peña T, Rojas-Mancilla E , et al. Short- and long-term consequences of perinatal asphyxia: looking for neuroprotective strategies. Adv Neurobiol 2015; 10: 169-198
• 2 Aridas JD, Yawno T, Sutherland AE , et al. Detecting brain injury in neonatal hypoxic ischemic encephalopathy: closing the gap between experimental and clinical research. Exp Neurol 2014; 261: 281-290
• 3 Vannucci RC. Mechanisms of perinatal hypoxic-ischemic brain damage. Semin Perinatol 1993; 17 (5) 330-337
• 4 Morales P, Bustamante D, Espina-Marchant P , et al. Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes?. EPMA J 2011; 2 (2) 211-230
• 5 Smith PF. Neuroprotection against hypoxia-ischemia by insulin-like growth factor-I (IGF-I). IDrugs 2003; 6 (12) 1173-1177
• 6 D'Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G. The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 1996; 13 (3) 227-255
• 7 Dinleyici EC, Tekin N, Colak O, Aksit MA. Cord blood IGF-1 and IGFBP-3 levels in asphyxiated term newborns. Neuroendocrinol Lett 2006; 27 (6) 745-747
• 8 Satar M, Ozcan K, Yapicioğlu H, Narli N. Serum insulin-like growth factor 1 and growth hormone levels of hypoxic-ischemic newborns. Biol Neonate 2004; 85 (1) 15-20
• 9 Clawson TF, Vannucci SJ, Wang GM, Seaman LB, Yang XL, Lee WH. Hypoxia-ischemia-induced apoptotic cell death correlates with IGF-I mRNA decrease in neonatal rat brain. Biol Signals Recept 1999; 8 (4–5) 281-293
• 10 Prévot A, Julita M, Tung DK, Mosig D. Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit. Pediatr Nephrol 2009; 24 (5) 973-981
• 11 Johnston BM, Mallard EC, Williams CE, Gluckman PD. Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs. J Clin Invest 1996; 97 (2) 300-308
• 12 George S, Bennet L, Weaver-Mikaere L , et al. White matter protection with insulin-like growth factor 1 and hypothermia is not additive after severe reversible cerebral ischemia in term fetal sheep. Dev Neurosci 2011; 33 (3–4) 280-287
• 13 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol 1976; 33 (10) 696-705
• 14 Brywe KG, Mallard C, Gustavsson M , et al. IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?. Eur J Neurosci 2005; 21 (6) 1489-1502
• 15 Dluzniewska J, Sarnowska A, Beresewicz M , et al. A strong neuroprotective effect of the autonomous C-terminal peptide of IGF-1 Ec (MGF) in brain ischemia. FASEB J 2005; 19 (13) 1896-1898
• 16 Guan J, Bennet L, Gluckman PD, Gunn AJ. Insulin-like growth factor-1 and post-ischemic brain injury. Prog Neurobiol 2003; 70 (6) 443-462
• 17 Aperghis M, Johnson IP, Cannon J, Yang SY, Goldspink G. Different levels of neuroprotection by two insulin-like growth factor-I splice variants. Brain Res 2004; 1009 (1–2) 213-218
• 18 Musarò A, Dobrowolny G, Rosenthal N. The neuroprotective effects of a locally acting IGF-1 isoform. Exp Gerontol 2007; 42 (1–2) 76-80
• 19 Beresewicz M, Majewska M, Makarewicz D, Vayro S, Zabłocka B, Górecki DC. Changes in the expression of insulin-like growth factor 1 variants in the postnatal brain development and in neonatal hypoxia-ischaemia. Int J Dev Neurosci 2010; 28 (1) 91-97
• 20 Wang JM, Hayashi T, Zhang WR, Li F, Iwai M, Abe K. Reduction of ischemic damage by application of insulin-like growth factor-1 in rat brain after transient ischemia. Acta Med Okayama 2001; 55 (1) 25-30
• 21 Brywe KG, Leverin AL, Gustavsson M , et al. Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation. Endocrinology 2005; 146 (11) 4665-4672
• 22 Dodge JC, Haidet AM, Yang W , et al. Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity. Mol Ther 2008; 16 (6) 1056-1064
• 23 Zhu W, Fan Y, Frenzel T , et al. Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice. Stroke 2008; 39 (4) 1254-1261
• 24 Lin S, Fan LW, Pang Y, Rhodes PG, Mitchell HJ, Cai Z. IGF-1 protects oligodendrocyte progenitor cells and improves neurological functions following cerebral hypoxia-ischemia in the neonatal rat. Brain Res 2005; 1063 (1) 15-26
• 25 Trejo JL, Llorens-Martín MV, Torres-Alemán I. The effects of exercise on spatial learning and anxiety-like behavior are mediated by an IGF-I-dependent mechanism related to hippocampal neurogenesis. Mol Cell Neurosci 2008; 37 (2) 402-411
• 26 Wood TL, Loladze V, Altieri S , et al. Delayed IGF-1 administration rescues oligodendrocyte progenitors from glutamate-induced cell death and hypoxic-ischemic brain damage. Dev Neurosci 2007; 29 (4–5) 302-310
• 27 Martín-Ancel A, García-Alix A, Pascual-Salcedo D, Cabañas F, Valcarce M, Quero J. Interleukin-6 in the cerebrospinal fluid after perinatal asphyxia is related to early and late neurological manifestations. Pediatrics 1997; 100 (5) 789-794
• 28 van Bel F, Dorrepaal CA, Benders MJ, Zeeuwe PE, van de Bor M, Berger HM. Changes in cerebral hemodynamics and oxygenation in the first 24 hours after birth asphyxia. Pediatrics 1993; 92 (3) 365-372
• 29 Nagdyman N, Grimmer I, Scholz T, Muller C, Obladen M. Predictive value of brain-specific proteins in serum for neurodevelopmental outcome after birth asphyxia. Pediatr Res 2003; 54 (2) 270-275
• 30 Golubnitschaja O, Yeghiazaryan K, Cebioglu M, Morelli M, Herrera-Marschitz M. Birth asphyxia as the major complication in newborns: moving towards improved individual outcomes by prediction, targeted prevention and tailored medical care. EPMA J 2011; 2 (2) 197-210
• 31 Guitelman M, Smithuis F, Garcia Basavilbaso N, Aranda C, Fabre B, Oneto A. Reference ranges for an automated chemiluminescent assay for serum insulin-like growth factor I (IGF-I) in a large population of healthy adults from Buenos Aires. J Endocrinol Invest 2015; 38 (9) 951-956
• 32 Shankaran S, Pappas A, McDonald SA , et al; Eunice Kennedy Shriver NICHD Neonatal Research Network. Childhood outcomes after hypothermia for neonatal encephalopathy. N Engl J Med 2012; 366 (22) 2085-2092
• 33 Azzopardi D, Strohm B, Marlow N , et al; TOBY Study Group. Effects of hypothermia for perinatal asphyxia on childhood outcomes. N Engl J Med 2014; 371 (2) 140-149
• 34 Jacobs SE, Morley CJ, Inder TE , et al; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med 2011; 165 (8) 692-700
• 35 Kim JJ, Buchbinder N, Ammanuel S , et al. Cost-effective therapeutic hypothermia treatment device for hypoxic ischemic encephalopathy. Med Devices (Auckl) 2013; 6: 1-10