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Increasing F2-isoprostanes in the first month after birth predicts poor respiratory and neurodevelopmental outcomes in very preterm infants

Journal of Perinatology volume 36, pages 779–783 (2016)Cite this article

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Abstract

Objective:

This study examined the association between increased early oxidative stress, measured by F2-isoprostanes (IsoPs), and respiratory morbidity at term equivalent age and neurological impairment at 12 months of corrected age (CA).

Study Design:

Plasma samples were collected from 136 premature infants on days 14 and 28 after birth. All participants were infants born at ⩽28 weeks of gestational age enrolled into the Prematurity and Respiratory Outcomes Program (PROP) study. Respiratory morbidity was determined at 40 weeks of postmenstrual age (PMA) by the Respiratory Severity Index (RSI), a composite measure of oxygen and pressure support. Neurodevelopmental assessment was performed using the Developmental Assessment of Young Children (DAYC) at 12 months of CA. Multivariable logistic regression models estimated associations between IsoP change, RSI and DAYC scores. Mediation analysis was performed to determine the relationship between IsoPs and later outcomes.

Results:

Developmental data were available for 121 patients (90% of enrolled) at 12 months. For each 50-unit increase in IsoPs, regression modeling predicted decreases in cognitive, communication and motor scores of −1.9, −1.2 and −2.4 points, respectively (P<0.001). IsoP increase was also associated with increased RSI at 40 weeks of PMA (odds ratio=1.23; P=0.01). RSI mediated 25% of the IsoP effect on DAYC motor scores (P=0.02) and had no significant impact on cognitive or communication scores.

Conclusions:

In the first month after birth, increases in plasma IsoPs identify preterm infants at risk for respiratory morbidity at term equivalent age and worse developmental outcomes at 12 months of CA. Poor neurodevelopment is largely independent of respiratory morbidity.

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References

  1. Anderson PJ, Doyle LW . Neurodevelopmental outcome of bronchopulmonary dysplasia. Semin Perinatol 2006; 30: 227–232.

    Article  Google Scholar 

  2. Natarajan G, Pappas A, Shankaran S, Kendrick DE, Das A, Higgins RD et al. Outcomes of extremely low birth weight infants with bronchopulmonary dysplasia: impact of the physiologic definition. Early Hum Dev 2012; 88: 509–515.

    Article  Google Scholar 

  3. Short EJ, Klein NK, Lewis BA, Fulton S, Eisengart S, Kercsmar C et al. Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics 2003; 112: e359.

    Article  Google Scholar 

  4. Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS, Whitfield MF et al. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003; 289: 1124–1129.

    Article  Google Scholar 

  5. Doyle LW, Anderson PJ . Long-term outcomes of bronchopulmonary dysplasia. Semin Fetal Neonatal Med 2009; 14: 391–395.

    Article  Google Scholar 

  6. Kobaly K, Schluchter M, Minich N, Friedman H, Taylor HG, Wilson-Costello D et al. Outcomes of extremely low birth weight (&lt;1 kg) and extremely low gestational age (&lt;28 weeks) infants with bronchopulmonary dysplasia: effects of practice changes in 2000 to 2003. Pediatrics 2008; 121: 73–81.

    Article  Google Scholar 

  7. Trittmann JK, Nelin LD, Klebanoff MA . Bronchopulmonary dysplasia and neurodevelopmental outcome in extremely preterm neonates. Eur J Pediatr 2013; 172: 1173–1180.

    Article  CAS  Google Scholar 

  8. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005; 116: 1353–1360.

    Article  Google Scholar 

  9. Back SA, Luo NL, Mallinson RA, O'Malley JP, Wallen LD, Frei B et al. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann Neurol 2005; 58: 108–120.

    Article  CAS  Google Scholar 

  10. Saugstad OD . Bronchopulmonary dysplasia-oxidative stress and antioxidants. Semin Neonatol 2003; 8: 39–49.

    Article  Google Scholar 

  11. Perrone S, Tataranno LM, Stazzoni G, Ramenghi L, Buonocore G . Brain susceptibility to oxidative stress in the perinatal period. J Matern Fetal Neonatal Med 2015; 28 (Suppl 1): 2291–2295.

    Article  Google Scholar 

  12. Inder T, Mocatta T, Darlow B, Spencer C, Volpe JJ, Winterbourn C . Elevated free radical products in the cerebrospinal fluid of VLBW infants with cerebral white matter injury. Pediatr Res 2002; 52: 213–218.

    Article  CAS  Google Scholar 

  13. Perrone S, Tataranno ML, Buonocore G . Oxidative stress and bronchopulmonary dysplasia. J Clin Neonatol 2012; 1: 109–114.

    Article  Google Scholar 

  14. Davis JM, Auten RL . Maturation of the antioxidant system and the effects on preterm birth. Semin Fetal Neonatal Med 2010; 15: 191–195.

    Article  Google Scholar 

  15. Montuschi P, Barnes PJ, Roberts LJ . Isoprostanes: markers and mediators of oxidative stress. FASEB J 2004; 18: 1791–1800.

    Article  CAS  Google Scholar 

  16. Cháfer-Pericás C, Rahkonen L, Sánchez-Illana A, Kuligowski J, Torres-Cuevas I, Cernada M et al. Ultra high performance liquid chromatography coupled to tandem mass spectrometry determination of lipid peroxidation biomarkers in newborn serum samples. Anal Chim Acta 2015; 886: 214–220.

    Article  Google Scholar 

  17. Song W-L, Lawson JA, Reilly D, Rokach J, Chang C-T, Giasson B et al. Neurofurans, novel indices of oxidant stress derived from docosahexaenoic acid. J Biol Chem 2008; 283: 6–16.

    Article  CAS  Google Scholar 

  18. Perrone S, Negro S, Tataranno ML, Buonocore G . Oxidative stress and antioxidant strategies in newborns. J Matern Fetal Neonatal Med 2010; 23 (Suppl 3): 63–65.

    Article  Google Scholar 

  19. Tataranno ML, Oei JL, Perrone S, Wright IM, Smyth JP, Lui K et al. Resuscitating preterm infants with 100% oxygen is associated with higher oxidative stress than room air. Acta Paediatr 2015; 104: 759–765.

    Article  CAS  Google Scholar 

  20. Buonocore G, Perrone S, Longini M, Vezzosi P, Marzocchi B, Paffetti P et al. Oxidative stress in preterm neonates at birth and on the seventh day of life. Pediatr Res 2002; 52: 46–49.

    Article  CAS  Google Scholar 

  21. Morrow JD, Roberts LJ . Mass spectrometric quantification of F 2-isoprostanes in biological fluids and tissues as measure of oxidant stress. Meth Enzymol 1999; 300: 3–12.

    Article  CAS  Google Scholar 

  22. Milne GL, Sanchez SC, Musiek ES, Morrow JD . Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nat Protoc 2007; 2: 221–226.

    Article  CAS  Google Scholar 

  23. Milne GL, Yin H, Hardy KD, Davies SS, Roberts LJ . Isoprostane generation and function. Chem Rev 2011; 111: 5973–5996.

    Article  CAS  Google Scholar 

  24. Milne GL, Gao B, Terry ES, Zackert WE, Sanchez SC . Measurement of F2- isoprostanes and isofurans using gas chromatography-mass spectrometry. Free Radic Biol Med 2013; 59: 36–44.

    Article  CAS  Google Scholar 

  25. Merrill JD, Ballard RA, Cnaan A, Hibbs AM, Godinez RI, Godinez MH et al. Dysfunction of pulmonary surfactant in chronically ventilated premature infants. Pediatr Res 2004; 56: 918–926.

    Article  CAS  Google Scholar 

  26. Iyer NP, Mhanna MJ . Non-invasively derived respiratory severity score and oxygenation index in ventilated newborn infants. Pediatr Pulmonol 2013; 48: 364–369.

    Article  Google Scholar 

  27. O'Shea TM, Kuban KCK, Allred EN, Paneth N, Pagano M, Dammann O et al. Neonatal cranial ultrasound lesions and developmental delays at 2 years of age among extremely low gestational age children. Pediatrics 2008; 122: e662–e669.

    Article  Google Scholar 

  28. Volpe JJ . The encephalopathy of prematurity—brain injury and impaired brain development inextricably intertwined. Semin Pediatr Neurol 2009; 16: 167–178.

    Article  Google Scholar 

  29. Maitre NL, Slaughter JC, Aschner JL . Early prediction of cerebral palsy after neonatal intensive care using motor development trajectories in infancy. Early Hum Dev 2013; 89: 781–786.

    Article  Google Scholar 

  30. Milne GL, Musiek ES, Morrow JD . F2-isoprostanes as markers of oxidative stress in vivo: an overview. Biomarkers 2005; 10 (Suppl 1): S10–S23.

    Article  CAS  Google Scholar 

  31. Buonocore G, Perrone S, Longini M, Terzuoli L, Bracci R . Total hydroperoxide and advanced oxidation protein products in preterm hypoxic babies. Pediatr Res 2000; 47: 221–224.

    Article  CAS  Google Scholar 

  32. Vento M, Moro M, Escrig R, Arruza L, Villar G, Izquierdo I et al. Preterm resuscitation with low oxygen causes less oxidative stress, inflammation, and chronic lung disease. Pediatrics 2009; 124: e439–e449.

    Article  Google Scholar 

  33. Perrone S, Tataranno ML, Negro S, Cornacchione S, Longini M, Proietti F et al. May oxidative stress biomarkers in cord blood predict the occurrence of necrotizing enterocolitis in preterm infants? J Matern Fetal Neonatal Med 2012; 25 (Suppl 1): 128–131.

    Article  CAS  Google Scholar 

  34. Khwaja O, Volpe JJ . Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008; 93: F153–F161.

    Article  CAS  Google Scholar 

  35. Bacharach VR, Baumeister AA . Effects of maternal intelligence, marital status, income, and home environment on cognitive development of low birthweight infants. J Pediatr Psychol 1998; 23: 197–205.

    Article  CAS  Google Scholar 

  36. Tong S, Baghurst P, Vimpani G, McMichael A . Socioeconomic position, maternal IQ, home environment, and cognitive development. J Pediatr 2007; 151: 284––288.e1.

    Article  Google Scholar 

  37. Vignochi CM, Miura E, Canani LH . Effects of motor physical therapy on bone mineralization in premature infants: a randomized controlled study. J Perinatol 2008; 28: 624–631.

    Article  CAS  Google Scholar 

  38. Miller ME . The bone disease of preterm birth: a biomechanical perspective. Pediatr Res 2003; 53: 10–15.

    Article  Google Scholar 

  39. Newman JB, Debastos AG, Batton D, Raz S . Neonatal respiratory dysfunction and neuropsychological performance at the preschool age: a study of very preterm infants with bronchopulmonary dysplasia. Neuropsychology 2011; 25: 666–678.

    Article  Google Scholar 

  40. Kuligowski J, Aguar M, Rook D, Lliso I, Torres-Cuevas I, Escobar J et al. Urinary lipid peroxidation byproducts: are they relevant for predicting neonatal morbidity in preterm infants? Antioxid Redox Signal 2015; 23: 178–184.

    Article  CAS  Google Scholar 

  41. Solberg R, Longini M, Proietti F, Vezzosi P, Saugstad OD, Buonocore G . Resuscitation with supplementary oxygen induces oxidative injury in the cerebral cortex. Free Radic Biol Med 2012; 53: 1061–1067.

    Article  CAS  Google Scholar 

  42. Buonocore G, Groenendaal F . Anti-oxidant strategies. Semin Fetal Neonatal Med 2007; 12: 287–295.

    Article  Google Scholar 

  43. Poindexter BB, Feng R, Schmidt B, Aschner JL, Ballard RA, Hamvas A et al. Comparisons and limitations of current definitions of bronchopulmonary dysplasia for the prematurity and respiratory outcomes program. Ann Am Thorac Soc 2015; 12: 1822–1830.

    Article  Google Scholar 

  44. Poindexter BB, Jobe AH . The diagnostic conundrum of bronchopulmonary dysplasia. J Pediatr 2015; 167: 517–518.

    Article  Google Scholar 

  45. Pryhuber GS . Postnatal infections and immunology affecting chronic lung disease of prematurity. Clin Perinatol 2015; 42: 697–718.

    Article  Google Scholar 

  46. Maitre NL, Ballard RA, Ellenberg JH, Davis SD, Greenberg JM, Hamvas A et al. Respiratory consequences of prematurity: evolution of a diagnosis and development of a comprehensive approach. J Perinatol 2015; 35: 313–321.

    Article  Google Scholar 

  47. Pryhuber GS, Maitre NL, Ballard RA, Cifelli D, Davis SD, Ellenberg JH et al. Prematurity and respiratory outcomes program (PROP): study protocol of a prospective multicenter study of respiratory outcomes of preterm infants in the United States. BMC Pediatr 2015; 15: 37.

    Article  Google Scholar 

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Acknowledgements

We thank Dr Lynn Taussig and the PROP Scholars program for supporting this work through NHLBI subaward U01 HL101794 to NL Maitre. This study was also supported by NHLBI U01 HL101456 to JL Aschner and NICHD 1K23HD074736-01A1 to NL Maitre. REDCap database was utilized for data collection and analysis through CTSA award UL1 TR000445 from NCATS/NIH. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences or the National Institutes of Health.

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Each author contributed to the manuscript and approved the final manuscript as submitted.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Texas Health Science Center, Houston, TX, USA

    M A Matthews

  2. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    J L Aschner, A R Stark, P E Moore, S Steele, A Beller & O Settles

  3. Departments of Pediatrics and Obstetrics and Gynecology and Woman's Health, Albert Einstein College of Medicine of Montefiore Health and The Children's Hospital at Montefiore, Bronx, NY, USA

    J L Aschner

  4. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA

    J C Slaughter

  5. Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    G L Milne

  6. Department of Pediatrics and the Center for Perinatal Research, Nationwide Children’s Hospital, Columbus, OH, USA

    O Chorna & N L Maitre

  7. Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, USA

    N L Maitre

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  1. M A Matthews
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Correspondence to N L Maitre.

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Matthews, M., Aschner, J., Stark, A. et al. Increasing F2-isoprostanes in the first month after birth predicts poor respiratory and neurodevelopmental outcomes in very preterm infants. J Perinatol 36, 779–783 (2016). https://doi.org/10.1038/jp.2016.74

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