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Association between neurodevelopmental outcomes and concomitant presence of NEC and IVH in extremely low birth weight infants

Journal of Perinatology (2023)Cite this article

Subjects

Abstract

Objective

To quantify the association between necrotizing enterocolitis (NEC) and neurodevelopmental disability (NDI) in extremely low birth weight (ELBW) infants with intraventricular hemorrhage (IVH).

Study design

ELBW survivors born 2011–2017 and evaluated at 16–26 months corrected age in the Vermont Oxford Network (VON) ELBW Follow-Up Project were included. Logistic regression determined the adjusted relative risk (aRR) of severe NDI in medical or surgical NEC compared to no NEC, stratified by severity of IVH.

Results

Follow-up evaluation occurred in 5870 ELBW survivors. Compared to no NEC, medical NEC had no impact on NDI, regardless of IVH status. Surgical NEC increased risk of NDI in patients with no IVH (aRR 1.69; 95% CI 1.36–2.09), mild IVH (aRR 1.36;0.97–1.92), and severe IVH (aRR 1.35;1.13–1.60).

Conclusions

ELBW infants with surgical NEC carry increased risk of neurodevelopmental disability within each IVH severity stratum. These data describe the additive insult of surgical NEC and IVH on neurodevelopment, informing prognostic discussions and highlighting the need for preventative interventions.

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Fig. 1: Incidence of severe neurodevelopmental disability in infants with necrotizing enterocolitis (NEC) and intraventricular hemorrhage (IVH).
Fig. 2: Forest plot of adjusted risk ratios (ARR) for severe neurodevelopmental disability.

Data availability

The code used for this analysis can be made available upon request.

References

  1. Mercier CE, Dunn MS, Ferrelli KR, Howard DB, Soll RF. Neurodevelopmental outcome of extremely low birth weight infants from the Vermont Oxford Network: 1998–2003 and the Vermont Oxford Network ELBW infant follow-up study group. Neonatology. 2010;97:329–38.

    Article  PubMed  Google Scholar 

  2. Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed. 2007;92:193–8.

    Article  Google Scholar 

  3. Vohr BR, Allen M. Extreme prematurity — the continuing dilemma. N Engl J Med. 2005;352:71–2.

    Article  CAS  PubMed  Google Scholar 

  4. Glass HC, Costarino AT, Stayer SA, Brett CM, Cladis F, Davis PJ. Outcomes for extremely premature infants. Anesth Analg. 2015;120:1337–51.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bell EF, Hintz SR, Hansen NI, Bann CM, Wyckoff MH, DeMauro SB, et al. Mortality, in-hospital morbidity, care practices, and 2-year outcomes for extremely preterm infants in the US, 2013-2018. JAMA. 2022;327:248–63.

    Article  PubMed  Google Scholar 

  6. Knell J, Han SM, Jaksic T, Modi BP. Current status of necrotizing enterocolitis. Curr Probl Surg. 2019;56:11–38.

    Article  PubMed  Google Scholar 

  7. Han SM, Hong CR, Knell J, Edwards EM, Morrow KA, Soll RF, et al. Trends in incidence and outcomes of necrotizing enterocolitis over the last 12 years: a multicenter cohort analysis. J Pediatr Surg. 2020;55:998–1001.

    Article  PubMed  Google Scholar 

  8. Hull MA, Fisher JG, Gutierrez IM, Jones BA, Kang KH, Kenny M, et al. Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. J Am Coll Surg. 2014;218:1148–55.

    Article  PubMed  Google Scholar 

  9. Salhab WA, Perlman JM, Silver L, Broyles RS. Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight infants < 1000 g. J Perinatol. 2004;24:534–40.

    Article  PubMed  Google Scholar 

  10. Sonntag J, Grimmer I, Scholz T, Metze B, Wit J, Obladen M. Growth and neurodevelopmental outcome of very low birthweight infants with necrotizing enterocolitis. Acta Paediatr Int J Paediatr. 2000;89:528–32.

    Article  CAS  Google Scholar 

  11. Hickey M, Georgieff M, Ramel S. Neurodevelopmental outcomes following necrotizing enterocolitis. Semin Fetal Neonatal Med. 2018;23:426–32.

    Article  PubMed  Google Scholar 

  12. Matei A, Montalva L, Goodbaum A, Lauriti G, Lauriti G, Zani A. Neurodevelopmental impairment in necrotising enterocolitis survivors: systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2020;105:432–9.

    Article  PubMed  Google Scholar 

  13. Fullerton BS, Hong CR, Velazco CS, Mercier CE, Morrow KA, Edwards EM, et al. Severe neurodevelopmental disability and healthcare needs among survivors of medical and surgical necrotizing enterocolitis: a prospective cohort study. J Pediatr Surg. 2018;53:101–7.

    Article  Google Scholar 

  14. Hintz SR, Kendrick DE, Stoll BJ, Vohr BR, Fanaroff AA, Donovan EF, et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005;115:696–703.

    Article  PubMed  Google Scholar 

  15. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr. 1978;92:529–34.

    Article  CAS  PubMed  Google Scholar 

  16. Miller SP, Ferriero DM, Leonard C, Piecuch R, Glidden DV, Partridge JC, et al. Early brain injury in premature newborns detected with magnetic resonance imaging is associated with adverse early neurodevelopmental outcome. J Pediatr. 2005;147:609–16.

    Article  PubMed  Google Scholar 

  17. Calisici E, Eras Z, Oncel MY, Oguz SS, Gokce IK, Dilmen U. Neurodevelopmental outcomes of premature infants with severe intraventricular hemorrhage. J Matern Neonatal Med. 2015;28:2115–20.

    Article  Google Scholar 

  18. Bolisetty S, Dhawan A, Abdel-Latif M, Bajuk B, Stack J, Lui K. Intraventricular hemorrhage and neurodevelopmental outcomes in extreme preterm infants. Pediatrics. 2014;133:55–62.

    Article  PubMed  Google Scholar 

  19. O’Shea TM, Allred EN, Dammann O, Hirtz D, Kuban KCK, Paneth N, et al. The ELGAN study of the brain and related disorders in extremely low gestational age newborns. Early Hum Dev. 2009;85:719–25.

    Article  PubMed  Google Scholar 

  20. Goldstein RF, Cotten CM, Shankaran S, Gantz MG, Poole WK, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage. J Perinatol. 2013;33:25–32.

    Article  CAS  PubMed  Google Scholar 

  21. Culbreath K, Knell J, Keefe G, Nes E, Han SM, Edwards EM, et al. Impact of concomitant necrotizing enterocolitis on mortality in very low birth weight infants with intraventricular hemorrhage. J Perinatol. 2022. https://doi.org/10.1038/s41372-022-01434-1.

  22. Vermont Oxford network manual of operations: Part 2. Data definitions and infant data forms. 2019. http://www.vtoxford.org/tools/ManualofOperationsPart2.pdf.%0A.

  23. Vermont Oxford Network. The infant follow-up project extremely-low-birth-weight infant manual of operations. 2019. hhttps://vtoxford.zendesk.com/hc/en-us/article_attachments/12077606050707/ELBW-FUP-Manual-2019_Cohort.pdf.

  24. Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months. J Am Med Assoc. 2003;289:11–6.

    Article  Google Scholar 

  25. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol. 2005;162:199–200.

    Article  PubMed  Google Scholar 

  26. Fullerton BS, Hong CR, Jaksic T. Long-term outcomes of pediatric intestinal failure. Semin Pediatr Surg. 2017;26:328–35.

    Article  PubMed  Google Scholar 

  27. Simon NP, Brady NR, Stafford RL, Powell RW. The effect of abdominal incisions on early motor development of infants with necrotizing enterocolitis. Dev Med Child Neurol. 1993;35:49–53.

    Article  CAS  PubMed  Google Scholar 

  28. Willis KA, Ambalavanan N. Necrotizing enterocolitis and the gut-lung axis. Semin Perinatol. 2021;45. https://doi.org/10.1016/j.semperi.2021.151454.

  29. Greenberg RG, McDonald SA, Laughon MM, Tanaka D, Jensen E, Van Meurs K, et al. Online clinical tool to estimate risk of bronchopulmonary dysplasia in extremely preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022;107:638–43.

    Article  Google Scholar 

  30. Davidson AJ, Disma N, De Graaff JC, Withington DE, Dorris L, Bell G, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet. 2016;387:239–50.

    Article  PubMed  Google Scholar 

  31. McCann ME, Berde C, Soriano S, Marmor J, Bellinger D, de Graaff JC, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019;393:664–77.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Adams-Chapman I, Bann CM, Vaucher YE, Stoll BJ. Association between feeding difficulties and language delay in preterm infants using Bayley scales of infant development-third edition. J Pediatr. 2013;163:680–5.e3.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. J Am Med Assoc. 2004;292:2357–65.

    Article  CAS  Google Scholar 

  34. Christensen RD. Associations between ‘early’ red blood cell transfusion and severe intraventricular hemorrhage, and between ‘late’ red blood cell transfusion and necrotizing enterocolitis. Semin Perinatol. 2012;36:283–9.

    Article  PubMed  Google Scholar 

  35. Bell EF, Strauss RG, Widness JA, Mahoney LT, Mock DM, Seward VJ, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005;115:1685–91.

    Article  PubMed  Google Scholar 

  36. Howarth C, Banerjee J, Aladangady N. Red blood cell transfusion in preterm infants: current evidence and controversies. Neonatology. 2018;114:7–16.

    Article  PubMed  Google Scholar 

  37. Zimmerman E, Lahav A. Ototoxicity in preterm infants: effects of genetics, aminoglycosides, and loud environmental noise. J Perinatol. 2013;33:3–8.

    Article  CAS  PubMed  Google Scholar 

  38. Chan SHT, Johnson MJ, Leaf AA, Vollmer B. Nutrition and neurodevelopmental outcomes in preterm infants: a systematic review. Acta Paediatr Int J Paediatr. 2016;105:587–99.

    Article  Google Scholar 

  39. Kirpalani H, Whyte RK, Andersen C, Asztalos EV, Heddle N, Blajchman MA, et al. The premature infants in need of transfusion (PINT) study: a liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149:301–7.

    Article  PubMed  Google Scholar 

  40. Kellogg M, Meador KJ. Neurodevelopmental effects of antiepileptic drugs. Neurochem Res. 2017;42:2065–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kirpalani H, Bell EF, Hintz SR, Tan S, Schmidt B, Chaudhary AS, et al. Higher or lower hemoglobin transfusion thresholds for preterm infants. N Engl J Med. 2020;383:2639–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vohr BR, Stephens BE, Higgins RD, Bann CM, Hintz SR, Das A, et al. Are outcomes of extremely preterm infants improving? Impact of Bayley assessment on outcomes. J Pediatr. 2012;161:222–8.e3.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Horbar JD, Edwards EM, Ogbolu Y. Our responsibility to follow through for NICU infants and their families. Pediatrics. 2020;146. https://doi.org/10.1542/peds.2020-0360.

  44. Jackson JL, Morack J, Harris M, DeSalvo J, Daniels CJ, Chisolm DJ. Racial disparities in clinic follow-up early in life among survivors of congenital heart disease. Congenit Heart Dis. 2019;14:305–10.

    Article  PubMed  Google Scholar 

  45. Fraiman YS, Stewart JE, Litt JS. Race, language, and neighborhood predict high-risk preterm infant follow up program participation. J Perinatol. 2022;42:217–22.

    Article  PubMed  Google Scholar 

  46. Banerjee R, Loren AW. Driving distances and loss to follow‐up after hematopoietic cell transplantation. EJHaem. 2021;2:272–5.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Sivagnanam P, Rhodes M. The importance of follow-up and distance from centre in weight loss after laparoscopic adjustable gastric banding. Surg Endosc. 2010;24:2432–8.

    Article  PubMed  Google Scholar 

  48. Wadhawan R, Oh W, Hintz SR, Blakely ML, Das A, Bell EF, et al. Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis. J Perinatol. 2014;34:64–70.

    Article  PubMed  Google Scholar 

  49. Moore T, Johnson S, Haider S, Hennessy E, Marlow N. Relationship between test scores using the second and third editions of the Bayley scales in extremely preterm children. J Pediatr. 2012;160:553–8.

    Article  PubMed  Google Scholar 

  50. Flynn RS, Huber MD, DeMauro SB. Predictive value of the BSID-II and the Bayley-III for early school age cognitive function in very preterm infants. Glob Pediatr Heal. 2020;7. https://doi.org/10.1177/2333794X20973146.

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Acknowledgements

We thank our colleagues who submit data to VON on behalf of infants and their families. Abstract previously presented at the annual meeting of the American Pediatric Surgical Association (APSA).

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Authors and Affiliations

  1. Boston Children’s Hospital, Department of Surgery and Center for Advanced Intestinal Rehabilitation, Boston, MA, USA

    Katherine Culbreath, Gregory Keefe, Emily Nes, Jamie Knell, Tom Jaksic & Biren P. Modi

  2. Vermont Oxford Network, Burlington, VT, USA

    Erika M. Edwards, Kate A. Morrow, Roger F. Soll & Jeffrey D. Horbar

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  1. Katherine Culbreath
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Contributions

KC was involved in analysis, interpretation of data, drafting of the manuscript, and critical revision of the manuscript. JK, TJ, and BPM were involved in study conception and design, analysis, interpretation of data, and critical revision of the manuscript. GK and EN were involved in analysis, interpretation of data, and critical revision of the manuscript. EME and KAM were involved in designing the data collection instruments, the acquisition of the data, interpretation of data, and critical revision of the manuscript. RFS and JDH were involved in coordinating data collection, interpretation of the data, and critical revision of the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Biren P. Modi.

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Competing interests

JDH, RFS, and KAM are employees of the Vermont Oxford Network. EME receives salary support from Vermont Oxford Network. The remaining authors do not have financial relationships to disclose.

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Culbreath, K., Keefe, G., Nes, E. et al. Association between neurodevelopmental outcomes and concomitant presence of NEC and IVH in extremely low birth weight infants. J Perinatol (2023). https://doi.org/10.1038/s41372-023-01780-8

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