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VOLUME 1 , ISSUE 1 ( January-March, 2022 ) > List of Articles


Extra-uterine Growth Restriction in Preterm Infants

Nitasha Bagga, Nalinikant Panigrahay, Akhil Maheshwari

Keywords : Development, Growth restriction, IUGR, Premature, Skeletal

Citation Information : Bagga N, Panigrahay N, Maheshwari A. Extra-uterine Growth Restriction in Preterm Infants. 2022; 1 (1):67-73.

DOI: 10.5005/jp-journals-11002-0019

License: CC BY-NC 4.0

Published Online: 31-03-2022

Copyright Statement:  Copyright © 2022; The Author(s).


Extra-uterine growth restriction (EUGR) is frequently seen in premature and critically ill infants. Even though advancements in neonatal intensive care have improved the survival of these high-risk infants, many new questions have emerged about the relationship between postnatal growth and neurodevelopmental outcome of these infants. EUGR has traditionally been ascribed to caloric restriction during postnatal periods of critical illness. Nutritional compromise, particularly during the first few weeks of life, may affect the overall growth and could also cause long-term neurodevelopmental impairment. The accidental and premature interruptions of pregnancy could also alter the normal mobilization and utilization of major nutrients from the ways that would have otherwise occurred during the last trimester of pregnancy, which is normally a period of maximal in utero growth. In this article, we review our current understanding of defining EUGR, various risk factors for EUGR, its pathophysiology, and possible ways with which our current healthcare protocols could prevent EUGR.

  1. Hack M, Merkatz IR, Gordon D, et al. The prognostic significance of postnatal growth in very low-birth weight infants. Am J Obstet Gynecol 1982;143(6):693–699. DOI: 10.1016/0002-9378(82)90117-x.
  2. Shah PS, Wong KY, Merko S, et al. Postnatal growth failure in preterm infants: ascertainment and relation to long-term outcome. J Perinat Med 2006;34(6):484–489. DOI: 10.1515/JPM.2006.094.
  3. Zozaya C, Diaz C, Saenz de Pipaon M. How should we define postnatal growth restriction in preterm infants? Neonatology 2018;114(2): 177–180. DOI: 10.1159/000489388.
  4. Franz AR, Pohlandt F, Bode H, et al. Intrauterine, early neonatal, and postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm infants after intensive neonatal nutritional support. Pediatrics 2009;123(1):e101–e109. DOI: 10.1542/peds.2008-1352.
  5. Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006;117(4):1253–1261. DOI: 10.1542/peds.2005-1368.
  6. Ong KK, Kennedy K, Castaneda-Gutierrez E, et al. Postnatal growth in preterm infants and later health outcomes: a systematic review. Acta Paediatr 2015;104(10):974–986. DOI: 10.1111/apa.13128.
  7. Belfort MB, Gillman MW, Buka SL, et al. Preterm infant linear growth and adiposity gain: trade-offs for later weight status and intelligence quotient. J Pediatr 2013;163(6):1564–1569.e2. DOI: 10.1016/j.jpeds.2013.06.032.
  8. Dusick AM, Poindexter BB, Ehrenkranz RA, et al. Growth failure in the preterm infant: can we catch up? Semin Perinatol 2003;27(4):302–310. DOI: 10.1016/s0146-0005(03)00044-2.
  9. Sammallahti S, Pyhala R, Lahti M, et al. Infant growth after preterm birth and neurocognitive abilities in young adulthood. J Pediatr 2014;165(6):1109–1115.e3. DOI: 10.1016/j.jpeds.2014.08.028.
  10. Raghuram K, Yang J, Church PT, et al. Head growth trajectory and neurodevelopmental outcomes in preterm neonates. Pediatrics 2017;140(1):e20170216. DOI: 10.1542/peds.2017-0216.
  11. Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 1999;104 (2 Pt 1):280–289. DOI: 10.1542/peds.104.2.280.
  12. Asbury MR, Unger S, Kiss A, et al. Optimizing the growth of very-low-birth-weight infants requires targeting both nutritional and nonnutritional modifiable factors specific to stage of hospitalization. Am J Clin Nutr 2019;110(6):1384–1394. DOI: 10.1093/ajcn/nqz227.
  13. Sakurai M, Itabashi K, Sato Y, et al. Extrauterine growth restriction in preterm infants of gestational age < or =32 weeks. Pediatr Int 2008;50(1):70–75. DOI: 10.1111/j.1442-200X.2007.02530.x.
  14. Ruth VA. Extrauterine growth restriction: a review of the literature. Neonatal Netw 2008;27(3):177–184. DOI: 10.1891/0730-0832.27.3.177.
  15. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107(2):270–273. DOI: 10.1542/peds.107.2.270.
  16. Wood NS, Costeloe K, Gibson AT, et al. The EPICure study: growth and associated problems in children born at 25 weeks of gestational age or less. Arch Dis Child Fetal Neonatal Ed 2003;88(6):F492–F500. DOI: 10.1136/fn.88.6.f492.
  17. Fenton TR, Cormack B, Goldberg D, et al. “Extrauterine growth restriction” and “postnatal growth failure” are misnomers for preterm infants. J Perinatol 2020;40(5):704–714. DOI: 10.1038/s41372-020-0658-5.
  18. Goldberg DL, Becker PJ, Brigham K, et al. Identifying malnutrition in preterm and neonatal populations: recommended indicators. J Acad Nutr Diet 2018;118(9):1571–1582. DOI: 10.1016/j.jand.2017.10.006.
  19. Tan MJ, Cooke RW. Improving head growth in very preterm infants–a randomised controlled trial I: neonatal outcomes. Arch Dis Child Fetal Neonatal Ed 2008;93(5):F337–F341. DOI: 10.1136/adc.2007.124230.
  20. Cooke RJ, Ainsworth SB, Fenton AC. Postnatal growth retardation: a universal problem in preterm infants. Arch Dis Child Fetal Neonatal Ed 2004;89(5):F428–F430. DOI: 10.1136/adc.2001.004044.
  21. Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 2003;111(5 Pt 1):986–990. DOI: 10.1542/peds.111.5.986.
  22. Zhong QH, Liang K, He XY. [Nutrition status of premature infants in the neonatal intensive care unit and risk factors of extrauterine growth retardation]. Zhongguo Dang Dai Er Ke Za Zhi 2012;14(1):20–23. PMID: 22289746.
  23. Shan HM, Cai W, Cao Y, et al. Extrauterine growth retardation in premature infants in Shanghai: a multicenter retrospective review. Eur J Pediatr 2009;168(9):1055–1059. DOI: 10.1007/s00431-008-0885-9.
  24. Lima PA, Carvalho M, Costa AC, et al. Variables associated with extra uterine growth restriction in very low birth weight infants. J Pediatr (Rio J) 2014;90(1):22–27. DOI: 10.1016/j.jped.2013.05.007.
  25. Embleton ND. Optimal protein and energy intakes in preterm infants. Early Hum Dev 2007;83(12):831–837. DOI: 10.1016/j.earlhumdev.2007.10.001.
  26. Ziegler EE. Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 2011;58 Suppl 1:8–18. DOI: 10.1159/000323381.
  27. Grover A, Khashu M, Mukherjee A, et al. Iatrogenic malnutrition in neonatal intensive care units: urgent need to modify practice. JPEN J Parenter Enteral Nutr 2008;32(2):140–144. DOI: 10.1177/0148607108314373.
  28. Hans DM, Pylipow M, Long JD, et al. Nutritional practices in the neonatal intensive care unit: analysis of a 2006 neonatal nutrition survey. Pediatrics 2009;123(1):51–57. DOI: 10.1542/peds.2007-3644.
  29. McNelis K, Fu TT, Poindexter B. Nutrition for the extremely preterm infant. Clin Perinatol 2017;44(2):395–406. DOI: 10.1016/j.clp.2017.01.012.
  30. Cooke R. Postnatal growth in preterm infants: have we got it right? J Perinatol 2005;25 Suppl 2:S12–S14. DOI: 10.1038/
  31. Henriksen C, Westerberg AC, Ronnestad A, et al. Growth and nutrient intake among very-low-birth-weight infants fed fortified human milk during hospitalisation. Br J Nutr 2009;102(8):1179–1186. DOI: 10.1017/S0007114509371755.
  32. Rochow N, Fusch G, Choi A, et al. Target fortification of breast milk with fat, protein, and carbohydrates for preterm infants. J Pediatr 2013;163(4):1001–1007. DOI: 10.1016/j.jpeds.2013.04.052.
  33. Corvaglia L, Aceti A, Paoletti V, et al. Standard fortification of preterm human milk fails to meet recommended protein intake: bedside evaluation by near-infrared-reflectance-analysis. Early Hum Dev 2010;86(4):237–240. DOI: 10.1016/j.earlhumdev.2010.04.001.
  34. Sauer PJ. Can extrauterine growth approximate intrauterine growth? Should it? Am J Clin Nutr 2007;85(2):608S–613S. DOI: 10.1093/ajcn/85.2.608S.
  35. Corpeleijn WE, Vermeulen MJ, van den Akker CH, et al. Feeding very-low-birth-weight infants: our aspirations versus the reality in practice. Ann Nutr Metab 2011;58 Suppl 1:20–29. DOI: 10.1159/000323384.
  36. Ruchat SM, Hivert MF, Bouchard L. Epigenetic programming of obesity and diabetes by in utero exposure to gestational diabetes mellitus. Nutr Rev 2013;71 Suppl 1:S88–S94. DOI: 10.1111/nure.12057.
  37. Choi SW, Friso S. Epigenetics: a new bridge between nutrition and health. Adv Nutr 2010;1(1):8–16. DOI: 10.3945/an.110.1004.
  38. Gonzalez-Rodriguez P, Cantu J, O'Neil D, et al. Alterations in expression of imprinted genes from the H19/IGF2 loci in a multigenerational model of intrauterine growth restriction (IUGR). Am J Obstet Gynecol 2016;214(5):625 e1–e11. DOI: 10.1016/j.ajog.2016.01.194.
  39. Tozzi MG, Moscuzza F, Michelucci A, et al. Extra Uterine Growth Restriction (EUGR) in preterm infants: growth patterns, nutrition, and epigenetic markers. A pilot study. Front Pediatr 2018;6:408. DOI: 10.3389/fped.2018.00408.
  40. Lillycrop KA, Phillips ES, Torrens C, et al. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr 2008;100(2):278–282. DOI: 10.1017/S0007114507894438.
  41. Rees WD, Hay SM, Brown DS, et al. Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. J Nutr 2000;130(7):1821–1826. DOI: 10.1093/jn/130.7.1821.
  42. Gong L, Pan YX, Chen H. Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics 2010;5(7):619–626. DOI: 10.4161/epi.5.7.12882.
  43. Dudzik D, Iglesias Platas I, Izquierdo Renau M, et al. Plasma metabolome alterations associated with extrauterine growth restriction. Nutrients 2020;12(4):1188. DOI: 10.3390/nu12041188.
  44. Eggermann T, Davies JH, Tauber M, et al. Growth restriction and genomic imprinting-overlapping phenotypes support the concept of an imprinting network. Genes (Basel) 2021;12(4):585. DOI: 10.3390/genes12040585.
  45. Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010;126(3):443–456. DOI: 10.1542/peds.2009-2959.
  46. Maas C, Poets CF, Franz AR. Avoiding postnatal undernutrition of VLBW infants during neonatal intensive care: evidence and personal view in the absence of evidence. Arch Dis Child Fetal Neonatal Ed 2015;100(1):F76–F81. DOI: 10.1136/archdischild-2014-306195.
  47. Stevens TP, Shields E, Campbell D, et al. Variation in enteral feeding practices and growth outcomes among very premature infants: a report from the New York State Perinatal Quality Collaborative. Am J Perinatol 2016;33(1):9–19. DOI: 10.1055/s-0035-1554794.
  48. Ehrenkranz RA. Early, aggressive nutritional management for very low birth weight infants: what is the evidence? Semin Perinatol 2007;31(2):48–55. DOI: 10.1053/j.semperi.2007.02.001.
  49. Dinerstein A, Nieto RM, Solana CL, et al. Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants. J Perinatol 2006;26(7):436–442. DOI: 10.1038/
  50. McCallie KR, Lee HC, Mayer O, et al. Improved outcomes with a standardized feeding protocol for very low birth weight infants. J Perinatol 2011;31 Suppl 1:S61–S67. DOI: 10.1038/jp.2010.185.
  51. Gephart SM, Hanson CK. Preventing necrotizing enterocolitis with standardized feeding protocols: not only possible, but imperative. Adv Neonatal Care 2013;13(1):48–54. DOI: 10.1097/ANC.0b013e31827ece0a.
  52. Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed 2005;90(2):F147–F151. DOI: 10.1136/adc.2004.059741.
  53. Moyses HE, Johnson MJ, Leaf AA, et al. Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. Am J Clin Nutr 2013;97(4):816–826. DOI: 10.3945/ajcn.112.042028.
  54. Christmann V, Visser R, Engelkes M, et al. Yes, we can–achieve adequate early postnatal growth in preterm infants. Acta Paediatr 2013;102(12):e530. DOI: 10.1111/apa.12302.
  55. Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 2003;53(1):24–32. DOI: 10.1203/00006450-200301000-00008.
  56. Trivedi A, Sinn JK. Early versus late administration of amino acids in preterm infants receiving parenteral nutrition. Cochrane Database Syst Rev 2013(7):CD008771. DOI: 10.1002/14651858.CD008771.pub2.
  57. Vlaardingerbroek H, Vermeulen MJ, Rook D, et al. Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J Pediatr 2013;163(3):638–644.e1–5. DOI: 10.1016/j.jpeds.2013.03.059.
  58. Sallakh-Niknezhad A, Bashar-Hashemi F, Satarzadeh N, et al. Early versus late trophic feeding in very low birth weight preterm infants. Iran J Pediatr 2012;22(2):171–176. PMID: 23056882.
  59. Sisk PM, Lovelady CA, Dillard RG. Effect of education and lactation support on maternal decision to provide human milk for very-low-birth-weight infants. Adv Exp Med Biol 2004;554:307–311. DOI: 10.1007/978-1-4757-4242-8_28.
  60. Meier PP, Johnson TJ, Patel AL, et al. Evidence-based methods that promote human milk feeding of preterm infants: an expert review. Clin Perinatol 2017;44(1):1–22. DOI: 10.1016/j.clp.2016.11.005.
  61. Spatz DL, Froh EB, Schwarz J, et al. Pump early, pump often: a continuous quality improvement project. J Perinat Educ 2015;24(3):160–170. DOI: 10.1891/1058-1243.24.3.160.
  62. Spatz DL. Ten steps for promoting and protecting breastfeeding for vulnerable infants. J Perinat Neonatal Nurs 2004;18(4):385–396. DOI: 10.1097/00005237-200410000-00009.
  63. Pineda RG, Foss J, Richards L, et al. Breastfeeding changes for VLBW infants in the NICU following staff education. Neonatal Netw 2009;28(5):311–319. DOI: 10.1891/0730-0832.28.5.311.
  64. Cacho NT, Parker LA, Neu J. Necrotizing enterocolitis and human milk feeding: a systematic review. Clin Perinatol 2017;44(1):49–67. DOI: 10.1016/j.clp.2016.11.009.
  65. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2018;6:CD002971. DOI: 10.1002/14651858.CD002971.pub3.
  66. Taylor SN. Solely human milk diets for preterm infants. Semin Perinatol 2019;43(7):151158. DOI: 10.1053/j.semperi.2019.06.006.
  67. Mukhopadhyay K, Narnag A, Mahajan R. Effect of human milk fortification in appropriate for gestation and small for gestation preterm babies: a randomized controlled trial. Indian Pediatr 2007;44(4):286–290. PMID: 17468524.
  68. Gathwala G, Shaw C, Shaw P, et al. Human milk fortification and gastric emptying in the preterm neonate. Int J Clin Pract 2008;62(7): 1039–1043. DOI: 10.1111/j.1742-1241.2006.01201.x.
  69. Di Natale C, Coclite E, Di Ventura L, et al. Fortification of maternal milk for preterm infants. J Matern Fetal Neonatal Med 2011;24 Suppl 1:41–3. DOI: 10.3109/14767058.2011.607569.
  70. Arslanoglu S, Boquien CY, King C, et al. Fortification of human milk for preterm infants: update and recommendations of the European Milk Bank Association (EMBA) working group on human milk fortification. Front Pediatr 2019;7:76. DOI: 10.3389/fped.2019.00076.
  71. McClave SA, Snider HL. Clinical use of gastric residual volumes as a monitor for patients on enteral tube feeding. JPEN J Parenter Enteral Nutr 2002;26(6 Suppl):S43–S48; discussion S9–S50. DOI: 10.1177/014860710202600607.
  72. Parker L, Torrazza RM, Li Y, et al. Aspiration and evaluation of gastric residuals in the neonatal intensive care unit: state of the science. J Perinat Neonatal Nurs 2015;29(1):51–59; quiz E2. DOI: 10.1097/JPN.0000000000000080.
  73. Bhatia P, Johnson KJ, Bell EF. Variability of abdominal circumference of premature infants. J Pediatr Surg 1990;25(5):543–544. DOI: 10.1016/0022-3468(90)90569-u.
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