Feeding the Preterm Neonate with Intrauterine Growth Restriction

  • Flavia Indrio
  • Luca Maggio
  • Francesco Raimondi


Intrauterine growth restriction (IUGR) is the failure to achieve the genetically predetermined growth potential and may be caused by fetal, maternal, placental, and external factors. IUGR is associated with significant perinatal mortality and morbidity and adverse long-term outcomes, in preterm, especially extremely preterm infants with gestation under 28 weeks at birth. Optimal enteral feeding is crucial in this population as suboptimal nutrition during a critical phase of postnatal life is associated with a negative impact on long term neurodevelopment. However, enteral nutrition is a difficult issue in these infants considering the adverse effects of chronic hypoxia on the fetal gastrointestinal tract, and the inherent susceptibility of this high-risk population to a potentially devastating illness such as necrotising enterocolitis (NEC). Signs of feeding intolerance such as abdominal distension, large/bile stained gastric residuals are almost universal in the first week or two in extremely preterm IUGR infants and are difficult to differentiate from early NEC. This is also the period when suboptimal nutrition constitutes a nutritional emergency. Animal data associate IUGR with reduced intestinal weight (proportionate to body weight), length and wall thickness, and reduced villous height and crypt depth at the microscopic level. Initial observations on a distinct gut colonization pattern may also be relevant to the specific health hazards in this population. This chapter reviews the current strategies for enteral feeding, and the potential long term adverse effects of catch up growth (e.g., increased risk of obesity, hypertension and diabetes mellitus) in the preterm infant with IUGR.


Short Chain Fatty Acid Enteral Feeding Crypt Depth Placental Insufficiency Villous Height 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Gardosi J, Chang A, Kalyan B, Sahota D, Symonds EM (1992) Customised antenatal growth charts. Lancet 339:283–287PubMedCrossRefGoogle Scholar
  2. 2.
    Baschat AA, Gembruch U, Gortner L, Reiss I, Weiner CP, Harman CR (2000) Coronary artery blood flow visualization signifies hemodynamic deterioration in growth-restricted fetuses. Ultrasound Obstet Gynecol 16:425–431PubMedCrossRefGoogle Scholar
  3. 3.
    Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A (2000) Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 182:198–206PubMedCrossRefGoogle Scholar
  4. 4.
    Murphy VE, Smith R, Giles WB, Clifton VL (2006) Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus. Endocrine Rev 27:141–169CrossRefGoogle Scholar
  5. 5.
    Organiszation WH (2002) WHO report: reducing risks, promoting healthy life. World Health Organization, GenevaGoogle Scholar
  6. 6.
    Barker DJ, Hales CN, Fall CH, Osmond C, Phipps K, Clark PM (1993) Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 36:62–67PubMedCrossRefGoogle Scholar
  7. 7.
    Hattersley AT, Tooke JE (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353:1789–1792Google Scholar
  8. 8.
    Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C (1994) Thinness at birth and insulin resistance in adult life. Diabetologia 37:150–154PubMedCrossRefGoogle Scholar
  9. 9.
    Wang T, Huo YJ, Shi F, Xu RJ, Hutz RJ (2005) Effects of intrauterine growth retardation on development of the gastrointestinal tract in neonatal pigs. Biol Neonate 88:66–72PubMedCrossRefGoogle Scholar
  10. 10.
    Xu RJ, Mellor DJ, Birtles MJ, Reynolds GW, Simpson HV (1994) Impact of intrauterine growth retardation on the gastrointestinal tract and the pancreas in newborn pigs. J Pediatr Gastroenterol Nutr 18:231–240PubMedCrossRefGoogle Scholar
  11. 11.
    Bauer R, Walter B, Hoppe A et al (1998) Body weight distribution and organ size in newborn swine (sus scrofa domestica)—a study describing an animal model for asymmetrical intrauterine growth retardation. Exp Toxicol Pathol 50:59–65PubMedCrossRefGoogle Scholar
  12. 12.
    Mostyn A, Litten JC, Perkins KS et al (2005) Influence of size at birth on the endocrine profiles and expression of uncoupling proteins in subcutaneous adipose tissue, lung, and muscle of neonatal pigs. Am J Physiol Regul Integr Comp Physiol 288:R1536–R1542PubMedCrossRefGoogle Scholar
  13. 13.
    Widdowson EM (1971) Intra-uterine growth retardation in the pig. I. Organ size and cellular development at birth and after growth to maturity. Biol Neonate 19:329–340PubMedCrossRefGoogle Scholar
  14. 14.
    Avila CG, Harding R, Rees S, Robinson PM (1989) Small intestinal development in growth-retarded fetal sheep. J Pediatr Gastroenterol Nutr 8:507–515PubMedCrossRefGoogle Scholar
  15. 15.
    D’Inca R, Gras-Le Guen C, Che L, Sangild PT, Le Huerou-Luron I (2011) Intrauterine growth restriction delays feeding-induced gut adaptation in term newborn pigs. Neonatology 99:208–216PubMedCrossRefGoogle Scholar
  16. 16.
    D’Inca R, Kloareg M, Gras-Le Guen C, Le Huerou-Luron I (2010) Intrauterine growth restriction modifies the developmental pattern of intestinal structure, transcriptomic profile, and bacterial colonization in neonatal pigs. J Nutr 140:925–931PubMedCrossRefGoogle Scholar
  17. 17.
    Simmonds A, LaGamma EF (2006) Toward improving mucosal barrier defenses: rhG-CSF plus IgG antibody. Indian J Pediatr 73:1019–1026PubMedCrossRefGoogle Scholar
  18. 18.
    Mackie RI, Sghir A, Gaskins HR (1999) Developmental microbial ecology of the neonatal gastrointestinal tract. Am J Clin Nutr 69:1045Google Scholar
  19. 19.
    Mariadason JM, Kilias D, Catto-Smith A, Gibson PR (1999) Effect of butyrate on paracellular permeability in rat distal colonic mucosa ex vivo. J Gastroenterol Hepatol 14:873–879PubMedCrossRefGoogle Scholar
  20. 20.
    Gaudier E, Jarry A, Blottiere HM et al (2004) Butyrate specifically modulates MUC gene expression in intestinal epithelial goblet cells deprived of glucose. Am J Physiol Gastrointest Liver Physiol 287:1168–1174CrossRefGoogle Scholar
  21. 21.
    Barcelo A, Claustre J, Moro F, Chayvialle JA, Cuber JC, Plaisancie P (2000) Mucin secretion is modulated by luminal factors in the isolated vascularly perfused rat colon. Gut 46:218–224PubMedCrossRefGoogle Scholar
  22. 22.
    Berman L, Moss R (2011) Necrotizing enterocolitis: an update. Semin Fetal Neonat Med 16:145–150CrossRefGoogle Scholar
  23. 23.
    Baschat AA, Hecher K (2004) Fetal growth restriction due to placental disease. Semin Perinatol 28:67–80PubMedCrossRefGoogle Scholar
  24. 24.
    Baschat AA (2004) Fetal responses to placental insufficiency: an update. Br J Obstet Gynaecol 111:1031–1041CrossRefGoogle Scholar
  25. 25.
    Gilbert WM, Danielsen B (2003) Pregnancy outcomes associated with intrauterine growth restriction. Am J Obstet Gynecol 188:1596–1599PubMedCrossRefGoogle Scholar
  26. 26.
    Aucott SW, Donohue PK, Northington FJ (2004) Increased morbidity in severe early intrauterine growth restriction. J Perinatol 24:435–440PubMedCrossRefGoogle Scholar
  27. 27.
    Baserga M, Bertolotto C, Maclennan NK et al (2004) Uteroplacental insufficiency decreases small intestine growth and alters apoptotic homeostasis in term intrauterine growth retarded rats. Early Hum Dev 79:93–105PubMedCrossRefGoogle Scholar
  28. 28.
    Maruyama K, Koizumi T (2001) Superior mesenteric artery blood flow velocity in small for gestational age infants of very low birth weight during the early neonatal period. J Perinat Med 29:64–70PubMedCrossRefGoogle Scholar
  29. 29.
    Gamsu HR, Kempley ST (1997) Enteral hypoxia/ischaemia and necrotizing enterocolitis. Semin Neonatol 2:245–254CrossRefGoogle Scholar
  30. 30.
    Murdoch EM, Sinah AK, Kempley ST (2003) Impaired splanchnic haemodynamic responses to enteral feeding in preterm growth restricted infants. Early Hum Dev 73:93–109CrossRefGoogle Scholar
  31. 31.
    Murdoch EM, Sinha AK, Shanmugalingam ST, Smith GCS, Kempley ST (2006) Doppler flow velocimetry in the superior mesenteric artery on the first day of life in preterm infants and the risk of neonatal necrotizing enterocolitis. Pediatrics 118:1999–2003PubMedCrossRefGoogle Scholar
  32. 32.
    Nowicki PT, Miller CE (1988) Autoregulation in the developing postnatal intestinal circulation. Am J Physiol 254:G189–G193PubMedGoogle Scholar
  33. 33.
    Bulkley GB, Kvietys PR, Parks DA, Perry MA, Granger DN (1985) Relationship of blood flow and oxygen consumption to ischemic injury in the canine small intestine. Gastroenterology 89:852–857PubMedGoogle Scholar
  34. 34.
    Szabo JS, Mayfield SR, Oh W, Stonestreet BS (1987) Postprandial gastrointestinal blood flow and oxygen consumption: effects of hypoxemia in neonatal piglets. Pediatr Res 21:93–98PubMedCrossRefGoogle Scholar
  35. 35.
    Nowicki PT, Stonestreet BS, Hansen NB, Yao AC, Oh W (1983) Gastrointestinal blood flow and oxygen consumption in awake newborn piglets: effect of feeding. Am J Physiol 245:697–802Google Scholar
  36. 36.
    Beeby PJ, Jeffery H (1992) Risk factors for necrotising enterocolitis: the influence of gestational age. Arch Dis Child 67:432–5PubMedCrossRefGoogle Scholar
  37. 37.
    Malcolm G, Ellwood D, Devonald K, Beilby R, Henderson-Smart D (1991) Absent or reversed end diastolic flow velocity in the umbilical artery and necrotising enterocolitis. Arch Dis Child 66:805–807PubMedCrossRefGoogle Scholar
  38. 38.
    Bhatt AB, Tank PD, Barmade KB, Damania KR (2002) Abnormal Doppler flow velocimetry in the growth restricted foetus as a predictor for necrotising enterocolitis. J Postgrad Med 48:182–185PubMedGoogle Scholar
  39. 39.
    Karsdorp VH, van Vugt JM, van Geijn HP et al (1994) Clinical significance of absent or reversed end diastolic velocity waveforms in umbilical artery. Lancet 344:1664–1668PubMedCrossRefGoogle Scholar
  40. 40.
    Adiotomre PN, Johnstone FD, Laing IA (1997) Effect of absent end diastolic flow velocity in the fetal umbilical artery on subsequent outcome. Arch Dis Child Fetal Neonat Ed 76:35–38CrossRefGoogle Scholar
  41. 41.
    Dorling J, Kempley S, Leaf A (2005) Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonat Ed 90:359–363CrossRefGoogle Scholar
  42. 42.
    Wilson DC, Harper A, McClure G (1991) Absent or reversed end diastolic flow velocity in the umbilical artery and necrotizing enterocolitis. Arch Dis Child 66:1467PubMedCrossRefGoogle Scholar
  43. 43.
    Kamoji VM, Dorling JS, Manktelow B, Draper ES, Field DJ (2008) Antenatal umbilical Doppler abnormalities: an independent risk factor for early onset neonatal necrotizing enterocolitis in premature infants. Acta Paediatr 97:327–331PubMedCrossRefGoogle Scholar
  44. 44.
    Manogura AC, Turan O, Kush ML et al (2008) Predictors of necrotizing enterocolitis in preterm growth-restricted neonates. Am J Obstet Gynecol 198:638. e1–e5Google Scholar
  45. 45.
    Mihatsch WA, Pohlandt F, Franz AR, Flock F (2002) Early feeding advancement in very low-birth-weight infants with intrauterine growth retardation and increased umbilical artery resistance. J Pediatr Gastroenterol Nutr 35:144–148PubMedCrossRefGoogle Scholar
  46. 46.
    Leaf A, Dorling J, Kempley S et al (2012) Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. Pediatrics 129:e1260–e1268Google Scholar
  47. 47.
    Gupta N, Kempley S (2010) on behalf of ADEPT study group. Analysis of feeding intolerance in growth restricted < 29 weeks infants. Presented at the Neonatal Society London, UK, Autumn Meeting.
  48. 48.
    Rigo J, Salle BL, Picaud JC, Putet G, Senterre J (1995) Nutritional evaluation of protein hydrolysate formulas. Eur J Clin Nutri 49:S26–S38Google Scholar
  49. 49.
    Maggio L, Zuppa AA, Sawatzki G, Valsasina R, Schubert W, Tortorolo G (2005) Higher urinary excretion of essential amino acids in preterm infants fed protein hydrolysates. Acta paediatr 94:75–84PubMedCrossRefGoogle Scholar
  50. 50.
    Szajewska H, Albrecht P, Stoitiska B, Prochowska A, Gawecka A, Laskowska-Klita T (2001) Extensive and partial protein hydrolysate preterm formulas: the effect on growth rate, protein metabolism indices, and plasma amino acid concentrations. J Pediatr Gastroenterol Nutr 32:303–309PubMedCrossRefGoogle Scholar
  51. 51.
    Mihatsch WA, Franz AR, Hogel J, Pohlandt F (2002) Hydrolyzed protein accelerates feeding advancement in very low birth weight infants. Pediatrics 110:1199–1203PubMedCrossRefGoogle Scholar
  52. 52.
    Florendo KN, Bellflower B, van Zwol A, Cooke RJ (2009) Growth in preterm infants fed either a partially hydrolyzed whey or an intact casein/whey preterm infant formula. J Perinatol 29:106–111PubMedCrossRefGoogle Scholar
  53. 53.
    Raimondi F, Spera AM, Sellitto M, Landolfo F, Capasso L (2012) Amino acid-based formula as a rescue strategy in feeding very-low-birth-weight infants with intrauterine growth restriction. J Pediatr Gastroenterol Nutr 54:608–612PubMedCrossRefGoogle Scholar
  54. 54.
    Painter RC, Roseboom TJ, Bleker OP (2005) Prenatal exposure to the Dutch famine and disease in later life: an overview. Reproductive Toxicol (Elmsford, NY) 20:345–352CrossRefGoogle Scholar
  55. 55.
    Pylipow M, Spector LG, Puumala SE, Boys C, Cohen J, Georgieff MK (2009) Early postnatal weight gain, intellectual performance, and body mass index at 7 years of age in term infants with intrauterine growth restriction. J Pediatr 154:201–206PubMedCrossRefGoogle Scholar
  56. 56.
    Casey PH, Whiteside-Mansell L, Barrett K, Bradley RH, Gargus R (2006) Impact of prenatal and/or postnatal growth problems in low birth weight preterm infants on school-age outcomes: an 8-year longitudinal evaluation. Pediatrics 118:1078–1086PubMedCrossRefGoogle Scholar
  57. 57.
    Wiedmeier JE, Joss-Moore LA, Lane RH, Neu J (2011) Early postnatal nutrition and programming of the preterm neonate. Nutr Rev 69:76–82PubMedCrossRefGoogle Scholar
  58. 58.
    Fu Q, Yu X, Callaway CW, Lane RH, McKnight RA (2009) Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J 23:2438–2449PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Flavia Indrio
    • 1
  • Luca Maggio
    • 2
  • Francesco Raimondi
    • 3
  1. 1.Department of PediatricsUniversity of BariBariItaly
  2. 2.Division of NeonatologyUniversità Cattolica del Sacro CuoreRomeItaly
  3. 3.Department of Medical Translational MedicineUniversità “Federico II”NaplesItaly

Personalised recommendations