Skeletal Muscle Damage in Intrauterine Growth Restriction

  • Leonard Năstase
  • Dragos Cretoiu
  • Silvia Maria Stoicescu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1088)


Intrauterine growth restriction (IUGR) represents a rate of fetal growth that is less than average for the population and the growth potential of a specific infant. IUGR produces infants who are small for gestational age (SGA) but also appropriate for gestational age (AGA). It refers to growth less than expected for gestational age and is most often under 10th percentiles for age. It develops during the late second and third trimesters of gestation. The etiology of IUGR is multifactorial. One of the most important factors which leads to IUGR is a decrease of nutrients and oxygen delivered to the fetus by the placenta. The growth of adipose tissue and skeletal muscle is limited by the declined fetal nutrient supply later in gestation. IUGR affects about 24% of babies born in developing countries. Worldwide, IUGR is the second cause of perinatal morbidity and mortality behind the premature birth and a major predisposing factor to metabolic disorders throughout postnatal life, even at adult age. Skeletal muscle represents about 35–40% of the body mass and plays an essential role in metabolic homeostasis, being responsible for 65% of fetal glucose consumption. A reduction in skeletal muscle growth characterizes IUGR fetuses compared to normal weight neonates. The decrease in muscle mass is not compensated after birth and persists until adulthood. This is a review of the literature, a neonatological, clinical point of view on the effects of IUGR on striated muscles. The available studies on this subject are currently the results of experimental research on animals, and information about the human fetus and newborn are scarce.


Intrauterine growth restriction Fetus Muscle Newborn Glucose 


  1. 1.
    Battaglia FC, Lubchenco LO (1967) A practical classification of newborn infants by weight and gestational age. J Pediatr 71(2):159–163CrossRefGoogle Scholar
  2. 2.
    Schlaudecker EP, Munoz FM, Bardaji A, Boghossian NS, Khalil A, Mousa H, Nesin M, Nisar MI, Pool V, Spiegel HML, Tapia MD, Kochhar S, Black S, Brighton Collaboration Small for Gestational Age Working Group (2017) Small for gestational age: case definition & guidelines for data collection, analysis, and presentation of maternal immunisation safety data. Vaccine 35(48 Pt A):6518–6528. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sharma D, Shastri S, Sharma P (2016) Intrauterine growth restriction: antenatal and postnatal aspects. Clin Med Insights Pediatr 10:67–83. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bocca-Tjeertes I, Bos A, Kerstjens J, de Winter A, Reijneveld S (2014) Symmetrical and asymmetrical growth restriction in preterm-born children. Pediatrics 133(3):e650–e656. CrossRefPubMedGoogle Scholar
  5. 5.
    Albu AR, Anca AF, Horhoianu VV, Horhoianu IA (2014) Predictive factors for intrauterine growth restriction. J Med Life 7(2):165–171PubMedPubMedCentralGoogle Scholar
  6. 6.
    de Boo HA, Harding JE (2006) The developmental origins of adult disease (barker) hypothesis. Aust N Z J Obstet Gynaecol 46(1):4–14. CrossRefPubMedGoogle Scholar
  7. 7.
    Sharma D, Shastri S, Farahbakhsh N, Sharma P (2016) Intrauterine growth restriction – part 1. J Matern Fetal Neonatal Med 29(24):3977–3987. CrossRefPubMedGoogle Scholar
  8. 8.
    Sharma D, Farahbakhsh N, Shastri S, Sharma P (2016) Intrauterine growth restriction – part 2. J Matern Fetal Neonatal Med 29(24):4037–4048. CrossRefPubMedGoogle Scholar
  9. 9.
    Jimbo T, Fujita Y, Yumoto Y, Fukushima K, Kato K (2015) Rare fetal complications associated with placental mesenchymal dysplasia: a report of two cases. J Obstet Gynaecol Res 41(2):304–308. CrossRefPubMedGoogle Scholar
  10. 10.
    Miller SL, Huppi PS, Mallard C (2016) The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome. J Physiol 594(4):807–823. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Lausman A, McCarthy FP, Walker M, Kingdom J (2012) Screening, diagnosis, and management of intrauterine growth restriction. J Obstet Gynaecol JOGC (Journal d’obstetrique et gynecologie du Canada: JOGC) 34(1):17–28. CrossRefGoogle Scholar
  12. 12.
    Lausman A, Kingdom J, Maternal Fetal Medicine C (2013) Intrauterine growth restriction: screening, diagnosis, and management. J Obstet Gynaecol JOGC (Journal d’obstetrique et gynecologie du Canada: JOGC) 35(8):741–748. CrossRefGoogle Scholar
  13. 13.
    Thorn SR, Rozance PJ, Brown LD, Hay WW Jr (2011) The intrauterine growth restriction phenotype: fetal adaptations and potential implications for later life insulin resistance and diabetes. Semin Reprod Med 29(3):225–236. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Yates DT, Macko AR, Nearing M, Chen X, Rhoads RP, Limesand SW (2012) Developmental programming in response to intrauterine growth restriction impairs myoblast function and skeletal muscle metabolism. J Pregnancy 2012:631038. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cosmi E, Grisan E, Fanos V, Rizzo G, Sivanandam S, Visentin S (2017) Growth abnormalities of fetuses and infants. BioMed Res Int 2017:3191308. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP (1999) Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 70(5):811–816. CrossRefPubMedGoogle Scholar
  17. 17.
    Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP (1994) Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37(6):624–631CrossRefGoogle Scholar
  18. 18.
    Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ (1996) Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 94(12):3246–3250CrossRefGoogle Scholar
  19. 19.
    Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett WC, Gillman MW, Hennekens CH, Speizer FE, Manson JE (1999) Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 130(4 Pt 1):278–284CrossRefGoogle Scholar
  20. 20.
    Kraus FT (2013) Fetal thrombotic vasculopathy: perinatal stroke, growth restriction, and other Sequelae. Surg Pathol Clin 6(1):87–100. CrossRefPubMedGoogle Scholar
  21. 21.
    Geremia C, Cianfarani S (2004) Insulin sensitivity in children born small for gestational age (SGA). Rev Diabet Stud RDS 1(2):58–65. CrossRefPubMedGoogle Scholar
  22. 22.
    Arends NJ, Boonstra VH, Duivenvoorden HJ, Hofman PL, Cutfield WS, Hokken-Koelega AC (2005) Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA). Clin Endocrinol 62(1):44–50. CrossRefGoogle Scholar
  23. 23.
    Calkins K, Devaskar SU (2011) Fetal origins of adult disease. Curr Probl Pediatr Adolesc Health Care 41(6):158–176. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hallows SE, Regnault TR, Betts DH (2012) The long and short of it: the role of telomeres in fetal origins of adult disease. J Pregnancy 2012:638476. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Alsaied T, Omar K, James JF, Hinton RB, Crombleholme TM, Habli M (2017) Fetal origins of adult cardiac disease: a novel approach to prevent fetal growth restriction induced cardiac dysfunction using insulin like growth factor. Pediatr Res 81(6):919–925. CrossRefPubMedGoogle Scholar
  26. 26.
    Langley-Evans SC (2009) Nutritional programming of disease: unravelling the mechanism. J Anat 215(1):36–51. CrossRefPubMedGoogle Scholar
  27. 27.
    Brown LD, Hay WW Jr (2016) Impact of placental insufficiency on fetal skeletal muscle growth. Mol Cell Endocrinol 435:69–77. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang J, Chen L, Li D, Yin Y, Wang X, Li P, Dangott LJ, Hu W, Wu G (2008) Intrauterine growth restriction affects the proteomes of the small intestine, liver, and skeletal muscle in newborn pigs. J Nutr 138(1):60–66. CrossRefPubMedGoogle Scholar
  29. 29.
    Tao C, Sifuentes A, Holland WL (2014) Regulation of glucose and lipid homeostasis by adiponectin: effects on hepatocytes, pancreatic beta cells and adipocytes. Best Pract Res Clin Endocrinol Metab 28(1):43–58. CrossRefPubMedGoogle Scholar
  30. 30.
    Roder PV, Wu B, Liu Y, Han W (2016) Pancreatic regulation of glucose homeostasis. Exp Mol Med 48:e219. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yang J (2014) Enhanced skeletal muscle for effective glucose homeostasis. Prog Mol Biol Transl Sci 121:133–163. CrossRefPubMedGoogle Scholar
  32. 32.
    Loos RJ, Beunen G, Fagard R, Derom C, Vlietinck R (2002) Birth weight and body composition in young women: a prospective twin study. Am J Clin Nutr 75(4):676–682. CrossRefPubMedGoogle Scholar
  33. 33.
    Finstad SE, Emaus A, Potischman N, Barrett E, Furberg AS, Ellison PT, Jasienska G, Thune I (2009) Influence of birth weight and adult body composition on 17beta-estradiol levels in young women. Cancer Causes Control CCC 20(2):233–242. CrossRefPubMedGoogle Scholar
  34. 34.
    Fall CH (2011) Evidence for the intra-uterine programming of adiposity in later life. Ann Hum Biol 38(4):410–428. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ballard PL (1980) Hormonal influences during fetal lung development. Ciba Found Symp 78:251–274PubMedGoogle Scholar
  36. 36.
    Forhead AJ, Fowden AL (2014) Thyroid hormones in fetal growth and prepartum maturation. J Endocrinol 221(3):R87–R103. CrossRefPubMedGoogle Scholar
  37. 37.
    Dunlop K, Cedrone M, Staples JF, Regnault TR (2015) Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity. Nutrients 7(2):1202–1216. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski JM, Bononi A, Giorgi C, Marchi S, Missiroli S, Poletti F, Wieckowski MR, Pinton P (2012) ATP synthesis and storage. Purinergic Signalling 8(3):343–357. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dimitriadis G, Mitrou P, Lambadiari V, Maratou E, Raptis SA (2011) Insulin effects in muscle and adipose tissue. Diabetes Res Clin Pract 93(Suppl 1):S52–S59. CrossRefPubMedGoogle Scholar
  40. 40.
    Limesand SW, Rozance PJ, Zerbe GO, Hutton JC, Hay WW Jr (2006) Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction. Endocrinology 147(3):1488–1497. CrossRefPubMedGoogle Scholar
  41. 41.
    Davis TA, Suryawan A, Orellana RA, Fiorotto ML, Burrin DG (2010) Amino acids and insulin are regulators of muscle protein synthesis in neonatal pigs. Animal Int J Anim Biosci 4(11):1790–1796. CrossRefGoogle Scholar
  42. 42.
    Orellana RA, Kimball SR, Suryawan A, Escobar J, Nguyen HV, Jefferson LS, Davis TA (2007) Insulin stimulates muscle protein synthesis in neonates during endotoxemia despite repression of translation initiation. Am J Phys Endocrinol Metab 292(2):E629–E636. CrossRefGoogle Scholar
  43. 43.
    Limesand SW, Rozance PJ, Brown LD, Hay WW Jr (2009) Effects of chronic hypoglycemia and euglycemic correction on lysine metabolism in fetal sheep. Am J Phys Endocrinol Metab 296(4):E879–E887. CrossRefGoogle Scholar
  44. 44.
    Yee D (2012) Insulin-like growth factor receptor inhibitors: baby or the bathwater. J Natl Cancer Inst 104(13):975–981. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sadaba MC, Martin-Estal I, Puche JE, Castilla-Cortazar I (2016) Insulin-like growth factor 1 (IGF-1) therapy: mitochondrial dysfunction and diseases. Biochim Biophys Acta 1862(7):1267–1278. CrossRefPubMedGoogle Scholar
  46. 46.
    Marconi AM, Paolini CL, Zerbe G, Battaglia FC (2006) Lactacidemia in intrauterine growth restricted (IUGR) pregnancies: relationship to clinical severity, oxygenation and placental weight. Pediatr Res 59(4 Pt 1):570–574. CrossRefPubMedGoogle Scholar
  47. 47.
    Rozance PJ, Anderson M, Martinez M, Fahy A, Macko AR, Kailey J, Seedorf GJ, Abman SH, Hay WW Jr, Limesand SW (2015) Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep. Diabetes 64(2):555–564. CrossRefPubMedGoogle Scholar
  48. 48.
    Bansal S, Deka D, Dhadwal V, Mahendru R (2016) Doppler changes as the earliest parameter in fetal surveillance to detect fetal compromise in intrauterine growth-restricted fetuses. Srp Arh Celok Lek 144(1–2):69–73CrossRefGoogle Scholar
  49. 49.
    Stott D, Bolten M, Salman M, Paraschiv D, Clark K, Kametas NA (2016) Maternal demographics and hemodynamics for the prediction of fetal growth restriction at booking, in pregnancies at high risk for placental insufficiency. Acta Obstet Gynecol Scand 95(3):329–338. CrossRefPubMedGoogle Scholar
  50. 50.
    Audette MC, Kingdom JC (2018) Screening for fetal growth restriction and placental insufficiency. Semin Fetal Neonatal Med 23(2):119–125. CrossRefPubMedGoogle Scholar
  51. 51.
    Turan S, Turan OM (2018) Harmony behind the trumped-shaped vessel: the essential role of the Ductus Venosus in fetal medicine. Balkan Med J 35(2):124–130. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Yan X, Zhu MJ, Dodson MV, Du M (2013) Developmental programming of fetal skeletal muscle and adipose tissue development. J Genomic 1:29–38. CrossRefGoogle Scholar
  53. 53.
    Yablonka-Reuveni Z, Rudnicki MA, Rivera AJ, Primig M, Anderson JE, Natanson P (1999) The transition from proliferation to differentiation is delayed in satellite cells from mice lacking MyoD. Dev Biol 210(2):440–455. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    White RB, Bierinx AS, Gnocchi VF, Zammit PS (2010) Dynamics of muscle fibre growth during postnatal mouse development. BMC Dev Biol 10:21. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Hernandez-Andrade E, Stampalija T, Figueras F (2013) Cerebral blood flow studies in the diagnosis and management of intrauterine growth restriction. Curr Opin Obstet Gynecol 25(2):138–144. CrossRefPubMedGoogle Scholar
  56. 56.
    Shamim B, Conceicao MS, Callahan MJ, Camera DM (2018) Where do satellite cells orbit? An endomysium space odyssey. J Physiol 596:1791. CrossRefPubMedGoogle Scholar
  57. 57.
    Rhoads RP, Baumgard LH, El-Kadi SW, Zhao LD (2016) Physiology and endocrinology symposium: roles for insulin-supported skeletal muscle growth. J Anim Sci 94(5):1791–1802. CrossRefPubMedGoogle Scholar
  58. 58.
    Widdowson EM, Crabb DE, Milner RD (1972) Cellular development of some human organs before birth. Arch Dis Child 47(254):652–655CrossRefGoogle Scholar
  59. 59.
    Karunaratne JF, Ashton CJ, Stickland NC (2005) Fetal programming of fat and collagen in porcine skeletal muscles. J Anat 207(6):763–768. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Stickland NC (1975) A detailed analysis of the effects of various fixatives on animal tissue with particular reference to muscle tissue. Stain Technol 50(4):255–264CrossRefGoogle Scholar
  61. 61.
    Wigmore PM, Stickland NC (1983) Muscle development in large and small pig fetuses. J Anat 137(Pt 2):235–245PubMedPubMedCentralGoogle Scholar
  62. 62.
    Li M, Zhou X, Chen Y, Nie Y, Huang H, Chen H, Mo D (2015) Not all the number of skeletal muscle fibers is determined prenatally. BMC Dev Biol 15:42. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Soto SM, Blake AC, Wesolowski SR, Rozance PJ, Barthel KB, Gao B, Hetrick B, McCurdy CE, Garza NG, Hay WW Jr, Leinwand LA, Friedman JE, Brown LD (2017) Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro. J Endocrinol 232(3):475–491. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Yates DT, Clarke DS, Macko AR, Anderson MJ, Shelton LA, Nearing M, Allen RE, Rhoads RP, Limesand SW (2014) Myoblasts from intrauterine growth-restricted sheep fetuses exhibit intrinsic deficiencies in proliferation that contribute to smaller semitendinosus myofibres. J Physiol 592(14):3113–3125. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Bailey P, Holowacz T, Lassar AB (2001) The origin of skeletal muscle stem cells in the embryo and the adult. Curr Opin Cell Biol 13(6):679–689CrossRefGoogle Scholar
  66. 66.
    Du M, Yan X, Tong JF, Zhao J, Zhu MJ (2010) Maternal obesity, inflammation, and fetal skeletal muscle development. Biol Reprod 82(1):4–12. CrossRefPubMedGoogle Scholar
  67. 67.
    Biressi S, Molinaro M, Cossu G (2007) Cellular heterogeneity during vertebrate skeletal muscle development. Dev Biol 308(2):281–293. CrossRefPubMedGoogle Scholar
  68. 68.
    Morrison JL, Regnault TR (2016) Nutrition in pregnancy: optimising maternal diet and fetal adaptations to altered nutrient supply. Nutrients 8(6):342. CrossRefPubMedCentralGoogle Scholar
  69. 69.
    Wang J, Feng C, Liu T, Shi M, Wu G, Bazer FW (2017) Physiological alterations associated with intrauterine growth restriction in fetal pigs: causes and insights for nutritional optimization. Mol Reprod Dev 84(9):897–904. CrossRefPubMedGoogle Scholar
  70. 70.
    Myrie SB, McKnight LL, King JC, McGuire JJ, Van Vliet BN, Cheema SK, Bertolo RF (2017) Intrauterine growth-restricted Yucatan miniature pigs experience early catch-up growth, leading to greater adiposity and impaired lipid metabolism as young adults. Appl Physiol Nutr Metab Physiologie appliquee, nutrition et metabolisme 42(12):1322–1329. CrossRefPubMedGoogle Scholar
  71. 71.
    Pardo CE, Berard J, Kreuzer M, Bee G (2013) Intrauterine crowding impairs formation and growth of secondary myofibers in pigs. Animal Int J Anim Biosci 7(3):430–438. CrossRefGoogle Scholar
  72. 72.
    Moss FP, Leblond CP (1971) Satellite cells as the source of nuclei in muscles of growing rats. Anat Rec 170(4):421–435. CrossRefPubMedGoogle Scholar
  73. 73.
    Mauro A (1961) Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol 9:493–495CrossRefGoogle Scholar
  74. 74.
    Kuang S, Kuroda K, Le Grand F, Rudnicki MA (2007) Asymmetric self-renewal and commitment of satellite stem cells in muscle. Cell 129(5):999–1010. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Boonen KJ, Post MJ (2008) The muscle stem cell niche: regulation of satellite cells during regeneration. Tissue Eng Part B Rev 14(4):419–431. CrossRefPubMedGoogle Scholar
  76. 76.
    Le Grand F, Rudnicki MA (2007) Skeletal muscle satellite cells and adult myogenesis. Curr Opin Cell Biol 19(6):628–633. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Allen RE, Rankin LL (1990) Regulation of satellite cells during skeletal muscle growth and development. Proc Soc Exp Biol Med 194(2):81–86CrossRefGoogle Scholar
  78. 78.
    Boldrin L, Muntoni F, Morgan JE (2010) Are human and mouse satellite cells really the same? The journal of histochemistry and cytochemistry: official journal of the. Hist Soc 58(11):941–955. CrossRefGoogle Scholar
  79. 79.
    Ono Y, Boldrin L, Knopp P, Morgan JE, Zammit PS (2010) Muscle satellite cells are a functionally heterogeneous population in both somite-derived and branchiomeric muscles. Dev Biol 337(1):29–41. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Katyal R, Singh SP, Joshi HS, Joshi G, Singh A (2016) An assessment of the validity of the nutritional indices among under-fives in the catchment area of rural health and training center of a teaching institute in Bareilly. J Fam Med Prim Care 5(2):383–386. CrossRefGoogle Scholar
  81. 81.
    Soundarya M, Basavaprabhu A, Raghuveera K, Baliga B, Shivanagaraja B (2012) Comparative assessment of fetal malnutrition by anthropometry and CAN score. Iran J Pediatr 22(1):70–76PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Leonard Năstase
    • 1
    • 2
  • Dragos Cretoiu
    • 1
    • 2
  • Silvia Maria Stoicescu
    • 1
    • 2
  1. 1.Carol Davila University of Medicine and PharmacyBucharestRomania
  2. 2.Alessandrescu-Rusescu National Institute for the Mother and Child Health, Polizu MaternityBucharestRomania

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