Heart and Vessels

, Volume 31, Issue 9, pp 1504–1513 | Cite as

Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study

  • Kaarin Mäkikallio
  • Jyotsna Shah
  • Cameron Slorach
  • Hong Qin
  • John Kingdom
  • Sarah Keating
  • Ed Kelly
  • Cedric Manlhiot
  • Andrew Redington
  • Edgar Jaeggi
Original Article


The association between low birth weight and premature cardiovascular disease has led to the “prenatal origin of adult disease-hypothesis”. We postulated that fetal growth restriction is associated with cardiovascular changes detectable at birth and in early infancy. Fifty-two appropriately grown fetuses (AGA) and 60 growth-restricted fetuses (FGR) with (n = 20) or without (n = 40) absent or reversed end-diastolic umbilical artery blood flow were prospectively examined by echocardiography before birth, at 1 week and 6 months of life. The impact of growth restriction on postnatal blood pressure, heart rate, cardiovascular dimensions, and function, as well as on vascular morphology of umbilical cord vessels was studied. FGR fetuses displayed significant blood flow redistribution and were delivered earlier with lower birth weights than AGA fetuses. After adjustment for gender, gestational age, and weight at birth, there were no intergroup differences in blood pressure, heart rate, left ventricular morphology, mass, and performance, and in cord vessel morphology. During the first 6 months of life brachioradial pulse wave velocity increased more in FGR fetuses, while other parameters describing vascular stiffness remained comparable between the groups. Fetal growth restriction had no detectable adverse impact on cardiovascular dimensions and function at birth. Cardiovascular findings also remained comparable during the first 6 months of life between the groups except a higher increase in brachioradial pulse wave velocity in the FGR group. Our observations suggest that abnormalities that link reduced intrauterine growth with premature cardiovascular diseases may commence later in childhood, indicating a potential window for screening and prevention.


Intrauterine growth restriction Placental insufficiency Echocardiography Doppler Pulse wave velocity 


  1. 1.
    Barker DJ (1992) The fetal origins of adult hypertension. J Hypertens Suppl 10(7):S39–S44PubMedGoogle Scholar
  2. 2.
    Barker DJ (1995) Fetal origins of coronary heart disease. BMJ 311(6998):171–174CrossRefPubMedGoogle Scholar
  3. 3.
    Launer LJ, Hofman A, Grobbee DE (1993) Relation between birth weight and blood pressure: longitudinal study of infants and children. BMJ 307(6917):1451–1454CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Johansson S, Iliadou A, Bergvall N, Tuvemo T, Norman M, Cnattingius S (2005) Risk of high blood pressure among young men increases with the degree of immaturity at birth. Circulation 112(22):3430–3436CrossRefPubMedGoogle Scholar
  5. 5.
    Law CM, Shiell AW, Newsome CA, Syddall HE, Shinebourne EA, Fayers PM, Barker DJ, Cruddas AM, Fall CH (2002) Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation 105(9):1088–1092CrossRefPubMedGoogle Scholar
  6. 6.
    Brodszki J, Lanne T, Marsal K, Ley D (2005) Impaired vascular growth in late adolescence after intrauterine growth restriction. Circulation 111(20):2623–2628CrossRefPubMedGoogle Scholar
  7. 7.
    Leeson CP, Kattenhorn M, Morley R, Lucas A, Deanfield JE (2001) Impact of low birth weight and cardiovascular risk factors on endothelial function in early adult life. Circulation 103(9):1264–1268CrossRefPubMedGoogle Scholar
  8. 8.
    Martin H, Hu J, Gennser G, Norman M (2000) Impaired endothelial function and increased carotid stiffness in 9-year-old children with low birthweight. Circulation 102(22):2739–2744CrossRefGoogle Scholar
  9. 9.
    Cosmi E, Fanelli T, Mautone AJ, Zanardo V (2009) Aortic intima media thickness in fetuses and children with intrauterine growth restriction. Obstet Gynecol 114(5):1109–1114CrossRefPubMedGoogle Scholar
  10. 10.
    Martyn CN, Gale CR, Jespersen S, Sherriff SB (1998) Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet 352(9123):173–178CrossRefPubMedGoogle Scholar
  11. 11.
    Silver LE, Decamps PJ, Korst LM, Platt LD, Castro L (2003) Intrauterine growth restriction is accompanied by decreased renal volume in the human fetus. Am J Obstet Gynecol 188(5):1320–1325CrossRefPubMedGoogle Scholar
  12. 12.
    Zanardo V, Fanelli T, Weiner G, Fanos V, Zaninotto M, Visentin S, Cavallin F, Trevisanuto D, Cosmi E (2011) Intrauterine growth restriction is associated with persistent aortic wall thickening and glomerular proteinuria during infancy. Kidney Int 80(1):119–123CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Keijzer-Veen MG, Dulger A, Dekker FW, Nauta J, van der Heijden BJ (2010) Very preterm birth is a risk factor for increased systolic blood pressure at a young adult age. Pediatr Nephrol 25(3):509–516CrossRefPubMedGoogle Scholar
  14. 14.
    Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271(5 Pt 1):C1424–C1437PubMedGoogle Scholar
  15. 15.
    Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJ (1999) Catch-up growth in childhood and death from coronary heart disease: longitudinal study. BMJ 318(7181):427–431CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Walker BR, McConnachie A, Noon JP, Webb DJ, Watt GC (1998) Contribution of parental blood pressures to association between low birth weight and adult high blood pressure: cross sectional study. BMJ 316(7134):834–837CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, Blondel B, Breart G (2001) A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 108(2):E35CrossRefPubMedGoogle Scholar
  18. 18.
    Acharya G, Wilsgaard T, Berntsen GK, Maltau JM, Kiserud T (2005) Reference ranges for serial measurements of blood velocity and pulsatility index at the intra-abdominal portion, and fetal and placental ends of the umbilical artery. Ultrasound Obstet Gynecol 26(2):162–169CrossRefPubMedGoogle Scholar
  19. 19.
    Giles WB, Trudinger BJ, Baird PJ (1985) Fetal umbilical artery flow velocity waveforms and placental resistance: pathological correlation. Br J Obstet Gynaecol 92(1):31–38CrossRefPubMedGoogle Scholar
  20. 20.
    Hadlock FP, Harrist RB, Carpenter RJ, Deter RL, Park SK (1984) Sonographic estimation of fetal weight. The value of femur length in addition to head and abdomen measurements. Radiology 150(2):535–540CrossRefPubMedGoogle Scholar
  21. 21.
    Makikallio K, Vuolteenaho O, Jouppila P, Rasanen J (2002) Ultrasonographic and biochemical markers of human fetal cardiac dysfunction in placental insufficiency. Circulation 105(17):2058–2063CrossRefPubMedGoogle Scholar
  22. 22.
    Nii M, Roman KS, Kingdom J, Redington AN, Jaeggi ET (2006) Assessment of the evolution of normal fetal diastolic function during mid and late gestation by spectral Doppler tissue echocardiography. J Am Soc Echocardiogr 19(12):1431–1437CrossRefPubMedGoogle Scholar
  23. 23.
    Schneider C, McCrindle BW, Carvalho JS, Hornberger LK, McCarthy KP, Daubeney PE (2005) Development of z scores for fetal cardiac dimensions from echocardiography. Ultrasound Obstet Gynecol 26(6):599–605CrossRefPubMedGoogle Scholar
  24. 24.
    Crispi F, Bijnens B, Figueras F, Bartrons J, Eixarch E, Le Noble F, Ahmed A, Gratacos E (2010) Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation 121(22):2427–2436CrossRefPubMedGoogle Scholar
  25. 25.
    Pettersen MD, Du W, Skeens ME, Humes RA (2008) Regression equations for calculation of z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study. J Am Soc Echocardiogr 21(8):922–934CrossRefPubMedGoogle Scholar
  26. 26.
    Sarkola T, Manlhiot C, Slorach C, Bradley TJ, Hui W, Mertens L, Redington A, Jaeggi E (2012) Evolution of the arterial structure and function from infancy to adolescence is related to anthropometric and blood pressure changes. Arterioscler Thromb Vascular Biol 32(10):2516–2524CrossRefGoogle Scholar
  27. 27.
    O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE (2002) Clinical applications of arterial stiffness; definitions and reference values. Am J Hypertens 15(5):426–444CrossRefPubMedGoogle Scholar
  28. 28.
    Sandor GG, Hishitani T, Petty RE, Potts MT, Desouza A, Desouza E, Potts JE (2003) A novel Doppler echocardiographic method of measuring the biophysical properties of the aorta in pediatric patients. J Am Soc Echocardiogr 16(7):745–750CrossRefPubMedGoogle Scholar
  29. 29.
    Cheung YF, Taylor MJ, Fisk NM, Redington AN, Gardiner HM (2000) Fetal origins of reduced arterial distensibility in the donor twin in twin-twin transfusion syndrome. Lancet 355(9210):1157–1158CrossRefPubMedGoogle Scholar
  30. 30.
    Koopman LP, Slorach C, Manlhiot C, McCrindle BW, Friedberg MK, Mertens L, Jaeggi ET (2010) Myocardial tissue Doppler velocity imaging in children: comparative study between two ultrasound systems. J Am Soc Echocardiogr 23(9):929–937CrossRefPubMedGoogle Scholar
  31. 31.
    Wladimiroff JW, vd Wijngaard JA, Degani S, Noordam MJ, van Eyck J, Tonge HM (1987) Cerebral and umbilical arterial blood flow velocity waveforms in normal and growth-retarded pregnancies. Obstet Gynecol 69(5):705–709PubMedGoogle Scholar
  32. 32.
    Hecher K, Bilardo CM, Stigter RH, Ville Y, Hackeloer BJ, Kok HJ, Senat MV, Visser GH (2001) Monitoring of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 18(6):564–570CrossRefPubMedGoogle Scholar
  33. 33.
    Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A, Pardi G, Battaglia FC, Galan HL (2002) Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 19(2):140–146CrossRefPubMedGoogle Scholar
  34. 34.
    Kiserud T, Ebbing C, Kessler J, Rasmussen S (2006) Fetal cardiac output, distribution to the placenta and impact of placental compromise. Ultrasound Obstet Gynecol 28(2):126–136CrossRefPubMedGoogle Scholar
  35. 35.
    Senzaki H, Akagi M, Hishi T, Ishizawa A, Yanagisawa M, Masutani S, Kobayashi T, Awa S (2002) Age-associated changes in arterial elastic properties in children. Eur J Pediatr 161(10):547–551CrossRefPubMedGoogle Scholar
  36. 36.
    Skilton MR, Evans N, Griffiths KA, Harmer JA, Celermajer DS (2005) Aortic wall thickness in newborns with intrauterine growth restriction. Lancet 365(9469):1484–1486CrossRefPubMedGoogle Scholar
  37. 37.
    Leipala JA, Boldt T, Turpeinen U, Vuolteenaho O, Fellman V (2003) Cardiac hypertrophy and altered hemodynamic adaptation in growth-restricted preterm infants. Pediatr Res 53(6):989–993CrossRefPubMedGoogle Scholar
  38. 38.
    Mikkola K, Leipala J, Boldt T, Fellman V (2007) Fetal growth restriction in preterm infants and cardiovascular function at five years of age. J Pediatr 151(5):494–499CrossRefPubMedGoogle Scholar
  39. 39.
    Sehgal A, Doctor T, Menahem S (2013) Cardiac function and arterial biophysical properties in small for gestational age infants: postnatal manifestations of fetal programming. J Pediatr 163(5):1296–1300CrossRefPubMedGoogle Scholar
  40. 40.
    Robel-Tillig E, Knupfer M, Vogtmann C (2003) Cardiac adaptation in small for gestational age neonates after prenatal hemodynamic disturbances. Early Hum Dev 72(2):123–129CrossRefPubMedGoogle Scholar
  41. 41.
    Bilge I, Poyrazoglu S, Bas F, Emre S, Sirin A, Gokalp S, Eryilmaz S, Hekim N, Darendeliler F (2011) Ambulatory blood pressure monitoring and renal functions in term small-for-gestational age children. Pediatr Nephrol 26(1):119–126CrossRefGoogle Scholar
  42. 42.
    Wen X, Triche EW, Hogan JW, Shenassa ED, Buka SL (2011) Prenatal factors for childhood blood pressure mediated by intrauterine and/or childhood growth? Pediatrics 127(3):e713–e721CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB (2000) Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ 320(7240):967–971CrossRefPubMedCentralGoogle Scholar
  44. 44.
    Gomes FM, Subramanian SV, Escobar AM, Valente MH, Grisi SJ, Brentani A, Fink G (2013) No association between low birth weight and cardiovascular risk factors in early adulthood: evidence from Sao Paulo, Brazil. PLoS ONE 8(6):e66554CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  1. 1.Fetal Cardiac Program, The Labatt Family Heart Centre, Department of PediatricsThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of Physiology and Experimental MedicineThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Departments of Obstetrics and Gynecology, Neonatology, and Pathology, Mount Sinai HospitalUniversity of TorontoTorontoCanada
  4. 4.Department of Obstetrics and GynecologyOulu University Hospital and University of OuluOuluFinland

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