Pediatric Cardiology

, 30:3 | Cite as

NT-Pro-B-type Natriuretic Peptide in Infants and Children: Reference Values Based on Combined Data from Four Studies

  • Amiram NirEmail author
  • Angelika Lindinger
  • Manfred Rauh
  • Benjamin Bar-Oz
  • Stephanie Laer
  • Lynn Schwachtgen
  • Andreas Koch
  • Jan Falkenberg
  • Thomas S. Mir


In cardiology, B-type natriuretic peptide and the amino terminal segment of its prohormone (NT-proBNP) are important biomarkers. The importance of these peptides as markers for heart disease in pediatric cardiology is reviewed. The peptide levels are dependent on age, assay, and possibly gender. The normal value range and upper limits for infants and children are needed. To determine reference values, data were combined from four studies that measured NT-proBNP levels in normal infants and children using the same electrochemiluminescence assay. The age intervals for the upper limits of normal were chosen for intervals in which no age-dependent change was observed. Statistical analysis was performed on log-transformed data. A total of 690 subjects (47% males) ages birth to 18 years were included in the review. The levels of NT-proBNP were highest in the first days of life, then showed a marked decline in the first week or weeks. The peptide levels continued to decline gradually with age (r = 0.43; p < 0.001). Male and female levels differed only for children ages 10 to 14 years. However, the upper limit of normal did not differ between the boys and girls in any age group. The findings lead to the conclusion that B-type natriuretic peptide (BNP) and NT-proBNP are important markers for heart disease in pediatric cardiology. The levels of NT-proBNP are highest in the first days of life and decrease drastically thereafter. A mild gradual decline occurs with age throughout childhood. Girls have somewhat higher levels of NT-proBNP during puberty.


Children Heart disease Infants Natriuretic peptides Reference values 



We thank Roche Diagnostics in supplying the test materials for some of the studies. Stephanie Laer was a recipient of the Heisenberg Program of the Deutsche Forschungsge meinschaft (DFG). A. Nir has received support in the form of travel expenses and speaker fees from Roche Diagnostics.


  1. 1.
    Albers S, Mir TS, Haddad M, Läer S (2006) N-terminal pro Brain natriuretic peptide: evaluation of pediatric reference values including method comparison and interlaboratory variability. Clin Chem Lab Med. 44:80–85PubMedCrossRefGoogle Scholar
  2. 2.
    Berry JG, Askovich B, Shaddy RE et al (2007) Prognostic value of B-type natriuretic peptide in surgical palliation of children with single-ventricle congenital heart disease. Pediatr Cardiol 29:70–75PubMedCrossRefGoogle Scholar
  3. 3.
    Bionda C, Bergerot C, Ardail D et al (2006) Plasma BNP and NT-proBNP assays by automated immunoanalyzers: analytical and clinical study. Ann Clin Lab Sci.36:299–306Google Scholar
  4. 4.
    Bland M (1995) The normal distribution. In: Bland M (ed) An introduction to medical statistics. Oxford University Press, Oxford, pp 111–118Google Scholar
  5. 5.
    Claudius I, Lan YT, Chang RK et al (2003) Usefulness of B-type natriuretic peptide as a noninvasive screening tool for cardiac allograft pathology in pediatric heart transplant recipients. Am J Cardiol 92:1368–1370PubMedCrossRefGoogle Scholar
  6. 6.
    Cohen S, Springer C, Perles Z et al (2005) Amino-terminal pro-brain-type natriuretic peptide: heart or lung disease in pediatric respiratory distress? Pediatrics 115:1347–1350PubMedCrossRefGoogle Scholar
  7. 7.
    Cowie MR, Mendez GF (2002) BNP and congestive heart failure. Prog Cardiovasc Dis 44:293–321PubMedCrossRefGoogle Scholar
  8. 8.
    Gerber IL, Stewart RAH, Legget ME et al (2003) Increased plasma natriuretic peptide levels reflect symptom onset in aortic stenosis. Circulation 107:1884–1890PubMedCrossRefGoogle Scholar
  9. 9.
    Gessler P, Knirsch W, Schmitt B et al (2006) Prognostic value of plasma n-terminal pro-brain natriuretic peptide in children with congenital heart defects and openheart surgery. J Pediatr 148:372–376PubMedCrossRefGoogle Scholar
  10. 10.
    Hsu JHL, Keller RL, Chikovani O et al (2007) B-type natriuretic peptide levels predict outcome after neonatal cardiac surgery. J Thorac Cardiovasc Surg 134:939–945PubMedCrossRefGoogle Scholar
  11. 11.
    Kawamura T, Wago M, Kawaguchi H et al (2000) Plasma brain natriuretic peptide concentrations in patients with Kawasaki disease. Pediatr Int 42:241–248PubMedCrossRefGoogle Scholar
  12. 12.
    Koch A, Rauh M, Zink S, Singer H (2006) Decreasing ratio of plasma N-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide according to age. Acta Paediatr 95:805–809PubMedCrossRefGoogle Scholar
  13. 13.
    Koch A, Singer H (2003) Normal values of B-type natriuretic peptide in infants, children, and adolescents. Heart 89:875–878PubMedCrossRefGoogle Scholar
  14. 14.
    Kunii Y, Kamada M, Ohtsuki S et al (2003) Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease. Acta Med Okayama 57:191–197PubMedGoogle Scholar
  15. 15.
    Law YM, Ettedgui J, Beerman L et al (2006) Comparison of plasma B-type natriuretic peptide levels in single ventricle patients with systemic ventricle heart failure versus isolated cavopulmonary failure. Am J Cardiol 98:520–524PubMedCrossRefGoogle Scholar
  16. 16.
    Lubien E, DeMaria A, Krishnaswamy P et al (2002) Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation 105:595–601PubMedCrossRefGoogle Scholar
  17. 17.
    Mair J, Hammerer-Lercher A, Puschendorf B (2001) The impact of cardiac natriuretic peptide determination on the diagnosis and management of heart failure. Clin Chem Lab Med 39:571–588PubMedCrossRefGoogle Scholar
  18. 18.
    McCullough PA, Sandberg KR (2003) Sorting out the evidence on natriuretic peptides. Rev Cardiovasc Med 4(Suppl 4):S13–S19PubMedGoogle Scholar
  19. 19.
    Mir TS, Flato M, Falkenberg J et al (2006) Plasma concentrations of N-terminal brain natriuretic peptide in healthy children, adolescents, and young adults: effect of age and gender. Pediatr Cardiol 27:73–77PubMedCrossRefGoogle Scholar
  20. 20.
    Mir TS, Laux R, Hellwege HH et al (2003) Plasma concentrations of aminoterminal pro atrial natriuretic peptide and aminoterminal pro brain natriuretic peptide in healthy neonates: marked and rapid increase after birth. Pediatrics 112:896–899PubMedCrossRefGoogle Scholar
  21. 21.
    Nakamura T, Sakamoto K, Yamano T et al (2002) Increased plasma brain natriuretic peptide level as a guide for silent myocardial ischemia in patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 39:1657–1663PubMedCrossRefGoogle Scholar
  22. 22.
    Nir A (2007) ABCs of the natriuretic peptides: cardiac aspects. Horm Res 67(Suppl 1):77–80CrossRefGoogle Scholar
  23. 23.
    Nir A, Bar-Oz B, Perles Z et al (2004) N-terminal pro-B-type natriuretic peptide: reference plasma levels from birth to adolescence: Elevated levels at birth and in heart diseases. Acta Paediatr 93:603–607PubMedCrossRefGoogle Scholar
  24. 24.
    Ohuchi H, Takasugi H, Ohashi H et al (2003) Stratification of pediatric heart failure on the basis of neurohormonal and cardiac autonomic nervous activities in patients with congenital heart disease. Circulation 108:2368–2376PubMedCrossRefGoogle Scholar
  25. 25.
    Price JF, Thomas AK, Grenier M et al (2006) B-type natriuretic peptide predicts adverse cardiovascular events in pediatric outpatients with chronic left ventricular systolic dysfunction. Circulation 114:1063–1069PubMedCrossRefGoogle Scholar
  26. 26.
    Rauh M, Koch A (2003) Plasma N-terminal pro-B-type natriuretic peptide concentrations in control population of infants and children. Clin Chem 49:1563–1564PubMedCrossRefGoogle Scholar
  27. 27.
    Reynolds EW, Ellington JG, Vranicar M, Bada HS (2004) Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics 114:1297–1304PubMedCrossRefGoogle Scholar
  28. 28.
    Schwachtgen L, Herrmann M, Georg T et al (2005) Reference values of NT-proBNP serum concentrations in the umbilical cord blood and in healthy neonates and children. Z Kardiol 94:399–404PubMedCrossRefGoogle Scholar
  29. 29.
    Shih CY, Sapru A, Oishi P et al (2006) Alterations in plasma B-type natriuretic peptide levels after repair of congenital heart defects: A potential perioperative marker. Thorac Cardiovasc Surg 131:632–638CrossRefGoogle Scholar
  30. 30.
    Suda K, Matsumura M, Matsumoto M (2003) Clinical implication of plasma natriuretic peptides in children with ventricular septal defect. Pediatr Int 45:249–254PubMedCrossRefGoogle Scholar
  31. 31.
    Takeuchi D, Saji T, Takatsuki S, Fujiwara M (2007) Abnormal tissue Doppler images are associated with elevated plasma brain natriuretic peptide and increased oxidative stress in acute Kawasaki disease. Circ J 7:357–362CrossRefGoogle Scholar
  32. 32.
    Tan LH, Jefferies JL, Liang JF et al (2007) Concentrations of brain natriuretic peptide in the plasma predicts outcomes of treatment of children with decompensated heart failure admitted to the intensive care unit. Cardiol Young 17:397–406PubMedCrossRefGoogle Scholar
  33. 33.
    Weil J, Bidlingmaier F, Döhlemann C et al (1986) Comparison of plasma atrial natriuretic peptide levels in healthy children from birth to adolescence and in children with cardiac diseases. Pediatr Res 20:1328–1331PubMedCrossRefGoogle Scholar
  34. 34.
    Westerlind A, Wahlander H, Lindstedt G et al (2004) Clinical signs of heart failure are associated with increased levels of natriuretic peptide types B and A in children with congenital heart defects or cardiomyopathy. Acta Paediatr 93:340–345PubMedCrossRefGoogle Scholar
  35. 35.
    Yoshibayashi M, Kamiya T, Saito Y et al (1995) Plasma brain natriuretic peptide concentrations in healthy children from birth to adolescence: marked and rapid increase after birth. Eur J Endocrinol 133:207–209PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Amiram Nir
    • 1
    Email author
  • Angelika Lindinger
    • 2
  • Manfred Rauh
    • 3
  • Benjamin Bar-Oz
    • 4
  • Stephanie Laer
    • 5
  • Lynn Schwachtgen
    • 2
  • Andreas Koch
    • 3
  • Jan Falkenberg
    • 6
  • Thomas S. Mir
    • 6
  1. 1.Pediatric CardiologyShaare Zedek Medical CenterJerusalemIsrael
  2. 2.Pediatric CardiologyUniversity Clinic of the SaarlandHomburg/SaarGermany
  3. 3.Pediatric CardiologyUniversity Clinic ErlangenErlangenGermany
  4. 4.Department of NeonatologyHadassah, Hebrew University Medical CenterJerusalemIsrael
  5. 5.Institute for Clinical Pharmacy and PharmacotherapyUniversity DuesseldorfDuesseldorfGermany
  6. 6.Pediatric CardiologyUniversity Heart CenterHamburgGermany

Personalised recommendations