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Factors affecting N-terminal pro-B-type natriuretic peptide levels in preterm infants and use in determination of haemodynamic significance of patent ductus arteriosus

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Abstract

This study aimed to investigate factors affecting N-terminal pro-B-type natriuretic peptide (NTproBNP) in preterm infants and the ability of NTproBNP to predict haemodynamically significant patent ductus arteriosus (HsPDA). Prospective cohort study of 51 infants < 30 weeks gestation. Blood NTproBNP and heart ultrasound were performed on day of life 3, 10, 28 and 36 weeks corrected age. NTproBNP levels analysed for prediction of HsPDA. The effect of gestational age, ventilation, hypoxia, bronchopulmonary dysplasia (BPD), creatinine and haemoglobin levels on NTproBNP levels were investigated. Infants with HsPDA had higher mean (SD) day 3 NTproBNP (1840 pmol/L (1058) versus 178 pmol/L (140) p < 0.001). Receiver operator curves of day 3 NTproBNP for prediction of day 3 and day 10 HsPDA had an area under the curve of 0.98 and 0.94, respectively. A chosen day 3 NTproBNP value of ≥ 287 pmol/L for the prediction of day 3 HsPDA correctly classified 92% (sensitivity 92%, specificity 92%). NTproBNP demonstrated only modest ability to predict severe BPD. Chronological but not gestational age affected NTproBNP. Ventilation, hypoxia and haemoglobin levels did not influence NTproBNP but creatinine level was positively correlated.

Conclusion: Day 3 NTproBNP is a useful biomarker to predict HsPDA and may be a valuable tool in future trial design.

What is Known:

• NTproBNP is a cardiac hormone used to diagnose and monitor cardiac dysfunction in adults and has been shown to be higher in premature infants with haemodynamically significant ductus arteriosus (HsPDA).

What is new:

• NTproBNP is highly predictive of ultrasound-defined HsPDA and may be a useful tool for further triage

• Early NTproBNP higher in infants who develop severe BPD and with renal impairment but not affected by gestational age, recent exposure to hypoxia or haemoglobin levels while late levels unexpectedly higher in those without BPD or HsPDA.

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Abbreviations

BPD:

Bronchopulmonary dysplasia

BNP:

B-type natriuretic peptide

Hb:

Haemoglobin

HsPDA:

Haemodynamically significant PDA

GA:

Gestational age

IQR:

Interquartile range

NICHD:

National Institute Child Health and Human Development

NTproBNP:

N-terminal pro-B-type natriuretic peptide

PDA:

Patent ductus arteriosus

ROC:

Receiver operating characteristic

SD:

Standard deviation

References

  1. Bagnoli F, Rossetti A, Casucci M, Mori A (2010) Aminoterminal B-type natriuretic peptide (NT-proBNP) in the therapy of patent ductus arteriosus. Minerva Pediatr 62(3 Suppl 1):67–70

    CAS  PubMed  Google Scholar 

  2. Bahlmann F, Krummenauer F, Spahn S, Gallinat R, Kampmann C (2011) Natriuretic peptide levels in intrauterine growth-restricted fetuses with absent and reversed end-diastolic flow of the umbilical artery in relation to ductus venosus flow velocities. J Perinat Med 39(5):529–537

    Article  CAS  PubMed  Google Scholar 

  3. Bakker J, Gies I, Slavenburg B, Bekers O, Delhaas T, van Dieijen-Visser M (2004) Reference values for N-terminal pro-B-type natriuretic peptide in umbilical cord blood. Clin Chem 50(12):2465. https://doi.org/10.1373/clinchem.2004.040253

    Article  CAS  PubMed  Google Scholar 

  4. Baptista MJ, Rocha G, Clemente F, Azevedo LF, Tibboel D, Leite-Moreira AF, Guimaraes H, Areias JC, Correia-Pinto J (2008) N-terminal-pro-B type natriuretic peptide as a useful tool to evaluate pulmonary hypertension and cardiac function in CDH infants. Neonatology 94(1):22–30

    Article  CAS  PubMed  Google Scholar 

  5. Barnes SC, Collinson PO, Galasko G, Lahiri A, Senior R (2004) Evaluation of N-terminal pro-B type natriuretic peptide analysis on the Elecsys 1010 and 2010 analysers. Ann Clin Biochem 41(Pt 6):459–463. https://doi.org/10.1258/0004563042466848

    Article  CAS  PubMed  Google Scholar 

  6. Bar-Oz B, Lev-Sagie A, Arad I, Salpeter L, Nir A (2005) N-terminal pro-B-type natriuretic peptide concentrations in mothers just before delivery, in cord blood, and in newborns. Clin Chem 51(5):926–927. https://doi.org/10.1373/clinchem.2005.048892

    Article  CAS  PubMed  Google Scholar 

  7. Benitz WE, Committee On Fetus And Newborn (2016) Patent ductus arteriosus in preterm infants. Pediatrics 137(1):e20153730. https://doi.org/10.1542/peds.2015-3730

    Article  Google Scholar 

  8. Bettencourt PM (2005) Clinical usefulness of B-type natriuretic peptide measurement: present and future perspectives. Heart 91(11):1489–1494. https://doi.org/10.1136/hrt.2005.063784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Casals G, Ros J, Sionis A, Davidson MM, Morales-Ruiz M, Jimenez W (2009) Hypoxia induces B-type natriuretic peptide release in cell lines derived from human cardiomyocytes. Am J Physiol Heart Circ Physiol 297(2):H550–H555. https://doi.org/10.1152/ajpheart.00250.2009

    Article  CAS  PubMed  Google Scholar 

  10. Chen S, Tacy T, Clyman R (2010) How useful are B-type natriuretic peptide measurements for monitoring changes in patent ductus arteriosus shunt magnitude? J Perinatol 30(12):780–785

    Article  CAS  PubMed  Google Scholar 

  11. Clyman RI, Chorne N (2007) Patent ductus arteriosus: evidence for and against treatment. J Pediatr 150(3):216–219. https://doi.org/10.1016/j.jpeds.2006.12.048

    Article  PubMed  PubMed Central  Google Scholar 

  12. Clyman RI, Couto J, Murphy GM (2012) Patent ductus arteriosus: are current neonatal treatment options better or worse than no treatment at all? Semin Perinatol 36(2):123–129. https://doi.org/10.1053/j.semperi.2011.09.022

    Article  PubMed  PubMed Central  Google Scholar 

  13. Condo M, Evans N, Bellu R, Kluckow M (2012) Echocardiographic assessment of ductal significance: retrospective comparison of two methods. Arch Dis Child Fetal Neonatal Ed 97(1):F35–F38. https://doi.org/10.1136/adc.2010.207233

    Article  PubMed  Google Scholar 

  14. Crispi F, Hernandez-Andrade E, Pelsers MM, Plasencia W, Benavides-Serralde JA, Eixarch E, Le Noble F, Ahmed A, Glatz JF, Nicolaides KH et al (2008) Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet Gynecol 199(3):254 e1–254 e8

    Article  Google Scholar 

  15. Cuna A, Kandasamy J, Fineberg N, Sims B (2013) B-type natriuretic peptide is a biomarker for pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. Res Rep Neonatology. 2013(3):33–36

    Google Scholar 

  16. da Graca RL, Hassinger DC, Flynn PA, Sison CP, Nesin M, Auld PA (2006) Longitudinal changes of brain-type natriuretic peptide in preterm neonates. Pediatrics 117(6):2183–2189. https://doi.org/10.1542/peds.2005-1387

    Article  PubMed  Google Scholar 

  17. Davlouros PA, Karatza AA, Xanthopoulou I, Dimitriou G, Georgiopoulou A, Mantagos S, Alexopoulos D (2011) Diagnostic role of plasma BNP levels in neonates with signs of congenital heart disease. Int J Cardiol 147(1):42–46. https://doi.org/10.1016/j.ijcard.2009.07.029

    Article  PubMed  Google Scholar 

  18. de Lemos JA, McGuire DK, Drazner MH (2003) B-type natriuretic peptide in cardiovascular disease. The Lancet 362(9380):316–322. https://doi.org/10.1016/S0140-6736(03)13976-1

    Article  Google Scholar 

  19. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, Wrage LA, Poole K (2005) National Institutes of Child Health and Human Development Neonatal Research Network. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 116(6):1353–1360. https://doi.org/10.1542/peds.2005-0249

    Article  PubMed  Google Scholar 

  20. El-Khuffash AF, Slevin M, McNamara PJ, Molloy EJ, Troponin T (2011) N-terminal pro natriuretic peptide and a patent ductus arteriosus scoring system predict death before discharge or neurodevelopmental outcome at 2 years in preterm infants. Arch Dis Child Fetal Neonatal Ed 96(2):F133–F137. https://doi.org/10.1136/adc.2010.185967

    Article  PubMed  Google Scholar 

  21. Evans N (2012) Diagnosis of the preterm patent ductus arteriosus: clinical signs, biomarkers, or ultrasound? Semin Perinatol 36(2):114–122. https://doi.org/10.1053/j.semperi.2011.09.021

    Article  PubMed  Google Scholar 

  22. Flynn PA, da Graca RL, Auld PA, Nesin M, Kleinman CS (2005) The use of a bedside assay for plasma B-type natriuretic peptide as a biomarker in the management of patent ductus arteriosus in premature neonates. J Pediatr 147(1):38–42. https://doi.org/10.1016/j.jpeds.2005.03.040

    Article  CAS  PubMed  Google Scholar 

  23. Foo JY, Wan Y, Schulz BL, Kostner K, Atherton J, Cooper-White J, Dimeski G, Punyadeera C (2013) Circulating fragments of N-terminal pro-B-type natriuretic peptides in plasma of heart failure patients. Clin Chem 59(10):1523–1531. https://doi.org/10.1373/clinchem.2012.200204

    Article  CAS  PubMed  Google Scholar 

  24. Fowlie PW, Davis PG, McGuire W (2010) Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 7:CD000174

    Google Scholar 

  25. Fried I, Bar-Oz B, Algur N, Fried E, Gavri S, Yatsiv I, Perles Z, Rein AJ, Zonis Z, Bass R et al (2006) Comparison of N-terminal pro-B-type natriuretic peptide levels in critically ill children with sepsis versus acute left ventricular dysfunction. Pediatrics 118(4):e1165–e1168. https://doi.org/10.1542/peds.2006-0569

    Article  PubMed  Google Scholar 

  26. Girsen A, Ala-Kopsala M, Makikallio K, Vuolteenaho O, Rasanen J (2007) Cardiovascular hemodynamics and umbilical artery N-terminal peptide of proB-type natriuretic peptide in human fetuses with growth restriction. Ultrasound Obstet Gynecol 29(3):296–303. https://doi.org/10.1002/uog.3934

    Article  CAS  PubMed  Google Scholar 

  27. Hammerer-Lercher A, Mair J, Tews G, Puschendorf B, Sommer R (2005) N-terminal pro-B-type natriuretic peptide concentrations are markedly higher in the umbilical cord blood of newborns than in their mothers. Clin Chem 51(5):913–915. https://doi.org/10.1373/clinchem.2004.046557

    Article  CAS  PubMed  Google Scholar 

  28. Hamrick SE, Hansmann G (2010) Patent ductus arteriosus of the preterm infant. Pediatrics 125(5):1020–1030. https://doi.org/10.1542/peds.2009-3506

    Article  PubMed  Google Scholar 

  29. Januzzi JL, Troughton R (2013) Are serial BNP measurements useful in heart failure management? Serial natriuretic peptide measurements are useful in heart failure management. Circulation 127(4):500–508. https://doi.org/10.1161/CIRCULATIONAHA.112.120485

    Article  PubMed  Google Scholar 

  30. Joseph L, Nir A, Hammerman C, Goldberg S, Ben Shalom E, Picard E (2010) N-terminal pro-B-type natriuretic peptide as a marker of bronchopulmonary dysplasia in premature infants. Am J Perinatol 27(5):381–386. https://doi.org/10.1055/s-0029-1243312

    Article  PubMed  Google Scholar 

  31. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C, Rosenfeld CR (2006) Prevalence of spontaneous closure of the ductus arteriosus in neonates at a birth weight of 1000 grams or less. Pediatrics 117(4):1113–1214. https://doi.org/10.1542/peds.2005-1528

    Article  PubMed  Google Scholar 

  32. Konig K, Guy KJ, Walsh G, Drew SM, Watkins A, Barfield CP (2014) The relationship between BNP, NTproBNP and echocardiographic measurements of systemic blood flow in very preterm infants. J Perinatol 34(4):296–300. https://doi.org/10.1038/jp.2014.2

    Article  CAS  PubMed  Google Scholar 

  33. Kort E (2016) Patent ductus arteriosus in the preterm infant: an update on morbidity and mortality. Curr Pediatr Rev 12(2):98–105. https://doi.org/10.2174/157339631202160506001621

    Article  PubMed  Google Scholar 

  34. Kulkarni M, Gokulakrishnan G, Price J, Fernandes CJ, Leeflang M, Pammi M (2015) Diagnosing significant PDA using natriuretic peptides in preterm neonates: a systematic review. Pediatrics 135(2):e510–e525. https://doi.org/10.1542/peds.2014-1995

    Article  PubMed  Google Scholar 

  35. Lechner E, Wiesinger-Eidenberger G, Wagner O, Weissensteiner M, Schreier-Lechner E, Leibetseder D, Arzt W, Tulzer G (2009) Amino terminal pro B-type natriuretic peptide levels are elevated in the cord blood of neonates with congenital heart defect. Pediatr Res 66(4):466–469. https://doi.org/10.1203/PDR.0b013e3181b3aee4

    Article  CAS  PubMed  Google Scholar 

  36. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA (2002) Breathing Not Properly Multinational Study Investigators. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 347(3):161–167. https://doi.org/10.1056/NEJMoa020233

    Article  CAS  PubMed  Google Scholar 

  37. Malviya MN, Ohlsson A, Shah SS (2013) Surgical versus medical treatment with cyclooxygenase inhibitors for symptomatic patent ductus arteriosus in preterm infants. Cochrane Database Syst Rev 3:CD003951

    Google Scholar 

  38. Mannarino S, Garofoli F, Mongini E, Cerbo RM, Codazzi AC, Tzialla C, Mazzucchelli I, Perotti G, Tinelli C, De Silvestri A, Manzoni P, Stronati M (2010) BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants. Early Hum Dev 86(5):295–298. https://doi.org/10.1016/j.earlhumdev.2010.04.003

    Article  CAS  PubMed  Google Scholar 

  39. McNamara PJ, Sehgal A (2007) Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 92(6):F424–F427. https://doi.org/10.1136/adc.2007.118117

    Article  PubMed  PubMed Central  Google Scholar 

  40. Merz W, Gembruch U (2014) Old tool – new application: NT-proBNP in fetal medicine. Ultrasound Obstet Gynecol 44(4):377–385. https://doi.org/10.1002/uog.13443

    Article  CAS  PubMed  Google Scholar 

  41. Mir TS, Laux R, Hellwege HH, Liedke B, Heinze C, von Buelow H, Laer S, Weil J (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(4):896–899. https://doi.org/10.1542/peds.112.4.896

    Article  PubMed  Google Scholar 

  42. Nir A, Lindinger A, Rauh M, Bar-Oz B, Laer S, Schwachtgen L, Koch A, Falkenberg J, Mir TS (2009) NT-pro-B-type natriuretic peptide in infants and children: reference values based on combined data from four studies. Pediatr Cardiol 30(1):3–8. https://doi.org/10.1007/s00246-008-9258-4

    Article  PubMed  Google Scholar 

  43. Occhipinti F, De Carolis M, De Rosa G, Bersani I, Lacerenza S, Cota F, Rubortone SA, Romagnoli C (2014) Correlation analysis between echocardiographic flow pattern and N-terminal-pro-brain natriuretic peptide for early targeted treatment of patent ductus arteriosus. J Matern Fetal Neonatal Med 27(17):1800–1804. https://doi.org/10.3109/14767058.2014.880879

    Article  CAS  PubMed  Google Scholar 

  44. Rauh M, Koch A (2003) Plasma N-terminal pro-B-type natriuretic peptide concentrations in a control population of infants and children. Clin Chem 49(9):1563–1564. https://doi.org/10.1373/49.9.1563

    Article  CAS  PubMed  Google Scholar 

  45. 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(5):1297–1304. https://doi.org/10.1542/peds.2004-0525

    Article  PubMed  Google Scholar 

  46. Sehgal A, Menahem S (2013) Interparametric ccorrelation between echocardiographic markers in preterm infants with patent ductus arteriosus. Pediatr Cardiol 34(5):1217–1217

    Article  Google Scholar 

  47. Sehgal A, Paul E, Menahem S (2013) Functional echocardiography in staging for ductal disease severity: role in predicting outcomes. Eur J Pediatr 172(2):179–184. https://doi.org/10.1007/s00431-012-1851-0

    Article  PubMed  Google Scholar 

  48. Sellmer A, Bjerre JV, Schmidt MR, McNamara PJ, Hjortdal VE, Host B, Bech BH, Henriksen TB (2013) Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 98(6):F505–F510. https://doi.org/10.1136/archdischild-2013-303816

    Article  PubMed  Google Scholar 

  49. Sellmer A, Hjortdal VE, Bjerre JV, Schmidt MR, McNamara PJ, Bech BH, Henriksen TB et al (2015) N-terminal pro-B type natriuretic peptide as a marker of bronchopulmonary dysplasia or death in very preterm neonates: a cohort study. PLoS One 10(10):e0140079. https://doi.org/10.1371/journal.pone.0140079

    Article  PubMed  PubMed Central  Google Scholar 

  50. Smith J, Goetze JP, Andersen CB, Vejlstrup N (2010) Practical application of natriuretic peptides in paediatric cardiology. Cardiol Young 20(4):353–363. https://doi.org/10.1017/S1047951110000211

    Article  PubMed  Google Scholar 

  51. Steinhelper ME (1993) Structure, expression, and genomic mapping of the mouse natriuretic peptide type-B gene. Circ Res 72(5):984–992. https://doi.org/10.1161/01.RES.72.5.984

    Article  CAS  PubMed  Google Scholar 

  52. Weber M, Hamm C (2006) Role of B-type natriuretic peptide (BNP) and NT-proBNP in clinical routine. Heart 92(6):843–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yajamanyam P, Kanani A, Rasiah S (2015) Management of patent ductus arteriosus in preterm infants-where do we stand? A UK national perspective. Congenit Heart Dis 10(1):86–87. https://doi.org/10.1111/chd.12170

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank BOPP Study infants and families and Neonatal research nurse Trish Graham for data entry support

Author information

Authors and Affiliations

  1. University of Otago, Christchurch, New Zealand

    Sarah Louise Harris, Richard Troughton, Chris Pemberton & John Horwood

  2. Neonatal Unit, Christchurch Women’s Hospital, Christchurch, New Zealand

    Kiran More, Bronwyn Dixon, Nicola Ellis & Nicola Austin

  3. Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand

    Richard Troughton

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  1. Sarah Louise Harris
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  2. Kiran More
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  3. Bronwyn Dixon
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  4. Richard Troughton
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  6. John Horwood
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  7. Nicola Ellis
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  8. Nicola Austin
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Contributions

Sarah Harris is a neonatologist who was responsible for study concept, trial design, consent and communication with study families, data collection including performing the majority of the heart ultrasounds, analysis and preparation of the manuscript.

Kiran More is a neonatologist performed some heart ultrasounds, classification of PDA significance and was involved in preparation of manuscript.

Bronwyn Dixon is a neonatologist who performed some heart ultrasounds and was involved in editing manuscript.

Richard Troughton is an adult cardiologist who offered cardiology advice and supervision in heart ultrasound protocol development and interpretation of NTproBNP and heart ultrasound results and was involved in editing manuscript.

Chris Pemberton is a research scientist who was responsible for advising on the laboratory testing and the processing of NTproBNP testing and advised on interpretation of these results.

John Horwood was the statistician who provided statistical advice and analysis.

Nicola Ellis is a research nurse who was involved in data entry and manuscript preparation.

Nicola Austin is a neonatologist who was responsible for senior oversight for the study and was involved in manuscript preparation.

Corresponding author

Correspondence to Sarah Louise Harris.

Ethics declarations

Disclosure of potential conflicts of interest and funding

Dr. Harris received salary for this study from the Freemasons of New Zealand administered by the University of Otago as a Child Health Fellowship.

Assoc Prof Austin received a grant from the Maurice and Phyllis Paykel Trust to fund the NTproBNP testing.

There are no conflicts of interest to declare.

Research involving human participants and/or animals

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The University of Otago Human Ethics Committee approved this study (12/298).

Informed consent

Informed consent was obtained from all individual participants (parental consent as subjects are children) included in the study.

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Communicated by Patrick Van Reempts

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Harris, S.L., More, K., Dixon, B. et al. Factors affecting N-terminal pro-B-type natriuretic peptide levels in preterm infants and use in determination of haemodynamic significance of patent ductus arteriosus. Eur J Pediatr 177, 521–532 (2018). https://doi.org/10.1007/s00431-018-3089-y

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