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BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants
Early Human Development 86 (2010) 295–298
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants Savina Mannarino a, Francesca Garofoli b,⁎, Elisa Mongini c, Rosa Maria Cerbo c, Alessia Claudia Codazzi a, Chryssoula Tzialla c, Iolanda Mazzucchelli b, Gianfranco Perotti c, Carmine Tinelli d, Annalisa De Silvestri d, Paolo Manzoni e, Mauro Stronati c a
Pediatric Cardiology, Department of Paediatrics, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy Neonatal Immunology Laboratory, Neonatal Intensive Care Unit Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy c Neonatology and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy d Biometric Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy e Neonatology and Neonatal Intensive Care Unit, Sant'Anna Hospital, Azienda Ospedaliera Regina Margherita-Sant'Anna, C-Spezia 60, 10126 Torino, Italy b
a r t i c l e
i n f o
Article history: Received 12 February 2010 Received in revised form 31 March 2010 Accepted 16 April 2010 Keywords: BNP Echocardiography Newborns
a b s t r a c t To evaluate and compare cardiovascular adaptation of 36 preterm and 34 fullterm newborns, we analyzed BNP concentration and echocardiographic parameters at day 3 of life and at day 28 (±2). On day 3 BNP concentrations (pg/ml) resulted higher in PDA preterm group (n = 11; 125, IQR 56.1–301) than preterm without PDA (n = 25; 25.5 IQR 10.9–49; p b 0.001) than fullterms (n = 34; 55.1 IQR 23.6–82.7; p = 0.013). No difference resulted in all groups at 28 days (respectively: 12.7 IQR 4.9–23.8; 15.6 IQR 10–22; 8.9 IQR 5.6–20.6). Because of the newborns' growth, all echocardiographic parameters increased with linear relationship with body weight. On day 3 BNP concentration and echocardiographic parameters were not correlated besides LA/AO in preterms with PDA (p = 0.0015). On day 28, BNP was significantly correlated with mVTI (p = 0.019), M (p = 0.007) and LA (p = 0.005) in fullterms and only with LA (p = 0.007) in preterms. In conclusion, BNP concentrations and echocardiographic measures confirm that preterm, and fullterm newborns conduct themselves in a similar manner during the transition from foetal to post-natal circulation, reaching low levels at a month of life. The presence of PDA during first days of life has no significant impact in this adaptation. LA is the echocardiographic parameter mostly related to BNP concentration in the newborns. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction B-Type natriuretic peptide (BNP) is part of the cardiac natriuretic hormones, mainly produced by the cardiomyocytes and is characterized by diuretic, natriuretic and vasodilatatory properties. In particular, BNP is produced by ventricular cells in response to volume expansion and pressure load and in cardiac heart failure [1–3]. The field of our attention is the newborns period, when BNP has a typical peak in concomitance to the transition from foetal to post-natal
Abbreviations: BNP, B-Type natriuretic peptide; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; IUGR, intrauterine growth restriction; PROM, premature rupture of membranes; IVS, interventricular septum thickness; LVDd, left ventricular diastolic diameter; LVPW, left ventricular posterior wall thickness; SF, shortening fraction; M, mass; LA/AO, ratio between diameter of the left atrium (LA) and from aortic root diameter; (AO) mVTI, velocity time integral of mitral valve; E/A, ratio of early (E) to late (A) transmitral inflow velocities. ⁎ Corresponding author. Neonatal Immunology Research Laboratories, Neonatology and Neonatal Intensive Care Unit Fondazione IRCCS Policlinico San Matteo, Pavia, Italy Piazzale Golgi 1, 27100 Pavia, Italy. Tel.: +39 0382 502865; fax: +39 0382 502802. E-mail address: [email protected] (F. Garofoli). 0378-3782/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2010.04.003
circulation, then a steady-state condition is reached, in physiologic situation. In fact, data from literature reports that BNP concentrations typically increase during the first days of life, then decrease to stable and low levels until the pre-pubertal period [3–6]. High levels of BNP in newborns may be linked to the patency of the ductus arteriosus (PDA) or to persistent pulmonary hypertension (PPHN) [7–14]. However, a high peak of BNP in the early post-natal days is not a fully reliable prognostic marker for cardiac disease because it can be found both during the physiologic switch from foetal to post-natal circulation and in the case of co-morbidities [4,5,15,16]. In order to evaluate the cardiovascular adaptation of the preterm compared to the fullterm newborns, we analyzed the BNP concentration at day 3 of life, (representing the time of BNP peak) and at day 28 (±2) representing the steady state, at the end of the newborn period. Since current literature does not advise the use of BNP as a stand-alone test for cardiovascular assessment in the first days of life we coupled it with echocardiographic evaluations [5,6,14,16]. Moreover in our knowledge, paired BNP concentration and echocardiography data in the preterm infants have been correlated only in few clinical studies.
296
S. Mannarino et al. / Early Human Development 86 (2010) 295–298
2. Materials and methods 2.1. Patients This was an observational, open study approved by the Bioethics Committee of the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Written informed consent was obtained from all parents before the enrolment. Thirty-four consecutive healthy, fullterm newborns were enrolled (gestational age ≥ 37 weeks), with echocardiographic, laboratory and clinical screenings negative for any diseases, born after a normal pregnancy from healthy mother. Thirty-six preterm babies admitted to our Neonatal Intensive Care Unit (NICU) were enrolled in the study (gestational age ≤ 35 weeks). Congenital cardiac diseases, malformations, genetic syndromes, blood transfusion were the main exclusion criteria. We decided to stratify this group into 2 subgroups according to the presence of medical/ surgical PDA, as reported in Table 1. All the newborns were enrolled from May 2008 to September 2009. PDA was diagnosed by Doppler echocardiographic evidence, as reported below. Significant PDA was evaluated since birth and medical or surgery action was started within the 3rd day of life. While cardiac anatomy and functions were confirmed during the examinations coupled with the newborns' BNP samplings on day 3, and on day 28 (±2).
2.2. Echocardiographic studies Echocardiography was performed following the above mentioned blood sampling when the infants were calm, after feeding, and sucking the pacifier. The investigators were blinded to BNP values, repeatability among raters, inter-observer and intra-observer variability has been already evaluated and validated before starting our BNP studies (intra- and inter-observer error: respectively 2.5% ± 0.6 and 2.7% ± 0.8, data not published, by our Echocardiographic Lab.). A Logiq 5 PRO ultrasound machine (GE, Medical System, Milwaukee, Wisconsin, USA) with a 8 MHz convex transducer incorporating pulse-wave and colour-flow was used Two-dimensional, M-mode and pulsed Doppler data were recorded. Interventricular septum thickness (IVS), left ventricular diastolic diameter (LVDd) and left ventricular posterior wall thickness (LVPW) were determined at the end of diastole according to the recommendations of the American Society of Echocardiography. Shortening fraction (SF%) was then derived. Mass (M) of the left ventricle was estimated using the Devereux method [17]. Ratio LA/AO was estimated from the diameter
of the left atrium (LA) and from aortic root diameter (AO) by a twodimensional parasternal long-axis view. Velocity time integral of mitral valve (mVTI) and the ratio of early (E) to late (A) transmitral inflow velocities (E/A), were recorded by pulsed Doppler in the four chambers view. PDA was diagnosed measuring: LA/A0: M-mode pictures of the LA and AO, by parasternal long-axis view; internal diameter of the ductus arteriosus (DA), by B-mode from the high left parasternal view, DA diameter was related to the newborn's weight and expressed mm/kg; flow velocity of the DA was measured by pulsed Doppler using a high left parasternal view (pattern growing or pulsed). 2.3. BNP assay The test was performed by using a commercial kit at bedside (Triage BNP test; Biosite Diagnostic Inc, San Diego, CA, USA), using 250 μl of whole EDTA blood. The measurable range of BNP concentrations by the Triage assay was 5 to 5000 pg/ml. 2.4. Statistical analysis Categorical variables are described by number and percentage; quantitative variables are expressed as mean ± standard deviation if normally distributed or as median and interquartile range if not; in the latter case were log-transformed in the further analysis. Quantitative variables were compared through t-test or ANOVA (post-hoc comparison between groups were performed and Scheffè correction for multiple test was applied). Pearson correlation was calculated to assess relationships between BNP log values and echocardiographic parameters. The echocardiographic parameters were adjusted with body weight. Multivariate GEE regression models with a stepwise procedure are applied to test the effects of covariate listed in Table 1. p b 0.05 was considered statistically significant. All tests were two-sided. Data analysis was performed with STATA statistical package (vers: 9; Stata Corporation, College Station, 2008, Texas, USA). 3. Results Demographic data of the groups are reported in Table 1. Eleven out of 36 preterm newborns resulted in PDA requiring medical treatment to recovery. Median plasma and interquartile range (IQR) BNP concentrations (pg/ml) in fullterm newborns were: on day 3 of life 55.1 (IQR 23.6–82.7), on day 30 of life 8.9 (IQR 5.6–20.6); in preterm
Table 1 Demographic data.
Patent ductus arteriosus, PDA: number (%) Birth weight, g: mean (± SD) Gestational age, weeks: median (range) Gender, male: number (%) Mother's age, years: mean (SD) Maternal hypertension: number (%) Intrauterine growth restriction, IUGR: number (%) Premature rupture of the membrane, PROM: number (%) Antenatal steroid: (2 doses): number (%) Maternal vaginal infections: number (%) Surfactant: yes (%) Bronchopulmonary dysplasia, BPD: number (%) Exitus: number (%)
Preterm newborns without PDA N = 25
Preterm newborns PDA N = 11
0 1450 (550) 32 (25–35) 16 (64) 31.5 (5.8) 10 (40) 2 (8) 7 (28) 14 (56) 8 (32) 14 (56) 3 (12) 0
11 1082 (480) 28 (25–33) 5 (45.4) 31.3 (7.2) 5 (45.4) 4 (36.3) 5 (45.4) 10 (90,9) 5 (45.4) 9 (81.8) 4 (36.3) 2 (18.1)
Maternal hypertension: systolic blood pressure ≥ 140 mm Hg and diastolic blood pressure ≥ 90 mm Hg. IUGR: estimated foetal weight below 10th percentile and Doppler pulsatility index in the umbilical artery of ≥2 standard deviation. Maternal vaginal infections: positivity to pathogenic bacteria to vaginal cultures. BDP: needs for supplemental oxygenation at 36 weeks postmenstrual age.
Fullterm newborns N = 34 0 3225 (641) 39 (38–40) 17 (50) 32.0 (4.7) 0 0 0 0 0 0 0 0
S. Mannarino et al. / Early Human Development 86 (2010) 295–298
newborns without PDA were: on day 3 of life 25.5 (IQR 10.9–49) on day 30 of life 15.6 (IQR 10–22) and in preterm newborns with PDA were: on day 3 of life 125 (IQR 56.1–301) on day 30 of life 12.7 (IQR 4.9–23.8). On day 3 BNP concentrations resulted higher in PDA group with respect of preterm without PDA (p b 0.001) and fullterm babies (p = 0.013), no difference was observed between fullterm and preterm without PDA. No statistical difference resulted in the three groups at the 30 days of evaluation (Fig. 1). In the study period, we found no significant association between sex, maternal age, gestational age, mode of delivery and newborns' BNP concentrations. For the preterm newborns no association was reported with maternal hypertension, presence of bacterial vaginosis, premature rupture of the membrane (PROM), and length of mechanical ventilation of the newborns. Echocardiographic parameters of the three groups are reported in Table 2. In all the newborns, LVDd (p b 0.0001), M (p b 0.0001), mVTI (p b 0.0001), were significantly higher at 30 than 3 days and in preterm newborns only, IVS (p b 0.0001), LVPW (p b 0.0001), E/A ratio (p = 0.037) were significantly higher too. SF and ratio LA/AO were not significantly different between 3 and 30 days of life even if LA/AO was significantly higher in babies with PDA (p = 0.023). In all the neonates a linear relationship was found between M (r = 0.74; p b 0.0001), LVDd (r = 0.76; p b 0.0001), and the increase of body weight. On day 3 plasma BNP concentration and echocardiographic parameters were not significantly correlated besides LA/AO in preterm neonates suffering from PDA (p = 0.0015). On day 30, taking into account the body weight of newborns, BNP values were significantly correlated with mVTI (p = 0.019), M (p = 0.007) and LA (p = 0.005) in fullterm babies and only with LA (p = 0.007) in preterm babies. In these neonates, this positive correlation with LA persisted when PDA and IUGR were included in the GEE regression model considering logBNP as dependent variable and LA, PDA, weight and IUGR as exploratory variables on longitudinal relationship (Table 3).
4. Discussion The present study underlined that BNP levels are high and spread in a wide range in the initial few days of life in fullterm and also in preterm newborns. Then at a month of life, we found low levels of BNP with a low and a narrow range of values, in all the studied groups. This pattern reflects the inter-individual differences in the perinatal transitional period or the concomitant presence of comorbidities for the preterm newborns. All the newborns, whether preterm or fullterm with or without PDA, go through this period characterized by widely scattered BNP levels.
Fig. 1. BNP concentrations. On day 3 BNP concentrations resulted higher in preterm newborns suffering from PDA than preterms without PDA (p b 0.001) and fullterm babies (p = 0.013). No differences were observed on day 28 (± 2) of life.
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It is important to note that preterm infants showed a similar trend, chronological age dependent, to healthy newborns in decreasing BNP levels [3–6]. In our study already on day 3, maternal influences, like hypertension, bacterial vaginosis, PROM, demonstrated not to be related to BNP plasma concentrations. Among the considered postnatal factors, only PDA influenced BNP values on day 3. In the PDA group, we recorded 2 deaths at the end of the third day of life, both because of critical conditions worsened by septicaemia plus sequelae of severe asphyxia for one of them. The preterm newborns with PDA that survived (9/11 patients) recovered with low BNP concentrations. All the preterm newborns reported BNP concentrations comparable to the healthy fullterm group. Therefore we believe that the preterms are able to normalize their cardiocirculatory conditions in spite of their previous status at birth and in the absence of major pathologies. Regarding echocardiographic data, as expected because of the newborns' growth, we found an increase in all the parameters from the 3rd day to a month of life, with linear relationship with body weight, chiefly in preterm newborns. We noted that all our newborns reported a SF in the normal range, including the preterm neonates with significative PDA and increased LA/AO on day 3. Moreover the preterm neonates showed a trend towards the increase of E/A ratio (p = 0.037) and the normalization of the diastolic function at a month of life. Therefore, in the studied period, we observed no relationship between BNP and the systolic and diastolic function as already reported in our previous data in healthy newborns [15]. It is known that plasma BNP increases significantly in left to right shunts and a positive correlation is present with significant PDA [7–11]. Our data on day 3 confirm the mentioned findings and are in agreement with data from other authors showing LA/AO to be the echocardiographic parameter mostly related to BNP [7]. Besides the presence of PDA, no other echocardiographic cofactors influenced the levels of the studied hormone. We can think that even the high BNP concentrations in preterm newborns, like in the fullterm neonates, are mainly related to circulatory changes occurring during the transition from foetal to post-natal period and not to a real impairment of the heart. Consequently, in the first days of life, we recommend to couple the BNP determination to the echocardiography to evaluate cardiovascular adaptation. At the steady state all the studied groups behave reporting low BNP concentrations. The systolic and diastolic function, on the basis of our data, seem not related to BNP concentrations, unlike patients with cardiac dysfunction. Nevertheless many mechanisms are involved in regulating BNP release, in the present study we confirmed a positive correlation with mVTI, E wave M and in healthy infants, but our experience LA size is the only echocardiographic parameter significantly correlated to BNP in both fullterm and preterm infants. These data indicate that in preterm infants BNP is influenced by the same cardio-circulatory mechanisms of the fullterm newborns. Nevertheless we did not find the exact correspondence of the echocardiographic parameters between fullterm and preterm newborns probably due to the fact that some of the latter were still below the 40 weeks of gestational age at the time of the month evaluation. As consequence, they were not at the same level of development as the fullterm infants at the same time control. In conclusion we showed that BNP concentrations and echocardiographic measures confirm that preterm and fullterm newborns conduct themselves in a similar manner during the transition period from foetal to post-natal circulation till reaching the stable period at a month of life, moreover LA is the echocardiographic parameter mostly related to BNP plasma concentration in the newborns. However, further studies would be necessary to define the range of normality for the echocardiographic parameters in preterm newborns, in order to clarify the relationship with BNP values during the first days of life.
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Table 2 Echocardiographic parameters: mean values (± SD). Preterm newborns
IVS cm LVDd cm LVPW cm SF% mVTI cm E/A LA/AO Mg
PDA
Non-PDA
Fullterm newborns
Day 3
Day 30
Day 3
Day 30
Day 3
Day 30
Day 3
Day 30
0.28 (0.07)
0.34 (0.08)
0.23 (0.07)
0.29 (0.07)
0.29 (0.07)
0.35 (0.08)
0.37 (0.07)
0.41 (0.08)
1.20 (0.20)
1.47 (0.33)
1.14 (0.21)
1.23 (0.26)
1.22 (0.20)
1.54 (0.37)
1.78 (0.18)
2.10 (0.26)
0.26 (0.07)
0.31 (0.07)
0.22 (0.06)
0.30 (0.07)
0.26 (0.07)
0.31 (0.07)
0.26 (0.06)
0.29 (0.07)
34.2 (8.2) 5.5 (1.2)
37.6 (7.8) 8.7 (2.0)
37.4 (10.1) 6.0 (0.70)
41.1 (7.2) 7.9 (1.4)
37.0 (8.7) 5.4 (1.3)
36.7 (7.8) 8.9 (2.2)
40.0 (6.21) 7.3 (1.5)
38.1 (4.11) 9.3 (1.7)
0.76 (0.24) 1.18 (0.29) 3.6 (1.5)
0.88 (0.20) 1.16 (0.15) 5.8 (3.3)
0.86 (0.28) 1.40 (0.42) 2.7 (1.2)
0.71 (0.12) 1.13 (0.12) 3.4 (2.1)
0.74 (0.22) 1.10 (0.19) 3.9 (1.5)
0.92 (0.18) 1.17 (0.16) 6.5 (3.3)
0.99 (0.15) 1.10 (0.12) 7.9 (1.6)
0.97 (0.13) 1.18 (0.16) 11.6 (3.1)
Table 3 Association between BNP and exploratory variables in preterm newborns.
LA PDA IUGR Weight (by 100 g)
β 95% (regression coefficient)
CI 95% (confidence interval)
1.65 −0.58 0.65 −0.07
0.39 −1.21 − 0.13 − 0.10
p
2.91 0.05 1.44 − 0.03
0.010 0.072 0.103 0.042
Conflict of interest The authors declare that: we have no commercial association (e.g., consultancies, stock ownership, equity interest, patent/licensing, arrangements, etc.) that may pose a conflict of interest in connection with the submitted article, moreover we have no competing interest, no industry relationship, no study sponsor. Acknowledgments We gratefully acknowledge Dr. Micol Angelini and Mrs. Claudia Cova of the Research Laboratories — Neonatal Immunology, IRCCS Policlinico San Matteo, Pavia, Italy for the technical assistance and expertise. We thankfully acknowledge Alessandra Rossi Ricci, intern in Neonatology IRCCS Policlinico San Matteo, Pavia, Italy, for her precious assistance. References [1] Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339: 321–8. [2] Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357–68.
[3] Cantinotti M, Clerico A, Murzi M, Vittorini S, Emdin M. Clinical relevance of brain natriuretic peptide and N-terminal pro-brain natriuretic peptide in pediatric cardiology. Clin Chim Acta 2008;390:12–22. [4] Koch A, Singer H. Normal values of B type natriuretic pepetide in infants, children and adolescents. Heart 2003;89:875–8. [5] da Graca RL, Hassinger DC, Flynn PA, Sison CP, Nesin M, Auld PAM. Longitudinal changes of brain-type natriuretic peptide in preterm neonates. Pediatrics 2006;117:2183–9. [6] Das BB, Raj S, Solinger S. Natriuretic peptides in cardiovascular diseases of fetus, infants and children. Cardiovasc Hematol Agents Med Chem 2009;7:43–51. [7] Choi BM, Lee KH, Eun BL, Yoo KH, Hong YS, Son CS, Lee JW. Utility of rapid B-type natriuretic peptide assay for diagnosis of symptomatic patent ductus arteriosus in preterm infants. Pediatrics 2005;115:255–61. [8] CZernik C, Metze Lemmer J, Koehne PS B, Meuller C, Obladen M. B-Type natriuretic peptide to predict ductus intervention in infants b 28 weeks. Pediatric Res 2008;64:286–90. [9] Flynn PA, da Graca RL, Auld PA, Nesin M, Kleinman CS. The use of a bedside assay for plasma B-type natriuretic peptide assay in the management of patent ductus arteriousus in premature neonates. J Pediatr 2005;147:38–42. [10] Holmstrom H, Hall C, Thaulow E. Plasma levels of natriuretic peptides and hemodynamic assessment of patent ductus arteriousus in preterm infants. Acta Paed 2001;90:184–91. [11] Puddy VF, Amirmansour C, Williams AF, Singer DRJ. Plasma brain-type natriuretic peptide as predictor of haemodynamically significant patent ductus arteriosus in preterm infants. Clin Sci 2002;103:75–7. [12] Sanjeev S, Pettersen M, Lua J, Thomas R, Shankaran S, L'Ecuyer T. Role of plasma Btype natriuretic peptide in screening for hemodynamically significant patent ductus arteriosus in preterm neonates. J Perinatol 2005;25:709–13. [13] Ko HK, Lee JH, Choi BM, Lee JH, Yoo KH, Son CS, Lee JW. Utility of the rapid B-type natriuretic peptide assay for detection of cardiovascular problems in newborn infants with respiratory difficulties. Neonatology 2008;94:16–21. [14] Reynolds EV, Ellington JG, Vranicar M, Bada HS. Brain-type natriuretic peptide in the diagnosis and management of persistent pulmonary hypertension of the newborn. Pediatrics 2004;114:1297–304. [15] Mannarino S, Ciardelli L, Garofoli F, Perotti G, Mongini E, Damiano S, Tinelli C, Cerbo RM, Rondini G, Stronati M. Correlation between cord blood, perinatal BNP values and echocardiographic parameters in healthy Italian newborns. Early Hum Dev 2009;85:13–7. [16] El-Khuffash, Molloy EJ. Are B-type natriuretic peptide (BNP) and N-terminal-proBNP useful in neonates? Arch Dis Child Fetal Neonatal Ed 2007;92:F320–4. [17] Deverux RB, Reichek N. Echocardiographic determination of left ventricular mass in man. Circulation 1977;55:613–8.
Contents lists available at ScienceDirect
Early Human Development j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e a r l h u m d ev
BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants Savina Mannarino a, Francesca Garofoli b,⁎, Elisa Mongini c, Rosa Maria Cerbo c, Alessia Claudia Codazzi a, Chryssoula Tzialla c, Iolanda Mazzucchelli b, Gianfranco Perotti c, Carmine Tinelli d, Annalisa De Silvestri d, Paolo Manzoni e, Mauro Stronati c a
Pediatric Cardiology, Department of Paediatrics, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy Neonatal Immunology Laboratory, Neonatal Intensive Care Unit Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy c Neonatology and Neonatal Intensive Care Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy d Biometric Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy e Neonatology and Neonatal Intensive Care Unit, Sant'Anna Hospital, Azienda Ospedaliera Regina Margherita-Sant'Anna, C-Spezia 60, 10126 Torino, Italy b
a r t i c l e
i n f o
Article history: Received 12 February 2010 Received in revised form 31 March 2010 Accepted 16 April 2010 Keywords: BNP Echocardiography Newborns
a b s t r a c t To evaluate and compare cardiovascular adaptation of 36 preterm and 34 fullterm newborns, we analyzed BNP concentration and echocardiographic parameters at day 3 of life and at day 28 (±2). On day 3 BNP concentrations (pg/ml) resulted higher in PDA preterm group (n = 11; 125, IQR 56.1–301) than preterm without PDA (n = 25; 25.5 IQR 10.9–49; p b 0.001) than fullterms (n = 34; 55.1 IQR 23.6–82.7; p = 0.013). No difference resulted in all groups at 28 days (respectively: 12.7 IQR 4.9–23.8; 15.6 IQR 10–22; 8.9 IQR 5.6–20.6). Because of the newborns' growth, all echocardiographic parameters increased with linear relationship with body weight. On day 3 BNP concentration and echocardiographic parameters were not correlated besides LA/AO in preterms with PDA (p = 0.0015). On day 28, BNP was significantly correlated with mVTI (p = 0.019), M (p = 0.007) and LA (p = 0.005) in fullterms and only with LA (p = 0.007) in preterms. In conclusion, BNP concentrations and echocardiographic measures confirm that preterm, and fullterm newborns conduct themselves in a similar manner during the transition from foetal to post-natal circulation, reaching low levels at a month of life. The presence of PDA during first days of life has no significant impact in this adaptation. LA is the echocardiographic parameter mostly related to BNP concentration in the newborns. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction B-Type natriuretic peptide (BNP) is part of the cardiac natriuretic hormones, mainly produced by the cardiomyocytes and is characterized by diuretic, natriuretic and vasodilatatory properties. In particular, BNP is produced by ventricular cells in response to volume expansion and pressure load and in cardiac heart failure [1–3]. The field of our attention is the newborns period, when BNP has a typical peak in concomitance to the transition from foetal to post-natal
Abbreviations: BNP, B-Type natriuretic peptide; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; IUGR, intrauterine growth restriction; PROM, premature rupture of membranes; IVS, interventricular septum thickness; LVDd, left ventricular diastolic diameter; LVPW, left ventricular posterior wall thickness; SF, shortening fraction; M, mass; LA/AO, ratio between diameter of the left atrium (LA) and from aortic root diameter; (AO) mVTI, velocity time integral of mitral valve; E/A, ratio of early (E) to late (A) transmitral inflow velocities. ⁎ Corresponding author. Neonatal Immunology Research Laboratories, Neonatology and Neonatal Intensive Care Unit Fondazione IRCCS Policlinico San Matteo, Pavia, Italy Piazzale Golgi 1, 27100 Pavia, Italy. Tel.: +39 0382 502865; fax: +39 0382 502802. E-mail address: [email protected] (F. Garofoli). 0378-3782/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2010.04.003
circulation, then a steady-state condition is reached, in physiologic situation. In fact, data from literature reports that BNP concentrations typically increase during the first days of life, then decrease to stable and low levels until the pre-pubertal period [3–6]. High levels of BNP in newborns may be linked to the patency of the ductus arteriosus (PDA) or to persistent pulmonary hypertension (PPHN) [7–14]. However, a high peak of BNP in the early post-natal days is not a fully reliable prognostic marker for cardiac disease because it can be found both during the physiologic switch from foetal to post-natal circulation and in the case of co-morbidities [4,5,15,16]. In order to evaluate the cardiovascular adaptation of the preterm compared to the fullterm newborns, we analyzed the BNP concentration at day 3 of life, (representing the time of BNP peak) and at day 28 (±2) representing the steady state, at the end of the newborn period. Since current literature does not advise the use of BNP as a stand-alone test for cardiovascular assessment in the first days of life we coupled it with echocardiographic evaluations [5,6,14,16]. Moreover in our knowledge, paired BNP concentration and echocardiography data in the preterm infants have been correlated only in few clinical studies.
296
S. Mannarino et al. / Early Human Development 86 (2010) 295–298
2. Materials and methods 2.1. Patients This was an observational, open study approved by the Bioethics Committee of the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Written informed consent was obtained from all parents before the enrolment. Thirty-four consecutive healthy, fullterm newborns were enrolled (gestational age ≥ 37 weeks), with echocardiographic, laboratory and clinical screenings negative for any diseases, born after a normal pregnancy from healthy mother. Thirty-six preterm babies admitted to our Neonatal Intensive Care Unit (NICU) were enrolled in the study (gestational age ≤ 35 weeks). Congenital cardiac diseases, malformations, genetic syndromes, blood transfusion were the main exclusion criteria. We decided to stratify this group into 2 subgroups according to the presence of medical/ surgical PDA, as reported in Table 1. All the newborns were enrolled from May 2008 to September 2009. PDA was diagnosed by Doppler echocardiographic evidence, as reported below. Significant PDA was evaluated since birth and medical or surgery action was started within the 3rd day of life. While cardiac anatomy and functions were confirmed during the examinations coupled with the newborns' BNP samplings on day 3, and on day 28 (±2).
2.2. Echocardiographic studies Echocardiography was performed following the above mentioned blood sampling when the infants were calm, after feeding, and sucking the pacifier. The investigators were blinded to BNP values, repeatability among raters, inter-observer and intra-observer variability has been already evaluated and validated before starting our BNP studies (intra- and inter-observer error: respectively 2.5% ± 0.6 and 2.7% ± 0.8, data not published, by our Echocardiographic Lab.). A Logiq 5 PRO ultrasound machine (GE, Medical System, Milwaukee, Wisconsin, USA) with a 8 MHz convex transducer incorporating pulse-wave and colour-flow was used Two-dimensional, M-mode and pulsed Doppler data were recorded. Interventricular septum thickness (IVS), left ventricular diastolic diameter (LVDd) and left ventricular posterior wall thickness (LVPW) were determined at the end of diastole according to the recommendations of the American Society of Echocardiography. Shortening fraction (SF%) was then derived. Mass (M) of the left ventricle was estimated using the Devereux method [17]. Ratio LA/AO was estimated from the diameter
of the left atrium (LA) and from aortic root diameter (AO) by a twodimensional parasternal long-axis view. Velocity time integral of mitral valve (mVTI) and the ratio of early (E) to late (A) transmitral inflow velocities (E/A), were recorded by pulsed Doppler in the four chambers view. PDA was diagnosed measuring: LA/A0: M-mode pictures of the LA and AO, by parasternal long-axis view; internal diameter of the ductus arteriosus (DA), by B-mode from the high left parasternal view, DA diameter was related to the newborn's weight and expressed mm/kg; flow velocity of the DA was measured by pulsed Doppler using a high left parasternal view (pattern growing or pulsed). 2.3. BNP assay The test was performed by using a commercial kit at bedside (Triage BNP test; Biosite Diagnostic Inc, San Diego, CA, USA), using 250 μl of whole EDTA blood. The measurable range of BNP concentrations by the Triage assay was 5 to 5000 pg/ml. 2.4. Statistical analysis Categorical variables are described by number and percentage; quantitative variables are expressed as mean ± standard deviation if normally distributed or as median and interquartile range if not; in the latter case were log-transformed in the further analysis. Quantitative variables were compared through t-test or ANOVA (post-hoc comparison between groups were performed and Scheffè correction for multiple test was applied). Pearson correlation was calculated to assess relationships between BNP log values and echocardiographic parameters. The echocardiographic parameters were adjusted with body weight. Multivariate GEE regression models with a stepwise procedure are applied to test the effects of covariate listed in Table 1. p b 0.05 was considered statistically significant. All tests were two-sided. Data analysis was performed with STATA statistical package (vers: 9; Stata Corporation, College Station, 2008, Texas, USA). 3. Results Demographic data of the groups are reported in Table 1. Eleven out of 36 preterm newborns resulted in PDA requiring medical treatment to recovery. Median plasma and interquartile range (IQR) BNP concentrations (pg/ml) in fullterm newborns were: on day 3 of life 55.1 (IQR 23.6–82.7), on day 30 of life 8.9 (IQR 5.6–20.6); in preterm
Table 1 Demographic data.
Patent ductus arteriosus, PDA: number (%) Birth weight, g: mean (± SD) Gestational age, weeks: median (range) Gender, male: number (%) Mother's age, years: mean (SD) Maternal hypertension: number (%) Intrauterine growth restriction, IUGR: number (%) Premature rupture of the membrane, PROM: number (%) Antenatal steroid: (2 doses): number (%) Maternal vaginal infections: number (%) Surfactant: yes (%) Bronchopulmonary dysplasia, BPD: number (%) Exitus: number (%)
Preterm newborns without PDA N = 25
Preterm newborns PDA N = 11
0 1450 (550) 32 (25–35) 16 (64) 31.5 (5.8) 10 (40) 2 (8) 7 (28) 14 (56) 8 (32) 14 (56) 3 (12) 0
11 1082 (480) 28 (25–33) 5 (45.4) 31.3 (7.2) 5 (45.4) 4 (36.3) 5 (45.4) 10 (90,9) 5 (45.4) 9 (81.8) 4 (36.3) 2 (18.1)
Maternal hypertension: systolic blood pressure ≥ 140 mm Hg and diastolic blood pressure ≥ 90 mm Hg. IUGR: estimated foetal weight below 10th percentile and Doppler pulsatility index in the umbilical artery of ≥2 standard deviation. Maternal vaginal infections: positivity to pathogenic bacteria to vaginal cultures. BDP: needs for supplemental oxygenation at 36 weeks postmenstrual age.
Fullterm newborns N = 34 0 3225 (641) 39 (38–40) 17 (50) 32.0 (4.7) 0 0 0 0 0 0 0 0
S. Mannarino et al. / Early Human Development 86 (2010) 295–298
newborns without PDA were: on day 3 of life 25.5 (IQR 10.9–49) on day 30 of life 15.6 (IQR 10–22) and in preterm newborns with PDA were: on day 3 of life 125 (IQR 56.1–301) on day 30 of life 12.7 (IQR 4.9–23.8). On day 3 BNP concentrations resulted higher in PDA group with respect of preterm without PDA (p b 0.001) and fullterm babies (p = 0.013), no difference was observed between fullterm and preterm without PDA. No statistical difference resulted in the three groups at the 30 days of evaluation (Fig. 1). In the study period, we found no significant association between sex, maternal age, gestational age, mode of delivery and newborns' BNP concentrations. For the preterm newborns no association was reported with maternal hypertension, presence of bacterial vaginosis, premature rupture of the membrane (PROM), and length of mechanical ventilation of the newborns. Echocardiographic parameters of the three groups are reported in Table 2. In all the newborns, LVDd (p b 0.0001), M (p b 0.0001), mVTI (p b 0.0001), were significantly higher at 30 than 3 days and in preterm newborns only, IVS (p b 0.0001), LVPW (p b 0.0001), E/A ratio (p = 0.037) were significantly higher too. SF and ratio LA/AO were not significantly different between 3 and 30 days of life even if LA/AO was significantly higher in babies with PDA (p = 0.023). In all the neonates a linear relationship was found between M (r = 0.74; p b 0.0001), LVDd (r = 0.76; p b 0.0001), and the increase of body weight. On day 3 plasma BNP concentration and echocardiographic parameters were not significantly correlated besides LA/AO in preterm neonates suffering from PDA (p = 0.0015). On day 30, taking into account the body weight of newborns, BNP values were significantly correlated with mVTI (p = 0.019), M (p = 0.007) and LA (p = 0.005) in fullterm babies and only with LA (p = 0.007) in preterm babies. In these neonates, this positive correlation with LA persisted when PDA and IUGR were included in the GEE regression model considering logBNP as dependent variable and LA, PDA, weight and IUGR as exploratory variables on longitudinal relationship (Table 3).
4. Discussion The present study underlined that BNP levels are high and spread in a wide range in the initial few days of life in fullterm and also in preterm newborns. Then at a month of life, we found low levels of BNP with a low and a narrow range of values, in all the studied groups. This pattern reflects the inter-individual differences in the perinatal transitional period or the concomitant presence of comorbidities for the preterm newborns. All the newborns, whether preterm or fullterm with or without PDA, go through this period characterized by widely scattered BNP levels.
Fig. 1. BNP concentrations. On day 3 BNP concentrations resulted higher in preterm newborns suffering from PDA than preterms without PDA (p b 0.001) and fullterm babies (p = 0.013). No differences were observed on day 28 (± 2) of life.
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It is important to note that preterm infants showed a similar trend, chronological age dependent, to healthy newborns in decreasing BNP levels [3–6]. In our study already on day 3, maternal influences, like hypertension, bacterial vaginosis, PROM, demonstrated not to be related to BNP plasma concentrations. Among the considered postnatal factors, only PDA influenced BNP values on day 3. In the PDA group, we recorded 2 deaths at the end of the third day of life, both because of critical conditions worsened by septicaemia plus sequelae of severe asphyxia for one of them. The preterm newborns with PDA that survived (9/11 patients) recovered with low BNP concentrations. All the preterm newborns reported BNP concentrations comparable to the healthy fullterm group. Therefore we believe that the preterms are able to normalize their cardiocirculatory conditions in spite of their previous status at birth and in the absence of major pathologies. Regarding echocardiographic data, as expected because of the newborns' growth, we found an increase in all the parameters from the 3rd day to a month of life, with linear relationship with body weight, chiefly in preterm newborns. We noted that all our newborns reported a SF in the normal range, including the preterm neonates with significative PDA and increased LA/AO on day 3. Moreover the preterm neonates showed a trend towards the increase of E/A ratio (p = 0.037) and the normalization of the diastolic function at a month of life. Therefore, in the studied period, we observed no relationship between BNP and the systolic and diastolic function as already reported in our previous data in healthy newborns [15]. It is known that plasma BNP increases significantly in left to right shunts and a positive correlation is present with significant PDA [7–11]. Our data on day 3 confirm the mentioned findings and are in agreement with data from other authors showing LA/AO to be the echocardiographic parameter mostly related to BNP [7]. Besides the presence of PDA, no other echocardiographic cofactors influenced the levels of the studied hormone. We can think that even the high BNP concentrations in preterm newborns, like in the fullterm neonates, are mainly related to circulatory changes occurring during the transition from foetal to post-natal period and not to a real impairment of the heart. Consequently, in the first days of life, we recommend to couple the BNP determination to the echocardiography to evaluate cardiovascular adaptation. At the steady state all the studied groups behave reporting low BNP concentrations. The systolic and diastolic function, on the basis of our data, seem not related to BNP concentrations, unlike patients with cardiac dysfunction. Nevertheless many mechanisms are involved in regulating BNP release, in the present study we confirmed a positive correlation with mVTI, E wave M and in healthy infants, but our experience LA size is the only echocardiographic parameter significantly correlated to BNP in both fullterm and preterm infants. These data indicate that in preterm infants BNP is influenced by the same cardio-circulatory mechanisms of the fullterm newborns. Nevertheless we did not find the exact correspondence of the echocardiographic parameters between fullterm and preterm newborns probably due to the fact that some of the latter were still below the 40 weeks of gestational age at the time of the month evaluation. As consequence, they were not at the same level of development as the fullterm infants at the same time control. In conclusion we showed that BNP concentrations and echocardiographic measures confirm that preterm and fullterm newborns conduct themselves in a similar manner during the transition period from foetal to post-natal circulation till reaching the stable period at a month of life, moreover LA is the echocardiographic parameter mostly related to BNP plasma concentration in the newborns. However, further studies would be necessary to define the range of normality for the echocardiographic parameters in preterm newborns, in order to clarify the relationship with BNP values during the first days of life.
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Table 2 Echocardiographic parameters: mean values (± SD). Preterm newborns
IVS cm LVDd cm LVPW cm SF% mVTI cm E/A LA/AO Mg
PDA
Non-PDA
Fullterm newborns
Day 3
Day 30
Day 3
Day 30
Day 3
Day 30
Day 3
Day 30
0.28 (0.07)
0.34 (0.08)
0.23 (0.07)
0.29 (0.07)
0.29 (0.07)
0.35 (0.08)
0.37 (0.07)
0.41 (0.08)
1.20 (0.20)
1.47 (0.33)
1.14 (0.21)
1.23 (0.26)
1.22 (0.20)
1.54 (0.37)
1.78 (0.18)
2.10 (0.26)
0.26 (0.07)
0.31 (0.07)
0.22 (0.06)
0.30 (0.07)
0.26 (0.07)
0.31 (0.07)
0.26 (0.06)
0.29 (0.07)
34.2 (8.2) 5.5 (1.2)
37.6 (7.8) 8.7 (2.0)
37.4 (10.1) 6.0 (0.70)
41.1 (7.2) 7.9 (1.4)
37.0 (8.7) 5.4 (1.3)
36.7 (7.8) 8.9 (2.2)
40.0 (6.21) 7.3 (1.5)
38.1 (4.11) 9.3 (1.7)
0.76 (0.24) 1.18 (0.29) 3.6 (1.5)
0.88 (0.20) 1.16 (0.15) 5.8 (3.3)
0.86 (0.28) 1.40 (0.42) 2.7 (1.2)
0.71 (0.12) 1.13 (0.12) 3.4 (2.1)
0.74 (0.22) 1.10 (0.19) 3.9 (1.5)
0.92 (0.18) 1.17 (0.16) 6.5 (3.3)
0.99 (0.15) 1.10 (0.12) 7.9 (1.6)
0.97 (0.13) 1.18 (0.16) 11.6 (3.1)
Table 3 Association between BNP and exploratory variables in preterm newborns.
LA PDA IUGR Weight (by 100 g)
β 95% (regression coefficient)
CI 95% (confidence interval)
1.65 −0.58 0.65 −0.07
0.39 −1.21 − 0.13 − 0.10
p
2.91 0.05 1.44 − 0.03
0.010 0.072 0.103 0.042
Conflict of interest The authors declare that: we have no commercial association (e.g., consultancies, stock ownership, equity interest, patent/licensing, arrangements, etc.) that may pose a conflict of interest in connection with the submitted article, moreover we have no competing interest, no industry relationship, no study sponsor. Acknowledgments We gratefully acknowledge Dr. Micol Angelini and Mrs. Claudia Cova of the Research Laboratories — Neonatal Immunology, IRCCS Policlinico San Matteo, Pavia, Italy for the technical assistance and expertise. We thankfully acknowledge Alessandra Rossi Ricci, intern in Neonatology IRCCS Policlinico San Matteo, Pavia, Italy, for her precious assistance. References [1] Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339: 321–8. [2] Daniels LB, Maisel AS. Natriuretic peptides. J Am Coll Cardiol 2007;50:2357–68.
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