European Journal of Obstetrics & Gynecology and Reproductive Biology 153 (2010) 12–15

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is a biomarker

of cardiac filling pressures in pre-eclampsia
Leonie Speksnijder a, Joost H.W. Rutten b, Anton H. van den Meiracker b, René J.A. de Bruin b,
Jan Lindemans c, Wim C.J. Hop d, Willy Visser a,*
a
Department of Obstetrics and Gynecology, Division of Obstetrics and Prenatal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
b
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
c
Department of Clinical Chemistry, Erasmus Medical Center, Rotterdam, The Netherlands
d
Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands

A R T I C L E I N F O A B S T R A C T

Article history: Objective: To evaluate if amino-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels reflect
Received 8 February 2010 intracardiac filling pressures in pre-eclamptic patients.
Received in revised form 24 May 2010 Study design: In a cross-sectional study we investigated 22 untreated critically ill pre-eclamptic women
Accepted 27 June 2010
between 22 and 34 weeks gestation. All patients underwent intra-arterial blood pressure and central
hemodynamic measurements and NT-proBNP was determined in stored plasma. Baseline character-
Keywords: istics, plasma NT-proBNP concentrations and relevant laboratory variables were investigated for
Pre-eclampsia
correlations with hemodynamic values using Spearman’s rank correlation test.
Natriuretic peptides
Pulmonary wedge pressure
Results: No significant correlations were demonstrated between NT-proBNP concentrations and
NT-proBNP variables associated with the severity of the pre-eclampsia. We found significant positive correlations
Central hemodynamic monitoring between NT-proBNP and diastolic pulmonary pressure (r = 0.59; p = 0.005) and pulmonary capillary
Biomarkers wedge pressure (PCWP) (r = 0.51; p = 0.015). Multiple linear regression analysis showed that the
association between NT-proBNP and PCWP was not affected by creatinine level.
Conclusion: NT-proBNP is a biomarker of left ventricular cardiac filling pressures in untreated pre-
eclamptic patients.
ß 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Such hemodynamic treatment in critically ill pre-eclamptic

Antihypertensive treatment to prevent further vascular and
circulatory damage forms a mainstay of clinical management of
pre-eclampsia [1]. The elevated arterial blood pressure is
associated with vasoconstriction and increased left ventricular
afterload, reduced cardiac output, hypovolemia and low to normal,
or slightly increased, cardiac filling pressures [2,3]. This makes
vasodilators the drugs of choice for antihypertensive treatment,
but the expansion of vascular space may induce hypotension and a
further reduction of cardiac output with adverse effects on
perfusion of maternal organs, including the kidney and the
uteroplacental unit [1,4]. For that reason plasma volume expansion
prior to vasodilating antihypertensive treatment has been
recommended, in particular with the use of fast-acting intravenous
medication [4,5].
* Corresponding author. Department of Obstetrics and Gynecology, Erasmus
Medical Center, Room SK 4130, P.O. Box 2060, 3000 CB Rotterdam, The Netherlands.
Tel.: +31 10 7036614; fax: +31 10 7036815.
E-mail address: willy.visser@erasmusmc.nl (W. Visser).
patients requires assessment of cardiovascular risk and monitoring
of hemodynamic responses. Central hemodynamic monitoring using
flow-directed balloon-tipped pulmonary artery (Swan-Ganz) cathe-
terization provides the most reliable means of assessing cardiac
afterload and filling pressures, but it carries significant risks and
should be reserved for critically ill patients [6]. Because non-invasive
methods for cardiac monitoring have limitations, in particular with
regard to measurement of left cardiac filling pressures [7], there is a
need for reliable biomarkers of cardiac function and risk assessment.
In non-pregnant patients with a wide range of hemodynamic
disturbances, circulating levels of atrial natriuretic peptides, in
particular amino-terminal pro-brain natriuretic peptide (NT-
proBNP), were shown to be independently associated with cardiac
stress and risk of progressive heart failure and death [8,9]. Results
of most studies indicate that circulating levels of atrial natriuretic
peptides, including NT-proBNP, are increased in healthy pregnan-
cies compared with non-pregnant controls and are higher in pre-
eclampsia than in normotensive pregnancies, although not all
studies agree [10–13].
We hypothesized that NT-proBNP could reflect the impaired
hemodynamics associated with pre-eclampsia, which could make

0301-2115/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejogrb.2010.06.011
 L. Speksnijder et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 153 (2010) 12–15 13

it a potential biomarker for cardiac risk. In order to test the Table 1

Baseline characteristics on admissiona.
hypothesis we assessed the association between maternal plasma
NT-proBNP and hemodynamic variables in untreated critically ill Characteristics N = 22
pre-eclamptic women managed under a protocol of central Age (years) 25 (20–41)
hemodynamic monitoring with the use of a balloon-tipped Gestational age (weeks) 29 (24–34)
pulmonary artery catheter. Nulliparous women 17 (77)
HELLP 6 (27)
Systolic blood pressure (mm Hg) 170 (135–214)
2. Materials and methods
Diastolic blood pressure (mm Hg) 105 (95–120)
Hemoglobin (mmol/l) 7.4 (5.3–9.2)
2.1. Subjects and study design Platelet count (109/l) 183 (20–395)
Uric acid (mmol/l) 0.39 (0.24–0.62)
Creatinine (mmol/l) 72 (47–95)
We selected 22 critically ill pre-eclamptic women between 24
Albumin (g/l) 30 (26–39)
and 34 weeks of gestation who were admitted to our obstetric high Urea (mmol/l) 4.8 (2.7–10.4)
care unit. They had not yet received any treatment, and they were ASAT (U/l) 26 (13–373)
not in labor. All women were known to have been normotensive ALAT (U/l) 17 (8–245)
and nonproteinuric before 20 weeks gestation without evidence of LD (U/l) 354 (212–1120)
NT-proBNP (pg/ml) 100 (23–2419)
chronic hypertension, cardiovascular or renal disease, or diabetes.
Proteinuria (g/24 h) 3.0 (0.6–15.5)
The patients underwent invasive hemodynamic monitoring by
a
Values shown represent median (range) or numbers of patients (%).
means of an intra-arterial catheter and a flow-directed thermistor-
tipped (Swan-Ganz) pulmonary artery catheter. We applied a
standardized protocol for catheterization, calculation and inter- NT-proBNP adjusting for creatinine level was assessed using linear
pretation of variables that was previously reported in detail multiple regression analysis. NT-proBNP concentrations were
[2,3,14]. Blood samples were drawn and measurements were logarithmically transformed in this analysis in order to get an
started at least 1 h after catheterization, when heart rate and approximately normal distribution. The statistical analysis was
systemic arterial blood pressure had reached a steady state, before performed using SPSS/PC (version 15.0, SPSS Inc., Chicago, IL). A
the start of pharmacologic treatment and administration of two-sided p-value < 0.05 was considered to indicate statistical
intravenous fluids. The following laboratory tests were carried significance.
out after admission: full blood cell count including platelets, liver
enzymes, uric acid and creatinine. 3. Results
Informed consent was obtained from all patients. The study
formed part of a clinical scientific project to assess the efficacy of 3.1. Baseline characteristics
temporising hemodynamic treatment of severe pre-eclampsia
approved by the University and Hospital Ethics Committee. The baseline clinical and biochemical characteristics of the pre-
Pre-eclampsia was defined as the occurrence of a repetitive eclamptic patients are presented in Table 1. HELLP syndrome was
diastolic pressure 110 mm Hg (cuff measurement, Korotkoff V) at present in six women. The distribution of NT-proBNP concentra-
least 6 h apart and proteinuria 0.3 g in a 24-h urine collection, or tions was markedly skewed towards the right, but logarithmic
the occurrence of repetitive diastolic blood pressures 90 mm Hg transformation resulted in an approximately normal distribution.
in combination with the HELLP syndrome (hemolysis, elevated No significant correlations were found between NT-proBNP
liver enzymes, low platelet count) after 20 weeks gestation. HELLP concentrations and maternal age, gestational age, peripheral blood
syndrome was defined as the simultaneous occurrence of serum pressures, serum concentration of creatinine, albumin and
alanine amino transferase and serum aspartate amino transferase proteinuria. NT-proBNP concentrations in the six patients with
concentrations >30 U/l (2SD above the mean in our hospital), a the HELLP syndrome were not significantly different from those in
platelet count < 100  109/l, and hemolysis defined by abnormal the other 16 pre-eclamptic patients.
peripheral smear.
3.2. Hemodynamic variables and correlations
2.2. Laboratory analysis
Hemodynamic variables and correlations with logarithmically
A blood sample was drawn from the radial artery catheter transformed values of NT-proBNP are presented in Table 2. The
inserted for arterial pressure measurement and collected in chilled intra-arterial diastolic blood pressures were 5–10 mm Hg lower
plastic tubes containing EDTA and aprotinin. Samples were than the indirectly measured pressures. We found significant
immediately centrifuged at 4 8C for 10 min at 3000  g, and positive correlations between NT-proBNP and diastolic pulmonary
plasma remained stored at 80 8C until assayed. We measured pressure (p = 0.005) and pulmonary capillary wedge pressure
plasma NT-proBNP levels using a validated electrochemilumines- (p = 0.015) as shown in Fig. 1. Multiple linear regression analysis
cence immunoassay (Elecsys proBNP, F. Hoffman-La Roche Ltd., showed that the association between NT-proBNP and pulmonary
Basel, Switzerland) on an Elecsys 2010 analyzer [15]. Determina- capillary wedge pressure (PCWP) was not affected by the
tions were performed in duplicate in a single batch. The lower limit creatinine level. An increase in PCWP with 1 mm Hg was
of detection was 17 pg/ml, within-assay variability was 6% and associated with an increase of NT-proBNP with 12% (95% CI: 2–
between-assay variability was 15%. Other biochemical tests were 24%; p = 0.001) adjusted for creatinine concentration.
performed using routine laboratory techniques.
4. Comments
2.3. Statistical analysis
The hemodynamic disturbances in critically ill pre-eclamptic
The association between different continuous variables was women require hemodynamic monitoring to titrate pharmacologic
analyzed using Spearman’s rank correlation tests. The Mann– and fluid management and assess its responses. Measurements
Whitney test was used in the comparison of groups. The with the pulmonary artery catheter, used in our study, are still
association between pulmonary capillary wedge pressure and acknowledged as the gold standard, but the ongoing debate over its
14 L. Speksnijder et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 153 (2010) 12–15
Table 2
Distributions of hemodynamic variables and associations with NT-proBNP levels.
Median (range)
Systolic arterial pressure (mm Hg) 168 (139–214)
Diastolic arterial pressure (mm Hg)
Mean arterial pressure (mm Hg) 119 (102–147)
Right atrial pressure (mm Hg)
Systolic pulmonary pressure (mm Hg)
Diastolic pulmonary pressure (mm Hg)
Mean pulmonary pressure (mm Hg)
Pulmonary capillary wedge pressure (mm Hg)
Cardiac index (l min 1 m 2)
Stroke volume index (ml beat 1 m 2)
Left ventricular stroke work index (J beat 1 m 2)
Right ventricular stroke work index (J beat 1 m 2)
Systemic vascular resistance index (dyn s cm 5 m2) 3007 (1493–3861)
Pulmonary vascular resistance index (dyn s cm 5 m2) 146 (30–270)
clinical benefits, risks and limitations has led to restraint in its use
and development and reappraisal of less invasive methods [16,17].
However, those methods, mainly based on Doppler ultrasound,
have shown limited accuracy when compared with absolute values
obtained with the pulmonary artery catheter, in particular with
regard to cardiac filling pressures [7]. Measurement of central
venous pressure is unreliable in pre-eclamptic patients [3,18].
Both atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP) are polypeptide neurohormones synthesized by
cardiac atrial and ventricular myocytes in response to stretch. They
are secreted as prohormones, proANP and proBNP, and split on
secretion into equimolar amounts of active ANP and BNP, and
inactive amino-terminal fragments NT-proANP and NT-proBNP.
ANP is more dependent upon atrial filling volume than filling
pressure. Determination of ANP is not a routine procedure and
therefore it is rarely measured clinically. From the clinician’s
prospective, BNP and NT-proBNP are mostly interchangeable and
can be used based on local preferences and availability. However,
there is some evidence that because of its longer half-life NT-
proBNP measurements are superior in the detection of mild
systolic or diastolic heart failure or asymptomatic left ventricular
dysfunction [19,20]. For that reason we selected NT-proBNP to
assess its association with hemodynamic variables.
Fig. 1. Correlation between NT-proBNP and pulmonary capillary wedge pressure
(PCWP). Spearman correlation r = 0.51, p = 0.015. Note the logarithmically scaled
vertical axis.
Rank correlation with NT-proBNP (p-value)
0.34 (0.12)
93 (79–111) 0.13 (0.55)
0.20 (0.38)
0 ( 2 to 9) 0.28 (0.2)
16 (4–31) 0.22 (0.34)
6 (0–16) 0.59 (0.005)
11 (1–23) 0.30 (0.19)
4 ( 2 to 21) 0.51 (0.015)
3.1 (2.3–5.3) 0.34 (0.12)
39 (26–76) 0.35 (0.11)
0.63 (0.40–1.07) 0.40 (0.06)
0.05 (0.01–0.16) 0.25 (0.28)
0.19 (0.41)
0.19 (0.41)
In accordance with results of other studies our values of NT-
proBNP showed a wide and skewed distribution that became
approximately normal after logarithmic transformation [11,12]. In
the absence of normotensive controls we cannot conclude whether
or not they were comparatively elevated. NT-proBNP concentra-
tions were shown to reflect diastolic pulmonary arterial pressure
and pulmonary capillary wedge pressure (PCWP) over a wide range
of values. In the absence of mitral valve disease PCWP is virtually
equal to the end-diastolic filling pressure of the left ventricle, the
left ventricular preload. Positive correlations of variable strength
between NT-proBNP and left ventricular preload have also been
demonstrated in non-pregnant critically ill patients with a variety
of cardiac dysfunction and various forms of treatment [21,22] but
we are not aware of other studies on the relationship between
cardiac filling pressures and NT-proBNP in pre-eclamptic women.
The increase in circulating NT-proBNP concentrations with rising
cardiac filling pressures is most likely explained by an increase in
the release of natriuretic peptides, in particular BNP, by
cardiomyocytes in response to stretch. Other factors may also
be involved, such as pro-inflammatory cytokines and endothelin-1
which are known to stimulate natriuretic peptide release, but their
relationship with cardiac filling pressures is unknown [23]. In
contrast with other investigators using Doppler ultrasound
techniques [24,25] and thoracic electrical impedance cardiography
[26] we found no correlation between NT-proBNP and the severity
of pre-eclampsia as judged by arterial pressures, systemic arterial
resistance and cardiac index. Renal clearance is considered a
pathway of NT-proBNP metabolism [27] but we could also not
demonstrate a correlation with serum creatinine and uric acid
concentrations, or with the amount of proteinuria.
In conclusion, in our study levels of NT-proBNP in pre-eclamptic
patients showed a significant positive correlation with left
ventricular cardiac filling pressures determined by means of
invasive central hemodynamic monitoring. This finding may serve
as a basis for further investigation into the potential clinical
usefulness of NT-proBNP as a marker of risk of pulmonary edema in
pre-eclamptic patients before and during treatment.
Acknowledgements
The authors would like to thank Prof. Dr. H.C.S. Wallenburg,
who provided advice throughout the study and supplied useful
comments on drafts of the paper.
References
[1] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99.
[2] Visser W, Wallenburg HC. Central hemodynamic observations in untreated
preeclamptic patients. Hypertension 1991;17:1072–7.
 L. Speksnijder et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 153 (2010) 12–15
[3] Wallenburg HC. Hemodynamics in hypertensive pregnancy. In: Rubin, editor.
Handbook of Hypertension. Amsterdam: Elsevier Science Publishers; 2000. p.
181–220.
[4] Visser W, Wallenburg HC. A comparison between the haemodynamic effects of
oral nifedipine and intravenous dihydralazine in patients with severe pre-
eclampsia. J Hypertens 1995;13:791–5.
[5] Bolte AC, Van Geijn HP, Dekker GA. Management and monitoring of severe
preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001;96:8–20.
[6] Chatterjee K. The Swan-Ganz catheters: past, present, and future. A viewpoint.
Circulation 2009;119:147–52.
[7] Solomon SD, Stevenson LW. Recalibrating the barometer: is it time to take a
critical look at noninvasive approaches to measuring filling pressures? Circu-
lation 2009;119:13–5.
[8] de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardio-
vascular disease. Lancet 2003;362:316–22.
[9] Weber M, Hamm C. Role of B-type natriuretic peptide (BNP) and NT-proBNP in
clinical routine. Heart 2006;92:843–9.
[10] Franz MB, Andreas M, Schiessl B, et al. NT-proBNP is increased in healthy
pregnancies compared to non-pregnant controls. Acta Obstet Gynecol Scand
2009;88:234–7.
[11] Fleming SM, O’Byrne L, Grimes H, Daly KM, Morrison JJ. Amino-terminal pro-
brain natriuretic peptide in normal and hypertensive pregnancy. Hypertens
Pregnancy 2001;20:169–75.
[12] Kale A, Kale E, Yalinkaya A, Akdeniz N, Canoruc N. The comparison of amino-
terminal probrain natriuretic peptide levels in preeclampsia and normoten-
sive pregnancy. J Perinat Med 2005;33:121–4.
[13] Frenkel Y, Blonder J, Mashiach S, Weiss M. Atrial natriuretic peptide plasma
level remains unchanged in various hypertensive disorders of pregnancy. Eur J
Obstet Gynecol Reprod Biol 1995;59:197–200.
[14] Visser W, Wallenburg HC. Maternal and perinatal outcome of temporizing
management in 254 consecutive patients with severe pre-eclampsia remote
from term. Eur J Obstet Gynecol Reprod Biol 1995;63:147–54.
[15] Collinson PO, Barnes SC, Gaze DC, Galasko G, Lahiri A, Senior R. Analytical
performance of the N terminal pro B type natriuretic peptide (NT-proBNP)
assay on the Elecsys 1010 and 2010 analysers. Eur J Heart Fail 2004;6:365–8.
15
[16] Gilbert WM, Towner DR, Field NT, Anthony J. The safety and utility of
pulmonary artery catheterization in severe preeclampsia and eclampsia.
Am J Obstet Gynecol 2000;182:1397–403.
[17] Cholley BP, Payen D. Noninvasive techniques for measurements of cardiac
output. Curr Opin Crit Care 2005;11:424–9.
[18] Bolte AC, Dekker GA, van Eyck J, Strack van Schijndel R, Van Geijn HP. Lack of
agreement between central venous pressure and pulmonary capillary wedge
pressure in preeclampsia. Hypertens Pregnancy 2000;19:261–71.
[19] Seino Y, Ogawa A, Yamashita T, et al. Application of NT-proBNP and BNP
measurements in cardiac care: a more discerning marker for the detection and
evaluation of heart failure. Eur J Heart Fail 2004;6:295–300.
[20] Steiner J, Guglin M. BNP or NTproBNP? A clinician’s perspective. Int J Cardiol
2008;129:5–14.
[21] Knebel F, Schimke I, Pliet K, et al. NT-ProBNP in acute heart failure: correlation
with invasively measured hemodynamic parameters during recompensation. J
Card Fail 2005;11(Suppl.):S38–41.
[22] Forfia PR, Watkins SP, Rame JE, Stewart KJ, Shapiro EP. Relationship between B-
type natriuretic peptides and pulmonary capillary wedge pressure in the
intensive care unit. J Am Coll Cardiol 2005;45:1667–71.
[23] Paarlberg KM, de Jong CL, Van Geijn HP, van Kamp GJ, Heinen AG, Dekker GA.
Vasoactive mediators in pregnancy-induced hypertensive disorders: a longi-
tudinal study. Am J Obstet Gynecol 1998;179:1559–64.
[24] Borghi C, Esposti DD, Immordino V, et al. Relationship of systemic hemody-
namics, left ventricular structure and function, and plasma natriuretic peptide
concentrations during pregnancy complicated by preeclampsia. Am J Obstet
Gynecol 2000;183:140–7.
[25] Rafik Hamad R, Larsson A, Pernow J, Bremme K, Eriksson MJ. Assessment of left
ventricular structure and function in preeclampsia by echocardiography and
cardiovascular biomarkers. J Hypertens 2009;27:2257–64.
[26] Tihtonen KM, Koobi T, Vuolteenaho O, Huhtala HS, Uotila JT. Natriuretic
peptides and hemodynamics in preeclampsia. Am J Obstet Gynecol
2007;196. 328.e1-7.
[27] Goetze JP, Jensen G, Moller S, Bendtsen F, Rehfeld JF, Henriksen JH. BNP and N-
terminal proBNP are both extracted in the normal kidney. Eur J Clin Invest
2006;36:8–15.