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The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage:

Early second-trimester plasma levels of NT-proBNP

in women who subsequently develop early-onset

Katja Junus, Anna-Karin Wikström, Anders Larsson & Matts Olovsson

To cite this article: Katja Junus, Anna-Karin Wikström, Anders Larsson & Matts Olovsson (2017)
Early second-trimester plasma levels of NT-proBNP in women who subsequently develop early-
onset preeclampsia, The Journal of Maternal-Fetal & Neonatal Medicine, 30:18, 2163-2165, DOI:

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View supplementary material Accepted author version posted online: 27

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Published online: 19 Oct 2016.

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ISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, 2017; 30(18): 2163–2165

! 2016 Informa UK Limited, trading as Taylor & Francis Group. DOI: 10.1080/14767058.2016.1241992


Early second-trimester plasma levels of NT-proBNP in women who

subsequently develop early-onset preeclampsia
Katja Junus1, Anna-Karin Wikström1,2, Anders Larsson3, and Matts Olovsson1
Department of Women’s and Children’s Health, 2Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden and
Department of Medical Sciences, Biochemical Structure and Function, Uppsala University, Uppsala, Sweden

Abstract Keywords
Plasma levels of NT-proBNP are elevated in women with preeclampsia at the time of diagnosis. B-type natriuretic peptide, biomarker, BNP,
The objective of this case-control study was to evaluate N-terminal proBNP (NT-proBNP) in hypertension, pregnancy
maternal plasma as an early second-trimester biomarker for prediction of early-onset
preeclampsia. In early second-trimester samples, women who later developed preeclampsia History
at gestational age 34 wk + 0 or earlier (n ¼ 16) had similar plasma levels of NT-proBNP (median
51.8, range 26.1–131.9 pg/ml) as women with uncomplicated pregnancy outcomes (n ¼ 43) Received 27 April 2016
(53.0, 14.9–184.2 pg/ml). The early second-trimester level of NT-proBNP cannot therefore be Accepted 24 September 2016
used as a predictive biomarker of early-onset preeclampsia. Published online 18 October 2016

Introduction elevated before clinically evident preeclampsia. If so,

NT-proBNP could possibly be used as a biomarker to predict
The pregnancy-specific syndrome preeclampsia is diagnosed
preeclampsia. To address this we compared early second-
when new onset of hypertension is present together with
trimester plasma levels of NT-proBNP in women who
proteinuria after 20 completed gestational weeks. Until the
subsequently developed early-onset preeclampsia with levels
woman presents with clinically evident preeclampsia there is
in women with uncomplicated pregnancy outcomes.
currently no accepted strategy to predict who will be afflicted
by the syndrome. A number of different biochemical markers
have been evaluated for prediction of preeclampsia but none
is good enough in terms of sensitivity and specificity to be The study was approved by the Regional Ethical Review
useful in routine clinical practice [1,2]. Preeclampsia is a Board, Uppsala, Sweden, and informed consent was obtained
heterogeneous and multifactorial condition characterized by from each woman included. The investigation was designed as
multi-organ dysfunction. The causes and the pathological a case-control study where cases (n ¼ 16) and controls
mechanisms underlying the syndrome are not fully under- (n ¼ 43) were selected from the population-based Uppsala
stood. Preeclampsia is often classified into subtypes to allow University Hospital Biobank of Pregnant Women. Since
for more homogeneous study groups. One way to classify the 31 May 2007, pregnant Swedish-speaking women above
syndrome is early- (534 gestational weeks) and late- 18 years of age, attending their second-trimester routine
(434 gestational weeks) onset preeclampsia. ultrasonographic examination have been approached for
B-type natriuretic peptide (BNP) and the inactive protein inclusion in the biobank. A venous blood sample is collected
N-terminal proBNP (NT-proBNP) are co-secreted from the from the participating women and brief maternal demo-
cardiac ventricles in response to ventricular volume expansion graphic data are collected. The coverage of the pregnant
and pressure overload. In nonpregnant populations, NT- population in the biobank is approximately 50%.
proBNP is used as a plasma marker of cardiac failure. In most The International Society for the Study of Hypertension in
studies, plasma levels of BNP and NT-proBNP are reported to Pregnancy defines early onset as preeclampsia presenting
be elevated in women with preeclampsia at the time of before 34 weeks of gestation [5] and we selected our cases
diagnosis, especially in cases of early-onset disease [3,4]. accordingly. Cases were women who later were diagnosed
However, it is not known if plasma levels of NT-proBNP are with preeclampsia at gestational age 34 weeks + 0 days or
earlier. Preeclampsia was defined as new onset of hyperten-
sion (140/90 mmHg) observed on at least two separate
Address for correspondence: Katja Junus, Department of Women’s and occasions six hours or more apart, combined with proteinuria
Children’s Health, Uppsala University, SE-751 85 Uppsala, Sweden.
Tel: +0046 18 611 57 72. Fax: +0046 18 55 97 75. E-mail: (2 on a dipstick, or a 24-h urine sample measuring 300 mg). Controls were women with an uncomplicated
2164 K. Junus et al. J Matern Fetal Neonatal Med, 2017; 30(18): 2163–2165

pregnancy outcome. Women who had chronic hypertension,

or who experienced preterm birth or delivered small-for-
gestational-age (SGA) infants were not included as controls.
Women with multiple pregnancies, diabetes mellitus or renal
disease were not included in either group. Clinical data for all
women were obtained from their medical records. SGA was
defined as birthweight at or below mean birthweight minus
2SD, based on the intrauterine curves published by Marsal
et al. [6]. Intrauterine growth restriction (IUGR) was defined
as SGA together with abnormal umbilical artery Doppler
ultrasonographic findings.
At the time of inclusion in the biobank, a total of 14 ml of
venous blood from the cubital vein were collected into two
sterile EDTA tubes. The samples were immediately placed in
a refrigerator and were centrifuged for 10 min at 1500g within
4 h of collection. The plasma was then stored at 80  C until
analyzed. Plasma levels of NT-proBNP were measured on Figure 1. Maternal plasma levels of NT-proBNP in early second
a Cobas E601 instrument (Roche Diagnostics, Basel, trimester in women who later developed early-onset preeclampsia and
Switzerland) according to the manufacturer’s instructions. in women with subsequent uncomplicated pregnancy outcome. The
The measuring range was 5–35,000 ng/l and the total horizontal line represents the median. The levels of NT-proBNP were
similar in the two groups (preeclampsia, 51.8 pg/ml versus control,
imprecision was 54%. The assay was calibrated and quality- 53.0 pg/ml).
controlled according to instructions from the manufacturer.
All statistical analyses were performed with an IBM SPSS
20 for Windows software package (IBM Corp., Armonk, NY). The plasma level of NT-proBNP did not differ between
Categorical background variables were analyzed by using women who later developed early onset preeclampsia
Pearson’s Chi-Square test or Fisher’s exact test. For continu- (51.8 [26.1–131.9] pg/ml) and women with an uncomplicated
ous variables the Kolmogorov–Smirnov test was used to test pregnancy outcome (53.0 [14.9–184.2] pg/ml) (Figure 1).
the data for normal distribution. Student’s t-test or the Mann–
Whitney U-test for independent samples were then used to
analyze the data. Data are presented as numbers (n) and
percentages, means ± standard deviation (SD) or medians and We found that the early second-trimester plasma levels of NT-
range. All tests were two-tailed and p values 50.05 were proBNP were similar in women who later developed early-
considered statistically significant. onset preeclampsia and women with an uncomplicated
pregnancy outcome. There are some previous studies of
second-trimester levels of NT-proBNP in relation to pre-
eclampsia and other obstetric conditions. Uyar and colleagues
Background characteristics of the women included in the found no difference in second-trimester NT-proBNP plasma
study are presented in supplementary table S1. The study levels between 18 women with bilateral notches and a mean
groups did not differ from each other in maternal age, body pulsatility index above the 90th centile in the uterine artery
mass index (BMI) or smoking habits. The numbers of earlier versus 50 women with normal findings, or between women
pregnancies, miscarriages and parity, were similar in the two with subsequent preeclampsia (n ¼ 8) and the rest of the
groups. Of the women with early-onset preeclampsia, seven cohort [8]. In another study, plasma NT-proBNP levels were
were not primipara and two had a history of previous elevated at gestational week 16 in 10 women with chronic
preeclampsia. Gestational ages at the time of inclusion in the hypertension who later developed preeclampsia compared
biobank, when the blood samples were taken, were similar in with 20 healthy pregnant women [9].
women that later developed early-onset preeclampsia (124 ± 6 There are two major reasons for studying the plasma level
[SD] days) and women with an uncomplicated pregnancy of NT-proBNP in the second trimester before the development
outcome (124 ± 8 days). More male than female infants were of clinically evident preeclampsia. First, to establish if NT-
born in both study groups, but the proportion of male infants proBNP could be used as a predictive biomarker of early-
was larger in women with early-onset preeclampsia (n ¼ 14, onset preeclampsia. Our results indicate that it cannot. A
87.5%) than in women with an uncomplicated pregnancy second reason for studying NT-proBNP in the second
outcome (n ¼ 26, 60.5%). trimester in relation to preeclampsia is that BNP might be
Women with early-onset preeclampsia are further described involved in the pathophysiological mechanisms of the
in supplementary table S2. Four of the women had chronic syndrome. Our current results indicate that NT-proBNP
hypertension. Gestational age at the time of preeclampsia levels increase later in the course of events leading to early-
diagnosis was 204 ± 26 (SD) days. Nine (56.2%) of the infants onset preeclampsia. The biological actions of BNP include
were SGA and five (31.2%) were IUGR. Three of the women increased natriuresis and decreased vascular resistance [10].
with early-onset preeclampsia had signs of HELLP syndrome, Preeclampsia on the other hand is characterized by general
with high levels of liver enzymes and thrombocytopenia, but vasoconstriction. One may speculate that the high levels of
none met the diagnostic criteria for hemolysis [7]. BNP in preeclampsia are part of a system to counteract the
DOI: 10.1080/14767058.2016.1241992 2nd trimester NT-proBNP 2165

cardiovascular changes present in the syndrome. To clarify 2. Anderson UD, Olsson MG, Kristensen KH, et al. Review:
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severe and early-onset preeclampsia. Statements from the
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Declaration of interest based on ultrasonically estimated foetal weights. Acta Paediatr
This work was supported by grants from the Erik, Karin and 7. Martin Jr. JN, Rose CH, Briery CM. Understanding and managing
Gösta Selanders Foundation. The authors declare no conflicts HELLP syndrome: the integral role of aggressive glucocorticoids
for mother and child. Am J Obstet Gynecol 2006;195:914–34.
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Supplementary material available online