The Journal of Maternal-Fetal & Neonatal Medicine

ISSN: 1476-7058 (Print) 1476-4954 (Online) Journal homepage: http://www.tandfonline.com/loi/ijmf20

Early second-trimester plasma levels of NT-proBNP

in women who subsequently develop early-onset
preeclampsia

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:
10.1080/14767058.2016.1241992

To link to this article: https://doi.org/10.1080/14767058.2016.1241992

View supplementary material Accepted author version posted online: 27

Sep 2016.
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

SHORT REPORT

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
1
Department of Women’s and Children’s Health, 2Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden and
3
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,

The pregnancy-specific syndrome preeclampsia is diagnosed
when new onset of hypertension is present together with
proteinuria after 20 completed gestational weeks. Until the
woman presents with clinically evident preeclampsia there is
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
useful in routine clinical practice [1,2]. Preeclampsia is a
heterogeneous and multifactorial condition characterized by
multi-organ dysfunction. The causes and the pathological
mechanisms underlying the syndrome are not fully under-
stood. Preeclampsia is often classified into subtypes to allow
for more homogeneous study groups. One way to classify the
syndrome is early- (534 gestational weeks) and late-
(434 gestational weeks) onset preeclampsia.
B-type natriuretic peptide (BNP) and the inactive protein
N-terminal proBNP (NT-proBNP) are co-secreted from the
cardiac ventricles in response to ventricular volume expansion
and pressure overload. In nonpregnant populations, NT-
proBNP is used as a plasma marker of cardiac failure. In most
studies, plasma levels of BNP and NT-proBNP are reported to
be elevated in women with preeclampsia at the time of
diagnosis, especially in cases of early-onset disease [3,4].
However, it is not known if plasma levels of NT-proBNP are
Address for correspondence: Katja Junus, Department of Women’s and
Children’s Health, Uppsala University, SE-751 85 Uppsala, Sweden.
Tel: +0046 18 611 57 72. Fax: +0046 18 55 97 75. E-mail:
katja.junus@kbh.uu.se
NT-proBNP could possibly be used as a biomarker to predict
preeclampsia. To address this we compared early second-
trimester plasma levels of NT-proBNP in women who
subsequently developed early-onset preeclampsia with levels
in women with uncomplicated pregnancy outcomes.
Methods
The study was approved by the Regional Ethical Review
Board, Uppsala, Sweden, and informed consent was obtained
from each woman included. The investigation was designed as
a case-control study where cases (n ¼ 16) and controls
(n ¼ 43) were selected from the population-based Uppsala
University Hospital Biobank of Pregnant Women. Since
31 May 2007, pregnant Swedish-speaking women above
18 years of age, attending their second-trimester routine
ultrasonographic examination have been approached for
inclusion in the biobank. A venous blood sample is collected
from the participating women and brief maternal demo-
graphic data are collected. The coverage of the pregnant
population in the biobank is approximately 50%.
The International Society for the Study of Hypertension in
Pregnancy defines early onset as preeclampsia presenting
before 34 weeks of gestation [5] and we selected our cases
accordingly. Cases were women who later were diagnosed
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
occasions six hours or more apart, combined with proteinuria
(2 on a dipstick, or a 24-h urine sample measuring
300 mg). Controls were women with an uncomplicated
2164 K. Junus et al.
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
a Cobas E601 instrument (Roche Diagnostics, Basel,
Switzerland) according to the manufacturer’s instructions.
The measuring range was 5–35,000 ng/l and the total
imprecision was 54%. The assay was calibrated and quality-
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).
Categorical background variables were analyzed by using
Pearson’s Chi-Square test or Fisher’s exact test. For continu-
ous variables the Kolmogorov–Smirnov test was used to test
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
range. All tests were two-tailed and p values 50.05 were
considered statistically significant.
Results
Background characteristics of the women included in the
study are presented in supplementary table S1. The study
groups did not differ from each other in maternal age, body
mass index (BMI) or smoking habits. The numbers of earlier
pregnancies, miscarriages and parity, were similar in the two
groups. Of the women with early-onset preeclampsia, seven
were not primipara and two had a history of previous
preeclampsia. Gestational ages at the time of inclusion in the
biobank, when the blood samples were taken, were similar in
women that later developed early-onset preeclampsia (124 ± 6
[SD] days) and women with an uncomplicated pregnancy
outcome (124 ± 8 days). More male than female infants were
born in both study groups, but the proportion of male infants
was larger in women with early-onset preeclampsia (n ¼ 14,
87.5%) than in women with an uncomplicated pregnancy
outcome (n ¼ 26, 60.5%).
Women with early-onset preeclampsia are further described
in supplementary table S2. Four of the women had chronic
hypertension. Gestational age at the time of preeclampsia
diagnosis was 204 ± 26 (SD) days. Nine (56.2%) of the infants
were SGA and five (31.2%) were IUGR. Three of the women
with early-onset preeclampsia had signs of HELLP syndrome,
with high levels of liver enzymes and thrombocytopenia, but
none met the diagnostic criteria for hemolysis [7].
J Matern Fetal Neonatal Med, 2017; 30(18): 2163–2165
Figure 1. Maternal plasma levels of NT-proBNP in early second
trimester in women who later developed early-onset preeclampsia and
in women with subsequent uncomplicated pregnancy outcome. The
horizontal line represents the median. The levels of NT-proBNP were
similar in the two groups (preeclampsia, 51.8 pg/ml versus control,
53.0 pg/ml).
The plasma level of NT-proBNP did not differ between
women who later developed early onset preeclampsia
(51.8 [26.1–131.9] pg/ml) and women with an uncomplicated
pregnancy outcome (53.0 [14.9–184.2] pg/ml) (Figure 1).
Discussion
We found that the early second-trimester plasma levels of NT-
proBNP were similar in women who later developed early-
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
found no difference in second-trimester NT-proBNP plasma
levels between 18 women with bilateral notches and a mean
pulsatility index above the 90th centile in the uterine artery
versus 50 women with normal findings, or between women
with subsequent preeclampsia (n ¼ 8) and the rest of the
cohort [8]. In another study, plasma NT-proBNP levels were
elevated at gestational week 16 in 10 women with chronic
hypertension who later developed preeclampsia compared
with 20 healthy pregnant women [9].
There are two major reasons for studying the plasma level
of NT-proBNP in the second trimester before the development
of clinically evident preeclampsia. First, to establish if NT-
proBNP could be used as a predictive biomarker of early-
onset preeclampsia. Our results indicate that it cannot. A
second reason for studying NT-proBNP in the second
trimester in relation to preeclampsia is that BNP might be
involved in the pathophysiological mechanisms of the
syndrome. Our current results indicate that NT-proBNP
levels increase later in the course of events leading to early-
onset preeclampsia. The biological actions of BNP include
increased natriuresis and decreased vascular resistance [10].
Preeclampsia on the other hand is characterized by general
vasoconstriction. One may speculate that the high levels of
BNP in preeclampsia are part of a system to counteract the
DOI: 10.1080/14767058.2016.1241992
cardiovascular changes present in the syndrome. To clarify
the role of BNP in preeclampsia, more research is needed.
A limitation of the study is the small study size and
no power calculation was done a priori due to limited
earlier data.
In conclusion, early second-trimester plasma levels of NT-
proBNP are similar in women who later develop early-onset
preeclampsia and women with an uncomplicated pregnancy
outcome. The early second-trimester level of NT-proBNP
cannot therefore be used as a predictive biomarker of early-
onset preeclampsia.
Declaration of interest
This work was supported by grants from the Erik, Karin and
Gösta Selanders Foundation. The authors declare no conflicts
of interest.
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