Hypertension in Pregnancy

ISSN: 1064-1955 (Print) 1525-6065 (Online) Journal homepage: http://www.tandfonline.com/loi/ihip20

Maternal levels of growth differentiation factor-15

in patients with preeclampsia

Ilkbal Temel Yuksel, Begum Aydogan Mathyk, Berna Aslan Cetin, Ugur
Turhan, Zihniye Gonca Okumus, Gonca Yetkin Yildirim & Deniz Kanber Acar

To cite this article: Ilkbal Temel Yuksel, Begum Aydogan Mathyk, Berna Aslan Cetin, Ugur
Turhan, Zihniye Gonca Okumus, Gonca Yetkin Yildirim & Deniz Kanber Acar (2018): Maternal
levels of growth differentiation factor-15 in patients with preeclampsia, Hypertension in Pregnancy,
DOI: 10.1080/10641955.2018.1524477

To link to this article: https://doi.org/10.1080/10641955.2018.1524477

Published online: 06 Oct 2018.

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HYPERTENSION IN PREGNANCY
https://doi.org/10.1080/10641955.2018.1524477

Maternal levels of growth differentiation factor-15 in patients with preeclampsia

Ilkbal Temel Yuksela, Begum Aydogan Mathyk b, Berna Aslan Cetina, Ugur Turhana, Zihniye Gonca Okumusa,
Gonca Yetkin Yildirima, and Deniz Kanber Acara
a
Department of Obstetrics and Gynecology, Kanuni Sultan Suleyman Research and Training Hospital, Istanbul, Turkey; bDepartment of
Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of North Carolina, Chapel Hill, North Carolina,
USA

ABSTRACT ARTICLE HISTORY

Objective: Growth differentiation factor-15 (GDF-15) is a stress-induced cytokine and related to Received 2 January 2018
the prognosis of cardiovascular diseases. Our purpose is to measure the maternal levels of GDF-15 Accepted 30 August 2018
in patients with early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE). KEYWORDS
Methods: This cross-sectional study was conducted including 72 pregnant women, 23 with Preeclampsia; growth
normal pregnancies and 49 with preeclampsia (26 with EOPE and 23 with LOPE). Maternal differentiation factor-15;
serum levels of GDF-15 were measured by using enzyme-linked immunosorbent assay kits. GDF-15; cytokine
Results: The median serum GDF-15 level was found to be the highest in the EOPE group (EOPE:
441.7 pg/ml). The median serum GDF-15 levels were higher in women with preeclampsia than in
the control group (309.7 pg/ml vs. 436.6 pg/ml, p: 0.009).
Conclusion: Our findings suggest GDF-15 increased as a response to endothelial injury caused by
cytokines triggered by preeclampsia.

Introduction stress (8,9). The development of atherosclerotic lesions is

mirrored with the upregulation of GDF-15, and lack of
Preeclampsia is the new onset of hypertension seen in
GDF-15 resulted in the reduction of atherosclerotic lesions
pregnant women after 20 weeks of gestation. It has been
(9). GDF-15 is induced by oxidized low-density lipoprotein
the focus of recent studies in medicine as it has proven to be
(oxLDL) and contributes to oxidative stress in atherosclero-
a leading cause of maternal and perinatal mortality and
tic lesions (10). Oxidative stress is also involved in the
morbidity. The etiology of the disease is very complex
pathogenesis of endothelial dysfunction in preeclampsia.
with several contributing factors, but the hallmark of pre-
Endothelial dysfunction in preeclampsia has been linked to
eclampsia is the endothelial dysfunction, as it is responsible
the oxLDL, and increased levels of oxLDL have been
for the development of symptoms. It can be classified
reported in patients with preeclampsia (11,12). GDF-15
according to the timing of the symptoms as early-onset
has been found in the placental tissue (13), and a recent
preeclampsia (EOPE) and late-onset preeclampsia (LOPE)
study showed an increased expression of GDF-15 in pre-
(1). EOPE presents before 34 weeks of gestation and is
eclamptic placentas (7). Data on GDF-15 in patients with
associated with more maternal–fetal complications (2).
preeclampsia are scarce, and the limited literature has pro-
Further, patients with preeclampsia are at risk of developing
duced inconsistent results about the levels of GDF-15 in
cardiovascular diseases both during pregnancy and later on
patents with preeclampsia.
in life (3). An important common point of preeclampsia
For these reasons, we decided to measure serum
and cardiovascular diseases is the presence of endothelial
GDF-15 levels in patients with preeclampsia and
dysfunction (4,5). A new marker used in identifying cardi-
further studied the differences between EOPE and
ovascular disease is called growth differentiation factor-15
LOPE in those patients.
(GDF-15) (6). GDF-15 is a transforming growth factor-beta
(TGF-β) family cytokine that has been linked to a growing
amount of cardiovascular problems including acute coron- Material methods
ary syndrome, heart failure, pulmonary hypertension, as
This cross-sectional study was conducted at a single
well as preeclampsia (6,7). The expression of GDF-15 has
tertiary center between August 2017 and December
been upregulated in inflammation, vascular injury, and
2017. Seventy-six patients were enrolled in our study.

CONTACT Begum Aydogan Mathyk begum_aydogan@hotmail.com Department of Obstetrics and Gynecology, Division of Reproductive
Endocrinology and Infertility, University of North Carolina, CB 7570 Chapel Hill, NC 27599, USA
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 I. TEMEL YUKSEL ET AL.
The ethics committee of our hospital approved the
study. The informed consent was given to all partici-
pants before their enrolment into this study.
A total number of 72 pregnant women, 23 with
normal pregnancy and 49 with preeclampsia (26 with
EOPE and 23 with LOPE), were included in this study.
The cases with preexisting hypertension were excluded
from the study. Preeclampsia was defined as the new
onset of hypertension (systolic and/or diastolic blood
pressure of ≥140 and/or 90 mmHg) after the 20th week
of pregnancy concomitant proteinuria (≥300 mg in a
24-h urine or 1(+) protein by dipstick test on two
random urine samples) (14). Patients with preeclampsia
were divided into two subgroups according to the tim-
ing of the disease. These subgroups were EOPE and
LOPE based on their time of diagnosis either before or
after 34 gestational weeks.
The normotensive control group consisted of age-
and body mass index (BMI)-matched singleton preg-
nancies without hypertension. Exclusion criteria were
multiple pregnancies, pregnancies with fetal anomalies,
pregnancies with chronic disease, preexisting hyperten-
sive disorders, premature rupture of membranes, dia-
betes mellitus, and gestational diabetes. The blood
samples were obtained from the participants at the
time of admission.
The serum GDF-15 concentrations were measured
using a sandwich enzyme-linked immunosorbent assay
(ELISA) kit (Human GDF-15 PicoKineTM ELISA kit,
Catalog No: EK0767, Boster Biological Technology,
Pleasanton CA, USA). The assay sensitivity was <10 pg/
ml. The detection range was 31.2–2000 pg/ml.
Manufacturer’s instructions were followed. In the final
step of the procedure, absorbance measurements made in
a microplate at 450 nm. By plotting a standard curve from
known concentrations versus measured absorbances, the
GDF-15 levels were expressed as pg/ml.
Sample size calculation was performed using the
G*Power software version 3.1. The mean and standard
deviation values of a previous study were used for the
sample size calculation (15). The differences between
Table 1. Clinical characteristics of control and preeclampsia groups.
Age (years)
BMI (kg/m2)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
MAP (mmHg)
Gestational age at blood sampling (weeks)
Gestational age at birth (weeks)
Birth weight (g)
Uterine artery pulsatility index
Serum GDF-15 (pg/ml)
Data are expressed as median and interquartile range (25th–75th percentiles) or mean ± SD. BMI: Body mass index; MAP: Mean arterial pressure; GDF-15:
growth differentiation factor 15. p value <0.05 is significant. *Statistically significant numbers.
two independent means method yielded a minimum
sample size of 44 in total.
All analyses were performed using the Statistical
Package for the Social Sciences (SPSS) software version
20.0 (Chicago, IL, USA). The Kolmogorov–Smirnov
test was used to assess the normality of the distribution
of variables. Using the independent samples t test, we
compared the variables with normal distributions and
the Mann–Whitney U test was used to analyze non-
normally distributed continuous variables. Data were
presented as mean ± standard deviation or median
(interquartile range). Kruskal–Wallis test was used to
analyze continuous variables among more than two
groups. The Kruskal–Wallis test indicated significant
differences, adjusted by using a Bonferroni-adjusted
Mann–Whitney U test. Spearman’s rank correlation
coefficient was performed to calculate correlations
between continuous variables. Receiver operating char-
acteristic (ROC) analysis was used to determine the
performance of GDF-15 in the diagnosis of preeclamp-
sia and the cutoff points for sensitivity and specificity
were calculated. A two-tailed p value of less than 0.05
was considered statistically significant.
Results
The clinical characteristics of preeclampsia and control
groups are summarized in Table 1. There were no
significant differences between the groups in terms of
age and BMI. Mean gestational age at delivery and
mean birth weights were significantly lower in the pre-
eclampsia group (PE) than in the control group. The
median uterine artery pulsatility index was higher in
patients with preeclampsia (Table 1). The median
serum GDF-15 level was found to be the highest in
the EOPE group [EOPE: 441.7pg/ml (331.8–899.3) vs.
control: 309.7 pg/ml (253.5–470.6), p = 0.01]. The
median serum GDF15 level was higher in preeclampsia
than in control [436.6 pg/ml vs. 309.7 pg/ml, p: 0.009]
(Table 1). However, median serum GDF-15 level was
not significantly different between the EOPE group and
Control (n = 23) Preeclampsia (n = 49) p value
29.2 ± 6.1 29.1 ± 5.6 0.959
28.3 ± 3.6 29.2 ± 3.7 0.373
100 (100–110) 150 (140–160) 0.000*
61 (60–70) 100 (90–100) 0.000*
77.9 (73.3–83.3) 115.9 (110–120) 0.000*
32.3 ± 3.1 31.4 ± 5.1 0.339
39.2 (39–39.6) 34.3 (29.2–37) 0.000*
3335 ± 308.6 1833 ± 1023 0.000*
0.8 (0.68–0.92) 1.3 (0.9–1.6) 0.000*
309.7 (253.5–470.6) 436.6 (318.7–558.5) 0.009*
 HYPERTENSION IN PREGNANCY 3

Table 2. Correlation analyses between maternal serum GDF-15 the prediction of preeclampsia (Figure 1). The AUC for
and clinical parameters. GDF-15 was 0.692 (95% CI: 0.559–0.826; sensitivity:
GDF-15 75.5%; specificity: 60.8%) with an optimal cutoff value
r p of 321.5 pg/ml.
Age (years) 0.152 0.201
BMI at blood sampling (kg/m2) 0.127 0.288
Systolic blood pressure (mmHg) 0.318 0.006*
Diastolic blood pressure (mmHg) 0.368 0.001*
GA at blood sampling (weeks) −0.227 0.056 Discussion
GA at delivery (weeks) −0.287 0.015*
Birth weight (g) −0.283 0.016* We found that women with preeclampsia have
GDF-15: growth differentiation factor 15; BMI: body mass index, GA: gesta- increased serum levels of GDF-15. Further, maternal
tional age. r = Spearman’s rho. p value <0.05 is significant. *Statistically
significant numbers. serum GDF-15 levels were positively correlated with
both systolic and diastolic blood pressures.
GDF-15, also known as macrophage inhibitory cyto-
the LOPE group [EOPE: 441.7 pg/ml (331.8–899.3) vs. kine-1 (MIC-1) or placental TGF-β, is a cytokine that
LOPE: 420.9 pg/ml (551.3–298.7), p = 0.34]. belongs to the TGF-β family. GDF-15 has been
In the Spearman correlation analysis, maternal serum reported to regulate inflammatory pathways after
GDF-15 concentrations did not correlate with maternal age injury, hypoxia, oxidative stress, and cell differentiation
and BMI (Table 2). However, maternal serum GDF-15 was (16,17). Another aspect of GDF-15 is that it works as a
positively correlated with systolic blood pressure (r = 0.318, stress-induced cytokine and has been linked to many
p = 0.006) and diastolic blood pressure (r = 0.368, diseases including diabetes, cardiovascular pathologies,
p = 0.001). Further, maternal serum GDF-15 was negatively and preeclampsia (6,17,18). In addition to being a
correlated with gestational age at delivery (r = –0.287, stress-related cytokine, GDF-15 has been proven to be
p = 0.015) and birth weight (r = −0.283, p = 0.016) (Table 2). a cardiovascular biomarker for the development and
The area under the curve (AUC) and Youden index progression of heart disease (17,19). GDF-15 is a pro-
were used to calculate the cutoff points for GDF-15 in duct of activated macrophages and its production can

Figure 1. Receiver operating characteristic curve (ROC) of GDF-15 for prediction of preeclampsia; optimal cutoff = 321.5 pg/ml; area
under the curve (AUC): 0.692; 95%CI: 0.559–0.826; sensitivity: 75.5%; specificity: 60.8%, p = 0.009.
4 I. TEMEL YUKSEL ET AL.
be triggered by proinflammatory cytokines including
tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2),
and IL-6 (20,21). GDF-15 is also induced by an oxida-
tive stress marker called oxLDL and contributes to the
inflammatory processes in atherosclerosis as well as
endothelial dysfunction (10). The close relation of
GDF-15 to cardiovascular pathologies arouses curiosity
in scientists to continue focusing on how this molecule
alters preeclampsia as preeclamptic women have an
increased risk of developing cardiovascular disease
later in life (22). Endothelial dysfunction presents in
both early- and late-onset forms of preeclampsia (23).
The placental hypoxia causes the release of various
cytokines in maternal system that induce endothelial
dysfunction (5). One study showed that GDF-15 is
expressed in placenta and its mRNA expressions were
found to be upregulated in preeclamptic placentas (7).
However, literature surrounding maternal levels of
GDF-15 in preeclampsia and normal pregnancy is
inconsistent. In our study, we found that serum levels
of GDF15 were significantly higher in patients with
preeclampsia than in the control group, and the highest
level was observed in the EOPE subgroup. On the
contrary, Chen et al. reported decreased levels of
GDF15 in women with preeclampsia in both EOPE
and LOPE groups and found the lowest level in the
LOPE group (15). Further, Marjono et al. showed no
difference in GDF-15 between patients with preeclamp-
sia and the controls in terms of both serum levels and
staining intensity of placentas (24). On the other hand,
our results were similar to Sugelle et al.’s (7) study
showing that maternal serum levels of GDF-15
increased in patients with preeclampsia. Our findings
suggest GDF-15 increased as a response to endothelial
injury caused by the systemic manifestations of pree-
clampsia. Endothelial dysfunction is a hallmark of pre-
eclampsia and the PI3 K/AKT/eNOS/NO signaling
pathway is disrupted in the endothelial system (25). It
has been reported that GDF-15 induces the PI3 K/
AKT/eNOS/NO pathway to ameliorate the unopposed
effects of cardiovascular disease and diabetes on vascu-
lar endothelium (6,18). Additionally, increasing plasma
levels of GDF-15 have been reported as a potential
biomarker of endothelial damage (26). Yilmaz et al.
also confirmed the relationship between GDF-15 and
atherosclerosis through the positive correlation of
serum GDF-15 levels and carotid intima-media thick-
ness (27). There is increasing evidence on GDF-15’s
potential role in endothelial dysfunction and its aug-
mentation under stress. In our study, we found that
serum levels of GDF-15 were significantly higher in
patients with preeclampsia than in the control group.
GDF-15 levels were found to be highest in the EOPE
subgroup. Moreover, for the first time in literature, we
reported that maternal serum GDF-15 positively corre-
lated with systolic blood pressure and diastolic blood
pressure.
Our findings suggest GDF-15 increased as a
response to endothelial injury caused by the endothelial
dysfunction seen in preeclampsia. Serum levels of GDF-
15 can be used in the diagnosis of preeclampsia.
Although there is an inconsistency among studies
which might be attributed to different sample sizes
and/or study populations, further research is needed
to evaluate the roles of GDF-15 in preeclampsia.
Recently, recombinant GDF-15 treatment corrected
metabolic dysfunction of mice in an obesity experiment
(28). Researchers also might be interested in investigat-
ing the regulation of GDF-15 in endothelium and its
downstreaming molecules as GDF-15 might be a ther-
apeutic target for preeclampsia.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Begum Aydogan Mathyk http://orcid.org/0000-0001-9832-
6284
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