The Journal of Maternal-Fetal & Neonatal Medicine

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

Maternal serum concentrations of s-Endoglin

and IL-6 in pregnancy complicated by preterm
premature membrane rupture

Smeyra Nergiz Avcolu, Selda Demircan Sezer, Mert Kk, Emre Zafer,
Hasan Yksel, Bars Akcan & Ozan Turgut

To cite this article: Smeyra Nergiz Avcolu, Selda Demircan Sezer, Mert Kk, Emre Zafer,
Hasan Yksel, Bars Akcan & Ozan Turgut (2015): Maternal serum concentrations of s-Endoglin
and IL-6 in pregnancy complicated by preterm premature membrane rupture, The Journal of
Maternal-Fetal & Neonatal Medicine, DOI: 10.3109/14767058.2015.1070137

To link to this article: http://dx.doi.org/10.3109/14767058.2015.1070137

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Jul 2015.
Published online: 13 Aug 2015.

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

J Matern Fetal Neonatal Med, Early Online: 16

! 2015 Taylor & Francis. DOI: 10.3109/14767058.2015.1070137

ORIGINAL ARTICLE

Maternal serum concentrations of s-Endoglin and IL-6 in pregnancy

complicated by preterm premature membrane rupture
Sumeyra Nergiz Avcoglu1, Selda Demircan Sezer1, Mert Kucuk2, Emre Zafer1, Hasan Yuksel1, Bars Akcan3, and
Ozan Turgut4
1
Department of Obstetrics & Gynecology, Faculty of Medicine, Adnan Menderes University, Aydn, Turkey, 2Department of Obstetrics & Gynecology,
Faculty of Medicine, Mugla Stk Kocman University, Mugla, Turkey, 3Department of Neonatology, Faculty of Medicine, Adnan Menderes University,
Aydn, Turkey, and 4Obstetric and Gynecology Clinic, Iskenderun State Hospital, Hatay Merkez/Hatay, Turkey
Downloaded by [ETH Zurich] at 23:12 02 November 2015

Abstract Keywords
Objective: This study aimed to investigate maternal serum concentrations of s-Endoglin and s-Endoglin, IL-6, preterm premature
compare s-Endoglin with other inflammatory markers in prediction of time to delivery, in membranes rupture, time to delivery
pregnancies complicated by preterm premature rupture of membranes (PPROM). interval
Materials and methods: Fifty five patients complicated by PPROM whose gestational age were
between 2433 weeks and 44 matched healthy pregnant women were included in present History
study. Maternal concentrations of s-Endoglin concentrations were measured by an enzyme-
linked immunosorbent assay (ELISA) and compared with maternal inflammatory markers Received 7 February 2015
including interleukin-6 (IL-6), white blood cell (WBC) count and serum C-reactive protein (CRP). Revised 12 June 2015
The best variable for prediction of preterm birth was computed. Accepted 3 July 2015
Results: Mean s-Endoglin levels in PPROM were lower than control groups (0.24 0.12 pg/ml Published online 13 August 2015
and 0.69 0.25 pg/ml, respectively, p50.01). Besides IL-6 (p50.01), WBC (p 0.016) and CRP
(p 0.010) levels were higher in PPROM group. In PPROM group, ROC analysis results of
s-Endoglin for prediction of preterm delivery 548 h, 57 days, 532 weeks were not different
(p40.05). For predicting preterm birth before 48 h and 7 days, only IL-6 at cut off value >0.70
(pg/ml) and >0.55 (pg/ml) had area under curve (AUC); 0.871 (0.7750.965), p50.01, AUC; 0.925
(0.8560.993), p50.001, respectively.
Conclusion: s-Endoglin as an anti-angiogenic marker seemed to have a role in pathogenesis but
results of present study showed that, unlike IL-6, it was unsatisfactory for estimating time to
delivery in PPROM.

Introduction Angiogenesis is the process of new vessels formation from

pre-existing vasculature. It is regulated by different families
Preterm premature rupture of membranes (PPROM) is one of
of growth factors [6]. Soluble endoglin (s-Endoglin) is known
the most common complications of pregnancy [1]. It is
as an anti-angiogenic factor [7]. As we know, pregnancy is a
defined as rupture of amniotic membranes before the 37th
condition requiring extensive angiogenesis in both foetal and
week of gestation. The incidence is reported to be between 6%
maternal compartments [8]. The levels of angiogenic and anti-
and 10% [2]. Nearly one-third (about 30%) of all deliveries
angiogenic factors change during pregnancy in maternal
occurring preterm are associated with PPROM [3].
circulation [9]. Change in levels of these markers may affect
The pathogenesis of PPROM causing preterm birth still
angiogenesis and placental development and function [10].
remains debate. However, many hypotheses have been
So, a balance between angiogenic and anti-angiogenic factors
claimed. Genetic predisposition, maternal infection, smoking,
is essential for feto-placental development [10,11].
mechanical damage, plasminogen activation, vitamin and
However, the impacts of angiogenesis process in partur-
nutritional deficiencies are the factors blamed for PPROM. In
ition both in term and preterm labour are mostly unknown. It
PPROM pathogenesis, intrauterine infection and following
was shown that the expression of angiogenesis-related genes
inflammation claimed synergistically to weaken the mem-
is significantly increased in the mouse uterus during spon-
branes and cause PPROM [4,5].
taneous labour at term and in preterm labour [12]. There is a
paucity of information about the role of angiogenetic factors
especially in PPROM [6]. In present study, we aimed to
investigate role of s-Endoglin, as an anti-angiogenic factor
and compare with inflammatory markers including interlekin-
Address for correspondence: Sumeyra Nergiz Avcoglu, Department of
Obstetrics & Gynecology, Faculty of Medicine, Adnan Menderes 6 (IL-6), white blood cell (WBC) count and serum C-reactive
University, Aydn, Turkey. E-mail: sumeyranergiz80@gmail.com protein (CRP) for prediction of time to delivery in PPROM.
 2 S. Nergiz Avcoglu et al. J Matern Fetal Neonatal Med, Early Online: 16

Materials and methods included 12 mg betamethasone or betamethasone disodium-

phospate (Celestone Chronodose, Schering-Eczacbas ,
This prospective study was conducted at Adnan Menderes
Luleburgaz, Turkey) applied intramuscularly, repeated at
University Hospital January 2013April 2014. The institu-
24 h interval. Patients were restricted to bed rest and a
tional review board approved the study and informed consent
foetal heart monitoring with uterine activity assessment was
was obtained from all of the patients. We declare, the study
performed twice daily.
followed principles in the declaration of Helsinki. A total of
Venous blood samples were collected from all cases within
99 patients with singleton pregnancies admitted to our
2 h before administration of any drugs in the study in order to
hospital were included in the study. The participants
determine levels of WBC, CRP, s-Endoglin and IL-6. All
as Group 1 included 44 matched healthy women at simi-
complete blood count analyses were performed by using a
lar gestational ages and Group 2 included 55 patients
Mindray BC 6800 analyser (M68 LH LYSE, Nanshan,
with PPROM gestational aged between 24 and 33 weeks
Shenzhen, China) in the haematology laboratory of our
of pregnancy maternal characteristics (age, obstetric his-
hospital. The CRP levels were measured by immunoturbidi-
tory and history of preterm labour in previous deliveries)
metry using CRP Reagent kit in the COBAS E411 (Roche,
were obtained by interview at the time of hospital
Poznan, Poland) instrument.
applications. Women with multiple pregnancies, clinical
The blood samples (5 mL) were collected in tubes and
signs of infection, cervical dilatations of 42 cm, patients
were immediately centrifuged for 15 min at 1000 g at 4  C
having vaginal bleeding, pregnancies lasting with preterm
within 30 min of collection. Serum was separated into vials
delivery due to medical causes such as abruptio placentae,
and stored at 80  C until measurement. s-Endoglin was
foetal distress, cord prolapse, foetal anomalies, patients with
measured by Human Endoglin (sCD105) instant ELISA kit
chronic hypertension and preeclampsia were all excluded in
Downloaded by [ETH Zurich] at 23:12 02 November 2015

(Ebioscience-Bendermed, San Diego, CA). IL-6 levels were

the study.
measured by Human IL-6 platinum ELISA kit (Ebioscience-
In present study, in addition to patient history of amnion
Bendermed).
leakage, rupture of membranes was diagnosed by sterile
Students t tests, MannWhitney U and chi-squared tests
speculum examination, determining pooling of amniotic fluid
were computed to compare study variables between patients
in the posterior vaginal fornix and positive nitrazine paper
complicated by PPROM and control subjects. Spearman
reaction. Also, PPROM was diagnosed by determining
correlations were also computed to quantify associations
amniotic fluid leakage from the cervical canal. Amniosure
between s-Endoglin WBC, CRP and obstetric measures.
test (OIAGEN Company, Boston, UK) was performed in
Receiver operator characteristic (ROC) analysis was used
suspicious cases. All of the patients in group 2 received
to establish the value of s-Endoglin and inflammatory
prophylactic i.v. antibiotics (ampicillin, Ampisina-Actavis,
_ markers in prediction of arrival time-to-delivery interval.
Istanbul, Turkey, 1.5 g every 6 h) after membrane rupture until
Cox regression analysis was used to test the relationship
delivery. In addition, steroid therapy was used for pulmonary
between s-endoglin level, IL6 and time to delivery. p50.05
maturation in all group 2 patients. Corticosteroid regimen
was regarded as statistically significant.

Table 1. Demographic characteristics, obstetric and biochemical variables of participants (mean SD%).

Control (n 44) PPROM (n 55) p

Age (years) 26.56 5.46 26.70 6.95 0.915
Gravidity (n, %)
1 15 (34.1%) 24 (43.6%) 0.506
2 17 (38.6%) 12 (21.8%)
3 12 (17.3%) 19 (34.6%)
Parity (n, %)
0 18 (40.9%) 26 (43.7%) 0.580
1 16 (36.4%) 15 (27.3%)
2 10 (22.7%) 14 (35.4%)
Obstetric history (n, %)
VB 13 (29.5%) 13 (23.6%) 0.1
CS 13 (29.5%) 16 (29.1%)
None 18 (40.9%) 26 (47.3%)
Gestational age at presentation (weeks) 29.09 2.90 30.16 3.56 0.102
Gestational age at delivery (weeks) 37.86 1.47 30.81 3.41 50.01
Presentation with uterine contraction to delivery interval (h) 1458.54 546.81 111.96 171.03 50.01
Birth weight (g) 2970.34 547.35 1827.12 806.305 50.01
1 min Apgar score 8.59 0.59 6.70 2.10 50.01
5 min Apgar score 9.50 0.62 8.14 1.72 50.01
WBC (109/L) 11.43 4.08 13.56 4.65 0.016
CRP (mg/L) 10.52 15.23 23.28 31.68 0.010
IL-6 (pg/mL) 0.21 0.52 0.66 0.15 50.01
s-Endoglin (pg/mL) 0.69 0.25 0.24 0.12 50.01

PPROM, preterm premature rupture of membrane; VB, vaginal birth; CS, caesarean section; WBC, white blood cell; CRP, C-reactive protein; IL-6,
interlekin-6. Statistical significance: p50.05 (bold).
 DOI: 10.3109/14767058.2015.1070137
Results
Baseline characteristics
Demographic characteristics of the study population are
shown in Table 1. Mean maternal age was 26.76 6.25 years
and mean gestational age was 29.68 3.31 weeks at recruit-
ment. Mean s-Endoglin levels in groups were 0.24 0.12 pg/
mL in group 2 and 0.69 0.25 pg/mL in group 1, respectively
(p50.01). Comparison of obstetric parameters and biochem-
ical variables of study and control groups is given in Table 1.
In present study, presentation with uterine contraction
to delivery interval (hours) was directly correlated with
s-Endoglin levels (r 0.651, p50.01) but inversely corre-
lated with IL-6 (r 0.559, p50.01), WBC (r 0.255,
p 0.011), CRP (r 0.347, p50.01). There was a positive
correlation between gestational age that PPROM happened
and s-Endoglin levels (r 0.309, p 0.022). In PPROM
group, 23 (41.8%) patients delivered before 32 weeks of
gestation, 25 (45.5%) patients delivered in 48 h, 44 (80%)
patients delivered before 7 days and 11 (20%) patients
Downloaded by [ETH Zurich] at 23:12 02 November 2015
delivered after 7 days.
In group 2, 12 (30.76%) patients were operated due to
symptoms of chorioamnionitis like increase in fever or
infection parameters like CRP and 9 (23.7%) patients were
operated due to anhydramniosis and unprogressive labour or
foetal distress. In PPROM group, 36 babies took care in
neonatology unit of hospital. Among them, 22 (75.9%) baby
had neonatal infection, 14 (48.3%) patients had mechanical
ventilation support but only 6 patients had positive blood
cultures of microorganism. Mean time of hospitalisation in
PPROM group was 22 26.07 (1122) days. No correlation
Figure 1. ROC curve of IL-6, s-Endoglin for
delivery 548 h in group 2. AUC for IL-6
0.871; 95% CI: 0.7750.965, p50.01, for s-
Endoglin AUC 0.516; 95% CI: 3600.672,
p 0.839.
s-Endoglin and IL-6 in PPROM 3
has been determined between maternal WBC count, CRP,
IL-6, s-Endoglin levels and WBC count, CRP levels of
babies. There was also no correlation between neonatal
infection and s-Endoglin levels (p40.05, r 0.274).
In PPROM group, ROC analysis results of s-Endoglin for
prediction of preterm delivery 548 h, 57 days, 532 weeks
were not statistically significant (p40.05). Again in PPROM
group, among the inflammatory markers, WBC, CRP had no
statistically significant predictive value for time to delivery
interval (p40.05). It was shown that in ROC analysis, only
IL-6, for predicting preterm birth before 48 h and 7 days, at
cut-off value 40.70 pg/mL and 40.55 pg/mL), had area under
curve (AUC): 0.871 (0.7750.965), p50.01; AUC: 0.925
(0.8560.993), p50.001, respectively (Figures 1 and 2).
According to multivariate analysis using Cox regression
analysis, decreased s-Endoglin level [hazard ratio of 0.004
(95% confidence interval 0.0010.022)] and increased IL-6
level [hazard ratio of 1.985 (95% confidence interval 1.292
3.051) were associated with shorter admission to delivery
interval in PPROM group (Figure 3).
Discussion
The results of this study showed that s-Endoglin levels were
lower in PPROM group than patients in control group at
similar gestational ages. To the best of our knowledge, there
are no data about maternal s-Endoglin concentrations in
PPROM. There is only one study about increased s-Endoglin
levels in the preterm labour group. However, in that study,
patients were followed from first to third trimesters and
s-Endoglin levels were higher several weeks before the onset
 4 S. Nergiz Avcoglu et al. J Matern Fetal Neonatal Med, Early Online: 16

Figure 2. ROC curve of IL-6, s-Endoglin for

delivery within 7 days in group 2. AUC for
IL-6 0.925; 95% CI: (0.8560.993),
p50.001, for s-Endoglin AUC 0.390; 95%
CI: 0.2180.563, p 0.265.
Downloaded by [ETH Zurich] at 23:12 02 November 2015

Figure 3. Survival curve of time to delivery

for IL-6 and s-Endoglin.

of labour, in patients with preterm labour [9]. So, con-
troversies may be due to the fact that the study included
only preterm labour group and there was no result about
s-Endoglin concentrations of patients at the time of presen-
tation of patients with preterm labour.
In literature, the researches about s-Endoglin levels were
performed especially in preeclamptic women. In the first and
second trimesters, high level of s-Endoglin in maternal
plasma showed an increased risk of the development of
preterm preeclampsia and small for gestational age [13]. Also,
there have been studies about angiogenic markers in preterm
labour. Similar to results of the present study, two previous
reports determined that low soluble fms-like tyrosine kinase-1
(sFlt-1) levels, which was an anti-angiogenic marker similar
to s-Endoglin, might suggest spontaneous preterm labour
[14]. Also, low sFlt-1 levels were associated with midpreg-
nancy preterm birth unexplained by preeclampsia or small for
gestational age [15]. Again in a study performed with another
 DOI: 10.3109/14767058.2015.1070137
anti-angiogenic factor, s-VEGFR (vascular endothelial growth
factor), showed that lower concentrations of s-VEGFR-1 in
amniotic fluid of patients complicated with PPROM [16].
In normal pregnancy, the plasma concentrations of
s-Endoglin decrease from the first to the second trimester,
but subsequently increase mildly [17]. In the present study, we
have determined low levels of s-Endoglin in PPROM group
compared with control group. In literature, that issue was
explained by mechanism of maternal placental oxygenation.
It was found that placental hypoxia associated with increase in
sFlt-1 expression, which was anti-angiogenic factor similar to
s-Endoglin, but placental hyperoxia [18] might decrease its
expression [15]. So, there should be an occasion resulting in
placental hyperoxia and lead to decrease of anti-angiogenic
factors in PPROM.
In the present study, higher WBC, CRP and IL-6 levels
were determined in the PPROM group. Similarly, parturition
is claimed to be an inflammatory process in both term and
preterm [19,20]. There are studies about increased concen-
trations of inflammatory markers in PPROM. Several studies
Downloaded by [ETH Zurich] at 23:12 02 November 2015
have determined that increased concentration of IL-6 in
maternal serum, cervicovaginal secretions and amniotic fluid
was associated with that preterm labour [2123]. Besides, in
the present study, s-Endoglin levels were inversely correlated
with inflammatory markers including WBC, CRP and IL-6.
That finding supported the cross-talk between inflammation,
which participates in the pathophysiology of spontaneous
preterm parturition and angiogenesis processes. So, there have
been two sides of PPROM; one is proinflammatory activation
of foetal endothelium in chorioamnionitis and the other is
cellular stress and changes in angiogenic homeostasis. Indeed,
during an inflammatory process like chorioamnionitis, newly
formed vessels supply the nutrients and oxygen to the
inflamed tissues. So, decrease in maternal s-Endoglin in
patients complicated with PPROM might be explained by
increased angiogenesis and hyperoxia due to inflammation in
foetal membranes and amniotic fluid. However, one limitation
of our study was that s-Endoglin was not investigated in foetal
membranes and amniotic fluid in addition to maternal blood.
Interestingly, in this study, no correlation has been
determined between maternal WBC, CRP, IL-6, s-endoglin
and WBC, CRP levels of babies, neonatal infection and body
culture positivity. In the literature, it was determined that an
increase in concentrations of s-Endoglin in the amniotic fluid
was associated with neonatal morbidity and histologic
chorioamnionitis, in patients with preterm labour and
PPROM. In that study, the amniotic fluid concentration of
s-Endoglin was positively correlated with indirect markers of
intra-amniotic infection, including IL-6 concentration and
WBC count in amniotic fluid [24]. Controversies in our study
were due to performance of our study in maternal blood but
not by amniotic fluid or foetal membranes and small number
of study population.
Clinical management of PPROM before 34 weeks of
gestation is generally expectant. The current standard of care
is hospitalisation and bed rest until there is evidence of
ascending infection or documentation of foetal lung maturity
in women without signs of infection [25]. Thus, predicting
time to delivery and detection of subclinical infection is very
important. In the literature there have been number of studies
s-Endoglin and IL-6 in PPROM 5
for prediction of time to delivery and neonatal infection in
PPROM. For example, procalcitonin is an important bio-
logical marker but studies claiming the role of its prediction
are inconclusive [26,27]. Similarly, it was determined that
vaginal fluid procalcitonin was also unsatisfactory for the
prediction of PPROM-to-delivery interval, histological chor-
ioamnionitis or newborns congenital infection [28]. IL-6 was
another marker to do that prediction [29]. Rizzo et al. [23]
and Jun et al. [30] demonstrated that the measurement of IL-6
in cervical secretions of patients with PPROM was a
non-invasive test. It was also a sensitive method to identify
the pregnant women who were at risk for preterm delivery,
microbial invasion of the amniotic cavity or neonatal
complications [31]. In another study, similar to results of
our study, in women with PPROM and high IL-6, there was a
trend towards more extreme PTDs and delivery within 7 days
compared to low IL-6 [32]. In the present study, another
marker, s-Endoglin was determined and it was positively
correlated with time to delivery in study population and ROC
curve results have shown that s-Endoglin had no predictive
value only for preterm delivery 48 h, 7 days, 532 weeks in
the PPROM group. Besides, no statistically significant
relationship was determined between neonatal infection and
s-Endoglin levels. However, our study is the first study
investigating role of maternal s-endoglin concentration in
prediction of time to delivery and large, multicentred studies
about molecular and genetic aspects of angiogenic and anti-
angiogenic markers, especially in fetomaternal circulation of
patients with PPROM, including high number of participants
are needed to confirm the results of our study. We investigated
s-Endoglin which is an anti-angiogenic factor. But, we also
suggest that proangiogenic factors in PPROM should be
investigated in further studies. We did not perform vaginal
culture in the current study due to financial cost. In further
studies, we also suggest performing vaginal culture, which
would allow correlation analysis with specific bacteria such as
group B streptococcus.
In conclusion, the s-Endoglin, as an anti-angiogenic
marker seemed to have a role PPROM due to the angiogenic
pathway mainly intercorrelated with inflammatory pathway or
by angiogenic pathway itself. However, results of present
study showed that, unlike IL-6, it was unsatisfactory for
estimating time to delivery in PPROM.
Acknowledgements
Special thanks to fellows of obstetrics and gynaecology for
personal assistance and contributions.
Declaration of interest
The authors declare that they have no conflict of interests and
there was no involvement of a pharmaceutical/other company.
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