Serum concentrations of PlGF (Placental Growth Factor) Severe Preeclampsia

Patients in Dr. Mohammad Hoesin Palembang General Hospital

Rodiani, Kurdi S, Nuswil B, Erial B

Department of Obstetrics and Gynecology
Medical Faculty Sriwijaya University
Dr. Mohammad Hoesin Palembang General Hospital

Abstract
Objective: To analyze the relationship between maternal serum concentration of PlGF
with severe preeclampsia
Methods: A case study on the control of severe preeclampsia group as a group of cases
and normal pregnancies as a control group. Data obtained dientry using SPSS version
21.0 software Windows. Analysis conducted in the form of univariate, bivariate
analysis, ROC analysis and multivariate analysis
Results: Based on the results of ROC analysis showed that the cut-off point of PlGF in
preeclampsia is predictive 123.35 pg / ml (sensitivity 93.3%, specificity 70.0%). The
percentage of Severe Preeclampsia majority occur in low PlGF level group (38.3% of
the 60 samples). The existence of a significant relationship with the occurrence of low
levels of PlGF in Severe Preeclampsia (p = <0.001). Based analisismultivariat also
obtained the best groups in the determination of gestational age through examination
PlGF in Severe Preeclampsia is a group of gestation> 29 weeks ( 75%)
Conclusion: There is a significant correlation with the incidence of low levels of PlGF
in Severe Preeclampsia
Keywords: Placental Growth Factor, Severe Preeclampsia

INTRODUCTION
PlGF (Placental Growth Factor) and VEGF (Vascular Endothelial Growth Factor) is a
factor proangiogenik best and most potent who work directly which increases vascular
permeability. PlGF is a member of the group other than VEGF VEGF-B, VEGF-C,
VEGF-D and VEGF-E. These molecules are secreted dimeric glycoproteins.1,2
In normal pregnancy PlGF worth 40-50 pg / ml at 7-15 weeks gestation. At the age of
28-30 weeks gestation increased dramatically PlGF worth 180-200 pg / ml, whereas the
term gestational age between 39-41 weeks gestation serum concentrations of PlGF
worth 55-65 pg / ml. Serum PlGF at the end of the second trimester increased up to four
times from the end of the first trimester. Whereas, if an interruption occurs in the
placenta of pregnancy with preeclampsia, the concentration of PlGF would decreased.3-5
In some hospitals in Indonesia the incidence of preeclampsia was not much different.
RSCM (Cipto Mangunkusumo Hospital), Jakarta reported that in 2002 there were the
incidence of preeclampsia by 9.17%. The incidence of preeclampsia in RSHS (RS
Hasan Sadikin) in 1998 amounted to 13.05, while in RSHAM (H. Adam Malik
Hospital) in 2002 amounted to 7.0%. Medical records at the Dr. Mohamad Hoesin
Palembang General Hospital, the incidence of preeclampsia in 2012 found 12% .6
Etiology of preeclampsia is still unknown. There are several hypotheses to explain the
pathogenesis of preeclampsia include placental ischemia theory, theory Maladaptation
immune, genetic theory and the theory of change in VLDL and activities antitoxin. 6,7 It
is considered important in the development of preeclampsia theory is incomplete
trophoblast invasion or with other terms be regarded as abnormal cytotrophoblast
invasion of the maternal spiral arteries, which cause bad perfusion trophoblast.
Furthermore, it has spread toxins that cause dysfunction of endothelial cells and
vascular endothelial function imbalance maternal vasodepresor.8-10
There is another theory says preeclampsia associated with an imbalance of circulating
angiogenic factors. The imbalance between antiangiogenic form of soluble fms-like
tyrosine kinase 1 (sFlt-1) and soluble soluble endoglin high with proangiogenik the

form of a low PlGF and VEGF. This condition triggers vascular endothelial cell injury
in the liver, kidney, brain and placenta. Endothelial dysfunction and injury causes a state
of hypertension, proteinuria and other systemic manifestations syndrome.2,11
The pathogenesis of preeclampsia is still being studied further, but allegedly associated
with angiogenesis and vasculogenesis process that occurs in fetomaternal circulation.
Both of these processes is necessary to anticipate the threat of hypoxia on fetomaternal
circulation along with the growth of the fetus. The process of angiogenesis and
vaskulogenesis require several growth factor. The main growth factor in this process are
VEGF and PIGF.11,12
Research shows that in pregnant women with preeclampsia, trophoblast implantation
less than perfect so that blood flow is reduced, and placental hypoxia and an increase in
the production of sFlt1 that will bind VEGF angiogenic factors are independent and free
P1GF so that the amount in circulation is reduced. This will cause the endothelial
dysfunction that would disrupt the blood brain barrier and cause intracranial
hypertension, causing edema, liver and affect the function of capillary gromelurus.
When VEGF on renal prodocyte decreased by 50%, glomerular endothelial cells will
swell, capillaries collapse and cause proteinuria.13-17
Petrozella et al. found increased levels of sFlt-1 and PlGF levels decrease compared to
both normal mRNA concentrations in placenta and serum levels in preeclampsia. 7 Grill
et al. observing the relationship between placental protein in patients with preeclampsia
and protein-protein sFlt proangiogenic such as VEGF and PlGF concentrations. 8 Grill
expressed in severe preeclampsia will decrease from the first trimester of pregnancy
until delivery. Thus the level of sFlt-1 increased maternal preeclampsia and vice versa
levels of VEGF and free PlGF decreased.9,18
Chaiworapongsa et al. continued evaluation of this antiangiogenic protein. They showed
concentrations of angiogenic and antiangiogenic factors from serum of pregnant women
with preeclampsia at 34-36 weeks of gestation. They showed that the combination of
soluble endoglin levels and the ratio of sFlt-1 by PlGF increases the predictive value of

preeclampsia, both of which occur earlier or slower, and also the prediction of severe
impact of this disease (fetal growth restriction and the HELLP syndrome) 10 weeks
before emerging clinical manifestations.9,18,19
Mutter et al. makes the size of the angiogenic protein as a potential test tool in
predicting preeclampsia, which is when the increase in the level of sFlt and lower levels
of free VEGF, PlGF is free, and urinary PlGF about 5 weeks prior to the manifestation
of preeclampsia. They conclude that VEGF and PlGF decreased, soluble endoglin
increased, each with a different mechanism causes endothelial dysfunction and mediate
the manifestation of preeclampsia. Research in Indonesia on PlGF in preeclampsia is
still has inadequate data as reported by Ekapatria et al. They compared the levels of
PlGF between early-onset preeclampsia group and slow in Dr Hasan Sadikin, Bandung.
This makes the interest of researchers to examine further why PlGF decreased in
patients with severe preeclampsia in. Dr. M. Hoesin Palembang General Hospital.19-22
Some researchers at the above also show that low serum levels of PlGF can be a useful
marker in predicting and diagnosing severe preeclampsia. Therefore, this research needs
to be done in the clinical management of severe preeclampsia in Department Obstetrics
and Gynecology Dr. M. Hoesin Palembang General Hospital.
METHODS
Case-control study in severe preeclampsia group as a group of cases and normal
pregnancies as a control group. Data obtained dientry using SPSS version 21.0 software
Windows. Analysis conducted in the form of univariate, bivariate analysis and ROC
analysis.
RESULT
Data taken in this study of primary data is to perform sampling of maternal blood were
diagnosed with severe preeclampsia from June 2013 to February 2014. Routine blood
tests, routine urine and blood chemistry that has been done before in the diagnosis of
severe preeclampsia. Researchers examined levels of PlGF in maternal blood serum of

30 people who suffer from severe preeclampsia and 30 normal pregnant women in the
lab PRODIA Palembang. The characteristics of the study sample are described as
follows.

A. CHARACTERISTICS OF RESEARCH
This study is a case-control study with the aim to determine the prevalence of PlGF
levels in the two groups and whether there is a connection with a reduction in the
incidence of severe preeclampsia serum PlGF levels. The subjects were normotensive
pregnant women and severe preeclampsia. Data collection is done in IRD (Emergency
Room), delivery room and outpatient clinic Obstetrics RSMH Palembang. Subject
recruitment carried out in accordance reference with full respect for the freedom of the
subject.
The following table below describes the characteristics of the study subjects which are
risk factors for preeclampsia

Table 3. Characteristics of Research Subjects

Characteristic
Age (Years)
< 20
20 35
> 35
Parity
1
2
>2
History of
hypertension
Hypertension (+)
Hypertension (-)
Gestational Age
13 28 weeks
> 29 weeks

PEB

Normal
%

Total
%

0
20
10

0
33,3
16,7

2
23
5

3,3
38,3
8,3

2
43
15

3,3
71,7
25

8
4
18

13,3
6,7
30

14
5
11

23,3
8,3
18,3

22
9
29

36,7
15
48,3

11
19

18,3
31,7

0
30

0
50

11
49

18.3
81,7

1
29

1,7
48,3

5
25

8,3
41,7

6
54

10
90

1. Maternal Age Relationship with Severe Preeclampsia

Table 4. Age Group Distribution of Severe Preeclampsia
Age

PEB (+)

PEB (-)

Total

< 20 Years
20 35 Years

0
20

0
33,3

2
23

3,3
38,3

N
2
43

%
3,3
71,7

> 35 Years

10
30

16,7
50

5
30

8,3
50

15
60

25
100

0,144

Descriptively shown that the percentage of SEVERE PREECLAMPSIA in majority

occur in maternal age group> 35 years (66.7% of the 15 samples), followed by maternal
age group 20-35 years (46.5% of 43 samples). This finding is consistent with the theory
of English et al. that maternal age above 40 years old have a risk of Severe
Preeclampsia in pregnancy. However no significant relationship was found between the
age group with the incidence of Severe Preeclampsia (p = 0.144), this can be caused by
a number of samples

2. Relationship between History of Hypertension with Severe Preeclampsia

Table 5. Distribution History of Hypertension with Severe Preeclampsia
History of
Hypertension
Hypertension (+)
Hypertension (-)

n
11
19
30

PEB (+)
%
18,3
31,7
50

PEB (-)
n
0
30
30

Total
%
0
50
50

N
11
49
60

%
18,3
81,7
100

P
<0,001

Descriptively apparent that the percentage of the majority of events occurred in the
group Severe Preeclampsia history of hypertension (+) (100% of 11 samples). This
finding is consistent with the theory Dildy et al. that women with a history of

hypertension (+) have a higher risk of occurrence of Severe Preeclampsia in

pregnancy.37 And analytically also found a significant association between a history of
hypertension with Severe Preeclampsia events (p <0.001) with Severe Preeclampsia risk
2,579 times greater in mothers history of hypertension (+) than maternal history of
hypertension (-) (OR 2.579)

3. Parity Relationship with Severe Preeclampsia

Table 6. Distribution of Parity against Severe Preeclampsia
Parity
1
2
>2

PEB (+)
n
8
4
18
30

%
13,3
6,7
30
50

PEB (-)
n
14
5
11
30

%
23,3
8,3
18,3
50

Total
N
22
9
29
60

%
36,7
15
48,3
100

P
0,179

Descriptively shown that the percentage of Severe Preeclampsia increases with the
addition of parity, the lowest on the parity 1 (36.4%), an increase in parity 2 (44.4%),
and highest in parity> 2 (62.1%). This is contrary to the theory Dildy et al. the risk
factors Severe Preeclampsia where the highest risks are owned by nulliparity, and
decreased in line with the addition of parity (based theory extends exposure to the
antigen husband). Occurrence of the phenomenon of increased risk of Severe
Preeclampsia in multiparas can be caused in part by the alternation of the couple, as
determined Trupin et al. found that 29% multigravida who suffer Severe Preeclampsia
make the turn pairs, are other possible causes are multiparas common in women older
age where old age itself is a risk factor for the development of Severe Preeclampsia..
Jasovic et al. expressed in much of the literature mentions the phenomenon binominal
highest probability which is owned by the Severe Preeclampsia risk nulliparous mothers
and mothers of young age multiparous old age.37,47

Nevertheless, analytically not found a significant relationship between parity with

Severe Preeclampsia events (p = 0.179). Samples required a larger and more diverse
number of parity to find a relationship maternal age and incidence of Severe
Preeclampsia.

4. Gestational Age Relationship with Severe Preeclampsia

Table 7. Gestational Age Distribution of Severe Preeclampsia
Gestational Category
> 29 weeks
1328 weeks

PEB (+)
N
29
1
30

%
48,3
1,7
50

PEB (-)
N
25
5
30

%
41,7
8,3
50

Total
N
54
6
60

%
90
10
100

P
0,0
97

Descriptively shown that the percentage of the majority Severe Preeclampsia incident
occurred in the age group of gestation> 29 weeks / trimester III (53.7% of 54 samples).
Of the 30 patients Severe Preeclampsia is known that the majority of patients with late
onset Severe Preeclampsia (83.3%).
However no significant relationship was found between gestational age at Severe
Preeclampsia events (p = 0.097), this can be caused by a number of samples that are too
small. The division of early onset and late onset severe preeclampsia follow the basic
research of Ghosh et al, which for early onset <34 gestational weeks.48,49

B. PlGF RELATIONSHIP WITH SEVERE PREECLAMPSIA

1. Cut off point PlGF

Area Under the Curve

Asymptotic 95% Confidence Interval
Asymptotic Sig.

.000

Lower Bound

Upper Bound
.754

.952

From the calculation of ROC and AUC (Area Under the Curve) PlGF levels, it can be
concluded that:

a. PlGF degree of sensitivity and specificity in determining the incidence of

preeclampsia was significantly (P <0.05) was excellent / good (AUC = 0.853, 95% CI
0.754 to 0.952)
b. PlGF cut-off point in the determination preeklampisa with the best sensitivity and
specificity were in the value of PlGF 123.35 pg / ml (sensitivity = 93.3%; specificity =
70.0%)

2. PlGF Relationship with Severe Preeclampsia

Table 9. Distribution Category PIGF levels with Severe Preeclampsia
PIGF
Category
< 123,35
> 123,35

PEB (+)
N
21
9
30

PEB (-)
%
35
15
50

N
2
28
30

%
3,3
46,7
50

Total
N
23
37
60

P
%
38,3
61,7
100

<0,001

Descriptively shown that the percentage of Severe Preeclampsia majority occur in low
PlGF level group (38.3% of the 60 samples). This finding is consistent with the theory
that low levels of PlGF is closely related to the high incidence of Severe Preeclampsia.
It is also strengthened by the statistical analysis showed a significant association PIGF
levels (cut off point = 123.35 pg / ml) with Severe Preeclampsia events with OR = 21,
which showed that patients with low levels of PIGF (PIGF <123.35 pg / ml) 21 times
greater risk of experiencing Severe Preeclampsia than patients with higher levels of
PIGF.

MULTIVARIATE ANALYSIS
From the logistic regression analysis found the best group in the determination of
gestational age through examination Severe Preeclampsia PlGF is a group of gestation>

29 weeks ( 75%). The best 29 weeks of pregnancy to determine PlGF is an important

predictor of preeclampsia, because as it has been presented by Schmid et al. that PlGF
concentration in normal women will peak at 28-32 weeks of pregnancy and only then
decreased. Instead of preeclampsia, a pregnancy rate of PlGF at 29 weeks is
decreased.50,51

Conclusion
Researchers can infer that PlGF concentrations in normal pregnancy> 123.35 pg / ml
with sensitivity 93.3% and specificity of 70% and in pregnancy with Severe
Preeclampsia <123.35 pg / ml with 93.3% sensitivity and 70% specificity. There is a
significant relationship between low levels of PlGF with events Severe Preeclampsia.
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