Predictive Value of Sflt-1/Plgf Ratio for
Occurrence of Preeclampsia in Singleton
Pregnancies: A Retrospective Study
Tanja Milić-Radić1*, Dobriša Radić2, Branka Čančarević-Đajić1 and Bojana Popović1
1Clinic for gynecology and obstetrics, University Clinical Center of Republic of Srpska, Bosnia and Herzegovina
2Health Insurance Fund of Republic of Srpska, Bosnia and Herzegovina
Submission: March 13, 2023; Published:April 12, 2023
*Corresponding author: Tanja Milić-Radić, Clinic for gynecology and obstetrics, University Clinical Center of Republic of Srpska, Bosnia and Herzegovina
How to cite this article: Tanja M-R, Dobriša R, Branka Č-Đ, Bojana P. Predictive Value of Sflt-1/Plgf Ratio for Occurrence of Preeclampsia in Singleton Pregnancies: A Retrospective Study. Glob J Reprod Med. 2023; 9(5): 555773. DOI: 10.19080/GJORM.2023.09.555773.
Introduction: Preeclampsia is multisystem disorder of pregnancy, characterized by endothelial and placental dysfunction. It is classified as an early onset (which occurs < 34 weeks) and late onset (which occurs ≥ 34 weeks). There is an increase of level of antiangiogenic factor of soluble form similar to tyrosine kinase 1 (sFlt-1) and decrease of level of proangiogenic placental growth factor (PlGF) at preeclampsia. High ratio sFlt-1/PlGF is connected to occurrence of preeclampsia.
Materials and Methods: There was a retrospective study of the Clinic for Gynecology and Obstetrics of the University Clinical Center of Republic of Srpska (KGA UKC RS), which was implemented in period January 1st, 2020 – December 31st, 2021 and which included 224 patients hospitalized at the Department of Perinatology for suspected preeclampsia development, from 26+0 weeks of gestation until birth. One of the key criteria for the inclusion of patients in the study is the use of the sFlt-1/PlGF ratio as a marker for the onset of preeclampsia, and the determination of protein values in 24-hour urine (biuret). The antenatal state of the fetus was also monitored by ultrasound measurement of the flow resistance ratio (Ri) through the middle cerebral artery and the umbilical artery (C/U), as well as the values of the newborn’s Apgar score in the first and fifth minute of life (AS 1 and 5). The patients included in the study were divided into two groups according to gestational age: group 1 (<33+6 NG) and group 2 (≥34NG). For the purposes of the research, data from patient protocol books for the specified period, as well as corresponding data from the Clinical Information System (KIS), were used.
Results: Calculated values for cut off 38 for group 1 are: NPV= 76.9%, PPV=72.0%, sensitivity=85.7%, specificity=58.8%, and for group 2 are: NPV= 89 ,1%, PPV=40.8%, sensitivity=72.1%, specificity=68.5%. For cut off 85, the calculated values for group 1 are: NPV= 82.4%, PPV=85.7%, sensitivity=85.7%, specificity=82.4%, and for group 2 they are: NPV= 84.9 %, PPV=70.4%, sensitivity=44.2%, specificity=94.4%. For cutt off 110, the calculated values for group 1 are: NPV= 77.8%, PPV=85%, sensitivity=81%, specificity=82.4%, and for group 2 they are: NPV= 83.5 %, PPV=72.7%, sensitivity=37.2%, specificity=95.8%. The measured value of protein in 24h urine (biuret) in comparison with the measured values of the sFlt-1/PlGF ratio have statistical significance for predicting the onset of preeclampsia. Statistical data processing obtained by examining the measured values of the sFlt-1/PlGF ratio and the antenatal and natal condition of the fetus (C/U and AS 1 and 5) showed statistical significance, except for C/U for group 2, where p=0.32.
Conclusion: Determination of the sFlt-1/PlGF ratio as well as biuret and monitoring of the antenatal and postnatal state of the fetus significantly contributes to the timely diagnostic of preeclampsia, which impacts reducing the incidence of undesirable outcomes for the mother and the fetus.
Preeclampsia is a multisystem disorder of pregnancy, characterized by endothelial and placental dysfunction . The definition that originally included hypertension and proteinuria after the 20th week of gestation (NG) was expanded to include hypertension in combination with renal and hepatic dysfunction, as well as thrombocytopenia. Preeclampsia is classified as early (occurring < 34NG) and late (occurring ≥ 34NG). The clinical picture varies from mild to severe, potentially life-threatening . On an annual level, it occurs in 2-8% of pregnant women and, according to available data, it is responsible for 50,000 maternal deaths worldwide [3-9]. The only known prevention is the use of Aspirin, and the only therapy is termination of pregnancy, i.e., childbirth, so it is one of the most common reasons for iatrogenic
Preeclampsia is primarily caused by diseases of the blood
vessels, especially the endothelium, and is considered to be
caused by reduced placental perfusion, hypoxia, inflammation and
oxidative stress. The balance of proangiogenic and antiangiogenic
factors in the circulation is disrupted in preeclampsia. There is
an increase in the level of antiangiogenic factor of soluble form
similar to tyrosine kinase 1 (sFlt-1) and a decrease in the level of
proangiogenic placental growth factor (PlGF). A high ratio of sFlt-
1/PlGF is associated with the occurrence of preeclampsia, which
was proven before clinical use [1,10].
The current “gold standard” for preeclampsia involves
measuring blood pressure and finding protein in the urine.
Considering the different clinical features of preeclampsia, the
specificity and sensitivity of these measurements to predict the
onset of preeclampsia, eclampsia and HELLP syndrome is quite
low. As a result, we often have unnecessary hospitalization
and intensive monitoring of pregnant women “waiting” for
preeclampsia to develop, and on the other hand, the necessary
hospitalization of patients who are not clinically predicted to
develop preeclampsia according to the mentioned criteria may
be missed . The German Association of Obstetricians and
Gynecologists, as well as the Austrian and Swiss Association of
Obstetricians and Gynecologists, currently recommend the use
of angiogenic biomarkers as a means of diagnosis and short-term
prediction of preeclampsia in patients suspected of developing
this disease. The 2018 Guideline of the European Association of
Cardiology recommends the use of the sFlt-1 /PlGF ratio for the
treatment of cardiovascular disease in pregnancy .
a) to determine the specificity, sensitivity, negative
predictive value (NPV) and positive predictive value (PPV)
of the sFlt-1/PlGF ratio in examined patients for the onset of
b) to examine the statistical significance of determining the
biuret value and the sFlt-1/PlGF ratio in preeclampsia diagnostics.
c) to examine the statistical significance of the influence of
the sFlt-1/PlGF ratio on the antenatal and neonatal condition of
In the Clinic for Gynecology and Obstetrics of the University
Clinical Center of the Republic of Srpska (KGA UKC RS), a crosssectional
retrospective study was conducted for the period
January 1, 2020 - December 31, 2021, which included 224 patients
hospitalized in the Department of Perinatology due to suspected
development of preeclampsia, from 26+0 weeks of gestation
until delivery. The criteria for identifying patients suspected of
developing preeclampsia are shown in table 1. One of the key
criteria for the inclusion of patients in the study is the clinical
use of the serum sFlt-1/PlGF ratio as a marker for the onset of
preeclampsia, which was measured on the day of admission (value
1), and in some cases, depending on the value of the sFlt-1/PlGF
ratio, the measurements were repeated two, three or four times at
intervals of seven days, as well as the measurement of the biuret
value. An ultrasound scan and C/U determination were routinely
done to patients, as well as AS 1 and 5 in the Maternity Ward. For
the purposes of the research, data from patient protocol books
for the specified period, as well as corresponding data from the
Clinical Information System (KIS), were used.
Criteria for inclusion in the study
I. pregnant women of gestational age over 26 weeks
of pregnancy until delivery, who have been diagnosed with
one or more criteria that indicate the possible development of
Criteria for exclusion from the study
I. essential hypertension without deterioration of the
II. proteinuria that existed before pregnancy without
deterioration of the clinical picture.
III. Twin pregnancy.
The patients included in the study were divided into two
groups according to gestational age:
group 1 (<33+6 NG) i
group 2 (≥34NG).
The ꭕ2 test, Mann Whitney non-parametric test and ROC
analysis were used for statistical data processing, and those with
p<0.05 were considered statistically significant differences.
In the observed period, 224 patients were hospitalized in the
Department of Perinatology at the KGA UKCRS due to suspected
development of pre-eclampsia from 26+0 weeks of gestation until
delivery, who met the requirements for inclusion in the study. The
results of the measured sFlt-1/PlGF ratios in the patients included
in the study were divided into two groups, according to gestation,
with the risk of early and late preeclampsia (<34NG and ≥34NG),
and the negative predictive value (NPV) and positive predictive
value (PPV), specificity, sensitivity of the sFlt-1/PlGF ratio
depending on gestation and the calculated value of the marker
were statistically calculated. The values of the sFlt-1/PlGF ratio
were calculated on the day of hospitalization, and depending on
the measured values, they were repeated two, three or four times
at intervals of 2-4 days.
Depending on the gestational age of the pregnancy, the sFlt-
1/PlGF ratio was examined for cut offs of 38, 85 and 110 for the
examined groups 1 and 2 after the first measurement, and for
each cut off for both groups the calculated values for NPV, PPV,
sensitivity, specificity and they are shown in tables 2-4.
Statistical processing of the data obtained by measuring the
value of the biochemical marker of preeclampsia, biuret, the
sFlt-1/PlGF ratio, as well as the age of the pregnant woman, the
week of gestation of the subjects at admission and at the end of
the pregnancy, and AS 1 and 5, showed statistical significance in
the first measurements of the sFlt-1/PlGF ration with p<0.05, and
all other measurements have a statistical significance of p>0.05
for both groups. The measured biuret values, as well as AS 1 and
5, have statistical significance for the occurrence of preeclampsia
in both groups. Gestation of pregnancy at the admission of the
pregnant woman has no statistical significance in the first group,
and in the second group it is p=0.15, while gestation of pregnancy
at delivery has statistical significance in both groups. The age of
the pregnant woman in the first group has statistical significance
of p=0.016, while in the second group it has no statistical
significance (Table 5).
Statistical processing of the data obtained by examining the
measured values of the sFlt-1/PlGF ratio and the antenatal state
of the fetus (C/U) showed a statistical value of p=0.01 in the first
group, while in the second group it was p>0.05 (Table 6).
Preeclampsia is one of the most important factors affecting
maternal morbidity and mortality and one of the most common
reasons for iatrogenic prematurity, and it requires improvement
in diagnostics and treatment. High values of blood pressure
and proteinuria have little predictive value and when they are
manifested in most cases they are associated with unfavorable
outcomes for mother and fetus [5-8]. Proangiogenic and
antiangiogenic factors are involved in the pathophysiology of the
mechanism of preeclampsia, and numerous studies have proven
high NPV, PPV, sensitivity and specificity of the sFlt-1/PlGF ratio in
predicting the onset of preeclampsia [11,12].
The patients included in our study met the criteria listed in table
1. The values of the sFlt-1/PlGF ratio and biuret were measured
and also upon admission to the Department of Perinatology, the
Doppler ultrasound with the C/U ratio was routinely done in order
to monitor the condition of the fetus. After delivery, AS 1 and 5
were determined in newborns by the competent gynecologist or
pediatrician in the Maternity Ward and we used this as parameter
for monitoring the delivery outcome.
The criteria for termination of pregnancy were initially
measured extremely high values of the sFlt-1/PlGF ratio, as well
as a significant increase in the value of the sFlt-1/PlGF ratio during
re-measurement if the initially measured value was higher than
85. The values were re-measured at 2- 4 days, according to current
guidelines. At our Clinic, biuret is routinely measured in patients
suspected of developing preeclampsia, so we included these values
in the study, which showed statistical significance as a parameter
in predicting the occurrence of preeclampsia.
Patients who are hospitalized at the Department of
Perinatology of the UKC RS have daily Doppler ultrasound
measurements of the C/U ratio, as a parameter to monitor the
state of the fetus. If the pathological flow values are measured,
termination of the pregnancy is planned, either by induced
delivery or caesarean section depending on the obstetric findings
and gestation of the pregnancy, regardless of the values of the sFlt-
1/PlGF and biuret ratio. During the observed period, we had one
stillborn child at 29weeks of gestation, where the measured value
of the sFlt-1/PlGF ratio before delivery was 1401. I must mention
that KGA UKC RS is a reference institution in our country, and we
provide care for all patients with pregnancy complications sent
from other institutions. Sometimes patients are not referred in a
timely manner, and because of this, an undesirable outcome can
occur. All patients included in the study were provided with care
in our clinic after giving birth and we had no adverse outcomes.
Our study showed a fairly high NPV, PPV, as well as the
sensitivity and specificity of the sFlt-1/PlGF ratio in the onset of
preeclampsia, but the results are partially different compared to
studies that included a significantly larger number of subjects.
In Zeisler’s study, measurements of the sFlt-1 /PlGF ratio for a
cutoff 38 show NPV 98.9%, PPV 40.7%, while sensitivity is 88.2%,
with specificity of 80% . In Hund’s study, the results for NPV,
PPV, sensitivity and specificity are similar to Zeisler’s . The
difference in the results between our study and those mentioned
is due to the smaller number of subjects included in study group 1,
which produced different statistical results. In the second group,
we had a significantly larger number of subjects, and we obtained
results that are closer to the results in Zeisler’s and Hund’s study.
Examination of the measured biuret values in correlation with
the sFlt-1/PLGF ratio showed that the diagnostic of preeclampsia
improves in both studied groups and this is also similar to the
results of the Zeisler study and to the recommendations of the
American Association of Obstetricians and Gynecologists (ACOG)
By examining the statistical association of the sFlt/PlGF ratio
with the antenatal condition of the fetus, which is shown by the
C/U ratio, it was proven that there is statistical significance in the
first group, while it does not exist in the second group. Examination
of the postnatal condition of the newborn by determining the AS
1 and 5 values was found to be statistically significant in both
examined groups. This confirms the main goal of the study, which
is to reduce the frequency of undesirable outcomes for the mother
and the fetus. Both Zeisler’s and Hudn’s study and numerous
international studies dealt with this issue, and they proved that the
measurement of the sFlt-1/PlGF ratio has statistical significance in
the prognosis of preeclampsia, and therefore in the improvement
of perinatal morbidity and mortality [3,12].
World guidelines for the management of preeclampsia in
pregnancy recommend measuring of the sFlt-1/PlGF ration in
the prediction of the preeclampsia occurrence, which is certainly
shown by our study .
There are numerous evidence proving that preeclampsia is
a systemic disease that affects multiple organs, and the isolated
clinical criteria are not adequate to predict adverse outcomes. The
use of markers related to angiogenesis, including the sFlt-1/PlGF
ratio, to predict the occurrence of preeclampsia has found wide
application in medical practice and it is recommended by certain
national guidelines for obstetricians and gynecologists. Our study,
with its results, which does not deviate significantly from other
similar studies, showed that the determination of the sFlt-1/
PlGF ratio significantly contributes to the timely diagnostics of
preeclampsia, and further contributes to reducing the frequency
of adverse outcomes for the mother and fetus, including iatrogenic
premature births, and thus also to reducing costs related to