European Journal of Cardiovascular Medicine

Pre-eclampsia, is a common complication in pregnancy.it is a multisystem disorder that continues to be one of the leading causes of maternal morbidity and mortality. [1].PE affects approximately 5% of all pregnant women. Annually this disease causes up to 500, 00 deaths among foetuses and newborns as well as 70,000 maternal deaths every year. Pre-eclampsia has been defined by the international society for study of hypertension in pregnancy (ISSHP)as gestational hypertension accompanied by at least one of the following new onset conditions at or after 20 weeks gestation: proteinuria, maternal organ dysfunctions (acute kidney injury, liver involvement neurological complications, haematological complications) or uteroplacental dysfunctions.[2]

It can deteriorate into eclampsia (a severe complications of PE, characterized by maternal seizures) or HELLP syndromes (maternal haemolysis, elevated liver enzymes and low platelets counts), which are leading causes of maternal morbidity and mortality. PE is also associated with adverse foetal outcomes including foetal growth restrictions (FGR) pre-term delivery and still birth.

Although the cause remains unclear, the syndrome may be initiated by placental factors that enter the maternal circulation and cause endothelial dysfunction resulting in hypertension and proteinuria [3].

Because of the unpredictable nature of adverse outcomes in the population, women with suspected Pre-eclampsia are often hospitalised for closed observation and monitoring, including frequent laboratory testing and evaluation of foetal wellbeing [4].

The biomolecules sflt-1 antagonises the action of pro- angiogenic proteins such as vascular growth factor and placental growth factors for normal vascular homeostasis.

Studies have revealed that circulating maternal serum levels of soluble fms like tyrosine kinase- 1 (sflt-1 are increased in pre-eclampsia) [5].

Studies have also claimed that circulating levels of sflt-1 alters 5 weeks prior to onset of PE.

[6] Therefore, altered plasma levels of angiogenesis related factors have been suggested as predictive biomarkers of pre-eclampsia.

According to Stepan et al, (2023) the imbalance between angiogenic and antiangiogenic factors underlies the placental dysfunction in PE. sFlt-1 is an antiangiogenic factor that is important for the regulation of angiogenic homeostasis during pregnancy. [7]

In normal pregnancy, sFlt-1 concentration increases steadily during the third trimester, but it increases prematurely in women who go on to develop PE and in women with pregnancy complicated by FGR. Circulating maternal sFlt-1 has been reported to increase approximately 5weeks before the onset of symptoms. sFlt-1 binds to PlGF, and a recent study suggests that decreased circulating levels of PlGF are mediated largely by excess circulating sFlt-146. PlGF is a proangiogenic factor that is expressed in the placenta and enhances the action of vascular endothelial growth factor-A (VEGF-A), which is essential for placental vascular development. This decrease in PlGF concentration is known to occur prematurely in women who go on to develop PE and is often detectable before the onset of symptoms. Increasing levels of sFlt-1 and decreasing levels of PlGF result in an increasing sFlt-1/PlGF ratio. [8].

This study was conducted over two years in a tertiary care hospital in the department of biochemistry in collaboration with department of Obstetrics and Gynaecology.

This was a case control study where 110 participants were included. The study was initiated upon obtaining the ethical permission from institutional ethics committee. The pregnancies having gestational age 11 to 28 weeks were enrolled. Pregnancies with new onset of

Hypertension, and other clinical features of Pre-eclampsia according to ISSHP (international society for study of hypertension in pregnancy) diagnostic criteria were considered as cases [2]. Voluntary written informed consent was obtained from the participants.

The cases having eclampsia, and other complications like hypertensive emergencies were excluded from the study group. Their anthropometrical, basic demographic characteristics were recorded on a pre designed case record form.

Maternal serum samples were collected according to a standard operative procedure. Samples were assayed for liver function test, renal function test in the automated bio analyser. Serum samples were assayed for estimation of sFlt-1 in ELISA in sandwich principle. The serum sflt was measured using Erba ELISA reader. Lab method sheet and expressed in pg/ ml. [9-12]

The data obtained were arranged in MS office Excel 2021. Descriptive statistics was applied for calculating frequencies, mean and standard deviation. Parametric data of case and control group were compared using unpaired T test. All categorical data were subjected to chi-square test. Data analyses were done using Graph pad Prism version 8.0. The minimum level of significance was set at P<0.05.

Table 1: Characteristics of study population at baseline

                  N denotes the number of subjects. Data expressed in Means±SD.

Figures in parenthesis denote the percentages out of the population in respective groups. Ns: Not significant. Categorical data were analysed using chi-square test with Yates correction. Continuous data were subjected to unpaired t test.

In this study population of pregnant women (n=110), equal number of participants were enrolled as pre-eclampsia(n=55) and controls (n=55). Table 1 shows that baseline characteristics of pregnant women enrolled in both the groups. Though the mean age of control group (28.1±1.5) is higher than that of cases (26.5±3.5), but not a significant difference. There was a highly significant difference (p<0.001) among the case and control group with respect to the body weight (control-46.0±1.0 vs cases-73.0±6.0).

Table 2: Comparison of serum biochemical markers (Mean±SD) among normal pregnant women and pre-eclamptic cases

Preeclampsia was previously defined as hypertension plus proteinuria after 20 weeks’ gestation. The growing understanding of preeclampsia as a heterogeneous hypertensive disorder of pregnancy triggered the ACOG’s hypertension 2013 task force to revise the definition of preeclampsia to include the presence of severe features with or without proteinuria. [13,14].

Table 3. Clinical Definition of Preeclampsia (ACOG Criteria)[13,14]

ACOG indicates American College of Obstetricians and Gynecologists. Reprinted from American College of Obstetricians and Gynecologists with permission. Copyright ©2019, Wolters Kluwer Health, Inc.

Clinical and pathological studies suggest that the placenta plays a central role in the pathogenesis of preeclampsia.[10]. Altered angiogenic biomarkers (sflt-1 or plgf) are indicative of placental dysfunctions. This study focussed on increase in circulating levels of sflt-1 in women having pre-eclampsia and compared with that of normal pregnant women. In our observations, both control and PE cases were of same age range. Considering the body weight we found that body weight of the PE cases were significantly higher than that of non PE controls. Our observation is in accordance with that of Carillon et al who noted a higher BMI in PE cases. [15]

We have noted that both Systolic and Diastolic BP were significantly higher in PE cases as compared to non-PE controls. Corroborating our findings Nukei et al, 2020 and Levine et al, 2004 observed the same. [6, 3]It is noteworthy to report that our study group of PE cases h a significant association with family history and previous history of PE. Moreover, history of coexisting hypertension was a significant associated morbidity in our PE cases. However, Diabetes, the comorbidity was not associated with PE (table 1). In our observation, the serum sflt-1 in PE cases were significantly higher than that of normal pregnancies (figure 1). Considering the range of sflt1 there was also a significant association of higher sflt-1 with development of PE. Our observation is in accordance that of Caillon et al 2018. [15] The serum urea, creatinine, liver AST and ALT in PE cases were significantly higher than that of normal pregnant women (figure2, table 2). A similar observation was made by Tesfa et al, 2022; Hazari et al, 2014; Dacaz et al, 2016; Verlohren et al, 2022. [16-19]

Despite consensus guidelines outlining the indication for delivery in patients associated pregnancy associated hypertension, risk assessment remains challenging because no signs, symptoms or lab tests has been shown to predict adverse outcomes with high accuracy.

Despite high prevalence of PE and its adverse outcomes in developing countries, studies in Indian scenario still lacking. This study in our tertiary care set up, brought an authentic report about the strong association of high sflt level in serum with PE. This brings an insight to detect preeclampsia by measuring this biomarker. However, how early we can predict preeclampsia, by measuring sflt could not be assessed in this study which was our study limitation.

To conclude, our observations closed the gap of knowledge on association of higher sflt-1 with development of PE in this research. Our study group were of gestational age 11 to 28 weeks. This study directs future research for prediction of PE at an early gestational age.

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