The predictive role of PlGF/sENG ratio in fetal growth restriction of early beginning associated with pre-eclampsia

doi:10.21203/rs.3.rs-1494247/v1

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The predictive role of PlGF/sENG ratio in fetal growth restriction of early beginning associated with pre-eclampsia

https://doi.org/10.21203/rs.3.rs-1494247/v1

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The aim of the study was to assess the concentrations of Placental Growth Factor (PlGF), soluble Endoglin (sENG), and PlGF/sENG ratio in pregnancy complicated by fetal growth restriction (FGR) associated with pre-eclampsia (PE). The study group included 35 patients and the control group − 45 healthy pregnant women. The concentrations of PlGF and sENG were measured with the use of immune-enzymatic methods. The concentrations of PLGF were significantly lower in the study group when compared to controls. The concentrations of sENG were significantly higher in study patients when compared to controls. The PlGF/sENG ratio in the study group was significantly lower when compared to healthy third trimester pregnant patients. The positive correlations have been observed between sENG concentrations and the levels of D-Dimers in the study group. On the other hand, in the study group the negative correlations were observed between sENG concentrations and Prothrombin time, the neonatal birth weight and the duration of pregnancy. The correlations between PlGF/sENG ratio and the markers of disease severity were more profound when compared to correlations of single angiogenic factors and clinical and laboratory markers of the disease. The higher concentrations of sENG and lower PlGF/sENG ratio in the study group can be associated with the impaired process of the vascular formation in placenta. The PlGF/sENG ratio can be useful in the prediction of FGR associated with PE. Moreover, the results suggest the potential usefulness of the PlGF/sENG ratio in the monitoring of the severity of the syndrome.

Endoglin (sENG)

Fetal Growth Restriction (FGR)

Placental Growth Factor (PlGF)

PlGF/sENG ratio

pre-eclampsia

pregnancy

Pre-eclampsia (PE) is a leading cause of perinatal morbidity and mortality of pregnant women and newborns, in developed as well as in developing countries [1, 2]. Placental insufficiency associated with PE is dangerous for the fetus, leading to fetal growth restriction (FGR), premature abruption of placenta and hypoxia, often causing stillbirth [3, 4]. Currently, PE is thought to be a state of inappropriate trophoblast invasion which leads to the production of inflammatory mediators by ischemic placenta and to the imbalance between pro- and anti-angiogenic factors [5, 6]. The release of soluble angiogenic factors from the ischemic placenta into maternal plasma seems to play a crucial role in the pathogenesis of PE. The proper trophoblast invasion and development of placenta needs an intensive angiogenesis. The process of angiogenesis, under normal physiological conditions, requires a dynamic balance between stimulants, such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), transforming growth factors α and β (TGF-α and TGF-β), basic and acidic fibroblast growth factors (bFGF and aFGF), hepatocyte growth factor (HGF), granulocyte-colony growth factor (G-CSF) and inhibitory components such as: a receptor for vascular endothelial growth factor (VEGFR), Endoglin (ENG), Angiostatin, Endostatin or Platelet Factor 4 [7–10].

Placental Growth Factor (PlGF) belongs to the family of vascular endothelial growth factors. PlGF plays a key role in the angiogenesis – proliferation, maturation and stabilisation of new blood vessels. The receptor for PlGF is called fms-related tyrosine kinase-1 (VEGFR-1, sFlt-1). It is found on endothelial cells, smooth muscle cells and monocytes. The receptor sFlt-1 binds to PlGF and VEGF and reduces their serum concentrations. This way, it blocks the interaction of VEGF with VEGFR-2 receptors which are present on endothelial cells and are responsible for the synthesis of nitric oxide [11–13].

One of the important anti-angiogenic factors is Endoglin (sENG). Endoglin (CD105) is a type I membrane glycoprotein located on cell surfaces. It is a homodimer protein which consists of two subunits (95kDa) joined with disulphide bridge. It is localized on the proliferating, active endothelial cells and it is present on syncytiotrophoblast cells [14, 15]. It plays a crucial role in the angiogenesis, in the development of the cardiovascular system and in vascular remodeling. Human Endoglin is also involved in platelet-endothelium interactions [16]. Upon the proteolytic processing of extracellular domaine of ENG by matrix metalloproteinase-14 (MMP-14) and by matrix metalloproteinase-12 (MMP-12), a circulating form of Endoglin (soluble Endoglin, sENG) can be released. Soluble Endoglin can be detected in the blood circulation [17, 18].

The identification of the most useful angiogenic or immune markers of pre-eclampsia and fetal growth restriction (FGR) is currently the subject of many studies. The purpose of our study was to estimate the role of PlGF, sENG and PlGF/sENG ratio in pregnancy complicated by FGR associated with PE and in normal uncomplicated pregnancy as well as the associations between PlGF, sENG and PlGF/sENG with clinical features of the syndrome.

The concentrations of PlGF were significantly lower in patients with FGR when compared to the controls (FGR vs. III trimester: 3.36 ± 0.54 pg/ml vs. 29.24 ± 5.82 pg/ml, p < 0.0001). The concentrations of PlGF in the third trimester of normal pregnancy were significantly higher when compared to the second trimester (III vs II trimester: 29.24 ± 5.82 pg/ml vs. 21.65 ± 3.75 pg/ml, p < 0.05). Moreover, the concentrations of PlGF in the second trimester of normal pregnancy were significantly higher when compared to the first trimester (II vs I trimester: 21.65 ± 3.75 pg/ml vs. 5.42 ± 0.89 pg/ml, p < 0.001). The results are presented in the Fig. 1.

In the group of patients with FGR the moderate positive correlations were noticed between the concentrations of PlGF and the level of plasma protein (R = 0.47, p < 0.05). On the other hand, there were weak negative correlations between the concentrations of PlGF and diastolic pressure (R=-0.37, p < 0.01) as well as the concentrations of PlGF and proteinuria in the group of patients with FGR and PE (R=-0.65, p < 0.01).

In normal pregnancy we observed the positive correlations between the concentrations of PlGF and the week of pregnancy when blood was taken (R = 0,8, p < 0.01).

The concentrations of sENG in patients with FGR were significantly higher when compared to healthy women in the third trimester of normal pregnancy (FGR vs. III trimester: 11.47 ± 4.65 ng/ml vs. 5.68 ± 2.78 ng/ml; p < 0.01). There were no statistically significant differences between the concentrations of sENG in the third and second as well as between second and first trimester of normal pregnancy (III vs. II trimester: 5.68 ± 2.78 ng/ml vs. 6.35 ± 2.52, ng/ml, NS; II vs. I trimester: 6.35 ± 2.52 ng/ml vs. 7.52 ± 3.58 ng/ml; NS). The results are presented in Fig. 2.

In FGR group there were the weak positive correlations observed between sENG concentrations and D-Dimers levels (R = 0.35, p < 0.01). On the other hand, there were moderate negative correlations between sENG concentrations and Prothrombin time (R=-0.45, p < 0.05), neonatal birth weight (R=-0.47, p < 0.01) and duration of pregnancy (R=-0.41, p < 0.05) in the study group.

In the study group the PlGF/sENG ratio was significantly lower when compared to the PlGF/sENG ratio of healthy women in the third trimester of normal pregnancy (PE vs. III trimester: 0.34 ± 0.15 vs. 6.02 ± 2.75; p < 0.0001).

The ratio of PlGF/sENG in the third trimester was significantly higher when compared to second trimester (III vs. II trimester: 6.02 ± 2.75 vs. 3.76 ± 2.04; p < 0.001). Similarly there were statistically significant differences in PlGF/ENG ratio between second and first trimester on normal pregnancy (II vs. I trimester: 3.76 ± 2.04 vs. 0.58 ± 0.22; p < 0.001). The results are presented in Fig. 3.

In our research the concentrations of PlGF were significantly lower in patients with FGR when compared to the control group. There were negative correlations between the concentrations of PlGF in the study group and diastolic blood pressure and proteinuria. Similarly, the correlations were more profound between the PlGF/sENG ratio and diastolic blood pressure and between the PlGF/sENG ratio and proteinuria.

We observed the increased concentrations of sENG in pregnancy complicated by FGR. There are the hypotheses that increased concentrations of sENG can play a role in the pathogenesis of pre-eclampsia and are associated with maternal vascular dysfunction [19]. Robinson et al. observed that concentrations of sENG start to increase in the second trimester of pregnancy before the clinical symptoms of PE [20]. However, the authors suggest that the combination of pro- and anti-angiogenic factors characterize PE and FGR better than any single marker [20].

Panusunan-Lubis N et al. found that the assessment of diastolic notches in uterine arteries alone cannot predict the incidence of early-onset PE. They concluded that PlGF levels and Pulsatile Index (PI) of Uterine Arteries can be used as predictors of early-onset PE although examination of PlGF levels alone is sufficient as a predictor of early-onset PE [21]. These results suggest that the Doppler velocimetry monitoring (PI and the assessment of diastolic notch) cannot be sufficient in the prediction and monitoring of PE. Furthermore, it emphasize the role of biochemical markers (especially PlGF) in the prediction and monitoring of this condition. Moreover, Chaiworapongsa et al. found that the incorporation of biochemical markers (sENG, PlGF, sVEGFR-1) significantly improves the risk assessment for these outcomes beyond that of clinical factors and uterine and Umbilical Artery Doppler velocimetry [22]. Undoubtedly, the prediction and monitoring of FGR and PE with the use of Doppler velocimetry (PI and the presence of diastolic notch in Uterine Arteries) comes to be a standard in the maternal-fetal medicine. However, we should consider the fact that the diastolic notch is absent in the Uterine Arteries of 50% of pregnant women, who later developped PE. On the other hand, about 50% of mothers with bilateral diastolic notch do not develop later FGR or PE. To take these facts into consideration, the role of biochemical markers in the prediction and monitoring of PE seems to be fundamental.

In the context of these observations as well as the results of our study it seems to be justified the use of angiogenic biochemical markers, especially their ratio (PlGF/sEng) in the detection of fetal growth restriction associated with pre-eclampsia.

The relationship of sENG with the severity of PE, clinical, and laboratory parameters, and the occurrence of adverse outcomes are not fully explained [23–26]. Venkatesha et al. found that the higher concentrations of sENG correlated with severe course of PE [24]. In the study of Leanos-Miranda et al. the concentrations of sENG correlated positively with blood pressure, proteinuria, and levels of creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase; and inversely with gestational age, infant's birth weight, and platelets counts. The authors suggest that the circulating concentrations of sENG seem to be a suitable marker to assess the severity of PE and they are associated with increased risk of adverse outcomes [25]. We observed the positive correlations between the concentrations of sENG and the levels of D-Dimer in the study group. On the other hand there were negative correlations between the concentrations of sENG and the length of the neonatal birth weight, the duration of pregnancy as well as Prothrombin time in pregnancy complicated by FGR and PE. The correlations between PlGF/sENG ratio and the clinical and laboratory markers of disease were more profound when compared to the correlations of single angiogenic factors and indicators of the severity of the syndrome.

It has been known that the pathophysiology of PE is characterised by the activation of the endothelium. Many studies suggest that the markers which are released by activated endothelial cells are responsible for the state of exaggerated hypercoagulability in pre-eclampsia. In our study we observed the increased concentrations of D-Dimer in patients with FGR and PE. The positive correlations between the coagulation parameters and the severity of PE were also observed in the study of Van Walraven C et al. The authors in their study observed the increased risk of subsequent thromboembolism in the group of patients with PE [26]. Similar results have been obtained by Oladosu-Olayiwola et al. [27]. They found the abnormal levels of D-Dimer, Plasminogen Activator Inhibitor-1 (PAI-1) and tissue Plasminogen Activator (tPA) in patients with PE suggesting that monitoring the levels of these parametrs can help in the management of the condition [28]. Hammerova et al. observed significantly shorter Prothrombin time, International Normalized Ratio (INR) and activated Partial Thrombplastin Time (aPTT), significantly higher plasma concentrations of D-Dimer and fibrinogen and higher activity of factor VII and X in the third trimester pregnant women with adverse pregnancy outcome [28]. On the other hand, prospective studies revealed increased t-PA levels and decreased PAI-2 levels in pregnant women who later developed PE or FGR [29, 30]. It seems that increased concentrations of D-Dimer found in the group of patients with FGR and PE are the results of the activation and damage of the endothelium observed in the pathophysiology of the disease. Furthermore, the increased concentrations of D-Dimer may be responsible for the subsequent incresead risks of the thromboembolic events which are observed in these group of patients [31].

Another important aspect of the assessment and monitoring of angiogenic and anti-angiogenic factors in patients with placental insufficinecy and healthy women with uncomplicated pregnancy are the factors which can influence the results. In our research we exluded from the study the women with pre-existing clinical disorders. The exclusion criteria were: chronic hypertension, renal diseases, autoimmune diseases, such as: diabetes, lupus or rheumathoid arthritis before pregnancy and obesity. We did not include to the study the women with multiple pregnancy. We did not have smoking patients in the study and control groups. In this context, the interesting results have been obtained by the Finnish group of Jääskeläinen et al. which studied the levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF) and soluble endoglin (sENG) in FINNPEC case-control cohort. The authors suggest that certain maternal characteristics, e.g. BMI, smoking and pre-existing diseases, should be taken into account when different angiogenic and anti-angiogenic factors are assessed in patients with placental insufficincy [36].

So far, no effective therapy has been described which would allow for the prevention or cure of placental disorders, such as: PE and FGR and still the only effective solution is a delivery of the placenta. Although the efficacy of small doses of aspirin has been proven, its administration should begin before the onset of clinical symptoms, which is possible only in patients with an identified high risk of placental insufficiency, most common in multiparous pregnant mothers, whose previous pregnancy was complicated by the syndrome. Finding an early biomarker of combinations of biomarkers of PE and FGR would allow for the protection of other patients at risk. The analysis of angiogenic and anti-angiogenic factors placental insufficiency showed that they correlate with the symptoms of the syndrome and can be useful in the monitoring of the disease severity.

The higher concentrations of sENG and the lower ratio of PlGF/sENG in pregnancy complicated by FGR can be associated with the impaired process of the vascular formation of placenta. The PlGF/sENG ratio can be useful in the prediction of FGR of early beginning. Furthermore, the results suggest the potential usefulness of the PlGF/sENG ratio in the monitoring of the severity of the disease.

The patients participating in the study were admitted to the Department of Gynecology and Obstetrics, University Hospital, Rzeszow, Poland. The study group included 35 pregnant patients with Fetal Growth Restriction (FGR) associated with pre-eclampsia (PE). The patients with pregnancy complicated by FGR associated with PE were diagnosed according to the diagnostic criteria of American College of Obstetricians and Gynecologists [32]. The diagnosis of fetal growth restriction (FGR) was made when less than 3th percentile weight for gestational age was found during ultrasound examination of patients with PE. The blood samples from patients with FGR were taken between 29th and 35th week of pregnancy. None of patients from the study group was affected by preexisting clinical disorders. The exclusion criteria were chronic hypertension, renal diseases, autoimmune diseases, such as: diabetes, lupus or rheumathoid arthritis before pregnancy and obesity. All pregnancies from the study and control groups were single. The patients with a multiple gestation were excluded from the study and control groups because of difficulties with the interpretation of the results of angiogenic factor concentrations in cases of multiple pregnancies when compared to single pregnancies [33]. The patients from the study and control groups were not in active labour. The control group included 45 healthy women with uncomplicated pregnancy. They were recruited from the outpatient clinic.

The blood samples from healthy women were taken in the first (8–12 week), second (18-24th week) and third trimester (28-34th week) of pregnancy. All patients gave their informed consent for the inclusion before they participated in the study and for peripheral blood sampling. The study was conducted in accordance with the Declaration of Helsinki. The study design and protocol were approved by the local Ethics Committee at University of Rzeszow. The clinical characteristics of patients from study and control groups are presented in Table 1.

Table 1

The clinical and laboratory characteristics of pregnant patients with FGR (n = 35) and normal women in the third trimester of uncomplicated pregnancy (n = 45).
	FGR	Normal pregnancy	Statistical significance
Number of cases	35	45	Statistical significance
Age (years)	33 ± 4	30 ± 5	NS
First pregnancy	21	17	NS
Subsequent pregnancy	12	27	NS
The duration of gestation (days)	245 ± 35	275 ± 18	< 0.005
Time of blood collection (weeks of gestation)	32 ± 3	32 ± 2	NS
Vaginal delivery	4	28	< 0.005
Caesarean section	29	16	< 0.005
Birth weight (g)	2278 ± 976	3210 ± 375	< 0.0001
Systolic blood pressure (mmHg)	155 ± 14	112 ± 13	< 0.001
Diastolic blood pressure (mmHg)	102 ± 10	73 ± 9	< 0.001
Total protein (g/dl)	5.8 ± 0.65	6.4 ± 0.3	< 0.01
Pulsatile Index (PI) in Umbilical Artery (UA)	0.62 ± 0.20	0.85 ± 0.25	< 0.05
Proteinuria (g/L)	545 ± 130	-	-
ALAT (U/L)	44 ± 12	22 ± 8	< 0.05
Platelets (10³/µL)	215 ± 75	233 ± 60	NS
Prothrombin time (s)	10.2 +/- 0.5	11.0 +/- 0.4	< 0.05
D-Dimer (µg/l)	1567 ± 1100	957 ± 240	< 0.05
Fibrinogen (g/l)	4.5 ± 1.1	4.8 ± 0.9	NS
Kalium (mmol/L)	4.2 ± 0.4	4.0 ± 0.3	NS
Natrium (mmol/L)	138 ± 3.4	135 ± 1.6	NS
Glomerular Filtration Rate (ml/min/1.73 m²)	87.8 ± 37.8	104 ± 32.3	< 0.05
Creatinine (mg/dl)	0.8 ± 0.3	0.6 ± 0.3	NS
Uric acid (mg/dl)	5.9 ± 1.6	3.9 ± 0.8	< 0.005
Urea (mg/dl)	22.45 ± 15	19.1 ± 5.2	NS

The sera concentrations of PlGF and sENG were measured with the use of immune-enzymatic method. The commercially available R&D (UK) and USCN Life Science Inc. (USA) were used in the study. For PlGF detection R&D Systems™ Human PlGF Quantikine ELISA Kit was used (Katalog No DPG00, the assay range: 15.6–1000 pg/ml, the assay sensitivity: 7 pg/ml). For soluble Endoglin detection Human CD105/soluble Endoglin ELISA Kit USCN Life Science Inc. (USA) was used (the assay range: 0–80 ng/ml, the assay sensitivity: 0.056 ng/ml). The measurements were performed according to the manufacturer’s protocols.

The results were presented as mean and the standard deviation. The test of normality performed according to Kolmogorov-Smirnov indicated normal distribution of data. The statistical differences between groups were estimated using Mann-Whitney U-test, chi-squared test and Fisher’s exact test. Differences were defined as a statistically significant at the level of p < 0.05. For the correlation analysis the rang-Spearman test was performed. Two-tailed p-values less than 0.05 were considered as statistically significant.

Author Contributions: Conceptualization, methodology, formal analysis - D.D.K; writing, original draft preparation, review and editing – DDK and AC. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest: The authors declare no conflict of interest.

Data Availability Statement: The datasets generated and analysed during the current study are available from the corresponding author on request.

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No competing interests reported.

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The predictive role of PlGF/sENG ratio in fetal growth restriction of early beginning associated with pre-eclampsia

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