Placental Expression Of Fibroblast Growth Factor 13 In Preeclampsia&First Trimester Risk Prediction Models For Preeclampsia

Objective:To explore the role of FGF13 in the placenta with preeclampsia(PE)and the underlying mechanisms.To investigate the predictive effect of serum PAPP-A,β-HCG,sFlt-1,PlGF and sEng on early preeclampsia during early pregnancy.To establish an early joint prediction model and its scoring system based on early maternal characteristics and serum PAPPA and β-hCG levels in early pregnancy.Methods:2153 pregnant women were enrolled in a prospective nested case-control cohort of preeclampsia.Serum samples were collected.Clinical data were recorded and traced to 3 months postpartum and some placenta samples were collected also.1.Immunofluorescence,quantitative RT-PCR and immunoblotting were used to measure the expression of FGF13 in the placenta samples from 19 early-onset PE patients and 36 normal pregnant women,respectively.The morphological changes in placenta with PE were observed by fluorescent microscopy.FGF13 mRNA levels in the primary trophoblast cells isolated from normal and PE placenta were detected by Q-PCR.The expression of FGF13 was manipulated in the trophoblast cell line HTR8/SVneo by gene overexpression and RNA interference,and the expression of E-cadherin was detected via immunofluorescence,quantitative RT-PCR and immunoblotting for mechanism exploring.The effects of FGF13 on trophoblasts were determined by permeability assay and invasion assay.2.The serum levels of sFlt-1,PlGF and sEngduring 84-90 days of gestation were measured by ELISA and compared between early preeclampsia(27 cases)and normal pregnant women(54 cases).According to the results of Down’sSyndromScreening,the PAPP-A and β-hCG levels were also compared,respectively.The predictive efficacy of the above indexes in early preeclampsia was evaluated by both univariate analysis and logistic regression analysis.3.Univariate analysis and logistic regression analysis were used to compare age,MAP,BMI,early history of bleeding,family history of hypertension,history of spontaneous abortion,first pregnancy,multiple pregnancy,assisted reproduction,medical complications,hypertensive historyin previous pregnancy,HCT,hCG-MoMand PAPPA-MOM,between early stage of preeclampsia(93 cases)and non-hypertensive diseases(1011 cases).A disease predictive model and itsscoring systemwere constructed accordingly and their effectivenesswas assessed.Results:1.Expression of FGF13 in placenta from PE patients was down-regulated compared to the normal control.The placental trophoblasts were badly arranged in the clinical placenta with PE.The expression of FGF13 in primary PE trophoblasts was down-regulated along with the decrease in the expression of E-cadherin.Knock-downof FGF13 expression leaded to the increase in the permeability of trophoblasts.FGF13 can regulate the expression of E-cadherin in trophoblasts.FGF13 promoted the invasion of trophoblasts.2.Between early-onset preeclampsia and normal pregnant women,there was no significant difference in the median serum levels of β-hCG and PlGF(P>0.05)with no significant difference in the area under ROC curves;while the serum PAPP-A,SEng,sFlt-1,and sFlt-1/PIGFduring early pregnancy were significantly different(P<0.05),and the areasunder ROC curves were 0.729,0.771,0.738 and 0.741,respectively.A logistic regression model established accordingly with an area of 0.896 under ROC curve,a critical value of 0.64,a sensitivity of 62.96%and a specificity of 98.15%,a correct index of 0.611,respectively.3.Univariate analysis and logistic regression analysis of preeclampsia and non-hypertensive disease showed that age,MAP,BMI,PAPPA-MOM,family history of hypertension,assisted reproductive,medical comorbidities and previous pregnant hypertensionwere of independent predictive value(P<0.05).Accordingly,a new Logistic regression model and its scoring system were established with finegoodness of fit and discrimination.When the total risk score was set to 4.5,the Jordan index(0.57)appeared largest,and its predictive efficiency becomes the best.To be more practical,the clinical diagnostic criteria was then set to 4 for this scoring system,of which the specificity,sensitivity,positive predictive value,negativepredictive value,positive likelihood ratio and negative likelihood ratio,respectively,were 84.37%,73.12%,83.42%,30.09%,97.15%,4.68 and 0.32,respectively.Conclusion:1.The expression of FGF13 in placental tissues from PE patients was down-regulated.FGF13 regulated the permeability of trophoblasts probably via its regulation of E-cadherin.FGF13 also enhanced the invasive capacity of trophoblasts,however,the mechanism remains unknown.The down-regulation of FGF in placenta with PE probably contributed to the increase in trophoblast permeability and the compromised invasion,which may be a novel mechanism of PE pathogenesis and deserves further study.2.There was no predictive value of serum β-hCG and PIGFfor early-onset preeclampsia duringearly pregnancy,but the serum PAPP-A,sEng,sFlt-1 and sFlt-1/PIGFwere of independent predictive value,while their joint prediction would do better.3.Age,MAP,BMI,PAPPA-MOM,family history of hypertension,assisted reproductive,medical comorbidities and previous pregnant hypertension can be used as independent predictorsfor preeclampsia.The predictive modeland scoring systemestablished accordingly,which setitsdiagnostic criteriascore to 4,can be clinically practical and used primarily as an earlypredictive model for preeclampsia.