Elevated mid-pregnancy plasma ratio of sFlt1/PlGF in women prior to the development of preeclampsia

Elevated mid-pregnancy plasma ratio of sFlt1/PlGF in women prior to the development of preeclampsia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Elevated mid-pregnancy plasma ratio of sFlt1/PlGF in women prior to the development of preeclampsia Tiantian Liu, Xiaobo He, Xiaoying Zhou, Fang Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7908857/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To evaluate whether the sFlt1/PlGF ratio is increased in mid-pregnancy in women developing preeclampsia later. Methods A case-control study was conducted in Department of Gynecology and Obstetrics at Women and Children' s Hospital of Ningbo University. We included 56 women during 24–26 gestational weeks who developed preeclampsia later (cases) and 268 women with uncomplicated pregnancy (controls). The concentrations of sFlt-1 and PlGF were measured with commercially available ELISA kits during 24–28 gestational weeks. Logistic regression was employed to model the relationship between selected biomarkers and the occurrence of preeclampsia. Results The mean sFlt-1/PlGF ratio during mid-pregnancy was 22.95 among patients with preeclampsia, significantly higher than that observed in the control group (mean 14.87; P < 0.001). In logistic regression analysis, the sFlt-1/PlGF ratio was positively associated with the occurrence of preeclampsia (adjusted OR 1.051, 95% CI 1.022–1.081; P = 0.001). The discriminative ability of the model was moderate, with an area under the receiver operating characteristic curve of 0.730 (95% CI 0.644–0.795). Conclusions The sFlt1/PlGF ratio is increased at mid-pregnancy in women developing preeclampsia later. Our study provides additional evidence supporting sFlt1/PlGF ratio as a predictive biomarker of preeclampsia. preeclampsia placental growth factor soluble vascular endothelial growth factor receptor-1 (sFlt-1) sFlt1/PlGF ratio Figures Figure 1 1 Background Preeclampsia complicates 2–9% pregnancies worldwide and is associated with increased risk of adverse maternal, fetal and neonatal outcomes [ 1 ] . It is a multi-systemic disease characterized by increased vascular resistance, endothelial dysfunction, proteinuria and coagulopathy, in addition to gestational hypertension [ 2 ] . The etiology of preeclampsia remains largely unknown, but studies suggest that incomplete trophoblast invasion, failure of normal spiral artery remodeling, and increased maternal vascular susceptibility may be implicated in the pathogenesis [ 3 – 4 ] , highlighting the relevance of angiogenic factors. The proangiogenic biomarker, placental growth factor (PlGF), and the antiangiogenic biomarker, Soluble fms-Like Tyrosine Kinase-1 (sFlt-1), are both mainly derived from the placental trophoblast [ 5 – 6 ] . In normal pregnancies, the level of sFlt-1starts to rise after 30–32 weeks of gestation, while PlGF level starts to decrease after 30 weeks of gestation [ 7 ] . The sFlt1 level is relatively constant until weeks 29–30, after which it starts to increase, peaking at week 40, and is low postpartum. While the PlGF level increases by 16 picograms per milliliter (pg/ml) per week from early pregnancy until weeks 29–30 and thereafter decreases by 14 pg/ml per week until week 40 [ 8 ] . The sFlt1:PlGF ratio starts to decrease from weeks 9–12, remains low from weeks 19–20 to 37–38 and then increases during weeks 39–40. Some studies have found that the imbalance between PlGF and sFlt-1 plays an important role in the development of preeclampsia [ 9 – 10 ] . Specifically, a high ratio of sFlt-1 to PlGF during mid-pregnancy is associated with an increased risk of preeclampsia. [ 11 ] Recent research [ 12 – 13 ] has explored the possibility of employing the sFlt1/PlGF ratio to improve the accuracy of predicting preeclampsia. Such studies were conducted mainly in north America, Israel, and elsewhere [ 14 ] . Due to differences in study participants and obstetrical practices among countries, the results of the previous studies may not be directly applicable to the context of China. Therefore, in this study, we aimed to assess the plasma sFlt-1/PlGF ratio during mid-pregnancy in Chinese women prior to the onset of preeclampsia and to integrate this biomarker into a model for predicting the occurrence of preeclampsia. 2 Methods 2.1 Study participants Participants are from the population-based cohort of pregnant women recruited at Women and Children's Hospital of Ningbo University since year 2018. For this case-control study, women with singleton pregnancy and no history of chronic hypertension or other pre-existing conditions, such as diabetes, renal disease, and collagen vascular disorders at recruitment were eligible for inclusion. Those with abnormal pregnancies during 24 to 26 gestational weeks were excluded. Written informed consent was obtained from all participants according to the protocols approved by the Ethical Committee of Women and Children's Hospital of Ningbo University (Approval number: EC2023-095). The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guidelines, and Chinese law. 2.2 Data collection Information related to the medical history of the participants was extracted from medical and surgical records. Maternal demographic data was collected at recruitment. A venous blood sample was taken during 24 to 26 gestational weeks when participants visited the hospital for the oral glucose tolerance test. The data of all women was anonymized before analysis. 2.3 Measurement of sFlt-1 and PlGF At the time of blood sampling all women selected for this study had a healthy pregnancy. The whole blood samples were centrifuged at 3000 grem for 20 minutes. Serum was extracted and aliquoted immediately into eppendorfs, protected from light, and stored at − 80◦C. Then the serum samples were sent to the central laboratory on dry ice within one month of blood collection and maintained at − 80 ◦ C until later analysis. Levels of sFlt-1 and PlGF were measured using ELISA (R&D System, Human VEGF R1/Flt1Immunoassay, Catalog Number DVR100B and Human PlGF Immunoassay, Catalog NumberDPG00) according to the protocol provided by the manufacturer. 2.4 Diagnosis of preeclampsia Preeclampsia was diagnosed based on the criteria recommended by the Chinese Society of Obstetrics and Gynecology as follows [ 15 ] : new onset hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) at or after 20 weeks of gestation, accompanied by one or more other features: proteinuria (dipstick readings ≥ 1+, random protein/creatinine ratio ≥ 30 mg/mmol or 0.3 g/24h); other maternal organ (including heart, lung, liver, kidney) dysfunction, or hematological, gastrointestinal, and neurological involvement, and/or uteroplacental dysfunction. The condition was defined severe if, more than one of the following criteria were met: (i) severe gestational hypertension; that is, systolic pressure > 160 mmHg or diastolic blood pressure > 110 mmHg on two or more occasions after gestational week 20, (ii) severe proteinuria; that is, protein ≥ 5 g in a 24-h urine specimen, (iii) oliguria, (iv) cerebral or visual disturbances, (v) pulmonary edema or cyanosis, (vi) epigastric or right upper quadrant pain, (vii) impaired liver function, (viii) thrombocytopenia or (ix) fetal growth restriction. Preeclampsia was classified as early-onset (< 34 weeks of gestation) or late-onset (≥ 34 weeks). We identified 56 women with preeclampsia and 268 healthy controls. 2.5 Statistical analysis Dependent on the distribution of data, Mann-Whitney U test or unpaired t -test was used for comparisons between women with preeclampsia and healthy controls. Data were shown as count (%), mean (± Standard deviation, SD), or median (interquartile range, IQR). Then we incorporated sFlt-1/PlGF ratio into a multiple logistic regression model for predicting the development of preeclampsia. Receiver Operating Characteristic (ROC) curve analysis was conducted to quantify the Area Under the Curve (AUC). A p -value of < 0.05 was considered statistically significant. SPSS ver. 20.0 was used to analyze the data. 3 Results As shown in Table 1 , in total 56 pregnant women were diagnosed with preeclampsia. Among them, 6 women had early-onset preeclampsia and 50 had late-onset preeclampsia. We did not observe statistically significant differences regarding maternal age ( P value = 0.277) and body mass index (BMI) before pregnancy ( P value = 0.135) between preeclampsia patients and healthy controls. The mean ratio of sFlt-1/PlGF was 22.95 in preeclampsia patients, which was significantly higher than that observed in the control group (mean: 14.87; P value < 0.001). The mean level of sFlt was 1785.00 pg/ml in PE patients and 1761.00 pg/ml in controls. Moreover, the mean level of PlGF was 111.50 pg/ml in PE patients, which was significantly lower compared to that in control group (84 pg/mL; P value = 0.004). Table 1 Demographic and clinical characteristics of the patients in the control and PE groups Characteristics Control (n = 268) PE (n = 56) P value Maternal age (years) 30.25 ± 5.61 31.13 ± 4.88 0.277 Pre-pregnancy BMI (kg/m 2 ) < 27 ≧27 24.56 ± 3.61 168(62.7%) 100(37.3%) 25.68 ± 2.89 41(73.2%) 15(26.8%) 0.135 Parity (times) 1.60 ± 0.72 1.41 ± 0.65 0.069 sFlt1 (pg/mL) 1761.00[691] 1785.00[1153] 0.03 PlGF (pg/mL) 111.50[166] 84.50[70] 0.004 sFlt1/PlGF 14.87[17] 22.95[26] 0.001 Data in the table are presented as n (%), mean ± standard deviation, or median [interquartile range]. BMI: body mass index. Table 2 presents the associations between various predictors and the occurrence of preeclampsia (yes/no) based on a multivariable logistic regression model. The sFlt1/PlGF ratio positively correlated with the defined adverse outcome (aOR 1.051, 95% CI 1.022–1.081; P = 0.001), meaning that each unit increase of sFlt1/PlGF was associated with a 5.1% increase in the odds of the outcome. Parity showed a potential protective effect (aOR = 0.564, 95% CI: 0.329–0.967, P = 0.037). Table 2 Multiple logistic regression model to identify predictors of preeclampsia Characteristics Coefficient (β) aOR 95% CI P value Maternal age,(years) 0.036 1.036 0.973–1.104 0.269 pre-pregnancy BMI(kg/m 2 ) 0.462 1.588 0.779–3.235 0.203 Parity(times) -0.573 0.564 0.329–0.967 0.037 sFlt1 (pg/mL) -0.00027 0.9997 0.999–1.000 0.148 PlGF (pg/mL) 0.0011 1.001 1.000–1.002 0.055 sFlt1/PlGF 0.050 1.051 1.022–1.081 0.001 Constant -2.869 aOR: adjusted odds ratio; CI: confidence interval; BMI: body mass index. The predicted risk of developing preeclampsia can be calculated using the following formula (For pre-pregnancy BMI: the value is 0 if < 27 kg/m 2 is true; value is 1 otherwise): Linear predictor (LP) = − 2.869 + 0.036×Maternal age + 0.462×pre-pregnancy BMI ( ≧ 27 kg/m 2 ) − 0.573×Parity + 0.000×sFlt1 + 0.001×PlGF + 0.050×sFlt1/PlGF. Predicted risk =(1 + exp(− LP)) −1 The area under the ROC curve (c-statistics) is 0.730 (95% CI: 0.644–0.795), which indicates a moderate discriminative ability of the model (Figure. 1). 4 Discussion In this study, we found that elevated sFlt-1/PlGF ratio during mid-pregnancy was predictive of preeclampsia in later pregnancy, which is consistent with most existing research. However, the AUC-ROC value (Area under the ROC curve) of the prediction model accommodating this biomarker developed in our study was lower than that reported in some literature, such as Pooneh's study (which reported an AUC of 0.90). Preeclampsia is a heterogeneous disease with marked differences in presentation and outcome especially between early-onset (≤ 33 + 6 weeks of gestation) and late-onset (≥ 34 + 0 weeks of gestation) cases [ 16 – 18 ] . The divergent underlying pathophysiological mechanisms of the early- and late-onset preeclampsia are reflected by different performances of sFlt-1, PlGF, and the sFlt-1/PlGF ratio [ 19 – 20 ] . In uncomplicated pregnancies, the sFlt-1/PlGF ratio exhibits a U-shaped pattern: declining between 9 and 12 weeks of gestation, remaining stably low from 19–20 to 37–38 weeks, and increasing again near term (39–40 weeks) as demonstrated in Kumar N and Stefan Verlohren’s studies [ 7 , 23 ] . During 20–28 gestational weeks, the sFlt1/PlGF ratio in normal pregnancy was 17, aligning with the results observed in Baert J’ s study [ 21 – 22 ] . In the last two decades, numerous clinical studies have reported that the sFlt1/PlGF ratio is a valuable biomarker related to preeclampsia [ 24 – 25 ] . In Germany and some other parts of Europe, the ratio has been used to guide routine clinical management, despite that it is emphasized that more investigations are required to fully justify its clinical utilization in the guidelines of ACOG updated in year 2020 [ 26 ] . In Asia, limited studies have confirmed that the sFlt1/PlGF ratio is a useful tool for predicting preeclampsia [ 27 – 28 ] . Our current real-world study in China provides additional evidence that supports the utility of sFlt1/PlGF ratio as a predictive biomarker of preeclampsia. To our best knowledge, this is the first study in China to predict the occurrence of preeclampsia incorporating the levels of sFlt-1, PlGF and sFlt1/PlGF ratio measured in mid-pregnancy women. The strength of the current study is that this is a real-world data analysis. Although many experiments showed that PlGF is a good predictor of preeclampsia, our findings demonstrated that including the sFlt1/PlGF ratio improves model performance compared with models using sFlt1 or PlGF alone. Moreover, we included a relatively large number of women with different hypertensive disorders of pregnancy in our cohort and collected detailed clinical information of adverse outcomes. Even so, we acknowledge some limitations of our study. First, our data are from a national medical center located in southern China and most participants are southern Chinese. The notable disparities in maternal profiles and risk factors between southern and northern China underscore the need to examine regional differences regarding the sFlt-1/PlGF ratio [ 29 – 30 ] . Second, biochemical index tests were not complete, which made it difficult to compare the performance between models built with angiogenic markers and those with traditional parameters. More studies with a larger cohort and among other ethnicities are required to determine the cost-effectiveness of sFlt-1/PlGF ratio as a biomarker for predicting preeclampsia. Future research may also investigate the optimal value of sFlt-1/PlGF ratio in a larger population. Conclusions Our study adds to the evidence that the sFlt-1/PlGF ratio during mid-pregnancy is a useful predictor of preeclampsia. The model incorporating this ratio hopefully contributes to more individualized care of pregnant women. Declarations · Ethics approval and consent to participate : This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethnic Committee of Women and Children's Hospital of Ningbo University(approval number: EC2023-095). All participants provided written informed consent. · Consent for publication : Not applicable. · Availability of data and materials : The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. · Competing interests : The authors declare no conflict of interest. ·Funding This study was supported by Medical Science and Technology Project of Zhejiang Province, China (2024ZL96, 2024KY1575 & 2025KY1412) and funded by the project of NINGBO Leading Medical & Health Discipline (2024S148, 2010-S04 and 2023Z183). · Acknowledgements We would like to express sincerely our gratitude to all those who made this project possible. Author Contribution TTL: Data Collection, Manuscript Writing and Data Analysis; XBH & XYZ: Data Collection, FH: Project Development, Manuscript Editing. All the authors reviewed and approved the final version of the manuscript. 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J Perinat Med. 2018;47(1):35–40. Palma Dos Reis CR, Brás S, Meneses T, et al. The sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction: A historical cohort study. Acta Obstet Gynecol Scand. 2023;102(5):635–43. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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18:53:31","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":72699,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7908857/v1/d63931281fe34bdc9d5344d2.html"},{"id":94135904,"identity":"1106b066-3449-4247-9e4e-d4a34093c43e","added_by":"auto","created_at":"2025-10-22 19:01:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":31265,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve of the model predicting occurrence of preeclampsia\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7908857/v1/995c7bbbb5d91af390da24da.png"},{"id":98774767,"identity":"ce440357-dbdd-4faf-938a-ed366722a648","added_by":"auto","created_at":"2025-12-22 12:14:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":574329,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7908857/v1/f5fbabb9-134e-4974-8766-09232fdec485.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Elevated mid-pregnancy plasma ratio of sFlt1/PlGF in women prior to the development of preeclampsia","fulltext":[{"header":"1 Background","content":"\u003cp\u003ePreeclampsia complicates 2\u0026ndash;9% pregnancies worldwide and is associated with increased risk of adverse maternal, fetal and neonatal outcomes\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. It is a multi-systemic disease characterized by increased vascular resistance, endothelial dysfunction, proteinuria and coagulopathy, in addition to gestational hypertension\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The etiology of preeclampsia remains largely unknown, but studies suggest that incomplete trophoblast invasion, failure of normal spiral artery remodeling, and increased maternal vascular susceptibility may be implicated in the pathogenesis\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e, highlighting the relevance of angiogenic factors. The proangiogenic biomarker, placental growth factor (PlGF), and the antiangiogenic biomarker, Soluble fms-Like Tyrosine Kinase-1 (sFlt-1), are both mainly derived from the placental trophoblast\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. In normal pregnancies, the level of sFlt-1starts to rise after 30\u0026ndash;32 weeks of gestation, while PlGF level starts to decrease after 30 weeks of gestation\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. The sFlt1 level is relatively constant until weeks 29\u0026ndash;30, after which it starts to increase, peaking at week 40, and is low postpartum. While the PlGF level increases by 16 picograms per milliliter (pg/ml) per week from early pregnancy until weeks 29\u0026ndash;30 and thereafter decreases by 14 pg/ml per week until week 40\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. The sFlt1:PlGF ratio starts to decrease from weeks 9\u0026ndash;12, remains low from weeks 19\u0026ndash;20 to 37\u0026ndash;38 and then increases during weeks 39\u0026ndash;40. Some studies have found that the imbalance between PlGF and sFlt-1 plays an important role in the development of preeclampsia\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Specifically, a high ratio of sFlt-1 to PlGF during mid-pregnancy is associated with an increased risk of preeclampsia.\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eRecent research \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003ehas explored the possibility of employing the sFlt1/PlGF ratio to improve the accuracy of predicting preeclampsia. Such studies were conducted mainly in north America, Israel, and elsewhere\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Due to differences in study participants and obstetrical practices among countries, the results of the previous studies may not be directly applicable to the context of China. Therefore, in this study, we aimed to assess the plasma sFlt-1/PlGF ratio during mid-pregnancy in Chinese women prior to the onset of preeclampsia and to integrate this biomarker into a model for predicting the occurrence of preeclampsia.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study participants\u003c/h2\u003e\u003cp\u003e Participants are from the population-based cohort of pregnant women recruited at Women and Children's Hospital of Ningbo University since year 2018. For this case-control study, women with singleton pregnancy and no history of chronic hypertension or other pre-existing conditions, such as diabetes, renal disease, and collagen vascular disorders at recruitment were eligible for inclusion. Those with abnormal pregnancies during 24 to 26 gestational weeks were excluded. Written informed consent was obtained from all participants according to the protocols approved by the Ethical Committee of Women and Children's Hospital of Ningbo University (Approval number: EC2023-095). The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice guidelines, and Chinese law.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data collection\u003c/h2\u003e\u003cp\u003eInformation related to the medical history of the participants was extracted from medical and surgical records. Maternal demographic data was collected at recruitment. A venous blood sample was taken during 24 to 26 gestational weeks when participants visited the hospital for the oral glucose tolerance test. The data of all women was anonymized before analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Measurement of sFlt-1 and PlGF\u003c/h2\u003e\u003cp\u003eAt the time of blood sampling all women selected for this study had a healthy pregnancy. The whole blood samples were centrifuged at 3000 grem for 20 minutes. Serum was extracted and aliquoted immediately into eppendorfs, protected from light, and stored at \u0026minus;\u0026thinsp;80◦C. Then the serum samples were sent to the central laboratory on dry ice within one month of blood collection and maintained at \u0026minus;\u0026thinsp;80\u003csup\u003e◦\u003c/sup\u003eC until later analysis. Levels of sFlt-1 and PlGF were measured using ELISA (R\u0026amp;D System, Human VEGF R1/Flt1Immunoassay, Catalog Number DVR100B and Human PlGF Immunoassay, Catalog NumberDPG00) according to the protocol provided by the manufacturer.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Diagnosis of preeclampsia\u003c/h2\u003e\u003cp\u003ePreeclampsia was diagnosed based on the criteria recommended by the Chinese Society of Obstetrics and Gynecology as follows\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e: new onset hypertension (systolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;140 mmHg and/or diastolic blood pressure\u0026thinsp;\u0026ge;\u0026thinsp;90 mmHg) at or after 20 weeks of gestation, accompanied by one or more other features: proteinuria (dipstick readings\u0026thinsp;\u0026ge;\u0026thinsp;1+, random protein/creatinine ratio\u0026thinsp;\u0026ge;\u0026thinsp;30 mg/mmol or 0.3 g/24h); other maternal organ (including heart, lung, liver, kidney) dysfunction, or hematological, gastrointestinal, and neurological involvement, and/or uteroplacental dysfunction. The condition was defined severe if, more than one of the following criteria were met: (i) severe gestational hypertension; that is, systolic pressure\u0026thinsp;\u0026gt;\u0026thinsp;160 mmHg or diastolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;110 mmHg on two or more occasions after gestational week 20, (ii) severe proteinuria; that is, protein\u0026thinsp;\u0026ge;\u0026thinsp;5 g in a 24-h urine specimen, (iii) oliguria, (iv) cerebral or visual disturbances, (v) pulmonary edema or cyanosis, (vi) epigastric or right upper quadrant pain, (vii) impaired liver function, (viii) thrombocytopenia or (ix) fetal growth restriction. Preeclampsia was classified as early-onset (\u0026lt;\u0026thinsp;34 weeks of gestation) or late-onset (\u0026ge;\u0026thinsp;34 weeks). We identified 56 women with preeclampsia and 268 healthy controls.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Statistical analysis\u003c/h2\u003e\u003cp\u003eDependent on the distribution of data, Mann-Whitney U test or unpaired \u003cem\u003et\u003c/em\u003e-test was used for comparisons between women with preeclampsia and healthy controls. Data were shown as count (%), mean (\u0026plusmn;\u0026thinsp;Standard deviation, SD), or median (interquartile range, IQR). Then we incorporated sFlt-1/PlGF ratio into a multiple logistic regression model for predicting the development of preeclampsia. Receiver Operating Characteristic (ROC) curve analysis was conducted to quantify the Area Under the Curve (AUC). A \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. SPSS ver. 20.0 was used to analyze the data.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, in total 56 pregnant women were diagnosed with preeclampsia. Among them, 6 women had early-onset preeclampsia and 50 had late-onset preeclampsia. We did not observe statistically significant differences regarding maternal age (\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.277) and body mass index (BMI) before pregnancy (\u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.135) between preeclampsia patients and healthy controls. The mean ratio of sFlt-1/PlGF was 22.95 in preeclampsia patients, which was significantly higher than that observed in the control group (mean: 14.87; \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The mean level of sFlt was 1785.00 pg/ml in PE patients and 1761.00 pg/ml in controls. Moreover, the mean level of PlGF was 111.50 pg/ml in PE patients, which was significantly lower compared to that in control group (84 pg/mL; \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic and clinical characteristics of the patients in the control and PE groups\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;268)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePE (n\u0026thinsp;=\u0026thinsp;56)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP value\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal age (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30.25\u0026thinsp;\u0026plusmn;\u0026thinsp;5.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31.13\u0026thinsp;\u0026plusmn;\u0026thinsp;4.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.277\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePre-pregnancy BMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003cp\u003e\u0026lt; 27\u003c/p\u003e\u003cp\u003e≧27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.56\u0026thinsp;\u0026plusmn;\u0026thinsp;3.61\u003c/p\u003e\u003cp\u003e168(62.7%)\u003c/p\u003e\u003cp\u003e100(37.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.68\u0026thinsp;\u0026plusmn;\u0026thinsp;2.89\u003c/p\u003e\u003cp\u003e41(73.2%)\u003c/p\u003e\u003cp\u003e15(26.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.135\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParity (times)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.069\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esFlt1 (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1761.00[691]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1785.00[1153]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlGF (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e111.50[166]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e84.50[70]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esFlt1/PlGF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.87[17]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.95[26]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eData in the table are presented as n (%), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, or median [interquartile range].\u003c/p\u003e\u003cp\u003eBMI: body mass index.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents the associations between various predictors and the occurrence of preeclampsia (yes/no) based on a multivariable logistic regression model. The sFlt1/PlGF ratio positively correlated with the defined adverse outcome (aOR 1.051, 95% CI 1.022\u0026ndash;1.081; P\u0026thinsp;=\u0026thinsp;0.001), meaning that each unit increase of sFlt1/PlGF was associated with a 5.1% increase in the odds of the outcome. Parity showed a potential protective effect (aOR\u0026thinsp;=\u0026thinsp;0.564, 95% CI: 0.329\u0026ndash;0.967, P\u0026thinsp;=\u0026thinsp;0.037).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eMultiple logistic regression model to identify predictors of preeclampsia\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCoefficient (β)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eaOR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95% CI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaternal age,(years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.036\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.973\u0026ndash;1.104\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.269\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003epre-pregnancy BMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.462\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.588\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.779\u0026ndash;3.235\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.203\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParity(times)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.573\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.564\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.329\u0026ndash;0.967\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esFlt1 (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-0.00027\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.9997\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.999\u0026ndash;1.000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.148\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlGF (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.0011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.000\u0026ndash;1.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.055\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esFlt1/PlGF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.050\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1.051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.022\u0026ndash;1.081\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConstant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e-2.869\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eaOR: adjusted odds ratio; CI: confidence interval; BMI: body mass index.\u003c/p\u003e\u003cp\u003eThe predicted risk of developing preeclampsia can be calculated using the following formula (For pre-pregnancy BMI: the value is 0 if\u0026thinsp;\u0026lt;\u0026thinsp;27 kg/m\u003csup\u003e2\u003c/sup\u003e is true; value is 1 otherwise):\u003c/p\u003e\u003cp\u003eLinear predictor (LP)\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;2.869\u0026thinsp;+\u0026thinsp;0.036\u0026times;Maternal age\u0026thinsp;+\u0026thinsp;0.462\u0026times;pre-pregnancy BMI (\u0026thinsp;≧\u0026thinsp;27 kg/m\u003csup\u003e2\u003c/sup\u003e)\u0026thinsp;\u0026minus;\u0026thinsp;0.573\u0026times;Parity\u0026thinsp;+\u0026thinsp;0.000\u0026times;sFlt1\u0026thinsp;+\u0026thinsp;0.001\u0026times;PlGF\u0026thinsp;+\u0026thinsp;0.050\u0026times;sFlt1/PlGF.\u003c/p\u003e\u003cp\u003ePredicted risk =(1\u0026thinsp;+\u0026thinsp;exp(\u0026minus;\u0026thinsp;LP))\u003csup\u003e\u0026minus;1\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe area under the ROC curve (c-statistics) is 0.730 (95% CI: 0.644\u0026ndash;0.795), which indicates a moderate discriminative ability of the model (Figure. 1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eIn this study, we found that elevated sFlt-1/PlGF ratio during mid-pregnancy was predictive of preeclampsia in later pregnancy, which is consistent with most existing research. However, the AUC-ROC value (Area under the ROC curve) of the prediction model accommodating this biomarker developed in our study was lower than that reported in some literature, such as Pooneh's study (which reported an AUC of 0.90).\u003c/p\u003e\u003cp\u003ePreeclampsia is a heterogeneous disease with marked differences in presentation and outcome especially between early-onset (\u0026le;\u0026thinsp;33\u0026thinsp;+\u0026thinsp;6 weeks of gestation) and late-onset (\u0026ge;\u0026thinsp;34\u0026thinsp;+\u0026thinsp;0 weeks of gestation) cases\u003csup\u003e[\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. The divergent underlying pathophysiological mechanisms of the early- and late-onset preeclampsia are reflected by different performances of sFlt-1, PlGF, and the sFlt-1/PlGF ratio\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In uncomplicated pregnancies, the sFlt-1/PlGF ratio exhibits a U-shaped pattern: declining between 9 and 12 weeks of gestation, remaining stably low from 19\u0026ndash;20 to 37\u0026ndash;38 weeks, and increasing again near term (39\u0026ndash;40 weeks) as demonstrated in Kumar N and Stefan Verlohren\u0026rsquo;s studies\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. During 20\u0026ndash;28 gestational weeks, the sFlt1/PlGF ratio in normal pregnancy was 17, aligning with the results observed in Baert J\u0026rsquo; s study\u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. In the last two decades, numerous clinical studies have reported that the sFlt1/PlGF ratio is a valuable biomarker related to preeclampsia \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e. In Germany and some other parts of Europe, the ratio has been used to guide routine clinical management, despite that it is emphasized that more investigations are required to fully justify its clinical utilization in the guidelines of ACOG updated in year 2020\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In Asia, limited studies have confirmed that the sFlt1/PlGF ratio is a useful tool for predicting preeclampsia\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Our current real-world study in China provides additional evidence that supports the utility of sFlt1/PlGF ratio as a predictive biomarker of preeclampsia.\u003c/p\u003e\u003cp\u003eTo our best knowledge, this is the first study in China to predict the occurrence of preeclampsia incorporating the levels of sFlt-1, PlGF and sFlt1/PlGF ratio measured in mid-pregnancy women. The strength of the current study is that this is a real-world data analysis. Although many experiments showed that PlGF is a good predictor of preeclampsia, our findings demonstrated that including the sFlt1/PlGF ratio improves model performance compared with models using sFlt1 or PlGF alone. Moreover, we included a relatively large number of women with different hypertensive disorders of pregnancy in our cohort and collected detailed clinical information of adverse outcomes. Even so, we acknowledge some limitations of our study. First, our data are from a national medical center located in southern China and most participants are southern Chinese. The notable disparities in maternal profiles and risk factors between southern and northern China underscore the need to examine regional differences regarding the sFlt-1/PlGF ratio \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Second, biochemical index tests were not complete, which made it difficult to compare the performance between models built with angiogenic markers and those with traditional parameters. More studies with a larger cohort and among other ethnicities are required to determine the cost-effectiveness of sFlt-1/PlGF ratio as a biomarker for predicting preeclampsia. Future research may also investigate the optimal value of sFlt-1/PlGF ratio in a larger population.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur study adds to the evidence that the sFlt-1/PlGF ratio during mid-pregnancy is a useful predictor of preeclampsia. The model incorporating this ratio hopefully contributes to more individualized care of pregnant women.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u0026middot;\u003cb\u003eEthics approval and consent to participate\u003c/b\u003e: This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethnic Committee of Women and Children's Hospital of Ningbo University(approval number: EC2023-095). All participants provided written informed consent.\u003c/p\u003e\u003cp\u003e\u0026middot;\u003cb\u003eConsent for publication\u003c/b\u003e: Not applicable.\u003c/p\u003e\u003cp\u003e\u0026middot;\u003cb\u003eAvailability of data and materials\u003c/b\u003e: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\u003cp\u003e\u0026middot;\u003cb\u003eCompeting interests\u003c/b\u003e: The authors declare no conflict of interest.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u0026middot;Funding\u003c/strong\u003e\u003cp\u003eThis study was supported by Medical Science and Technology Project of Zhejiang Province, China (2024ZL96, 2024KY1575 \u0026amp; 2025KY1412) and funded by the project of NINGBO Leading Medical \u0026amp; Health Discipline (2024S148, 2010-S04 and 2023Z183).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003e\u0026middot; Acknowledgements\u003c/h2\u003e\u003cp\u003eWe would like to express sincerely our gratitude to all those who made this project possible.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eTTL: Data Collection, Manuscript Writing and Data Analysis; XBH \u0026amp;amp; XYZ: Data Collection, FH: Project Development, Manuscript Editing. All the authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChappell LC, Cluver CA, Kingdom J, et al. Preeclampsia Lancet. 2021;398(10297):341\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJung E, Romero R, Yeo L, et al. The etiology of preeclampsia. Am J Obstet Gynecol. 2022;226(2S):S844\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi Q, Sharkey A, Sheridan M, et al. Human uterine natural killer cells regulate differentiation of extravillous trophoblast early in pregnancy. Cell Stem Cell. 2024;31(2):181\u0026ndash;e1959.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStaff AC, Fjeldstad HE, Fosheim IK, et al. Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. Am J Obstet Gynecol. 2022;226(2S):S895\u0026ndash;906.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStepan H, Galindo A, Hund M, et al. Clinical utility of sFlt-1 and PlGF in screening, prediction, diagnosis and monitoring of preeclampsia and fetal growth restriction. Ultrasound Obstet Gynecol. 2023;61(2):168\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZeisler H, Llurba E, Chantraine F, et al. Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia. N Engl J Med. 2016;374(1):13\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVerlohren S, Herraiz I, Lapaire O, et al. New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension. 2014;63(2):346\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChaemsaithong P, Gil MM, Chaiyasit N, et al. Accuracy of placental growth factor alone or in combination with soluble fms-like tyrosine kinase-1 or maternal factors in detecting preeclampsia in asymptomatic women in the second and third trimesters: a systematic review and meta-analysis. Am J Obstet Gynecol. 2023;229(3):222\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBurns LP, Potchileev S, Mueller A et al. Real-world evidence for the utility of serum soluble fms-like tyrosine kinase 1/placental growth factor test for routine clinical evaluation of hospitalized women with hypertensive disorders of pregnancy. Am J Obstet Gynecol. 2024 Jul 17:S0002-9378(24)00758-0.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHanson E, Rull K, Ratnik K, et al. Value of soluble fms-like tyrosine kinase-1/placental growth factor test in third trimester of pregnancy for predicting preeclampsia in asymptomatic women. J Perinat Med. 2022;50(7):939\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTang J, Xiao D, Yang S, Fang L, Liu H, Chen D, He F. sFlt-1/PlGF Ratio Predicts Short-Term Maternal-Fetal Outcomes in Chinese Hypertensive Pregnancies: A Prospective Cohort Study. Hypertension. 2025 Sep 15.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKinugawa M, Kumasawa K, Nemoto K, Nakajima K, Ichinose M, Toshimitsu M, Sayama S, Seyama T, Iriyama T, Hirota Y, Osuga Y. Impact of parity and pre-pregnancy BMI on second-trimester sFlt-1 and PlGF levels in normotensive pregnancies. Hypertens Pregnancy. 2025;44(1):2534022.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLane A, Amy LU, Parange A, Dekker G. Clinical Experience and Major Learning Points Following the Implementation of the sFlt-1/PlGF Ratio in the Management of Suspected Preeclampsia in a South Australian Tertiary Hospital. Aust N Z J Obstet Gynaecol. 2025 Jul 18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRana S, Lemoine E, Granger JP, et al. Preeclampsia: Pathophysiology, Challenges, and Perspectives. Circ Res. 2019;124(7):1094\u0026ndash;112.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePoon LC, Shennan A, Hyett JA, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on preeclampsia: A pragmatic guide for first-trimester screening and prevention. Int J Gynaecol Obstet. 2019;145(1):1\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChinese Medical Association Obstetrics and Gynecology Section Hypertensive Diseases in Pregnancy Group. Hypertensive Diseases in Pregnancy Guidelines for the Diagnosis and Treatment of Hypertensive Diseases in Pregnancy (2020). Chin J Obstet Gynecol. 2020;55(04).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRoberts JM. Preeclampsia epidemiology(ies) and pathophysiology(ies). Best Pract Res Clin Obstet Gynaecol. 2024;94:102480.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTurbeville HR, Sasser JM. Preeclampsia beyond pregnancy: long-term consequences for mother and child. Am J Physiol Ren Physiol. 2020;318(6):F1315\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYagel S, Cohen SM, Admati I, et al. Expert review: preeclampsia Type I and Type II. Am J Obstet Gynecol MFM. 2023;5(12):101203.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVerlohren S, Brennecke SP, Galindo A, et al. Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia. Pregnancy Hypertens. 2022;27:42\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBaert J, McCarey C, Berkane N, et al. The role of sFlt1/PlGF ratio in the assessment of preeclampsia and pregnancy-related hypertensive disorders. Swiss Med Wkly. 2021;151:w20533.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarrido-Gim\u0026eacute;nez C, Cruz-Lemini M, \u0026Aacute;lvarez FV, et al. Predictive Model for Preeclampsia Combining sFlt-1, PlGF, NT-proBNP, and Uric Acid as Biomarkers. J Clin Med. 2023;12(2):431.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKumar N, Das V, Agarwal A, et al. Correlation of sFlt/PlGF ratio with severity of preeclampsia in an Indian population. AJOG Glob Rep. 2023;3(2):100177.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChirilă CN, Mărginean C, Chirilă PM, et al. The Current Role of the sFlt-1/PlGF Ratio and the Uterine-Umbilical-Cerebral Doppler Ultrasound in Predicting and Monitoring Hypertensive Disorders of Pregnancy: An Update with a Review of the Literature. Child (Basel). 2023;10(9):1430.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJeon HR, Jeong DH, Lee JY, et al. sFlt-1/PlGF ratio as a predictive and prognostic marker for preeclampsia. J Obstet Gynaecol Res. 2021;47(7):2318\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGraupner O, Verlohren S, Groten T, et al. Significance of the sFlt-1/PlGF Ratio in Certain Cohorts - What Needs to be Considered? Geburtshilfe Frauenheilkd. 2024;84(7):629\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStepan H, Hund M, Andraczek T. Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome. Hypertension. 2020;75(4):918\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGestational Hypertension and Preeclampsia. ACOG Practice Bulletin, Number 222. Obstet Gynecol. 2020;135(6):e237\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChuah TT, Tey WS, Ng MJ, et al. Serum sFlt-1/PlGF ratio has better diagnostic ability in early- compared to late-onset preeclampsia. J Perinat Med. 2018;47(1):35\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePalma Dos Reis CR, Br\u0026aacute;s S, Meneses T, et al. The sFlt1/PlGF ratio predicts faster fetal deterioration in early fetal growth restriction: A historical cohort study. Acta Obstet Gynecol Scand. 2023;102(5):635\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"preeclampsia, placental growth factor, soluble vascular endothelial growth factor receptor-1 (sFlt-1), sFlt1/PlGF ratio","lastPublishedDoi":"10.21203/rs.3.rs-7908857/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7908857/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo evaluate whether the sFlt1/PlGF ratio is increased in mid-pregnancy in women developing preeclampsia later.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA case-control study was conducted in Department of Gynecology and Obstetrics at Women and Children' s Hospital of Ningbo University. We included 56 women during 24\u0026ndash;26 gestational weeks who developed preeclampsia later (cases) and 268 women with uncomplicated pregnancy (controls). The concentrations of sFlt-1 and PlGF were measured with commercially available ELISA kits during 24\u0026ndash;28 gestational weeks. Logistic regression was employed to model the relationship between selected biomarkers and the occurrence of preeclampsia.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe mean sFlt-1/PlGF ratio during mid-pregnancy was 22.95 among patients with preeclampsia, significantly higher than that observed in the control group (mean 14.87; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In logistic regression analysis, the sFlt-1/PlGF ratio was positively associated with the occurrence of preeclampsia (adjusted OR 1.051, 95% CI 1.022\u0026ndash;1.081; P\u0026thinsp;=\u0026thinsp;0.001). The discriminative ability of the model was moderate, with an area under the receiver operating characteristic curve of 0.730 (95% CI 0.644\u0026ndash;0.795).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThe sFlt1/PlGF ratio is increased at mid-pregnancy in women developing preeclampsia later. Our study provides additional evidence supporting sFlt1/PlGF ratio as a predictive biomarker of preeclampsia.\u003c/p\u003e","manuscriptTitle":"Elevated mid-pregnancy plasma ratio of sFlt1/PlGF in women prior to the development of preeclampsia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-22 18:53:26","doi":"10.21203/rs.3.rs-7908857/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"35c7d89d-93a3-4558-9002-a63efa2aecc6","owner":[],"postedDate":"October 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-18T07:09:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-22 18:53:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7908857","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7908857","identity":"rs-7908857","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}