{"paper_id":"0fe71142-2ced-46ef-be7f-82440d5941f6","body_text":"The Predictive Value and Clinical Treatment Guidance of Uterine Artery Blood Flow Parameters for Recurrent Pregnancy Loss | 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 The Predictive Value and Clinical Treatment Guidance of Uterine Artery Blood Flow Parameters for Recurrent Pregnancy Loss Liang Xu, Fangfang Zhou, Tian Qiu, Weimei Li, Xiong Miao, Ziqiu He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7686237/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 investigate the relationship between uterine artery blood flow parameters (S/D, RI, PI, PSV) and the number of miscarriages, etiology, treatment methods, and pregnancy outcomes in patients with recurrent pregnancy loss (RPL). Methods A retrospective analysis was conducted on data from patients with RPL and women with normal pregnancy who visited Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine and the International Peace Maternity and Child Health Hospital between October 2017 and December 2024. The study observed various parameters of uterine artery blood flow, comparing differences in the number of miscarriages, causes, treatment methods, and pregnancy outcomes. Receiver Operating Characteristic (ROC) curves were used to evaluate the predictive value of blood flow parameters on pregnancy outcomes. Results The study included 652 patients with RPL and 432 pregnant women with normal pregnancy. 1) With increasing gestational age, the uterine artery systolic/end-diastolic velocity (S/D), pulsatility index (PI), and blood flow resistance index (RI) showed a downward trend in patients with normal pregnancy. 2) As the number of spontaneous miscarriages increased, the uterine artery blood flow S/D ratio and PI value gradually increased, while the Peak systolic velocity (PSV) and RI values showed no significant correlation with the number of miscarriages. 3) In RPL patients caused by immunological factors (APS, SLE, etc.), the uterine artery S/D ratio, PI, and RI values were significantly elevated. In contrast, in RPL patients caused by endocrine factors, although the S/D ratio, PI, and RI values also tended to increase, the magnitude of increase was much less compared to RPL caused by immunological factors. In patients with unexplained RPL (URPL), the uterine artery S/D ratio, PI, and RI values were also significantly elevated. In RPL patients due to chromosomal factors, the uterine artery blood flow parameters showed no significant difference compared to the normal group. 4) After treatment, the S/D, RI, and PI values significantly decreased (p < 0.05), and PSV increased (p < 0.05), suggesting a significant negative correlation between pre-treatment uterine artery S/D ratio, PI value, and pregnancy outcomes (p < 0.05). 5) Combined medication (aspirin + nifedipine + sildenafil citrate) was most effective, significantly reducing S/D, PI, and RI (p < 0.05), and markedly improving pregnancy outcomes (p < 0.05). 6) ROC analysis showed that S/D (AUC = 0.8385) and PI (AUC = 0.8130) had a high predictive value for adverse pregnancy outcomes, with optimal thresholds of 22.69 and 5.83, respectively. Conclusion Uterine artery blood flow parameters (particularly S/D and PI) can serve as predictive indicators of pregnancy outcomes in patients with RPL. Combined pharmacological treatment can significantly improve hemodynamics and reduce the risk of miscarriage. recurrent pregnancy loss uterine artery blood flow pregnancy outcome aspirin nifedipine sildenafil citrate Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction RPL refers to the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation with the same partner [ 1 ] . The etiology of RPL is complex and varied, with identifiable causes including genetic factors from both partners, anatomical abnormalities, endocrine disorders, autoimmune abnormalities, and thrombophilic states. However, approximately 50% of cases have no clear cause, termed unexplained recurrent pregnancy loss (URPL). Currently, there is a lack of evidence-based medicine for the diagnosis and treatment of URPL. Recent studies suggest that uterine artery blood flow parameters, such as the S/D ratio, RI, PI and PSV, can reflect placental perfusion [ 2 – 4 ] . These parameters are closely associated with various pathological pregnancies [ 5 – 7 ] , including hypertensive disorders of pregnancy, fetal growth restriction [ 8 ] (FGR), placental insufficiency [ 7 ] , and RPL [ 9 , 10 ] . However, there is no established standard for normal uterine artery blood flow values during pregnancy. The correlation between the frequency of pregnancy loss, the etiology of spontaneous abortion, and uterine artery blood flow parameters is unclear. Furthermore, there is limited research on whether abnormalities in uterine artery blood flow parameters require treatment and the effective measures and timing of such treatments. This study utilizes transvaginal color Doppler ultrasound to continuously measure uterine artery blood flow parameters in both normal pregnant women and RPL patients. It aims to compare the relationship between the frequency and etiology of spontaneous abortion and uterine artery blood flow parameters. Additionally, the study explores the differences in uterine artery blood flow parameters before and after treatment, as well as among different pregnancy outcomes. The influence of various treatment methods on uterine artery blood flow parameters and pregnancy outcomes is analyzed, with the aim of early prediction of pathological pregnancy risks, timely intervention, and the implementation of effective treatment measures to improve pregnancy outcomes. Materials and Methods Study Subjects : A retrospective analysis was conducted on data from RPL patients and women with normal pregnancies who visited Xinhua Hospital and the International Peace Maternity & Child Health Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, between October 2017 and December 2024. The participants aged between 20 and 40 years met the criteria for RPL diagnosis. The inclusion criteria for RPL included [ 1 , 11 ] : ① a history of two or more spontaneous miscarriages; ② ultrasound confirmation of intrauterine pregnancy with a singleton gestation. Exclusion criteria were: ① concurrent conditions that could cause uterine abnormalities, such as adenomyosis, intrauterine adhesions, inflammation, or tumors; ② hypertension, diabetes, arrhythmias, or other diseases affecting hemodynamics; ③ chromosomal abnormalities in either partner. This study was approved by the Ethics Committee of the International Peace Maternity & Child Health Hospital of Shanghai Jiao Tong University, and informed consent was obtained from all participants. The criteria for embryonic arrest were [ 11 , 12 ] : ① crown-rump length (CRL) ≥ 7 mm without a heartbeat; ② mean gestational sac diameter ≥ 25 mm with no visible embryo; ③ ultrasound showing a gestational sac without a yolk sac, with no cardiac activity detected upon re-examination after ≥ 2 weeks; ④ ultrasound showing a gestational sac with a yolk sac, with no cardiac activity in the embryo after ≥ 11 days. Women with normal pregnancies and RPL patients underwent transvaginal ultrasound to assess uterine artery hemodynamic parameters before and during pregnancy (every 2 weeks). RPL patients who did not undergo transvaginal ultrasound for uterine artery blood flow assessment during pregnancy were excluded. Methods A Philips HD-15 color Doppler ultrasound diagnostic instrument, produced by the American company Philips, was used, with a transvaginal ultrasound probe frequency of 4 ~ 8 MHz [ 10 ] . ① The size, position, and morphology of the uterus and gestational sac were examined to observe the presence or absence of a yolk sac, embryo, and primitive heart tube pulsation. ② The four parameters of blood flow of the left and right uterine arteries were monitored separately. Typically, six consecutive, stable cardiac cycle spectra were taken. The system's automatic envelope and calculation function was utilized to measure and record the blood flow RI, PI, PSV and S/D for both the left and right uterine arteries. The average values were taken for analysis. The relationship between early pregnancy uterine artery blood flow resistance parameters and different pregnancy outcomes in patients with RPL was analyzed. ③ All study subjects were measured three times by a professional. Grouping 1) Grouped by the number of spontaneous miscarriages: 2 times, 3 times, 4 times, 5 times, ≥ 6 times; 2) Grouped by treatment regimen: aspirin alone, in combination with nifedipine and/or sildenafil; 3)Stratified by pregnancy outcome :Full-term birth、Preterm birth、Miscarriage; Treatment Regimen 1)Aspirin (50–100 mg/day, oral); 2) Aspirin (50–100 mg/day, oral) + Nifedipine (10–30 mg/day, oral); 3) Aspirin (50–100 mg/day, oral) + Nifedipine (10–30 mg/day, oral) + Sildenafil (25–50 mg/day, vaginal administration). Statistical Analysis: Data analysis and plotting were performed using GraphPad Prism 5.0. Measurement data conforming to a normal distribution are expressed as mean ± standard deviation (± s), and comparisons between groups were conducted using the t-test. Categorical data are expressed as percentages (%), with comparisons between groups carried out using the χ² test. All P-values were two-tailed, and a P-value of less than 0.05 was considered statistically significant. Results Baseline Characteristics The study included a total of 652 patients with RPL and 432 women with normal pregnancies. The age of the RPL group was higher compared to the normal group, while there was no statistically significant difference in body mass index between the two groups (Table 1). Relationship between RPL frequency and the uterine artery blood flow parameters To observe the relationship between different abortion frequencies and uterine artery blood flow parameters, we measured the relevant parameters of uterine artery blood flow in RPL patients with different abortion frequencies. The results showed that with the increase in spontaneous abortion frequency, the S/D ratio of uterine artery blood flow gradually increased (p<0.001). The PI value also showed the same trend, increasing with the number of abortions. However, there was no significant correlation between PSV and RI and the frequency of abortions (p>0.05)（Fig1）. Relationship between the etiology of RPL and the uterine artery blood flow parameters The etiology of RPL is very complex, including genetic factors, anatomical factors, infectious factors, immune factors, and pre-thrombotic states. We grouped patients based on different etiologies of RPL to analyze the relationship between different causes and uterine artery blood flow parameters. The results showed that compared with the normal control group, patients with APS, SS, UCTD, AS, RA, and SLE had significantly higher uterine artery S/D ratios, PI, and RI, with statistically significant differences. Although patients with RPL caused by endocrine factors also showed increasing trends in S/D ratios, PI, and RI, the magnitude of increase was much lower than that seen in immunological factors-related RPL. Patients with URPL also had significantly higher uterine artery S/D ratios, PI, and RI (p<0.05). There were no significant differences in uterine artery blood flow parameters between patients with RPL caused by chromosomal abnormalities and the normal group (p>0.05). PSV values showed no statistical differences among patients with RPL caused by different etiologies (p>0.05)（Fig2）. Changes in uterine artery blood flow parameters in RPL patients with different abortion histories before and after treatment A literature review reveals that abnormal uterine artery blood flow parameters may lead to adverse pregnancy outcomes such as miscarriage and FGR. We retrospectively observed changes in uterine artery-related parameters before and after treatment in 652 patients with RPL (with different numbers of miscarriages). The results showed significant changes in uterine artery blood flow S/D ratio, RI, PI, and PSV after treatment. Compared with pre-treatment values, the S/D ratio, RI, and PI decreased significantly after treatment (p<0.05). In contrast, PSV showed an increasing trend after treatment, with a statistically significant difference compared with pre-treatment values (p<0.05) （Fig3）. Changes in uterine artery blood flow parameters before and after treatment in RPL patients with different etiologies We retrospectively observed the changes in uterine artery-related parameters before and after treatment in 652 patients with RPL (different etiologies). The results showed significant changes in S/D ratio, RI, PI, and PSV after treatment. Compared with pre-treatment, the S/D ratio, RI, and PI values decreased significantly after treatment (p<0.05). However, there were no statistical differences in S/D ratio, RI, and PI values of uterine artery blood flow between patients with different etiologies before and after treatment (p>0.05). PSV showed an increasing trend after treatment, with a statistically significant difference compared with pre-treatment (p<0.05) （Fig4）. Effects of different treatment methods on uterine artery blood flow parameters We retrospectively observed the treatment outcomes of 652 patients with RPL. For the treatment of elevated uterine artery blood flow, in addition to dietary and lifestyle adjustments, three main medications were used: aspirin, nifedipine, and sildenafil citrate. During medication, dynamic monitoring of uterine artery blood flow parameters was conducted, and medication was adjusted based on parameter changes. According to actual medication usage, patients were divided into four groups: Group 1: low-dose aspirin monotherapy; Group 2: low-dose aspirin combined with nifedipine; Group 3: low-dose aspirin combined with sildenafil citrate; Group 4: low-dose aspirin + nifedipine + sildenafil citrate. The dosage of aspirin was 50-100mg/day, nifedipine 10-30mg/day, and sildenafil citrate 25-50mg/day (vaginal use). The medication indication mainly referred to the S/D ratio. We conducted a large-scale study in the early stage and found significant changes in S/D ratio at different gestational weeks in normal pregnant women. With increasing gestational weeks, uterine artery blood flow S/D showed a decreasing trend, approximately 0.2-0.3 per week. Therefore, we established the reference range for bilateral uterine artery blood flow S/D ratio (sum of left and right sides): pre-pregnancy S/D <12, before 10 weeks S/D <10.5, before 12 weeks S/D <8.5, 16 weeks S/D <7.5, 20 weeks S/D <6.5, 24 weeks S/D <5.5, 28 weeks S/D <5.0, 30 weeks S/D <4.5, see Fig 5-1. Uterine artery blood flow parameters were measured every 2 weeks throughout pregnancy, and medication dosage and types were adjusted based on S/D ratio. The results showed that the decrease in uterine artery blood flow parameters S/D ratio, PI, and RI was significantly higher in combination therapy groups compared to low-dose aspirin monotherapy group. Among them, the effect of aspirin monotherapy group was lower than aspirin combined with nifedipine or aspirin combined with sildenafil citrate groups (p<0.05). When low-dose aspirin + nifedipine + sildenafil citrate were used in combination, the decrease in S/D ratio, PI, and RI was the largest, showing statistical significance compared to other groups (p<0.05). There was no statistical difference in PSV between different treatment methods (p>0.05) (Fig5-2). Relationship between different pregnancy outcomes and uterine artery blood flow parameters We retrospectively observed the uterine artery blood flow S/D ratio before and after treatment in 652 RPL patients with different pregnancy outcomes. The pregnancy outcomes were divided into three categories: full-term delivery, preterm delivery, and spontaneous abortion. These outcomes were scored as follows: 1 point for full-term delivery, 2 points for preterm delivery, and 3 points for abortion. A higher score indicated a less ideal pregnancy outcome. The results showed that the S/D ratio decreased in all three groups after treatment. Among them, the spontaneous abortion group showed the smallest decrease in S/D ratio after treatment (p<0.05). The preterm delivery group also showed a decreasing trend in S/D ratio before and after treatment, but the decrease was significantly less than that in the normal pregnancy group. The full-term delivery group showed the most significant change in S/D ratio before and after treatment (p<0.05), suggesting that a high S/D ratio may predict adverse pregnancy outcomes (Fig 6). The impact of different treatment methods on pregnancy outcomes We further observed the relationship between different treatment methods and pregnancy outcomes in RPL patients, and found that the combination of low-dose aspirin, nifedipine, and sildenafil citrate had the lowest pregnancy loss rate in RPL patients, while the low-dose aspirin group had the highest pregnancy loss rate, (p<0.05) （Fig7）. Receiver operating characteristic (ROC) Previous studies have found that as the number of natural miscarriages increases, the S/D, PI, and RI values of miscarriage patients gradually increase. Further evaluation of the efficacy of uterine artery parameters in predicting pregnancy outcomes using ROC curves and providing clinical optimal thresholds. The predictive accuracies of S/D, PI, RI, and PSV for pregnancy outcomes during early pregnancy were 0.8385, 0.8130, 0.7796, and 0.6629, respectively, with clinically optimal thresholds of 22.69, 5.83, 1.935, and 204, respectively. It is believed that S/D, PI/, and RI have a good predictive effect on adverse pregnancy outcomes (Fig 8). Discussion In recent years, research on the pathogenesis of RPL related to abnormal uterine artery blood flow has made significant progress. Studies have shown that increased resistance in the uterine artery blood flow is primarily due to the ineffective invasion of trophoblastic cells into the uterine spiral arteries [ 13 , 14 ] . This impedes vascular remodeling, resulting in narrowed vascular lumens, obstructed placental blood circulation, and potentially abnormal coagulation function [ 15 , 16 ] . These factors further increase the risk of placental thrombosis, affect fetal blood supply, and may ultimately lead to adverse pregnancy outcomes. Uterine artery blood flow parameters mainly include the PI, RI, and S/D ratio. These parameters assess uterine artery blood flow resistance and vascular elasticity through Doppler ultrasound technology, reflecting the condition of uterine-placental blood circulation [ 17 , 18 ] . However, there is still a lack of unified normal reference ranges for uterine artery blood flow parameters in clinical practice. Our study included 3000 normal pregnant women and measured the S/D ratio of uterine artery blood flow at different gestational stages, establishing reference ranges for the S/D ratio at various gestational weeks (6–32 weeks). The results showed that uterine artery blood flow parameters demonstrate specific trends during normal pregnancy. The S/D ratio of uterine arteries high in early pregnancy and gradually decreases with increasing gestational weeks. This change reflects the physiological remodeling process of uterine vessels shifting from a high-resistance state to a low-resistance state during pregnancy, thereby better meeting the blood flow and oxygen supply demands for fetal growth and development. In early pregnancy, uterine artery blood flow resistance is high due to insufficient erosion of uterine spiral arterioles by trophoblasts [ 6 , 19 , 20 ] . As pregnancy progresses, vascular resistance gradually decreases until it disappears in the third trimester. This physiological change is crucial for ensuring normal placental blood circulation and fetal development. Therefore, understanding the normal reference range of uterine artery blood flow parameters is helpful for predicting and diagnosing potential adverse pregnancy outcomes. The parameters of uterine artery blood flow are closely associated with RPL [ 18 , 21 – 24 ] . The results of this study demonstrate a significant upward trend in the uterine artery S/D ratio and PI values with an increase in the number of miscarriages, which is consistent with several studies conducted both domestically and internationally [ 23 , 25 , 26 ] . Zhang et al [ 27 ] . found in their study of RPL patients that those with three or more miscarriages had significantly higher uterine artery RI and PI values compared to those with two miscarriages. Similarly, a prospective cohort study by Metwally et al. also confirmed that a high-resistance blood flow pattern is closely related to an increased risk of miscarriage [ 28 ] . From a pathophysiological perspective, increased uterine artery resistance may lead to inadequate placental perfusion, resulting in intervillous space thrombosis and trophoblast invasion impairment, which could be one of the important mechanisms of RPL. It is noteworthy that this study found no significant correlation between PSV and the number of miscarriages, which differs from some studies. Kadir Arslan et al. reported that reduced PSV is associated with adverse pregnancy outcomes [ 29 ] , although their sample size was relatively small. This discrepancy may arise from the heterogeneity of study populations or differences in measurement methods, highlighting the need for standardized measurement protocols in future research. The parameters of uterine artery blood flow are influenced by various factors [ 30 ] . Our study found significant hemodynamic differences in patients with RPL due to different etiologies. In the group with autoimmune diseases (such as APS, SLE, and other rheumatological immune disorders), the S/D, PI, and RI values were significantly increased, aligning with international consensus. Patients with APS commonly experience endothelial damage and a predisposition to thrombosis, leading to impaired remodeling of the uterine spiral arteries [ 31 ] . Recent research indicates that increased resistance of uterine artery blood flow in APS patients is positively correlated with the titer of anti-β2 glycoprotein I antibodies [ 32 ] . In the group with chromosomal factors, the blood flow parameters showed no significant difference compared to the normal pregnancy group, supporting the viewpoint that chromosomal abnormalities primarily result in miscarriage through embryonic aneuploidy rather than maternal blood flow factors. Patients with URPL also exhibited significant abnormalities in blood flow, suggesting the presence of yet unidentified vascular pathological mechanisms. This finding aligns with the \"occult placental insufficiency\" hypothesis. Research into uterine artery blood-flow abnormalities has increasingly focused on individualized treatment strategies [ 4 , 15 , 27 , 33 – 35 ] . In this first systematic comparison of pharmacologic regimens targeting uterine artery hemodynamics, triple therapy with aspirin, nifedipine, and sildenafil demonstrated the greatest benefit, reducing the S/D ratio by 42.3%—a significantly larger decrease than with any single agent. This result builds on prior findings that aspirin improves blood flow by inhibiting thromboxane A₂ [ 36 – 38 ] , nifedipine, as a calcium-channel blocker, lowers vascular resistance [ 39 – 41 ] , and sildenafil enhances the NO-cGMP pathway via PDE5 inhibition [ 42 , 43 ] . Their synergistic, multi-target action likely promotes spiral-artery remodeling. Notably, PSV increased significantly after treatment, indicating improved vasodilatory function, who reported a 28% PSV increase with sildenafil monotherapy. In our cohort, triple therapy not only produced superior hemodynamic improvements but also yielded better pregnancy outcomes, with a markedly reduced spontaneous miscarriage rate compared to the other two groups. All three RPL cohorts received low-molecular-weight heparin concurrently, but only for standard indications such as autoimmune disorders or thrombophilia-not specifically to correct uterine blood flow. The detection of uterine artery blood flow parameters holds significant diagnostic and predictive value in clinical applications. ROC analysis indicates that the S/D ratio (AUC = 0.8385) and PI value (AUC = 0.8130) have a good predictive value for adverse pregnancy outcomes, with optimal cut-off values of 22.69 and 5.83, respectively. These parameters outperform traditional clinical parameters: their predictive efficacy is close to but slightly lower than the uterine artery pulsatility index [ 44 ] , and significantly superior to serum PAPP-A and β-hCG [ 45 ] . In accordance with the latest European guidelines [ 1 ] , we recommend incorporating uterine artery blood flow monitoring into the routine assessment protocol for patients with RPL, particularly for those with immunological factors or unexplained RPL. Formulating individualized treatment plans for RPL patients with different etiologies can effectively improve uterine artery blood flow and enhance pregnancy success rates. In conclusion, addressing uterine artery blood-flow abnormalities with tailored pharmacotherapy is crucial for improving pregnancy outcomes. Doppler indices S/D ratio and PI correlate positively with miscarriage frequency-particularly in immune-mediated RPL-and can serve as dynamic markers to guide treatment. Combined aspirin, nifedipine, and sildenafil therapy significantly lowers vascular resistance through antiplatelet and vasodilatory mechanisms, optimizing placental perfusion. The application of Doppler ultrasound and individualized regimens offers new directions for RPL diagnosis and management. Study limitations include its retrospective design, lack of molecular biomarkers (e.g., VEGF), and limited long-term follow-up. Future research should involve multicenter prospective cohorts, explore the molecular underpinnings of arterial remodeling (such as gene expression related to vascular remodeling), and refine individualized treatment protocols to maximize live‐birth rates and ensure maternal–fetal health. Declarations Ethics approval and consent to participate: The study received approval from the Human Research Ethics Committee of the Xinhua Hospital（Number：XHEC-NSFC-2025-034）. Consent for publication: All authors agree to publish in the journal. Availability of data and materials: The authors confirm that the supporting data for the study's findings are contained within the article. Competing interest s : The authors declare no conflicts of interest with the content of this article. Funding: This research received financial assistance from the National Natural Science Foundation of China (Grant Nos. 81671481 and 81871179), as well as from the Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Grant No. ynhglg 202413 and ynhg202211). Author contribution statement: Methodology, Miao Xiong; Software, Tian Qiu; Validation, Tian Qiu; Formal Analysis, Miao Xiong and Ziqiu He; Investigation, Ziqiu He; Resources, Liang Xu; Data Curation, Miao Xiong and Ziqiu He; Writing – Original Draft Preparation, Miao Xiong; Writing – Review & Editing, Liang Xu, Tian Qiu and Miao Xiong; Visualization, Weimei Li; Supervision, Ziqiu He; Project Administration, Miao Xiong and Ziqiu He; Funding Acquisition, Liang Xu and Miao Xiong. 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Chen, J.Y., et al., The value of placental vascularization indices for predicting preeclampsia and fetal growth restriction in different stages of gestation: A prospective and longitudinal study. Placenta, 2022. 122 : p. 1-8. Cui, J., et al., Study on the Relationship and Predictive Value of First-Trimester Pregnancy-Associated Plasma Protein-A, Maternal Factors, and Biochemical Parameters in Gestational Diabetes Mellitus: A Large Case-Control Study in Southern China Mothers. Diabetes, Metabolic Syndrome & Obesity: Targets & Therapy, 2023. 16 . Table Table 1 is available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Tab1.docx 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. 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19:29:08\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":91309,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eRelationship between RPL frequency and the uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(A)Uterine artery blood flow parameters S/D ratio in patients with different numbers of spontaneous abortions. (B) Uterine artery blood flow parameters RI in patients with different numbers of spontaneous abortions. (C)Uterine artery blood flow parameters PSV in patients with different numbers of spontaneous abortions. (D) Uterine artery blood flow parameters PI in patients with different numbers of spontaneous abortions. Error bars indicate standard deviation. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/72c2b4f0f536178159e15d62.png\"},{\"id\":94136863,\"identity\":\"8d12e8ae-75a3-4fdc-b4f6-23b68ac52f37\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:21:08\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":90511,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eRelationship between the etiology of RPL and the uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(A)Uterine artery blood flow parameters S/D ratio in patients with different etiology of spontaneous abortions. (B) Uterine artery blood flow parameters RI in patients with different etiology of spontaneous abortions. (C)Uterine artery blood flow parameters PSV in patients with different etiology of spontaneous abortions. (D) Uterine artery blood flow parameters PI in patients with different etiology of spontaneous abortions. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/0f4f40e68040d569c9ccea01.png\"},{\"id\":94136865,\"identity\":\"9d5047cf-b373-445d-8e62-b72b93890335\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:21:08\",\"extension\":\"png\",\"order_by\":3,\"title\":\"Figure 3\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":119717,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eUterine artery blood flow parameters in RPL patients with different abortion histories before and after treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(A)Uterine artery blood flow parameters S/D ratio in patients with different abortion histories before and after treatment. (B) Uterine artery blood flow parameters RI in patients with different abortion histories before and after treatment. (C)Uterine artery blood flow parameters PSV in patients with different abortion histories before and after treatment. (D) Uterine artery blood flow parameters PI in patients with different abortion histories before and after treatment. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"3.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/eb6658198ac1413e0026b6c1.png\"},{\"id\":94136868,\"identity\":\"402adbb6-5037-4915-b629-dc41a79bcc29\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:21:08\",\"extension\":\"png\",\"order_by\":4,\"title\":\"Figure 4\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":125212,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eUterine artery blood flow parameters before and after treatment in RPL patients with different etiologies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(A)Uterine artery blood flow parameters S/D ratio in patients with different abortion etiologies before and after treatment. (B) Uterine artery blood flow parameters RI in patients with different abortion etiologies before and after treatment. (C)Uterine artery blood flow parameters PSV in patients with different abortion etiologies before and after treatment. (D) Uterine artery blood flow parameters PI in patients with different abortion etiologies before and after treatment. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"4.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/fcf004ecf0ed25eef651c6ac.png\"},{\"id\":94139921,\"identity\":\"723974fd-e35e-44e6-9f6f-7eb7872e98c6\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:37:08\",\"extension\":\"png\",\"order_by\":5,\"title\":\"Figure 5\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":156883,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eEffects of different treatment methods on uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(Figure 5-1) Uterine artery blood flow parameters in normal pregnant women at different gestational weeks. (Figure 5-2A) Uterine artery blood flow parameters S/D ratio in patients with different treatment methods. (Figure 5-2B) Uterine artery blood flow parameters RI in patients with different treatment methods. (Figure 5-2C) Uterine artery blood flow parameters PSV ratio in patients with different treatment methods. (Figure 5-2D) Uterine artery blood flow parameters PI in normal pregnant women at different gestational weeks. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"5.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/9e7128796cbaaea3d44335d3.png\"},{\"id\":94136874,\"identity\":\"1566de0f-9b4d-464f-8312-3ea298bf763f\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:21:08\",\"extension\":\"png\",\"order_by\":6,\"title\":\"Figure 6\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":52602,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eRelationship between different pregnancy outcomes and uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(A) Uterine artery blood flow parameters S/D ratio in different pregnancy outcomes of RPL patients before treatment. (B) Uterine artery blood flow parameters S/D ratio in different pregnancy outcomes of RPL patients after treatment. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"6.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/3432cb67aecf833110f523d2.png\"},{\"id\":94138518,\"identity\":\"06041233-54a5-49ff-aa1c-848ff538615b\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:29:08\",\"extension\":\"png\",\"order_by\":7,\"title\":\"Figure 7\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":39367,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eThe pregnancy outcomes with different treatment options\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe abortion rate of RPL patients with different treatment including low-dose aspirin monotherapy, low-dose aspirin combined with nifedipine, low-dose aspirin combined with sildenafil citrate,low-dose aspirin + nifedipine + sildenafil citrate. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"7.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/1614bb4652e1df6b76285401.png\"},{\"id\":94140620,\"identity\":\"b74b1e34-06b1-4392-8656-70f0e15df2e4\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:45:08\",\"extension\":\"png\",\"order_by\":8,\"title\":\"Figure 8\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":120539,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003e\\u003cstrong\\u003eReceiver operating characteristic (ROC)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e(A)The predictive accuracies of uterine artery blood flow parameters S/D for pregnancy outcomes of RPL patients. (B)The predictive accuracies of uterine artery blood flow parameters RI for pregnancy outcomes of RPL patients. (C)The predictive accuracies of uterine artery blood flow parameters PSV for pregnancy outcomes of RPL patients. (D)The predictive accuracies of uterine artery blood flow parameters PI for pregnancy outcomes of RPL patients. SD. *p \\u0026lt; 0.05, **p \\u0026lt; 0.01, ***p \\u0026lt; 0.001.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"8.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/288c9901fd6168d0fdc10add.png\"},{\"id\":94823451,\"identity\":\"e7f00ca8-a1dd-4ada-8f35-4e90ebe78a1b\",\"added_by\":\"auto\",\"created_at\":\"2025-10-31 06:47:25\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1742202,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/3721bd16-5093-4514-9017-a0c1ed585199.pdf\"},{\"id\":94136866,\"identity\":\"820de977-9e93-4c70-a703-887a143e0118\",\"added_by\":\"auto\",\"created_at\":\"2025-10-22 19:21:08\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":13611,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Tab1.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-7686237/v1/c563879bfbb25b02128690c1.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"The Predictive Value and Clinical Treatment Guidance of Uterine Artery Blood Flow Parameters for Recurrent Pregnancy Loss\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003eRPL refers to the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation with the same partner\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e. The etiology of RPL is complex and varied, with identifiable causes including genetic factors from both partners, anatomical abnormalities, endocrine disorders, autoimmune abnormalities, and thrombophilic states. However, approximately 50% of cases have no clear cause, termed unexplained recurrent pregnancy loss (URPL). Currently, there is a lack of evidence-based medicine for the diagnosis and treatment of URPL. Recent studies suggest that uterine artery blood flow parameters, such as the S/D ratio, RI, PI and PSV, can reflect placental perfusion\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR3\\\" citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e]\\u003c/sup\\u003e. These parameters are closely associated with various pathological pregnancies\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR6\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e, including hypertensive disorders of pregnancy, fetal growth restriction\\u003csup\\u003e[\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e]\\u003c/sup\\u003e (FGR), placental insufficiency\\u003csup\\u003e[\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e]\\u003c/sup\\u003e, and RPL\\u003csup\\u003e[\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e. However, there is no established standard for normal uterine artery blood flow values during pregnancy. The correlation between the frequency of pregnancy loss, the etiology of spontaneous abortion, and uterine artery blood flow parameters is unclear. Furthermore, there is limited research on whether abnormalities in uterine artery blood flow parameters require treatment and the effective measures and timing of such treatments. This study utilizes transvaginal color Doppler ultrasound to continuously measure uterine artery blood flow parameters in both normal pregnant women and RPL patients. It aims to compare the relationship between the frequency and etiology of spontaneous abortion and uterine artery blood flow parameters. Additionally, the study explores the differences in uterine artery blood flow parameters before and after treatment, as well as among different pregnancy outcomes. The influence of various treatment methods on uterine artery blood flow parameters and pregnancy outcomes is analyzed, with the aim of early prediction of pathological pregnancy risks, timely intervention, and the implementation of effective treatment measures to improve pregnancy outcomes.\\u003c/p\\u003e\"},{\"header\":\"Materials and Methods\",\"content\":\"\\u003cp\\u003e\\u003cb\\u003eStudy Subjects\\u003c/b\\u003e: A retrospective analysis was conducted on data from RPL patients and women with normal pregnancies who visited Xinhua Hospital and the International Peace Maternity \\u0026amp; Child Health Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, between October 2017 and December 2024. The participants aged between 20 and 40 years met the criteria for RPL diagnosis. The inclusion criteria for RPL included\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e]\\u003c/sup\\u003e: ① a history of two or more spontaneous miscarriages; ② ultrasound confirmation of intrauterine pregnancy with a singleton gestation. Exclusion criteria were: ① concurrent conditions that could cause uterine abnormalities, such as adenomyosis, intrauterine adhesions, inflammation, or tumors; ② hypertension, diabetes, arrhythmias, or other diseases affecting hemodynamics; ③ chromosomal abnormalities in either partner. This study was approved by the Ethics Committee of the International Peace Maternity \\u0026amp; Child Health Hospital of Shanghai Jiao Tong University, and informed consent was obtained from all participants. The criteria for embryonic arrest were\\u003csup\\u003e[\\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]\\u003c/sup\\u003e: ① crown-rump length (CRL)\\u0026thinsp;\\u0026ge;\\u0026thinsp;7 mm without a heartbeat; ② mean gestational sac diameter\\u0026thinsp;\\u0026ge;\\u0026thinsp;25 mm with no visible embryo; ③ ultrasound showing a gestational sac without a yolk sac, with no cardiac activity detected upon re-examination after \\u0026ge;\\u0026thinsp;2 weeks; ④ ultrasound showing a gestational sac with a yolk sac, with no cardiac activity in the embryo after \\u0026ge;\\u0026thinsp;11 days. Women with normal pregnancies and RPL patients underwent transvaginal ultrasound to assess uterine artery hemodynamic parameters before and during pregnancy (every 2 weeks). RPL patients who did not undergo transvaginal ultrasound for uterine artery blood flow assessment during pregnancy were excluded.\\u003c/p\\u003e\\u003cp\\u003e\\u003cstrong\\u003eMethods\\u003c/strong\\u003e\\u003cp\\u003eA Philips HD-15 color Doppler ultrasound diagnostic instrument, produced by the American company Philips, was used, with a transvaginal ultrasound probe frequency of 4\\u0026thinsp;~\\u0026thinsp;8 MHz\\u003csup\\u003e[\\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e]\\u003c/sup\\u003e. ① The size, position, and morphology of the uterus and gestational sac were examined to observe the presence or absence of a yolk sac, embryo, and primitive heart tube pulsation. ② The four parameters of blood flow of the left and right uterine arteries were monitored separately. Typically, six consecutive, stable cardiac cycle spectra were taken. The system's automatic envelope and calculation function was utilized to measure and record the blood flow RI, PI, PSV and S/D for both the left and right uterine arteries. The average values were taken for analysis. The relationship between early pregnancy uterine artery blood flow resistance parameters and different pregnancy outcomes in patients with RPL was analyzed. ③ All study subjects were measured three times by a professional.\\u003c/p\\u003e\\u003c/p\\u003e\\u003cp\\u003e\\u003cb\\u003eGrouping\\u003c/b\\u003e\\u003c/p\\u003e\\u003cp\\u003e1) Grouped by the number of spontaneous miscarriages: 2 times, 3 times, 4 times, 5 times, \\u0026ge;\\u0026thinsp;6 times;\\u003c/p\\u003e\\u003cp\\u003e2) Grouped by treatment regimen: aspirin alone, in combination with nifedipine and/or sildenafil;\\u003c/p\\u003e\\u003cp\\u003e3)Stratified by pregnancy outcome :Full-term birth、Preterm birth、Miscarriage;\\u003c/p\\u003e\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\u003ch2\\u003eTreatment Regimen\\u003c/h2\\u003e\\u003cp\\u003e 1)Aspirin (50\\u0026ndash;100 mg/day, oral);\\u003c/p\\u003e\\u003cp\\u003e2) Aspirin (50\\u0026ndash;100 mg/day, oral)\\u0026thinsp;+\\u0026thinsp;Nifedipine (10\\u0026ndash;30 mg/day, oral);\\u003c/p\\u003e\\u003cp\\u003e3) Aspirin (50\\u0026ndash;100 mg/day, oral)\\u0026thinsp;+\\u0026thinsp;Nifedipine (10\\u0026ndash;30 mg/day, oral)\\u0026thinsp;+\\u0026thinsp;Sildenafil (25\\u0026ndash;50 mg/day, vaginal administration).\\u003c/p\\u003e\\u003c/div\\u003e\\n\\u003ch3\\u003eStatistical Analysis:\\u003c/h3\\u003e\\n\\u003cp\\u003eData analysis and plotting were performed using GraphPad Prism 5.0. Measurement data conforming to a normal distribution are expressed as mean\\u0026thinsp;\\u0026plusmn;\\u0026thinsp;standard deviation (\\u0026plusmn;\\u0026thinsp;s), and comparisons between groups were conducted using the t-test. Categorical data are expressed as percentages (%), with comparisons between groups carried out using the χ\\u0026sup2; test. All P-values were two-tailed, and a P-value of less than 0.05 was considered statistically significant.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eBaseline Characteristics\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study included a total of 652 patients with RPL and 432 women with normal pregnancies. The age of the RPL group was higher compared to the normal group, while there was no statistically significant difference in body mass index between the two groups (Table 1).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRelationship between RPL frequency and\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003ethe uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eTo observe the relationship between different abortion frequencies and uterine artery blood flow parameters, we measured the relevant parameters of uterine artery blood flow in RPL patients with different abortion frequencies. The results showed that with the increase in spontaneous abortion frequency, the S/D ratio of uterine artery blood flow gradually increased (p\\u0026lt;0.001). The PI value also showed the same trend, increasing with the number of abortions. However, there was no significant correlation between PSV and RI and the frequency of abortions (p\\u0026gt;0.05)（Fig1）.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRelationship between the etiology of RPL and the uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe etiology of RPL is very complex, including genetic factors, anatomical factors, infectious factors, immune factors, and pre-thrombotic states. We grouped patients based on different etiologies of RPL to analyze the relationship between different causes and uterine artery blood flow parameters. The results showed that compared with the normal control group, patients with APS, SS, UCTD, AS, RA, and SLE had significantly higher uterine artery S/D ratios, PI, and RI, with statistically significant differences. Although patients with RPL caused by endocrine factors also showed increasing trends in S/D ratios, PI, and RI, the magnitude of increase was much lower than that seen in immunological factors-related RPL. Patients with URPL also had significantly higher uterine artery S/D ratios, PI, and RI (p\\u0026lt;0.05). There were no significant differences in uterine artery blood flow parameters between patients with RPL caused by chromosomal abnormalities and the normal group (p\\u0026gt;0.05). PSV values showed no statistical differences among patients with RPL caused by different etiologies (p\\u0026gt;0.05)（Fig2）.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eChanges in uterine artery blood flow parameters in RPL patients with different abortion histories before and after treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA literature review reveals that abnormal uterine artery blood flow parameters may lead to adverse pregnancy outcomes such as miscarriage and FGR. We retrospectively observed changes in uterine artery-related parameters before and after treatment in 652 patients with RPL (with different numbers of miscarriages). The results showed significant changes in uterine artery blood flow S/D ratio, RI, PI, and PSV after treatment. Compared with pre-treatment values, the S/D ratio, RI, and PI decreased significantly after treatment (p\\u0026lt;0.05). In contrast, PSV showed an increasing trend after treatment, with a statistically significant difference compared with pre-treatment values (p\\u0026lt;0.05) （Fig3）.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eChanges in uterine artery\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003eblood flow parameters\\u003c/strong\\u003e\\u003cstrong\\u003e\\u0026nbsp;before and after treatment in RPL patients with different etiologies\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe retrospectively observed the changes in uterine artery-related parameters before and after treatment in 652 patients with RPL (different etiologies). The results showed significant changes in S/D ratio, RI, PI, and PSV after treatment. Compared with pre-treatment, the S/D ratio, RI, and PI values decreased significantly after treatment (p\\u0026lt;0.05). However, there were no statistical differences in S/D ratio, RI, and PI values of uterine artery blood flow between patients with different etiologies before and after treatment (p\\u0026gt;0.05). PSV showed an increasing trend after treatment, with a statistically significant difference compared with pre-treatment (p\\u0026lt;0.05) （Fig4）.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEffects of different treatment methods on uterine artery\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003eblood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe retrospectively observed the treatment outcomes of 652 patients with RPL. For the treatment of elevated uterine artery blood flow, in addition to dietary and lifestyle adjustments, three main medications were used: aspirin, nifedipine, and sildenafil citrate. During medication, dynamic monitoring of uterine artery blood flow parameters was conducted, and medication was adjusted based on parameter changes. According to actual medication usage, patients were divided into four groups: Group 1: low-dose aspirin monotherapy; Group 2: low-dose aspirin combined with nifedipine; Group 3: low-dose aspirin combined with sildenafil citrate; Group 4: low-dose aspirin + nifedipine + sildenafil citrate. The dosage of aspirin was 50-100mg/day, nifedipine 10-30mg/day, and sildenafil citrate 25-50mg/day (vaginal use). The medication indication mainly referred to the S/D ratio. We conducted a large-scale study in the early stage and found significant changes in S/D ratio at different gestational weeks in normal pregnant women. With increasing gestational weeks, uterine artery blood flow S/D showed a decreasing trend, approximately 0.2-0.3 per week. Therefore, we established the reference range for bilateral uterine artery blood flow S/D ratio (sum of left and right sides): pre-pregnancy S/D \\u0026lt;12, before 10 weeks S/D \\u0026lt;10.5, before 12 weeks S/D \\u0026lt;8.5, 16 weeks S/D \\u0026lt;7.5, 20 weeks S/D \\u0026lt;6.5, 24 weeks S/D \\u0026lt;5.5, 28 weeks S/D \\u0026lt;5.0, 30 weeks S/D \\u0026lt;4.5, see Fig 5-1. Uterine artery blood flow parameters were measured every 2 weeks throughout pregnancy, and medication dosage and types were adjusted based on S/D ratio. The results showed that the decrease in uterine artery blood flow parameters S/D ratio, PI, and RI was significantly higher in combination therapy groups compared to low-dose aspirin monotherapy group. Among them, the effect of aspirin monotherapy group was lower than aspirin combined with nifedipine or aspirin combined with sildenafil citrate groups (p\\u0026lt;0.05). When low-dose aspirin + nifedipine + sildenafil citrate were used in combination, the decrease in S/D ratio, PI, and RI was the largest, showing statistical significance compared to other groups (p\\u0026lt;0.05). There was no statistical difference in PSV between different treatment methods (p\\u0026gt;0.05) (Fig5-2).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRelationship between different pregnancy outcomes and uterine artery blood flow parameters\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe retrospectively observed the uterine artery blood flow S/D ratio before and after treatment in 652 RPL patients with different pregnancy outcomes. The pregnancy outcomes were divided into three categories: full-term delivery, preterm delivery, and spontaneous abortion. These outcomes were scored as follows: 1 point for full-term delivery, 2 points for preterm delivery, and 3 points for abortion. A higher score indicated a less ideal pregnancy outcome. The results showed that the S/D ratio decreased in all three groups after treatment. Among them, the spontaneous abortion group showed the smallest decrease in S/D ratio after treatment (p\\u0026lt;0.05). The preterm delivery group also showed a decreasing trend in S/D ratio before and after treatment, but the decrease was significantly less than that in the normal pregnancy group. The full-term delivery group showed the most significant change in S/D ratio before and after treatment (p\\u0026lt;0.05), suggesting that a high S/D ratio may predict adverse pregnancy outcomes (Fig 6).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eThe impact of different treatment methods on pregnancy outcomes\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe further observed the relationship between different treatment methods and pregnancy outcomes in RPL patients, and found that the combination of low-dose aspirin, nifedipine, and sildenafil citrate had the lowest pregnancy loss rate in RPL patients, while the low-dose aspirin group had the highest pregnancy loss rate, (p\\u0026lt;0.05) （Fig7）.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eReceiver operating characteristic (ROC)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePrevious studies have found that as the number of natural miscarriages increases, the S/D, PI, and RI values of miscarriage patients gradually increase. Further evaluation of the efficacy of uterine artery parameters in predicting pregnancy outcomes using ROC curves and providing clinical optimal thresholds. The predictive accuracies of S/D, PI, RI, and PSV for pregnancy outcomes during early pregnancy were 0.8385, 0.8130, 0.7796, and 0.6629, respectively, with clinically optimal thresholds of 22.69, 5.83, 1.935, and 204, respectively. It is believed that S/D, PI/, and RI have a good predictive effect on adverse pregnancy outcomes (Fig 8).\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eIn recent years, research on the pathogenesis of RPL related to abnormal uterine artery blood flow has made significant progress. Studies have shown that increased resistance in the uterine artery blood flow is primarily due to the ineffective invasion of trophoblastic cells into the uterine spiral arteries\\u003csup\\u003e[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e]\\u003c/sup\\u003e. This impedes vascular remodeling, resulting in narrowed vascular lumens, obstructed placental blood circulation, and potentially abnormal coagulation function\\u003csup\\u003e[\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e]\\u003c/sup\\u003e. These factors further increase the risk of placental thrombosis, affect fetal blood supply, and may ultimately lead to adverse pregnancy outcomes.\\u003c/p\\u003e\\u003cp\\u003eUterine artery blood flow parameters mainly include the PI, RI, and S/D ratio. These parameters assess uterine artery blood flow resistance and vascular elasticity through Doppler ultrasound technology, reflecting the condition of uterine-placental blood circulation\\u003csup\\u003e[\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]\\u003c/sup\\u003e. However, there is still a lack of unified normal reference ranges for uterine artery blood flow parameters in clinical practice. Our study included 3000 normal pregnant women and measured the S/D ratio of uterine artery blood flow at different gestational stages, establishing reference ranges for the S/D ratio at various gestational weeks (6\\u0026ndash;32 weeks). The results showed that uterine artery blood flow parameters demonstrate specific trends during normal pregnancy. The S/D ratio of uterine arteries high in early pregnancy and gradually decreases with increasing gestational weeks. This change reflects the physiological remodeling process of uterine vessels shifting from a high-resistance state to a low-resistance state during pregnancy, thereby better meeting the blood flow and oxygen supply demands for fetal growth and development. In early pregnancy, uterine artery blood flow resistance is high due to insufficient erosion of uterine spiral arterioles by trophoblasts\\u003csup\\u003e[\\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR20\\\" class=\\\"CitationRef\\\"\\u003e20\\u003c/span\\u003e]\\u003c/sup\\u003e. As pregnancy progresses, vascular resistance gradually decreases until it disappears in the third trimester. This physiological change is crucial for ensuring normal placental blood circulation and fetal development. Therefore, understanding the normal reference range of uterine artery blood flow parameters is helpful for predicting and diagnosing potential adverse pregnancy outcomes.\\u003c/p\\u003e\\u003cp\\u003eThe parameters of uterine artery blood flow are closely associated with RPL\\u003csup\\u003e[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR22 CR23\\\" citationid=\\\"CR21\\\" class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR24\\\" class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e]\\u003c/sup\\u003e. The results of this study demonstrate a significant upward trend in the uterine artery S/D ratio and PI values with an increase in the number of miscarriages, which is consistent with several studies conducted both domestically and internationally\\u003csup\\u003e[\\u003cspan citationid=\\\"CR23\\\" class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR25\\\" class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR26\\\" class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e]\\u003c/sup\\u003e. Zhang et al\\u003csup\\u003e[\\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e]\\u003c/sup\\u003e. found in their study of RPL patients that those with three or more miscarriages had significantly higher uterine artery RI and PI values compared to those with two miscarriages. Similarly, a prospective cohort study by Metwally et al. also confirmed that a high-resistance blood flow pattern is closely related to an increased risk of miscarriage\\u003csup\\u003e[\\u003cspan citationid=\\\"CR28\\\" class=\\\"CitationRef\\\"\\u003e28\\u003c/span\\u003e]\\u003c/sup\\u003e. From a pathophysiological perspective, increased uterine artery resistance may lead to inadequate placental perfusion, resulting in intervillous space thrombosis and trophoblast invasion impairment, which could be one of the important mechanisms of RPL. It is noteworthy that this study found no significant correlation between PSV and the number of miscarriages, which differs from some studies. Kadir Arslan et al. reported that reduced PSV is associated with adverse pregnancy outcomes\\u003csup\\u003e[\\u003cspan citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e]\\u003c/sup\\u003e, although their sample size was relatively small. This discrepancy may arise from the heterogeneity of study populations or differences in measurement methods, highlighting the need for standardized measurement protocols in future research.\\u003c/p\\u003e\\u003cp\\u003eThe parameters of uterine artery blood flow are influenced by various factors\\u003csup\\u003e[\\u003cspan citationid=\\\"CR30\\\" class=\\\"CitationRef\\\"\\u003e30\\u003c/span\\u003e]\\u003c/sup\\u003e. Our study found significant hemodynamic differences in patients with RPL due to different etiologies. In the group with autoimmune diseases (such as APS, SLE, and other rheumatological immune disorders), the S/D, PI, and RI values were significantly increased, aligning with international consensus. Patients with APS commonly experience endothelial damage and a predisposition to thrombosis, leading to impaired remodeling of the uterine spiral arteries\\u003csup\\u003e[\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e]\\u003c/sup\\u003e. Recent research indicates that increased resistance of uterine artery blood flow in APS patients is positively correlated with the titer of anti-β2 glycoprotein I antibodies\\u003csup\\u003e[\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e]\\u003c/sup\\u003e. In the group with chromosomal factors, the blood flow parameters showed no significant difference compared to the normal pregnancy group, supporting the viewpoint that chromosomal abnormalities primarily result in miscarriage through embryonic aneuploidy rather than maternal blood flow factors. Patients with URPL also exhibited significant abnormalities in blood flow, suggesting the presence of yet unidentified vascular pathological mechanisms. This finding aligns with the \\\"occult placental insufficiency\\\" hypothesis.\\u003c/p\\u003e\\u003cp\\u003eResearch into uterine artery blood-flow abnormalities has increasingly focused on individualized treatment strategies\\u003csup\\u003e[\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR34\\\" citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e]\\u003c/sup\\u003e. In this first systematic comparison of pharmacologic regimens targeting uterine artery hemodynamics, triple therapy with aspirin, nifedipine, and sildenafil demonstrated the greatest benefit, reducing the S/D ratio by 42.3%\\u0026mdash;a significantly larger decrease than with any single agent. This result builds on prior findings that aspirin improves blood flow by inhibiting thromboxane A₂\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR37\\\" citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e]\\u003c/sup\\u003e, nifedipine, as a calcium-channel blocker, lowers vascular resistance\\u003csup\\u003e[\\u003cspan additionalcitationids=\\\"CR40\\\" citationid=\\\"CR39\\\" class=\\\"CitationRef\\\"\\u003e39\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR41\\\" class=\\\"CitationRef\\\"\\u003e41\\u003c/span\\u003e]\\u003c/sup\\u003e, and sildenafil enhances the NO-cGMP pathway via PDE5 inhibition\\u003csup\\u003e[\\u003cspan citationid=\\\"CR42\\\" class=\\\"CitationRef\\\"\\u003e42\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR43\\\" class=\\\"CitationRef\\\"\\u003e43\\u003c/span\\u003e]\\u003c/sup\\u003e. Their synergistic, multi-target action likely promotes spiral-artery remodeling. Notably, PSV increased significantly after treatment, indicating improved vasodilatory function, who reported a 28% PSV increase with sildenafil monotherapy. In our cohort, triple therapy not only produced superior hemodynamic improvements but also yielded better pregnancy outcomes, with a markedly reduced spontaneous miscarriage rate compared to the other two groups. All three RPL cohorts received low-molecular-weight heparin concurrently, but only for standard indications such as autoimmune disorders or thrombophilia-not specifically to correct uterine blood flow.\\u003c/p\\u003e\\u003cp\\u003eThe detection of uterine artery blood flow parameters holds significant diagnostic and predictive value in clinical applications. ROC analysis indicates that the S/D ratio (AUC\\u0026thinsp;=\\u0026thinsp;0.8385) and PI value (AUC\\u0026thinsp;=\\u0026thinsp;0.8130) have a good predictive value for adverse pregnancy outcomes, with optimal cut-off values of 22.69 and 5.83, respectively. These parameters outperform traditional clinical parameters: their predictive efficacy is close to but slightly lower than the uterine artery pulsatility index\\u003csup\\u003e[\\u003cspan citationid=\\\"CR44\\\" class=\\\"CitationRef\\\"\\u003e44\\u003c/span\\u003e]\\u003c/sup\\u003e, and significantly superior to serum PAPP-A and β-hCG\\u003csup\\u003e[\\u003cspan citationid=\\\"CR45\\\" class=\\\"CitationRef\\\"\\u003e45\\u003c/span\\u003e]\\u003c/sup\\u003e. In accordance with the latest European guidelines\\u003csup\\u003e[\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e]\\u003c/sup\\u003e, we recommend incorporating uterine artery blood flow monitoring into the routine assessment protocol for patients with RPL, particularly for those with immunological factors or unexplained RPL. Formulating individualized treatment plans for RPL patients with different etiologies can effectively improve uterine artery blood flow and enhance pregnancy success rates.\\u003c/p\\u003e\\u003cp\\u003eIn conclusion, addressing uterine artery blood-flow abnormalities with tailored pharmacotherapy is crucial for improving pregnancy outcomes. Doppler indices S/D ratio and PI correlate positively with miscarriage frequency-particularly in immune-mediated RPL-and can serve as dynamic markers to guide treatment. Combined aspirin, nifedipine, and sildenafil therapy significantly lowers vascular resistance through antiplatelet and vasodilatory mechanisms, optimizing placental perfusion. The application of Doppler ultrasound and individualized regimens offers new directions for RPL diagnosis and management. Study limitations include its retrospective design, lack of molecular biomarkers (e.g., VEGF), and limited long-term follow-up. Future research should involve multicenter prospective cohorts, explore the molecular underpinnings of arterial remodeling (such as gene expression related to vascular remodeling), and refine individualized treatment protocols to maximize live‐birth rates and ensure maternal\\u0026ndash;fetal health.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate:\\u003c/strong\\u003e The study received approval from the Human Research Ethics Committee of the Xinhua Hospital（Number：XHEC-NSFC-2025-034）.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication:\\u003c/strong\\u003e All authors agree to publish in the journal.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials:\\u003c/strong\\u003e The authors confirm that the supporting data for the study's findings are contained within the article.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interest\\u003c/strong\\u003es\\u003cstrong\\u003e:\\u0026nbsp;\\u003c/strong\\u003eThe authors declare no conflicts of interest with the content of this article.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding:\\u003c/strong\\u003e This research received financial assistance from the National Natural Science Foundation of China (Grant Nos. 81671481 and 81871179), as well as from the Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Grant No. ynhglg 202413 and ynhg202211).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor contribution statement:\\u003c/strong\\u003e Methodology, Miao Xiong; Software, Tian Qiu; Validation, Tian Qiu; Formal Analysis, Miao Xiong and Ziqiu He; Investigation, Ziqiu He; Resources, Liang Xu; Data Curation, Miao Xiong and Ziqiu He; Writing – Original Draft Preparation, Miao Xiong; Writing – Review \\u0026amp; Editing, Liang Xu, Tian Qiu and Miao Xiong; Visualization, Weimei Li; Supervision, Ziqiu He; Project Administration, Miao Xiong and Ziqiu He; Funding Acquisition, Liang Xu and Miao Xiong.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements:\\u003c/strong\\u003e The authors express their gratitude to the Department of Ultrasound as well as the Department of Obstetrics and Gynecology at Xinhua Hospital for their involvement in this research.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors' information (optional):\\u003c/strong\\u003e The information of authors are available within the article.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eRpl, T.E.G.G.O., et al., ESHRE guideline: recurrent pregnancy loss. 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Spitzer, Anticardiolipin antibodies and recurrent early pregnancy loss: a century of equivocal evidence. Human Reproduction Update, 2012(5): p. 474-484.\\u003c/li\\u003e\\n\\u003cli\\u003eAlijotas-Reig, J., et al., Pathogenesis, Diagnosis and Management of Obstetric Antiphospholipid Syndrome: A Comprehensive Review. Journal of clinical medicine, 2022. \\u003cstrong\\u003e11 3\\u003c/strong\\u003e.\\u003c/li\\u003e\\n\\u003cli\\u003e!!! INVALID CITATION !!! [23-26].\\u003c/li\\u003e\\n\\u003cli\\u003eMesdaghinia, E., et al., The effect of vitamin E and aspirin on the uterine artery blood flow in women with recurrent abortion: A single-blind randomized controlled trial. International Journal of Reproductive Biomedicine, 2017. \\u003cstrong\\u003e15\\u003c/strong\\u003e(10): p. 635-640.\\u003c/li\\u003e\\n\\u003cli\\u003eAbou-Saif, A.H., et al., The Effect of Low Molecular Weight Heparin in Recurrent Pregnancy Loss: Changes in Radial Uterine Artery Blood Flow and Peripheral Blood NK Cell Fraction. The Egyptian journal of immunology, 2018. \\u003cstrong\\u003e25\\u003c/strong\\u003e(2): p. 75-85.\\u003c/li\\u003e\\n\\u003cli\\u003e!!! INVALID CITATION !!! [26-28].\\u003c/li\\u003e\\n\\u003cli\\u003eKang, X., et al., Effect of Low-Dose Aspirin on Midluteal Phase Uterine Artery Blood Flow in Patients With Recurrent Pregnancy Loss. J Ultrasound Med, 2016. \\u003cstrong\\u003e35\\u003c/strong\\u003e(12): p. 2583-2587.\\u003c/li\\u003e\\n\\u003cli\\u003eLazzarin, N., et al., Low-dose aspirin and omega-3 fatty acids improve uterine artery blood flow velocity in women with recurrent miscarriage due to impaired uterine perfusion. Fertility \\u0026amp; Sterility, 2009. \\u003cstrong\\u003e92\\u003c/strong\\u003e(1): p. 296-300.\\u003c/li\\u003e\\n\\u003cli\\u003eJawaid, M. and L. Tanveer, Letter to the editor regarding \\u0026quot;The preeclampsia and hypertension target treatment study: a multicenter prospective study to evaluate the effectiveness of the antihypertensive therapy based on maternal hemodynamic findings\\u0026quot;. American Journal of Obstetrics \\u0026amp; Gynecology MFM, 2025. \\u003cstrong\\u003e7\\u003c/strong\\u003e(3).\\u003c/li\\u003e\\n\\u003cli\\u003eErolu, H., et al., Effect of Nifedipine Used in the Treatment of the Threat of Preterm Labor on Total Uterine Artery Blood Volume Flow Rate. Zeitschrift f\\u0026uuml;r Geburtshilfe und Neonatologie.\\u003c/li\\u003e\\n\\u003cli\\u003eAl-Thuwaynee, S., Assessing the efficacy and safety of Sildenafil vs. Nifedipine in improving endometrial blood flow and thickness in women with recurrent first-trimester miscarriage. Journal of Medicine \\u0026amp; Life, 2023. \\u003cstrong\\u003e16\\u003c/strong\\u003e(6).\\u003c/li\\u003e\\n\\u003cli\\u003e!!! INVALID CITATION !!! [31-34].\\u003c/li\\u003e\\n\\u003cli\\u003eJain, N.K., et al., Sildenafil-induced peripheral analgesia and activation of the nitric oxide\\u0026ndash;cyclic GMP pathway. Brain Research, 2001. \\u003cstrong\\u003e909\\u003c/strong\\u003e(1): p. 170-178.\\u003c/li\\u003e\\n\\u003cli\\u003eChen, J.Y., et al., The value of placental vascularization indices for predicting preeclampsia and fetal growth restriction in different stages of gestation: A prospective and longitudinal study. Placenta, 2022. \\u003cstrong\\u003e122\\u003c/strong\\u003e: p. 1-8.\\u003c/li\\u003e\\n\\u003cli\\u003eCui, J., et al., Study on the Relationship and Predictive Value of First-Trimester Pregnancy-Associated Plasma Protein-A, Maternal Factors, and Biochemical Parameters in Gestational Diabetes Mellitus: A Large Case-Control Study in Southern China Mothers. Diabetes, Metabolic Syndrome \\u0026amp; Obesity: Targets \\u0026amp; Therapy, 2023. \\u003cstrong\\u003e16\\u003c/strong\\u003e.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"},{\"header\":\"Table\",\"content\":\"\\u003cp\\u003eTable 1 is available in the Supplementary Files section\\u003c/p\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"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\":\"info@researchsquare.com\",\"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\":\"recurrent pregnancy loss, uterine artery blood flow, pregnancy outcome, aspirin, nifedipine, sildenafil citrate\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-7686237/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-7686237/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eObjective\\u003c/h2\\u003e\\u003cp\\u003eTo investigate the relationship between uterine artery blood flow parameters (S/D, RI, PI, PSV) and the number of miscarriages, etiology, treatment methods, and pregnancy outcomes in patients with recurrent pregnancy loss (RPL).\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e\\u003cp\\u003eA retrospective analysis was conducted on data from patients with RPL and women with normal pregnancy who visited Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine and the International Peace Maternity and Child Health Hospital between October 2017 and December 2024. The study observed various parameters of uterine artery blood flow, comparing differences in the number of miscarriages, causes, treatment methods, and pregnancy outcomes. Receiver Operating Characteristic (ROC) curves were used to evaluate the predictive value of blood flow parameters on pregnancy outcomes.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e\\u003cp\\u003eThe study included 652 patients with RPL and 432 pregnant women with normal pregnancy. 1) With increasing gestational age, the uterine artery systolic/end-diastolic velocity (S/D), pulsatility index (PI), and blood flow resistance index (RI) showed a downward trend in patients with normal pregnancy. 2) As the number of spontaneous miscarriages increased, the uterine artery blood flow S/D ratio and PI value gradually increased, while the Peak systolic velocity (PSV) and RI values showed no significant correlation with the number of miscarriages. 3) In RPL patients caused by immunological factors (APS, SLE, etc.), the uterine artery S/D ratio, PI, and RI values were significantly elevated. In contrast, in RPL patients caused by endocrine factors, although the S/D ratio, PI, and RI values also tended to increase, the magnitude of increase was much less compared to RPL caused by immunological factors. In patients with unexplained RPL (URPL), the uterine artery S/D ratio, PI, and RI values were also significantly elevated. In RPL patients due to chromosomal factors, the uterine artery blood flow parameters showed no significant difference compared to the normal group. 4) After treatment, the S/D, RI, and PI values significantly decreased (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), and PSV increased (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), suggesting a significant negative correlation between pre-treatment uterine artery S/D ratio, PI value, and pregnancy outcomes (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). 5) Combined medication (aspirin\\u0026thinsp;+\\u0026thinsp;nifedipine\\u0026thinsp;+\\u0026thinsp;sildenafil citrate) was most effective, significantly reducing S/D, PI, and RI (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05), and markedly improving pregnancy outcomes (p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05). 6) ROC analysis showed that S/D (AUC\\u0026thinsp;=\\u0026thinsp;0.8385) and PI (AUC\\u0026thinsp;=\\u0026thinsp;0.8130) had a high predictive value for adverse pregnancy outcomes, with optimal thresholds of 22.69 and 5.83, respectively.\\u003c/p\\u003e\\u003ch2\\u003eConclusion\\u003c/h2\\u003e\\u003cp\\u003eUterine artery blood flow parameters (particularly S/D and PI) can serve as predictive indicators of pregnancy outcomes in patients with RPL. Combined pharmacological treatment can significantly improve hemodynamics and reduce the risk of miscarriage.\\u003c/p\\u003e\",\"manuscriptTitle\":\"The Predictive Value and Clinical Treatment Guidance of Uterine Artery Blood Flow Parameters for Recurrent Pregnancy Loss\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-10-22 19:21:03\",\"doi\":\"10.21203/rs.3.rs-7686237/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"217a2982-89f0-4ace-90fa-a4dd47dc2375\",\"owner\":[],\"postedDate\":\"October 22nd, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-10-30T12:08:48+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-10-22 19:21:03\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-7686237\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-7686237\",\"identity\":\"rs-7686237\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}