Changes in Day 4 and day 0 Neutrophil-lymphocytes ratio in predicting single-dose methotrexate treatment failure for ectopic pregnancies

Changes in Day 4 and day 0 Neutrophil-lymphocytes ratio in predicting single-dose methotrexate treatment failure for ectopic pregnancies | 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 Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Changes in Day 4 and day 0 Neutrophil-lymphocytes ratio in predicting single-dose methotrexate treatment failure for ectopic pregnancies Rukeyemu Abuduxukuer, Xiaoyue Chen, N Jingyi, Na Liu, Bailian Cai, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2383650/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 Purpose We aimed to evaluate changes in neutrophil/lymphocyte ratio between the day 4 and day 0 of ectopic pregnancy (EP) patients treated with single-dose methotrexate (MTX). And to further investigate whether the NLR change is an indicator for MTX treatment outcome. Methods Totally 406 patients underwent single-dose MTX therapy for EP at Shanghai First Maternity and Infant Hospital from 2013/01/10 to 2019/09/30 were studied. A multivariate model was structured to predict the treatment outcome. Results Finally, 281 patients were in the successful treatment group, and their NLR at day 4 dropped 25% when compared with day 0. The success rate was significantly declined when the NLR decreased less than 23% (74.8% vs 58.5%, p = 0.004). Multivariate regression analysis revealed that day 4/day 0 NLR reduced less than 23% (OR:2.09, 95%CI:[1.27–3.44]); hCG decreased no more than 15% (OR:3.17,95% CI: [1.62–6.34] and increased over 15% on day 4 (OR:5.47, 95% CI: [3.05–10.22]) were independent risk factors for single-dose MTX treatment failure. Our final predictive model had a sensitivity of 0.768 and specificity of 0.569 when we chose 3 as the cut-off value. The area under the receiver operating characteristic curve was 0.712. Patients with a predictive score of ≥ 3 are more likely to fail in a single-dose MTX therapy. Conclusion In this study, we concluded that NLR decreased less than 23% on day 4 compared with day 0, a plateau or increased serum hCG on day 4 and hCG value over1000 mIU/ml at day 0 were predictors of single-dose MTX treatment failure. Ectopic pregnancy Methotrexate Neutrophil-lymphocytes ratio Predictor serum hCG Figures Figure 1 Figure 2 Background Ectopic pregnancy (EP) accounts approximately 2% of all recognized pregnancies, and is the leading cause of maternal death in the first trimester [ 1 ]. Methotrexate (MTX), a folic acid antagonist, is the most widely used conservative treatment for those EP patients with stable hemodynamic. The system MTX therapy including the single-dose or multiple-dose protocol. The single-dose MTX protocol, developed by Stovall et al in 1991 is by far the most widely accepted regimen, because of its simplicity and safety [ 2 ]. The treatment success rate of single-dose MTX administration in asymptomatic EP is reported from 70 to 90% [ 3 – 6 ]. However, treatment failure is associated with ectopic mass rupture and even life-threatening shock. So that patients treated with this protocol are usually anxious during the 7 day course before assessing the treatment outcome. Identifying patients who are more likely to get a single-dose MTX treatment success or failure is essential but remains a problem in clinical practice. The most widely accepted protocol to monitor treatment outcome was firstly proposed by Stovall et al [ 2 ]. The test of serum hCG is performed on day 4 and day 7 after a single dose MTX shot. To those patients with hCG level declined more than 15% between day 4 and day 7, a weekly hCG is tested until it back to normal. If the hCG dropped less than 15% between day 4 and day 7, patients are recommended to repeat the MTX treatment. According to this standard, about 20% of patients underwent repeated MTX therapy [ 1 , 7 ]. About 60% patients will experience a surge in hCG on day 4 after a single-dose MXT treatment[ 8 ], while there are still nearly 2/3 among them get treatment success[ 3 , 8 – 10 ]. Whether an increased hCG on the fourth day of MTX therapy is a pharmacophysiological effect or indicator of treatment failure remains unclear. Other markers such as progesterone, size of the ectopic mass, the ectopic cardiac activity, and the free peritoneal cells have been studied to predict treatment success of ectopic pregnancy [ 11 ]. Unfortunately, none of them is acknowledged as reliable marker [ 12 ]. An ideal prognostic factor ought to be cheap and easy to access for patients as well as practical and precious for doctors. Recently, a systemic immune-inflammation index based on peripheral blood parameter, the neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognosticators for lymphoma treated with MTX[ 13 ]. It was also reported that EP patients received a single-dose MTX had significantly lower NLR levels on days 0, day 4, and day 7 compared to those required surgery [ 14 ]. However, whether NLR changes are associated with the outcome of single-dose MXT regimen in EP remains unknown. In this retrospective study, we investigated the possibility of using NLR changes as a treatment outcome predictor of single-dose MTX administration in EP. Methods Clinical data was collected retrospectively at the Department of Gynecology, Shanghai First Maternity and Infant Hospital affiliated to Tongji University School of Medicine from Jan. 1, 2013, to Sept 30, 2019. This research was approved by the ethic committee and permitted to omitted patients' personal informed consent. All methods were carried out in accordance with the Declaration of Helsinki. The need for Informed Consent was waived off by Ethical Committee as it is a retrospective study. The inclusion criteria were listed as follows: (1) clinically diagnosed ectopic pregnancy according to the American Congress of Obstetricians and Gynecologists guidelines; (2) treated with single-dose MTX therapy; (3) complete clinical data. EP diagnosis was based on the serum levels of hCG and transvaginal sonography. Ectopic pregnancy was diagnosed when transvaginal ultrasound indicated ectopic sac outside of the uterus, increasing hCG levels within 48h were < 66%, and/or the lack of products of conception after uterine evacuation[ 15 ].Ultrasound exam was performed by two experienced physicians in our hospital. Patients with non-tubular ectopic pregnancy or with initial serum hCG level > 5000 mIU/mL, or with fetal heart activity in the adnexa were in the surgery group. Patients with stable hemodynamic status, without contraindications to MTX and agree to take MTX treatment were treated with single dose MTX. A single dose MTX (50 mg/m 2 ) was given intramuscularly (IM) on day 0. Serum hCG and complete blood cell count were tested on the 4th and 7th day after treatment. If there is a 15% decline in hCG between day 4 and day 7, these women are considered treatment success and followed up with weekly hCG measurements until back to normal. If no reduction of 15% in hCG titer was observed during this period, an additional dose was injected on the 7th day. Patients were followed for 6 weeks, and the success or failure of treatment was assessed. MTX treatment failure was defined as the need for surgical intervention to those patients with clinical symptoms during treatment or hCG decrease less than 15% even after the second dosage MTX injection. The success of single‑dose treatment was defined a 5% reduction in serum hCG levels after 1 week and a serum hCG < 5 mIU/mL after 6 weeks. The student t test was used to compare continuous variables, while the χ 2 statistic was used to analyze categorical variables. We used a stratified proportional Cox risk model to analyze the association between the success rate of a single-dose MTX administration and the change in NLR levels between day 0 and day 4. Statistical analyses were performed using the SPSS v22.0 and R statistical package v.3.4.4 (R Project for Statistical Computing, www.r-project.org ). All tests were two sided, with a significance level set at p < 0.05. Results Patient characteristics A total of 6069 ectopic pregnancy patients were treated at our hospital during the study period. Among them 2012 were initially treated with surgery, 2992 patients received expectant management and 1065 received MTX treatment. 878 received a single-dose MTX regimen. We further excluded 400 with missing hCG or NLR values and anther 72 patients with initial serum hCG level > 5000 mIU/mL or non-tubular ectopic pregnancy. Finally, 406 patients met our criteria were studied. A flow chart of the patients’ selection is shown in Fig. 1 . There were no significant differences with respect to age (mean, 30.82 vs 30.95, P = 0.68), initial hCG level （mean, 651.26 vs 575.77, P = 0.21）and treatment success rate of single-dose MTX treatment（69.4% vs 73.0%, P = 0.24）between the included and excluded cohort. As was shown in Table 1 , the basic characteristics of patients are listed. Compared to day 0, the NLR on day 4 dropped by an average of 25% (range, -0.91 to 4.57). There was no statistical difference between the three groups in terms of patient’s age, gestational age, gravidity, parity, pelvic surgery history, and assisted reproductive technology (ART) application. The overall success rate of single-dose MTX treatment is 69.2% (281/406). The success rate was significantly reduced when the NLR on day 4 decreased less than 23% compared to day 0 (74.8% vs 58.5%, p = 0.004). There was no increased treatment success rate of MXT therapy when NLR on day 4 drop over 23%. Table 1 Baseline characteristics. Variable Overall 1st tertile ≤-0.49 2nd tertile (-0.49,-0.23] 3rd tertile ＞-0.23 p No 406 136 135 135 / Age, y, mean (SD) 30.83 (4.70) 30.56 (4.85) 31.14 (5.11) 30.78 (4.11) 0.59 BMI, mean (SD) 21.59 (3.10) 21.05 (2.77) 21.81 (2.94) 21.91 (3.50) 0.09 Gestational age, days, mean (SD) 48.83 (11.53) 47.10 (9.14) 50.11 (12.75) 49.30 (12.26) 0.08 Gravidity,mean (SD) 1.44 (1.47) 1.37 (1.61) 1.47 (1.44) 1.49 (1.34) 0.76 Parity,mean (SD) 0.35 (0.56) 0.30 (0.55) 0.32 (0.56) 0.44 (0.58) 0.10 Diameter of adnexal mass by TVUS, mm, mean (SD) 20.52 (7.41) 21.96 (7.97) 19.49 (7.02) 20.12 (7.03) 0.02 Prior ectopic pregnancy,n (%) 47 (11.58) 8 ( 5.88) 15 (11.11) 24 (17.78) 0.01 Prior pelvic surgery, n (%) 90 (22.17) 22 (16.18) 33 (24.44) 35 (25.93) 0.11 Using ART, n (%) 30 (7.38) 11 ( 8.09) 10 ( 7.41) 9 ( 6.67) 0.91 Day 0 hCG, mIU/mL, mean (SD) 645 (629) 611 (579) 632 (653) 691(656) 0.56 Day 4 hCG, mIU/mL, mean (SD) 787 (1012) 745 (960) 735 (1066) 882 (1007) 0.41 hCG change percentage, mean (SD) 0.20 (0.77) 0.16 (0.78) 0.10 (0.69) 0.33 (0.82) 0.04 Day 0 NLR, mean (SD) 3.32 (1.67) 4.48 (1.95) 2.90 (0.97) 2.58 (1.23) < 0.001 Day 4 NLR, mean (SD) 2.18 (1.65) 1.54 (0.45) 1.86 (0.64) 3.13 (2.49) < 0.001 NLR change percentage, mean (SD) -0.25 (0.57) -0.63 (0.10) -0.36 (0.07) 0.24 (0.75) < 0.001 MTX treatment success, n (%) 281 (69.21) 101 (74.26) 101 (74.81) 79 (58.52) 0.00 NLR:Change percentage of NLR and hCG = D4/D0-1, ART: assisted reproductive technologies Changes in NLR and hCG are associated with the treatment outcome of single-dose MTX in EP We found that insufficient NLR or hCG reduction on day 4, as well as high hCG on day 0 are all related to single-dose MTX therapy failure. Other factors including patient’s age, previous ectopic pregnancy, a history of pelvic surgery, diameter of the mass, and gestational age, were not related to the treatment success of single-dose MTX therapy. Multivariate regression analysis showed that NLR decreased more than 23% in day 4 compared to day 0 (OR: 2.09, 95% confidence interval (CI): [1.27–3.44]), unchanged (OR:3.17, 95% CI: [1.62–6.34]) or increased (OR: 5.47, 95% CI: [3.05–10.22]) hCG on day 4 compared to day 0 as well as hCG > 1000 on day 0 (OR:2.11, 95% CI: [1.23–3.61]) were associated with treatment failure of single-dose MTX (Table 2 ). Table 2 Multivariate analyses for NLR change and other factors predicting outcome of single-dose MTX administration. OR 95%CI P NLR change ≤-0.23 1.0 (Reference) ＞-0.23 2.09 1.27–3.44 0.00 hCG change drop (≤-0.15) 1.0 (Reference) plateau ((-0.15,0.15]) 3.17 1.62–6.34 0.00 increase (> 0.15) 5.47 3.05–10.22 < 0.001 Day 0 hCG ＜1000 1.0 (Reference) ≥1000 2.11 1.23–3.61 0.01 Day 0 NLR 1.13 0.97–1.31 0.11 Age 0.97 0.92–1.02 0.24 Prior ectopic pregnancy 1.18 0.55–2.50 0.66 Prior pelvic surgery 1.21 0.65–2.22 0.55 Diameter of adnexal mass 1.03 0.99–1.06 0.12 Gestational age 1.00 0.99–1.03 0.64 Predictive model development The change of NLR and hCG on day 4 compared to day 0, and hCG level on day 0 were all included in the final prediction model for single-dose MTX treatment outcomes. OR were calculated for each predictor variable and each variable was assigned a score. The sums of the scores correspond to the single-dose MTX treatment failure risk (Table 3 ). ROC analysis was utilized to establish the best cut-off value for the score. The highest sensitivity and specificity were 76.8% and 56.9% (corresponding to the score cut-off value at 3) (Table 4 ). When the cut-off set at 3, the positive predictive value (PPV) was 0.442 and negative predictive value (NPV) was 0.847. The area under the ROC was 0.712 as was shown in Figure. 2. We thus subdivided the patients into a low-risk treatment failure group (< 3) and a high-risk treatment failure group (≥ 3) according to the predictive scores, univariate regression analysis showed that the OR value of the high-risk treatment failure group is 4.38 (95% CI, [2.74–7.15]). Table 3 Final model for single-dose MTX administration. Variable Score assigned NLR change ≤-0.23 0 ＞-0.23 1 hCG change drop (≤-0.15) 0 plateau ((-0.15,0.15]) 2 increase (> 0.15) 3 Day 0 hCG ＜1000 0 ≥1000 1 Table 4 Estimated single-dose MTX administration according to the risk score . Score Sensitivity Specificity Positive predictive value Negative predictive value 1 0.928 0.306 0.373 0.905 2 0.872 0.413 0.398 0.879 3 0.768 0.569 0.442 0.847 4 0.392 0.854 0.544 0.760 5 0.048 0.975 0.462 0.697 Discussion Treatment failure occurs in 10–30% of EP patients primarily treated with single-dose MTX. It causes inconveniences and makes patients under risk of tubal pregnancy rupture as well [ 3 – 6 , 16 ]. The purpose of this study is to identify EP patients who may fail single-dose MTX treatment and require follow-up surgery and/or medical interventions. After reviewing the 406 EP patients previously received a single-dose of MTX in our hospital, we established a predictive model to evaluate the outcome of their treatment. Our model comped of the commonly used hCG levels and changes of NLR on days 4 compared to day 0. As far as we know, we are the first to identify the change of NLR between day 4 and day 0 besides hCG changes as statistically significant predictive factors for single-dose MTX treatment outcome. We found when the NLR on day 4 decreased more than 23% compared to day 0, the single dose MTX treatment success rate reached nearly to 75%, which was significantly higher than the 58.5% treatment success rate of patients with an NLR decreased less than 23%. The NLR is a potent indicator of systemic immune inflammation [ 17 ]. It was demonstrated to be an independent predictor of mortality in patients with cardiovascular diseases and outcomes in primary central nervous system lymphoma treated with high-dose methotrexate-based therapy[ 13 , 18 , 19 ]. There are few published studies on the relation between NLR changes and the efficacy of MTX treatment in EP patients. In a study of 161 EP patients received a single dose of MTX, it reported much lower NLR on day 0, day 4, and day 7 compared to patients who received surgery. However, the changes in NLR was not improved to be as effective in predict treatment success as a 15% decrease in hCG between days 4 and 7[ 14 ]. In our study, multivariate analyses showed that NLR decrease less than 23% on day 4 as an independent risk factor for treatment failure with the OR value of 2.09. To the best of our knowledge, it is the only study focused on early NLR change in single-dose MTX treatment, therefore, it is difficult to compare our findings to those of other studies. This alteration in NLR might due to the immuno-suppressive effect of MTX [ 13 ]. Several studies indicated NLR as a potential biomarker of MTX response in the treatment of autoimmune diseases, such as psoriasis and rheumatoid arthritis [ 20 , 21 ]. Using single-dose MTX without citrovorum rescue factor for EP was first implemented at the University of Tennessee in 1991[ 2 ]. Contrast to multi-dose MTX procedures, single-dose MTX has a lot of advantages such as more cost-effective, has fewer side effects, needs less extensive patient monitoring, and has higher patient acceptability [ 12 ]. The success rate of single-dose MTX was reported varied from 70 to 90%. The different study population, the non-uniform criteria for providing the medicine, and the various definition of treatment effectiveness can explain the variations[ 22 ]. The success rate in our study was 69.2%, which is consistent with other studies that used comparable single-dose procedures [ 3 – 6 , 16 ]. Since the MTX treatment of EP was proposed for the first time, a lot of scholars attempted to identify factors which would influence the treatment success rate. Nowadays, the serum hCG level prior to MTX treatment is the most well accepted indicator. But the thresholds of hCG described in literatures varies from 1000 to 5000 mIU/ml[ 3 , 9 , 16 , 23 – 25 ]. In a retrospective study conducted by L. Bonin et al, totally 400 EP patients received a single-dose MTX treatment. It reported that an initial hCG value of < 1000 mIU/ml was associated with a 90% treatment success rate [ 9 ]. And the hCG value 1000 mIU/ml was used as the criteria for treatment outcome by several other studies [ 26 – 28 ]. Surprisingly, in our study, 27.9% of the patients with initial serum hCG levels below 1000 mlU/ml and 43.8% of those who had serum hCG levels no less than 1000 mlU/ml failed in MTX therapy. The treatment success rate is lower in our study compared to other previous studies. We think it can be explained by the number of patients who received the second MTX injection. It is worth noting that in the study performed by Bonin et al, 20.5% of patients received the second dose of MTX while the corresponding number in our study is 5.2% (21/406). It is reported that a second MTX injection could increase the total success rate from 63.5–73.2% [ 9 ]. The single-dose MTX protocol was supposed to reduce the hospital visits. But to those hCG level decrease less than 15% in the given week and need a repeated MTX treatment, the follow up procedure is time consuming according to Stovall’s protocol. In fact, approximately 20% of patients will require a repeated MTX treatment in practice [ 7 , 29 , 30 ]. The two-dose MTX protocol is administer a second MTX dosage on day 4 in addition to the single-dose MTX therapy. It supposed to combine the greater treatment success from an extra MTX doses, and the convenience visit schedule of the single-dose regimen. A well performed meta-analysis compared the “single-dose” and “two-doses” MTX protocols indicated that the “two-doses” are superior to “single-dose” MTX with higher treatment success rate (OR:1.84, 95%CI: [1.13-3.00]) and 7.9 days shorter to reach treatment success (95%CI: [-12.2-3.5])[ 22 ]. The assessment on days 0 and day 4 in our model is of clinical value, because it can provide earlier prognostic information, which make it possible to reduced follow up visit for individuals who are likely to have favorable outcomes and to give an earlier second injection to those who would fail in single dose MTX therapy. We aim to construct a predictive model for single-dose MTX, which is clinical friendly as well as ahead of time (get the treatment outcome on day 4 instead of day 7 after initial treatment). In our study, we concluded that treatment success rate was statically higher in those patients experienced significant reductions in NLR and hCG on day 4, and those patients with hCG < 1000 mIU/ml on day 0. When the three factors (NLR and hCG change between day 4 and day 0, hCG value on day 0) are independently used as predictive value, the AUC are 0.583, 0.671, 0.555, respectively. When all the three parameters were put into the model and with a combined score cut-off at 3, the AUC was 0.712. The PPV is 0.422 and the NPV is 0.847. In this study, we proposed that patients with a score ≥ 3 in our model are 4 times more likely to fail a single-dose MTX therapy than those with a score of ＜3 (OR:4.38,95%CI: [2.74, 7.15]). We believe our model has referential value on clinical decision-making to those EP patients underwent MTX therapy. We can identify those patients who would fail in the single dose MTX therapy on day 4 instead of day with this scoring system. Thus, make it possible to give the second dosage of MTX on day 4 to increase the treatment success rate and shorten the duration of treatment. It is worth noting that among patients with an hCG plateau on day 4 (score = 2), NLR reduced over 23% had a substantially higher treatment success rate than NLR dropped less than 23% (78.6% vs 50.0%, p = 0.006). This is of special value to those patients with unchanged hCG value on day 4 compared to day 0. We can give those patients a prejudgment of treatment outcome according to their NLR changes between day 4 and day 0. The pearl of our model is it’s ahead of time. This predictive scoring system make it possible to identify patients who would not benefit from single-dose MTX treatment and require an earlier second dosage. The main drawback of our study comes from the limitation from a retrospective, single center and hypothesis-generating study, and should be verified with a prospective, randomized trial in the future. Conclusions To sum up, we propose a novel treatment outcome predicting score system for EP patients treated with single-dose MTX. The changes of NLR and hCG are important parameter in our model. Declarations Ethical Statement and consent to participate. This study was performed in accordance with the Declaration of Helsinki and has been granted an exemption from requiring ethics approval from ethic committee of Shanghai First Maternity and Infant Hospital affiliated to Tongji University School of Medicine. All experimental protocols were approved by The Ethical Committee of Shang Hai First Maternity and Infant Health Hospital. The need for Informed Consent was waived off by The Ethical Committee of Shang Hai First Maternity and Infant Health Hospital as it’s a retrospective study. Consent to publish. NOT APPLICABLE Funding This work was supported by the National Natural Science Foundation of China (No. 81971338), Natural Science Foundation of Shanghai (22ZR1449400), and Science and Technology Innovation Plan of Shanghai Science and Technology Commission (21Y11907700). Conflict of Interest None Acknowledgement None Author Contribution Rukeyemu Abuduxukuer performed the major data collection and take part in the writing the manuscript. Xiaoyue Chen was a major contributor in writing the manuscript. Jingyi Ni perform the statistics and made the figures. Na Liu, Bailian Cai and Yuting Shen participated in the data collection. Shuangdi Li was a major contributor in editing the manuscript and provide funding. Zhen Li supervise the metastasis. Wen Lu designed the study and supervised the perform the statistics and manuscript draft. 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Dai Y, Zhang G, Zhu L, Lang J, Liu ZJJomig: Routine β-Human Chorionic Gonadotropin Monitoring for Single-Dose Methotrexate Treatment in Ectopic Pregnancy . 2017, 24 (7):1195-1199. 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. Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2383650","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":163235052,"identity":"dc46bf07-aa56-4a63-8f3c-8322aa606f79","order_by":0,"name":"Rukeyemu Abuduxukuer","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rukeyemu","middleName":"","lastName":"Abuduxukuer","suffix":""},{"id":163235053,"identity":"c80eff1b-eb4f-45a2-88e9-0b04c4bc12a1","order_by":1,"name":"Xiaoyue Chen","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoyue","middleName":"","lastName":"Chen","suffix":""},{"id":163235054,"identity":"c458b3a2-ce5f-417c-93c9-997209e40b5a","order_by":2,"name":"N Jingyi","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"N","middleName":"","lastName":"Jingyi","suffix":""},{"id":163235055,"identity":"70c96231-1311-4f21-a041-f3c6e872db77","order_by":3,"name":"Na Liu","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Liu","suffix":""},{"id":163235056,"identity":"9f237437-51c4-4d72-9b83-8cc0fb578ecd","order_by":4,"name":"Bailian Cai","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bailian","middleName":"","lastName":"Cai","suffix":""},{"id":163235057,"identity":"689a3a80-cf46-4560-9e06-fabdcb5e1328","order_by":5,"name":"Yuting Shen","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuting","middleName":"","lastName":"Shen","suffix":""},{"id":163235058,"identity":"3f97a434-ba30-44ba-b439-880a1c9bfe6f","order_by":6,"name":"Shuangdi Li","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shuangdi","middleName":"","lastName":"Li","suffix":""},{"id":163235059,"identity":"bb6c398a-6f35-47b1-9ed2-99055a2c28a7","order_by":7,"name":"Zhen Li","email":"","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhen","middleName":"","lastName":"Li","suffix":""},{"id":163235060,"identity":"1528b8be-8969-4c8f-99d4-ebd6abcb8278","order_by":8,"name":"Wen Lu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYFAD9saGAx8qJOT4idfCc/jgwxlnLIwlG4jWIpGWbMzbVpG4gZAWg+O9xyQ+7jgsZ3Agx0yCd54E4wYG5oePbuDTcuZcmuTMM4eNDQ6cMZOQ3CbBbM7AZmycg0eL2Y0cs9u8bYcTNxzsMZMw3CbBZtnAwyaNV8v9N2a3/4K0HOYxk0icI8FjcICQlhs8ZrcZQVqOsSUbHGyQkCCoxf5MjvnP3rZ0Y8kzzAcfNhyTMJBsJuAXyfYzxgY/26zl+O4/bDj8p6auvp+9+eFjfFqgoBmJzUxYOQjUEadsFIyCUTAKRiYAAJf+Upt9pr0iAAAAAElFTkSuQmCC","orcid":"","institution":"Shanghai First Maternity and Infant Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Wen","middleName":"","lastName":"Lu","suffix":""}],"badges":[],"createdAt":"2022-12-16 02:29:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2383650/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2383650/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":31097912,"identity":"1b42596e-3e48-41fe-874d-24d7932b685e","added_by":"auto","created_at":"2023-01-04 15:32:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":99275,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flowchart. This figure shows the procedure of patient selection.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2383650/v1/29a34dabc7df22b8cf51da62.jpg"},{"id":31097911,"identity":"8ef4d44c-4984-472f-8d8e-2308aca704cf","added_by":"auto","created_at":"2023-01-04 15:32:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":55870,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve for the ability of the scoring model to predict treatment outcome. Area under the curve: 0.712±0.027 (95% confidence interval: 0.659-0.764).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2383650/v1/265a0e3620b843dd6c11042d.jpg"},{"id":37631487,"identity":"180d4619-294f-4f45-9c16-73d3b17d7813","added_by":"auto","created_at":"2023-05-30 05:14:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1144838,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2383650/v1/f2112f50-acc6-45b7-812a-dc04057059fe.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Changes in Day 4 and day 0 Neutrophil-lymphocytes ratio in predicting single-dose methotrexate treatment failure for ectopic pregnancies","fulltext":[{"header":"Background","content":"\u003cp\u003eEctopic pregnancy (EP) accounts approximately 2% of all recognized pregnancies, and is the leading cause of maternal death in the first trimester [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. Methotrexate (MTX), a folic acid antagonist, is the most widely used conservative treatment for those EP patients with stable hemodynamic. The system MTX therapy including the single-dose or multiple-dose protocol. The single-dose MTX protocol, developed by Stovall et al in 1991 is by far the most widely accepted regimen, because of its simplicity and safety [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. The treatment success rate of single-dose MTX administration in asymptomatic EP is reported from 70 to 90% [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, treatment failure is associated with ectopic mass rupture and even life-threatening shock. So that patients treated with this protocol are usually anxious during the 7 day course before assessing the treatment outcome. Identifying patients who are more likely to get a single-dose MTX treatment success or failure is essential but remains a problem in clinical practice.\u003c/p\u003e\n\u003cp\u003eThe most widely accepted protocol to monitor treatment outcome was firstly proposed by Stovall et al [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. The test of serum hCG is performed on day 4 and day 7 after a single dose MTX shot. To those patients with hCG level declined more than 15% between day 4 and day 7, a weekly hCG is tested until it back to normal. If the hCG dropped less than 15% between day 4 and day 7, patients are recommended to repeat the MTX treatment. According to this standard, about 20% of patients underwent repeated MTX therapy [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. About 60% patients will experience a surge in hCG on day 4 after a single-dose MXT treatment[\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e], while there are still nearly 2/3 among them get treatment success[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. Whether an increased hCG on the fourth day of MTX therapy is a pharmacophysiological effect or indicator of treatment failure remains unclear.\u003c/p\u003e\n\u003cp\u003eOther markers such as progesterone, size of the ectopic mass, the ectopic cardiac activity, and the free peritoneal cells have been studied to predict treatment success of ectopic pregnancy [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. Unfortunately, none of them is acknowledged as reliable marker [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. An ideal prognostic factor ought to be cheap and easy to access for patients as well as practical and precious for doctors. Recently, a systemic immune-inflammation index based on peripheral blood parameter, the neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognosticators for lymphoma treated with MTX[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. It was also reported that EP patients received a single-dose MTX had significantly lower NLR levels on days 0, day 4, and day 7 compared to those required surgery [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, whether NLR changes are associated with the outcome of single-dose MXT regimen in EP remains unknown.\u003c/p\u003e\n\u003cp\u003eIn this retrospective study, we investigated the possibility of using NLR changes as a treatment outcome predictor of single-dose MTX administration in EP.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eClinical data was collected retrospectively at the Department of Gynecology, Shanghai First Maternity and Infant Hospital affiliated to Tongji University School of Medicine from Jan. 1, 2013, to Sept 30, 2019. This research was approved by the ethic committee and permitted to omitted patients' personal informed consent. All methods were carried out in accordance with the Declaration of Helsinki. The need for Informed Consent was waived off by Ethical Committee as it is a retrospective study.\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were listed as follows: (1) clinically diagnosed ectopic pregnancy according to the American Congress of Obstetricians and Gynecologists guidelines; (2) treated with single-dose MTX therapy; (3) complete clinical data. EP diagnosis was based on the serum levels of hCG and transvaginal sonography. Ectopic pregnancy was diagnosed when transvaginal ultrasound indicated ectopic sac outside of the uterus, increasing hCG levels within 48h were \u0026lt;\u0026thinsp;66%, and/or the lack of products of conception after uterine evacuation[\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e].Ultrasound exam was performed by two experienced physicians in our hospital.\u003c/p\u003e\n\u003cp\u003ePatients with non-tubular ectopic pregnancy or with initial serum hCG level\u0026thinsp;\u0026gt;\u0026thinsp;5000 mIU/mL, or with fetal heart activity in the adnexa were in the surgery group. Patients with stable hemodynamic status, without contraindications to MTX and agree to take MTX treatment were treated with single dose MTX. A single dose MTX (50 mg/m\u003csup\u003e2\u003c/sup\u003e) was given intramuscularly (IM) on day 0. Serum hCG and complete blood cell count were tested on the 4th and 7th day after treatment. If there is a 15% decline in hCG between day 4 and day 7, these women are considered treatment success and followed up with weekly hCG measurements until back to normal. If no reduction of 15% in hCG titer was observed during this period, an additional dose was injected on the 7th day. Patients were followed for 6 weeks, and the success or failure of treatment was assessed. MTX treatment failure was defined as the need for surgical intervention to those patients with clinical symptoms during treatment or hCG decrease less than 15% even after the second dosage MTX injection. The success of single‑dose treatment was defined a 5% reduction in serum hCG levels after 1 week and a serum hCG\u0026thinsp;\u0026lt;\u0026thinsp;5 mIU/mL after 6 weeks.\u003c/p\u003e\n\u003cp\u003eThe student \u003cem\u003et\u003c/em\u003e test was used to compare continuous variables, while the \u0026chi;\u003csup\u003e2\u003c/sup\u003e statistic was used to analyze categorical variables. We used a stratified proportional Cox risk model to analyze the association between the success rate of a single-dose MTX administration and the change in NLR levels between day 0 and day 4. Statistical analyses were performed using the SPSS v22.0 and R statistical package v.3.4.4 (R Project for Statistical Computing, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.r-project.org\" target=\"_blank\"\u003ewww.r-project.org\u003c/a\u003e\u003c/span\u003e\u003c/span\u003e). All tests were two sided, with a significance level set at \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003ePatient characteristics\u003c/h2\u003e\n\u003cp\u003eA total of 6069 ectopic pregnancy patients were treated at our hospital during the study period. Among them 2012 were initially treated with surgery, 2992 patients received expectant management and 1065 received MTX treatment. 878 received a single-dose MTX regimen. We further excluded 400 with missing hCG or NLR values and anther 72 patients with initial serum hCG level\u0026thinsp;\u0026gt;\u0026thinsp;5000 mIU/mL or non-tubular ectopic pregnancy. Finally, 406 patients met our criteria were studied. A flow chart of the patients\u0026rsquo; selection is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no significant differences with respect to age (mean, 30.82 vs 30.95, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.68), initial hCG level （mean, 651.26 vs 575.77, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.21）and treatment success rate of single-dose MTX treatment（69.4% vs 73.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.24）between the included and excluded cohort.\u003c/p\u003e\n\u003cp\u003eAs was shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, the basic characteristics of patients are listed. Compared to day 0, the NLR on day 4 dropped by an average of 25% (range, -0.91 to 4.57). There was no statistical difference between the three groups in terms of patient\u0026rsquo;s age, gestational age, gravidity, parity, pelvic surgery history, and assisted reproductive technology (ART) application. The overall success rate of single-dose MTX treatment is 69.2% (281/406). The success rate was significantly reduced when the NLR on day 4 decreased less than 23% compared to day 0 (74.8% vs 58.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). There was no increased treatment success rate of MXT therapy when NLR on day 4 drop over 23%.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOverall\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e1st tertile\u003c/p\u003e\n\u003cp\u003e\u0026le;-0.49\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e2nd tertile\u003c/p\u003e\n\u003cp\u003e(-0.49,-0.23]\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e3rd tertile\u003c/p\u003e\n\u003cp\u003e＞-0.23\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNo\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e406\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e136\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e135\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, y, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30.83 (4.70)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30.56 (4.85)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e31.14 (5.11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30.78 (4.11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.59\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBMI, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.59 (3.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.05 (2.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.81 (2.94)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.91 (3.50)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.09\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestational age, days, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48.83 (11.53)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.10 (9.14)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e50.11 (12.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49.30 (12.26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.08\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGravidity,mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.44 (1.47)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.37 (1.61)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.47 (1.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.49 (1.34)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.76\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eParity,mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.35 (0.56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.30 (0.55)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.32 (0.56)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.44 (0.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiameter of adnexal mass by TVUS, mm, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.52 (7.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.96 (7.97)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.49 (7.02)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.12 (7.03)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.02\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior ectopic pregnancy,n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (11.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 ( 5.88)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (11.11)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24 (17.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior pelvic surgery, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e90 (22.17)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e22 (16.18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (24.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (25.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUsing ART, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (7.38)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11 ( 8.09)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10 ( 7.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 ( 6.67)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.91\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0 hCG, mIU/mL, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e645 (629)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e611 (579)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e632 (653)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e691(656)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.56\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 4 hCG, mIU/mL, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e787 (1012)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e745 (960)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e735 (1066)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e882 (1007)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.41\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehCG change percentage, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.20 (0.77)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.16 (0.78)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.10 (0.69)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.33 (0.82)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.04\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0 NLR, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.32 (1.67)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4.48 (1.95)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.90 (0.97)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.58 (1.23)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 4 NLR, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.18 (1.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.54 (0.45)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.86 (0.64)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.13 (2.49)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLR change percentage, mean (SD)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.25 (0.57)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.63 (0.10)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e-0.36 (0.07)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.24 (0.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMTX treatment success, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e281 (69.21)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e101 (74.26)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e101 (74.81)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79 (58.52)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003eNLR:Change percentage of NLR and hCG\u0026thinsp;=\u0026thinsp;D4/D0-1, ART: assisted reproductive technologies\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003eChanges in NLR and hCG are associated with the treatment outcome of single-dose MTX in EP\u003c/h2\u003e\n\u003cp\u003eWe found that insufficient NLR or hCG reduction on day 4, as well as high hCG on day 0 are all related to single-dose MTX therapy failure. Other factors including patient\u0026rsquo;s age, previous ectopic pregnancy, a history of pelvic surgery, diameter of the mass, and gestational age, were not related to the treatment success of single-dose MTX therapy. Multivariate regression analysis showed that NLR decreased more than 23% in day 4 compared to day 0 (OR: 2.09, 95% confidence interval (CI): [1.27\u0026ndash;3.44]), unchanged (OR:3.17, 95% CI: [1.62\u0026ndash;6.34]) or increased (OR: 5.47, 95% CI: [3.05\u0026ndash;10.22]) hCG on day 4 compared to day 0 as well as hCG\u0026thinsp;\u0026gt;\u0026thinsp;1000 on day 0 (OR:2.11, 95% CI: [1.23\u0026ndash;3.61]) were associated with treatment failure of single-dose MTX (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariate analyses for NLR change and other factors predicting outcome of single-dose MTX administration.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOR\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e95%CI\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLR change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;-0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0 (Reference)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e＞-0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.09\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.27\u0026ndash;3.44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehCG change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003edrop (\u0026le;-0.15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0 (Reference)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eplateau ((-0.15,0.15])\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.17\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.62\u0026ndash;6.34\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.00\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eincrease (\u0026gt;\u0026thinsp;0.15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.47\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3.05\u0026ndash;10.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0 hCG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e＜1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.0 (Reference)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.11\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.23\u0026ndash;3.61\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.01\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0 NLR\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.97\u0026ndash;1.31\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.11\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.97\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.92\u0026ndash;1.02\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.24\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior ectopic pregnancy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.55\u0026ndash;2.50\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.66\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePrior pelvic surgery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.21\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.65\u0026ndash;2.22\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.55\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiameter of adnexal mass\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.99\u0026ndash;1.06\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.12\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eGestational age\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.00\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.99\u0026ndash;1.03\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.64\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003ePredictive model development\u003c/h2\u003e\n\u003cp\u003eThe change of NLR and hCG on day 4 compared to day 0, and hCG level on day 0 were all included in the final prediction model for single-dose MTX treatment outcomes. OR were calculated for each predictor variable and each variable was assigned a score. The sums of the scores correspond to the single-dose MTX treatment failure risk (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). ROC analysis was utilized to establish the best cut-off value for the score. The highest sensitivity and specificity were 76.8% and 56.9% (corresponding to the score cut-off value at 3) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). When the cut-off set at 3, the positive predictive value (PPV) was 0.442 and negative predictive value (NPV) was 0.847. The area under the ROC was 0.712 as was shown in \u003cstrong\u003eFigure. 2.\u003c/strong\u003e We thus subdivided the patients into a low-risk treatment failure group (\u0026lt;\u0026thinsp;3) and a high-risk treatment failure group (\u0026ge;\u0026thinsp;3) according to the predictive scores, univariate regression analysis showed that the OR value of the high-risk treatment failure group is 4.38 (95% CI, [2.74\u0026ndash;7.15]).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eFinal model for single-dose MTX administration.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eScore assigned\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNLR change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026le;-0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e＞-0.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ehCG change\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003edrop (\u0026le;-0.15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eplateau ((-0.15,0.15])\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eincrease (\u0026gt;\u0026thinsp;0.15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDay 0 hCG\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e＜1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026ge;1000\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eEstimated single-dose MTX administration according to the risk score .\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eScore\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSensitivity\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eSpecificity\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePositive predictive value\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eNegative predictive value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.928\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.306\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.373\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.905\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.872\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.413\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.398\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.879\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.768\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.569\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.442\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.847\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.392\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.854\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.544\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.760\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.048\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.975\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.462\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.697\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTreatment failure occurs in 10\u0026ndash;30% of EP patients primarily treated with single-dose MTX. It causes inconveniences and makes patients under risk of tubal pregnancy rupture as well [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. The purpose of this study is to identify EP patients who may fail single-dose MTX treatment and require follow-up surgery and/or medical interventions. After reviewing the 406 EP patients previously received a single-dose of MTX in our hospital, we established a predictive model to evaluate the outcome of their treatment. Our model comped of the commonly used hCG levels and changes of NLR on days 4 compared to day 0.\u003c/p\u003e\n\u003cp\u003eAs far as we know, we are the first to identify the change of NLR between day 4 and day 0 besides hCG changes as statistically significant predictive factors for single-dose MTX treatment outcome. We found when the NLR on day 4 decreased more than 23% compared to day 0, the single dose MTX treatment success rate reached nearly to 75%, which was significantly higher than the 58.5% treatment success rate of patients with an NLR decreased less than 23%. The NLR is a potent indicator of systemic immune inflammation [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. It was demonstrated to be an independent predictor of mortality in patients with cardiovascular diseases and outcomes in primary central nervous system lymphoma treated with high-dose methotrexate-based therapy[\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. There are few published studies on the relation between NLR changes and the efficacy of MTX treatment in EP patients. In a study of 161 EP patients received a single dose of MTX, it reported much lower NLR on day 0, day 4, and day 7 compared to patients who received surgery. However, the changes in NLR was not improved to be as effective in predict treatment success as a 15% decrease in hCG between days 4 and 7[\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our study, multivariate analyses showed that NLR decrease less than 23% on day 4 as an independent risk factor for treatment failure with the OR value of 2.09. To the best of our knowledge, it is the only study focused on early NLR change in single-dose MTX treatment, therefore, it is difficult to compare our findings to those of other studies. This alteration in NLR might due to the immuno-suppressive effect of MTX [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. Several studies indicated NLR as a potential biomarker of MTX response in the treatment of autoimmune diseases, such as psoriasis and rheumatoid arthritis [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eUsing single-dose MTX without citrovorum rescue factor for EP was first implemented at the University of Tennessee in 1991[\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e]. Contrast to multi-dose MTX procedures, single-dose MTX has a lot of advantages such as more cost-effective, has fewer side effects, needs less extensive patient monitoring, and has higher patient acceptability [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. The success rate of single-dose MTX was reported varied from 70 to 90%. The different study population, the non-uniform criteria for providing the medicine, and the various definition of treatment effectiveness can explain the variations[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. The success rate in our study was 69.2%, which is consistent with other studies that used comparable single-dose procedures [\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eSince the MTX treatment of EP was proposed for the first time, a lot of scholars attempted to identify factors which would influence the treatment success rate. Nowadays, the serum hCG level prior to MTX treatment is the most well accepted indicator. But the thresholds of hCG described in literatures varies from 1000 to 5000 mIU/ml[\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. In a retrospective study conducted by L. Bonin et al, totally 400 EP patients received a single-dose MTX treatment. It reported that an initial hCG value of \u0026lt;\u0026thinsp;1000 mIU/ml was associated with a 90% treatment success rate [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. And the hCG value 1000 mIU/ml was used as the criteria for treatment outcome by several other studies [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Surprisingly, in our study, 27.9% of the patients with initial serum hCG levels below 1000 mlU/ml and 43.8% of those who had serum hCG levels no less than 1000 mlU/ml failed in MTX therapy. The treatment success rate is lower in our study compared to other previous studies. We think it can be explained by the number of patients who received the second MTX injection. It is worth noting that in the study performed by Bonin et al, 20.5% of patients received the second dose of MTX while the corresponding number in our study is 5.2% (21/406). It is reported that a second MTX injection could increase the total success rate from 63.5\u0026ndash;73.2% [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eThe single-dose MTX protocol was supposed to reduce the hospital visits. But to those hCG level decrease less than 15% in the given week and need a repeated MTX treatment, the follow up procedure is time consuming according to Stovall\u0026rsquo;s protocol. In fact, approximately 20% of patients will require a repeated MTX treatment in practice [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e]. The two-dose MTX protocol is administer a second MTX dosage on day 4 in addition to the single-dose MTX therapy. It supposed to combine the greater treatment success from an extra MTX doses, and the convenience visit schedule of the single-dose regimen. A well performed meta-analysis compared the \u0026ldquo;single-dose\u0026rdquo; and \u0026ldquo;two-doses\u0026rdquo; MTX protocols indicated that the \u0026ldquo;two-doses\u0026rdquo; are superior to \u0026ldquo;single-dose\u0026rdquo; MTX with higher treatment success rate (OR:1.84, 95%CI: [1.13-3.00]) and 7.9 days shorter to reach treatment success (95%CI: [-12.2-3.5])[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. The assessment on days 0 and day 4 in our model is of clinical value, because it can provide earlier prognostic information, which make it possible to reduced follow up visit for individuals who are likely to have favorable outcomes and to give an earlier second injection to those who would fail in single dose MTX therapy.\u003c/p\u003e\n\u003cp\u003eWe aim to construct a predictive model for single-dose MTX, which is clinical friendly as well as ahead of time (get the treatment outcome on day 4 instead of day 7 after initial treatment). In our study, we concluded that treatment success rate was statically higher in those patients experienced significant reductions in NLR and hCG on day 4, and those patients with hCG\u0026thinsp;\u0026lt;\u0026thinsp;1000 mIU/ml on day 0. When the three factors (NLR and hCG change between day 4 and day 0, hCG value on day 0) are independently used as predictive value, the AUC are 0.583, 0.671, 0.555, respectively. When all the three parameters were put into the model and with a combined score cut-off at 3, the AUC was 0.712. The PPV is 0.422 and the NPV is 0.847. In this study, we proposed that patients with a score\u0026thinsp;\u0026ge;\u0026thinsp;3 in our model are 4 times more likely to fail a single-dose MTX therapy than those with a score of ＜3 (OR:4.38,95%CI: [2.74, 7.15]). We believe our model has referential value on clinical decision-making to those EP patients underwent MTX therapy. We can identify those patients who would fail in the single dose MTX therapy on day 4 instead of day with this scoring system. Thus, make it possible to give the second dosage of MTX on day 4 to increase the treatment success rate and shorten the duration of treatment. It is worth noting that among patients with an hCG plateau on day 4 (score\u0026thinsp;=\u0026thinsp;2), NLR reduced over 23% had a substantially higher treatment success rate than NLR dropped less than 23% (78.6% vs 50.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006). This is of special value to those patients with unchanged hCG value on day 4 compared to day 0. We can give those patients a prejudgment of treatment outcome according to their NLR changes between day 4 and day 0.\u003c/p\u003e\n\u003cp\u003eThe pearl of our model is it\u0026rsquo;s ahead of time. This predictive scoring system make it possible to identify patients who would not benefit from single-dose MTX treatment and require an earlier second dosage. The main drawback of our study comes from the limitation from a retrospective, single center and hypothesis-generating study, and should be verified with a prospective, randomized trial in the future.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eTo sum up, we propose a novel treatment outcome predicting score system for EP patients treated with single-dose MTX. The changes of NLR and hCG are important parameter in our model.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Statement and consent to participate.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in accordance with the Declaration of Helsinki and has been granted an exemption from requiring ethics approval from ethic committee of Shanghai First Maternity and Infant Hospital affiliated to Tongji University School of Medicine.\u003c/p\u003e\n\u003cp\u003eAll experimental protocols were approved by The Ethical Committee of Shang Hai First Maternity and Infant Health Hospital.\u003c/p\u003e\n\u003cp\u003eThe need for Informed Consent was waived off by The Ethical Committee of Shang Hai First Maternity and Infant Health Hospital as it\u0026rsquo;s a retrospective study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNOT APPLICABLE\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (No. 81971338), Natural Science Foundation of Shanghai (22ZR1449400), and Science and Technology Innovation Plan of Shanghai Science and Technology Commission (21Y11907700).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRukeyemu Abuduxukuer performed the major data collection and take part in the writing the manuscript. Xiaoyue Chen was a major contributor in writing the manuscript. Jingyi Ni perform the statistics and made the figures. Na Liu, Bailian Cai and Yuting Shen participated in the data collection. Shuangdi Li was a major contributor in editing the manuscript and provide funding. Zhen Li supervise the metastasis. Wen Lu designed the study and supervised the perform the statistics and manuscript draft.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMarion L, Meeks GJCo, gynecology: \u003cstrong\u003eEctopic pregnancy: History, incidence, epidemiology, and risk factors\u003c/strong\u003e. 2012, \u003cstrong\u003e55\u003c/strong\u003e(2):376-386.\u003c/li\u003e\n\u003cli\u003eStovall T, Ling F, Gray LJO, gynecology: \u003cstrong\u003eSingle-dose methotrexate for treatment of ectopic pregnancy\u003c/strong\u003e. 1991, \u003cstrong\u003e77\u003c/strong\u003e(5):754-757.\u003c/li\u003e\n\u003cli\u003eUstunyurt E, Duran M, Coskun E, Ustunyurt \u0026Ouml;, Simşek HJAog, obstetrics: \u003cstrong\u003eRole of initial and day 4 human chorionic gonadotropin levels in predicting the outcome of single-dose methotrexate treatment in women with tubal ectopic pregnancy\u003c/strong\u003e. 2013, \u003cstrong\u003e288\u003c/strong\u003e(5):1149-1152.\u003c/li\u003e\n\u003cli\u003eBarnhart K, Gosman G, Ashby R, Sammel MJO, gynecology: \u003cstrong\u003eThe medical management of ectopic pregnancy: a meta-analysis comparing \u0026quot;single dose\u0026quot; and \u0026quot;multidose\u0026quot; regimens\u003c/strong\u003e. 2003, \u003cstrong\u003e101\u003c/strong\u003e(4):778-784.\u003c/li\u003e\n\u003cli\u003eGuvendag Guven E, Dilbaz S, Dilbaz B, Aykan Yildirim B, Akdag D, Haberal AJAoegS: \u003cstrong\u003eComparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study\u003c/strong\u003e. 2010, \u003cstrong\u003e89\u003c/strong\u003e(7):889-895.\u003c/li\u003e\n\u003cli\u003eSaadati N, Najafian M, Masihi S, Safiary S, Abedi PJIRCmj: 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MJEjoo, gynecology,, biology r: \u003cstrong\u003eCut-off value of initial serum \u0026beta;-hCG level predicting a successful MTX therapy in tubal ectopic pregnancy: a retrospective cohort study\u003c/strong\u003e. 2014, \u003cstrong\u003e179\u003c/strong\u003e:175-180.\u003c/li\u003e\n\u003cli\u003eRabischong B, Tran X, Sleiman A, Larra\u0026iacute;n D, Jaffeux P, Aublet-Cuvelier B, Pouly J, Fernandez HJF, sterility: \u003cstrong\u003ePredictive factors of failure in management of ectopic pregnancy with single-dose methotrexate: a general population-based analysis from the Auvergne Register, France\u003c/strong\u003e. 2011, \u003cstrong\u003e95\u003c/strong\u003e(1):401-404, 404.e401.\u003c/li\u003e\n\u003cli\u003eNazac A, Gervaise A, Bouyer J, de Tayrac R, Capella-Allouc S, Fernandez HJUio, Obstetrics gtojotISoUi, Gynecology: \u003cstrong\u003ePredictors of success in methotrexate treatment of women with unruptured tubal pregnancies\u003c/strong\u003e. 2003, \u003cstrong\u003e21\u003c/strong\u003e(2):181-185.\u003c/li\u003e\n\u003cli\u003ePotter M, Lepine L, Jamieson DJAjoo, gynecology: \u003cstrong\u003ePredictors of success with methotrexate treatment of tubal ectopic pregnancy at Grady Memorial Hospital\u003c/strong\u003e. 2003, \u003cstrong\u003e188\u003c/strong\u003e(5):1192-1194.\u003c/li\u003e\n\u003cli\u003eThurman A, Cornelius M, Korte J, Fylstra DJAjoo, gynecology: \u003cstrong\u003eAn alternative monitoring protocol for single-dose methotrexate therapy in ectopic pregnancy\u003c/strong\u003e. 2010, \u003cstrong\u003e202\u003c/strong\u003e(2):139.e131-136.\u003c/li\u003e\n\u003cli\u003eDai Y, Zhang G, Zhu L, Lang J, Liu ZJJomig: \u003cstrong\u003eRoutine \u0026beta;-Human Chorionic Gonadotropin Monitoring for Single-Dose Methotrexate Treatment in Ectopic Pregnancy\u003c/strong\u003e. 2017, \u003cstrong\u003e24\u003c/strong\u003e(7):1195-1199.\u003c/li\u003e\n\u003c/ol\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":"[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":"Ectopic pregnancy, Methotrexate, Neutrophil-lymphocytes ratio, Predictor, serum hCG","lastPublishedDoi":"10.21203/rs.3.rs-2383650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2383650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eWe aimed to evaluate changes in neutrophil/lymphocyte ratio between the day 4 and day 0 of ectopic pregnancy (EP) patients treated with single-dose methotrexate (MTX). And to further investigate whether the NLR change is an indicator for MTX treatment outcome.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTotally 406 patients underwent single-dose MTX therapy for EP at Shanghai First Maternity and Infant Hospital from 2013/01/10 to 2019/09/30 were studied. A multivariate model was structured to predict the treatment outcome.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFinally, 281 patients were in the successful treatment group, and their NLR at day 4 dropped 25% when compared with day 0. The success rate was significantly declined when the NLR decreased less than 23% (74.8% vs 58.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). Multivariate regression analysis revealed that day 4/day 0 NLR reduced less than 23% (OR:2.09, 95%CI:[1.27\u0026ndash;3.44]); hCG decreased no more than 15% (OR:3.17,95% CI: [1.62\u0026ndash;6.34] and increased over 15% on day 4 (OR:5.47, 95% CI: [3.05\u0026ndash;10.22]) were independent risk factors for single-dose MTX treatment failure. Our final predictive model had a sensitivity of 0.768 and specificity of 0.569 when we chose 3 as the cut-off value. The area under the receiver operating characteristic curve was 0.712. Patients with a predictive score of \u0026ge;\u0026thinsp;3 are more likely to fail in a single-dose MTX therapy.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eIn this study, we concluded that NLR decreased less than 23% on day 4 compared with day 0, a plateau or increased serum hCG on day 4 and hCG value over1000 mIU/ml at day 0 were predictors of single-dose MTX treatment failure.\u003c/p\u003e","manuscriptTitle":"Changes in Day 4 and day 0 Neutrophil-lymphocytes ratio in predicting single-dose methotrexate treatment failure for ectopic pregnancies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-01-04 15:32:25","doi":"10.21203/rs.3.rs-2383650/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":"23d1230b-55f3-4b1d-b3a4-7411daa2409b","owner":[],"postedDate":"January 4th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-05-30T05:14:29+00:00","versionOfRecord":[],"versionCreatedAt":"2023-01-04 15:32:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2383650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2383650","identity":"rs-2383650","version":["v1"]},"buildId":"V5aR-dtovt5O2cv8Agveh","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}