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Background Tubal ectopic pregnancy (tEP) is the most common life-threatening condition in gynaecology. Treatment options include surgery and medical management. Stable women with tEPs with pre-treatment serum human chorionic gonadotrophin (hCG) levels < 1000 IU/L respond well to outpatient medical treatment with intramuscular methotrexate. However, tEPs with hCG > 1000 IU/L can take significant time to resolve with methotrexate and require multiple outpatient monitoring visits. In pre-clinical studies, we found that tEP implantation sites express high levels of epidermal growth factor receptor. In early-phase trials, we found that combination therapy with gefitinib, an orally active epidermal growth factor receptor antagonist, and methotrexate resolved tEPs without the need for surgery in over 70% of cases, did not cause significant toxicities, and was well tolerated. We describe the protocol of a randomised trial to assess the efficacy of combination gefitinib and methotrexate, versus methotrexate alone, in reducing the need for surgical intervention for tEPs. Methods and analysis We propose to undertake a multi-centre, double-blind, placebo-controlled, randomised trial (around 70 sites across the UK) and recruit 328 women with tEPs (with pre-treatment serum hCG of 1000–5000 IU/L). Women will be randomised in a 1:1 ratio by a secure online system to receive a single dose of intramuscular methotrexate (50 mg/m 2 ) and either oral gefitinib or matched placebo (250 mg) daily for 7 days. Participants and healthcare providers will remain blinded to treatment allocation throughout the trial. The primary outcome is the need for surgical intervention for tEP. Secondary outcomes are the need for further methotrexate treatment, time to resolution of the tEP (serum hCG ≤ 15 IU/L), number of hospital visits associated with treatment (until resolution or scheduled/emergency surgery), and the return of menses by 3 months after resolution. We will also assess adverse events and reactions until day of resolution or surgery, and participant-reported acceptability at 3 months. Discussion A medical intervention that reduces the need for surgery and resolves tEP faster would be a favourable treatment alternative. If effective, we believe that gefitinib and methotrexate could become standard care for stable tEPs. Trial registration ISRCTN Registry ISRCTN67795930 . Registered 15 September 2016.

Purpose To compare the effectiveness of expectant management versus methotrexate in selected cases of tubal ectopic pregnancy. Methods A double-blind randomized trial included 23 selected patients with a confirmed diagnosis of tubal pregnancy who met the inclusion criteria (hemodynamic stability, initial serum β-hCG concentration <2,000 mIU/mL, declining titers of β-hCG 48 h prior to treatment, visible tubal pregnancy on transvaginal ultrasound, a tubal mass <5.0 cm and fertility desire). The patients were divided into two groups: 10 patients in the methotrexate group (MTX 50 mg/m 2 administered as a single intramuscular dose) and 13 patients in the placebo group (saline solution administered in a single intramuscular dose). Quantitative variables were expressed as means ± standard deviations and compared by Student’s t test or Mann–Whitney test. Dichotomous variables (success/treatment failure) were presented as proportions and compared by the Fisher exact test. Results Successful treatment with negative titers of β-hCG occurred in 9 cases (90.0 %) of the methotrexate group and in 12 (92.3 %) of the placebo group ( p  > 0.999). The β-hCG values became undetectable at 22 ± 15.4 days in the methotrexate group and 20.6 ± 8.4 days in the placebo group ( p  = 0.80). Conclusion This study showed no statistically significant difference between the treatment with methotrexate and placebo, with similar success rates and similar time interval for β-hCG to become undetectable.

Introduction Ectopic pregnancy is an important health condition which affects up to 1 in 100 women. Women who present with mild symptoms and low serum human chorionic gonadotrophin (hCG) are often treated with methotrexate (MTX), but expectant management with close monitoring is a feasible alternative. Studies comparing the two treatments have not shown a statistically significant difference in uneventful resolution of ectopic pregnancy, but these studies were too small to define whether certain subgroups could benefit more from either treatment. Material and methods We performed a systematic review and individual participant data meta‐analysis (IPD‐MA) of randomized controlled trials comparing systemic MTX and expectant management in women with tubal ectopic pregnancy and low hCG (<2000 IU/L). A one‐stage IPD‐MA was performed to assess overall treatment effects of MTX and expectant management to generate a pooled intervention effect. Subgroup analyses and exploratory multivariable analyses were undertaken according to baseline serum hCG and progesterone levels. Primary outcome was treatment success, defined as resolution of clinical symptoms and decline in level of serum hCG to <20 IU/L, or a negative urine pregnancy test by the initial intervention strategy, without any additional treatment. Secondary outcomes were need for blood transfusion, surgical intervention, additional MTX side‐effects and hCG resolution times. Trial registration number: PROSPERO: CRD42021214093. Results 1547 studies reviewed and 821 remained after duplicates removed. Five studies screened for eligibility and three IPD requested. Two randomized controlled trials supplied IPD, leading to 153 participants for analysis. Treatment success rate was 65/82 (79.3%) after MTX and 48/70 (68.6%) after expectant management (IPD risk ratio [RR] 1.16, 95% confidence interval [CI] 0.95–1.40). Surgical intervention rates were not significantly different: 8/82 (9.8%) vs 13/70 (18.6%) (RR 0.65, 95% CI 0.23–1.14). Mean time to success was 19.7 days (95% CI 17.4–22.3) after MTX and 21.2 days (95% CI 17.8–25.2) after expectant management (P = 0.25). MTX specific side‐effects were reported in 33 MTX compared to four in the expectant group. Conclusions Our IPD‐MA showed no statistically significant difference in treatment efficacy between MTX and expectant management in women with tubal ectopic pregnancy with low hCG. Initial expectant management could be the preferred strategy due to fewer side‐effects. Our IPD‐MA showed no statistically significant difference in treatment efficacy between MTX and expectant management in women with tubal EP with low hCG. Initial expectant management could be the preferred strategy due to fewer side‐effects.

Tubal pregnancy is one of the common emergencies in obstetrics and gynecology. There are various treatment options for tubal pregnancy. However, there is no consensus on how patients should choose among the treatment options that preserve the fallopian tube. This study aims to investigate the difference in prognosis between different treatment options when the tube is preserved in patients with tubal pregnancy. We conducted a search for studies on tubal pregnancy in the PubMed, EMBASE, Web of Science, and Cochrane Library databases. Ultimately, we obtained 8 studies that met the screening criteria. The Jadad scale and NOS were used to evaluate the quality of the studies, and the evidence quality was evaluated and graded according to GRADE guidelines. Stata 17.0 software was used for data analysis. A total of 8 studies involving 677 patients were included. Meta-analysis revealed a significant overall difference in the failure rate between methotrexate treatment and salpingostomy for tubal pregnancy(OR=1.582, 95%CI(1.062, 2.358), p = 0.024). Subgroup analysis demonstrated that a single dose of methotrexate was associated with a higher failure rate compared to salpingostomy(OR = 2.044,95%CI(1.20, 3.47), p = 0.008). In contrast, two or more doses of methotrexate did not show a significant difference in failure rate compared to salpingostomy(OR = 1.130, 95% CI(0.62, 2.07), p = 0.692). However, salpingostomy combined with methotrexate showed a lower failure rate compared to salpingostomy alone(OR = 0.11, 95% CI (0.03-0.48), p = 0.003). Network meta-analysis indicated that the salpingostomy combined with methotrexate had the lowest failure rate, while there was no significant difference in failure rates between salpingostomy and methotrexate alone. For hemodynamically stable patients with a desire for future fertility, salpingostomy combined with methotrexate is an excellent option for treating tubal pregnancy. This approach has a lower failure rate compared to either methotrexate or salpingostomy alone and appears to have minimal impact on the patient's quality of life.

Background Ectopic pregnancy (EP) accounts for approximately 2% of all pregnancies, with tubal ectopic pregnancies (TEPs) being the most common type. Methotrexate (MTX) is a noninvasive and effective medical management option for TEP, but failure rates range from 10 to 36%, posing challenges in clinical practice. Identifying risk factors for MTX treatment failure is crucial to improve patient outcomes and guide clinical decision-making. This study aimed to determine the risk factors associated with MTX failure in TEP patients and support personalized treatment strategies. Methods This retrospective study included female patients who were diagnosed with TEP at Peking Union Medical College Hospital (PUMCH) between January 2016 and December 2022. Patients received MTX treatment initially, with dosing intervals and protocols varying according to clinical practice. MTX treatment failure was defined as the need for surgery after MTX administration. The study included two groups: patients who failed MTX treatment ( n  = 91) and those who succeeded in treatment ( n  = 268). Univariate and multivariate logistic regression analyses were performed to identify significant predictors of MTX treatment failure. A nomogram was developed to visualize the predictive factors. Results A total of 359 patients were included, with 268 (74.7%) succeeding with MTX and 91 (25.3%) required surgery. Specifically, 282 patients (78.6%) received 1-dose MTX, whereas 77 (21.4%) received 2-dose MTX. Univariate analysis revealed that gravidity, previous EP, gestational age, pretreatment β-human chorionic gonadotropin (β-hCG) level, number of MTX treatments, and presence of a visible yolk sac in ultrasound were significant predictors (all P  < 0.05). Multivariate analysis confirmed that higher gravidity (odds ratio (OR) = 1.2487, 95% confidence interval (CI): 1.0103 – 1.5433, P  = 0.040) and elevated pretreatment β-hCG levels (OR = 1.0006, 95% CI: 1.0004 – 1.0008, P  < 0.001) were independent risk factors. Number of MTX treatments was a significant protective factor (OR = 0.4409, 95% CI: 0.2153 – 0.9025, P  = 0.025). The nomogram incorporating these six risk factors was developed. Conclusion Higher gravidity and elevated β-hCG levels were significant predictors of MTX failure, while more MTX doses provided a protective effect. These findings underscore the importance of personalized MTX treatment strategies to improve outcomes in TEP. However, the limitations of this study, including its retrospective and single-center design, suggest that further prospective multicenter studies are needed to validate these results. Trial registration The trial is registered at http://www.chictr.org.cn . [registration number: ChiCTR2400081314; registration date: 2024–02-28 (prospectively registered)].

Background and Objectives: Ectopic pregnancy (EP) is a potentially life-threatening condition and the leading cause of maternal mortality in the first trimester. Although both surgical and medical approaches are effective, selection criteria for Methotrexate (MTX) treatment remain inconsistent across international guidelines. Additionally, limited data on long-term reproductive outcomes are available. Materials and Methods: We conducted a single-center retrospective cohort study of 107 patients diagnosed with tubal EP and treated at the Obstetrics and Gynecology Unit of the University Hospital of Parma between 2019 and 2023. MTX (50 mg/m2) was offered to patients with β-hCG < 5000 mIU/mL, sac diameter < 40 mm, and no embryonic cardiac activity or hemoperitoneum; others underwent salpingectomy. Treatment outcomes, predictors of MTX success, and fertility outcomes were analyzed. Results: Medical treatment was offered to 36 patients (33.6%), with an overall success rate of 72%: in total, 20 resolved after a single dose and 6 after a second dose. Surgical conversion was necessary in 10 patients. The remaining 71 patients (66.4%) underwent primary salpingectomy. Initial β-hCG levels and gestational age did not significantly predict MTX failure (p 0.14 and 0.73, respectively), whereas gestational sac diameter was identified as a reliable predictor of treatment success (p = 0.01). In particular, a gestational sac maximum diameter of <2 cm emerged as a positive factor for MTX success (OR 1.13, 95% CI: 1.1–1.3, p = 0.04). Among the 50 patients with follow-up data, 68% achieved a term live birth, with no significant difference between the MTX (52.9%) and surgical (75.8%) groups (p 0.12). Most of the pregnancies (90%) occurred spontaneously, while only 10% required assisted reproductive technologies. Conclusions: MTX is a safe and effective treatment for tubal EP when patients are appropriately selected. Gestational sac diameter appears to be a reliable predictor of success. Both medical and surgical treatments yielded comparable reproductive outcomes, supporting individualized care models that prioritize fertility preservation.

Objective To systematically review and compare the clinical efficacy and impact on fertility function between laparoscopic surgery and methotrexate treatment for tubal pregnancy. Methods Five English databases and four Chinese databases were systematically searched from the database establishment to January 31, 2024, and a meta-analysis was conducted using Review Manager 5.3. Results Ten articles were included, with a total of 1,034 study patients. The meta-analysis showed that compared with a single intramuscular injection of methotrexate, laparoscopic surgery for tubal pregnancy was associated with a significantly higher tubal patency rate [OR = 2.47, 95% CI 1.72–3.53, P  < 0.001]; and a significantly higher spontaneous pregnancy rate [OR = 2.10, 95% CI 1.28–3.46, P  = 0.003]; and a shorter time for serum HCG levels to return to normal [MD = -7.10, 95% CI − 7.84–6.36, P  < 0.001]. However, there was no statistically significant difference in treatment success rate between the two treatment methods [OR = 1.88, 95% CI 0.53–6.69, P  = 0.33], and no statistically significant difference in recurrent EP rate [OR = 1.09, 95% CI 0.41–2.87, P  = 0.87]. Conclusion Compared with a single intramuscular injection of methotrexate, laparoscopic surgery for tubal pregnancy is associated with better fertility function in the future, while the difference in clinical efficacy needs further exploration.

Aim The single-dose methotrexate (MTX) regimen is effective and minimizes side effects but an additional second dose is needed in case of failure in an ectopic pregnancy (EP). We aimed to predict the additional MTX dose by evaluating the change in β-hCG values between day 0 and day 4 in EPs with administered single-dose MTX regimen. Method A total of 454 tubal EPs between 2013 and 2019 were evaluated retrospectively. Cases cured with a single dose of MTX without an additional dose were accepted as the control group, and cases under a single-dose regimen were cured by applying a second dose of MTX on the 7th day were accepted as the study group. Obstetric and demographic characteristics and the change in β-hCG values compared in both groups. Results Age, body mass index (BMI), gravida, smoking, abdominal surgery, presence of IUDs, initial β-hCG levels (0th day), and EP size were similar in both groups, but the presence of previous EP history was significantly higher in the study group. The change of β-hCG from days 0 and 4 determined that a 20% increase predicts the need for a second dose of MTX with 72.4% sensitivity, and 87.8% negative predictive value (NPV). Conclusion The single-dose MTX protocol is successful in 83.3% of convenient cases (as the control group), but an increase of 20% in β-hCG between days 0 and 4 predicts the patients who need to be administered second-dose MTX, and thus, a double-dose MTX protocol will be achieved early.

OBJECTIVES: Inhibition of estradiol production by letrozole may interfere with physiological effects of progesterone necessary to maintain the pregnancy. Treatment of tubal pregnancy (TP) with letrozole would allow to avoid the disadvantages of methotrexate (MTX). The aim was to compare the effectiveness of letrozole with MTX in the management of TP. MATERIAL AND METHODS: A prospective open-label cohort study was conducted among women with TP and increasing B-human chorionic gonadotropin (B-hCG) concentrations. MTX was administered in a single dose of 100 mg intravenously, while letrozole in a dose of 5 mg orally for 10 days. Blood parameters (B-hCG, hemoglobin, creatinine, urea, transaminases, bilirubin) were tested on days 0, 4 and 7. RESULTS: Out of 22 eligible women, 14 received MTX and received 8 letrozole. Mean age, lesion diameter, gestation age in the MTX vs letrozole arm were: 31 vs 32 years (p = 0.3), 13.2 vs 16.3 mm (p = 0.1), 7 + 1 vs 7 + 0 weeks (p = 0.6), respectively. In case of 4 women treated with letrozole and in 2 treated with MTX (4/8, 50% vs 2/14, 14.3%, p = 0.07) the treatment was unsuccessful. There were no significant differences in blood parameters on days 0, 4 and 7 between both arms, except for the increasing urea concentration in the letrozole arm (p = 0.01). CONCLUSIONS: Even though the results did not reach statistical significance, it is likely that a larger study sample would confirm the trend of letrozole being less effective. The results did not support the use of letrozole in the studied regimen as an alternative to MTX.

IntroductionTubal ectopic pregnancy (TEP) frequently presents as a gynaecological emergency, often necessitating prompt medical intervention. Although methotrexate therapy offers the advantage of being non-invasive, it still poses the risk of tubal rupture and consequent haemorrhage, which may require emergency surgery. The major challenges encountered in practice are the lack of reliable methods to anticipate the likelihood of failure of single-dose methotrexate therapy and identify associated risk factors and thereby preclude unnecessary medical procedures. Effective counselling, therefore, remains a pivotal step in clinical management. This study is aimed at developing a predictive model to assess response to single-dose methotrexate therapy in cases of TEP by employing a dynamic prediction model approach based on the clinical data of a large cohort.Methods and analysisThis multicentre study will encompass 100 and 900 participants for the prospective and retrospective cohorts with TEP, respectively. Between 2010 and 2024, eligible patients who are diagnosed with TEP and opt for single-dose methotrexate therapy will be recruited as part of a retrospective cohort, from three participating hospitals in Zhejiang province, China. The comprehensive medical and obstetric histories of the patients will be collected, along with their clinical data, including the results of serological tests following the initial consultation. The control group will comprise patients who achieve uneventful, complete resolution of TEP, as evidenced by serum human chorionic gonadotropin level of <5 IU/L, without necessitating further treatment. The case group will include individuals requiring additional medical (further methotrexate) or surgical interventions. The dynamic prediction model developed in this manner will be employed on the longitudinal data. Additionally, data will be collected from two other hospitals between 2024 and 2026, as an external prospective cohort to validate the accuracy of the prediction model.Ethics and disseminationEthical approval for data collection has been obtained from the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (No. 2024-KLS-346–02), Hangzhou First People’s Hospital (No. ZN-20240627-0219-01), Anji Hospital of Chinese Medicine (No. 2025年第5号), Qingyuan Hospital of Chinese Medicine (No. (2024)伦审第(9)号) and Beilun Hospital of Chinese Medicine (No. 2024年伦审第12号). Additionally, written informed consent will be obtained from all participants and they will retain the right to withdraw from the study at any stage. The findings of this study will be disseminated through publication in a peer-reviewed journal.Trial registration numberChiCTR2400085829.