Efficacy of letrozole for the treatment of tubal ectopic pregnancy: A meta-analysis.

BACKGROUND: Tubal ectopic pregnancy (EP) is a life-threatening condition, especially if undiagnosed or misdiagnosed, tipically in low income countries and/or where women have limited access to health care. The current management protocol of tubal EP consists of either surgical management, or medical management with methotrexate. Recent studies, while few, have suggested that letrozole, an aromatase inhibitor, may play a role in the medical treatment of tubal EP. OBJECTIVES: To evaluate the effectiveness of letrozole alone in the medical treatment of tubal EP. SEARCH STRATEGY: Electronic databases were searched until 31 December 2023. SELECTION CRITERIA: Retrospective or prospective studies reporting the treatment of tubal EP with letrozole alone were considered eligible for inclusion. DATA COLLECTION AND ANALYSIS: Pooled results were expressed as OR with 95 %CI. Heterogeneity was assessed using Higgins I2. Subgroup analysis was performed to compare outcomes according to time after intervention. Subgroup differences were checked through χ2 test. RESULTS: A total of 152 patients were included. Seventy-nine patients (51.97 %) were treated with letrozole, 39 patients (16.54 %) with methotrexate, and 34 patients (31.49 %) underwent surgical treatment. Pooled data analysis supports the consistency of the effect of letrozole in reducing ß-hCG over time at a comparable rate among studies, and that treatment with letrozole is superior to surgery and has the same efficacy as methotrexate. However, all the included studies were judged at high risk of bias in terms of study design, sample representativeness, and sampling technique. Furthermore, short and long term side effects were not reported in any of the included studies. CONCLUSIONS: Letrozole is a promising alternative to methotrexate and surgical therapy in the treatment of tubal EP. Although this meta-analysis suggests efficacy and low hazard of the drug and encourages its application, the data available today remain extremely sparse, which weakens any claims that can be made, and is not sufficient to assert that letrozole is safe and effective in the treatment of EPs. There is an absolute need for randomized studies with accurate patient selection, fixed doses, large sample sizes, and reporting of short- and long-term side effects to refute or confirm this assumption.

The predictors of successful methotrexate treatment of tubal ectopic pregnancy.

BACKGROUND: The pre-treatment characteristics of the patient and ectopic pregnancy to determine the patients who are likely to successfully respond to methotrexate (MTX) therapy remain controversial. This study investigated the outcomes of ectopic pregnancy after one and two MTX doses and their independent predictors. METHODS: Retrospective cross-sectional study of women who consented to MTX treatment in 2017-2018 at our institution (N = 317). Of these, patients with Caesarean scar pregnancies were excluded because they require different treatment protocols (n = 25). All patients were treated according to our institution's protocol based on international guidelines and standardised across the three hospitals included in the current study. We retrieved patients' demographics, laboratory, ultrasonography, and clinical characteristics from our hospital database. Serum ß-human chorionic gonadotropin (ß-hCG) was measured using electrochemiluminescence immunoassay; ectopic pregnancy was diagnosed using ultrasonography (transvaginal probe). RESULTS: Two ninety-two patients were included in the current analysis. Age, pre-treatment ß-hCG levels, sonographic presence of yolk sac, presence of foetal cardiac activity, and pelvic pain were significantly different between patients with successful and unsuccessful outcomes. Younger age (adjusted odds ratio [aOR] 2.33, 95% confidence interval (CI) 1.16-4.66, p = .017), no pelvic pain (aOR 2.65, 95%CI 1.03-6.83, p = .043), lower initial ß-hCG level (aOR 1.32, 95%CI 1.08-1.59, p = .005), and absence of foetal cardiac activity (aOR 12.63; 95% CI 1.04-153.6; p = .047) were independently associated with success. Treatment failure odds were >2 folds higher for each 10-year age increase (p = .017), 32% higher for each 1000 IU/L increase in initial ß-hCG level (p = .005), and >2 folds higher in presence of pelvic pain (p = .043). CONCLUSIONS: MTX is effective in most patients, averting invasive surgery, which might affect fertility. Pre-treatment ß-hCG levels, age, pelvic pain, and foetal cardiac activity was independently associated with outcomes. Research should assess the relationship between the ectopic pregnancy size and treatment outcomes and refine ß-hCG titres where treatment would be ineffective.

Ectopic pregnancy is a pregnancy that occurs outside the uterus. It needs to be identified and treated quickly to prevent serious health complications. Ectopic pregnancies can be treated surgically or medically using a drug called methotrexate. Medical treatment of ectopic pregnancy is not always successful. Identifying the factors that predict the failure of medical treatment helps patients and doctors to choose more accurately between surgical and medical treatment options.A total of 292 women who received methotrexate for ectopic pregnancy and the factors that influence the outcomes of treatment were examined, 39 patients had treatment failure and required surgery. Older age, higher initial levels of ß-human chorionic gonadotropin (ß-hCG) hormone, the presence of pelvic pain, and foetal cardiac activity had increased risk of treatment failure. In the future, research could consider the relationship between the size of the ectopic pregnancy and the treatment outcomes and refine the ß-hCG level cut-off for better treatment effects.

[Management of tubal ectopic pregnancies with methotrexate : is it an effective treatment ?] / La prise en charge des grossesses extra-utérines tubaires par méthotrexate : un traitement efficace ?

Ectopic pregnancy is a gynecological emergency. The hCG level, the clinical presentation and the ultrasound remain the key steps for the diagnosis. The criteria tend to be more and more codified to decide on the optimal treatment, however, there is no consensus. The aim of this study was to evaluate the impact of applying a mathematical formula to predict the failure rate of metho-trexate for tubal ectopic pregnancy. A retrospective, monocentric study was conducted on a cohort of 193 patients for whom the formula could be calculated. Regarding our professional practice, the success rate of first-line metho-trexate is 93 %. It would increase to 96 % if the formula had been applied. The use of the formula would also reduce the rate of first-line surgery by 12 %.

La grossesse extra-utérine est une urgence gynécologique. Le taux d'hCG, la clinique et l'échographie restent les examens clé pour le diagnostic. Les critères tendent à être de plus en plus codifiés pour décider du traitement optimal. Cependant, il n'existe aucun consensus. Le but de cette étude était d'évaluer l'impact de l'application d'une formule mathématique permettant de prédire le taux d'échec du méthotrexate pour une grossesse extra-utérine tubaire. Une étude rétrospective et monocentrique a été menée sur une cohorte de 193 patientes pour lesquelles la formule a pu être calculée. Concernant notre pratique professionnelle, le taux de réussite du méthotrexate en 1ère intention est de 93 %. Il passerait à 96 % si la formule avait été appliquée. L'emploi de la formule permettrait également de diminuer de 12 % le taux de chirurgie réalisée en première intention.

Have we overlooked the role of mifepristone for the medical management of tubal ectopic pregnancy?

Ectopic pregnancy is a risk of both spontaneous and assisted reproduction pregnancies. The majority of ectopic pregnancies abnormally implant within a fallopian tube (extrauterine pregnancies). In haemodynamically stable women, medical or expectant treatment can be offered. Currently accepted medical treatment is using a drug called methotrexate. However, methotrexate has potential adverse effects, and a significant proportion of women will still require emergency surgery (up to 30%) to remove the ectopic pregnancy. Mifepristone (RU-486) has anti-progesterone effects and has a role in managing intrauterine pregnancy loss and termination of pregnancy. On reviewing the literature and given progesterone's pivotal role in sustaining pregnancy, we propose that we may have overlooked the role of mifepristone in the medical management of tubal ectopic pregnancy in haemodynamically stable women.

Subsequent pregnancy outcomes among women with tubal ectopic pregnancy treated with methotrexate.

Lay summary: An ectopic pregnancy occurs when an embryo implants outside of the uterus, usually in a fallopian tube. When detected early, treatment is often with a medication called methotrexate. When methotrexate does not work, surgery is required. A recent clinical trial of ectopic pregnancy treatment (called GEM3) found that adding a drug called gefitinib to methotrexate did not reduce the need for surgery. We have used data from the GEM3 trial, combined with data collected 12 months after the trial finished, to investigate post-methotrexate pregnancy outcomes. We found no difference in pregnancy rates, pregnancy loss rates and recurrent ectopic pregnancy rates between those treated medically only and those who subsequently also needed surgery. The surgical technique used also did not affect pregnancy rates. This research provides reassurance that women with ectopic pregnancies treated medically who need surgery have similar post-treatment pregnancy outcomes to those treated successfully medically.

Evaluation of the effect of multi-dose methotrexate therapy on ovarian reserve in ectopic pregnancies: is polycystic ovarian morphology a protective condition for ovarian reserve?

OBJECTIVES: The study aims to evaluate the effects of multi-dose methotrexate (MTX) or subsequent salpingectomy on ovarian reserve and explain the conditions that cause the change in serum anti-müllerian hormone (AMH) levels. MATERIAL AND METHODS: Our department had 58 tubal ectopic pregnancy (EP) patients treated with a multiple-dose MTX protocol or subsequent salpingectomy between 2017-2020. Serum AMH level was measured in each patient before the medication and 3-6 months after therapy. Patients' details were recorded and analyzed later. RESULTS: The mean AMH value decreased in 32 patients (-17.8%), increased in 26 patients (+31.5%) (p < 0.0001). In the group with an increase, there was a significantly high number of patients with a polycystic ovary (PCO) condition compared to the other group (p = 0.0001). The post-treatment serum AMH levels increased in patients with PCO, whereas those decreased in patients without PCO (p < 0.001). CONCLUSIONS: Multiple-dose MTX or subsequent salpingectomy treatment in tubal ectopic pregnancy (EP) patients might not refer to significant differences in patients' AMH levels. Remarkably, post-treatment AMH levels were significantly increased in EP patients with PCO and decreased in those without this condition. PCO may be a protective condition for ovarian reserve.

The importance of ß-hCG values in prediction of the effectiveness of single dose methotrexate therapy in tubal ectopic pregnancy.

OBJECTIVES: To investigate the importance of ß-hCG values on the day of onset and on the fourth and seventh day after treatment in the effectiveness of treatment in tubal ectopic pregnancies treated with a single dose of methotrexate (MTX). MATERIAL AND METHODS: One hundred sixty-two patients with tubal ectopic pregnancy treated with a single dose MTX treatment were retrospectively evaluated. ß-hCG values and changes on Days 0, 4 and 7 of the MTX treatment successful group and the unsuccessful group were analyzed. RESULTS: MTX treatment was successful in 125 (77.2%) and unsuccessful in 37. When the ß-hCG values on Days 0, 4 and 7 were compared in pairs, the differences between groups were statistically significant (p < 0.001). The mean ß-hCG value was 783.0 in the MTX successful group and 1802.0 in unsuccessful group (p < 0.001). There was a 21.6% decrease in ß-hCG values between Days 0 and day 4 in the MTX successful group and a 25.7% increase in the MTX unsuccessful group (p < 0.001). On Days 0, 4 and 7, ROC curve analysis's values are , respectively; 755/939/486 for cut off, 86.49/83.78/94.59% for sensitivity and 48.80/69.60/72.36% for specificity. CONCLUSIONS: Success rates of single-dose MTX treatment increase in tubal ectopic pregnancies with low initial ß-hCG value. Patients with a decrease in ß-hCG value and/or a cut-off decrease of 20% or more on the fourth day of treatment can be called for weekly ß-hCG monitoring without the need for close follow-up. The change in ß-hCG between Day 0 and Day 4 can be used to predict the efficacy of treatment.

Time to resolution of tubal ectopic pregnancy following methotrexate treatment: A retrospective cohort study.

OBJECTIVE: To determine the time to resolution of tubal ectopic pregnancy after methotrexate treatment. METHODS: A 14-year retrospective cohort study was performed from 2004-2018 and assessed 216 women treated with single-dose methotrexate for tubal ectopic pregnancy. Women were treated using a single-dose protocol of intramuscular methotrexate (50mg/m2) for confirmed tubal ectopic pregnancy on ultrasound. Ectopic pregnancies were included if the ectopic pregnancy mass was <35mm, no evidence of rupture and no embryonic cardiac activity. Serum hCG was measured on day 1, 4 and 7 of treatment and then at standard weekly intervals until resolution. Where there was not a ≥15% decline in hCG from day 4 and day 7, a second dose of methotrexate was administered. The primary outcome was time to resolution (days), with serum hCG <5 IU/L considered resolved. The secondary outcome was need for rescue surgery. RESULTS: Among women who did not proceed to surgery, the median time to resolution was 22 days (IQR 14,34). Time to resolution and need for rescue surgery increased with baseline hCG. When hCG was <1000 IU/L, the median was 20 days (IQR 13,29) but 34.5 days (IQR 22,48) with hCG >2000 IU/L. Early hCG trends were predictive of time to resolution and likelihood of rescue surgery; a hCG rise of >1000 IU/L between Days 1-4 increased time to resolution to 61 days (IQR 35,80) and an odds ratio of rescue surgery of 28.6 (95% C.I. 5.3,155.4). CONCLUSION: The median time to resolution for ectopic pregnancies treated with methotrexate is 22 days and associated with baseline hCG levels. The predictive value of baseline hCG may be useful in clinical decision making and counselling women considering methotrexate for ectopic pregnancy.

Cost-Effectiveness Analysis of Different Methods of Treatment of Tubal Ectopic Pregnancy in the South of Iran.

OBJECTIVES: The aim of the study was to evaluate the cost-effectiveness of different methods of treating tubal ectopic pregnancy in the south of Iran. METHODS: This study was an economic evaluation that analyzed and compared the cost-effectiveness and cost utility of 3 treatment methods, including single-dose methotrexate, double-dose methotrexate, and surgery in patients with tubal ectopic pregnancy. In this study, a decision tree model was used. The outcomes included in the model were the percentage of successful treatment and the average utility score of each treatment method. The study was conducted from the social perspective, and a one-way and probabilistic sensitivity analysis was performed to measure the effects of uncertainty. RESULTS: The incremental cost-effectiveness ratio of surgery compared with single-dose methotrexate was positive and equal to $5812 purchasing power parity; moreover, the results of one-way analysis showed the highest sensitivity toward the effectiveness of single-dose methotrexate. Scatter plots also revealed that surgery in 82% and 96% of simulations was at the acceptable region compared with a single-dose and double-dose methotrexate, respectively and was below the threshold. It was identified as a more cost-effective strategy. Furthermore, the acceptability curves showed that in 81.4% of simulations, surgery was the most cost-effective treatment for thresholds less than $20 950 purchasing power parity. CONCLUSIONS: On the basis of the results of this study, surgery can be used as the first line of treatment for ectopic pregnancy. In addition, the best drug strategy was single-dose methotrexate because this strategy reduced costs and increased treatment success and quality-adjusted life-years compared with double-dose methotrexate.

Can the Additional Dose Requirement be Determined before the Seventh Day to Successfully Treat Tubal Ectopic Pregnancy with a Single-dose Methotrexate Protocol?

OBJECTIVE: To investigate the relationship of beta-hCG changes between the first, fourth and seventh days as a predictor of the additional dose requirement in single-dose methotrexate protocol in tubal ectopic pregnancy. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynecology, Bursa Yüksek Ihtisas Training and Research Hospital, between January 2017 and June 2020. METHODOLOGY: Data of 123 patients with tubal ectopic pregnancy, treated with a single-dose methotrexate protocol, were retrospectively analysed. Patients who received methotrexate on the first day and achieved treatment success constituted one group. Patients who received additional doses on the seventh day and achieved treatment success, constituted the other group. Treatment success was defined as normalisation of beta-hCG levels without surgical intervention. RESULTS: The percentage of beta-hCG change between day-one and day-four was a significant independent variable for the additional dose treatment requirement (OR:1.07, CI:1.01-1.13, p=0.022). The cut-off value of the beta-hCG change percentage between the first and fourth day, was calculated as 4% (sensitivity 72.9%, specificity 78.9%, positive predictive value [PPV] 88.6%, negative predictive value [NPV] 56.6%). CONCLUSION: In the single-dose methotrexate protocol applied in the medical treatment of tubal ectopic pregnancy, the change in beta-hCG value between the first and fourth days may predict the need for additional doses. Administration of an additional dose of methotrexate on the fourth day may be considered, if there is less than a 4% decrease or any increase in beta-hCG value between the first and fourth days. Key Words: Ectopic pregnancy, Methotrexate, Beta human chorionic gonadotropin, Tubal pregnancy, Single-dose protocol.

Tubal Ectopic Pregnancy with Undetectable Initial Serum ß-Human Chorionic Gonadotropin Level.

We present a case of a tubal ectopic pregnancy (EP) in a patient with an initially undetectable serum ß-human chorionic gonadotropin (ß-hCG) level. A 33-year-old woman in a same-sex relationship underwent timed donor intrauterine insemination. Her serum ß-hCG level was <5 mIU/mL 14 days after the intrauterine insemination. She reported menstrual bleeding 3 days after her negative pregnancy test and returned to the office 10 days later to begin a new treatment cycle. Her serum levels of estradiol, progesterone, and ß-hCG were 119 pg/mL, 6.1 ng/mL and 1157 mIU/mL, respectively. Transvaginal ultrasonography did not show an intrauterine pregnancy. Her ß-hCG level increased to 1420 mIU/mL the next day. She was diagnosed with a pregnancy of unknown location and treated with methotrexate. Her ß-hCG levels continued to increase despite 3 methotrexate doses, necessitating laparoscopy. The diagnostic laparoscopy demonstrated approximately 100 mL of hemoperitoneum in the posterior cul-de-sac with an intact right fallopian tube that was dilated at its distal end by the EP. A total right salpingectomy was performed. Her ß-hCG level was <5 mIU/mL 3 weeks later. The current case supports that although rare, an undetectable serum ß-hCG level does not completely rule out the diagnosis of an EP.

Day 1 to day 4 serum hCG change in predicting single-dose methotrexate treatment failure for tubal ectopic pregnancies.

OBJECTIVE: To determine if changes in Day 1 to Day 4 serum human chorionic gonadotropin (hCG) levels can predict treatment failure of single-dose methotrexate (MTX) in medical management of tubal ectopic pregnancies (EP). STUDY DESIGN: This retrospective cohort study was conducted at a tertiary level hospital. Files were reviewed for all women who received at least one dose of 50 mg/m2 intramuscular MTX for treatment of ultrasound-confirmed tubal EPs between 2013 and 2018. "Treatment failure" is defined as needing additional MTX or surgery to manage the EP. The primary purpose is to establish a threshold percentage change in Day 1 to Day 4 (Day 1/4) hCG that best predicts treatment failure, with clinically and statistically significant sensitivity and specificity, based on receiver-operator characteristic (ROC) analysis. RESULTS: 252 files were reviewed, with 108 included for final analysis. 17% of cases required a second dose of MTX and 12% required surgery to manage the EP. Women in the treatment failure group had significantly higher median hCG levels on Day 1, 4 and 7, but were otherwise similar to women who were successful in age, parity, history of previous EP, and EP size. ROC curve analysis of Day 1/4 hCG demonstrates that ≥5% rise best predicts treatment failure with sensitivity 68% (95% confidence interval [CI] 49-83%), specificity 69% (95%CI 56-78%), and AUC 0.77 (95%CI 0.68-0.86, p < 0.001). The positive predictive value is 46% (95%CI 36-56%) and negative predictive value is 84% (95%CI 75-90%). In comparison, ROC analysis of Day 4 to Day 7 hCG demonstrates that a drop of ≤17% best predicted failure, with sensitivity 83% (95%CI 64-94%), specificity 82% (95%CI 71-90%), and AUC 0.90 (95%CI 0.84-0.96), p < 0.001. CONCLUSION: This study suggests that ≥5% rise in Day 1/4 serum hCG levels could potentially predict treatment failure of single-dose MTX for tubal EPs, and that conversely, <5% rise or any drop in Day 1/4 hCG levels can reliably predict treatment success. Clinicians could consider factoring-in Day 1/4 hCG changes during the course of medically managing patients. They must bear in mind, however, that acting on the Day 1/4 hCG change would lead to increased interventions.

A Model to Predict Treatment Failure of Single­Dose Methotrexate in Patients with Tubal Pregnancy.

BACKGROUND In China, approximately 15% of tubal pregnancy patients treated with MTX eventually required surgery because the ectopic mass was ruptured; therefore, it is essential to develop a model to predict the risk of failure with methotrexate treatment in tubal pregnancy. MATERIAL AND METHODS In this research, 168 patients met the eligibility criteria, and 29 candidate risk factors for treatment failure were collected. Multivariable logistic regression analysis was used to analyze the factors, and a full model was developed. We used a multiple fractional polynomial model and a stepwise model to increase the reliability. Bootstrap resampling for 500 times was used to internally test the prediction model. The integral performance of the model depends on the evaluation of the nomogram, the discriminative performance by receiver operating characteristic (ROC) curve analysis, and calibration. RESULTS The model showed excellent discrimination and calibration. The area under the ROC curve for the prediction model, mfp model, and stepwise model were 0.879 (95% CI: 0.812-0.942), 0.872 (95% CI: 0.805-0.931), and 0.880 (95% CI: 0.817-0.949), respectively. At a cutoff value of ≥0.40, sensitivity was 60%, specificity was 91%, positive predictive value (PPV) was 81%, and negative predictive value (NPV) was 77%. The model provides a net benefit when clinical decision thresholds are between 0% and 40% of predicted risk. CONCLUSIONS This model indicated good accuracy in predicting methotrexate treatment failure for tubal pregnancy patients.

Prognostic accuracy of a novel methotrexate protocol for the resolution of tubal ectopic pregnancies.

OBJECTIVE: To evaluate if a decreasing human chorionic gonadotropin (hCG) between day (D) 1 and D7 is an equal or better predictor of tubal ectopic pregnancy (EP) resolution following methotrexate (MTX) treatment than the current standard of care. STUDY DESIGN: This was a retrospective cohort prognostic accuracy study of women with a transvaginal ultrasound (TVS)-confirmed tubal EP (November 2006-December 2015). After single-dose MTX treatment, D4/7 hCG ratios were compared with that of D1/D7 in terms of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) to predict EP resolution. RESULTS: Tubal EP was diagnosed in 301/7350 (4.1%) women who underwent TVS for early pregnancy-related complaints. The patients were managed accordingly: expectant, 84/301 (27.9%); MTX, 65/301 (21.6%); surgery, 152/301 (50.5%). A D1/D7 hCG ratio ≤0.85 predicted successful resolution of tubal EPs (P < 0.001) treated with MTX with sensitivity 0.84 [95% confidence interval (CI), 0.69-0.94]), specificity 0.71 [95%CI, 0.48-0.89], PPV 0.84 [95%CI, 0.69-0.94], NPV 0.84 [95%CI, 0.69-0.94], which is comparable to the prognostic performance of the D4/7 protocol. CONCLUSION: In patients with tubal EP carefully selected for and treated with MTX, it may be reasonable to eliminate the D4 hCG in the follow-up algorithm.

Success rate of methotrexate treatment for recurrent vs. primary ectopic pregnancy: a case-control study.

The aim of this study was to compare the success rate of methotrexate (MTX) treatment in patients with recurrent ectopic pregnancy (REP) and primary EP (PEP). A retrospective cohort study. The study cohort comprised all patients diagnosed with an EP and treated by intention with single-dose regimen of intramuscular MTX in a tertiary medical centre during 2010-2018. Cases (REP) and controls (PEP) were compared.262 patients had PEP and 32 had a REP. Women with REP had significantly higher gravidity order and higher incidence of previous abortions (5 vs. 3, median, p < .001, 59.3% vs. 32.8%, p < .001, respectively). Women with REP had a higher proportion of a history of previous surgery in general, and specifically pelvic surgery (46.8% vs. 20.6%, p < .001, 24.4% vs. 7.2%, p < .001, respectively). Treatment success was lower in the REP group (40.6% vs. 66.4%, p = .006, Odds ratio 0.34, 95% confidence interval 0.16, 0.73). In a logistic regression analysis, the only factor found to be independently associated with treatment failure was REP (adjusted odds ratio 0.30, 95% confidence interval 0.12, 0.77, p = .01). Our study suggests that medical treatment success with a single-dose regimen of MTX is lower than expected among REP cases, suggesting that different treatment approach should be considered in this setting.Impact statementWhat is already known on this subject ? There is paucity of data regarding success rate of methotrexate treatment for a recurrent ectopic pregnancy (REP).What do the results of this study add? Medical treatment success with a single-dose regimen of MTX in patients with a REP is lower than expectedWhat are the implications of these findings for future clinical practice and/or further research? As medical treatment success with a single-dose regimen of MTX for women with a REP is lower than expected, different treatment approach should be considered. Further and prospective studies with a larger sample size are needed to confirm our findings.

Multidose Methotrexate Treatment of Ectopic Pregnancies with High initial ß-Human Chorionic Gonadotropin: Can Success Be Predicted?

OBJECTIVE: To investigate the clinical results and prognostic factors of multiple dose methotrexate (Mtx) treatment of ectopic pregnancy patients with high initial serum (human chorionic gonadotropin [hCG]). DESIGN: Retrospective cohort study. PATIENTS: Twenty-six ectopic pregnancy patients with serum (ßhCG) > 5,000 mIU/mL who received multiple doses of Mtx (1 mg/kg) with folinic acid rescue on the alternating days. RESULTS: Success rate was 88.5%. All failures were tubal ruptures in those who underwent surgery. Median initial hCG values of the success and the failure patients were 8,582 (5,058-31,114) and 5,280 (5,042-13,563) mIU/mL respectively (p > 0.05). Side effects were seen in 18 patients (69.2%, one bone marrow suppression and 17 minor side effects). The number of Mtx injections (7.04 ± 1.71), Mtx dose (71.35 ± 13.16 mg) and follow-up period (42.04 ± 23.77 days) did not differ between groups. Body mass index (BMI), Mtx dose, number of Mtx and change in ßhCG levels between the initials and the levels measured 2 days after the 3rd, 4th, and 5th Mtx injections were found to be highly predictive for tubal rupture. CONCLUSIONS: Multiple-dose Mtx treatment of ectopic pregnancies with high initial hCG is safe and effective. BMI, Mtx dose, number of Mtx injections and the decrement of ßhCG levels were found as highly predictive for the success of the treatment.

A multi-centre, double-blind, placebo-controlled, randomised trial of combination methotrexate and gefitinib versus methotrexate alone to treat tubal ectopic pregnancies (GEM3): trial protocol.

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/m2) 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.

A risk prediction model for medical treatment failure in tubal pregnancy.

OBJECTIVE: Methotrexate is an alternative treatment for tubal pregnancy. However, despite initial treatment, ∼15% of women eventually require surgery. This study aimed to identify the risk factors for medical treatment failure in tubal pregnancy and apply them to a risk prediction model. STUDY DESIGN: This single-center retrospective cohort study included 123 participants initially treated medically for tubal pregnancy between January 2006 and December 2015. Logistic regression analysis was used to construct a risk prediction model (visually presented as a nomogram) for medical treatment failure. Model performance was assessed using discrimination and calibration. The medical treatment failure rate was 36.6%. The prediction model integrated the presence of a gestational sac, ectopic mass size, and follow-up ß-human chorionic gonadotropin levels above cut-off values on days 4 and 7. The model used the following cut-off values: increased ß-human chorionic gonadotropin levels by 1028.6 mIU/mL, 1.0457-fold higher than baseline level on day 4; and increased ß-human chorionic gonadotropin levels by 1233 mIU/mL, 1.3025-fold higher than baseline level on day 7. RESULTS: The corresponding areas under the receiver-operating characteristic curves were 0.8135 (95% confidence interval, 0.733-0.893) for the day 4 model and 0.8600 for the day 7 model (95% confidence interval, 0.788-0.932). Comparison of the day 4 and 7 models revealed no significant difference in their predictive abilities (P = 0.4318). CONCLUSIONS: This model identified a substantial proportion of the participants who experienced medical treatment failure for tubal pregnancy. It was visualized as a nomogram, facilitating clinical application.

Evaluation of Tubal Pregnancy After Treatment With Methotrexate by Ultrasound Elastography.

OBJECTIVES: The purpose of this study was to evaluate the application of ultrasound elastography in the assessment of methotrexate (MTX) treatment for tubal pregnancy and the association with the elasticity score and human chorionic gonadotropin (hCG) concentration. METHODS: A total of 73 cases of unruptured tubal pregnancy were diagnosed and treated systemically with MTX. The sonographic characters of conventional transvaginal sonography and elastography and serum hCG concentrations before and after MTX therapy were retrospectively reviewed and analyzed. RESULTS: The mean elasticity score was statistically significantly lower for the ectopic tubal masses of the success group (mean ± SD, 2.58 ± 0.68) than for the failure group (3.33 ± 0.47) on day 7 (P < .001) and similar on day 0. The median elasticity score for the success group on day 7 was 3, and for the failure group, it was 4. When elasticity scores of 3 and 2 were used for the criterion of successful MTX treatment, the elastography had 94.5% sensitivity, 61.1% specificity, 88.1% positive predictive value, and 78.6% negative predictive value. Elastography of the ectopic masses and subsequent hCG concentration at 1 week after the MTX injection in the success group had a strong relationship. CONCLUSIONS: Our results suggest that transvaginal elastography was a useful tool in the evaluation of tubal pregnancy after pharmacologic management.