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.

Early (Days 1-4) post-treatment serum hCG level changes predict single-dose methotrexate treatment success in tubal ectopic pregnancy.

STUDY QUESTION: What is the capacity of the change between Day 1 and Day 4 post-treatment serum human chorionic gonadotropin (hCG) levels for predicting single-dose methotrexate treatment success in tubal ectopic pregnancy? SUMMARY ANSWER: Any fall in Days 1-4 serum hCG signified an 85% (95% CI 76.8-90.6) likelihood of treatment success for women with tubal ectopic pregnancy (initial hCG of ≥1000 and ≤5000 IU/l) managed with single-dose methotrexate. WHAT IS KNOWN ALREADY: For those with tubal ectopic pregnancy managed by single-dose methotrexate, current guidelines advocate intervention if Days 4-7 hCG fails to fall by >15%. The trajectory of hCG over Days 1-4 has been proposed as an early indicator that predicts treatment success, allowing early reassurance for women. However, almost all prior studies of Days 1-4 hCG changes have been retrospective. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study of women with tubal ectopic pregnancy (pre-treatment hCG of ≥1000 and ≤5000 IU/l) managed with single-dose methotrexate. The data were derived from a UK multicentre randomized controlled trial of methotrexate and gefitinib versus methotrexate and placebo for treatment of tubal ectopic pregnancy (GEM3). For this analysis, we include data from both treatment arms. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were categorized according to single-dose methotrexate treatment success or failure. Treatment success for this analysis was defined as complete and uneventful resolution of tubal ectopic pregnancy to serum hCG <30 IU/l following single-dose methotrexate treatment without additional treatment. Patient characteristics of the treatment success and failure groups were compared. Changes in Days 1-4, 1-7, and 4-7 serum hCG were evaluated as predictors of treatment success through receiver operating characteristic curve analysis. Test performance characteristics were calculated for percentage change ranges and thresholds including optimal classification thresholds. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 322 women with tubal ectopic pregnancy were treated with single-dose methotrexate. The overall single-dose methotrexate treatment success rate was 59% (n = 189/322). For any fall in serum hCG on Days 1-4, likelihood ratios were >3, while for any fall of serum hCG >20% on Days 1-7, likelihood ratios reached 5. Any rise of serum hCG on Days 1-7 and 4-7 strongly reduced the chance of success. Any fall in Days 1-4 hCG predicted single-dose methotrexate treatment success with a sensitivity of 58% and specificity 84%, resulting in positive and negative predictive values of 85% and 57%, respectively. Any rise in Days 1-4 serum hCG <18% was identified as an optimal test threshold that predicted treatment success with 79% sensitivity and 74% specificity, resulting in 82% positive predictive value and 69% negative predictive value. LIMITATIONS, REASONS FOR CAUTION: Our findings may be limited by intervention bias resulting from existing guidelines which influences evaluation of hCG changes reliant on Day 7 serum hCG levels. WIDER IMPLICATIONS OF THE FINDINGS: Examining a large prospective cohort, we show the value of Days 1-4 serum hCG changes in predicting single-dose methotrexate treatment success in tubal ectopic pregnancy. We recommend that clinicians provide early reassurance to women who have a fall or only a modest (<18%) rise in Days 1-4 serum hCG levels, that their treatment will likely be effective. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by funding from the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant reference number 14/150/03). A.W.H. has received honoraria for consultancy for Ferring, Roche, Nordic Pharma and AbbVie. W.C.D. has received honoraria from Merck and Guerbet and research funding from Galvani Biosciences. L.H.R.W. has received research funding from Roche Diagnostics. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). B.W.M. also reports consultancy for ObsEva and Merck and travel support from Merck. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: This study is a secondary analysis of the GEM3 trial (ISRCTN Registry ISRCTN67795930).

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.

Methotrexate vs expectant management for treatment of tubal ectopic pregnancy: An individual participant data meta-analysis.

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.

Reproductive outcomes after expectant and surgical management for tubal pregnancy: a retrospective study.

Background: The management of ectopic pregnancy is widely debated. Salpingectomy, salpingostomy, and expectant management are widely performed, but the best approach in terms of keeping good future spontaneous fertility chances is yet to be determined. Material and methods: We performed a retrospective analysis (Clinical Trial ID: NCT05479786) of the medical records of patients with an ultrasonographic or surgical diagnosis of tubal ectopic pregnancy that were admitted to the University of Debrecen Clinical Centre between 2012 and 2020. Results: A total of 312 patients were included in the analysis. Patients managed expectantly and patients treated with salpingostomy had significantly higher rates of clinical pregnancy than patients treated with salpingectomy. Pregnancy outcomes and recurrence rates were comparable between the study groups. Salpingectomy was found to decrease the likelihood of conceiving spontaneously by 65%. A stratified analysis based on serum ß-HCG levels demonstrated that all treatment modalities carry the same reproductive opportunities for patients presenting with ß-HCG levels ≤ 1745 IU/L. Conclusion: Salpingectomy was found to decrease the patient's chance of achieving a natural conception. Conservative approaches should be considered with caution only when the patient's clinical condition permits, and the patient is appropriately counseled.

[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.

Tubal patency assessment using sequential transvaginal ultrasound and hysterosalpingo-foam sonography after methotrexate treatment for tubal pregnancy.

RESEARCH QUESTION: What is the efficacy of sequential two-dimensional transvaginal ultrasound (2D-US) and hysterosalpingo-foam sonography (HyFoSy) after methotrexate (MTX) treatment for tubal pregnancy among patients who desire a future pregnancy? DESIGN: A prospective trial conducted between May 2019 and November 2020. Patients who had a suspected tubal ectopic pregnancy diagnosed by ultrasound and treated by MTX were included. These patients underwent sequential transvaginal 2D-US assessment of the pelvic organs and a complementary HyFoSy for tubal patency. The primary outcome was tubal obstruction in the affected side. RESULTS: A total of 360 women underwent sequential transvaginal 2D-US assessment of the pelvic organs and a complementary HyFoSy for tubal patency. Of these, 40 (11.1%) women fulfilling the inclusion criteria were enrolled. In six out of 40 (15%), hydrosalpinx of the affected tube was found during the initial transvaginal ultrasound examination and were excluded from further investigation. In the remaining 34 (85%) patients, HyFoSy was carried out. Tubal block was found in 10 out of 34 (29.4%) patients. Of these, eight out of 34 (23.5%) and two out of 34 (5.9%) had a proximal block of the affected tube and bilateral proximal obstruction, respectively. Hysterosalpingography confirmed the tubal obstruction in all the affected cases. No procedure-related complications were documented. CONCLUSIONS: Forty per cent of women who were treated by MTX for tubal pregnancy were diagnosed with tubal obstruction. We recommend that sequential transvaginal ultrasound and HyFoSy become part of routine follow-up for these women, thus offering them timely referral to the appropriate specialist.

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.

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.

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.

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.

Common Methylenetetrahydrofolate Reductase Polymorphisms (A1298C & C677T) in Ectopic Trophoblasts and Methotrexate Treatment Failure in Tubal Pregnancies.

OBJECTIVES: The success rate of methotrexate (MTX) therapy varies among tubal ectopic pregnancies. Common methylenetetrahydrofolate reductase (MTHFR) polymorphisms (C677T&A1298C) have been suggested to alter MTX effect. This study aimed to assess and compare MTX treatment failure rates with respect to MTHFR polymorphisms in trophoblasts of ectopic tubal pregnancies. MATERIAL AND METHODS: A retrospective chart review of tubal ectopic pregnancies was conducted and 34 eligible cases were found. Paraffinized blocks of ectopic trophoblastic tissues were retrieved from the archives of pathology department. Common MTHFR polymorphisms were studied on microdissected trophoblastic tissues. Sixteen cases with history of failed MTX therapy (study group) and 18 control cases were compared for their pertinent clinical characteristics and common MTHFR polymorphisms (C677T&A1298) data. RESULTS: In the study group, there were 8 (50%) C677T single nucleotide polymorphisms (SNP) and 9 (56.7%) A1298C SNP. Polymorphism rates were not found to be different between two groups for neither polymorphism (p > 0.05 for both). Number of compound heterozygotes was 3 (18.7%) in study group and 5 (27.7%) in controls (p = 0.693). In addition, MTHFR polymorphism presence seemed to have no effect on interval serum ß-hCG concentration change in MTX-fail group (p=0.693). CONCLUSIONS: Our data implied that common MTHFR polymorphisms of ectopic trophoblastic tissue are not associated with MTX failure in patients with tubal pregnancies. Additionally, serum ß-hCG concentration changes caused by MTX treatment and studied MTHFR polymorphisms are likely independent.

Disparities in the management of ectopic pregnancy.

BACKGROUND: Ectopic pregnancy is common among young women. Treatment can consist of either surgery with salpingectomy or salpingostomy or medical management with methotrexate. In addition to acute complications, treatment of ectopic pregnancy can result in long-term sequelae that include decreased fertility. Little is known about the patterns of care and predictors of treatment in women with ectopic pregnancy. Similarly, data on outcomes for various treatments are limited. OBJECTIVE: We examined the patterns of care and outcomes for women with ectopic pregnancy. Specifically, we examined predictors of medical (vs surgical) management of ectopic pregnancy and tubal conservation (salpingostomy vs salpingectomy) among women who underwent surgery. STUDY DESIGN: The Perspective database was used to identify women with a diagnosis of tubal ectopic pregnancy treated from 2006-2015. Perspective is an all-payer database that collects data on patients at hospitals from throughout the United States. Women were classified as having undergone medical treatment, if they received methotrexate, and surgical treatment, if treatment consisted of salpingostomy or salpingectomy. Multivariable models were developed to examine predictors of medical treatment and of tubal conserving salpingostomy among women who were treated surgically. RESULTS: Among the 62,588 women, 49,090 women (78.4%) were treated surgically, and 13,498 women (21.6%) received methotrexate. Use of methotrexate increased from 14.5% in 2006 to 27.3% by 2015 (P<.001). Among women who underwent surgery, salpingostomy decreased over time from 13.0% in 2006 to 6.0% in 2015 (P<.001). Treatment in more recent years, at a teaching hospital and at higher volume centers, were associated with the increased use of methotrexate (P<.05 for all). In contrast, Medicaid recipients (adjusted risk ratio, 0.92; 95% confidence interval, 0.87-0.98) and uninsured women (adjusted risk ratio, 0.87; 95% confidence interval, 0.82-0.93) were less likely to receive methotrexate than commercially insured patients. Among those who underwent surgery, black (adjusted risk ratio, 0.76; 95% confidence interval, 0.69-0.85) and Hispanic (adjusted risk ratio, 0.80; 95% confidence interval, 0.66-0.96) patients were less likely to undergo tubal conserving surgery than white women and Medicaid recipients (adjusted risk ratio, 0.69; 95% confidence interval, 0.64-0.75); uninsured women (adjusted risk ratio, 0.60; 95% confidence interval, 0.55-0.66) less frequently underwent salpingostomy than commercially insured patients. CONCLUSION: There is substantial variation in the management of ectopic pregnancy. There are significant race- and insurance-related disparities associated with treatment.

Single-dose systemic methotrexate vs expectant management for treatment of tubal ectopic pregnancy: a placebo-controlled randomized trial.

OBJECTIVE: Methotrexate is used routinely worldwide for the medical treatment of clinically stable women with a tubal ectopic pregnancy. This is despite the lack of robust evidence to show its superior effectiveness over expectant management. The aim of our multicenter randomized controlled trial was to compare success rates of methotrexate against placebo for the conservative treatment of tubal ectopic pregnancy. METHODS: This study took place in two early-pregnancy units in the UK between August 2005 and June 2014. Inclusion criteria were clinically stable women with a conclusive ultrasound diagnosis of a tubal ectopic pregnancy, presenting with a low serum beta human chorionic gonadotropin (ß-hCG) level of < 1500 IU/L. Women were assigned randomly to a single systemic injection of either 50 mg/m2 methotrexate or placebo. The primary outcome was a binary indicator for success of conservative management, defined as resolution of clinical symptoms and decline of serum ß-hCG to < 20 IU/L or a negative urine pregnancy test without the need for any additional medical intervention. An intention-to-treat analysis was followed. RESULTS: We recruited a total of 80 women, 42 of whom were assigned to methotrexate and 38 to placebo. The arms of the study were matched in terms of age, ethnicity, obstetric history, pregnancy characteristics and serum levels of ß-hCG and progesterone. The rates of success were similar for the two study arms: 83% with methotrexate and 76% with placebo. On univariate analysis, this difference was not statistically significant (χ2 (1 degree of freedom) = 0.53; P = 0.47). On multivariate logistic regression, the serum level of ß-hCG was the only covariate found to be significantly associated with outcome. The odds of failure increased by 0.15% for each unit increase in ß-hCG (odds ratio, 1.0015 (95% CI, 1.0002-1.003); P = 0.02). In 14 women presenting with serum ß-hCG of 1000-1500 IU/L, the success rate was 33% in those managed expectantly compared with 62% in those receiving methotrexate. This difference was not statistically significant and a larger sample size would be needed to give sufficient power to detect a difference in the subgroup of women with higher ß-hCG. In women with successful conservative treatment, there was no significant difference in median ß-hCG resolution times between study arms (17.5 (interquartile range (IQR), 14-28.0) days (n = 30) in the methotrexate group vs 14 (IQR, 7-29.5) days (n = 25) in the placebo group; P = 0.73). CONCLUSIONS: The results of our study do not support the routine use of methotrexate for the treatment of clinically stable women diagnosed with tubal ectopic pregnancy presenting with low serum ß-hCG (< 1500 IU/L). Further work is required to identify a subgroup of women with tubal ectopic pregnancy and ß-hCG ≥ 1500 IU/L in whom methotrexate may offer a safe and cost-effective alternative to surgery. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Comparación entre una sola dosis de metotrexate sistémico y la conducta expectante en el tratamiento de casos de embarazo ectópico tubárico: un ensayo aleatorio controlado con placebo RESUMEN OBJETIVO: El metotrexate se utiliza de modo rutinario en todo el mundo para el tratamiento de las mujeres clínicamente estables con un embarazo ectópico tubárico. Esto sucede a pesar de la falta de evidencia rigurosa que demuestre que su eficacia es superior a la conducta expectante. El objetivo de este ensayo controlado aleatorio multicéntrico fue comparar las tasas de éxito del metotrexate con las de un placebo para el tratamiento cauteloso del embarazo ectópico tubárico. MÉTODOS: Este estudio se llevó a cabo en dos clínicas de control de gestación temprana en el Reino Unido entre agosto de 2005 y junio de 2014. Los criterios de inclusión fueron mujeres clínicamente estables con un diagnóstico ecográfico concluyente de embarazo ectópico tubárico, las cuáles presentaban una concentración sérica baja de la ß hormona coriónica gonadotrópica (ß-hCG) inferior a 1500 UI/L. Las mujeres fueron asignadas aleatoriamente a una sola inyección sistémica de 50 mg/m2 de metotrexate o a placebo. El resultado primario fue un indicador binario del éxito del tratamiento conservador, definido como la resolución de los síntomas clínicos y la disminución en el suero de la ß-hCG a <20 UI/L o una prueba de embarazo negativa en orina sin la necesidad de ninguna intervención médica adicional. Se hizo un análisis por intención de tratar. RESULTADOS: Se reclutó un total de 80 mujeres; a 42 de ellas se les asignó el metotrexate y a 38 el placebo. Los grupos del estudio se realizaron en función de la edad, el origen étnico, los antecedentes obstétricos, las características del embarazo y los niveles séricos de la ß-hCG y la progesterona. Las tasas de éxito fueron similares para los dos grupos de estudio: 83% con metotrexate y 76% con placebo. En el análisis univariante, esta diferencia no fue estadísticamente significativa (χ2 (1 grado de libertad) = 0,53; P = 0,47). En la regresión logística multivariante, el nivel sérico de la ß-hCG fue la única covariable que se encontró significativamente asociada con el resultado. Las probabilidades de fracaso aumentaron en un 0,15% por cada unidad de aumento de la ß-hCG (cociente de probabilidad 1,0015 (IC 95%, 1,0002-1,003); P = 0,02). La tasa de éxito en las 14 mujeres con un nivel sérico de la ß-hCG de 1000-1500 UI/L fue del 33% en las tratadas con conducta expectante frente al 62% en las que recibieron metotrexate. Esta diferencia no fue estadísticamente significativa, por lo que se necesitaría un tamaño de muestra mayor, lo suficiente como para poder detectar diferencias en el subgrupo de mujeres con una ß-hCG más elevada. En las mujeres en las que el tratamiento conservador tuvo éxito, no hubo una diferencia significativa en la mediana de los tiempos de resolución de la ß-hCG entre los grupos del estudio (17,5 (amplitud intercuartílica (IQR), 14-28,0) días (n = 30) en el grupo de metotrexate frente a 14 (IQR, 7-29.5) días (n = 25) en el grupo de placebo; P = 0,73). CONCLUSIONES: Los resultados de este estudio no apoyan el uso rutinario de metotrexate para el tratamiento de las mujeres clínicamente estables diagnosticadas con un embarazo ectópico tubárico que presenta un nivel sérico bajo la ß-hCG (<1500 UI/L). Serán necesarios estudios adicionales para identificar un subgrupo de mujeres con embarazo ectópico tubárico y ß-hCG ≥1500 UI/L para quienes el metotrexate puede ofrecer una alternativa segura y rentable en comparación con la cirugía. : : ,,。。 : 2005820146,2。,,ß(beta human chorionic gonadotropin,ß-hCG)<1500 IU/L。,(50 mg/m2 )。,ß-hCG<20 IU/L,。。 : 80,42,38。2、、、ß-hCG。2:83%,76%。,[χ2 (1)=0.53;P=0.47]。logistic,ß-hCG。ß-hCG,0.15%[,1.0015(95% CI,1.0002~1.003);P=0.02]。14ß-hCG1000~1500 IU/L,33%,62%。,ß-hCG。,2ß-hCG(P=0.73),17.5[(interquartile range,IQR),14~28.0](n=30),14 (IQR,7~29.5)(n=25)。 : 、、ß-hCG(<1500 IU/L)。,ß-hCG>1500 IU/L、。.

Comparison of alternative ßhCG follow-up protocols after single-dose methotrexate therapy for tubal ectopic pregnancy.

PURPOSE: To evaluate the performances of five different ßhCG follow-up protocols after single-dose methotrexate therapy for tubal ectopic pregnancy (EP). METHODS: Data of patients who received single-dose methotrexate therapy for tubal EP at a university hospital between January 2011 and July 2016 were reviewed. A 'successful methotrexate treatment' was defined if the EP treated with no need for surgery. The performances of different protocols were tested by comparing with the currently used '15% ßhCG decrease between days 4 and 7' protocol. The tested follow-up protocols were '20, 25%, and any ßhCG decrease between days 0/1 and 7' and '20% and any ßhCG decrease between days 0/1 and 4'. RESULTS: Among the 96 patients evaluated, 12 (12.5%) required second dose. Totally, 91 (94.8%) patients treated successfully with no need for surgery. Four patients were operated within 4 days following the second dose. One patient who did not need second dose according to the standard follow-up protocol was operated on the 10th day due to rupture (specificity = 80%). Two protocols, namely '20% ßhCG decrease between days 0/1 and 7' and 'any ßhCG decrease between days 0/1 and 7' did not show statistically significant differences from the index protocol regarding the number of patients who should be assigned to 2nd dose. CONCLUSIONS: 'Any ßhCG decrease between days 0/1 and 7' protocol may substitute the currently used one to decide second dose methotrexate in tubal EP management. Omitting 4th day measurement seems to be more convenient and cost effective.

Medical management of ectopic pregnancy with single-dose and 2-dose methotrexate protocols: human chorionic gonadotropin trends and patient outcomes.

BACKGROUND: Ectopic pregnancy, although rare, is an important cause of female morbidity and mortality and early, effective treatment is critical. Systemic methotrexate has become widely accepted as a safe and effective alternative to surgery in the stable patient. As the number and timing of methotrexate doses differ in the 3 main medical treatment regimens, one might expect trends in serum human chorionic gonadotropin and time to resolution to vary depending on protocol. Furthermore, human chorionic gonadotropin trends and time to resolution may predict ultimate treatment success. OBJECTIVE: This study hypothesized that the 2-dose methotrexate protocol would be associated with a faster initial decline in serum human chorionic gonadotropin levels and a shorter time to resolution compared to the single-dose protocol. STUDY DESIGN: A prospective multicenter cohort study included clinical data from women who received medical management for ectopic pregnancy. Rates of human chorionic gonadotropin change and successful pregnancy resolution were assessed. Propensity score modeling addressed confounding by indication, the potential for differential assignment of patients with better prognosis to the single-dose methotrexate protocol. RESULTS: In all, 162 ectopic pregnancies were in the final analysis; 114 (70%) were treated with the single-dose methotrexate and 48 (30%) with the 2-dose protocol. Site, race, ethnicity, and reported pain level were associated with differential protocol allocation (P < .001, P = .011, P < .001, and P = .035, respectively). Women had similar initial human chorionic gonadotropin levels in either protocol but the mean rate of decline of human chorionic gonadotropin from day 0 (day of administration of first dose of methotrexate) to day 7 was significantly more rapid in women who received the single-dose protocol compared to those treated with the 2-dose protocol (mean change -31.3% vs -10.4%, P = .037, adjusted for propensity score and site). The 2 protocols had no significant differences in success rate or time to resolution. CONCLUSION: In a racially and geographically diverse group of women, the single- and double-dose methotrexate protocols had comparable outcomes. The more rapid human chorionic gonadotropin initial decline in the single-dose group suggested these patients were probably at lower risk for ectopic rupture than those getting the 2-dose protocol. A prospective randomized controlled design is needed to remove confounding by indication.

Role of mean platelet volume and neutrophil/lymphocyte ratio to predict single-dose methotrexate treatment success in tubal ectopic pregnancy.

OBJECTIVE: The aim of the study was to evaluate the value of mean platelet volume (MPV) and neutrophil/lymphocyte ratio (NLR) to predict single-dose methotrexate (MTX) treatment success in ectopic pregnancy (EP). MATERIALS AND METHODS: A total of 115 EP diagnosed and hemodynamically stable women were enrolled in the study and divided into two groups as group 1, the treatment success group (n= 78) and group 2, the treatment failure group (n = 37). The authors compared the groups in terms of MPV and NLR. RESULTS: MPV and NLR levels were higher in MTX treatment successful group than in failure group.The cut-off values of MPV and NLR were determined as 10.1 fL and 1.82, respectively. These cut off values showed similar sensitivity and specificity in prediction of MTX treat- ment success. CONCLUSION: MPV and NLR can be used as reliable markers to predict single-dose MTX treatment success however further studies are needed.

Effectiveness of expectant management versus methotrexate in tubal ectopic pregnancy: a double-blind randomized trial.

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 ß-hCG concentration <2,000 mIU/mL, declining titers of ß-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 ß-hCG occurred in 9 cases (90.0%) of the methotrexate group and in 12 (92.3%) of the placebo group (p > 0.999). The ß-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 ß-hCG to become undetectable.

Nonsurgical management of live tubal ectopic pregnancy by ultrasound-guided local injection and systemic methotrexate.

STUDY OBJECTIVE: To evaluate outcomes relative to treatment using systemic methotrexate (MTX) alone or systemic MTX combined with ultrasound (US)-guided local injection of potassium chloride (KCl) or MTX in women with live tubal ectopic pregnancies. DESIGN: Case-control study (Canadian Task Force classification II-2). SETTING: Departments of Obstetrics and Gynecology in 2 hospitals in China. PATIENTS: Eighty-two women with live tubal ectopic pregnancies. INTERVENTION: Participants in the study received treatment using either systemic MTX (n = 37; systemic treatment group) or systemic MTX and US-guided local injection of either MTX or KCl (n = 45; combined treatment group). MEASUREMENTS AND MAIN RESULTS: Patient clinical features and outcomes were compared. There were no significant differences between the patient groups insofar as baseline gestational age, ß-human chorionic gonadotropin concentration, or size of conceptus. The success rate in patients who received combined therapy (93.3%) was much higher than in those who received only systemic treatment (73.0%) (p < .05). In the combined treatment group, the success rate was similar between women who received locally injected KCl (95.2%) and those who received locally injected MTX (91.7%). CONCLUSION: The significantly higher success rate in patients who received combined US-guided local injection and systemic MTX suggests that this is an efficient nonsurgical option in women with tubal pregnancy, high serum ß-human chorionic gonadotropin concentration, and fetal cardiac activity.