[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.

Prediction of Rupture by Complete Blood Count in Tubal Ectopic Pregnancies Treated with a Single-Dose Methotrexate Protocol.

OBJECTIVE: The availability of reliable and inexpensive markers that can be used to determine the risk of rupture during methotrexate (MTX) treatment in ectopic pregnancies (EPs) is considerable. The aim of the present study is to investigate the role of systemic inflammatory markers such as leukocytes (or white blood cells, WBCs), the neutrophil-to-lymphocyte ratio (NLR), and platelet distribution width (PDW), which are among the parameters of the complete blood count (CBC), in the prediction of rupture of EPs under MTX treatment. MATERIALS AND METHODS: A total of 161 patients with tubal EP who underwent a single-dose methotrexate (MTX) protocol were retrospectively analyzed, and the control group (n = 83) included patients cured by MTX, while the ruptured group (n = 78) included patients who were operated on for tubal rupture during the MTX treatment. The features of EP, beta-human chorionic gonadotropin (ß-hCG) levels, sonographic findings, and CBC-derived markers such as WBC, NLR, and PDW, were investigated by comparing both groups. RESULTS: The NLR was found to be higher in the ruptured group, of 2.92 ± 0.86%, and significantly lower in the control group, of 2.09 ± 0.6%. Similarly, the PDW was higher (51 ± 9%) in the ruptured group, and it was significantly lower a (47 ± 13%) in the control group (p < 0.05). Other CBC parameters were similar in both groups (p > 0.05). CONCLUSION: Systemic inflammation markers derived from CBC can be easily applied to predict the risk of tubal rupture in Eps, since the CBC is an inexpensive and easy-to-apply test, which is first requested from each patient during hospitalization.

OBJETIVO: A disponibilidade de marcadores confiáveis e baratos que podem ser usados para determinar o risco de ruptura durante o tratamento com metotrexato (MTX) em gestações ectópicas (GEs) é considerável. O objetivo do presente estudo é investigar o papel de marcadores inflamatórios sistêmicos, como leucócitos (ou glóbulos brancos, glóbulos brancos), a relação neutrófilo-linfócito (NLR) e largura de distribuição de plaquetas (PDW), que estão entre os parâmetros do hemograma completo (hemograma), na predição de ruptura de PEs sob tratamento com MTX. MATERIAIS E MéTODOS: Foram analisados retrospectivamente 161 pacientes com EP tubária submetidas a protocolo de dose única de metotrexato (MTX), sendo que o grupo controle (n = 83) incluiu pacientes curadas com MTX, enquanto o grupo roto (n = 78) incluíram pacientes operadas por ruptura tubária durante o tratamento com MTX. As características de EP, beta-gonadotrofina coriônica humana (ß-hCG), achados ultrassonográficos e marcadores derivados de CBC, como WBC, NLR e PDW, foram investigados comparando os dois grupos. RESULTADOS: A RNL foi maior no grupo roto, de 2,92 ± 0,86%, e significativamente menor no grupo controle, de 2,09 ± 0,6%. Da mesma forma, o PDW foi maior (51 ± 9%) no grupo roto, e foi significativamente menor a (47 ± 13%) no grupo controle (p < 0,05). Outros parâmetros do hemograma foram semelhantes em ambos os grupos (p > 0,05). CONCLUSãO: Marcadores inflamatórios sistêmicos derivados do hemograma podem ser facilmente aplicados para predizer o risco de ruptura tubária na Eps, uma vez que o hemograma é um exame de baixo custo e fácil aplicação, solicitado primeiramente a cada paciente durante a internação.

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.

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.

Adaptation of a Brazilian university hospital to clinical treatment of ectopic pregnancy: Lessons learned over 17 years.

OBJECTIVE: To describe and compare the annual success rates of medical treatment in the analyzed period and to evaluate the associated factors. METHODS: Retrospective study with 158 women with tubal pregnancy followed up over 17 years. Statistical analysis was performed using the Cochran-Armitage test, the χ2 test, Mann-Whitney test, and multiple logistic regression. RESULTS: The success rate was 47.4%. There was a trend of significant change in the success rate of clinical treatment over time (Z = 2.01, P = 0.044); it was associated to undergoing treatment between 2012 and 2017 (P = 0.028), the absence of abdominal pain (P = 0.020), receiving a higher dose of methotrexate (P < 0.001), and less time hospitalized (P < 0.001). In the final statistical model, we observed that receiving a higher dose of methotrexate (P = 0.025, odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00-1.06), having a low serum ß-HCG concentration before treatment (P = 0.003, OR 0.87, 95% CI 0.79-0.95), and not having abdominal pain (P = 0.004, OR 4.26, 95% CI 1.61-11.28) were factors associated with a higher chance of successful clinical treatment for tubal pregnancy. CONCLUSION: A greater chance of success was observed among women undergoing clinical treatment from 2012 onwards, who used higher doses of methotrexate, were asymptomatic at admission, and had low concentrations of ß-hCG.

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).

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.

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.

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.

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.

Live tubal ectopic pregnancy managed with localised injection of methotrexate into gestational sac.

Ectopic pregnancy is a pregnancy outside the uterine cavity and is, in majority of cases, a non-viable pregnancy. There are multiple methods of managing patients with ectopic pregnancy including expectant, medical and surgical management. Live tubal ectopic pregnancies, also known as ectopic pregnancies present in the fallopian tube with fetal heartbeat still present, are most commonly treated via surgical route. This case outlines the presentation and an unusual method of management of a patient diagnosed with a live tubal ectopic pregnancy with extensive medical and surgical history.

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.

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.

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.