{"paper_id":"1e851260-ddf8-426f-b226-65d3eff08b26","body_text":"Ectopic Pregnancy (EP) refers to a condition where a developing embryo (blastocyst)\nimplants and grows in tissue other than the endometrial lining of the uterus.\nEctopic pregnancies most frequently occur within the fallopian tube. However, they\ncan also develop in other locations, such as the interstitial area, cornua of the\nuterus, ovaries, cervix, surgical scars, abdominal cavity, or in combination with an\nintrauterine pregnancy, known as a heterotopic pregnancy [ 1 ]. Ruptured ectopic pregnancy is the leading cause of maternal\nmortality in the first trimester, accounting for 9% to 14% of maternal deaths and\nrepresenting 5% to 10% of all pregnancy-related deaths [ 2 ]. Women with EP may exhibit non-specific symptoms such as\nlower abdominal pain and vaginal bleeding, which can clinically resemble\nappendicitis, urinary stones, early miscarriage, or trauma [ 3 ].\nThe current standard for diagnosis includes ultrasound imaging (US)—either\ntransvaginal (TVUS) or transabdominal (TAUS)—and monitoring of beta-human chorionic\ngonadotropin (β-hCG) levels [ 4 ]. Early and\naccurate diagnosis of EP can help reduce maternal mortality rates. Notably, no\nidentifiable risk factor exists in half of the diagnosed EP cases. Risk factors\ninclude a history of EP, fallopian tube damage, prior pelvic surgery, pelvic\ninfections, prior fallopian tube pathology or surgery, infertility, smoking,\nadvanced maternal age (over 35 years), pelvic inflammatory disease, endometriosis,\nanatomical abnormalities of the reproductive system, pregnancy with an intrauterine\ndevice (IUD) in place [ 5 ][ 6 ]. EPs are particularly challenging and have\nbecome more common due to the rise in assisted reproductive technologies (ART). The\nincidence is approximately 1 in 100 pregnancies involving in vitro fertilization\n(IVF) and 1 in 7000 pregnancies using ART with ovulation induction [ 7 ]. The growing use of IVF has contributed to\nhigher rates of EPs, with studies reporting 2.1%-8.6% of IVF pregnancies\nexperiencing EP after embryo transfer, compared to 2% in spontaneous conceptions\n[ 8 ]. Additionally, the World Health\nOrganization (WHO) highlights a global increase in cesarean sections, now accounting\nfor 21% of all deliveries. This trend is linked to a rising incidence of cesarean\nscar pregnancies (CSPs), a specific type of EP [ \n9 ].\nAfter confirming the diagnosis of EP, treatment can be either conservative or\ninvasive, depending on the location of the EP, gestational age, and size of the\ngestational sac (GS). There are three primary approaches to managing EP: medical\ntreatment, surgical intervention, and expectant management [ 10 ]. The current standard for medical management of EP involves\nintramuscular injection of methotrexate (MTX), a folate antagonist that inhibits\nrapid cell division, thereby terminating the EP [ \n11 ]. Additionally, given the significant health risks associated with\nectopic pregnancies, timely and effective management is crucial. Methotrexate has\nemerged as a key medical treatment for unruptured ectopic pregnancies, offering a\nnon-invasive alternative to surgical intervention. However, the efficacy and safety\nof methotrexate, as well as the factors influencing treatment outcomes, remain areas\nof active research. Scientific reports estimate the success rate of MTX treatment\nwithout the need for surgical intervention at 70% to 95%, although its efficacy is\nlower in patients with higher initial β-hCG levels. However, recent meta-analyses\nhave shown inconsistent findings regarding the success rates and risk of side\neffects with different treatment regimens, highlighting the need for further\nresearch in this area. Several studies have identified predictive factors that may\ninfluence the success of methotrexate treatment in ectopic pregnancies. For\ninstance, a study by Stovall et al. (4) found that lower serum human chorionic\ngonadotropin (hCG) levels at the time of treatment are associated with higher\nsuccess rates. Specifically, patients with initial hCG levels below 5,000 mIU/mL had\na significantly greater likelihood of successful treatment without the need for\nsurgical intervention[ 12 ]. A better\nunderstanding of the factors influencing MTX efficacy in EP treatment could help\nclinicians select the most appropriate therapeutic approaches. Identifying\npredictors of treatment success could prevent side effects from ineffective\ntherapies, reduce treatment costs, and improve both the physical and mental\nwell-being of patients. Therefore, the purpose of this study was to determine the\nfactors associated with and predictive of successful medical management of EP using\nMTX.\n\nThe study was a case-control design and conducted with the approval of the Medical\nEthics Committee of Iran University of Medical Sciences (Ethics Code:\nIR.IUMS.FMD.REC.1403.159). Patients diagnosed with tubal ectopic pregnancy who had\nundergone single-dose methotrexate medical treatment at Akbarabadi Hospital in\nTehran between 2017 and 2023 were included in the study. These patients were\ncategorized into two groups: those with successful medical treatment (case group)\nand those with failed medical treatment (control group).\nPatients were categorized into two groups based on treatment outcomes:\n• Successful Treatment (Case Group): Defined as a decrease in serum beta-hCG\nlevels\nto less than 15 mIU/mL within 4-6 weeks following methotrexate administration,\nwithout the need for surgical intervention. Successful treatment was also\nconfirmed\nby follow-up ultrasound showing resolution of the ectopic mass.\n• Unsuccessful Treatment (Control Group): Defined as either a failure to achieve\nthe\naforementioned decrease in serum beta-hCG levels or the need for surgical\nintervention (laparoscopy or laparotomy) due to persistent or increasing hCG\nlevels\nor clinical symptoms indicating complications.\n•\nThe study included a total of 100 patients diagnosed with tubal ectopic pregnancy\nwho\nunderwent single-dose methotrexate (MTX) treatment. To ensure that this sample\nsize\nwas adequate for the analyses performed, a power analysis was conducted prior to\nthe\nstudy. Based on previous literature, we anticipated an expected success rate of\n80%\nfor single-dose MTX treatment. Our goal was to detect a minimum difference of\n15% in\nsuccess rates between the successful and unsuccessful treatment groups. Assuming\na\nsignificance level (alpha) of 0.05 and a desired power (1 - beta) of 0.80, we\ncalculated the required sample size using the following formula for comparing\ntwo\nproportions:\nn=(p1 −p2 )2(Zα/2 +Zβ )2.(p1 (1−p1 )+p2 (1−p2 ))\nWhere:\n• Zα/2 is the Z-value for a two-tailed test at the 0.05 significance level\n(approximately 1.96).\n• Zβ is the Z-value for the desired power (approximately 0.84 for 80% power).\n• p1 is the expected success rate in the case group (0.80).\n• p2 is the expected success rate in the control group (0.65, assuming a 15%\nlower\nsuccess rate).\nThe power analysis indicated that a minimum sample size of approximately 60\npatients\nper group would be required to achieve adequate power for detecting a\nsignificant\ndifference in treatment success rates. However, we acknowledge that our final\nsample\nincluded 60 patients in the case group and only 40 patients in the control\ngroup,\nresulting in a case-to-control ratio that is not optimal. This limitation may\naffect\nthe statistical power of our comparisons and the generalizability of our\nfindings.\nDemographic data, including age, gestational age, gravidity, parity, history of\nectopic pregnancy in previous pregnancies, use of assisted reproductive\ntechnology\n(ART), and contraceptive methods (e.g., IUD placement), were extracted from\narchived\npatient records and documented in the study checklist. Additionally, serum\nbeta-hCG\nlevels and ultrasound findings—such as the size and location of the ectopic\npregnancy, presence of hematoma, fluid in the cul-de-sac, tubal ring shape,\nendometrial thickness, and Doppler findings—were recorded and compared between\nthe\ntwo groups. Data analysis was performed using IBM SPSS Statistics for Windows,\nversion 30 (IBM Corp., Armonk, N.Y., USA). Qualitative variables were expressed\nas\nfrequency and percentage, while quantitative variables were presented as mean\nand\nstandard deviation. Comparisons between the two groups were conducted using\nT-tests\nand Chi-square tests (Fisher’s exact test), with a P-value of less than 0.05\nconsidered statistically significant. Logistic regression was performed to\nevaluate\nthe association of multiple clinical variables with the likelihood of successful\ntreatment. Univariate analyses were conducted to identify variables\nsignificantly\nassociated with treatment success, with those having a P-value of less than 0.1\nconsidered for inclusion in the multivariate logistic regression model. This\napproach helps ensure that the final model accounts for potential confounders\nwhile\nmaintaining statistical power. The final logistic regression model was assessed\nfor\ngoodness-of-fit using the Hosmer-Lemeshow test, and multicollinearity among\npredictor variables was evaluated using variance inflation factors (VIF), with a\nVIF\nvalue greater than 10 indicating multicollinearity.\n\nThe results of this study may have limited applicability to broader populations due\nto the\nspecific characteristics of the study cohort. A total of 100 patients were included,\nwith 60\nachieving successful treatment with a single dose of methotrexate, resulting in a\nsuccess rate\nof 93.75% for ectopic pregnancy (EP) management. In the successful treatment group,\nthe mean age\nwas 31.84 ± 4.59 years, while the failed treatment group had a mean age of 34.50 ±\n1.71 years,\nwith no significant difference observed (P = 0.272). The mean parity in the\nsuccessful group was\n1.45 ± 1.54 compared to 2.25 ± 1.50 in the failed group, also showing no significant\ndifference\n(P = 0.203). Similarly, the mean gravidity was 3.25 ± 1.50 in the successful group\nversus 2.50 ±\n1.29 in the failed group, with no significant difference (P = 0.259). The mean\ngestational age\nin the successful treatment group was 37.00 ± 6.63 days, compared to 39.26 ± 12.80\ndays in the\nfailed treatment group, with no significant difference (P = 0.732). The mean β-hCG\nlevel was\n1395 ± 1464 IU/L in the successful group and 1135 ± 481.5 IU/L in the failed group,\nwith no\nsignificant difference (P = 0.806). The frequency of IUD usage was 8% in the\nsuccessful group\nand 0% in the failed group, with no significant difference (P = 0.547). The\nfrequency of prior\nEP was 15% in the successful group and 0% in the failed group, also showing no\nsignificant\ndifference (P = 0.900). The presence of hematoma was observed in 53% of the\nsuccessful group and\n50% of the failed group, with no significant difference (P = 0.900). The frequency\nof tubal ring\nobservation was 86% in the successful group and 50% in the failed group, with no\nsignificant\ndifference (P = 0.111). Additional details of other variables studied are provided\nin\nTable- 1 . To assess the relationship between\nkey clinical\nfeatures—such as history of EP, tubal ring presence, hematoma, and endometrial\nthickness—and\ntreatment success, we conducted logistic regression analysis. As shown in\nTable- 2 , gestational age was not a\nsignificant predictor of\nsuccessful treatment (odds ratio [OR]: 1.006, 95% confidence interval [CI]: 0.915 -\n1.106, P =\n0.902). A history of ectopic pregnancy demonstrated a non-significant association\nwith treatment\nsuccess (OR: 0.529, 95% CI: 0.049 - 5.672, P = 0.599). Although the reduced odds\nratio suggests\na potential trend, the wide confidence interval indicates high variability in the\ndata. The\npresence of a tubal ring was borderline significant (OR: 6.500, 95% CI: 0.799 -\n52.897, P =\n0.080), suggesting that patients with tubal ring findings were approximately six\ntimes more\nlikely to experience successful medical management compared to those without. The\npresence of\nhematoma was not a significant predictor of success (OR: 1.143, 95% CI: 0.151 -\n8.654, P =\n0.897). Endometrial thickness emerged as a borderline significant factor, with an\nodds ratio of\n1.317 (95% CI: 0.971 - 1.786, P = 0.077).\nRight pelvic inflammatory disease (PID) was not a significant predictor (OR: 1.174,\n95% CI: 0.191\n- 7.227, P = 0.863). Similarly, left PID showed no significant association with\nsuccessful\ntreatment (OR: 1.966, 95% CI: 0.515 - 7.505, P = 0.322). HCG levels did not\nsignificantly\npredict treatment success (odds ratio [OR]: 1.000, 95% confidence interval [CI]:\n0.999 - 1.001,\nP = 0.654). Similarly, the presence of fluid in the cul-de-sac did not demonstrate a\nsignificant\neffect on treatment success (OR: 0.436, 95% CI: 0.043 - 4.436, P = 0.483). Patient\nage exhibited\na negative but non-significant association with treatment success (OR: 0.808, 95%\nCI: 0.626 -\n1.044, P = 0.104). Although older patients may have slightly lower odds of\nsuccessful treatment,\nthis finding was not statistically conclusive. The observed negative association\nbetween patient\nage and treatment success, while not statistically significant, raises important\nconsiderations\nfor clinical practice. Older patients may face marginally lower odds of successful\ntreatment,\npotentially due to age-related factors such as decreased ovarian reserve or altered\npharmacokinetics of methotrexate. Clinicians should be mindful of these potential\ndifferences\nand consider them when counseling older patients about treatment options and\nexpectations.\n\nThe results of the present study indicate that single-dose methotrexate (MTX) therapy\nfor the\ntreatment of tubal ectopic pregnancy (EP) achieves a high success rate. However,\ngiven the\nlimited sample size, none of the examined variables demonstrated a significant\nimpact or\npredictive power on treatment success. This finding suggests that while MTX therapy\nis\neffective, the small sample may restrict our ability to draw definitive conclusions\nregarding\nthe influence of specific clinical factors on treatment outcomes. Future studies\nwith larger\nsample sizes are needed to better understand the predictors of success in this\ncontext.\nMTX (Methotrexate) is a folic acid antagonist that inhibits the synthesis of new\ncellular DNA.\nThis antineoplastic and antimetabolic drug has been increasingly used for the\ntreatment of EP\nsince it was first reported by Tanaka and colleagues in 1982 [ \n13 ]. For many patients, single-dose systemic MTX protocols are commonly\nemployed as a\nstandard treatment option, with no significant difference in success rates. Various\nstudies in\ndifferent populations have reported the success rate of single-dose methotrexate in\ntreating EP\nto be as high as 89%, as noted in the study by Bottin et al. [ \n14 ]. In the present study, the success rate of single-dose MTX treatment\nwas reported\nto be 93.75%, which falls within an acceptable range and is higher and more\neffective compared\nto other studies. Proper patient selection for medical treatment and early detection\nof EP are\nlikely factors that ultimately result in a positive impact on the success rate of\nmedical\ntreatment. This is because the longer the time since the onset of symptoms, the\nhigher the\nlikelihood of requiring surgical intervention.\nIn the present study, maternal age, parity, and gravidity parameters showed no\nsignificant\nassociation with the effectiveness of single-dose MTX therapy. This finding aligns\nwith the\nresults of other studies, such as those by Ghanaie et al. [ \n15 ] and Mirbolouk et al. [ 16 ],\nwhere these\nparameters also lacked predictive power. No opposing studies have been reported in\nthis regard,\nand various sources have not reported a significant effect of these parameters on\nthe efficacy\nof MTX treatment for EP. The presence of a hematoma in ectopic pregnancy (EP) can\nnegatively\nimpact the success of methotrexate (MTX) treatment and increase the likelihood of\nrequiring\nsurgical interventions [ 17 ]. In some studies,\nsuch as\nthat by Chegini et al. [ 17 ], the presence of\na hematoma\nhas demonstrated predictive power. However, in most studies, these parameters did\nnot show\npredictive value for the success of medical treatment with MTX [ \n18 ][ 5 ]. Similarly, in the present\nstudy, no\nsignificant association between hematoma presence and treatment success was\nreported, aligning\nwith the majority of studies.\nIn the present study, the size of the EP was larger in the unsuccessful treatment\ngroup compared\nto the successful treatment group, but this difference was not statistically\nsignificant. These\nfindings are consistent with studies by Arafa et al. [ 18 ]\nand Mirbolouk et al. [ 16 ], where the EP size\nwas also\nlarger in the unsuccessful treatment groups. This aligns with the understanding that\nlarger\nectopic masses are more resistant to medication, complicating treatment and\nincreasing the need\nfor further interventions.\nIn our study, the ampulla of the fallopian tube was the most frequent location of EP.\nHowever,\nthe frequency of this variable did not significantly differ between the two study\ngroups, which\nis consistent with other studies and reports indicating that the ampulla is the most\ncommon site\nof EP in women. Gestational age in our study did not have predictive value for the\nsuccess of EP\ntreatment with single-dose MTX. This finding is in line with studies by Bonin et al.\n[ 19 ], Mirbolouk et al. [ \n16 ], and others, which also reported no significant differences in\ngestational age\nbetween successful and unsuccessful treatment groups.\nIn the present study, the serum β-hCG level at the start of treatment was 1395 in the\nresponder\ngroup and 1135 in the non-responder group, with no significant difference between\nthe two.\nAlthough the range of β-hCG levels in our study participants aligns with other\nstudies, such as\nthose by Shatkin Hamish et al. [ 20 ] and\nGhanaie et al.\n[ 15 ], the lower levels in the unsuccessful\ntreatment\ngroup cannot be explained except by the small sample size. This is because various\nstudies have\nreported that serum β-hCG levels have predictive power for the success of EP\ntreatment with\nsingle-dose MTX. In 2023, Ghanaie et al. reported that serum β-hCG levels at the\nstart of\ntreatment and their reduction on days 4 and 7 post-treatment can predict the success\nof\nsingle-dose MTX treatment [ 15 ]. Similarly, a\n2024 study\nby Deniz et al. highlighted that the predictive power of β-hCG levels, as well as\ntheir\nreduction by day 4, can guide decisions regarding the need for additional drug dose\n[ 21 ].\nOne of the other notable trends observed was the borderline significance of\nendometrial thickness\nand tubal ring findings. An increased endometrial thickness was associated with\nhigher odds of\nsuccessful treatment, which aligns with prior studies suggesting that endometrial\nthickness may\nplay a role in the body’s responsiveness to medical management [ \n22 ]. Similarly, the presence of a tubal ring was borderline significant,\nindicating\nits potential as a prognostic marker. However, these findings must be interpreted\ncautiously due\nto the p-values being slightly above the threshold for significance.\nInterestingly, patient age also showed a non-significant trend toward a negative\nassociation with\nsuccessful treatment. While older age has been linked to reduced reproductive\noutcomes in\ngeneral, its specific role in predicting the success of medical management for\nectopic\npregnancies remains unclear.\nThe use of methotrexate as a medical approach for treating ectopic pregnancy has\nshown promising\nresults. However, only a limited number of factors have been identified as\npredictors of its\nsuccess, indicating the need for further research in this area.\nThis study has several limitations that should be considered when interpreting\nthe\nresults:\n1. Small Sample Size: The total number of participants (100 patients) is\nrelatively\nsmall,\nparticularly in the control group, which consisted of only 40 patients. This\nlimited\nsample size\nmay restrict the statistical power of the analyses and the ability to detect\nsignificant\nassociations between clinical variables and treatment success.\n2. Case-to-Control Ratio: The disproportionate case-to-control ratio (60:40) may\naffect the\ngeneralizability of the findings. An optimal case-to-control ratio is essential\nfor\nrobust\nconclusions in case-control studies, and the current ratio may limit the\nreliability\nof the\ncomparisons made.\n3. Single-Center Study: The study was conducted at a single institution, which\nmay\nlimit the\ndiversity of the patient population. Results may not be generalizable to other\nsettings or\npopulations with different demographic or clinical characteristics.\n4. Retrospective Data Collection: Data were extracted from archived patient\nrecords,\nwhich may\nintroduce biases related to incomplete or inconsistent documentation.\nRetrospective\nstudies are\ninherently limited by the quality of the available data.\n5. Potential Confounding Variables: While we attempted to control for various\nclinical factors,\nthere may be unmeasured confounders that could influence treatment outcomes.\nFactors\nsuch as\npatient adherence to follow-up, variations in treatment protocols, and\nindividual\nresponses to\nmethotrexate were not fully accounted for.\n6. Short Follow-Up Period: The follow-up period for assessing treatment success\nmay\nnot have been\nlong enough to capture all relevant outcomes. Longer follow-up may be necessary\nto\nevaluate the\nlong-term effectiveness and potential complications associated with MTX therapy.\n7. Limited Predictive Power: Despite the high success rate observed, none of the\nexamined\nvariables demonstrated significant predictive power for treatment success, which\nmay\nbe\nattributed to the small sample size and the inherent variability in patient\nresponses.\nIn conclusion, while the study provides valuable insights into the effectiveness\nof\nsingle-dose\nMTX therapy for tubal ectopic pregnancy, these limitations highlight the need\nfor\nfurther\nresearch with larger, multi-center cohorts to validate the findings and explore\nthe\npredictors\nof treatment success more comprehensively.\n\nAlthough the variables examined in this study did not demonstrate predictive power\nfor EP\ntreatment outcomes with MTX, various studies suggest that the success of\nmethotrexate treatment\nfor ectopic pregnancy is influenced by multiple factors. These include β-hCG levels,\nthe\npresence of fetal cardiac activity, the number of doses required, patient clinical\ncharacteristics, and the timing of diagnosis. Identifying these factors can assist\nphysicians in\nselecting more suitable patients for treatment and achieving better outcomes. The\nresults\nsuggest that clinicians can confidently recommend methotrexate to eligible patients,\nparticularly those with lower initial hCG levels and without significant\ncomplications, as it\nmay lead to favorable outcomes while minimizing the risks associated with surgery.\nFurther\nresearch is essential to thoroughly investigate these factors and their impacts on\ntreatment\noutcomes, with the goal of developing more effective treatment protocols. Moreover,\nfuture\nstudies should focus on larger, multicenter trials to validate the results and\nimprove the\ngeneralizability of the findings across diverse populations, confirming the\neffectiveness of\nmethotrexate treatment and identifying any variations in outcomes based on\ndemographic or\nclinical factors.\n\nNone.","source_license":"CC-BY-4.0","license_restricted":false}