Laparoscopic Surgery vs. Methotrexate for Tubal Pregnancy: A Comprehensive Analysis of Clinical Efficacy and Future Fertility

Abstract

This article provides a systematic comparison of laparoscopic surgery and methotrexate for treating tubal ectopic pregnancy, with a specific focus on outcomes critical to researchers and drug development professionals. It synthesizes recent meta-analyses and large-scale cohort studies to evaluate treatment success rates, reproductive outcomes, and economic impacts. The analysis covers foundational pathophysiology, methodological applications in patient selection, strategies for optimizing success and managing failures, and a direct comparative validation of clinical efficacy and long-term fertility. Evidence indicates that while laparoscopic surgery is associated with superior tubal patency and spontaneous pregnancy rates, medical management with methotrexate may offer advantages in future live birth rates for specific cohorts, highlighting a complex risk-benefit profile that informs clinical practice and future therapeutic development.

Understanding Tubal Ectopic Pregnancy: Epidemiology, Pathophysiology, and Clinical Burden

Global Epidemiology and Incidence Trends of Tubal Ectopic Pregnancy

Tubal ectopic pregnancy (tEP), the implantation of a fertilized egg outside the uterine cavity, represents a significant global health challenge and the leading cause of maternal mortality in the first trimester of pregnancy [1] [2]. This condition affects 1-2% of all pregnancies worldwide, with approximately 95-98% of ectopic pregnancies occurring in the fallopian tubes [1] [3]. The epidemiological landscape of tEP has evolved substantially in recent decades, influenced by factors including changing reproductive patterns, advances in assisted reproductive technologies, and improvements in diagnostic capabilities. Understanding the global incidence trends and epidemiological characteristics of tubal ectopic pregnancy provides essential context for clinical decision-making and research prioritization, particularly in the comparative evaluation of treatment efficacy between laparoscopic surgery and methotrexate therapy. This analysis examines the current global burden, geographical variations, temporal trends, and risk factors associated with tubal ectopic pregnancy, framing this epidemiological context within the broader thesis of clinical efficacy comparison between primary treatment modalities.

Global Burden and Epidemiological Trends

Current Global Incidence and Temporal Patterns

The worldwide burden of ectopic pregnancy remains substantial despite diagnostic and therapeutic advances. According to the most recent Global Burden of Disease (GBD) data from 2021, there were approximately 8.38 million cases of ectopic pregnancy globally, with an age-standardized incidence rate of 212.87 per 100,000 women [4]. This represents a significant decline of 30.41% since 1990, indicating improved preventive strategies and possibly earlier detection methods [4]. The age-standardized point prevalence was reported at 1.75 per 100,000, showing a parallel decline of 30.42% over the same period [4].

Despite these improvements in incidence rates, ectopic pregnancy continues to cause substantial mortality and morbidity worldwide. In 2021, ectopic pregnancies resulted in approximately 6,442 deaths globally, with an age-standardized mortality rate of 0.16 per 100,000 [4]. The discrepancy between the significant reduction in incidence (30.41%) and the comparatively modest reduction in mortality (2.78%) since 1990 highlights persistent challenges in access to care and emergency management, particularly in resource-limited settings [4].

Table 1: Global Epidemiological Indicators for Ectopic Pregnancy (1990-2021)

Indicator	1990 Value	2021 Value	Percentage Change (1990-2021)
Cases (millions)	Not specified	8.38	Not specified
Age-standardized incidence rate (per 100,000)	Not specified	212.87	-30.41%
Age-standardized prevalence rate (per 100,000)	Not specified	1.75	-30.42%
Deaths	Not specified	6,442	-2.78%
DALYs	Not specified	4.21	-1.49%

Geographical Disparities and Regional Variations

Significant geographical disparities exist in the distribution and outcomes of tubal ectopic pregnancy. Analysis of GBD data reveals distinct patterns across regions and socio-demographic index (SDI) categories [4]. High-income countries generally demonstrate lower mortality rates despite comparable or higher incidence rates, reflecting more robust healthcare systems and better emergency response capabilities.

In high-income developed countries, the mortality ratio for tEP remains relatively low, with reported rates of 0.4 per 100,000 live births in the UK and 0.5 per 100,000 live births in the United States [1]. Conversely, in low-middle income developing countries such as Brazil, the mortality ratio is significantly higher at 1.2 per 100,000 live births [1]. In resource-poor developing countries in Africa, mortality ratios are thought to be substantially higher, though precise data remains limited [1].

The Socio-demographic Index (SDI) serves as an important determinant of ectopic pregnancy outcomes. High-SDI regions, including North America and Western Europe, benefit from advanced healthcare infrastructure leading to earlier detection and management [4] [5]. Meanwhile, low- and middle-SDI regions continue to face challenges related to healthcare access, diagnostic capabilities, and emergency surgical services, contributing to higher mortality rates despite similar incidence patterns [4].

Table 2: Regional Variations in Ectopic Pregnancy Epidemiology

Region/Country	Incidence Trends	Mortality Rate (per 100,000)	Key Contributing Factors
Global	30.41% decrease since 1990	0.16 (age-standardized)	Improved diagnostics and treatment
United Kingdom	Stable	0.4	Advanced emergency care systems
United States	Stable	0.5	Early diagnosis capabilities
Brazil	Not specified	1.2	Healthcare access limitations
African nations	Not specified	Significantly higher	Limited resources for emergency care
High-SDI regions	Decreasing	Lower	Advanced healthcare infrastructure
Low-SDI regions	Variable	Higher	Limited access to care and diagnostics

Distribution Patterns and Anatomical Sites

Tubal ectopic pregnancies demonstrate specific distribution patterns within the fallopian tubes themselves. The ampullary portion represents the most common site of implantation, accounting for approximately 80% of tubal ectopic pregnancies [6]. The isthmic portion follows at 12%, while fimbrial, cornual, and interstitial implantations occur at frequencies of 5%, 2%, and 2-3% respectively [6].

Recent trends indicate a changing distribution of ectopic pregnancy sites. While tubal pregnancies still dominate, accounting for 84.70% of cases in a recent large study, non-tubal sites have shown increasing incidence [3]. Notably, caesarean scar pregnancy has demonstrated a significant upward trend, increasing from 5.74% to 11.81% of ectopic pregnancies between 2012-2015 and 2016-2019 [3]. This change reflects rising caesarean delivery rates globally and highlights the evolving nature of ectopic pregnancy epidemiology in response to changing obstetric practices.

Other uncommon sites of implantation include ovarian pregnancy (1.56%), abdominal pregnancy (0.61%), cornual pregnancy (2.68%), cervical pregnancy (0.49%), and heterotopic pregnancy (0.43%) [3]. The anatomical site of implantation significantly influences clinical presentation, management approaches, and potential complications, making site-specific understanding crucial for appropriate clinical decision-making.

Risk Factors and Demographic Determinants

Established Risk Factors

Multiple demographic and clinical factors influence the risk of developing tubal ectopic pregnancy. The most significant risk factors include:

• Tubal damage: Accounting for approximately one-third of all tEP cases, tubal damage can result from pelvic inflammatory disease, previous tubal surgery, or infections such as Chlamydia trachomatis [1]. A history of pelvic inflammatory disease represents a particularly strong risk factor due to the potential for post-inflammatory tubal scarring and functional impairment.

• Previous ectopic pregnancy: Women with a prior ectopic pregnancy face substantially increased risk of recurrence, with odds ratios ranging from 4.7 to 10.0 after one previous event [1]. This risk increases dramatically with multiple prior ectopic pregnancies, reaching an odds ratio of 17.16 [1].

• Maternal age: Advanced maternal age represents an independent risk factor, with women aged ≥44 years showing an odds ratio of 6.9 compared to younger populations [1]. The physiological basis for this association may involve age-related changes in tubal function, including delayed embryo transport [1].

• Cigarette smoking: Current smokers face a 4.21-fold increased risk of ectopic pregnancy, potentially mediated by the effects of cigarette smoke components on tubal motility and ciliary function [1].

• Assisted reproductive technologies (ART): Women undergoing in vitro fertilization (IVF) and related procedures experience elevated risk, with ectopic pregnancy rates ranging from 1.6-8.9% after IVF [1]. The highest risk occurs in women with tubal factor infertility (OR 3.9) [1].

• Contraceptive use: The increasing utilization of intrauterine devices (IUDs) represents a potential risk factor, though the absolute risk remains low [5].

Emerging and Environmental Risk Factors

Recent research has identified additional risk factors that contribute to the evolving epidemiological landscape of tubal ectopic pregnancy:

• Ambient air pollution: Emerging evidence suggests a significant association between exposure to air pollutants and increased ectopic pregnancy risk, with an adjusted odds ratio of 2.68 reported in IVF patients [1]. This association highlights potential environmental influences on reproductive health outcomes.

• Cesarean section rates: The rising incidence of cesarean scar pregnancy directly correlates with increasing cesarean delivery rates globally [3]. This trend represents an iatrogenic contributor to changing ectopic pregnancy patterns.

• Socioeconomic factors: Significant health disparities exist in ectopic pregnancy outcomes, with worse outcomes associated with ethnic minority groups and low-income populations, even in high-income countries [1]. These disparities reflect differential access to timely diagnosis and appropriate management.

The following diagram illustrates the relationship between major risk factors and their pathophysiological mechanisms in tubal ectopic pregnancy:

Research Methods and Epidemiological Assessment

Global Burden of Disease Methodology

The comprehensive assessment of global ectopic pregnancy epidemiology relies substantially on the Global Burden of Disease (GBD) study methodology. The GBD 2021 study, the most recent iteration, represents a multinational collaborative effort that quantifies health losses across 204 countries and territories over a 32-year observation window (1990-2021) [4]. This systematic approach enables standardized comparison of epidemiological trends across diverse geographical and socioeconomic contexts.

The GBD methodology incorporates multiple data sources, including vital registration systems, health surveys, and published scientific literature, employing sophisticated statistical models to generate estimates where direct data is limited [4]. For ectopic pregnancy specifically, diagnosis is typically established through a combination of transvaginal ultrasound and serial serum β-hCG measurements, though more advanced cases may be confirmed surgically [4] [2]. The consistent application of diagnostic criteria across settings strengthens the comparability of epidemiological data.

Analytical Approaches in Epidemiological Research

Epidemiological research on tubal ectopic pregnancy employs various study designs and analytical methods:

• Retrospective cohort studies: These designs facilitate the examination of risk factors and long-term outcomes using existing clinical data [7] [2]. Recent studies have utilized this approach to investigate recurrence risk and fertility outcomes following different treatment modalities.

• Systematic reviews and meta-analyses: These methodologies synthesize evidence from multiple studies to strengthen conclusions regarding incidence patterns and treatment efficacy [8] [9]. Network meta-analyses enable indirect comparison of multiple interventions when head-to-head trials are limited [9].

• Trend analysis: Statistical approaches including χ2 tests for trend enable researchers to identify significant temporal patterns in ectopic pregnancy distribution and incidence [3]. These methods have demonstrated the rising proportion of cesarean scar pregnancies in recent years.

The following experimental workflow outlines the standard methodological approach for epidemiological studies in this field:

Epidemiological and clinical research on tubal ectopic pregnancy requires specific methodological tools and resources. The following table outlines key research reagents and their applications in this field:

Table 3: Essential Research Reagents and Methodological Tools

Research Tool/Resource	Primary Application	Significance in tEP Research
Serum β-hCG assays	Diagnosis and treatment monitoring	Quantitative measurement essential for diagnosis and monitoring treatment response; discriminatory zone (1500-1800 mIU/mL) guides clinical decision-making [6] [2]
Transvaginal ultrasonography	Anatomical localization	Primary imaging modality for identifying implantation site; enables differentiation between tubal, interstitial, and other ectopic sites [6]
GBD database	Epidemiological analysis	Comprehensive global data on incidence, prevalence, mortality, and DALYs; enables trend analysis across regions and time periods [4]
ICD classification systems	Case identification and categorization	Standardized coding for epidemiological surveillance and healthcare utilization studies [4]
Laparoscopic visualization	Diagnostic confirmation	Criterion standard for diagnosis, though increasingly reserved for complex cases or surgical management [6]
Methotrexate therapy protocols	Medical management	Standardized treatment regimens (single vs. multi-dose) for conservative management; requires specific eligibility criteria [2]

Implications for Clinical Management and Research

The epidemiological trends and patterns of tubal ectopic pregnancy have significant implications for clinical practice and research priorities. The declining global incidence but persistent mortality highlights the need for targeted interventions in high-risk populations and regions with limited healthcare resources [4]. The changing distribution of implantation sites, particularly the rising incidence of cesarean scar pregnancies, necessitates ongoing training in ultrasound diagnosis and development of site-specific management protocols [3].

From a research perspective, several key areas require continued investigation:

• Refinement of risk prediction models: Integration of emerging risk factors, including environmental exposures, may enhance early identification of high-risk women [1].

• Optimization of treatment selection criteria: Better understanding of how epidemiological factors influence treatment success could guide more personalized approaches to managing tubal ectopic pregnancy [10] [2].

• Health services research: Examination of barriers to timely diagnosis and treatment, particularly in low-resource settings, could inform interventions to reduce mortality disparities [1] [4].

• Long-term reproductive outcomes: Further research on how epidemiological factors influence future fertility after different treatment approaches would enhance counseling and decision-making [7] [8].

In conclusion, the global epidemiology of tubal ectopic pregnancy reflects complex interactions between demographic trends, clinical practices, and healthcare systems. Understanding these patterns provides essential context for evaluating treatment efficacy and guiding future research directions aimed at reducing the global burden of this potentially life-threatening condition.

Tubal ectopic pregnancy (EP), accounting for over 95% of all ectopic pregnancies, remains a leading cause of maternal morbidity and mortality in the first trimester [11] [12] [13]. Its pathogenesis is primarily anchored in the dysfunction of the fallopian tubes, which compromises the transport of a fertilized ovum to the uterine cavity and creates an environment conducive to ectopic implantation [14] [11]. Understanding the core pathophysiological mechanisms—tubal damage and impaired embryo transit—is fundamental to evaluating and improving therapeutic interventions. This analysis situates these mechanisms within the context of comparing two primary tubal-preserving treatments: laparoscopic surgery and methotrexate (MTX) therapy. The objective is to delineate how these treatments interact with the underlying tubal pathology and influence subsequent reproductive outcomes, providing a scientific basis for clinical decision-making aimed at preserving fertility.

Pathophysiological Pathways to Ectopic Implantation

The Foundation of Tubal Function and Dysfunction

Under normal physiological conditions, the timely transit of the embryo from the site of fertilization in the ampulla to the uterine cavity for implantation is a critical process. This journey is facilitated by the coordinated action of ciliary beating and rhythmic smooth muscle contractions within the fallopian tube wall [11]. The integrity of this transport mechanism is paramount for a successful intrauterine pregnancy.

The core pathophysiology of tubal ectopic pregnancy arises from disruptions to this delicate system, which can be broadly categorized into anatomical and functional disturbances.

• Anatomical Damage and Tubal Scaffolding: Anatomical alterations physically hinder the embryo's passage. The most common cause is pelvic inflammatory disease (PID), particularly infections with Chlamydia trachomatis and Neisseria gonorrhoeae, which incite an inflammatory response leading to tubal scarring, adhesions, and luminal narrowing [14] [11]. Other surgical procedures on the fallopian tubes, including those for sterilization or fertility restoration, and conditions like endometriosis also result in peritubal adhesions and anatomical distortion that impede transit [14] [12].

• Functional Impairment of Tubal Dynamics: Even in the absence of gross anatomical defects, the tube's functional capacity can be compromised. Cigarette smoking is a significant risk factor, as components of tobacco smoke have been shown to reduce ciliary beat frequency and negatively affect smooth muscle contractility [14] [11]. Furthermore, hormonal imbalances throughout the menstrual cycle can also influence ciliary function, while progesterone-only contraceptives are associated with decreased tubal motility, increasing the relative risk of EP if conception occurs [14] [11].

Molecular and Inflammatory Cascades

At the molecular level, tubal damage initiates a pro-inflammatory cascade that paradoxically facilitates ectopic implantation. Infections or other insults trigger an upregulation of proinflammatory cytokines, such as interleukin-1 (IL-1), within the tubal epithelium [11]. While IL-1 plays a role in embryonic implantation within the endometrium, its presence in the fallopian tube creates a receptive environment for the attaching embryo. This inflammatory milieu promotes trophoblast invasion and angiogenesis directly within the tubal wall, cementing the ectopic pregnancy [11]. The tubal mucosa, lacking a robust decidualized layer like the endometrium, is highly vulnerable to invasion by trophoblastic tissue, leading to the erosion of surrounding blood vessels and the risk of tubal rupture [13].

The diagram below synthesizes these pathophysiological pathways into a cohesive visual model.

Comparative Clinical Efficacy: Surgery vs. Pharmacotherapy

The primary clinical goal in managing tubal pregnancy is to resolve the ectopic gestation while preserving future fertility. The choice between laparoscopic surgery and systemic methotrexate is influenced by the patient's clinical stability, but the impact of each treatment on the underlying tubal pathophysiology and subsequent reproductive potential is a critical consideration.

A large meta-analysis from 2025, which synthesized data from 10 randomized controlled trials involving 1,034 patients, provides high-quality evidence for this comparison [8] [15]. The analysis focused on patients treated with a single intramuscular injection of methotrexate versus those undergoing various forms of laparoscopic tubal-preserving surgery (e.g., salpingotomy, salpingostomy).

Table 1: Key Fertility Outcomes from Meta-Analysis (Laparoscopy vs. Single-Dose Methotrexate)

Outcome Measure	Odds Ratio (OR)	95% Confidence Interval	P-value	Conclusion
Tubal Patency Rate	2.47	1.72 – 3.53	< 0.001	Significantly higher with laparoscopy [8]
Spontaneous Pregnancy Rate	2.10	1.28 – 3.46	0.003	Significantly higher with laparoscopy [8]
Recurrent Ectopic Pregnancy Rate	1.09	0.41 – 2.87	0.87	No significant difference [8]
Treatment Success Rate	1.88	0.53 – 6.69	0.33	No significant difference [8]

The data reveals that while both treatments are clinically effective in resolving the immediate crisis, laparoscopic surgery offers superior outcomes in terms of restoring tubal anatomy and function, leading to a doubled chance of subsequent spontaneous pregnancy [8] [16]. This suggests that surgical removal of the ectopic tissue may more effectively address the physical obstruction and inflammatory focus caused by the implanted pregnancy, thereby better restoring the tube's functional integrity.

The Failure Rate Perspective and Combination Therapy

Another critical metric is treatment failure, which necessitates a secondary intervention. A separate 2025 network meta-analysis of 8 studies (677 patients) investigated failure rates across different regimens [17] [18]. It found that a single dose of methotrexate had a significantly higher failure rate compared to salpingostomy alone (OR=2.04, 95% CI: 1.20–3.47, p=0.008) [18]. However, this difference was negated when two or more doses of methotrexate were used [18].

Most notably, the most effective strategy for minimizing failure was salpingostomy combined with postoperative methotrexate, which had a significantly lower failure rate than salpingostomy alone (OR=0.11, 95% CI: 0.03–0.48, p=0.003) [17] [18]. This combined approach likely addresses both the macroscopic issue (the ectopic tissue) and any residual microscopic trophoblastic cells, thereby providing a more comprehensive treatment.

Table 2: Summary of Treatment Failure Rates (Network Meta-Analysis)

Treatment Modality	Comparative Failure Rate	Clinical Implication
Single-Dose Methotrexate	Higher than salpingostomy	May be less reliable; requires careful patient selection [18].
Multi-Dose Methotrexate	No significant difference vs. salpingostomy	Improved efficacy over single-dose, but with more side effects [18].
Salpingostomy Alone	Baseline for comparison	Effective, but risk of persistent trophoblastic tissue [17].
Salpingostomy + MTX	Lowest failure rate	Superior efficacy by preventing persistent trophoblast [17] [18].

Experimental Models and Research Methodologies

Research into tubal pregnancy and its treatments relies on specific clinical study designs and diagnostic protocols. The evidence cited in this guide is primarily derived from meta-analyses of randomized controlled trials (RCTs), which represent the gold standard for comparing treatment efficacy.

Diagnostic and Treatment Protocols

The management of tubal pregnancy follows a standardized diagnostic and therapeutic workflow. The following diagram outlines the key decision points and treatment pathways based on current clinical guidelines and research findings.

Key Experimental and Clinical Definitions:

• Treatment Success (Methotrexate): Defined as achieving a progressive decline in serum β-hCG levels without the need for surgical intervention [8].
• Treatment Failure (Methotrexate): Operationally defined as a reduction of less than 15% in serum β-hCG levels between days 4 and 7 post-injection, often leading to a need for additional doses or surgery [17].
• Treatment Failure (Laparoscopic Surgery): Defined as a rise or lack of decrease in serum β-hCG levels on the fourth postoperative day, indicating persistent trophoblastic tissue [17].
• Fertility Outcomes: Measured via hysterosalpingography to assess tubal patency (usually 6 weeks to 4 months post-treatment) and long-term follow-up (often 12-36 months) to determine spontaneous pregnancy rates and recurrent ectopic pregnancy rates [8].

The Scientist's Toolkit: Key Reagents and Materials

The diagnosis, treatment, and study of tubal ectopic pregnancy involve a suite of specific reagents, biologics, and technological tools.

Table 3: Essential Research and Clinical Tools for Tubal Pregnancy Studies

Tool / Reagent	Primary Function / Utility	Research & Clinical Context
Beta-human Chorionic Gonadotropin (β-hCG)	Biochemical marker for trophoblastic tissue.	Diagnosis & Monitoring: Serial measurements are the cornerstone for diagnosis and for monitoring response to both medical and surgical treatment [14] [11].
Methotrexate	Folate antagonist inhibiting dihydrofolate reductase.	Medical Intervention: The primary pharmacologic agent for conservative management; induces trophoblast cell death [8] [14]. A key comparator in clinical trials.
Mifepristone	Progesterone receptor antagonist.	Investigational Combination Therapy: Studied in combination with methotrexate (e.g., AMETHYST trial) to potentially improve medical treatment efficacy [13].
Transvaginal Ultrasonography	High-resolution pelvic imaging.	Primary Diagnostic Tool: Enables visualization of an empty uterine cavity, adnexal mass, or extrauterine gestational sac, crucial for diagnosis and staging [14] [12].
Laparoscopic System	Minimally invasive surgical access.	Surgical Intervention & Gold-Standard Diagnosis: The platform for performing salpingostomy/salpingectomy. Used for definitive diagnosis and as the intervention in surgical arms of RCTs [8] [14].
CO₂ Laser / Electrosurgical Units	Precision tissue dissection and ablation.	Surgical Tool: Used during laparoscopic salpingostomy for linear incision and removal of ectopic pregnancy tissue [8].

The pathophysiological triad of anatomical damage, functional impairment, and localized inflammation creates the conditions for tubal ectopic pregnancy by disrupting embryo transit and facilitating ectopic implantation. The comparison between laparoscopic surgery and methotrexate therapy reveals a nuanced clinical picture. While both are effective in resolving the acute condition, laparoscopic tubal-preserving surgery demonstrates a significant advantage in restoring tubal patency and achieving subsequent spontaneous pregnancy [8] [16]. However, the risk of treatment failure with single-dose methotrexate is a critical consideration, and the emerging evidence for combined salpingostomy and methotrexate points to a potent strategy for minimizing this risk [17] [18].

For researchers and clinicians, these findings underscore that treatment choice must extend beyond immediate efficacy to consider long-term fertility outcomes. The superior reproductive performance of surgery suggests it may more effectively reverse or mitigate the local pathophysiological consequences of the ectopic implantation. Future research should focus on refining combination therapies and better understanding the molecular healing of the fallopian tube post-intervention to further optimize fertility preservation.

Pelvic Inflammatory Disease (PID), previous ectopic pregnancy (EP), smoking, and assisted reproduction represent interconnected risk factors that significantly influence female reproductive health, particularly in the context of tubal ectopic pregnancy. Tubal pregnancy, accounting for approximately 95% of all ectopic pregnancies, presents a major clinical challenge in gynecology [8]. The delicate functional anatomy of the fallopian tubes can be compromised by inflammatory processes and surgical interventions, creating environments conducive to ectopic implantation. Understanding these risk factors is crucial for both prevention strategies and treatment selection, especially for patients with future fertility aspirations.

The relationship between PID and tubal damage is well-established, with sexually transmitted bacteria, particularly Chlamydia trachomatis and Neisseria gonorrhoeae, initiating an inflammatory cascade that can result in permanent tubal scarring, adhesions, and functional impairment [19]. This structural damage mechanically impedes embryo transport while simultaneously altering the tubal microenvironment. Similarly, cigarette smoking introduces toxic substances that may disrupt normal tubal motility and ciliary function, further compromising embryo transportation [20]. For patients undergoing assisted reproduction, particularly those with preexisting tubal pathology, the risk of ectopic implantation remains substantial despite bypassing natural conception mechanisms [21] [22].

This complex interplay of risk factors informs clinical decision-making when treating tubal pregnancy. The comparative efficacy of laparoscopic surgery versus methotrexate therapy must be evaluated not only through immediate treatment success but also through long-term reproductive outcomes. This analysis provides a comprehensive examination of these risk factors while presenting structured experimental data on therapeutic interventions for tubal pregnancy.

Pathophysiological Pathways and Risk Factor Analysis

Pelvic Inflammatory Disease and Tubal Damage

PID represents a spectrum of upper genital tract infections that cause progressive and often irreversible damage to fallopian tubes. The primary mechanism involves ascending infection from the cervix or vagina, leading to endometritis, salpingitis, and eventually tubal scarring [19]. The inflammatory response triggers several pathological changes: deciliation of tubal epithelial cells, loss of tubal folds due to fibrosis, and adhesion formation that physically obstructs tubal patency. These structural alterations significantly increase ectopic pregnancy risk by impairing ovum pickup, sperm migration, and embryo transport toward the uterine cavity.

A case-control study investigating PID risk factors demonstrated that age below 25 years, early sexual debut (before 20 years), previous sexually transmitted infection history, and exposure to Chlamydia trachomatis were significantly associated with PID development [23]. Notably, a substantial proportion (64%) of PID cases were classified as idiopathic, suggesting multiple pathways beyond classic sexually transmitted infections can initiate tubal inflammation and damage [23]. The long-term reproductive sequelae of PID are profound, with untreated cases dramatically increasing infertility risk due to permanent tubal damage [19].

Previous Ectopic Pregnancy as a Risk Factor

A history of ectopic pregnancy substantially increases recurrence risk, with studies indicating that approximately 20% of patients with previous ectopic pregnancy have a subsequent ectopic implantation [24]. This recurrence pattern suggests either persistent underlying tubal pathology or congenital factors affecting tubal function. Research indicates that after one ectopic pregnancy, the recurrence rate is 15-20%, and this risk doubles after two or more ectopic pregnancies [19].

In assisted reproduction populations, tubal factor infertility emerges as the most prominent risk factor for ectopic pregnancy [21] [22]. A retrospective cohort study of 725 women who conceived after IVF identified tubal factor infertility and previous myomectomy as significant predictors of ectopic implantation [22]. The presence of hydrosalpinx—a distally blocked, fluid-filled fallopian tube—further exacerbates this risk by creating an environment hostile to embryo development and implantation [21].

Smoking and Reproductive Risk

Cigarette smoking constitutes an independent, modifiable risk factor for both PID and ectopic pregnancy. A hospital-based case-control study demonstrated that current smokers had a 1.7-fold increased risk of PID compared to non-smokers, while former smokers exhibited an even higher relative risk of 2.3 [20]. The biological mechanisms likely involve impaired immune surveillance in the reproductive tract, reduced ciliary clearance of pathogens in the fallopian tubes, and altered tubal motility.

The association between smoking and ectopic pregnancy may be explained by nicotine's effect on fallopian tube physiology. Animal and in vitro studies suggest that nicotine and its metabolites interfere with tubal smooth muscle contractility, disrupt ciliary function, and alter gene expression in tubal epithelium. These functional changes can delay embryo transit through the fallopian tube, increasing the likelihood of ectopic implantation before the embryo reaches the uterine cavity.

Assisted Reproduction Technologies

Despite bypassing tubal transport through direct embryo transfer to the uterus, assisted reproduction technologies, particularly in vitro fertilization (IVF), carry a 2-4% risk of ectopic pregnancy—approximately double the rate observed in natural conceptions [21] [22]. This paradox highlights that tubal pathology affects implantation beyond mere mechanical transport issues. Possible mechanisms include embryo migration from the uterine cavity to the fallopian tube, preexisting inflammatory mediators in the endometrium that drive embryo movement, or technical aspects of embryo transfer that inadvertently deposit embryos near tubal ostia.

The type of transfer catheter, depth of embryo placement, and transfer volume have been investigated as potential technical factors influencing ectopic pregnancy risk in IVF cycles [21]. Additionally, the underlying infertility diagnosis, particularly tubal factor infertility, remains the predominant risk factor rather than the IVF procedure itself [22].

Table 1: Risk Factor Profiles for Tubal Ectopic Pregnancy

Risk Factor Category	Specific Factors	Proposed Mechanisms	Clinical Implications
Inflammatory Conditions	PID, Chlamydia infection, post-abortal infection	Tubal scarring, adhesion formation, ciliary damage	Screening and prompt treatment of STIs; hysterosalpingography for at-risk patients
Reproductive History	Previous ectopic pregnancy, previous myomectomy, multiple abortions	Persistent tubal pathology, uterine structural changes, Asherman's syndrome	Early ultrasound monitoring in subsequent pregnancies; consider prophylactic measures
Behavioral Factors	Cigarette smoking, multiple sexual partners, douching	Altered tubal motility, impaired immunity, disrupted vaginal flora	Smoking cessation counseling, education on safe sex practices
Assisted Reproduction	Tubal factor infertility, hydrosalpinx, specific transfer catheters	Embryo migration, inflammatory tubal environment, technical factors	Consider salpingectomy for hydrosalpinx before IVF; optimize transfer technique
Demographic Factors	Age >35 years, non-white ethnicity, lower socioeconomic status	Cumulative risk exposure, healthcare access disparities	Targeted patient education and screening programs

Methodological Approaches in Treatment Comparison

Diagnostic Protocols and Patient Selection

The comparative analysis between laparoscopic surgery and methotrexate treatment for tubal pregnancy requires rigorous diagnostic protocols and appropriate patient selection criteria. Diagnostic confirmation typically involves transvaginal ultrasound (TVUS) coupled with serial beta-human chorionic gonadotropin (β-hCG) measurements. TVUS criteria for tubal pregnancy include an empty uterine cavity, non-cystic adnexal mass, and occasionally visualization of an extrauterine gestational sac with or without cardiac activity [24]. Serum β-hCG levels provide crucial information for both diagnosis and treatment eligibility, with levels >5,000 IU/L generally contraindicating medical management [24].

Patient selection for conservative management (either medical or surgical) follows strict criteria: hemodynamic stability, no signs of tubal rupture or significant hemoperitoneum, willingness to comply with post-treatment monitoring, and no contraindications to methotrexate (such as liver disease, renal impairment, or active pulmonary disease) [8] [24]. The size of the ectopic pregnancy and presence of fetal cardiac activity also influence treatment selection, with larger masses (>3.5-4.0 cm) and cardiac activity often favoring surgical intervention [24].

Laparoscopic Surgical Protocol

Laparoscopic tubal-preserving surgery represents the standard surgical approach for hemodynamically stable patients desiring future fertility. The procedure typically follows this protocol:

• Anesthesia and Pneumoperitoneum: General anesthesia is administered, followed by creation of carbon dioxide pneumoperitoneum to 12-15 mmHg pressure.
• Trocar Placement: Standard three-port technique (umbilical, suprapubic, lateral).
• Pelvic Exploration: Systematic examination of pelvis, uterus, fallopian tubes, and ovaries.
• Salpingostomy: Linear incision on the antimesenteric border of the fallopian tube over the ectopic pregnancy using monopolar or bipolar energy, scissors, or laser.
• Extraction of Products: Gentle hydrodissection and extraction of gestational tissue.
• Hemostasis: Precise electrosurgical coagulation of bleeding points.
• Irrigation and Inspection: Copious pelvic irrigation and confirmation of hemostasis.
• Tissue Removal: Extraction of gestational tissue via endobag through extended port incision.
• Closure: Fascial closure at >10mm port sites and skin approximation.

Intraoperative challenges include persistent bleeding from the salpingostomy site, which may require conversion to salpingectomy if hemostasis cannot be achieved. The extracted tissue is routinely sent for histopathological confirmation [8] [18].

Methotrexate Administration Protocol

Methotrexate therapy, typically administered as a single intramuscular injection, follows specific protocols:

• Baseline Assessment: Document β-hCG levels, complete blood count, renal and liver function tests, blood type and Rh status.
• Dosing: Single-dose methotrexate (50 mg/m²) administered intramuscularly.
• Monitoring Protocol:
  • Day 1: Baseline β-hCG
  • Day 4: First follow-up β-hCG (expected 15-30% increase in successful cases)
  • Day 7: Second follow-up β-hCG (must show 15% decrease from day 4)
• Additional Doses: Second dose administered if β-hCG decrease is <15% between days 4-7.
• Weekly Monitoring: Continued until β-hCG becomes undetectable.

Treatment success is defined as a progressive decline in β-hCG levels without surgical intervention [8] [24]. The single-dose regimen demonstrates approximately 55.9% success after the first dose, increasing to 93.8% after a second dose when needed [24]. Contraindications include liver disease, renal impairment, active pulmonary disease, and immunodeficiency [24].

Outcome Assessment Methods

Standardized outcome measures enable direct comparison between treatment approaches:

• Primary Efficacy Endpoints:

  • Treatment success rate (resolution without additional intervention)
  • Tubal patency rate (assessed by hysterosalpingography at 3 months)
  • Subsequent spontaneous pregnancy rate
  • Recurrent ectopic pregnancy rate

• Secondary Endpoints:

  • Time to β-hCG normalization
  • Complication rates (including tubal rupture)
  • Need for additional interventions
  • Post-treatment pain scores
  • Return to normal activities

Follow-up protocols typically extend for 3-6 months post-treatment, with long-term fertility outcomes tracked for 1-2 years [8] [18].

Table 2: Experimental Protocols for Tubal Pregnancy Management

Protocol Component	Laparoscopic Surgery	Methotrexate Therapy
Patient Selection Criteria	Hemodynamically stable, tubal mass >3.5cm, fetal cardiac activity, desire for future fertility	Hemodynamically stable, β-hCG <5,000 IU/L, no fetal cardiac activity, reliable for follow-up
Contraindications	Hemodynamic instability, massive hemoperitoneum, contraindication to anesthesia	Liver/renal disease, active pulmonary disease, immunodeficiency, breastfeeding
Procedure Details	Salpingostomy under general anesthesia, 3-port technique, extraction via endobag	Single IM injection (50 mg/m²), potential second dose if β-hCG decline inadequate
Monitoring Protocol	Post-op day 1 β-hCG, then weekly until negative	β-hCG days 4 and 7, then weekly until negative
Success Definition	Complete removal of gestational tissue with tubal preservation, declining β-hCG	15% β-hCG decline between days 4-7, eventual resolution without surgery
Primary Efficacy Measures	Treatment success, tubal patency, subsequent pregnancy, recurrence rate	Treatment success, tubal patency, subsequent pregnancy, recurrence rate
Follow-up Duration	HSG at 3 months, fertility assessment up to 2 years	HSG at 3 months, fertility assessment up to 2 years

Comparative Outcomes Analysis

Primary Treatment Efficacy

Meta-analyses of randomized controlled trials demonstrate nuanced differences in primary efficacy between laparoscopic surgery and methotrexate therapy. When analyzing treatment success rates—defined as resolution without additional intervention—no statistically significant difference exists between the two approaches (OR=1.88, 95% CI 0.53-6.69, P=0.33) [8] [15]. However, subgroup analyses reveal important distinctions based on methotrexate dosing regimens.

Single-dose methotrexate protocols show significantly higher failure rates compared to laparoscopic salpingostomy (OR=2.044, 95% CI 1.20-3.47, P=0.008), whereas multiple-dose methotrexate regimens demonstrate comparable efficacy to surgical intervention (OR=1.130, 95% CI 0.62-2.07, P=0.692) [18]. The most favorable outcomes emerge from combined approaches, with salpingostomy complemented by methotrexate administration showing the lowest failure rates (OR=0.11, 95% CI 0.03-0.48, P=0.003) [18].

The time to resolution represents another significant differentiating factor. Laparoscopic surgery achieves significantly faster β-hCG normalization compared to single-dose methotrexate (mean difference -7.10 days, 95% CI -7.84 to -6.36, P<0.001) [8]. This temporal advantage reduces the prolonged monitoring period required with medical management and potentially decreases patient anxiety during the resolution phase.

Fertility Preservation Outcomes

Future reproductive potential constitutes a critical consideration in treatment selection, particularly for patients desiring subsequent pregnancy. Meta-analyses demonstrate superior tubal patency rates following laparoscopic surgery compared to single-dose methotrexate (OR=2.47, 95% CI 1.72-3.53, P<0.001) [8] [15]. This advantage in anatomical preservation translates into improved spontaneous pregnancy rates post-treatment (OR=2.10, 95% CI 1.28-3.46, P=0.003) [8].

The spontaneous pregnancy rate following laparoscopic surgery ranges from 40-60% within 12-18 months post-treatment, compared to 20-40% after methotrexate therapy [8] [24]. Importantly, this reproductive advantage persists regardless of polyp characteristics, suggesting that the mechanical removal of pathological tissue restores endometrial receptivity through mechanisms beyond simple cavity restoration [25].

Despite concerns that tubal preservation might increase recurrence risk, meta-analyses show no significant difference in recurrent ectopic pregnancy rates between surgical and medical approaches (OR=1.09, 95% CI 0.41-2.87, P=0.87) [8]. This suggests that the underlying tubal pathology rather than the treatment modality dictates recurrence risk.

Complication Profiles and Secondary Outcomes

The complication profiles differ substantially between approaches. Laparoscopic surgery carries standard surgical risks including anesthesia complications, bleeding, infection, and visceral injury, with an overall incidence of 3-8% [8]. Persistent trophoblastic tissue occurs in 5-10% of salpingostomy cases, necessitating additional methotrexate treatment or reoperation [18].

Methotrexate therapy avoids surgical risks but introduces medication-related side effects, including transaminitis, stomatitis, gastrointestinal symptoms (nausea, vomiting, diarrhea), and bone marrow suppression in 10-30% of patients [24]. The most significant risk during methotrexate treatment remains tubal rupture (3-10%), which can occur despite declining β-hCG levels and requires emergency surgical intervention [24].

Patient-reported outcomes show mixed preferences. While methotrexate avoids surgery and general anesthesia, the prolonged monitoring period (4-6 weeks until β-hCG normalization) generates significant anxiety for some patients. Laparoscopic surgery provides more immediate resolution but involves longer recovery time and postoperative discomfort.

Table 3: Comparative Outcomes of Tubal Pregnancy Treatments

Outcome Measure	Laparoscopic Surgery	Single-Dose Methotrexate	Multiple-Dose Methotrexate	Combined Approach
Treatment Success Rate	88-94% [8]	55.9% after 1st dose [24]	69-75% [24]	>95% [18]
Tubal Patency Rate	75-85% [8]	50-65% [8]	60-70% [18]	80-90% [18]
Subsequent Spontaneous Pregnancy	40-60% [8]	20-40% [8]	30-45% [18]	50-65% [18]
Recurrent EP Rate	8-12% [8]	10-15% [8]	10-12% [18]	5-8% [18]
Time to Resolution	14-21 days [8]	21-35 days [8]	28-42 days [18]	14-28 days [18]
Major Complications	3-8% (surgical) [8]	3-10% (rupture) [24]	5-12% (rupture + toxicity) [18]	4-9% (combined) [18]
Patient Satisfaction	High (immediate resolution)	Variable (prolonged monitoring)	Moderate (side effects)	High (comprehensive approach)

Research Reagents and Methodological Tools

Table 4: Essential Research Reagents for Tubal Pregnancy Studies

Reagent/Category	Specific Examples	Research Applications	Functional Role
Biochemical Markers	β-hCG assays, progesterone, CA-125	Diagnosis, treatment monitoring, prognosis	Serological confirmation of pregnancy, monitoring treatment response
Imaging Contrast Agents	Microbubble contrast (SonoVue), saline infusion	Saline infusion sonography, contrast-enhanced ultrasound	Uterine cavity assessment, polyp identification, tubal patency evaluation
Histopathological Stains	Hematoxylin and eosin, CD146 immunostaining	Tissue confirmation, implantation site analysis	Confirmatory diagnosis of ectopic pregnancy, placental site evaluation
Molecular Biology Reagents	PCR for Chlamydia trachomatis, HOXA10/11 gene expression assays	Pathogen detection, endometrial receptivity analysis	Identify infectious etiology, assess molecular markers of implantation
Cell Culture Models	Human tubal epithelial cells, JAR cells	Methotrexate mechanism studies, tubal physiology	In vitro modeling of tubal environment, drug response assessment

Conceptual Framework for Treatment Decision-Making

The following diagram illustrates the key decision pathways and physiological relationships informing tubal pregnancy management:

Decision Pathways for Tubal Pregnancy Management

The interrelationship between PID, previous EP, smoking, and assisted reproduction creates a complex risk profile that significantly influences both the occurrence of tubal pregnancy and subsequent treatment outcomes. The comparative analysis between laparoscopic surgery and methotrexate therapy reveals a nuanced clinical landscape where treatment selection must be individualized based on patient characteristics, risk factors, and fertility goals.

For hemodynamically stable patients with strong future fertility desires, laparoscopic tubal-preserving surgery demonstrates superior fertility outcomes, including significantly higher tubal patency rates (OR=2.47) and subsequent spontaneous pregnancy rates (OR=2.10) compared to single-dose methotrexate [8] [15]. The combined approach of salpingostomy with adjunctive methotrexate appears to offer the most favorable balance of efficacy and fertility preservation, with the lowest failure rates (OR=0.11) among all strategies [18].

Conversely, methotrexate therapy provides a non-invasive alternative with comparable efficacy when utilizing multiple-dose regimens, particularly suitable for patients with low initial β-hCG levels, no fetal cardiac activity, and contraindications to surgery. The 93.8% success rate after two methotrexate doses demonstrates its viability as a conservative management option [24].

Future research directions should include standardized protocols for fertility assessment post-treatment, long-term follow-up of subsequent pregnancy outcomes, and molecular studies identifying biomarkers predictive of treatment success. The development of risk stratification tools incorporating the key factors discussed—PID history, smoking status, previous EP, and ART exposure—will enable more personalized treatment selection and improved reproductive outcomes for patients with tubal ectopic pregnancy.

Clinical Presentation and the Critical Importance of Early Diagnosis

Ectopic pregnancy (EP), a condition where a fertilized ovum implants outside the uterine cavity, represents a significant cause of maternal morbidity and first-trimester mortality, affecting approximately 1-2% of all pregnancies [2] [26]. Tubal pregnancies account for over 95% of all ectopic pregnancies [8] [17]. The clinical challenge lies not only in managing this potentially life-threatening condition but also in preserving future fertility, making early diagnosis and appropriate treatment selection paramount.

The clinical presentation of ectopic pregnancy is often subtle and nonspecific, potentially including pelvic pain, abnormal uterine bleeding, or signs of hemodynamic instability [2]. However, symptoms can be minimal, leading to delayed recognition and increasing the risk of tubal rupture and massive hemorrhage [2] [17]. Timely diagnosis, facilitated by transvaginal ultrasound and serial serum β-human chorionic gonadotropin (β-hCG) measurements, is crucial for implementing effective management strategies before complications arise [2].

The central therapeutic dilemma for clinicians involves selecting between methotrexate (MTX) therapy and laparoscopic surgery, each offering distinct advantages and limitations. This article provides a comprehensive comparison of these modalities, focusing on their clinical efficacy, impact on fertility outcomes, and the critical role of early diagnosis in enabling successful treatment.

Comparative Clinical Efficacy: Laparoscopic Surgery versus Methotrexate

Treatment Success Rates

Table 1: Comparative Treatment Success Rates for Tubal Ectopic Pregnancy

Treatment Modality	Success Rate Range	Key Influencing Factors	Representative Study Findings
Laparoscopic Surgery	87.7% - 98.5% [26]	Surgical technique (salpingostomy/salpingectomy), surgeon experience	98.46% success in a 2024 comparative study (128/130 patients) [26]
Methotrexate (Single-Dose)	~65% - 95% [27]	Pretreatment β-hCG level, gestational sac diameter, presence of cardiac activity	87.69% success in a 2024 comparative study (114/130 patients) [26]; 81.1% success with fixed-dose (90mg) protocol [28]
Methotrexate (Multi-Dose)	Varies; can improve success	Number of doses administered, β-hCG response between doses	72% overall success in a 2025 cohort study (26/36 patients), with 6 requiring a second dose [2]

Treatment success is fundamentally defined as the complete resolution of the ectopic pregnancy without the need for additional intervention [26]. As illustrated in Table 1, laparoscopic surgery consistently demonstrates high success rates. A 2024 prospective comparative study reported a 98.46% success rate for surgery, significantly higher than the 87.69% success rate for single-dose MTX in the same study [26].

For MTX treatment, success is highly dependent on appropriate patient selection. Key predictors of MTX success include low initial serum β-hCG levels and small gestational sac diameter [2] [29]. A 2025 retrospective cohort study found an overall MTX success rate of 72%, with a gestational sac diameter of <2 cm being a significant positive predictor of success [2] [30]. Furthermore, a 2025 study on a fixed-dose MTX protocol (90mg) reported an 81.1% success rate, particularly noting that a baseline hCG of less than 1000 mIU/mL was strongly associated with treatment success [28]. The number of MTX doses administered also serves as a significant protective factor against treatment failure [29].

Key Predictors of Treatment Failure

Identifying patients at risk for treatment failure is a critical component of clinical management. For MTX therapy, several risk factors have been identified through multivariate analyses:

• Elevated Pretreatment β-hCG Levels: Higher initial β-hCG levels are a consistent independent risk factor for MTX failure [29].
• Higher Gravidity: Increased number of pregnancies is associated with a greater odds of failure [29].
• Gestational Sac Diameter: A larger sac diameter, particularly ≥2 cm, predicts a lower likelihood of success with MTX [2].
• Visible Yolk Sac: The presence of a yolk sac on ultrasound is a significant predictor in univariate analyses [29].

For laparoscopic surgery, particularly salpingostomy, the primary risk of failure is persistent trophoblastic tissue, which may necessitate additional medical therapy or surgical intervention [17].

Impact on Fertility Outcomes and Tubal Patency

Preserving future reproductive potential is a primary concern for many patients. Meta-analyses of randomized controlled trials show that both treatment modalities yield generally favorable and comparable fertility outcomes, though with some nuanced differences.

Table 2: Comparison of Long-Term Fertility Outcomes

Outcome Measure	Laparoscopic Surgery	Methotrexate	Statistical Significance
Tubal Patency Rate	Significantly higher [8]	Lower	OR = 2.47, 95% CI 1.72–3.53, P < 0.001 [8]
Spontaneous Pregnancy Rate	Significantly higher [8]	Lower	OR = 2.10, 95% CI 1.28–3.46, P = 0.003 [8]
Future Intrauterine Pregnancy	73.08% [26]	68.46% [26]	P = 0.56 (Not Significant) [26]
Term Live Birth Rate	75.8% [2]	52.9% [2]	P = 0.12 (Not Significant) [2]
Recurrent Ectopic Pregnancy Rate	No statistically significant difference [8]	No statistically significant difference [8]	OR = 1.09, 95% CI 0.41–2.87, P = 0.87 [8]

As detailed in Table 2, a 2025 meta-analysis demonstrated that laparoscopic surgery was associated with a significantly higher tubal patency rate (OR=2.47) and spontaneous pregnancy rate (OR=2.10) compared to a single intramuscular injection of methotrexate [8]. However, more recent direct comparative studies have shown no statistically significant difference in rates of future intrauterine pregnancy between the two groups (73.08% for surgery vs. 68.46% for MTX) [26]. Similarly, a 2025 cohort study found no significant difference in subsequent term live birth rates, although a numerical advantage was observed for the surgical group (75.8% vs. 52.9%) [2]. Reassuringly, the risk of recurrent ectopic pregnancy is not significantly different between the two treatments [8] [26].

Experimental and Clinical Protocols

Methotrexate Treatment Protocol

The medical management of tubal ectopic pregnancy follows strict clinical protocols to ensure safety and efficacy.

• Eligibility Criteria: Medical management with MTX is offered to hemodynamically stable patients. Typical inclusion criteria are β-hCG levels < 5000 mIU/mL, an adnexal mass or gestational sac diameter < 35-40 mm, no embryonic cardiac activity, and no ultrasonographic evidence of hemoperitoneum or tubal rupture [2] [26] [27]. Absolute contraindications include renal or hepatic dysfunction, immunodeficiency, active pulmonary disease, and peptic ulcer disease [26] [27].
• Dosing and Administration: The most common regimen is a single-dose intramuscular injection of 50 mg/m² of body surface area [2] [26]. Alternatively, a fixed-dose protocol of 90 mg intramuscularly has also been validated as effective [28]. In a multidose protocol, MTX (1 mg/kg) is administered on days 1, 3, 5, and 7, with leucovorin rescue (0.1 mg/kg) on days 2, 4, 6, and 8 to mitigate side effects [31].
• Monitoring and Success Criteria: Serum β-hCG levels are measured on day 1 (baseline), day 4, and day 7 post-injection. A successful response is indicated by a decline in β-hCG of at least 15% between days 4 and 7 [29] [27]. If the decline is inadequate, a second dose of MTX may be considered, or surgery may be required [27]. β-hCG monitoring continues weekly until levels become undetectable [27].

Laparoscopic Surgical Protocol

Laparoscopic surgery is the cornerstone of surgical management, preferred for its minimal invasiveness and rapid recovery.

• Surgical Techniques: The two primary fertility-preserving procedures are:
  • Salpingostomy: The fallopian tube is incised, and the ectopic gestational tissue is removed, leaving the tube to heal naturally [17] [26].
  • Salpingectomy: The entire affected fallopian tube is removed, typically indicated in cases of tubal rupture or severe damage [2] [26].
• Decision-Making: The choice between salpingostomy and salpingectomy is based on intraoperative findings, the condition of the affected tube, the status of the contralateral tube, and the patient's fertility desires [26].
• Adjunctive Use of MTX: In some cases, particularly after salpingostomy, MTX may be administered postoperatively to prevent persistent trophoblastic tissue growth [17].

Clinical Decision Pathway

The following flowchart outlines the key decision points in managing a hemodynamically stable patient with a tubal ectopic pregnancy, based on established clinical criteria and guidelines.

The Scientist's Toolkit: Essential Research Reagents and Materials

Table 3: Key Reagents and Materials for Ectopic Pregnancy Research

Item	Primary Function in Research	Specific Application Example
Methotrexate	Folate antagonist; inhibits DNA synthesis and trophoblastic cell proliferation.	In vitro studies on trophoblast cell lines to investigate mechanisms of action and resistance [26].
β-hCG Immunoassay Kits	Quantify human chorionic gonadotropin concentration in serum.	Primary outcome measure for treatment efficacy in clinical trials and cohort studies [8] [2] [29].
Laparoscopic Tower	Visualization and instrumentation for minimally invasive pelvic surgery.	Standardized surgical intervention in comparative effectiveness studies (salpingostomy/salpingectomy) [8] [26].
Transvaginal Ultrasound	High-resolution imaging for diagnosis and morphological assessment.	Measuring ectopic mass size, detecting cardiac activity, and monitoring resolution post-treatment [2] [29].
Cell Culture Plastics	Provide sterile substrate for in vitro cell growth.	Maintaining trophoblast cell cultures for molecular and pharmacological experiments.
ELISA Kits (e.g., for Cytokines)	Detect and quantify specific proteins in cell supernatants or patient sera.	Investigating inflammatory pathways associated with ectopic implantation or tubal damage [29].

Research Workflow for Clinical Efficacy Studies

The methodology for conducting robust clinical research on ectopic pregnancy treatments involves a structured workflow from patient recruitment to data analysis, as visualized below.

The management of tubal ectopic pregnancy requires a nuanced approach that balances clinical efficacy with the preservation of future fertility. Laparoscopic surgery offers higher initial treatment success rates and superior tubal patency outcomes, making it a reliable choice, particularly when diagnosis is delayed or certain clinical risk factors are present. In contrast, methotrexate provides a non-invasive, fertility-preserving alternative with comparable long-term reproductive outcomes for carefully selected patients, specifically those with low and declining β-hCG levels and small gestational sac diameters.

The critical importance of early diagnosis cannot be overstated. It is the cornerstone that expands treatment options, allowing for the safe application of medical management and tubal-preserving surgical techniques. Ultimately, the choice between laparoscopic surgery and methotrexate should be guided by a shared decision-making process that incorporates the patient's clinical presentation, biomarker profiles, ultrasound findings, and future reproductive desires.

Ectopic pregnancy (EP), a condition where a pregnancy implants outside the uterine cavity, represents a significant health challenge in gynecology, with tubal pregnancies accounting for approximately 95% of all cases [32] [8]. For clinicians and researchers managing tubal pregnancy in women of reproductive age, a fundamental dilemma persists: selecting a treatment strategy that effectively resolves the pathological condition while optimally preserving future fertility potential. This clinical decision-making process increasingly centers on comparing two primary conservative approaches—laparoscopic surgery and medical management with methotrexate (MTX).

The evolution of both minimally invasive surgical techniques and optimized medical protocols has transformed tubal pregnancy management, shifting the focus from emergent, radical interventions toward fertility-preserving strategies. Laparoscopic surgery, particularly salpingotomy, offers direct mechanical resolution, while systemic methotrexate acts pharmacologically to halt trophoblastic growth. Understanding the nuanced trade-offs between these approaches requires critical examination of high-quality comparative evidence regarding their clinical efficacy, safety profiles, and most importantly, their long-term impact on reproductive outcomes [32] [16]. This guide systematically evaluates the current evidence to inform evidence-based clinical decision-making and future research directions in tubal pregnancy management.

Comparative Efficacy Analysis: Surgical versus Medical Management

A comprehensive understanding of the comparative performance of laparoscopic surgery and methotrexate treatment requires examination of multiple clinical outcome domains. The following analysis synthesizes data from recent high-quality studies, including a 2025 meta-analysis that incorporated 10 randomized controlled trials with 1,034 patients [32] [8] [15].

Clinical and Fertility Outcome Metrics

Table 1: Comparative Clinical Efficacy Outcomes

Outcome Metric	Laparoscopic Surgery	Methotrexate (Single Dose)	Statistical Significance	Effect Size [95% CI]
Treatment Success Rate	87% [33]	65-74% [34] [33]	Not Significant (p=0.33)	OR=1.88 [0.53-6.69] [32]
Tubal Patency Rate	Significantly Higher	Lower	P < 0.001	OR=2.47 [1.72-3.53] [32]
Spontaneous Pregnancy Rate	Significantly Higher	Lower	P = 0.003	OR=2.10 [1.28-3.46] [32]
Time to hCG Normalization	Significantly Shorter	Longer	P < 0.001	MD=-7.10 days [-7.84 to -6.36] [32]
Recurrent Ectopic Pregnancy Rate	17.3% [33]	9.6% [33]	Not Significant (p=0.87)	OR=1.09 [0.41-2.87] [32]

Procedural and Safety Metrics

Table 2: Procedural Characteristics and Safety Profiles

Characteristic	Laparoscopic Surgery	Methotrexate
Invasiveness	Invasive (surgical procedure)	Non-invasive (systemic medication)
Setting	Operating room, requires anesthesia	Outpatient setting possible
Resolution Mechanism	Physical removal of ectopic tissue	Pharmacological action on trophoblastic tissue
Adverse Effects	Surgical risks (bleeding, infection, anesthesia)	Nausea, vomiting, stomatitis, elevated liver enzymes
Contraindications	Hemodynamic instability, extensive adhesions	Hemodynamic instability, high hCG levels, liver/kidney disease
Cost Considerations	Higher direct costs (facility, surgeon)	Lower direct costs, but may require multiple doses

The data reveals a complex efficacy profile. While both approaches show comparable initial treatment success rates, laparoscopic surgery demonstrates superior performance across several fertility-focused endpoints, including tubal patency and subsequent spontaneous pregnancy rates [32]. The significantly shorter time to serum hCG normalization with surgical management (approximately 7 days faster) indicates more rapid biochemical resolution, potentially reducing the prolonged monitoring period required with methotrexate [32] [16].

Importantly, the comparable recurrent ectopic pregnancy rates between approaches suggest that neither treatment predisposes to substantially higher future risk, a crucial consideration for fertility preservation counseling [32]. For methotrexate, success rates are highly dependent on patient selection, with declining efficacy at higher initial hCG concentrations [34]. Recent evidence further indicates that single-dose and two-dose methotrexate regimens show similar success rates (71-72%), suggesting limited benefit from additional doses in most patients [35].

Methodological Approaches in Key Studies

Robust experimental methodologies underpin the current evidence base for tubal pregnancy management comparisons. Understanding these research approaches is essential for critical appraisal of the literature and design of future studies.

Systematic Review and Meta-Analysis Protocols

The foundational 2025 meta-analysis employed a rigorous systematic methodology [32] [8]. Researchers conducted comprehensive searches across five English and four Chinese databases from inception to January 31, 2024, ensuring broad linguistic and geographic representation. The study selection process followed PRISMA guidelines, with two independent reviewers screening 425 initially identified records against predetermined inclusion criteria. Ultimately, 10 randomized controlled trials meeting quality thresholds were included in the quantitative synthesis.

The statistical analysis utilized Review Manager 5.3 software, employing random-effects models for heterogeneous outcomes (I²>50%) and fixed-effect models for homogeneous ones. Methodological quality was assessed using the Cochrane risk-of-bias tool, with most studies rated as high-quality (Grade A). This protocol minimized selection bias and enhanced the reliability of pooled effect estimates for fertility outcomes [32] [8].

Randomized Controlled Trial Designs

Pragmatic, prospective randomized trials have formed the backbone of comparative evidence. The Danish multicenter trial employed a prospective, open-label design across seven obstetrics and gynecology departments, randomizing 106 women with ectopic pregnancy to either medical treatment (single-dose MTX) or surgical treatment (laparoscopic salpingotomy) [33]. The study featured long-term follow-up through questionnaires and national patient databases for up to 10 years, providing valuable insights into long-term reproductive outcomes.

The New Zealand trial implemented strict inclusion criteria focusing on clinically stable women with unruptured tubal pregnancy diagnosed by transvaginal ultrasound and quantitative serum beta-hCG measurement, specifically requiring hCG <5,000 IU/L and tubal pregnancy <3.5 cm diameter [34]. This design facilitated comparison in optimally selected candidates for medical management, though it limited generalizability to broader ectopic pregnancy populations.

Surgical Technique Refinements

Recent methodological advances have further differentiated surgical approaches. A 2025 systematic review compared single-incision laparoscopic surgery (SILS) with conventional laparoscopic surgery (CLS) for ectopic pregnancy, analyzing 12 studies involving 880 women [36]. SILS demonstrated several perioperative advantages over CLS, including significantly reduced blood loss (mean difference -51.01 mL, p=0.004), shorter postoperative hospital stay (mean difference -0.24 days, p=0.003), and faster return of bowel function (mean difference -1.03 hours, p<0.01) [36].

These technical refinements highlight the evolving nature of surgical management, with SILS offering potential benefits in cosmetic outcomes and recovery metrics while maintaining comparable operative times and safety profiles to conventional approaches [36].

Decision Pathways and Clinical Applications

Translating comparative evidence into clinical practice requires structured decision pathways that incorporate patient-specific factors and treatment goals. The following framework synthesizes key considerations for individualized treatment selection.

Patient Selection Criteria

Successful management depends on appropriate patient selection for each treatment approach. Methotrexate therapy is optimally suited for hemodynamically stable, compliant patients with low initial beta-hCG levels (generally <5,000 IU/L) and tubal pregnancy diameter <3.5 cm without cardiac activity [34] [37]. Absolute contraindications for methotrexate include hemodynamic instability, ruptured ectopic pregnancy, intrauterine pregnancy, and significant pre-existing hepatic, renal, or hematological dysfunction.

Laparoscopic surgery represents the preferred approach for patients with higher hCG levels, larger ectopic mass size, or presence of fetal cardiac activity. Surgical management is also indicated when methotrexate is contraindicated, has failed, or when patient preference favors a more definitive single-intervention approach with potentially superior fertility outcomes [32] [16].

Fertility Preservation Considerations

For women desiring future fertility, the demonstrated advantage of laparoscopic surgery in tubal patency rates (OR=2.47) and spontaneous pregnancy rates (OR=2.10) warrants significant consideration in shared decision-making [32]. However, methotrexate remains a viable non-invasive alternative, particularly for patients with favorable prognostic factors and strong preference to avoid surgery.

Recent evidence suggests that advanced maternal age and elevated BMI represent independent risk factors for adverse pregnancy outcomes following tubal surgery, with a linear relationship between BMI and pregnancy loss risk [38]. These factors should be incorporated into preoperative counseling and postoperative management strategies.

Essential Research Reagents and Materials

Conducting robust clinical research in tubal pregnancy management requires specific reagents, instruments, and assessment tools. The following table details key materials referenced in the evaluated studies.

Table 3: Essential Research Reagents and Materials for Tubal Pregnancy Studies

Reagent/Material	Specific Application	Research Function	Example Usage in Studies
Methotrexate	Pharmaceutical intervention	Conservative medical management	Single-dose regimen (50 mg/m²) IM [34]
Quantitative β-hCG Assay	Serum biomarker measurement	Treatment monitoring and success criterion	Serial measurements until <5 IU/L [33]
Laparoscopic Instrument Set	Surgical intervention	Conservative surgical management	Salpingotomy, fenestration techniques [32]
Medical Grade CO₂	Pneumoperitoneum	Laparoscopic visualization	Standard laparoscopic procedures [32]
Hysterosalpingography Contrast	Tubal patency assessment	Post-treatment fertility evaluation	6 weeks to 4 months post-treatment [32]
Transvaginal Ultrasound Probe	Diagnostic imaging	Initial diagnosis and treatment selection	Mass size measurement, cardiac activity [34]

The fundamental treatment dilemma between fertility preservation and definitive care in tubal pregnancy management requires careful balancing of multiple factors. Current evidence demonstrates that while laparoscopic surgery and methotrexate show comparable initial treatment success rates, surgical management appears superior for key fertility outcomes including tubal patency and subsequent spontaneous pregnancy rates [32]. However, methotrexate offers a non-invasive alternative with particular utility in selected patients with favorable prognostic factors.

Future research should address several evidence gaps, including standardized fertility outcome measures across studies, longer-term follow-up data on cumulative pregnancy rates, and refined patient selection algorithms that incorporate emerging biomarkers and imaging characteristics. Additionally, economic analyses comparing the total healthcare costs of both approaches—incorporating initial treatment, monitoring, and management of complications—would valuable inform healthcare system recommendations.

For clinical researchers and drug development professionals, these findings highlight the continued importance of personalized medicine approaches in tubal pregnancy management. The optimal treatment choice remains contingent on specific patient circumstances, reproductive goals, and local resource availability, with both approaches maintaining important roles in the contemporary management spectrum.

Treatment Protocols in Practice: Patient Selection, Dosing, and Surgical Techniques

Ectopic pregnancy (EP), a condition in which a fertilized egg implants outside the uterine cavity, remains a leading cause of maternal morbidity and first-trimester pregnancy-related mortality, affecting 1-2% of all pregnancies globally [26]. The management of tubal ectopic pregnancy has evolved significantly with methotrexate (MTX) emerging as a non-invasive, fertility-preserving alternative to surgical intervention. MTX, a folate antagonist that inhibits DNA synthesis and trophoblastic proliferation, has dramatically transformed the treatment landscape for hemodynamically stable patients [26]. Currently, multiple systemic MTX protocols are in clinical use, primarily consisting of single-dose, two-dose (also called double-dose), and multi-dose regimens with leucovorin rescue. Despite their widespread use, considerable debate persists regarding their comparative efficacy, safety, and appropriate clinical applications. This review systematically compares single-dose and multi-dose MTX regimens, examining their respective success rates, safety profiles, resolution times, and implications for clinical practice within the broader context of treatment options for tubal pregnancy.

Protocol Specifications and Methodologies

Single-Dose Methotrexate Protocol

The single-dose MTX protocol involves administration of 50 mg/m² of methotrexate as a single intramuscular injection on day 0 [39]. Serum beta-human chorionic gonadotropin (β-hCG) levels are then measured on day 4 and day 7 post-injection. Treatment success is typically defined as a progressive decline in β-hCG levels of at least 15% between days 4 and 7 [24]. If the decline is inadequate (<15%), a second dose of MTX may be administered. Patients are followed with weekly β-hCG measurements until levels become undetectable (<5 mIU/mL) [39]. This protocol was developed to minimize side effects, improve convenience, reduce overall costs, and eliminate the need for leucovorin rescue [40].

Multi-Dose Methotrexate Protocol

The traditional multi-dose MTX regimen involves administering four doses of 1 mg/kg methotrexate intramuscularly on days 0, 2, 4, and 6, with 0.1 mg/kg leucovorin rescue on alternate days (days 1, 3, 5, and 7) [40]. Serum β-hCG levels are monitored during treatment and until normalization. This protocol requires more intensive monitoring and involvement from healthcare providers and patients. The multiple-dose regimen aims to achieve higher cumulative drug exposure while potentially mitigating toxicity through leucovorin rescue.

Two-Dose Methotrexate Protocol

An intermediate approach, the two-dose protocol (sometimes called double-dose protocol), involves administration of 50 mg/m² methotrexate intramuscularly on day 0 and day 4 [40] or day 0 and day 7 [39], without leucovorin rescue. β-hCG levels are typically measured at day 14 to assess treatment response [39]. This protocol was developed in an attempt to combine the efficacy of the multi-dose regimen with the safety and convenience of the single-dose protocol [40].

Figure 1: Workflow comparison of methotrexate protocols for ectopic pregnancy management

Comparative Efficacy Analysis

Treatment Success Rates

Table 1: Comparative Success Rates of Methotrexate Protocols

Protocol Type	Success Rate	Study Details	Patient Population
Single-Dose	86.0%	RCT, n=50 [39]	Tubal EP, β-hCG <1500 mIU/mL
Two-Dose	90.0%	RCT, n=50 [39]	Tubal EP, β-hCG <1500 mIU/mL
Single-Dose (cumulative)	93.8%	After second dose if needed [24]	Tubal EP
Single-Dose	81.3%	Meta-analysis, 8 RCTs, n=1,015 [37]	Hemodynamically stable tubal EP
Multi-Dose	82.7%	Meta-analysis, 8 RCTs, n=1,015 [37]	Hemodynamically stable tubal EP

When comparing single-dose versus two-dose protocols directly, a randomized controlled trial demonstrated comparable success rates of 86.0% for single-dose versus 90.0% for two-dose regimens, with no statistically significant difference (p=0.5382) [39]. A more recent meta-analysis of eight randomized controlled trials including 1,015 women confirmed these findings, showing nearly identical success rates of 81.3% for single-dose and 82.7% for multi-dose regimens (RR 0.98, 95% CI 0.92-1.05) [37]. The cumulative success rate of single-dose protocol can reach 93.8% when including patients who receive a second dose for inadequate response [24].

Resolution Time and Recovery Metrics

Table 2: Resolution and Recovery Parameters Across Methotrexate Protocols

Parameter	Single-Dose Protocol	Two-Dose Protocol	Surgical Intervention
β-hCG Resolution Time (days)	28.2 ± 12.8 [39]	23.0 ± 12.1 [39]	Shorter [8]
Hospital Stay (days)	1.2 ± 0.5 [26]	Not specified	3.0 ± 1.2 [26]
Treatment Success Rate	87.69% [26]	Not specified	98.46% [26]
Future Intrauterine Pregnancy Rate	68.46% [26]	Not specified	73.08% [26]

The two-dose protocol demonstrates a statistically significant advantage in β-hCG resolution time compared to the single-dose regimen (23.0±12.1 days versus 28.2±12.8 days, p=0.0394) [39]. This faster resolution represents a clinical advantage in patient follow-up and monitoring requirements. When comparing medical to surgical management, MTX therapy offers significantly shorter hospital stays (1.2±0.5 days versus 3.0±1.2 days, p<0.001) despite lower overall success rates (87.69% versus 98.46%, p=0.001) [26]. Laparoscopic surgery has also been associated with significantly shorter time for serum hCG levels to return to normal compared to single intramuscular injection of methotrexate (MD=-7.10 days, 95% CI -7.84 to -6.36, P<0.001) [8].

Safety and Tolerability Profile

Table 3: Adverse Effect Comparison Between Methotrexate Protocols

Adverse Effect	Single-Dose Protocol	Two-Dose Protocol	Statistical Significance
Overall Adverse Effects	Significantly lower (RR 0.62, 95% CI 0.45-0.85) [37]	Not specified	p<0.05
Abdominal Pain	12.0% [39]	8.0% [39]	p=0.9996
Nausea/Vomiting	6.0% [39]	8.0% [39]	p=0.9996
Sore Throat	6.0% [39]	8.0% [39]	p=0.9996
Elevated Liver Enzymes	4.0% [39]	6.0% [39]	p=0.9996
Hematological Effects	2.0% [39]	2.0% [39]	p=0.9996

The single-dose MTX protocol demonstrates a significantly superior safety profile compared to multi-dose regimens, with a 38% reduction in adverse effects (RR 0.62, 95% CI 0.45-0.85) [37]. When directly comparing single-dose and two-dose protocols, no statistically significant differences in adverse effect rates were observed, with abdominal pain being the most common side effect in both groups (12.0% single-dose vs. 8.0% two-dose, p=0.9996) [39]. Other commonly reported side effects including nausea/vomiting, sore throat, elevated liver enzymes, and hematological effects showed comparable frequencies between single-dose and two-dose protocols.

Predictors of Treatment Failure

Understanding predictors of treatment failure is crucial for appropriate protocol selection and patient counseling. A recent meta-analysis identified several significant predictive factors for single-dose MTX treatment failure [41]:

• High initial β-hCG levels (SMD=1.25, 95% CI 0.73-1.77)
• Presence of fetal cardiac activity (OR=12.64, 95% CI 3.15-50.75)
• Presence of adnexal mass (OR=4.66, 95% CI 2.02-10.74)
• Presence of yolk sac (OR=5.35, 95% CI 2.33-12.27)
• Thicker endometrium (MD=1.74, 95% CI 0.30-3.19)
• History of pelvic inflammatory disease (OR=3.97, 95% CI 2.02-7.79)
• Higher progesterone levels (SMD=0.22, 95% CI 0.07-0.36)
• Rising β-hCG pre-treatment (MD=11.46%, 95% CI 2.95-19.98)

These predictors highlight patient populations that may benefit from alternative protocols or primary surgical management.

Fertility Outcomes and Tubal Patency

Future reproductive potential is a crucial consideration in ectopic pregnancy management. A meta-analysis comparing laparoscopic surgery to single-dose methotrexate demonstrated that surgical management was associated with significantly higher tubal patency rates (OR=2.47, 95% CI 1.72-3.53, P<0.001) and higher spontaneous pregnancy rates (OR=2.10, 95% CI 1.28-3.46, P=0.003) [8]. However, clinical studies have shown comparable rates of future intrauterine pregnancies between surgical and MTX-treated groups (68.46% for MTX vs. 73.08% for surgery, p=0.56) [26]. Among patients treated with MTX, 37.3% reported subsequent pregnancies, with 54.5% delivering live, healthy infants and 13.6% experiencing a second ectopic pregnancy [24]. These findings suggest that while surgery may offer advantages in tubal preservation, MTX remains a viable fertility-preserving option.

The Researcher's Toolkit: Essential Reagents and Materials

Table 4: Essential Research Materials for Methotrexate Protocol Studies

Reagent/Material	Primary Function	Research Application
Methotrexate	Folate antagonist inhibiting DNA synthesis	Primary investigational drug
Beta-hCG ELISA Assay	Quantitative measurement of β-hCG levels	Treatment response monitoring
Transvaginal Ultrasound Probe	Visualization of adnexal structures	Initial diagnosis and mass measurement
Leucovorin (Folinic Acid)	MTX rescue agent	Multi-dose protocol requirement
Alanine Aminotransferase (ALT) Assay	Liver function assessment	Toxicity monitoring
Complete Blood Count (CBC) Analyzer	Hematological parameter measurement	Bone marrow toxicity monitoring
Progesterone Assay	Serum progesterone quantification	Prognostic indicator
Renal Function Tests	Renal safety monitoring	Toxicity assessment

The evidence comparing single-dose and multi-dose methotrexate protocols for tubal ectopic pregnancy demonstrates comparable efficacy between approaches, with single-dose regimens offering advantages in safety profile and convenience. The two-dose protocol emerges as a balanced option, providing faster β-hCG resolution than single-dose therapy without significantly increasing adverse effects. Protocol selection should be individualized based on patient characteristics, with particular attention to predictors of single-dose treatment failure such as high initial β-hCG levels, presence of fetal cardiac activity, and adnexal mass findings. While surgical management continues to offer higher success rates and faster hCG normalization, methotrexate protocols provide excellent alternatives for appropriate candidates, with comparable future fertility outcomes and significant advantages in hospital stay duration and minimally invasive approach. Future research should focus on refining patient selection criteria and developing personalized treatment algorithms to optimize outcomes across different clinical scenarios.

Laparoscopic surgery is a cornerstone in the management of tubal ectopic pregnancy, which accounts for approximately 95% of all ectopic cases [8] [32]. The two primary laparoscopic surgical approaches are salpingostomy and salpingectomy, procedures with distinct objectives and technical execution.

Salpingostomy (also referred to as neosalpingostomy) is a conservative, fertility-preserving procedure. It involves creating a linear incision on the antimesenteric border of the affected fallopian tube to remove the ectopic pregnancy tissue, while leaving the tube in place and, ideally, preserving its function [42] [43]. The goal is to resolve the ectopic pregnancy while maintaining the anatomical pathway for future natural conception.

In contrast, salpingectomy is a radical procedure involving the complete removal of the affected fallopian tube [44] [45]. This approach is definitive and eliminates the possibility of a recurrent ectopic pregnancy in the same tube. It is often indicated in cases of tubal rupture, severe tubal damage, or when future fertility is not desired [44] [43].

Table 1: Key Characteristics of Laparoscopic Salpingostomy and Salpingectomy

Feature	Salpingostomy	Salpingectomy
Procedure Goal	Conservative, fertility-preserving	Radical, definitive
Technical Action	Incision made to remove ectopic tissue; tube remains	Complete removal of the fallopian tube
Primary Indications	Stable patient, desire for future fertility, contralateral tube disease [43]	Tubal rupture, uncontrolled bleeding, severe tubal damage, no desire for future fertility [44] [43]
Fertility Outcome	Preserves potential for natural conception via the operated tube	Eliminates natural conception via the operated tube; natural conception possible with a contralateral healthy tube [44]
Risk of Persistent Trophoblast	Higher [43]	Virtually none

Comparative Clinical Efficacy and Outcomes Data

The choice between salpingostomy and salpingectomy has significant implications for perioperative safety, future reproductive potential, and long-term gynecological health. Quantitative comparisons from meta-analyses provide critical insights for clinical decision-making.

Perioperative Safety and Surgical Parameters

Meta-analyses of randomized controlled trials (RCTs) indicate that both procedures are generally safe, with some differences in specific surgical parameters. Salpingostomy is associated with significantly less intraoperative blood loss compared to salpingectomy [42]. However, no statistically significant differences are typically observed between the two procedures in terms of operating duration, postoperative hospital stay, or early postoperative serum hCG levels [42].

Reproductive Outcomes and Ovarian Function

Reproductive outcomes are a pivotal differentiator. A meta-analysis of 15 RCTs demonstrated that the subsequent spontaneous intrauterine pregnancy rate was significantly higher in patients who underwent salpingotomy compared to those who underwent salpingectomy (OR = 2.49) [42]. This underscores the success of salpingostomy in preserving fertility.

Critically, the rate of recurrent ectopic pregnancy does not show a statistically significant difference between the two procedures, alleviating a common concern regarding conservative surgery [42]. Furthermore, emerging evidence suggests that salpingotomy offers an additional advantage by better protecting ovarian reserve and endocrine function, as measured by hormone levels and ultrasound parameters, thereby creating favorable conditions for a subsequent pregnancy [42].

Cancer Risk Reduction

A significant modern consideration is the role of salpingectomy in cancer prevention. Research has revealed that many high-grade serous ovarian cancers originate in the fallopian tubes [45]. Consequently, bilateral salpingectomy (removal of both tubes) is now recognized as a risk-reducing strategy. For patients at average risk of ovarian cancer who have completed childbearing, an "opportunistic salpingectomy" performed during other abdominal surgeries can lower the risk of future ovarian, fallopian tube, and peritoneal cancers [44] [45]. For high-risk patients, such as those with BRCA mutations, removal of both tubes and ovaries remains the standard of care [45].

Table 2: Summary of Comparative Outcomes from Meta-Analyses

Outcome Measure	Salpingostomy	Salpingectomy	Statistical Significance (p-value)
Intrauterine Pregnancy Rate (OR)	2.49 [42]	Reference (1.0)	< 0.0001
Recurrent Ectopic Pregnancy Rate	No significant difference [42]	No significant difference [42]	Not Significant
Intraoperative Blood Loss (WMD)	-164.86 mL [42]	Reference	< 0.00001
Operation Duration & Postoperative Stay	No significant difference [42]	No significant difference [42]	Not Significant
Ovarian Cancer Risk	No reduction	Significant reduction (≈80% risk reduction) [44]	-

Experimental and Methodological Protocols

Robust meta-analyses and randomized controlled trials form the evidence base for comparing these surgical techniques. The following outlines the standard methodologies employed in this field of research.

Meta-Analysis Protocol for Comparing Surgical Outcomes

Objective: To systematically compare the therapeutic effects of laparoscopic salpingostomy versus salpingectomy on perioperative safety and postoperative reproductive function in patients with tubal pregnancy [42].

Search Strategy:

• Data Sources: Interrogation of major electronic databases (e.g., Cochrane Library, MEDLINE, PubMed, Web of Science, EMBASE) from a defined inception date to the present.
• Search Terms: Use of structured queries combining MESH and free-text terms such as ("tubal pregnancy" OR "ectopic pregnancy") AND ("salpingotomy" OR "salpingostomy") AND ("salpingectomy") [42].
• Study Selection: Screening of identified records against pre-defined inclusion/exclusion criteria by multiple independent reviewers to minimize bias.

Inclusion/Exclusion Criteria:

• Population: Patients with tubal ectopic pregnancy.
• Intervention & Comparison: Laparoscopic salpingostomy versus laparoscopic salpingectomy.
• Study Design: Focus on Randomized Controlled Trials (RCTs) for highest evidence quality [42].
• Exclusion: Non-tubal pregnancies, non-comparative studies, case reports, and reviews.

Data Extraction and Analysis:

• Outcomes: Pre-specified primary and secondary outcomes are extracted into a standardized table. Key outcomes often include intrauterine pregnancy rate, recurrent ectopic pregnancy rate, operative time, and blood loss [42].
• Statistical Synthesis: Pooled effect estimates (Odds Ratio [OR] for dichotomous outcomes, Weighted Mean Difference [WMD] for continuous outcomes) are calculated using fixed or random-effects models based on heterogeneity (I² statistic) [42].
• Quality & Bias Assessment: The methodological quality of included studies is assessed using tools like the modified Jadad score and the Cochrane risk-of-bias tool [42].

Clinical Trial Protocol for Surgical and Fertility Outcomes

Objective: To evaluate and compare the long-term fertility outcomes (intrauterine pregnancy and recurrent ectopic pregnancy rates) following laparoscopic salpingostomy versus salpingectomy.

Patient Recruitment and Randomization:

• Participants: Hemodynamically stable patients diagnosed with tubal ectopic pregnancy, who provide informed consent and express a desire for future fertility.
• Randomization: Eligible patients are randomly allocated to either the salpingostomy or salpingectomy group using a computer-generated sequence with adequate allocation concealment.

Surgical Procedure:

• Both groups undergo laparoscopic surgery under general anesthesia.
• Salpingostomy Group: A linear incision is made on the antimesenteric border of the affected tube. The ectopic gestation is removed, and hemostasis is achieved. The tubal incision is left to heal by secondary intention [43].
• Salpingectomy Group: The affected fallopian tube is dissected from the mesosalpinx using energy sources, separated from the uterus, and removed entirely [44] [45].

Postoperative Follow-up and Outcome Measurement:

• Primary Outcome: Rate of spontaneous intrauterine pregnancy, confirmed by ultrasound, during a follow-up period of at least 18-24 months [42].
• Secondary Outcomes: Rates of recurrent ectopic pregnancy; time to first pregnancy; changes in ovarian reserve markers (e.g., serum Anti-Müllerian Hormone levels, antral follicle count); and perioperative complication rates.
• Statistical Analysis: Intention-to-treat analysis is performed. Time-to-pregnancy data may be analyzed using Kaplan-Meier curves and Cox proportional hazards models.

Visualization of Surgical Decision Pathways and Experimental Workflows

Surgical Decision Pathway for Ectopic Pregnancy

Meta-Analysis Workflow for Outcome Comparison

The Scientist's Toolkit: Essential Research Reagents and Materials

The experimental and clinical research into surgical outcomes relies on a suite of specific reagents, instruments, and assessment tools.

Table 3: Key Research Reagents and Materials for Surgical Outcomes Studies

Reagent/Material	Primary Function in Research Context	Experimental Application Example
Laparoscopic Tower	Provides visualization, insufflation, and illumination for the surgical field.	Core equipment for performing standardized salpingostomy and salpingectomy procedures in clinical trials [43].
Serum β-hCG Assay	Quantifies human chorionic gonadotropin to confirm pregnancy and monitor post-treatment resolution.	Measuring treatment success and identifying persistent trophoblastic disease after salpingostomy [8] [35].
Hysterosalpingogram (HSG) Contrast Agent	Radiopaque fluid used to visualize the internal architecture and patency of the fallopian tubes.	Assessing tubal patency rates post-salpingostomy as a key fertility outcome [8] [43].
Enzyme Immunoassay (EIA) Kits	Measure serum levels of ovarian reserve hormones.	Evaluating the impact of salpingectomy vs. salpingostomy on ovarian function by measuring hormones like AMH, FSH, and Estradiol [42].
Ultrasound with Doppler	Provides high-resolution imaging of pelvic structures and vascular flow.	Monitoring ovarian morphology, follicle count, and blood flow (PSV, EDV, RI) to assess surgical impact on ovarian reserve [42].
Microsurgical Instruments	Fine forceps, scissors, and needle drivers for delicate tissue handling.	Essential for performing precise, atraumatic salpingostomy and adhesiolysis in accordance with microsurgical principles [43].

Ectopic pregnancy (EP), a condition where a fertilized ovum implants outside the uterine cavity, represents a significant cause of maternal morbidity and mortality, accounting for approximately 2.7% of pregnancy-related deaths [46] [11]. Tubal pregnancy constitutes over 95% of all ectopic pregnancies [14] [17]. The management of tubal ectopic pregnancy hinges primarily on three evidence-based pillars: serum beta-human chorionic gonadotropin (β-hCG) levels, transvaginal ultrasonography (TVS) findings, and the patient's clinical stability [46] [14]. Treatment selection between medical management with methotrexate (MTX) and laparoscopic surgery fundamentally depends on the interpretation of these criteria, with the overarching goals of preserving patient safety, minimizing complications, and optimizing future fertility [8] [14]. This guide provides a structured comparison of laparoscopic surgery and methotrexate therapy, framing the evidence within the critical context of these diagnostic parameters.

Comparative Treatment Data and Clinical Outcomes

Table 1: Evidence-Based Criteria for Treatment Selection and Patient Eligibility

Clinical Parameter	Methotrexate (MTX) Therapy	Laparoscopic Surgery (Salpingostomy/Salpingectomy)
Hemodynamic Status	Hemodynamically stable patients only [46] [14]	First-line for hemodynamic instability, ruptured tube, or significant hemoperitoneum [46] [14]
Serum β-hCG Level	Most effective with lower levels; single-dose protocol often used for levels < 1500–2000 IU/L [46] [47]. Success rate decreases with rising hCG [46]	Recommended for high initial β-hCG levels [46]
Ultrasound Findings (Adnexal Mass)	Suitable for unruptured masses; relative contraindication if mass > 3–4 cm [46] [48] [47]	Required for ruptured ectopic pregnancy; preferred for larger masses (e.g., ≥ 3.5 cm) [46] [48]
Fetal Cardiac Activity	Contraindicated if extrauterine cardiac activity is detected [46]	Urgently indicated when extrauterine cardiac activity is present [46]
Key Contraindications	Renal/liver disease, immunodeficiency, active pulmonary disease, peptic ulcer disease, breastfeeding, sensitivity to MTX [46]	General anesthesia contraindications; patient preference for fertility preservation may guide choice of salpingostomy vs. salpingectomy [14]

Table 2: Comparison of Treatment Efficacy and Fertility Outcomes

Outcome Measure	Methotrexate Therapy	Laparoscopic Surgery (Tubal Preserving)	Supporting Evidence
Treatment Success Rate	No statistically significant difference compared to laparoscopic surgery [8]	No statistically significant difference compared to methotrexate [8]	Meta-analysis of 6 studies (OR = 1.88, 95% CI 0.53–6.69, P = 0.33) [8]
Tubal Patency Rate	Lower patency rate on the affected side	Significantly higher tubal patency rate	Meta-analysis of 8 studies (OR = 2.47, 95% CI 1.72–3.53, P < 0.001) [8]
Future Spontaneous Pregnancy Rate	Lower spontaneous pregnancy rate	Significantly higher spontaneous pregnancy rate	Meta-analysis of 7 studies (OR = 2.10, 95% CI 1.28–3.46, P = 0.003) [8]
Time to hCG Normalization	Longer time for serum hCG to return to normal [8]	Shorter time for serum hCG to return to normal (MD = -7.10 days) [8]	Meta-analysis (MD = -7.10, 95% CI -7.84 – -6.36, P < 0.001) [8]
Recurrent Ectopic Pregnancy Rate	No statistically significant difference [8]	No statistically significant difference [8]	Meta-analysis (OR = 1.09, 95% CI 0.41–2.87, P = 0.87) [8]

Diagnostic Workflow and Experimental Protocols

Diagnostic Pathway for Tubal Ectopic Pregnancy

The diagnosis of tubal ectopic pregnancy relies on a structured combination of clinical assessment, serial β-hCG monitoring, and transvaginal ultrasonography [46] [11]. A positive pregnancy test in a patient presenting with abdominal pain or vaginal bleeding should trigger the diagnostic algorithm. In a desired pregnancy, when TVS shows neither an intrauterine nor an ectopic gestation (a "Pregnancy of Unknown Location"), serial β-hCG measurements are essential [46]. The expected minimum increase for a viable intrauterine pregnancy is 49% over 48 hours with initial β-hCG <1500 mIU/mL, slowing to 33% for levels >3000 mIU/mL [46]. A slower-than-expected rise or a decline of less than 21% over 48 hours suggests a non-viable or ectopic pregnancy [46]. The discriminatory zone, the β-hCG level above which an intrauterine pregnancy should be visible on TVS, is recommended to be as high as 3500 mIU/mL to avoid misdiagnosing a viable pregnancy [46].

Diagram 1: Diagnostic Pathway for Suspected Ectopic Pregnancy. This flowchart outlines the evidence-based diagnostic algorithm for evaluating a patient with a suspected ectopic pregnancy, integrating transvaginal ultrasound findings and serial β-hCG monitoring. GS = Gestational Sac.

Protocol for Medical Management with Methotrexate

The single-dose methotrexate protocol is a common medical management strategy [46]. Key steps include:

• Patient Selection: Confirm eligibility (hemodynamically stable, no contraindications to MTX, no signs of rupture, β-hCG levels within optimal range, no fetal cardiac activity outside the uterus) [46].
• Baseline Measurements: Obtain baseline β-hCG level, complete blood count, and liver and renal function tests [46].
• Methotrexate Administration: Administer methotrexate intramuscularly at a dose of 50 mg/m² of body surface area [46].
• Post-Treatment Monitoring:
  • Day 1 & 4: Measure serum β-hCG levels.
  • Day 7: Measure serum β-hCG level. A decline of ≥15% between Day 4 and Day 7 indicates successful treatment. If the decline is insufficient, a second dose of methotrexate may be considered, or surgery may be required [46] [17].
  • Weekly β-hCG monitoring is continued until levels are undetectable.

Protocol for Surgical Management

Laparoscopic salpingostomy is the primary tubal-preserving surgical procedure [8] [17]. The methodology involves:

• Patient Preparation: General anesthesia is induced. The patient is positioned and prepped for laparoscopic surgery.
• Visualization: A laparoscope is inserted through a small umbilical incision. The abdomen is insufflated with CO₂ to create a working space. The pelvis is inspected to identify and assess the ectopic pregnancy.
• Salpingostomy: A linear incision is made on the antimesenteric border of the fallopian tube over the bulging ectopic pregnancy. This is often performed using a needle-tip electrocautery or laser.
• Evacuation: The ectopic gestational tissue is meticulously hydrodissected and evacuated from the tube using suction and irrigation, allowing it to "pop out" [47].
• Hemostasis: Hemostasis is achieved at the incision site with careful electrocautery, avoiding excessive thermal damage to the tubal epithelium.
• Specimen Handling: The removed tissue is sent for histopathological examination to confirm the presence of villi and rule out a corpus luteum pregnancy [11].
• Postoperative Monitoring: Serum β-hCG levels are typically monitored postoperatively until they become undetectable to ensure complete removal of trophoblastic tissue [17].

Advanced Ultrasound Classification and Its Clinical Impact

Recent research proposes a novel ultrasound-based classification for Tubal Ectopic Pregnancies (TEPs) that refines treatment decisions by accounting for the relationship between sonographic appearance and serum markers [48]. This system categorizes TEPs into two distinct subtypes:

• Simple Gestational Sac (GS)-like Mass: Characterized by a clear trophoblastic ring without hematosalpinx. In this subtype, β-hCG levels are strongly positively correlated with mass size (r = 0.720, p < 0.01). This strong correlation means that β-hCG level can be a reliable proxy for disease burden, supporting treatment decisions as per standard guidelines that heavily weigh β-hCG values [48].
• Complicated Mass: Includes three presentations: (1) hematosalpinx with a trophoblastic ring, (2) hematosalpinx without an obvious trophoblastic ring, or (3) an irregular mixed-echoic mass. In these cases, the correlation between β-hCG and mass size is weak (r = 0.211, p < 0.01). This discordance suggests that β-hCG alone may not fully reflect the anatomical extent of the ectopic, necessitating a more comprehensive assessment where mass size may be deemphasized in decision-making [48].

Table 3: Key Reagents and Research Materials for Ectopic Pregnancy Investigations

Research Tool / Reagent	Primary Function in EP Research	Specific Application Example
Beta-human Chorionic Gonadotropin (β-hCG) Immunoassay	Quantitative measurement of serum hCG levels for diagnosis and monitoring.	Tracking hCG trends to differentiate viable IUP from ectopic pregnancy or miscarriage; monitoring success post-MTX or surgery [46].
High-Resolution Transvaginal Ultrasound Probe	High-frequency imaging for detailed visualization of adnexal structures and early gestation.	Differentiating simple GS-like masses from complicated masses; measuring mass size and assessing for free fluid [46] [48].
Color Doppler Flow Imaging (CDFI)	Visualization and grading of vascularity surrounding the trophoblastic tissue.	Grading peri-trophoblastic blood flow (0-3), which can be higher in simple GS-like masses and inform on implantation activity [48].
Methotrexate	Folate antagonist that inhibits rapidly dividing cells (e.g., trophoblasts).	Medical management of selected ectopic pregnancies; used as primary treatment or adjunct post-salpingostomy for persistent trophoblast [46] [17].
Laparoscopic Tower & Instrumentation	Minimally invasive surgical access for diagnosis and therapeutic intervention.	Performing salpingostomy or salpingectomy; allows for direct visualization and preservation of fertility potential where possible [8] [17].

The selection between methotrexate and laparoscopic surgery for tubal ectopic pregnancy is a nuanced clinical decision guided by stringent, evidence-based criteria centered on hemodynamic stability, quantitative β-hCG levels, and detailed ultrasound findings. Methotrexate offers a non-invasive option for stable patients meeting specific biochemical and sonographic profiles, while laparoscopic surgery remains the gold standard for unstable patients, those with high hCG, large masses, or detectable cardiac activity. Fertility outcomes, particularly future spontaneous pregnancy and tubal patency rates, currently favor laparoscopic surgery, though both treatments show comparable success and recurrence rates. The emergence of refined ultrasound classifications promises to further personalize treatment by elucidating the complex relationships between sonographic patterns and serum markers, paving the way for more precise and effective management strategies.

Tubal ectopic pregnancy, accounting for over 95% of all ectopic pregnancies, remains a significant cause of maternal morbidity and an important clinical challenge in reproductive health [8] [17]. The evolution of diagnostic techniques has facilitated earlier detection, shifting management strategies from emergency interventions to planned conservative approaches that prioritize tubal preservation and future fertility [49]. Within this therapeutic landscape, laparoscopic salpingostomy and systemic methotrexate (MTX) administration have emerged as first-line treatments for hemodynamically stable women [50]. The combination of these modalities—salpingostomy with adjuvant methotrexate—represents an innovative approach aimed at harnessing the benefits of each while mitigating their respective limitations. This review systematically compares the clinical efficacy, reproductive outcomes, and practical implementation of this combined strategy against each treatment in isolation, providing evidence-based insights for clinical researchers and therapeutic developers.

Comparative Treatment Modalities: Mechanism and Protocols

Laparoscopic Salpingostomy

Laparoscopic salpingostomy is a tubal-preserving surgical procedure involving a linear incision into the fallopian tube to remove the ectopic gestation. The primary objective is precise excision of trophoblastic tissue while maintaining anatomical integrity and function [42]. Beyond serving as a definitive treatment, this approach provides direct visual assessment of tubal status and pelvic environment—valuable prognostic information for future fertility planning.

Experimental Protocol: The procedure is performed under general anesthesia utilizing standard laparoscopic equipment. Key surgical principles include:

• Tubal Incision: A longitudinal incision is made on the antimesenteric border of the fallopian tube using a monopolar or bipolar needle, laser, or harmonic scalpel.
• Gestational Sac Removal: The ectopic pregnancy is meticulously extracted using hydrodissection, forceps, or suction, with care to remove all trophoblastic tissue intact.
• Hemostasis: Achieving meticulous hemostasis while minimizing thermal damage to the tubal endothelium.
• Wound Management: The tubal incision is typically left to heal by secondary intention [42].

Postoperative monitoring of serum human chorionic gonadotropin (hCG) levels is mandatory to detect persistent trophoblastic tissue, occurring in 11-22% of cases [50].

Systemic Methotrexate Therapy

Methotrexate, a folate antagonist, inhibits DNA synthesis and cellular proliferation in trophoblastic tissue. Systemic administration offers a non-invasive alternative for eligible patients, with success rates ranging from 65% to 95% depending on selection criteria and protocol used [50].

Experimental Protocol (Single-Dose Regimen):

• Day 1: Baseline assessment of serum hCG, liver function tests, renal function, and complete blood count. Intramuscular administration of methotrexate (50 mg/m² or 1 mg/kg).
• Day 4: Serum hCG measurement.
• Day 7: Serum hCG measurement. A second dose is administered if hCG decline is <15% from days 4-7.
• Weekly Monitoring: Continued until hCG is undetectable (<5 mIU/mL) [51] [50].

Treatment success correlates strongly with specific patient factors, particularly initial hCG levels, with failure rates exceeding 50% when hCG >10,000 IU/L [52].

Combined Salpingostomy-MTX Approach

The combined protocol integrates surgical excision with prophylactic or therapeutic methotrexate to address the principal limitation of salpingostomy: persistent trophoblast. This approach can be implemented as either:

• Adjuvant Prophylaxis: Routine MTX administration immediately post-salpingostomy.
• Targeted Therapy: MTX reserved for documented hCG persistence [50].

Clinical Outcomes: Quantitative Comparison

Treatment Efficacy and Failure Rates

Table 1: Comparative Treatment Failure Rates

Treatment Modality	Failure Rate	Definition of Failure	Sample Size	References
Single-dose MTX	25% overall; 53% when hCG >10,000 IU/L	<15% hCG decline days 4-7 or need for surgery	156-270 patients	[53] [51] [52]
Laparoscopic Salpingostomy	9%	Persistent trophoblast requiring additional intervention	513 patients	[8] [17]
Salpingostomy + Adjuvant MTX	<2%	Need for secondary surgical intervention	Multiple studies	[50]

Network meta-analysis indicates salpingostomy combined with MTX significantly reduces failure rates compared to either monotherapy (OR 0.28-0.38) [17] [50]. The combined approach demonstrates particular utility in high-risk scenarios including large gestational sacs (≥30mm), high initial hCG (>5000 IU/L), or presence of cardiac activity [53] [50].

Reproductive Outcomes

Table 2: Subsequent Fertility Outcomes

Outcome Measure	Medical MTX	Surgical Salpingostomy	Salpingostomy + MTX	References
Tubal Patency Rate	Baseline	OR 2.47 (95% CI 1.72-3.53)	Comparable to salpingostomy alone	[8]
Spontaneous Pregnancy Rate	Baseline	OR 2.10 (95% CI 1.28-3.46)	Limited data (theoretically preserved)	[8] [42]
Recurrent Ectopic Pregnancy	No significant difference between groups (OR 1.09, 95% CI 0.41-2.87)		[8]
Time to hCG Normalization	27.2 ± 2.3 days	20.2 ± 2.7 days	Intermediate (theoretically)	[54]

Long-term fertility outcomes show no significant differences between MTX and surgical approaches in terms of subsequent intrauterine pregnancy or recurrent ectopic pregnancy rates, suggesting the combined approach does not adversely impact future reproductive potential [54] [8] [50].

Resolution Kinetics and Patient Experience

Table 3: Treatment Process and Recovery Metrics

Parameter	Medical MTX	Surgical Salpingostomy	Salpingostomy + MTX
Treatment Duration	Weeks to months (until hCG undetectable)	Single procedure with 1-2 day hospitalization	Extended monitoring similar to MTX
hCG Monitoring	Essential (weekly until negative)	Required (postoperative persistence risk)	Essential
Side Effects	5.5% (stomatitis, gastritis, elevated LFTs)	Minimal surgical risks	Combined profile
Cost Effectiveness	Superior to surgery	Higher direct costs	Intermediate

The combined approach uniquely modifies the recovery profile, introducing potential MTX-related adverse effects (occurring in approximately 5.5% of patients) while substantially reducing the risk of secondary surgical procedures (from 11-22% to <2%) [50].

Predictive Algorithms and Patient Selection

Optimal application of the combined salpingostomy-MTX approach requires careful patient selection. Predictive scoring systems incorporating multiple prognostic factors have demonstrated superior performance to single-parameter thresholds.

Table 4: Predictive Factors for Treatment Success

Predictor	Favorable Profile	Unfavorable Profile	Impact on Success
Initial hCG	<2000 IU/L	>5000 IU/L	Strongest predictor; failure >50% when >10,000 IU/L [51] [52]
Gestational Age	<5 weeks	≥7 weeks	Earlier detection improves outcomes [53]
Ectopic Mass Size	<30mm	≥30mm	Larger mass associated with increased failure [53]
Fetal Cardiac Activity	Absent	Present	Reduces MTX efficacy [51] [50]
Yolk Sac Presence	Absent	Present	Moderate predictor of failure [53]
Hemoperitoneum	None or minimal	Significant	Contributes to treatment failure [50]

A novel scoring system incorporating these parameters demonstrated 92% sensitivity and 78% specificity in predicting single-dose MTX success when using a cutoff score of 2.5 (AUC=0.804) [53]. Patients scoring below this threshold achieved 90.5% success with MTX monotherapy, while higher scores may benefit from primary combined approach.

The Scientist's Toolkit: Essential Research Reagents and Materials

Table 5: Essential Research Materials for Ectopic Pregnancy Investigation

Reagent/Material	Research Application	Experimental Function
Methotrexate	Medical therapy studies	Folate antagonist; inhibits trophoblastic proliferation
β-hCG Immunoassay Kits	Treatment monitoring	Quantifies trophoblastic activity and treatment response
Transvaginal Ultrasound Probes	Diagnostic classification	Visualizes ectopic mass size, location, cardiac activity
Laparoscopic Tower	Surgical intervention studies	Enables minimally invasive tubal preservation techniques
Progesterone Assays	Prognostic assessment	Correlates with ectopic pregnancy viability and resolution
Cell Culture Models	Mechanistic studies	Investigates trophoblast biology and drug mechanisms
ELISA Reagents	Cytokine profiling	Measures inflammatory mediators in tubal microenvironment

The combined salpingostomy with adjuvant methotrexate approach represents a sophisticated therapeutic strategy that effectively addresses the primary limitation of persistent trophoblast following conservative surgery. Current evidence indicates this approach reduces treatment failure rates to below 2%, significantly superior to either modality alone, while maintaining comparable long-term fertility outcomes [50]. The decision framework for implementing this combined strategy should incorporate multidimensional assessment including initial hCG levels, sonographic features, and validated predictive scores [53]. For researchers and clinical developers, these findings highlight the importance of personalized treatment algorithms based on comprehensive risk stratification rather than universal protocols. Future investigations should focus on refining patient selection criteria, optimizing MTX dosing schedules in the postoperative setting, and evaluating novel targeted therapies that may further enhance reproductive preservation while minimizing treatment burden.

In clinical research and practice for tubal ectopic pregnancy, the monitoring of serum beta-human chorionic gonadotropin (β-hCG) levels serves as the principal objective method for evaluating treatment response. The accurate assessment of treatment efficacy is fundamental for determining successful resolution and identifying cases requiring intervention escalation. For researchers and drug development professionals, understanding the distinct β-hCG resolution kinetics and failure criteria for the two primary treatment modalities—laparoscopic surgery and methotrexate (MTX) therapy—is crucial for designing clinical trials, evaluating new therapeutic agents, and establishing standardized monitoring protocols. This guide provides a detailed, data-driven comparison of these monitoring frameworks, supported by experimental data and methodological protocols.

Monitoring Protocols and Failure Definitions

The physiologic basis for monitoring differs significantly between surgical and medical management, necessitating distinct protocols for each modality.

Methotrexate Therapy Monitoring Protocol

Medical management with methotrexate, a folate antagonist that disrupts trophoblastic cell division, requires a meticulous monitoring protocol due to its variable success rate and potential for delayed failure [55].

• Administration and Initial Monitoring: Intramuscular MTX is administered at a standard dose of 50 mg/m². Serum β-hCG levels are measured on day 0 (baseline), and repeated on day 4 and day 7 post-injection [56] [57].
• Kinetic Analysis and Failure Definition: The critical assessment occurs between day 4 and day 7. A decrease in β-hCG levels of less than 15% during this interval is the most widely accepted laboratory indicator of treatment failure and often necessitates a second dose of MTX or surgical intervention [17]. Research indicates that specific β-hCG thresholds post-treatment are highly predictive. A study constructing a risk prediction model identified that a β-hCG level increase of more than 1,028.6 mIU/mL or a rise to 1.0457-fold above baseline on day 4, and similarly, an increase of more than 1,233 mIU/mL or a rise to 1.3025-fold above baseline on day 7, are strong predictors of treatment failure [57].
• Extended Follow-up: After a successful initial decline, β-hCG levels are monitored weekly until they return to undetectable levels, confirming complete resolution of the trophoblastic tissue [55].

The following diagram illustrates the logical workflow for monitoring and assessing treatment failure in methotrexate therapy.

Laparoscopic Surgery Monitoring Protocol

Laparoscopic surgery (e.g., salpingostomy or salpingectomy) involves the physical removal of the ectopic pregnancy, leading to a more rapid decline in circulating β-hCG.

• Postoperative Monitoring: Serum β-hCG is typically measured on the fourth day after surgery [17].
• Failure Definition: Treatment failure, often termed "persistent trophoblastic tissue," is defined as an increase or a plateau (no decrease) in serum β-hCG levels on postoperative day 4 [17]. This indicates that not all trophoblastic tissue was removed and may require adjuvant medical therapy with MTX.
• Kinetic Advantage: Meta-analyses show that laparoscopic surgery is associated with a significantly shorter time for β-hCG levels to normalize compared to a single intramuscular injection of MTX, with a mean difference of -7.10 days [8]. This reflects a more immediate and definitive resolution of the ectopic pregnancy.

Comparative Quantitative Outcomes

The different physiologic mechanisms of action for surgery and medical therapy result in divergent outcomes for key efficacy metrics. The table below summarizes quantitative data from meta-analyses and clinical studies comparing the two treatments.

Table 1: Comparative Outcomes of Laparoscopic Surgery vs. Methotrexate for Tubal Pregnancy

Outcome Measure	Laparoscopic Surgery	Methotrexate Therapy	Comparative Data (95% CI)	P-value
Time to β-hCG Normalization	Significantly Shorter	Significantly Longer	MD: -7.10 days (-7.84 to -6.36) [8]	<0.001
Treatment Failure Rate	No significant difference	No significant difference	OR: 1.88 (0.53 to 6.69) [8]	0.33
Tubal Patency Rate	Higher	Lower	OR: 2.47 (1.72 to 3.53) [8]	<0.001
Spontaneous Pregnancy Rate	Higher	Lower	OR: 2.10 (1.28 to 3.46) [8]	0.003
Predictors of Failure	Incomplete removal	High initial β-hCG, High gravidity, Presence of yolk sac [56]	N/A	N/A

Abbreviations: MD, Mean Difference; OR, Odds Ratio; CI, Confidence Interval.

Beyond the direct comparison, specific risk factors predictive of MTX treatment failure have been identified. A 2024 retrospective study of 359 patients confirmed that higher gravidity and elevated pretreatment β-hCG levels are independent risk factors for failure, while receiving more than one dose of MTX was a protective factor [56]. The success rate of a single-dose MTX protocol drops significantly when the initial β-hCG level is greater than 1,418–1,500 mIU/mL [58] [46].

The Scientist's Toolkit: Research Reagents and Materials

For researchers designing clinical or translational studies in this field, several key reagents and materials are essential. The following table outlines critical components for investigating treatment efficacy and failure.

Table 2: Essential Research Reagents for Investigating hCG Kinetics and Treatment Failure

Research Reagent / Material	Function in Experimental Design
Serum β-hCG Immunoassay Kits	Quantifying serum β-hCG concentrations for pharmacokinetic/pharmacodynamic studies and defining primary efficacy endpoints.
Methotrexate (Pharmaceutical Grade)	The active comparator in medical intervention arms; used to establish baseline kinetic models for β-hCG decline.
Transvaginal Ultrasound Probes	High-resolution imaging for initial diagnosis, characterizing ectopic mass size/morphology, and monitoring structural changes post-treatment.
Laparoscopic Tower & Instrumentation	Standardized equipment for the surgical intervention arm, including cameras, insufflators, and specific tools for salpingostomy/salpingectomy.
Risk Prediction Nomogram	A clinical tool integrating variables (e.g., β-hCG levels, ectopic mass size) to stratify patients by risk of treatment failure for enriched trial designs [57].

Serial β-hCG measurement is the cornerstone of monitoring treatment efficacy for tubal ectopic pregnancy, with distinct failure definitions for methotrexate therapy (<15% decline between days 4-7) and laparoscopic surgery (increase or plateau on postoperative day 4). While both treatments are clinically effective, they present different kinetic profiles: surgery leads to a faster β-hCG resolution, while medical therapy requires a more prolonged and nuanced monitoring protocol due to identifiable risk factors for failure, particularly elevated initial β-hCG. For researchers, this comparative data is vital for designing robust clinical trials, developing predictive models, and advancing personalized therapeutic strategies for tubal ectopic pregnancy.

Managing Complications and Optimizing Outcomes for Future Fertility

Tubal ectopic pregnancy (EP), accounting for approximately 98% of all ectopic pregnancies, remains a significant cause of maternal morbidity and early pregnancy-related mortality. The management of tubal pregnancy primarily involves two conservative approaches: medical treatment with systemic methotrexate (MTX) and laparoscopic surgery. The choice between these strategies hinges on multiple factors, including patient clinical stability, future fertility desires, and, critically, the risk of treatment failure. A comprehensive analysis of failure rates, their predictive factors, and subsequent salvage strategies is essential for optimizing patient outcomes, guiding clinical decision-making, and framing future research. This review, situated within a broader thesis on the clinical efficacy comparison of laparoscopic surgery versus methotrexate, systematically examines the evidence surrounding treatment failure to inform researchers, scientists, and drug development professionals.

Comparative Analysis of Treatment Failure Rates

Table 1: Overview of Treatment Failure Rates and Key Fertility Outcomes

Outcome Measure	Laparoscopic Surgery	Single-Dose Methotrexate	Statistical Significance (P-value)	Sources
Treatment Success Rate	93% (26/28)	65% (22/34)	P < 0.01	[34]
Persistent Ectopic Pregnancy (PEP) Rate	1.4% - 15.7%	Not Applicable	Varies	[59] [60]
Need for Secondary Intervention	~7% (Primarily for PEP)	25.3% - 36.6%	Not Reported	[61] [29] [34]
Tubal Patency Rate	Significantly Higher	Baseline	P < 0.001	[8]
Subsequent Spontaneous Pregnancy Rate	Significantly Higher	Baseline	P = 0.003	[8]

A meta-analysis of randomized controlled trials (RCTs) concluded that there was no statistically significant difference in the overall treatment success rate between the two modalities (OR = 1.88, 95% CI 0.53–6.69, P = 0.33) [8]. However, this finding masks crucial nuances. A landmark RCT by Sowter et al. demonstrated a stark contrast, with a 93% success rate for laparoscopic salpingotomy compared to 65% for single-dose MTX [34]. This MTX failure rate, necessitating further doses or surgery, is consistently reported between 25% and 36% in larger cohort studies [61] [29] [57].

For laparoscopic surgery, the primary failure mode is Persistent Ectopic Pregnancy (PEP), occurring when trophoblastic tissue is incompletely removed. Rates vary from 1.4% to 15.7% [59] [60]. Prophylactic administration of MTX (50 mg) during laparoscopic salpingostomy has been shown to drastically reduce the PEP rate from 15.7% to 1.4% (P=0.003) [59].

Crucially, despite the potential for initial failure, laparoscopic surgery demonstrates superior performance in preserving future fertility. A meta-analysis showed laparoscopic surgery leads to significantly higher tubal patency rates (OR = 2.47, 95% CI 1.72–3.53, P < 0.001) and higher subsequent spontaneous pregnancy rates (OR = 2.10, 95% CI 1.28–3.46, P = 0.003) compared to single-dose MTX [8].

Predictive Factors for Treatment Failure

Identifying patients at high risk for treatment failure is paramount for personalizing therapeutic strategies. The evidence points to distinct predictive factors for medical and surgical treatment failure.

Predictive Factors for Methotrexate Failure

Table 2: Risk Factors for Methotrexate Treatment Failure

Risk Factor	Impact Description	Study Details
Pretreatment β-hCG Level	Strong, independent predictor. Higher levels correlate with increased failure risk.	Multivariate analysis (OR = 1.0006, 95% CI: 1.0004–1.0008, P < 0.001) [61] [29].
High Gravidity	Independent predictor of MTX failure.	Multivariate analysis (OR = 1.25, 95% CI: 1.01–1.54, P = 0.040) [61] [29].
Visible Yolk Sac on Ultrasound	Significant predictor in univariate analysis.	P < 0.05 [61] [29].
History of Previous Ectopic Pregnancy	Significant predictor in univariate analysis.	P < 0.05 [61] [29].
Rate of β-hCG Change Post-Treatment	Failure likely if β-hCG does not decline ≥15% from Day 4 to 7.	Established protocol for second MTX dose [61] [29]. A study proposed specific cut-offs: <1028.6 mIU/mL increase on day 4 and <1.0457-fold rise from baseline [57].
Number of MTX Doses	A two-dose regimen is a significant protective factor against failure.	Multivariate analysis (OR = 0.44, 95% CI: 0.22–0.90, P = 0.025) [61] [29].

A 2024 retrospective cohort study of 359 patients identified higher gravidity and elevated pretreatment β-hCG levels as independent risk factors for MTX failure, while administration of more MTX doses was a significant protective factor [61] [29]. The presence of a visible yolk sac on ultrasound and a history of previous EP were also significant predictors in univariate analyses [61] [29]. The trend in β-hCG levels after treatment initiation is a critical dynamic indicator. A less than 15% decrease in β-hCG levels between day 4 and day 7 is a standard indicator for requiring a second MTX dose [61] [29]. A risk prediction model further proposed that absolute increases in β-hCG above 1028.6 mIU/mL on day 4 or a fold-increase greater than 1.0457 from baseline are predictive of failure [57].

Predictive Factors for Surgical Failure (Persistent Ectopic Pregnancy)

The risk of PEP after conservative laparoscopic surgery is influenced by patient and disease factors. A key postoperative predictor is the trend of β-hCG levels. A retrospective cohort study found that the change in β-hCG levels between postoperative days 5 and 10 (ChCGD5-10) was a highly predictive factor, with a cutoff of a 93.1% decrease from baseline showing 85.7% sensitivity and 100% specificity for predicting PEP [60].

When considering only perioperative variables, a lower Body Mass Index (BMI) was identified as a predictor. A BMI cutoff of ≤22 kg/m² had a high specificity for predicting PEP [60]. Furthermore, a larger study (n=226) found that a higher preoperative serum hCG level, a larger maximal diameter of the tubal gestational sac, and a greater volume of peritoneal bleeding were all significant factors influencing the success of initial laparoscopic conservative surgery [62]. Specifically, the tubal patency rate was 65% for gestational sacs <5 cm versus 32% for those ≥5 cm, and 72% for hCG <2000 IU/L versus 15% for hCG >5000 IU/L [62].

Experimental Protocols and Clinical Workflows

Protocol for Medical Management with Methotrexate

Objective: To eliminate trophoblastic tissue in tubal ectopic pregnancy using systemic methotrexate while minimizing failure rates and complications.

Inclusion Criteria: Hemodynamically stable patients with an unruptured tubal pregnancy. Typical criteria include an adnexal mass <3.5-4 cm in diameter, no fetal cardiac activity, and pretreatment β-hCG levels ideally <1500-5000 IU/L, with the ability to ensure follow-up [61] [29] [34].

Exclusion Criteria: Absolute contraindications to MTX (e.g., active liver disease, blood dyscrasias), breastfeeding, evidence of tubal rupture or hemodynamic instability, and inability to comply with monitoring.

Methodology:

• Baseline Assessment: Obtain informed consent after detailed counseling. Conduct baseline transvaginal ultrasound to confirm diagnosis and measure ectopic mass. Draw blood for baseline β-hCG, complete blood count, and renal and liver function tests.
• MTX Administration: Administer a single intramuscular dose of MTX at 50 mg/m² of body surface area.
• Post-Treatment Monitoring:
  • Measure serum β-hCG levels on post-treatment days 4 and 7.
  • The expected response is a ≥15% decrease in β-hCG levels from day 4 to day 7.
  • If the decline is <15%, a second dose of MTX (50 mg/m²) is administered [61] [29].
  • After a satisfactory decline, continue weekly β-hCG monitoring until levels become undetectable.
• Salvage Strategy: Surgical intervention (typically laparoscopic salpingectomy or salpingotomy) is indicated forMTX failure, which is defined by a plateau or rise in β-hCG levels after multiple doses, severe or worsening symptoms, or signs of tubal rupture [61] [29] [57].

Protocol for Surgical Management with Laparoscopic Salpingostomy

Objective: To surgically remove the tubal pregnancy while preserving the fallopian tube, and to prevent Persistent Ectopic Pregnancy (PEP).

Inclusion Criteria: Hemodynamically stable patients desiring future fertility, with an unruptured tubal pregnancy amenable to conservative surgery.

Methodology:

• Preoperative Workup: Informed consent, including discussion of PEP risk. Baseline serum β-hCG level.
• Surgical Procedure: Perform laparoscopic salpingostomy. This involves a linear incision on the antimesenteric border of the fallopian tube over the ectopic pregnancy, evacuation of products of conception, and meticulous hemostasis.
• PEP Prophylaxis (Optional): Consider prophylactic intramuscular injection of methotrexate (50 mg) within 24 hours post-surgery to significantly reduce PEP risk [59].
• Postoperative Monitoring: Monitor serum β-hCG levels postoperatively on days 1, 5, and 10, and weekly until negative. A decline of <93.1% in β-hCG between days 5 and 10 is highly predictive of PEP [60].
• Salvage Strategy: If PEP is diagnosed (based on inadequate β-hCG decline or plateau), administer a single dose of MTX (50 mg/m²) as salvage medical therapy. Second-look laparoscopy or repeat surgery is reserved for cases with symptoms or MTX failure.

The Scientist's Toolkit: Research Reagent Solutions

Table 3: Essential Reagents and Materials for Clinical Research

Item	Specific Function/Example	Research Application
Serum β-hCG Immunoassay Kits	Quantitative measurement of human chorionic gonadotropin.	Primary outcome marker for diagnosing EP, monitoring treatment response, and defining failure (e.g., <15% decline D4-D7 for MTX) [61] [29] [60].
Methotrexate	Lyophilized powder or solution for injection (50 mg/m²).	The active pharmaceutical ingredient for medical management; used in protocols for primary treatment, multi-dose regimens, and PEP prophylaxis/salvage [8] [61] [59].
Laparoscopic Tower & Instruments	High-definition camera, light source, monitor, trocars, graspers, scissors, and bipolar electrocautery.	Essential equipment for performing laparoscopic salpingostomy/salpingotomy and salpingectomy; crucial for comparing surgical efficacy and safety [8] [62].
Hysterosalpingography (HSG) Contrast Media	Radio-opaque contrast agents.	To assess tubal patency post-treatment as a key fertility outcome measure in clinical trials [8] [62].
ELISA Kits for Biomarkers	Kits for measuring potential biomarkers like PIGF, VEGF-A, ADAM12.	For investigative studies into novel predictive biomarkers for ectopic pregnancy diagnosis or treatment success [59].

The analysis of treatment failure rates reveals a complex clinical landscape. While single-dose methotrexate offers a non-invasive first-line option, its higher failure rate, particularly in patients with high pretreatment β-hCG, high gravidity, and adverse sonographic features, necessitates careful patient selection and vigilant monitoring. The implementation of multi-dose regimens can mitigate this risk. Laparoscopic surgery, though more invasive, provides a higher initial success rate and superior subsequent fertility outcomes, with its principal failure mode—PEP—being manageable through prophylactic or salvage MTX. The decision between these treatments should be a shared process, incorporating patient preferences and a clear understanding of individual risk factors for failure. Future research should focus on validating and refining dynamic prediction models using β-hCG kinetics and exploring novel biomarkers to further personalize therapy and optimize reproductive futures.

Managing Methotrexate Side Effects and Contraindications

The clinical management of tubal ectopic pregnancy presents a critical therapeutic decision point in gynecologic care, involving a fundamental choice between medical management with methotrexate (MTX) and surgical intervention via laparoscopy. This comparison guide objectively analyzes the safety profiles, contraindications, and side effect management strategies for methotrexate within the broader context of treatment efficacy for tubal pregnancy. For researchers and drug development professionals, understanding the pharmacovigilance data and risk-benefit ratios of these interventions is essential for advancing therapeutic protocols.

Methotrexate, a folate antagonist antimetabolite, functions by competitively inhibiting dihydrofolate reductase, thereby disrupting DNA synthesis and cellular replication in trophoblastic tissue [63]. This mechanism underlies its efficacy in treating ectopic pregnancies but also contributes to its characteristic adverse effect profile. Laparoscopic surgery, in contrast, offers direct mechanical resolution through salpingostomy or salpingectomy, presenting different risk considerations including surgical trauma and anesthesia complications [64]. Recent meta-analyses directly comparing these approaches have revealed significant differences in fertility outcomes, with laparoscopic surgery demonstrating superior tubal patency rates (OR = 2.47, 95% CI 1.72-3.53) and spontaneous pregnancy rates (OR = 2.10, 95% CI 1.28-3.46) while achieving comparable treatment success rates [8] [16].

This analysis synthesizes current evidence to guide clinical decision-making and research directions, with particular emphasis on managing methotrexate's side effects and understanding its contraindications within a risk-stratified treatment framework.

Methotrexate Safety Profile: Adverse Reaction Analysis

Comprehensive safety data from the FDA Adverse Event Reporting System (FAERS) database reveals significant patterns in methotrexate-related adverse events. A recent analysis of 130,818 MTX-related adverse event reports identified that females accounted for 64.2% of reporters, with adults aged 18-64.9 years constituting the largest demographic (42.5%) [65]. The most frequently affected systems included immune, musculoskeletal, and hematologic systems, with "General Disorders and Administration Site Conditions" representing the most common system organ class (n=106,183), while "Immune System Disorders" demonstrated the strongest signal strength [n=13,313, ROR (95% CI)=2.35 (2.31-2.39)] [65].

Demographic Variations in Adverse Reactions

The FAERS analysis revealed important demographic variations in adverse reaction profiles. Females demonstrated significantly higher reporting of Drug Hypersensitivity reactions [n=6,192, ROR (95% CI)=4.69 (4.57-4.82)], while males more frequently reported Nausea [n=1,624, ROR (95% CI)=1.17 (1.12-1.23)] [65]. Elderly patients (≥65 years) showed markedly increased risk of drug hypersensitivity [n=2,894, ROR (95% CI)=7.91 (7.61-8.22)], highlighting the importance of age-specific monitoring protocols [65]. Reporting patterns also differed between consumer and healthcare professional reporters, with consumers more frequently reporting "Drug Ineffective" [n=5,729, ROR (95% CI)=2.24 (2.18-2.3)] and "Pain" [n=1,746, ROR (95% CI)=1.69 (1.61-1.77)], while healthcare professionals focused more on DRUG INEFFECTIVE [n=9,982, ROR (95% CI)=4.16 (4.08-4.25)] [65].

Table 1: Most Frequently Reported Methotrexate Adverse Reactions by System Organ Class

System Organ Class	Report Count	Signal Strength (ROR)	Most Common Manifestations
General Disorders and Administration Site Conditions	106,183	1.21 (1.21-1.22)	Fatigue, pain, injection site reactions
Immune System Disorders	13,313	2.35 (2.31-2.39)	Hypersensitivity, anaphylaxis
Gastrointestinal Disorders	38,457	1.84 (1.82-1.86)	Nausea, vomiting, stomatitis, diarrhea
Skin and Subcutaneous Tissue Disorders	25,891	1.45 (1.43-1.47)	Rash, photosensitivity, alopecia
Blood and Lymphatic System Disorders	18,324	2.12 (2.09-2.15)	Leukopenia, thrombocytopenia, anemia
Hepatobiliary Disorders	12,668	1.96 (1.92-2.00)	Transaminase elevation, hepatic fibrosis

Contraindications and Precautions for Methotrexate Therapy

Absolute and Relative Contraindications

Methotrexate therapy for ectopic pregnancy carries specific absolute contraindications that preclude its use. These include pre-existing blood dyscrasias such as leukopenia (low white blood cells), thrombocytopenia (low platelet blood level), or severe anemia; significant hepatic impairment; active infection; immunodeficiency states including HIV/AIDS; peptic ulcer disease; ulcerative colitis; and known hypersensitivity to methotrexate [27] [63] [66]. Additionally, renal impairment with creatinine >1.4 mg/dL represents a strong contraindication due to reduced methotrexate clearance and increased toxicity risk [63] [26].

Relative contraindications and circumstances requiring cautious evaluation include diabetes, obesity, ascites (extra fluid in the stomach area), pleural effusion (extra fluid in the lung), active pulmonary disease, breastfeeding, and alcohol abuse [27] [66]. The presence of these conditions necessitates careful risk-benefit analysis and may warrant alternative management approaches. For ectopic pregnancy specifically, additional exclusion criteria for methotrexate therapy include hemodynamic instability, signs of tubal rupture, adnexal mass ≥4 cm, β-hCG ≥5,000 mIU/mL, presence of embryonic cardiac activity, or significant hemoperitoneum (>100-300 mL) [26] [67].

Drug Interactions and Compatibility

Methotrexate exhibits numerous clinically significant drug interactions that can alter its efficacy and toxicity profile. Concomitant use with non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, proton pump inhibitors, and sulfonamides may potentiate methotrexate toxicity and requires careful monitoring [66]. Live vaccines are contraindicated during methotrexate therapy due to immunosuppression, including Bacillus of Calmette and Guerin Vaccine, Live; Measles Virus Vaccine, Live; Mumps Virus Vaccine, Live; and Varicella Virus Vaccine, Live [66].

Table 2: Methotrexate Contraindications and Precautions in Ectopic Pregnancy Management

Category	Specific Conditions	Clinical Concern
Absolute Contraindications	Blood dyscrasias (leukopenia, thrombocytopenia, severe anemia)	Exacerbated myelosuppression
	Severe liver disease	Impaired metabolism and increased hepatotoxicity
	Active infection or immunodeficiency	Inability to mount appropriate immune response
	Renal impairment (creatinine >1.4 mg/dL)	Reduced clearance and increased toxicity
	Peptic ulcer disease or ulcerative colitis	Exacerbated gastrointestinal toxicity
	Known methotrexate hypersensitivity	Allergic reactions
Ectopic Pregnancy-Specific Exclusions	Hemodynamic instability	Requires immediate surgical intervention
	Tubal rupture or significant hemoperitoneum	Surgical emergency
	Adnexal mass ≥4 cm	Reduced methotrexate efficacy
	β-hCG ≥5,000 mIU/mL	Higher failure rates with medical management
	Embryonic cardiac activity	Reduced efficacy and increased rupture risk
Therapy Precautions	Concomitant hepatotoxic drugs	Additive liver injury
	NSAIDs, aspirin, proton pump inhibitors	Increased methotrexate levels and toxicity
	Live vaccines	Risk of vaccine-derived infection

Monitoring Protocols and Management Strategies

Standardized Monitoring Guidelines

Effective methotrexate therapy for ectopic pregnancy requires rigorous monitoring protocols to ensure safety and detect complications early. Baseline assessment must include complete blood count with differential, comprehensive metabolic panel (renal and hepatic function), serum β-hCG quantification, transvaginal ultrasound to confirm eligibility criteria, and hepatitis serology [27] [63]. For women with ectopic pregnancies in a Fallopian tube treated with methotrexate, clinical data indicates that 14% require a second dose of methotrexate and 29% require surgery despite treatment with methotrexate [27].

During treatment, serial β-hCG levels are measured on day 1 (injection day), day 4, and day 7 post-treatment [27] [67]. A second dose is administered if the β-hCG decrease is less than 15% between days 4 and 7 [27]. Patients require weekly monitoring until β-hCG is undetectable, which typically takes an average of 28 days for successful treatment [27]. Complete blood counts and liver function tests should be monitored weekly for the first month, then at least bi-monthly during continued therapy [63].

Methotrexate Therapy Monitoring Protocol for Ectopic Pregnancy

Management of Common Side Effects

Effective management of methotrexate side effects requires both prophylactic and reactive strategies. Cramping abdominal pain occurring during the first 2-3 days of treatment is the most common side effect and must be carefully differentiated from tubal rupture, requiring prompt reporting to healthcare providers [27]. Nausea, vomiting, and indigestion may be managed with antiemetics, while stomatitis often responds to topical analgesics and meticulous oral hygiene. Fatigue affects many patients, with some experiencing "sheer exhaustion" during treatment, necessitating activity modification and adequate rest [27].

To mitigate adverse effects, patients should avoid folic acid supplements and folate-enriched foods during therapy, refrain from heavy lifting or strenuous exercise until β-hCG levels decline consistently, avoid sexual intercourse until β-hCG normalizes, limit alcohol consumption completely, and use acetaminophen rather than NSAIDs for pain management [27]. The concomitant administration of folic or folinic acid supplementation can reduce certain adverse effects without compromising efficacy for non-oncologic indications [66].

Comparative Clinical Outcomes: Methotrexate vs. Laparoscopic Surgery

Efficacy and Fertility Outcomes

Recent meta-analyses provide robust comparative data on clinical outcomes between methotrexate and laparoscopic surgery for tubal pregnancy. A comprehensive meta-analysis of 10 studies with 1,034 patients found no statistically significant difference in treatment success rates between the two approaches [OR = 1.88, 95% CI 0.53-6.69, P = 0.33] [8]. However, significant differences emerged in fertility preservation metrics, with laparoscopic surgery demonstrating superior tubal patency rates [OR = 2.47, 95% CI 1.72-3.53, P < 0.001] and higher spontaneous pregnancy rates [OR = 2.10, 95% CI 1.28-3.46, P = 0.003] [8] [16].

A separate prospective comparative study of 260 women with unruptured ectopic pregnancies demonstrated successful treatment in 98.46% of surgical patients versus 87.69% in the MTX group (p=0.001) [26]. Importantly, this study found comparable future intrauterine pregnancy rates between groups (73.08% surgical vs. 68.46% MTX, p=0.56), suggesting that while surgery has higher initial success, long-term reproductive outcomes may be similar [26]. The time for serum hCG normalization was significantly shorter with laparoscopic surgery (mean difference -7.10 days, 95% CI -7.84 to -6.36, P < 0.001) [8], potentially explaining the faster recovery trajectory.

Safety and Tolerability Comparisons

When comparing safety profiles, each approach demonstrates distinct advantage and risk considerations. Methotrexate offers a non-invasive alternative that avoids surgical risks and anesthesia complications, with significantly shorter hospital stays (1.2 ± 0.5 days for MTX vs. 3.0 ± 1.2 days for surgery, p<0.001) [26]. However, medical management carries unique adverse effects including gastrointestinal symptoms, stomatitis, transient hepatotoxicity, and potential for treatment failure requiring salvage surgery.

Laparoscopic surgery provides immediate resolution with direct visualization of pelvic anatomy, but entails risks of surgical complications including bleeding, infection, visceral injury, and adhesion formation [64]. Notably, recurrent ectopic pregnancy rates show no significant difference between approaches [OR = 1.09, 95% CI 0.41-2.87, P = 0.87] [8], indicating neither method preferentially impacts this specific reproductive outcome.

Table 3: Comparative Outcomes of Methotrexate versus Laparoscopic Surgery for Tubal Pregnancy

Outcome Measure	Methotrexate	Laparoscopic Surgery	Statistical Significance
Treatment Success Rate	87.7% [26]	98.5% [26]	P = 0.001 [26]
Tubal Patency Rate	Reference	OR = 2.47 (1.72-3.53) [8]	P < 0.001 [8]
Spontaneous Pregnancy Rate	Reference	OR = 2.10 (1.28-3.46) [8]	P = 0.003 [8]
Recurrent Ectopic Pregnancy	OR = 1.09 (0.41-2.87) [8]	Reference	P = 0.87 [8]
Time to hCG Normalization	Reference	MD = -7.10 days (-7.84 to -6.36) [8]	P < 0.001 [8]
Hospital Stay	1.2 ± 0.5 days [26]	3.0 ± 1.2 days [26]	P < 0.001 [26]
Need for Additional Intervention	29% require surgery [27]	1.5% require re-operation [26]	-
Future Intrauterine Pregnancy	68.5% [26]	73.1% [26]	P = 0.56 [26]

Research Reagents and Methodological Considerations

Essential Research Materials and Assays

High-quality research comparing methotrexate and surgical management of ectopic pregnancy requires standardized laboratory reagents and methodological approaches. Key research reagents include quantitative β-hCG immunoassay systems with high sensitivity and precision for monitoring treatment response; high-resolution transvaginal ultrasound equipment with Doppler capability for accurate diagnosis and follow-up; complete blood count analyzers with differential for hematologic toxicity monitoring; automated chemistry analyzers for hepatic and renal function assessment; and methotrexate assay systems for pharmacokinetic studies [27] [67].

For advanced mechanistic research, essential reagents include dihydrofolate reductase activity assays to verify target engagement; folate pathway metabolite quantification systems (e.g., for tetrahydrofolate); apoptosis detection kits for evaluating trophoblast response; inflammatory cytokine panels to assess immune modulation; and adhesion formation assay components for surgical comparison studies [63] [65]. Genotyping platforms for folate pathway polymorphisms may help identify patients at increased risk of toxicity or suboptimal response [65].

Table 4: Essential Research Reagents for Ectopic Pregnancy Management Studies

Research Category	Essential Reagents/Assays	Research Application
Diagnostic Confirmation	Quantitative β-hCG Immunoassay Kits	Treatment response monitoring
	High-Resolution Transvaginal Ultrasound	Initial diagnosis and follow-up
	Laparoscopic Visualization Systems	Surgical confirmation and treatment
Safety Monitoring	Complete Blood Count Analyzers	Hematologic toxicity assessment
	Hepatic Function Panels (ALT, AST, Albumin)	Hepatotoxicity evaluation
	Renal Function Assays (Creatinine, BUN)	Nephrotoxicity risk assessment
Mechanistic Studies	Dihydrofolate Reductase Activity Assays	Target engagement verification
	Folate Pathway Metabolite LC-MS/MS	Metabolic pathway analysis
	Apoptosis Detection Kits (Caspase assays)	Trophoblast response mechanism
	Inflammatory Cytokine Panels (IL-6, TNF-α)	Immune response characterization
Surgical Research	Adhesion Formation Scoring Systems	Post-surgical tissue response
	Tubal Patency Assessment Dyes	Fertility outcome measures

The comprehensive analysis of methotrexate side effects and contraindications within the context of tubal pregnancy management reveals a complex risk-benefit profile that must be individualized to patient characteristics and reproductive goals. Methotrexate offers a non-invasive approach with specific advantages for appropriate candidates, but requires careful patient selection, vigilant monitoring, and proactive management of expected adverse effects. Laparoscopic surgery demonstrates superior fertility preservation outcomes in terms of tubal patency and subsequent spontaneous pregnancy rates, supporting its consideration for patients with strong future fertility desires.

For researchers and drug development professionals, these findings highlight several strategic priorities: developing improved risk stratification algorithms to optimize treatment selection; creating targeted management protocols for high-risk demographic groups; establishing standardized monitoring guidelines that balance safety with practicality; and exploring novel therapeutic approaches that maximize efficacy while minimizing adverse effects. The evolving landscape of ectopic pregnancy management will continue to benefit from rigorous comparative effectiveness research that places patient-centered outcomes, including fertility preservation and quality of life, at the forefront of therapeutic development.

Persistent ectopic pregnancy (PEP) represents a significant complication following conservative surgical management of tubal pregnancy, occurring when trophoblastic tissue remains incompletely removed after salpingostomy. This condition poses considerable clinical challenges due to its potential for delayed rupture, life-threatening hemorrhage, and compromised future fertility. The incidence of PEP varies between 3-20% across different surgical series, with its prevalence trending upward alongside the increased adoption of fertility-sparing laparoscopic procedures [59]. The management of PEP demands a nuanced approach balancing efficacy against fertility preservation, necessitating evidence-based protocols for both prevention and treatment. This review comprehensively compares contemporary prevention strategies and management options, analyzing their clinical efficacy, impact on reproductive outcomes, and appropriate clinical applications within the broader context of tubal pregnancy management research.

Pathophysiology and Risk Factors

Persistent trophoblastic tissue results from incomplete removal of viable gestational products during salpingostomy, with remnants typically located at the original tubal implantation site, though rare cases of disseminated peritoneal implants have been documented [68]. The pathophysiological basis involves continued β-human chorionic gonadotropin (β-hCG) production by retained trophoblastic cells, which can lead to delayed tubal rupture and intra-abdominal bleeding if undetected. Several patient-specific and operative factors elevate PEP risk, including:

• Early gestational age (<40 days) and smaller gestational mass (<2 cm) [59]
• High preoperative β-hCG levels, with progressively declining success rates for conservative management as levels increase [51]
• Surgical technique limitations, particularly with laparoscopic approaches that may not achieve complete trophoblastic excision [68]
• Tubal characteristics such as extensive intraluminal implantation or friable tissue that fragments during removal

Recognition of these risk factors enables preoperative identification of patients who might benefit from prophylactic interventions or alternative primary management approaches.

Prevention Protocols

Prophylactic Methotrexate Administration

Table 1: Efficacy of Prophylactic Methotrexate in Preventing Persistent Ectopic Pregnancy

Study Design	Sample Size	Intervention	PEP Rate with MTX	PEP Rate without MTX	P Value	Effect Size
Randomized Clinical Trial [59]	140	Single-dose MTX (50 mg) post-salpingostomy	1.4% (1/70)	15.7% (11/70)	0.003	OR: 0.08 (95% CI: 0.01-0.62)
Japanese Clinical Study [59]	Not specified	MTX prophylaxis	Not reported	17.5%	Not reported	Significant reduction
Turkish Study [59]	Not specified	MTX prophylaxis	0%	14.5%	Not reported	Complete prevention

The administration of prophylactic methotrexate following linear salpingostomy demonstrates significant efficacy in reducing persistent ectopic pregnancy rates. The foundational research supporting this approach comes from a randomized clinical trial conducted at Yas Hospital, Tehran, which implemented a protocol of single-dose methotrexate (50 mg) administered within 24 hours post-salpingostomy [59]. This intervention resulted in a statistically significant reduction in PEP incidence from 15.7% to 1.4%, representing an approximately 90% relative risk reduction. The mechanism of action involves inhibition of dihydrofolate reductase, thereby disrupting DNA synthesis and cellular replication in rapidly dividing trophoblastic tissue.

Experimental Protocol for Prophylactic Methotrexate:

• Patient Selection: Hemodynamically stable patients undergoing linear laparoscopic salpingostomy for unruptured tubal pregnancy
• Exclusion Criteria: Tubal pregnancy size >5 cm, significant tubal adhesions, previous ectopic pregnancy in same tube, contraindications to methotrexate (renal impairment, hepatic dysfunction, blood dyscrasias, active pulmonary disease, peptic ulcer disease) [59]
• Dosage and Administration: Single intramuscular injection of methotrexate 50 mg/m² within 24 hours post-surgery
• Monitoring Protocol: Serial β-hCG measurements preoperatively, then on postoperative days 1-2, 3-4, 5-6, and 7-8
• PEP Diagnostic Criteria: Increase in serum β-hCG levels or decrease of less than 20% between measurements [59]
• Adverse Effect Monitoring: Stomatitis, gastrointestinal symptoms, myelosuppression, hepatotoxicity

Surgical Technique Optimization

Refinements in surgical approach can substantially impact PEP rates. Meticulous technique during salpingostomy is paramount, including complete evacuation of all products of conception, systematic irrigation and aspiration of blood clots and tissue fragments, and judicious use of electrosurgical coagulation to minimize tissue destruction while achieving hemostasis [68]. The use of tissue retrieval bags for extracted products may prevent iatrogenic dissemination and implantation of trophoblastic tissue within the peritoneal cavity [68]. Surgical decision-making should also consider selective application of salpingectomy over salpingostomy in high-risk cases, particularly when future fertility is not a priority or when tubal architecture is severely compromised.

Management Strategies for Established Persistent Trophoblast

Medical Management with Methotrexate

Table 2: Comparative Efficacy of Management Strategies for Persistent Ectopic Pregnancy

Management Approach	Success Rate	Time to β-hCG Normalization	Future Intrauterine Pregnancy Rate	Recurrent EP Rate	Key Determinants of Success
Systemic Methotrexate [69] [51]	87.7% [26]	Prolonged (specific data not provided)	68.5% [26]	Not significantly different from surgery [8]	Lower initial β-hCG, absence of cardiac activity, early β-hCG decline [51]
Laparoscopic Surgery [8]	98.5% [26]	Shorter (MD: -7.10 days) [8]	73.1% [26]	Not significantly different from MTX [8]	Surgical technique, complete trophoblast removal
Local Ethanol Injection [70]	83.6% (after repeat injection in some cases)	Not reported	18.2% (1-year post-treatment)	Not reported	HCG decrease rate post-procedure

For established persistent trophoblast, systemic methotrexate represents a first-line medical management option, particularly for hemodynamically stable patients without evidence of active bleeding. The historical foundation for this approach dates to 1986 when methotrexate was first successfully employed to treat persistent trophoblastic tissue after salpingostomy, providing a fertility-preserving alternative to salpingectomy [69]. Contemporary protocols typically utilize single-dose methotrexate regimens (50 mg/m²) with success rates approximately 87.7% in appropriate candidates [26]. Predictors of successful medical management include lower initial β-hCG levels (<5000 IU/L), absence of fetal cardiac activity, earlier gestational age, and early β-hCG decline (≥15%) between days 0-4 of treatment [51].

Experimental Protocol for Therapeutic Methotrexate:

• Candidate Selection: Hemodynamically stable patients with PEP, no evidence of active intra-abdominal bleeding, normal renal and hepatic function
• Contraindications: Hemodynamic instability, ruptured ectopic pregnancy, intra-abdominal bleeding, hypersensitivity to methotrexate
• Dosage Regimen: Single intramuscular methotrexate 50 mg/m², with possible additional doses if β-hCG decline <15% between day 4-7
• Combination Therapy: Emerging evidence suggests potential enhanced efficacy with mifepristone (200 mg orally) as adjunctive therapy, though statistical significance not consistently demonstrated [51]
• Monitoring Protocol: Serum β-hCG levels on days 0, 4, and 7, then weekly until undetectable (<5 mIU/mL)
• Rescue Criteria: <15% β-hCG decline between measurements, worsening symptoms, hemodynamic instability

Surgical Management Options

Surgical intervention remains the definitive management for PEP, particularly in cases of hemodynamic instability, rupture, or medical treatment failure. Laparoscopic approach is preferred over laparotomy when feasible, demonstrating advantages including reduced operative time (SMD: -1.28), decreased blood loss (SMD: -3.06), shorter hospital stay (SMD: -1.74), and fewer complications (RR: 0.22) [71]. The surgical principle involves complete excision of persistent trophoblastic tissue, typically requiring salpingectomy in most cases, though repeat salpingostomy may be considered in selected patients with limited disease and strong fertility preservation goals.

Experimental Protocol for Surgical Management:

• Preoperative Preparation: β-hCG confirmation, blood product availability, informed consent regarding potential salpingectomy
• Surgical Approach: Laparoscopic preference when feasible and surgically appropriate
• Technical Considerations: Complete excision of trophoblastic tissue, copious pelvic irrigation, careful tissue extraction using endoscopic bag
• Intraoperative Adjuncts: Consideration of prophylactic methotrexate if repeat conservative surgery performed
• Postoperative Monitoring: Serial β-hCG until normalization

Comparative Outcomes and Fertility Considerations

The selection between management strategies requires careful consideration of efficacy, safety, and reproductive outcomes. While surgical management demonstrates higher primary success rates (98.5% vs. 87.7%), medical approaches offer non-invasiveness and tubal preservation [26]. Fertility outcomes show no statistically significant difference in future intrauterine pregnancy rates between surgery (73.1%) and methotrexate (68.5%) according to recent comparative studies [26]. Similarly, recurrent ectopic pregnancy rates do not significantly differ between approaches [8]. However, laparoscopic surgery demonstrates advantages in tubal patency rates (OR: 2.47) and spontaneous pregnancy rates (OR: 2.10) compared to single-dose methotrexate, though these findings must be interpreted within the context of varying patient selection criteria [8].

Quality of life considerations also factor into management decisions, with one multicenter randomized trial demonstrating more favorable health-related quality of life metrics after laparoscopic salpingostomy compared to systemic methotrexate, including better physical functioning, role functioning, social functioning, and fewer depressive symptoms [72].

Clinical Decision Pathways

Research Reagents and Methodological Toolkit

Table 3: Essential Research Reagents for Persistent Trophoblast Investigation

Reagent/Resource	Specific Application	Research Utility	Example Implementation
β-hCG Immunoassay	Quantitative serum monitoring	Primary outcome measure for treatment response	Weekly measurements until <5 mIU/mL [59]
Methotrexate	Medical intervention	Gold-standard antimetabolite for trophoblast suppression	50 mg/m² single-dose regimen [59]
Mifepristone	Adjunctive therapy	Progesterone receptor antagonist	200 mg oral dose with MTX [51]
Transvaginal Ultrasound	Anatomical assessment	Localization of ectopic mass, exclusion of rupture	Pre-treatment evaluation and follow-up [70]
Laparoscopic System	Surgical management and diagnosis	Gold-standard for definitive treatment and confirmation	Stryker Corporation systems [73]
Absolute Ethanol	Local ablative therapy	Chemical destruction of trophoblastic tissue	Ultrasound-guided local injection [70]

The prevention and management of persistent trophoblast following salpingostomy requires a multifaceted approach incorporating risk stratification, prophylactic interventions in high-risk cases, and tailored management based on clinical presentation and fertility goals. Prophylactic methotrexate demonstrates significant efficacy in preventing PEP, while established persistent trophoblast can be effectively managed with systemic methotrexate in stable patients or surgical intervention in more complex presentations. Future research directions should focus on optimized patient selection algorithms, refined combination medical regimens, and enhanced surgical techniques to further improve outcomes while preserving reproductive potential.

Strategies to Minimize Post-Treatment Adhesions and Tubal Damage

Post-treatment adhesions represent a significant pathological complication following surgical procedures or medical management of tubal ectopic pregnancy (EP), often leading to chronic pain, bowel obstruction, and infertility [74] [75]. Within the context of clinical efficacy comparison between laparoscopic surgery and methotrexate (MTX) for tubal pregnancy, understanding and mitigating adhesion-related tubal damage becomes paramount for preserving future fertility. Adhesions are pathological fibrotic connections that form between organ surfaces and surrounding body cavities following tissue trauma and ischemia [74]. Despite advances in treatment modalities, adhesions remain a common complication, developing after 50-95% of all operations regardless of procedure or anatomical location [74]. This comprehensive analysis examines the pathophysiological mechanisms underlying adhesion formation and evaluates evidence-based strategies to minimize post-treatment adhesions and tubal damage within the framework of comparing laparoscopic and methotrexate interventions for tubal pregnancy.

Pathophysiology of Adhesion Formation

The formation of postoperative adhesions follows a complex cascade of biological events initiated by tissue trauma. Surgical injury or inflammatory processes trigger mast cell disruption, releasing vasoactive substances including histamine and kinins that increase vascular permeability [75]. This trauma-induced response creates oxidative stress through tissue hypoxia, with free oxygen and nitrogen radicals enhancing the inflammatory cascade that results in further tissue injury [75].

Cellular and Molecular Mechanisms

Post-surgical adhesion formation involves three core processes: (1) inhibition of fibrinolytic and extracellular matrix degradation systems, (2) induction of an inflammatory response involving cytokine production and transforming growth factor-β (TGF-β), and (3) induction of tissue hypoxia leading to increased expression of vascular endothelial growth factor (VEGF) [74]. The disruption of the balance between fibrin production and fibrinolysis represents a critical event, with dysregulation between plasminogen-plasmin and plasminogen activator inhibitors (PAIs) enabling fibrin matrix persistence that allows fibroblast adhesion and extracellular matrix maturation [74].

Table 1: Key Molecular Mediators in Adhesion Formation

Factor Category	Specific Component	Role in Adhesion Formation
Cellular Mediators	Fibroblasts & Myofibroblasts	Subperitoneal fibroblast deposition required for adhesion development; transition to myofibroblast phenotype associated with long-lasting adhesions [74]
	Mesothelial Cells	Insult induces pro-fibrotic phenotype and secretion of inflammatory mediators; mesothelial to mesenchymal transition (MMT) drives adhesion formation [74]
	Macrophages	Fundamental in adhesion formation; secrete fibrinolytic mediators and interleukins; recruit and influence mesothelial cells [74]
Signaling Factors	TGF-β	Key fibrotic mediator; elevated in adhesions; stimulates myofibroblast migration and activation; induces ECM production [74]
	Matrix Metalloproteinases (MMPs)	Post-surgical shifts in ratios of MMPs to tissue inhibitors of MMPs (TIMPs); chronic suppression of MMP/TIMP ratios lead to adhesions [74]
	VEGF	Promotes angiogenesis; increases vascular permeability and promotes fibrin matrix deposition [74]

The following diagram illustrates the key molecular pathways involved in adhesion formation:

Comparative Analysis of Treatment Modalities

Laparoscopic Surgery for Tubal Pregnancy

Laparoscopic intervention represents a conservative surgical approach for tubal pregnancy, typically involving salpingotomy, CO2 laser salpingotomy, laparoscopic fenestration embryo extraction, or salpingectomy [8] [32]. The theoretical advantage of laparoscopic approaches centers on reduced tissue trauma through minimal incisions, gentle tissue handling, meticulous hemostasis, and constant irrigation [74] [76]. However, it is crucial to note that the extent of tissue injury, not merely the surgical approach, determines adhesion risk [75].

Recent meta-analyses demonstrate that laparoscopic surgery for tubal pregnancy is associated with significantly higher tubal patency rates (OR = 2.47, 95% CI 1.72-3.53, P < 0.001) and spontaneous pregnancy rates (OR = 2.10, 95% CI 1.28-3.46, P = 0.003) compared with single intramuscular injection of methotrexate [8] [32]. Additionally, laparoscopic approaches result in a shorter time for serum human chorionic gonadotropin (HCG) levels to return to normal (mean difference = -7.10 days, 95% CI -7.84 to -6.36, P < 0.001) [32].

Methotrexate Treatment for Tubal Pregnancy

Methotrexate, a folate antagonist, serves as the cornerstone of medical management for hemodynamically stable tubal ectopic pregnancy [67]. It functions by inhibiting the growth of rapidly dividing cells, including trophoblastic tissue, thereby resolving the ectopic pregnancy without surgical intervention. The single-dose regimen (50 mg/m² intramuscularly) demonstrates overall treatment success rates of approximately 81.3%, with significantly fewer adverse effects compared to multidose regimens [67].

The inflammatory response triggered by the extrauterine implantation itself and subsequent tissue resolution following methotrexate therapy may contribute to adhesion formation. The extrauterine implantation induces tissue damage and inflammation mediated by various pro-inflammatory cells, cytokines, chemokines, integrins, and adhesion molecules [77]. This inflammatory milieu, combined with the prolonged resolution time (evidenced by slower declining HCG levels), may foster adhesion development despite the non-surgical approach.

Table 2: Comparative Outcomes: Laparoscopic Surgery vs. Methotrexate for Tubal Pregnancy

Outcome Measure	Laparoscopic Surgery	Methotrexate (Single-Dose)	Statistical Significance
Treatment Success Rate	84.2%	81.3%	OR = 1.88, 95% CI 0.53-6.69, P = 0.33 [8] [32] [67]
Tubal Patency Rate	71.2%	48.5%	OR = 2.47, 95% CI 1.72-3.53, P < 0.001 [8] [32]
Spontaneous Pregnancy Rate	65.8%	45.1%	OR = 2.10, 95% CI 1.28-3.46, P = 0.003 [8] [32]
Time for HCG Normalization	14.2 days	21.3 days	MD = -7.10 days, 95% CI -7.84 to -6.36, P < 0.001 [32]
Recurrent EP Rate	5.8%	5.3%	OR = 1.09, 95% CI 0.41-2.87, P = 0.87 [8] [32]
Adverse Effects	Surgical complications (bleeding, infection)	Nausea, vomiting, stomatitis, elevated liver enzymes	Significantly lower with single-dose MTX vs. multidose (RR 0.62, 95% CI 0.45-0.85) [67]

Adhesion Prevention Strategies

Surgical Technique Optimization

Meticulous surgical technique remains fundamental to adhesion prevention during laparoscopic procedures. Adherence to microsurgical principles includes gentle tissue handling with minimal grasping of fallopian tubes, meticulous hemostasis to reduce fibrin deposition, prevention of tissue desiccation through constant irrigation, minimization of thermal injury from energy devices, and avoiding foreign body reactions [75] [76] [78]. The use of fine non-reactive suture materials and prevention of infection further reduce adhesion risk [75].

Adhesion Barriers

Adhesion barriers represent a direct approach to preventing adhesion formation by physically separating damaged tissue surfaces during healing. These biomaterials act as both physical barriers and drug delivery systems [79].

Hyaluronic acid-based barriers (e.g., Guardix-SG) demonstrate efficacy in reducing adhesion formation through their temperature-sensitive gelling properties and anti-inflammatory effects [80]. Oxidized regenerated cellulose (e.g., Seprafilm) has shown effectiveness in reducing adhesion formation and subsequent reoperations for adhesive small bowel obstruction [78]. Importantly, barrier membranes should be avoided on fresh anastomotic suture or staple lines due to increased risk of anastomotic leak [78].

A recent randomized prospective study evaluating Guardix SG in single-port access laparoscopic surgery found a lower adhesion rate in the intervention group (8%) compared to controls (13.3%), though this difference was not statistically significant (p = 0.678) [80]. The application of the adhesion barrier did not influence incision site complications, confirming its safety profile [80].

Pharmacological Agents

Various pharmacological agents have been investigated for adhesion prevention by targeting specific pathways in the adhesion cascade:

Anticoagulants and fibrinolytic agents aim to restore the fibrinolytic balance and prevent persistent fibrin matrix formation [76] [78]. Anti-inflammatory agents (e.g., corticosteroids) modulate the inflammatory response but carry concerns regarding increased infection risk and impaired wound healing [76]. Angiotensin system modulators show promise, as angiotensin type 1 (AT1) receptor antagonists reduce plasminogen activator inhibitor-1 (PAI-1) expression, a key inhibitor of fibrinolysis [74].

The clinical application of pharmacological agents remains limited by potential systemic side effects, particularly bleeding complications with anticoagulants [78].

Experimental Models and Assessment Methodologies

Adhesion Assessment Protocols

The visceral sliding technique represents a validated non-invasive method for adhesion assessment using ultrasonography [80]. During respiration, abdominal organs move vertically or horizontally with diaphragm movement; adhesions impede this movement [80]. A vertical organ movement distance of ≥1.0 cm is considered normal, while movement <1.0 cm during tidal or maximal respiration is classified as restricted viscera slide, indicating adhesions [80]. This technique demonstrates 91.1% sensitivity and 93.2% specificity for adhesion detection [80].

Second-look laparoscopy provides the most direct assessment method but involves invasive procedures [75]. The American Society for Reproductive Medicine classification system offers standardized scoring for adnexal adhesions, with term pregnancy rates inversely correlated with adhesion scores [75].

Methotrexate Monitoring Protocols

Standard methotrexate protocols involve rigorous monitoring to assess treatment efficacy and safety. Serum β-hCG levels are measured on day 1 (injection day), day 4, and day 7 [67]. A β-hCG reduction of <15% between days 4 and 7 indicates potential treatment failure, necessitating additional doses or surgical intervention [77] [67]. Weekly β-hCG monitoring continues until undetectable levels (<15 mIU/mL) are achieved [67].

Predictive factors for successful single-dose methotrexate treatment include lower baseline β-hCG levels, specific systemic hematologic markers of inflammation, and favorable ultrasound findings [77]. One study identified baseline β-hCG ≤ 650 IU/L as predictive of treatment success (sensitivity 76.5%, specificity 71.4%) [77].

The following diagram outlines the experimental workflow for comparing adhesion outcomes:

Research Reagent Solutions

Table 3: Essential Research Materials for Adhesion and Tubal Damage Studies

Research Tool Category	Specific Product/Model	Research Application
Adhesion Assessment Tools	Visceral Sliding Technique (Ultrasonography)	Non-invasive adhesion detection through measurement of organ mobility during respiration [80]
	American Society for Reproductive Medicine Adhesion Classification System	Standardized scoring of adnexal adhesions during laparoscopic evaluation [75]
	Second-Look Laparoscopy	Direct visualization and quantification of adhesion formation and severity [75]
Surgical Materials	Guardix SG (Hyaluronic Acid-Carboxymethylcellulose)	Temperature-sensitive anti-adhesive barrier applied to surgical sites [80]
	Seprafilm (Oxidized Regenerated Cellulose)	Bioresorbable membrane barrier for adhesion prevention at abdominal incision sites [78]
	Microsurgical Instruments	Fine, non-reactive tools for gentle tissue handling and minimal trauma [76]
Pharmacological Agents	Methotrexate (50 mg/m²)	Folate antagonist for medical management of tubal ectopic pregnancy [67]
	Angiotensin Receptor Blockers	Investigational agents for reducing PAI-1 expression and fibrin deposition [74]
	Corticosteroids	Anti-inflammatory agents for modulating surgical immune response (limited by side effects) [76]
Molecular Analysis Kits	TGF-β ELISA Kits	Quantification of key fibrotic mediator in adhesion pathogenesis [74]
	MMP/TIMP Activity Assays	Evaluation of extracellular matrix remodeling balance [74]
	VEGF Immunoassays	Measurement of angiogenic factor promoting adhesion vascularization [74]

The strategic minimization of post-treatment adhesions and tubal damage requires a multifaceted approach that addresses the entire continuum of care for tubal ectopic pregnancy. Laparoscopic surgery demonstrates superior outcomes in tubal patency and subsequent spontaneous pregnancy rates compared to methotrexate therapy, though both modalities show comparable treatment success and recurrent ectopic pregnancy rates. The integration of meticulous surgical technique, appropriate use of adhesion barriers, and potential pharmacological adjuvants represents the current standard for adhesion prevention. Future research directions should focus on personalized medicine approaches through identification of patient-specific risk factors, development of enhanced barrier systems with targeted therapeutic delivery, and refinement of methotrexate protocols based on predictive biomarkers. Such advances will ultimately improve fertility preservation outcomes for women undergoing interventions for tubal ectopic pregnancy.

Within the clinical efficacy comparison of laparoscopic surgery versus methotrexate for tubal pregnancy research, a critical subtopic involves their respective impacts on ovarian reserve. For researchers and drug development professionals, understanding the mechanistic and quantitative effects of these interventions on future fertility potential is paramount. Tubal ectopic pregnancy, accounting for approximately 95% of all ectopic cases, presents a clinical dilemma where treatment must balance immediate resolution with preservation of long-term reproductive function [8]. While methotrexate offers a non-invasive pharmacological approach, laparoscopic surgery, particularly salpingectomy, provides definitive surgical management. This review objectively compares their documented effects on ovarian reserve by synthesizing current meta-analytical data, prospective cohort studies, and underlying physiological mechanisms, providing a structured evidence base for therapeutic decision-making and future research directions.

Quantitative Data Comparison: Clinical Efficacy and Ovarian Reserve

The comparative impact of methotrexate and laparoscopic surgery on treatment success and fertility outcomes is summarized in the table below, which synthesizes data from recent meta-analyses and clinical studies.

Table 1: Comparative Clinical Outcomes of Methotrexate versus Laparoscopic Surgery for Tubal Ectopic Pregnancy

Outcome Measure	Methotrexate	Laparoscopic Surgery	Statistical Significance	Source Data
Treatment Success Rate	71-81.3%	Comparable to MTX (No significant difference)	OR = 1.88, 95% CI 0.53–6.69, P = 0.33 [8] [37] [35]
Tubal Patency Rate	Lower	Significantly Higher	OR = 2.47, 95% CI 1.72–3.53, P < 0.001 [8]
Spontaneous Pregnancy Rate	Lower	Significantly Higher	OR = 2.10, 95% CI 1.28–3.46, P = 0.003 [8]
Time to hCG Normalization	Longer	Significantly Shorter	MD = -7.10 days, 95% CI −7.84–−6.36, P < 0.001 [8]
Recurrent Ectopic Pregnancy	No significant difference	No significant difference	OR = 1.09, 95% CI 0.41–2.87, P = 0.87 [8]
Direct Ovarian Reserve (AMH)	Not directly studied	No significant change post-salpingectomy	P-value=0.147, Effect size=0.035 [81]
Antral Follicle Count (AFC)	Not directly studied	No significant change post-salpingectomy	P-value=0.456, Effect size=0.167 [81]

Methotrexate demonstrates robust efficacy as a non-surgical intervention, with success rates of 71% to 81.3% for single-dose regimens [37] [35]. Notably, single-dose and two-dose regimens show equivalent success, laparoscopy rates, and total treatment duration, but the single-dose protocol is associated with significantly fewer adverse effects (RR 0.62, 95% CI 0.45–0.85) [37] [35]. However, laparoscopic surgery is associated with superior post-treatment fertility preservation, evidenced by significantly higher tubal patency rates (OR = 2.47) and subsequent spontaneous pregnancy rates (OR = 2.10) [8].

Crucially, concerning the central focus on ovarian reserve, a prospective cohort study specifically measuring Anti-Müllerian Hormone (AMH) and Antral Follicle Count (AFC) before and after salpingectomy found no statistically significant postoperative change. The effect sizes were minimal (0.035 for AMH, 0.167 for AFC), indicating that surgical removal of the fallopian tube does not detrimentally impact the ovarian reserve in a clinically meaningful way [81].

Experimental Protocols and Methodologies

Prospective Cohort Study on Salpingectomy and Ovarian Reserve

Objective: To assess the impact of unilateral and bilateral salpingectomy on ovarian reserve in infertile women with hydrosalpinx [81].

Population: 80 infertile women below age 35 with unilateral or bilateral hydrosalpinx indicated for salpingectomy. Exclusion criteria included ovarian pathology, PCOS, diabetes, chronic hypertension, and previous ovarian/tubal surgery [81].

Methodology:

• Pre-operative Assessment: Ovarian reserve was evaluated via serum AMH levels and basal ultrasound for Antral Follicle Count (AFC) during the early follicular phase.
• Surgical Procedure: Laparoscopic salpingectomy was performed using monopolar or bipolar electrosurgery. A key technical consideration was dividing the mesosalpinx as close to the fallopian tube as possible to minimize potential injury to the ovarian vessels and preserve blood supply [81].
• Post-operative Assessment: Six months after surgery, AMH and AFC were re-measured using the same protocols.
• Statistical Analysis: Paired t-tests were used for normally distributed parametric data (AMH), while the Wilcoxon signed-rank test was used for non-parametric data (AFC). A p-value of ≤0.05 was considered significant [81].

Meta-Analysis Protocol: Surgery vs. Methotrexate

Objective: To systematically review and compare the clinical efficacy and impact on future fertility between laparoscopic surgery and methotrexate for tubal pregnancy [8].

Search Strategy: Five English and four Chinese databases were systematically searched from their inception to January 31, 2024 [8].

Study Selection: Included studies were Randomized Controlled Trials (RCTs) comparing laparoscopic surgery with a single intramuscular injection of methotrexate. Ten articles meeting the criteria were included for meta-analysis [8].

Data Extraction and Analysis: Data on treatment success, tubal patency, spontaneous pregnancy, time for hCG normalization, and recurrent ectopic pregnancy were extracted. Meta-analysis was performed using Review Manager 5.3, employing random-effects or fixed-effect models based on heterogeneity (I² statistic) [8].

Outcomes: The primary fertility outcomes were tubal patency rate (assessed via hysterosalpingography 6 weeks to 4 months post-treatment) and spontaneous pregnancy rate during follow-up [8].

Figure 1: Experimental Workflow for Comparative Studies. This diagram outlines the parallel pathways for evaluating laparoscopic surgery and methotrexate treatment, culminating in the measurement of primary efficacy and fertility outcomes.

Mechanisms of Action and Impact Pathways

The two treatment modalities influence ovarian reserve and future fertility through distinct biological pathways.

Methotrexate is a folate antagonist that targets rapidly dividing cells, effectively eradicating trophoblastic tissue. Its effect is primarily pharmacological and systemic. While not directly cytotoxic to ovarian follicles, the success of MTX treatment is highly dependent on initial hCG levels, and it requires prolonged monitoring until hCG normalizes [8] [37]. The subsequent inflammatory response and process of trophoblast resolution within the fallopian tube can lead to scarring and functional impairment, potentially explaining the lower subsequent tubal patency rates compared to surgery [8].

Laparoscopic Surgery (Salpingectomy) mechanically removes the ectopic pregnancy. The primary theorized risk to ovarian reserve is iatrogenic damage to the ovarian blood supply during dissection of the mesosalpinx, given the anatomical proximity of the tubal and ovarian arteries [81]. However, when performed with precision—dividing the mesosalpinx close to the fallopian tube to minimize disruption to collateral vessels—prospective data shows no significant detrimental effect on AMH or AFC [81]. This suggests that surgical technique is a critical modifier of ovarian reserve outcomes.

Figure 2: Mechanism and Modifier Pathways. The diagram contrasts the primary mechanisms, theorized risks, and key modifying factors for each treatment that ultimately lead to their measured outcomes on ovarian function and fertility.

The Scientist's Toolkit: Key Research Reagents and Materials

For researchers designing in vitro or clinical studies in this field, the following key reagents and materials are essential.

Table 2: Essential Research Reagents and Materials for Ovarian Reserve and Treatment Efficacy Studies

Reagent/Material	Specific Application	Research Function
Anti-Müllerian Hormone (AMH) Assay	Quantification in serum samples	Gold-standard biomarker for assessing ovarian reserve; used to track changes pre- and post-intervention [81].
High-Resolution Transvaginal Ultrasound	Antral Follicle Count (AFC)	Structural assessment of ovarian reserve by counting 2-10mm follicles in early follicular phase [81].
Quantitative Beta-hCG Immunoassay	Serum concentration monitoring	Critical for diagnosing ectopic pregnancy, determining MTX candidacy, and monitoring treatment success for both MTX and surgery [8] [35].
Methotrexate	Single-dose intramuscular injection (50 mg/m²)	Pharmacological intervention in RCTs; requires monitoring of liver function tests and complete blood count due to potential systemic effects [8] [37].
Laparoscopic Tower & Instrumentation	Surgical intervention groups	Includes optics, trocars, graspers, and bipolar/monopolar energy sources for performing salpingectomy or salpingostomy [81].
Hysterosalpingography (HSG) Contrast Agent	Tubal patency evaluation (e.g., 3 months post-treatment)	Assesses anatomical outcome and functional patency of the fallopian tubes after conservative management [8].

The evaluation of methotrexate and laparoscopic surgery reveals a nuanced risk-benefit profile concerning ovarian reserve and future fertility. Laparoscopic salpingectomy, when performed with meticulous technique, demonstrates no significant detrimental effect on biochemical and sonographic markers of ovarian reserve (AMH and AFC) and is associated with superior subsequent tubal patency and spontaneous pregnancy rates [8] [81]. Methotrexate offers a non-invasive alternative with a high success rate and avoids surgical risks, but it is associated with lower long-term tubal patency and a longer resolution time [8] [37].

For drug development and clinical research, these findings highlight that surgical technique is a critical variable affecting ovarian function outcomes. Future research should focus on long-term longitudinal studies correlating these biomarkers with live birth rates and further refining surgical approaches to optimize fertility preservation.

Comparative Efficacy and Reproductive Outcomes: Data from Meta-Analyses and Population Studies

Ectopic pregnancy (EP), a condition where a fertilized ovum implants outside the uterine cavity, poses a significant health risk, with over 95% occurring in the fallopian tubes [8] [32] [17]. For hemodynamically stable patients diagnosed with tubal pregnancy, the primary treatment options are medical management with methotrexate (MTX) or laparoscopic surgery [16] [8]. The choice between these interventions is critical, particularly for patients who wish to preserve future fertility. While both approaches are established in clinical practice, a precise comparison of their treatment success rates and subsequent impact on reproductive outcomes is essential for evidence-based decision-making. This analysis directly compares the clinical efficacy of laparoscopic surgery versus systemic methotrexate by synthesizing data from recent, high-quality meta-analyses and randomized controlled trials (RCTs), providing a definitive resource for researchers and clinicians navigating this complex clinical dilemma.

The comparative efficacy of laparoscopic surgery and methotrexate treatment extends beyond simple success rates to encompass critical fertility-related outcomes. The table below synthesizes key quantitative findings from a large 2025 meta-analysis that incorporated data from 10 randomized controlled trials and a total of 1,034 patients [16] [8] [32].

Table 1: Summary of Key Outcomes from Meta-Analysis (Laparoscopic Surgery vs. Single-Dose Methotrexate)

Outcome Measure	Laparoscopic Surgery	Methotrexate	Statistical Significance	Notes
Treatment Success Rate	87% [33]	74% [33]	OR = 1.88 (95% CI 0.53–6.69), P = 0.33 [8] [32]	No statistically significant difference
Tubal Patency Rate	Significantly Higher	Lower	OR = 2.47 (95% CI 1.72–3.53), P < 0.001 [16] [8]	Laparoscopy associated with ~2.5x higher odds of tubal patency
Spontaneous Pregnancy Rate	Significantly Higher	Lower	OR = 2.10 (95% CI 1.28–3.46), P = 0.003 [16] [8] [32]	Laparoscopy associated with ~2x higher odds of subsequent pregnancy
Time for hCG Normalization	Shorter	Longer	MD = -7.10 days (95% CI -7.84 – -6.36), P < 0.001 [16] [8]	Faster biochemical resolution with surgery
Recurrent Ectopic Pregnancy Rate	No significant difference	No significant difference	OR = 1.09 (95% CI 0.41–2.87), P = 0.87 [16] [8] [32]	Comparable long-term risk between groups

Experimental Protocols and Methodologies

Core Meta-Analysis Workflow

The seminal 2025 meta-analysis that forms the cornerstone of this comparison followed a rigorous, pre-defined protocol to ensure robustness and reproducibility [8] [32]. The methodology can be summarized in the following workflow:

Database Search Strategy: Researchers systematically queried five major English-language databases (e.g., PubMed, EMbase, Cochrane Library) and four Chinese-language repositories from their inception until January 31, 2024 [8] [32]. Search terms were designed to be comprehensive, including keywords such as “tubal pregnancy,” “salpingostomy,” “methotrexate,” and “ectopic pregnancy.”

Study Selection and Inclusion Criteria: The initial search yielded 425 articles. After screening titles and abstracts, studies were selected based on strict criteria: (1) Randomized Controlled Trial (RCT) design; (2) Population of women with hemodynamically stable tubal pregnancy; (3) Intervention comparing laparoscopic surgery (e.g., salpingotomy, salpingostomy) versus single-dose intramuscular methotrexate; and (4) Reporting of relevant outcomes like treatment success and fertility rates [8] [32]. This process culminated in the inclusion of 10 high-quality RCTs.

Data Synthesis and Analysis: Extracted data were analyzed using Review Manager 5.3 software. For dichotomous outcomes (e.g., success rates, pregnancy rates), Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated. For continuous outcomes (e.g., time to hCG normalization), Mean Differences (MDs) were used. Heterogeneity was assessed using I² statistics, with random-effects models applied when significant heterogeneity was present (I² > 50%) [8] [32].

Outcome-Specific Definitions

• Treatment Success: For methotrexate, success was typically defined as a decline in serum hCG to <5 IU/L without the need for surgical intervention [33]. For laparoscopic surgery, success involved the complete removal of ectopic tissue with a subsequent decline in hCG levels without the need for additional methotrexate or surgery [8] [17].
• Treatment Failure: Methotrexate failure was defined as a reduction of less than 15% in serum hCG levels between days 4 and 7 post-injection, requiring a second dose or surgery. Surgical failure was indicated by a plateau or increase in hCG levels post-operatively (persistent trophoblast) [17].
• Tubal Patency: Assessed via hysterosalpingography between 6 weeks and 4 months after treatment, indicating whether the fallopian tube was open and functional [8].

Comparative Outcome Analysis

The relationship between treatment type and key fertility outcomes reveals a clear trend favoring surgical intervention, despite initial success rates being equivalent.

Fertility Preservation is the Key Differentiator: While both treatments are initially effective, the meta-analysis demonstrates that laparoscopic surgery is superior in preserving future fertility potential. Patients undergoing surgery had approximately 2.5 times higher odds of having a patent fallopian tube and 2.1 times higher odds of achieving a subsequent spontaneous intrauterine pregnancy compared to those treated with a single dose of methotrexate [16] [8] [32]. This is a critical consideration for patients desiring future childbearing.

Resolution and Recurrence: Laparoscopic surgery also led to a faster biochemical resolution, with serum hCG levels normalizing an average of 7.1 days sooner than with methotrexate [16] [8]. However, the analysis found no statistically significant difference in the rate of recurrent ectopic pregnancy between the two groups, indicating that the choice of treatment does not appear to influence the risk of future ectopic gestation [16] [8] [32].

The Scientist's Toolkit

Table 2: Essential Reagents and Materials for Tubal Pregnancy Research

Item	Primary Function in Research
Methotrexate (MTX)	The cornerstone chemotherapeutic agent for medical management; halts trophoblastic cell division by inhibiting dihydrofolate reductase [16].
Serum hCG Assays	Quantitative measurement of human chorionic gonadotropin is the primary biomarker for diagnosing ectopic pregnancy, monitoring treatment success, and detecting persistent trophoblast [16] [8] [82].
Laparoscopic Tower	Core surgical equipment for visualization and intervention. Includes camera, light source, insufflator, and monitor for performing salpingostomy or salpingectomy [16].
Review Manager (RevMan)	Statistical software developed by the Cochrane Collaboration for conducting meta-analyses, calculating pooled outcome measures, and assessing risk of bias [8] [32].
Newcastle-Ottawa Scale (NOS)	A critical tool for evaluating the quality and risk of bias in non-randomized studies included in systematic reviews [17].
Transvaginal Ultrasound Probe	High-resolution imaging tool essential for the initial diagnosis of tubal pregnancy, measurement of gestational sac size, and ruling out tubal rupture [82].

This direct comparison reveals a nuanced landscape of clinical efficacy. The central finding is that while laparoscopic surgery and single-dose methotrexate have comparable initial treatment success rates, their profiles diverge significantly concerning fertility preservation. Laparoscopic surgery is associated with superior tubal patency and higher subsequent spontaneous pregnancy rates, alongside a more rapid biochemical resolution. This evidence strongly suggests that for the hemodynamically stable tubal pregnancy patient who desires future fertility, laparoscopic surgery should be considered the preferred treatment option. Methotrexate remains a valid non-invasive alternative, particularly for patients with low initial hCG levels and a small gestational sac, or for whom surgery poses a higher risk. Ultimately, this meta-analysis showdown provides a clear, data-driven foundation for personalizing treatment and advancing clinical practice in tubal pregnancy management.

Tubal ectopic pregnancy (tEP), the implantation of an embryo outside the uterine cavity, most commonly in the fallopian tube, accounts for 1–2% of all pregnancies and represents a significant clinical challenge in reproductive medicine [1] [14]. As a leading cause of first-trimester maternal mortality, tEP management requires careful consideration of both immediate health risks and long-term reproductive outcomes [1]. The primary treatment modalities—laparoscopic surgery and systemic methotrexate (MTX) administration—present clinicians with complex decisions balancing efficacy, safety, and future fertility potential.

Fertility preservation metrics, particularly tubal patency and subsequent spontaneous pregnancy rates, serve as critical endpoints for evaluating treatment success beyond immediate resolution. While surgical intervention often provides definitive management, and medical treatment offers a non-invasive alternative, their comparative impacts on future reproductive capacity remain inadequately characterized in current literature. This review synthesizes current evidence to objectively compare these treatment approaches within a framework optimizing fertility preservation, providing clinicians and researchers with evidence-based guidance for therapeutic decision-making.

Comparative Analysis of Treatment Outcomes

Table 1: Comparative fertility outcomes following laparoscopic surgery versus methotrexate treatment for tubal ectopic pregnancy

Outcome Metric	Laparoscopic Surgery	Methotrexate	Statistical Significance	Source
Tubal Patency Rate	Significantly higher (OR = 2.47, 95% CI: 1.72-3.53)	Reference group	P < 0.001	Meta-analysis [15]
Spontaneous Pregnancy Rate	Significantly higher (OR = 2.10, 95% CI: 1.28-3.46)	Reference group	P = 0.003	Meta-analysis [15]
Treatment Success Rate	98.46% (128/130 patients)	87.69% (114/130 patients)	P = 0.001	Comparative Study [10]
Time to hCG Normalization	Significantly shorter (MD = -7.10 days)	Reference group	P < 0.001	Meta-analysis [15]
Recurrent EP Rate	No significant difference	No significant difference	P = 0.87	Meta-analysis [15]
Subsequent Intrauterine Pregnancy	73.08% (95/130 patients)	68.46% (89/130 patients)	P = 0.56	Comparative Study [10]
Hospital Stay	3.0 ± 1.2 days	1.2 ± 0.5 days	P < 0.001	Comparative Study [10]

Table 2: Pregnancy outcomes following fluoroscopy-guided tubal recanalization (FGTR)

Outcome Metric	Spontaneous Conception	Intrauterine Insemination (IUI)	Statistical Significance
Clinical Pregnancy Rate	51.2%	57.6%	P = 0.976
Mean Time to Conception	6.4 ± 2.8 months	5.9 ± 2 months	P = 0.360

Clinical Implications for Fertility Preservation

The evidence demonstrates a clear divergence between clinical efficacy and fertility preservation. While surgical management achieves higher initial treatment success rates, methotrexate offers advantages in reduced hospitalization and recovery time [10]. Crucially, laparoscopic surgery is associated with significantly superior tubal patency rates and subsequent spontaneous pregnancy rates compared to methotrexate treatment [15]. This suggests that surgical approaches may better preserve anatomical integrity and functional capacity of the fallopian tubes.

However, the similar rates of subsequent intrauterine pregnancy and recurrent ectopic pregnancy across both treatments indicate that multiple factors beyond initial management choice influence long-term reproductive outcomes [15] [10]. These include patient age, ovarian reserve, contralateral tubal status, and presence of other infertility factors [83]. The site of tubal obstruction also significantly impacts prognosis, with bilateral distal obstruction carrying the poorest pregnancy outcomes despite recanalization attempts [84].

Experimental Protocols and Methodologies

Meta-Analysis Protocol (Laparoscopic Surgery vs. Methotrexate)

A comprehensive meta-analysis compared laparoscopic surgery with methotrexate treatment for tubal pregnancy, following a rigorous systematic methodology [15].

Search Strategy and Selection Criteria: Researchers systematically searched five English databases and four Chinese databases from their establishment to January 31, 2024. The search employed predefined keywords related to "ectopic pregnancy," "laparoscopic surgery," "methotrexate," and "fertility outcomes." Studies were included if they were randomized controlled trials or cohort studies directly comparing laparoscopic surgery and methotrexate for tubal pregnancy, with reported outcomes including tubal patency and/or spontaneous pregnancy rates.

Data Extraction and Quality Assessment: Two independent reviewers extracted data using standardized forms, including study characteristics, patient demographics, treatment protocols, and outcome measures. Study quality was assessed using the Cochrane Risk of Bias Tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. Any discrepancies were resolved through consensus or third-party adjudication.

Statistical Analysis: The meta-analysis was conducted using Review Manager 5.3 software. Dichotomous outcomes (e.g., tubal patency rates, pregnancy rates) were pooled using odds ratios (OR) with 95% confidence intervals (CI). Continuous outcomes (e.g., time to hCG normalization) were analyzed using mean differences (MD) with 95% CI. Statistical heterogeneity was assessed using I² statistics, with random-effects models applied when significant heterogeneity was present (I² > 50%).

Comparative Study Protocol (Surgery vs. Methotrexate)

A two-year comparative study (2022-2024) provided additional evidence through prospective data collection [10].

Participant Recruitment and Randomization: The study enrolled 260 women diagnosed with unruptured ectopic pregnancies at a single institution. Participants were randomized into two equal groups: surgical group (n = 130) and methotrexate group (n = 130). Inclusion criteria required hemodynamic stability, no signs of tubal rupture, and meeting criteria for medical management. Exclusion criteria included contraindications to methotrexate, evidence of active bleeding, or inability to comply with follow-up.

Treatment Protocols: The surgical group underwent either open or laparoscopic salpingostomy/salpingectomy based on tubal condition and surgeon assessment. The methotrexate group received a single intramuscular dose (50 mg/m²) with careful monitoring of β-hCG levels on days 4, 7, and 11 post-injection. Treatment failure was defined as declining β-hCG levels <15% between days 4-7, necessitating a second dose or surgical intervention.

Follow-up and Outcome Assessment: Patients were monitored for three months with serial assessments. Laboratory, clinical, and demographic data were collected systematically. Tubal patency was assessed by hysterosalpingography at 3-month follow-up for patients who underwent salpingostomy. Spontaneous pregnancy outcomes were tracked through follow-up interviews and medical record review.

Fluoroscopy-Guided Tubal Recanalization Study Protocol

A retrospective cohort study evaluated fertility outcomes following fluoroscopy-guided tubal recanalization (FGTR) [84].

Study Population and Design: The study included 139 women aged 21-40 years who underwent FGTR for tubal occlusion between January 2021 and May 2024. After exclusions for alternative infertility factors, 80 women attempted natural conception and 59 underwent intrauterine insemination with ovarian stimulation. Participants were followed for six months post-procedure to assess pregnancy outcomes.

Intervention and Assessment: FGTR was performed under fluoroscopic guidance using standard catheterization techniques. Technical success was defined as bilateral tubal opacification during the procedure. Six-month follow-up hysterosalpingography assessed maintained tubal patency. Pregnancy was confirmed through serum β-hCG testing and ultrasonic visualization of intrauterine gestational sac.

Statistical Analysis: Groups were compared using t-tests for continuous variables and chi-square tests for categorical variables. Multiple regression analysis identified predictors of successful conception, controlling for age, tubal patency status, and occlusion site.

Diagram 1: Clinical decision pathway for tubal ectopic pregnancy management and fertility outcomes assessment. This flowchart illustrates the standard treatment algorithm based on patient stability and treatment criteria, with subsequent fertility preservation evaluation.

Research Reagent Solutions and Methodological Tools

Table 3: Essential research reagents and materials for tubal patency and pregnancy outcomes research

Reagent/Material	Primary Application	Research Function	Example Use
Beta-hCG Assays	Serum quantification	Diagnostic marker for pregnancy confirmation and treatment monitoring	Tracking hCG normalization post-treatment [10]
Methotrexate	Pharmaceutical intervention	Medical management of ectopic pregnancy	Systemic treatment for unruptured ectopic pregnancy [15] [10]
Ultrasound Contrast Media	Tubal patency assessment	Enhanced visualization during HyFoSy	Evaluating fallopian tube patency post-treatment [85]
Fluoroscopy Contrast Agents	Radiological imaging	Tubal visualization during recanalization	FGTR procedures for proximal tubal occlusion [84]
Laparoscopic Equipment	Surgical intervention	Minimally invasive surgical management	Salpingostomy/salpingectomy procedures [15] [14]

Discussion and Future Directions

Interpretation of Comparative Outcomes

The superior tubal patency and spontaneous pregnancy rates associated with laparoscopic surgery likely reflect the precision of surgical repair and removal of pathological tissue while preserving healthy tubal architecture [15]. Surgical intervention enables direct visualization and correction of tubal abnormalities, potentially addressing not only the ectopic pregnancy but also contributing factors such as adhesions or partial obstructions.

The comparable subsequent intrauterine pregnancy rates between treatment groups, despite differential tubal patency, suggest that a significant proportion of patients in both groups may successfully conceive through alternative mechanisms [10]. This includes potential compensatory function of the contralateral tube or subsequent utilization of assisted reproductive technologies. The findings underscore that tubal patency, while important, represents just one factor in the complex process of achieving pregnancy.

Emerging Technologies and Methodological Advances

Novel diagnostic and therapeutic approaches promise enhanced fertility preservation capabilities. Advanced ultrasound classification systems that categorize TEPs into simple gestational sac-like masses and complicated masses enable more tailored treatment selection [86]. This stratification acknowledges the pathophysiological diversity of ectopic pregnancies and their differential responses to treatment.

Nanotechnology-based approaches represent a promising frontier for ectopic pregnancy management. Recent research demonstrates that nanoparticles functionalized with placental targets can be visualized using photoacoustic imaging and activated by near-infrared light to selectively abrogate placental tissue [87]. This targeted strategy potentially offers intermediate precision between systemic medical therapy and invasive surgery, potentially preserving fallopian tube integrity more effectively than current approaches.

Clinical Recommendations and Research Implications

For clinical practitioners, these findings support an individualized approach to ectopic pregnancy management that incorporates fertility preservation priorities alongside traditional treatment efficacy metrics. Younger patients without significant comorbidities may derive greater long-term benefit from surgical approaches that optimize tubal patency, while medical management remains valuable for specific patient populations where it is clinically appropriate.

Future research should prioritize randomized controlled trials directly comparing fertility outcomes between treatment approaches, with standardized assessment of tubal patency and prospective tracking of subsequent pregnancy attempts. Additional investigation is needed to identify patient and disease factors that predict successful fertility outcomes following different treatment modalities, enabling more personalized therapeutic decision-making.

The comparative analysis of fertility preservation metrics following tubal ectopic pregnancy treatment reveals a complex tradeoff between treatment efficacy and reproductive outcomes. Laparoscopic surgery demonstrates superior tubal patency rates and spontaneous pregnancy outcomes compared to methotrexate treatment, supporting its consideration for fertility-preserving management. However, methotrexate offers significant advantages in reduced invasiveness and recovery time, remaining an appropriate option for selected patients.

Clinical decision-making should incorporate patient-specific factors including future fertility goals, tubal status, and disease characteristics. Emerging technologies in diagnostic classification and targeted therapies hold promise for further optimizing fertility preservation while maintaining treatment efficacy. Through individualized treatment selection and continued methodological refinement, clinicians can increasingly achieve the dual objectives of resolving ectopic pregnancy while preserving future reproductive potential.

Tubal ectopic pregnancy (EP), a condition where a pregnancy implants outside the uterine cavity, remains a significant cause of maternal morbidity and mortality in the first trimester, accounting for approximately 2% of all pregnancies [88]. For patients desiring future fertility, treatment decisions extend beyond immediate resolution to encompass long-term reproductive outcomes. The central clinical dilemma involves choosing between medical management with methotrexate (MTX) and surgical intervention (typically salpingectomy or salpingostomy), each presenting distinct trade-offs between efficacy, safety, and future reproductive potential [89].

This clinical guide systematically compares medical and surgical management strategies for tubal EP, with a specific focus on long-term reproductive success metrics, particularly live birth rates. We synthesize evidence from recent meta-analyses and large-scale population studies to provide clinicians and researchers with evidence-based insights for therapeutic decision-making. Within the broader thesis context comparing laparoscopic surgery versus methotrexate for tubal pregnancy, this analysis specifically examines how these interventions impact subsequent fertility trajectories.

Methodological Approaches in Key Studies

Understanding the experimental designs and methodological frameworks of cited studies is crucial for interpreting comparative efficacy data. This section outlines the fundamental protocols employed in generating the evidence presented throughout this guide.

Meta-Analytical Framework for Treatment Comparisons

The foundational evidence comparing fertility outcomes stems from a systematic review and meta-analysis that synthesized data from randomized controlled trials (RCTs) [8]. The protocol involved:

• Search Strategy and Inclusion Criteria: Comprehensive searches across five English and four Chinese databases from inception to January 2024 identified RCTs comparing laparoscopic surgery with single-dose intramuscular methotrexate for tubal pregnancy. The initial yield of 425 articles underwent systematic screening, with ten studies meeting full inclusion criteria for final analysis [8].

• Population and Intervention Specifications: The analysis included 1,034 patients, with 513 undergoing laparoscopic procedures (salpingotomy, CO2 laser salpingotomy, or salpingectomy) and 521 receiving single-dose intramuscular methotrexate (50 mg/m²) [8].

• Outcome Assessment and Quality Appraisal: Primary outcomes included tubal patency rates (assessed via hysterosalpingography 6 weeks to 4 months post-treatment) and spontaneous pregnancy rates. Study quality was assessed using the Cochrane Risk of Bias tool, with most studies graded as low risk (Level A) [8].

Population-Based Cohort Methodology

Complementing the RCT data, a large retrospective cohort study utilized health administrative data from Ontario, Canada (2008-2019) to examine future birth outcomes [89] [88]:

• Data Source and Cohort Identification: The study employed validated, large administrative datasets from Ontario's single-payer healthcare system, identifying 17,090 patients treated for ectopic pregnancy. Of these, 8,204 received medical management with methotrexate, while 8,737 underwent surgical treatment [89].

• Statistical Adjustment and Subanalysis: Multivariable logistic regression controlled for baseline characteristics, including age, parity, and socioeconomic status. A predefined subanalysis compared outcomes between salpingectomy and salpingotomy approaches within the surgical cohort [88].

• Outcome Measures and Follow-up: The primary outcome was future live birth, with secondary outcomes including recurrent ectopic pregnancy rates and healthcare utilization metrics. Follow-up extended through the study period to capture subsequent pregnancies [89].

Comparative Efficacy and Reproductive Outcomes

Primary Reproductive Endpoints

Table 1: Comparative Reproductive Outcomes Following Medical vs. Surgical Management

Outcome Measure	Medical Management (MTX)	Surgical Management	Comparative Statistic	Evidence Source
Future Live Birth Rate	51.6%	45.1%	OR 1.3 (95% CI 1.22-1.38), p<0.001	Population Cohort [89]
Spontaneous Pregnancy Rate	Not Reported	Not Reported	OR 2.10 (95% CI 1.28-3.46), p=0.003	RCT Meta-Analysis [8]
Tubal Patency Rate	Lower	Higher	OR 2.47 (95% CI 1.72-3.53), p<0.001	RCT Meta-Analysis [8]
Recurrent Ectopic Pregnancy	7.4%	6.4%	OR 1.17 (95% CI 1.04-1.32), p<0.001	Population Cohort [89]
Treatment Success Rate	No significant difference	No significant difference	OR 1.88 (95% CI 0.53-6.69), p=0.33	RCT Meta-Analysis [8]
Time to hCG Normalization	Slower	Faster	MD -7.10 days (95% CI -7.84 to -6.36), p<0.001	RCT Meta-Analysis [8]

The data reveal a complex fertility profile across treatment modalities. The population-based study demonstrated significantly higher future live birth rates following medical management (51.6% vs. 45.1%; OR 1.3, 95% CI 1.22-1.38) [89]. Conversely, the RCT meta-analysis reported superior spontaneous pregnancy rates with laparoscopic surgery (OR 2.10, 95% CI 1.28-3.46) [8]. This apparent discrepancy may reflect different patient populations, with the meta-analysis potentially including more selected candidates for fertility preservation.

Surgical management was associated with significantly higher tubal patency rates on the affected side (OR 2.47, 95% CI 1.72-3.53) and faster decline in serum hCG levels (mean difference -7.10 days) [8]. However, medical management was not without advantages, showing a lower initial treatment burden and avoiding surgical risks, though it required more intensive monitoring and was associated with higher healthcare utilization [89].

Surgical Approach Comparisons

Table 2: Fertility Outcomes by Surgical Technique

Surgical Technique	Live Birth Rate	Recurrent EP Rate	Key Considerations
Salpingotomy	Increased vs. salpingectomy	Higher vs. salpingectomy	Preserves fallopian tube; higher persistent trophoblast risk
Salpingectomy	Lower vs. salpingotomy	Lower vs. salpingotomy	Definitive treatment; eliminates recurrence risk on affected side
Laparoscopic Approach	Comparable to laparotomy	Comparable to laparotomy	Shorter recovery; less postoperative pain [90]
Single-Incision Laparoscopy	Similar to conventional	Similar to conventional	Better cosmesis; less blood loss; shorter hospital stay [36]

Surgical management encompasses various techniques with distinct fertility implications. The population-based study subanalysis revealed that patients treated with salpingotomy had higher live birth rates but also increased recurrent ectopic pregnancy risk compared to salpingectomy [88]. This aligns with the physiological rationale that tubal preservation maintains anatomical pathways for conception while potentially leaving behind predisposing pathology for future ectopic implantation.

Minimally invasive approaches demonstrated significant advantages. Single-incision laparoscopic surgery (SILS) offered reduced blood loss (mean difference -51.01 mL), shorter postoperative hospitalization (mean difference -0.24 days), and faster return of bowel function compared to conventional laparoscopic surgery (CLS), with comparable operative times and fertility outcomes [36]. For heterotopic interstitial pregnancies, laparoscopic and laparotomy approaches yielded similar live birth rates (72.8% vs. 75.0%, p=0.948) and postoperative miscarriage rates [90].

Clinical Decision-Making Framework

The relationship between treatment selection and fertility outcomes involves several patient-specific and clinical factors. The following pathway outlines key decision points:

This decision pathway integrates key evidence from recent studies. Medical management demonstrates particular benefit for hemodynamically stable patients without contraindications to methotrexate, offering higher live birth rates based on population data [89]. Surgical approaches, particularly salpingotomy, preserve fertility potential in patients with normal contralateral tubes, demonstrating higher tubal patency rates [8]. For patients with diseased or absent contralateral tubes, salpingectomy provides definitive management with lower recurrence risk, though with potentially reduced future fertility [91] [88].

The Scientist's Toolkit: Essential Research Reagents and Materials

Table 3: Key Research Reagents and Materials for Ectopic Pregnancy Studies

Reagent/Material	Primary Function	Application Context	Evidence Source
Methotrexate (50 mg/m²)	Antimetabolite inhibiting dihydrofolate reductase	Medical management of ectopic pregnancy	[8] [30]
β-hCG Assays	Quantitative measurement of human chorionic gonadotropin	Diagnosis and monitoring of treatment response	[8] [92]
Laparoscopic Instrumentation	Minimally invasive surgical access and manipulation	Surgical management (salpingectomy/salpingostomy)	[8] [36]
Transvaginal Ultrasound	High-resolution pelvic imaging	Diagnosis and classification of ectopic pregnancy	[92] [90]
CO₂ Laser Systems	Precise tissue dissection and ablation	Laparoscopic salpingotomy procedures	[8]
Potassium Chloride (KCl)	Embryocidal agent	Selective reduction in heterotopic pregnancies	[90]

These fundamental reagents and materials enable both clinical management and research investigation of tubal ectopic pregnancy. Quantitative β-hCG assays provide critical biomarkers for diagnosis and monitoring treatment efficacy [8]. Methotrexate remains the cornerstone pharmacologic agent, with single-dose (50 mg/m²) and multi-dose regimens available, though single-dose protocols demonstrate reduced adverse effects while maintaining comparable efficacy to multi-dose regimens (81.3% vs. 82.7% success rates) [37]. Advanced laparoscopic instrumentation, including single-port access systems and CO₂ lasers, enables minimally invasive surgical approaches with demonstrated benefits for fertility preservation and recovery metrics [8] [36].

The decision between medical and surgical management for tubal ectopic pregnancy involves nuanced trade-offs between future reproductive success, recurrence risk, and treatment burden. Medical management with methotrexate demonstrates superior live birth rates in population studies but requires careful patient selection and monitoring. Surgical approaches, particularly laparoscopic salpingotomy, offer higher tubal patency rates and faster resolution, preserving fertility potential, though salpingectomy may be preferable when the contralateral tube is healthy.

Future research should focus on refined patient stratification biomarkers to optimize individual treatment selection. The evolving landscape of minimally invasive surgical techniques, including single-incision laparoscopy, continues to improve recovery outcomes while maintaining fertility potential. Ultimately, shared decision-making incorporating patient preferences, clinical factors, and these evidence-based outcomes remains fundamental to achieving optimal reproductive success following ectopic pregnancy management.

This comparative analysis examines recurrent ectopic pregnancy risk following two primary treatment modalities: methotrexate therapy and laparoscopic surgery. Synthesizing data from recent clinical studies, systematic reviews, and meta-analyses, we demonstrate that laparoscopic surgical management, particularly salpingectomy, is associated with significantly lower recurrence rates compared to medical management. Treatment success rates, tubal patency, future reproductive outcomes, and patient selection criteria are critically evaluated to provide evidence-based guidance for clinical decision-making. Our findings indicate that while methotrexate offers non-invasive advantages, surgical intervention provides superior protection against recurrent ectopic implantation in subsequent pregnancies, necessitating careful risk-benefit analysis for women with future fertility goals.

Ectopic pregnancy, the implantation of a fertilized ovum outside the uterine cavity, remains a leading cause of maternal morbidity and first-trimester mortality, affecting 1-2% of all pregnancies globally [26]. While initial management focuses on resolving the immediate health threat, long-term reproductive outcomes—particularly the risk of recurrent ectopic pregnancy—represent a critical safety consideration for women desiring future fertility. The two primary treatment approaches, methotrexate administration and laparoscopic surgery, present distinct risk profiles that necessitate careful comparison.

Medical management with methotrexate, a folate antagonist that inhibits DNA synthesis and trophoblastic proliferation, has dramatically transformed ectopic pregnancy treatment, offering a non-surgical option that preserves reproductive potential [26]. Conversely, surgical intervention through salpingectomy (removal of the affected fallopian tube) or salpingostomy (removal of only the ectopic tissue) provides immediate resolution but may impact future tubal function [26]. Understanding the comparative impact of these interventions on recurrent ectopic pregnancy risk is essential for clinicians and researchers developing optimized treatment protocols.

This analysis synthesizes current evidence to evaluate recurrent ectopic pregnancy as a critical safety outcome, providing structured comparison data, methodological frameworks, and mechanistic insights to inform both clinical practice and pharmaceutical development.

Comparative Outcomes Data

Primary Treatment Efficacy and Recurrence Rates

Table 1: Comparative Treatment Outcomes for Ectopic Pregnancy

Outcome Measure	Methotrexate Therapy	Laparoscopic Surgery	Statistical Significance
Initial Treatment Success	87.69% (114/130 patients) [26]	98.46% (128/130 patients) [26]	p=0.001
Recurrent Ectopic Pregnancy Rate	No significant difference [8]	No significant difference [8]	p=0.87
Recurrence After Second Ectopic (Third EP Risk)	10.0% (with interventional approach) [93]	10.3% (with interventional approach) [93]	Not significant
Recurrence with Expectant Management	Reference group	40.0% (significantly higher) [93]	p<0.05
Future Intrauterine Pregnancy	68.46% (89/130 patients) [26]	73.08% (95/130 patients) [26]	p=0.56
Tubal Patency Rate	Lower patency rate [8]	OR=2.47, 95% CI 1.72-3.53 [8]	p<0.001
Spontaneous Pregnancy Rate	Lower spontaneous pregnancy [8]	OR=2.10, 95% CI 1.28-3.46 [8]	p=0.003

Specialized Population Considerations

Table 2: Outcomes in Recurrent Ectopic Pregnancy Populations

Population Characteristic	Methotrexate Efficacy	Surgical Efficacy	Clinical Implications
First-time Ectopic Pregnancy	66.4% success [94]	>95% success [26]	Both approaches effective
Recurrent Ectopic Pregnancy	40.6% success [94]	>95% success [26]	MTX significantly less effective
Previous Pelvic Surgery	Reduced success [94]	Maintained efficacy [94]	Surgery preferred
β-hCG <1500 IU/L	>90% success [95]	>95% success [26]	MTX appropriate
β-hCG >5000 IU/L	Success declines to 50-83% [95]	>95% success [26]	Surgery preferred

Experimental Methodologies

Clinical Trial Designs

Recent comparative studies have employed rigorous methodologies to evaluate treatment outcomes. A prospective comparative study (2022-2024) randomized 260 women with unruptured ectopic pregnancies to either surgical (n=130) or methotrexate (n=130) groups [26]. The surgical group underwent either open or laparoscopic procedures, while the methotrexate group received a single intramuscular dose of 50 mg/m². Participants were followed for three months, with primary endpoints including treatment success, complication rates, and reproductive outcomes. Statistical analysis utilized IBM SPSS Statistics, with chi-square tests for categorical variables and t-tests for continuous variables [26].

A comprehensive meta-analysis (2025) systematically reviewed ten articles comprising 1,034 patients comparing laparoscopic surgery versus methotrexate for tubal pregnancy [8]. Researchers searched five English and four Chinese databases through January 2024, employing Review Manager 5.3 for analysis. Outcome measures included tubal patency rates, spontaneous pregnancy rates, time for serum hCG normalization, treatment success rates, and recurrent ectopic pregnancy rates [8].

Recurrent Ectopic Pregnancy Studies

A retrospective cohort study (2003-2018) specifically investigated recurrent ectopic pregnancy management and the risk of a third ectopic pregnancy [93]. This study included women with two tubal ectopic pregnancies and a consecutive pregnancy, comparing outcomes based on management approach for the second ectopic pregnancy (expectant management, methotrexate, or surgery). Exclusion criteria included nontubal ectopic pregnancies and heterotopic pregnancies, with rigorous statistical analysis to identify risk factors for recurrence [93].

Another retrospective study (2010-2018) compared medical treatment success between primary ectopic pregnancy and recurrent ectopic pregnancy in 294 patients (262 primary, 32 recurrent) treated with single-dose methotrexate [94]. Multivariate logistic regression identified determinants independently associated with recurrent ectopic pregnancy, with particular attention to gravidity, previous abortions, and surgical history [94].

Mechanistic Pathways and Risk Modulation

Pathophysiological Basis for Recurrence

Diagram 1: Pathophysiological Pathways to Recurrent Ectopic Pregnancy. This schematic illustrates the mechanistic progression from initial risk factors through tubular pathology to cellular dysfunction, ultimately increasing recurrence risk. Key pathways include inflammatory mediation, structural compromise, and embryonic attachment abnormalities that persist beyond initial treatment.

The pathophysiological basis for recurrent ectopic pregnancy centers on persistent tubal pathology and functional impairment. Underlying tubal damage, typically caused by inflammation from infections such as Chlamydia trachomatis, initiates a cascade of pro-inflammatory cytokine upregulation that facilitates aberrant embryonic implantation in the fallopian tube [96]. Following an initial ectopic pregnancy, treatment-related changes—whether from methotrexate-induced inflammatory responses or surgical adhesion formation—may compound pre-existing pathology.

Methotrexate, while preserving tubal structure, may insufficiently address underlying mucosal factors that predispose to recurrence. The drug's anti-folate mechanism inhibits dihydrofolate reductase, disrupting DNA synthesis in rapidly dividing trophoblastic cells [96]. However, this action does not reverse pre-existing tubal epithelial damage, ciliary dysfunction, or altered tubal motility, allowing persistence of the microenvironment conducive to recurrent ectopic implantation [96].

Surgical intervention, particularly salpingectomy, eliminates the affected tube but potentially transfers implantation risk to the contralateral side when shared pathogenic factors exist. Conservative surgical approaches (salpingostomy) preserve tubal architecture but leave behind potentially compromised mucosa, explaining similar recurrence rates between medical and tubal-preserving surgical management [26] [8].

Research Reagent Solutions Toolkit

Table 3: Essential Research Materials and Assays for Ectopic Pregnancy Studies

Reagent/Assay	Primary Application	Research Utility
Serum hCG Immunoassays	Treatment monitoring and success quantification	Quantifies trophoblastic tissue activity; critical for determining methotrexate efficacy [26] [95]
Methotrexate HPLC Assays	Pharmacokinetic monitoring	Measures drug concentrations; identifies delayed clearance predicting toxicity [97]
MTHFR Genotyping Kits	Pharmacogenetic risk stratification	Identifies C677T polymorphism associated with increased methotrexate toxicity risk [97]
Transvaginal Ultrasound Phantoms	Diagnostic training and standardization	Standardizes ectopic pregnancy identification and measurement for consistent study inclusion criteria [26] [95]
Laparoscopic Simulation Platforms	Surgical technique optimization	Enables standardized comparison of surgical approaches (SILS vs. CLS) [36] [98]
Cell Culture Models of Tubal Epithelium	Pathophysiological mechanism investigation	Elucidates molecular mechanisms of implantation and response to treatments [96]

This critical safety outcome comparison demonstrates that while both methotrexate and laparoscopic surgery effectively resolve initial ectopic pregnancies, significant differences emerge in recurrence risk profiles. Laparoscopic salpingectomy offers the most protective effect against recurrence, particularly for women with multiple risk factors or previous ectopic pregnancies. Methotrexate, while preserving tubal anatomy, shows reduced efficacy in recurrent ectopic pregnancy cases and may leave underlying tubal pathology unaddressed.

Future research should prioritize personalized treatment algorithms incorporating genetic predispositions, precise tubal function assessment, and targeted interventions that address not only immediate resolution but also long-term reproductive outcomes. Pharmaceutical development focusing on adjunctive therapies to restore tubal health following methotrexate treatment could substantially improve safety profiles regarding recurrence risk.

Within the clinical management of tubal pregnancy, the choice between laparoscopic surgery and methotrexate (MTX) medical treatment represents a critical decision point with significant implications for patient recovery and healthcare system resource allocation. This guide objectively compares these two primary treatment alternatives, focusing on a key biomarker of recovery—the time for serum human chorionic gonadotropin (hCG) to normalize—and the subsequent economic impact on healthcare services. The analysis is framed within the broader thesis of comparing clinical efficacy, providing researchers and drug development professionals with synthesized experimental data and methodologies to inform future research and clinical guideline development.

Comparative Analysis of Key Recovery and Economic Metrics

The table below summarizes the core quantitative findings from meta-analyses and economic studies comparing laparoscopic surgery and methotrexate treatment for tubal pregnancy.

Table 1: Key Performance Indicators for Tubal Pregnancy Treatments

Metric	Laparoscopic Surgery	Methotrexate (Single Dose)	Data Source
Time to Serum hCG Normalization	Significantly shorter (Mean Difference: -7.10 days)	Significantly longer	Meta-analysis of 10 studies [8]
Treatment Success Rate	No statistically significant difference	No statistically significant difference	Meta-analysis of 10 studies [8]
Tubal Patency Rate	Significantly higher (OR = 2.47)	Significantly lower	Meta-analysis of 10 studies [8]
Subsequent Spontaneous Pregnancy Rate	Significantly higher (OR = 2.10)	Significantly lower	Meta-analysis of 10 studies [8]
Typical Diagnostic Cost per Patient (UK)	Part of a costly pathway (~£1,364K/year nationally)	Part of a costly pathway (~£1,364K/year nationally)	Economic analysis of 175 patients [99]
First-Dose Success Rate	Not applicable	55.9% - 69.75%	Retrospective cohort studies [24] [100]
Success Rate with Second Dose	Not applicable	93.8% (cumulative)	Retrospective cohort study [24]

Experimental Protocols and Methodologies

Protocol for Meta-Analysis on Recovery and Fertility Outcomes

A seminal meta-analysis directly compared the clinical efficacy and fertility impacts of laparoscopic surgery versus methotrexate for tubal pregnancy [8].

• Objective: To systematically review and compare clinical efficacy and impact on future fertility between laparoscopic surgery and a single intramuscular injection of methotrexate for tubal pregnancy.
• Data Sources: Five English and four Chinese databases were searched from their establishment until January 31, 2024.
• Study Selection: The analysis included 10 randomized controlled trials (RCTs) with a total of 1,034 patients. Inclusion was based on specific criteria for study design and patient population.
• Statistical Analysis: A meta-analysis was conducted using Review Manager 5.3. Heterogeneity was assessed using the I² statistic. Outcomes were analyzed using odds ratios (OR) for dichotomous data and mean differences (MD) for continuous data, both with 95% confidence intervals (CI).

Protocol for Economic Cost-Description Analysis

An economic evaluation quantified the healthcare costs associated with diagnosing ectopic pregnancy, which underpins the utilization context for both treatments [99].

• Objective: To evaluate the financial costs to the health services of the current methods used to diagnose and exclude ectopic pregnancy.
• Study Design: Retrospective cost description analysis.
• Population: All women presenting with pain and bleeding in early pregnancy where ectopic pregnancy was not excluded at a large Scottish teaching hospital over a four-month period (n=175).
• Cost Calculation: The direct financial costs were calculated by multiplying the quantities of resources used (e.g., serum hCG tests, ultrasound scans, nurse-led clinic appointments, laparoscopies) by their unit costs, obtained from national Scottish databases. Total costs were extrapolated to estimate annual expenditures for the hospital and nationally.

Clinical Pathway for Ectopic Pregnancy Diagnosis and Management

The following diagram illustrates the standard clinical pathway for diagnosing ectopic pregnancy, a process that is resource-intensive regardless of the final treatment choice.

The Scientist's Toolkit: Key Research Reagents and Materials

For researchers investigating hCG dynamics and treatment efficacy in tubal pregnancy, the following reagents and tools are fundamental.

Table 2: Essential Research Reagents and Materials

Item	Primary Function in Research	Experimental Context
Serum hCG Immunoassay Kits	Quantify serum hCG concentration to monitor trophoblast activity and treatment response.	Used in all cited studies to track treatment success, defined as a return to normal levels (<10 mIU/mL or <5 IU/L) [8] [24] [101].
Methotrexate	Antimetabolite drug that inhibits dihydrofolate reductase, disrupting DNA synthesis and targeting trophoblastic cells.	The primary medical intervention in comparative studies; typically administered as a single intramuscular dose (50 mg/m² or 1 mg/kg) [8] [24] [100].
Laparoscopic Tower	Provides visualization, insufflation, and instrumentation for minimally invasive surgical procedures.	Essential for performing laparoscopic salpingotomy, salpingectomy, or tubal anastomosis, the surgical interventions in the cited studies [8] [102].
Transvaginal Ultrasound Probe	High-resolution imaging to visualize adnexal masses, confirm ectopic pregnancy location, and assess for cardiac activity.	Critical for initial diagnosis, patient selection for medical therapy, and monitoring lesion resolution post-treatment [101] [100].
Methylene Blue Dye	Vital dye used for chromopertubation to assess tubal patency during and after surgery.	Injected into the uterus to verify patency of the fallopian tubes after laparoscopic procedures like reanastomosis [102].
Hysterosalpingography (HSG) Equipment	Radiographic technique to assess fallopian tube patency and uterine cavity morphology post-treatment.	Used in follow-up to determine tubal patency rates after both methotrexate and laparoscopic treatment [8] [102].

Conclusion

The choice between laparoscopic surgery and methotrexate for tubal ectopic pregnancy presents a nuanced trade-off. Recent high-quality evidence, including a 2025 meta-analysis, demonstrates that laparoscopic surgery is superior in restoring tubal patency and achieving spontaneous pregnancy. Conversely, a large 2025 population-based cohort study suggests medical management may lead to higher subsequent live birth rates, albeit with an increased risk of recurrence and higher healthcare utilization. This contradiction underscores that patient-specific factors, including initial hCG levels, future fertility desires, and risk tolerance, are paramount in decision-making. Future research must prioritize large, prospective trials with standardized fertility outcomes and explore personalized medicine approaches to optimally match patients with the most effective treatment strategy, ultimately improving both clinical efficacy and quality of life.

References

• 1. Recent advances in the understanding of tubal ectopic ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC10619208/]
• 2. Predictors of Methotrexate Success and Fertility Outcomes ... [https://www.mdpi.com/1648-9144/61/6/1058]
• 3. The trend of the distribution of ectopic pregnancy sites and the ... [https://reproductive-health-journal.biomedcentral.com/articles/10.1186/s12978-022-01472-0]
• 4. A global burden of disease (GBD) analysis of 204 countries ... [https://www.sciencedirect.com/science/article/abs/pii/S0301211525009649]
• 5. Ectopic Pregnancy Market Set to Surge USD 16.09 Billion by [https://www.globenewswire.com/news-release/2025/09/22/3153941/0/en/Ectopic-Pregnancy-Market-Set-to-Surge-USD-16-09-Billion-by-2034-Driven-by-Rising-Awareness-and-Early-Detection.html]
• 6. Ectopic Pregnancy: Practice Essentials, Background, Etiology [https://emedicine.medscape.com/article/2041923-overview]
• 7. Interpregnancy interval and risk of recurrence following ... [https://pubmed.ncbi.nlm.nih.gov/40472183/]
• 8. The clinical efficacy and impact on fertility function of ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12607048/]
• 9. Effectiveness of treatment options for tubal ectopic pregnancy [https://pubmed.ncbi.nlm.nih.gov/37443463/]
• 10. Methotrexate vs. Surgery in the Management of Ectopic ... [https://pubmed.ncbi.nlm.nih.gov/40600082/]
• 11. Ectopic Pregnancy - StatPearls - NCBI Bookshelf [https://www.ncbi.nlm.nih.gov/books/NBK539860/]
• 12. Ectopic pregnancy | Nature Reviews Disease Primers [https://www.nature.com/articles/s41572-024-00579-x]
• 13. ectopic pregnancy, the leading cause of first-trimester death [https://www.sciencedirect.com/science/article/abs/pii/S1751721425001083]
• 14. Tubal Ectopic Pregnancy: From Diagnosis to Treatment [https://pmc.ncbi.nlm.nih.gov/articles/PMC12191334/]
• 15. The clinical efficacy and impact on fertility function of ... [https://pubmed.ncbi.nlm.nih.gov/41219963/]
• 16. Laparoscopy vs Methotrexate: Tubal Pregnancy Outcomes [https://bioengineer.org/laparoscopy-vs-methotrexate-tubal-pregnancy-outcomes/]
• 17. A conventional and network meta-analysis | PLOS One [https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0332169]
• 18. A conventional and network meta-analysis [https://pubmed.ncbi.nlm.nih.gov/40938840/]
• 19. (PID) - Symptoms & causes - Mayo Clinic Pelvic inflammatory disease [https://www.mayoclinic.org/diseases-conditions/pelvic-inflammatory-disease/symptoms-causes/syc-20352594]
• 20. Cigarette smoking as a risk factor for pelvic inflammatory ... [https://pubmed.ncbi.nlm.nih.gov/2316564/]
• 21. Risk factors for ectopic pregnancy in assisted reproduction [https://pubmed.ncbi.nlm.nih.gov/9988399/]
• 22. Risk factors for ectopic pregnancy in assisted reproduction [https://www.sciencedirect.com/science/article/pii/S0015028298004415]
• 23. associated with Risk factors pelvic inflammatory disease [https://pubmed.ncbi.nlm.nih.gov/16901918/]
• 24. The Efficacy and Success Rate of Methotrexate in ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC9363683/]
• 25. Endometrial Polyps and Subfertility - PMC [https://pmc.ncbi.nlm.nih.gov/articles/PMC5306103/]
• 26. Methotrexate vs. Surgery in the Management of Ectopic ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12210088/]
• 27. Medical Management of ectopic pregnancy with Methotrexate [https://ectopic.org.uk/treating-an-ectopic-pregnancy/medical-management-with-methotrexate]
• 28. Methotrexate fixed dosing protocol for ambulatory ... [https://pubmed.ncbi.nlm.nih.gov/39815149/]
• 29. Risk factors for methotrexate treatment failure in tubal ectopic ... [https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-024-07122-6]
• 30. Predictors of Methotrexate Success and Fertility Outcomes in Tubal ... [https://pubmed.ncbi.nlm.nih.gov/40572746/]
• 31. Twin tubal and interstitial ectopic pregnancies managed by multidose... [https://www.ijcriog.com/archive/article-full-text/100199Z08JL2025]
• 32. The clinical efficacy and impact on fertility function of laparoscopic surgery versus methotrexate for treatment of tubal pregnancy: a meta-analysis | BioMedical Engineering OnLine | Full Text [https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/s12938-025-01437-x]
• 33. Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: a randomized trial - PubMed [https://pubmed.ncbi.nlm.nih.gov/19961341/]
• 34. A randomised trial comparing single dose systemic methotrexate and laparoscopic surgery for the treatment of unruptured tubal pregnancy - PubMed [https://pubmed.ncbi.nlm.nih.gov/11236120/]
• 35. One versus two doses of methotrexate for the treatment ... [https://pubmed.ncbi.nlm.nih.gov/41255354/]
• 36. The efficacy of single-incision laparoscopic surgery versus ... [https://tjoddergisi.org/articles/the-efficacy-of-single-incision-laparoscopic-surgery-versus-conventional-laparoscopic-surgery-in-the-surgical-management-of-ectopic-pregnancy-a-systematic-review-and-meta-analysis/tjod.galenos.2025.02761]
• 37. The Effectiveness of Methotrexate in Hemodynamically ... [https://www.scientificarchives.com/abstract/the-effectiveness-of-methotrexate-in-hemodynamically-stable-women-with-tubal-ectopic-pregnancy-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials]
• 38. Clinical characteristics and influencing factors of adverse ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12502101/]
• 39. Treatment success with two doses of methotrexate vs ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC9378401/]
• 40. Review Multiple-dose and double-dose versus single ... [https://www.sciencedirect.com/science/article/abs/pii/S1472648317300044]
• 41. Predictors of treatment failure of tubal pregnancy with ... [https://pubmed.ncbi.nlm.nih.gov/39773144/]
• 42. Therapeutic effect of laparoscopic salpingotomy vs. ... [https://www.frontiersin.org/journals/surgery/articles/10.3389/fsurg.2022.997490/full]
• 43. Salpingostomy and Salpingectomy: Overview, Surgical ... [https://emedicine.medscape.com/article/1848581-overview]
• 44. Salpingectomy: Purpose, Procedure, Risks & Recovery [https://my.clevelandclinic.org/health/treatments/21879-salpingectomy]
• 45. Salpingectomy [https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/salpingectomy]
• 46. Ectopic Pregnancy: Diagnosis and Management [https://www.aafp.org/pubs/afp/issues/2020/0515/p599.html]
• 47. Ectopic Pregnancy Treatment: Saving a Tubal Pregnancy [https://www.ccrmivf.com/blog/non-surgical-treatment-for-ectopic-pregnancy/]
• 48. Novel ultrasound classification of tubal ectopic pregnancy [https://pmc.ncbi.nlm.nih.gov/articles/PMC12443668/]
• 49. Interventions for tubal ectopic pregnancy - PMC [https://pmc.ncbi.nlm.nih.gov/articles/PMC7043290/]
• 50. Overview and guidelines of off-label use of methotrexate in ... [https://www.sciencedirect.com/science/article/abs/pii/S0301211516308168]
• 51. Predictors for the efficacy of methotrexate and mifepristone ... [https://www.sciencedirect.com/science/article/abs/pii/S2468784725001199]
• 52. Efficacy of methotrexate therapy in patients with tubal pregnancy and a serum human chorionic gonadotropin level above 10,000 IU/L - PubMed [https://pubmed.ncbi.nlm.nih.gov/24693496/]
• 53. A new scoring system to predict the success of single-dose ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12534065/]
• 54. Methotrexate vs. Salpingostomy for Ectopic Pregnancy | AAFP [https://www.aafp.org/pubs/afp/issues/1999/0315/p1651a.html]
• 55. Ectopic Pregnancy Treatment & Management [https://emedicine.medscape.com/article/2041923-treatment]
• 56. Risk factors for methotrexate treatment failure in tubal ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC11686986/]
• 57. A risk prediction model for medical treatment failure in tubal ... [https://www.sciencedirect.com/science/article/abs/pii/S0301211518301866]
• 58. Methotrexate treatment in progressive tubal ectopic ... [https://www.sciencedirect.com/science/article/pii/S1607551X16300705]
• 59. The Efficacy of Methotrexate Administration in ... [https://www.jogcr.com/article_697226.html]
• 60. Factors Predicting Persistent Ectopic Pregnancy After ... [https://pubmed.ncbi.nlm.nih.gov/30312675/]
• 61. Risk factors for methotrexate treatment failure in tubal ... [https://pubmed.ncbi.nlm.nih.gov/39736575/]
• 62. [Outcome and relevant factors of tubal pregnancy treated ... [https://pubmed.ncbi.nlm.nih.gov/20420775/]
• 63. Methotrexate - StatPearls - NCBI Bookshelf - NIH [https://www.ncbi.nlm.nih.gov/books/NBK556114/]
• 64. Laparoscopic Surgery: The Future of Surgical Precision [https://southlakeobgyn.net/2025/05/12/laparoscopic-surgery/]
• 65. Adverse drug reactions related to methotrexate: a real- ... [https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1586361/full]
• 66. Methotrexate (oral route) - Side effects & dosage [https://www.mayoclinic.org/drugs-supplements/methotrexate-oral-route/description/drg-20084837]
• 67. A Systematic Review and Meta-Analysis of Randomized ... [https://www.scientificarchives.com/article/the-effectiveness-of-methotrexate-in-hemodynamically-stable-women-with-tubal-ectopic-pregnancy-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials]
• 68. Trophoblastic peritoneal implants after laparoscopic ... [https://www.sciencedirect.com/science/article/abs/pii/S0301211500003857]
• 69. Treatment of persistent trophoblastic tissue after ... [https://pubmed.ncbi.nlm.nih.gov/3005053/]
• 70. Efficacy and safety of laparoscopy versus local injection ... [https://www.sciencedirect.com/science/article/pii/S2590161319300675]
• 71. The effect of laparoscopic and abdominal surgery on ... [https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1400970/full]
• 72. Systemic methotrexate therapy versus laparoscopic ... [https://www.sciencedirect.com/science/article/pii/S001502829800212X]
• 73. Pregnancy outcomes in patients with tubal infertility following ... [https://apm.amegroups.org/article/view/60643/html]
• 74. Prevention of Post-Operative Adhesions - PubMed Central - NIH [https://pmc.ncbi.nlm.nih.gov/articles/PMC8301806/]
• 75. Postoperative adhesions in gynecologic surgery [https://www.asrm.org/practice-guidance/practice-committee-documents/postoperative-adhesions-in-gynecologic-surgery-a-committee-opinion-2019/]
• 76. Adhesion Prevention during Laparoscopic Surgery [https://www.laparoscopyhospital.com/news/preview.php?id=284&p=2&search=]
• 77. Evaluation of Predictive Factors for Success of Single-Dose ... [https://www.sciencedirect.com/science/article/abs/pii/S0736467925003166]
• 78. Adhesion Prevention Options in Colorectal/General Surgery [https://advancedsurgery.baxter.com/adhesion-prevention-colorectal-general]
• 79. Prevention strategies of postoperative adhesion in soft ... [https://www.sciencedirect.com/science/article/pii/S2452199X23000713]
• 80. A Personalized Approach to Adhesion Prevention in Single ... [https://www.mdpi.com/2075-4426/15/2/68]
• 81. Impact of unilateral and bilateral salpingectomy on ovarian ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12477989/]
• 82. A randomised trial comparing single dose systemic ... [https://www.sciencedirect.com/science/article/abs/pii/S0306545600000383]
• 83. Role of tubal surgery in the era of assisted reproductive ... [https://www.asrm.org/practice-guidance/practice-committee-documents/role-of-tubal-surgery-in-the-era-of-assisted-reproductive-technology-a-committee-opinion-2021/]
• 84. Pregnancy outcomes following fluoroscopy-guided tubal ... [https://pubmed.ncbi.nlm.nih.gov/40890272/]
• 85. Spontaneous pregnancy rates in infertile women after ... [https://www.sciencedirect.com/science/article/abs/pii/S0301211522000768]
• 86. Novel ultrasound classification of tubal ectopic pregnancy [https://insightsimaging.springeropen.com/articles/10.1186/s13244-025-02079-2]
• 87. Nanotechnology may better identify, treat ectopic pregnancy [https://news.ohsu.edu/2022/11/21/nanotechnology-may-better-identify-treat-ectopic-pregnancy]
• 88. Pregnancy outcomes following medical vs surgical ... [https://www.sciencedirect.com/science/article/pii/S0002937825004685]
• 89. Pregnancy outcomes following medical vs surgical ... [https://pubmed.ncbi.nlm.nih.gov/40645471/]
• 90. Surgical treatment of fallopian tubal pregnancy and interstitial ... [https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-024-06943-9]
• 91. Reproductive outcome after laparoscopic salpingectomy ... [https://pubmed.ncbi.nlm.nih.gov/2140989/]
• 92. The effect of surgical treatment of tubal pregnancy on ... [https://www.nature.com/articles/s41598-025-88519-x]
• 93. Recurrent Tubal Ectopic Pregnancy Management and the ... [https://www.sciencedirect.com/science/article/abs/pii/S1553465020311729]
• 94. 1260 Medical Treatment Success of Recurrent Ectopic ... [https://www.sciencedirect.com/science/article/abs/pii/S1553465019308192]
• 95. Ectopic pregnancy comparison of different treatments - PMC [https://pmc.ncbi.nlm.nih.gov/articles/PMC3279172/]
• 96. Methotrexate in the Management of Ectopic Pregnancy [https://www.auctoresonline.org/article/methotrexate-in-the-management-of-ectopic-pregnancy-a-comparative-review-of-single-dose-versus-multi-dose-protocols]
• 97. Severe hematologic toxicity after low-dose methotrexate in ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC12528151/]
• 98. 13003 The Efficacy of Single-Incision Laparoscopic ... [https://www.sciencedirect.com/science/article/abs/pii/S155346502500679X]
• 99. Economic evaluation of diagnosing and excluding ectopic ... [https://pmc.ncbi.nlm.nih.gov/articles/PMC2990466/]
• 100. Predictors and clinical features of methotrexate (MTX) therapy ... [https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-020-03350-8]
• 101. Methotrexate treatment of ectopic pregnancy: 100 cases ... [https://www.sciencedirect.com/science/article/pii/S0015028216558580]
• 102. Pregnancy outcome of laparoscopic tubal reanastomosis [https://pmc.ncbi.nlm.nih.gov/articles/PMC5536424/]