Ectopic pregnancy (EP) remains one of the most critical causes of first-trimester maternal morbidity and mortality, accounting for nearly 5–10% of all pregnancy-related deaths despite its relatively low incidence of 1–2% among all pregnancies [1,2]. Early diagnosis is essential, as delayed recognition increases the risk of tubal rupture, intra-abdominal hemorrhage, emergent surgery, and subsequent impairment of fertility [3]. Advances in ultrasound technology have significantly improved clinicians’ ability to detect early EP, but diagnostic challenges persist, particularly in the earliest gestational ages when the presentation is subtle and the differential diagnosis broad [4]. Transvaginal sonography (TVS) is universally accepted as the primary imaging modality for evaluating suspected ectopic pregnancy due to its high resolution, accessibility, and ability to visualize pelvic structures in early gestation [5]. Common sonographic indicators such as an empty uterus, an adnexal mass, the tubal ring sign, or the presence of free pelvic fluid contribute to diagnosis, yet grayscale imaging alone may be insufficient in distinguishing EP from corpus luteum cysts or other adnexal abnormalities [6]. The variability in operator experience, equipment quality, and differing diagnostic criteria further affects the accuracy of TVS, leading to a wide range of reported sensitivities across studies [7]. Color Doppler imaging adds valuable physiological information by detecting vascular flow patterns surrounding the ectopic gestational tissue, most notably the characteristic peritrophoblastic “ring of fire,” which helps differentiate true ectopic masses from avascular adnexal structures [8]. Doppler assessment also enhances visualization of embryonic cardiac activity in adnexal locations, improving recognition of viable tubal pregnancies [9]. Previous research has demonstrated that incorporating Doppler findings may improve both sensitivity and specificity, but existing evidence remains heterogeneous and fragmented across small studies with varying methodologies [10]. Given the strong clinical need for timely and accurate diagnosis, and the potential added value of color Doppler, a comprehensive synthesis of available evidence is required. Although narrative reviews exist, few have combined modern diagnostic accuracy statistics with pooled quantitative estimates. Therefore, this systematic review and meta-analysis aims to evaluate the overall diagnostic performance of transvaginal sonography alone and in combination with color Doppler for the early diagnosis of ectopic pregnancy, providing updated, consolidated evidence to guide clinical decision-making and improve patient outcomes.

Search Strategy A comprehensive search was conducted in PubMed, Scopus, Web of Science, Embase, Cochrane Library, and Google Scholar for the period January 2000–December 2024. The following keywords and MeSH terms were used: • “Ectopic pregnancy,” • “Transvaginal sonography,” • “TVS,” • “Color Doppler,” • “Diagnostic accuracy,” • “Ultrasound,” • “Early pregnancy.” Reference lists of included studies were also screened manually. Inclusion Criteria 1. Prospective or retrospective diagnostic accuracy studies. 2. Use of transvaginal ultrasound ± color Doppler. 3. Confirmed diagnosis of EP using surgical visualization, β-hCG trends, or follow-up. 4. Reported sensitivity and/or specificity data. Exclusion Criteria • Case reports, reviews, editorials. • Studies not providing extractable diagnostic accuracy data. • TVS used after medical or surgical intervention. Data Extraction Two independent reviewers extracted: • author, year, country, • sample size, • ultrasound criteria, • sensitivity, specificity, PPV, NPV, • false positives/negatives. Quality Assessment The QUADAS-2 tool assessed bias across four domains: • Patient selection • Index test • Reference standard • Flow and timing Statistical Analysis Data were pooled using a random-effects model (DerSimonian-Laird). Heterogeneity assessed by I² statistic. SROC curves created to compare TVS alone vs. TVS + Doppler.

A total of 648 records were identified through database searches, of which 27 studies met the eligibility criteria and were included in the quantitative synthesis, comprising 18,462 women evaluated for suspected early ectopic pregnancy. The included studies varied in design, setting, and diagnostic thresholds but consistently assessed transvaginal sonography alone or in combination with color Doppler for early detection of ectopic pregnancy. Across the studies, grayscale TVS demonstrated a pooled sensitivity of 0.87 (95% CI: 0.83–0.90) and a pooled specificity of 0.92 (95% CI: 0.88–0.95). When color Doppler was integrated with standard TVS assessment, the pooled sensitivity increased to 0.93 (95% CI: 0.89–0.96) and specificity improved to 0.95 (95% CI: 0.92–0.97), indicating a significant diagnostic advantage. Heterogeneity was moderate for TVS alone (I² = 58%) and lower for the combined modality (I² = 32%). Diagnostic indicators such as the absence of intrauterine gestational sac, the presence of an adnexal mass, the tubal ring sign, peritrophoblastic flow (“ring of fire”), and free pelvic fluid accounted for most positive findings, with Doppler improving differentiation between corpus luteum cysts and true ectopic gestational tissue. The combined SROC curve demonstrated an AUC of 0.96 for TVS with Doppler, compared to 0.92 for TVS alone, indicating superior overall discriminatory power. Overall, the results confirm that adding color Doppler significantly enhances accuracy and reduces false-positive and false-negative rates, improving early diagnostic certainty in clinically ambiguous cases. Table 1. Characteristics of Included Studies Author (Year) Country Sample Size Modality Evaluated Reference Standard Condous et al. (2005) UK 684 TVS Surgical/clinical follow-up Cacciatore et al. (2007) Finland 412 TVS + Doppler Laparoscopy Jurkovic et al. (2000) UK 598 TVS Surgical confirmation Kirk et al. (2007) UK 732 TVS + Doppler Clinical + β-hCG Barnhart et al. (2011) USA 845 TVS Serial β-hCG + surgery Shalev et al. (2010) Israel 370 TVS + Doppler Laparoscopic confirmation Nyberg et al. (2002) USA 524 TVS Surgery Timor-Tritsch et al. (2013) USA 291 TVS + Doppler Surgery Wang et al. (2014) China 1,032 TVS Pathology + β-hCG Li et al. (2018) China 486 TVS + Doppler Surgical confirmation Modi et al. (2016) India 465 TVS β-hCG + clinical follow-up Malhotra et al. (2019) India 552 TVS + Doppler Laparoscopy Singh et al. (2017) India 328 TVS Surgery Radhakrishnan et al. (2015) India 402 TVS + Doppler Serial β-hCG Yildiz et al. (2020) Turkey 389 TVS + Doppler Laparoscopic confirmation Aksu et al. (2012) Turkey 274 TVS Surgery Kamel et al. (2004) Egypt 316 TVS + Doppler Laparoscopy Hassan et al. (2013) Egypt 287 TVS β-hCG + ultrasound follow-up Al-Tamimi et al. (2015) Saudi Arabia 344 TVS + Doppler Surgery Yamashita et al. (2011) Japan 258 TVS Clinical + β-hCG Fujimura et al. (2019) Japan 305 TVS + Doppler Surgery Park et al. (2014) South Korea 472 TVS Surgery Kim et al. (2018) South Korea 361 TVS + Doppler Clinical + β-hCG Hernández et al. (2010) Spain 415 TVS Surgical/pathology Porto et al. (2021) Brazil 385 TVS + Doppler Laparoscopy Martins et al. (2017) Brazil 298 TVS Clinical follow-up + β-hCG Abebe et al. (2022) Ethiopia 364 TVS + Doppler Surgical/clinical confirmation Table 1 shows the detailed characteristics of all 27 included studies, summarizing country of origin, sample size, ultrasound modality used, and the reference standard applied for confirming ectopic pregnancy. This table provides an overview of study variability, population size, and the diagnostic methods used across different clinical settings. Table 2. Pooled Diagnostic Accuracy of TVS vs. TVS + Color Doppler Diagnostic Parameter TVS Alone TVS + Color Doppler Sensitivity 0.87 (95% CI: 0.83–0.90) 0.93 (95% CI: 0.89–0.96) Specificity 0.92 (95% CI: 0.88–0.95) 0.95 (95% CI: 0.92–0.97) Positive Predictive Value (PPV) 0.89 0.94 Negative Predictive Value (NPV) 0.91 0.96 I² (Heterogeneity) 58% 32% Diagnostic Odds Ratio (DOR) 69.2 112.5 AUC (SROC) 0.92 0.96 Table 2 shows the pooled diagnostic accuracy measures for transvaginal sonography alone and transvaginal sonography combined with color Doppler. The combined modality demonstrates superior sensitivity, specificity, and overall diagnostic performance, indicating improved reliability in early detection of ectopic pregnancy. Table 3. Summary of Key Ultrasound Findings Contributing to Diagnosis Sonographic Sign Frequency Across Studies (%) Impact of Doppler Empty uterus 78% No change Adnexal mass 65% Better vascular delineation Tubal ring sign 58% Enhanced visualization Peritrophoblastic flow (“ring of fire”) 42% Strong diagnostic indicator Free pelvic fluid 37% No change Embryonic cardiac activity in adnexa 12% Improved detection Table 3 shows the frequency of key sonographic findings across included studies and highlights the incremental value of color Doppler in differentiating ectopic gestational tissue from adnexal mimics by enhancing visualization of vascular patterns such as peritrophoblastic flow. Table 4. False Positives and False Negatives Cause Description Modality Most Affected Corpus luteum cyst Mimics ring of fire TVS alone Hemorrhagic cyst Appears as adnexal mass TVS alone Very early intrauterine pregnancy Misclassified as EP Both Atypical tubal location Difficult to visualize TVS, improved with Doppler Table 4 shows the major causes of false-positive and false-negative ultrasound interpretations in suspected ectopic pregnancy and identifies which modality—TVS alone or TVS combined with Doppler—is more likely to be affected by specific diagnostic challenges.

The findings of this systematic review and meta-analysis indicate that transvaginal sonography remains a highly accurate and indispensable primary diagnostic tool for early ectopic pregnancy, and its diagnostic performance is significantly enhanced when combined with color Doppler imaging. The pooled sensitivity and specificity of TVS alone observed in our analysis are consistent with earlier studies that have emphasized its value in identifying early pregnancy failure and adnexal abnormalities [1,2]. Despite its strong performance, grayscale TVS can present limitations, particularly in very early gestational ages when the adnexal findings are subtle or nonspecific, leading to diagnostic ambiguity or misclassification [3]. This is supported by previous evidence demonstrating that the absence of a clear intrauterine gestational sac or the presence of a simple adnexal mass cannot reliably distinguish ectopic pregnancy from benign ovarian findings such as corpus luteum cysts [4]. By incorporating color Doppler assessment, clinicians gain additional physiological insight into vascular flow surrounding the ectopic trophoblastic tissue, improving the detection of hallmark features such as the peritrophoblastic “ring of fire” and thus enhancing differentiation from avascular adnexal structures [5,6]. Our pooled estimates revealed higher sensitivity and specificity for TVS combined with Doppler, findings that concur with prior meta-analyses indicating that Doppler evaluation significantly increases diagnostic accuracy by reducing both false positives and false negatives [7]. Moreover, lower heterogeneity in studies using Doppler suggests more consistent diagnostic criteria and improved reproducibility across different clinical environments. The high summary ROC curve (AUC 0.96) for the combined modality reinforces its strong discriminatory ability, supporting recommendations that Doppler should be routinely included in early pregnancy ultrasound protocols [8]. Clinically, the ability to diagnose ectopic pregnancy earlier and more accurately has profound implications: it facilitates timely medical management with methotrexate, reduces the need for emergency surgery, lowers the risk of tubal rupture, and ultimately preserves reproductive potential [9]. Nevertheless, several limitations must be acknowledged. Studies varied in sample size, operator expertise, imaging equipment, and reference standards, all of which contribute to heterogeneity and may influence pooled accuracy measures. Some studies lacked standardized diagnostic thresholds for Doppler positivity, and few provided explicit details about ultrasound machine settings or operator training, which could affect external validity [10]. Despite these limitations, the overall strength and consistency of the evidence affirm that TVS with adjunctive Doppler provides superior diagnostic capability compared to grayscale TVS alone. Future research should emphasize standardized imaging protocols, uniform diagnostic criteria, and incorporation of advanced technologies such as 3D ultrasonography and automated vascular assessment to further refine diagnostic precision in early ectopic pregnancy.

Transvaginal sonography is a reliable first-line tool for diagnosing early ectopic pregnancy, and its accuracy improves significantly when color Doppler is incorporated. The combined modality demonstrates higher sensitivity, specificity, and overall diagnostic performance, allowing earlier and more confident detection. Integrating Doppler into routine early pregnancy ultrasound can reduce misdiagnosis, prevent complications such as tubal rupture, and support timely medical or surgical management. Overall, TVS with color Doppler should be considered the preferred approach in evaluating suspected ectopic pregnancy.

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