Predictors of Tubal Rupture in Ectopic Pregnancy: A Retrospective Analysis of Clinical and Laboratory Factors

Summary

This retrospective study analyzed 150 patients with tubal pregnancy to identify predictors of tubal rupture. A history of pelvic inflammatory disease (PID), serum human chorionic gonadotropin (β-hCG) > 3,000 IU/L, neutrophil-to-lymphocyte ratio (NLR) ≥ 4, and ultrasonographic detection of a yolk sac were independent risk factors.

Abstract

Tubal rupture is a major cause of intra-abdominal hemorrhage and maternal mortality in early pregnancy. Early identification of high-risk patients is clinically important; however, standardized predictive tools integrating multidimensional indicators remain limited, particularly in Chinese populations. The aim of this study was to investigate clinical, laboratory, and ultrasound predictors of tubal rupture in ectopic pregnancy and provide evidence for early risk assessment. This retrospective study included 150 patients with tubal pregnancy treated surgically or medically in our hospital between January 2023 and December 2025. Based on intraoperative findings or ultrasound diagnosis, patients were classified into a ruptured group (n = 51) and an unruptured group (n = 99). Clinical characteristics, laboratory indicators [serum human chorionic gonadotropin (β-hCG), progesterone, hemoglobin, and neutrophil-to-lymphocyte ratio (NLR)], and ultrasound features were analyzed. Univariate and multivariable logistic regression analyses were performed to identify independent risk factors for tubal rupture. Patients in the ruptured group had significantly higher rates of pelvic inflammatory disease (PID) history and moderate-to-severe abdominal pain (P < 0.05). Serum β-hCG and NLR levels were significantly elevated in the ruptured group (P < 0.05). Ultrasound findings showed a larger adnexal mass diameter, greater pelvic fluid depth, and a higher proportion of fetal cardiac activity in ruptured cases (P < 0.05). Multivariable logistic regression identified PID history (odds ratio [OR] = 2.983, 95% confidence interval [CI]: 1.306–6.811, P = 0.009), serum β-hCG > 3,000 IU/L (OR = 4.119, 95% CI: 1.661–10.214, P = 0.002), NLR ≥ 4 (OR = 3.597, 95% CI: 1.613–8.023, P = 0.002), and ultrasonographic detection of a yolk sac (OR = 2.506, 95% CI: 1.015–6.190, P = 0.046) as independent risk factors for tubal rupture. These factors may aid early clinical risk stratification and decision-making.

Introduction

Ectopic pregnancy refers to the implantation and development of a fertilized ovum outside the uterine cavity, with approximately 95% occurring in the fallopian tubes¹. Ectopic pregnancy is a common cause of acute abdominal emergencies in obstetrics and gynecology, with an incidence of approximately 1%–2% among women of reproductive age². Despite the widespread use of high-resolution transvaginal ultrasound (TVUS) and dynamic monitoring of serum human chorionic gonadotropin (β-hCG) in recent years, which have enabled early diagnosis and conservative treatment (such as methotrexate or expectant treatment) for most ectopic pregnancies, tubal rupture remains the most serious and fatal complication of ectopic pregnancy^3,4,5.

When the fallopian tube wall ruptures due to the invasion of trophoblasts and the growth of embryos, it can lead to severe intra-abdominal bleeding, hemorrhagic shock, and even maternal death. According to statistics, deaths caused by ectopic pregnancy rupture account for 6% to 13% of all maternal deaths in early pregnancy⁶. Therefore, in the clinical management of ectopic pregnancy, accurately and quickly identifying patients at high risk of rupture before rupture occurs is a major challenge faced by obstetrics and gynecology emergency departments. Accurate prediction can help physicians determine whether emergency surgical intervention is needed while avoiding unnecessary overtreatment of low-risk patients and preserving fertility⁷. Previous studies have shown that the occurrence of ectopic pregnancy rupture is a complex pathophysiological process involving multiple factors, including the anatomical characteristics of the fertilized egg implantation site, the invasive ability of trophoblasts, the local microenvironment of the patient's body, and the systemic immune-inflammatory response^8,9.

The traditional risk factors for rupture mainly include prolonged amenorrhea, a history of ectopic pregnancy, high serum β-hCG levels, and ultrasound findings of large adnexal masses or the presence of fetal poles and heartbeats. However, the sensitivity and specificity of a single indicator in predicting tubal rupture are often limited. At present, many studies have examined the predictive factors for tubal rupture, but the results are not entirely consistent. Some studies suggest that serum β-hCG levels are associated with the risk of rupture¹⁰, while others have not found such an association. In addition, clinical and ultrasound features such as abdominal pain, pelvic fluid accumulation, and mass size are considered potential predictive factors¹¹. In recent years, some inflammatory indicators, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio, have also been found to be associated with tubal rupture¹².

In recent years, the use of systemic inflammatory response indicators to predict acute abdominal conditions and obstetric complications has attracted widespread attention. Among them, the NLR, as a nonspecific systemic immune-inflammatory marker, has been confirmed by multiple studies to be closely associated with the pathological progression of ectopic pregnancy due to its ease of acquisition, low cost, and ability to sensitively reflect the body's inflammatory status¹³. The invasion of trophoblasts into the muscular layer of the fallopian tube can cause local inflammatory reactions and tissue necrosis. Cytokine release from this local damage may increase circulating neutrophils and reduce lymphocytes. However, there are still few large-scale and systematic studies on the comprehensive value of laboratory indicators such as NLR combined with traditional ultrasound and clinical features in predicting ectopic pregnancy rupture, particularly in Chinese populations, and the existing research conclusions are still controversial^14,15,16.

Although several studies have investigated risk factors for tubal rupture, many were limited by small sample sizes, the evaluation of a single biomarker, or limited evidence from Chinese populations. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker that has not been systematically evaluated alongside clinical symptoms and ultrasound parameters in Chinese cohorts. Accordingly, this study retrospectively analyzed clinical, laboratory, and ultrasound data from 150 patients with tubal pregnancy treated at our hospital between January 2023 and December 2025. The aim was to identify factors associated with tubal rupture using multivariable logistic regression and to provide evidence to support early risk assessment and clinical decision-making.

Protocol

The study protocol was approved by the Ethics Committee of Jinhua Municipal Central Hospital (2026, Ethics approval No.277). Because of the retrospective study design, the requirement for informed consent was waived. Data collection and retrospective analysis were conducted in accordance with the Declaration of Helsinki¹⁷. The study used deidentified medical records and involved no direct contact with participants.

Research subjects
Patient identification and screening
This retrospective study reviewed the hospital electronic medical record system for records coded as tubal pregnancy (International Classification of Diseases, 10th Revision [ICD-10] code O00.1) from January 2023 to December 2025. The initial search identified 187 potentially eligible records. Two trained reviewers independently screened all records against the inclusion and exclusion criteria, and disagreements were resolved by a senior attending physician. In total, 150 patients met all criteria and were enrolled (Figure 1).

Classification into ruptured and unruptured groups
Patients were classified using direct intraoperative visualization as the primary reference standard for surgically treated cases. For surgically treated patients, rupture was defined as a visible full-thickness defect in the tubal wall with active bleeding or hemoperitoneum estimated at ≥500 mL that required hemostasis. An unruptured tube was defined as an intact tube without a wall defect, regardless of dilation or congestion. For patients initially managed conservatively, rupture was assigned only when ultrasound showed an ill-defined mass with a large volume of free fluid (>3 cm depth), hemodynamic instability (shock index ≥ 1.0), and subsequent emergency surgery. Patients were classified as unruptured when the mass remained intact without progressive fluid accumulation, and they underwent methotrexate or expectant management, followed by a decline in β-hCG to nonpregnant levels without surgery. When surgical and ultrasound findings conflicted, intraoperative findings took precedence. Two senior attending physicians adjudicated ambiguous cases.

Inclusion criteria
Patients were included if tubal pregnancy was confirmed by postoperative pathological examination or by a combination of clinical findings, serum β-hCG results, and transvaginal ultrasonography (TVUS). Complete clinical history and physical examination records at admission were required. Complete blood count, coagulation function, serum β-hCG, and progesterone measurements obtained within 24 h of admission were required. A gynecological transvaginal or transabdominal ultrasound examination performed within 24 h of admission was required.

For conservatively managed patients, tubal pregnancy was confirmed by all three of the following criteria: serum β-hCG above the institutional discriminatory zone (>1,500 IU/L) with a suboptimal increase (<66% at 48 h); TVUS showing an adnexal mass distinct from the ovary without an intrauterine gestational sac; and clinical symptoms consistent with ectopic pregnancy. Patients with β-hCG < 1,500 IU/L were diagnosed using serial β-hCG measurements showing abnormal kinetics together with ultrasound findings suggestive of ectopic pregnancy, including an adnexal mass, an empty uterus, and/or free fluid.

Exclusion criteria
Patients with cervical, ovarian, abdominal, rudimentary horn, heterotopic, or other nontubal ectopic pregnancies were excluded. Patients were excluded if they had concurrent conditions that could affect inflammatory markers or bleeding risk, including hepatic dysfunction (alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal), renal dysfunction (creatinine >2.0 mg/dL), New York Heart Association class III or IV heart failure, active malignancy, or a hematological disorder (hemoglobin <7 g/dL or platelet count <50 × 10⁹/L). Patients with acute or chronic infectious diseases, such as pneumonia or acute gastroenteritis, or autoimmune diseases that could affect the peripheral white blood cell count were excluded. Patients who had received immunosuppressants, glucocorticoids, or a blood transfusion within 2 weeks before admission were excluded. Patients missing any key variable required for analysis, including the admission visual analog scale score, serum β-hCG, complete blood count measures (white blood cell count, absolute neutrophil count, and absolute lymphocyte count), or ultrasound measurements (adnexal mass diameter and pelvic fluid depth), were excluded before group allocation.

Data collection and indicator definitions
Demographic characteristics and medical history
The recorded variables were age, body mass index (BMI), duration of amenorrhea, parity, history of pelvic inflammatory disease (PID), history of ectopic pregnancy, history of pelvic or abdominal surgery, use of assisted reproductive technology for conception, and smoking. PID history was defined as a documented clinical diagnosis in the medical record rather than patient self-report alone. Smoking was defined as any tobacco use within 3 months before admission, regardless of daily quantity.

Clinical manifestations
Abdominal pain severity was assessed using the visual analog scale (VAS)^18,19, with a score >5 indicating moderate-to-severe pain²⁰. The admitting nurse recorded the VAS score within 2 h of arrival using a 10 cm horizontal line, where 0 indicated no pain, and 10 indicated the worst imaginable pain. Vaginal bleeding was recorded as present or absent from the admission examination; present bleeding was defined as active bleeding observed during speculum examination or patient-reported vaginal blood loss within the preceding 24 h, including minimal spotting. The shock index (SI) was calculated as heart rate divided by systolic blood pressure using the first documented vital signs at admission. Because an SI ≥ 0.81 has been associated with rupture²¹, the number of patients with SI > 0.8 was recorded in each group.

Laboratory tests
Venous blood test results from the emergency visit or first admission were extracted. Peripheral venous blood samples were collected within 30 min of admission. Complete blood count parameters were measured in dipotassium ethylenediaminetetraacetate (K₂-EDTA) anticoagulated tubes using an automated hematology analyzer. Serum samples for β-hCG and progesterone analysis were obtained in separator tubes, kept at room temperature for 30 min to permit clot formation, and then centrifuged at 1500 × g for 10 min under ambient conditions. Serum β-hCG and progesterone were measured using an electrochemiluminescence immunoassay analyzer. Recorded variables included serum β-hCG, serum progesterone, hemoglobin (Hb), total white blood cell count (WBC), absolute neutrophil count (NEU), absolute lymphocyte count (LYM), and NLR, calculated as NEU/LYM. Daily calibration and three-level internal quality controls were performed with each batch for both analyzers. Total coefficients of variation were ≤4.2% for β-hCG and ≤5.1% for progesterone during the study period. The β-hCG assay measurement range was 0.100–10,000 IU/L; samples above 10,000 IU/L were automatically diluted and reassayed. Laboratory reference ranges were Hb 110–150 g/L, WBC 3.5–9.5 × 10⁹/L, NEU 1.8–6.3 × 10⁹/L, LYM 1.1–3.2 × 10⁹/L, β-hCG < 5 IU/L in nonpregnant patients, and progesterone 0.2–1.5 ng/mL in the follicular phase. Previous studies reported an increased risk of tubal rupture at serum β-hCG > 3,000 IU/L²² and NLR ≥ 4²³; therefore, these thresholds were recorded for both groups.

Serum β-hCG monitoring
Serum β-hCG was measured at admission in all patients with suspected ectopic pregnancy. For patients managed expectantly or with methotrexate, serial measurements were obtained on days 4 and 7 and then weekly until the concentration declined to <5 IU/L, according to the institutional protocol. A decline < 15% between days 4 and 7, or a plateau or increase, prompted reassessment and consideration of surgery. For patients who underwent immediate surgery, only the baseline β-hCG value was used in the analysis. All measurements were performed using the same electrochemiluminescence immunoassay analyzer with a range of 0.100–10,000 IU/L; samples above 10,000 IU/L were automatically diluted and reassayed.

Ultrasound imaging features
The first gynecological ultrasound report obtained at admission was reviewed. Recorded parameters were the maximum diameter of the adnexal mass, the depth of pelvic free fluid, the detection of a yolk sac, and the detection of a fetal pole with cardiac activity. The maximum diameter of the adnexal mass was recorded as the largest linear dimension among three orthogonal planes. Pelvic fluid depth was measured as the maximum anteroposterior diameter of an anechoic or echogenic fluid collection in the pouch of Douglas on a sagittal view. Yolk sac detection and fetal cardiac activity were recorded as binary variables. Fetal cardiac activity was defined as visible pulsation > 100 beats/min confirmed by motion mode or color Doppler. All images were stored in the picture archiving and communication system. A random 20% sample was remeasured offline by a second blinded reviewer; the intraclass correlation coefficient was >0.90.

Data extraction and quality control
Two trained reviewers independently extracted data using a standardized case report form and were blinded to the outcome group during extraction. The reviewers completed a 2 h training session covering form completion, variable definitions, and source-document navigation. Interreviewer agreement was assessed in a random 10% sample (κ ≥ 0.90 for all categorical variables). Discordant entries were resolved by review of the source records, with adjudication by a senior attending physician when disagreement persisted; fewer than 5% of variables required adjudication.

Statistical analysis
Distributional assumptions for continuous variables were evaluated with the Kolmogorov-Smirnov test. Variables showing a normal distribution were summarized as mean ± standard deviation and compared between groups with an independent-samples t-test. Variables that were not normally distributed were expressed as median (first quartile [Q1], third quartile [Q3]) and analyzed with the Mann-Whitney U test. Categorical variables were presented as n (%) and assessed using either the chi-square test or Fisher’s exact test, depending on cell frequencies. Potential predictors of tubal rupture were examined by univariate and multivariable logistic regression. Statistical significance was defined as a two-sided P value < 0.05.

Because patients with missing key variables were excluded according to the exclusion criteria, no imputation was needed (complete-case analysis). Candidate predictors with P < 0.05 in univariate analysis were entered into the multivariable logistic regression model. The variance inflation factor (VIF) was calculated to evaluate multicollinearity, and values below 5 were interpreted as indicating no meaningful collinearity among the predictors.

Results

Baseline characteristics
This study included 150 patients with tubal pregnancy, including 51 (34.0%) in the ruptured group and 99 (66.0%) in the unruptured group. As shown in Table 1, there were no statistically significant differences between groups in age, BMI, number of pregnancies, parity, duration of amenorrhea, history of ectopic pregnancy, history of pelvic or abdominal surgery, use of assisted reproductive technology, or smoking (P > 0.05). However, the proportion of patie...

Discussion

Multivariable analysis in this study showed that serum β-hCG > 3,000 IU/L is an independent risk factor for rupture of tubal pregnancy. β-hCG is secreted by embryonic syncytiotrophoblasts, and its serum concentration may reflect the proliferation activity and metabolic level of trophoblasts²⁴. In a normal intrauterine pregnancy, the endometrium undergoes sufficient decidualization reaction, forming physical and immune barriers to limit the excessive invasion of trophoblasts. However,...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Automated hematology analyzer	Sysmex Corporation, Kobe, Japan	XN-9000	Used for complete blood count measurements
Electrochemiluminescence immunoassay analyzer	Roche Diagnostics, Mannheim, Germany	Cobas e601	Used for serum β-hCG and progesterone measurements
K2-EDTA vacuum blood collection tube	Becton Dickinson, Franklin Lakes, NJ, USA	Vacutainer K2-EDTA	Used for complete blood count collection
Sample size calculation software	Heinrich Heine University, Düsseldorf, Germany	G*Power, version 3.1.9.7; RRID: SCR_013726	Used for sample size estimation
Serum separator tube	Becton Dickinson, Franklin Lakes, NJ, USA	Vacutainer SST	Used for serum β-hCG and progesterone collection
Statistical software	IBM Corp., Armonk, NY, USA	SPSS Statistics, version 25.0; RRID: SCR_002865	Used for statistical analyses
Ultrasound system	GE Healthcare, Milwaukee, WI, USA	Voluson E8	Equipped with RIC5-9-D transvaginal probe (5-9 MHz) and C1-5-D transabdominal convex probe (3.5-5 MHz)