Patients
We enrolled women diagnosed with RPOC at Nagoya University Hospital, Nagoya, Japan, between February 2017 and May 2020. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Hospital (#2016-0448). All patients included in this study provided written informed consent.
RPOC was diagnosed using transvaginal ultrasonography as persistent intrauterine tissue after spontaneous or induced abortion, or delivery. The diagnosis was confirmed with other diagnostic imaging techniques, such as three-dimensional computed tomography, when equivocal. Massive hemorrhage was defined as the presence of active bleeding and at least one of the following: loss of consciousness, shock index greater than 1, or serum hemoglobin (Hb) level < 10 g/dL. Women included in this study were recorded of massive hemorrhage which occurred after their first visit until the RPOC resolution. Women who presented with massive hemorrhage upon their first visit to our hospital were excluded, as well as women with a history of intrauterine diseases (endometrial polyps and submucous myomas).
Endpoints
The primary endpoint was to validate the usefulness of PDCS as a predictive factor for massive hemorrhage in women with RPOC. The secondary endpoint was the identification and evaluation of other potential predictive factors.
Protocol
Women with RPOC underwent expectant management unless they experienced massive hemorrhage. Expectant management is defined as a careful “watch” approach. Massive hemorrhage was treated using UAE and/or HR. UAE prior to HR was performed because HR would be limited by massive bleeding, which creates poor visual field and increases the risk of bleeding from the hypervascular uterus. HR was also performed for non-bleeding, but persistent residual tumors measuring ≥ 2 cm. Complete resolution was defined as no evidence of RPOC on transvaginal ultrasound and complete regression (< 5 IU/mL) of serum β-human chorionic gonadotropin (βhCG). At the first visit, women were interviewed for their past pregnancy history and details of the preceding pregnancy responsible for RPOC. The latter included the method for achieving pregnancy, outcome of the pregnancy, trimester at delivery or abortion, and whether intrauterine interventions, such as dilatation and curettage and/or manual removal of the placenta, were required. The clinical findings at the first visit were also obtained. PDCS and maximum RPOC diameter by transvaginal ultrasound, serum βhCG level, and Hb level were recorded. The length of follow-up was calculated as the time from first visit to RPOC resolution. The time from delivery to massive hemorrhage, complete regression (< 5 IU/mL) of serum βhCG level, and RPOC resolution were also calculated.
Sonography
RPOC was diagnosed based on the presence of a measurable focus of hyperechoic material within the endometrial cavity on two-dimensional gray-scale transvaginal ultrasonography. A subjective qualitative assessment of flow within the RPOC was performed. The transvaginal ultrasound settings were adjusted to allow maximal sensitivity to blood flow. The ultrasonic frequency was set to 8.0 MHz, and the power Doppler gain was reduced until the artifacts disappeared.
The use of subjective semi-quantitative assessment of flow to describe vascular features has been suggested in previous reports17,18,20,21. In this study, PDCS was used to describe the amount of blood flow to the residual tissue. PDCS ranges from a score of 1 to 4, with a score of 1, 2, 3, and 4 indicating no detectable blood flow, minimal flow, moderate flow, and highly vascular flow, respectively17,18,21. The PDCS refers only to the color Doppler image and not the Doppler shift spectrum.
Statistical analysis
Data were compared between women who did not experience massive hemorrhage and those who did (no hemorrhage group vs. hemorrhage group). Continuous variables are presented as medians with minimum and maximum ranges and analyzed using the Mann–Whitney U test. Categorical variables are presented as frequencies with proportions and analyzed using the Fisher’s exact test. For a preliminary analysis to determine the optimal cutoff for each predictive factor for massive hemorrhage, receiver operating characteristic (ROC) curves and area under the curve (AUC) were calculated. For the main analysis, we performed logistic regression analysis to estimate the odds ratio (OR) with a 95% confidence interval (CI) of the predictive factors for massive hemorrhage. Because of the small number of cases, the logistic regression model was corrected using Firth’s method, and four models were created for multivariate analysis. Furthermore, a decision tree analysis was performed to assess predictive factors from multiple perspectives. In all analyses, a P value < 0.05 was considered statistically significant. Microsoft Excel, IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, USA) and R 3.6.1 for Mac were used to generate graphs and perform statistical analyses.
