Hydatidiform mole (HM) is a pregnancy-related condition predominantly affecting women of reproductive age, with potential for malignant progression (1). Global epidemiological patterns demonstrate marked geographical variation (2–5). Developed regions such as Europe and North America report comparatively low incidence rates of 1-3 cases per 1,000 pregnancies (or deliveries) (2–4), while historically, developing regions across Asia, Africa, and parts of South America have documented rates as high as 10 cases per 1,000 deliveries (5). However, emerging data suggest epidemiological convergence, with Asian incidence rates now comparable to Western countries (6). Specifically, recent reports from South Korea (1.1/1,000 pregnancies) (7) and Japan (1.02-2.70/1,000 live births) (8) reflect this epidemiological transition.

China’s HM epidemiology remains incompletely characterized, with only two nationwide studies conducted to date (9, 10). The initial 1979-1983 survey across 26 provinces, municipalities, and autonomous regions reported an incidence rate of 0.81/1,000 pregnancies (9), while a subsequent 1991–2000 hospital-based study across 7 provinces documented 2.50 cases/1,000 pregnancies (10). Since then, research on HM in China has primarily been regional and has shown disparities (11). In addition, China currently lacks a national GTD registry. Given the rapid demographic changes in China over the past few decades, the current incidence and temporal trends of HM remain largely unknown. Therefore, comprehensive characterization of HM demographics, risk factors, and outcomes is essential for optimal health resource allocation.

The preferred treatment for HM is evacuation, with most patients achieving spontaneous remission following the removal of molar tissue. However, there remains a risk of malignant progression to postmolar gestational trophoblastic neoplasia (pGTN) (1). HM can be classified into complete hydatidiform mole (CHM) and partial hydatidiform mole (PHM), which demonstrate significant differences in morphology, histopathology, cytogenetics, and risk of malignant progression (1, 12). The progression rates to pGTN are 15%-20% for CHM and 0.5%-5% for PHM, respectively (13, 14). Various clinical, genetic, and molecular factors have been identified as risk factors for pGTN. Well-studied risk factors include maternal age over 40 years, advanced gestational age, theca lutein cysts larger than 6 cm, uterine size exceeding gestational age, history of molar pregnancy, and pre-evacuation beta human chorionic gonadotropin (β-hCG) levels higher than 100,000 mIU/mL (15–19). Nevertheless, some controversies persist regarding these risk factors. From a genetic perspective, NLRP7 mutations have been implicated in increasing the risks of both HM recurrence and pGTN development (20).

Current standard monitoring strategies for patients with HM after evacuation involve routine follow-up, which mainly relies on clinical variables, including regular measurement of serum β-hCG levels and imaging examinations such as ultrasound (5, 21). While these methods are effective for early detection and timely treatment of pGTN, frequent follow-up visits and repeated blood sampling can reduce patient compliance and impose significant psychological and economic burdens. Recent studies have shown that patients with GTD generally experience a lower quality of life after treatment compared to the general population, particularly in mental health, social functioning, and intention to conceive (22). Therefore, early identification of high-risk HM patients and the development of individualized management plans are crucial to optimizing outcomes.

This study aims to analyze the demographics, risk factors, and pregnancy outcomes of patients with HM, using data from the largest GTD treatment center in Shanghai, eastern China.

During the study period, there were a total of 1,103 suspected GTD cases at our GTD referral center. After excluding cases based on multidisciplinary consultation only (n=494), exclusion by short tandem repeats (STR) or chromosome analysis (n=61), and incomplete information (n=14), eventually 534 patients with tissue specimens were diagnosed with GTD by histopathology and/or short tandem repeat (STR) analysis at our referral center. Of these, 506 patients underwent uterine evacuation and were pathologically diagnosed with HM ( Figure 1 ).

In this large retrospective cohort study, we described the demographics of patients with HM from 2019 to 2023. We validated that HM subtypes (CHM vs. PHM) are an independent risk factor for malignant progression in HM. Additionally, we identified ultrasound measurements as potential effective predictors for monitoring progression to pGTN. We subsequently developed a predictive model for pGTN risk, which may prove useful in the clinical management of patients with HM. Furthermore, we reported that pregnancy outcomes in these patients were comparable to those in the general population, suggesting that a history of HM or subsequent pGTN does not adversely affect fertility.

Previous studies have demonstrated that the clinical presentation of HM has evolved with advancements in first-trimester ultrasonography and β-hCG measurement. The average gestational age at diagnosis has decreased from 16 weeks to approximately 9 weeks. This shift has led to a decline in the incidence of presenting classic symptoms, such as vaginal bleeding, anemia, preeclampsia, excessive uterine enlargement, and hyperemesis gravidarum, along with an increase in asymptomatic patients (25, 26). A study conducted at the New England Trophoblastic Disease Center between 1994 and 2013, which included 180 patients with CHM, reported that the incidence of vaginal bleeding was significantly lower than in the preceding decade (46% vs. 84%, p < 0.001). However, vaginal bleeding remained the most prevalent symptom, noted in 80 patients (27). Consistent with these findings, our data demonstrated that the average gestational age at diagnosis was approximately 10 weeks, as ultrasound examinations are routinely conducted in the first trimester. The predominant clinical presentation was vaginal bleeding, which accounted for 52% of patients, followed by asymptomatic individuals, who comprised 42% of the cohort. Only a small proportion exhibited abdominal pain and hyperemesis gravidarum. Additionally, we observed a reduction in typical symptoms and an increase in asymptomatic patients, with more than half (57.9%) of the patients initially diagnosed with a missed abortion. This underlines the necessity for improved diagnostic protocols to differentiate HM from other miscarriages, particularly in the context of atypical histopathological findings.

However, early diagnosis has not significantly reduced the risk of malignant progression, which persists at around 10% (8, 27). The pathologic type of HM has been consistently identified as a significant predictor of pGTN in both our analysis and previous studies (13), highlighting the critical importance of accurate subtype classification for effective clinical management. In our cohort, the ratio of CHM to PHM (258/216) was lower than that reported in a northern Chinese cohort (413/263) (11), which may explain the relatively lower malignant progression rate observed in our study population. Overall, our findings revealed a malignant progression rate of approximately 8%, which is consistent with previous studies (8, 11). Previous research has indicated that pGTN is usually diagnosed several weeks to months after molar evacuation (5). In our cohort, the mean time to malignant progression was approximately 6 weeks following evacuation. Nevertheless, the early diagnosis of HM poses significant challenges due to its atypical histopathological features, which may resemble edematous villi or trisomies. Specific analytical techniques such as p57KIP2 immunostaining are increasingly employed in the diagnosis of CHM. As most CHM cases lack maternal chromosomes, they typically exhibit negative p57KIP2 immunostaining, as this marker is normally maternally expressed. In contrast, both PHM and non-molar abortions contain maternal chromosomes, resulting in positive p57KIP2 immunostaining, which can complicate pathological differentiation. While the latest World Health Organization (WHO) blue book has recommended STR analysis for definitive PHM diagnosis, its clinical implementation remains constrained by substantial costs and specialized personnel requirements (28).

Serum β-hCG levels, reflecting trophoblast proliferation activity, are an important indicator for monitoring the prognosis of HM patients after treatment. Current clinical guidelines recommend monitoring β-hCG levels every 1–2 weeks after evacuation. For cases of PHM, follow-up can be discontinued upon β-hCG normalization, whereas CHM patients require extended monitoring with monthly β-hCG testing for 6 months after achieving three consecutive negative results (29). However, frequent blood sampling during follow-up may impose physical discomfort, psychological distress, and financial burdens on patients, potentially compromising patient compliance. This not only hinders effective monitoring and management of patients but also affects their overall well-being. Notably, recent data from the UK national retrospective population study suggest that surveillance protocols could be safely modified to one confirmatory normal hCG value for CHM patients achieving β-hCG normalization within 56 days of evacuation (30).

Our study identified that ultrasound characteristics as valuable predictors of pGTN. Transvaginal ultrasound, a non-invasive and cost-effective approach, is widely employed in diagnosing and monitoring HM. Previous studies have suggested that increased myometrial vascularization and lower uterine artery Doppler indices may be related to invasive diseases (31, 32). However, only a few studies have characterized the morphology and vascular patterns of early GTN lesions (33, 34). It was reported that about 80% (28/36) of pGTN patients presented with detectable uterine lesions at the time of diagnosis (34), suggesting that patients with HM who do not meet the β-hCG diagnostic criteria but exhibit suspicious lesions in the myometrial layer on ultrasound should undergo prompt evaluation for potential malignant progression. It is likely that ultrasound examinations may reveal uterine lesions or vascular flow alterations precede measurable changes in serum β-hCG levels. Consequently, patients with suspected ultrasound characteristics are possibly at high risk and warrant vigilant follow-up.

In contrast to previous prediction models relying solely on β-hCG values (35–37), our study developed comprehensive predictive models incorporating ultrasound parameters and multiple clinical characteristics to assess malignant progression risk. Through systematic evaluation of various prediction models, we identified Model 3 with age, hCG ratio, and ultrasound indices, as the most effective. Model 3 achieved superior discriminative ability, as evidenced by the highest AUC value among all tested models (AUC=0.84, 95% CI: 0.78-0.89). This robust performance reflects the model’s multidimensional design that combines clinical, biochemical, and imaging parameters, thereby capturing the complex pathophysiology of pGTN development. The model’s enhanced reliability was further supported by its favorable information criteria values (AIC=180.93; BIC=196.72), indicating an optimal balance between model parsimony and predictive accuracy. Notably, the significant correlation between ultrasound indices and HM subtypes provides biological plausibility for including imaging parameters in the prediction algorithm. The incorporation of ultrasound metrics is particularly clinically relevant given their non-invasive nature, widespread availability, and ability to provide real-time morphological assessment. When combined with serial β-hCG monitoring, these imaging parameters offer valuable complementary information for early risk stratification. While Model 3 shows promising predictive accuracy and clinical utility for identifying high-risk pGTN cases, external validation in independent cohorts is warranted to confirm its generalizability. Future studies should investigate its potential for guiding personalized clinical management decisions and optimizing patient outcomes.

Our current livebirth rate was comparatively lower than rates reported in previous studies (38). This discrepancy may be attributable to the fact that most of our patients diagnosed and treated with fertility intentions in 2023 (n=35) have not yet achieved successful conception (n=32, 91.4%). As our longitudinal follow-up data mature, we anticipate the fertility outcomes will improve. A meta-analysis of six studies including a total of 25,222 patients found that adverse obstetric outcomes in patients with molar pregnancies were comparable to those in the general population (38). Although HM does not appear to adversely affect future pregnancy outcomes, our findings revealed that only 60% (304/506) of patients expressed an intention to conceive. This underscores the critical need for psychological assessment and targeted interventions, such as preconception counseling, to alleviate their fears and hesitations. In the context of China’s rapid socioeconomic development, particularly in the more affluent eastern coastal regions, we observed distinct demographic shifts including advanced maternal age. The mean age of our cohort was close to 33 years, slightly older than the 31.7 ± 6.8 years reported from northern China (11). Additionally, an increasing proportion of women are resorting to assisted reproductive technology (ART). While ART utilization in our cohort remained relatively low (n=13, 2.6%), its potential influence on gestation-related diseases merits further investigation.

To the best of our knowledge, our study provides a comprehensive analysis of the demographics and pregnancy outcomes of patients with HM in eastern China, utilizing a large hospital-based retrospective cohort. Our study advances previous research by systematically evaluating multiple traditional risk factors using our large dataset. Previous studies have predominantly focused on individual risk factors and/or had small sample sizes, making it challenging to draw robust conclusions. Importantly, we developed a predictive model that integrates several simple predictive variables, which are effective in screening for high-risk patients. The implementation of this model could optimize clinical practice by reducing unnecessary interventions and improve patient outcomes. Our study can provide evidence for more efficient health resource allocation, risk stratification, and development of personalized clinical management and follow-up strategies for patients with HM.

However, as this study is a retrospective, single-center analysis, it carries inherent limitations, including potential selection and/or recall biases. Our hospital serves as one of China’s largest referral centers for GTD. Notably, patients referred to our center tend to have higher educational attainment and socioeconomic status compared to the general population. Consequently, these particularities may limit the generalizability of our findings, necessitating external validation of the proposed predictive model. To address this, a prospective, multi-center cohort study is currently being conducted. This follow-up study aims to validate our preliminary results, provide updated epidemiological on HM in China, and contribute to evidence-based strategies for enhancing population health in general and women’s health in particular.

In conclusion, in our large hospital-based cohort study of over 500 patients in eastern China, we reported demographics and pregnancy outcomes of HM, which were similar to those observed in developed regions and countries. The identified risk factors and the predictive model we developed offer valuable tools for risk stratification and the clinical management optimization. While the clinical benefits of these approaches require further validation, our findings provide updated evidence to inform both clinical practice and healthcare policy formulation regarding HM management.