Effects of management of heavy menstrual bleeding of patients undergoing haploidentical hematopoietic stem cell transplantation.

RH contributed to data curation, formal analysis, investigation, and writing—original draft preparation; FZ contributed to data curation, investigation, and writing—original draft preparation; XJ contributed to data curation; CW contributed to methodology, data curation, and supervision; and XY contributed to methodology, writing—reviewing and editing, and funding acquisition.

The study was supported by Roche Diagnostics: Dynamic study for the effects of chemotherapy and bone marrow transplantation on ovarian function in pre‐adolescent hematologic disease survivors (Project no.2018PHB085‐01).

The general conditions of the study population are shown in Table  1 . This study ultimately included a total of 330 patients who underwent HSCT for hematologic diseases. There were 112 patients in the intervention group (112/330, 33.9%) and 218 patients in the control group (218/330, 66.1%). The age of patients at the time of transplantation ranged from 11 to 51 years old. The mean age of patients in the intervention group at admission was 25.73 ± 7.37 years, whereas in the control group, it was 28.23 ± 8.27 years, with no significant difference between the two groups ( p  = 0.051). The primary hematologic diseases were malignant hematologic diseases, with acute lymphocytic leukemia, acute myelogenous leukemia, and myelodysplastic syndrome accounting for 32.7% (108/330), 37.0% (125/330), and 11.5% (38/330) of the total number of patients, respectively. A total of 10.61% (35/330) had non‐malignant hematologic disease, aplastic anemia (AA), and other hematologic diseases for HSCT included chronic myeloid leukemia, Hodgkin lymphoma, and non‐Hodgkin lymphoma. There was a statistically significant difference between the two groups in terms of the primary hematologic diseases ( p  = 0.004). Because of different treatment regimens for primary hematologic diseases (patients with benign hematologic diseases do not undergo chemotherapy), there was a statistically significant difference between the two groups in whether they underwent chemotherapy (85.3% versus 67.0%, p  < 0.001). Human leukocyte antigen haploidentical HSCT was the primary transplantation method for both groups (80.7% versus 85.7%, p  = 0.260), and there was no significant difference in the incidence of GVHD between the two groups after transplantation ( p  = 0.664). Patient characteristics according to whether they received menstrual management. a Abbreviations: AA, aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; GVHD, graft versus host disease; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome. Data are presented as mean ± standard deviation or as number (percentage). P values indicate the differences between the two groups. Most patients had varying degrees of anemia before HSCT; only 16.1% of patients were free of anemia. Mild anemia was the most common (54.6%) degree, with 3.9% of patients having hemoglobin levels below 60 g/L. Compared with the control group, a higher proportion of patients in the intervention group had anemia and had more severe anemia compared with the control group (Figure  2 ); 35.2% (116/330) of patients required medication for hemostasis. In total, 90.0% (297/330) of patients experienced HMB (accompanied by anemia or required medication for hemostasis). Anemia grade of patients before HSCT (a) Proportions of anemia degree among all enrolled patients. (b) Proportions of degrees of anemia between the intervention group and the control group. Mild anemia: 90 g/L ≤hemoglobin <120 g/L; Moderate anemia: 60 g/L ≤hemoglobin <90 g/L; Severe anemia: Hemoglobin <60 g/L. More patients in the intervention group had already required medication for menstrual management before HSCT (43.8% versus 30.7%, p  = 0.019). There were no differences between the two groups in terms of hemoglobin levels, coagulation parameters (prothrombin time, activated partial thromboplastin time, fibrinogen), and liver and kidney function on the day of admission. However, the platelet levels of patients in the intervention group on the day of admission were significantly lower than those in the control group, although their mean values were within the normal range (126.63 ± 93.39 × 10 9 /L versus 168.02 ± 83.58 × 10 9 /L, p  < 0.001) (Table  2 ). Menstrual pattern and general conditions of patients before HSCT. a Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; Cr, creatinine; FIB, fibrinogen; HMB, heavy menstrual bleeding; HSCT, hematopoietic stem cell transplantation; PT, prothrombin time. Data are presented as mean ± standard deviation or as number (percentage). P values indicate the differences between the two groups. In the control group, 83.5% (182/218) of patients experienced varying degrees of bleeding within the LAFR, whereas in the intervention group, only 22.3% (25/112) did. This difference was statistically significant ( p  < 0.001). There were no differences between the two groups in terms of minimum hemoglobin and platelet count in the LAFR. The number of days with severe thrombocytopenia was 11.75 ± 6.37 days in the control group and 10.79 ± 4.97 days in the intervention group ( p  = 0.247). Among the patients who underwent menstrual management 65.2% (73/112) in the intervention group and 57.3% (125/218) in the control group recovered to 90 g/L hemoglobin within 30 days after reaching the lowest hemoglobin level, but this difference was not statistically significant ( p  = 0.169). There was no difference in the rate of liver and kidney function abnormalities between the two groups. Mann–Whitney U test was used to assess whether there were differences in the transfusion volume of red blood cells, plasma, and platelets between the intervention and control groups and results showed no statistically significant differences in the transfusion volume of these three blood components between the two groups ( p  = 0.661, p  = 0.848, p  = 0.186, respectively). Furthermore, we recorded instances of bleeding in other systems within the cabin. Patients in the intervention group had higher rates of bleeding in skin and mucous membranes, as well as major organ systems, compared with the control group, but there were no statistically significant differences between the two groups ( p  = 0.050). The rate of recurrent uterine bleeding after HSCT was significantly higher in the control group compared with the intervention group (50.9% versus 17.9%, p  < 0.001). In the control group, 83.5% (182/218) of patients experienced menstrual bleeding in the LAFR, whereas in the intervention group, only 22.3% (25/112) did. The rate of menstrual bleeding in the LAFR in the control group was significantly higher than that in the intervention group ( p  < 0.001). The degree of bleeding in the LAFR in patients is shown in Table  3 . In both the intervention and control groups, the majority of patients with new bleeding was similar to menstrual flow. Although there was no statistical difference, no cases of bleeding exceeding menstrual flow occurred in the intervention group, while there were three cases (3/218, 1.4%) in the control group (Table  3 ). Uterine bleeding and related hematologic examinations of patients in the LAFR. a Abbreviation: LAFR, laminar air‐flow room. Data are presented as #mean ± standard deviation, **median (range), or as number (percentage). P values indicate the differences between the two groups. In addition, among patients who had anemia after HSCT, the bleeding rate of patients who chose menstrual management was 21.9% (21/96), whereas the bleeding rate of patients without intervention was 84.0% (152/181), and the difference was statistically significant ( p  < 0.001). In order to screen for risk factors of menstrual bleeding in the LAFR of HSCT patients, factors with a single‐factor analysis P value less than 0.2 were included in the logistic regression analysis. Logistic regression analysis showed that only whether menstrual management was performed before admission was related to menstrual bleeding. Patients who did not undergo menstrual management had a significantly higher risk of bleeding than those who did experience menstrual management (odds ratio [OR] 18.12, 95% confidence interval [CI] 9.638–34.066, p  < 0.001) (Table  4 ). Risk factors for menstrual bleeding in the LAFR. a Abbreviations: APTT, activated partial thromboplastin time; CI, confidence interval; FIB, fibrinogen; GvHD, graft versus host disease; HLA, human leukocyte antigen; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; LAFR, laminar air‐flow room; PT, prothrombin time. P values indicate the differences between the two groups. Severe anemia was defined as hemoglobin less than 60 g/L, and factors related to a decrease in hemoglobin to severe anemia in the LAFR were analyzed. After conducting a single‐factor correlation analysis of factors related to intra‐LAFR hemoglobin, variables with p  < 0.2 and whether menstrual management was chosen were included in the logistic regression analysis. The results suggested that factors related to severe anemia included the occurrence of GVHD, the presence of menstrual bleeding, and the hemoglobin level before pretreatment. Patients without menstrual bleeding were less likely to develop severe anemia (OR 0.243, 95% CI 0.097–0.608, p  = 0.003) (Table  5 ). Risk factors for severe anemia after HSCT. a Abbreviations: AA, aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; APTT, activated partial thromboplastin time; CI, confidence interval; FIB, fibrinogen; GVHD, graft versus host disease; HLA, human leukocyte antigen; HR, hazard ratio; HSCT, hematopoietic stem cell transplantation; LAFR, laminar air‐flow room; MDS, myelodysplastic syndrome; PT, prothrombin time. P values indicate the differences between the two groups. A total of 112 patients were included in the intervention group of the study, including 85 who chose GnRHa, 19 who chose continuous COC, and 8 who chose oral mifepristone. The LAFR menstrual bleeding rates in the GnRHa group, COC group, and mifepristone group were 12.9% (11/85), 73.7% (14/19), and 0%, respectively, all lower than the control group (182/218, 83.5%). The post‐LAFR uterine bleeding rates for the GnRHa and mifepristone groups were 7.1% (6/85) and 12.5% (1/8), respectively, both lower than the control group (111/218, 50.9%). Furthermore, we observed that the mifepristone group had lower pre‐processing levels of hemoglobin and platelets than the other three groups (Table  6 ). The outcomes of different menstrual management methods. a Abbreviations: COC, combined oral contraceptive; GnRHa, gonadotropin‐releasing hormone agonist; HSCT, hematopoietic stem cell transplantation; LAFR, laminar air‐flow room. Data are presented as mean ± standard deviation or as number (percentage).

Patients with benign or malignant hematologic diseases may experience abnormal hematologic conditions, particularly thrombocytopenia, due to underlying diseases, chemotherapy regimens, HSCT conditioning, and other reasons, making them susceptible to HMB. Current research has found that in patients with normal ovarian function, chemotherapy‐induced thrombocytopenia can lead to HMB in 40% of cases. 8 However, the potent gonadotoxicity of chemotherapy during HSCT conditioning often results in ovarian dysfunction and subsequent hormonal imbalances, further increasing the incidence of HMB, and complicating the patient's condition. Therefore, menstrual management of premenopausal women scheduled for HSCT is crucial in reducing the incidence of menstruation during transplantation and preventing HMB. There is relatively limited research on the feasibility and effectiveness of premenstrual management before HSCT to prevent secondary HMB due to hematologic changes in patients after conditioning. Our study aims to investigate the impact of menstrual management before HSCT on uterine bleeding in the LAFR and provide a reference for the menstrual management of patients with HMB. In clinical admissions, there is a high proportion of blood disorder patients complaining of HMB. With the poor correlation between patient perception and objective menstrual blood volume, as well as the lack of validated diagnostic tools, HMB is an under‐diagnosed and under‐treated disease. 5 NICE pointed out that HMB should be defined as excessive menstrual blood loss that interferes with the woman's physical, emotional, social, and material quality of life, and can occur alone or in combination with other symptoms 6 Anemia can be used as a reference for HMB. Anemia has a wide range of health impacts on female patients, including causing nonspecific symptoms such as fatigue, irritability, hair loss, lack of concentration, palpitations, and dizziness. Severe anemia can lead to arrhythmias, edema, and even heart failure in patients, as well as an increased need for blood transfusions. 12 , 13 The present study found that 83.9% of patients had varying degrees of anemia before HSCT, suggesting a high likelihood of HMB. Including patients who need medication for hemostasis before HSCT, the proportion of HMB patients in the enrolled population can reach 90% (297/330). At the same time, these patients were a high‐risk group for HMB in the LAFR. Menstrual management before HSCT significantly reduced the incidence of bleeding in HSCT patients in the LAFR. The incidence of menstrual bleeding in the LAFR was as high as 83.5% in the control group, but in the intervention group was only 22.3%. Compared with the incidence of bleeding in the LAFR reported by Meirow et al. 14 in a retrospective study in 2006 (13/20, 65.0%), the control group in the present study had a higher incidence. Regarding the outcomes of patients who had HMB before HSCT (patients with anemia), menstrual management could significantly reduce the risk of bleeding during HSCT for these patients. In both groups, bleeding pattern was mainly equivalent to menstrual bleeding. It is important to note that bleeding that patients describe as “similar to menstrual flow” may amount to HMB. In the intervention group, there was no bleeding greater than menstrual bleeding, which may indicate that menstrual management can effectively prevent significant uterine bleeding in the LAFR. The medical records revealed that among the 25 patients who experienced bleeding in the intervention group, 14 were users of COC. The incidence of bleeding in the COC group reached 73.7%. The occurrence of bleeding in COC users may be related to breakthrough bleeding during the low‐dose maintenance phase of COC. 15 There was a statistically significant difference between the two groups in post‐discharge uterine bleeding. In the control group, 50.9% of patients experienced uterine bleeding at least once, whereas in the intervention group, only 17.9% had bleeding. Patients who used GnRHa or mifepristone had a lower rate of recurrence of uterine bleeding after discontinuation, indicating that GnRHa and mifepristone may have a better induction effect on amenorrhea, with a lower risk of recurrence of bleeding after discontinuation. The intervention group exhibited a higher proportion of drug‐induced AUB hemostasis and lower platelet levels before HSCT, indicating a higher likelihood of previous experience with HMB in these patients. Consequently, they were more vigilant about the risk of HMB and had a stronger awareness of menstrual management. During retrospective collection of medical records it was found that some patients did not undergo gynecologic consultations or seek advice on menstrual management before HSCT. Though the awareness of routine gynecologic examinations for HSCT patients before transplantation is gradually increasing, the awareness of menstrual management is lacking. Most patients seek acute hemostasis in gynecology clinics when HMB has already occurred, but this undoubtedly increases the difficulty and risk of hemostasis, and even endangers the patient's life. This suggests the importance of strengthening collaboration between hematology and obstetrics and gynecology departments in the future. Analysis of factors related to uterine bleeding in the LAFR suggested that only menstrual management was associated with it. The risk of menstrual bleeding in patients who did not undergo menstrual management was 18.12 times that of patients who underwent menstrual management. This indicates that regardless of the patient's primary disease or her menstrua; status before HSCT, menstrual management can effectively reduce the risk of bleeding in the LAFR, thereby preventing the occurrence of HMB before platelet engraftment. After analyzing the factors related to severe anemia in the LAFR, although there was no correlation between menstrual management and severe anemia, there was a correlation between menstrual bleeding and hemoglobin reaching severe anemia levels. The intervention group's patients were managed with three menstrual management methods: GnRHa, COC, and mifepristone. The mifepristone group achieved a 100% rate of amenorrhea in the LAFR, followed by the GnRHa group with 87.1%. The COC group had a bleeding rate of 73.7%. However, regardless of the intervention method, the bleeding rate in the LAFR was lower than that in the control group (83.5%). When comparing the pre‐processing conditions before HSCT, we found that the pretreatment hemoglobin and platelet levels of the three menstrual management methods were lower than those in the control group. Especially in the mifepristone group, the hemoglobin and platelet levels were lower than in the other two intervention groups. Mifepristone, as a synthetic selective progesterone‐receptor modulator, was initially used for early pregnancy medical abortion because of its anti‐progestin effects, and its indications have expanded to include common gynecologic conditions such as uterine fibroids and endometriosis. Mifepristone not only has anti‐progestin effects but also affects the hypothalamic–pituitary‐ovarian axis. It can act on the hypothalamus to inhibit the secretion of GnRH, affecting follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) secretion, and it can also directly act on the pituitary gland to inhibit FSH and LH release, further lowering serum FSH and LH levels, inducing amenorrhea. 16 Mifepristone is now used as a drug for inducing amenorrhea and improving anemia during perioperative treatment of uterine leiomyoma and as a treatment of HMB caused by leiomyoma‐associated AUB (AUB‐L) and adenomyosis‐associated AUB (AUB‐A). Studies in AUB caused by AUB‐L and AUB‐A have observed that low‐dose (2.5–10 mg) mifepristone can achieve amenorrhea rates of 41%–98.9%, 17 , 18 , 19 , 20 , 21 , 22 , 23 and high‐dose (50 mg) mifepristone can achieve a 100% amenorrhea rate. 24 In our gynecologic endocrine clinic, in patients with refractory HMB who still have poor hemostasis with ultra‐high‐dose hormone drugs, adding mifepristone and gradually reducing the dose of hormone drugs can gradually transition patients to amenorrhea. This may explain why the hemoglobin and platelet levels before pretreatment in the mifepristone group were lower than those in the other two groups. Mifepristone is often chosen by patients because of low platelet counts and the poor effectiveness of hormone drugs. Because the time for using mifepristone as a menstrual management option is relatively short, this study included only eight patients using mifepristone. However, in these eight patients, the amenorrhea induction effect was satisfactory (8/8, 100%), at a dose of 25 mg daily. Nevertheless, further studies with a larger sample size are needed to validate its amenorrhea rate and safety. Each of the three menstrual management methods has its advantages and disadvantages. GnRHa induces amenorrhea by promoting the release of gonadotropins, leading to desensitization of GnRH receptors and inhibiting pulsatile secretion of GnRH, thereby achieving menstrual management in a low gonadotropin state. The advantage of GnRHa is that it does not require daily use. However, the guidelines require patients to receive a GnRHa injection at least 14 days before pretreatment to prevent heavy uterine bleeding. 8 Platelet count less than 10 × 10 9 /L is a contraindication for its use. 8 The effectiveness of GnRHa in reducing bleeding during the period of platelet reduction has been confirmed. 25 In a 2006 retrospective study, the intra‐LAFR amenorrhea rate of GnRHa was 76.9% (30/39), 14 and a 2016 retrospective study showed an amenorrhea rate of up to 88% (29/33) in the LAFR, 26 which is similar to the results of this study (74/85, 87.1%). Both COC and mifepristone require daily oral maintenance doses of medication, but they do not have specific requirements for the time and platelet levels before HSCT pretreatment, and can be started at any time. COC can suppress ovulation and stabilize hormone levels to suppress menstruation. However, COC is associated with increased breakthrough bleeding after missed doses and continuous medication, and it requires some degree of patient compliance. This study also found that even in patients taking medication regularly, there was still a 73.7% intra‐LAFR uterine bleeding rate. In addition, COC has relatively more contraindications and a risk of deep vein thrombosis. 27 The present study is the first to describe the impact of pretransplant menstrual management on menstrual bleeding in Chinese HSCT patients and proposes mifepristone as an amenorrhea‐inducing medication for high‐risk bleeding populations. However, this study has limitations: a small sample size, various confounding factors, and the selection bias and recall bias associated with a retrospective design. Our research team is also conducting a prospective clinical trial to verify that mifepristone can be used as an effective drug for preventing menstruation and reducing bleeding in the LAFR in HSCT patients. We hope that in the future, large‐sample prospective randomized controlled studies can further validate the effectiveness and safety of menstrual management methods in preventing menstrual bleeding in HSCT patients. We also hope to work with hematologists to raise awareness of gynecologic management before transplantation in patients with hematologic diseases to reduce treatment risks and improve patients' quality of life. In conclusion, menstrual management significantly reduces the incidence of HMB in HSCT patients and acts as a protective factor to prevent menstrual bleeding in the LAFR. In this study, the rates of menstrual bleeding for all three menstrual management methods were lower than in the control group. Mifepristone demonstrated a good effect in inducing amenorrhea in this study, but its effectiveness still requires confirmation through large‐sample prospective research.

Bleeding complications from different systems are important complications of hematopoietic stem cell transplantation (HSCT). High‐dose chemotherapy in HSCT conditioning regimens can damage bone marrow cells and blood cells. Before HSCT, patients face varying degrees of overall blood cell reduction. Other post‐HSCT complications, such as graft versus host disease (GVHD), may also exacerbate bleeding and affect patients' clotting function, thereby increasing the risk of post‐transplant bleeding. Post‐transplant bleeding is associated with decreased patient survival rates. 1 , 2 , 3 Pulmonary bleeding and gastrointestinal bleeding are the most common life‐threatening bleeding sites, followed by the central nervous system. 3 However, most studies focus on overall bleeding after HSCT. Currently, the domestic consensus on the management of bleeding complications after HSCT mainly focuses on skin and mucous membranes, the urinary tract, the digestive tract, and intracranial and alveolar bleeding. 4 Premenopausal women constitute a special group, as they experience periodic menstrual cycles before HSCT. However, there is a very limited number of studies evaluating menstrual bleeding during HSCT. Heavy menstrual bleeding (HMB) is defined as excessive menstrual blood loss that affects quality of life. As a result of the poor correlation between patient perception and objective menstrual blood volume, as well as the lack of validated diagnostic tools, this is an under‐diagnosed and under‐treated disease. 5 The National Institute for Health and Care Excellence (NICE) pointed out that HMB should be defined as excessive menstrual blood loss that interferes with the woman's physical, emotional, social, and material quality of life, and that can occur alone or in combination with other symptoms. 6 For reproductive‐aged women, the symptom of HMB is highly prevalent and a major contributor to iron deficiency anemia. 7 Moreover, the clinical management of abnormal uterine bleeding due to clotting‐related disorders (referred to as AUB‐C) is challenging. HMB is the most common manifestation of AUB in patients with hematologic diseases. For HSCT patients, underlying hematologic conditions, chemotherapy regimens, and pretransplant conditioning can lead to platelet reduction, potentially causing HMB. Among female patients who have not undergone menstrual management before HSCT, the incidence of HMB can be as high as 40%, 8 significantly affecting the treatment of underlying diseases and patient safety. Due to the lack of emphasis on menstrual management for premenopausal females, there are instances of hematologists using combined oral contraceptives (COC) or hormonal agents inappropriately for gynecologic hemostasis. Menstrual management refers to the use of hormonal medications to decrease the frequency and volume of physiologic menses and, in some cases, achieving amenorrhea. 9 Uncontrollable HMB in the laminar air‐flow room (LAFR) will seriously affect the patient's treatment and life safety. According to the recommendations of existing guidelines, 8 comprehensive assessments in the field of obstetrics and gynecology should be conducted for HSCT patients before entering the transplant unit. Currently, the focus on female HSCT patients is primarily on preserving fertility and protecting ovarian function. However, there is also a lack of data concerning menstrual bleeding during HSCT for premenopausal patients, and menstrual management for these patients has not received sufficient attention. The high HMB rate in premenopausal women with hematologic diseases and the high risk of HMB in the LAFR suggest that we should pay attention to this group of patients. Previous studies by our team have shown that gonadotropin‐releasing hormone agonists (GnRHa) can effectively reduce the rate of bleeding in the LAFR in HSCT patients. 10 This study aims to investigate the menstrual status in the LAFR 11 and associated risks in HSCT patients, providing a reference for the assessment and management of gynecologic aspects for patients with hematologic disease, especially those with HMB, in the future.

The authors have no conflicts of interest.

This was a retrospective cohort study. We affirm that the study was approved by the Ethics Committee of Peking University People's Hospital (No. 2015PHB087‐01), including any relevant details; and that all experiments were performed in accordance with the relevant guidelines and regulations. All research was performed in accordance with relevant regulations, and appropriate consent was obtained from all participants and/or their legal guardians and signed by the patients or their families. From December 2012 to December 2022, premenopausal female patients who had undergone or were to undergo HSCT in the Gynecological Endocrinology Clinic of Peking University People's Hospital were included. Patients with hematologic diseases at Peking University People's Hospital routinely undergo gynecologic physical examination before HSCT. The inclusion criteria were as follows: (1) women undergoing myeloablative chemotherapy HSCT for hematologic diseases; (2) premenopausal patients; and (3) patients who underwent HSCT at the Blood Research Institute of Peking University People's Hospital. The exclusion criteria were as follows: (1) patients who did not use drugs regularly; (2) patients who did not survive during HSCT; (3) patients with incomplete clinical data; (4) patients who received less than two courses of GnRHa treatment before myeloablative chemotherapy; and (5) patients who had not yet undergone HSCT. After screening 479 patients, 330 patients were finally included in the study (Figure  1 ). Flow chart explaining patient dropout. Hematology and gynecology data of all participants were collected. After supplying informed consent, patients could choose whether to receive menstrual management before HSCT. The patients who received menstrual management were included in the intervention group. The main management methods were GnRHa injection, COC, or 25 mg daily mifepristone. Patients who were not counseled on menstrual management before HSCT or did not adopt such management after counseling were included in the control group. Hematology‐related information and gynecology‐related information was collected by gynecology doctors. The present study involved the following definitions: (1) Mild anemia: 90 g/L ≤hemoglobin <120 g/L; Moderate anemia: 60 g/L ≤hemoglobin <90 g/L; Severe anemia: hemoglobin <60 g/L; (2) Severe thrombocytopenia: platelet count 40 U/L or alanine aminotransferase >40 U/L; and (4) Abnormal kidney function: creatinine >104 μmol/L. All data were statistically processed using SPSS 22.0 (IBM, Armonk, NY, USA). Continuous variables are described as mean ± standard deviation and compared using the Student t test. For continuous variables that did not follow a normal distribution, descriptions are provided using the median (interquartile range), and analysis was conducted using the Mann–Whitney U test. Categorical variables are described using frequencies and proportions, and comparisons of categorical variables are made using the χ 2 test or Fisher exact test. Logistic regression analysis was performed to identify factors related to menstrual bleeding in the LAFR and severe anemia. A P value less than 0.05 indicated statistical significance.