Transfer learning for clustering single-cell RNA-seq data crossing-species and batch, case on uterine fibroids.

Due to the high dimensionality and sparsity of the gene expression matrix in single-cell RNA-sequencing (scRNA-seq) data, coupled with significant noise generated by shallow sequencing, it poses a great challenge for cell clustering methods. While numerous computational methods have been proposed, the majority of existing approaches center on processing the target dataset itself. This approach disregards the wealth of knowledge present within other species and batches of scRNA-seq data. In light of this, our paper proposes a novel method named graph-based deep embedding clustering (GDEC) that leverages transfer learning across species and batches. GDEC integrates graph convolutional networks, effectively overcoming the challenges posed by sparse gene expression matrices. Additionally, the incorporation of DEC in GDEC enables the partitioning of cell clusters within a lower-dimensional space, thereby mitigating the adverse effects of noise on clustering outcomes. GDEC constructs a model based on existing scRNA-seq datasets and then applying transfer learning techniques to fine-tune the model using a limited amount of prior knowledge gleaned from the target dataset. This empowers GDEC to adeptly cluster scRNA-seq data cross different species and batches. Through cross-species and cross-batch clustering experiments, we conducted a comparative analysis between GDEC and conventional packages. Furthermore, we implemented GDEC on the scRNA-seq data of uterine fibroids. Compared results obtained from the Seurat package, GDEC unveiled a novel cell type (epithelial cells) and identified a notable number of new pathways among various cell types, thus underscoring the enhanced analytical capabilities of GDEC. Availability and implementation: https://github.com/YuzhiSun/GDEC/tree/main.

Loss of the repressor REST affects progesterone receptor function and promotes uterine leiomyoma pathogenesis.

Uterine leiomyomas (UL) are benign tumors that arise in the myometrial layer of the uterus. The standard treatment option for UL is hysterectomy, although hormonal therapies, such as selective progesterone receptor modulators, are often used as temporary treatment options to reduce symptoms or to slow the growth of tumors. However, since the pathogenesis of UL is poorly understood and most hormonal therapies are not based on UL-specific, divergent hormone signaling pathways, hallmarks that predict long-term efficacy and safety of pharmacotherapies remain largely undefined. In a previous study, we reported that aberrant expression of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes activate UL growth due to the near ubiquitous loss of REST. Here, we show that ablation of the Rest gene in mouse uterus leads to UL phenotype and gene-expression patterns analogous to UL, including altered estrogen and progesterone signaling pathways. We demonstrate that many of the genes dysregulated in UL harbor cis-regulatory elements bound by REST and progesterone receptor (PGR) adjacent to each other. Crucially, we identify an interaction between REST and PGR in healthy myometrium and present a putative mechanism for the dysregulation of progesterone-responsive genes in UL ensuing in the loss of REST. Using three Rest conditional knockout mouse lines, we provide a comprehensive picture of the impact loss of REST has in UL pathogenesis and in altering the response of UL to steroid hormones.

The independent and joint associations of hysterectomy and uterine fibroids or endometriosis with ovarian cancer incidence: results from a US-based cohort.

Uterine fibroids and endometriosis may be associated with an increased risk of ovarian cancer. Less is known about the role of hysterectomy in these associations. We estimated the independent and joint associations of hysterectomy, fibroids, and endometriosis with ovarian cancer incidence in the prospective Sister Study cohort (2003-2009). We used time-varying Cox proportional hazards models to estimate covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). By the end of follow-up, 34% of 40,928 eligible participants had fibroids, 13% had endometriosis, and 7% had both. A total of 274 women developed ovarian cancer during follow-up (median=12.3 years). In mutually adjusted models, fibroids (HR=1.65, 95% CI: 1.28, 2.12) and possibly endometriosis (HR=1.16, 95% CI: 0.82, 1.63), were positively associated with ovarian cancer. Hysterectomies (20% of participants) were also positively associated with ovarian cancer (HR=1.29, 95% CI: 0.95, 1.74). There was some evidence that hysterectomies may mitigate ovarian cancer risk among women with fibroids (HR=0.83, 95% CI: 0.56, 1.24), but not among women with endometriosis (HR=1.20, 95% CI: 0.65, 2.22). Identifying these joint associations adds to our understanding of ovarian cancer etiology and may help inform decisions about how women with fibroids, endometriosis, and hysterectomies are treated and surveilled for ovarian cancer.

Vaginal and rectal microbiome contribute to genital inflammation in chronic pelvic pain.

BACKGROUND: Chronic pelvic pain (CPP) is a multifactorial syndrome that can substantially affect a patient's quality of life. Endometriosis is one cause of CPP, and alterations of the immune and microbiome profiles have been observed in patients with endometriosis. The objective of this pilot study was to investigate differences in the vaginal and gastrointestinal microbiomes and cervicovaginal immune microenvironment in patients with CPP and endometriosis diagnosis compared to those with CPP without endometriosis and no CPP. METHODS: Vaginal swabs, rectal swabs, and cervicovaginal lavages (CVL) were collected among individuals undergoing gynecologic laparoscopy. Participants were grouped based on patients seeking care for chronic pain and/or pathology results: CPP and endometriosis (CPP-Endo) (n = 35), CPP without endometriosis (n = 23), or patients without CPP or endometriosis (controls) (n = 15). Sensitivity analyses were performed on CPP with endometriosis location, stage, and co-occurring gynecologic conditions (abnormal uterine bleeding, fibroids). 16S rRNA sequencing was performed to profile the microbiome, and a panel of soluble immune mediators was quantified using a multiplex assay. Statistical analysis was conducted with SAS, R, MicrobiomeAnalyst, MetaboAnalyst, and QIIME 2. RESULTS: Significant differences were observed between participants with CPP alone, CPP-Endo, and surgical controls for body mass index, ethnicity, diagnosis of ovarian cysts, and diagnosis of fibroids. In rectal microbiome analysis, both CPP alone and CPP-Endo exhibited lower alpha diversity than controls, and both CPP groups revealed enrichment of irritable bowel syndrome-associated bacteria. CPP-Endo exhibited an increased abundance of vaginal Streptococcus anginosus and rectal Ruminococcus. Patients with CPP and endometrioma (s) demonstrated increased vaginal Streptococcus, Lactobacillus, and Prevotella compared to other endometriosis sites. Further, abnormal uterine bleeding was associated with an increased abundance of bacterial vaginosis-associated bacteria. Immunoproteomic profiles were distinctly clustered by CPP alone and CPP-Endo compared to controls. CPP-Endo was enriched in TNF⍺, MDC, and IL-1⍺. CONCLUSIONS: Vaginal and rectal microbiomes were observed to differ between patients with CPP alone and CPP with endometriosis, which may be useful in personalized treatment for individuals with CPP and endometriosis from those with other causes of CPP. Further investigation is warranted in patients with additional co-occurring conditions, such as AUB/fibroids, which add additional complexity to these conditions and reveal the enrichment of distinct pathogenic bacteria in both mucosal sites. This study provides foundational microbiome-immunoproteomic knowledge related to chronic pelvic pain, endometriosis, and co-occurring gynecologic conditions that can help improve the treatment of patients seeking care for pain.

First Australian estimates of incidence and prevalence of uterine fibroids: a data linkage cohort study 2000-2022.

STUDY QUESTION: What is the estimated prevalence and incidence of uterine fibroids diagnosed in Australian women of reproductive age? SUMMARY ANSWER: An estimated 7.3% of Australian women had a diagnosis of uterine fibroids by the age of 45-49 years, with age-specific incidence highest in women aged 40-44 years (5.0 cases per 1000 person-years). WHAT IS KNOWN ALREADY: Uterine fibroids are associated with a high symptom burden and may affect overall health and quality of life. Studies in different countries show a wide variation in both the prevalence (4.5-68%) and incidence (2.2-37.5 per 1000 person-years) of uterine fibroids, which may be partly explained by the type of investigation, method of case ascertainment, or the age range of the study population, necessitating the reporting of country-specific estimates. STUDY DESIGN, SIZE, DURATION: This observational prospective cohort study using self-report survey and linked administrative data (2000-2022) included 8066 women, born between 1973 and 1978, in the Australian Longitudinal Study on Women's Health. PARTICIPANTS/MATERIALS, SETTING, METHODS: A combination of self-report survey and linked administrative health data (hospital, emergency department, the Medicare Benefits Schedule, and the Pharmaceutical Benefits Scheme) were used to identify women with a report of a diagnosis of uterine fibroids between 2000 and 2022. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 8066 Australian women followed for 22 years, an estimated 7.3% of women (95% CI 6.9, 7.6) had a diagnosis of uterine fibroids by the age of 45-49 years. The incidence increased with age and was highest in women aged 40-44 years (5.0 cases per 1000 person-years, 95% CI 4.3, 5.7 cases per 1000 person-years). Women with uterine fibroids were more likely to experience heavy or painful periods. They were also more likely to report low iron levels, endometriosis, and poor self-rated health and to have two or more annual visits to their general practitioner. LIMITATIONS, REASONS FOR CAUTION: Our estimates are based on self-report of doctor diagnosis or treatment for fibroids and/or data linked to treatment and procedure administrative records. This predominantly captures women with symptomatic fibroids, but has the potential for misclassification of asymptomatic women and an underestimate of overall prevalence and incidence. In addition, questions on fibroids were only asked in surveys when women were 37-42 years of age to 43-48 years of age, so cases at younger ages may have been underestimated (particularly in women with less severe symptoms) as these were only ascertained through data linkage. WIDER IMPLICATIONS OF THE FINDINGS: These are the first population-based estimates of the prevalence and incidence of uterine fibroids in women of reproductive age in Australia. Establishing these first estimates will help inform health policy and health care provision in the Australian context. STUDY FUNDING/COMPETING INTEREST(S): The ALSWH is funded by the Australian Government Department of Health and Aged Care. L.FW. was supported by an Australian National Health and Medical Research Council (NHMRC) Centres for Research Excellence grant (APP1153420) and G.D.M. was supported by an NHMRC Leadership Fellowship (APP2009577). The funding bodies played no role in the design, the collection, analysis or interpretation of data, the writing of the manuscript, or the decision to submit the manuscript for publication. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Bipedalism and the dawn of uterine fibroids.

The high prevalence and burden of uterine fibroids in women raises questions about the origin of these benign growths. Here, we propose that fibroids should be understood in the context of human evolution, specifically the advent of bipedal locomotion in the hominin lineage. Over the ≥7 million years since our arboreal ancestors left their trees, skeletal adaptations ensued, affecting the pelvis, limbs, hands, and feet. By 3.2 million years ago, our ancestors were fully bipedal. A key evolutionary advantage of bipedalism was the freedom to use hands to carry and prepare food and create and use tools which, in turn, led to further evolutionary changes such as brain enlargement (encephalization), including a dramatic increase in the size of the neocortex. Pelvic realignment resulted in narrowing and transformation of the birth canal from a simple cylinder to a convoluted structure with misaligned pelvic inlet, mid-pelvis, and pelvic outlet planes. Neonatal head circumference has increased, greatly complicating parturition in early and modern humans, up to and including our own species. To overcome the so-called obstetric dilemma provoked by bipedal locomotion and encephalization, various compensatory adaptations have occurred affecting human neonatal development. These include adaptations limiting neonatal size, namely altricial birth (delivery of infants at an early neurodevelopmental stage, relative to other primates) and mid-gestation skeletal growth deceleration. Another key adaptation was hyperplasia of the myometrium, specifically the neomyometrium (the outer two-thirds of the myometrium, corresponding to 90% of the uterine musculature), allowing the uterus to more forcefully push the baby through the pelvis during a lengthy parturition. We propose that this hyperplasia of smooth muscle tissue set the stage for highly prevalent uterine fibroids. These fibroids are therefore a consequence of the obstetric dilemma and, ultimately, of the evolution of bipedalism in our hominin ancestors.

Uterine fibroids in women diagnosed with acromegaly: a systematic review.

The review discusses the relationship between acromegaly and uterine fibroids. It highlights variations in research methodologies and inconsistent findings, emphasizing the complex nature of fibroid development and the role of the somatotropic axis. Additionally, it addresses demographic factors and examines the potential impact of therapies on the risk and prevalence of uterine fibroids in individuals with acromegaly. We conducted an analysis of previously published literature that examined the repercussions of acromegaly on gynecological health in female cohorts, with specific attention directed towards elucidating the prevalence of uterine fibroids. We suggest that larger, more focused studies are needed to understand the specific impact of different treatments on the occurrence of gynecological issues in acromegaly patients. Additionally, our study emphasizes the importance of factors such as disease duration and treatment effectiveness. We hypothesize that a relationship between acromegaly and uterine fibroids may occur. However, it remains an area of ongoing research, with the need for larger, multi-center studies to draw more definitive conclusions.

Causal relationship between female reproductive factors, sex hormones and uterine leiomyoma: a Mendelian randomization study.

RESEARCH QUESTION: Are the observed associations between female reproductive factors and sex hormones with the risk of uterine leiomyoma truly causal associations? DESIGN: The putative causal relationships between female reproductive factors and sex hormones with uterine leiomyoma were investigated using two-sample Mendelian randomization. Statistics on exposure-associated genetic variants were obtained from genome-wide association studies (GWAS). The uterine leiomyoma GWAS from the FinnGen and FibroGENE consortia were used as outcome data for discovery and replication analyses, respectively. Results were pooled by meta-analysis. Sensitivity analyses ensured robustness of the Mendelian randomization analysis. RESULTS: When FinnGen GWAS were used as outcome data, a causal relationship was found between age at menarche (OR 0.84, P < 0.0001), age at menopause (OR 1.08, P < 0.0001), number of live births (OR 0.25, P < 0.001) and total testosterone levels (OR 0.90, P < 0.001) with the risk of uterine leiomyoma. When FibroGENE GWAS were used as outcome data, Mendelian randomization results for age at menopause, the number of live births and total testosterone levels were replicated. In the meta-analysis, a later age at menopause (OR 1.08, P < 0.0001) was associated with an increased risk of uterine leiomyoma. A higher number of live births (OR 0.25, P < 0.0001) and higher total testosterone levels (OR 0.90, P < 0.0001) were associated with a decreased risk of uterine leiomyoma. CONCLUSIONS: A causal relationship between later age at menopause, lower number of live births and lower total testosterone levels with increased risk of uterine leiomyoma was found.

Uterine artery embolization vs myomectomy for the management of women with uterine leiomyomas: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to investigate whether uterine artery embolization offers a better quality of life than myomectomy in premenopausal women diagnosed with leiomyomas of the uterus. DATA SOURCES: A literature search was performed using the electronic databases of PubMed and Cochrane Central Register of Controlled Trials from inception to January 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing uterine artery embolization with myomectomy in women of premenopausal age suffering from uterine leiomyomas were considered. METHODS: The primary outcome was quality of life. The secondary outcomes were reintervention rate and timing, successful pregnancy, stillbirth and miscarriage, cesarean delivery on delivery, and perioperative morbidity. Moreover, time-to-event and standard pairwise meta-analyses were performed, as appropriate. The certainty of the evidence was assessed in line with the Grading of Recommendations, Assessment, Development, and Evaluations methodology. RESULTS: A total of 6 randomized controlled trials met our inclusion criteria. The meta-analysis suggested little to no difference in terms of quality of life between uterine artery embolization and myomectomy (standard mean difference, 0.05; 95% confidence interval, -0.38 to 0.48; I2=92%; very low certainty of evidence). Sensitivity analysis, including randomized controlled trials, which included solely myomectomy procedures in the control arm, demonstrated better quality of life for women treated with myomectomy (standard mean difference, -0.32; 95% confidence interval, -0.49 to -0.15; I2=15%). Concerning reintervention, myomectomy was likely associated with a decreased risk of future reintervention (risk ratio, 0.32; 95% confidence interval, 0.15-0.69; I2=60%; low certainty of evidence) and a more prolonged time interval since a potential reintervention because of recurrence than uterine artery embolization (hazard ratio, 0.41; 95% confidence interval, 0.22-0.77; I2=77%; low certainty of evidence). No difference was found between the 2 interventions concerning severe perioperative adverse events (relative risk, 4.13; 95% confidence interval, 0.44-39.20; I2=0%; low certainty of evidence). CONCLUSION: Uterine artery embolization is likely associated with increased reintervention rates and less time to reintervention compared with myomectomy in premenopausal women diagnosed with uterine leiomyomas. Evidence suggests no difference between the 2 interventions regarding perioperative morbidity. Uterine artery embolization may exert no effect on quality of life and successful pregnancy; however, the evidence is very uncertain.

Multiomic analysis of uterine leiomyomas in self-described Black and White women: molecular insights into health disparities.

BACKGROUND: Black women are at an increased risk of developing uterine leiomyomas and experiencing worse disease prognosis than White women. Epidemiologic and molecular factors have been identified as underlying these disparities, but there remains a paucity of deep, multiomic analysis investigating molecular differences in uterine leiomyomas from Black and White patients. OBJECTIVE: To identify molecular alterations within uterine leiomyoma tissues correlating with patient race by multiomic analyses of uterine leiomyomas collected from cohorts of Black and White women. STUDY DESIGN: We performed multiomic analysis of uterine leiomyomas from Black (42) and White (47) women undergoing hysterectomy for symptomatic uterine leiomyomata. In addition, our analysis included the application of orthogonal methods to evaluate fibroid biomechanical properties, such as second harmonic generation microscopy, uniaxial compression testing, and shear-wave ultrasonography analyses. RESULTS: We found a greater proportion of MED12 mutant uterine leiomyomas from Black women (>35% increase; Mann-Whitney U, P<.001). MED12 mutant tumors exhibited an elevated abundance of extracellular matrix proteins, including several collagen isoforms, involved in the regulation of the core matrisome. Histologic analysis of tissue fibrosis using trichrome staining and secondary harmonic generation microscopy confirmed that MED12 mutant tumors are more fibrotic than MED12 wild-type tumors. Using shear-wave ultrasonography in a prospectively collected cohort, Black patients had fibroids that were firmer than White patients, even when similar in size. In addition, these analyses uncovered ancestry-linked expression quantitative trait loci with altered allele frequencies in African and European populations correlating with differential abundance of several proteins in uterine leiomyomas independently of MED12 mutation status, including tetratricopeptide repeat protein 38. CONCLUSION: Our study shows that Black women have a higher prevalence of uterine leiomyomas harboring mutations in MED12 and that this mutational status correlates with increased tissue fibrosis compared with wild-type uterine leiomyomas. Our study provides insights into molecular alterations correlating with racial disparities in uterine leiomyomas and improves our understanding of the molecular etiology underlying uterine leiomyoma development within these populations.

Characteristics associated with blood transfusion among women undergoing laparoscopic myomectomy: a National Surgical Quality Improvement Program study.

BACKGROUND: Uterine fibroids are the most common benign tumors that affect females. A laparoscopic myomectomy is the standard surgical treatment for most women who wish to retain their uterus. The most common complication of a myomectomy is excessive bleeding. However, risk factors for hemorrhage during a laparoscopic myomectomy are not well studied and no risk stratification tool specific for identifying the need for a blood transfusion during a laparoscopic myomectomy currently exists in the literature. OBJECTIVE: This study aimed to identify risk factors for intraoperative and postoperative blood transfusion during laparoscopic myomectomies and to develop a risk stratification tool to determine the risk for requiring a blood transfusion. STUDY DESIGN: This was a retrospective cohort study of the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2020. Women who underwent a laparoscopic (conventional or robotic) myomectomy were included. Women who received 1 or more blood transfusions within 72 hours after the start time of a laparoscopic myomectomy were compared with those who did not require a blood transfusion. A multivariable analysis was performed to identify risk factors independently associated with the risk for transfusion. Two risk stratification tools to determine the need for a blood transfusion were developed based on the multivariable results, namely (1) based on preoperative factors and (2) based on preoperative and intraoperative factors. RESULTS: During the study period, 11,498 women underwent a laparoscopic myomectomy. Of these, 331(2.9%) required a transfusion. In a multivariable regression analysis of the preoperative factors, Black or African American and Asian races, Hispanic ethnicity, bleeding disorders, American Society of Anesthesiologists class III or IV classification, and a preoperative hematocrit value ≤35.0% were independently associated with the risk for transfusion. Identified intraoperative factors included specimen weight >250 g or ≥5 intramural myomas and an operation time of ≥197 minutes. A risk stratification tool was developed in which points are assigned based on the identified risk factors. The mean probability of transfusion can be calculated based on the sum of the points. CONCLUSION: We identified preoperative and intraoperative independent risk factors for a blood transfusion among women who underwent a laparoscopic myomectomy. A risk stratification tool to determine the risk for requiring a blood transfusion was developed based on the identified risk factors. Further studies are needed to validate this tool.

Relugolix combination therapy in Black/African American women with symptomatic uterine fibroids: LIBERTY Long-Term Extension study.

BACKGROUND: In the LIBERTY Long-Term Extension study, once-daily relugolix combination therapy (40 mg relugolix, estradiol 1 mg, norethindrone acetate 0.5 mg) substantially improved uterine fibroid-associated heavy menstrual bleeding throughout the 52-week treatment period in the overall study population. OBJECTIVE: Black or African American women typically experience a greater extent of disease and symptom burden of uterine fibroids vs other racial groups and have traditionally been underrepresented in clinical trials. This secondary analysis aimed to assess the efficacy and safety of relugolix combination therapy in the subgroup population of Black or African American women with uterine fibroids in the LIBERTY Long-Term Extension study. STUDY DESIGN: Black or African American premenopausal women (aged 18-50 years) with uterine fibroids and heavy menstrual bleeding who completed the 24-week randomized, placebo-controlled, double-blind LIBERTY 1 (identifier: NCT03049735) or LIBERTY 2 (identifier: NCT03103087) trials were eligible to enroll in the 28-week LIBERTY Long-Term Extension study (identifier: NCT03412890), in which all women received once-daily, open-label relugolix combination therapy. The primary endpoint of this subanalysis was the proportion of Black or African American treatment responders: women who achieved a menstrual blood loss volume of <80 mL and at least a 50% reduction in menstrual blood loss volume from the pivotal study baseline to the last 35 days of treatment by pivotal study randomized treatment group. The secondary outcomes included rates of amenorrhea and changes in symptom burden and quality of life. RESULTS: Overall, 241 of 477 women (50.5%) enrolled in the LIBERTY Long-Term Extension study self-identified as Black or African American. In Black or African American women receiving continuous relugolix combination therapy for up to 52 weeks, 58 of 70 women (82.9%; 95% confidence interval, 72.0%-90.8%) met the treatment responder criteria for reduction in heavy menstrual bleeding (primary endpoint). A substantial reduction in menstrual blood loss volume from the pivotal study baseline to week 52 was demonstrated (least squares mean percentage change: 85.0%); 64.3% of women achieved amenorrhea; 59.1% of women with anemia at the pivotal study baseline achieved a substantial improvement (>2 g/dL) in hemoglobin levels; and decreased symptom severity and distress because of uterine fibroid-associated symptoms and improvements in health-related quality of life through 52 weeks were demonstrated. The most frequently reported adverse events during the cumulative 52-week treatment period were hot flush (12.9%), headache (5.7%), and hypertension (5.7%). Bone mineral density was preserved through 52 weeks. CONCLUSION: Once-daily relugolix combination therapy improved uterine fibroid-associated heavy menstrual bleeding in most Black or African American women who participated in the LIBERTY Long-Term Extension study. The safety and efficacy profile of relugolix combination therapy in Black or African American women was consistent with previously published results from the overall study population through 52 weeks. Findings from this subanalysis will assist shared decision-making by helping providers and Black or African American women understand the efficacy and safety of relugolix combination therapy as a pharmacologic option for the management of uterine fibroid-associated symptoms.

Placental, maternal, fetal, and technical origins of false-positive cell-free DNA screening results.

The introduction of noninvasive prenatal testing has resulted in substantial reductions to previously accepted false-positive rates of prenatal screening. Despite this, the possibility of false-positive results remains a challenging consideration in clinical practice, particularly considering the increasing uptake of genome-wide noninvasive prenatal testing, and the subsequent increased proportion of high-risk results attributable to various biological events besides fetal aneuploidy. Confined placental mosaicism, whereby chromosome anomalies exclusively affect the placenta, is perhaps the most widely accepted cause of false-positive noninvasive prenatal testing. There remains, however, a substantial degree of ambiguity in the literature pertaining to the clinical ramifications of confined placental mosaicism and its potential association with placental insufficiency, and consequentially adverse pregnancy outcomes including fetal growth restriction. Other causes of false-positive noninvasive prenatal testing include vanishing twin syndrome, in which the cell-free DNA from a demised aneuploidy-affected twin triggers a high-risk result, technical failures, and maternal origins of abnormal cell-free DNA such as uterine fibroids or unrecognized mosaicisms. Most concerningly, maternal malignancies are also a documented cause of false-positive screening results. In this review, we compile what is currently known about the various causes of false-positive noninvasive prenatal testing.

Considerations on implementation of the newest treatment for symptomatic uterine fibroids: Oral GnRH antagonists.

Novel gonadotrophin releasing hormone (GnRH) antagonist treatments have recently been developed in combination with hormonal add-back therapy, as an oral treatment option for women suffering from uterine fibroids. Registration trials assessing the GnRH antagonist combination preparations with relugolix, elagolix and linzagolix have assessed treatment efficacy for fibroid-related heavy menstrual blood loss in comparison to placebo. Marketing authorization has been granted by several agencies including those in Europe, the United Kingdom and the United States. While the registration trials report a robust effect on the reduction of heavy menstrual blood loss and improvement in quality of life scores, reticence is advised before widespread prescription. In this review, we demonstrate limitations in the trial data, namely a lack of generalizability due to the restricted study population, the lack of transparency in the distribution of disease-level characteristics limiting the predictability of treatment success in the real-world diverse population, and the absence of any comparison to current alternative treatment methods. Importantly, no clinically meaningful volume reductions were found with GnRH antagonist combination preparations, and long-term safety data, particularly concerning modest but stable bone mineral density decline, need further addressing. Symptoms related to uterine fibroids adversely affect many women's quality of life and effective medical treatments are lacking. However, despite the urgent need for conservative treatments, it is vitally important that novel drugs, like combination oral GnRH antagonists, undergo sufficiently rigorous evaluation of safety, effectiveness and cost-effectiveness in a representative population and are compared with alternative treatment methods before introduction into mainstream clinical practice.

Uterine fibroids and non-informative cell-free DNA screening results.

OBJECTIVE: Uterine fibroids are monoclonal tumors, which are often genetically abnormal and associated with false-positive genome-wide cell-free DNA (cfDNA) screening results, particularly when large. It is plausible that fibroids may also increase the risk of cfDNA failure by affecting fetal fraction or due to their genetic anomalies confounding cfDNA algorithms. We aimed to investigate a possible association between fibroids and cfDNA non-informative results. METHODS: This was a retrospective cohort study of women undergoing cfDNA screening for fetal chromosomal abnormalities between 2013 and 2020, comparing pregnancies with vs without uterine fibroids recorded on any obstetric ultrasound before 24 weeks' gestation. Univariable and multivariable logistic regression models were used to investigate the association between fibroids and cfDNA failure, adjusting for gestational age, maternal age, weight and height at blood sampling, mode of conception, multiple gestation and test platform (chromosome-selective or genome-wide). Analyses were stratified according to the number of fibroids and total fibroid volume. The impact of fibroids on fetal fraction was assessed using linear regression, adjusting for the same covariates. RESULTS: Among 19 818 pregnancies undergoing cfDNA screening, fibroids were reported in 2038 (10.28%) and cfDNA failure at the first screening attempt occurred in 228 (1.15%) pregnancies. Non-informative results occurred in 1.96% of pregnancies with fibroids and 1.06% of pregnancies without fibroids (adjusted odds ratio (aOR), 2.40 (95% CI, 1.65-3.48)). The risk of failure in the first screening attempt increased progressively with the number of fibroids (aOR, 5.05 (95% CI, 2.29-11.13) in women with four or more fibroids) and total fibroid volume, with greater than a 5-fold and 14-fold increase in risk among women with fibroid volumes of 100.1-400 mL (aOR, 5.52 (95% CI, 2.30-13.25)) and > 400 mL (aOR, 14.80 (95% CI, 4.50-48.69)), respectively. Although test failure was more common with chromosome-selective than genome-wide screening, fibroids similarly increased the risk of failure of both screening platforms. Compared to pregnancies without fibroids, those with fibroids had a fetal fraction on average 0.61% lower (adjusted mean difference, -0.61% (95% CI, -0.77% to -0.45%)). CONCLUSION: Uterine fibroids are associated with lower fetal fraction and an increased risk of cfDNA screening failure. The strength of this association increases with increasing fibroid number and volume. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Feasibility, safety and efficacy of high intensity focused ultrasound ablation as a preoperative treatment for challenging hysteroscopic myomectomy.

PURPOSE: To investigate the feasibility, safety and efficacy of high intensity focused ultrasound ablation (HIFU) as a preoperative treatment for challenging hysteroscopic myomectomies. MATERIALS AND METHODS: A total of 75 patients diagnosed with types 0-III of uterine fibroids were enrolled. Based on the Size, Topography, Extension of the base, Penetration and lateral Wall position (STEPW) classification scoring system, 25 cases with a score ≥ 5 points were treated with HIFU followed by hysteroscopic myomectomy (HIFU + HM group), whereas 50 cases with a score < 5 points were treated with hysteroscopic myomectomy (HM group). RESULTS: The median preoperative STEPW score was 7 in the HIFU + HM group and 2 in the HM group. The average non-perfused volume (NPV) ratio achieved in fibroids after HIFU was 86.87%. Patients in the HIFU + HM group underwent hysteroscopic myomectomy one to four days after HIFU, and downgrading was observed in 81.81% of fibroids. The operation time for patients in the HIFU + HM group was 73 min and the success rate of myomectomy in a single attempt was 60%. The volume of distention medium used during the operation was greater in the HIFU + HM group than in the HM group (15,500 ml vs. 7500 ml). No significant difference was observed between the two groups in terms of intraoperative blood loss, the incidence of intraoperative and postoperative complications, menstrual volume score, or uterine fibroid quality of life score. CONCLUSION: HIFU can be utilized as a preoperative treatment for large submucosal fibroids prior to hysteroscopic myomectomy. HIFU offers a novel approach in the management of this subset of patients.

Risk factors affecting long-term efficacy of ultrasound-guided high-intensity focused ultrasound treatment for multiple uterine fibroids.

OBJECTIVES: To investigate the long-term efficacy of ultrasound-guided high-intensity focused ultrasound (USgHIFU) for multiple uterine fibroids and the factors associated with recurrence. MATERIALS AND METHODS: Five hundred and forty-nine patients with multiple uterine fibroids treated with USgHIFU from June 2017 to June 2019 were retrospectively analyzed. The Pictorial Blood Loss Assessment Chart (PBAC) was used to assess menstrual blood loss. The patients were asked to undergo pre- and post-USgHIFU magnetic resonance imaging (MRI) and complete routine follow-up after USgHIFU. Cox regression analysis was used to investigate the risk factors associated with recurrence. RESULTS: The median number of fibroids per patient was 3 (interquartile range: 3-4), and a total of 1371 fibroids were treated. Among them, 446 patients completed 3 years follow-up. Recurrence, defined as PBAC score above or equal to 100 and/or the residual fibroid volume increased by 10%, was detected in 90 patients within 3 years after USgHIFU, with a cumulative recurrence rate of 20.2% (90/446). The multi-factor Cox analysis showed that age was a protective factor for recurrence. Younger patients have a greater chance of recurrence than older patients. Mixed hyperintensity of fibroids on T2WI and treatment intensity were risk factors for recurrence. Patients with hyperintense uterine fibroids and treated with lower treatment intensity were more likely to experience recurrence than other patients after USgHIFU. No major adverse effects occurred. CONCLUSIONS: USgHIFU can be used to treat multiple uterine fibroids safely and effectively. The age, T2WI signal intensity and treatment intensity are factors related to recurrence.

Risk assessment and prediction of occult uterine sarcoma in patients with presumed uterine fibroids before high-intensity focused ultrasound treatment.

OBJECTIVE: To develop a diagnostic model for predicting occult uterine sarcoma in patients with presumed uterine fibroids. MATERIALS AND METHODS: We retrospectively reviewed 41631 patients with presumed uterine fibroids who presented for HIFU treatment in 13 hospitals between November 2008 and October 2023. Of these patients, 27 with occult uterine sarcoma and 54 with uterine fibroids were enrolled. Univariate analysis and multivariate logistics regression analysis were used to determine the independent risk factors for the diagnosis of occult uterine sarcoma. A prediction model was constructed based on the coefficients of the risk factors. RESULTS: The multivariate analysis revealed abnormal vaginal bleeding, ill-defined boundary of tumor, hyperintensity on T2WI, and central unenhanced areas as independent risk factors. A scoring system was created to assess for occult uterine sarcoma risk. The score for abnormal vaginal bleeding was 56. The score for ill-defined lesion boundary was 90. The scores for lesions with hypointensity, isointensity signal/heterogeneous signal intensity, and hyperintensity on T2WI were 0, 42, and 93, respectively. The scores for lesions without enhancement on the mass margin, uniform enhancement of tumor, and no enhancement in the center of tumor were 0, 20, and 100, respectively. Patients with a higher total score implied a higher likelihood of a diagnosis of occult uterine sarcoma than that of patients with a lower score. The established model showed good predictive efficacy. CONCLUSIONS: Our results demonstrated that the diagnostic prediction model can be used to evaluate the risk of uterine sarcoma in patients with presumed uterine fibroids.

A novel scoring system based on magnetic resonance imaging for the prediction of the difficulty of ultrasound-guided high-intensity focused ultrasound ablation for uterine fibroids.

OBJECTIVE: To develop a novel scoring system based on magnetic resonance imaging (MRI) for predicting the difficulty of ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation for uterine fibroids. MATERIALS AND METHODS: A total of 637 patients with uterine fibroids were enrolled. Sonication time, non-perfused volume ratio (NPVR), and ultrasound energy delivered for ablating 1 mm3 of fibroid tissue volume (E/V) were each classified as three levels and assigned scores from 0 to 2, respectively. Treatment difficulty level was then assessed by adding up the scores of sonication time, NPVR and E/V for each patient. The patients with score lower than 3 were categorized into low difficulty group, with score equal to or greater than 3 were categorized into high difficulty group. The potential predictors for treatment difficulty were compared between the two groups. Multifactorial logistic regression analysis model was created by analyzing the variables. The difficulty score system was developed using the beta coefficients of the logistic model. RESULTS: Signal intensity on T2WI, fibroid location index, largest diameter of fibroids, abdominal wall thickness, homogeneity of the signal of fibroids, and uterine position were independent influencing factors for the difficulty of USgHIFU for uterine fibroids. A prediction equation was obtained: difficulty score = 17 × uterine position (anteverted =0, retroverted =1)+71 × signal intensity (hypointense = 0, isointense/hyperintense = 1) +8 × enhancement (homogenous = 0, heterogeneous = 1)+25×(largest diameter of fibroids-20) +35 × (fibroid location index -0.2) +1×(abdominal wall thickness -5). CONCLUSIONS: This scoring system established based on MRI findings can be used to reliably predict the difficulty level of USgHIFU treatment of uterine fibroids.

Long-term re-intervention after USgHIFU and prediction of NPVR in different ages of patients with uterine fibroids.

OBJECTIVE: Long-term re-intervention after ultrasound-guided high intensity focused ultrasound (USgHIFU) ablation was reported, and the prediction of non-perfusion volume ratio (NPVR) in differently aged patients with uterine fibroids (UFs) was explored. MATERIALS AND METHODS: Patients with UFs who underwent USgHIFU ablation from January 2012 to December 2019 were enrolled and divided into < 40-year-old and ≥ 40-year-old groups. Cox regression was used to analyze the influencing factors of re-intervention rate, and receiver operating characteristic (ROC) curve was used to analyze the correlation between NPVR and re-intervention rate. RESULTS: A total of 2141 patients were enrolled, and 1558 patients were successfully followed up. The 10-year cumulative re-intervention rate was 21.9%, and the < 40-year-old group had a significantly higher rate than the ≥ 40-year-old group (30.8% vs. 19.1%, p < 0.001). NPVR was an independent risk factor in both two groups. When the NPVR reached 80.5% in the < 40-year-old group and 75.5% in the ≥ 40-year-old group, the risk of long-term re-intervention was satisfactory. CONCLUSION: The long-term outcome of USgHIFU is promising. The re-intervention rate is related to NPVR in differently aged patients. Young patients need a high NPVR to reduce re-intervention risk.