Assessment of rare bleeding disorders in adolescents with heavy menstrual bleeding.

INTRODUCTION: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. AIM: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. METHODS: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. RESULTS: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. CONCLUSION: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

Real-world experience of direct oral anticoagulant use in a single pediatric center.

BACKGROUND: Pediatric venous thromboembolism has increased by 130%-200%, specifically in hospitalized children, and direct oral anticoagulants (DOACs) offer several therapeutic advantages. METHODS: This study aims to evaluate the real-world epidemiological and outcome data from a retrospective review of pediatric patients treated with DOACs from January 1, 2013 to December 31, 2022. In this single-center, IRB-approved study, 65 patients were identified and analyzed using SPSS statistical software, and a descriptive statistical analysis was conducted. RESULTS: Of the 65 patients, 37% were on apixaban, 61.5% were on rivaroxaban, and 1.5% were on dabigatran. Per the 2023 ISTH outcome definitions, one (2%) patient had a major bleeding episode, six (9%) had clinically relevant non-major bleeding, three (5%) patients had patient-important heavy menstrual bleeding (HMB), and one (1.5%) patient had minor bleeding. Seven (19%) of 37 postmenarchal patients had evidence of HMB. Six (9.2%) patients had recurrent venous thromboembolism while on a DOAC (one was on apixaban, and five were on rivaroxaban) and were transitioned to other forms of anticoagulation. CONCLUSION: Thus, bleeding rates after DOAC therapy are comparable to previous DOAC trials, as well as other anticoagulants in pediatrics. HMB is an important outcome measure and should continue to be investigated. This study reports a higher rate of recurrent thrombosis (9.2%) compared to other trials. However, this observation may be attributed to patients who had ongoing risk factors, as well as a longer duration of study follow-up. Additional multicentered outcome studies evaluating DOAC use in children are needed to determine long-term recurrence and HMB risks.

Parity, mode of birth, and long-term gynecological health: A follow-up study of parous and nonparous women in the Australian Longitudinal Study on Women's Health cohort.

BACKGROUND: Although gynecological health issues are common and cause considerable distress, little is known about their causes. We examined how birth history is associated with urinary incontinence (UI), severe period pain, heavy periods, and endometriosis. METHODS: We studied 7700 women in the Australian Longitudinal Study on Women's Health with an average follow-up of 10.9 years after their last birth. Surveys every third year provided information about birth history and gynecological health. Logistic regression was used to estimate how parity, mode of birth, and vaginal tears were associated with gynecological health issues. Presented results are adjusted odds ratios (OR) with 95% confidence intervals. RESULTS: UI was reported by 16%, heavy periods by 31%, severe period pain by 28%, and endometriosis by 4%. Compared with women with two children, nonparous women had less UI (OR 0.35 [0.26-0.47]) but tended to have more endometriosis (OR 1.70 [0.97-2.96]). Also, women with only one child had less UI (OR 0.77 [0.61-0.98]), but more severe period pain (OR 1.24 [1.01-1.51]). Women with 4+ children had more heavy periods (OR 1.42 [1.07-1.88]). Compared with women with vaginal birth(s) only, women with only cesarean sections or vaginal birth after cesarean section had less UI (ORs 0.44 [0.34-0.58] and 0.55 [0.40-0.76]), but more endometriosis (ORs 1.91 [1.16-3.16] and 2.31 [1.25-4.28]) and heavy periods (ORs 1.21 [1.00-1.46] and 1.35 [1.06-1.72]). Vaginal tear(s) did not increase UI after accounting for parity and birth mode. CONCLUSION: While women with vaginal childbirth(s) reported more urinary incontinence, they had less menstrual complaints and endometriosis.

Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials.

BACKGROUND: Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids. METHODS: PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed. FINDINGS: Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8-66·6%) in the 100 mg group, 66·4% (56·6-75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8-79·8%) in the 200 mg group, and 75·5% (66·0-83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8-45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3-66·7%) in the 100 mg group, 77·2% (67·8-85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4-85·3%) in the 200 mg group, and 93·9% (87·1-97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8-39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3-14% in all other groups). INTERPRETATION: Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy. FUNDING: ObsEva.

Infertility in patients with uterine fibroids: a debate about the hypothetical mechanisms.

Fibroids are benign tumours of the myometrium and are the most common gynaecologic abnormality. Although most fibroids are asymptomatic, they can cause symptoms like heavy menstrual bleeding, pelvic pain, sexual dysfunction, pressure complaints, and infertility. The association between fibroids and infertility has been debated for decades. It is generally acknowledged that the closer the fibroid is to the uterine cavity and the endometrium lining, the more unfavourable effect it might have on fertility, reducing the odds for successful implantation and gestation. Based on the limited available literature, we propose and discuss seven hypotheses on the underlying mechanism by which fibroids may reduce fertility. (i) Fibroids can cause sexual dysfunction, as fibroids can cause dyspareunia, pelvic pain, and prolonged and heavy menstrual bleeding, which could interfere with sexual arousal and as a consequence the frequency of intercourse, resulting in a reduced probability of conception. (ii) Mechanical compression by fibroids on theinterstitial part of the fallopian tubes or deformation of uterine cavity could disturb oocyte and sperm transport. (iii) Fibroids can disturb peristalsis of the junctional zone in the myometrium, which could negatively influence oocyte and sperm transport as well as implantation. In addition, fibroids could induce a detrimental environment for implantation in other ways, by: (iv) changing the vagino-uterine microbiome; (v) disturbing the levels of inflammation and autophagy; (vi) inducing molecular changes in the endometrium; and (vii) inducing aberrant angiogenesis and altering the endometrial blood supply. After the discussion of these hypotheses, the implication of the influence of fibroids on early pregnancy loss is discussed. Surgical fibroid treatment is not tailored nor focussed on the pathophysiology of the fibroid; consequently it may be accompanied by recurrence of fibroids and risks of complications. Unravelling the pathogenic mechanisms about how fibroids influence fertility is essential to evolve classic surgical fibroid treatment. Instead of treatment of fibroid-related symptoms, the research should supports development of fibroid-targeted (pharmaceutical) treatment that is compatible with an active wish to become pregnant.

Women and girls with haemophilia: A retrospective cohort study in China.

INTRODUCTION: Women and girls with haemophilia (WGH) may have spontaneous/traumatic bleeding similar to that in males with haemophilia, and in addition excessive bleeding during menstruation and delivery. AIM: To characterize WGH in China and provide guidance for better management. METHODS: We retrospectively analysed the characteristics of WGH registered in the Haemophilia Treatment Center Collaborative Network of China (HTCCNC) Registry, including demographics, diagnosis and treatment, bleeding characteristics, obstetrical and gynaecological experiences, and surgical history. RESULTS: A total of 61 females had confirmed haemophilia. Diagnosis and treatment were typically delayed, longer in mild haemophilia than in severe and moderate. The most frequently reported bleeding manifestations were haemarthrosis in severe and moderate patients, and cutaneous bleeding in mild patients. Among 45 postmenarcheal WGH, 21 (46.7%) had history of heavy menstrual bleeding, but only three received treatments. Prenatal diagnosis and management of perinatal haemorrhage were inadequate. Of 34 deliveries in 30 women, nine deliveries were complicated by postpartum haemorrhage, and 22 offspring carried mutations causing haemophilia. Forty-four surgical procedures were performed in 29 patients. Those procedures receiving preoperative coagulation factors coverage were significantly less likely to have excessive bleeding than those who did not (P = .003). CONCLUSION: This is the first and largest study describing WGH in China. There are currently deficiencies in the identification, diagnosis, and management of these patients. Improving health insurance policies, establishing haemophilia centres, and multidisciplinary teams for bleeding and perinatal or perioperative management will help reduce morbidity and mortality.

Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: Systematic and targeted literature reviews.

INTRODUCTION: Debilitating clinical complications in von Willebrand disease (VWD) can affect health-related quality of life (HRQoL), increase healthcare costs and cause long-lasting consequences. However, the magnitude of these burdens needs to be more fully explored. AIM: To estimate the prevalence and burden of clinical complications, the impact on HRQoL and the economic burden associated with VWD. METHODS: Embase® , MEDLINE® , the Cochrane Library and conference proceedings were searched for studies on VWD evaluating clinical complications, HRQoL and cost and resource use. RESULTS: Among 16 studies assessing clinical complications in VWD, the most prevalent bleeding symptoms were menorrhagia (2%-95% [n = 7 studies]), epistaxis (12%-80% [n = 6]) and easy bruising (46%-65% [n = 2]). Among 17 studies evaluating HRQoL, the most common assessment scales were the generic SF-36 (n = 8 studies) and the EQ-5D (n = 2). Bleeding symptoms were associated with reduced QoL in six of seven studies, and of six studies evaluating treatment impact, four reported improvements in one or more HRQoL components. Among 25 studies on cost and resource use, key observations included higher post-surgery healthcare costs in VWD versus non-VWD patients (n = 1 study) and higher costs and resource use in VWD patients with bleeding complications versus those without (n = 1). CONCLUSION: Although limited, available evidence suggests that VWD patients experience a high burden of clinical complications, reduced QoL and high healthcare costs. Haemarthrosis is more common in severe VWD than is often assumed, and bleeds (including haemarthrosis) can reduce QoL. Research efforts to improve QoL and other outcomes should be prioritized.

Comprehensive Analysis of Iron Deficiency Anemia and Its Related Disorders in Premenopausal Women Based on a Propensity Score Matching Case Control Study Using National Health Insurance Service Database in Korea.

BACKGROUND: Menorrhagia is a common cause of iron deficiency anemia (IDA) in premenopausal women. However, the effects of menorrhagia on IDA in premenopausal women have been underestimated compared to those on other IDA-related disorders (IRDs) such as gastrointestinal malignancies (GIMs). To better understand the relationship between menorrhagia and IDA in premenopausal women, we analyzed the National Health Insurance Service-National Health Information Database (NHIS-NHID). METHODS: From 2005 to 2008, data about women between the age of 20 and 59 years were extracted from the NHIS-NHID to create a propensity score-matched case (IDA) and control group. The annual incidence of IDA was calculated per age group. A 10-year follow up of the study population was determined to detect IRDs in case and control groups. We compared the risk of detection (ROD) of IRDs, including GIM and gynecological disorders associated with menorrhagia - leiomyoma of uterus (LM) and adenomyosis (AM), in the case and the control group. RESULTS: From 2005 to 2008, women diagnosed with IDA (n = 535,249) and healthy women as a control group (n = 1,070,498) were identified from the NHIS-NHID. The annual incidence of IDA was 767.4 (2005), 948.7 (2006), 981.6 (2007), and 897.7 (2008) per 100,000 women. The age distribution of IDA was similar each year; IDA was common in women aged 30-39 years (36-37%) and 40-49 years (30-32%), and its incidence was significantly decreased in women aged 50-59 years (< 10%). The ROD of IRDs were significantly higher in the IDA group than in the control group (LM: 20.8% vs. 6.9%, AM: 5.6% vs. 1.6%, and GIM: 2.6% vs. 0.7%). The corresponding hazard ratios were 3.89 (95% confidence interval [CI], 3.85-3.93) for LM, 4.99 (95% CI, 4.90-5.09) for AM, and 3.43 (95% CI, 3.32-3.55) for GIM. The ROD of the IRDs varied; the ROD of LM in the IDA group increased with age and decreased in the age group 50-59 years. AM was more frequently detected in women with IDA aged 30-39 years and less in women older than 40 years. The frequency of GIM increased with age. CONCLUSION: In this study, we found that the gynecologic disease is the main cause of IDA in premenopausal women. Gynecological evaluations should be performed more actively in the clinic to prevent and control IDA and IRDs.

Iron deficiency and fatigue among adolescents with bleeding disorders.

Iron deficiency anemia is associated with heavy menstrual bleeding (HMB) and, by extension, a bleeding disorder (BD). It is unknown if iron deficiency without anemia is associated with a BD in adolescents. Moreover, the threshold of ferritin associated with fatigue in adolescents with HMB is unclear. In this multicenter study, we enrolled adolescents with HMB without BD. Participants underwent BD and anemia work-up in Young Women's Hematology Clinics and completed the Peds QL™ fatigue scale. BDs were defined as von Willebrand Disease, platelet function defect, clotting factor deficiencies, and hypermobility syndrome. Two hundred and fifty consecutive adolescents were enrolled, of whom 196 met eligibility criteria. Overall, 43% (95% confidence interval: 36%-50%) were diagnosed with BD. A total of 61% (n = 119) had serum ferritin levels < 15 ng/mL, 23.5% (n = 46) had iron deficiency only, and 37% (n = 73) had iron deficiency anemia. Low ferritin or ferritin dichotomized as < 15 or ≥ 15 ng/mL was not associated with BD on univariable analysis (p = .24) or when accounting for age, race, ethnicity, body mass index, and hemoglobin (p = .35). A total of 85% had total fatigue score below the population mean of 80.5, and 52% (n = 102) were > 2 SD (or < 54) below the mean, the cut-off associated with severe fatigue. A ferritin threshold of < 6 ng/mL had a specificity of 79.8% but a sensitivity of 36% for severe fatigue. In conclusion, iron deficiency without anemia is not a predictor of BD in adolescents with HMB in a specialty setting. Severe fatigue, especially sleep fatigue, is prevalent in adolescents with BD. Ferritin of < 6 ng/mL has ~80% specificity for severe fatigue in adolescents with HMB.

Development of the Bleeding and Pelvic Discomfort Scale for Use in Women With Heavy Menstrual Bleeding Associated With Uterine Fibroids.

OBJECTIVES: This study aimed to define a cardinal symptom burden measure based on items from the Uterine Fibroid Symptom and Quality of Life questionnaire for use as a clinical trial endpoint. METHODS: Exploratory factor analysis was computed to assess the Uterine Fibroid Symptom and Quality of Life symptom severity scale factor structure, using phase 2 data. Pooled blinded data from phase 3 studies were used for the confirmatory factor analysis and the psychometric evaluation of the new measure. Exit interviews in 30 patients from phase 3 studies provided additional qualitative evidence. A meaningful change threshold was determined using anchor-based analyses supported by patient feedback in the exit interviews. RESULTS: Three factors emerged from the exploratory factor analysis. Factor 1, called the bleeding and pelvic discomfort (BPD) scale, consists of cardinal symptoms, measuring menstrual distress owing to heavy bleeding, passing blood clots, and feeling tightness or pressure in pelvic area. Patients generally understood the items in the scale and the recall period as intended. The BPD scale had good item performance and internal consistency reliability, strong item-to-total correlations, good item discrimination, known-groups validity, and ability to detect change. A 20-point change on the BPD scale was determined as the clinically meaningful change threshold. CONCLUSIONS: The BPD scale assesses symptom burden owing to bleeding, passing blood clots, and pelvic pressure. The subscale is based on a subset of items selected to measure the cardinal symptoms of uterine fibroids in a clinical trial setting. The responder threshold evaluates whether patients experience a meaningful treatment benefit over the on-treatment period.

Characteristics of Submucous Myomas and the Risk of Anemia.

Background and Objectives: Uterine fibroids still represent the most common indication for hysterectomy for benign pathologies. In the United States, more than 479,000 hysterectomies are performed annually, 46.6% for myomas and 47.7% in women aged from 18 to 44 years. By applying appropriateness criteria to this procedure, it has been estimated that overuse ranges from 16 to 70%. One of the main reasons that induce patients and gynecologists to consider hysterectomy is represented by severe anemia. Materials and Methods: This is a retrospective cohort study of 202 patients with uterine fibroids diagnosed by transvaginal ultrasound who underwent a hysteroscopic procedure. Myoma grade, size, location, and number were assessed by transvaginal scan and office hysteroscopy and correlated to the pre-treatment hemoglobin level. Results: Univariate analysis showed that anemia does not have a statistically significant association with myoma number and with age considered as a numerical predictor. In the patients with myoma type 0, there is a possibility of 81% having anemia regardless of menorrhagia. On the contrary, in patients with myoma type 1 or type 2, the possibility of having anemia varies according to the presence or absence of menorrhagia. If there is menorrhagia, the risk of moderate anemia is only present for myomas >60 mm. Conclusions: The results of this study may contribute to defining objective criteria for the management of submucous myomas and anemia. Our data suggest that submucosal myomas type 0 >10 mm should always be treated, putting patients at risk for anemia. Myomas type 2 and 3 should be treated for the risk of anemia in the presence of menorrhagia episodes or if > of 60 mm. Adequate management of anemia and myomas could reduce the rate of unnecessary hysterectomies.

Evaluating the effectiveness of let's talk period's high school educational outreach program: A pilot study.

INTRODUCTION: Menorrhagia impacts ~40% of adolescent females, with about half having an underlying bleeding disorder, most commonly von Willebrand Disease (VWD). VWD affects ~1 in 1000 individuals, though many are unaware of their condition. Let's Talk Period (LTP) is an online knowledge translation platform aimed at increasing awareness of bleeding disorders symptoms, with a validated self-administered bleeding assessment tool (Self-BAT). AIM: To evaluate the effectiveness of the LTP high school outreach program in Grade 9 girls' health classes quantitatively, using baseline, post-presentation, and follow-up quiz scores, and qualitatively, with student and teacher feedback forms. METHODS: The 75-minute in-class presentations, developed in alignment with the 2015 Ontario Curriculum for Grade 9 Health and Physical Activity, were led by a haemophilia nurse, clinical research assistant, and undergraduate student from the LTP team. Students completed baseline, post-presentation, and 4-6-week follow-up Kahoot quizzes featuring the same nine questions to evaluate change in knowledge levels and retention. Both student and teacher feedback were collected. RESULTS: There was a significant increase (p < 0.001) from baseline to post-presentation scores, with a significant gain in knowledge, for all questions (p < 0.01). Students found content related to the basics and management of menstruation to be most interesting. Many had constructive feedback on how the presentation method could be improved. On average, the presentations were rated an 8.6 of 10 by students and 8.75 of 10 by teachers. CONCLUSION: The LTP high school outreach program effectively increases student knowledge of menorrhagia and bleeding disorders. It was well-received by students and staff alike.

Central retinal vein occlusion secondary to severe iron-deficiency anaemia resulting from a plant-based diet and menorrhagia: a case presentation.

In this case presentation, we present a young vegan patient who developed a CRVO secondary to severe iron-deficiency anaemia (IDA) attributable to menstrual losses and limited iron intake. CRVO is a rare complication of IDA.With rising calls for sustainable diets and rising evidence for a plant-based diet, there has been a rise in popularity of such diet forms. While there are ocular benefits from this diet trend, the potential for nutritional deficiencies including iron needs to be monitored especially in susceptible individuals. Iron is essential for retina metabolism and function; however, excess iron contributes to disease states in the eye. Therefore, supplementation needs to be judicious.

Anemia management in non-menopausal women in a primary care setting: a prospective evaluation of clinical practice.

BACKGROUND: The study aimed to analyze anemia management in non-pregnant, and non-menopausal women aged from 18 to 50 years old, in a French primary care setting. METHODS: An observational descriptive prospective study was conducted between November 2018 and February 2019. Inclusion criteria were as followed: anemia diagnosed in women aged from 18 to 50, not pregnant and not menopausal. Quantitative and qualitative data were anonymized and collected through an electronic survey. Investigating general practitioners completed the questionnaire for each newly diagnosed woman. Mean values and medians were calculated for the quantitative data. Answers to the open questions were encoded manually and proportions of the different modalities have been calculated. RESULTS: Altogether, 43 women with anemia were ascertained. Moderate microcytic anemia, due to an iron deficiency in a context of menorrhagia, was the most observed anemia profile. The mean value of hemoglobin was 10.5 ± 1 g/dl. Among these women: 32 (74%) presented an iron deficiency, 17 (53%) had inappropriate intakes, and 9 (28%) reported menorrhagia. For 17 (40%) women, unnecessary or inappropriate exams were prescribed. The investigations did not allow to establish a differential diagnosis for 12 women (28%). Even for similar clinical situations, anemia management was variable. Among the women who presented iron deficiency, 15 (47%) were informed about an iron-rich diet and received a daily iron supplementation of ferrous sulfate between 80 mg and 160 mg. CONCLUSIONS: Our study highlights that, in the absence of specific national guidelines for anemia management in non-pregnant, non-menopausal women in primary care settings, French GPs undergo various clinical management strategies leading to a heterogeneous, sometimes inappropriate follow-up. Women with iron deficiency were prescribed higher daily iron supplementation than recommended, according to new evidence, suggesting a maximal daily dose of 50 mg of elementary iron in a context of Hepcidin up-regulation in the case of an iron overload. Additional longitudinal studies with a bigger sample size and randomized controlled trials are needed to confirm our results and to elaborate national guidelines.

Incidence of Thyroid Disease in Adolescent Females Presenting with Heavy Menstrual Bleeding.

The incidence of thyroid disease in adolescents with heavy menstrual bleeding is unknown. A retrospective cross-sectional study of 427 adolescents presenting with heavy menstrual bleeding found 0.23% (95% CI 0%-0.7%) had thyroid disease, lower than that expected in the general population. Thyroid testing should only be considered when other symptomatology is present.

Safety and efficacy of the selective progesterone receptor modulator asoprisnil for heavy menstrual bleeding with uterine fibroids: pooled analysis of two 12-month, placebo-controlled, randomized trials.

STUDY QUESTION: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY: In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION: In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE: In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION: Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS: Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER: NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT'S ENROLMENT: 12 September 2002; 6 September 2002.

Successful Pregnancies in Women with Diffuse Uterine Leiomyomatosis after Hysteroscopic Management Using the Hysteroscopy Endo Operative System.

STUDY OBJECTIVE: To evaluate the feasibility, effectiveness, and reproductive outcome of hysteroscopic management using the Hysteroscopy Endo Operative system (HEOS) in patients with diffuse uterine leiomyomatosis (DUL). DESIGN: Retrospective study (Canadian Task Force classification III). SETTING: Beijing Tiantan Hospital, Capital Medical University, Beijing, China. PATIENTS: Eight women of reproductive age suffering from menorrhagia and anemia or infertility diagnosed with DUL by ultrasonography and hysteroscopy. INTERVENTIONS: Hysteroscopic surgery using cold graspers combined with electric loop by the HEOS was performed to excise submucous myomas (including types 0, I, and II), leaving other intramural myomas in place. The fenestration method is used in electrical hysteroscopic myomectomy. Postoperative endometrial repair and synechiae, menstrual improvement, conception, and pregnancy were recorded. MEASUREMENTS AND MAIN RESULTS: Two patients underwent a single hysteroscopic myomectomy, whereas 6 patients underwent 2 to 3 myomectomies. No complications were observed. The mean follow-up period was 39.13 ± 17.01 months (range, 21-67). The endometrium recovered 2 to 3 months after the initial surgery, and 100% improvement in menstruation was observed. Two patients had mild synechia after the first hysteroscopic surgery. Seven patients conceived spontaneously (postoperative pregnancy rate, 87.5%), 6 of whom had a full-term pregnancy. One patient suffered a miscarriage in the second trimester (live birth rate, 75%). CONCLUSION: Hysteroscopic surgery using cold graspers combined with electric loop by the HEOS is a feasible and effective for treatment of DUL because it preserves the uterus and yields favorable reproductive outcomes. The cold surgery and fenestration method minimizes electrical and thermal damage to the endometrium surrounding the myoma, consequently reducing surgical risks.

Women prefer proactive support from providers for treatment of heavy menstrual bleeding: A qualitative study in adult women with moderate or severe Von Willebrand disease.

OBJECTIVE: To explore key factors for successful support in women with moderate or severe Von Willebrand disease (VWD) who are faced with heavy menstrual bleeding (HMB) and surgery. DESIGN: A qualitative study design with focus-group interviews and thematic analysis of the discussions. SETTINGS AND POPULATION: Eleven VWD women aged 41-68 years (median age 58 years) who had had a hysterectomy or bipolar radiofrequency ablation (BRA) because of HMB participated in this study. Three of the 11 participants had VWD diagnosed before surgery. Two focus groups were conducted in the summer of 2012. Patients were identified through participation in a nationwide study on Von Willebrand disease in the Netherlands (WiN study). Inclusion criteria were at least 18 years of age, fluent in Dutch, diagnosed with VWD (based on Von Willebrand factor (VWF) antigen and/or activity levels < 30 IU/dL) and previous surgical therapy for HMB. FINDINGS: The following key factors were identified during focus-group interviews: receiving information, proactive support from providers and considering bleeding disorders as a cause of HMB. Other topics were as follows: experiences with VWD and/or surgery, how relieved patients were when menses stopped, patients hoped that in future, providers would work better together so that women receive the best care. CONCLUSIONS: In this focus-group study among women with VWD who underwent surgery because of HMB, support by professionals could be improved by considering a bleeding disorder in women with HMB, providing information about different types of surgery and shared decision-making regarding type of interventions.

Differences in bleeding phenotype and provider interventions in postmenarchal adolescents when compared to adult women with bleeding disorders and heavy menstrual bleeding.

INTRODUCTION: Due to lack of patient/health care provider awareness causing delayed diagnosis, the bleeding phenotype and provider interventions in adolescents with heavy menstrual bleeding (HMB) and bleeding disorders (BD) may be different when compared to adults. AIM: The aim of this study was to compare/characterize bleeding phenotype and provider interventions in postmenarchal adolescents < 18 years and premenopausal adults ≥ 18 years with HMB and BD. METHODS: Patient demographics, BD, and provider interventions/therapy details for HMB were compared between both age groups enrolled in the Centers for Disease Control and Prevention (CDC) Female Universal Data Collection (UDC) surveillance project in United States hemophilia treatment centres. Cross-sectional descriptive analyses including frequency distributions, summary statistics, bivariate and logistic regression analyses were performed. RESULTS: Of 269 females (79 adolescents; median age 16 years, interquartile range (IQR) = 2; 190 adults; median age 27 years, IQR = 13) evaluated, BD distribution was similar in both groups. Compared to adolescents, adults more often had family history of bleeding (Adjusted odds ratios [AOR] = 2.6, 1.3-5.6), delay in diagnosis (AOR = 2.5, 1.2-4.9), bleeding with dental procedures (AOR = 2.0, 1.0-4.0), gastrointestinal bleeding (AOR = 4.6, 1.0-21.9), anaemia (AOR = 2.7, 1.4-5.2), utilized desmopressin less often (AOR = 0.4, 0.2-0.8) and underwent gynaecologic procedure/surgery more frequently (AOR = 5.9, 1.3-27.3). CONCLUSION: Bleeding phenotypes of adolescents and adults with HMB and BD were different with more frequent bleeding complications, anaemia, gynaecologic procedures/surgeries, less desmopressin use and more delay in diagnosing BD in adults. Longitudinal studies are needed to determine whether improved patient/provider awareness and education will translate to early diagnosis and timely management of BD/HMB in adolescents that may prevent/reduce future haematologic/gynaecologic complications.