Inherited bleeding disorders in obstetrics and gynaecology

The aim of this thesis is to investigate the obstetric and gynaecological problems and their management in women with inherited bleeding disorders, as well as the role of such disorders in obstetric and gynaecological haemorrhage. The uptake of prenatal diagnosis and termination of an affected pregnancy is low in carriers of haemophilia. Fetal gender determination has important implications in the management of labour in carriers who do not wish to have specific prenatal diagnosis. The attitude of women towards reproductive choices is influenced by ethnic and cultural issues and family experience with the disease. Haemostatic response to pregnancy is variable in different types and subtypes of inherited bleeding disorders and in the same patient in different pregnancies. Haemorrhagic complications are confined to post-abortal and post-partum period. The incidence of primary and secondary post-partum haemorrhage was 22% and 11% in carriers of haemophilia, 18.5% and 20% in vWD and 16% and 24% in FXI deficient women, respectively. Women with low factor levels (<50 iu/dl) and no prophylactic treatment for labour and puerperium are especially at risk. There are great inter- and intra-individual variations in coagulation markers in women due to different physiological conditions including age, ethnicity, blood group and hormonal changes during different phases of the menstrual cycle. Women with inherited bleeding disorders suffer from heavy and prolonged menstruation which adversely affects their quality of life. Objectively confirmed menorrhagia is significantly higher in these women (67%) compared with the control group (29%). On the other hand, undiagnosed inherited bleeding disorders can be the underlying cause in a significant proportion (17%) of women presenting with unexplained menorrhagia. The DDAVP nasal spray was shown not to be superior to placebo in the treatment of menorrhagia. Increased awareness among clinicians responsible for women's health of these disorders and their morbidity and the availability of management guidelines are essential for optimal care and improvement of the quality of life of these patients

Reproductive health and hemostatic issues in women and girls with congenital factor VII deficiency: A systematic review

BACKGROUND: Congenital factor VII (FVII) deficiency is an inherited bleeding disorder, with heterogenous bleeding symptoms. Women with FVII deficiency face hemostatic challenges during menstruation, ovulation, and childbirth. This systematic review evaluated prevalence and management of bleeding symptoms associated with gynecological and obstetric issues in women with FVII deficiency. METHODS: Databases (BIOSIS Previews, Current Contents Search, Embase, and MEDLINE) were searched for studies reporting FVII deficiency and gynecological or obstetric issues in women. Articles were screened using Joanna Briggs Institute checklists and relevant data extracted. RESULTS: One hundred fourteen women were identified from 62 publications. Forty-six women had severe deficiency (FVII:C < 5% or <5 IU/dl). Heavy menstrual bleeding (HMB) was the most common bleeding symptom (n = 94; 82%); hospitalization and urgent medical/surgical interventions for acute HMB episodes were required in 16 women (14%). Seven women reported ovarian bleeding (6%); other bleeding symptoms varied. Patient management was inconsistent and included hemostatic and hormonal treatments. Only four women (7%) reporting vaginal bleeding during pregnancy. Postpartum hemorrhage (PPH) occurred following 12/45 deliveries (27%; 5 [42%] requiring blood transfusion) and was not necessarily prevented by prophylaxis (8 women). CONCLUSION: Women with congenital FVII deficiency have an increased risk of HMB, ovarian bleeding, and PPH, impacting quality of life. Recognition of a bleeding disorder as the cause is often delayed. Management of bleeding complications is heterogeneous due to lack of treatment guidelines. Harmonizing severity classification of FVII deficiency may help standardize treatment strategies and development of specific guidelines for these women

Desmopressin to prevent and treat bleeding in pregnant women with an inherited bleeding disorder:a systematic literature review

Background: Although desmopressin (DDAVP) is an accessible and inexpensive hemostatic drug, its use in pregnancy is still debated due to safety uncertainties. Objectives: We aimed to review the safety and effectiveness of DDAVP in women with an inherited bleeding disorder during pregnancy and delivery. Methods: Databases were searched for articles up to July 25, 2022, reporting maternal and/or neonatal outcomes. PRISMA methodology for systematic reviews and meta-analyses was followed (PROSPERO CRD42022316490). Results: Fifty-three studies were included, comprising 273 pregnancies. Regarding maternal outcomes, DDAVP was administered in 73 women during pregnancy and in 232 during delivery. Safety outcome was reported in 245 pregnancies, with severe adverse events reported in 2 (1%, hyponatremia with neurologic symptoms). Overall, DDAVP was used as monotherapy in 234 pregnancies, with effectiveness reported in 153 pregnancies (82% effective; 18% ineffective). Regarding neonatal outcomes, out of 60 pregnancies with reported neonatal outcomes after DDAVP use during pregnancy, 2 children (3%) had a severe adverse event (preterm delivery n = 1; fetal growth restriction n = 1). Of the 232 deliveries, 169 neonates were exposed to DDAVP during delivery, and in 114 neonates, safety outcome was reported. Two children (2%) experienced a moderate adverse event (low Apgar score n = 1; transient hyperbilirubinemia not associated with DDAVP n = 1). Conclusion: DDAVP use during pregnancy and delivery seems safe for the mother, with special attention to the occurrence of hyponatremia and for the child, especially during delivery. However, due to poor study designs and limited documentation of outcomes, a well-designed prospective study is warranted.</p

Preface

Reproductive tract bleeding in women is a naturally occurring event during menstruation and childbirth. In women with menorrhagia, however, congenital bleeding disorders historically have been underdiagnosed. This consensus is intended to allow physicians to better recognize bleeding disorders as a cause of menorrhagia and consequently offer effective disease-specific therapies. © 2009 Mosby, Inc. All rights reserved

Clinical management of woman with bleeding disorders: A survey among European haemophilia treatment centres

Introduction: The impact of bleeding for women with bleeding disorders (WBD) is of increasing focus and importance. Despite this, optimal management strategies are unclear and knowledge gaps persist. Aim: To examine practices and define research priorities on diagnosis and management of WBD in Europe. Methods: An electronic survey on clinical management of WBD was sent to 136 European haemophilia treatment centres (HTCs), including open questions on knowledge gaps and research priorities. Results: Fifty-nine HTCs from 12 Western (WE) and 13 Central/Eastern European (CEE) countries completed the survey. Less than half runs a joint clinic (24 HTCs, 42%). Most centres without a joint clinic have a named obstetrician (81%) and/or gynaecologist (75%) available for collaboration. Overall 18/54 (33%) European HTCs do not offer preimplantation genetic diagnosis. Third trimester amniocentesis to guide obstetric management is available 28/54 HTCs (52%), less frequent in CEE compared to WE countries (5/17 vs 23/37, P =.03). 53% of HTCs (28/53) reported that only 0%-25% of WBD seek medical advice for heavy menstrual bleeding (HMB). An algorithm managing acute HMB in WBD is lacking in 22/53 (42%) HTCs. The main reported knowledge and research gaps are lack of awareness & education on WBD among patients and caregivers, optimal diagnostic strategies and effective multidisciplinary management of pregnancy & HMB. Conclusion: Joint clinics, prenatal diagnostics and algorithms for managing acute HMB are lacking in many European HTCs. HMB may be an underestimated issue. This survey highlights the need to prioritize improvement of knowledge and patient care for WBD across Europe

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH

Hemophilia A and B predominantly attracts clinical attention in males due to X-linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01–0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research

European principles of care for women and girls with inherited bleeding disorders

INTRODUCTION: Despite increasing awareness of issues faced by women and girls with inherited BDs (WGBD), standards of care are lacking, with disparities in diagnosis and treatment for WGBD across Europe. We aimed to develop practical principles of care (PoC) to promote standardization of care for WGBD within European Haemophilia Treatment and Comprehensive Care Centres (HTC/CCCs). METHODS: The co-creation process, supported by the European Association for Haemophilia and Allied Disorders, consisted of four multidisciplinary meetings with health care providers (HCPs) experienced in WGBD care, and European Haemophilia Consortium representatives, combined with broad patient and HCP consultations in the European haemophilia community. Relevant medical societies outside Europe were contacted for confirmation. RESULTS: We developed ten PoC for WGBD, stressing the importance and benefits of a centralized, multidisciplinary, comprehensive, family-centred approach to support and manage WGBD during all life stages. These PoC emphasise the right to equitable access and quality of care for all people with BDs, irrespective of gender. Multiple medical societies outside Europe also confirmed their support for endorsement. CONCLUSIONS: Ten PoC for WGBD evolved from an iterative process among stakeholders, supported by relevant medical societies worldwide. These PoC can serve as a benchmark for diagnosis and comprehensive multidisciplinary management of WGBD, and improve awareness of their unique challenges. They offer a framework to guide HTC/CCCs in providing equitable care for all WGBD, both in their own services and in other healthcare settings. Implementation of these principles aims to positively impact the health, wellbeing and quality of life for WGBD

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication