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The essential guide for understanding and treating women with inherited bleeding disorders, revised and updated Now in its second edition, Inherited Bleeding Disorders in Women includes the most recent developments and research in the field. This important guide offers the most current information available for the effective management of these complex and difficult to diagnose disorders. Treating women with inherited bleeding disorders can be challenging and requires close collaboration among practitioners in different specialties. This important guide is written by a team of international experts who offer advice and practical suggestions for treating women with inherited bleeding disorders. Inherited Bleeding Disorders in Women comprehensively covers obstetric and gynecological issues for carriers of hemophilia, women with von Willebrand disease, rare bleeding disorders and inherited platelet disorders. This important resource: * Offers an updated guide for hematologists, obstetricans and gynecologists and other clinicians treating women with inherited bleeding disorders * Includes information for treating both common and rare bleeding disorders * Contains the most recent developments and advances in the field for the treatment and management of inherited bleeding disorders in women * Presents information from noted experts in the field * Offers a multidisciplinary approach to the topic Written for hematologists, obstetricians and gynecologists and other clinicians working with women, Inherited Bleeding Disorders in Women has been fully revised and updated and continues to serve as a trusted guide for the management and treatment of women with inherited bleeding disorders.

Researchers have developed approaches for the noninvasive prenatal testing of single gene diseases. One approach that allows for the noninvasive assessment of both maternally and paternally inherited mutations involves the analysis of single nucleotide polymorphisms (SNPs) in maternal plasma DNA with reference to parental haplotype information. In the past, parental haplotypes were resolved by complex experimental methods or inferential approaches, such as through the analysis of DNA from other affected family members. Recently, microfluidics-based linked-read sequencing technology has become available and allows the direct haplotype phasing of the whole genome rapidly. We explored the feasibility of applying this direct haplotyping technology in noninvasive prenatal testing. We first resolved the haplotypes of parental genomes with the use of linked-read sequencing technology. Then, we identified SNPs within and flanking the genes of interest in maternal plasma DNA by targeted sequencing. Finally, we applied relative haplotype dosage analysis to deduce the mutation inheritance status of the fetus. Haplotype phasing and relative haplotype dosage analysis of 12 out of 13 families were successfully achieved. The mutational status of these 12 fetuses was correctly classified. High-throughput linked-read sequencing followed by maternal plasma-based relative haplotype dosage analysis represents a streamlined approach for noninvasive prenatal testing of inherited single gene diseases. The approach bypasses the need for mutation-specific assays and is not dependent on the availability of DNA from other affected family members. Thus, the approach is universally applicable to pregnancies at risk for the inheritance of a single gene disease.

The objective was to review all obstetric admissions to the intensive care unit (ICU) at the Royal Free Hospital, London, UK, and to identify the risk factors for obstetric admissions to the ICU. We carried out a retrospective case-control study. The cases consisted of women admitted to the ICU during pregnancy and up to 42 days postpartum between 1 January 1993 and 31 December 2003. Controls were women who delivered immediately before and after the indexed case. Demographic data, medical and surgical histories, pregnancy, and intrapartum and postpartum data were collected. Statistical analysis was done using SPSS software. Thirty-three obstetric patients were admitted to the ICU, representing 0.11% of all deliveries. The ICU utilization rate was 0.81%. Eighty percent of the admissions were postpartum. The main indications for admission were hypertensive disorders (39.4%), and obstetric haemorrhage (36.4%). There was no difference between cases and controls in, age, parity, smoking and employment status. Compared with controls, women admitted to the ICU were significantly more likely to be black (P<0.05), have a shorter mean duration of pregnancy (36.6 vs. 39.2 weeks; P=0.006), delivered by emergency caesarean section (P<0.001), and have higher mean blood loss at delivery (1,173 vs. 296 ml; P<0.001). The risk factors for obstetric ICU admission were black race (odds ratio [OR] =2.8, 95% confidence interval [CI] 1.05-6.28), emergency caesarean section (OR=14.9, 95% CI 5.38-41.45) and primary postpartum haemorrhage (OR=5.4, 95% CI 1.79-4.35). Women of black race, those delivered by emergency caesarean section and those with primary postpartum haemorrhage are more likely to be admitted to the ICU.

Under normal physiological circumstances menstruation is a highly regulated, complex process that is under strict hormonal control. During normal menstruation, progesterone withdrawal initiates menstruation. The cessation of menstrual bleeding is achieved by endometrial haemostasis via platelet aggregation, fibrin deposition and thrombus formation. Local endocrine, immunological and haemostatic factors interact at a molecular level to control endometrial haemostasis. Tissue factor and thrombin play a key role locally in the cessation of menstrual bleeding through instigation of the coagulation factors. On the other hand, fibrinolysis prevents clot organisation within the uterine cavity while plasminogen activator inhibitors (PAI) and thrombin-activatable fibrinolysis inhibitors control plasminogen activators and plasmin activity. Abnormalities of uterine bleeding can result from imbalance of the haemostatic factors. The most common abnormality of uterine bleeding is heavy menstrual bleeding (HMB). Modern research has shown that an undiagnosed bleeding disorder, in particular von Willebrand disease (VWD) and platelet function disorders, can be an underlying cause of HMB. This has led to a change in the approach to the management of HMB. While full haemostatic assessment is not required for all women presenting with HMB, menstrual score and bleeding score can help to discriminate women who are more likely to have a bleeding disorder and benefit from laboratory haemostatic evaluation. Haemostatic agents (tranexamic acid and DDAVP) enhance systemic and endometrial haemostasis and are effective in reducing menstrual blood loss in women with or without bleeding disorders. Further research is required to enhance our understanding of the complex interactions of haemostatic factors in general, and specifically within the endometrium. This will lead to the development of more targeted interventions for the management of abnormal uterine bleeding in the future.

Haemophilia is an X-linked inherited disorder that affects males and females, though the bleeding risk in girls and women has traditionally been under-recognised. About one third of haemophilia cases occur in individuals where there is no known family history. The gene mutations for rare bleeding disorders are not carried on the X chromosome and are therefore not sex-linked; however, the risk of passing on the condition is greatly increased for consanguineous parents where both parents may carry a copy of the fault in the genetic code which causes the condition. Genetic testing should be offered to every prospective mother, ideally before conception. This should be supported by counselling as the implications for family planning are profound. Von Willebrand factor (VWF) has an important role in primary and secondary haemostasis. Loss of function or low levels of VWF are associated with spontaneous bleeding causing nosebleeds, heavy periods and bruising as well as jpost-surgical bleeding. Joint bleeding and intracranial haemorrhage can also occur in those with a severe type of VWF. Diagnosis depends on bleeding assessment, family history and measurement of VWF. There are three types of VWD: Types 1 and 3 are caused by low or absent levels of VWD; Type 2 is caused by loss of function. Of these, Type 3 VWD is associated with the most severe bleeding risk but there is wide variation in bleeding phenotype among the other sub-types. The correlation between genetic mutation and bleeding phenotype is weak in VWD; therefore genetic testing is mainly useful for interpreting the risk when planning a family and to allow prenatal diagnosis in severe bleeding disorders. Genetic testing is essential for prospective parents to make fully informed decisions about having a family and how or whether to proceed with a pregnancy. The rationale for prenatal testing is to determine the bleeding status of the foetus and to inform decisions about managing delivery. Women may choose to terminate a pregnancy to avoid having a child with severe haemophilia. For some couples the option of adoption or not having children may be explored. Options for prenatal diagnostic testing include non-invasive methods, e.g. assessment of free foetal DNA in maternal plasma to determine the sex of a baby from 10 weeks in pregnancy, and invasive methods, e.g. chorionic villus sampling or amniocentesis, to determine the inheritance of the genetic mutation. Invasive methods are associated with a very small increased risk of pregnancy loss or early labour, which many couples feel is an unacceptable risk. Advanced techniques such as preimplantation screening also available, but require a huge commitment as this involves an IVF technique.

Prolonged menstrual bleeding interferes with daily life and causes marked blood loss, resulting in anaemia and fatigue. Treatment centres should address the issue of heavy menstrual bleeding (HMB) with pre-pubertal girls in advance of their first period, in order to best prepare them. It is common for a bleeding disorder to be overlooked in primary care and in gynaecology clinics, and women sometimes struggle to get a correct diagnosis. There are cultural taboos that inhibit open discussion of menstruation, and women tend to minimise the severity of their symptoms. Health professionals should work to destigmatise the issue and seek an accurate account of bleeding severity, with diagnosis and treatment provided in a joint clinic combining gynaecology and haematology expertise. Treatment should be individualised, taking into account personal, social and medical factors, with the aim of improving quality of life. Great care is needed with regard to choice of language when talking about treatment, and treatment centres should consider offering open access to women who need support in dealing with adverse effects. National member organisations have an important role to play in educating people with bleeding disorders, health professionals and the wider public about the burden of HMB associated with bleeding disorders.

Although menorrhagia is a common gynaecological symptom, a specific cause is identified in less than 50% of affected women. We investigated the frequency of inherited bleeding disorders in women with menorrhagia. Women referred for investigation of menorrhagia whose pelvis was normal on clinical examination and who had an estimated menstrual blood loss of more than 80 mL were studied. A detailed menstrual history and history about other bleeding symptoms was taken. The activated partial thromboplastin time, factor VIII activity, von-Willebrand-factor antigen and activity, and factor XI (FXI) were measured in all patients; further tests were done when results were at or outside the limits of the assays. 150 women were screened. An inherited bleeding disorder was diagnosed in 26 (17%) patients: the disorders were von Willebrand's disease of mild (15) or moderate severity (three), mild FXI deficiency (four), mild von Willebrand's disease and FXI deficiency (one), combined von Willebrand's disease, FXI deficiency, and factor X deficiency (one), carriage of haemophilia-A gene (one), and platelet dysfunction (one). The frequency of von Willebrand's disease and FXI deficiency were 13% (95% CI 7·9–18·8%) and 4% (1·5–8·5%), respectively. Menorrhagia since menarche was noted in 11 (8·9%) of 123 women without a bleeding disorder compared with 13 (65%) of 20 women with von Willebrand's disease (p=0·001) and four (66·7%) of six women with FXI deficiency (p<0·001). Inherited bleeding disorders are found in a substantial proportion of women with menorrhagia and a normal pelvis examination. We suggest that such patients should be investigated for these disorders—especially von Willebrand's disease—before invasive procedures are done.

The objective was to review all emergency peripartum hysterectomies performed at a tertiary hospital in London, UK, and to identify the risk factors for emergency peripartum hysterectomy. A retrospective case control study. The cases consisted of all women who had emergency peripartum hysterectomy between 1 January 1993 and 31 December 2003. Controls were women who delivered immediately before and after the indexed case. Demographic data, medical and surgical histories, pregnancy, intrapartum and postpartum data were collected. Differences between cases and controls were compared with chi2, Fisher exact and Student t tests. Multiple logistic regression analysis was performed to identify independent risk factors for emergency peripartum hysterectomy. There were 15 cases of emergency peripartum hysterectomy in 31,079 deliveries, giving a rate of 0.48 per 1,000. Women who had emergency peripartum hysterectomy were significantly older (mean age 37 years vs. 29 years, P<0.001) and multiparous (P=0.02). More of the cases had a history of uterine surgery (67 vs. 30%, P=0.01), placenta praevia (60 vs. 3%, P<0.0001) and were delivered by caesarean section (86.7 vs. 30%, P=0.003). Eighty percent of the hysterectomies were performed in the daytime and all were done by consultants. Haemorrhage due to placenta praevia was the main indication for emergency peripartum hysterectomy (47%). Independent risk factors for emergency peripartum hysterectomy were older age (odds ratios [OR] 1.2, 95% confidence interval [95% CI] 1.2-1.6), multiparity (OR 2.6, 95% CI 1.3-10.2), history of previous caesarean section (OR 13.5, 95% CI 2.7-65.4), caesarean delivery in index pregnancy (OR 11.6, 95% CI 2.1-68.6) and caesarean delivery in index pregnancy for placenta praevia (OR 18, 95% CI 3.6-69). Caesarean deliveries, especially repeat caesareans in women with placenta praevia, significantly increase the risk of emergency peripartum hysterectomy.