Davies, JS; (2017) Women with inherited bleeding disorders and their offspring - the unresolved issues. Doctoral thesis , UCL (University College London).

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Abstract

The past few decades have seen major advances in management of gynaecological conditions and multidisciplinary obstetric care in women with inherited bleeding disorders (IBDs) and their offspring. However, there remain many unresolved issues within the field. A series of observational studies were conducted to address these issues with an overarching aim of improving patient care. A case-control study determined if there was an association between IBDs and endometriosis. Women with a surgically confirmed diagnosis of endometriosis (n = 84) and controls (n = 30) underwent investigations of haemostasis. Women with endometriosis had significantly more platelet aggregation defects to one and multiple agonists compared to controls (31% vs 4%, p = 0.005 and 15% vs 4%, p < 0.05, respectively). Reduced von willebrand factor (VWF) activity correlated with increased laparoscopic stage of endometriosis (r = -0.35, p = 0.01). A 10-year review and questionnaire study was carried out in carriers of haemophilia to determine their attitudes towards prenatal diagnosis. Sixty-one carriers of haemophilia had obstetric care in 73 pregnancies. Forty-one out of 61 women responded to the questionnaire. The uptake for invasive prenatal diagnosis of haemophilia was reduced compared to previous studies published at the Royal Free Hospital (15% versus 20% in 2008 [1], and 35% in 1997 [2]). Invasive testing to confirm the haemophilia status of the fetus was used to guide management decisions of labour and delivery. The rate of termination of pregnancy (TOP) for haemophilia was lower than in previous case series [1]. Non-invasive determination of fetal gender using free fetal DNA (ffDNA) was carried out in 58 pregnancies (79%). Fifty-nine deliveries were managed at the Royal Free Hospital over 10-years. The majority of women (66%) in this series underwent elective caesarean section (CS). The primary indication for CS was for haemophilia in 59% of deliveries. A literature review and meta-analysis assessed the incidence of cranial bleeding at birth in newborns with haemophilia. The incidence of symptomatic intracranial haemorrhage (ICH) was determined by mode of delivery (MOD). Newborns with haemophilia were 44 times (95%CI 34.7-57.1, p < 0.01) more likely to experience symptomatic ICH, and 8 times (95%CI 5.38-12.6, p < 0.01) more likely to experience extracranial haemorrhage (ECH) at birth, compared to the general population. The OR of experiencing ICH following an assisted vaginal delivery was 4.4 (95%CI 1.46-13.7, p = 0.008) compared to vaginal delivery in newborns with haemophilia. The OR of experiencing ICH following CS was 0.34 (95%CI 0.14-0.83, p = 0.018) compared to vaginal delivery. CS was associated with the lowest risk of ICH in newborns with haemophilia. A prospective MRI screening study in term newborns with severe IBDs was undertaken to determine feasibility and incidence of asymptomatic ICH. Cranial MRI within 72 hours of delivery excluded asymptomatic ICH in affected infants. No cases of ICH were reported among eight participants. One newborn experienced cephalohaematoma following an emergency CS. Two of the eight newborns experienced spontaneous ICH in early infancy. A case-control study analysed the differences in rotational thromboelastometry (ROTEM®) parameters between parturient women with FXI deficiency, and parturient and non-parturient controls. Women with FXI deficiency achieved a hypercoagulable status during the third trimester of pregnancy; however, the changes were not as pronounced as in pregnant controls. Women with prolonged clotting time and clot formation time were considered to have an increased risk of bleeding. A prospective cohort study evaluated the role of ROTEM® analysis in assessment of bleeding risk in women with FXI deficiency. Pregnancy outcomes and haemostatic cover was reviewed in 57 deliveries in women with FXI deficiency. ROTEM® enabled treatment decision and reduced the need for treatment with factor concentrate in women with severe FXI deficiency. A cohort study assessed the correlation between bleeding score, haemostatic and prothrombotic variables in women with VWD and carriers of haemophilia. The presence of a thrombotic marker (anticoagulant deficiency or prothrombotic gene mutation) altered the bleeding score for a given VWF:RCo level in women with VWD (p = 0.015). Co-inheritance of thrombophilia reduces bleeding severity in women with IBDs, and thrombotic risk must be considered in these women.

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