Children with hemophilia have a significantly higher risk of intracranial hemorrhage (ICH) compared to the normal population. Prophylaxis reduces the risk of ICH and earlier initiation of prophylaxis may now be feasible, especially in hemophilia A (HA). The aim of the study is to explore the potential for preventing ICH by earlier start of prophylaxis by assessing the natural course of ICH before the initiation of prophylaxis and describe timing and incidence (clinicaltrials gov. Identifier: NCT02979119). In total, 2,727 children (2,275 with HA; 452 with hemophilia B [HB]) were included from the PedNet Registry, followed from 28 days until 36 months of life. ICH was observed in 61 children (incidence 2.2%; 10 per 1,000 patient years), with 75% of cases occurring before 1 year of age. Cumulative incidence was significantly lower in HB (0.9%) compared to HA (2.5%) and in non-severe HA (0.7%) compared to severe HA (3.5%). ICH occurred early, with a rise at 3 months, and a median age of 7.0 months in severe HA and 5.4 months in severe HB. In 40% of children, ICH occurred before the diagnosis of hemophilia was established, underscoring the importance of early diagnosis. Assuming that prophylaxis would have been started at the time of diagnosis and preventing all ICH in children with severe HA, the number needed to treat with prophylaxis would be 44 patients to prevent one ICH. Hopefully, prophylaxis options allowing initiation early in life, ideally before 3 months of age for children with severe HA, will reduce the incidence of ICH in the future.

Center for Benign Haematology Thrombosis and Haemostasis Van Creveld Kliniek University Medical Center Utrecht Utrecht The Netherlands; Department of Paediatric Haematology and Oncology 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic

Center for Thrombosis and Haemostasis Skåne University Hospital Malmö Sweden; Department of Paediatric Haematologu and Oncology Skåne University Hospital Lund Sweden; Department of Clinical Sciences and Paediatrics Lund University Lund

Centre de Référence de l'Hémophilie et des Maladies Hémorragiques Constitutionnelles et HITh UMR_S1176 INSERM Hopital Bicêtre APHP Université Paris Saclay Le Kremlin Bicêtre

Department of Oncology Careggi University Hospital Florence

Department of Paediatric Haematologu and Oncology Skåne University Hospital Lund

Department of Paediatric Haematology Our Lady's Children's Hospital for Sick Children Crumlin Dublin

Department of Paediatrics Medical University Hospital of Vienna Vienna

Goethe University Frankfurt University Hospital Department of Paediatrics and Adolescent Medicine Clinical and Molecular Haemostasis Frankfurt

Medical Faculty Masaryk University Brno Czech Republic

National Hemophilia Center Sheba Medical center Hashomer and Amalia Biron Research Institute of Thrombosis and Hemostasis Aviv University

Paediatric Haematology Royal Hospital for Children Glasgow

Paediatric Thrombosis and Haemostasis Unit Paediatric Haemophilia Center Dr von Hauner Children's Hospital LMU Munich Munich

PedNet Haemophilia Research Foundation Baarn

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