Defining Incidence and Mortality Rates of Intracranial Hemorrhage in Patients With Hemophilia

Compared with the general population, intracranial hemorrhage (ICH) rates are higher in all patients with hemophilia, according to a study published in Blood. Reported incidences peak in neonates and decline with age. Senior author Karin Fijnvandraat, MD, PhD, of Amsterdam University Medical Centers in the Netherlands, said the increased risk of ICH in this population is concerning and calls for improvements in hemophilia care worldwide, given the overall burden the bleeding disorder places on patients.

“We hope that this review provides a reference from the era of clotting factor concentrates for studies evaluating effects of novel therapies on ICH in hemophilia,” Dr. Fijnvandraat told ASH Clinical News.

A systematic review of the literature, led by Anne-Fleur Zwagemaker, PhD-c and Dr. Fijnvandraat, was conducted to identify the rate of ICH in patients with hemophilia. In total, 45 studies with 54,470 patients were included. The hemophilia population comprised 809,151 person-years and 5,326 live births.

The studies spanned up to 60 years, and most of the studies were primarily performed in high-income regions. Data were available for patients with severe hemophilia (46%) and non-severe hemophilia (54%). Patients in the studies were from 43 countries, including those in Europe, East Asia, Southeast Asia, West Asia, Australia, North America, South America, and Africa.

The investigators performed pooled analyses of ICH incidence and mortality rates in the following groups:

  • all ages
  • <25 years of age
  • neonates

Pooled incidence of ICH and mortality rate in the all ages group was 2.3 (95% CI 1.2-4.8) and 0.8 (95% CI 0.5-1.2), respectively, per 1,000 person-years. In children and young adults under the age of 25, pooled ICH incidence was 7.4 (95% CI 4.9-11.1) and the mortality rate was 0.5 (95% CI 0.3-0.9), per 1,000 person-years. In neonates, the pooled cumulative incidence of ICH was 2.1% (95% CI 1.5-2.8) per 100 live births.

Across all ages, 52% of ICH events were considered spontaneous, with a corresponding weighted pooled proportion of 0.58 (95% CI 0.40-0.73). In contrast, 35% of all ICH events in children and young adults were deemed spontaneous, with a corresponding weighted pooled proportion of 0.35 (95% CI 0.28-0.43).

According to the researchers, these findings call for increased vigilance in the care of patients with hemophilia, as well as adequate follow-up and monitoring, particularly in those with certain risk factors. However, their review was unable to identify the effect of risk factors on ICH in patients with hemophilia.

The high rate of ICH in infants, as demonstrated in the study, raises a question regarding the appropriate timing of prophylaxis initiation. Long-term studies are required to determine the impact of very early prophylaxis with non-replacement products on the incidence of ICH.

According to the investigators, counseling patients with hemophilia and their families on ICH risks and symptoms may be appropriate. “In neonates, our data support the need for an active pedigree approach for genetic testing and comprehensive counselling of pregnant carriers,” the authors added.

The considerable heterogeneity of the study settings and populations is a limitation of the review. Additionally, most studies included in the review were retrospective.

This work was supported by a grant from Sobi.


Zwagemaker AF, Gouw SC, Jansen JJ, et al. Incidence and mortality rates of intracranial hemorrhage in hemophilia: a systematic review and meta-analysis [published online ahead of print, 2021 Aug 19]. Blood. doi: 10.1182/blood.2021011849.