It has been several decades since the publishing of large U.S. studies of neurodevelopment and other cognitive functions in children and young adults with hemophilia. Results of this earlier research that evaluated hemophilia and neurocognitive development suggested that the disease was associated with poorer outcomes compared with the general U.S. These lesser outcomes were observed specifically in areas such as academic achievement, attention, behaviors, and emotional and adaptive functioning.
However, these studies reflected a very different time, when HIV viral infections placed a significant burden on patients and before enhanced, contemporary standards of care were available. Investigators of a newly published observational study set out to capture new data that accounts for advances in care and other factors.
“Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK),” was published in The Journal of Pediatrics.
“The only large study examining neurodevelopment in hemophilia (HGDS - Hemophilia Growth and Development Study) was conducted over 30 years ago. Since then, many disease and treatment-related factors have evolved, making the current study an important update of the existing literature,” explained the authors. HGDS was published in the spring of 1994.
The new study assessed the impacts of hemophilia type and severity, intracerebral hemorrhage (ICH), hemophilia treatment type, socioeconomic status, and neurodevelopmental disorders or symptoms (i.e., ADHD, attention problems) on cognitive, adaptive, and social-emotional functioning compared with the general population. Between September 2018 and October 2019, eTHINK investigators at hemophilia treatment centers enrolled 551 males aged 1-21 years with hemophilia A or B of any severity, with or without inhibitors.
The tools used for assessing things such as intellectual ability, attention, processing speed, adaptive skills, and behavioral function were selected by experts in pediatric neuropsychology and neurology. Further data was collected from HTC chart information and medical history obtained from the parent/child/family. Developmental and cognitive assessment of the affected individuals were completed by patients or guardians/parents via questionnaires.
Investigators found that male children and young adults with hemophilia performed within or above age expectations on standardized tests of “higher-order” intellectual ability. This stands in contrast to the earlier HGDS study results showing decreased intellectual functioning associated with HIV presence. As HIV is not a significant comorbidity for hemophilia patients in developed countries, the authors suggest that this is a contributing factor in higher intellectual performance.
They also observed that while individuals with increased hemophilia severity had a lower IQ in the HGDS, severity-related results of eTHINK show a different picture.
“The current study assessed a broader range of disease severity than did the HGDS, including patients with mild, moderate, and severe hemophilia; however, we did not find that patients with moderate or severe hemophilia performed worse or reported more significant problems than those with mild hemophilia,” explained the authors. “This may be attributable to changes in treatment and improved HTC-led patient/family education that has emerged over the past 3 decades.”
In addition, while ICH is historically associated with a high risk for developmental and cognitive problems, eTHINK did not yield robust data on the subject. This is due to much lower rates of ICH in current pediatric hemophilia populations, as compared to earlier generations. Investigators were therefore unable to analyze the impact of ICH in light of the modest data sample.
The authors were also surprised to find that they did not identify relationships between hemophilia type or severity and early development or cognitive function. They posit one possible explanation - that the regular use of more effective therapies has helped to mitigate the kinds of developmental risks often associated with severe disease. In addition, the need for moderate/severe patients to carefully monitor activities for injury risk may lessen associations between disease severity and cognitive morbidity.
The authors did observe a higher prevalence of ADHD in some groups, particularly in boys 13-17 years old. Attention deficits and/or ADHD diagnoses were associated with considerably reduced attention, executive function, and adaptive skills, along with more reported behavioral/emotional symptoms and more problems at school. These findings provide greater impetus for screening for ADHD and other neurobehavioral or neurodevelopmental disorders in hemophilia patients to facilitate early intervention and improved outcomes.
Overall, the results of eTHINK suggest that when compared to the general population, boys with hemophilia develop and function within the normal range for their age in several cognitive and behavioral areas. That said, investigators clearly identified specific groups at higher risk for poor outcomes.
“These include individuals with comorbid neurobehavioral disorders, young adults and adolescents transitioning into adulthood, and patients from more disadvantaged socioeconomic backgrounds. Identifying at-risk individuals within the hemophilia population should allow for more individualized monitoring, assessment, and intervention,” concluded the authors.
Read the full paper to read the full results, plus learn more about the study methods, limitations, and further comparisons to the HGDS.
Citation
Mrakotsky C, Walsh KS, Buranahirun Burns C, Croteau SE, Markert A, Geybels M, Hannemann C, Rajpurkar M, Shapiro KA, Wilkening GN, Ventola P, Cooper DL; eTHINK Study Group. The eTHINK Study: Cognitive and Behavioral Outcomes in Children with Hemophilia. J Pediatr. 2024 May 9;272:114089. doi: 10.1016/j.jpeds.2024.114089. Epub ahead of print. PMID: 38734133.
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