Pediatric ischemic stroke : Epidemiological aspects of validity, risk factors, and outcomes

Abstract: Pediatric ischemic stroke is divided into perinatal stroke, 20 weeks gestation until the 28th day of life, and childhood stroke, the 29th day of life until 18 years of age. Perinatal and childhood stroke differ in risk factors and outcomes but both cause increased mortality and morbidity in the pediatric population. The overall aim of this thesis was to identify factors associated with risk of pediatric ischemic stroke or, risk of adverse outcome and morbidity after pediatric ischemic stroke, in a validated cohort.This thesis consists of four register-based epidemiological studies. First, a validation study of pediatric ischemic stroke diagnoses (International classification of diseases [ICD]-10: I63, I64; ICD-8 and 9: 433, 434, 436) in children 1969-2016. Through medical chart review, we validated the diagnoses of pediatric ischemic stroke and found a positive predictive value of 89% (95% CI 0.85-0.92) in the Swedish National Patient Register. About 2/3 of the ischemic stroke cases were identified in the later years (1997-2016), during which 98% of the diagnoses were confirmed by radiology. Second, a matched cohort study of long-term mortality after pediatric ischemic stroke showed that mortality was elevated over 20 years after the stroke, without difference between perinatal and childhood stroke. Mortality risk was also elevated in first-degree relatives of individuals with childhood stroke. Third, a matched cohort study showed that 32% (280 of 877) of the children with ischemic stroke were diagnosed with adverse motor outcome (i.e., cerebral palsy or hemiparesis). The risk of adverse motor outcome was higher after ischemic stroke in childhood compared to the perinatal period, but neither male sex, low gestational age nor high parental age showed any association. Fourth, a cohort study of all births in Sweden 1998-2019 assessed maternal body mass index (BMI) as a risk factor for perinatal ischemic stroke. In mothers with obesity (BMI >30) the risk of perinatal ischemic stroke in the infant increased two-fold.Pediatric ischemic stroke has a high positive predictive value in the National Patient Register, enabling high-quality register-based research using these diagnoses. Limitation to later years (>1997) give higher identification rate, with almost complete confirmation by radiology. Although there was no difference in long-term mortality risk between childhood and perinatal ischemic stroke, the underlying mechanisms are diverse. The analysis of the cause-specific mortality could indicate factors relevant to the risk of mortality after pediatric ischemic stroke. Adverse motor outcome is common after pediatric ischemic stroke, especially in childhood. The ICD codes of adverse motor outcome diagnoses were used imprecisely, limiting detailed analysis (e.g., difference between acute or long-term adverse motor outcome). Although the absolute risk of perinatal ischemic stroke is low, the two-fold increased risk in infants of mothers with obesity indicates maternal BMI as a possible risk factor for perinatal ischemic stroke. Additional analyses of mediating factors are of interest to understand the underlying mechanisms of perinatal ischemic stroke.

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