Deaths from stroke in US children, 1979 to 1998

Methods.

We searched mortality databases of the NCHS to determine rates of death from childhood stroke for 1979 through 1998.11 These databases contain information on primary cause of death as listed on death certificates in the United States. Deaths due to stroke were identified using the following International Classification of Diseases, 9th revision (ICD-9) codes: for hemorrhagic stroke, 431 (ICH), 430 (SAH), and 772.2 (SAH in children less than 1 month old); for ischemic stroke, 433 (occlusion and stenosis of precerebral arteries), 434 (occlusion of cerebral arteries), 436 (acute, but ill-defined, cerebrovascular disease), and 437.6 (nonpyogenic thrombosis of intracranial venous sinus).12,13⇓ We did not include deaths from subdural hemorrhage, neonatal intraventricular hemorrhage or intrauterine hypoxia or birth asphyxia, and the corresponding codes were not used in our analysis.

Because the NCHS databases group together children aged 15 to 19 years, childhood was defined as <20 years of age. Childhood included the neonatal period (the first month of life). The ethnicity classification system of the NCHS from 1977 was used. Individuals were classified into one of four groups: black, white, American Indian or Alaska Native, or Asian or Pacific Islander.14 The NCHS mortality database grouped the latter two categories together as ‘other.’ Persons of Hispanic origin were considered to be ‘of any race’ by this classification system; therefore, white Hispanics were classified as white and black Hispanics were classified as black.15

Death rates for infants (less than 1 year of age) were calculated as the number of deaths per 100,000 live births.11 Death rates (not age-adjusted) for all other ages were calculated as the number of deaths per 100,000 people in a population. Age-, race-, and sex-specific population data were obtained from the US Census Bureau.16 Person-years were defined as the average number of persons in a category multiplied by the number of years of study.

Time-trend data were age-adjusted to the US population in 1990 by the direct method of standardization.17 For graphical purposes only, these data were smoothed using a three-point moving average and averaging endpoints with their nearest neighbors; unsmoothed data were used for statistical analyses. For comparison, time trends for stroke mortality in adults were also analyzed using the same NCHS mortality database. Adults were defined as over 20 years of age.

To test significance of the comparison of two mortality rates, exact binomial confidence intervals were calculated using a described method of interval estimation for incidence rate data.18 Test for trend methodology was based on linear regression.19 Rates of decline were defined as the percent change between observations in 1979 and observations in 1998. We used Stata (version 7.0, College Station, TX) for statistical calculations and Cricket Graph (Version 1.3, Malvern, PA) for graphical representations.

Results.

A total of 1,457,848,237 person-years were included in the study (table 1). Whites accounted for 81% of the population; sex was evenly distributed. There were 4,881 deaths attributed to childhood stroke in the United States from 1979 to 1998, yielding an average of 244 deaths per year. Ischemic strokes accounted for 26% of deaths, whereas hemorrhagic strokes (ICH and SAH) accounted for 74% (table 2). Average annual mortality rates were 0.09 per 100,000 person-years for ischemic stroke, 0.14 for ICH, and 0.11 for SAH (data not shown).

Male children were at greater risk than female children for mortality from hemorrhagic strokes (ICH and SAH) but not ischemic strokes (table 3). Black ethnicity was a risk factor for all stroke types. Infants (children under 1 year old) had the highest mortality rates of any age group: 0.57 per 100,000 person-years for ischemic stroke, 0.60 for SAH, and 1.04 for ICH (figure 1). Although only 5% of the children were infants (see table 1), approximately one third of stroke deaths occurred in this age group (35% of ischemic stroke deaths, 30% of SAH deaths, and 39% of ICH deaths).

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Figure 1. Mortality rates from childhood stroke in the United States for 1979 to 1998 by age at time of death. Solid bar represents ischemic stroke; hatched bar represents subarachnoid hemorrhage; shaded bar represents intracerebral hemorrhage.

Between 1979 and 1998, mortality from stroke in children declined 58%, from 0.55 to 0.23 per 100,000 person-years. Mortality from all stroke subtypes declined (figure 2): ischemic stroke declined 19%, from 0.10 to 0.08 per 100,000 person-years; SAH declined 79%, from 0.24 to 0.05 per 100,000 person-years; and ICH declined 54%, from 0.21 to 0.10 per 100,000 person-years. The time trends were significant for each stroke subtype (p = 0.010 for ischemic stroke, p < 0.0001 for SAH and ICH). The decline in childhood mortality from SAH was greater for blacks than for whites (figure 3A). In 1979, the mortality rate in blacks was 2.1 times that for whites; by 1998, the ratio had decreased to 1.6. For ICH, the gap between black and white mortality rates increased from a ratio of 1.8 in 1979 to 2.4 in 1998 (see figure 3B). For ischemic stroke mortality, the ratio of black to white death rates was 1.7 in 1979 and 1.4 in 1998 (see figure 3C).

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Figure 2. Time trends in mortality from childhood stroke in the United States from 1979 to 1998. Data points are smoothed values to facilitate evaluation of general trends. Triangles represent intracerebral hemorrhage; circles represent subarachnoid hemorrhage; squares represent ischemic stroke.

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Figure 3. Racial differences in time trends in mortality from childhood subarachnoid hemorrhage (A), intracerebral hemorrhage (B), and ischemic stroke (C) in the United States from 1979 to 1998. Squares represent black ethnicity; circles represent white ethnicity.

Rates of decline in stroke mortality in children were compared to those in adults (20 years of age or older; figure 4). The death rates for hemorrhagic stroke (ICH and SAH) have declined more among children than among adults, whereas death rates for ischemic stroke have dropped twice as much for adults (45%) as for children (19%).

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Figure 4. Percent decline in stroke mortality in the United States from 1979 to 1998 in children (solid bar) versus adults (hatched bar). ICH = intracerebral hemorrhage; SAH = subarachnoid hemorrhage.

Discussion.

Numerous studies have evaluated trends in adult stroke mortality, documenting declining death rates from all stroke types in the United States over the past several decades.1,20-22⇓⇓⇓ We found that between 1979 and 1998, US children had an even greater decline in hemorrhagic stroke mortality, with a minimal decline in ischemic stroke mortality (see figure 4). Improved control of modifiable stroke risk factors such as hypertension, smoking, and blood cholesterol levels have been credited with the reduction in stroke risk among adults.1 These improvements in adult preventive health care are unlikely to account for the decline in children, however, for whom these stroke risk factors are unimportant. Improvements in pediatric critical care may contribute to the declining mortality rate in children; however, one might expect such improvements to equally affect outcomes for ischemic and hemorrhagic strokes, and the decline in ischemic stroke mortality is relatively small. Control of certain childhood stroke risk factors has undoubtedly improved with new protocols for blood transfusions for primary stroke prevention in children with sickle cell disease, and lower rates of bacterial meningitis with the widespread use of Haemophilus influenza type b vaccination.23-25⇓⇓ However, known risk factors for childhood stroke—including congenital heart disease, sickle cell disease, hereditary prothrombotic states such as homocystinuria, acquired prothrombotic states such as iron deficiency anemia, hemophilia, dehydration, meningitis, and varicella—are many, and any one identifiable risk factor is unlikely to account for more than 40% of all childhood strokes.26-32⇓⇓⇓⇓⇓⇓ Thus, improved control of any single known risk factor could not account for the dramatic decline in childhood stroke mortality we observed. This decline must be due either to simultaneous improvements in several of these known risk factors, or to improvements in as yet unidentified risk factors.

Considerable data link ethnicity to stroke rates in adults. Compared to whites, black adults have a higher incidence of stroke,13,33,34⇓⇓ greater initial stroke severity,35 and a higher mortality rate from stroke.3,36,37⇓⇓ Among different adult age groups, young black men in particular have the greatest relative risk for stroke mortality compared to whites.38 Similarly, we found that black children were at greater risk for mortality from all stroke types compared to white children (relative risk of 1.74 for ischemic stroke to 2.06 for ICH). A population-based study in the Cincinnati metropolitan area found similar stroke incidence rates for black and white children, but with only 16 incident cases, it lacked the power to evaluate for ethnic differences.8 It is therefore unclear whether the ethnic difference we observed in childhood stroke mortality represents a difference in stroke incidence or in case fatality.

Stroke risk factors such as hypertension and diabetes mellitus are more prevalent in black adults than whites, but although they may contribute to ethnic differences in adult stroke mortality,39 they would not affect childhood stroke rates. Sickle cell disease, however, affects black children and is a risk factor for childhood stroke. Based on the prevalence of sickle cell disease in black children,40 the incidence of stroke in sickle cell disease (285 per 100,000 per year),41 and the estimated case fatality of childhood stroke (19%),13 the expected mortality rate for stroke due to sickle cell disease in black children would be 0.19 per 100,000 person-years. We observed a stroke mortality rate of 0.55 per 100,000 person-years in black children; therefore, sickle cell disease could account for 35% of these deaths, and 66% of the difference in stroke mortality between black and white children. However, whereas 75% of strokes in children with sickle cell disease are ischemic,42,43⇓ we found that 76% of stroke deaths in black children were due to hemorrhagic stroke. In addition, although stroke from sickle cell disease occurs most commonly in mid-childhood,44 the highest mortality rates from stroke in our study were in infants. Thus, although sickle cell disease may contribute to the excess stroke mortality in black children, other factors must be involved.

Sex differences in stroke mortality have been well studied in adults, and contrast with our findings in children. Among adults, men have a higher mortality from both ischemic stroke and ICH than do women.4,5⇓ We found, however, that rates of ischemic stroke mortality for boys and girls are similar. Lifestyle factors, such as cigarette smoking,4 may contribute to greater ischemic stroke mortality in men, but are unlikely to play a role in children’s mortality rates. Regarding death rates from ICH, we found that boys were at greater risk than girls, which parallels findings for adults. Hormonal or lifestyle differences independent of predominantly adult risk factors may contribute to this male risk in both children and adults. Finally, among adults, females have greater mortality from SAH than males,22 whereas the opposite is true in children. Given that oral contraceptive pills increase risk of SAH,45 higher levels of estrogen and progesterone in women compared to girls may play a role in this difference. Interestingly, estrogen has been shown to have both neuroprotective and neurodeleterious effects,46,47⇓ which may contribute to the variable sex effect on ischemic and hemorrhagic stroke mortality risk at different ages.

Among the different age groups analyzed in our study, we found that infants have the highest rate of ischemic and hemorrhagic stroke mortality, and account for a disproportionately high percentage of all childhood deaths due to stroke, particularly ICH. We would suspect that most strokes leading to death in the first year of life actually occur during the neonatal period, although the timing of stroke onset could not be determined in this study. Potential etiologies of ICH in the neonate include certain disorders (vitamin K deficiency, immune thrombocytopenia, disseminated intravascular coagulation secondary to sepsis) that are not important risk factors in older children.48,49⇓ These disorders may, therefore, contribute to the higher risk of mortality from ICH we observed in infants. It is unlikely, however, that these risk factors fully account for the dramatically higher stroke mortality in infants, suggesting that other unidentified risk factors must exist.

Our study has several limitations. First, criteria for death certificate diagnoses are not clearly defined. Diagnosis may vary depending on the extent of work-up performed, the clinician completing the death certificate, and the administrator responsible for assigning an ICD-9 code to a diagnosis. However, when used as discharge codes, the primary ICD-9 codes used in our study (430, 431, 433, 434, 436) have been shown to have a 98% sensitivity for stroke in adults.13 In addition, death certificate diagnosis of stroke has been shown to have both high specificity and positive predictive value.50 Poor precision of the stated cause of neonatal deaths on death certificates, however, has also been reported.51 Second, the NCHS mortality database includes only the age at the time of death from stroke, and not the age at the time the stroke occurred. For this reason, we could not isolate mortality from neonatal strokes (strokes occurring in the first month of life), which may represent different etiologies than strokes occurring in later infancy and childhood. Although we excluded from our analysis codes for birth asphyxia, intraventricular hemorrhage, and cerebral hemorrhage due to birth trauma, it is possible that some deaths due to these diagnoses were miscoded and therefore included in our study. Third, because the NCHS mortality database does not provide the location of a patient’s treatment, changes in the availability of pediatric tertiary care as a possible explanation for changing mortality rates could not be assessed. Fourth, because the database includes only the primary cause of death, no analysis of the specific etiologies of fatal stroke in children could be done. Finally, venous sinus thrombosis, an etiology of ischemic and hemorrhagic stroke in children, was not a reported cause of death in our study. This may be due to the low mortality rate associated with this disorder in children, as well as underdiagnosis, particularly in the pre-MRI era.52 In addition, ischemic or hemorrhagic stroke may be considered the proximate cause of death in some cases of venous sinus thrombosis.

Despite the potential limitations to our study, our findings of ethnic and sex differences and declining mortality rates in childhood stroke are compelling. Similar findings in adults have been attributed to differences in the control of identifiable stroke risk factors such as hypertension, diabetes mellitus, and smoking. The same risk factors cannot account for the time trends and ethnic and sex differences seen in children, as the effects of these risk factors are not seen in childhood. Known etiologies of childhood stroke are many, and the improved control of any one of these could not account for the dramatic decline in childhood stroke mortality we observed. Unidentified risk factors for childhood stroke mortality may be important. Moreover, it is possible that differences in these unidentified risk factors contribute to the similar time trends and ethnic differences observed in adults. As our observations regarding the demographics and time trends of childhood stroke mortality could reflect differences or changes in either stroke incidence or case fatality, the epidemiology of childhood stroke incidence needs to be investigated. Additionally, other risk factors for stroke mortality must be sought in children as well as in adults.