Among 11 770 persons 4 to 19 years of age surveyed in NHANES in 1999 through 2004, there were 2295 (19.5%) for whom severe or recurrent headaches were reported. The prevalence of headache rose with increasing, age. Before puberty, rates of headache were comparable in boys and girls, but after the age of 12 years, girls with headache outnumbered boys.16
The highest headache prevalence, 27.4%, was observed in girls aged 16 to 18 years. Headaches were reported more frequently in African American individuals and in persons with low income as measured by the PIR.16
Mean BMI was higher among children with headache, the difference in BMI between children with and without headaches being highly significant statistically in boys, girls, and the total (). Mean BMI rose with age but remained higher in children with than without headache in each age group. There was an excess of children with headache in the highest quintile of BMI values (as derived from the nonheadache population; see “Methods” section). Body mass index in the highest quintile was 35% more frequent in children for whom recurrent or severe headaches were reported (, odds ratio adjusted for age, race, and PIR).
Mean Values of Biological Measures by Headache Statusa
Logistic Regression of Headache Status on the Odds of Being in the “Risk” Quintile for Selected Biological Factors
Children with headaches had higher mean CRP values than children without headache (), and girls had higher mean CRP values than boys, within headache status groups (data not shown). There was no significant difference in CRP values between boys with and without headaches. More children with headache were in the top quintile for CRP value (, second odds ratio also adjusted for BMI).
Mean values for homocysteine were higher in children with headache in boys, girls, and the total. Boys with and without headache had higher mean homocysteine levels than girls in the same groups (data not shown). Mean values of homocysteine rose over the ages studied in both the nonheadache and headache groups. More children aged 4 to 11 years with headache were in the highest risk quintile, while the difference between the nonheadache and headache groups was smaller in magnitude and not formally significant in children 12 years or older. Serum and red blood cell folate levels were lower in children with headache, without difference by sex. More children with headache were in the highest risk quintile (ie, the lowest folate levels). Vitamin B12 mean values were lower in children with headaches. Mean values of lipids and quintiles of risk were not consistently different by headache status, although HDL cholesterol level was lower in boys with than without headache. There was no clear association of headache status with low platelet count or uric acid level.
More children with severe or recurrent headache were in the highest risk quintile for BMI and levels of CRP, homocysteine, and folate () and more were in the riskiest quintile for 3 or more factors measured.
Percentage with body mass index (BMI), serum folate level, C-reactive protein (CRP) level, and homocysteine level in risk quintiles by headache status.
With asthma added to the group of clustered characteristics, almost twice as many young children with headache (31.7% vs 17.9%) had 3 or more of these characteristics. Thus, the factors measured in this study tended to cluster in children with headache. Children with headaches were more often in the highest quintile of risk with respect to CRP level than children with neither asthma nor headaches or with asthma alone. Children with both asthma and headaches were still more often in the highest quintile of risk with regard to CRP level (). Factor analysis suggested 2 factors, one primarily represented by homocysteine and serum folate levels, the other by CRP level and asthma.
Percentage with C-reactive protein (CRP) level in risk (highest) quintile by asthma and headache status.
In summary, a number of examined characteristics, including clinical and biochemical factors, were associated with risk for later cardiovascular and cerebrovascular morbidity and tended to cluster in children and adolescents with headaches.
In this large and representative American sample, children and adolescents with severe or recurrent headache or migraine had higher mean BMI, higher levels of CRP and homocysteine, and lower levels of serum and red blood cell folate. More children with headache were in the quintile of highest risk for each of these biomarkers, and more were in the highest quintile of risk for 3 or more. Our results suggest that there may be 2 subgroups of children with headaches: one characterized by elevated levels of homocysteine and lower serum folate levels and the other by relatively high CRP levels and asthma. These observations suggest that different mechanisms may contribute to vascular changes in these 2 groups, and these subgroups may index potential endophenotypes that could be examined in future genetic research.
Elevated CRP level is a marker of inflammation, its concentration in blood correlating with levels of inflammatory cytokines, and is a biomarker of risk for cardiovascular disease and stroke.29
The results of the study presented herein are consistent with a previous one showing increased CRP levels in young adults with migraine.9
There is a strong relationship of CRP levels and BMI in children and adolescents, such that a 1-SD increase in BMI associates with a 52% increase in CRP concentration.30
Indeed, adiposity was the major determinant of CRP levels in children.31
Persons with an elevated CRP level at initial measurement tend to continue to have elevated levels of CRP in subsequent years.32
Abnormalities in homocysteine levels are also associated with vascular risk.
In the NHANES survey years examined in this study, values for homocysteine, folate, methylmalonic acid, and vitamin B12
were all measured after the initiation of fortification of foodstuffs with folate.33
Many of the clinical or demographic indicators explored in this study are related to one another. In analyzing the association of the several factors with headache, we have tried to take the known relationships into account in multivariate analysis but cannot rule out unrecognized confounding.
While NHANES has important advantages for the study of disorders of health and their correlates, this data source has significant limitations. Information available in NHANES on headache status does not distinguish between migraine and its variants, including aura, and other frequent or severe headache types. In fact, as indicated, headaches in childhood are not easy to classify. Diagnostic categories of headache in young children are not stable over time, the proportion with a diagnosis of migraine at pubertal age being similar among those diagnosed at age 6 years with migraine or with tension-type headache.20
The basic distinction between tension-type headache and migraine has been questioned.34,35
Severe or recurrent headache or migraine, as identified in NHANES, marks a group of young people who have characteristics associated with cardiovascular risk. Identifying early indicators of vascular disease may enhance our ability to define targets for prevention of these conditions. While cardiovascular and cerebrovascular disease usually do not become symptomatic until midlife or later, changes in arteries that are detectable in childhood are thought to be part of its pathogenesis. Chronic low-grade inflammation, as measured by CRP level, appears to play a role in the development of such vascular pathology.36,37
Elevated levels of homocysteine may also contribute.
Recent randomized trials indicate that treatment with a statin to lower CRP levels reduces the risk of stroke and other vascular events.38
Statin use in children with hyperlipidemia is apparently effective and safe.39,40
Dietary improvement can lower homocysteine levels and decrease BMI. Wärnberg and Marcos stress
the possibility of using markers of low-grade inflammation for screening high-risk young subjects during the long presymptomatic phase … while most damage is likely to be reversible.41(pp13–14)
Risk of asymptomatic vascular disease can be identified early, and severity rises with increasing number of risk factors.42
We report that biomarkers of risk for vascular disease appear to cluster in children and adolescents with severe or recurrent headaches or migraine. Such young people may be an appropriate target for further study and for screening, follow-up, and efforts to prevent long-term vascular pathology and resulting cardiovascular disease and stroke.