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Learning and Attention Problems Among Children

With Pediatric Primary Hypertension

WHAT’S KNOWN ON THIS SUBJECT: Children with sustained primary hypertension exhibit neuropsychological impairments in attention, working memory, and parent ratings of executive function skills. Previous studies excluded children with learning disabilities or attention-deficit/hyperactivity disorder, which precluded examination of associations between hypertension and academic problems.

WHAT THIS STUDY ADDS: This study found increased prevalence of learning problems among children with sustained primary hypertension, irrespective of attention-deficit/hyperactivity disorder history, in comparison with children without hypertension.

abstract

OBJECTIVE:The objective was to determine whether children with sustained primary hypertension are at increased risk for learning disabilities (LDs), as a school-related manifestation of neurocogni-tive problems.

METHODS:A total of 201 children 10 to 18 years of age who were referred because of elevated blood pressure (BP) were included. Pa-tients were categorized as having or not having hypertension, on the basis of BP evaluation at the initial hypertension clinic visit and subse-quent confirmation of sustained elevated BP outside the clinic setting. Parents reported whether their child had a provider-confirmed LD or attention-deficit/hyperactivity disorder (ADHD).

RESULTS:A total of 101 children without hypertension and 100 chil-dren with hypertension were evaluated; 18% of the chilchil-dren (n

37) had LDs. In comparison with children without hypertension, children with hypertension were significantly more likely to have LDs (18% vs 9%; P⬍ .001), irrespective of comorbid ADHD. With adjustment for demographic variables and obesity, the odds of having LDs were elevated for subjects with hypertension, in com-parison with subjects without hypertension (odds ratio: 4.1 [95% confidence interval: 1.8 –9.4]).

CONCLUSIONS:The rate of LDs, with or without ADHD treatment, was significantly higher for children with sustained primary hypertension, compared with children without hypertension. These findings add to the growing evidence for an association between primary hyperten-sion and cognitive function and may inform treatment and monitoring decisions for these children who may be at risk for learning problems.

Pediatrics2010;126:e1425–e1429 AUTHORS:Heather R. Adams, PhD,aPeter G. Szilagyi, MD,

MPH,bLaura Gebhardt, BA,band Marc B. Lande, MD, MPHb

Departments ofaNeurology andbPediatrics, University of

Rochester Medical Center, Rochester, New York

KEY WORDS

attention-deficit/hyperactivity disorder, hypertension, learning disorders, neurobehavioral manifestations

ABBREVIATIONS

ADHD—attention-deficit/hyperactivity disorder BP—blood pressure

LD—learning disability SES—socioeconomic status OR—odds ratio

CI—confidence interval

Ms Gebhardt’s current affiliation is Baystate Health Systems Inc, Springfield, MA.

www.pediatrics.org/cgi/doi/10.1542/peds.2010-1899

doi:10.1542/peds.2010-1899

Accepted for publication Sep 2, 2010

Address correspondence to Heather R. Adams, PhD, University of Rochester Medical Center, Division of Child Neurology, Box 631, 601 Elmwood Ave, Rochester, NY 14642. E-mail: heather_adams@ urmc.rochester.edu

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE:The authors have indicated they have no financial relationships relevant to this article to disclose.

Funded by the National Institutes of Health (NIH).

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tive testing, compared with

normo-tensive control subjects. Some of the largest and most consistent associa-tions are noted within the domains of executive function and working

memory.1 This difference in

cogni-tion between subjects with and with-out hypertension has been found to be more pronounced among young adults, compared with middle-aged

or older adults,2which lends

biolog-ical plausibility to the possibility of a similar hypertension-cognition link for children.

In an analysis of a large, nationally representative database, our group showed that children with elevated

systolic blood pressure (BP) demon-strated decreased performance on the digit span test, a measure of attention and working memory.3 We showed

subsequently that children with sus-tained primary hypertension had de-creased parental ratings of executive function, compared with normotensive control subjects.4 The latter results

suggest that childhood hypertension might lead to observable deficits in the performance of daily activities, outside the isolated setting of formal neuro-psychological examinations. However,

our previous investigations intention-ally excluded children with a history of learning disabilities (LDs) or attention-deficit/hyperactivity disorder (ADHD),

to limit enrollment of subjects with pathophysiologic processes other than hypertension that might influence performance in neurocognitive test-ing. As a consequence, our previous

studies did not allow us to investigate the association between primary hy-pertension and school-related learn-ing difficulties. The objective of the

present study was to determine whether children with primary hyper-tension are at increased risk for LDs,

METHODS

We performed a retrospective review of data for patients referred to the pe-diatric hypertension clinic at the Uni-versity of Rochester Medical Center over a 3-year period. All patients had been referred to the clinic because of elevated BP measurements obtained in their primary physician’s office. We included all patients 10 to 18 years of age who were not receiving antihyper-tensive medication at the time of refer-ral. Patients with secondary hyperten-sion or known developmental delay were excluded. For comparison, sub-jects were categorized as either hav-ing or not havhav-ing hypertension. To be considered as having hypertension, subjects were required to have sys-tolic and/or diassys-tolic BP measure-ments ofⱖ95th percentile at the initial hypertension clinic visit and subse-quent confirmation of sustained hy-pertension outside the clinic setting, either through 24-hour ambulatory BP monitoring or through elevated BP readings on ⱖ3 occasions, as mea-sured by the school nurse or through home self-monitoring. All other sub-jects were considered to have prehy-pertension, were categorized as not having hypertension, and constituted the comparison group for this study.

During the study period, all referred patients were asked during the initial hypertension clinic visit about the presence of a LD and whether their child was receiving medication for ADHD. LDs were strictly defined as hav-ing a current individualized education plan or section 504 plan, both formal indicators of a student’s need for ser-vices to address an educational prob-lem. Because students can receive these plans for various reasons, we re-quired the educational plan to address a LD specifically, rather than a

behav-was defined as currently receiving a psychostimulant or other medication indicated for the management of ADHD

symptoms. We chose this definition (ie, formal treatment for the diagnosis of ADHD) because of potential confusion or misuse of the diagnostic term ADHD.

For this study, the independent vari-able was hypertension status. The de-pendent variables were LDs and ADHD, as defined above. As covariates, we in-cluded the following demographic and medical variables available from our retrospective review: age, gender, low

socioeconomic status (SES), and obe-sity. Low SES was defined as Census tract median income in the lowest quartile and/or residing in the inner city of Rochester, New York (defined as Census tracts within city limits where

⬎50% of the children were enrolled in Medicaid). Obesity was defined as BMI

ofⱖ95th percentile according to age and gender. SES was selected as a co-variate because of the close link be-tween SES and health care utilization.5

Obesity was included as a covariate be-cause of the known interactive effect on cognition with hypertension.6

We performed bivariate analyses to compare the groups with and with-out hypertension with respect to de-mographic and dependent variables. We used Fisher’s exact test for

pro-portions and 2-tailed Student’sttest or the Mann-WhitneyUtest, as indi-cated, for continuous variables. We then performed multivariate logistic regression analysis to examine the relationship between hypertension and LDs, with adjustment for age, gender, obesity, and low SES. All analyses were performed with SAS

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sub-jects review board at the University of Rochester Medical Center.

RESULTS

Two hundred one consecutive referred patients met the inclusion criteria. Of those patients, 101 were classified as not having hypertension and 100 were classified as having hypertension. There were no significant differences between the groups with and without hypertension with respect to gender, age, low SES, BMI percentile, or obesity (Table 1).

A total of 37 (18%) of 201 children had LDs, and 27 children (13%) were re-ceiving treatment for ADHD. Among the 37 children with LDs, 10 (27%) were receiving ADHD treatment; among chil-dren without LDs, 17 (10%) were re-ceiving ADHD treatment. In bivariate analysis, subjects with hypertension were more likely to have ADHD and LDs, compared with subjects without hy-pertension. The results for LDs were similar regardless of whether the sub-ject was also receiving ADHD medica-tions (Table 2).

Multivariate analysis showed that the odds of having LDs were elevated for subjects with hypertension, com-pared with subjects without

hyper-tension, with adjustment for age, gender, obesity, and low SES (odds ratio [OR]: 4.1 [95% confidence inter-val [CI]: 1.8 –9.4]). The results were similar regardless of whether the subjects were receiving ADHD medi-cations (LD without ADHD, OR: 4.0 [95% CI: 1.6 –10.2]). Crude and ad-justed ORs and 95% CIs for LDs and hypertension, with and without ADHD, are presented in Table 3.

DISCUSSION

We found that children with primary hypertension had higher LD rates, in comparison with a control group with-out hypertension. Regardless of ADHD medication history, children with hy-pertension had fourfold higher odds of LDs, compared with children without hypertension. In fact, 28% of the sub-jects with hypertension had a diagno-sis of a LD, a proportion far in excess of the general population estimate for

LDs of 5% among all school-aged chil-dren.7The fact that the prevalence of

LDs among subjects with hypertension was similar even among subjects who were not receiving medication for ADHD suggests that the association be-tween LDs and hypertension was not an artifact of stimulant medication in-creasing BP and thereby biasing the results toward hypertension for the subjects with LDs.

Both ADHD treatment (ie, stimulant medications) and anxiety may con-found the assessment of hypertension in children. Stimulants prescribed for ADHD can increase BP during active treatment, an observation that might have resulted in the increased rate of ADHD in the group with hypertension, because we defined the diagnosis of ADHD as receiving medication because of inattention.8,9 ADHD and LDs are

highly comorbid, however; ⱖ50% of subjects in ADHD samples may have a formal diagnosis of a LD or some prob-lem with learning, and at least one-half of children in groups with LDs either meet the diagnostic criteria for ADHD or may have some attention prob-lems.10–12 Although it is possible that

some of the children with ADHD exhib-ited hypertension because they were receiving stimulants for treatment of ADHD, it also is possible that the in-creased prevalence of ADHD in the hy-pertensive group is in part a reflection of neurocognitive difficulties among children with hypertension. We also note that anxiety is both an indepen-dent and comorbid disorder among children with ADHD and LDs;⬃25% of children with ADHD have a comorbid

TABLE 1 Baseline Demographic Characteristics of Subjects With and Without Hypertension No Hypertension (N⫽101) Hypertension (N⫽100) P

Male/female, % 71/30 78/22 .26

Age, median (IQR), y 15 (13–16) 15 (13–17) .56

Low SES, % 24 26 .74

BMI percentile, median (IQR) 97 (82–99) 98 (87.5–99) .09

Obese, % 57 66 .24

IQR indicates interquartile range.

TABLE 2 Prevalence of ADHD and LDs According to BP Group

Diagnosis n(%) P

Total (N⫽201)

No Hypertension (N⫽101)

Hypertension (N⫽100)

ADHD 27 (13) 7 (7) 20 (20) .007

LD

All subjects 37 (18) 9 (9) 28 (28) ⬍.001

Without ADHD 27 (13) 7 (7) 20 (20) .002

With ADHD 10 (5) 2 (2) 8 (8) .67

Univariate analysis and Fisher’s exact test were used.

TABLE 3 Multivariate Logistic Regression Analysis of Association Between Hypertension and LD Diagnosis

All Subjects Without ADHD

␤, Estimate⫾SE OR (95% CI) ␤, Estimate⫾SD OR (95% CI)

Crude 1.38⫾0.41 4.0 (1.8–9.0) 1.42⫾0.47 4.1 (1.6–10.4)

Adjusteda 1.420.42 4.1 (1.8–9.4) 1.390.48 4.0 (1.6–10.2)

aAdjusted for age, gender, proportion with obesity, and proportion with low SES.

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suggests an interaction between hy-pertension and internalizing mood problems (anxiety and depression).4

These observations suggest a poten-tial interplay among primary hyperten-sion, anxiety, and LDs in children.

Finally, the prevalence of primary hy-pertension in children is now esti-mated to be nearly 4%,14and many of

these children may fail to be identi-fied,15,16a remarkable number that

un-derscores the importance of under-standing the potential impact of hypertension on neurocognition in childhood. Hypertension may lead to reversible neurocognitive problems in childhood.17If so, then better

identifi-cation and treatment of pediatric pri-mary hypertension potentially could reduce the burden of LDs.

The reason for neurocognitive prob-lems in children with hypertension is not known. However, even mild/moder-ate hypertension may be associmild/moder-ated with central nervous system abnor-malities.18,19Although this is not yet

es-tablished anatomically in children, adults with chronic essential hyper-tension have a greater likelihood of re-gional changes in frontal lobe integrity (reduced prefrontal cortex and

in-trol subjects with normotension, and the extent of these changes may corre-late positively with disease duration.20

What remains equivocal is whether there is a primary relationship be-tween the presumed hypertension-related brain abnormalities and neu-rocognitive test performance.20

The current study has several limita-tions. First, because of the retrospec-tive nature of the study design, the clinical evidence for sustained hyper-tension versus no hyperhyper-tension was not based on uniform criteria; some subjects had ambulatory BP monitor-ing data and others had less-rigorous evidence such as school nurse or home self-monitoring data. Therefore, it is possible that there were subjects in the hypertensive group who actually did not have hypertension and sub-jects in the nonhypertensive group who had hypertension. However, this limitation would bias the results to-ward no difference between the groups. Second, as noted above, the definition of ADHD was based solely on medication history, which would result in the inclusion of children taking stim-ulant medications that are known to increase BP.9Last, the cross-sectional

nature of the study prevents

infer-ple, we cannot discern whether children with ADHD are more likely to have hypertension or whether having hypertension somehow predisposes children to ADHD. In addition, it is pos-sible that some other factors resulted in both hypertension and LDs.

CONCLUSIONS

We report the novel finding of in-creased prevalence of learning prob-lems in children diagnosed as having sustained primary hypertension. These results provide additional evi-dence of the emerging association be-tween primary hypertension and neu-rocognitive problems in children. Future studies on the mechanism of this association and the impact of treatment of hypertension on learning and other cognitive skills in children are warranted.

ACKNOWLEDGMENTS

This work was supported by a grant from the National Institutes of Health to Dr Lande (grant 5K23HL080068-05).

We gratefully acknowledge the contri-butions of Donna Palumbo, PhD, in study design and Andrew Blumkin, MS, in data programming.

REFERENCES

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2. Waldstein S, Jennings J, Ryan C, et al. Hy-pertension and neuropsychological per-formance in men: interactive effects of age.Health Psychol. 1996;15(2):102–109 3. Lande MB, Kaczorowski JM, Auinger P,

Schwartz GJ, Weitzman M. Elevated blood pressure and decreased cognitive function among school-age children and adoles-cents in the United States.J Pediatr. 2003; 143(6):720 –724

4. Lande MB, Adams H, Falkner B, et al.

Paren-tal assessments of internalizing and exter-nalizing behavior and executive function in children with primary hypertension.J Pedi-atr. 2009;154(2):207–212

5. Stein R, Siegel M, Bauman L. Double jeopardy: what social risk adds to biomedical risk in understanding child health and health care utilization.AcadPediatr. 2010;10(3):165–171 6. Waldstein S, Katzel L. Interactive relations of

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7. US Department of Education.Twenty-Fourth Annual Report to Congress on the Imple-mentation of the Individuals With Disabili-ties Education Act. Washington, DC: US De-partment of Education; 2001

8. Samuels JA, Franco K, Wan F, Sorof JM. Ef-fect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial.Pediatr Nephrol. 2006;21(1):92–95

9. Wilens T, Biederman J, Lerner M, et al. Ef-fects of once-daily osmotic release methyl-phenidate on blood pressure and heart rate in children with attention-deficit/ hyperactivity disorder: results from a one-year follow-up study.J Clin Psychopharma-col. 2004;24(1):36 – 41

10. Mayes S, Calhoun S, Crowell E. Learning abilities and ADHD: overlapping spectrum dis-orders.JLearn Disabil. 2000;33(5):417– 424 11. Barkley R. What to look for in a school for a

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12. Semrud-Clikeman M, Biederman J, Sprich-Buckminster S, Lehman BK, Faraone SV, Norman D. Comorbidity between ADHD and learning disability: a review and report in a clinically referred sample.J Am Acad ChildAdolesc Psychiatry. 1992; 31(3):439 – 448

13. Jensen PS, Martin D, Cantwell DP. Comor-bidity in ADHD: implications for research, practice, and DSM-V.J Am Acad Child Ado-lesc Psychiatry. 1997;36(8):1065–1079

14. Flynn J. Hypertension in the young: epidemi-ology, sequelae and therapy.Nephrol Dial Transplant. 2009;24(2):370 –375

15. Hansen M, Gunn P, Kaelber D. Underdiagno-sis of hypertension in children and adoles-cents.JAMA. 2007;298(8):874 – 879 16. Brady TM, Solomon BS, Neu AM, Siberry

GK, Parekh RS. Patient-, provider-, and clinic-level predictors of unrecognized elevated blood pressure in children.

P e d i a t r i c s. 2 0 1 0 ; 1 2 5 ( 6 ) . A v a i l a b l e at: www.pediatrics.org/cgi/content/full/ 125/6/e1286

17. Lande M, Adams H, Falkner B, et al. Paren-tal assessment of executive function and internalizing and externalizing behavior in primary hypertension after

anti-hypertensive therapy. J Pediatr. 2010; 157(1):114 –119

18. Carmelli D, Swan GE, Reed T, Wolf PA, Miller BL, DeCarli C. Midlife cardiovascular risk factors and brain morphology in identical older male twins.Neurology. 1999;52(6):1119 –1124 19. Salerno J, Murphy D, Horwitz B, et al. Brain

atrophy in hypertension: a volumetric mag-netic resonance imaging study. Hyperten-sion. 1992;20(3):340 –348

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DOI: 10.1542/peds.2010-1899 originally published online November 8, 2010;

2010;126;e1425

Pediatrics

Heather R. Adams, Peter G. Szilagyi, Laura Gebhardt and Marc B. Lande

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http://pediatrics.aappublications.org/content/126/6/e1425

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DOI: 10.1542/peds.2010-1899 originally published online November 8, 2010;

2010;126;e1425

Pediatrics

Heather R. Adams, Peter G. Szilagyi, Laura Gebhardt and Marc B. Lande

Hypertension

Learning and Attention Problems Among Children With Pediatric Primary

http://pediatrics.aappublications.org/content/126/6/e1425

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 3 Multivariate Logistic Regression Analysis of Association Between Hypertension and LDDiagnosis

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