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Screening for Hypertension in Children and Adolescentsto Prevent Cardiovascular Disease
abstractBACKGROUND AND OBJECTIVE: The prevalence of hypertension is in-creasing in children, and may persist into adulthood. This systematicreview was conducted for the US Preventive Services Task Force rec-ommendation on the effectiveness of screening asymptomatic childrenand adolescents for hypertension in order to prevent cardiovasculardisease.
METHODS: Eligible studies were identified from Medline and theCochrane Library (through July 2012). We included trials and controlledobservational studies in asymptomatic children and adolescents on theeffectiveness and harms of screening and treatment, as well as accu-racy of blood pressure measurement. One author extracted study char-acteristics and results, which were checked for accuracy by a secondauthor.
RESULTS: No studies evaluated the effects of screening for hyperten-sion on health outcomes. Two studies of screening tests for elevatedblood pressure reported moderate sensitivities (0.65, 0.72) and speci-ficities (0.75, 0.92). Sensitivities and specificities of child hypertensionfor the later presence of adult hypertension (7 studies) were wideranging (0–0.63 and 0.77–1.0, respectively), and associations betweenchild hypertension and carotid intima media thickening and protein-uria in young adults (3 studies) were inconsistent. Seven studiesreported that drug interventions effectively lowered blood pressurein adolescents over short follow-up periods. No serious treatment-related adverse effects were reported.
CONCLUSIONS: There is no direct evidence that screening for hyper-tension in children and adolescents reduces adverse cardiovascularoutcomes in adults. Additional studies are needed to improve diagnosisand risk stratification of children with elevated blood pressure and toquantify risks and benefits of interventions. Pediatrics 2013;131:490–525
AUTHORS: Matthew Thompson, MD, MPH, DPhil,a,b TracyDana, MLS,a Christina Bougatsos, MPH,a Ian Blazina, MPH,a
and Susan L. Norris, MD, MPH, MSca
aOregon Evidence-Based Practice Center, Oregon Health andScience University, Portland, Oregon; and bDepartment ofPrimary Care Health Sciences, Oxford University, Oxford, UnitedKingdom
ABBREVIATIONSADAPT—Dietary/Exercise Alteration Program TrialCI—confidence intervalDBP—diastolic blood pressureOR—odds ratioRCT—randomized controlled trialSBP—systolic blood pressureUSPSTF—US Preventive Services Task Force
Dr Thompson made substantial contributions to conception anddesign, acquisition of data, analysis and interpretation of data,drafted the article and revised it critically for importantintellectual content, and gave final approval of the version to bepublished. He is guarantor for this article. Ms Dana andBougatsos, Mr Blazina, and Dr Norris made substantialcontributions to conception and design, acquisition of data,analysis and interpretation of data, revised the article criticallyfor important intellectual content, and gave final approval of theversion to be published.
The staff at the Agency for Healthcare Research Quality andmembers of the US Preventive Services Task Force developedthe scope of the work and reviewed draft manuscripts. Approvalfrom the Agency for Healthcare Research Quality was requiredbefore the manuscript was submitted for publication, but theauthors are solely responsible for the content and the decisionto submit it for publication.
www.pediatrics.org/cgi/doi/10.1542/peds.2012-3523
doi:10.1542/peds.2012-3523
Accepted for publication Dec 19, 2012
Address correspondence to Matthew Thompson, MD, MPH, DPhil,Department of Primary Care Health Sciences, Oxford University,New Radcliffe House, Woodstock Road, Oxford OX2 6GG, UK. E-mail:[email protected]
FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.
FUNDING: This review was supported by the Agency forHealthcare Research Quality for the US Preventive Services TaskForce under contract 290-2007-10057-I to support the work ofthe US Preventive Services Task Force.
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Between 1% and 5% of children andadolescents have hypertension, and itsprevalence has risen in the UnitedStates by 1% to 2% over recent deca-des.1–4 Hypertension is usually asymp-tomatic, and a significant proportion ofchildren with hypertension are un-diagnosed.5,6 Screening children andadolescents for elevated blood pres-sure could identify hypertension at anearly stage where interventions couldbe initiated, potentially decreasing therate of progression of hypertensionfrom childhood to adulthood and re-ducing the clinical consequences ofhypertension in adulthood.7
The strongest risk factor for primaryhypertension in children of all ages andboth genders is elevated BMI8–14; chil-dren who are overweight or obese havea two- to threefold increased risk ofhypertension.8–10 This increased risk isparticularly concerning given that∼17% of children and adolescents inthe United States are now obese15 andhave higher risk of other cardiovascu-lar risk factors such as an adverselipid profile and insulin resistance.16
Other risk factors for primary hyper-tension include low birth weight, gen-der, ethnicity, and a positive familyhistory.2,3,9,10,17–19
Secondary hypertension is most com-monly related to underlying renal pa-renchymal or renovascular disease;less common causes include aorticcoarctation and endocrine disorders.20,21 Elevated blood pressure is usuallyonly 1 clinical manifestation of the un-derlying disorder, and treatment istypically directed at correcting theunderlying cause.
For the majority of children and ado-lescents, the rationale for identifyingelevated blood pressure lies in the po-tential to stratify risk of future cardio-vascular disease. There is convincingevidence that structural and functionalchanges in the cardiovascular system,which indicate early atherosclerosis,can be detected in adolescents andyoung adults. What is less clear are thenature and magnitude of the relation-ship between elevated blood pressureand other cardiovascular risk factors inchildren or adolescents and cardiovas-cular risk in adults. Cohort studies thathave followed children to young adult-hood suggest that adiposity, insulin re-sistance, and an adverse lipid profileprogress at an increased rate in pre-hypertensive and hypertensive childrenand adolescents compared with nor-motensive children.7,22,23
AIMS OF THIS REVIEW
Thepurpose of this systematic review isto provide the US Preventive ServicesTask Force (USPSTF) with evidence toupdate their 2003 recommendation onscreening for high blood pressure inchildren and adolescents.24 The largerreview is available at www.uspreventi-veservicestaskforce.org.25 With the in-put of members of the USPSTF, wedeveloped an analytic framework (Fig 1)and key questions to guide our litera-ture search and review.
1. Is screening for hypertension inchildren/adolescents effective indelaying the onset or reducing ad-verse health outcomes related tohypertension?
2. What is the diagnostic accuracy ofscreening tests for elevated bloodpressure in children/adolescents?
3. What is the association between hy-pertension in children/adolescentsand hypertension and other inter-mediate outcomes in adults?
4. What are the adverse effects ofscreening for hypertension in children/adolescents, including labeling andanxiety?
5. What is the effectiveness of drug, non-drug, and combination interventions
FIGURE 1Analytic framework and key questions. aThe assessment and treatment of secondary hypertension is beyond the scope of this review. bIncludes left ventricularhypertrophy, urinary albumin excretion (microalbuminuria), intima media thickness (measured at carotid and/or femoral arteries), and retinal vascularchanges. KQ, key question.
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for treating primary hypertensionin children/adolescents?
6. What is the effectiveness of drug,nondrug, and combination inter-ventions initiated for the treatmentof primary hypertension in children/adolescents for reducing blood pres-sure and other intermediate outcomesin adults?
7. What is the effectiveness of drug,nondrug, and combination inter-ventions initiated for the treatmentof primary hypertension in children/adolescents for reducing adversehealth outcomes in adults relatedto primary hypertension?
8. What are the adverse effects ofdrug, nondrug, and combinationinterventions for treating primaryhypertension in children/adoles-cents?
METHODS
ThisreviewwasdevelopedbytheOregonEvidence-Based Practice Center undercontract with the Agency for HealthcareResearch Quality (contract 290-2007-10057-I) and follows the systematic re-view methods of the USPSTF.26,27
Search Strategies
We searched the Cochrane CentralRegister of Controlled Trials and theCochrane Database of SystematicReviews (through July 2012) and Med-line (1946 to July 9, 2012) for relevantstudies and systematic reviews, andmanually reviewed reference lists forrelevant citations (Appendix 1).
Study Selection and Processes
Papers were selected for full review ifthey met predefined inclusion criteria(Appendix 2). Controlled studies ofscreening for hypertension in asymp-tomatic children and adolescents wereincluded. For studies of diagnostic ac-curacy, eligible studies included a refer-encestandardcomparisonandprovided
adequate data to reproduce contingencytables. Evidence from randomizedplacebo-controlled trials was used toassess the efficacy of treatments onmultiple outcomes, including bloodpressure, other intermediate healthoutcomes, and final health outcomes, inchildhood, adolescence, and adulthood.Studies with ,30 participants andstudies of interventions for the treat-ment of obesity and lipid disorders inchildren were excluded, because thesepopulations are considered in otherUSPSTF recommendations.28,29 To assessharms of treatment, studies withouta comparison or a placebo group wereincluded. Studies of secondary hyper-tension were excluded, although somestudies included proportions of partic-ipants with secondary hypertension.
All citations identified throughsearchesand other sources were independentlyreviewed by 2 authors for inclusion andexclusion. Discrepancies at the full-textlevelwere resolved through consensus.One author extracted data on the pa-tient population, study design, testingmethods, analysis, follow-up, and re-sults, andasecondauthorcheckeddataextraction for accuracy.
Quality Assessment and Synthesis
By using predefined criteria developedby the USPSTF,26 2 authors rated thequality of studies (good, fair, poor) andresolved discrepancies by consensus.Authors assessed the overall strengthof the body of evidence for each keyquestion as good, fair, or poor by usingmethods developed by the USPSTF onthe basis of the number, quality, andsample size of studies, as well as theconsistency of results among studiesand directness of the evidence.26 Thelimited number of studies and theheterogeneity of study designs, inter-ventions, and diagnostic tests pre-cluded meta-analyses; results aretherefore summarized qualitatively asmeans or as ranges, as appropriate.
RESULTS
Our literature search identified a totalof 6435 citations, of which we reviewed1059 full-text publications and included34 studies (Fig 2).
Key Question 1: Is Screening forHypertension in Children/Adolescents Effective in Delayingthe Onset or Reducing AdverseHealth Outcomes Related toHypertension?
No randomized trials compared healthoutcomes related to hypertension inscreened versus nonscreened child oradolescent populations.
Key Question 2: What Is theDiagnostic Accuracy of ScreeningTests for Elevated Blood Pressurein Children and Adolescents?
We identified 2 fair-quality studies thatprovided data on the diagnostic accu-racyof screening tests (Appendix 3).30,31
Compared with a reference standardof 24-hour ambulatory measurement,office-based blood pressure measure-ment (3 measurements at each of 2clinic visits) had a sensitivity of 0.65(95% confidence interval [CI], 0.45–0.80) and a specificity of 0.75 (95% CI,0.63–0.84).31 The positive predictivevalue was 0.37 (95% CI, 0.28–0.47) andthe negative predictive value was 0.63(95% CI, 0.53–0.72). All 105 participants(mean age, 13 years) had been re-ferred for evaluation at a specialtyclinic, so they may not have been rep-resentative of screened populations ofasymptomatic children. In addition,ambulatory measurement is not yetan internationally accepted referencestandard in children and adolescents.A second study examined a randomsample of 9017 eighth graders, ofwhom about 10% (900/9017) had bloodpressure .95th percentile on initialscreening, whereas the remainder(8117/9017) were normotensive.30 Atfollow-up in 10th grade, the sensitivity
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and specificity of initial elevated bloodpressure for persistent elevation ofblood pressure were 0.72 (95% CI,0.65–0.78) and 0.92 (95% CI, 0.91–0.92),respectively; however, the positivepredictive value was low (0.17 [95% CI,0.15–0.20]). This study primarily fol-lowed only the sample of childrenwhose initial screening test was posi-tive rather than the entire population,which may have biased the diagnosticaccuracy in this study.
In addition, 12 studies compared $1measurement of blood pressure withsubsequent reference measurementsbut did not meet our inclusion criteriabecause either they failed to apply thereference tests to participants whoinitially screened negative or they didnot use an acceptable reference stan-dard.11,32–42 Positive predictive valuesamong these studies ranged from 0.04to 0.53. The reasons for this heteroge-neity were unclear but did not appear
to be related to varying prevalence ofhypertension, method or device usedfor testing, or thresholds used to de-fine positive tests.
Key Question 3: What Is theAssociation Between Hypertensionin Children/Adolescents andHypertension and OtherIntermediate Outcomes in Adults?
Ten longitudinal studies provided evi-dence on the association between ele-vated blood pressure or hypertensionin childhood and elevated blood pres-sure, hypertension, or intermediateoutcomes in adults (Appendix 4).7,43–51
These studies used different thresh-olds for defining elevated blood pres-sure and hypertension in childhoodand different definitions of hyperten-sion in adults. The sensitivities andspecificities of elevated blood pressureor hypertension in childhood for pre-dicting adult hypertension ranged from
0 to 0.63 and 0.77 to 1, respectively,depending on thresholds.45,47,51 Positivepredictive values (ie, the probability ofadult hypertension given the presenceof elevated blood pressure or hyper-tension in childhood) ranged from 0.19to 0.65.45,47 Five studies reported sig-nificant associations between elevatedblood pressure in childhood and hy-pertension in adults, with odds ratios(ORs) ranging from 1.1 to 4.57,47 andrelative risks ranging from 1.5 to 9.43,44,48
Two studies reported conflicting find-ings on the association between child-hood hypertension and carotid intimamedia thickness in young adults. Sys-tolic blood pressure (SBP) .80th per-centile in adolescence was mildlyassociated with carotid intima mediathickness in adulthood in 1 study (re-gression coefficient, 0.013; P, .001).50
A second study, however, found no in-creased risk of carotid intima mediathickness in adulthood related to
FIGURE 2Literature search flow diagram. aCochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of SystematicReviews. bOther sources include reference lists, suggested by peer reviewers, etc. cSome articles are included for.1 key question. dTwelve of these studiesdid not provide enough data to recreate 2 3 2 tables or calculate sensitivity and specificity.
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elevated systolic blood pressure inchildhood (highest quartile versuslower 3 quartiles: OR, 1; 95% CI, 0.80–1.25), although the level of SBP elevationis not defined in this study.49 Childhoodhypertension was significantly associ-ated with microalbuminuria in blackbut not white adults in a single study.46
We found no evidence for associationsbetween diagnosed hypertension inchildhood and other intermediate orfinal health outcomes.
Key Question 4: What Are theAdverse Effects of Screening forHypertension in Children andAdolescents, Including Labelingand Anxiety?
One small good-quality study compared85 children (10–18 years of age) withelevated blood pressure identified byscreening to children matched by ageand gender from the same commu-nity.52 The only outcome reported wasrates of school absenteeism, which didnot differ significantly between the 2groups.
Key Question 5: What Is theEffectiveness of Drug, Nondrug,and Combination Interventions forTreating Primary Hypertension inChildren and Adolescents?
Fourteen fair-quality randomized con-trolled trials (RCTs)33,53–66 (in 15 pub-lications) of treatment of hypertensionin children and adolescents met in-clusion criteria (Table 1; Appendix 5). Theproportion of children with primary hy-pertension ranged from 31%54 to 56%55;however, most studies did not report theproportion of participants with second-ary hypertension.53,57–60,62,64–66
Drug Interventions
All seven included trials of drug inter-ventions examined different drugs.53–59
Most compared active drug (in differ-ent doses) to placebo, with follow-up ofonly 4 weeks. The magnitude of effects
on SBP and diastolic blood pressure(DBP) varied and were not consis-tently different from changes inblood pressure in the placebo group(or these differences were not re-ported).
Five studies53,54,57–59 reported the per-centage of participants achieving tar-get blood pressure at the end of thefollow-up period, and all noted an in-crease in those who achieved targetlevels with the active drug (range 15–86% of subjects). However, 26% to 47%of children in the placebo groups alsoachieved normal blood pressure at theend of the study period.53–59 Moststudies reported significant reductionsinmean SBP (range, 1.9–10.2mm Hg) andDBP (range, 0.4–8.1 mm Hg). Eplerenone(50 mg/day) produced a small increasein mean SBP and no change in DBP.55
Most studies had limitations, most no-tably the failure to report the statisticalsignificance of differences between treat-ment groups in addition to within-grouptreatment differences. Also, comparisonamong studies was difficult because ofvarying drug dosages.
Drug Plus Lifestyle Interventions
The school-based A Dietary/ExerciseAlteration Program Trial (ADAPT) ex-amined the effectiveness of a multi-component, school-based intervention,including nutrition education for andpromotion of diet modification to chil-drenandparents; expandedcommunityavailability of low-sodium foods in gro-cery stores, restaurants, and schoollunches; a school-based exercise pro-gram; and propranolol and chlorthali-done compared with a no interventiongroup.60,61 This complex interventionresulted in a significant decrease inboth SBP and DBP at the 6-monthfollow-up (mean SBP change: 27.6mm Hg [P, .0001]; mean DBP change:26.9 mm Hg [P, .01]) compared withthe control group. At 30 months, how-ever, SBP increased from baseline in
both the intervention (1.4 mm Hg) andcontrol groups (3.5 mm Hg), althoughDBP remained below baseline levels(mean change: 24.2 mm Hg in the in-tervention group and 23.3 mm Hg inthe control group).
Lifestyle Interventions
Most of the six trials examining lifestyleinterventions included support relatedto the interventions (eg, regular check-ins) in addition to diet, exercise, ormeditation.33,62–66 Only 1 study demon-strated statistically significant reduc-tions in blood pressure comparedwith untreated controls.64 This small,school-based RCT compared the effectsof 5 versus 3 weekly physical educationclasses in hypertensive children andreported that blood pressure de-creased significantly more in partic-ipants receiving 5 weekly classes overthe 8-month follow-up period (meanbetween-group difference in SBP =24.9mm Hg and DBP =23.8 mm Hg; P, .05for both outcomes).64 In another trial,a low-sodium diet combined with per-sonalized support from a nutritionistand/or potassium chloride supplemen-tation was effective in reducing bloodpressure compared with usual careplus placebo at 36 months among girlsbut not among boys.66 Other studies ofmeditation,63 relaxation,33 and dietarychanges62,65 reported no significantdifferences between intervention andcontrol groups.
Key Question 6: What Is theEffectiveness of Drug, Nondrug,and Combination InterventionsInitiated for the Treatment ofPrimary Hypertension in Children/Adolescents for Reducing BloodPressure and Other IntermediateOutcomes in Adults?
No RCTs examined the effectiveness ofinterventions for hypertension in chil-dren or adolescents for reducing bloodpressure or other intermediate out-comes in adults.
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Drug plus lifestyle interventionsBerenson et al 198360 (6 mo) ADAPT program 116.6 77.7 109.0 70.8 27.6 26.9 26.5 23.6
Control 118.5 78.3 115.5 74.4 23.0 23.9 — —
Berenson et al 199061 (30 mo)b ADAPT program 116.6 77.7 118.0 73.5 1.4 24.2 23.6 21.7Control 118.5 78.5 122.0 75.2 3.5 23.3 — —
Lifestyle interventionsCouch et al 200862 (6 mo) DASH diet 129.4 80.4 120.1 75.2 29.3 25.2 0.1 21.2
Routine care 124.3 81.7 120.0 76.4 24.3 25.3 — —
Ewart et al 198733 (9 mo) Relaxation training 127.0 79.1 118.6 72.9 28.4 26.2 22.3 23.1No intervention 126.5 80.4 120.9 76.0 25.6 24.4 — —
Gregoski et al 201163 (3 mo) Meditation 119.4 68.1 116.6 66.3 22.8 21.8 24.4 22.4LifeSkills training 119.6 68.0 119.8 68.2 0.2 0.2 21.2 20.5Regular health education 121.4 69.3 121.0 68.7 20.4 20.6 — —
Hansen et al 199164 (3 mo) Extra physical education classes Not reported 24.9 23.8No extra classes — —
Howe et al 199165 (4 wk) Low sodium diet 115.0a 60.1a 112.6 59.1 Not reported 21.2 20.9High sodium diet 113.8 60 — —
DASH, Dietary Approaches to Stop Hypertension; —, indicates that data is not available.a Values for total cohort; data not stratified according to treatment group.b Continuation of Berenson et al 1983 study.
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Key Question 7: What Is theEffectiveness of Drug, Nondrug,and Combination InterventionsInitiated for the Treatment ofPrimary Hypertension in Children/Adolescents for Reducing AdverseHealth Outcomes in Adults Relatedto Primary Hypertension?
No RCTs examined the effectiveness ofinterventions for hypertension in chil-dren or adolescents for reducing clin-ical outcomes in adults.
Key Question 8: What Are theAdverse Effects of Drug, Nondrug,and Combination Interventions forTreating Primary Hypertension inChildren and Adolescents?
Drug Interventions
Twelve trials reported adverse eventswith drug therapy (Appendix 6).53–59,67–71
One study was rated good quality67; theremainderwereof fairquality.53–55,57–59,68–71
Four of the studies included childrenwithprimary hypertension,53,57–59 whereas theremainder included children with pri-mary or secondary hypertension.54,55,67–71
The number of children enrolled in thestudies ranged from 76 to 304, the meanage ranged from 12 to 14 years, and theduration of follow-up for reporting ad-verse events ranged from 4 weeks to 1year.
Serious adverse events were rarelyreported, and there were no deaths inany of the studies. One study of meto-prolol reported 1 case each of pneu-monia andmetometrorrhagia.53 Anotherstudy reported a case of near syncopeand an elevated creatinine in a patientwho received an incorrect dose of tel-misartan. A third study reported 8 seri-ous adverse events among 304 patients,although none were considered to betreatment related.55
Adverse event data were often poorlyreported, and most studies reportednoncomparative data from open-labelextensions of RCTs. Five studies ofmonotherapy reported similar rates of
adverse events in the intervention(range, 27–77%) and placebo groups(range, 25–66%).55,57,59,67,68 Childrentaking a combination of bisoprolol plushydrochlorothiazide had lower overallrates of adverse events compared withplacebo (53–75%, P = .05) after 12weeks of follow-up.56 Withdrawalscaused by adverse events ranged from0% to 7% in children receiving activetreatments53,54,56–59,67–71 and 0% to6.2% in placebo groups.53,56,58,59,67,68
Headache was the most common spe-cific adverse event in most studies:rates ranged from 2% to 33% in childrenreceiving active treatments,53,56,57,59,68,71
but only 2 studies reported rates forthe placebo group. One study reportedthat no headaches occurred in theplacebo group compared with 11%of active treatment patients,59 where-as in a second study, headache wasreported in 31% versus 26% (pla-cebo versus combination treatment,significance not reported).56 Othercommonly reported adverse eventsassociated with active treatmentswere cough, upper respiratory in-fections, and gastrointestinal events,including nausea and diarrhea, al-though specific rates were not alwaysreported.53,54,56–59,68–71
Two studies pooled adverse event datafrom selected drug trials submittedto the Food and Drug Administrationover a 7-year period; however, neitherstudyusedstandardsystematic reviewmethods.72,73 Pooled patient-level datafrom 1707 children from 10 placebo-controlled RCTs of 10 different activeagents72 revealed similar rates of ad-verse events between active treat-ment (0.83 events per patient) andplacebo groups (0.76 per patient) af-ter 2 to 4 weeks of follow-up (between-group P = .37). Pooled data from 8 RCTsof hypertensive children revealed nodifference in the incidence of coughbetween active treatment and placebogroups (3% in both groups; P = .86).73
Other Interventions
The fair-quality ADAPT of a propranololand chlorthalidone/lifestyle interventiondescribed inkeyquestion54reportednoadverse events.60,61 No studies of life-style modification alone reported ad-verse events.
DISCUSSION
Direct evidence linking screening ofchildren and adolescents for hyper-tension and delaying the onset orreducing the risk cardiovascular out-comes in adults is not available, andindirect evidence is sparse and of vari-able quality. We did not identify evidencefor the effectiveness of interventionsused to treat primary hypertension inchildren on lowering blood pressurelevels or reducing adverse health out-comes in adults. A summary of the evi-dence is provided in Table 2.
High-quality data on the diagnostic ac-curacy of blood pressuremeasurementto detect hypertension were alsosparse and suggest moderate sensi-tivities (0.65 and 0.72), with somewhathigher specificities (0.75 and 0.92).These data suggest that many childrenwho have elevated blood pressure onscreening will not have hypertension.There are also some data to suggestthat hypertension in childhood is as-sociated with hypertension in youngadults (OR range, 1.1–4.5; relative riskrange, 1.5–9) or has low to moderatesensitivities (0 and 0.63) and specific-ities (0.77 and 1) for predicting adulthypertension. Moreover, the associa-tion between childhood hypertensionand carotid intima media thicknessand microalbuminura in young adultswas also inconclusive, and direct evi-dence on other intermediate or finalhealth outcomes was lacking.
The effectiveness of antihypertensivemedications in children and adoles-cents has been examined in 7 trials, allof which were small and of short du-ration, and each examined a different
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Limitations Consistency Applicability toPrimary Care
Summary of Findings
Key question 1: Is screening for hypertension in children/adolescents effective in delaying the onset or reducing adverse health outcomes related to hypertension?No studies NA NA NA NA
Key question 2: What is the diagnostic accuracy of screening tests for elevated blood pressure in children/adolescents?2 trials (poor) Studies were flawed or not directly applicable
to an asymptomatic US population. Only 1included a comparisonwith a gold standardof ambulatory monitoring.
Consistent Low Sensitivity and specificity of office-basedscreening for hypertension was 0.65 and0.75 (positive predictive value, 0.37)compared with ambulatory screening in 1study of a referred population.
A second, school-based study comparing aninitial positive screen to subsequentdiagnosis of hypertension had sensitivity(0.72) and specificity (0.92), but the positivepredictive value was lower (0.17).
Key question 3: What is the association between hypertension in children/adolescents and hypertension and other intermediate outcomes in adults?10 cohort studies (poor) Studies used different thresholds for defining
elevated blood pressure and hypertensionin children and different definitions ofhypertension in adults. Studies hadmethodologic shortcomings.
Inconsistent Moderate Sensitivities and specificities of elevated bloodpressure or hypertension from childhood toadult hypertension ranged from0 to 0.66 andspecificities of 0.77 to 1. PPVs ranged from0.19 to 0.65. Five studies reported significantassociations between elevated bloodpressure in childhood and hypertension inadults, with ORs ranging from 1.1 to 4.5 andRRs of 1.5 to 9. Two studies reportedassociations between childhoodhypertension and carotid intima mediathickness in young adults, with conflictingfindings. One study reported a significantassociation between childhood hypertensionand microalbuminuria only in blackindividuals.
Key question 4: What are the adverse effects of screening for hypertension in children/adolescents, including labeling and anxiety?1 study (poor) Evidence limited to results from1, good-quality
studyNA (1 study) High Children labeled as hypertensive did not miss
more days of school in the year afterdiagnosis compared with prelabeling orcompared with nonhypertensive children.Other harms associated with screeningwere not reported.
Key question 5: What is the effectiveness of drug, nondrug, and combination therapies for treating primary hypertension in children/adolescents?14 RCTs (poor) Longest drug study duration was only 4 wk Consistent Moderate Children achieving normotensive status (on the
basis of varyingdefinitions) ranged from15%to86%inpatients takingdrugtreatmentsand11% to 48% in patients taking placebo.
For many studies, the proportion of childrenwith secondary hypertension was unclear
There were significant reductions ofmean SBP(range 2–10 mm Hg), and mean DBP (range0.4–8 mm Hg) with some drugs anddosages. The difference betweenintervention and placebo groups rangedfrom 0 to 9mm Hg for SBPand 0.5 to 10mmHg for DBP. However, reductions were oftenonly at higher doses of active treatments,and studies only lasted for 4 wk.
One school-based study of a drug plus lifestyleintervention reported a significant,sustained reduction in blood pressure in thecombination group versus the control group.
Studies of nondrug therapies were limited, andonly 1 study examining the effect ofadditional physical education classes inschool reported a sustainedmean reductionin blood pressure in for both boys and girls.
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agent. Most importantly, their antihy-pertensive effects varied in magnitude,were not consistently present fora given agent for both SBP and DBP, andwere not consistently different fromplacebo or from baseline. Blood pres-sures inplacebogroupsoften improvedalong with those of the interventiongroup, suggesting regression to themean. From the limited data we iden-tified, medications appeared to be welltolerated, with no serious adverseeffects.
Interventions for treating elevatedblood pressure that involve lifestyleinterventions alone or in combinationwith an antihypertensive medicationfound inconsistent results. Of the 3studies that had positive results, in-creased physical education at schoolwas effective at reducing blood pres-sure in 1 study,64 whereas in a secondlonger-term school-based study, the
effects of an antihypertensive com-bined with a complex lifestyle program(the ADAPT program) were not sus-tained,60,61 and finally, a low sodiumdiet combined with personalized sup-port was only effective in girls.66
Themost important potential limitationof this review was the absence of anyevidence to address several of the keyquestions and the limited quantity andquality of evidence for others. This lackof evidence inevitably limits the con-clusions that can be drawn from thisreview. Second, our search strategy,although rigorous, may have failed toidentify relevant studies. We used ci-tation searching of included articlesand reviewed all articles identified bythe expert reviewers to augment oursearch strategy. We limited our searchto English language publications, whichcould have limited eligible studies.We cannot exclude the possibility of
publication and selective reportingbiases, but we were not able to formallytest for this. In addition, by includingonly studies where the interventionswere directed against treatment of hy-pertension (eg, rather than obesity),indirect evidence was excluded. Finally,identified studies had multiple defi-ciencies in reporting and methodology,which limited the data available foranalysis and interpretation. Limitationsincluded the lack of studies that exam-ined 1 intervention in .1 trial or obvi-ous clinical heterogeneity, precludingthe use of meta-analyses.
Future research in this area needs toaddress the followingmajor gaps in thecurrent state of evidence.
� Diagnostic accuracy of blood pres-sure measurement in primarycare and community settings forscreening children of varying agesand characteristics. This includes
TABLE 2 Continued
Number of Studies(Overall Quality)
Limitations Consistency Applicability toPrimary Care
Summary of Findings
Key question 6: What is the effectiveness of drug, nondrug, and combination therapies initiated for the treatment of primary hypertension in children/adolescents forreducing blood pressure and other intermediate outcomes in adults?No studies NA NA NA NA
Key question 7: What is the effectiveness of drug, nondrug, and combination therapies initiated for the treatment of primary hypertension in children/adolescents forreducing adverse health outcomes in adults related to primary hypertension?No studies NA NA NA NA
Key question 8: What are the adverse effects of drug, nondrug, and combination therapies for treating primary hypertension in children/adolescents?15 studies (13 RCTs, 2 FDA
analyses) (fair)Numerous trials from key question 5 did notreport comparative events rates betweenactive treatment and placebo arms, andadverse event rates overall ere not well-reported in most studies.
Consistent Moderate Studies of antihypertensive drugs in childrenand adolescents generally reported nosignificant difference between activetreatments and placebo in adverse eventrates or in withdrawals due to adverseevents. In one study, a combination ofbisoprolol and hydrochlorothiazide wasassociated with lower adverse event ratesthan placebo.
Four studies reported serious adverse events,although with the exception of 1 case ofsyncope due to a dosing error, seriousadverse events were generally not deemedtreatment related. Analysis of FDA datarevealed no significant difference betweendrug treatments and placebo in theincidence of specific adverse events,including headache (the most commonlyreported adverse event), cardiac events,gastrointestinal events, and cough.
No studies reported on harms associated withnondrug treatments.
FDA, Food and Drug Administration; NA, not applicable; PPV, positive predictive value; RR, relative risk.
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identifying the number, frequency,and timing of readings neededto confirm or rule out hyperten-sion.74
� Adverse effects of screening, in-cluding health care utilization, bur-den on the family, and discomfortand anxiety for the child and fam-ily.
� Epidemiologic studies to describethe natural history of elevatedblood pressure and hypertensionin children and adolescents, id-entifying factors that predictpersistence into adulthood, andregression to normal based onbaseline characteristics such asage, BMI, and pattern of bloodpressure. Such studies need touse current definitions of hyper-tension and be of sufficient dura-tion to draw clinically usefulconclusions.74,75
� Epidemiologic studies to better de-fine thresholds used to definehypertension in children and ado-lescents and their association withboth structural (eg, carotid intimamedia thickening, left ventricularmass) and functional (eg, arterialstiffening) markers of target endorgan damage related to hyperten-sion.
� Longer-term trials of benefits andrisks of all antihypertensive agents(as monotherapy and in combina-tion) and evidence for both short-and long-term safety. Given theexpected duration of antihyperten-sive therapy, the absence of long-term safety data is a significantlimitation.
� Large, controlled, good-quality trialsof feasible nondrug interventionsfor children and adolescents usingmore sophisticated approaches tocomplex interventions to identifycomponents that provide the great-est benefit over prolonged periods.
CONCLUSIONS
The prevalence of hypertension inchildren and adolescents is increasingin the United States, largely driven byincreased BMI. Screening children forelevated blood pressure or hyperten-sion has the potential to shift themanagement of hypertension to youn-ger age groups and potentially reducefuture cardiovascular disease risk inadults. However, at present, the evi-denceneeded tosupport thesepracticesis limited. Although it would be logisti-cally (and ethically) very challengingto demonstrate the effects of inter-ventions in children and adolescents
with elevated blood pressure on car-diovascular outcomes occurring manydecades later in adults, there areclearly a number of outstanding re-search gaps that can be addressed byfeasible research designs in a muchshorter time frame. Increasingly, bloodpressure is being viewed within a par-adigm of overall cardiovascular riskstratification, along with other riskfactors, such as lipid profiles, insulinresistance, and BMI.16 We anticipatethat addressing these current gaps inthe evidence for blood pressure will becritical to add to clinicians’ ability toidentify children and adolescents withincreased cardiovascular risk and alsoto offer a balanced assessment of theoverall benefit of interventions to re-duce this risk and prevent future car-diovascular disease.
ACKNOWLEDGMENTSThe authors thank the responsibleMed-ical Officer at the Agency of HealthcareResearch and Quality, Iris Mabry-Hernandez, MD,MPH, and US PreventiveServices Task Force members KirstenBibbins-Domingo, PhD, MD, DavidGrossman, MD, MPH, BernadetteMelnyk, PhD, RN, CPNP/NPP, andWandaNicholson, MD, MPH. We also thankMatthew Gillman, MD, for providingclinical expertise.
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Database: Ovid Medline(R) and Ovid OLDMEDLINE(R)1 Hypertension or hypertension.mp.2 prehypertension.mp.3 pre-hypertension.mp.4 2 or 35 high blood pressure.mp.6 or/1–57 Mass screening8 6 and 79 Limit 8 to (English language and humans)10 Limit 9 to “all child (0 to 18 years)”11 9 and (child$ or pediatri$ or adolescen$ or school-age).mp.12 10 or 11
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Settings All Primary care clinics, well-child/adolescent visits, school orcommunity-based screening
Pediatric specialty/subspecialty clinics, inpatient, or long-termcare settings, emergency or urgent care facilities
Populations 1, 2, and 4 Asymptomatic, otherwise healthy children and adolescents, 0–18y of age, with no known diagnosis of hypertension
Pregnant adolescents
3 and 5–8: Primary hypertension defined as average blood pressurebetween 95th percentile and 5 mm Hg above the 99thpercentile
Majority of study population included secondary hypertension
Interventions 1–4: Blood pressure measurements using auscultatory oroscillometric devices that can be performed in a primary careclinic
24-h, ambulatory, or home-based blood pressuremeasurements.Diagnostic tests or investigations used to identify or confirmpossible causes of secondary hypertension
5–8: Drug: Antihypertensive medications which are currently FDA-approved for use in children/adolescents
Interventions for treatment of secondary hypertension
Lifestyle: Diet, exercise, etc. Interventions where reduction in blood pressure was nota primary objective of the study (eg, weight loss studies)
Outcomes 4, 5, and 6: Blood pressure Measures of cognitive functionLeft ventricular hypertrophy (defined using left ventricular mass
index and/or measures of left ventricular geometry)Bloodpressurevariability, suchasdiurnalvariationsornocturnalblood pressure dipping
Urinary albumin excretion (microalbuminuria) Arterialwall dysfunction, includingmeasuresofarterial stiffness,pulse wave velocity, or augmentation index
Intima-medial thickness (measured at carotid and/or femoralarteries)
Metabolicmeasures, eg,measuresof impairedglucose tolerance,levels of insulin, lipid profiles, homocysteine levels
Retinal vascular changes uric acid levelsInflammatory markers including C-reactive proteinBody changes in weight or BMI
1 and 7: Severe visual impairment Studies reporting intermediate outcomesStage IV or V chronic kidney diseaseCardiovascular events, including ischemic heart disease, heart
failureCerebrovascular events, including hemorrhagic and thrombotic
stroke, Hypertensive encephalopathyMortality (all-cause and disease-specific)
2 Measures of predictive validity of screening tests (eg, predictivevalue, likelihood ratios, sensitivity, specificity)
Studies that do not provide enough data to recreate 23 2 tablesor calculate sensitivity and specificity
Studies that do not use a true reference standard forcomparison
3 Measures of association (eg, odds ratio; risk ratio, sensitivity,specificity, correlation or regression coefficients)
Studies not reporting measures of association
8 Side effects of hypertension treatments or interventions —
Study designs 1 Randomized controlled trials, controlled clinical trials,observational studies with a comparison group (eg,comparative cohort and case-control studies), and systematicreviews
Study designs other than those specified
2 Studies of predictive validity that compare with a referencestandard (eg, ambulatory monitoring)
Study designs other than those specified
3 Longitudinal cohort and epidemiology studies Study designs other than those specified4 and 8 Randomized controlled trials, controlled clinical trials,
observational studies with a comparison group (eg, largecohort and case-control studies), and systematic reviews. Ifnone were identified, uncontrolled before-after studies wereexamined.
Study designs other than those specified
5–7 Randomized controlled trials, controlled clinical trials,observational studies with a comparison group (eg, largecohort and case-control studies), and systematic reviews
Study designs other than those specified
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