Hypertension is one of the most common chronic diseases of childhood, affecting 4% of children, including 15% of children with obesity.1 Historically, hypertension in most children has been attributed to secondary causes, 2,3 with renal disease or renovascular disease reported in up to 77%-97% of children with secondary hypertension.4-6 In cohorts of children with hypertension followed in pediatric nephrology or pediatric hypertension clinics, 45%-85% of patients have secondary hypertension.4-10
The high prevalence of secondary hypertension observed in subspecialty clinics may not reflect the prevalence of secondary hypertension in children encountering hypertension in the primary care setting.11 Studies have found that secondary hypertension is rare in asymptomatic children with hypertension detected in screening tests.12-15
The US Preventive Services Task Force has identified the lack of accurate prevalence estimates of secondary hypertension in asymptomatic children as an important gap in pediatric research.16 Defining the pretest probability of secondary hypertension in a healthy child with a new diagnosis of hypertension may help. to inform shared decision-making between providers and families considering further diagnostic work and minimizing the harms and costs of extensive testing.
The purpose of this systematic review and meta-analysis was to estimate the pooled prevalence of secondary hypertension among children undergoing hypertension evaluation in the outpatient setting. The authors hypothesized that the prevalence of secondary hypertension in otherwise healthy children diagnosed with hypertension would be lower than the high prevalence observed in all children with hypertension followed in referral clinics.
This systematic review protocol has been registered in the database of the International Prospective Register of Systematic Reviews (registration number CRD42021229313). The systematic review and meta-analysis were conducted according to the PRISMA statement.17
We included observational studies describing youth and young adults aged ≤20 years diagnosed with hypertension in the outpatient setting who underwent further evaluation for secondary hypertension.
Secondary hypertension was defined as an identifiable cause of hypertension due to renal, renovascular, cardiac, endocrine, or genetic disorders or other environmental or medication exposures. Studies were included if the underlying cause of hypertension in each child was not known at the time of diagnostic evaluation.
Studies were excluded if they included children with chronic diseases associated with hypertension, such as chronic kidney disease, who were known at the time of the initial hypertension evaluation. We included studies in which hypertension was diagnosed based on at least 2 ambulatory blood pressure measurements. Although the aim of some studies may not have been to report the prevalence of secondary hypertension among children with hypertension, studies were included if this information was available from the results.
MEDLINE, PubMed Central, Embase, Web of Science, and the Cochrane Library were searched on January 7, 2021, since the inception of studies reporting the prevalence of secondary hypertension in youth diagnosed with hypertension.
Searches were limited to human studies. No date or language limits were imposed on the search. Articles that were not in English were translated into English using Google Translate.18
An experienced medical librarian was consulted on methodology and a medical subject heading analysis of known key articles (mesh.med.yale.edu) was performed. Scoping searches were conducted in each database and an iterative process was used to translate and refine the searches.
To maximize sensitivity, the formal search used controlled vocabulary terms and synonymous free text words to capture the concepts of “children” and “secondary hypertension.” The reviewers searched for additional relevant citations and cited articles using the included studies.
The final search recovered 4846 references, which were grouped in EndNote and deduplicated (www.endnote.com). This set of search results was uploaded to Covidence (www.covidence.org) for the research. Covidence identified more duplicates, leaving 3,039 studies for investigation. Each title and abstract were evaluated by 2 independent authors; Any titles and abstracts identified for inclusion by at least 1 author were reviewed at the full-text stage.
Two independent authors reviewed each full-text article for inclusion. For studies that met the inclusion criteria in the systematic review, 2 authors independently extracted the following data: first author, year of publication, study design, years of study, setting of study, country of study, age group , definition of hypertension, study for secondary hypertension, number of cases of hypertensive patients with secondary hypertension and total number of cases with hypertension. Disagreements in article selection or data extraction were resolved through discussion to reach consensus.
Studies were critically appraised using a checklist adapted from the Joanna Briggs Institute Quality Assessment Tool for Systematic Prevalence Reviews. 19,20 This critical appraisal checklist compared the characteristics of each study with those of a high-quality study evaluating the prevalence of hypertension in children who were evaluated for hypertension. The study sample size was assessed according to the Joanna Briggs Institute tool20 using a baseline risk hypothesis for secondary hypertension of 20% in otherwise healthy children with hypertension.21,22
Prevalence estimates of secondary hypertension were pooled in a random effects meta-analysis using the approach of DerSimonian and Laird.23 CIs for individual studies were calculated using the scoring method.24 Individual study variances were stabilized by transforming Freeman-Tukey double arc,25 and the study weights are represented by the inverse of the variance of the transformed proportion. The pooled transformed proportion and its CI were then back-transformed to the pooled prevalence estimate.24,25
Risk of bias assessment was not used for weighting effect estimates.26,27 Statistical heterogeneity between studies was assessed using the I 2 statistic. For suspected heterogeneity between study populations in primary care and school settings compared with referral clinics, the authors stratified by study setting before conducting additional subgroup analyses.
They used bivariate random-effects meta-regression to explore the association between the prevalence of secondary hypertension and the following variables: study design (prospective vs. retrospective), country (US vs. non-US studies), method of blood pressure measurement (24-hour ambulatory blood pressure monitoring [ABPM], age range of participants (only adolescent patients ≥10 years vs. general pediatric population), diagnostic criteria for hypertension, and study quality.
Because only children with complete follow-up blood pressure data who underwent diagnostic testing were included in the pooled prevalence estimates, a sensitivity analysis was performed in which the pooled prevalence was calculated after excluding studies with missing significant during follow-up. To determine whether the authors’ results were influenced by the individual study proportion transformation method, the authors conducted an additional sensitivity analysis in which they fitted a generalized linear mixed model to the data using the proportion transformation logit. .28
They assessed publication bias through visual inspection of funnel plots and Egger Tests.29 Statistical analyzes were performed using Stata/SE version 17.0 (StataCorp).
Results
Of the 3039 unique titles and abstracts screened, 141 full-text articles were evaluated for eligibility, and 26 studies met the inclusion criteria for this meta-analysis. The most common reasons for excluding full-text articles were incorrect study design (n = 33), inclusion of children whose cause of hypertension was already known (n = 19), and failure to specify the number of children. with primary hypertension and secondary hypertension (n = 13).
The median number of patients with hypertension included in the studies was 65 (range, 9-486). In 18 prospective cohort studies,12-15,30-43 children with hypertension were initially identified through blood pressure screening at school or during primary care visits and then underwent further evaluation for underlying causes. secondary after verification of hypertension in more than 1 measurement.
The remaining 7 retrospective cohort studies21,22,44-48 and 1 prospective cohort study49 included a reference population of children with hypertension evaluated in pediatric nephrology or pediatric hypertension clinics. Two studies confirmed hypertension by 24-hour ABPM,47,48 and the other studies diagnosed hypertension based solely on office measurements. Among the 23 studies that described the method of office blood pressure measurement, 19 used auscultatory measurement exclusively, 3 used a combination of auscultatory and automated measurement, and 1 used auscultatory measurement for all patients plus Doppler ultrasound for infant measurements.
The age of included patients varied, with 7 studies including only adolescents ≥10 years and 19 studies including a broad general pediatric age range. Twelve studies defined hypertension as blood pressure > 95th percentile, 5 studies used a higher percentile cutoff point, 2 studies used a combination of the 95th percentile cutoff point and an absolute blood pressure threshold of 140/90 mmHg, 5 studies of adolescents used an absolute threshold alone, 1 study used the 90th percentile as the threshold, and 1 study did not specify diagnostic criteria.
The 7 studies that incorporated absolute blood pressure thresholds into their diagnostic criteria for adolescents used thresholds higher than the 130/80 mmHg cutoff for stage 1 hypertension defined in the most recent AAP guideline.50 For the 20 studies that used blood pressure percentiles to diagnose hypertension based on office measurement, 1 study47 used the percentiles from the 2017 AAP guideline50; 6 studies21,22,41,42,45,48 used the guideline of the National Heart, Lung and Blood Institute 200451; 2 studies39,46 used the 1987 Workforce Report 52; 2 studies38,44 used the 1977 Workforce Report 53; 6 studies12,14,34,36,40,43 used the distribution of blood pressures from their own study cohort to calculate percentiles; 1 study13 used a previously published blood pressure index derived from a cohort of children measured at the same site54; and 2 studies15,35 did not specify the reference population.
Of the 8 specialized clinical studies, 7 studies defined hypertension according to clinical practice guidelines at the time of publication, 50-53 and 1 study49 did not specify a definition. All included studies checked for hypertension across multiple measurements; however, the number of visits varied between studies. Quality scores ranged from 3 to 9 on a 10-point scale.
Loss to follow-up affected several studies. In 1 school-based screening study,33 55% of children with hypertension detected at initial screening never had a repeat blood pressure test confirmed, and in 4 other school-based studies,30-32,36 >15% of children with hypertension did not undergo diagnostic workup.
Although the studies applied different approaches, all 26 studies appear to have performed diagnostic evaluations with at least the limited laboratory tests recommended in the AAP guidelines, with measurement of serum creatinine, electrolytes, and urinalysis.50 In the 24 studies he described the specific etiology for each case of secondary arterial hypertension, 68% of secondary cases were due to kidney disease or structural abnormalities and 9% were due to renovascular causes.
Among the 2,575 youth being evaluated for hypertension, there were 457 cases of secondary hypertension.
The random-effects model of these 26 studies yielded a pooled prevalence of secondary hypertension of 8% (95% CI, 4%-13%) among otherwise healthy youth with hypertension. There was high heterogeneity between studies ( I 2=93%).
Studies conducted in primary care or school settings reported a lower pooled prevalence of secondary hypertension (3.7%; 95% CI, 1.2%-7.2%; I 2 = 78.9%) compared with studies carried out in referral clinics (20.1%; 95% CI, 11.5%-30.3%; I 2=94.6%).
When stratified by study setting, there were no significant differences between subgroups in the prevalence of secondary hypertension based on prospective or retrospective study design, country of study, age range of participant, number of visits required for diagnosis of hypertension, threshold blood pressure, method of blood pressure measurement, or quality of the study.
For stratified analysis, funnel plots and Egger tests do not suggest publication bias. In a sensitivity analysis excluding the 5 studies with significant loss to follow-up of the group prevalence estimate in the primary care and school settings, 30-33, 36 the prevalence remained similar to that in the primary analysis ( 3.8%; 95% CI, 0.9%-7.9%; I 2=80.3%).
In the 2 landmark clinical studies that used ABPM in addition to office blood pressure measurement to diagnose hypertension, the prevalence of secondary hypertension was 17%48 and 49%47 among youth with ABPM-confirmed hypertension, compared with 13%48 and 38%,47 respectively, among young people with hypertension diagnosed only by office measurements. In additional sensitivity analyzes using a generalized linear mixed model, the results were consistent with the primary analysis.
This systematic review and meta-analysis found that the majority of youth with hypertension who underwent evaluation for secondary causes had primary hypertension.
The prevalence of secondary hypertension was significantly lower in prospective studies in which youth with hypertension were identified at screening in school or primary care settings compared with predominantly retrospective studies of youth with hypertension referred to pediatric nephrology or pediatric nephrology clinics. hypertension (3.7% [95% CI, 1.2%-7.2%] vs. 20.1% [95% CI, 11.5%-30.3%]).
The literature documenting a high prevalence of secondary hypertension among children with hypertension may not be generalizable to apparently normal children who are found to have hypertension during routine examinations, because those previous studies include children with known chronic kidney disease and other comorbidities that cause hypertension, 5,6,8,11 define hypertension using severely increased blood pressure cutoff values rather than age-based norms from AAP clinical practice guidelines,55,56 or describe hospitalized patient populations.57 -59
Consistent with the hypothesis that most otherwise healthy children ≥6 years of age with hypertension will not have a secondary cause, the yield of diagnostic laboratory and imaging investigations is low in children with mild to moderate hypertension.45 In 2 retrospective cohorts of children referred to pediatric hypertension clinics for further evaluation, none of the children had a clinically relevant abnormality on their basic metabolic panel or urinalysis, and 5%46 to 8%45 had a contributing abnormality identified on kidney ultrasound.
The authors’ findings reinforce 2 aspects of the 2017 AAP hypertension clinical practice guidelines, namely that most children older than 6 years do not require extensive evaluation for secondary causes of hypertension unless there is a history or physical examination characteristics suggestive of a secondary cause, and that ABPM should be performed to confirm hypertension in children and adolescents.50
Clinical characteristics such as obesity5,60,61 or a family history of hypertension in older adults5,8,47 may also reduce the likelihood that a child’s hypertension is due to a secondary cause and thus obviate the need for extensive studies.50 Alternatively, younger age4,8,62 and history of prematurity8,47 may increase the likelihood that a child’s hypertension is due to a secondary cause and warrants further diagnostic investigation.
Given a prevalence of white coat hypertension in up to half of children diagnosed with hypertension in the office, 63-65 the application of 24-hour ABPM to diagnose hypertension may be a cost-effective strategy65 to prevent unnecessary testing for secondary causes in children. with white coat hypertension. Additionally, certain ABPM findings, such as non-immersion status47,66 and elevated diastolic load,66,67 are more common in children with secondary hypertension than in children with primary hypertension and may help identify which children have a higher pre-diastolic proof of a secondary cause.
Since only 2 studies included in this meta-analysis used ABPM to diagnose hypertension, additional data are needed on the prevalence of secondary hypertension in children with a new hypertension diagnosis confirmed by ABPM. However, the authors’ findings support performing 24-hour ABPM in a child with hypertension who appears well and is asymptomatic before extensive diagnostic testing.
Although it is critical to consider the etiologies of secondary hypertension in the differential diagnosis when evaluating a child with hypertension, the perception that secondary hypertension is the predominant form of hypertension among otherwise healthy children may be a barrier to treatment. of hypertension in the primary care setting. A survey of general pediatricians regarding their approach to children with hypertension found that 82% refer to a specialist and 40% are uncomfortable evaluating and treating hypertension, due in part to the risk of missing a case of secondary hypertension. 68
Qualitative interviews with pediatric primary care providers have shown that pediatricians feel their training focused on the initial workup of hypertension and subspecialty referral but not on lifestyle management of primary hypertension.69 For Conversely, studies of pediatric cardiologists and nephrologists’ perspectives have found that these subspecialists may want primary care providers to take a larger role in the management of children with hypertension, particularly in adolescents, since referrals to subspecialties for all children with hypertension it may not be necessary.70,71
Awareness of the low prevalence of secondary hypertension among children with screening-detected hypertension may help alleviate primary care providers’ concerns about managing hypertension in otherwise healthy children and encourage pediatricians to try lifestyle management before referral.50
The authors’ meta-analysis has several limitations. Most studies conducted in referral clinics were retrospective. Excluding patients from the pooled prevalence estimate due to lack of a secondary study in these retrospective studies could have introduced selection bias, such that children with hypertension who are more likely to have a secondary cause may have had more likelihood of undergoing diagnostic testing.
Only 2 studies used 24-hour ABPM to diagnose hypertension, which likely resulted in some children with white-coat hypertension in the other studies undergoing negative diagnostic studies for secondary causes. Although all studies verified hypertension through multiple measurements, including studies that measured blood pressure on <3 occasions, they may have included children with milder hypertension who were less likely to have a secondary cause.
The lower prevalence of secondary hypertension among children evaluated in school or primary care settings emphasizes the need to confirm the diagnosis of hypertension in the community with at least 3 independent measurements using an appropriate technique before proceeding with any further diagnostic evaluation. .
Blood pressure thresholds for the diagnosis of hypertension also varied between studies; however, all diagnostic thresholds were at least as high as the absolute blood pressure cutoff points recommended in the AAP50 guideline or the 95th percentile derived from blood pressure standards at the time of publication or distribution. of study-specific blood pressure, except 1 study that used the 90th percentile cutoff.43
The authors found no difference in the prevalence of secondary hypertension in the sensitivity analysis excluding the study using the 90th percentile cut-off point. The absence of primary studies published since 2017 implies that the prevalence estimates depend in part on older studies that They used different blood pressure reference standards and may have used outdated laboratory and imaging tests. However, all studies appear to have incorporated blood and urine testing recommended by current guidelines.50 It is also possible that the included studies may have misclassified some diagnoses as secondary causes that may not actually cause hypertension.
Additionally, the studies included different age groups. Although they did not observe any difference in pooled prevalence for studies that included only adolescents compared with studies that included a wide general pediatric age range, data were not available to calculate a prevalence estimate for the subgroup of children under 10 years who may be more likely to have a secondary cause of hypertension.
Data from individual studies did not allow extraction of prevalence estimates by hypertension stage, so the authors were unable to evaluate guideline recommendations51 that support larger studies for children with stage 2 hypertension.
Finally, pooled prevalence estimates may be sensitive to the transformation method used to stabilize individual study variances, particularly with sparse data.28 However, in additional sensitivity analysis using a generalized linear mixed model, pooled prevalence estimates remained consistent with the primary analysis.
The practice of blood pressure monitoring in outpatient settings allows for the screening of high blood pressure in otherwise healthy children and adolescents .
In this work, it is postulated that the prevalence of secondary arterial hypertension screened in this way is low , which is why extensive additional testing in this population would not be justified. The need to train clinical pediatricians in the management of hypertension is emphasized to avoid unnecessary referrals of patients without evidence of secondary hypertension.
