Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension

Cal H Robinson; Junayd Hussain; Nivethika Jeyakumar; Graham Smith; Catherine S Birken; Allison Dart; Janis Dionne; Anika Garg; Sujane Kandasamy; Sabine Karam; Stacey Marjerrison; Andrew M South; Lehana Thabane; Gita Wahi; Michael Zappitelli; Rahul Chanchlani

doi:10.1001/jamapediatrics.2024.1543

. 2024 May 6;178(7):688–698. doi: 10.1001/jamapediatrics.2024.1543

Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension

Cal H Robinson ^1,², Junayd Hussain ³, Nivethika Jeyakumar ⁴, Graham Smith ^4,⁵, Catherine S Birken ¹, Allison Dart ⁶, Janis Dionne ⁷, Anika Garg ⁸, Sujane Kandasamy ⁹, Sabine Karam ¹⁰, Stacey Marjerrison ^11,¹², Andrew M South ¹³, Lehana Thabane ^12,^14,¹⁵, Gita Wahi ¹¹, Michael Zappitelli ¹, Rahul Chanchlani ^5,^11,^12,^✉

¹Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

²Institute of Health Policy, Management, and Evaluation, University of Toronto, Toronto, Ontario, Canada

³Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada

⁴Lawson Health Research Institute and London Health Sciences Centre, London, Ontario, Canada

⁵ICES, Toronto, Ontario, Canada

⁶Department of Pediatrics and Child Health, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada

⁷Department of Pediatrics, Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada

⁸Infant, Child, and Youth Health Lab, Brock University, St Catharine’s, Ontario, Canada

⁹Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada

¹⁰Department of Medicine, Division of Nephrology and Hypertension, University of Minnesota, Minneapolis

¹¹Division of Pediatric Nephrology, Department of Pediatrics, McMaster Children’s Hospital, McMaster University, Hamilton, Ontario, Canada

¹²Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada

¹³Department of Pediatrics, Brenner Children’s, Wake Forest University School of Medicine, Winston-Salem, North Carolina

¹⁴Biostatistics Unit, St Joseph’s Healthcare, Hamilton, Ontario, Canada

¹⁵Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa

Accepted for Publication: April 15, 2024.

Published Online: May 6, 2024. doi:10.1001/jamapediatrics.2024.1543

^✉

Corresponding Author: Rahul Chanchlani, MBBS, MD, MSc, Division of Pediatric Nephrology, Department of Pediatrics, McMaster Children’s Hospital, McMaster University, 1280 Main St W, Hamilton, ON L8N 3Z5, Canada (chanchlr@mcmaster.ca).

Author Contributions: Drs Robinson and Smith had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Robinson, Jeyakumar, Birken, Dart, Dionne, Garg, Kandasamy, Marjerrison, Thabane, Zappitelli, Chanchlani.

Acquisition, analysis, or interpretation of data: Robinson, Hussain, Jeyakumar, Smith, Birken, Dart, Karam, Marjerrison, South, Thabane, Wahi, Zappitelli, Chanchlani.

Drafting of the manuscript: Robinson, Hussain, Smith, Chanchlani.

Critical review of the manuscript for important intellectual content: Hussain, Jeyakumar, Birken, Dart, Dionne, Garg, Kandasamy, Karam, Marjerrison, South, Thabane, Wahi, Zappitelli, Chanchlani.

Statistical analysis: Robinson, Hussain, Jeyakumar, Smith, Thabane, Zappitelli, Chanchlani.

Obtained funding: Robinson, Birken, Wahi, Chanchlani.

Administrative, technical, or material support: Hussain, Birken, Garg, Marjerrison.

Supervision: Dionne, South, Thabane, Chanchlani.

Conflict of Interest Disclosures: Dr Birken reported receiving grants from the Canadian Institute of Health Research, Edwin S.H Leong Center for Child Health, Wallmart Community Grant, Physician Services Inc, and Heart and Stroke Foundation of Canada risk outside the submitted work. Dr South reported receiving consultant fees from Conjupro Biotherapeutics Inc and CSPC Pharmaceutical Company Ltd outside the submitted work. Dr Zappitelli reported receiving consultant fees from Bioporto Inc outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded in part by a 2021/2022 CoRE Builder Team Grant from the Department of Pediatrics at McMaster University; ICES Western site, which is funded by an annual grant from the Ontario Ministry of Health and Ministry of Long-Term Care. Core funding for ICES Western is provided by the Academic Medical Organization of Southwestern Ontario, the Schulich School of Medicine and Dentistry, Western University, and the Lawson Health Research Institute; parts of this material are based on data and information compiled and provided by the Ministry of Health (MOH) and or the Canadian Institute for Health Information; the research was conducted by members of the ICES Kidney, Dialysis, and Transplantation team at the ICES Western facility, and they are supported by a grant from the Canadian Institutes of Health Research; income quintile analysis was adapted from Statistics Canada Postal CodeOM Conversion File and/or Postal CodesOM by Federal Ridings File and/or Postal CodeOM Conversion File Plus (November 2018), which is based on data licensed from Canada Post Corporation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred.

Meeting Presentation: This study was presented as an abstract at the Pediatric Academic Societies 2024 Meeting; May 6, 2024; Toronto, Ontario, Canada.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank the Toronto Community Health Profiles Partnership for providing access to the Ontario Marginalization Index.

^✉

Corresponding author.

PMCID: PMC11217870 PMID: 38709137

This cohort study investigates the association between hypertension and risk of major adverse cardiac events in children and adolescents.

Key Points

Question

Are children and adolescents diagnosed with hypertension at a higher associated risk of major adverse cardiac events?

Findings

In this population-based cohort study of 25 605 youth diagnosed with hypertension and 128 025 matched controls, those with hypertension had a 2.1-times higher associated risk of major adverse cardiac events over a median of 12.9 years of follow-up. Youth with hypertension had 2- to 3-times higher associated risk of stroke, hospitalized myocardial infarction or unstable angina, and congestive heart failure but not cardiovascular death.

Meaning

In youth diagnosed with hypertension, there is a higher associated risk of long-term cardiovascular disease, justifying the improvement of blood pressure follow-up and control strategies among youth with hypertension.

Abstract

Importance

Hypertension affects 6% of all children, and its prevalence is increasing. Childhood hypertension tracks into adulthood and is associated with subclinical cardiovascular disease; however, there is a lack of evidence linking childhood hypertension to cardiovascular outcomes, which may contribute to underdiagnosis and undertreatment.

Objective

To determine the long-term associated risk of major adverse cardiac events (MACE) among children diagnosed with hypertension.

Design, Setting, and Participants

This was a population-based, retrospective, matched cohort study conducted from 1996 to 2022. The study included all children (aged 3-18 years) alive in Ontario, Canada, from 1996 to 2021, who were identified using provincial administrative health databases. Children with prior kidney replacement therapy were excluded.

Exposure

Incident hypertension diagnosis, identified by validated case definitions using diagnostic and physician billing claims. Each case was matched with 5 controls without hypertension by age, sex, birth weight, maternal gestational hypertension, prior comorbidities (chronic kidney disease, diabetes, cardiovascular surgery), and a propensity score for hypertension.

Main Outcomes and Measures

The primary outcome was MACE (a composite of cardiovascular death, stroke, hospitalization for myocardial infarction or unstable angina, or coronary intervention). Time to MACE was evaluated using the Kaplan-Meier method and Cox proportional hazards regression.

Results

A total of 25 605 children (median [IQR] age, 15 [11-17] years; 14 743 male [57.6%]) with hypertension were matched to 128 025 controls without hypertension. Baseline covariates were balanced after propensity score matching, and prior comorbidities were uncommon (hypertension vs control cohort: malignancy, 1451 [5.7%] vs 7908 [6.2%]; congenital heart disease, 1089 [4.3%] vs 5408 [4.2%]; diabetes, 482 [1.9%] vs 2410 [1.9%]). During a median (IQR) of 13.6 (7.8-19.5) years of follow-up, incidence of MACE was 4.6 per 1000 person-years in children with hypertension vs 2.2 per 1000 person-years in controls (hazard ratio, 2.1; 95% CI, 1.9-2.2). Children with hypertension were at higher associated risk of stroke, hospitalization for myocardial infarction or unstable angina, coronary intervention, and congestive heart failure, but not cardiovascular death, compared with nonhypertensive controls.

Conclusions and Relevance

Children diagnosed with hypertension had a higher associated long-term risk of MACE compared with controls without hypertension. Improved detection, follow-up, and control of pediatric hypertension may reduce the risk of adult cardiovascular disease.

Introduction

Hypertension is one of the most common causes of preventable death in adults worldwide.^1,2,3 There are strong, graded associations between the duration and severity of hypertension and the risk of cardiovascular disease (CVD; including myocardial infarction [MI] and stroke).^1,2,3,4,5 This has led to the development of clear, outcomes-based guidelines on blood pressure (BP) screening, management, and follow-up for adults.^6,7 Among youth, there has been a 5-fold increase in hypertension prevalence over the past 3 decades, from 1.3% (1990-1999) to 6.0% (2010-2014).^8,9 There is strong evidence that pediatric BP tracks into adulthood and is associated with subclinical CVD (such as left ventricular hypertrophy and high carotid intima-media thickness).^10,11,12,13 In adults, these subclinical CVD markers are associated with future CVD and death.¹⁴ However, there is currently a lack of evidence that youth diagnosed with hypertension have a higher risk of CVD across their life course.

Despite the rising prevalence of pediatric hypertension and known associations with subclinical CVD, pediatric hypertension remains underrecognized and inadequately treated.¹⁵ Only 11% to 35% of children have regular BP screening (ie, at least annually).^16,17,18 Few hypertensive youth have appropriate follow-up, are ever diagnosed, or are treated.^{16,17,18,19,20,21,22} There is a lack of consensus on the significance of pediatric hypertension and conflicting society recommendations for pediatric BP screening and follow-up.^6,10,23 Current Hypertension Canada, American Academy of Pediatrics, European Society of Hypertension, and the National Heart, Lung, and Blood Institute guidelines recommend regular BP screening for healthy children between the ages of 3 and 18 years.^10,24,25,26 However, the US Preventive Services Task Force, American Academy of Family Physicians, and the UK National Screening Committee do not recommend childhood BP screening, based on insufficient evidence.^6,27,28 Few studies have evaluated associations between pediatric hypertension and long-term CVD because this requires a large sample size, long follow-up, and low attrition.²⁹ This study, therefore, aimed to leverage long-term follow-up data from population-based health administrative databases to determine the associated risk and timing of major adverse cardiovascular events (MACE) among children diagnosed with hypertension compared with children without hypertension.

Methods

Study Design and Setting

We conducted a population-based retrospective cohort study of all children (aged 3-18 years) living in Ontario, Canada, with Ontario Health Insurance Plan (OHIP) coverage between April 1, 1996, and March 31, 2021. Ontario is Canada’s largest province, with a pediatric population of approximately 7 million during our study period.³⁰ Ontario residents are covered by a government-funded universal health care system. This project was authorized under section 45 of Ontario’s Personal Health Information Protection Act and does not require research ethics board approval or informed consent. Our study is reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines³¹ and the Reporting of Studies Conducted Using Observational Routinely Collected Health Data (RECORD) guidelines³² (eAppendix 1 in Supplement 1).

Data Sources

We used multiple linked provincial health administrative databases housed at ICES. ICES is an independent, nonprofit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze deidentified health care and demographic data, without consent, for health system evaluation and improvement. Emigration from Ontario is very low (<0.5% annually) and is the sole reason for attrition other than death.³³ The Registered Persons Database contains demographic, birth, and death information. The Canadian Institute for Health Information Discharge Abstract Database, Same Day Surgery, and National Ambulatory Care Reporting System were used to identify diagnoses, comorbidities, procedures, and outcomes recorded during inpatient, same-day surgery, and emergency department visits. The OHIP database contains physician billing records (diagnostic and procedural) for all outpatient and inpatient services. The Ontario Mother-Baby database links maternal records with all hospital-based births in Ontario. These databases were linked using unique encoded identifiers and data analysis was performed at ICES Western. Complete, uncleaned data were available to study investigators for analysis. eAppendix 2 in Supplement 1 includes descriptions of each database and administrative definitions used.

Study Population

First, we identified children aged 3 to 18 years in Ontario between April 1, 1996, and March 31, 2021. We excluded non-Ontario residents and those ineligible for OHIP coverage. We also excluded individuals with a previous hypertension diagnosis or kidney replacement therapy (dialysis or kidney transplant) between April 1, 1988 (start of data availability), and March 31, 1996. Because this was a population-based study, a formal sample size calculation was not performed. Child ethnicity, identified by a surname-based algorithm, included Chinese, South Asian, and other (which included all non-Chinese or non–South Asian individuals). Ethnicity information was gathered for this study because it is a known contributor to pediatric and adult hypertension and cardiovascular disease risk.

Exposed and Control Cohorts

Our main exposure, incident hypertension diagnosis, was defined using a validated algorithm (eAppendix 1 in Supplement 1) using International Classification of Diseases, Ninth Revision (ICD-9; [1996-2002]), ICD-10 (2003-2021), and OHIP diagnostic codes.³⁴ Hypertension was defined as an outpatient physician billing claim or hospital discharge diagnosis of hypertension (primary or secondary causes). This definition has high specificity (99%) and positive predictive value (74%) but low sensitivity (24%) for pediatric hypertension defined by office-based BP or antihypertensive treatment.³⁴ The cohort entry date for children with hypertension was the date of first hypertension diagnosis during the study period. All Ontario children not diagnosed with hypertension were eligible controls. Their cohort entry date was randomly assigned based on the distribution of cohort entry dates in exposed children.

Starting from April 1996, we chronologically matched each child with hypertension with 5 children without hypertension. Each matched set was removed to prevent these individuals from further matching (ie, sampling without replacement). Matching was performed using the following criteria: age at cohort entry (±365 days), index date (before/after July 1, 2000), sex, birth weight (low, normal, missing), maternal gestational hypertension, chronic kidney disease (CKD) diagnosis, diabetes diagnosis, previous cardiovascular surgery, and the logit of the propensity score for hypertension (±0.2 SD). The propensity score was calculated using a multivariable logistic regression model for hypertension.

Baseline Characteristics

The propensity score model for hypertension included the following sociodemographic characteristics (age, sex, ethnicity [by surname-based algorithm],³⁵ neighborhood income quintile [by postal code],³⁶ socioeconomic marginalization [using the Ontario Marginalization Index],³⁷ geographic area [by Local Health Integration Network], rural status [community <10 000 persons],³⁸ and cohort entry year), pregnancy and birth characteristics (gestational age, birth weight, maternal age, maternal hypertension, maternal diabetes, maternal smoking, and maternal body mass index); the child’s preexisting comorbidities (obesity, CKD, diabetes, malignancy, nonkidney solid organ transplant, congenital heart disease, cardiac surgery, chronic liver disease, and sickle cell disease [from April 1988 or their date of birth until study enrollment]), the child’s Pediatric Medical Complexity Algorithm (PMCA) classification during a 3-year lookback period (complex chronic, noncomplex chronic or nonchronic disease),³⁹ and the child’s prior health care resource utilization during a 1-year lookback period (emergency department visits, hospitalizations, and outpatient visits). These variables were included in the propensity score because they are potential confounders of the association between hypertension and MACE. Missing baseline characteristic data was handled using missing categories.

Outcomes

The primary outcome was MACE, a composite of cardiovascular death, stroke, hospitalization for acute MI or unstable angina, or coronary intervention, defined using validated diagnostic codes.^40,41 MACE is an important, patient-centered outcome that is recommended for CVD outcome research,^41,42,43 and its components are reliably captured in health administrative databases.^40,41 Secondary outcomes included individual MACE components, congestive heart failure, other cardiovascular diagnoses (including angina, atherosclerotic and ischemic heart disease, atrial/ventricular arrythmias, and peripheral vascular disease), and cardiovascular procedures (including cardiac surgery, vascular surgery, and device insertion [pacemaker/defibrillator]).^33,44 All primary and secondary outcomes were ascertained using administrative data (eAppendix 2 in Supplement 1). Outcome assessment started at the cohort entry date and continued until the date of death, loss to follow-up (90 days after the end of OHIP eligibility), or March 31, 2022 (administrative censoring).

Statistical Analysis

Baseline characteristics were reported using descriptive statistics, before and after propensity score matching. Standardized differences were used to identify residual baseline differences between the matched hypertension and control cohorts. A standardized difference of 0.1 or greater is considered substantial.⁴⁵ We determined the cumulative incidence and incidence rates (events per 1000 person-years) of each primary and secondary outcome throughout follow-up. Time-to-event analysis was performed using the Kaplan-Meier method. We used Cox proportional hazards models with a robust sandwich estimator (to account for correlation within matched sets) to determine the association (hazard ratios [HR] and 95% CIs) between incident hypertension diagnosis and the primary and secondary outcomes. For the MACE analysis specifically, children were censored when they experienced their first MACE component. Multivariable adjustment was not performed because there were no substantial residual imbalances after propensity score matching. Proportional hazards assumptions were verified for each model.

To evaluate for effect heterogeneity, we performed exploratory subgroup analyses using interaction terms and stratified Cox proportional hazards models to determine the association between hypertension and MACE in prespecified subgroups: (1) age (<13 years vs ≥13 years [ie, adolescent] at cohort entry), (2) sex, (3) prior CKD, (4) prior diabetes, (5) prior cardiovascular surgery, (6) birth weight for gestational age (small for gestation [<10th percentile]⁴⁶ vs normal/large for gestation vs missing), and (6) birth weight category. These subgroups were selected as potential effect modifiers that are reliably captured in health administrative data. All significance tests were 2-sided, using α = .05 level of significance. We did not adjust the α for multiple hypothesis testing of subgroup analysis because these analyses were prespecified and exploratory. All analyses were performed at ICES using SAS, version 9.4 (SAS Institute).

Results

Study Population and Baseline Characteristics

Between April 1996 and March 2021, there were 6 951 975 children aged 3 to 18 years living in Ontario (eFigure 1 in Supplement 1). After exclusions, we identified 27 651 eligible children diagnosed with hypertension and 4 465 559 eligible controls without hypertension. Before matching, substantial differences between children diagnosed with hypertension and controls existed (eTable in Supplement 1). Children diagnosed with hypertension had higher rates of obesity, CKD, malignancy, congenital heart disease, and prior health care utilization. After propensity score matching, we included a final cohort of 25 605 children (median [IQR] age, 15 [11-17] years; 10 862 female [42.4%]; 14 743 male [57.6%]; 1055 Chinese [4.1%], 788 South Asian [3.1%], and 23 755 other [92.8%]) with an incident hypertension diagnosis (92.6% of eligible children with hypertension) and 128 025 controls without hypertension. Baseline characteristics were well balanced after matching (all standardized differences <0.1) (Table 1).^35,38,39 In both cohorts, 87% of youth had an urban residence (hypertension cohort: 22 278 [87.0%]; control cohort: 111 [86.8%]), and there were no substantial differences in income or marginalization indices. Preexisting comorbidities were uncommon. In the hypertension vs control cohort, children had a history of obesity (3550 [13.9%] vs 18 202 [14.2%]), malignancy (1451 [5.7%] vs 7908 [6.2%]), congenital heart disease (1089 [4.3%] vs 5408 [4.2%]), and diabetes (482 [1.9%] vs 2410 [1.9%]).

Table 1. Baseline Characteristics of the Pediatric Hypertension and Control Cohorts After Propensity Score Matching.

Variable	Hypertension cohort	Control cohort	Weighted standardized difference ^a
Total patients, No.	25 605	128 025	NA
Baseline characteristics
Age at cohort entry, median (IQR), y	15 (11-17)	15 (11-17)	NA
Sex, No. (%)
Female	10 862 (42.4)	54 310 (42.4)	0
Male	14 743 (57.6)	73 715 (57.6)	0
Income quintile, No. (%)^b
1 (Lowest)	5355 (20.9)	27 292 (21.3)	0.01
2	5015 (19.6)	25 793 (20.1)	0.01
3	5240 (20.5)	26 280 (20.5)	0
4	5200 (20.3)	25 944 (20.3)	0
5 (Highest)	4795 (18.7)	22 716 (17.7)	0.03
Material deprivation quintile, No. (%)^c
1 (Least deprived)	4153 (19.9)	20 348 (19.4)	0.01
2	4062 (19.5)	19 437 (18.6)	0.02
3	3942 (18.9)	19 766 (18.9)	0
4	4074 (19.5)	21 582 (20.6)	0.03
5 (Most deprived)	4651 (22.3)	23 628 (22.6)	0.01
Ethnicity, No. (%)^d
Chinese	1055 (4.1)	5657 (4.4)	0.02
South Asian	788 (3.1)	3675 (2.9)	0.01
Other	23 755 (92.8)	118 686 (92.7)	0
Rural status^e	3327 (13.0)	16 902 (13.2)	0.01
Pregnancy and birth characteristics
Gestational age, wk
<28	23 (0.1)	77 (0.1)	0.01
28-<32	37 (0.1)	154 (0.1)	0.01
32-<37	309 (1.2)	1654 (1.3)	0.01
≥37	3069 (12.0)	16 012 (12.5)	0.02
Missing	22 167 (86.6)	110 128 (86.0)	0.02
Small for gestational age, No. (%)^f
Yes	380 (1.5)	2016 (1.6)	0.01
No	11 819 (46.2)	58 979 (46.1)	0
Missing	13 406 (52.4)	67 030 (52.4)	0
Maternal age, median (IQR), y^g	29 (25-33)	29 (25-33)	NA
Maternal gestational hypertension, No. (%)	9 (3.1)	45 (3.1)	0
Maternal preexisting diabetes, No. (%)	6 (2.0)	42 (2.9)	0.05
Maternal gestational diabetes, No. (%)	25 (8.5)	117 (8.0)	0.02
Maternal smoking, No. (%)	34 (11.6)	202 (13.8)	0.07
Preexisting comorbidities (5-y lookback period), No. (%)
Obesity	3550 (13.9)	18 202 (14.2)	0.01
Chronic kidney disease	334 (1.3)	1670 (1.3)	0
Malignancy	1451 (5.7)	7908 (6.2)	0.02
Diabetes	482 (1.9)	2410 (1.9)	0
Nonkidney solid organ transplant	12 (0.1)	35 (0)	0.01
Chronic liver disease	568 (2.2)	2965 (2.3)	0.01
Sickle cell disease	56 (0.2)	221 (0.2)	0.01
Congenital heart disease	1089 (4.3)	5408 (4.2)	0
Cardiac surgery	147 (0.6)	735 (0.6)	0
PMCA classification (3-y lookback period), No. (%)^h
No chronic disease	3699 (14.4)	21 102 (16.5)	0.06
Noncomplex chronic disease	683 (2.7)	3840 (3.0)	0.02
Complex chronic disease	2149 (8.4)	8687 (6.8)	0.06
No claims (ie, no chronic disease)	19 074 (74.5)	94 396 (73.7)	0.02
Prior health care resource utilization (1-y lookback period), No. (%)
≥1 Emergency department visitⁱ	8753 (43.3)	39 227 (38.8)	0.08
≥1 Hospitalization	3863 (15.1)	18 162 (14.2)	0.03
No. of outpatient visits, median (IQR)	4 (0-8)	4 (1-7)	0.09

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Abbreviations: NA, not applicable; PMCA, Pediatric Medical Complexity Algorithm.

^{^a}

Weighted standardized difference, which accounts for the number of controls within each matched set, was used to compare the hypertension and control cohorts. Standardized differences are less sensitive to sample size than traditional hypothesis tests. They provide a measure of difference between groups with respect to a pooled SD. A standardized difference of 0.1 or greater is considered a meaningful difference between groups.

^{^b}

Income quintile was defined as neighborhood income quintile by postal code.

^{^c}

Ontario Marginalization Index–Material Deprivation scale. An ordinal scale ranking postal codes by material deprivation, including education, single parent family status, government assistance, unemployment, low-income status, and dwellings in need of major repair. Marginalization Index data was missing in 27 987 individuals (18.2%) in the matched cohorts.

^{^d}

Ethnicity was defined using the ETHNIC surname-based database for Chinese and South Asian individuals.³⁵ Other ethnicity included all non-Chinese or non–South Asian individuals.

^{^e}

Rural status was defined as residence within a community with less than 10 000 persons.³⁸ Rural status was missing in 232 individuals (0.2%) in the matched cohorts.

^{^f}

Small for gestational age was defined as birth weight less than 10th percentile for their corresponding gestational age.

^{^g}

Maternal characteristics were missing in 83 301 individuals (54.2%) in the matched cohorts. Maternal characteristics were restricted to children who could be linked with a valid maternal record in the MOMBABY database.

^{^h}

PMCA classification is a validated algorithm, used to classify children with chronic disease according to medical complexity using administrative data. To classify PMCA, we used a 3-year lookback period with the least conservative strategy.³⁹

^ⁱ

Emergency department visit data was available from July 1, 2000, onward. We, therefore, restricted analysis of baseline emergency department utilization to individuals with an index hospitalization admission date on or after July 1, 2000.

MACE

Median (IQR) follow-up was 13.6 (7.8-19.5) years overall in the matched cohort (13.5 years in the hypertension cohort vs 13.7 years in the control cohort). Median (IQR) age at last follow-up was 27 (21-34) years in both cohorts. Complete follow-up until March 2022 occurred in 137 176 of 153 630 youth (89.3%); 2349 of 153 630 (1.5%) were censored for death, and 14 105 of 153 630 (9.2%) were censored for provincial emigration. Throughout follow-up, MACE occurred in 1557 children (6.1%) with hypertension vs 3901 controls (3.1%) (Table 2). Incidence of MACE was 4.6 events per 1000 person-years (95% CI, 4.4-4.9 events) among children with hypertension vs 2.2 events per 1000 person-years (95% CI, 2.2-2.3 events) among controls. Children with hypertension had a higher associated risk of MACE throughout follow-up, compared with controls without hypertension (HR, 2.1; 95% CI, 1.9-2.2) (Figure 1).

Table 2. Cardiovascular Outcomes Throughout Follow-Up.

Outcomes	Hypertension cohort (n = 25 605)^a		Control cohort (n = 128 025)^a		HR (95% CI)^b
Outcomes	No. (%)	Incidence per 1000 p-y (95% CI)	No. (%)	Incidence per 1000 p-y (95% CI)	HR (95% CI)^b
Primary outcomes
MACE^c	1557 (6.1)	4.6 (4.4-4.9)	3901 (3.1)	2.2 (2.2-2.3)	2.1 (1.9-2.2)
Secondary outcomes
Cardiovascular death	147 (0.6)	0.4 (0.4-0.5)	709 (0.6)	0.4 (0.4-0.4)	1.0 (0.9-1.2)
Stroke	805 (3.1)	2.4 (2.1-2.5)	1540 (1.2)	0.9 (0.8-0.9)	2.7 (2.4-2.9)
Hospitalization for MI or unstable angina	651 (2.5)	1.9 (1.8-2.0)	1794 (1.4)	1.0 (1.0-1.1)	1.8 (1.7-2.0)
Coronary intervention	117 (0.5)	0.3 (0.3-0.4)	143 (0.1)	0.1 (0.1-0.1)	4.1 (3.2-5.3)
Congestive heart failure	597 (2.3)	1.7 (1.6-1.9)	1148 (0.9)	0.7 (0.6-0.7)	2.6 (2.4-2.9)
Other cardiovascular diagnosis^d	3649 (14.3)	11.5 (11.1-11.9)	11 315 (8.8)	6.7 (6.6-6.9)	1.7 (1.6-1.8)
Cardiovascular procedure^e	652 (2.6)	1.9 (1.8-2.0)	1291 (1.0)	0.7 (0.7-0.8)	2.6 (2.3-2.8)

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Abbreviations: HR, hazard ratio; MACE, major adverse cardiac event; MI, myocardial infarction; p-y, person-years.

^{^a}

Median follow-up time was 13.5 years for the cohort with hypertension and 13.7 years for the control cohort.

^{^b}

Using Cox proportional hazards models with robust sandwich variance for time-to-event outcome.

^{^c}

MACE was defined as a composite of cardiovascular death, stroke, hospitalization for MI or unstable angina, or coronary intervention.

^{^d}

Other cardiovascular diagnosis is a composite of cardiovascular events not included in the MACE outcome. This includes nonhospitalized angina, atherosclerotic and ischemic heart disease, atrial and ventricular arrythmias, and peripheral vascular disease. eAppendix 1 in Supplement 1 contains a full description of diagnostic codes used.

^{^e}

Cardiovascular procedures is a composite of all cardiac surgery, peripheral vascular surgery, or device insertion (pacemaker or defibrillator) procedures. eAppendix 1 in Supplement 1 contains a full description of procedural codes used.

Secondary Outcomes

The cumulative incidence, incidence rates, and HR for all secondary outcomes are presented in Table 2. Children diagnosed with hypertension had a higher associated risk of stroke (HR, 2.7; 95% CI, 2.4-2.9), hospitalization for MI or unstable angina (HR, 1.8; 95% CI, 1.7-2.0), and coronary intervention (HR, 4.1; 95% CI 3.2-5.3) compared with controls without hypertension. However, there was no difference in the risk of CVD death (HR, 1.0; 95% CI, 0.9-1.2). Children diagnosed with hypertension also had a higher associated risk of developing congestive heart failure (HR, 2.6; 95% CI, 2.4-2.9), other cardiovascular diagnoses (HR, 1.7; 95% CI, 1.6-1.8), and undergoing cardiovascular procedures (HR, 2.6; 95% CI, 2.3-2.8) than controls.

Subgroup Analyses

We evaluated the association between pediatric hypertension and MACE within prespecified subgroups (Figure 2 and eFigure 2 in Supplement 1). There was a stronger association between hypertension and MACE in children who were younger than 13 years at the time of hypertension diagnosis, female children, and children who were born small for gestational age. The association between hypertension and MACE was also greater among children with preexisting CKD, although this was not statistically significant (interaction P = .06). There was no evidence of outcome modification by diabetes or cardiac surgery history. Incidence of MACE was higher among children with diabetes and prior cardiac surgery, with and without hypertension.

Discussion

In this population-based cohort study of 25 605 children with incident hypertension diagnosis and 128 025 matched controls, we examined the association between pediatric hypertension and MACE. Over a median 14-year follow-up, we found that children diagnosed with hypertension had double the associated risk of developing MACE compared with controls without hypertension. Children with hypertension also had a higher associated risk of stroke, hospitalization for MI or unstable angina, coronary intervention, congestive heart failure, other cardiovascular diagnoses, and cardiovascular procedures but not cardiovascular death.

In adults, there is a strong and graded association between hypertension and CVD.^47,48,49,50 A recent meta-analysis found that young adults (aged 18-45 years) with high BP (≥140/90 mm Hg) are also had a 2- to 3-times greater associated risk of CVD over a mean of 14.7 years of follow-up compared with those with normal BP.⁴ However, this association cannot be directly extended to children because key CVD risk factors (eg, diabetes, smoking, and dyslipidemia) are more common in adults.^13,15 There is a lack of direct evidence linking youth hypertension to major CVD, such as MI, stroke, and cardiovascular death. As a result, current pediatric guidelines provide conflicting recommendations for BP surveillance among children.^{6,10,24,25,27,28}

There are strong associations between pediatric hypertension and subclinical CVD (including left ventricular hypertrophy,^{13,51,52,53,54,55,56,57,58,59,60} higher carotid intima-media thickness,^{60,61,62,63,64} higher pulse wave velocity,^60,65,66 atherosclerotic changes,^{67,68,69,70,71} retinal microvascular disease,^72,73,74 and albuminuria^75,76). In adults, these subclinical CVD measures are associated with major CVD and death.^77,78,79,80 A recent meta-analysis found that children and adolescents with high BP (≥90th percentile) had a 1.4- to 1.8-times greater odds of subclinical CVD.⁸¹ They also found that high BP was associated in a small number of studies with incident CVD and cardiovascular death (HR ranging from 1.04-1.51) but could not perform a meta-analysis due to heterogenous exposure and outcome definitions.^{82,83,84,85,86}

Among 38 589 participants in the prospective International Childhood Cardiovascular Cohort study, childhood hypertension (BP ≥95th percentile) was associated with a 2.3-times greater hazard of fatal or nonfatal cardiovascular events over a longer than 30-year follow-up.²⁹ Compared with these previous studies, we found that pediatric hypertension was associated with a 2.1-times greater risk of MACE but no difference in cardiovascular death compared with controls without hypertension. The higher risk for nonfatal cardiovascular events that we observed may be explained by between-study differences in hypertension definitions and follow-up duration. Previous studies screened for hypertension among asymptomatic schoolchildren and young adult military conscripts,^{82,83,84,85,86} whereas we defined hypertension using hospitalization or physician claims. Because asymptomatic hypertension is commonly undiagnosed, our administrative definition may bias toward selection of children with more severe, persistent, secondary, or symptomatic hypertension leading to physician diagnosis. Prior validation of this definition demonstrated that it has a very high specificity (99%) but low sensitivity (24%) for pediatric hypertension, suggesting that up to three-quarters of children with hypertensive BP are missed.³⁴

Our study found that younger children (age <13 years) and those with CKD were at higher associated risk of experiencing MACE after hypertension diagnosis. Young age at diagnosis is associated with more severe and secondary hypertension and a greater duration of hypertension exposure, if inadequately treated.¹⁰ In youth with CKD, hypertension is common (50%-70%), often inadequately treated, and strongly associated with CKD progression^{87,88,89,90,91,92} and subclinical CVD.^93,94,95 Our findings emphasize the stronger association between hypertension and long-term CVD in the population of children with CKD.

Pediatric hypertension is an epidemic, with a 5-fold increase in prevalence over the last 3 decades.^8,9 Worldwide, 6% of children have hypertension, and another 8% have elevated BP.⁸ Increasing pediatric hypertension has been associated with more obesity, less physical activity, higher dietary sodium intake, and urbanization.¹⁵ However, most children (up to 90%) do not undergo regular BP screening,^16,17,18 more than three-quarters with hypertension are undiagnosed,^16,19,20,21 and very few with hypertension are adequately treated.^{16,17,19,20,21} The association we found between pediatric hypertension and MACE may have substantial health and financial implications. Policies and initiatives to improve the uptake of pediatric BP screening, increase clinician and family awareness of pediatric hypertension, and optimize pediatric hypertension care may help prevent future CVD.

Strengths and Limitations

This study has several strengths. We followed up large, population-based cohorts over a long period with low attrition, allowing us to evaluate the association between pediatric hypertension and MACE. Propensity score matching balanced these cohorts for many potential confounders. The use of diagnostic codes to define pediatric hypertension makes our findings more applicable to children who are diagnosed with hypertension by a health care practitioner. Conversely, the generalizability of these results to children with undiagnosed hypertension is uncertain.

However, there are also limitations of this study. Health care administrative data can misclassify study exposures, outcomes, and covariates. Our study exposure and primary outcome definitions have been previously validated, with high specificity and positive predictive value but low sensitivity.^34,40,41 We did not have access to data on additional effect modifiers or confounders, including hypertension detection method (eg, ambulatory vs office-based BP), BP values to determine hypertension stage, subclinical CVD presence, body mass index, hypertension duration, and antihypertensive treatment. Further, data were limited or missing for several baseline characteristics (eg, birth and maternal history), causing potential residual confounding. Ethnicity data were limited to a surname-based algorithm used to identify Chinese and South Asian individuals. Children in the nonhypertension control cohort could have undiagnosed hypertension. However, this is likely uncommon based on the prevalence of pediatric hypertension and would have decreased effect size and bias toward the null hypothesis. Finally, there is potential detection bias if children with hypertension have more health care visits and CVD screening. To limit this, propensity score matching included preexisting comorbidities and health care resource utilization variables. Further, all MACE components are significant health events that would require hospitalization and treatment, making them less susceptible to detection bias.

Conclusions

In this population-based cohort study, we found that children diagnosed with hypertension had a 2-times associated risk of MACE, compared with children without hypertension. Optimizing the care provided to youth with hypertension may help prevent long-term adult CVD, with substantial health and cost-saving benefits. Further research should confirm these findings among children with hypertension defined by standardized BP criteria and evaluate CVD prevention strategies, including dietary modification, lifestyle interventions, and antihypertensive medications.

Supplement 1.

eFigure 1. Participant Flow Diagram

eFigure 2. Additional Subgroup Analysis for the Association Between Pediatric Hypertension and Major Adverse Cardiac Events (MACE), by Small for Gestational Age Status and Birth Weight

eTable. Baseline Characteristics of the Pediatric Hypertension and Control Cohorts Before Propensity Score Matching

eAppendix 1. The RECORD Statement—Checklist of Items, Extended From the STROBE Statement, That Should Be Reported in Observational Studies Using Routinely Collected Health Data

eAppendix 2. Administrative Codes Used for Cohort Selection, Exposures, Baseline Characteristics, and Outcomes

eReferences.

jamapediatr-e241543-s001.pdf^{(860.9KB, pdf)}

Supplement 2.

Data Sharing Statement.

jamapediatr-e241543-s002.pdf^{(14.8KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eFigure 1. Participant Flow Diagram

eFigure 2. Additional Subgroup Analysis for the Association Between Pediatric Hypertension and Major Adverse Cardiac Events (MACE), by Small for Gestational Age Status and Birth Weight

eTable. Baseline Characteristics of the Pediatric Hypertension and Control Cohorts Before Propensity Score Matching

eAppendix 1. The RECORD Statement—Checklist of Items, Extended From the STROBE Statement, That Should Be Reported in Observational Studies Using Routinely Collected Health Data

eAppendix 2. Administrative Codes Used for Cohort Selection, Exposures, Baseline Characteristics, and Outcomes

eReferences.

jamapediatr-e241543-s001.pdf^{(860.9KB, pdf)}

Supplement 2.

Data Sharing Statement.

jamapediatr-e241543-s002.pdf^{(14.8KB, pdf)}

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PERMALINK

Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension

Cal H Robinson, MD

Junayd Hussain, MSc

Nivethika Jeyakumar, MSc

Graham Smith, PhD

Catherine S Birken, MD, MSc

Allison Dart, MD, MSc

Janis Dionne, MD

Anika Garg, BHSc

Sujane Kandasamy, PhD

Sabine Karam, MD

Stacey Marjerrison, MD, MSc

Andrew M South, MD, MS

Lehana Thabane, PhD

Gita Wahi, MD, PhD

Michael Zappitelli, MD, MSc

Rahul Chanchlani, MD, MSc

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Exposure

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Study Design and Setting

Data Sources

Study Population

Exposed and Control Cohorts

Baseline Characteristics

Outcomes

Statistical Analysis

Results

Study Population and Baseline Characteristics

Table 1. Baseline Characteristics of the Pediatric Hypertension and Control Cohorts After Propensity Score Matching.

MACE

Table 2. Cardiovascular Outcomes Throughout Follow-Up.

Figure 1. Cumulative Probability of Major Adverse Cardiac Events (MACE) Among Children Diagnosed With Hypertension (HTN) vs Controls Without HTN.

Secondary Outcomes

Subgroup Analyses

Figure 2. Subgroup Analyses for Major Adverse Cardiac Events (MACE) Among Children Diagnosed With Hypertension (HTN) vs Controls Without HTN.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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