3. Screening for Cardiovascular Risk Factors

Reducing lifetime risk for cardiovascular (CV) disease (CVD) is the principle that underlies all CVD prevention strategies, including those beginning in childhood. Especially important is the prevention of CVD events occurring relatively early in life (e.g., before ages 50–60 years). In these Guidelines, the Expert Panel highlights two complementary prevention strategies:  (1) primordial prevention, which seeks to prevent the development of risk factors in all children and (2) primary prevention, a high-risk strategy aimed at reducing risk in children with dyslipidemia, hypertension, obesity, diabetes mellitus, or other identified factors associated with accelerated development of atherosclerotic CVD. In contrast with primordial prevention, primary prevention requires knowledge of risk factor levels through the screening of individuals. This section focuses on the principles of screening within the context of the need for practical clinical recommendations even in the presence of insufficient evidence.

Screening is common practice in regular pediatric care with age-based recommendations designed to identify conditions at appropriate times relative to both the disease process and the stage of growth and development. For example, the American Academy of Pediatrics recommends universal newborn screening for metabolic conditions, hemoglobinopathy, and hearing loss, and selective screening for elevated levels of lead in infancy and early childhood.^[1] Although many screening programs have been widely adopted, they are not always evidence based. This section reviews the criteria for an effective screening program and provides discussions of both scientific and practical considerations involved in screening for CV risk factors in childhood.

Empirically, a recommendation for universal screening requires a high burden of proof. First, by definition, screening is performed on asymptomatic individuals. Second, all of the downstream consequences of screening, both beneficial and harmful, are important to consider; sometimes they are not obvious. Third, widespread screening programs are costly.

The highest quality evidence for establishing the utility of a screening program derives from randomized controlled trials (RCTs) of screening versus no screening. Such trials compare clinical outcomes among children randomly allocated to no screening with outcomes among children allocated to screening, followed by interventions among those with identified risk. For a CV risk factor screening trial, the children in both groups would be followed for decades to determine disease incidence, and the analysis would allow balancing of benefits, risks, and costs. For CV risk factors such as dyslipidemia, hypertension, and obesity, it is unlikely that such a large, long-term study will ever exist because of the time and costs involved, as well as the great degree of difficulty in achieving high levels of adherence and followup over decades. Furthermore, by the time substantial numbers of definitive end points occurred decades later, knowledge and technology most likely would have made the initial screening test obsolete. An RCT of CV risk factor screening with shorter term followup to examine change(s) in risk factor levels or surrogate outcomes (such as noninvasive measures of subclinical atherosclerosis) may be more feasible. However, like most surrogate measures and as described in the preceding Section II, subclinical measures of atherosclerosis do not perfectly predict clinical CVD outcomes.

One argument for screening is the knowledge that extreme elevations of risk factors are associated with early and severe clinical outcomes. For example, children with coarctation of the aorta have elevation of upper body blood pressure (BP) from infancy. When surgical repair of coarctation is delayed, early death from heart attack, stroke, and aortic rupture has been well-documented.^[2]  Similarly, in children with extreme elevations of low-density lipoprotein cholesterol (LDL–C) levels due to the rare inherited homozygous form of familial hypercholesterolemia, clinical CVD events begin as early as the first decade of life.^[3]

The question that the Expert Panel faced is whether childhood screening to identify less severe forms of these risk factors is a useful strategy to prevent CVD events from occurring in middle-aged adults. Without definitive evidence from RCTs of screening programs, the Expert Panel was left to determine the wisdom of recommending screening in the face of suboptimal evidence but with knowledge that the atherosclerotic process begins in childhood and that the long time period required between screening during youth and clinical end points makes the most rigorous test of a CV risk factor screening program infeasible. In this situation, assessing the usefulness of screening involves evaluating alternative criteria, including attributes of the test, outcomes of interventions among children with actionable levels of test results, and the program as a whole.

TEST CHARACTERISTICS

Reproducibility

Lipids, BP, height, and weight are measurements with intrinsic biologic and measurement variability. For BP and total cholesterol (TC), LDL–C, and high-density lipoprotein cholesterol (HDL–C) levels, two or three measurements, taken several days to weeks apart, appear necessary to place most children in the categories of normal, borderline, or high with reasonable confidence.^[4],[5]  As described in Section X. Overweight and Obesity, height, weight, and body mass index (BMI) measurements are reliably reproducible, but measurements over time are needed to provide consistent information on growth trends and to determine whether there has been an inappropriate change in the BMI percentile relative to age- and gender-specific norms.

Validity/Accuracy

To be useful, a screening test must detect the condition of interest with sufficient reliability, sensitivity, and specificity to determine whether intervention is warranted or to mandate a second test to confirm the presence of the risk factor or disease. For most screening tests, the frequency of the screened condition is low, so even high sensitivity and specificity translate into a low positive predictive value—a consideration in screening for all rare conditions.^[6]  From a long-term perspective, this means that a majority of children with an identified CV risk factor in childhood will not develop premature CVD events (i.e., myocardial infarction, sudden cardiac death, or stroke by ages 50–60 years). Although counted statistically as false positives, pathology studies demonstrate that these individuals develop atherosclerosis faster than children with normal risk factor levels and are at increased risk for morbidity from a range of vascular complications (see Section II. State of the Science: Cardiovascular Risk Factors and the Development of Atherosclerosis in Childhood). The destructive effects of early heart attacks and strokes, the impact of multiple risk factors in increasing the risk for such events, and especially the potential to reduce the risk of sudden death as the first manifestation of early atherosclerotic CVD mean that decisionmakers might consider a lower positive predictive value for CV risk factor screening than for childhood screening for other disease processes. Specifically, because sudden cardiac death often occurs in asymptomatic individuals, the threshold for CV screening could be lower than that for diseases that always manifest with symptoms.

Risk factors that are considered to be most strongly associated with disease can nonetheless be suboptimal as screening tests. For example, adults with TC values in the highest fifth of the population distribution have approximately a threefold higher 10-year risk of fatal ischemic heart disease than adults in the bottom fifth of the distribution. Although this appears to be a strong association, assessing a screening test requires estimating the absolute risk for individuals rather than the relative risk. If one assumes that 5 percent of unaffected individuals will have TC levels in the top fifth of the distribution, a relative risk of 3 means that among these individuals, the test will detect only 15 percent of those destined to die from ischemic heart disease.^[7]  In fact, even a relative risk of 200 would increase this detection rate (i.e., the sensitivity) to just over 50 percent. In the case of a 10-year death rate of 1 percent, for every 100 persons identified with high cholesterol levels, only 3 would die of ischemic heart disease and the other 97 would be false positives. This example is simplistic since it does not take into account other coexisting risk factors for heart disease, other manifestations of vascular disease, or the fact that lifetime CVD risk is higher than a 10-year risk; however, it does convey the point that relying on relative risk can lead to overestimation of screening test performance. These considerations also underscore that, for maximal benefit, a strong population approach should accompany any high-risk approach to CVD prevention beginning in childhood.

Role of Selective Screening

Updating recommendations for lipid screening was one of the most important tasks for the Expert Panel. The original 1992 National Cholesterol Education Program (NCEP) report National Cholesterol Education Program:  Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents (NCEP Pediatric Guidelines) recommended screening for elevated cholesterol levels only among children with either a family history of early CVD or elevated TC levels.^[8]  The rationale was that, compared with universal screening, this selective approach would identify the majority of children with elevated LDL–C levels by screening fewer individuals with similar benefits at lower costs, because a group with higher prevalence was being screened. As outlined in Section IX. Lipids and Lipoproteins, the evidence review indicates that office-based, family history-directed CV risk factor screening identifies significantly fewer children with abnormal LDL–C levels than would universal screening. When this evidence is combined with the knowledge that a complete family history is unavailable for many children, a family history-based screening approach for cholesterol does not appear to be effective. One caveat to this conclusion is that few data address whether family history-directed screening provides a useful approach for detecting extreme LDL–C levels (i.e., those high enough to warrant medication use). Also, as described in detail in Section IX. Lipids and Lipoproteins, most studies of medication use involve positive family history as an entry criterion, so that more research is needed about the efficacy of treatment among family history-negative children with elevated LDL–C.

The obesity epidemic makes more intensive lipid screening among overweight and obese children worthy of consideration, beyond the importance of identifying obesity as an independent risk factor for future CVD. As described in these Guidelines, particularly in Section X. Overweight and Obesity, evaluation of obese children will identify a large number with dyslipidemia, typically moderate to severe elevation of triglycerides (TG), mild elevation of LDL‑C and reduced HDL–C, as well as elevated BP. A very small number also will have type 2 diabetes mellitus (T2DM). Primary treatment for any of these risk factors is weight control. TG levels in particular are very responsive to weight loss and to dietary change. HDL–C levels rise in response to regular exercise. As presented in Section IX. Lipids and Lipoproteins and in Section X. Overweight and Obesity, dietary change, exercise, and weight loss can contribute to normalization of lipid levels and BP and elimination of the metabolic abnormalities in T2DM. An unanswered question for both children and adults, however, is the extent to which treatment of the dominant lipid abnormalities associated with obesity will result in reduced risk of early CV events.

Acceptability

Obtaining risk factor measurements from children requires that testing be feasible and acceptable to parents and children. Measurement of length/height and weight are routine and well-accepted in pediatric care from birth onward. Measurement of BP, recommended for all children beginning at 3 years of age,^[9] is also routine in most practices. Lipid testing requires a blood test and in the past has required overnight fasting. As described in detail in Section IX. Lipids and Lipoproteins, measuring non-HDL–C, which is accurate in the nonfasting state,^[10] as the first step in lipid screening should be a major improvement in feasibility for clinical practice and acceptability to parents and children. Additional blood draws in the fasting state are needed to confirm initially abnormal levels; their acceptability to children and parents is an open question. Some older research suggests low compliance by parents and children with followup screening recommendations in real-world practice, but current data are sparse.^[11]

Evaluation of Interventions among Children with Abnormal Risk Factors

As reviewed throughout these Guidelines, the major rationale for CV risk factor screening in youth, followed by treatment of abnormal levels, derives from knowledge that atherosclerosis begins in childhood and that its severity is greater in children with a higher burden of atherogenic risk factors. However, these observations do not directly address interventions to reduce this burden. A sine qua non of useful screening programs is that interventions based on abnormal screening results must be not only efficacious but also more efficacious than interventions that occur later in the disease process. If earlier interventions are not more efficacious than those initiated later in life, they incur cost and potential risk with no benefit. Studies in adults indicate that treating prehypertension with medication or lifestyle change is associated with a lower subsequent incidence of hypertension.^{[12],[13],[14]} In children with coarctation of the aorta, long-term followup studies demonstrate that early surgical repair is associated with reduced incidence of subsequent CVD.^[15]  The extent to which efficacy of intervention in youth extends to primary and less severe hypertension is not known. For obesity and lipids, no studies directly address the benefits (or risks) of early childhood treatment over treatment later in life on clinical disease.

The case of heterozygous familial hypercholesterolemia (FH) provides partial proof of the concept that early reduction of risk factors may reduce future disease rates. Individuals with FH are at increased risk for early CVD because of elevated LDL–C levels from infancy. In natural history studies, 50 percent of males and 25 percent of females with FH develop clinical CVD by age 50 years.^[16],[17]  In RCTs among older children and adolescents with FH, statin treatment substantially lowers LDL–C levels and slows progression of atherosclerosis as assessed by noninvasive testing.^[18]  Although pediatric medication trials are of relatively short duration, they suggest that sustained LDL–C-lowering therapy in children with FH will lower the risk of early clinical CVD. By extension and by analogy with adult treatment guidelines, the Expert Panel recommends treating less extreme elevations of LDL–C in childhood, especially in the setting of multiple CV risk factors. The extent to which either lifestyle change or medication treatment of lipids in youth reduces the atherosclerotic burden or risk of CV events is not yet known, nor is the long-term safety of treatment with statins beginning in childhood, although published trials do not show any adverse impact on growth, pubertal maturation, or hormonal metabolism over several years (see Section IX. Lipids and Lipoproteins).

It is vital to know how well primary care clinicians can incorporate recommended screening programs, including testing and interventions, into routine practice. Unfortunately, evidence is meager regarding repeated testing strategies or the effectiveness or sustainability of interventions in real-world practices. Thus, the evidence review almost exclusively identified studies that addressed intervention efficacy in a research setting. Nevertheless, the Expert Panel anticipates that practices will be better equipped to adopt its recommendations in the future than they are today. The recommendations may very well effect changes in policy and systems, as well as additional research that will assist clinicians in overcoming current time, space, personnel, and reimbursement challenges.

Other Issues

A potential ancillary benefit of childhood CV risk factor screening is to alert older family members of the need to have their own risk factors checked, especially lipids. If they have not been screened previously, parents and grandparents of children with abnormal lipid values should have their own lipid levels checked by their primary care providers. Several studies have shown that first-degree relatives of children with elevated LDL–C levels have both higher LDL–C levels themselves and higher rates of CV events.^{[19],[20],[21]}

It is also possible that knowledge of an abnormal risk factor in a child could spur lifestyle changes for the whole family. Many clinicians can cite anecdotes of families who made salutary changes after learning of a child's elevated cholesterol, BP, or BMI. However, the extent to which this phenomenon occurs is unclear, nor is it known whether this effect adds substantially to a concerted primordial prevention approach aimed at all children and families. Certainly, the literature is clear that, in general, knowledge alone is insufficient for effective behavior change.

FURTHER RESEARCH NEEDED

One of the most difficult issues to address in CV risk factor screening in childhood is the potential value of slowing or reversing atherosclerosis in its early stages. This issue is particularly important with respect to lipids. Statin treatment among high-risk adults reduces CV events within months of initiation.^[22]  However, statin therapy does not eliminate risk, and adult trials cannot include those who have already died of very early CV events, of which sudden death is a particular concern. Thus, an RCT of childhood CV risk factor screening and treatment of elevated levels with a noninvasive measure of atherosclerosis as the primary outcome is an appealing study design. This study design could apply to any of the childhood CV risk factors, not just elevated LDL–C. As described in the previous section, one caveat of using measures of subclinical atherosclerosis as end points is that, whether invasive or noninvasive, all of those measures are surrogates for the true outcome of clinical CV events. Trials with surrogate end points have sometimes led to misleading recommendations and harmful clinical practices.^[23]

Through the assessment of benefit, risk, and cost, the science of clinical decisionmaking offers an alternative to large long-term trials for the evaluation of CV risk factor screening in children. A decision analytic framework allows modeling of the immediate and downstream consequences of assessing childhood risk factors and intervening among those with abnormal results. As with any analytic method, decision analysis has strengths and weaknesses. The most important attribute of decision analysis is to ask the right questions. In the case of childhood CV risk factor screening, one strength of decision analysis is the ability to compare a number of strategies, including no screening or intervention, primordial prevention approaches only, universal or selective screening at specific ages, and the marginal benefit of screening at younger versus older ages. If a model contains appropriate decision points and outcomes, it can be a valuable method for assessing effects on long-term health outcomes without having to wait decades. In such a model, empirical evidence drives the quantitative comparison of one decision versus another. A good decision analysis not only will point out where data are lacking but also, through sensitivity analysis, will identify the most important new data to collect. The cost to society at large will likely be a major factor in decisions regarding screening. When added to a decision analytic model, the costs of screening, followup, and intervention can lead to estimation of the cost-effectiveness of various screening strategies, and sensitivity analysis can show where variability in costs is meaningful or irrelevant. Cost-effectiveness can be a major driver of policy decisions to support prevention programs. For these reasons, well-considered cost-effectiveness analyses of childhood CV risk factor screening should be a priority for future research.

CONCLUSIONS

The Expert Panel recommends two complementary strategies to reduce future risk for clinical CVD. Primordial prevention seeks to prevent the acquisition of risk factors by optimizing CV health for all, beginning in infancy. Primary prevention requires screening to identify children at increased risk for CVD. This section focused on screening and reviewed the limitations of current knowledge within the requirements for a useful screening program. Taking these factors into account, the Expert Panel recommends routine measurement of length/height and weight beginning in infancy, with calculation of BMI annually beginning at age 2 years to identify growth trends; yearly assessment of BP from age 3 years; and universal screening for lipid abnormalities by a nonfasting non-HDL–C level at age 10 years. These screening strategies, described in detail in the respective risk factor sections of these Guidelines, will identify a relatively large number of children for whom the Expert Panel recommends intensified lifestyle intervention. Only a small number of children will require pharmacologic therapy. While they await the results of future research, the Expert Panel members conclude that recommending these assessments, followed by interventions as part of routine pediatric care, represents the best current primary prevention strategy to lower lifetime risk of atherosclerotic vascular disease.

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