Screening in Pediatric and Congenital Cardiac Disease

Introduction

“Screening” in the field of pediatric cardiology is currently implemented in many different areas. The interest and opportunities for screening have increased and evolved along with the increase in our knowledge base. Screening currently includes in utero screening for congenital heart disease (CHD), pulse oximetry after birth screening for CHD, screening for at-risk entities for sudden cardiac death, screening for neurodevelopmental issues, screening for familial forms of CHD, and screening for other familial, genetic, and preventive issues such as the hyperlipidemias, as well as environmental issues such as hypertension and metabolic disorders. This chapter reviews these complex issues and suggests potential future endeavors in these areas.

Fetal Echocardiographic Screening (see also Chapters 7 and 8 )

Malformations of the cardiovascular system are some of the most common birth defects. The incidence of CHD in the live-born population is estimated at slightly less than 1%. However, the incidence of CHD in the fetus may be significantly higher, as cardiac defects are estimated to be much more frequent in stillborn infants.

Detecting a cardiac defect, if present, in the fetus is dependent on the timing of the examination, the training and experience of the ultrasonographer and interpreting physician, and the equipment use. At minimum, two-dimensional, color and spectral Doppler should be used. As the echocardiographic appearance of some congenital heart defects can change throughout gestation, one exam at one time point may not be sufficient.

Accurate and sensitive fetal diagnosis is important as the prenatal diagnosis of CHD can affect not only the family's desire to continue with the pregnancy but can allow for planning delivery at or near a cardiac surgical center, psychological preparation of the family prior to delivery, as well as surgical planning. Over recent years, criteria for fetal echocardiographic screening of fetuses at higher risk of CHD have been established ( Table 89.1 ). For these higher-risk pregnancies, a thorough fetal echocardiogram should be performed in the second trimester.

However, approximately 80% of children with CHD are born to mothers who have no risk factors for CHD in their offspring and are therefore low risk. While ideal prenatal ultrasound can provide detection rates as high as 85%, the population detection rate of CHD is 30% to 50% in most developed countries. Barriers to diagnosis include later initiation of prenatal care, maternal residence in an area with a high incidence of poverty, and a higher number of previous pregnancies. Cost-effective analysis simulations have identified that the most cost-effective strategy for prenatal screening of CHD is a four-chamber and outflow tract view in the second trimester with direct referral to a pediatric cardiologist if abnormalities are found. To maximize the prenatal diagnosis of CHD, the American Institute of Ultrasound Medicine has recommended that anatomic screening for all pregnancies include a four-chamber view and outflow tract views (American Institute of Ultrasound in Medicine practice parameter). The addition of outflow tract views to the four-chamber view has an estimated sensitivity of 67% with a specificity of 99%.

Recently, research has been evaluating whether screening for congenital heart defects is possible in the first trimester. First-trimester screening has been shown to reliably visualize single ventricle lesions as well as transposition of the great arteries. Some studies have suggested that the vast majority of major CHDs can be detected during a first-trimester ultrasound if performed by an experienced fetal sonographer and obstetrician as early as 11 to 13 weeks' gestation. Analysis of first-trimester screening shows that cardiac abnormalities identified in the first trimester were more commonly associated with chromosomal abnormalities (50% to 73%) compared to 17% to 21% in second-trimester screening. Some authors suggest that early prenatal diagnosis may alter the natural outcome of pregnancies with CHD as it may increase early termination of first-trimester pregnancies. However, caution should be exercised when counseling families in the first trimester as it is not always possible to detect cardiac abnormalities in enough detail to provide accurate estimation of the natural history of the suspected lesion. Furthermore, some cardiac lesions may not be fully diagnosable in early pregnancy, and first-trimester screening should not replace second-trimester screening.

Extracardiac and chromosomal abnormalities are frequently present when CHD is diagnosed prenatally. For that reason, when CHD is diagnosed prenatally, consideration should be given to chromosomal testing and secondary anatomic screening if these have not already been completed ( Table 89.2 ).

Pulse Oximetry Screening

The calculated prevalence of critical CHD (requiring intervention in the first year of life) varies from study to study, but based on most recent estimates is approximately 2 infants per 1000 live births, with an overall prevalence of any type of CHD of 9 infants per 1000 births. Early diagnosis, particularly of critical CHD, can prevent significant morbidity and mortality. Newborns with critical CHD can have profound and rapid deterioration in clinical status in the first days or weeks of life, usually related to closure of the ductus arteriosus and physiologic changes in pulmonary vascular resistance. Identification of these newborns prior to hospital discharge, and prior to the development of significant hemodynamic compromise, can allow for timely intervention and medical management such as prostaglandin therapy to maintain ductal patency. The relatively high prevalence combined with a period of time where critical CHD can be diagnosed prior to clinical deterioration makes critical CHD an ideal subject for population-based screening.

Early studies evaluating the use of pulse oximetry in neonates demonstrated that lower-extremity oxygen saturation in infants with critical CHD was lower than age-matched control subjects without critical CHD. In determining the most effective screening strategy, sensitivity and specificity should be maximized. False-positive results can be a public health concern as they require subsequent testing, which in some settings may delay hospital discharge of the infant or require transfer to another institution, resulting in added familial anxiety, stress, and cost. However, increasing specificity at the expense of sensitivity will increase the false-negative rate, possibly resulting in a less effective screening regimen overall. The American Heart Association and American Academy of Pediatrics convened a writing group to compose a scientific statement in 2009 to evaluate the evidence on the routine use of pulse oximetry in newborns to detect critical CHD. They analyzed ten studies, including over 123,000 infants total. Overall, the sensitivity of pulse oximetry screening for critical CHD ranged from 0% to 100% with specificity ranging from 95.5% to 100%. False-positive screens were found in a mean of 0.9% of infants with a decrease in the false-positive rate to 0.04% after 24 hours. The writing group suggested that a single lower-extremity pulse oximetry reading at an age greater than 24 hours with a threshold of 95% or greater was the most appropriate large-scale screening strategy. Further study is necessary to determine if the threshold to maximize sensitivity and specificity is different at moderate or greater altitude, as the normal saturation of neonates at altitude is around 95%.

In September 2011, the United States Secretary of Health recommended that pulse-oximetry screening before discharge should be added to the newborn screening panel for the early detection of critical CHD for all infants born in the United States. By 2014, 43 of 50 states had instituted legislation or regulations mandating pulse-oximetry screening with seven states and the District of Columbia supporting pulse-oximetry screening as the standard of care with no legislation in place. There have not been many studies assessing the accuracy of screening since the implementation of universal pulse-oximetry screening. An initial study in the UK in 2011 showed a false-positive rate of 0.8% with a negative predictive value of 99.7%. Of 20,055 newborn infants, 24 had critical CHD. Of these 24, 6 were not identified by pulse-oximetry screening. The critical lesions most likely to be missed by using pulse oximetry as a screening method were obstructive arch lesions such as coarctation and interrupted aortic arch. In recent studies in the United States, pulse oximetry screening has been shown to be cost effective.

Screening and Sudden Cardiac Death

Screening First-Degree Relatives After Sudden Cardiac Death in the Young

The incidence of sudden death has been reported between 2.7 and 7.5 events per 100,000 patient-years among young people (age 1 to 40 years) who were previously thought to be well. Exact numbers remain unknown, but these rates would result in 10,000 children and young adults experiencing sudden unexplained death in the United States every year. Italy, France, the Netherlands, and international communities have rolled out screening programs and registries. Most of these deaths ultimately will be attributed to cardiac causes. A large, prospective population-based study from Australia and New Zealand diagnosed cardiomyopathy on autopsy in 16% of cases. This correlates closely with a Danish population-based registry with autopsy-based cardiomyopathy in 17% of cases. Arrhythmogenic causes of sudden death are harder to quantify because the hearts tend to be structurally normal or near-normal; a potentially arrhythmogenic cause was present in 45% of cases in the large Australia/New Zealand series. In addition, pathogenic or likely pathogenic variants in genes associated with congenital arrhythmia susceptibility and familial cardiomyopathy have been demonstrated in 3% to 35% of postmortem samples from cases of sudden unexplained death (see Table 89.1 ). Because these diseases may be inherited, screening for affected family members is critical. In work from several centers, approximately 15% of families are found to be affected with a heritable cardiac disease when first-degree relatives receive screening after sudden death in the family.

Screening of first-degree relatives after sudden unexplained death is particularly important because therapy can alter the natural history of these diseases among surviving family members. Long QT syndrome has become the prototypical channelopathy because it has the highest known incidence rate in the population and because β-blocker therapy for primary prevention is associated with a 42% to 78% reduction in risk of aborted cardiac arrest or sudden cardiac death. Among the remaining channelopathies and cardiomyopathies there have been successes with various combinations of medications, left cardiac sympathetic denervation, ablation therapy, lifestyle modification, and avoidance of triggering medications. The most common channelopathy and cardiomyopathy diseases are long and short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), ARVD, HCM and dilated cardiomyopathy (DCM). For exceptionally high-risk patients, primary prevention implantable cardioverter defibrillators (ICDs) may be offered although most electrophysiologists follow one or more ICDs that were placed in anticipation of a high-risk outcome before subsequent research helped downgrade the patient's risk in the patient's particular disease. Therefore extensive risk-benefit consideration and patient counseling are required to help families understand the balance between the benefits of primary prevention ICDs and the potential risks of ICD placement, including infection, shocks, device malfunction, subsequent interventions, device failure, and psychosocial implications.

Other diagnoses found in surviving relatives call for therapy that does not directly impact acute arrhythmia risk, but may decrease long-term morbidity and mortality. For example, early and severe atherosclerotic coronary heart disease on autopsy should trigger screening for familial hyperlipidemia. Autopsy may also uncover conditions such as undiagnosed CHD, vascular malformations that may have ruptured or otherwise caused sudden death, toxicology findings consistent with overdose, or myocarditis. While there are suggestions that there may be a heritable component to several of these disorders, the primary work to date has focused on channelopathies and cardiomyopathies, which are amenable to genetic testing for monogenetic autosomal dominant variants.

In summary, a sudden death event in a previously healthy young person is a dramatic signal that first-degree relatives—siblings, parents, and children—require risk stratification.