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Literature review current through: Jun 2014. | This topic last updated: Jul 07, 2014.

INTRODUCTION — Congenital heart disease (CHD) is the most common congenital disorder in newborns [1-3]. Critical CHD, defined as requiring surgery or catheter based intervention in the first year of life, occurs in approximately 25 percent of those with CHD [4]. Although many newborns with critical CHD are symptomatic and identified soon after birth, others are not diagnosed until after discharge from the birth hospitalization [5-7]. In infants with a critical cardiac lesion, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary center with expertise in treating these patients [8].

Factors that should lead clinicians to suspect CHD and screen for critical congenital heart lesions will be reviewed here. The evaluation and management of specific cardiac conditions are discussed separately [9]. (See "Cardiac causes of cyanosis in the newborn" and "Diagnosis and initial management of cyanotic heart disease in the newborn".)

EPIDEMIOLOGY — The reported prevalence of congenital heart disease (CHD) at birth ranges from 6 to 13 per 1000 live births [10-15]. Variation is primarily due to the use of different methods to detect CHD, such as referral to a cardiac center or fetal echocardiographic data [14,16].

The following studies provide a global perspective on the incidence of neonatal CHD:

In one English health region, reported prevalence of cardiovascular malformations was 6.5 per 1000 live births [5,13].

In a population-based study from Atlanta, the prevalence of CHD was 8.1 per 1000 live births from 1998 to 2005 [12]. The most common diagnosis was muscular and perimembranous ventricular septal defect (VSD), followed by secundum atrial septal defect (ASD) (prevalence of 2.7, 1.1, and 1 per 1000 live births, respectively). Tetralogy of Fallot was the most common cyanotic CHD (0.5 per 1000 births).

In a population-based study of all Danish live births from 1977 to 2005, the prevalence of CHD was 10.3 per 1000 live births [17]. Chromosomal defects were detected in 7 percent of those patients, and extracardiac anomalies in 22 percent. In a population-based study, the prevalence of CHD in Greater Paris was 9 per 1000 live births [15]. With the exclusion of VSD, 40 percent of the patients were diagnosed prenatally.

The highest prevalence for CHD was observed in a population-based study from Taiwan with a prevalence of 13.1 per 1000 live births between 2000 and 2006 [9]. The most common defect was VSD, followed by secundum ASD and patent ductus arteriosus (prevalence of 4, 3.2, and 2 per 1000 live births, respectively).

In preterm infants (gestational age <37 weeks), CHD is two to three times that found in term infants [11]. In addition, reported maternal conditions that increase the risk of CHD include multifetal pregnancy, diabetes mellitus, hypertension, maternal CHD, thyroid disorders, systemic connective tissue disorders, and epilepsy and mood disorders [18].

CHD is one of the leading causes of perinatal and infant death from congenital malformations [1,13,19]. In a report from the United Kingdom Northern Congenital Abnormality Survey, 10 percent of deaths in this pediatric cohort with at least one congenital anomaly were associated with CHD [1].

CRITICAL CHD — Critical CHD, defined as requiring surgery or catheter based intervention in the first year of life, occurs in approximately 25 percent of those with CHD [4]. In infants with critical CHD, the risk of morbidity and mortality increases when there is a delay in diagnosis and timely referral to a tertiary center with expertise in treating these patients [8]. Over the past several decades, outcomes have significantly improved for patients with critical CHD with the advancement of corrective or palliative interventions [1,20]. Therefore, timely diagnosis and subsequent intervention, particularly during the newborn hospitalization, are essential to further reduce the mortality associated with critical CHD [9].

Timing of presentation — Infants with critical CHD may be diagnosed prenatally or present during the birth hospitalization, often with serious and life-threatening clinical findings that require immediate intervention [15]. However, in other affected neonates, especially those with ductal dependent lesions, the diagnosis of critical CHD may be missed prior to discharge because the infant appears normal on routine examination. (See 'Early serious or life-threatening presentation' below and 'Few or no symptoms during birth hospitalization' below.)

The timing of presentation varies with the underlying lesion and its dependence upon a patent ductus arteriosus.

Ductal-dependent lesions, delayed diagnosis, and death — Many critical congenital heart lesions are ductus dependent. The affected neonate may not be symptomatic during the birth hospitalization because the ductus arteriosus has not yet closed prior to discharge. The magnitude of the failure to detect critical CHD during the first few days of life was demonstrated in a review of 10 studies that reported 30 percent of patients with critical CHD were diagnosed after birth hospitalization discharge [21]. The lesions that were not diagnosed prior to discharge were primarily ductal dependent and included coarctation of the aorta (COA), interrupted aortic arch, aortic stenosis, hypoplastic left heart syndrome (HLHS), and transposition of the great arteries. Nonductal-dependent cyanotic lesions with potentially only mild desaturation or tachypnea initially, such as truncus arteriosus, tetralogy of Fallot, and total anomalous pulmonary venous connection were also missed.

Closure of a patent ductus arteriosus can precipitate rapid clinical deterioration with potentially life-threatening consequences (ie, severe metabolic acidosis, seizures, cardiogenic shock, cardiac arrest, or end-organ injury) [22]. The risk for death in infants with ductal-dependent critical CHD who are not diagnosed during the birth hospitalization is illustrated by the following studies:

In a population-based study from the California statewide death registry, more than half of the 152 neonates with a missed diagnosis of critical CHD died after their initial birth hospitalization [23]. The median age at death was 13.5 days. The most common diagnoses were HLHS and COA.

In a retrospective study of 4390 children with CHD, 800 patients died in the first year of life including 76 who died before a diagnosis of heart disease was made (1.7 percent of the entire cohort) [8].

EARLY SERIOUS OR LIFE-THREATENING PRESENTATION — Neonates with critical CHD can precipitously present with serious and life-threatening manifestations of their cardiac disease during the birth hospitalization.

Urgent consultation/referral to a pediatric cardiologist should be made when severe, potentially lethal CHD is suspected in critically ill neonates who present with shock, cyanosis, or pulmonary edema [24].

Shock — A variety of mechanisms can lead to cardiogenic shock in newborns with ductal-dependent CHD when the ductus arteriosus closes:

In left heart obstructive lesions (eg, hypoplastic left heart syndrome, critical aortic stenosis, coarctation of the aorta, and interrupted aortic arch), systemic perfusion is lost.

In right-sided obstructive lesions (eg, total anomalous pulmonary venous connection, tricuspid atresia, and mitral atresia), restricted pulmonary blood flow results in reduced systemic blood flow, which may result in shock.

In lesions with parallel pulmonary and systemic circulations (eg, transposition of the great arteries with intact ventricular septum), mixing between the two circulations is decreased, leading to hypoxia and metabolic acidosis, which results in failure and shock.

Cardiogenic shock must be differentiated from other causes of shock, such as sepsis. In newborns who present with shock, cardiomegaly is a helpful finding indicating a cardiac etiology [25]. (See "Etiology, clinical manifestations, and evaluation of neonatal shock".)

Cyanosis — Cyanosis, usually detected when the concentration of reduced hemoglobin is 4 to 5 g/dL, is an important sign of CHD and is present in a number of congenital cardiac diseases. Patent ductus arteriosus (PDA) is an essential component of circulation in some, but not all, cyanotic cardiac lesions.

The normal closure of the PDA in the first days of life can precipitate profound cyanosis in the following scenarios:

When the PDA is the only mechanism of pulmonary blood flow, such as in patients with critically obstructive right heart lesions (eg, critical pulmonary stenosis/atresia). These patients will present with progressive cyanosis as the ductus closes.

When the PDA supplies the majority of systemic circulation in critically obstructive left heart lesions (including hypoplastic left heart syndrome and critical aortic valve stenosis). With ductal closure, these patients will present with decreased peripheral perfusion. (See "Clinical manifestations and diagnosis of coarctation of the aorta" and "Valvar aortic stenosis in children", section on 'Critical AS' and "Hypoplastic left heart syndrome".)

When the PDA provides mixing between parallel pulmonary and systemic circulations (transposition of the great arteries). (See "Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot", section on 'Clinical presentation' and "Pathophysiology, clinical manifestations, and diagnosis of D-transposition of the great arteries", section on 'Postnatal presentation'.)

In these patients, profound cyanosis is a manifestation of severe hypoxia that is associated with significant metabolic acidosis that may result in cardiac dysfunction (failure) and cardiogenic shock. Initiation of prostaglandin E1 (generic drug name, alprostadil) to re-open or maintain the ductus arteriosus, is life saving in these patients. Timely prostaglandin E1 infusion can prevent the development of shock, severe hypoxemia, acidosis, and resultant end-organ damage. The use of prostaglandin E1 is discussed separately in neonates with cyanotic heart disease and in reviews of specific cardiac lesions. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1' and "Management and outcome of D-transposition of the great arteries", section on 'Prostaglandin (alprostadil) infusion' and "Total anomalous pulmonary venous connection", section on 'Initial medical management' and "Hypoplastic left heart syndrome", section on 'Initial medical management'.)

Lesions associated with cyanosis in nonductal-dependent congenital heart defects include:

Total anomalous pulmonary venous connection (TAPVC). (See "Total anomalous pulmonary venous connection".)

Truncus arteriosus. (See "Cardiac causes of cyanosis in the newborn", section on 'Truncus arteriosus'.)

Lesions may or may not be ductal dependent depending upon the degree of outflow tract obstruction including tetralogy of Fallot and tricuspid atresia. (See "Pathophysiology, clinical features, and diagnosis of tetralogy of Fallot" and "Cardiac causes of cyanosis in the newborn".)

Other lesions may exhibit differential cyanosis, such as critical coarctation of the aorta or interrupted arch, where the deoxygenated flow through the ductus supplies the lower half of the body's circulation, but oxygenated blood flow from the left heart supplies the upper body via the vessels proximal to the site of arch obstruction.

Severe pulmonary edema — Pulmonary edema, resulting in tachypnea and increased work of breathing, can occur when there is a massive, rapid increase in pulmonary blood flow associated with a fall in pulmonary vascular resistance at delivery in conditions such as truncus arteriosus [24] or PDA in premature infants, or pulmonary venous circulation obstruction in total anomalous pulmonary venous connection with obstruction [26]. (See "Pathophysiology, clinical manifestations, and diagnosis of patent ductus arteriosus in premature infants" and "Total anomalous pulmonary venous connection", section on 'Obstructed forms'.)

FEW OR NO SYMPTOMS DURING BIRTH HOSPITALIZATION

Overview — As discussed above, identifying all infants with critical CHD during the first few days of life would reduce mortality by allowing either corrective or palliative intervention. However, early detection of neonatal CHD remains challenging because clinical findings may be subtle or absent immediately after birth, and prenatal screening does not reliably detect all cases of CHD. Data have shown that pulse oximetry is an effective screening measure. Thus, the American Academy of Pediatrics (AAP), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF) [27] have recommended universal screening of all newborns with pulse oximetry to improve the recognition of CHD. (See 'Pulse oximetry screening' below.)

Variability of prenatal ultrasound — The sensitivity of prenatal screening with echocardiography for major heart disease is highly variable, ranging from 0 to 80 percent detection rates. Factors affecting sensitivity include operator training and experience, gestational age, maternal weight, fetal position, and type of defect. The efficacy of prenatal sonographic screening for CHD is discussed separately. (See "Fetal cardiac abnormalities: Screening, evaluation, and pregnancy management".)

Limitation of history and physical examination — Assessment of the newborn to detect CHD is focused on the history and physical examination, but several studies have shown that the newborn assessment can miss a significant number of patients with critical CHD [23,28,29].

This was illustrated in a retrospective English study of 1067 infants (diagnosed with CHD by 12 months of age) born between 1987 and 1994, in which 82 percent were not recognized to have CHD before hospital discharge [28]. Of these undiagnosed infants, 306 (35 percent) became symptomatic or died without a diagnosis before six weeks of age.

Despite these limitations, the history and physical examination can still contribute to the identification of neonates with critical CHD.

History — Identifying historical factors that are associated with CHD heightens the awareness of the clinician of the possibility of an underlying cardiac defect, thereby focusing his/her examination to detect any subtle cardiac finding in the well-appearing neonate.

Maternal and prenatal history — The following maternal medical conditions or prenatal disorders increase the risk of CHD.

Preterm infants (gestational age <37 weeks): CHD is two to three times that found in term infants [11]. (See 'Epidemiology' above.)

Maternal conditions that increase the risk of neonatal congenital heart disease include the following [18]:

Maternal diabetes (see "Infant of a diabetic mother")

Maternal obesity (see "The impact of obesity on female fertility and pregnancy")

Maternal hypertension (see "Gestational hypertension", section on 'Perinatal outcome')

Maternal CHD – refer to family history

Maternal thyroid conditions

Maternal epilepsy and mood disorders

Maternal fever or influenza [30]

Smoking in the first trimester [31]

Congenital complete heart block in offspring of mothers with connective tissue disorders and anti-Ro/SSA and anti-La/SSB antibodies. (See "Neonatal lupus".)

Congenital infections such as cytomegalovirus, herpesvirus, rubella, or coxsackie virus. (See "Clinical manifestations and diagnosis of enterovirus and parechovirus infections" and "Overview of TORCH infections", section on 'Clinical features of TORCH infections'.)

Drugs taken in pregnancy such as hydantoin (eg, pulmonary and aortic stenosis), lithium (eg, Ebstein's anomaly) [32-34], and alcohol (eg, atrial and ventricular septal defects) [35] can be associated with cardiac defects. (See "Risks associated with epilepsy and pregnancy", section on 'Phenytoin' and "Fetal alcohol spectrum disorder: Clinical features and diagnosis", section on 'Structural birth defects'.)

Assisted reproductive technology (ART) increases the risk for congenital heart disease, particularly for malformations of the outflow tracts and ventriculoarterial connections. It is unclear if this risk is related to the underlying etiology of infertility in the couple or the ART per se [36].

Family history — There is an overall threefold increased risk for CHD when a first degree relative has CHD [17,37]. The familial risk of specific malformations is even greater, suggesting a stronger genetic effect in these conditions.

This was illustrated in a Danish population-based study that identified about 18,000 individuals with CHD over 28 years with the following findings [17]:

The risk of CHD in singletons births with first-, second-, or third-degree relatives with CHD was 3.2 (95% CI 3.0-3.5), 1.8 (95% CI 1.1-2.9), or 1.1 (95% CI 0.8-1.5), respectively.

When patients with chromosomal aberrations were excluded, the relative risk of CHD decreased to 2.2 in first degree relatives.

The relative risk for CHD for monozygotic twins was 15.2 and for dizygotic twins was 3.3 (similar to that of any first degree relative).

Heterotaxy syndrome was the congenital anomaly with the highest relative risk for familial recurrence (79.1) followed by right ventricular outflow tract obstruction (48.6), atrioventricular septal defect (24.3), left ventricular outflow tract obstruction (12.9), conotruncal defect (11.7), isolated atrial septal defect (7.1), and isolated ventricular defect (3.4).

In addition to inquiring about CHD among family members, parents should be questioned about familial occurrence of cardiomyopathies, sudden death, or unexpected death in infancy or childhood that could potentially uncover genetic preponderance of potential congenital cardiac abnormalities within the family. (See "Clinical features of congenital long QT syndrome".)

Physical examination — Although many infants with critical CHD are asymptomatic, subtle clinical findings may be detected that identify underlying cardiac disease. The following discussion reviews the physical findings that may be seen in an infant with CHD; however, as noted above, findings may be absent in those infants with a ductal-dependent lesion and a patent ductus arteriosus (PDA) during their birth hospitalization. (See 'Limitation of history and physical examination' above.)

Cardiovascular examination — Cardiovascular findings suggestive of CHD include abnormal heart rate, precordial activity, and heart sounds; pathologic murmurs; and diminished or absent peripheral pulses, all of which merit further evaluation and perhaps referral to clinicians with expertise in caring for neonates with CHD.

Abnormal heart rate — In infants with heart rates that are higher or lower than the normal range of 90 to 160 beats per minute for neonates up to six days of age, electrocardiography is initially performed to determine whether there is an arrhythmia, and to guide further assessment and management [38].

Causes of abnormal neonatal heart rate include:

Sinus tachycardia in myocarditis, large left to right shunts, and other etiologies of heart failure [39-41].

Supraventricular tachycardia (SVT) may present as a fetal arrhythmia or in early infancy [42]. One cause of SVT is Wolff-Parkinson-White syndrome, which is associated with Ebstein's anomaly, rhabdomyomas, ventricular inversion, hypertrophic cardiomyopathy, and other congenital heart defects [43,44]. Infants with SVT should always be evaluated for structural heart defects. (See "Supraventricular tachycardia in children: AV reentrant tachycardia (including WPW) and AV nodal reentrant tachycardia", section on 'Neonates'.)

Ventricular tachycardia may be associated with long QT syndrome, intracardiac tumors, cardiomyopathy, and ventricular dysfunction. (See "Causes of wide QRS complex tachycardia in children", section on 'Ventricular tachycardia'.)

Bradycardia can be associated with long QT syndrome as well as congenital atrioventricular (AV) block [45]. A prolonged QTc has been correlated with sudden infant death syndrome [46]. Screening of infants at high risk with family history of long QT syndrome, sudden infant death syndrome, or acute life threatening event has been advocated [47].

Atrial and ventricular arrhythmias have been reported as presenting symptoms in infants with fatty acid oxidation disorders [48]. (See "Approach to the metabolic myopathies".)

Precordial activity — Precordial palpation ascertains whether the heart is normally located on the left side of the chest. Dextrocardia is often associated with complex CHD. In addition, palpation may detect the following:

Cardiac enlargement, which, in a newborn with respiratory symptoms, is more suggestive of cardiac than pulmonary disease [49].

Ventricular impulse in the lower left parasternal area suggestive of right ventricular volume or pressure overload.

Increased apical activity suggestive of left ventricular volume or pressure overload.

Thrill due to outflow tract obstruction or a restrictive ventricular septal defect.

S2 splitting — The second heart sound (S2) normally splits physiologically with inspiration, and becomes single during expiration. Although the presence of S2 splitting reduces the likelihood of severe CHD, the newborn's rapid heart rate often makes it challenging to detect S2 splitting. Splitting is audible in 80 percent of normal newborns by 48 hours of age, usually when the heart rate is less than 150 beats per minute [32,50]. As an infant's heart is positioned more horizontally, splitting may be easier to hear along the mid to lower sternal border than in children or adults. Listening may be facilitated by a gentle breath into the baby's face that may temporarily slow the heart rate. (See "Assessment of the newborn infant" and "Auscultation of heart sounds".)

A single second heart sound occurs in the following conditions:

Aortic atresia

Pulmonary atresia

Truncus arteriosus

Conditions with pulmonary hypertension, as increased impedance in the pulmonary circuit causes early closure of the pulmonary valve, resulting in a single S2

In transposition of the great arteries, the pulmonary artery is located posterior and directly behind the aorta; thus, the softer pulmonary component of the second heart sound is often inaudible.

A widely or fixed split S2 occurs with atrial septal defect (ASD) and other lesions associated with right ventricular volume overload or right sided conduction delays. However, the absence of a widely split S2 in an infant does not rule out an ASD. The abnormal splitting may develop later with increasing volume of flow crossing the defect after pulmonary resistance has fallen.

Other heart sounds — The following additional heart sounds may be associated with cardiac abnormalities. Infants with these extra heart sounds should be evaluated by a clinician with expertise in caring for neonates with CHD.

Early systolic clicks, which occur with semilunar valve stenosis, bicuspid aortic valve, and truncus arteriosus.

Mid-systolic clicks, which are heard with mitral valve prolapse and with Ebstein's anomaly of the tricuspid valve.

An S3 gallop, which, in infants, can result from ventricular dysfunction.

Pericardial friction rubs occur with small to moderate pericardial effusions and pericarditis. Purulent pericarditis is an unusual complication of neonatal sepsis [51,52]. Pericarditis is also seen in neonatal lupus that may occur in infants of mothers with connective tissue disorders and anti-Ro/SSA and/or anti-La/SSB bodies [53]. (See "Neonatal lupus".)

Murmurs — The presence of a murmur is often associated with CHD. Detection of a murmur depends upon the examiner's skill and experience, and the timing, frequency, and the conditions under which examination takes place. The evaluation of a heart murmur is important because of potentially adverse outcomes when serious CHD remains undetected. In one report, a murmur had been detected in the neonatal period in 38 percent of infants who presented with heart failure due to a left heart obstructive lesion by six weeks of age [54]. In another study, a neonatal murmur was heard in 57 percent of infants who died with CHD after discharge [55].

However, many infants with murmurs do not have structural lesions, and CHD occurs in infants who do not have murmurs. This was illustrated by a study in which echocardiography was performed in all 46 of 7204 newborns (0.6 percent) with murmurs detected during routine examination by obstetric or pediatric house officers [56].

Of 46 newborns with a murmur, 13 had normal hearts and 8 had normal hearts with physiologic findings that would account for a murmur (eg, patent ductus arteriosus [PDA] or mild pulmonary artery branch stenosis). Of the 25 infants (54 percent) with cardiac malformations, all of whom were asymptomatic, ventricular septal defect (VSD) occurred in 15, coarctation of the aorta in 3, tetralogy of Fallot in 3, atrial septal defect in 2, and pulmonary stenosis and aortic valve stenosis in 1 each.

CHD was also detected before 12 months of age in 32 infants who had no murmur on the initial examination.

In another report, echocardiography was performed in 170 of 20,323 newborns (0.8 percent) between one and five days of age, who were referred for evaluation of murmur with an otherwise normal examination [57]. Structural heart disease was identified in 146 (86 percent). The most common lesions were VSD (n = 54) and patent ductus arteriosus (n = 34). Seven had complex cardiac disease, and stenosis of the pulmonary or aortic valve occurred in six and three infants, respectively.

Innocent murmurs — A substantial proportion of murmurs heard in the newborn period are innocent. In the studies cited above, no structural heart disease was found in 23 and 13 percent of healthy newborns with murmurs, respectively [56,57].

The majority of innocent murmurs in term infants are due to benign pulmonary branch stenosis (PBS), also known as peripheral pulmonary stenosis. This condition is usually detected as a grade 1-2/6, mid-systolic, high-pitched or blowing ejection murmur heard best in the pulmonary area with radiation to the axilla and back after the infant is 24 hours of age, when most PDAs have closed [58]. The murmur may be due to the relative hypoplasia at birth of the branch pulmonary arteries compared with the main pulmonary artery (which is large because it feeds the PDA and systemic circulation in utero) and its sharp angle of origin [59-63].

Another innocent finding on auscultation in infants is a Still's murmur thought to arise from the vibrations of the attachments of the pulmonic valve leaflets. These low pitched, vibratory, musical, grade 1-2/6 systolic ejection murmurs are usually best heard between the lower left sternal border and apex. They typically decrease in intensity or resolve with a Valsalva maneuver, which can be induced in infants by gentle pressure on the abdomen. Still's murmurs tend to vary with heart rate, becoming more evident as the heart rate slows; however, they are relatively uncommon in the newborn.

The natural history of neonatal innocent murmurs was investigated with serial two dimensional and pulsed Doppler echocardiograms in 50 healthy term infants with a clinical diagnosis of an innocent murmur and 50 controls without a murmur [58]. Cardiac findings were more frequent in the murmur group than controls, including PBS (50 versus 12 percent) and PDA (30 versus 12 percent). The murmur had disappeared in 64 and 98 percent of babies by six weeks and six months of age, respectively. Structural heart disease (pulmonary stenosis) was diagnosed in only one patient by six months of age.

Pathologic murmurs — The intensity and quality of the murmur and associated findings differentiate innocent murmurs from those associated with heart disease [64-66]. The following features of murmurs are associated with structural heart disease [65]:

Murmur intensity grade 3 or higher

Harsh quality

Pansystolic duration

Loudest at upper left, upper right sternal border, or apex

Abnormal S2

Murmurs that are also accompanied with absent or diminished femoral pulses or noncardiac abnormalities are associated with CHD.

Pathologic murmurs associated with specific cardiac lesions are discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Murmur'.)

Absence of a murmur — Many infants with CHD do not have a murmur [56,67] and therefore the absence of a murmur does not rule out congenital heart disease. The following factors may account for the absence of a murmur:

The velocity of turbulent blood flow may not be high enough to generate a murmur. This typically occurs in hypoplastic left heart syndrome, simple transposition of the great arteries, total anomalous pulmonary venous connections, pulmonary atresia, and cardiomyopathy.

Decreased ventricular function can limit the generation of a murmur. As an example, if the left ventricular myocardium cannot generate enough contraction to create sufficient flow across a critically obstructed aortic valve, a murmur of aortic stenosis will not be heard.

Elevated pulmonary resistance may limit flow. The volume or velocity of flow across a ventricular septal defect may not be sufficient to be audible until the resistance has fallen [57].

Peripheral arterial pulses — Assessment of symmetric peripheral arterial pulses is an essential part of the neonatal evaluation. The diagnosis of coarctation of the aorta (COA) or other aortic arch obstruction is strongly suggested in the infant with decreased or absent pulses in the lower extremities with strong upper extremity pulses, or blood pressures that are 10 mmHg or more higher in the arms than legs. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Manifestations according to age'.)

Infants with significant COA may have cool and/or mottled lower extremities that must be distinguished from cutis marmorata, a purplish, marble-like mottling that appears with exposure to cold [32]. Cutis marmorata is probably caused by constriction of the small cutaneous arterioles, causing the small venules to appear prominent. It is not usually limited to the lower extremities, and disappears once the infant is warm. COA should also be considered in the differential diagnosis of neonatal hypertension [68].

Some cases of COA escape early diagnosis [69]. In the study of the utility of routine exams to detect CHD cited above, 19 of 95 (20 percent) infants diagnosed with COA by 12 months of age were not diagnosed before 12 weeks of age [28]. (See 'Limitation of history and physical examination' above.)

Cyanosis — Cyanosis is an important sign of CHD, but mild desaturation may be difficult to appreciate visually. Cyanosis can usually be detected when the concentration of reduced hemoglobin is >3 g/dL. Therefore, cyanosis may not be apparent in those with mild desaturation (>80 percent saturation) or anemia (hemoglobin of 10, would require to have a saturation <60 percent to appear cyanotic) [70]. Cyanosis can be especially difficult to appreciate in darkly pigmented infants. Pulse oximetry is helpful to detect mild desaturation in patients with ductal-dependent lesions. (See "Overview of cyanosis in the newborn", section on 'Central cyanosis' and 'Pulse oximetry screening' below.)

Noncardiac causes — Noncardiac conditions also can cause cyanosis and are differentiated from CHD by the cardiovascular examination and/or results of the hyperoxia tests. (See 'Hyperoxia test' below.)

Pulmonary disorders are the most common cause of cyanosis and include structural abnormalities of the lung, ventilation-perfusion mismatching due to respiratory distress syndrome, congenital or acquired airway obstruction, pneumothorax, and hypoventilation. (See "Overview of neonatal respiratory distress: Disorders of transition".)

Abnormal forms of hemoglobin (eg, methemoglobin) can result in cyanosis, and polycythemic infants may appear cyanotic even if they are adequately oxygenated. (See "Genetic disorders of hemoglobin oxygen affinity" and "Neonatal polycythemia".)

Poor peripheral perfusion with cyanosis may result from sepsis, hypoglycemia, dehydration, and hypoadrenalism.

Right-to-left shunting through the ductus arteriosus, resulting in differences in oxygen saturation measured in the arm (preductal) and leg (postductal), can occur with primary or persistent pulmonary hypertension [71]. (See "Persistent pulmonary hypertension of the newborn".)

Acrocyanosis refers to bluish color in the hands and feet and around the mouth (circumoral cyanosis). The mucus membranes generally remain pink. Acrocyanosis usually reflects benign vasomotor changes in the diffuse venous structures in the affected areas. It does not indicate pathology unless cardiac output is extremely low, resulting in cutaneous vasoconstriction [32].

Hyperoxia test — The hyperoxia test is useful in distinguishing cardiac from noncardiac causes of cyanosis, especially pulmonary disease. In this test, arterial oxygen tension (PaO2) is measured in the right radial artery (preductal) and in a lower extremity artery (postductal) during the administration of room air and 100 percent oxygen. The relative changes in PaO2 are used to differentiate the various cardiac and noncardiac causes of neonatal cyanosis (table 1 and table 2). This test and its interpretation are discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Hyperoxia test'.)

Respiratory abnormalities — Respiratory abnormalities may be a sign of CHD that must be distinguished from those due to pulmonary disease. Persistently elevated respiratory rate (normal is 45 to 60 breaths per minute), increased respiratory effort at rest, or distress during feeding merit further investigation including chest radiograph, hyperoxia test, and referral to a pediatric cardiologist for echocardiography. (See "Overview of neonatal respiratory distress: Disorders of transition", section on 'Diagnosis'.)

Tachypnea — Cardiac neonatal tachypnea may reflect increased pulmonary venous pressure or volume secondary to a large left-to-right shunt, pulmonary venous obstruction, or increased left ventricular end-diastolic pressure [32]. Tachypnea in heart failure is also thought to have a neurohormonal basis.

Infants with CHD and mild to moderate pulmonary over-circulation frequently have tachypnea without significant increased work of breathing at rest, sometimes referred to as "happy" tachypnea. Infants may become more dyspneic with increasing pulmonary edema or during feeding, and exhibit grunting, nasal flaring, retractions, and head bobbing.

Coughing and wheezing — Cough and wheeze are more likely to be of pulmonary etiology, but they can occur with cardiac malformations. As an example, a tight vascular ring can compress the trachea, leading to wheezing, coughing, or stridor [72,73]. Lesions that cause elevated pulmonary venous pressure result in bronchial edema and bronchial compression by a distended left atrium and tense left pulmonary artery [32,72,74]. These include large left-to-right shunts, mitral stenosis, left ventricular dysfunction (eg, from myocarditis), or pulmonary venous obstruction [32,72,74,75].

Extracardiac abnormalities — Extracardiac abnormalities are frequently detected in children with CHD. Skeletal abnormalities, especially those of the hand and arm, are often associated with cardiac malformations. CHD may be a component of many specific syndromes and chromosomal disorders [76]. In a review of the population-based surveillance data from the Metropolitan Atlanta Congenital Defects Program, 12.3 percent of infants with CHD had a chromosomal abnormality [77]. Infants with conditions listed in the linked table should be evaluated for possible cardiac abnormalities (table 3).

The frequency of extracardiac abnormalities was demonstrated in a retrospective study of 1058 children with CHD evaluated during a 10-year period at a tertiary center in Belgium [78]. About 20 percent of patients (n = 224) had noncardiac abnormalities. Eleven percent (n =118) had an identifiable syndrome or chromosomal disorder. In the previously mentioned Danish population-based study, chromosomal defects were detected in 7 percent of patients with CHD, and extracardiac anomalies in 22 percent [17].

Pulse oximetry screening — Data have shown that universal neonatal screening with pulse oximetry improves the identification of patients with critical CHD compared with physical examination alone [29,79-84].

This was illustrated in a large Swedish study that showed universal pulse oximetry screening was better at detecting infants with mild oxygen desaturation and those with critical CHD compared with physical examination alone [29]. In this cohort, 6 of 16 infants with a SpO2 (hemoglobin saturation) between 90 and 95 percent not detected by physical examination by the pediatrician were identified by pulse oximetry. There was also a lower rate of missed diagnoses of critical CHD for infants in the region that screened with universal pulse oximetry compared with infants born in regions of the country where universal screening with pulse oximetry was not performed (8 versus 28 percent). In addition, no infant died from a ductal-dependent lesion in the region utilizing routine pulse oximetry versus five deaths from regions without routine oximetry.

In a 2012 meta-analysis of 13 studies with data for 229,421 newborn infants, the overall sensitivity of pulse oximetry for detection of critical CHD was 76.5 percent (95% CI 67.7-83.5) and specificity was 99.9 percent (95% CI 99.7-99.9) [82]. All the studies in the analysis used a cutoff SpO2 threshold of <95 percent. The overall false-positive rate was 0.14 percent (95% CI 0.06-0.33).

In a large multicenter prospective Chinese study of 122,738 newborn infants born between 2011 and 2012, the sensitivity of detecting critical CHD was greatest using the combination of pulse oximetry plus clinical assessment (93 percent) compared with either pulse oximetry alone (84 percent) or clinical assessment alone (77 percent) [85]. In this cohort, the false positive rate for pulse oximetry alone was 0.3 percent (394 of 120,561 patients).

The following factors affect the sensitivity and specificity of pulse oximetry screening for critical CHD [86]. These factors may be more prevalent in a nonstudy setting, which may increase the false-positive rate and negatively impact the cost-benefit of pulse oximetry screening.

Criteria used for an abnormal test – The choice of the SpO2 cutoff threshold directly affects the sensitivity and specificity of oximetry screening in detecting critical CHD [71,87]. As the SpO2 threshold is decreased, the sensitivity of oximetry decreases and the specificity increases. As an example, in one study measuring the postductal SpO2 at 24 hours of age or discharge, the sensitivity and specificity were 0.75 and 0.88, respectively, using a SpO2 threshold of <95 percent. The sensitivity decreased to 0.53 while specificity increased to 1 when the SpO2 was lowered to <90 percent [71]. This higher specificity for the lower SpO2 threshold decreased the number of false-positives and thus reduced costs by avoiding unnecessary transfers, echocardiograms, and pediatric cardiology consultations. However, this comes at the costs of a lower sensitivity and potentially missing critical CHD.

Of note, although there may be a false-positive test for CHD, the lower pulse oximetry reading may be related to a true positive for other hypoxic diseases, some of which may require clinical intervention. In one of the previously large prospective multicenter studies, there were 169 false-positive cases (0.8 percent of the cohort), of which 40 patients had significant illness that required urgent medical intervention [81].

A cutoff SpO2 <95 percent is generally used as it provides a sensitivity around 75 percent and specificity of 90 percent or greater [82]. Data in mechanically ventilated children have shown that pulse oximetry overestimates SaO2 (arterial oxygen tension based on arterial blood gas measurement), especially in hypoxemic children with SaO2 below 90 percent [88]. However, this is less of a concern clinically with the current threshold for a positive screening test that is a SpO2 <95 percent.

Pulse oximetry fails to identify some patients with left-sided obstructive lesions with a patent ductus arteriosus, and will not detect noncyanotic congenital heart lesions, such as ventricular septal defect. (See 'Ductal-dependent lesions, delayed diagnosis, and death' above.)

Timing of screening – The first hour of life is not suitable for screening because there are a large number of false-positives as the infant transitions from intrauterine to extrauterine life [87,89,90]. In addition, although first day screening detects CHD earliest, it is also not as specific as later screening because other conditions, such as transient tachypnea of the newborn, result in a low SpO2 [87,91]. In the previously mentioned 2012 meta-analysis, the false-positive rate was higher in the six studies in which pulse oximetry was performed before 24 hours after delivery (0.5 percent, 95% CI 0.29-0.86) compared with the rate observed in studies that tested after 24 hours of life (0.05 percent, 95% CI, 0.02-0.12) [82]. In contrast, sensitivity rate was not affected by the timing of the pulse oximetry test (ie, pre or post 24 hours of life).

Signal quality and infant behavior – Measurements should not be performed when the infant is crying or moving because it reduces the quality of the signal and the accuracy of the test [87,92]. Oximetry testing also may miss hypoxia because of interference from ambient light, partial probe detachment, electromagnetic interference, poor perfusion at the site of measurement, and the presence of dyshemoglobinemias [93].

Healthcare workers expertise – Training of healthcare personnel in the proper duration and techniques of measurement improves the reliability and accuracy of measurements [94].

Probe placement – Postductal probe placement is optimal because defects with right-to-left shunting of desaturated blood through the ductus arteriosus will not be detected with only preductal placement. In the 2012 meta-analysis, postductal measurements were performed in all studies [82]. There was no difference in false-positive rates in the studies (40 percent) that also included preductal measurements.

US Health and Human Services report — In 2011, a report from the United States Health and Human Services Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children recommended routine pulse oximetry newborn screening to detect infants with critical CHD [95]. Newborn screening is specifically directed towards identifying seven specific lesions:

Hypoplastic left heart syndrome (HLHS)

Pulmonary atresia (PA)

Tetralogy of Fallot (TOF)

Total anomalous pulmonary venous return (TAPVR)

Transposition of the great arteries (TGA)

Tricuspid atresia (TA)

Truncus arteriosus (TAC)

AAP, AHA, and ACCF screening approach — The AAP, AHA, and ACCF endorse the following strategy of universal newborn screening based on a review of the available literature that included the previously discussed prospective studies [27,29,79-81]:

Timing − Screening should not be performed until after 24 hours of life or as late as possible if early discharge is planned.

Instrumentation − The screening should be performed using a motion-tolerant pulse oximeter. Either disposable or reusable probes can be used. Reusable probes reduce the cost of screening, but must be appropriately cleaned to minimize the risk of infection.

Probe placement − Screening is recommended in the right hand (preductal) and either foot (postductal). Screening at both locations can occur simultaneously or in direct sequence.

Personnel − Screening is performed by qualified and trained personnel.

Criteria for positive screen − A positive screening test includes fulfilling one of the following three criterion:

SpO2 measurement <90 percent

SpO2 measurement <95 percent in both upper and lower extremities on three measurements, each separated by one hour

SpO2 difference >3 percent between the upper and lower extremities

Altitude − The pulse oximetry screening guidelines recommended by the American Academy of Pediatrics are feasible up to an elevation of 2643 ft (806 m) without any needed adjustments [96] because infants born at mild altitude (2660 feet [780 m]) do not appear to have a higher false-positive rate compared with those born at sea level [97].

However, criteria have not been validated for newborns cared for at centers at altitudes greater than 2660 feet (780 m). A subsequent study published after the AAP, AHA, and ACCF review reported that neonates born at ≥35 weeks gestation screened at a moderate altitude (5560 feet [1694 m]) had a higher pulse oximetry screening failure rate compared with reported rates of infants screened at sea level (1.1 versus 0.2 percent) when using the guidelines established by studies at sea level [98]. These results demonstrate that further research is needed to determine the parameters of a positive screening test in neonates screened at moderate to high altitudes.

In hospital evaluation − Each birthing institution should establish a protocol to ensure a timely evaluation for newborns with a positive screening test. Assessment includes the performance of high-quality echocardiography and interpretation by a clinician with expertise in the diagnosis of CHD. Patients should have access to these diagnostic services at the center, via telemedicine, or via short-distance transport.

Outpatient follow-up − At the first outpatient visit, primary care providers should ascertain whether screening was performed during the birth hospitalization, and if not, develop strategies for appropriate screening.

Cost-benefit — The cost of a universal pulse oximetry screening program includes the direct costs of pulse oximetry (equipment, training of personnel, staff time required for screening), and the follow-up costs of further evaluation and possible transfer of patients who fail the initial screening oximetry test [95]. The cost and quality of follow-up vary depending on the accessibility and cost of pediatric cardiac subspecialty care and the need for transfer. In the United States, the additional cost for pulse oximetry universal screening has been estimated to be around five to six dollars per newborn [99,100].

One population-based observational study from Florida, which identified 3603 infants with critical CHD due to 12 targeted defects from the state Birth Defects Registry, reported that about one-quarter of these patients were not diagnosed during the birth hospitalization [101]. In this group of late detected critical CHD (n = 825), 15 deaths were deemed to be potentially preventable (1.8 percent). In addition, adjusted multivariable analysis showed that infants with late detected critical CHD had a greater number of admissions, more hospitalized days, and higher inpatient costs. The authors suggest that screening may lead to decreased hospital costs and avoid preventable deaths, but future prospective studies are needed to determine if pulse oximetry is cost-effective and reduces mortality.

However, as noted above, pulse oximetry fails to identify some patients with left obstructive lesions and will not detect noncyanotic congenital heart lesions, such as ventricular septal defect. As a result, both care providers and parents must be educated about the limitations of the screening test, and be aware that a negative result does not exclude the possibility of CHD.

Finally, universal pulse oximetry screening has an additional benefit of identifying noncardiac disorders in term infants that also present with low oxygen saturation [83,102]. These include pneumonia, sepsis, pulmonary hypertension of the newborn, meconium aspiration syndrome, pneumothorax, and hemoglobinopathies with low oxygen affinity.

Implementation status in the United States — There are an increasing number of states in the United States that require mandatory newborn pulse oximetry screening to detect critical CHD. A map from the Centers of Disease Control (CDC) provides a legislation update on newborn pulse oximetry screening for each state (http://cchdscreeningmap.org).

Institutional- and regional-based strategy must be developed to provide the necessary organization and funding to establish standardized and validated screening programs at each regional birthing center, and the essential diagnostic services infrastructure to ensure timely and high-quality cardiac evaluation for all newborns with a positive screening test [95].

In 2012, an expert panel developed the following consensus recommendations for implementation of newborn pulse oximetry screening [103]:

Selection of screening equipment, which should be approved for hospital use in neonates by the Food and Drug Administration (FDA), be tolerant of motion, use a neonatal sensor, and not require a fixation method. Of note, the FDA has not tested the performance of oximeters in critical CHD screening protocols.

Establishment of reporting standards for each birth facility and state public health monitoring. This includes patient demographic information, results of oximetry screening, type of protocol and oximeter used, and the requirements for reporting by birth facilities to public health programs.

Training of healthcare providers and education of families – Development of educational material for both staff and families.

Ongoing assessment of the outcome of screening, particularly in the context of other screening efforts (eg, fetal ultrasound), noncardiac conditions, the quality of the equipment, cost of screening including educational efforts, and reimbursement.

A statewide screening program in all of New Jersey’s birthing facilities was successfully implemented with the screening of 99 percent of all eligible 75,324 infants born between August 31, 2011 through May 31, 2012 [104]. Other findings included:

Of the 49 infants who failed pulse oximetry screening, 30 had diagnostic evaluation solely based on a failed screening result. Three of the 30 infants were diagnosed with previously unsuspected critical CHD that included d-TGA, TA, and aortic coarctation with aortic arch hypoplasia. Overall the false-positive rate was 0.04 percent with 17 patients diagnosed with other conditions including culture-negative sepsis, noncritical CHD (eg, ventricular septal defect), pneumonia, and pulmonary hypertension; the remaining 10 patients had no identified abnormality.

Nineteen patients who failed pulse oximetry screening had clinical indicators that would have resulted in diagnostic evaluation including four with critical CHD (TGA, HLHS, TAPVC, and interrupted aortic arch). Of the remaining 15 patients, 13 had other cardiac or noncardiac conditions (eg, pneumothorax), and in two patients, no diagnosis was made.

Forty-nine infants were diagnosed with critical CHD without a reported failed oximetry screening test. In review of these patients, some patients had prenatal diagnosis, were transferred out of the birthing hospital within the first day of life, had clinical monitoring in the neonatal intensive care unit, or passed oximetry screening.

In a cross-sectional survey of birth centers in Minnesota, two-thirds of newborns are born in centers that have the necessary resources for screening, initial diagnosis, and management of critical CHD [99]. This study identified potential problems with universal implementation including the need to simplify the clinical algorithm used, additional training for healthcare providers, and development of a centralized reporting mechanism.

LATER PRESENTATION — As noted above, some newborns who have critical CHD but are asymptomatic at the time of hospital discharge will develop signs and symptoms of cardiac disease, often by two weeks of age [23,28,56]. Thus, clinicians should be alert to clinical manifestations of CHD that may be detected in the course of initial routine visits.

In the previously discussed California population study, the diagnoses of critical CHD most commonly missed after discharge that resulted in death were hypoplastic left heart syndrome, coarctation of the aorta, and tetralogy of Fallot [23]. The median age of death in these infants occurred before two weeks of age. It is unclear whether these infants might have been identified with a careful cardiovascular evaluation for left heart obstructive CHD during the first postdischarge visit at the pediatrician's office at three to five days of age, which would have allowed for life-saving palliative or corrective intervention. (See 'Routine examination' below.)

Clinical manifestations — In affected newborn infants, parents most commonly notice difficulty with feeding. This may be manifested by intake of a limited volume of milk, or feedings that are taking too long or are frequently interrupted by sleeping or resting, choking, gagging, and/or vomiting. Infants may have respiratory distress that is reported by parents as fast or hard breathing, worse with feedings, or a persistent cough or wheeze.

Other manifestations include:

Color changes, such as central cyanosis or persistent pallor

Excessive, unexplained irritability

Excessive sweating that is increased with feeding and may occur during sleep

Poor weight gain

Decreased activity or excessive sleeping

Delay in motor milestones [105]

Routine examination — The routine examination should include careful cardiac auscultation and assessment of peripheral pulses.

Murmurs detected for the first time in a routine examination at six weeks of age can lead to the detection of CHD. In one report, 47 of 5395 babies (0.9 percent) had heart murmurs at six weeks [6]. Of these, 11 of the 25 referred for echocardiographic evaluation had CHD. Ventricular septal defect was the most common lesion. CHD was later diagnosed in six other infants before 12 months of age from the initial cohort who did not have a documented murmur at the six week check-up. (See "Pathophysiology and clinical features of isolated ventricular septal defects in infants and children", section on 'Cardiac examination'.)

Diminished and absent peripheral pulses are findings consistent with the diagnosis of coarctation of the aorta (COA), which is frequently delayed. In the regional study from the United Kingdom of all infants with CHD diagnosed before 12 months of age, 27 and 20 percent of infants with coarctation remained undiagnosed by six weeks and three months, respectively [28]. In a retrospective review of patients older than one year who had repair of COA, pulses were decreased but not absent in the majority of patients [69]. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Manifestations according to age'.)

SUMMARY AND RECOMMENDATIONS — Congenital heart disease (CHD) is the most common congenital disorder in newborns.

Critical CHD, defined as lesions requiring surgery or catheter based intervention in the first year of life, occurs in approximately 25 percent of neonates with CHD and is one of the leading causes of infant mortality. The risk of morbidity and mortality increases when there is a delay in diagnosis and treatment. (See 'Critical CHD' above.)

Urgent consultation/referral to a pediatric cardiologist should be made when severe, potentially lethal, CHD is suspected in critically ill neonates who present with shock, cyanosis, or pulmonary edema. In patients with ductal-dependent cardiac lesions and profound cyanosis, we recommend prostaglandin E1 (alprostadil) infusion to re-open or maintain patency of the ductus arteriosus (Grade 1A). (See 'Early serious or life-threatening presentation' above and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)

Other infants, especially those with ductal-dependent lesion, may appear normal with either no or very subtle signs and symptoms during the birth hospitalization. As a result, the diagnosis of critical CHD may be missed prior to discharge. In these infants, closure of the ductus arteriosus may precipitate rapid clinical deterioration that may be life-threatening. (See 'Ductal-dependent lesions, delayed diagnosis, and death' above and 'Few or no symptoms during birth hospitalization' above.)

Early detection of neonatal CHD remains challenging because clinical findings may be subtle or absent immediately after birth, and prenatal screening does not reliably detect all cases of CHD. (See 'Few or no symptoms during birth hospitalization' above.)

The risk of CHD is increased in infants who have a positive history of maternal medical conditions or prenatal disorders associated with CHD, or a positive family history. If present, these factors should increase the awareness of the clinician for the possibility of CHD in the newborn infant. (See 'History' above.)

Physical findings associated with CHD include abnormal cardiovascular examination (ie, abnormal heart rate, precordial activity, and heart sounds; pathologic murmurs; and diminished/absent peripheral pulses), presence of cyanosis, respiratory symptoms, and noncardiac anomalies. (See 'Physical examination' above.)

In a cyanotic neonate, hyperoxia test can be used to differentiate between cardiac and respiratory etiologies. (See 'Hyperoxia test' above.)

Routine pulse oximetry is an effective screening test to detect critical CHD. The United States Health and Human Services Secretary’s Advisory Committee on Heritable Disorder and several American medical societies have endorsed the use of a pulse oximetry as a universal screening test for critical CHD. Although there are challenges in implementing a successful pulse oximetry screening program including training personnel to ensure reliable and accurate universal screening and establishing services that can accurately diagnosis critical CHD in a timely manner in patients with a positive screening test, successful implementation of pulse oximetry programs has been achieved. (See 'Pulse oximetry screening' above.)

Because the diagnosis of critical CHD may be missed during the birth hospitalization, clinicians should be aware and look for clinical manifestations of CHD during the first discharge visit at three to five days of age. Symptoms are nonspecific and include difficulty in feeding, poor weight gain, cyanosis, respiratory findings, decreased activity, irritability, and excessive sweating. The routine examination should include careful auscultation to detect a cardiac murmur and assessment of lower extremity pulses. (See 'Later presentation' above.)

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