●   INCIDENCE OF CONGENITAL HEART DISEASE

Congenital heart diseases (CHDs) are the most common severe congenital abnormalities (1). Half of the CHD cases are, however, minor and are easily corrected by surgery, the remainder accounting for over half of the deaths from congenital abnormalities in childhood (1). Moreover, CHD results in the most costly hospital admissions for birth defects in the United States (2). The incidence of CHD is dependent on the age at which the population is initially examined and the definition of CHD used. Inclusion of a large number of premature neonates in a study may increase the incidence of CHD. Both patent ductus arteriosus and ventricular septal defects are common in premature infants. An incidence of 8 to 9 per 1,000 live births has been reported in large population studies (1). Of all cases of CHD, 46% are diagnosed by the first week of life, 88% by the first year of life, and 98% by the fourth year of life (1). The incidence of CHD is also influenced by the inclusion of bicuspid aortic valve, the incidence of which is estimated at 10 to 20 per 1,000 live births (3). Bicuspid aortic valve may be associated with considerable morbidity and mortality in affected persons (3). Furthermore, accounting for subtle anomalies such as persistent left superior vena cava (5–10 per 1,000 live births) and isolated aneurysm of the atrial septum (5–10 per 1,000 live births) results in an overall incidence of CHD approaching 50 per 1,000 live births (4). CHD remains the most common severe abnormality in the newborn; its prenatal diagnosis allows for better pregnancy counseling and improved neonatal outcome. Table 1.1 lists the incidence of CHD by various subtypes (5). Several risk factors for CHD have been identified, including fetal and maternal risk factors, which are discussed in detail in the following sections.

●   FETAL RISK FACTORS

Extracardiac Anatomic Abnormalities

The presence of extracardiac abnormalities in a fetus is frequently associated with CHD and is thus an indication for fetal echocardiography. The risk of CHD with fetal extracardiac abnormalities is increased even in the presence of normal karyotype (6). The risk of CHD is dependent on the specific type of fetal malformation. Abnormalities detected in more than one organ system increase the risk of CHD and also of concomitant chromosomal abnormalities (7). Nonimmune hydrops in the fetus is frequently associated with CHD. Incidence of abnormal cardiac anatomy is reported in about 10% to 20% of fetuses with nonimmune hydrops (8, 9). Table 1.2 lists associated extracardiac anomalies detected in fetuses with fetal cardiac anomalies (7).

VSD, ventricular septal defect; PDA, patent ductus arteriosus; ASD, atrial septal defect; AVSD, atrioventricular septal defect; PS, pulmonary stenosis; AS, aortic stenosis; CoA, coarctation of the aorta; TOF, tetralogy of Fallot; D-TGA, complete transposition of the great arteries; HRH, hypoplastic right heart; HLH, hypoplastic left heart; DORV, double outlet right ventricle; SV, single ventricle; TAPVC, total anomalous pulmonary venous connection.

Modified from Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890–1900, with permission.

Modified from Song MS, Hu A, Dyamenahalli U, et al. Extracardiac lesions and chromosomal abnormalities associated with major fetal heart defects: comparison of intrauterine, postnatal and postmortem diagnoses. Ultrasound Obstet Gynecol. 2009;33:552–559, with permission.

Fetal Cardiac Arrhythmia

The presence of fetal cardiac rhythm disturbances may be associated with an underlying structural heart disease. The association of CHD with fetal arrhythmia is dependent on the type of cardiac rhythm disturbances. Overall, about 1% of fetal cardiac arrhythmias are associated with CHD (8). Fetal tachycardia and isolated extrasystoles are rarely associated with CHD. Complete heart block, on the other hand, resulting from abnormal atrioventricular (AV) node conduction, is associated with structural cardiac abnormalities in about 50% of fetuses, with the remaining pregnancies associated with the presence of maternal Sjögren antibodies (10, 11). A fetal echocardiogram should be performed in all fetuses with suspected or confirmed arrhythmias to assess cardiac structure and function. This includes fetuses with irregular fetal rhythm, such as that caused by frequent extrasystoles, as this may be the harbinger of more malignant arrhythmias if it is persistent (12). In fetuses with less frequent extrasystoles, a fetal echocardiogram is reasonable to perform, especially if the ectopic beats persist beyond 1 to 2 weeks (13). Diagnosis and management of fetal cardiac rhythm disturbances are discussed in detail in Chapter 33.

Suspected Cardiac Anomaly on Routine Ultrasound

A risk factor with one of the highest yields for CHD is the suspicion for the presence of a cardiac abnormality during routine ultrasound scanning. Fetal echocardiogram should therefore be performed in all fetuses with a suspected cardiac abnormality noted on obstetric ultrasound. CHD is confirmed in about 40% to 50% of pregnancies referred with this finding (8, 9). In view of this, and the fact that most infants born with CHD are born to pregnancies without risk factors, ultrasound evaluation of the fetal heart should not be limited to pregnant mothers with known risk factors. Indeed, recent guidelines of cardiac screening have been expanded to include evaluation of the great vessels (14–16). The value of routine ultrasound in the screening for CHD is discussed in Chapter 2.

Known or Suspected Chromosomal or Genetic Abnormality

The presence of a fetal genetic or chromosomal abnormality is associated with a high risk of cardiac and extracardiac defects and thus a fetal echocardiogram should be performed. Please refer to Chapter 4 for a more comprehensive discussion on this topic.

Thickened Nuchal Translucency

Measurement of fetal nuchal translucency (NT) thickness in the late first and early second trimesters of pregnancy is currently established as an effective method for individual risk assessment of fetal chromosomal abnormalities. Several reports have noted an association between increased NT and genetic syndromes and major fetal malformations, including cardiac defects (17–19). The prevalence of major cardiac defects increases exponentially with fetal NT thickness, without an obvious predilection to a specific type of CHD (18). An NT thickness of greater than or equal to 3.5 mm in a chromosomally normal fetus has been correlated with a prevalence of CHD of 23 per 1,000 pregnancies, a rate that is higher than pregnancies with a family history of CHD (17, 20). In this setting of an NT that is greater than or equal to 3.5 mm, referral for fetal echocardiography is thus warranted. Finding an NT thickness of greater than or equal to 3.5 mm may lead to an earlier diagnosis of all major types of CHD (21). Chapter 16 provides a more detailed discussion on the ultrasound examination of the fetal heart in early gestation.

Monochorionic Placentation

The incidence of CHD in fetuses of monochorionic placentation is higher (22, 23) and is estimated at 2% to 9% (22, 24, 25). Twin–twin transfusion syndrome (TTTS), a complication of monochorionic twin placentation, has been reported to occur in about 10% of cases. TTTS has been associated with acquired cardiac abnormalities, including right ventricular outflow tract obstruction, which occurs in about 10% of recipient twin fetuses (26). The increased risk of CHD in fetuses of monochorionic placentation is noted even after excluding cardiac effects of TTTS (23). In a cohort study of 165 sets of monochorionic twins, the overall risk of at least one of a twin pair having a structural CHD was 9.1% (23). This risk was 7% for monochorionic–diamniotic twins and 57.1% for at least one twin member of monochorionic– monoamniotic twins (23). If one twin member is affected, the risk that the other twin member is also affected is 26.7% (23). A systemic literature review of 830 fetuses from monochorionic–diamniotic twin pregnancies confirmed an increased risk of CHD independent of TTTS (22). Ventricular septal defects were the most common type of CHD in non-TTTS fetuses, and pulmonary stenosis and atrial septal defects were significantly more prevalent in fetuses of pregnancies complicated with TTTS (22). Fetal echocardiogram is therefore recommended in all monochorionic twin gestations.

●   MATERNAL RISK FACTORS

Maternal Metabolic Disease

Maternal metabolic disorders, primarily including pregestational diabetes mellitus and phenylketonuria, have a significant effect on the incidence of CHD. In the presence of maternal metabolic disease, preconception counseling and tight metabolic control immediately prior to and during organogenesis are recommended in order to reduce the incidence of fetal CHD.

Diabetes Mellitus

The incidence of CHD is fivefold higher in infants of pregestational diabetic mothers than in controls, with a higher relative risk noted for specific cardiac defects, including 6.22 for heterotaxy, 4.72 for truncus arteriosus, 2.85 for transposition of the great arteries, and 18.24 for single-ventricle defects (27). Poor glycemic control in the first trimester of gestation, as evidenced by an elevated glycohemoglobin level (HbA_1c), has been strongly correlated with an increased risk of structural defects in infants of diabetic mothers (28, 29). Although some studies have identified a level of glycohemoglobin above which the risk of fetal structural abnormalities is increased (28), other studies have failed to identify a critical level of glycohemoglobin that provides an optimal predictive power for CHD screening (30). Therefore, it appears that although the risk may be highest in those with increased HbA_1c levels (>8.5%), all pregnancies of pregestational diabetic women are at some increased risk. Given this information, a fetal echocardiogram should be performed in all women with pregestational diabetes mellitus. Gestational diabetes, which is diagnosed beyond the first trimester of pregnancy, does not increase the risk of CHD in the fetus, and thus a fetal echocardiogram is not indicated for these pregnancies. Fetal ventricular hypertrophy in late gestation (third trimester) is a complication of poor glycemic control in pregestational and gestational diabetic pregnancies, and the degree of hypertrophy is related to the level of glycemic control. Fetal echocardiogram in the third trimester to assess for ventricular hypertrophy is thus recommended for pregestational and gestational diabetic pregnancies if the HbA_1c is greater than 6% in the second trimester (31).

Phenylketonuria

Another metabolic disorder that is associated with CHD is phenylketonuria. Women with phenylketonuria should be aware of the association of fetal CHD with elevated maternal phenylalanine levels (32). This is particularly important as phenylketonurics usually follow unrestricted dietary regimens in adulthood. Fetal exposure during organogenesis to maternal phenylalanine levels exceeding 15 mg/dL is associated with a 10- to 15-fold increase in CHD (33). Other fetal abnormalities in phenylketonurics include microcephaly and growth restriction (32). The risk of CHD in fetuses has been reported to be 12% if maternal dietary control is not achieved by 10 weeks of gestation (34). With maternal phenylalanine levels at <6 mg/dL before conception and during early organogenesis, the risk of CHD was noted to be no different from controls in a large prospective study (35). Unless you have evidence of strict dietary control in early gestation with a phenylalanine levels at <10 mg/dL, fetal echocardiogram is recommended in phenylketonurics (13).

Maternal Teratogen Exposure (Drug-Related Congenital Heart Disease)

The effects of maternal exposure to drugs during cardiogenesis have been widely studied. Numerous drugs have been implicated as cardiac teratogens. Evidence suggests that the overall contribution of teratogens to CHD is small (36). Available literature suggests that maternal use of lithium, anticonvulsants, ethanol, isotretinoin, indomethacin, angiotensin-converting enzyme (ACE) inhibitors, and selective serotonin reuptake inhibitors (SSRIs) may increase the risk of cardiovascular abnormalities in the newborn (Table 1.3).

ACE, angiotensin-converting enzyme; SSRIs, selective serotonin reuptake inhibitors; PPHN, persistent pulmonary hypertension of the newborn.

Lithium

Initial retrospective reports regarding the teratogenic risk of lithium treatment in pregnancy showed a strong association between lithium use and Ebstein anomaly in the fetus (37). More recent controlled studies, however, have consistently reported a lower risk of CHD in exposed fetuses. Four case-control studies of Ebstein anomaly involving a total of 208 affected children found no association with maternal lithium intake in pregnancy (38–40). A cohort study on the effect of lithium exposure in pregnancy showed no significant risk to the fetus (41). These findings suggest that the teratogenic risk of lithium exposure is lower than previously reported, and that the risk–benefit ratio of prescribing lithium in pregnancy should be evaluated in light of this modified risk estimate. Fetal echocardiogram may be considered in pregnancies exposed to lithium during embryogenesis, although its usefulness has not been established given a very low likelihood of CHD.

Anticonvulsants

Anticonvulsants, a class of drugs that includes hydantoin/phenytoin, carbamazepine, trimethadione, and sodium valproate, are occasionally used in the treatment of epilepsy or pain management in pregnancy. An incidence of congenital defects varying from 2.2% to 26.1% has been noted in pregnancies exposed to phenytoin (42). Some evidence suggests that the teratogenic effect of phenytoin is related to elevated amniotic fluid oxidative metabolites secondary to low activity of the clearing enzyme epoxide hydrolase (43). A fetal hydantoin syndrome, consisting of variable degrees of hypoplasia and ossification of distal phalanges and craniofacial abnormalities, has been described (44). CHD is often observed in conjunction with this syndrome (45). Trimethadione, an anticonvulsant primarily used in the treatment of petit mal seizures, is associated with a high incidence of congenital defects. Defects include craniofacial deformities, growth abnormalities, mental retardation, limb abnormalities, and genitourinary abnormalities (45). Cardiac abnormalities are common, with septal defects occurring in about 20% of exposed fetuses (45). Sodium valproate has also been associated with congenital defects, with the most serious abnormality being neural tube defects (1%–2%) (45). Although some reports have suggested an increased risk of CHD in fetuses exposed to valproate (46), others could not establish a causal relationship (47). Carbamazepine has been associated with 1.8% risk of CHD when compared to controls (48). Fetal echocardiogram may be considered in pregnancies exposed to anticonvulsants in early gestation.

Alcohol

The fetal alcohol syndrome, consisting of facial abnormalities, growth restriction, mental retardation, and cardiac abnormalities, has been well described in women consuming heavy amounts of alcohol in pregnancy (49). Cardioteratogenic effects of ethanol in the chick embryo have been confirmed in concentrations comparable to human blood alcohol levels (50). CHD has been identified in 25% to 30% of infants with fetal alcohol syndrome, with septal defects representing the most common lesions (49, 51). Fetal echocardiogram is recommended for pregnancy exposure to alcohol in early gestation.

Retinoic Acid

Retinoic acid is a vitamin A derivative prescribed for the treatment of severe cystic acne. Since its introduction, several reports have appeared in the literature describing the teratogenic effect of this medication. A characteristic pattern of malformations is observed, which includes central nervous system, craniofacial, branchial arch, and cardiovascular abnormalities (52). Cardiac abnormalities are usually conotruncal defects and aortic arch abnormalities (45, 53). The mechanism of teratogenicity is probably related to free radical generation by metabolism with prostaglandin synthase (54). Fetal echocardiogram is recommended for exposure to retinoic acid in pregnancy.

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of preterm labor or in pain control in pregnancy. Indomethacin is an NSAID that is commonly used for tocolysis in the second and third trimesters of pregnancy. In the fetus, indomethacin therapy may lead to premature constriction of the ductus arteriosus (see Chapter 24 for details). Doppler evidence of ductal constriction is evident in up to 50% of fetuses exposed to indomethacin in the late second and third trimesters of pregnancy (55, 56). Typically, the ductal constriction is mild and resolves with drug discontinuation. Ductal constriction may also occur with the use of other NSAIDs (57). Several neonatal complications, which appear to be limited to indomethacin exposure beyond 32 weeks of gestation, include oliguria, necrotizing enterocolitis, and intracranial hemorrhage (58). Fetal echocardiogram is recommended with NSAID use in the late second or third trimester.

Angiotensin-Converting Enzyme Inhibitors

ACE inhibitors are commonly used antihypertensive medications. Fetal exposure to ACE inhibitors in the first trimester of pregnancy has been associated with an increased risk of major congenital malformation that was 2.7 times greater than the background risk or the risk of fetuses exposed to other antihypertensive medications (59). The increase in major malformations primarily affects the cardiovascular (risk ratio, 3.72) and central nervous systems (risk ratio, 4.39) (59). Atrial and ventricular septal defects represent the most common cardiac abnormalities (59). Fetal exposure to ACE inhibitors in the second and third trimesters of pregnancy is associated with “ACE inhibitor fetopathy,” which includes oligohydramnios, intrauterine growth restriction, hypocalvaria, renal failure, and death (60). Fetal echocardiogram is recommended for pregnancies exposed to ACE inhibitors.

Selective Serotonin Reuptake Inhibitors

SSRIs represent a class of antidepressants that has gained wide acceptance for the treatment of depression and anxiety during pregnancy (61). Specific SSRI medications include citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). Pregnancies exposed to SSRIs in the first trimester have shown an increased risk of congenital heart defects in some studies (62–64). Paroxetine has been singled out as the SSRI with the greatest association with congenital heart malformations, primarily atrial and ventricular septal defects (64). A meta-analysis of seven studies noted a significant overall increased risk of 74% for cardiac malformations in women exposed to paroxetine in the first trimester of pregnancy (65). Recent large population studies have provided conflicting information with regards to the association of SSRI with CHD. A cohort study of 72,280 pregnancies, reviewed with high case ascertainment from the Danish administrative register data for the period 1995 to 2008, has shown that maternal use of SSRIs during the first trimester is associated with a fourfold increase in the risk of severe CHD (66). This study did not support an increased risk of septal defects, however, as has been shown before (66). In a population-based cohort study in Quebec, from 1998 to 2010 and involving 18,493 pregnancies, sertraline use during the first trimester of pregnancy was associated with an increased risk of atrial/ventricular defects (RR, 1.34; 95% CI, 1.02–1.76) and craniosynostosis (RR, 2.03; 95% CI, 1.09–3.75) above and beyond the effect of maternal depression (67). Nonsertraline SSRIs were associated with an increased risk of craniosynostosis and musculoskeletal defects (67). The risk of major CHD among infants born to women who took antidepressants during the first trimester was compared to the risk among infants born to women who did not use antidepressants in a large cohort of 949,504 pregnant women from Medicaid data for the period of 2000 through 2007 (68). When the data were fully adjusted for confounding variables, no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester was noted. Furthermore, there was no significant association between the use of paroxetine and right ventricular outflow tract obstruction or between the use of sertraline and ventricular septal defects. Despite the large cohort size of these recent studies, conflicting evidence still exists with regards to the association of SSRIs use in pregnancies and CHD in infants.

SSRI exposure after the 20th week of gestation has been associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN) (69). PPHN occurs in 1 to 2 per 1,000 live births and is associated with increased morbidity and mortality. SSRI exposure increases this risk to about 6 to 12 per 1,000 neonates, a sixfold increase over the background risk (69). Possible mechanisms of action include an accumulation of serotonin in the lung in exposed fetuses (70). Serotonin has vasoconstrictor properties and a mitogenic effect on pulmonary smooth muscle cells, which may result in the proliferation of smooth muscle cells, the characteristic histologic pattern in PPHN (71, 72). In general, in women suffering from major depression and responding to a pharmacologic treatment, introduction or continuation of an SSRI should be encouraged in order to prevent maternal complications and to preserve maternal–infant bonding (73). Overall, it should be recognized that the specific defects implicated are rare and the absolute risks are small (74, 75). Despite the controversial data, performing a fetal echocardiogram on pregnant women exposed to SSRI is currently reasonable.

Pregnancies of Assisted Reproductive Technology

Infants born to pregnancies of assisted reproductive technology are more likely to be born preterm, of low birth weight, and small for gestational age (76). This increased neonatal morbidity applies to multiple and singleton births (77). The evidence relating to the risk of birth defects is somewhat less clear. A report of systematically reviewed and pooled epidemiologic data assessing the risk of birth defects suggests a 30% to 40% increase following assisted reproductive technologies (in vitro fertilization [IVF] and/or intracytoplasmic sperm injection [ICSI]) (78). Another population-based study on congenital malformations in children born after IVF with matched controls noted a fourfold increase in CHD in the IVF population, with the majority of cardiac anomalies representing atrial and ventricular septal defects (79). This same rate of fourfold increase in CHD was also noted in pregnancies conceived through ICSI (80). Fetal echocardiogram is reasonable to perform in pregnancies of assisted reproductive technologies.

Maternal Obesity

The prevalence of obesity, which is defined as a body mass index (BMI) greater than or equal to 30 kg/m², is increasing at an exponential rate. An established association between neural tube defects and pre-pregnancy maternal obesity exists (38). Several studies have noted an increased risk of congenital heart defects in obese pregnant mothers when compared with average-weight mothers (81, 82). This increased risk is relatively small: 1.18-fold for the obese mother and 1.40-fold for the morbidly obese mother (BMI, >35 kg/m²). Atrial and ventricular septal defects contribute to the majority of this increased risk (82). Given the small increased risk, performing detailed cardiac screening rather than fetal echocardiogram is considered reasonable.

Familial Cardiac Disease

The risk of recurrence of CHD is increased in the presence of nonsyndromic or nonchromosomal CHD in the family. It is twofold higher if the mother is affected versus a sibling or the father (83, 84). For the majority of maternal CHD, the risk of recurrence is in the range of 3% to 7%; for an affected sibling, the risk of recurrence is at 2% to 6%; and for paternal CHD, the risk of recurrence is at 2% to 3% (85–87). There is an increased risk, however, with some specific cardiac malformations such as aortic stenosis or atrioventricular septal defect (83, 87). Overall, the risk of recurrence is low with isolated CHD in second- or third-degree relatives. The genetic aspect of CHD is discussed in more detail in Chapter 4. Fetal echocardiogram is indicated in the presence of CHD in the immediate family.

●   INDICATIONS FOR FETAL ECHOCARDIOGRAM

Indications for fetal echocardiogram are based on identified maternal and fetal risk factors as discussed in this chapter. Guidelines for the performance of the fetal echocardiogram and expert opinion have listed fetal and maternal indications for the fetal echocardiogram (Table 1.4) (13, 14). This allowed for uniformity in exam indications, and consistency in practice. It is of note that these indications change with the available evidence. Furthermore, as the majority of fetuses with CHD have no known risk factors (88), cardiac screening during the ultrasound examination is thus recommended. Chapter 2 presents a detailed overview on guidelines for cardiac screening and for the fetal echocardiogram examination.

●   PREVENTION OF CONGENITAL HEART DISEASE

Current evidence suggests that folic acid supplementation taken preconceptionally significantly reduces the risk of CHD (89–92). Analysis of a randomized controlled trial evaluating the efficacy of 0.8 mg of folic acid showed a 50% reduction in the risk of a range of cardiac malformations (89). Other studies have shown a significant reduction in conotruncal abnormalities in newborns of pregnant women who took folic acid prenatally (90, 91).

The mechanism of action of the folic acid effect on the reduction in the risk of cardiac malformations has not been elucidated. Methylenetetrahydrofolate reductase (MTHFR) enzyme activity may be involved in this process (93). An association exists between homocysteine elevations, MTHFR gene variants, and CHD (93–95). In a controlled study, fasting homocysteine levels have been shown to be higher in mothers of infants affected by CHD (89). Current data support folic acid as the active ingredient involved in fetal cardiac embryogenesis and that periconceptional folic acid use may reduce the risk of congenital cardiac malformations (96).

ACE, angiotensin-converting enzyme; CHD, congenital heart disease; NSAID, nonsteroidal anti-inflammatory drug; NIPT, noninvasive prenatal testing; SSRI, selective serotonin reuptake inhibitor.

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