Pediatr Cardiol 25:210–222, 2004 DOI: 10.1007/s00246-003-0587-z

Indications for Fetal Echocardiography M. Small, J.A. Copel Section on Maternal–Fetal Medicine, Department of Obstetrics & Gynecology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208063, New Haven, CT 06520-8063, USA

Abstract. Congenital heart disease is one of the most common congenital malformations diagnosed in liveborns. As more women undergo prenatal diagnosis, the need for screening fetal echocadiography increases. The fetal, maternal, and familial indications for fetal echocadiography are outlined in order to improve the identification of women in greatest need for this screening modality. Keywords: Fetal echocardiography — Prenatal diagnosis — Congenital heart defects — Diabetes mellitus — Congenital anomalies — Nuchal translucency Congenital heart disease (CHD) is present in 0.8% of all live births and therefore is one of the most common congenital malformations [35, 77]. The impact of this disease is further magnified by the fact that up to half of these malformations result in lethal conditions or require surgical intervention [77]. Advances in ultrasound imaging permit greater antenatal assessment and diagnosis of CHD. Prenatal diagnosis results in appropriate referral of affected fetuses to tertiary care institutions for neonatal management. The discovery of cardiac defects may prompt evaluation of the fetal karyotype or a more careful inspection for other abnormalities consistent with a genetic syndrome. Appropriate antenatal diagnosis may also result in fetal treatment (i.e., fetal arrhythmias). These findings, as with most antenatally detected congenital anomalies, can result in great stress to affected families. Our approach is to use a multidisciplinary group of specialists to address these issues. From the initial assessment, the collaboration between the fetal imager and pediatric cardiologist is essential to define the nature of the fetal cardiac lesion. Neither specialist typically has sufficient breadth Correspondence to: J.A. Copel, email: [email protected]

of training and experience to work independently. The appreciation of fetal cardiac anomalies and possible associated extracardiac anomalies requires this type of collaborative approach [26, 36]. Our team includes obstetricians/perinatologists, pediatric cardiologists, geneticists, and cardiac surgeons. For Which Pregnancies Should Fetal Echocardiography Be Performed? The goals of fetal echocardiography are to document normal fetal cardiac anatomy and rhythm in the fetus at risk for an abnormality and to describe the malformations or rhythm disturbances when an abnormality has been identified through a screening fetal ultrasound examination [37]. Indications for fetal cardiac echocardiography can be stratified into three major categories: fetal, maternal, and familial risk factors (Table 1). The discovery of fetal extracardiac anomalies may initiate echocardiographic assessment. Sonographic findings of extracardiac abnormalities in both high-risk and low-risk populations for CHDs increase the risk of fetal cardiac defect and warrant echocardiographic evaluation [26, 27]. The cumulating worldwide data and experience with first-trimester genetic screening for aneuploidy detection have resulted in the recognition of a new marker for fetal cardiac disease. The presence of an increased fetal nuchal translucency thickness (Fig. 1) is emerging as a significant risk factor and its measurement is a potential screening tool for CHD [49].

Major Fetal Structural Malformations Some risk factors for fetal CHD are intrinsic to the fetus and impart substantially higher risks for heart disease (Table 2). We perform fetal echocardiography on virtually all fetuses with sonographically identified structural abnormalities [27].

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Table 1. Indications for Fetal Echocardiographya Fetal Extracardiac anomalies Omphalocele Duodenal atresia Spina bifida VACTERL Trisomies DiGeorge/velocardiofacial syndrome (chromosome 22q11 microdeletion) Increased first-trimester nuchal translucency measurement Nonimmune hydrops (20–30%) Arrhythmias Irregular Tachycardia Paroxysmal atrial (reentrant) Atrial fibrillation/flutter Bradycardia Immunologic Structural Abnormal four-chamber view Abnormal cardiac axis Maternal Maternal congenital heart defect Teratogen exposure Metabolic disorders Diabetes Phenylketonuria Methylene tetrahydrofolate reductase enzyme deficiency (?) Familial Previous child with congenital heart defect Paternal congenital heart defect Mendelian syndromes (autosomal dominant, recessive) Tuberous sclerosis Noonan syndrome DiGeorge/velocardiofacial syndrome a

See Shipp et al. [97].

Syndrome identification is dependent on complete ascertainment of all effects in the fetus. For families choosing to terminate a pregnancy with multiple fetal anomalies, the combination of ultrasound, and perhaps autopsy, will be relied on to make a full diagnosis. Accurate counseling regarding recurrence risks depends on a correct diagnosis. For families continuing pregnancies with a fetus with multiple anomalies, preparation for postnatal management can be planned based on the information available from prenatal studies.

Polyhydramnios Fetuses with polyhydramnios have a high rate of congenital anomalies, especially when the amniotic fluid index exceeds 24 cm [22]. In one of the largest published series, Dashe et al. [30] retrospectively reviewed 672 pregnancies complicated by polyhy-

Fig. 1. Fetal omphalocele. In association with Beckwith–Wideman, the incidence of congenital heart disease may be as high as 92% [3].

dramnios. Of these, 77 (11%) were complicated by fetal anomalies, of which 20 (25%) were cardiac defects. However, the antenatal detection rate for cardiac defects was approximately 40%. This detection rate may have been due to the generally low detection rate of lesions such as atrial septal defects in neonates not undergoing antenatal diagnosis. The overall prevalence of aneuploidy was 10% in this series and was not associated with the degree of hydramnios. We have also found that a great many fetuses with nonimmune hydrops have either structural cardiac anomalies or fetal arrhythmias as the underlying cause [9, 101].

Fetal Hydrops Fetal hydrops is the pathologic accumulation of fluid in two or more fetal cavities and affects 1 in 1500– 4000 deliveries [13]. The mechanisms governing the development of fetal hydrops are similar to those governing the development of excessive fluid in the child or adult: excessive fluid in the extracellular space, increased intravascular hydrostatic pressure, decreased intravascular colloid oncotic pressure, primary cardiac failure, high-output cardiac failure (e.g., severe fetal anemia), lymphatic obstruction, or obstruction of vascular return [4, 39, 47]. Approximately 10% of cases result from maternal red cell alloimmunization against fetal red blood cell antigens; the resulting anemia may cause high-output failure in the fetus and hydrops [13]. Fetal echocar-

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Table 2. Extracardiac Malformations and Incidence of Associated Congenital Heart Diseasea Extracardiac malformation

%

No./total

Single umbilical artery Ureteral obstruction [43] Bilateral renal agenesis [43] Unilateral renal agenesis [43] Horseshoe kidney [43] Renal dysplasia [43] Isolated hydrocephalus [44] Agenesis of the corpus callosum [45] Tracheoesophageal fistula [46] Duodenal atresia [47] Jejunal/ileal atresia [48] Imperforate anus [50] Omphalocele [49] Pentalogy of Cantrell [51] Beckwith–Wideman syndrome [52] Diaphragmatic hernia [53] Meckel–Gruber syndrome [54] Dandy–Walker malformation [55]

9.1 2.1 42.8 16.9 38.8 5.4 4.4 14.8 14.7 17.1 5.2 11.7 19.5 77.8 92.3 9.6 13.8 4.3

7/77 1/48 3/77 12/71 7/18 2/37 9/205 7/47 48/326 86/503 12/233 26/222 31/159 28/36 12/13 33/345 5/36 1/23

a

See Antolin et al. [3].

diography is an essential diagnostic tool in the evaluation of the fetus with hydrops due to the high incidence of underlying cardiovascular lesions [63]. Careful Doppler assessment of the fetus may give additional diagnostic support for the mechanism governing a noncardiac source of fetal hydrops. Approximately 15–25% of cases of fetal hydrops are cardiac in origin, resulting from either structural malformations or fetal arrhythmias. The most common tachycardia associated with fetal hydrops is supraventricular tachycardia. The cardiac structural malformations associated with fetal hydrops are heterogeneous and the severity of the lesions is associated with the risk of hydrops. Fetal echocardiography is necessary for the evaluation of the fetus with hydrops both for the determination of structural anomalies and as an adjunct to determine the potential nature of myocardial dysfunction arising from myocarditis, infiltrative lesions, compression, arrhythmia, or high-output failure [57].

Fetal Arrhythmias There is an association between fetal bradycardia and structural heart disease; approximately half of fetuses with complete heart block have complex cardiac anomalies [9, 64, 93, 95, 101]. These are usually either abnormalities of situs (the heterotaxy syndromes, including left and right atrial isomerism) or other lesions, such as atrioventricular septal defects and corrected transposition of the great arteries (atrio-

ventricular discordance with ventriculoarterial discordance), interrupting the normal electrical connection between the atria and ventricles.Bashat et al. [8] describe a series of four cases of first-trimester (11–14 weeks) fetal bradycardia in fetuses with increased nuchal translucencies. Transvaginal fetal echocardiography confirmed second- and third-degree atrioventricular (AV) block in all cases. In the three cases in which an autopsy was performed, complex cardiac malformations were confirmed. Fetal tachycardia is rarely associated with structural heart disease. Supraventricular tachycardia (atrioventricular reentry tachycardia), in particular, is typically not associated with structural heart disease, although atrial flutter may be.

Maternal Factors Metabolic Disease Maternal Diabetes Mellitus. The ‘‘maternal metabolic milieu’’ described by Reece is a potential cause of fetal embryopathy [42, 79]. Pregestational maternal diabetes and maternal phenylketonuria are examples of metabolic conditions that may result in teratogenicity. In both conditions, the fetal heart is a target organ. Diabetes mellitus is one of the most common medical conditions complicating pregnancy. The prevalence varies depending on the population under study; approximately 3–10% of all pregnancies are affected. Of those affected, 20% have pregestational diabetes [79]. In pregestational diabetes, the overall congenital malformation rate may be as high as 6–10%, more than double the background rate of 2–5%. Congenital cardiac defects comprise 40–50% and thus encompass a large proportion of the infants affected [10, 73]. Roland et al. [90] demonstrated a 4% incidence of CHD in 470 diabetic patients, a fivefold higher risk for CHDs in the offspring of diabetic mothers. A disproportionate number of these anomalies consist of transposition of the great vessels, ventricular septal defects, and abnormalities of cardiac looping [90]. The impact of glycemic control on the risk for cardiac and other abnormalities is directly proportional; the better the maternal metabolic control during embryogenesis, the closer the anomaly rate is to the background rate [10, 73]. Miller et al. [73] demonstrated an increase in congenital malformation among diabetic pregnancies when first-trimester hemoglobin A1c levels were higher than 8.5%. Shields et al. [96] reported outcomes of 193 type 1 and type 2 diabetic pregnancies. In their population, no threshold hemoglobin A1c level predicted an increased risk for CHD.

Small and Copel: Indications for Fetal Echocardiography

The embryopathic effect of hyperglycemia on the developing fetus may result in either structural congenital defects, if it occurs during fetal organogenesis, or fetal myocardial hypertrophy, if it occurs later. This generalized myocardial hypertrophic effect typically manifests in the late second or third trimester. Hyperglycemia produces a hyperinsulinemic state in the fetus that results in hypertrophy of the fetal organs. The fetal heart, rich in insulin receptors, is particularly vulnerable to this type of growth stimulus [103]. The majority of fetuses diagnosed with maternal diabetes-induced hypertrophic cardiomyopathy—as identified by increased ventricular septal thickness (more than 6 mm in the third trimester), restricted ventricular filling, left ventricular outflow obstruction, and generalized myocardial hypertrophy—have normalization of cardiac dimensions and function by 6 months after birth [107]. However, in rare, severe cases congestive heart failure may develop postnatally [86]. Jaeggi et al. [54] described 45 type 1 diabetic pregnancies with structurally normal hearts for which echocardiographic studies were performed at 20 and 35 weeks of gestation. All patients underwent close glycemic monitoring with plasma glucose determinations and hemoglobin A1c determination. Mean hemoglobin A1c values were less than 6% in these uncomplicated diabetic pregnancies. Their patients were still noted to have progressive septal hypertrophy in comparison to normal, nondiabetic controls. However, the degree of septal hypertrophy was mild (up to 5 mm), and no clinical manifestations of neonatal heart failure were observed. They concluded that third-trimester echocardiography is not necessary in the well-controlled diabetic. Their findings further support the evidence for continued pathologic effects of diabetes on fetal organ development despite documented maternal euglycemia [54]. Normoglycemia during embryogenesis does not completely lower the pregestational diabetic’s risk of fetal CHD to that of the nondiabetic patient [73]. For this reason, all diabetics should be offered screening fetal echocardiographic assessment. The gestational diabetic, the woman diagnosed with diabetes only during routine second-trimester screening, does not have an additional risk of fetal structural heart disease above the baseline risk because she was presumably euglycemic during the first-trimester period of organogenesis [42, 86]. Given the increasing prevalence of diabetes in the population and the considerable increase in risk for fetal cardiac disease in these pregnancies, fetal echocardiographic screening remains an important diagnostic tool for these patients. Nuchal translucency screening and first-trimester echocardiographic screening may also prove beneficial for this group of

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patients in early pregnancy evaluation. Firs-trimester echocardiography, with transvaginal approaches, may also result in earlier visualization of defects that may otherwise be inaccessible secondary to maternal habitus, gestational age, or fetal positioning [16, 48]. Given the frequent comorbidity of obesity in the diabetic patient, these tools may prove useful as adjuncts or as primary screening for earlier anomaly detection. Whether these tests will reduce the need for midtrimester echocardiography remains to be seen. Maternal Phenylketonuria. Maternal phenylketonuria presents risks similar to those of diabetes to the fetus. Lenke and Levy [66] reported adverse outcomes of mental retardation (92%), microcephaly (73%), growth restriction (40%) and CHDs (12%) in offspring of women with untreated hyperphenylalaninemia. Maternal dietary consumption of phenylalanine may result in excessive levels of the amino acid. Phenylalanine levels higher than 15 mg/dl are associated with a 10- 15- to fold increased risk of CHD [66]. In 1984, the Maternal Phenylketonuria Collaborative Study began an investigation of the effect of phenylalanine dietary restriction on reproductive outcome [67, 84, 85]. Women with hyperphenylalaninemia were enrolled if they were planning pregnancy or if they were pregnant, irrespective of gestational age. The control population was 99 normal women. The study had a target phenylalanine level of less than 10 mg/dl. Because this target range still demonstrated a decrease in head circumference after 4 years of investigation, the target phenylalanine level was decreased to 6 mg/dl. The study demonstrated a significant decrease in the adverse effects of elevated phenylalanine levels when women had dietary control early in pregnancy or preconceptionally. The incidence of CHDs was 7.5% in cases and 1% in the control population. They reported a frequency of coarctation of the aorta and hypoplastic left heart syndrome above the background rate. Prenatal echocardiography identified 30% of the defects. Six percent of the nondetected cardiac malformations were patent ductus arteriosus and not identifiable antenatally. None of the malformations occurred in women with mild hyperphenylalaninemia or preconceptional dietary control. Levy et al. also reported a threshold value of 15 mg/dl for the development of CHDs in this cohort [67]. Tight preconceptional and metabolic control during fetal organogenesis is essential for the prevention of CHD in this population. Methylene Tetrahydrofolate Reductase Enzyme Deficiency. The epidemiological association between folic acid deficiency and neural tube defects

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was well described prior to the understanding of the molecular mechanisms governing this relationship [80]. The association between methylene tetrahydrofolate reductase (MTHFR), a folate-dependent enzyme responsible for the remethylation of homocysteine, and methionine has been associated with the development of hyperhomocysteinemia in patients homozygous for the most common form of the mutation. Hyperhomocysteinemia has been associated with neural tube defects and oral clefts [74, 75]. An association has also been reported between homozygosity for the C677T MTHFR mutation and congenital cardiac malformations [59, 108]. Wenstrom et al. [108] studied stored amniotic fluid from 26 cases of isolated CHD and 116 normal pregnancies. They evaluated heterozygosity or homozygosity for the MTHFR mutation and homocysteine levels. They found that 50% of isolated cardiac defects demonstrated either an elevated amniotic fluid homocysteine level or the presence of the C677T mutation. Junker et al. [59] evaluated 114 Caucasian patients and found 18% of cases and 9% of age- and gendermatched controls demonstrated homozygosity for the MTHFR 677TT genotype. This study demonstrated that twice as many patients with CHD had MTHFR C677T mutations. If a woman is a known carrier of this mutation, we offer her fetal echocardiography. Further study is necessary to determine whether maternal heterozygosity with an unknown paternal mutation status also warrants fetal echocardiographic assessment and to assess whether this mutation is truly a causal factor for CHD. Folic acid supplementation has been shown to correct the hyperhomocysteinemia associated with this mutation and may reduce the risks of CHD just as it reduces the risk of open neural tube defects [33]. Maternal Autoantibodies Maternal autoantibodies, particularly to ribonucleoproteins, designated anti-Ro/SSA and anti-La/SSA, are associated with fetal bradycardia and varying degrees of heart block [33, 65, 68, 94]. Approximately 85% of women whose fetuses are identified with congenital heart block (CHB) and normal cardiac anatomy possess these autoantibodies [19]. This finding is most commonly associated with the anti-Ro antibody; 75% of cases have anti-Ro/SSA autoantibodies [17]. These antibodies against soluble tissue ribonucleoproteins are associated with an HLA-DR3 histocompatibility antigen haplotype and are commonly identified with connective tissue diseases, such as maternal Sjogren’s syndrome (prevalence of antibodies, 40–95%) and systemic lupus erythematosus

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(prevalence of antibodies, 15–35%). The correlation between CHB and maternal autoimmunity was initially identified in these populations with autoimmune disease [23, 71]. The fetal risk of CHB is 1 or 2% in the setting of positive maternal anti-Ro/anti-La antibody status and no history of a previously affected fetus. This risk is independent of maternal connective tissue disease status. In the setting of a previously affected fetus, the recurrence risk is 15–20% [21]. The impact of this disease can be devastating. Approximately 65% of neonates with congenital complete heart block receive permanent cardiac pacing; the mortality rate is 20% [21]. This immunologic response can also result in the fetal neonatal lupus syndrome, characterized by hematologic (thrombocytopenia and anemia), hepatic (cholestatic liver disease), cutaneous, and cardiac (fetal heart block) manifestations. The syndrome derives its name from the presence of the cutaneous skin lesions that resemble characteristic lupus lesions [68]. However, unlike lupus, the neonatal lupus syndrome typically resolves. Circulating maternal IgG autoantibodies are not detectable by 8 months of age. However, the heart block associated with this syndrome is irreversible. The exact mechanism of action of these autoantibodies is unknown; however, most theories support activation of an inflammatory process, which ultimately leads to fibrosis, scarring, and permanent damage to the fetal myocardium and conducting system [19]. Resolution of the immunologic insult occurs with all other tissues except cardiac tissues. In addition to conduction system manifestations, prolonged fetal bradycardia and myocarditis may result in fetal hydrops [92]. These autoantibodies are of the IgG type and therefore cross the placenta and affect the fetus. The targeted antigens are intracellular, whereas the maternal autoantibodies are extracellular. How this antigen–antibody complex interacts is an area of active research. Proposed mechanisms include apoptosis-mediated translocation of these antigens from the intracellular domain to the cell surface, where they can initiate an inflammatory cascade following contact with maternal antibodies [76], and possible cross-reactivity between the autoantibodies and a fetal cardiac receptor [32]. Although only 1 or 2% of fetuses will be affected when the mother has positive anti-Ro/anti-La antibodies, it is not possible to predict, on a molecular level, which fetuses are at greatest risk for CHB [32]. Buyon et al. [6] reviewed 187 cases of CHB in children with neonatal lupus. Of 9 children with PR interval prolongation, 4 were noted to have progression of their AV block. This report supports the finding that autoantibody-associated CHB represents a spectrum or a progression in conducting system

Small and Copel: Indications for Fetal Echocardiography

delay from first- through third-degree block. This work demonstrates the need for neonatal electrocardiogram (ECG) for the child born to a woman with anti-Ro/anti-La antibodies. Small series and case reports have demonstrated possible benefit from fluorinated steroid therapy, b-sympathomimetics, intravenous c-globulin, and plasmapheresis for the treatment of CHB. Reversal of complete heart block has not been reported [92]. The timing of treatment may explain the varying success of steroid therapy: if instituted following the development of third-degree heart block, there may already be irreversible damage and fibrosis. Fetal heart block is commonly identified between 18 weeks of gestation and term. The fetal mechanical PR interval can be calculated through M-mode or spectral Doppler echocardiography. No significant difference in the fetal PR interval (0.12 ± 0.02 sec) is observed throughout gestation [40]. Progressive lengthening of the fetal mechanical PR interval in the fetus as the heart block progresses from second to third trimester has been reported. Preliminary studies suggest a possible benefit from steroid therapy when prolongation of the PR interval is first identified. Prospective trials are under way to evaluate the possible benefit of steroid therapy for patients with early stages of fetal heart block [21]. If maternal autoantibodies are present, fetal echocardiography should be performed at baseline between 18 and 24 weeks. Serial ultrasound for evaluation of fetal growth and assessment should be offered. Patients with evidence of fetal myocarditis or PR interval prolongation may benefit from intervention with steroids that cross the placenta. Unfortunately, no large randomized trials are available to guide our management of this rare disease. Prophylactic therapy is not practical given the low incidence of CHB in women with autoantibodies (1–2% affected children) and the potential morbidity of prolonged maternal and fetal steroid exposure. The unaffected newborn should still undergo ECG following birth and close follow-up if early conduction abnormalities are observed. The woman with a fetus affected by CHB should be offered testing for antiRo/anti-La antibodies. Maternal Medication Exposure Many medications have been identified as potential cardiac teratogens and a partial listing of these is shown in Table 3. Most studies have been based on retrospective patient interviews or voluntary report registries, either of which may reflect the recall bias of affected individuals. For any medically indicated medication, such as anticonvulsants, the risk to the mother of not taking the medication must be care-

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Table 3. otential Cardiac Teratogens Vitamin A analogues Isotretinoin [57] Topical preparations are not a risk [59] Nutritional supplement [60] Antiseizure medications Phenytoin [61, 62] Carbamazepine [63] Valproic acid [64] Trimethadione [65] Alcohol [57] Lithium carbonate [57]

fully balanced against the potential teratogenic risk to the fetus [114]. For more elective medications, such as isotretinoin (Accutane), or oral vitamin A supplements, discontinuation of the medication well before conception is prudent [55, 89, 113]. The vitamin A analogues are fat soluble and therefore may be retained in maternal adipose tissues for extended periods even after discontinuation of treatment. Topical retinoic acid does not present an increased risk for congenital anomalies. The teratogenicity of the antiseizure medications [5, 43, 58, 78, 112] may be attenuated with folic acid supplementation [29]. First-Trimester Screening The first-trimester genetic ultrasound is performed between 10 and 14 weeks of gestation [81]. Indications for general first-trimester sonographic assessment include gestational age determination, confirmation of live pregnancy, detection of gestation number, and the possible presence of prominent malformations such as anencephaly. Because of the early nature of this ultrasound, it is somewhat limited by fetal size and early organ development . This scan has been employed as a screening tool for aneuploidy detection. Through these studies, an association between abnormal first-trimester nuchal translucency measurements and the subsequent detection of fetal cardiac defects in both chromosomally normal and abnormal fetuses has been observed [81]. As more women undergo nuchal translucency measurement, either as part of a routine first-trimester ultrasound or in combination with first-trimester maternal biochemical screening for aneuploidy detection, the finding of an abnormal nuchal translucency may trigger evaluation for fetal cardiac defects. The nuchal translucency has been utilized as a screen for aneuploidy largely through the work of Nicolaides at the Fetal Medicine Foundation. The nuchal translucency is composed of subcutaneous fluid behind the fetal cervical spine (Fig. 2). The first-

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Fig. 2. Increased nuchal translucency in a first-trimester fetus. Chorionic villous sampling revealed trisomy 18.

trimester embryo’s lymphatic system drains primarily into the jugular veins [87]. Excessive fetal fluid may manifest as visible enlargement of this region. After 10–14 weeks, the fetal lymphatic and vascular system undergoes further development and these changes may not be visualized sonographically. The measurement is performed between 10 and 14 weeks with a fetal crown rump length between 45 and 84 mm [81]. The fetus is measured in the longitudinal sagittal plane so that the fetal head is in a neutral position. To maximize accuracy of measurement, the image must be enlarged to occupy at least 75% of the screen. The importance of technical precision in measurement is essential to its usage as a screening modality [81]. Quality assurance has been encouraged through rigorous certification procedures and periodic examiner reassessments. Other technical recommendations for accurate assessment include the use of equipment capable of high resolution [81]. Enlarged nuchal translucency measurements are associated with an increased risk of aneuploidy [102]. The usage of the nuchal translucency measurement alone as a measure for aneuploidy is associated with a 70–80% detection rate of Down’s syndrome and a 5% false-positive rate, which is similar to that of secondtrimester biochemical screening [81]. However, the presence of an abnormal first-trimester nuchal translucency may prove incidental and the newborn may be normal. This finding, even in the presence of normal karyotype, has also been independently associated with a heterogeneous group of CHDs and syndromes [49–52, 81]. Hyett et al. [51] demonstrated the utility of firsttrimester fetal nuchal thickness as a screening tool for fetal cardiac defects. They utilized the standard 95th percentile cutoff for the nuchal translucency measurement of 2.2 mm for a crown–rump length of 38 mm and 2.8 mm for a crown–rump length of 84 mm. In one of the largest series, they reviewed a total of

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29,154 chromosomally normal fetuses from singleton pregnancies that had undergone nuchal translucency measurement to determine the prevalence of CHDs. The positive and negative predictive values for CHD detection with nuchal translucency measurements greater than the 95th percentile were 1.5 and 99.9, respectively. The sensitivity was 56% and specificity 94% (Table 4). Their study demonstrated that 55% of fetuses with major cardiac malformations had abnormal nuchal translucency measurements at 10–14 weeks of gestation. This study also supported the observed trend of increased prevalence of cardiac defects with increasingly abnormal nuchal translucency values. The prevalence of congenital cardiac defects was 5.3/1000 (‡95th percentile), with a nuchal translucency of >3.4 mm and 195/1000 if the measurement was ‡5.5 mm. Using the 99th percentile as a cutoff, they increased the specificity of the testing to 99% but the sensitivity decreased to 40%. The negative predictive value of the test remained high at 99%. The overall prevalence of major CHDs was 2% for patients with abnormal nuchal translucency measurements. These data support the use of nuchal translucency for the screening of patients at high risk for CHDs. The advantage of this approach is the timing during pregnancy because the measurement can be taken as early as 10 weeks of gestation. Advances in transvaginal sonographic techniques may allow for earlier, thorough imaging of the fetal heart [16, 31, 48]. Haak et al. [41] performed three transvaginal ultrasounds on 85 low-risk singleton pregnancies between 11 and 13 + 6 weeks of gestation for visualization of the four-chamber view, aortic root, long axis, pulmonary trunk, and aortic diameter. They achieved 20% visualization of these structures at 11 weeks of gestation and 92% at 32 weeks. [41]. As a screening tool, nuchal translucency measurement has specificity limitations that do not affect fetal echocardiography. Increased fetal nuchal translucency measurement may indicate the presence of noncardiac pathology, such as complex genetic syndromes and aneuploidy. The technique has not been widely employed in a patient population at low risk for cardiac defects [31]. Its practicality as a screening tool for the general population is under investigation. The finding of a nuchal translucency above the 95th percentile occurs in 5% of patients screened. If the cutoff is set at the 99th percentile, the sensitivity of the test is reduced; however, echocardiography would be required in only 1% of the population [31]. The clinical data are compelling so that this finding should prompt further fetal investigation, including fetal echocardiography.

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Table 4. Nuchal Translucency (NT) and Risk for Congenital Heart Defect (CHD)a NT thickness

Prevalence of major CHD (per 1000 fetuses)

<95th percentile ‡95th percentile– 3.4 mm 3.5–4.4 mm 4.5–5.4 mm ‡5.5 mm

28.9 90.9 195.1

NT percentile

Sensitivity

Specificity

PPV

NPV

95th 99th

56 40

93.8 99

1.5 6.3

99.9 99.9

a

0.8 5.3

See Matias et al. [70] PPV, positive predictive value; NPV, negative predictive value.

Fig. 3. Septated cystic hygroma in a second-trimester fetus.

Cystic Hygroma Cystic hygromas are cystic masses that usually form secondary to abnormalities in fetal lymphatic development. This lesion is typically located in the head and neck region and distinguished from the nuchal translucency by a large, often septated appearance (Fig. 3). This finding is highly associated with Turner and Noonan syndromes as well as aneuploidy, such as trisomy 18 and 21 [56, 82]. This finding is an indication for cytogenetic analysis [38]. Noonan’s syndrome is associated with heart defects in 60% of cases [72]. Menasche et al. [72] reviewed 29 cases of Noonan’s syndrome and noted cystic hygromas or enlarged nuchal translucencies in the majority of cases. They reported poor antenatal detection of CHDs in the cases reviewed, primarily because the cardiac lesions consist mostly of defects such as pulmonary stenosis and hypertrophic cardiomyopathies. These defects do not lend themselves easily to antenatal detection because the hemodynamic manifestations may only present late in gestation or after birth. In the chromosomally normal fetus with a cystic hyg-

roma, the increased risk of congenital cardiac defect warrants fetal echocardiographic assessment [51].

Abnormal First-Trimester Ductus Venosus Flow Abnormal ductus venosus blood flow has been demonstrated in the chromosomally abnormal firsttrimester fetus [3, 70, 82]. The ductal velocity is a good measure of fetal central venous pressure, and the absence or reversal of flow during atrial contraction has been associated with adverse fetal conditions, such as fetal cardiac defects, hypoxia-related cardiac failure, anemia, and hydrops [61]. Matias et al. [70] performed ductus venosus Doppler ultrasound assessment on 200 fetuses with nuchal translucencies above the 95th percentile prior to chorionic villous sampling and noted abnormal ductal flow in 11/142 chromosomally normal fetuses. These patients subsequently underwent fetal echocardiography at 14–16 and at 19–21 weeks of gestation. Of those tested, 6/11(55%) patients were noted to have a broad spectrum of structural cardiac defects. Bilardo et al.

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Table 5. Nuchal Thickness (NT) Measurement and Frequency of Postnatal Congenital Heart Defectsa NT (mm)

Normal

Cardiac defect

Frequency

<1.0 1.0–2.0 >2.0

1445 1456 7

37 57 1

25.6/1000 39.2/1000 142.9/100

a

See Rose et al. [88].

[14] demonstrated a CHD in 6/23 fetuses with increased nuchal translucency measurements and normal karyotype. The limitations of this technique are the unknown potential effects of the higher acoustic energy required for color and spectral Doppler on the first-trimester fetus and the lack of data available on its utility in the low-risk population [44]. For the purpose of screening for CHD, it is unclear whether this mode of screening will add more information than that provided by an increased nuchal measurement. Second-Trimester Screening Thickened Nuchal Fold Langdon Down was the first to describe the thickened nuchal skin fold as a characteristic of trisomy 21. Benacerraf et al. [11, 12] identified an association between this finding on fetal ultrasound and an increased risk for fetal aneuploidy. The finding of an enlarged nuchal fold is an indication for referral for targeted fetal ultrasound and genetic counseling. Bahado-Singh et al. [7] reported an association with cardiac defects in chromosomally normal fetuses referred for targeted ultrasound or fetal echocardiography. In their study, 3003 midtrimester fetuses were studied; 95 patients (3.5%) had postnatally confirmed CHD. The sensitivity of nuchal thickness was 47.4% and the specificity was 70.5% for the prediction of CHD in their high-risk population (Table 5). The study found the combination of a previously affected child and an increased nuchal thickness to be a significant predictor of CHD; the combined detection rate for CHD was 54% and specificity was 68% for that group. This study also showed significance for the detection of left-sided cardiac lesions through use of nuchal translucency alone. This work suggests a potential role for fetal echocardiography in the fetus noted to have an increased nuchal fold.

for carrying a fetus with CHD. Reliance on small antenatal or postnatal case series is insufficient to accurately determine risks for rare events. The background risk of CHD in large neonatal screening studies from unselected populations is generally estimated to be approximately 3–8/1000 live births, although the true number may be higher [46, 77]. Neonatal case ascertainment is likely to underestimate the true incidence of cardiac anomalies since some children do not have their CHD diagnosed until after the ductus arteriosus closes and/or pulmonary vascular resistance decreases, which may occur several days postpartum. Additionally, some children with ventricular septal defects may not develop clinically noticeable murmurs until weeks or months after birth, and some mild lesions such bicuspid aortic valve may not become apparent for months or years [83]. The incidence of CHD may be even higher in fetuses, especially if case detection is sought in the midtrimester, because spontaneous loss of severely anomalous fetuses may result in the removal these fetuses from postnatal series [52]. Families with a child with CHD (in the absence of a recognized genetic syndrome) have a 2 or 3% risk of recurrence with subsequent pregnancies, although there maybe some variation with different lesions [15, 77, 83]. If the child had a cardiac anomaly as part of a syndrome, then the recurrence risk is the same as that for the syndrome (e.g., autosomal dominant or autosomal recessive). With advances in our understanding of the genetic basis of fetal anomalies, including CHD, our counseling regarding recurrence risks is evolving (Table 2). Mothers with CHD have an increased risk of delivering a child with a cardiac anomaly of 5–10% [2, 15, 83, 88, 109]. The child may have more or less severe disease than the mother or may in many cases have an apparently different type of disease (e.g., the first affected family member has coarctation of the aorta and next family member has tetralogy of Fallot). Recurrence risks for affected fathers are slightly lower than those for maternal CHD (2%) [18, 88]. The recurrence risks for more distant family histories of CHD, such as second- and third-degree relatives, approach those of the general population. In clinical practice, we find that many of these families have been emotionally traumatized by the loss of a child, and the reassurance provided by a normal fetal ECG is significant.

Recurrence

The Four-Chamber View

Many patients referred for fetal cardiac evaluation are sent because of epidemiologically established historical risk factors placing them at increased risk

In 1987, we reported our experience with the fourchamber view as part of a formal fetal ECHO (Fig. 4) [25]. In that retrospective study, we found that 94% of

Small and Copel: Indications for Fetal Echocardiography

Fig. 4. Normal four-chamber view. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

fetuses with CHD had an identifiable abnormality on one of the four chamber views of the heart. That study was imperfect as an evaluation of the fourchamber view as a screening test for several important reasons. It was not a prospective study in a lowrisk population; rather, the study was retrospective in a population referred for the risk of having a fetus with CHD. Furthermore, the examiners knew the diagnoses at the time the studies were reviewed. Nevertheless, the point of the report was to stimulate examination of the four-chamber view in a more general population. The four-chamber view has been the subject of numerous other reports [9, 34, 45, 69, 98, 99, 106], with the sensitivity in low-risk populations ranging from as low as 0% [34] to as high as 81% [99]. The final sensitivity numbers are, in part, dependent on the postnatal case ascertainment method because without careful follow-up for all fetuses examined, there might be an inflation of the sensitivity should failures to appreciate pathology not be reported to the study center. The wide variation in sensitivity makes interpretation of the literature difficult. However, we believe that the final consensus will be approximately 50% sensitivity. Todros et al. [105] summarized much of the world’s literature, showing that 23% of 661 cases of CHD were prenatally detected among 108,182 patients screened (prevalence of CHD, 5.8/1000). Far from indicating a lack of value to the four-chamber view, we believe that this portion of the population with CHD represents the most severe cases, those most likely to benefit from prenatal diagnosis, and that detecting half of affected fetuses is better than detecting none. Whether the addition of outflow tract views will enhance sensitivity to heart defects remains preliminary [60], but common sense suggests that the more of the fetus we scrutinize as part of our routine examination, the more defects we will find. The most extreme extension of screening is the findings of Stumfplen et al. [104] and Yagel et al.

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[111] that the performance of a full fetal ECHOcardiogram in low-risk patients had sensitivity for the presence of cardiac anomalies of approximately 90%. In an editorial accompanying the Stumfplen paper, Kleinert [62] estimated that in Great Britain alone, there would be a need for 400 additional cardiac specialists to provide this level of expertise for every pregnant woman. Clearly, this is not an achievable goal. Conversely, the referral of fetuses with abnormal four-chamber views remains a major contributor to the pool of prenatal diagnosis of CHD. We have found that 50–60% of fetuses referred for this indication do, in fact, have cardiac abnormalities (unpublished data). The success of four-chamber screening in our area of Connecticut is attested to by the fact that 47% of cardiac admissions to the Yale Newborn Special Care Unit in 1997 were prenatally diagnosed cases. Cardiac Axis The axis of the ventricular septum relative to the midline of the chest should be approximately 45. Ninety-five percent of normal fetuses have an axis from 30 to 60 [24, 97, 100]. Deviation toward the right suggests mesocardia, which may be seen with the heterotaxy syndromes, atrioventricular septal defects, or right lung hypoplasia [24]. Deviation to the left can be seen with double-outlet right ventricle and other outflow tract abnormalities [100]. Including cardiac axis as part of the four-chamber view may improve the sensitivity of CHD detection [28]. Noncardiac defects can also affect the axis, with deviation to the left seen in omphalocele and gastroschisis and deviation to the right seen in left congenital diaphragmatic hernia. Conclusion The traditional risk factors for CHD screening have primarily included known maternal disease, fetal anomalies, and familial history of CHD. In the current era of lower gestational age for antenatal genetic screening, the first-trimester detection of fetal anomalies such as increased nuchal translucency has broadened the indications for fetal screening echocardiography. The combination of first-trimester genetic testing and improved imaging modalities has initiated a trend toward earlier fetal echocardiography. Earlier patient diagnosis and possibly earlier invasive testing for aneuploidy, where appropriate, allow patients more time for decision making and preparation for the pregnancy affected by a CHD. Continued research in this area is necessary to test its

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broad-spectrum validity and effectiveness for screening for fetal CHD.

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