Fetal Ebstein Anomaly

Ebstein Anomaly and Tricuspid Valve Dysplasia: A Comprehensive Overview

Ebstein anomaly and tricuspid valve dysplasia are rare congenital heart diseases that are often grouped together due to their similar presentation and severe outcomes in the fetus. These conditions represent a wide spectrum of anatomical and morphological variations of the tricuspid valve, but both ultimately lead to severe tricuspid regurgitation (TR) in the fetus, which is poorly tolerated due to the right ventricle being the dominant ventricle in fetal circulation.

1. Definition and Pathology

• Ebstein Anomaly: Named after Wilhelm Ebstein who discovered it in the 19th century, this condition is characterized by an apically displaced septal leaflet of the tricuspid valve, an atrialized right ventricle, and an abnormal appearance of the myocardium. The orifice of the tricuspid valve is displaced downwards.

• Tricuspid Valve Dysplasia: Pathologically distinct, this entity involves non-displaced septal leaflets but a very dysplastic valve, often appearing nodular, irregular, and tethered with limited mobility. It can also be characterized by abnormal myocardium, similar to Ebstein anomaly.

Despite their pathological differences, they are grouped together because both produce severe tricuspid regurgitation in the fetus, significantly impacting central venous pressures and cardiac output. These diseases are rare, and a large multinational cohort of 250 fetuses revealed a 45% paranatal mortality rate, one of the highest among all congenital heart diseases.

2. Pathophysiology and Risk Factors The severity of tricuspid regurgitation and the health of the right ventricle are central to the pathophysiology. The condition's presentation varies based on the function of the right ventricular outflow tract (RVOT) and pulmonary valve:

• Stable Form (Normal Pulmonary Valve Function): Even with severe TR, a well-functioning right ventricle and normal pulmonary valve can maintain normal antegrade pulmonary blood flow and normal intrauterine shunting from right to left across the patent ductus arteriosus (PDA). This is considered the most stable form, though it can change during gestation.

• Fixed Anatomic RVOT Obstruction: About 20% of fetuses in this population have fixed anatomic RVOT obstruction, leading to left-to-right shunting at the PDA to perfuse the fetal pulmonary vascular bed.

• Functional Pulmonary Atresia (Failing Right Ventricle): When the pulmonary valve appears normal but the right ventricle is failing (often due to severe TR and low right ventricular systolic pressure), there is reversed intrauterine shunting (left to right) in the ductus arteriosus because of insufficient forward flow across the pulmonary valve. These cases are more concerning.

• Circular Shunting / "Circle of Death" (termed coined by Dr Normal Silverman): This is the most severe and worrying scenario, evolving when pulmonary regurgitation (PR) occurs in the presence of left-to-right ductal flow. This creates a vicious cycle where backflow into the weak right ventricle leads to severe TR, shunting across the foramen ovale to the left side of the heart, and then systemic blood steeling back through the ductus arteriosus into the right ventricle. This results in unhealthy ventricular loading, lack of systemic perfusion, and can be seen with significant PR and retrograde ductal flow. This finding of circular shunting is a critical independent predictor of paranatal mortality.

Independent risk factors for paranatal mortality include:

• Earlier gestational age at diagnosis: Reflects more severe disease.

• Larger tricuspid valve annulus z-score: Indicative of overall TR severity.

• Cardiac enlargement.

• Pulmonary regurgitation (PR).

• Pericardial effusion: A sign of evolving hydrops, related to elevated right atrial and central venous pressures.

• Abnormal umbilical arterial Doppler: Suggests systemic steal and poor systemic perfusion. Specifically, the absence or reversed pattern of diastolic flow in the umbilical artery signals an almost tenfold increased odds of fetal demise or neonatal mortality.

Other important downstream indices that are carefully monitored include:

• Ductus venosus A-wave reversal: Indicates high right atrial and central venous pressures.

• Decreased end-diastolic flow in the middle cerebral artery: Suggests reduced brain perfusion.

• Umbilical vein notching: Often considered a pre-terminal finding.

Fetal cardiac MRI can quantitatively show decreased perfusion to the brain, body, and placenta in the context of circular shunting, with cardiac output potentially reduced by 50%.

3. Fetal Management Strategies Management for these patients must begin in utero and continue until delivery, as they often worsen significantly around the time of birth.

• NSAID Therapy (e.g., Indomethacin): This is a key intervention for severe fetuses with circular shunting.

  • Rationale: NSAIDs can cause constriction of the ductus arteriosus, which in this specific situation, can mitigate the "circle of death" by stabilizing fetal circulation, improving brain and body perfusion, and allowing the baby to survive longer in pregnancy, closer to term.

  • Indications: Severe circular shunting, low right ventricular systolic pressure, and abnormal extracardiac Dopplers.

  • Outcomes: Studies show that successful ductal constriction with NSAIDs significantly increases live birth rates and gestational age at delivery (median 36 vs. 33 weeks). Physiologically, NSAIDs lead to significant jumps in flow to the brain, body, and placenta. This also positively impacts neurodevelopment, as treated fetuses tend to have higher fetal brain weights compared to untreated ones with circular shunting. NSAIDs can also help mitigate hydrops.

  • Dosage & Monitoring: Indomethacin is typically started at 100 mg twice daily, but the dose is titrated based on the fetus's response and requires very close monitoring with repeated studies. The duct becomes more responsive to NSAIDs as gestation progresses, but not all fetuses respond (70-80% response rate).

  • Risks: While generally well-tolerated by the mother (after checking renal function and contraindications like bleeding diatheses or gastrointestinal ulcers), NSAIDs can affect fetal renal function, leading to acute oligohydramnios. This is typically transient and resolves upon stopping the medication. The overall benefit-risk ratio is considered favourable given the high mortality of severe cases.

• Anti-arrhythmia Therapy: Fetuses with Ebstein anomaly are at risk for arrhythmias like re-entrant SVT and atrial flutter, which can cause rapid instability and necessitate anti-arrhythmia treatment.

• Close Surveillance and Delivery Planning: Very close surveillance is required to manage these babies as close to term as possible (ideally 37 weeks). A comprehensive multidisciplinary team approach for delivery planning is essential, and an EXIT (Ex Utero Intrapartum Treatment) backup should be discussed for cases with significant circular shunting to mechanically interrupt it at birth.

4. Neonatal Management and Surgical Approaches Mortality rates remain high in the neonatal period, with 7% dying within the first 24 hours of life and an additional 20-25% dying before hospital discharge. Understanding the right ventricle's capability is crucial.

• Medical Management Limitations: Neonates with Ebstein anomaly or tricuspid valve dysplasia, circular shunting, hemodynamic instability, and low right ventricular systolic pressure (measured by TRJ velocity) generally cannot be medically managed. Those with the lowest TRJ jet velocity have the highest mortality.

• Surgical Intervention (Interrupting Circular Shunt): Urgent surgical interruption of the circular shunt is necessary to stabilize the neonate.

  • Right Ventricular Exclusion (Starnes Procedure): This is the only surgical approach that has consistently led to all children surviving the neonatal period in some studies. The procedure involves:

    • Placing a fenestrated patch over the tricuspid valve to exclude the deconditioned right ventricle and torrential TR from circulation. This temporarily makes the child a single ventricle patient.

    • Often includes ligation or patch placement of the main pulmonary artery.

    • A modified BT shunt to provide pulmonary blood flow.

    • Atrial septostomy.

    • Reduction and plication of the right atrium and right ventricle to allow for greater lung expansion and stability.

    • This decompression of the right ventricle also facilitates left ventricular cardiac output and dynamics, crucial in this fragile period.

  • Alternative Interventions: An isolated main pulmonary artery ligation can be performed initially if a full Starnes procedure is not feasible due to stability or resource limitations.

• Beyond Single Ventricle: A significant and exciting development is that the Starnes procedure does not necessarily commit the patient to lifelong single ventricle management. Later, tricuspid valve repair using the cone technique can restore a one-and-a-half or biventricular physiology. Growing experience, notably from Dr. Dilva's group, shows successful conversion of Starnes patients to these higher-functioning circulations with no early mortality.

5. Role of Fetal Magnetocardiography (FMCG) and Silent Arrhythmias While echocardiography can detect many arrhythmias, FMCG offers additional insights.

• Advantages of FMCG: Provides beat-to-beat continuous recordings, detects transient events missed by echo, allows measurement of cardiac time intervals (P, PR, QRS, QTC), assesses heart rate variability, and can detect silent conduction abnormalities.

• Silent Conduction Disorders: FMCG can detect abnormalities like large/wide/fragmented P waves, enlarged P/QRS complexes (suggesting hypertrophy), complete bundle branch block, unstable QRS morphology, and prolongation of QTC. Crucially, it has revealed transient first- and second-degree AV block in Ebstein patients, a finding not previously appreciated by echo.

• Impact on Prognosis: Arrythmias and conduction abnormalities are important prognostic indicators. In Ebstein anomaly, FMCG studies show that:

  • Fetal tachyarrhythmias are predictors of neonatal demise.

  • QRS duration greater than a z-score of +4 or 90 milliseconds is a significant predictor of neonatal demise, with progression in QRS widening between the second and third trimesters being particularly important. This widening likely underlies many hemodynamic changes. There may be a QRS width (around 100 milliseconds) beyond which survival is unlikely.

  • Transient AV block suggests underlying conduction system disease, possibly related to ischemia or fibrosis.

  • Low heart rate variability patterns are concerning and suggest fetuses may not reach 39 weeks gestation without intervention.

  • ST depression has been observed, though its prognostic significance is still under study.

  • QTC prolongation was not observed in Ebstein cases in one study, though it is seen in other congenital heart diseases.

• Dynamic Nature of the Disease: The severity of Ebstein anomaly progresses between the second and third trimesters, with risk factors becoming more prevalent later in gestation. This highlights the need for ongoing monitoring.

• Clinical Impact: FMCG has altered clinical management in a significant portion of congenital heart disease cases (e.g., 10 out of 33 in one study). The goal is to make FMCG technology more accessible to all fetal care centers, similar to how ECG is used in other life stages.

6. Genetic Considerations Like other major fetal anomalies, baseline genetic testing is recommended. Trisomy 21 (Down syndrome) is the most common genetic abnormality associated with Ebstein anomaly and tricuspid valve dysplasia, occurring in up to 10% of these cohorts.

7. Collaborative Efforts and Future Directions The FEAT (Fetal Ebstein Anomaly and Tricuspid Valve Dysplasia) Registry is a crucial initiative for prospective and retrospective data collection, aimed at understanding the disease course, including neurodevelopmental outcomes. Given the rarity of the disease, collaborative efforts across institutions and continents are vital for improving outcomes.

8. Spectrum of Prognosis and Counseling Ebstein anomaly presents a wide spectrum:

• Mild Cases: Characterized by significant tricuspid valve displacement but minimal TR, with antegrade flow across the RVOT and ductus. These patients are typically stable and may only require elective or semi-elective cone repair later in childhood, with minimal neonatal management.

• Severe Cases: Marked by circular shunting (no antegrade flow, pulmonary regurgitation), evidence of low cerebral and systemic perfusion, high filling pressures, and hydrops. Arrhythmias, when they occur in severe cases, can rapidly destabilize the patient. Counseling often focuses on the pathophysiology (right ventricular function, TR jet velocity, RVOT status) rather than solely relying on quantitative metrics like tricuspid valve z-score, as these are surrogates for severe disease and part of a larger picture. The dynamic nature of the disease means that initial findings in the second trimester do not always predict later severity, emphasizing the need for ongoing monitoring.

Reference: Ebstein Anomaly in the Fetus: Outcomes by Dr Lindsay Freud for the Congenital Heart Academy.

SAS score

The SAS score (0 to 10) is a prognostication score developed based on fetal echocardiography for evaluating Ebstein's anomaly. It combines five echocardiographic measurements (cardiothoracic ratio, Celermajer index, RV-to-LV ratio, pulmonary flow, and ductal flow) into a single score to predict the likelihood of fetal and neonatal mortality. Higher scores indicate a greater risk of adverse outcomes. SAS for Simpson Andrews Sharland (authors’ initials).

Key Components of the SAS Score: 

• Cardiothoracic Ratio (CTR): Compares the heart's size to the chest cavity. 

  • <0.65 = 0 

  • 0.65 to 0.75 = 1

  • >0.75 = 2 

• Celermajer Index: Measures the ratio of the right atrium and atrialized right ventricle to the combined area of the functional right ventricle, left atrium, and left ventricle. 

  • <1.0 = 0

  • 1.0-1.5 = 1

  • >1.5 = 2

• Right Ventricle to Left Ventricle (RV/LV) Ratio: Compares the size of the right and left ventricles. Ratio of RV/LV size (measured in 2 dimensions just below the mitral valve annulus at end-diastole in a 4-chamber view). In the study - expressing the latter as a z score did not improve prediction.

  • <1.5 = 0

  • 1.5-2.0 = 1

  • >2.0 = 2

• Pulmonary Blood Flow: Assesses the flow of blood through the pulmonary artery, with reduced or absent flow indicating a more severe defect. 

  • Normal =0

  • Reduced = 1

  • Absent = 2

• Ductal Flow: Examines the flow through the ductus arteriosus, looking for retrograde flow, which can be associated with worse outcomes. 

  • Anterograde = 0

  • Both = 1

  • Retrograde = 2

• Scoring and Interpretation: Each of the five parameters is assigned a score of 0, 1, or 2 based on its severity, with 0 indicating normal or mild abnormality and 2 indicating a severe abnormality. The scores for each parameter are then added together to create a total SAS score, ranging from 0 to 10. A higher score is associated with a higher risk of fetal or neonatal death. 

Reference: Andrews RE, Tibby SM, Sharland GK, Simpson JM. Prediction of outcome of tricuspid valve malformations diagnosed during fetal life. Am J Cardiol. 2008 Apr 1;101(7):1046-50. doi: 10.1016/j.amjcard.2007.11.049. Epub 2008 Feb 6. PMID: 18359329.

Fetal Echocardiography Example

Moderate Ebstein's malformation of tricuspid valve with moderate to severe regurgitation. Severe right atrial dilation. Moderate RV dilatation. 

Case by Dr Wadi Mawad - Pediatric Cardiology at the Montreal Children's Hospital

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