Fetal Aortic Valvuloplasty for Evolving Hypoplastic Left Heart Syndrome: A Decision Analysis

Abstract

Background: Fetal aortic valvuloplasty (FAV) may prevent progression of midgestation aortic stenosis to hypoplastic left heart syndrome. However, FAV has well-established risks, and its survival benefit remains unknown. Our primary aim was to determine whether FAV for midgestation aortic stenosis increases survival from fetal diagnosis to age 6 years.

Methods and results: We performed a retrospective analysis of 143 fetuses who underwent FAV from 2000 to 2017 and a secondary analysis of the Pediatric Heart Network Single Ventricle Reconstruction trial. Using these results, we developed a decision model to estimate probability of transplant-free survival from fetal diagnosis to age 6 years and postnatal restricted mean transplant-free survival time. FAV was technically successful in 84% of 143 fetuses with fetal demise in 8%. Biventricular circulation was achieved in 50% of 111 live-born infants with successful FAV but in only 16% of the 19 patients with unsuccessful FAV. The model projected overlapping probabilities of transplant-free survival to age 6 years at 75% (95% CI, 67%-82%) with FAV versus 72% (95% CI, 61%-82%) with expectant fetal management, resulting in a restricted mean transplant-free survival time benefit of 1.2 months. When limiting analyses to the improved FAV experience since 2009 to reflect current practice, (probability of technical success [94%], fetal demise [4%], and biventricular circulation [66%]), the model projected that FAV increased the probability of survival to age 6 years to 82% (95% CI, 73%-89%). Expectant management is favored if risk of fetal demise exceeded 12% or probability of biventricular circulation fell below 26%, but FAV remained favored over plausible recent range of technical success.

Conclusions: Our model suggests that FAV provides a modest, medium-term survival benefit over expectant fetal management. Appropriate patient selection and low risk of fetal demise with FAV are critical factors for obtaining a survival benefit.

Keywords: fetal heart; hypoplastic left heart syndrome; infant; probability.

Figure 1:. Decision Tree for the Management of Mid-gestation Aortic Stenosis with Evolving Hypoplastic Left Heart Syndrome

Decision tree with the square representing a decision node for the choice between fetal aortic valvuloplasty versus expectant management for the management of mid-gestation aortic stenosis with evolving hypoplastic left heart syndrome. The circles represent chance nodes, and the triangles represent terminal nodes (dead or alive).

Figure 2. Kaplan-Meier Postnatal Survival Analysis

Kaplan-Meier curve demonstrating the transplant-free survival from live birth to age 6 for patients with biventricular circulation (Biv) status post fetal aortic valvuloplasty (FAV) and with single ventricle (mitral stenosis/aortic stenosis) circulation enrolled in the Single Ventricle Reconstruction (SVR) Trial, excluding those who underwent FAV or biventricular conversion.

Figure 3. Two-way Sensitivity Analysis

Two-way sensitivity analysis of optimal strategy to maximize 6-year survival for management of mid-gestation aortic stenosis over a range of probabilities of fetal demise (x axis) and postnatal biventricular (Biv) circulation after technically successful fetal aortic valvuloplasty (FAV) (y axis). Values for the two parameters that fall in the shaded blue area favor FAV, and those that fall in the shaded red area favor no FAV. The asterisks represent the base case and post-2009 values, both of which are in the blue area.

Figure 4. Frequency Histogram of Difference in Restricted Mean Transplant-free Survival Time (RMST) for Fetal Aortic Valvuloplasty (FAV) versus Expectant Management.

The delta RMST value (months) to age 6 years for each of the 10,000 simulations (FAV – No FAV) was plotted as a frequency distribution. The Y axis is the number of simulations with that delta RMST value. A value of 0 indicates the two strategies had equal expected RMST and is represented by the black bar. A positive value indicates FAV had a greater expected RMST (preferred strategy) and a negative value indicates expectant management (No FAV) had a greater expected RMST.

Figure 5.. Classification and Regression Tree Analysis (CART) for Mid-gestation Echocardiographic Parameters

Our model identified a threshold probability of biventricular circulation above which fetal aortic valvuloplasty provides a 6-year transplant-free survival benefit. The threshold value (26%) is applied to the previously published CART diagram, which identified probabilities of postnatal biventricular circulation based on fetal echocardiographic parameters. Green boxes exceed the threshold, i.e., perform FAV; orange is within +/− 10% of the threshold; red boxes fall below the threshold, i.e., No FAV. Adapted with permission from Friedman et al, Improved technical success, postnatal outcome and refined predictors of outcome for fetal aortic valvuloplasty. Ultrasound Obstet Gynecol. 2018;52:212-220.