Fetal circulatory physiology and brain development in complex congenital heart disease: A multi-modal imaging study

Abstract

Objective: Fetuses with complex congenital heart disease have altered physiology, contributing to abnormal neurodevelopment. The effects of altered physiology on brain development have not been well studied. We used multi-modal imaging to study fetal circulatory physiology and brain development in hypoplastic left heart syndrome (HLHS) and d-transposition of the great arteries (TGA).

Methods: This prospective, cross-sectional study investigated individuals with fetal congenital heart disease and controls undergoing fetal echocardiography and fetal brain MRI. MRI measured total brain volume and cerebral oxygenation by the MRI quantification method T2*. Indexed cardiac outputs (CCOi) and vascular impedances were calculated by fetal echocardiography. Descriptive statistics assessed MRI and echocardiogram measurement relationships by physiology.

Results: Sixty-six participants enrolled (control = 20; HLHS = 25; TGA = 21), mean gestational age 33.8 weeks (95% CI: 33.3-34.2). Total brain volume and T2* were significantly lower in fetuses with cardiac disease. CCOi was lower in HLHS, correlating with total brain volume - for every 10% CCOi increase, volume increased 8 mm³ (95% CI: 1.78-14.1; p = 0.012). Echocardiography parameters and cerebral oxygenation showed no correlation. TGA showed no CCOi or aortic output correlation with MRI measures.

Conclusions: In HLHS, lower cardiac output is deleterious to brain development. Our findings provide insight into the role of fetal cardiovascular physiology in brain health.

Figure 1:

Scatterplot and linear fit demonstrating relationship between indexed combined cardiac output and fetal total brain volume (dependent variable) among fetuses with hypoplastic left heart syndrome (regression coefficient= 0.22, p= 0.03, r-squared= 0.28). After adjustment for gestational age at the time of imaging, for every 10% increase in indexed combined cardiac output, TBV increased by ~ 8 mm³ (p = 0.01).

Figure 2:

A) Fetal total brain volume for HLHS fetuses with antegrade flow across the aortic valve compared to aortic atresia (p= 0.18) and b) Fetal total brain volume for HLHS fetuses with antegrade flow in the aortic arch compared to retrograde flow (p= 0.28). Mean is noted by the red solid circle and error bars represent the 95% confidence interval. Hollow black circles represent individual fetuses.

Figure 3:

A) Scatterplot and linear fit demonstrating relationship between indexed combined cardiac output with fetal total brain volume (dependent variable) among fetuses with d-Transposition of the great arteries. No correlation was noted (regression coefficient 0.011, p-value= 0.84, r-squared= 0.003); B) Scatterplot and linear fit demonstrating relationship between aortic output as a percentage of combined cardiac output with total brain volume among fetuses with d-TGA. No correlation was noted (regression coefficient= −38.3, p-value= 0.44, r-squared= 0.04).