DISCUSSION
CMH therapy in the third trimester results in fetal pulmonary vasodilation following larger venous return to the left fetal heart and increased left ventricle filling with significantly increasing anterograde flow in the aortic isthmus. With this manipulation it is anticipated to augment blood flow-directed remodeling of the left heart structures and improve left heart growth spanning from the mitral valve to the aortic isthmus (8). It has been shown in animals that increased ventricular preload was followed by myocyte proliferation in hypoplastic left ventricles due to an increase in cardiac preload from pulmonary vasodilation, which may also increase hypoplastic fetal cardiovascular dimensions in humans (15). To date, there have been a limited number of studies published on intrauterine fetal treatment of HLHS in humans with CMH (2-7).
Kohl (2) was the first to demonstrate the effects of CMH on cardiac dimensions, which suggested therapy after 28–29 weeks of gestation in 15 fetuses with various grades of hypoplastic cardiovascular structure. Kohl (2) reported that CMH therapy improved ventricular volume, atrioventricular valve diameter, semilunar valve diameter, and great artery and aortic isthmus diameters in most fetuses.
In a related case study, Kohl (3) also reported that additional cardiac defects, such as ventricular septal defects (VSDs) and obstruction in ventricular filling or emptying neutralized the effect of CMH therapy. In the current study VSD and mitral stenosis had no deleterious effect on fetal therapy.
Zeng et al. (5, 6) used a similar fetal oxygenation protocol several hours each day in cases with coarctation of the aorta (CoA) during the third trimester until delivery. Zeng et al. (5, 6) found an association between the CMH therapy time interval and cardiac measurements; specifically, the longer the hyperoxygenation period, the better the increase in left heart size. The same group also reported (6) an increase in the strain and strain rate of both ventricles in fetuses treated with CMH compared to untreated fetuses with CoA, suggesting that CMH leads to an improvement in ventricular function.
Finally, Lara et al. (7) examined the effects of CMH on fetuses with HLHS and showed progression in AV and MV dimensions, although the difference was not statistically significant because of the small sample size. Lara et al. (7) concluded that CMH > 9 h/d was related to better aortic annular development.
There is growing evidence of brain dysmaturation in fetuses with congenital heart disease (CHD) originating during the fetal period (16). The decrease in fetal brain oxygenation has been demonstrated in fetuses with CHD, which has been related to smaller fetal brain volumes (17, 18). The fetal brain has a protective autoregulatory mechanism to avoid the difference between cerebral metabolic demand and supply by increasing cerebral blood flow with a decrease in cerebrovascular resistance (CVR). Better hemodynamic status may be achieved with MH administration to augment global oxygen saturation and increase aortic flow; however, only one study described the practice of CMH in the third trimester as a possible treatment method to improve fetal brain growth (9). Edwards et al. (9) reported nine fetuses with left heart hypoplasia (LHH) treated with CMH that resulted in a significant decrease in fetal biparietal diameter (BPD) development during pregnancy and a smaller head circumference (HC) Z-score 6 months postpartum. Although umbilical artery resistance and placental growth were not significantly different between groups and there was no apparent change in the MCA CVR, Edwards et al. (9) hypothesized that CMH may have a negative effect on placental function and growth. MH administration for greater than 9 h/d had a positive effect on MCA CVR, suggesting an improvement in cerebral oxygenation. Furthermore, a higher duration of weeks and hours on CMH were related to a superior increase in BPD. Based on these findings, Edwards et al. (9) hypothesized that the dosing and timing of CMH may be important. In a fetal lamb study conducted by Accurso et al. (19), MH caused a peak in pulmonary blood flow at 45 min, which returned to baseline within 2 h. Such temporary peaks and normalizations in blood flow with intermittent periods of increased oxygen may have consequences, resulting in numerous periods of pulmonary and systemic vascular fluctuations, which may disturb cerebral blood flow and impact BPD and HC growth. Compared to the Kohl (3) and Zeng et al. (5,6) studies, another difference in the current cases was starting CMH at 26 gestational weeks instead of ≥28-29 gestational weeks. Finally, Edwards et al. (9) modified the CMH protocol to longer daily exposure with fewer interruptions and a lower FiO2 for corollary studies.
In addition, Hogan et al. (20) reported that the affected structural anatomy and related cardiovascular physiology differed from the cerebrovascular autoregulatory responses in CHD. Fetuses with left-sided obstructive lesions (LSOLs) had the lowest CR compared to right-sided obstructive lesions (RSOLs) and transposition of the great arteries (TGAs). The reason for the lower CR pattern in LSOLs was due to both intracardiac mixing and reduced aortic output.
Furthermore, You et al. (21) demonstrated differences in single- and two-ventricle fetuses brain oxygen autoregulation during AMH. While single-ventricle and aorta-obstructed fetuses had a blood oxygen level dependent magnetic resonance imaging (MRI), two-ventricle CHD and healthy fetuses had no change in brain oxygenation with progressing gestation. They concluded that single-ventricle and aorta obstructed fetuses had lower baseline cerebral oxygen delivery, whereas the absence of increased brain oxygenation during AMH in two-ventricle CHD and healthy fetuses reflected the existence of a stable cerebrovascular regulatory system, which proved that essential oxygen delivery to the brain was preserved in these fetuses.
The possibility of adverse impulse on brain development in CMH was also discussed by Rudolph (22) in a fetal lamb study. With a reduction in cerebral blood flow, even though the cerebral oxygen supply was maintained, cerebral glucose delivery and consumption was significantly reduced. These metabolic changes did not occur in our cases.
Finally, Lee et al. (23) and Co-Vu et al. (24) both concluded in their reviews of MH therapy that current evidence suggests an increase in pulmonary blood flow, pulmonary venous return, ductal flow, and left heart dimensions in fetuses and that it has the potential to be used as a diagnostic tool, as well as therapeutic tool in fetuses with CHD. Lee et al. (23) and Co-Vu et al. (24) also highlighted that well-designed randomized controlled trials are needed and that it is difficult to ascertain whether CMH therapy provides improved outcomes on fetuses with CHD to baseline.