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.