Structural evaluation of the fetal heart has now become an accepted component of the
modern morphology scan, and increasingly cardiac structural evaluation is being performed
in the first trimester along with evaluation of risk at the nuchal translucency scan.
While a number of complex cardiac anomalies still elude 100% detection, and others
may be subtle at the time of morphological evaluation and evolve later in gestation,
prenatal detection and accurate diagnosis of fetal structural cardiac abnormalities
and integrated multidisciplinary care has become a standard part of tertiary care.
Within the fetal medicine community and in the international literature, there has
for over a decade been an increasing demand for measures to non‐invasively and accurately
evaluate fetal cardiac function. There are numerous conditions that may be associated
with fetal cardiac impairment, either intrinsic to the heart itself, or extrinsic,
such as the heart strain seen in intrauterine growth restriction (IUGR) or twin‐twin
transfusion syndrome (TTTS), the overload of sacrococcygeal teratomas, vascular compression
of congenital diaphragmatic hernia or chest masses etc. This has resulted in a relative
explosion of publications with a plethora of novel functional indices and techniques,
the majority of which been extrapolated from adult applications.
For two of the more common conditions in fetal medicine practice (IUGR and TTTS),
fetal evaluation is serially performed to determine timing of intervention or delivery.
Additionally, when counselling regarding long‐term outcome, one of the major determinants
in these conditions is potential cardiac dysfunction, though in the absence of validated
Doppler indices, evaluation for this remains relatively crude. Most practitioners
will be familiar with ‘eyeballing’ the fetus to evaluate cardiac orientation, size,
shape, rate and rhythm and to a crude degree evidence of effective contractility.
The enlarged, ‘floppy’ and hypo‐contractile heart may be visually determined, but
this may be a late appearance, as may signs of heart failure with development of hydrops.
Attempts have been made to even quantify the ‘floppiness’ or irregularity of the heart
using a pseudo‐scientific ‘sphericity index’ though one might anticipate that alterations
in cardiac dimensions would be a relatively late feature and represent at least some
degree of cardiac failure. It is the time period before this failure, when there is
subclinical cardiac dysfunction and cardiac remodelling, that is the target of indices
of fetal cardiac function, and it is here that interventions may be optimally directed.
Functional and unique circulatory properties of the fetal heart
A starting point for evaluation of fetal cardiac function is to consider basic cardiac
functions. Simplistically, the heart fills, pauses, contracts, then perfuses, moving
blood effectively and appropriately around the body to provide adequate tissue perfusion.
As has been previously described, ideal function involves preservation of both systolic
and diastolic function, with synchronised time events leading the heart through the
phases of: Isovolumetric relaxation; Early (passive) diastole; Atrial contraction;
Isovolumetric relaxation; Ejection.
1
The fetal heart has two parallel circuits with the two ventricles contributing to
perfusion of the systemic circulation, with three shunts (foramen ovale, ductus arteriosus
and ductus venosus) connecting them. The right ventricle predominantly supplies the
subdiaphragmatic circulation and placenta while the left ventricle is responsible
for supplying highly oxygenated blood to the brain and coronary arteries. Between
these lies the Aortic Isthmus, an important watershed that may give valuable information
about the relative function of the two sides of the heart. The fetal heart is accepted
to show a right heart dominance with 52–65% of cardiac output going through the right
ventricle, 75–90% of which shunts through the ductus arteriosus to the systemic circulation.
2
Perfusion is dependent upon stroke volume, determined in turn by preload, afterload
and contractility. The cerebral and subdiaphragmatic/placental vascular beds determine
ventricular preload and afterload. Venous return is the main factor determining preload
which influences ventricular filling. In conditions of volume overload such as recipient
TTTS, there will be dilatation of the cardiac chambers. Afterload is determined by
the pressure in the outflow vessels, whether aorta or pulmonary artery, against which
the heart must contract. Whilst it may appear simple to deconstruct cardiac function
into individual factors such as preload, afterload, electrical activity and myocardial
contractility, the picture is of course not this clear with each of these factors
showing a strong interdependence. The result of this is that any test that appears
to evaluate one of these components will of course be influenced by the others. This
may be one of the reasons why researchers have proposed complex ‘scoring’ systems
to more comprehensively evaluate cardiac function, though underlying inadequacies
and poor standardisation for each of the components of these scores reduce their potential
impact.
3
,
4
Available techniques for evaluation of fetal cardiac function
Numerous parameters have been proposed to quantify fetal cardiac function, from measurements
including Doppler flow mapping, heart biometry and timing of cardiac events.
2
The basis of many of the novel indices of fetal cardiac function include techniques
familiar to most fetal medicine practitioners and cardiologists such as pulsed wave,
5
M‐mode,
6
and tissue Doppler
7
as well as the relatively new technique of speckle tracking.
8
Traditionally, cardiologists have been trained in, and fetal medicine practitioners
have shied away from M‐mode though it is a very sensitive tool for cardiac measurements.
Speckle tracking involves tracking bright points of myocardium that are generated
by natural acoustic reflections. When these individual points are followed, it is
possible to evaluate the overall deformation of the myocardium, and when a time integral
is introduced this generates velocity vectors, that can be used to calculate displacement,
velocity, deformation (strain) and velocity of deformation (strain rate) in the cardiac
wall.
9
Readers are directed to a number of extensive reviews of techniques for evaluating
fetal cardiac function,
2
,
10
one of which was contained within a focussed fetal cardiac function edition of the
journal Fetal Diagnosis and Therapy from 2012 that can be accessed at the following
location: http://www.karger.com/Book/Home/257215.
Table 1 briefly summarises some of the key two‐dimensional ultrasound techniques that
are now available for evaluation of fetal cardiac function.
11
–
16
Table 1
Key two‐dimensional image‐based functional cardiac tests.
Cardiac parameter
Description
Method
Systolic function
Blood volume estimation: ejection fraction or cardiac output.
Indicative of the volumetric fraction of blood ejected from the ventricle with each
heartbeat, though may only show changes late in progression of some diseases.
1
Volume measurements notoriously prone to inaccuracy of vessel diameter measurement.
M‐mode, speckle tracking.
1
Myocardial deformation: strain and strain rate
Strain and strain rates represent the magnitude and rate respectively of myocardial
deformation.
11
Disagreements remain on how strain and strain rate alter with gestation,
1
and whether frame rates are too low for reliable fetal measurement.
12
Tissue Doppler or speckle tracking.
1
Left ventricular shortening fraction
The difference in ventricular chamber diameter between end‐diastole and end‐systole
divided by the end‐diastolic diameter.
8
Longitudinal motion uses endocardial longitudinal fibres,
8
furthest from the epicardial blood supply so sensitive to hypoxia. This can be challenging
to acquire in the fetus because it depends on the fetal lie to obtain the required
transverse view of the heart.
13
M‐mode.
8
Myocardial motion: fetal tricuspid annular plane systolic excursion (f‐TAPSE) – also
mitral (f‐MAPSE)
A modified method to measure the vertical movement of the tricuspid valve annulus
for assessment of right heart function, providing a quantification of ventricular
contraction.
14
As a parameter reflecting longitudinal function, the f‐TAPSE typically shows changes
earlier in disease progression.
1
M‐mode, speckle tracking.
1
Diastolic function
E/A ratio
Ratio of the two peaks in flow velocity observed over the atrioventricular valves
in diastole, during early (E) passive diastolic filling and during the atrial (A)
‘kick’ or contraction'.
5
,
515
This provides an independent assessment of both sides of the heart.
10
However, results for the E/A ratio have been mixed
10
as respiratory and body movements may have a lot of influence and the fast fetal heart
rate may fuse these waveforms.
Pulsed‐wave Doppler.
10
Global function
Myocardial performance index (MPI)
A measure of global myocardial function using a ratio of isovolumetric to ejection
time intervals. Most commonly performed using the valvular clicks as landmarks
16
using pulsed‐wave Doppler with one plane for the left heart and two separate planes
for the physically separated tricuspid and pulmonary valves. Alternatively performed
using tissue Doppler, especially for the right ventricle
7
where otherwise dual pulsed‐wave Doppler strips are required.
Pulsed‐Doppler, tissue Doppler.
Modified from Crispi, et al,
1
Pitfalls and limitations of fetal cardiac functional evaluation
It is important to note that each of the functional imaging methods may have inherent
methodological limitations, and these may be the reasons why they have not fully translated
from research to clinical tools. One of the major issues that functional fetal cardiac
imaging has suffered from has been a lack of precision, uniformity and consistency
of adopted technique by different research groups. This is not solely a problem for
fetal cardiac imaging. Too frequently, new techniques and technologies are enthusiastically
grasped, a flurry of papers is produced that contribute to academic careers, and the
authors move on to the next area of whim or interest. In their wake they may well
leave a potentially useful tool that has been poorly evaluated and discarded as useless.
Equally, many new proposed software techniques may generate a multitude of multi‐coloured
graphs though on close analysis be little more than ‘random number generators’ with
limited repeatability or reproducibility. Therefore prudence and caution are necessary.
It is becoming increasingly difficult to publish ‘boring’ repeatability studies in
influential imaging journals, when in fact it may be this work that is of most value
to those attempting to translate imaging research into clinical practice.
Our own group at UNSW has focused for the last five years on the Myocardial Performance
Index. This tool was introduced into medicine nearly 20 years ago, extrapolated to
the fetus 15 years ago, and then refined as the ‘Modified MPI’ by use of valvular
clicks in 2005
16
followed by a wide output of research papers into its clinical utility. Soon, the
enthusiastic ‘first adopters’ realised that they were generating differing normal
ranges, so moved on to new fields. When we evaluated this carefully we realised that
the published literature at that stage showed huge variation in normal mean MPIs from
different research groups.
17
Subsequent evaluation of these studies showed widely differing techniques that would
result in over‐ or under‐estimation of true Mod‐MPI. We have since published a number
of technical papers working towards a unified methodology,
18
and have now developed an automated system that will ensure at least that all researchers
can be using the same tool. In the meantime, five years of MPI research and publications
have taken place with a relatively subjective user‐dependent tool. Only with a standardised,
and we feel automated, tool can a detailed evaluation of its utility be considered,
though it may be too late to convince the enthusiastic first adopters to revisit MPI.
So where to in the future?
So what does the future hold for functional fetal cardiology? There is no doubt that
the drive for this will continue to come from the fetal medicine practitioner, striving
to determine which Stage I TTTS case requires laser, or when the IUGR fetus at 28
weeks with redistribution and absent end‐diastolic frequencies in the umbilical artery
should be optimally delivered. Fetal cardiology services in Australia will benefit
from diversifying from structural evaluation to more functional tools. Ideally these
services will follow the lead of international practitioners and literature, evaluating
tools that are superior to ‘eyeballing, while equally learning from the mistakes of
the early‐adopters who may have overlooked tools with true clinical utility. There
must be a continued focus on the laborious and seemingly tedious process of determining
the following: repeatability; influence of machine settings; normal range estimation
with optimised settings; then finally evaluation of pathology. Those publishing results
for pathology must only do so with equally valid normal ranges from their own group
against which to compare. Methodology needs to be explicitly detailed in order for
others to repeat their findings and thus ascribe meaning, and standardised techniques
should be adopted internationally.
In the ultrasound literature over the last few years, there has been a strong focus
upon the optimal tools for demonstrating test repeatability. Repeatability may be
defined as ‘variation in repeat measurements made on the same subject under identical
conditions’, whereas the more commonly used (and probably inaccurate) terminology
is reproducibility which refers to the variation in measurements made on a subject
under changing conditions, whether different methods or instruments or over a period
of time.
19
,
20
Measures favoured to best demonstrate repeatability are the Intraclass Correlation
Coefficient (specifically the two‐way mixed model) and the Bland‐Altman plot for 95%
limits of agreement. For this work we need the support of appropriately funded PhD
students who will make that particular ‘pinhead of science’ the focus of up to four
years of their life.
There is no doubt that there will be a clinically useful Doppler ultrasound tool for
fetal functional cardiology, but the exciting point is that we do not know yet what
that will be. Our own group feels that as well as a focus on global cardiac or individual
ventricular function there is great benefit in evaluating differential ventricular/cardiac
strain, as numerous fetal pathologies show a strain on one side before the other (e.g.
right ventricular strain in TTTS recipients or IUGR), that may not be so clearly determined
by measurement of individual ventricular function. We are in the process of publishing
the normal range and early pathological findings for one such measure, the ‘Delta’
MPI, though it is likely that others will emerge.
21