Functional echocardiography in the fetus with non cardiac disease

REVIEW
Functional echocardiography in the fetus with non-cardiac disease
Tim Van Mieghem1*, Ryan Hodges1
, Edgar Jaeggi2
and Greg Ryan1
1
Fetal Medicine Unit, Mount Sinai Hospital, University of Toronto, Toronto, Canada
2
Fetal Cardiac Program, Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Canada
*Correspondence to: Tim Van Mieghem. E-mail: t.vanmieghem@gmail.com
ABSTRACT
We describe the hemodynamic changes observed in fetuses with extra cardiac conditions such as intrauterine growth
restriction, tumors, twin–twin transfusion syndrome, congenital infections, and in fetuses of mothers with diabetes. In
most fetuses with mild extra cardiac disease, the alterations in fetal cardiac function remain subclinical. Cardiac
function assessment has however helped us to achieve a better understanding of the pathophysiology of these
diseases. In fetuses at the more severe end of the disease spectrum, functional echocardiography may help in guiding
clinical decision-making regarding the need for either delivery or fetal therapy.
The growth-restricted fetus represents a special indication for routine cardiac function assessment, as in utero
hemodynamic changes may help optimize the timing of delivery. Moreover, in intrauterine growth restriction, the
altered hemodynamics causes cardiovascular remodeling, which can result in an increased risk of postnatal
cardiovascular disease. © 2013 John Wiley & Sons, Ltd.
Funding sources: None
Conflicts of interest: None declared
INTRODUCTION
Fetal cardiac function is routinely examined in the context
of congenital heart disease. More recently, functional
echocardiography has also been applied to fetuses with a
structurally normal heart and hemodynamic challenges due
to extra cardiac conditions. This experience has provided
novel insights into fetal cardiac adaptation to a range of
different fetal and maternal pathologies. Furthermore, novel
imaging tools to assess disease progression, prognosis and fetal
well-being have been proposed. The aim of this manuscript is
(1) to review the literature regarding the more common
pathologies seen in clinical practice (Table 1) and (2) to
demonstrate how functional echocardiography can help guide
clinical management decisions of some of these conditions.
BASIC FETAL CARDIOVASCULAR PHYSIOLOGY
In a healthy fetus, oxygenated blood returns from the placenta
through the umbilical vein and the ductus venosus to the right
atrium. The ductus venosus streams this blood preferentially
through the foramen ovale toward the left atrium, where it
mixes with the pulmonary venous return,1
and the left
ventricle then ejects this blood into the aorta. A small
percentage of the left ventricular output is distributed to the
coronary arteries to perfuse the heart, whereas three quarters
of the blood flows to the head and upper body. The remainder
of the oxygenated blood is directed into the descending aorta
and the lower body.
The right ventricle on the other hand receives lower
saturated blood from the systemic veins, which is forwarded
into the main pulmonary artery. About one third of the right
ventricular stroke volume passes via the lung circulation,
whereas two thirds advances via the ductus arteriosus into
the descending aorta, the lower body, and the placenta.2
It is important to note that the left and right heart
circulations work in parallel and are connected at the level of
the foramen ovale, the ductus arteriosus and the aortic
isthmus. Although the cardiac chambers appear symmetrical
in size, the right ventricle is dominant in a healthy fetus and
provides about 60% of the combined fetal cardiac output,
whereas the left ventricle contributes about 40%.3
Functional
or anatomic changes that may occur at the level of these
communications allow the fetus to favor one part of the
circulation over another. The change in cardiac loading may
then lead to a discrepancy in ventricular dimensions.
HOW TO ASSESS FETAL CIRCULATION WITH ULTRASOUND?
Multiple non-invasive, ultrasound-based, methods are available
to assess the fetal circulation. Here, we will describe the basic
tools required to understand the hemodynamic changes that
occur in fetuses with extra cardiac disease. We direct the
interested reader to recent review articles4,5
for a more in-
depth discussion of the different indices of cardiac function
and their specific application in individual pathologies. It is
important to appreciate that most methods described are
Prenatal Diagnosis 2013, 33, 1–10 © 2013 John Wiley & Sons, Ltd.
DOI: 10.1002/pd.4254

Table1Summaryofprenatalandlong-termcardiacﬁndingsinfetuseswithnon-cardiacdisease
CardiacoutputCardiacsizeHypertrophyDiastolicfunctionSystolicfunctionArrhythmiaLong-termconsequences
IUGRNormal,shift
towardLV
RelativecardiomegalyRV,lateRVdysfunction
(increasedafterload)
Normal—Globularheart,impaired
relaxationandhypertension
SCTandTRAPIncreasedCardiomegaly——Increased—Normalizationafterresection
CCAMDecreasedDecreased—Poorﬁllingduetoextrinsic
compression
Normal—Normalizationafterresection
Left-sidedCDHNormal,shift
towardRV
SmallLV——Normal—NormalafterCDHrepair
TTTS(recipient)Normal/
decreased
CardiomegalyRV>LVIntrinsicRV
dysfunction>LV
dysfunction
Decreased,late—Fullrecoveryafterfetoscopiclaserandhigherarterial
stiffnessindonorafteramniodrainage
FetalanemiaIncreasedCardiomegaly—NormalIncreased—Partialcorrectionaftertransfusion,yetreducedLVmassin
childhood
PelvicmassesNormalNormal/increasedif
pulmonaryhypoplasia
RVRVdysfunctiondueto
increasedafterload
Normal—?
MaternalGravesdiseaseIncreasedNormalRVNormalNormalSinustachycardiaNormalizationpostnatally
MaternaldiabetesNormalCardiomegalyInterventricularseptum>
freewall,RV=LV
DecreasedDecreased(mild)—Normalizationpostnatally
Myocarditis
(SLE,infections)
Normal/
decreased
Cardiomegaly—VariableDecreasedHeartblockDilatedcardiomyopathy
IUGR,intrauterinegrowthrestriction;LV,leftventricle;RV,rightventricular;SCT,sacrococcygealteratoma;TRAP,twinreversedarterialperfusion;CCAM,congenitalcysticadenomatoidmalformation;CDH,congenitaldiaphragmatichernia;TTTS,
twin–twintransfusionsyndrome;SLE,systemiclupuserythematosus.
T. V. Mieghem et al.

indirect reflections of fetal cardiac function and that they are
strongly influenced by cardiac preload (venous return) and
afterload (peripheral vascular resistance). Moreover, most
methods are subject to large inter-observer and intra-observer
variability, which, although acceptable in a research setting,
limits application in clinical practice.
Cardiac output measurements reflect the volume of blood
flowing through the heart per unit of time. When measured
using Doppler ultrasound of the outflow valves, combined
left and right ventricular outputs per fetal weight stay stable
throughout gestation at around 400–450 ml/kg/min6,7
Cardiac output is a crude estimate of the cardiac global
‘pump’ function and is influenced by heart rate, preload,
afterload, ventricular volume, and myocardial contractility.
Methods that look more specifically at myocardial function
include the measurement of the shortening fraction8
(the
percentage of radial narrowing of the ventricle during systole
measured using M-mode echocardiography, which ranges
around 32 ± 6%) or cardiac strain and strain rate (the relative
myocardial shortening over time, which can be measured
using speckle tracking or tissue Doppler9
). Longitudinal
ventricular contractility can be assessed by evaluating the
atrioventricular annulus motion (tricuspid or mitral annular
plane systolic excursion10,11
). Eyeballing ventricular
contractility, albeit less objective, is a valid clinical tool and
commonly used. Although the aforementioned methods are
more reflective of intrinsic myocardial function, they are still
influenced by preload and afterload.
Another commonly used tool in fetal cardiology is the
myocardial performance index (MPI) or Tei index,12
which
is the sum of the isovolumetric contraction and relaxation
time (ICT + IRT) divided by the ejection time (Figure 1).
These time intervals, during which the heart contracts to
overcome the systemic pressure or relaxes in preparation
for ventricular filling, can be measured using either
combined Doppler sampling of blood flow through the
atrioventricular and the outflow valves (Figures 1 and 2) or
using tissue Doppler. The ICT reflects systolic function
(contraction), with longer contraction times reflecting
worse function. The IRT on the other hand reflects diastolic
myocardial function (relaxation). As such, the complete MPI is
a measure of global systolic and diastolic cardiac function,
which is strongly dependent on intrinsic myocardial function.
Finally, the E/A index is the ratio of early (E, passive
ventricular filling) and late (A, atrial contraction) ventricular
inflow through the atrioventricular valves. In the fetus, the
E/A index is typically less than 1, and the normal inflow
pattern is ‘biphasic’ (Figures 1 and 2) with distinct E and A
peaks. In fetuses with diastolic myocardial dysfunction in
whom the heart becomes less compliant and more dependent
on atrial contraction for ventricular filling, the E/A index
decreases. The E and A waves can also fuse, resulting in a
‘monophasic’ inflow pattern. With worsening diastolic
function, the inflow duration, which usually makes up >35%
of the total cardiac cycle length,13
will shorten. Poor
atrioventricular valve function can also result in valvular
regurgitation, which can be documented with color or pulsed
Doppler. Mitral or tricuspid valve regurgitation can either be
due to intrinsic valve abnormalities or can arise as a
consequence of dilatation of the atrioventricular valve ring
secondary to increased volume loading, myocardial
dysfunction, or high ventricular pressures.
In most situations, the cardiac sonographer will combine
different indices to assess the different aspects of
ventricular function or select a particular parameter, which
is most for a specific disease process, as will be discussed
later.
INTRAUTERINE GROWTH RESTRICTION (IUGR)
The fetus with progressive placental dysfunction and ensuing
IUGR is probably the most comprehensively studied to date
from a cardiovascular perspective, and this clinical scenario is
one of the most common indications for fetal hemodynamic
assessment. With advancing placental disease, the resistance
in the umbilical artery rises, reflecting a reduction in patent
downstream villous vessels. This can be imaged by Doppler
ultrasound, initially as a decrease in end-diastolic velocity,
which then progresses to absent and eventually reversed
diastolic flow. The increased placental resistance (afterload)
leads to a lower portion of the fetal cardiac output being
Figure 1 Graphical representation of the Doppler waveform used to measure the myocardial performance index. This waveform is obtained
by placing the Doppler sample volume over the mitral and aortic valve together in an apical or basal five-chamber view
Fetal hemodynamics in non-cardiac disease

directed to the placenta14
and hence a decreased return
through the umbilical vein. Overall however, cardiac output
is maintained because of an increased recirculation within
the fetal body.14
Fetal hypoxia causes an increase in sympathetic tone
and constriction of the portal hepatic vascular bed. This
constriction is more pronounced in the portal vessels than
in the ductus venosus and hence favors ductus venosus
shunting at the cost of decreased liver perfusion.15
This effect is further augmented by a dilatation of the
ductus venosus.16
As outlined earlier, the ductus venosus
preferentially directs blood through the foramen ovale
toward the left ventricle. The changes in hepatic and
ductus venosus blood flow observed in IUGR therefore
favor the left rather than the right ventricular venous
return.17
The left ventricular output is further augmented by
cerebral18
and coronary vasodilatation19
(heart and brain
sparing effect), which decrease the left ventricular
afterload. The biologic utility of this dominant left-sided
circulation is that the oxygenated blood from the
placenta is now preferentially shunted toward the heart
and brain, which are essential for survival and
metabolically the most demanding. The heart and brain
sparing effect is clinically expressed as an increased head
circumference relative to the abdominal circumference
and a relative cardiomegaly in severe IUGR (normally
grown heart in a small chest).
Despite this protective redistribution of oxygenated blood
toward the heart, subclinical myocardial impairment occurs
as demonstrated by an abnormal MPI antenatally and evidence
of myocardial cell damage at delivery.20
Moreover, the fetal
heart remodels to a more globular configuration,21
the
implications of which will be discussed later. Of clinical
relevance, an abnormal MPI seems to predate decompensation
or fetal death by 26 days.22
As placental resistance increases, and now with a vasodilated
left-sided vascular bed, the blood expelled from the right
ventricle takes the path of least resistance, and retrograde
shunting occurs at the level of the aortic isthmus (Figure 3).
This finding has been reported to become evident
approximately 12 days prior to decompensation or fetal
death.22
In the presence of retrograde aortic isthmus flow,
poorly oxygenated right ventricular blood, intended for the
placenta and lower body, mixes with oxygenated left
ventricular blood and perfuses the brain, thereby reducing
the mean oxygen tension in the cerebral vascular bed. The
exact meaning of this finding is unknown, but some studies
suggest that this may negatively affect long-term
developmental outcomes of the affected offspring.23
If IUGR is allowed to progress even further, usually in
the setting of extreme prematurity, where the clinician
attempts to maximize gestational age before delivery,
extensive diastolic cardiac dysfunction will result in
impaired preload handling. This can be documented as a
progressive increase in pulsatility index in the ductus
venosus,22
manifested initially as deepening and ultimately
reversal of the a-wave.24
A pulsatile flow pattern can occur
in the umbilical vein. If the fetus remains in utero, the risk
of demise is very high. A prospective multicenter study,
which included more than 600 live-born growth-restricted
infants, showed that the ductus venosus Doppler was a
strong predictor of neonatal mortality and morbidity in
infants born after 27 weeks gestation whose birth weight
was over 600 g.25
In survivors, the cardiac changes observed antenatally may
not resolve at birth. Cripsi et al. reported that these children
maintain more globular hearts with impaired ventricular
relaxation, whereas others documented decreased stroke
volumes, early onset hypertension and increased intima-media
thickness,21,26,27
resulting in a significantly increased risk for
premature cardiovascular disease.28
Functional echocardiography has given us a better
understanding of the sequence of events starting at
placental failure and ending with postnatal cardiovascular
disease. The challenge for clinicians and researchers now
lies in identifying how to modulate the growth-restricted
neonate’s primed phenotype to prevent adverse events
later in life. This area must become a priority in
perinatal research.
Figure 2 Representative Doppler waveforms in a monochorionic twin pair affected by stage IV twin–twin transfusion syndrome. Legend: left
pane: donor; right pane: recipient. Top line: myocardial performance index, middle line umbilical vein and ductus venosus; bottom line:
tricuspid valve flow. ICT, isovolumetric contraction time; ET, ejection time and IRT, isovolumetric relaxation time. Note prolongation of ICT
and IRT, biphasic umbilical vein pulsations, reversal of a-wave in ductus venosus, tricuspid regurgitation and decreased E/A ratio in the
recipient fetus

VASCULAR TUMORS AND TWIN REVERSED ARTERIAL
PERFUSION (TRAP) SEQUENCE
Vascular fetal or placental tumors such as solid sacrococcygeal
teratomas (SCT), cavernous hemangiomas or chorioangiomas
are rare. These masses can function as large arteriovenous
anastomoses leading to a hyperdynamic fetal circulation.
A slightly different but similar situation is encountered in
TRAP sequence, wherein a healthy ‘pump’ fetus perfuses its
monochorionic acardiac parasitic co-twin through placental
vascular anastomoses.
The hemodynamic effects of volume load on the fetal heart
largely depend on the size and vascularization of the tumor
mass or acardiac twin. The typical echocardiographic image
seen is a dilated heart with an increased cardiothoracic ratio.29
The cardiac output is increased and, in SCT, the inferior vena
cava, which drains the blood from the tumor to the heart, is
often widely dilated, suggesting an increased preload (Figure 4).
Intrinsic myocardial function, as measured by the MPI,
is typically preserved.29
In more advanced disease states,
however, cardiac failure develops, leading to polyhydramnios,
hydrops and placentamegaly. At that stage, reversal of the a-
wave in the ductus venosus and atrioventricular valve
regurgitation may be observed, and the risk of intrauterine
fetal demise is high.30
Close surveillance during pregnancy and timely diagnosis of
fast tumor growth with progression to high output failure are
warranted as these predict a worse fetal outcome.29,31
In the
presence of fetal decompensation (i.e. hydrops), delivery
should be considered. In the previable period, fetal therapy
directed at interrupting the blood supply toward the parasitic
mass may be an option. In TRAP, this can be performed by
occlusion of the acardiac twin’s umbilical cord (either by
radiofrequency ablation or bipolar cautery), which results in
80% survival of the pump twin.32,33
In SCT, open fetal surgery
or minimal invasive strategies aimed at interrupting the flow
to the tumor may be attempted.34,35
Following successful fetal
therapy, cardiac output typically normalizes, and the high
output state resolves.36
Figure 4 Sagittal magnetic resonance image (left) and ultrasound (right) demonstrating a widely dilated inferior vena cava (arrow) in a fetus
with a massive sacrococcygeal teratoma at 26 weeks gestation
Figure 3 Graphical representation of the blood flow in the aortic isthmus in a normally grown fetus (A) and in severe growth restriction (B). (C)
Clinical example of reversed aortic isthmus flow in a fetus with severe intrauterine growth restriction. Legend: red, oxygenated blood; blue,
deoxygenated blood and purple, mixed oxygenated and deoxygenated blood

For now, assessment of cardiac output is used in adjunct to
other (non-cardiac) parameters to select patients for fetal
therapy.31
Decisions on prenatal intervention should not
be taken on the basis of cardiac output alone, as in some
fetuses’ high output states can be well tolerated for relatively
long periods.
INTRATHORACIC SPACE OCCUPYING LESIONS
Large lung lesions such as bronchopulmonary sequestrations
and congenital cystic adenomatoid malformations can
compress the heart and thus extrinsically limit right ventricular
filling. On echocardiography, this is evident as an increased
right ventricular MPI,37
an increased E/A ratio38
or a short,
monophasic inflow pattern, and decreased cardiac output.37
Moreover, cardiac tamponade increases ventricular filling
pressure and the hydrostatic central venous pressure,39
which,
if severe enough, will lead to hydrops. Similar hemodynamic
changes are also seen in other intrathoracic space occupying
lesions, such as congenital high airway obstruction, pleural or
pericardial effusions, and pericardial teratomas.40–45
Although detection of hydrops in the previable period is an
indication for fetal therapy,46
detailed monitoring of fetal
hemodynamics has no role in the clinical management of
fetuses with congenital cystic adenomatoid malformations,
and changes in cardiac output or ventricular filling alone are
not indications for intervention.47
Assessment of tumor size
may be more indicative of the need for fetal therapy.48
The role
of functional echocardiography may be more important in
evaluating pericardial effusions. Indeed, small effusions with
rapid onset (such as those seen after an intracardiac fetal
procedure49
) may sometimes be hemodynamically more
challenging for the fetus than large, gradually appearing
effusions, and echocardiography can help in guiding the need
for therapy.
In the left-sided congenital diaphragmatic hernia, the
abdominal organs herniating into the chest cause mediastinal
shift and result in altered ductus venosus streaming over the
foramen ovale50
and a decreased left ventricular preload.
Moreover, the hypoplastic lungs of diaphragmatic hernia
fetuses have a more muscularized pulmonary vasculature,
which is more resistant to blood flow. As a consequence,
venous return from the lungs to the left atrium is reduced,
again decreasing the left ventricular preload. This leads to an
underfilled and thus smaller left ventricle51
and redistribution
of the cardiac output toward the right ventricle.52
The opposite
observations are true in the right-sided diaphragmatic hernia,
where the right ventricle is smaller than in controls, and the
right-sided cardiac output is reduced.53
Myocardial function
is nevertheless preserved.51
The degree of prenatal ventricular
hypoplasia is not related to postnatal survival in infants with
congenital diaphragmatic hernia, but pulmonary blood flow
may be a predictor of pulmonary hypertension.54,55
Fetal
therapy for diaphragmatic hernia, which is aimed at promoting
lung growth by temporarily occluding the fetal trachea, does
not adversely affect cardiac function.51
Postnatally, with recovery of the preload and closure of
the shunts between the left and right circulations, the
ventricular volumes recover, and long-term cardiac outcomes
are normal.56
TWIN–TWIN TRANSFUSION SYNDROME (TTTS)
Twin–twin transfusion syndrome complicates 10–15% of all
monochorionic twin pregnancies. Although its
pathophysiology is poorly understood, vascular anastomoses
in the placenta lead to a polyuric polyhydramnios in the
recipient twin and oliguric oligohydramnios in the donor co-
twin.57
In addition, the recipient fetus is hypertensive58
and,
related to the high afterload, typically displays phenotypic
signs of hypertrophic cardiomyopathy with biventricular
hypertrophy, atrioventricular valve regurgitation, diastolic
dysfunction and later also systolic dysfunction.59–63
These
findings can be demonstrated both by ultrasound (ventricular
wall thickening, mitral and tricuspid regurgitation,
monophasic ventricular inflows, increased MPI, decreased
ventricular strain63
and a-wave reversal in the ductus venosus;
Figure 2) and biochemical markers of cardiac function in the
amniotic fluid (natriuretic peptides and troponin).64
The
typical TTTS phenotype predominantly affects the right
ventricle and often precedes the picture of the full-blown
clinical syndrome.65
Fetal cardiac function is worse in the more
advanced Quintero stages66
of the disease, and, at least in stage
I TTTS, worse cardiac function is predictive of disease
progression.67
In more severe TTTS, high afterload can result
in an acute right or less commonly, left ventricular failure with
a picture of (reversible) functional pulmonary or aortic artresia
with no antegrade flow over the cardiac outlets and retrograde
flow in the ductus arteriosus or aortic arch.68,69
The echocardiographic findings in TTTS suggest that the
disease process is not only mediated by interfetal volume shifts
(which would result in a picture of volume overload rather
than a hypertensive cardiopathy) but that intertwin exchange
of vasoactive endocrine mediators such as endothelin-170
and
the renin-angiotensin system71
probably also plays an
important role. We find it interesting that, similar, but often
milder, changes in cardiac function to those seen in TTTS can
be observed in the larger fetus of monochorionic twin
pregnancies affected by severe intertwin growth
discordance,35,72,73
suggesting an overlap in pathophysiology
between these conditions.
Fetal therapy, that is, fetoscopic laser ablation of the culprit
placental vascular anastomoses, has shown TTTS to be an
excellent demonstration of the regenerative capacity and
plasticity of the fetal heart. Fetoscopic laser ablation that is
now the standard of care for severe TTTS74,75
does not only
reverse the amniotic fluid discordance but after days to weeks
also leads to a full recovery of fetal cardiac function.69,76–78
Despite this, however, recipient twins remain at a higher risk
for congenital heart disease, including mainly pulmonary
stenosis and septal defects78
and therefore, require close
antenatal and postnatal echocardiographic follow-up.
FETAL ANEMIA
The moderately anemic fetus typically is in a hyperdynamic
high output state as it tries to recirculate the available
hemoglobin more rapidly to maintain adequate tissue

perfusion. This, in combination with less viscous blood, leads
to higher blood flow velocities in the middle cerebral artery.
Non-invasive Doppler measurement of these velocities can
be used to accurately assess the degree of fetal anemia.79
In the heart, a hypercontractile state can be observed,
with increased shortening fractions and strain,80
resulting in a
higher cardiac output.81
Cardiomegaly seen in this ,setting
is a sign of fetal compensation (increased ventricular
volumes to achieve a higher output) rather than a sign of
decompensation.82
Severe anemia may lead to cardiac
ischemia, poor cardiac contractility and ultimately, fetal
demise.
Importantly, and unlike the middle cerebral artery Doppler,
cardiac findings do not necessarily correlate with the severity
of fetal anemia and are therefore not helpful in the clinical
management of this condition.83
Intrauterine transfusion,
which is the state-of-the-art therapy for severe fetal anemia,
partially corrects the cardiac findings in utero.80
In childhood,
however, reduced left ventricular mass and left atrial area have
still been reported,84
the clinical implications of which are
unclear as of yet.
PELVIC MASSES
Dilated intra-abdominal structures such as a megacystis due
to lower urinary tract obstruction 85
or large ovarian cysts86
can compress the fetal abdominal and pelvic vessels and
cause increased downstream resistance on the right
ventricle. This can result in ventricular hypertrophy, altered
ventricular filling (higher reliance on the atrial contraction
as evidenced by a decreased E/A index and a higher
pulsatility index in the ductus venosus), tricuspid
regurgitation, cardiomegaly and pericardial effusions.85
These changes are however reversible after therapy87
and
likely of little clinical significance.
CONGENITAL INFECTIONS
The most common infections causing fetal myocarditis are
cytomegalovirus88
and human parvovirus B19.89
Although
cytomegalovirus is most commonly present with other
evidence of infection, such as ventriculomegaly and
intracranial and abdominal calcifications or IUGR, the
infection can also be present in dilated cardiomyopathy.90
The fetus with parvovirus B19 on the other hand, when
symptomatic, almost always has cardiac signs, either due
to severe fetal anemia (see previous discussion) or
occasionally to acute myocarditis, which is present on
ultrasound as cardiomegaly with variably abnormal diastolic
and systolic function parameters, marked ascites or full-
blown hydrops.91
Arrhythmias, due to inflammation of the
electric conduction system, are very rare.89
MATERNAL CONDITIONS AFFECTING THE FETAL HEART
Maternal Graves disease can cause fetal hyperthyroidism
through transplacental passage of thyroid stimulating
antibodies. Similar to experiments in lambs,92
fetal
hyperthyroidism will cause sinus tachycardia in the range of
180–200 beats per minute with an ensuing increase in fetal
cardiac output. In case of mild to moderate fetal
hyperthyroidism, additional findings can include right
ventricular hypertrophy with preserved ventricular function
and pericardial effusions.93
These signs disappear after birth,
when thyroid function normalizes.93
In more extreme cases,
if the tachycardia is uncontrolled, fetal cardiac failure, hydrops
and intrauterine death can occur.
The cardiomyopathy observed in fetuses of diabetic
mothers is the consequence of fetal hyperinsulinism94
and
occurs both in well and poorly controlled diabetics.95,96
Severity of the disease, however, is dependent on glycemic
control, and severe forms affecting cardiac function are
almost exclusively seen in poorly controlled diabetes.
Diabetic cardiopathy occurs both in pre-gestational and
gestational diabetes. The myocardial hypertrophy
predominantly affects the interventricular septum but may
also involve the free walls symetrically.97
This myocardial
hypertrophy resolves after birth, when insulin levels
normalize, leaving no long-term consequences98,99
but may
have severe implications antenatally when obstruction
occurs at the level of the outflow tracts.
Although usually only noticed by echocardiography in
the third trimester of pregnancy, the myocardium of
diabetic fetuses may already be abnormal from early
pregnancy onwards, with decreased ventricular compliance
(diastolic dysfunction), as evidenced by abnormal
ventricular inflow patterns,100
atrial shortening fraction
and isovolumetric relaxation time.101,102
Interestingly, some
of these changes are also noted in diabetic fetuses without
myocardial hypertrophy. Systolic function was typically
thought to be preserved, yet use of more sensitive
ultrasound techniques reveals that subtle changes in
cardiac strain may be present in the hearts of fetuses of
diabetic mothers.103
Similar to the observations in congenital infections,
maternal systemic lupus erythematosus can cause a fetal
myocarditis with ensuing endocardial fibroelastosis, dilated
cardiomyopathy and complete heart block due to
transplacental passage of anti-Ro antibodies.104
Although the
incidence of neonatal heart block is low (less than 2% of infants
of mothers with anti-Ro antibodies), the mortality and
morbidity are significant and related to the life-long
dependency on postnatal pacing.104
CONCLUSIONS
We have described the alterations in fetal cardiac function that
are seen in the more common non-cardiac fetal pathologies. In
most cases, when the extra cardiac fetal disease is mild, these
changes will remain subclinical, go unnoticed on routine
obstetric ultrasound and reverse after treatment. In more
severe cases, however, alterations in fetal cardiac function
may become clinically apparent and lead to fetal
decompensation (hydrops and death).
In selected conditions, functional echocardiography may
help in guiding clinical decision-making regarding a need for
early delivery or offering antenatal therapeutic intervention.
Obstetricians, sonographers and fetal medicine specialists
should therefore be familiar with the (basic) fetal cardiac
function assessment to evaluate the hemodynamic state in a

fetus with extra cardiac disease. This would include at least
rough estimates of systolic (eyeballing ventricular contractility)
and diastolic functions (ventricular inflow pattern, valvular
regurgitation and ductus venosus Doppler). If function appears
impaired, a more detailed assessment in a fetal cardiology unit
is indicated.
The growth-restricted fetus may represent a special
indication for performing routine functional cardiac
assessment. More research is needed to define which, if any,
novel functional indices should become part of our clinical
armamentarium when evaluating the fetus with IUGR
antenatally and in following, the growth-restricted neonate.
WHAT’S ALREADY KNOWN ABOUT THIS TOPIC?
• Fetal cardiac function can be altered in fetuses with extra cardiac
disease.
WHAT DOES THIS STUDY ADD?
• This article summarizes the changes in fetal hemodynamics seen in
fetuses with non-cardiac disease and demonstrates how fetal
cardiac function assessment can improve our understanding of the
pathophysiology of these conditions.
• The manuscript reviews how fetal hemodynamic assessment can
help in guiding the clinical management of the sick fetus.
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