REVIEWS

Prenatal screening for structural congenital

heart disease
Lindsey E. Hunter and John M. Simpson
Abstract | Congenital heart defects can be diagnosed during fetal life using echocardiography. Prenatal
diagnosis allows full investigation of affected fetuses for coexisting abnormalities, and gives time for parents
to be informed about the prognosis of the fetus and treatments that might be required. In a minority of cases,
where the natural history suggests an unfavourable outcome, prenatal diagnosis provides an opportunity for
fetal cardiac intervention. For some cardiac lesions, notably hypoplastic left heart syndrome, transposition
of the great arteries, and coarctation of the aorta, prenatal diagnosis has been shown to reduce postnatal
morbidity and mortality. Some costs of care, notably the transport of critically ill infants, are reduced by
prenatal diagnosis. Prenatal screening programmes typically recommend detailed assessment of fetuses
judged to be at high risk of congenital heart disease. However, most cases of congenital heart disease arise in
the low-risk population, and detection of affected fetuses in this setting depends on recognizing abnormalities
of the heart during the midtrimester scan. Evidence supports the use of structured training interventions and
feedback to those undertaking sonographic examinations, to improve the prenatal detection of congenital
heart disease.
Hunter, L. E. & Simpson, J. M. Nat. Rev. Cardiol. 11, 323–334 (2014); published online 25 March 2014; doi:10.1038/nrcardio.2014.34

Introduction
Congenital heart disease (CHD) is the most-common
group of malformations affecting fetuses and new-born
infants. The incidence of moderate-to-severe CHD has
been estimated to be 5–6 per 1,000 live-born infants, but
is higher in fetal life because some affected fetuses do not
survive to full term, probably as a result of the complex-
ity of the cardiac disease or associated abnormalities.1–3
Prenatal detection of CHD is a particular challenge,
because both the right and left sides of the heart support
the systemic arterial circulation, atrial and arterial shunts
are present, and the placental circulation provides both
oxygenation and nutritional support for developing
fetuses (Figure 1). Consequently, the majority of fetuses
affected by CHD do not show overt signs of cardiac
failure during fetal life, because one side of the heart can
compensate for an abnormality on the other side. For
example, in hypoplastic left heart syndrome (HLHS),
systemic output can be maintained by left-to-right atrial
shunting and patency of the arterial duct, coupled with
high pulmonary vascular resistance allowing the right
ventricle to pump blood to the systemic arterial circu-
lation. Consequently, identification of affected fetuses
Fetal Cardiology Unit,
Department of depends either on detection during routine sonographic
Congenital Heart examination or by identifying factors that put a fetus at
Disease, Evelina
London Children’s
an increased risk of CHD.
Hospital, London In this Review, we examine current screening strate-
SE1 7EH, UK gies for prenatal diagnosis of CHD, including individ-
(L.E.H., J.M.S.).
uals judged to be at either high or low risk of cardiac
Correspondence to:
J.M.S.
john.simpson@ Competing interests
gstt.nhs.uk The authors declare no competing interests.
abnormalities. The ease with which various forms of
CHD can be diagnosed prenatally is discussed, along
with the effect of prenatal diagnosis on outcome. For
any prenatal screening programme, diagnostic accu-
racy, potential for prenatal intervention, and universal
applicability are important considerations and are also
addressed in this Review.
Detecting CHD
Identifying high-risk fetuses
Risk factors for CHD can be subdivided into those
directly affecting a fetus, for example increased nuchal
translucency (NT); maternal factors, for example expo-
sure to teratogenic medications; and ‘historical’ factors,
such as a history of CHD in a first-degree relative. The
relationship between CHD and maternal drug therapy
can be confounded by the potential for the underlying
disease state to predispose to CHD, rather than the drug
itself. Modifiable risk factors for CHD are addressed in a
joint position statement from the AHA and the American
Academy of Pediatrics, published in 2007.4 The authors
recommended periconceptual multi­vitamins (includ-
ing folate) potentially to reduce the risk of CHD, and for
pregnant mothers to seek medical advice before any drug
ingestion. Fairly good agreement exists between profes-
sional bodies as to the risk factors that merit detailed
assessment of the fetal heart (Box 1).5–9
NT (also known as the nuchal fold) is the sono-
graphic appearance of the fluid-filled space at the back
of the fetal neck, and is measured between 11 weeks
and 13 weeks and 6 days. The NT measurement was

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Key points cardiac disease, rather than a specific threshold or cut-off

■■ Prenatal diagnosis of congenital heart disease (CHD) is important for investigation
of affected fetuses for comorbidities, prognostication, preparation for postnatal
management, and parental choice about continuation of pregnancy
■■ Historical risk factors, such as a family history of CHD, or fetal risk factors,
including increased nuchal translucency, warrant investigation with detailed
fetal echocardiography
■■ Most fetuses with CHD present in the ‘low-risk’ population, and prenatal
detection depends on recognizing abnormalities during obstetric scans
■■ Cardiac anomalies characterized by an abnormal four-chamber view of the heart
have a higher detection rate than those in which the abnormality is primarily of
the outflow tracts
■■ For particular cardiac lesions, including transposition of the great arteries,
coarctation of the aorta, and hypoplastic left heart syndrome, prenatal
diagnosis improves outcomes
■■ Prenatal diagnosis of CHD allows the preparation of postnatal intervention in
most instances; in a minority of cases (mainly critical left-heart lesions), fetal
cardiac intervention can be considered
originally instigated to identify fetuses at high risk of
trisomy 21 (also known as Down syndrome), but its
association with fetal CHD was quickly recognized and
found to be independent of the fetal karyotype.10 The
relationship between NT and CHD demonstrates that a
correlation exists between the NT value and the risk of
value.11,12 The initial data suggested that the majority
of CHD could be detected by using the 95th percentile of
NT as a threshold for detailed fetal echocardiography.10
The logistical implication of offering fetal echocardio­
graphy in all pregnancies in which the NT is >95th per-
centile would be substantial, owing to the sheer number
of pregnancies that would subsequently be considered
to be at increased risk. Even among fetuses with an NT
>99th percentile (3.5 mm), the absolute incidence of CHD
has been reported to be only 6–7%.10,11 Accepting that the
relationship between the NT value and the risk of CHD
is a continuum, the value of NT at which detailed fetal
echocardiography should be prompted has been much
debated, owing to the logistical and cost–benefit impli-
cations. Results of meta-analyses have not suggested as
strong an association between NT and CHD as originally
reported, with a detection rate of 30% when using NT
as a screening tool.13 The results of one meta-analysis
showed that, among chromosomally normal fetuses with
CHD, 44% had an NT >95th percentile, and 20% were
>99th percentile.14 Therefore, other screening markers
have been proposed to refine risk stratification and
increase the predictive value of the initial screening test.
These markers include the presence of tricuspid valve

a Ductus b c
arteriosus
Pulmonary
artery

Aorta

Foramen
ovale
LA
RA

LV
RV

Umbilical cord
attaches to
baby’s circulation
To placenta
Figure 1 | Fetal and postnatal circulations. a | Fetal circulation. Oxygenated blood from the placenta returns to the RA via the
umbilical vein and ductus venosus. Blood passes from the RA to the LA via the patent foramen ovale. The second fetal shunt
occurs between the main pulmonary artery and the descending aortic arch in the form of the arterial duct (ductus arteriosus).
Fetal PVR is high compared with in the postnatal circulation. Therefore, most blood being pumped out of the RV passes through
the arterial duct into the descending aorta. b | Immediate postnatal circulation. Physiological adaptations that occur after birth
result in a marked drop in PVR and an increase in the pulmonary venous return to the left atrium. This change results in
functional closure of the foramen ovale. A postnatal increase in systemic vascular resistance and arterial pressure occurs,
coupled with the fall in PVR. Consequently, blood flows from the aorta to the pulmonary circulation via the arterial duct until it
constricts and finally closes after birth. c | Normal postnatal circulation. Deoxygenated blood passing through the right-heart
structures is completely separated from the oxygenated blood passing through the left-heart structures. The foramen ovale
and arterial duct have closed, preventing shunting between the atria and the great arteries, respectively. Abbreviations: LA, left
atrium; LV, left ventricle; PVR, pulmonary vascular resistance; RA, right atrium; RV, right ventricle.

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Box 1 | Indications for detailed fetal echocardiography
Fetal
■■ Suspicion or detection of congenital heart disease on obstetric anomaly scan
■■ Increased nuchal translucency thickness in first trimester: >99th percentile
(>3.5 mm) or >95th percentile (>2.2–2.6 mm) according to crown–rump length
■■ Major extracardiac abnormality, such as congenital diaphragmatic hernia,
exomphalos, duodenal atresia, or cystic hygroma
■■ Fetal hydrops
■■ Fetal arrhythmias, including fetal tachycardia, bradycardia, or ectopic beats
■■ Abnormal fetal karyotype, such as trisomy 13 (Patau syndrome), trisomy 18
(Edwards syndrome), trisomy 21 (Down syndrome), or monosomy XO
(Turner syndrome)
■■ Monochorionic pregnancy, owing to risk of cardiac abnormality or twin–twin
transfusion syndrome
Maternal
■■ Maternal drugs: use of prostaglandin synthetase inhibitors, such as ibuprofen;
risk of teratogenicity, such as from use of lithium or anticonvulsants
■■ Diabetes mellitus or other metabolic conditions, such as phenylketonuria
■■ Maternal infection, such as with Parvovirus
■■ Maternal antibody status or connective tissue disease, such as positive anti‑Ro,
anti‑La antibodies
Historical
■■ History of congenital heart disease in a first-degree relative
Other
■■ Assisted conception or in vitro fertilization
■■ Increased risk of fetal heart failure, such as absent ductus venosus, fetal
anaemia, or presence of fetal tumours with large vascular supply
regurgitation, and absence or reversal of the a‑wave flow
in the ductus venosus.15,16 Studies have shown that an
altered ductus venosus flow pattern is associated with a
threefold increase in the incidence of CHD in chromo­
somally normal fetuses.17 These refinements have been
introduced with the aim to reduce the number of false–
positive screening tests, and also to minimize any adverse
effect on the sensitivity of the test. Importantly, the addi-
tion of ductus venosus flow patterns and tricuspid valve
regurgitation to refine screening has currently been
adopted at a limited number of specialist centres, and is
not universally implemented.
First-trimester NT screening has been used to iden-
tify fetuses at risk of CHD, even though the primary
intention was to use this technique to identify fetuses
with genetic abnormalities. In the past 3 years, non­
invasive screening techniques for trisomy 21, 13 (Patau
syndrome), and 18 (Edwards syndrome) have become
available by analysing cell-free DNA in maternal blood,
and have increasingly been used to examine not only
major trisomies, but also sex-chromosome abnormalities
and microdeletion syndromes, such as 22q11 deletion.
Although promising, these genetic techniques are fairly
new, and current guidelines advise that they should be
adjuncts to routine screening with ultrasonography and
blood tests.18–20 The introduction of these techniques has
substantial implications for screening for CHD, particu-
larly early fetal echocardiography. If this form of testing
proves to be both highly specific and sensitive, then the
individuals presenting to fetal cardiologists will be more-
effectively risk stratified for major chromosomal abnor-
malities than is currently the case.21 Furthermore, fetal
free-DNA techniques might mean that NT screening
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is not undertaken at all. The incremental value of NT
screening to identify fetuses at risk of isolated CHD
would consequently be lost.
A family history of CHD is one of the most-common
reasons for referral for detailed fetal echocardiography.
Most physicians accept that such a history in a first-
degree relative is a valid indication for specialist fetal
cardiac examination. Screening of more-distant rela-
tives is not usually undertaken, because the added risk
beyond that in the general population is negligible, and
would add substantially to the number of pregnancies
that would need to be assessed at specialist centres. In the
absence of a known syndrome or genetic association,
the risk of CHD in such pregnancies has been reported
to be 2–3%,22 and some studies have shown an increased
risk if the mother is affected.23 At our own unit (Evelina
London Children’s Hospital, UK), threefold more fetuses
are referred because of maternal CHD than because of
paternal CHD,22 despite a recurrence risk with either
sex that is as high or higher than if a sibling has CHD.24
The precise recurrence risk should be adjusted accord-
ing to the type of CHD, because studies have shown
an increased recurrence risk for left-heart lesions and
d­isorders of laterality.25–27
Screening in low-risk fetuses
Despite the identification of risk factors for CHD, most
cases occur in the population deemed to be at low risk.
Diagnosis of CHD in this group depends on a sono­
grapher recognizing that the appearance of the heart
deviates from normal. Debate exists as to which views
of the fetal heart should be obtained to screen for CHD.
The most-established screening view is the four-chamber
view of the fetal heart. This view has the advantage of
having external fetal reference points, because the plane
of the fetal ribs matches that of the four-chamber view
during fetal life (Figure 2b). Incorporating this view into
obstetric anomaly scanning is supported by all the major
international obstetric and paediatric cardiology soci-
eties and organizations. 5–9 Many cardiac lesions, for
example HLHS, tricuspid atresia, and atrioventricular
septal defects, have manifest abnormalities on the four-
chamber view. Conversely, other major cardiac lesions
have a normal or near-normal four-chamber view.
Detection of these lesions, for example transposition
of the great arteries, tetralogy of Fallot, and common
arterial trunk (truncus arteriosus), require the cardiac
outflow tracts to be accurately visualized (Box 2).28
In a major population-based series, the detection rate
of lesions affecting only the cardiac outflow tracts was
significantly lower than that of lesions detected by an
abnormal four-chamber view.29 Prioritizing the train-
ing of sonographers to recognize abnormalities of the
outflow tracts has enhanced the detection rate, but it
remains suboptimal.30,31 Given that the cardiac outflow
tracts pose the greatest difficulty for a screening sono­
grapher to recognize an abnormality, the challenge has
been to develop a systematic approach to screening views
that can be obtained in the vast majority of fetuses, that
are achievable within the time constraints of the obstetric
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a b c Left
Left ventricle
A L ventricle A Right
Left
L R P A atrium L R ventricle
P R P

IVC LVOT
Spine Aortic
valve
Right
Descending ventricle Spine
aorta Right
Stomach
Spine atrium Right
atrium

d e
A R A R
L P L P
Right Aortic
Aorta ventricle arch

SVC SVC
Main PA Trachea
Right PA
Duct
Pulmonary
valve
Spine Arterial Spine
duct

Figure 2 | Sonographic screening for congenital heart disease. This series of images shows the near-transverse cuts of
the fetal thorax that can be performed as a sonographic, inferior-to-superior sweep, which allows the rapid identification
of the major cardiac chambers and vessels. a | View of cardiac situs just below the four-chamber view, showing the fetal
stomach and aorta to the left and the IVC anterior and to the right. b | Four-chamber view of the fetal heart, showing a
single rib around the fetal thorax. The left-sided and right-sided chambers are balanced in size. c | View of the LVOT and
aortic valve leaving the left ventricle. d | View of the PA passing in an anteroposterior direction. The right PA can be seen to
arise from the main PA. The aorta and SVC are seen in short axis to the right of the PA. e | Three-vessel view of the upper
mediastinum, showing the PA leading into the arterial duct alongside the transverse aortic arch. The SVC is to the right, and
the trachea is to the right of the V shape formed by the aortic arch and arterial duct. Abbreviations: IVC, inferior vena cava;
LVOT, left ventricular outflow tract; PA, pulmonary artery; SVC, superior vena cava.

anomaly scan, and that can be used to detect most of the
major abnormalities. Current recommendations propose
an approach based on transverse or near-transvers­e sono-
graphic cuts of the fetal thorax (Figure 2).5–9 This approach
produces images of the fetal heart that are similar to those
obtained using CT or MRI. An advantage of this method
is that a sonographer can acquire the necessary anatomi-
cal cuts by using the four-chamber projection as a refer-
ence point, and subsequent images are obtained by cranial
or caudal angulation of the probe.
Despite the introduction of this approach, inter­
national population-based series have shown that the
accurate prenatal detection of CHD remains sub­optimal.
The reasons for this shortcoming are complex. In some
pregnancies, the fetal position or maternal habitus might
make high-quality imaging of the fetal heart very dif-
ficult, and technical factors, such as the quality of the
imaging equipment, can also influence accuracy. To add
to the difficulties associated with body habitus, evidence
shows an increased incidence of CHD in pregnancies
associated with an elevated maternal BMI.32 The train-
ing and clinical experience of screening sonographers is
central to the accurate prenatal recognition of CHD.33–35
Therefore, sonographers must be encouraged and sup-
ported by physician colleagues to continue to enhance
their skills and professional development.36,37 Failure to
detect a cardiac abnormality antenatally can have impor-
tant implications for postnatal management, particularly
for duct-dependent lesions, because clinical deteriora-
tion can occur during the transition to the postnatal
circulation (Figure 1b). If a cardiac abnormality is not
detected, associated anomalies, such as chromosomal
abnormalities, can remain undiagnosed before birth.
These factors have important clinical and medicolegal
implications. Data have also shown that prenatal diag-
nosis of CHD is cost-effective in avoiding the costs of
transporting sick new-born infants who are diagnosed
after birth with severe CHD to a tertiary cardiac centre.38
An important consideration for a CHD screening
programme in the general population is a central record
of cases of CHD. Such a registry allows the prenatal
diagnostic rates of CHD to be calculated in a region or
country and, to some extent, in screening centres
or districts. Unfortunately, most countries fall short of
this ideal. In the UK, for example, a central agency, the
National Institute for Cardiovascular Outcome Research
(NICOR), records all infants who undergo surgery in
infancy. However, this registry excludes cases where
the pregnancy does not continue to delivery, where pre­
operative death occurs, and where an infant is not

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deemed a surgical candidate owing to clinically signifi-
cant comorbidities. Consequently, major problems of
selection bias in the recording of cases exist. Investigators
in one study painstakingly linked all data from maternity
records and NICOR results to gauge the performance of
screening centres in the detection of CHD.39 Obtaining
such information prospectively in a systematic manner
has the potential to identify units where specific training
initiatives could be undertaken.39
Detailed fetal echocardiography
Referral to fetal cardiology or fetal medicine sub­
specialists for further assessment is warranted when a
fetus is considered to be at high risk of developing CHD,
or when a cardiac abnormality is suspected during a
routine anomaly scan. Recommended standards for
detailed fetal echocardiography have been published by
both European and US professional bodies.6,8 Detailed
fetal echocardiographic assessment involves not only
comprehensive imaging of the cardiac connections by a
sequential segmental approach, but further anatomical
assessment in the form of longitudinal views of the ductal
and aortic arch, bicaval views, and short-axis views of the
heart. Functional assessment in the form of pulsed-wave
and colour-flow Doppler imaging is also undertaken. In
specialist units, a high degree of diagnostic accuracy can
be expected, and large series confirm that virtually every
form of CHD has been reported during fetal life.40,41
Particular cardiac lesions, however, remain a challenge
to diagnose antenatally, even in specialist units, and these
lesions merit special consideration.
Coarctation of the aorta
Coarctation of the aorta is most-commonly suspected
prenatally because of an asymmetry between the size
of the right ventricle and pulmonary artery compared
with the left ventricle and aorta, with dominance of
right-heart structures. During fetal life, the duct is patent,
which means that high Doppler-derived pressure drops
are not observed in the aortic arch, in contrast to the post-
natal situation. A coarctation ‘shelf ’ (a posterior inden-
tation of the aortic arch in the region where the arterial
duct inserts into the aortic arch) is observed in the lon-
gitudinal view of the aortic arch in some, but not all,
fetuses. One series suggested additional value of Doppler
investi­gation of the aortic isthmus to check for continu-
ous flow during systole and diastole.42 A high suspicion
of coarctation is suggested antenatally by the presence of
right and left ventricular asymmetry or a discrepancy in
the calibre of the aortic arch and pulmonary artery.43,44
Accurate measurement of the aortic arch, in the longitu-
dinal or three-vessel tracheal view, and of the diameter of
the aortic isthmus can help with the antenatal diagnosis
of coarctation of the aorta, including transformation of
a measurement into a size-specific or gestation-specific
Z‑score.42,45,46 Z‑scores are an expression of how many
standard deviations above or below a population mean
a given observation lies. This scoring system is particu-
larly helpful given the increase in fetal size with advancing
gestational age.47 Management of coarctation of the aorta
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Box 2 | Detection of cardiac abnormalities
Using the four-chamber view
Septal defects
■■ Atrioventricular septal defect
■■ Large ventricular septal defects (inlet types)
Left-heart anomalies
■■ Hypoplastic left heart syndrome
■■ Critical aortic stenosis
■■ Severe coarctation of the aorta
Right-heart abnormalities
■■ Tricuspid atresia
■■ Pulmonary atresia with intact ventricular septum
■■ Ebstein anomaly of the tricuspid valve
Double inlet ventricles
■■ Double inlet left or right ventricle
Using extended views of the outflow tracts*
■■ Transposition of the great arteries
■■ Tetralogy of Fallot with or without pulmonary atresia
■■ Common arterial trunk
■■ Some forms of double outlet right ventricle
■■ Some forms of coarctation of the aorta
*Normal or near-normal four-chamber view.
can range from limited surgery to resect discrete obstruc-
tion of the aortic arch through to a scenario in which the
left-heart structures are so hypoplastic that management
is similar to that for HLHS, in which a normal biven-
tricular circulation cannot be achieved. In this scenario,
management is a staged surgical palliation involving con-
nection of the systemic veins to the pulmonary arteries,
and the dominant right ve­ntricle supports the systemic
arterial circulation.
Despite normative fetal values and recommenda-
tions to assess fetuses suspected of having coarctation
of the aorta, an overlap remains between cases with a
confirmed postnatal diagnosis of coarctation of the aorta
and false–positive cases. Owing to this uncertainty, a
policy of scanning neonates with a prenatal suspicion
of coarctation is established, to assess whether aortic
arch obstruction has developed during closure of the
arterial duct. Even this policy has limitations, because
coarctation has been reported in infants with prenatally
suspected coarctation several months after closure of the
arterial duct.48
Total anomalous pulmonary venous drainage
Another important and challenging antenatal diagnosis
is isolated total anomalous pulmonary venous drainage
(TAPVD). Pulmonary vascular resistance is higher in the
fetal circulation than in the postnatal circulation and,
therefore, colour-flow Doppler visualization of antegrade
flow from the pulmonary veins directly into the left
atrium can be more difficult to demonstrate. In prenatal
TAPVD, the pulmonary venous confluence lies in close
proximity to the posterior wall of the left atrium and can
give a falsely reassuring impression of normality. Volume
loading of the right heart might be thought to be always
evident in TAPVD, but is actually a sign of this condition
that appears late in fetal life.49,50 A multicentre study has
shown that only a minority of cases of isolated TAPVD
were accurately diagnosed, even when assessment was
REVIEWS
undertaken at a specialist unit.51 Ideally, investigation of
the pulmonary veins should involve visualization by 2D
and colour-flow imaging with appropriate reduction of
colour Doppler scales to detect low-velocity flow. This
modality can be coupled with pulsed Doppler imaging
to check for a normal phasic flow pattern, which is
f­requently lost in TAPVD.
Valve stenosis
Disease progression is another important consideration
that affects particular cardiac lesions, and complicates the
diagnosis of these abnormalities in the second trimester,
when most anomaly scans are performed. In particular,
aortic valve and pulmonary valve stenosis can progress
with advancing gestational age. Aortic and pulmonary
valve flow velocities measured by Doppler imaging can
be within normal limits or mildly elevated in early gesta-
tion, but subsequently progress to severe or even critical
stenosis.52 Therefore, explaining to parents the limita-
tions of fetal echocardiography in the second trimester
is important. In practice, if suspicion of aortic or pul-
monary valve stenosis exists, sequential fetal echocardio­
graphy will be undertaken to gauge any progression
with advancing gestational age, and parental counselling
might change according to disease progression.
Ventricular septal defects
Ventricular septal defects are much more of a challenge
to diagnose prenatally than postnatally, owing to both
anatomical and physiological factors. During fetal life,
the pressures in the left and right ventricles are similar.53
If a ventricular septal defect is revealed, colour-flow
Doppler typically shows bidirectional flow at low veloc-
ity, rather than the more-obvious left-to-right shunting
noted after birth as the pulmonary vascular resistance
falls. Anatomically, the membranous portion of the fetal
ventricular septum is very thin. In the small fetal heart, a
membranous ventricular septal defect is often suspected
when none is actually present and, conversely, defects in
this region are easily overlooked.54 The location of the
ventricular septal defect can also affect the risk of asso-
ciated fetal chromosomal anomalies, with a higher inci-
dence of anomalies associated with membranous than
with muscular defects.54,55
Timing of assessment
The timing of detailed fetal cardiac assessment is itself
being influenced by the techniques used to identify
high-risk groups. For example, if NT is increased at
10–12 weeks of gestation, parents might opt for an inva-
sive test for fetal karyotyping. After karyotypic abnormal-
ities, CHD is the largest group of fetal diseases asso­ciated
with increased NT, which often prompts a referral for
early fetal echocardiography. This referral is performed
with the aim to provide either an early diagnosis of CHD,
or reassurance of normality. Technological advances
have made early sonographic imaging of the fetal heart,
by either a transvaginal or a transabdominal approach,
increasingly feasible. Several series have shown that
these early scans, when performed at specialist centres,
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© 2014 Macmillan Publishers Limited. All rights reserved
accurately detect major cardiac lesions.56–60 Even if the
initial early assessment is deemed normal, most units
electively repeat the scan subsequently during gestation,
because minor lesions can become evident with advanc-
ing gestational age. Equally, disease progression, such
as that of semilunar valve stenosis or cardiomyopathy,
can occur. A major issue affecting early fetal echocardio­
graphy (gestational age 11–14 weeks) is the potential for
diagnostic error, because the heart is very small and at
the resolution limit of current ultrasound systems. Even
if the heart can be confidently diagnosed as being abnor-
mally formed, all the necessary prognostic information
might not be obtainable at this early stage. In this setting,
correlation of prenatal findings with postnatal or post-
mortem findings assumes an even greater importance
than prenatal diagnosis in the midtrimester.21,61
Consequences of prenatal CHD diagnosis
Parental perception
Prenatal counselling after severe CHD has been detected
can be a detailed, complex, and emotional process. Often,
several counselling sessions are required to ensure that
parents have appropriate insight, understanding, and
acceptance of the prognosis and management of the
cardiac condition and the effect of any comorbidities.
This process allows parents to reach a decision that is
both informed and appropriate to their family beliefs,
circumstances, and life experiences. Parental percep-
tions and experiences of a prenatal diagnosis of CHD
have been studied, showing a clear preference for com-
prehensive information, particularly pertaining to future
quality of life.62 However, a marked variation has been
shown to exist in the options offered to parents after a
prenatal diagnosis of severe CHD, such as HLHS.63,64
Nevertheless, parental knowledge about CHD does seem
to be better when a prenatal diagnosis has been made,
compared with a diagnosis only after birth.65 Internet-
based studies of prenatally diagnosed CHD have shown
that the mention of termination of pregnancy after
parents had declined this option made them less positive
about prognosis, and that the parental perception of a
cardiologist’s level of compassion was inversely linked to
the likelihood of them seeking a second opinion.66,67 How
parents perceive the prognosis and long-term quality of
life associated with a congenital condition is unique to
their own life experiences and often differs from that of
health-care providers.68 Finally, the manner in which a
diagnosis is initially presented to a family, the informa-
tion provided, and how the family interprets the infor-
mation are all factors that influence parental perception
and subsequent decisions.67
Fetal and postnatal outcomes
For a prenatal screening programme to be viable, evi-
dence must exist for an effective intervention or treat-
ment after diagnosis. CHD is known to be associated
with other fetal anomalies, although the strength of
the association varies according to the cardiac lesion.41
Some forms of CHD, for example atrioventricular septal
defects,69 and tetralogy of Fallot,70 have a very strong

association with chromosomal abnormalities, including
trisomy 21 or chromosome 22q11 deletions. Therefore,
prenatal detection of the cardiac defect can result in
the identification of an associated extracardiac abnor-
mality, which affects the fetal and postnatal prognosis.
Consequently, full investigation of fetuses with CHD can
involve multiple subspecialties, with the aim to identify
all comorbidities. For many fetuses, parental decision-
making about the pregnancy is more influenced by the
extent of coexisting abnormalities than by the cardiac
abnormality itself.
Prenatal diagnosis of CHD gives parents the benefit
of time before the birth of their child to understand the
nature of the cardiac lesion, discuss the available treat-
ment options, and understand the immediate and long-
term prognoses.71,72 This time and preparation can assist
parental decision-making and ensure that consent is as
informed as possible before postnatal surgical or cath-
eter interventions are undertaken. Prenatal diagnosis
has been proposed to improve the ability of parents to
adapt to caring for an infant through cardiac surgery and
into later life, but evidence confirms that parents require
continued support, regardless of when the ­diagnosis
is made.73
Fundamental to the justification of prenatal CHD
screening is whether detection improves the outcome of
affected infants. However, designing a study to address
this crucial question is extremely difficult. Midtrimester
anomaly scanning might have a tendency to detect
fetuses with a screening view of the heart that is par-
ticularly abnormal, whereas the postnatal cohort would
contain all neonates with the condition, thereby intro-
ducing a major potential for selection bias. Therefore,
even for a particular form of cardiac lesion, a strict com-
parison between prenatal and postnatal diagnosis might
not be valid. For some cardiac lesions, observational evi-
dence indicates that prenatal diagnosis improves post­
natal outcomes. The types of CHD studied have been
those in which unrecognized conditions present acutely
in the early postnatal period after constriction of the arte-
rial duct or closure of the foramen ovale. HLHS was one
of the first lesions to be studied. One large series showed
reduced morbidity and mortality for infants diagnosed
prenatally compared with those diagnosed postnatally.74
However, results from other studies have not confirmed
a survival advantage, although the clinical condition at
presentation was improved.75,76 An important aspect of
prenatal diagnosis that remains under-reported com-
pared with mortality, is quality of survival and, in par-
ticular, neurological morbidity. A prenatal diagnosis
of HLHS has been associated with a reduction in early
neonatal neurological morbidity when directly compared
with infants diagnosed postnatally.77 This outcome is not
unexpected, given the severe circulatory collapse that
can occur after postnatal ductal constriction in neonates
with HLHS.
Coarctation of the aorta is another lesion in which
study data suggest that prenatal diagnosis benefits neo-
natal outcomes.78 An important aspect of this study was
the inclusion of infants diagnosed at autopsy who had
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REVIEWS
not presented to a cardiac centre during life. Although
this group might be small, such infants are often not
included in studies in which the cohort is defined by
presentation to a tertiary cardiac centre.
The most-compelling evidence for the effect of pre-
natal diagnosis of CHD on outcome is the detection of
transposition of the great arteries. Postnatally, adequate
systemic arterial oxygen saturations are achieved if
sufficient mixing of blood occurs at the atrial septum,
arterial duct, or both. A landmark study showed signifi-
cantly reduced preoperative and postoperative mortality
in infants with a prenatal diagnosis.79 Subsequently, the
same investigators described the prenatal sonographic
findings associated with transposition of the great
a­rteries that might predict the need for early neonatal
septo­stomy, including restriction of the foramen ovale
and constriction of the ductus arteriosus.80
Researchers in some studies have examined the effect
of prenatal diagnosis on the duct-dependent pulmo-
nary circulation. Although prenatal diagnosis improves
oxygen saturations at presentation, no effect on short-
term morbidity or mortality was observed.81 Particular
cardiac conditions, such as pulmonary obstruction, are
most-easily identified in the perinatal period by the pres-
ence of cyanosis, which can be detected clinically or by
pulse oximetry.82,83
Risk stratification of fetuses with CHD
After a prenatal diagnosis of CHD has been made, the
timing, mode, and site of management should be opti-
mized to improve postnatal outcomes. Important con-
siderations include the circulatory changes that occur
in the transitional circulation, such as closure of the
foramen ovale, constriction of the arterial duct, fall in
pulmonary vascular resistance, and increase in systemic
vascular resistance (Figure 1). Particular cardiac lesions,
for example an isolated ventricular septal defect, would
not be expected to cause haemodynamic compromise
im­mediately and, therefore, management can be consid-
ered to be fairly routine. Conversely, fetuses with HLHS
and a restrictive atrial septum might be critically ill
immediately after delivery, owing to the oxygenated pul-
monary venous blood being obstructed from leaving the
left atrium and failing to reach the systemic arterial cir-
culation. The arrangements for management are tailor­ed
according to the type of cardiac lesion and expected
initial postnatal problems. Examples of cardiac lesions for
which urgent postnatal cardiac intervention or high‑level
intensive care are anticipated are shown in Table 1.
So far, we have discussed risk stratification according
to the type of cardiac lesion. However, within each group
of cardiac lesions, a spectrum of severity often exists, and
each diagnostic group cannot be regarded as homogene-
ous. Increasingly, the role of fetal echocardiography is
to identify both positive and negative prognostic factors
within each subset of cardiac lesions. The group of lesions
for which such stratification has been most-extensively
studied is left-heart disease, particularly HLHS and
aortic valve stenosis. In HLHS, a number of important
adverse prognostic factors exist, including tricuspid valve
REVIEWS
Table 1 | Cardiac lesions and situations requiring immediate perinatal attention
Cardiac lesion Potential complication
Simple transposition of the great Metabolic acidosis
arteries (associated with a restrictive Profound hypoxaemia
atrial septum and arterial duct)
Hypoplastic left heart syndrome or Profound hypoxaemia
critical aortic stenosis (associated with Metabolic acidosis
an intact or restrictive atrial septum)
Obstructed total anomalous pulmonary Profound hypoxaemia
venous drainage
Absent pulmonary valve syndrome Airway compression
Respiratory compromise or failure
Air trapping
Severe Ebstein anomaly of the Pulmonary hypoplasia
tricuspid valve Respiratory failure
Severe hypoxaemia
Management of hydrops
Complete heart block with or without Cardiac failure
congenital heart disease Hydrops
regurgitation, mitral valve regurgitation, and restriction
of the atrial septum.84–86 A means of assessment based
on the pulmonary venous Doppler waveforms has been
proposed to predict the need for early postnatal interven-
tion of the atrial septum.87 Disease progression is known
to occur in fetal aortic valve stenosis, which is charac-
terized by failure of left-heart structures to grow, and
deterioration of left ventricular function.88 In a subset
of fetuses, the progression is so marked that postnatal
management is similar to that for HLHS, rather than a
biventricular circulation. Echocardiographic markers,
including monophasic mitral valve inflow, reversal of
flow in the aortic arch during systole, and left-to-right
atrial shunting of blood, can be used to predict dis­
ease progression.89 The use of fetal echocardiographic
markers of disease severity is not restricted to left-heart
disease and has been extended to other lesions, includ-
ing pulmonary atresia with intact ventricular septum,90,91
Ebstein anomaly,92 and tetralogy of Fallot.70 Therefore, in
current practice, effective prenatal screening for CHD
not only leads to an accurate diagnosis, but also assists
with perinatal management planning and allows tailored
counselling that takes individual prognostic factors into
account. Good communication between all the relevant
services is essential and, in most centres, includes multi-
disciplinary meetings to discuss individual patients and
formulate an appropriate management plan.
Fetal intervention
An important facet of any screening programme for fetal
cardiac anomalies is whether intervention can be offered
after diagnosis. The strongest evidence for the benefit
associated with prenatal intervention is in the treatment
of fetal arrhythmias, particularly fetal tachycardias.93–95
Fetuses with other arrhythmias, notably immune-
mediate­d atrioventricular block, can also benefit from
therapy with corticosteroids or salbutamol to reduce
inflammation and accelerate fetal heart rate, but patient
selection in this setting remains controversial.96–98
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© 2014 Macmillan Publishers Limited. All rights reserved
Potential interventions
Urgent balloon atrial septostomy
Urgent balloon atrial septostomy or surgical
septectomy
Early surgical intervention
Mechanical ventilation (positive pressure)
Plication of pulmonary arteries
Oxygen therapy
Mechanical ventilation (positive pressure)
Inhaled nitric oxide
Drainage of associated pleural effusions or ascites
Medical therapy with chronotropic agents
Temporary cardiac pacing
Drainage of associated pleural effusions or ascites
Fetal intervention for structural heart lesions has been
advocated for severe aortic valve stenosis, severe pul-
monary valve stenosis, and HLHS with an intact atrial
septum. In a number of cases with severe fetal aortic
valve stenosis, postnatal biventricular repair is precluded,
owing to the subnormal growth and function of the left
heart with advancing gestational age.88 Prenatal aortic
valvuloplasty has been shown to be technically feasible
and has been associated with improved growth of the
aortic valve, ascending aorta, and mitral valve during
fetal life.89,99,100 Despite these advances, and even after
technically successful prenatal intervention, a substan-
tial proportion of fetuses still have left-heart structures
that are insufficiently developed to support the systemic
arterial circulation and, therefore, are managed with
a staged surgical palliation towards a single-ventricle
c­i rculation. 101–103 Fetuses who achieve a biventricu-
lar circulation after prenatal intervention commonly
require further surgery on the mitral valve, aortic valve,
and resection of endocardial fibroelastosis, and continue
to have evidence of diastolic dysfunction.104,105 Debate,
therefore, remains as to whether aggressive pursuit of a
biventricular circulation is always preferable to accepting
a single-ventricle physiology.106
Intrauterine perforation of the pulmonary valve has
been undertaken, mainly in fetuses with incipient fetal
hydrops, where a poor outcome was anticipated without
intervention.107 After initial reports of technical success,
other groups have attempted prenatal intervention for
severe right ventricular outflow tract obstruction, with
improved growth of the right heart compared with con-
trols.108 The number of fetuses who have undergone
intervention for severe right ventricular outflow tract
obstruction is far fewer than for critical aortic stenosis,
most likely because the postnatal outcome of this con­
dition, even if untreated during intrauterine life, is thought
to have a better prognosis than with HLHS.
Fetuses with HLHS and an intact or near-intact atrial
septum are an extremely high-risk group during postnatal

management. Early neonatal hypoxia, metabolic acidosis,
and circulatory failure can be anticipated, which prompts
emergency surgery or catheter intervention. Additionally,
restriction of the atrial septum is a major risk factor for
achieving a viable total cavopulmonary circulation,109
possibly because of the intrauterine development of pul-
monary vascular disease and lymphangiectasia secondary
to obstruction of pulmonary venous return.110 Prenatal
intervention on the atrial septum has been technically
successful, but a proportion of septal perforations have
been reported to reseal,111,112 prompting the use of stents
to maintain septal patency.112,113 Fetuses who have had
a technically successful intervention tend to have an
improved outcome, but long-term data are lacking.114
Although the results of fetal intervention are impor-
tant, the number of fetuses who are candidates for such
interventions is a small minority (<5%) of those diag-
nosed prenatally with CHD. Therefore, prenatal d­iagnosis
of structural lesions generally remains focused on prepa-
ration and planning for postnatal, rather than in utero,
intervention.
Universal applicability
When assessing the efficacy of any prenatal screening
test, including prenatal detection of CHD, applicability
to a wide range of health-care systems is important. The
current system of screening for CHD depends on skilled
personnel identifying risk factors for CHD (for example,
measuring NT), and a high level of training to recognize
deviation from normality during obstetric scans. If an
abnormality is recognized, access to associated sub­
specialties and high-level perinatal centres, including
those offering cardiac surgery, becomes integral to the
care of both mothers and babies. Most published data on
this topic are from the developed world, where availabil-
ity of appropriate subspecialists and facilities is expected,
both for prenatal diagnosis and for postnatal manage-
ment. Situations where resources are limited, including
in the developing world, pose challenges. Data from
India show that, among parents of children with CHD,
only 2.2% of families were aware of fetal echocardio­
graphy.115 Therefore, a major education barrier exists
for affected families even to enter the prenatal screening
programme. In a series of fetuses in India with abnor-
malities of the outflow tracts,116 many of which would be
considered repairable, referrals tended to be on the basis
of abnormal screening views late in gestation, the rate of
termination of pregnancy was high, and few cases came
to be managed at the cardiac referral centre after birth.
Much work needs to be undertaken on the place of pre-
natal screening for CHD in environments with limited
resources, which are often characterized by high birth
rates and a lack of facilities available for prenatal and
postnatal management, as well as the potential financial
implications for families.
A further consideration is the introduction of changes
to the assessment of new-born infants. Pulse-oximetry
screening is being advocated with the aim of early
postnatal detection of reduced preductal or postductal
oxygen saturations, and a meta-analysis has confirmed
NATURE REVIEWS | CARDIOLOGY VOLUME 11  |  JUNE 2014  |  331
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REVIEWS
its potential value in postnatal screening for major
CHD.83,117 Although this form of postnatal screening has
not been uniformly introduced at an international level,
prompt postnatal detection of CHD by pulse oximetry
might weaken the argument for prenatal screening (if the
rationale of the latter is to reduce the delay in postnatal
diagnosis). Conversely, postnatal pulse oximetry is not
completely accurate, with both false–positive and false–
negative results reported in large series.83,117 Prenatal
diagnosis also allows identification of malformations
and chromosomal abnormalities associated with CHD
at a time when parents have the option to discontinue
the pregnancy, and time for full counselling about treat-
ment options and prognosis. Given that current pre­
natal detection strategies leave a substantial proportion
of abnormalities undetected, prenatal sonography and
postnatal pulse oximetry are highly likely to emerge as
complementary techniques to optimize the diagnosis and
care of infants with CHD.
Emerging technologies
Developments in echocardiography
The mainstay of fetal cardiac diagnosis continues to be
cross-sectional echocardiography with conventional
additions including colour-flow and pulsed-wave
Doppler imaging. Advances in image resolution mean
that fetal echocardiography is technically feasible as
early as the first trimester by either a transabdominal or
a transvaginal approach.118 Spatiotemporal image corre-
lation (STIC) is a technique that involves a sonographic
sweep over the area of interest, acquired over several
seconds, and is reconstructed into either multiple sono-
graphic projections or a 3D-rendered view. The diag-
nostic capacities of this technique have been confirmed,
particularly in terms of remote investigation or to guide
the repair of complex lesions.119–121 However, investiga-
tion of the 3D datasets remains operator-dependent,119
and some clinically relevant information, for example
Doppler imaging, is not included. Several groups have
investigated the transmission of 3D echocardiographic
volumes over the Internet for specialist review at a
remote site.121 Although STIC has major attractions for
subspecialist evaluation, the technique has not been
widely adopted as a screening tool for fetal CHD, despite
reports of its application in this setting.122 A degree of
automation using a technique of intelligent navigation,
which allows orientation of the STIC volume into a series
of standardized sonographic projections, might facilitate
and accelerate recognition of the core screening views for
prenatal detection of CHD.123
Telemedicine
Novel modalities include live telemedicine links to
facilitate specialized review of fetal cardiac images from
remote centres. Use of telemedicine has been associated
with a high level of operator and parent satisfaction.124,125
As cardiac services are increasingly being provided by
large tertiary centres, this service might reduce patient
anxiety, provide reassurance, and overcome the obstacle
of geographic location.
REVIEWS

Fetal MRI on the prenatal detection of CHD warrant further inves-

MRI is being increasingly applied to the prenatal diagno-
sis and evaluation of CHD. The use of MRI to compute
flow volume can provide unique insights into fetal physio­
logy, including flow distribution in normal or abnormal
circulations.126 When assessing cardiac anatomy, MRI can
be used to overcome the problems of acoustic windows
and to provide diagnostic information,127,128 although
problems associated with temporal resolution, fetal
motion, and gating of images to the cardiac cycle remain
unresolved. In high-risk situations, for example fetuses
with HLHS and a restrictive atrial septum, fetal MRI can
provide important clinical information, such as the pres-
ence of pulmonary lymphangiectasia, which adversely
affects prognosis.110 Importantly, current indications for
fetal MRI are for fetuses diagnosed using sono­graphy
as having CHD, and a screening role for fetal MRI is
not defined.
Conclusions
The overriding challenge for CHD screening programmes
is the training and education of those performing screen-
ing examinations in the midtrimester, because the major-
ity of affected fetuses do not have established risk factors
that warrant specialist assessment. Continued training and
feedback is essential to maintain and improve standards,
but delivery remains a major problem for fetal cardio­logy
centres. Reliance on the midtrimester anomaly scan is
likely to become even more important if the use of NT
screening is reduced after the introduction of noninvasive
fetal free-DNA techniques to identify genetic abnormali-
ties early in gestation. Potential effects of this technique
tigation. At specialist centres, most forms of fetal CHD
should be diagnosed accurately. The focus in this setting
has increasingly moved towards risk stratification within
and between diagnostic groups to develop a tailored man-
agement plan and individualized estimation of risk. After
diagnosis of CHD, parents value information that is deliv-
ered in a supportive manner by health-care professionals.
Parental perception is heavily affected by the manner in
which this information is provided, and considerable vari-
ation remains in the content of counselling. In a minor-
ity of cases of fetal CHD, cardiac intervention might be
considered to improve prognosis. Technical success is
improving, and follow-up data are providing increasing
information on the progress of infants who have under-
gone prenatal intervention, so that risk–benefit analyses
can be better informed. Finally, the vast majority of data
from CHD screening programmes have come from highly
developed countries, but the practicality, implementa-
tion, and consequences of prenatal screening for CHD in
c­ountries with limited resources warrant further study.
Review criteria
The authors searched the PubMed database for full
text papers, published in English, up to January 2014.
The following search terms were used: “fetal heart”,
“prenatal diagnosis”, “prenatal screening”, “cf DNA”,
“nuchal translucency”, “fetal intervention”, “fetal MRI”,
“telemedicine”, and “fetal STIC”. Practice guidelines from
Canada, Europe, the UK, and the USA were consulted for
additional references.

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Author contributions
Both authors researched data for the article,
contributed substantially to discussion of its content,
wrote the manuscript, and reviewed and edited it
before submission.