The Combined Use of Ultrasound and

Fetal Magnetic Resonance Imaging for a

Comprehensive Fetal Neurological
Assessment in Fetal Congenital Cardiac
Defects

Scientific Impact Paper No. 60

May 2019

Please cite this paper as: Pasupathy D, Denbow ML, Rutherford MA, on behalf of the Royal College of Obstetricians and
Gynaecologists. The Combined Use of Ultrasound and Fetal Magnetic Resonance Imaging for a Comprehensive Fetal
Neurological Assessment in Fetal Congenital Cardiac Defects. Scientific Impact Paper No. 60. BJOG 2019;126:e143–51.
 DOI: 10.1111/1471-0528.15620 RCOG Scientific Impact Paper

The Combined Use of Ultrasound and Fetal Magnetic Resonance Imaging

for a Comprehensive Fetal Neurological Assessment in Fetal Congenital
Cardiac Defects

D Pasupathy, ML Denbow, MA Rutherford, on behalf of the Royal College of Obstetricians and

Gynaecologists

Correspondence: Royal College of Obstetricians and Gynaecologists, 27 Sussex Place, Regent’s Park, London NW1 4RG.
Email: clinicaleffectiveness@rcog.org.uk

Plain language summary

Heart problems are common in newborn babies, affecting approximately 5–10 in 1000 babies. Some are more
serious than others, but most babies born with heart problems do not have other health issues. Of those babies
who have a serious heart problem, almost 1 in 4 will have heart surgery in their first year. In the UK, pregnant
women are offered a scan at around 20 weeks to try and spot any heart problems. In most cases there is not a
clear reason for the problem, but sometimes other issues, such as genetic conditions, are discovered. In recent
years the care given to these babies after they are born has improved their chances of surviving. However, it is
recognised that babies born with heart problems have a risk of delays in their learning and development. This may
be due to their medical condition, or as a result of surgery and complications after birth.
In babies with heart problems, there is a need for more research on ultrasound and magnetic resonance imaging
(MRI) to understand how the brain develops and why these babies are more likely to have delays in learning and
development. This paper discusses the way ultrasound and MRI are used in assessing the baby’s brain. Ultrasound
is often used to spot any problems, looking at how the baby’s brain develops in pregnancy. Advances in
ultrasound technologies have made this easier. MRI is well-established and safe in pregnancy, and if problems in
the brain have been seen on ultrasound, MRI may be used to look at these problems in more detail. While it is
not always clear what unusual MRI findings can mean for the baby in the long term, increased understanding may
mean parents can be given more information about possible outcomes for the baby and may help to improve the
counselling they are offered before their baby’s birth.

1. Background

1.1 Epidemiology of congenital heart defects (CHDs)

Congenital heart defects (CHDs) are the most common congenital anomaly with a birth prevalence of approximately 5–10/
1000 live births, and a recognised cause of infant death.1,2 Approximately 25% of infants with CHDs will have serious defects
requiring surgery within their first year.3 Most cardiac lesions are isolated with no other congenital anomalies identified.
At present, approximately 50–60% of cases are detected antenatally through local and national screening programmes.4–7

The definition of CHD varies significantly. Mitchell et al.8 define CHD as ‘a gross structural abnormality of the heart
or intrathoracic great vessels that is actually or possibly of functional significance’. This definition includes a significant

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group of clinically relevant defects with outcomes that have improved in recent decades through advances in
surgery.1 In accordance with this definition, abnormalities of the systemic veins, systemic artery branches, valvular
abnormalities, cardiomyopathy and congenital arrhythmias are excluded.1

1.2 Etiology of CHD

In only 15–30% of all cases of CHD is a cause identified; in the remainder the cause is unknown.1,9 Chromosomal
aneuploidy is a well-recognised cause accounting for approximately 10% of all cases of CHD. For example, the
prevalence of CHD in Down syndrome is approximately 45%,1other associated chromosomal aneuploidies include
trisomy 13 and 18 and Turner syndrome.10 Single gene defects account for a further 3–5% of cases of CHD, including
DiGeorge syndrome, Alagille syndrome, Holt–Oram syndrome and Noonan syndrome.11–13 Nonchromosomal or
genetic causes include some well recognised associations, such as maternal diabetes, phenylketonuria, maternal obesity,
rubella infection, alcohol use and drug exposure (e.g. retinoic acid, thalidomide and organic solvents).1,14,15 In the
remaining cases of CHD the aetiology appears multifactorial, with a suggestion of interaction between genetic and
environmental factors. The recurrence risks observed in families with CHD suggest a multifactorial interactive model
although the evidence base is limited.1 The recurrence risk of nonsyndromic CHD in a family with one affected sibling is
approximately 1–6% increasing to 3–10% in cases of two affected siblings.1,16–19 The risk to the offspring of inheriting
CHD from an affected parent is higher at approximately 4%, and two- to three-fold higher in cases of maternal CHD
compared with paternal CHD.1,10 Nutritional factors have also been implicated; up to 40% reduction in the incidence of
CHD was reported in a meta-analysis of prenatal multivitamin supplementation.20

1.3 Prognosis of CHD

Recent decades have seen a significant advancement in cardiothoracic surgery and cardiac care. In the 2016 National
Congenital Heart Disease Audit of UK centres,21 the 30-day survival rates associated with surgical interventions were over
97.5%, depending on the complexity of the cardiac lesion. The survival rate in the first year of life is approximately 85%.22,23
Of these infants, more than 90% will be alive at the age of 16 years. Analysis of data from a national registry in the
Netherlands24 have reported a mean age of 34 years in patients with CHD, and 85% of patients registered are below the
age of 45 years. In some cardiac lesions, there has been a reported 50–70% decrease in mortality in the past two decades.25
The improvement in survival has been coupled with an increase in the prevalence of neurological deficit in this group, which
mainly includes patients with transposition of the great arteries (TGA) and hypoplastic left heart (HLH). There are now
robust data showing the prevalence of these deficits can be up to 50%,26–28 highlighting the need to focus on
neurodevelopmental deficits as primary outcomes in patients with CHD. The prevalence and severity of
neurodevelopmental delay is associated with the complexity of CHD and selected genetic syndromes.9 The areas of
neurodevelopmental delay include intelligence and academic achievement, language (development, expressive and
receptive), visual construction and perception, attention, executive functioning, fine and gross motor skills and psychosocial
maladjustment.9 A list of potential causative and contributory factors for these deficits has been proposed.29–32 Many infants
with CHD require corrective or palliative surgery in the neonatal period, and the use of cardiopulmonary bypass, deep
hypothermic circulatory arrest, and various surgical and postoperative factors have all been implicated in contributing to
adverse neurodevelopmental outcomes.29–32 Chromosomal and other syndromic conditions associated with CHDs are
independently associated with impaired neurodevelopmental status.33 Other genetic factors, for example expression of
neuroprotective apolipoprotein E, may help to modulate brain injury following surgery in certain patients.34 Socio-economic
and parental factors will also influence later intellectual development.35,36

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Increasingly, however, preoperative and prenatal brain dysgenesis, immaturity and white matter injury are being
recognised in infants with CHDs. There is substantial clinical evidence of neurological developmental deficits prior to
surgery in these infants, with this association more established in some cardiac defects, such as HLH.9,26 There is a
higher prevalence of microcephaly in infants with HLH and the effect of surgery on further neurological deficit in this
group is unclear.26 In addition to global delay, localised neurological deficits have been observed in all domains.26
Evidence from the neuroimaging literature demonstrates more than half of newborns with CHD (in high-risk groups
of HLH and TGA) have evidence of white matter brain injury, which are varyingly termed ischaemic lesions, white
matter injury, focal stroke and periventricular leukomalacia.9,27,37 Furthermore, studies on fetuses incorporating
magnetic resonance imaging (MRI), magnetic resonance spectroscopy and diffusion tension imaging (DTI) have
revealed abnormalities of brain microstructure and metabolism before birth, as well as shortly after birth and before
surgery.38 The origin of these changes is almost certainly multifactorial, with congenital brain abnormalities,
intrauterine haemodynamic alterations and acquired brain injury all implicated.37 At present, the correlation of fetal
neurological findings with longstanding neurodevelopmental consequences is not well established.39 With continuing
advancement in prenatal screening and diagnosis incorporating modalities, such as 3D and 4D ultrasound
reconstruction, MRI and fetal genotyping, including array comparative genomic hybridisation, there is an opportunity
to improve fetal characterisation, with a particular focus on neurological development, to inform counselling,
perinatal management and neonatal care and surgery. Future research and advancement in clinical care must tackle
the associated long-term morbidity of CHDs.

2. Fetal neurological assessment and antenatal diagnosis

2.1 Ultrasound including 3D

The challenge for those involved in prenatal diagnosis, namely fetal medicine and fetal cardiology specialists, clinical
geneticists, paediatric neurologists and neuroradiologists, is to obtain an accurate diagnosis that allows women to
make informed decisions about their pregnancy. This includes an assessment of the fetal central nervous system
(CNS) which can be challenging; a good understanding of developmental anatomy and an appreciation of the
spectrum of the postnatal course is necessary for a given diagnosis.

The mainstay of fetal ultrasound screening and assessment is transabdominal scanning (TAS) and transvaginal scanning
(TVS), which permits routine views of the fetal intracranial anatomy (in both the transthalamic and transcerebellar
planes) enabling the detection of anomalies such as ventriculomegaly, severe cerebellar hypoplasia, holoprosencephaly
and the Arnold-Chiari malformation. Indeed, from approximately 18 weeks of gestation, fetal cortical development as
assessed by ultrasound correlates closely with that obtained by MRI.40 Furthermore, advances in ultrasound
technologies has led to improved visualisation of the fetal cerebral architecture; for example, with colour Doppler
flow imaging and higher frequency probes.40–42

In 2000, Carroll et al.43 documented the difficulties in establishing a correct diagnosis of posterior fossa anomalies;
this has been confirmed in later studies.44,45 Crucially, improved detection rates and accuracy of diagnosis have been
achieved by the use of TVS and 3D assessment.46–48 The advent of 3D and 4D ultrasound has also led to the
acquisition of volumetric datasets for off-line assessment; this has been particularly useful for assessment of gyra and
sulcal formation from 20 weeks of gestation.49

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2.2 Fetal MRI

MRI is increasingly a feature of clinical practice, and has been used antenatally for approximately 20 years with no
known reported hazards to the fetus when applied according to radiological guidelines. Fetal MRI is also a well-
established, safe, complimentary technique for assessing the fetus, particularly the brain, in fetal medicine. It offers a
larger field of view, which is useful as pregnancy progresses, and enables successful image acquisition regardless of
fetal position or maternal size. MRI may be used to confirm ultrasound findings, provide more detail about a
suspected anomaly or detect new abnormalities not identified with prior ultrasound, such as foci of infarction, and
cerebellar and cortical abnormalities.50,51 In a publication from 2017, the use of MRI in the diagnosis of fetal brain
abnormalities led to increased diagnostic accuracy and changes in clinical management in more than a third of cases,
alongside high patient acceptability.52 Furthermore, newer MRI technologies, including DTI tractography which allows
white matter tracts to be imaged and mapped, and connectomics which allows structural connectivity data to be
combined with functional activity, may aid in detecting atypical brain development and should ultimately provide
information on neurodevelopmental prognosis.53,54 However, it is important to note that MRI, despite its merits, is
not the gold standard and each modality has its own advantages; in one small series55 ultrasound was found to be
superior to MRI in 3/26 cases.

Ventriculomegaly is an example of an ultrasound diagnosis with a complex aetiology, including acquired injury, and
hence, the rate of associated malformation ranges from 10–76%.56 While the ultrasound diagnosis of ventriculomegaly
is straightforward, the accurate inclusion and exclusion of additional intracranial anomalies is more challenging.
Numerous studies from the early-2000s indicated that additional information is found in up to 44% of cases of
mild ventriculomegaly using MRI.57,58 However, by using just conventional high-frequency 2D ultrasound scanning
(either TAS or TVS), the amount of additional information falls to 5–17%.59,60 Presumably, with the advancement of
other modalities (colour Doppler imaging, 3D and 4D, etc.) this may improve further. The main additional abnormality
missed by ultrasound is agenesis of the corpus callosum.61 Other diagnoses, including intraventricular haemorrhage
and subependymal heterotopia, often secondary to in utero ischaemic injury, are best made by MRI.62 The exclusion
of additional anomalies using MRI can also provide reassurance to the woman.

Proliferation disorders may be secondary to environmental insult.63 The initial concern is often revisited later in
gestation by the presence of microcephaly (head circumference more than three SD below the mean).63,64 The
necessary assessment for gyral anomalies is best performed by MRI. In 2013, the first in utero use of the combined
modalities of ultrasound scanning and MRI, the so-called MRI ultrasound fusion, was reported.65 This proof of
concept demonstrated the potential of the technique to enable real-time ultrasound scanning views to be
superimposed on MRI images.

2.3 Fetal brain MRI assessment in CHDs

Brain imaging has a major role in the detection of injury or aberrations in development, with follow-up studies of such
patients necessary to determine the clinical significance of the findings. In a meta-analysis27 of 13 studies of infants with
CHDs (n = 425 cases) reporting on brain abnormalities either preoperatively or in those who did not undergo
congenital cardiac surgery, and nine studies (n = 512 cases) reporting preoperative data on neurodevelopmental
assessment, the prevalence of brain lesions on neuroimaging was 34% (95% CI 24–46; I2* = 0%) in TGA, 49% (95% CI
25–72; I2 = 65%) in left-sided heart lesions and 46% (95% CI 40–52; I2 = 18.1%) in mixed/unspecified cardiac lesions,

*I2, statistic describes the percentage of variation across studies that is due to heterogeneity rather than chance.

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while the prevalence of neurodevelopmental delay was 42% (95% CI 34–51; I2 = 68.9%). In many instances, brain
abnormalities will be detected on postnatal imaging performed prior to, or post, surgical procedures. In a fetus with a
confirmed or suspected congenital cardiac defect, MRI may be used to assist in the detection of additional fetal
anomalies, with the main emphasis being on the brain. Conventional MRI techniques may identify overt brain anomalies,
not previously detected on ultrasound, suggesting or increasing the likelihood of a specific underlying diagnosis. MRI has
an improved capability over ultrasound to detect previously undetected agenesis of the corpus callosum,66 cerebellar
defects, cortical abnormalities, such as polymicrogyria, and migration abnormalities, such as subependymal heterotopia.
Ultrasound guidelines suggest reserving MRI examination to those fetuses where there is a suspicion of abnormality on
ultrasound.67 The ability of MRI to detect abnormalities not seen on ultrasound in this group of patients is as yet
unknown, although evidence from other cohorts suggests that significant abnormalities may be detected.66

The majority of fetal MRI is still being carried out at 1.5 T, but several units are using 3 T for research and clinical practice.
Fetal MRI is usually acquired without resorting to maternal sedation, but as for any MRI examination maternal
contraindications include: claustrophobia, metallic implants, some cardiac pacemakers, being overweight or obese (new
wide-bore magnets with a diameter of 70 cm [rather than 60 cm] may be better tolerated by those with a high BMI or with
claustrophobia). Image acquisition is by single-shot techniques, minimising the effects of fetal and, to a lesser extent,
maternal, motion on image quality.68 Image acquisition may take 20–60 minutes depending on the number of sequences
used and the availability of motion correction techniques. Without the latter, in a very mobile fetus sequence acquisitions
may have to be repeated several times to acquire interpretable scans. T2-weighted images are the mainstay sequence
providing excellent contrast of brain structures. T1-weighted techniques are useful for confirming the presence of
haemorrhage, but are more challenging to obtain at sufficient quality.69 In a clinical setting, diffusion-weighted imaging can be
used to identify areas of acute ischaemia.70 Motion correction approaches, such as snapshot to volume reconstruction,
produce volumetric datasets suitable for post-acquisition quantification using manual or automatic segmentation to assess
regional volumes and cortical maturation.71,72 Other advanced approaches include DTI to assess tissue microstructure and
brain connectivity,70 MRI spectroscopy to assess cerebral metabolites,73 and phase contrast and T2 mapping techniques to
assess fetal cerebral blood flow and oxygen extraction,74 but these all remain largely in the research environment. MRI
studies also need to consider imaging outside the brain to detect subtler abnormalities not identifiable with ultrasound that
may increase the risk of a specific syndrome, e.g. absence of the semicircular canals in CHARGE syndrome (a condition
composed of the following features: coloboma of the eye, heart defects, atresia choanae, growth retardation, genital and/or
urinary abnormalities, and ear abnormalities and hearing impairment). Larger, long-term studies are needed to appreciate
the importance of obtaining antenatal information about not only overt abnormalities but quantifiable deviations in brain
development alongside diagnostic accuracy in CHD, with respect to counselling, birth management and longer term
neurodevelopmental outcomes.

3. Opinion

 Cardiac disease remains the most prevalent congenital fetal anomaly.

 Improvements in antenatal screening have led to an increase in prenatal diagnosis, which is associated with
improved neonatal outcomes. Furthermore, advances in neonatal, infant and paediatric surgical interventions
have contributed to the increase in survival in CHDs.
 Longer term follow-up has revealed the neurological morbidity associated with CHDs.
 At present, the focus of antenatal and perinatal counselling has been on the risk of mortality and cardiovascular
morbidity associated with specific cardiac anomalies. However, antenatal diagnosis using ultrasound and fetal MRI,
alongside improvements in technologies and image acquisition, provide the opportunity to improve the detection
of fetal neurological abnormalities and their association with long term neurodevelopmental outcomes.

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 Antenatal diagnosis of neurological abnormalities may potentially direct further investigations and inform
antenatal counselling. Multidisciplinary management with a clinical geneticist and a neurologist should be
considered, given the spectrum of possible neurological abnormalities and impact on prognosis.
 Long-term neurodevelopment will be further influenced by additional injuries to the brain that may occur during
birth, or during initial interventions including septostomy and more definitive surgical procedures.
 There is an argument for conducting additional imaging studies at serial time points to detect not only
alterations in development but the acquisition of lesions in this vulnerable group.
 At present fetal ultrasound remains the primary screening tool in babies with CHD, with MRI used in some
instances for those with suspected brain abnormalities following primary screening.
 The ability of MRI to detect abnormalities not seen on ultrasound in patients with CHD is unknown. Further
development/research in this area might therefore be of value and has the potential to inform practitioners of the
risk of neurological morbidity in relation to antenatal brain developments and postnatal pre- and post-surgical
interventions, ultimately leading to improved counselling of parents in the antenatal period.

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 This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by:
Dr D Pasupathy MRCOG, London; Mr ML Denbow FRCOG, Bristol; and Professor MA Rutherford,
King’s College London
and peer reviewed by:
Mr DI Fraser FRCOG, Norfolk; Mr M Griffiths FRCOG, Dunstable; RCOG Women’s Network; Dr AJ Thomson MRCOG,
Glasgow; Dr A Toi, Mount Sinai Hospital, Toronto, Ontario, Canada; and Professor F Ventriglia, Department of Pediatrics,
University of Rome “Sapienza”, Rome, Italy.
The Scientific Advisory Committee lead reviewer was: Miss MK Dhanjal FRCOG, London.
The chair of the Scientific Advisory Committee was: 1Professor MD Kilby FRCOG, Birmingham; and 2Dr S Ghaem-Maghami
MRCOG, London.
1
chair from June 2018; 2until May 2018.

All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising
any conflicts of interest for this Scientific Impact Paper is available from: https://www.rcog.org.uk/en/
guidelines-research-services/guidelines/sip60/.
The final version is the responsibility of the Scientific Advisory Committee of the RCOG.

The paper will be considered for update 3 years after publication, with an
intermediate assessment of the need to update 2 years after publication.

DISCLAIMER
The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice.
They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by
obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular
clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented
by the patient and the diagnostic and treatment options available.
This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be
prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or
guidelines should be fully documented in the patient’s case notes at the time the relevant decision is taken.

RCOG Scientific Impact Paper No. 60 e151 of e151 ª 2019 Royal College of Obstetricians and Gynaecologists