Fetal and Maternal Medicine Review 2004; 15:4 327–341 C© 2004 Cambridge University PressDOI: 10.1017/S0965539504001330

IMPACT OF PRENATAL DIAGNOSIS ON THE PAEDIATRICMANAGEMENT OF HEART DEFECTS

LINDSEY ALLAN

King’s College Hospital, London

INTRODUCTION

Ultrasound has been used in cardiac diagnosis since the 1960s. The original modalityused was M-mode, which recorded the movement of heart structures relative to asingle line of sound passed through the heart and was displayed as a paper tracing.During the 1970s, a two-dimensional image became possible, but it was a staticimage, which had limited value for cardiac evaluation. However, by the end of the1970s, advances in ultrasound equipment allowed the heart to be displayed in real-time. This technology was applied initially in the adult and subsequently in thechild. Echocardiography proved particularly suitable for children, partly because it isnon-invasive and repeatable, but also because most heart disease in children is dueto malformation of anatomical structure, which ultrasound can ideally display. Atthe same time, obstetric ultrasound was progressing rapidly and descriptions of theappearances of malformations in most fetal systems began to be published by theend of the 1970s. It was not until real-time equipment became generally available inobstetrics that the fetal heart could be satisfactorily evaluated. This led to descriptionsby several authors of normal fetal cardiac anatomy as seen echocardiographically in1980.1,2,3 The appearances of the echocardiogram in different forms of congenitalheart disease (CHD) in children were published in the late 1970’s, setting the stage fordiagnosis in fetal life. As a result, by the mid-1980’s, most major forms of CHD hadbeen detected prenatally.4

At this time, detailed fetal cardiac evaluation was confined to specialists in fetalechocardiography and to those patients selected for expert analysis because theyfell into a high-risk category for CHD. These high-risk categories included motherswith a family history of CHD, those with maternal diabetes and in fetuses whereextracardiac malformations had been identified. However, a novel idea, which hadthe potential of greatly increasing the impact of fetal echocardiography, was putforward by a French group in 1985. Building on their nationwide network of skilled

Address for correspondence: Lindsey Allen, Consultant in Fetal Cardiology, Harris Birthright Centre forFetal Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.

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obstetric ultrasonographers, they suggested teaching them to incorporate a single viewof the fetal heart, namely the four chamber view, into routine obstetric scanning.Although this single view of the heart would not detect all major structural heartmalformations, theoretically, if systematically applied, it could detect about 60%of them.5 This introduced the concept of screening the normal pregnant populationfor CHD. At the time, it appeared that about 90% of CHD occurred in low-riskpregnancies, therefore an effective screen of the heart during the obstetric scanenormously expanded the potential for the detection of CHD. The stimulus todetect cardiac abnormalities prenatally is partly driven by the fact that they arestill an important cause of mortality in infancy with severe cardiac abnormalitiesaccounting for approximately 20% of neonatal deaths.6 In a significant proportion ofthese cases the cardiac defect is not recognised during life, but found on post mortemexamination.7

As the skill of the obstetric ultrasonographer and the image quality of ultrasoundequipment has improved over the years, great artery assessment has been added tothe four chamber view during routine examination, such that over 90% of majorCHD is potentially detectable in skilled hands. The reality is, however, that successof detection of cardiac anomalies varies8,9,10 widely and tends to be linked to thestandard and intensity of more general ultrasound screening. Thus, where a routinefetal anomaly scan, applied to all pregnancies and performed to a high specification,is in place, detection of all anomalies, including heart defects, is high. However,the use of ultrasound during pregnancy varies widely nationally and geographicallyand even between neighbouring obstetric units, although overall detection of cardiacanomalies of all kinds has shown steady improvement over the 25 years that fetalechocardiography has been possible. As the four-chamber view is technically easier toobtain and analyse, defects which alter the appearance of this view, are preferentiallydetected prenatally. This was clearly shown in a UK-wide study published in 1999,11 ofall cases of CHD found over a 3 year period. In the cases detected in fetal life, diagnosessuch as the hypoplastic left heart syndrome, univentricular heart and atrioventricularseptal defect predominated, in contrast to the postnatal series where arch anomalies,tetralogy of Fallot and ventricular septal defects predominated.

The detection of a possible cardiac abnormality during the routine scan allowsthe patient to be referred to the fetal cardiologist for more detailed diagnosis andcounselling. The ideal fetal cardiologist has skill in obstetric imaging, a thoroughunderstanding of the fetal spectrum of CHD, coupled with up-to-date knowledge oflocal and international results of the management of different types of CHD, bothimmediate and long-term, in order to offer the detailed counselling which the parentsneed when a cardiac malformation is found in the fetus.

The advent in the mid-1990s of screening for nuchal translucency (NT) at12 weeks gestation was a further significant advance in the fetal echocardiographicfield.12,13 Nuchal translucency detected a significant group of pregnancies at high-risk of CHD, which had not been identified as such before. It was shown thatif the NT measurement was above the 95th centile, there was an association notonly with chromosomal defects, which was the primary aim of nuchal translucency

Impact of prenatal diagnosis on the paediatric management of heart defects 329

Table 1 Incidence of CHD per 1000, with increasing NT

0

20

40

60

80

100

120

140

160

180

200

2.5-3.5 3.5-4.5 4.5-5.5 5.5-6.5 >6.5

measurement, but also with CHD. The incidence of CHD increases with increasedlevels of NT. In a recent analysis of our own data, there was a rate of CHD at twicenormal if the NT was between the 95–99th centile (about 2.6–3.5 mm) increasing totwenty-six times the normal rate if the NT was over 6.5 mm (Table 1). The groupof patients with NT > 95th centile is probably the most useful high-risk groupfor selection for detailed fetal echocardiography. Interestingly, increased NT is notassociated with any particular form of CHD. Table 2 shows a recent analysis of thetype of CHD seen in 123 cases with increased NT and normal chromosomes, where asimilar scatter of CHD was seen to the spectrum which might be expected in infants.Coarctation was slightly over-represented in the fetus but some of these cases arelikely to have progressed to the hypoplastic left heart syndrome by birth. There hasbeen some debate about the incidence of increased NT in those with CHD, with ratesof 17% and 56% found in different studies.14,15 The real figure is probably around25%.

The incidence of CHD is about 8/1000 livebirths. About 4–5 of these 8 children haveventricular septal defects, secundum atrial septal defects, mild pulmonary stenosis orpersistent arterial ducts. With the exception of moderate to large ventricular septaldefects, none of these lesions are detectable in the fetus. However, all these lesionscan be readily treated surgically or by catheter techniques, or even may not requireintervention at all, and are compatible with a normal quality of life and life-span. Incontrast, about 3/8 cases of CHD per 1000 are major forms of CHD, which nearly allrequire surgical treatment, and sometimes repeated intervention, at a varying risk ofmortality and morbidity, depending on the type of defect. These forms of CHD can

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Table 2 Types of CHD seen in a series of 123 cases with increased NT and normal chromosomes.DIV = double inlet ventricle, HLH = hypoplastic left heart syndrome, DORV = double outlet right ventricle,VSD = ventricular septal defect, TOF = tetralogy of Fallot, AVSD = atrioventricular septal defect.

0 5 10 15 20 25

Pulmonary atresia

Mitral atresia

Ebsteins

Isomerism

Aortic stenosis

Tricuspid atresia

DIV

HLH

DORV

Transposition

VSD

TOF

AVSD

Coarctation

severely impact the child’s life and, even if successfully treated, will nearly all impairthe quality of life and/or shorten the lifespan. It is this severe spectrum of disease thatis typically detected in fetal life.

TERMINATION OF PREGNANCY

The detection of CHD during pregnancy offers the patient the possibility oftermination of pregnancy. In the UK, prior to 24 weeks gestation, this course ofaction may be chosen legally for fetal anomalies. However, in the setting of CHD,termination is more likely to be chosen by the parents when there are associatedextracardiac anomalies and/or chromosomal anomalies, or where the complexityof the heart malformation is such that a poor outlook is anticipated. In addition,in general, the earlier the diagnosis is made of fetal abnormality, the more likelytermination is to be chosen. Thus, the more widespread application of nuchaltranslucency screening has led to earlier diagnosis of CHD, even as early as 12 weeksgestation, which in turn is likely to lead to a higher rate of pregnancy interruption forCHD in the future. Termination of pregnancy after 24 weeks gestation is confinedto the most severe forms of CHD or those with multiple malformations and isuncommon.

Impact of prenatal diagnosis on the paediatric management of heart defects 331

As a result of increasing detection of major CHD prenatally, the prevalence ofsome major forms of heart malformation has been shown to have fallen as a resultof termination.16 In a study of all cases of pulmonary atresia with intact ventricularseptum seen in the UK between 1991 and 1995, the prevalence in postnatal life wasshown to have fallen from 5.6 to 4.1 in England because of prenatal detection andtermination of pregnancy. It is likely that this effect may increase in the future asprenatal detection of CHD improves, reducing the number of the most complex casesof CHD coming to the paediatric cardiologist. However, counterbalancing this isthe fact that as the prognosis for surgical repair of many heart defects continues toimprove, the counsellor is able to be more optimistic about the results and terminationmay be chosen less often.

PROGRESSION OF CHD

One of the most interesting observations in fetal cardiology has been that some formsof CHD progress in fetal life. This has been seen in both aortic and pulmonary stenosiswhere the valve appeared echocardiographically normal in early pregnancy but becamestenosed later, or where the degree of stenosis has progressed from mild to severe oreven to atresia during gestation. In pulmonary stenosis, this can occur in isolatedvalve disease or in more complex CHD where pulmonary stenosis is a component.Thus, for example, in tetralogy of Fallot, transposition with ventricular septal defector double outlet right ventricle, the pulmonary valve obstruction can increase duringpregnancy to pulmonary atresia and thus duct dependency after birth.17 In some casesof critical aortic stenosis, the left ventricle is usually dilated in early pregnancy but itfails to keep pace with normal growth resulting in a small left ventricle by term, withquite different implications for surgical management.18 In coarctation, poor growth ofthe aortic arch can occur, such that an extended arch repair through a sternotomy isnecessary after birth, with a higher morbidity and mortality, rather than the simplersurgical approach of a lateral thoractomy. Valvar incompetence can also progress inutero, particularly in the tricuspid valve, leading to hydrops and even intrauterinedeath. In addition, there are some cardiac lesions which are not usually evident earlyin pregnancy but which evolve towards term. Examples include cardiac tumours andcardiomyopathies. Thus, although a normal fetal cardiac scan in competent handsat 20 weeks can exclude most major heart disease, there are forms of major diseasewhich progress from milder disease or may develop in later pregnancy. However, suchexamples are rare.

FETAL THERAPY

There are some fetal conditions where prenatal treatment is appropriate. In fetaltachycardias, the fetus can be treated by maternal anti-arrhythmic drugs whichcross the placenta. Treatment can prevent the development of cardiac failure, if thetachycardia is detected soon after its initiation. Once the fetus is in cardiac failure

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RV

LVspine

Figure 1 The left ventricle is dilated, globular in shape and poorly contracting in the moving image. Thisappearance is typically seen associated with a critically obstructed aortic valve, which is amenable to prenatalballoon valvoplasty. LV = left ventricle, RV = right ventricle.

due to a tachycardia, the fetus is at considerable risk of mortality and treatment canbe life-saving.19 Although these cases are uncommon, treatment is well-establishedin this context.

Prenatal balloon valvoplasty was first suggested at the end of the 1980s forconditions where an isolated obstructive lesion was present, such as aortic stenosis(Figure 1). It was observed that as pregnancy advanced in a fetus with a criticallyobstructed aortic valve, the left ventricle either failed to grow sufficiently or becameirreparably damaged by endocardial fibroelastosis. At this time, there was no surgicaltreatment available for a hypoplastic or inadequate left ventricle, and thus these caseswere associated with a high mortality after birth. The rationale for prenatal treatmentwas to relieve valvar obstruction sufficiently early in pregnancy to avoid the secondaryeffects of the obstructed valve on the left ventricle and give it “recovery time” priorto birth, while the circulation was also supported by the right ventricle. The leftventricular apex was punctured directly using a needle through which a guide wire

Impact of prenatal diagnosis on the paediatric management of heart defects 333

and subsequent balloon catheter could be passed. It was then positioned and inflatedin the valve orifice. There was limited success in the early cases and some difficultieswith balloon technology,20 while at the same time, treatment strategies in the formof the Norwood operation for the hypoplastic left heart syndrome began to achievebetter results21 and thus the technique fell out of use. Interest has been rekindledmore recently, partly because of improved technology, and partly in an attempt toavoid one ventricle repair on either the right or left sides of the heart.22,23 It remainsto be seen whether this technique will find an established role in Fetal/PaediatricCardiology practise.

DELIVERY OF A FETUS WITH CHD

Depending on the type of defect, presentation in CHD varies from acutedecompensation soon after birth to gradual deterioration over the first months oflife, with all stages in between. Examples of conditions which can cause symptomsimmediately after birth include severe Ebstein’s malformation and tricuspid dysplasia,transposition of the great arteries and total anomalous pulmonary venous drainage.Ebstein’s malformation is an anomaly of the tricuspid valve in which the orificeof the tricuspid valve is displaced into the right ventricle. With a mild degree ofdisplacement, the neonate is likely to be asymptomatic but with more severe degrees,especially if there is severe tricuspid regurgitation, postnatal ventilation can bedifficult due to lung hypoplasia. This, in turn, is due to compression of the fetallung fields by cardiomegaly. If the neonate can be supported through the early periodand there is sufficient lung volume, tricuspid regurgitation tends to lessen as thepulmonary pressure falls in the first weeks of life. However, some extreme examplesdo not survive this early period despite maximum support.

In the majority of cases of transposition of the great arteries (Figure 2), the neonateis noticed to be cyanosed in the first days of life but about 20% present moreacutely, becoming hypoxic and acidotic within even an hour of birth. This subgroup ofcases have a restrictive or intact atrial septum, preventing oxygenated blood reachingthe systemic circulation, resulting in rapid deterioration and even death before theneonate can reach a cardiology centre. These infants can be successfully treated byultrasound-guided tearing of the atrial septum by a balloon catheter, if they reach helpin time.

In total anomalous pulmonary venous drainage, if the pulmonary veins drain to anobstructed confluence, which can occur with both supra and infracardiac drainage,the neonate can become severely cyanosed and require urgent surgical relief. Intransposition and total anomalous pulmonary venous drainage, maintaining ductalpatency is not usually of much benefit. However, there is a group of patients who aretermed “duct-dependent” and who do benefit from maintaining the duct open usingprostaglandins. In these cases, depending on the cardiac defect, either the pulmonaryor systemic circulation is dependent on the patency of the arterial duct. The arterialduct naturally starts to close some hours or days after birth but can do so acutely, eithercausing severe cyanosis (if the pulmonary blood flow is affected) or systemic collapse

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RV Ao

LVPA

Figure 2 The great arteries do not show their usual spiral relationship but arise in parallel orientation.This is characteristic of transposition of the great arteries. In this condition, delivery where immediatecardiological care can be instituted can improve the outcome. LV = left ventricle, RV = right ventricle,Ao = aorta, PA = pulmonary artery.

(if the aortic blood flow is affected). Conditions where the pulmonary circulation isduct dependent include severe pulmonary stenosis or atresia, which can be isolated orbe a component of different forms of intracardiac malformation such as tetralogy ofFallot (Figure 3), or double outlet right ventricle. Conditions where the systemiccirculation is duct dependent include aortic stenosis or atresia (Figure 4), andinterruption or coarctation of the aortic arch. In contrast, many conditions, such asan atrioventricular septal defect, for example, are associated with the gradual devel-opment of cardiac failure over the first 2–4 months of life and do not present urgently(Figure 5).

From the time of the earliest reports of fetal cardiac diagnosis, it has been clearthat the outcome for the fetus with CHD is less good than would be expected inpostnatal life.24,25 This is because of the bias towards detecting the most severeCHD prenatally, due to the way patients are selected for fetal echocardiography.

Impact of prenatal diagnosis on the paediatric management of heart defects 335

LV

RV<Ao

RV

PA>

<Ao

spine

Figure 3 In the left panel, there is a ventricular septal defect with the aorta overriding the crest of theventricular septum. The scan plane immediately above this level is shown in the right hand panel, where thepulmonary artery is seen crossing over the aortic origin in a normal fashion. However, the pulmonary arteryis smaller than the aorta, which is the reverse of normal. This finding in association with aortic override,indicates a diagnosis of tetralogy of Fallot. Some cases of tetralogy of Fallot are duct dependent and shouldbenefit from prenatal diagnosis.

Those fetuses with gross cardiac abnormalities detected on screening and thosewith extracardiac anomalies or hydrops are preferentially referred. There is a higherincidence of chromosomal anomalies in fetal series than in live-births.25 There isa small but fairly consistent incidence of spontaneous intrauterine death of between5–10% in fetal series, partly due to the presence of associated chromosomal anomaliesbut not entirely. Some fetuses with CHD die in utero for no apparent reason. Theoutcome after the diagnosis of CHD in a recent series of 956 cases is shown in Table 3.A high rate of termination reflects our high incidence of chromosomal anomalies, asmany of our cases of CHD come from the NT screening programme, but there is alsoan incidence of spontaneous intrauterine death and neonatal loss despite maximaltreatment.

In a series of cases of the hypoplastic left heart syndrome diagnosed in fetal life, themortality in the fetally diagnosed cases was almost twice that of those submitted tofirst stage Norwood surgery in the same institution.26 This could be accounted for bychromosomal anomalies, other extracadiac malformations or extreme prematurity inthe fetal “intention-to-treat” group, all of which were less common in the postnatalgroup, or such postnatal patients were not submitted for surgery and therefore notcounted in the surgical series. In addition, there were some cases of a restrictiveatrial septum in the fetal series who decompensated so acutely after birth, that theywould have died before reaching the surgical centre, had they not been prenatallydiagnosed.

There is no evidence that early or operative delivery in CHD will improveoutcome, although both might be considered in the rare cases where cardiac functiondeteriorates in late gestation. Early delivery might be considered in the setting of

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RA

RVLA

Figure 4 In this four chamber view, the mitral valve is atretic and the left ventricle hypoplastic. Thiswas a case of the hypoplastic left heart syndrome. In such a fetus the systemic perfusion is dependent onthe patency of the arterial duct which naturally closes within hours or days of birth, sometimes acutely. Ifthe neonate is not treated urgently with prostaglandins, irreparable damage can occur to the kidneys andliver. Thus, this cardiac condition would be expected to benefit from prenatal detection and delivery in aspecialised centre.

increasing hydrops in CHD or in a fetal tachycardia resistant to therapy but thedisadvantages of prematurity, and lung immaturity in particular, must be weighedagainst any possible advantage. However, it seems intuitively obvious that those caseswhere early or urgent cardiological treatment is required must benefit from prenataldiagnosis, by being delivered at, or close to, the site of cardiological care. This isparticularly relevant in settings where the specialised cardiac centre is geographicallyremote, as intrauterine transfer is much more stable than the transfer of a sick

Impact of prenatal diagnosis on the paediatric management of heart defects 337

RVLV

<

<

Figure 5 This four-chamber view shows a defect at the crux of the heart, an atrioventricular septal defect.Such a malformation will not cause immediate symptoms in the newborn, so can be safely delivered locally.

neonate. Although many authors have tried to prove the benefit of planned deliveryafter prenatal diagnosis, it has been difficult to show for various reasons. In manycases, this is because the numbers of prenatally diagnosed cases are not sufficientfor statistical analysis.27,28 Some authors have looked at mixed diagnostic groups,with the more severe lesions predominating in the fetal series.29 Also, in general,this question cannot be addressed by a tertiary referral centre, as they do not usuallyhave a method to ascertain cases who have died in the periphery prior to referral.Had they been included, such cases would have had the effect of increasing themortality in the postnatally diagnosed cases, but they are not usually recognised.Deaths from unrecognised CHD occurred in up to 15% of cases of the hypoplasticleft heart syndrome in one reported series.7 Subsets of cases of the hypoplastic leftheart syndrome which are at especially high risk of early death, such as those witha restrictive atrial septum are over-represented in the fetal series, supporting theconcept that these cases would not have reached the referral centre had they not beendetected prenatally. The only series which was sufficiently large to analyse and waspopulation based and therefore ascertained all cases in a geographical area, whether

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Table 3 Outcome of 956 cases of fetal CHD evaluated between 1998 and 2004. TOP = termination ofpregnancy, IUD = intrauterine death, NND = neonatal death, InfD = infant death, uk = unknown or presentlycontinuing pregnancies

0

100

200

300

400

500

600

TOP IUD Alive NND InfD uk

they reached the referral centre or not, was that of Bonnet et al.30 This was a tenyear study of a single diagnostic category, transposition of the great arteries, andwas based in the Paris area of France. This showed a clear advantage for the casesprenatally diagnosed with no mortality in this group, as compared to an 8% mortalityprior to surgery, plus an 8% mortality after surgery in the postnatally diagnosedgroup. More recently, similar results were reported in a study of neonates withcoarctation of the aorta, demonstrating that the risk of postnatal death was decreasedin the prenatally diagnosed group and that they were more haemodynamically stablepreoperatively.31

Clearly, mortality is rather a crude outcome measure and long-term morbidity ininfants with CHD should be explored in more detail. In all the studies which havelooked at prenatal versus postnatal diagnosis in terms of outcome, the prenatallydiagnosed cases have been haemodynamically more stable in the immediate postnatalperiod than those postnatally diagnosed.32 This would be expected to translate into abetter neurological result in the long-term for those prenatally diagnosed. A numberof studies have shown that after staged surgical reconstruction for hypoplastic leftheart there is a major risk of long-term neurodisability.33,34,35 This risk appears to beimproving with advancing era36 but such data still gives cause for concern. Thereis clear evidence to show a correlation between length of stay in the intensivecare unit and IQ.37 In a significant number of neonates requiring intervention,prenatal diagnosis reduces the time in the intensive care unit and this in turnmay influence long-term morbidity and neurological outcome. Only large studies,evaluating neurological development in children 5–15 years after treatment for CHDwill prove this point and these are notoriously hard to perform.

Impact of prenatal diagnosis on the paediatric management of heart defects 339

SUMMARY

Prenatal diagnosis of CHD disease has influenced the practise of Paediatric Cardiologyin a variety of ways and is likely to have an increasing effect in the future. Fetalechocardiography now constitutes a significant proportion of the work of a specialisedPaediatric Cardiology unit. Early diagnosis and termination of pregnancy may reducethe prevalence of complex disease in postnatal series. At the present time, at leasta third of neonates presenting to most units will have been identified in fetal life andthis figure is likely to increase as routine screening continues to improve, and nuchaltranslucency screening becomes more widely adopted. Planning the delivery whereskilled and experienced cardiac support can be initiated immediately, and interventionperformed where appropriate, will potentially salvage those with urgently presentingor duct dependent lesions. Long-term morbidity associated with the repair of CHD ininfancy is likely to improve as a result of ideal perinatal management.

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