Abstract
The chapter opens with observations on the normal fetal heart and proceeds to a discussion of fetal hydrops and its associated cardiac causes. There follows a treatment of the syndromes associated with congenital heart disease in the fetus. Common congenital heart defects as they appear in the fetus are illustrated. Fetal cardiomyopathy, myocarditis and arrhythmia all have separate discussions. The chapter closes with a series of discussions on the pathology of twins as it affects the heart: twin–twin transfusion syndrome, conjoined twins and acardiac twins.
12.1 Introduction
Perhaps nowhere in the broad field of cardiology has so much improvement been made in the past three decades than in the understanding and imaging of the fetal heart. Anatomy and function can be assessed even in the first trimester fetus, and lesions can now be identified that previously were invisible. The progression of heart disease over the weeks of pregnancy can be monitored and the possibility of in utero intervention can be contemplated. The fetus is now regarded as a patient in its own right, albeit one intimately connected with and critically dependent on the mother. Heart disease in the fetus may take the form of structural congenital heart disease, cardiomyopathy, myocarditis or cardiac arrhythmia. There is frequently overlap of these conditions. For example, structural heart disease may be associated with cardiac dysfunction, and primary cardiac arrhythmia may progress to dilated cardiomyopathy.
In the European Union, it is estimated that 23 000 children are born every year with congenital heart disease and that a further 3000 who are diagnosed with congenital heart disease die as a result of termination of pregnancy, late fetal death or early neonatal death [1]. In a normal population, the risk of a woman having a child with a congenital heart malformation is of the order of 0.8–1% [2]. If a heart defect was present in a previous pregnancy, the risk of having a child with a congenital heart malformation rises to 2–3% [3], and if the mother herself has a congenital heart defect the risk approaches 6%.
There is great variation between countries in the antenatal detection of heart defects, being lowest in those countries without ultrasound antenatal screening programmes (8–11%), but in Western Europe the detection rates range between 19 and 48%. Detection depends crucially on the skill of the operator. High-resolution echocardiography enables assessment of precise structures during the second trimester or even earlier.
For those pregnant women who have had a previous child with a congenital heart defect, or those with an ultrasound finding such as increased nuchal translucency that may be associated with a cardiac defect, or those with a family history of congenital heart defect, evaluation of the fetal heart by ultrasound scan between 11 weeks and 14 weeks’ gestation is advised [4].Transvaginal ultrasound is optimal for fetal cardiac examination before 12 weeks’ gestation, but after 12 weeks, the fetal heart can be adequately assessed by transabdominal ultrasound. However, the likelihood that cardiac defects such as VSDs, tetralogy of Fallot, Ebstein’s anomaly or cardiac tumours will be identified at less than 14 weeks’ gestation is low [5].
In the United Kingdom, in about half of all cases in which structural heart disease is detected antenatally, the pregnancy is terminated. Termination is more likely if there are associated malformations or chromosomal abnormality [6]. Some heart defects may not be detected early on but may progress during pregnancy. This has been well documented with obstructive right- and left-sided lesions [7,8]. The defects most likely to be detected are those that affect the size of the ventricles or cause in utero heart failure. Thus, the spectrum of heart lesions seen in cases of termination of pregnancy is not the same as that seen in live-born children [9]. In particular, there are higher incidence rates of coarctation of the aorta, double inlet left ventricle, hypoplastic left heart, truncus arteriosus, double outlet right ventricle and atrioventricular septal defect among stillbirths [10].
The death rate in utero of fetuses with congenital heart disease is high, and this also causes a difference in the populations of live and non-live-born [11]. There is also evidence that preterm infants have more than twice as many cardiovascular malformations as do infants born at term, and that 16% of all infants with cardiovascular malformations are preterm [12].
Data suggest that in those cases without chromosomal abnormality or other associated defects, detection of heart disease in utero can improve outcome [13].
12.2 The Normal Fetal Heart
The fetal heart shows right-sided dominance with up to two-thirds of cardiac output going through the right ventricle. Between 75 and 90% of the right ventricular output is shunted through the arterial duct to the systemic circulation[14]. The long-axis of the left ventricle is more horizontal in the second trimester fetus because the left ventricular apex is displaced cranially by the large liver (Figure 12.1).
Figure 12.1 Horizontal position of the fetal heart in the second trimester. Miscarriage at 21 weeks showing the opened chest. The thymus has been removed and the pericardial cavity has been opened to display the heart. The long-axis of the heart lies more horizontally at this age than later in gestation.
In the second and third trimester right and left ventricular pressure waveforms are similar to the post-natal forms [15] and increase linearly with gestation.
The fetus normally directs one-third of its cardiac output to the placenta during the second half of pregnancy and one-fifth during the last couple of months of gestation. The growth-restricted fetus directs a reduced volume of blood towards the placenta, both in absolute and relative terms, while maintaining a normal cardiac output [16].
Fetal heart growth occurs by hyperplasia, that is to say cell division, and hypertrophy (increase in cell size by addition of sarcomeres), and is regulated at each developmental stage by growth factors and haemodynamic load [17]. During organogenesis it is tightly regulated by growth factors when haemodynamic strain is low. With the formation of the septated heart the haemodynamic load increases and becomes more important as a regulator of hypertrophy and hyperplasia [18]. Studies of isolated cardiac myocytes have shown that sarcomeres are added either in series or in parallel in response to mechanical stretching [19].
The myocardial fibres are organised as geodesic curves around toroid nested layers. Additionally, myofibres run from epicardium to endocardium at oblique angles to the surface geodesics. The interface of the right and left tori is the interventricular septum (Figure 12.2). There are differences in the arrangement of the tori in right and left ventricles. The left is more regular while the right is distorted by the pulmonary infundibulum [20].
Figure 12.2 Disposition of myocytes in the ventricular walls. A diagrammatic representation of the disposition of muscle bundles in the ventricular walls. They resemble two sets of “nested” doughnuts, placed side by side. The left ventricular arrangement is the more regular of the two. The right ventricular arrangement is complicated by the presence of the pulmonary trunk. The interventricular septum is a composite of the apposed edges of both doughnuts. Windows have been cut in both ventricles to show the nested arrangement with muscle bundles at different levels having different orientation.
12.3 Fetal Hydrops
The term fetal hydrops refers to the excessive accumulation of fluid in the fetus in at least two serous cavities (peritoneum, pleura, pericardium) or in body tissues (subcutaneous oedema) [21]. In any case of fetal hydrops, the finding of an accompanying congenital heart defect arouses in the pathologist an almost irresistible temptation causally to link the two. The temptation should be resisted. Most fetuses with congenital heart defects do not develop hydrops. It is only those with a severe mechanical defect, disease of the heart muscle or those with arrhythmia who do so [22]. There should be compelling evidence to ascribe hydrops to a cardiac defect that in any particular case is more likely to be coincidental. This is particularly so in trisomy 21 where cardiac disease is frequent, as is hydrops. In comparison with controls with normal or increased nuchal translucency, cardiac function in a trisomy 21 fetus is abnormal, irrespective of the presence of congenital heart disease. Evidence for increased cardiac preload and afterload with first trimester left ventricular systolic and later diastolic dysfunction can be observed [23].
The commoner recognised cardiac causes of fetal hydrops are listed in Table 12.1 [24–36]. In the setting of fetal hydrops abnormal cardiac function is a strong predictor of fetal death [37].
| Reference | ||
|---|---|---|
| Structural | Ebstein’s anomaly | 24 |
| Unguarded tricuspid orifice | 24 | |
| Tetralogy of Fallot – absent pulmonary valve | 25 | |
| ? Chiari network | 26 | |
| Aorto-left ventricular tunnel | 27 | |
| Cardiomyopathy | Cardiomyopathy | 28 |
| Tumour | Rhabdomyoma Teratoma Angioma Fibroma | 29 |
| Inflammatory | Maternal lupus | 30 |
| Myocarditis | ||
| Closure of fetal shunt | Premature closure of: arterial duct foramen ovale venous duct | 32 33 34 |
| Arrhythmia | Long QT | 35 |
| Other | Idiopathic infantile calcification |
The cardiac abnormalities that seem to predispose to fetal hydrops are:
Premature closure of fetal shunts (venous duct [34], foramen ovale [33], arterial duct [32])
Disease of the heart muscle, particularly of the right ventricular myocardium (hypertrophic cardiomyopathy, myocarditis, ventricular non-compaction [28])
Ebstein’s anomaly [24] and tetralogy of Fallot with absent pulmonary valve [25]. It is likely that this is more than simple valvar regurgitation and that there is associated intrinsic right ventricular abnormality [38]
Cardiac tumours, by a mechanical obstruction of venous return or arterial output [29]
Severe cardiac arrhythmia [30]
Possibly Chiari network [26]
Idiopathic arterial calcification [36]
12.3.1 Premature Shunt Closure
Hydrops with intrauterine death has been described in association with absence of the venous duct, and that structure should be examined carefully in all cases of fetal hydrops [39].
Premature closure of the arterial duct in utero causes multiple effects on the right heart and pulmonary circulation, resulting in secondary pathology. Disproportionate right ventricular hypertrophy, right atrial and right ventricular dilation, and moderate to severe tricuspid and pulmonary valvar regurgitation are the most frequent echocardiographic abnormalities. Dysplasia of the pulmonary valve associated with regurgitation may be a marker of fetal ductal dysfunction. Clinical outcomes range from antenatal hydrops to mild, reversible respiratory distress and even neonatal death [40].
The foramen ovale may also close prematurely in utero resulting in fetal hydrops (Figure 12.3).
(A) Viewed from the right side the oval fossa appears patent with redundant flap tissue.
(B) Viewed from the left side the flap valve of the oval fossa bulges into the left atrium as a sac-like structure. There was a dilated arterial duct and right ventricular hypertrophy, a small peri-membranous VSD partly closed by tissue tags from the tricuspid valve and a bicuspid aortic valve with narrow aortic arch. Obstructive left-sided lesions are well described in cases of premature closure of the foramen ovale.
Idiopathic arterial calcification is typically associated with fetal hydrops, cardiomegaly and heart failure (Figure 12.4).
12.3.2 Arrhythmia
Fetal arrhythmia may cause hydrops. The fetal myocardium does not relax very well. With fetal tachycardia there tends to be mitral and tricuspid regurgitation, and with sustained and early tachycardia there is a 50% risk of hydrops. Normally, there is continuous antegrade flow in the venous duct, but with tachycardia there is biphasic flow, with reversal in atrial systole. Pulsatility in umbilical venous flow is an ominous sign. In the fetus a net outward fluid shift is compensated by avid lymphatic flow (approximately four times the lymphatic flow in an adult). This lymphatic flow is very susceptible to increases in venous pressure. Mortality of fetal tachycardia is 25–50% with treatment, and greater than 50% without treatment. Atrioventricular block is rare in the fetus and is usually an incidental finding. In the structurally normal heart with complete heart block there is variability in atrial rate. If not, the ventricular rate is very, very slow. In complete heart block secondary to structural heart disease there is no variability in the atrial or ventricular rates. Cardiomyopathy develops in 50% of cases of complete heart block. However, when atrioventricular block occurs in the setting of congenital heart disease (usually left atrial isomerism or double discordance), approximately 50% of cases have a dismal outcome. Left atrial isomerism and AV block has 100% mortality at 3 months. Double discordance with AV block has 25% mortality at one month [41].
12.3.3 Maternal Lupus
In maternal lupus anti-Ro antibodies cross the placenta from 16 weeks’ gestation onwards – and damage the atrioventricular conduction tissue and other cardiac tissues. With the presence of maternal anti-Ro or anti-La antibodies, the risk of complete heart block in the fetus is in the order of 3%. There is a recurrence rate of 15% [42]. Echocardiographically, the affected fetus shows a dilated heart with pericardial effusion and atrioventricular valvar regurgitation in systole and diastole. The atrial rate is in the normal range with a variable ventricular rate [30]. There is evidence that the level of maternal antibody is important in determining the presence of fetal disease, with high titres of anti-Ro antibody correlating with fetal heart disease [43]. Pathologically there is destruction of tissue at the atrioventricular junction, in particular of the atrioventricular conduction tissue. This is frequently manifest pathologically as fibrosis and calcification. In addition there may be endocardial fibroelastosis of the left ventricle and involvement of the atrioventricular (including tension apparatus) and arterial valves [44] (Figure 12.5). Although an inflammatory cell infiltrate, mostly lymphocytic, may be evident, it is striking how frequently there is minimal inflammatory cell infiltration. The tissue destruction leads to heart block and valvar regurgitation [45], but the exact mechanisms of tissue destruction are not yet clear.
(A) A histological section of the right ventricular outflow in an affected fetus. At the insertion points of the pulmonary artery the myocardium shows bluish areas of necrosis and calcification.
(B) At higher power the loss of myocytes with dystrophic calcification is evident. There is little inflammatory cell infiltration.
(C) Elsewhere in the heart there is loss of muscle at the tips of the papillary muscles with fibrous replacement.
(D) In this case the placenta shows massive perivillous fibrin deposition, most of the placenta parenchyma being replaced by grey (pale pink) fibrin. Massive perivillous fibrin is a recognised complication of lupus.
12.4 Syndromes with Heart Malformations
Structural congenital heart disease is common in many syndromes. Some have characteristic associations.
12.4.1 Chromosomal Abnormality
A recent population-based study from Atlanta in the United States showed that one in eight (12.3%) children with congenital heart disease (live-born and fetal deaths) had a chromosomal abnormality [46]. The commonest chromosomal abnormalities observed were trisomy 21 (52.8%), trisomy 18 (12.8%), 22q11.2 deletion (12.2%) and trisomy 13 (5.7%).
12.4.1.1 Down’s Syndrome: Trisomy 21
Most fetuses (66–76%) with trisomy 21 have a structurally normal heart on echocardiography [47]. There is an increased incidence of atrioventricular septal defect [48]. Congenital heart disease does not appear to increase the chance of spontaneous intrauterine loss in ongoing pregnancies. Atrioventricular septal defect (AVSD) is the commonest defect (Figure 12.6), occurring in 44% of cases of trisomy 21 fetuses with heart disease [49]. Conversely, 43% of fetuses with an AVSD have trisomy 21. In Down’s syndrome, the membranous septum is abnormally large [50]. An aberrant right subclavian artery has been proposed as a marker for Down’s syndrome [51].
For the most common congenital heart disease operations patients with Down’s syndrome do not have a significantly greater mortality risk in comparison with patients without Down’s syndrome [52]. A subgroup of patients with a functionally univentricular heart undergoing staged palliation do appear to have significantly increased in-hospital mortality rates, compared with patients without Down’s syndrome. Patients undergoing ASD repair, VSD repair or tetralogy of Fallot repair appear to have prolonged lengths of stay, as well as more post-operative complications, including infections, respiratory complications and pulmonary hypertension. A greater proportion of patients with Down’s syndrome undergoing VSD repair also developed complete heart block requiring pacemaker placement.
A 1.77-Mb critical region, which includes the promoter and a portion of the Down’s syndrome cell adhesion molecule (DSCAM) gene (highly expressed in the developing heart) has been implicated as a likely candidate for causing Down’s syndrome congenital heart disease [53].
12.4.1.2 Trisomy 18
These fetuses are usually growth deficient and show facial dysmorphism with low-set ears. There is frequently omphalocele. The hands tend to be clenched with overlapping of the fingers. Almost any form of complex heart malformation can be associated with trisomy 18 [54]. Ventricular septal defects, atrioventricular septal defects, left heart disease and tetralogy of Fallot are the most frequently encountered (Figure 12.7) [55].
Figure 12.7 Trisomy 18. Termination of pregnancy at 13 weeks’ gestation for a diagnosis of trisomy 18. The head is large and the body thin, in keeping with growth restriction. The face is dysmorphic with low-set ears and sunken nasal bridge. There is an omphalocele that has ruptures with coils of intestine visible around the umbilicus. Internally, there was horseshoe kidney and perimembranous VSD.
12.4.1.3 Trisomy 13
In trisomy 13 the commonest heart defects are atrioventricular or VSDs, valvar abnormalities, narrowing of the aortic isthmus or truncus arteriosus (Figure 12.8) [56].
12.4.1.4 Triploidy
Triploidy is said to occur in 2–3% of pregnancies, often ending in early spontaneous abortion, but occasionally resulting in the birth of an abnormal fetus or infant. Triploidy may be the result of either digyny (extra haploid set from mother) or diandry (extra haploid set from father) [57]. The diandric phenotype is characterised by a normally sized or mildly symmetrically growth-restricted fetus with normal adrenal glands, and is associated with an abnormally large, cystic placenta with histological features of partial hydatidiform mole. The digynic phenotype is characterised by marked asymmetrical intrauterine growth restriction, marked adrenal hypoplasia and a very small, non‐molar placenta.
Triploid fetuses have a wide variety of congenital anomalies such as complete syndactyly of the third and fourth fingers, syndactyly of the toes, abnormal genitalia, and cardiac, urinary tract and brain anomalies. These abnormalities do not differ between the digynic and diandric triploids. This may well be because the parent-of-origin effect observed is a manifestation of altered intrauterine growth, possibly mediated through placental phenotype or function, determined by parental origin [58]. Cardiac defects occur in approximately 40% of cases (Figure 12.9) [59].
12.4.1.5 Turner’s Syndrome (45,XO)
Cardiac defects occur in approximately 20% of cases of Turner’s syndrome. The most common are bicuspid aortic valve, hypoplastic aortic arch and valvar aortic stenosis (Figure 12.10) [60]. There is a three-fold excess mortality in patients with Turner’s syndrome, and cardiovascular disease is responsible for about half of this excess. The cardiovascular manifestations of Turner’s syndrome include congenital heart disease, aortic dilation [61] and dissection [62], valvar heart disease, hypertension, thromboembolism, myocardial infarction and stroke.
12.4.1.6 Other Chromosomal Abnormalities
Cardiac defects are described in fetuses with:
1p36 deletion [63]: It is the commonest human terminal deletion syndrome and manifests as multiple congenital abnormalities with mental retardation. Affected infants may have patent arterial duct or develop infantile dilated cardiomyopathy [64]
4p-syndrome (Wolf–Hirschhorn syndrome) [65]
9p-syndrome [66]
13q-syndrome [67]
18q-syndrome [68]
12.4.1.7 22q11.2 Microdeletion Syndrome
Chromosome 22q11.2 microdeletion syndrome is the most common microdeletion syndrome in humans and involves the loss of genetic material on the short arm of one of the chromosome 22 alleles [69]. Until advanced testing was available, this syndrome was known by various names including DiGeorge syndrome and velo-cardio-facial syndrome. The main features of DiGeorge syndrome are congenital heart disease, absence or hypoplasia of the thymus (with consequent immunodeficiency and infections), hypoparathyroidism with hypocalcaemia, gastrointestinal problems, delayed psychomotor development, abnormalities of the head and face, and a tendency to develop seizures and psychiatric disorders. Eighty per cent of cases have conotruncal heart defects (i.e. tetralogy of Fallot, interrupted aortic arch, VSDs, vascular rings) (Figure 12.11).
(A) A heart showing pulmonary atresia. The pulmonary trunk is reduced to a fibrous thread running from the anterior ventricular mass to the undersurface of the aortic arch. The lungs were supplied with blood by aortopulmonary collateral arteries. Internally the heart showed VSD.
(B) A heart showing common arterial trunk. The right ventricle is to the left and the left ventricle to the right of the picture. The ventricular septum has been cut. Above its crest there is an interventricular septal defect overlain by the truncal valve.
12.4.1.8 Arteriohepatic Dysplasia (Alagille Syndrome)
Alagille syndrome, an autosomal dominant condition, is due to mutations in one of two genes in the Notch signalling pathway – JAG1 (ligand) or NOTCH2 (receptor) [70]. It shows variable expression and may occur sporadically. The main presenting feature is neonatal cholestasis (because of paucity of intrahepatic bile ducts) [71] that rarely develops into cirrhosis, but may be responsible for disabling pruritus and xanthomas. The other features are abnormal facies, cardiac abnormalities, butterfly vertebrae and ocular embryotoxon. The most common cardiac defect is peripheral pulmonary artery stenosis [72]. The prognosis depends on the severity of the liver and heart disease. Hepatocellular carcinoma has been reported.
12.4.1.9 CHARGE Syndrome
This comprises multiple congenital abnormalities – Coloboma, Heart disease, Atresia choanae, Retarded growth, Genital anomalies and Ear anomalies. Autosomal dominant mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene are found in about two-thirds of cases [73]. Congenital heart disease is present in about two-thirds of cases [74]. The spectrum of abnormalities is similar to that in DiGeorge syndrome with conotruncal anomalies (tetralogy of Fallot, double outlet right ventricle, truncus arteriosus) and aortic arch anomalies (vascular ring, aberrant subclavian artery, interrupted aortic arch). Heart defects are equally common in CHD7 positive and negative cases [75].
12.4.1.10 Noonan’s Syndrome
Noonan’s syndrome (1 per 1000–2500 live births) is the most common non-chromosomal syndrome seen in children [76]. It is an autosomal dominantly inherited disorder and the most common syndromal cause of congenital heart disease after Down’s syndrome. It is characterised by short stature, dysmorphic facial features (hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears), chest deformity, a wide range of congenital heart defects and developmental delay of variable degree. Mutations in the RAS/MAPK signalling pathways cause about 70% of Noonan’s syndrome cases with a KRAS mutation present in about 2% [77]. Approximately 60% of Noonan’s syndrome cases are sporadic and are presumed to be the result of de novo mutations or parental germline mosaicism.
The cardiac defects include hypertrophic cardiomyopathy, polyvalvar dysplasia and pulmonary stenosis (Figure 12.12) [78].
Figure 12.12 Noonan’s syndrome. An infant with hypertrophic cardiomyopathy and polyvalvar dysplasia typical of Noonan’s syndrome. A close-up view of a four-chamber cut of the heart clearly shows the hypertrophy of the ventricular myocardium and the nodular and myxoid thickening of the atrioventricular valves.
12.4.1.11 Williams Syndrome
Williams syndrome is due to a contiguous gene deletion at 7q11.23 and is associated with a distinctive facial appearance, cardiac abnormalities, infantile hypercalcaemia, and growth and developmental retardation [79]. The deletion causes haploinsufficiency of multiple genes including the elastin gene (ELN). Supravalvar aortic stenosis is the characteristic cardiac abnormality. Supravalvar pulmonary stenosis, branch pulmonary artery stenosis and ASDs and VSDs also occur. There is a high risk of sudden death (Figure 12.13) [80]. Haploinsufficiency of ELN is largely responsible for the cardiovascular manifestations of the syndrome. The supravalvar stenosis is usually progressive, but the pulmonary manifestations usually regress [81]. Point mutations in ELN give rise to autosomal dominant supravalvar aortic stenosis [82].
12.4.1.12 Marfan Syndrome
Marfan syndrome is an autosomal dominant condition with an estimated prevalence of 1 in 10 000–20 000 individuals. The diagnosis is established by application of diagnostic criteria, known as the Ghent nosology. This is based on a combination of major and minor clinical manifestations in organ systems, and family history [83]. The pathogenesis of Marfan syndrome involves fibrillin-1 gene mutations that exert a dominant negative effect. Marfan syndrome is, thus, termed a fibrillinopathy, along with other connective tissue disorders with subtle differences in clinical manifestations.
Sixty percent of children with Marfan syndrome have a cardiovascular abnormality [84]. Aortic root dilation and mitral valve prolapse are the main cardiovascular abnormalities. Aortic root dilatation is present in 35% of children with Marfan syndrome by the age of 5 years and in 68–80% of individuals by the age of 19 years [85]. Histologically the degree of abnormality in affected aortae is variable. The characteristic abnormality is cystic medial degeneration with fragmentation of elastic fibres and accumulation of glycosaminoglycans in the aortic tunica media (Figure 12.14).
12.4.1.13 VACTERL/VATER Association
The associations include Vertebral defects, Anal atresia, Cardiac defects, Tracheo-oEsophageal fistula, Renal anomalies and Limb abnormalities [86]. Vascular abnormalities are also present in some cases. Between 40 and 80% of patients with VACTERL association have heart disease. There are no characteristic defects (Figure 12.15).
Figure 12.15 VACTERL. A composite photograph showing some of the features of the condition. The radiograph on the left shows right radial aplasia, the central photograph a fetus with anal atresia. On the right is a specimen of oesophageal atresia with tracheo-oesophageal atresia. The proximal oesophagus ends blindly at mid-tracheal level. The distal oesophagus takes origin via a fistula from the trachea, the origin of which is visible just above the carina.
12.4.1.14 Holt–Oram Syndrome
Holt–Oram syndrome is an autosomal dominant condition characterised by upper limb abnormalities, typically absent or triphalangeal thumb and cardiac disease [87]. It is linked to point mutations in TBX5 on the short arm of chromosome 4 [88]. The heart abnormality is typically an ASD, but VSD, hypoplastic left heart and left ventricular non-compaction may also be observed.
12.4.1.15 Carney Complex
An autosomal dominant multiple neoplasia syndrome characterised by cardiac and extracardiac myxomas, schwannomas, and skin pigmentation and endocrine abnormalities. It is caused by inactivating mutations of the PRKAR1A gene on chromosome 17q24.2-q24.3 [89]. Heart myxomas occur in about half of the patients with the complex. They occur at a younger age than with non-Carney cases and may occur in any or all cardiac chambers.
12.4.1.16 Loeys–Dietz Syndrome
An autosomal recessive disorder caused by mutations in the genes for TGF beta receptor 1 or 2 (TGFBR1 or TGFBR2). About two-thirds of patients with the disorder have aortic aneurysm with dissection [90]. The syndrome is divided clinically into types 1 and 2. Type 1 patients share phenotypic features with Marfan syndrome and manifest more severe cardiovascular disease. Type 2 patients share phenotypic features with Ehlers–Danlos IV. Cardiovascular features in Loeys–Dietz syndrome are mainly aortic valvar regurgitation, aortic root dilation, aortic aneurysm and aortic dissection. Aortic aneurysms in the syndrome are prone to rupture at diameters smaller than those seen in patients with Marfan syndrome. Pathologically there is medial degeneration in the aorta that tends to be more severe and more diffuse than in Marfan syndrome (Figure 12.16) [91].
Figure 12.16 Loeys–Dietz syndrome. A section of the aortic wall removed from a 13-year-old boy with the syndrome undergoing aortic root replacement for aortic dilatation. The EvG stained preparation shows mild intimal fibrosis. The outer tunica media shows fragmentation and separation of the elastic lamellae.
12.4.1.17 Ehlers–Danlos Syndrome
An inherited connective tissue disorder. Six types are described, with major cardiovascular manifestations in type IV. Type IV Ehlers–Danlos syndrome results from mutations in the COL3A gene; there is facial dysmorphism, skin manifestations and cardiovascular disease [92]. Aortic dissection is characteristic, occurring in up to 10% of affected individuals. Histopathological features are mild and non-specific.
12.4.1.18 Homozygous Familial Hypercholesterolaemia
An inherited disorder of lipid metabolism caused by mutations in the low-density lipoprotein receptor gene (LDLR). This causes hypercholesterolaemia and premature atherosclerosis [93]. Affected children have coronary artery narrowing and supravalvar aortic stenosis caused by atheromatous plaques at the sinotubular junction. The cusps of the aortic valve may be involved (Figure 12.17) [94].
Figure 12.17 Hypercholesterolaemia. Thirteen-year-old girl with familial hypercholesterolaemia. A section of aortic wall removed during correction of supravalvar aortic stenosis stained with Elastic vanGieson. There is adventitial fibrosis. The media shows focal fragmentation. There is dense intimal fibrosis and at the extreme left of the field there is an area of pallor caused by accumulation of lipid-filled macrophages – an atheromatous plaque.
12.5 Structural Heart Disease in the Fetus
It is, perhaps, stating the obvious that structural heart disease begins in the embryo during heart development. Some defects progress with increasing gestational age, so for example an aortic valve initially with stenosis may become atretic with time. There are also secondary effects that develop from the primary abnormality. All the abnormalities listed in Chapters 4 and 5 may be seen in the fetus, and their morphology is basically the same whether seen in the fetus or the older child once differences in size are taken into account. There are technical difficulties in examining very small hearts, particularly if there is also maceration – a situation frequently the case if the pregnancy has been terminated. If there has been feticide by injection of potassium chloride into the heart, the fatal puncture site in the epicardium is frequently visible at post-mortem (Figure 12.18). However, even in complex cases such as isomerism of the atrial appendages, it is possible to establish all the main abnormalities with a little care and attention to detail (Figure 12.19). Imaging nowadays is so good that it may be better than the ability to demonstrate the abnormality at post-mortem, and sometimes micro-CT may be the preferred method of examination, particularly in very small fetuses (Figure 12.20). Histology is useful in confirming abnormality in some cases, e.g. dysplasia of a valve (Figure 12.21). There is considerable variation in the severity of heart defects from simple small VSD to complex problems such as hypoplastic left heart. There may be associated extracardiac abnormalities and there may be heart failure of arrhythmia, all of which impart a graver outlook. If there is attempted intrauterine correction, the post-mortem will show the abnormality (Figure 12.22).
Figure 12.19 Macerated heart. Termination of pregnancy at 21 weeks’ gestation for tetralogy of Fallot with absent pulmonary valve. The fetus was retained in utero for three days following feticide before delivery. Despite the obvious maceration, the morphology of the narrowed right ventricular outflow with absent valve and post-stenotic dilatation of the pulmonary trunk is still visible. The dilated pulmonary trunk is to the top of the field, the narrowed valvar region in the middle and the right ventricular cavity to the bottom left.
(A) The right ventricle opened to display the ventricular septal defect with overriding aorta. The narrowed right ventricular outflow can be seen in the photo to the right of the aorta.
(B) The micro-CT image of the heart and lungs shows the right ventricle with overriding aorta. The tiny pulmonary trunk is visible to the right of the root of the aorta. The imaging shows the ventricular myocardium in exquisite detail.
Figure 12.20 Micro-CT. A demonstration of the capabilities of microfocus CT for examination of macerated fetal heart. Termination of pregnancy at 21 weeks’ gestation for tetralogy of Fallot.
(A) In the heart there is dysplasia of the pulmonary valve, with thickened, myxoid leaflets.
(B) Histology confirms thickened dysplastic valvar tissue (Elastin stain).
Figure 12.21 Histology. Termination of pregnancy at 18 weeks’ gestation for multiple congenital abnormalities.
(A) the needle entry point of the right ventricle. To the left is a large intrapericardial blood clot.
(B) The opened right ventricular outflow tract. The anterior right ventricular wall is to the left of the field and the cut edge of the supraventricular crest in the centre with the pulmonary artery above. The pulmonary valve is visible with fusion of the cusps. Extending vertically downwards for a short distance from the valve there is a tear in the posterior outflow wall.
(C) An expanded view of the heart with removal of some of the pulmonary valvar tissue to show that the tear extends into the posterior wall of the pulmonary trunk. This is the site of perforation that resulted in the fatality.
(D) Histological section of the perforated area showing fibrin and neutrophil accumulation at the site of perforation.
Figure 12.22 Fetal in utero intervention: attempted dilatation of pulmonary valvar stenosis. Severe pulmonary stenosis detected on scan. At 22 weeks fetal balloon valvoplasty was attempted. The first attempt was unsuccessful but was repeated when the valve was breached and perforated. Tamponade and pleural effusion developed. The fetus became bradycardic and was transfused and appeared to stabilise but was dead the following day.
Figure 12.23 shows some of the commoner congenital heart defects as they appear in the fetus.
(A) Ventricular septal defect – termination of pregnancy 24 weeks for trisomy 18. The opened left ventricle shows a muscular VSD.
(B) Atrioventricular septal defect – termination of pregnancy at 20 weeks for AVSD; the superior bridging leaflet is clearly seen.
(C) Tetralogy of Fallot viewed from the right side with overriding aorta, VSD and subpulmonary narrowing (termination of pregnancy 22 weeks).
(D) Hypoplastic aortic arch in Turner’s syndrome (termination of pregnancy 18 weeks).
(E) Ostium primum AVSD viewed from the left side.
(F) Left atrial isomerism – bilateral left atrial appendages (termination of pregnancy 14 weeks).
(G) Common arterial trunk – viewed from above the pulmonary arteries arise from the common trunk anterior to the bronchi (20 weeks).
(H) Arterial ring: right aortic arch with left-sided arterial duct forming a vascular ring around trachea and oesophagus (23 weeks).
(I) Ebstein’s anomaly – intrauterine death 32 weeks.
(J) Termination of pregnancy 23 weeks for right atrial isomerism – note bilateral tri-lobed lungs. Multiple aortopulmonary collateral arteries arise from the descending aorta and supply the lungs.
(K) Tricuspid atresia (termination of pregnancy 20 weeks). Right atrium opened to show absence of the right atrioventricular connection.
(L) hypoplastic left heart (termination of pregnancy 21 weeks). The thread-like ascending aorta lies between the superior caval vein and the enlarged pulmonary trunk.
(M) Double outlet right ventricle (termination of pregnancy 22 weeks). A very macerated heart with very narrow pulmonary outflow and a muscular outlet septum separating it from the aorta with underlying VSD.
(N) AV-VA discordance (termination of pregnancy 23 weeks). The right atrium is connected to a morphologically left ventricle with right-sided topology. The valve is a mitral valve.
(O) Transposition – term. The characteristic side-by-side arrangement of the great arteries.
