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Review article

Advances in fetal cardiology

Comparetto, Ciroa; Borruto, Francob

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Evidence Based Women's Health Journal: February 2014 - Volume 4 - Issue 1 - p 1-22
doi: 10.1097/01.EBX.0000438947.86514.90
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The delineation of the structural and functional abnormalities of fetal heart by echocardiography has led to the emergence of a new and vital subspecialty, that of fetal cardiology. Its practitioners are from disciplines such as genetics, obstetrics, and pediatrics, whose common interests in the well-being of the unborn child have converged as technologic advances in ultrasound have enabled detailed evaluations and sometimes treatment of fetal hemodynamic abnormalities 1. Fetal cardiology is a well-established field of pediatric cardiology. It is no longer a simple exercise of prenatal diagnosis of cardiac malformations 2 and includes the following:

  • the assessment of fetal heart for congenital heart diseases (CHD) and arrhythmias;
  • the management of affected fetuses, including parental counseling for therapeutic options;
  • planning of the delivery;
  • postnatal care.

This requires a close collaboration between obstetricians, neonatologists, pediatric cardiologists, medical and molecular genetists, and pediatric radiologists. Because of restricted financial sources, extensive fetal echocardiographic assessment is reserved for pregnancies with an increased risk for CHD, which includes the following:

  • a family history of CHD;
  • suspicion of cardiac or extracardiac fetal abnormalities at obstetric routine ultrasonography;
  • fetal arrhythmias;
  • chromosomal anomalies.

As most CHD occur in pregnancies without an increased risk, an ultrasound screening of fetal heart during routine pregnancy ultrasound is recommended. Most forms of CHD can potentially be detected in utero, especially the severe ones, with considerable fetal and postnatal morbidity and mortality. Prenatal diagnosis of a major cardiac malformation requires further assessments for extracardiac and chromosomal disorders. The delivery of patients with major cardiac anomalies in a tertiary obstetric center close to a pediatric cardiac facility enables optimal perinatal and postnatal management. This may be of crucial importance for cardiac malformations that are arterial duct dependent postnatally.

Many CHD have genetic causes. The association of CHD and the trisomies 13, 18, and 21, as well as the monosomy X0 (Turner syndrome) is well established. During the last few years, increasingly more molecular genetics causes for CHD could be found. The most significant are the 22q11 (Di George syndrome) and 7q (Williams syndrome) microdeletions, which are associated with different conotruncal anomalies. Also, for various other congenital cardiac malformations and syndromes, a genetic cause could be found. The search for genetic cofactors is important as it affects parental counseling and patient care 3–5.

In Europe and North America, a dramatic decrease in the incidence of rheumatic fever and rheumatic heart disease has coincided with advances in the medical and surgical management of CHD and has resulted in a shift in the relative incidence of these two categories of cardiac disorders in women of childbearing age 6. Prenatal detection of CHD has improved, and continues to improve, with the increasingly widespread incorporation of the four-chamber view and outflow tracts into the routine screening fetal ultrasound evaluation. Increasingly sophisticated computer processing systems and improvements in imaging technology have enabled the development of automated three-dimensional (3-D) ultrasound imaging systems that promise to revolutionize both prenatal detection and the diagnosis of CHD. Conventional two-dimensional (2-D) imaging approaches may soon become obsolete. There has been an increasing ability to intervene successfully prenatally not only for fetal arrhythmias and heart failure but also for some forms of structural heart disease. In some cases of left or right ventricular outflow tract obstruction, early intervention during the second trimester may prevent the development of ventricular hypoplasia. Finally, several recent studies suggest that prenatal diagnosis may improve neonatal outcome for fetuses with CHD 7.

Prenatal detection of heart malformations has become a crucial part of the management of life-threatening malformations of the neonate, such as the transposition of the great arteries or the coarctation of the aorta. The development of preventive cardiovascular medicine starting from childhood thanks to new techniques of echo-tracking and, finally, 3-D reconstruction of heart defects by using ultrasound, radiograph, or MRI have markedly improved the diagnosis and the therapeutic strategies of cardiac diseases 8,9. Among advances in diagnosis, new diagnostic imaging methods are as follows:

  • 3-D echocardiography;
  • MRI;
  • computed tomography (CT) angiography (CTA); and
  • tissue Doppler imaging.

Advances in fetal interventions are as follows:

  • percutaneous balloon aortic valvuloplasty (BAV);
  • percutaneous balloon pulmonary valvuloplasty;
  • intact or restrictive balloon atrial septostomy.

Advances have been made in the application of percutaneous techniques to adult CHD to help solve problems resulting from previous surgery and new devices to enable the percutaneous closure of muscular and membranous ventricular septal defects (VSDs). A number of developments in valved conduits and in aortic translocation in patients with complex transposition of the great arteries are of particular interest 10,11. Advances in genetics and computing have contributed toward a better understanding of the mechanisms underlying cardiovascular development, its programming, and possible therapeutic manipulation. Preconceptual folate can reduce the prevalence of cardiac malformations and improvements in imaging allow us to detect CHD and assess function at earlier gestations. 3-D and four-dimensional (4-D) imaging may improve the surgeons’ understanding of complex vascular malformations and also aid a remote diagnosis. Treatment of fetal arrhythmias may be rationalized by fetal ECG and magnetocardiography (MCG) and by further defining the natural history of congenital heart block (CHB) and mechanisms of tachyarrhythmia. Tissue engineering and robotics may improve the surgical outcome for children by creating conduits with growth potential, thus reducing the need for multiple surgical procedures. These technologies may enable successful fetal surgical procedures. Cross-discipline collaboration has been key in enabling the advances that have changed the face of fetal cardiology 12. These critical and exciting developments in fetal cardiology promise to increase the clinical impact of fetal echocardiography markedly during the years to come 7,13.

Embryology, anatomy, and pathophysiology of fetal heart and circulation

The development of the heart occurs rapidly in humans from embryonic day 18 to the 12th week of fetal life. The stages include the following:

  • gastrulation and formation of the primitive heart tube, with rhythmic contractions appearing at day 21;
  • segmentation of the primitive heart tube;
  • looping, realignment of inflow and outflow segments;
  • septation of the atria, ventricles, and outflow segments;
  • formation of atrioventricular (AV) valves;
  • development of aortic and pulmonary trunks and aortic arches 14.

Although it is during this time that many of the major cardiovascular defects develop, many of these lesions continue to evolve and others develop in the latter half of gestation. There may be development or progression of ventricular inflow or outflow tract and arch obstruction, and ventricular or great artery hypoplasia. There may be progressive AV or semilunar valve regurgitation that can compromise fetal circulation. There may be development of dysrhythmias, primary myocardial disease, and heart failure. Fetal shunts, the foramen ovale and ductus arteriosus, may change in form and function. Finally, cardiac tumors may develop, grow, or regress 15–24. The heart undergoes marked ultrastructural alterations during fetal and postnatal development. Early in fetal development, cardiac myocytes contain abundant pools of glycogen, scattered mitochondria, and sparse peripheral myofibrils. Transverse tubules are absent and sarcoplasmic reticulum and intercalated discs are poorly developed. During late fetal and early postnatal development, myofibrils extend into the myocyte interior and attain a mature appearance, and the glycogen pools are reduced in size. In addition, transverse tubules develop and the morphological appearance of the sarcoplasmic reticulum and intercalated disc becomes increasingly complex. Experimental studies in sheep, corroborated by clinical studies in humans, also point to marked functional changes during development. In the fetus, the right ventricle is the dominant pumping chamber because right ventricular output exceeds left ventricular output, whereas pulmonary arterial and aortic pressures are similar. This functional difference is reflected in myocardial blood flow patterns, with blood flow to the right ventricle exceeding that to the left ventricle. The ventricular outputs equalize after birth, but a functional left ventricular dominance rapidly emerges following a postnatal increase in systemic vascular resistance and a decrease in pulmonary vascular resistance. This postnatal switchover in functional dominance is accompanied by a corresponding alteration in the relative level of ventricular myocardial blood flows. Consistent with right ventricular dominance in utero, myocytes in the right ventricle of fetal sheep are larger and contain more myofibrillar material than those in the left ventricle. Left ventricular myocytes become larger than right ventricular myocytes after birth, but this adaptation to altered postnatal hemodynamics requires some weeks to become fully established 25.

The ability to diagnose fetal cardiovascular malformations prenatally has been established during the past 30 years. This has naturally led to an increased interest in the possibility of providing timely therapy in the neonatal period and has raised the prospects for prenatal intervention. Before medical, catheter, and/or surgical interventions are performed, however, it is important to understand the normal and abnormal physiology of the fetal cardiovascular system. Significant insights have been gained into human fetal cardiovascular physiology utilizing data previously obtained from fetal lamb models and correlating anatomic, pulsed Doppler, and color flow Doppler observations that have been made echocardiographically during the second and third trimesters of human fetal cardiac development. Regional blood flow distribution studies in the human have shown a relative right ventricular volume dominance in the human fetus of a somewhat lesser magnitude than described previously in the lamb. Observations of ventricular filling characteristics suggest a relative paucity of diastolic ‘reserve’ in human fetal heart, implying a relative sensitivity to acute volume overloading. Human fetal heart, like that of fetal lamb, also appears to have a relatively modest amount of ‘systolic reserve’, making the heart particularly susceptible to acute ventricular afterload. Further studies have shown the ability to recognize altered intrauterine shunt flow across fetal ductus arteriosus and foramen ovale. As predicted in fetal lamb models, alterations in shunt flow accompany major malformation complexes including ventricular hypoplasia. Studies to date suggest that attempts at a surgical intervention should be made very cautiously because of the inability to ascertain whether altered shunt flow patterns precede or follow the development of structural abnormalities 27–33.

As mentioned before, the right ventricle is the dominant ventricle during fetal life. Postnatally, the right ventricle rapidly loses its ability to sustain systemic load. In several forms of CHD, the right ventricle is the dominant or systemic ventricle. Patients with these lesions often develop progressive right ventricle dysfunction over time. This may be related to differences in morphology, genetic profile, and hemodynamic exposure between the left ventricle and the right ventricle 34. The primary function of the circulatory system of both the fetus and the newborn is to deliver oxygen (O2) to metabolizing organs and return deoxygenated blood to the gas exchange organ to replenish the O2 and eliminate the waste product carbon dioxide (CO2). In the fetus, the gas exchange organ is the placenta, and its vascular connections are in a parallel arrangement with the other systemic organs, remote from the pulmonary circulation. In order to supply deoxygenated blood to the placenta and return oxygenated blood to the systemic organs, a series of extracardiac shunts (ductus venosus, ductus arteriosus) and an intracardiac communication (foramen ovale) are necessary 35. Starting in the left cardiac ventricle, fetal blood as measured by Doppler ultrasound up in the ascending aorta moves through the aortic isthmus to the descending aorta and the internal umbilical arteries, which fuse around the umbilical cord. With fresh O2 from the placenta, the erythrocytes move in an accelerating continuous flow along the umbilical vein to the ductus venosus. After having reached the left ventricle again, the blood now passes through a coronary artery to the right atrium and eventually the ductus arteriosus or the pulmonary circulation 36. Venous return of fetal circulation consists of 70% blood from the lower body and of 30% blood from the upper body. Blood of the left hepatic vein contains more O2 than that of the right hepatic vein. This rather well-oxygenated blood from the left hepatic lobe joins the blood of the ductus venosus, carrying high concentrations of O2 and glucose predominantly to the left ventricle, ascending aorta, and brachiocephalic trunk. Less O2-saturated blood of the right hepatic lobe, together with the venous return of the superior vena cava, reaches the right ventricle through the tricuspid valve, then the ductus arteriosus and descending aorta. The hepatic microcirculation seems to be important for regulations of the fetal venous return. However, the supply of organs with O2 and nutrients is mainly dependent on regional vascular resistances 37.

Fetal cardiac output is high and the heart has not been shown to have the sustained reserves shown in adult heart. About 40% (∼200 ml/kg/min) of the combined ventricular output (CVO) in unanesthetized fetal lambs in late gestation is directed to the umbilical circulation. At least one-half of the systemic flow (∼300 ml/kg/min) goes to the skin and carcass. The brain, heart, kidney, and other viscera share about 50% of the remainder (10% CVO). Less than 6% CVO perfuses the lungs. Hypoxemia, acidemia, and various vasomotor agents influence the partition of cardiac output between systemic and umbilical circulations, with or without relatively small changes in blood pressure, which is low by adult standards. In general, the conductance of systemic circuits is more susceptible to change than that of the umbilical one. Both cerebral and myocardial blood flow increase several-fold during hypoxemia. The additional volume flow of blood demanded by such vasodilation in organs forming a relatively small proportion of body weight is more than accounted for by concurrent vasoconstriction in muscle (which contributes a considerable fraction of body weight) and other tissues. Both humoral and reflex neural mechanisms are involved in these adjustments 38–47.

The refinements of modern ultrasound techniques enable a renewed examination of old concepts of fetal circulation. The concept of preferential streaming of umbilical blood through the foramen ovale has been verified by animal experiments, and ultrasound studies have confirmed that a similar mechanism operates in human fetuses. However, the normalized umbilical flow appears to be less in human than in fetal sheep, and decreases with advancing gestational age (115 ml/kg/min at 20 weeks and 64 ml/kg/min at 40 weeks). Compared with the 50% shunting of umbilical blood through the ductus venosus found in animal experiments, the degree of shunting in the human fetus under physiological conditions is considerably less, 30% at 20 weeks, which decreases to 18% at 32 weeks, suggesting a higher priority of fetal liver than realized previously. Augmented pulsatility in the precordial veins, ductus venosus, and umbilical vein is an important clinical sign that has been poorly understood. Recent fluid dynamic studies show that, apart from the pressure generated in the atria, it is the stiffness of the vessel wall, compliance, and notably impedance that modify these waves. Particularly, the considerable shift in impedance at the ductus venosus–umbilical vein junction causes wave reflection and reduced transmission of waves, the result being reduced or absent pulsation in the umbilical vein 48. Thus, fetal circulation has two major vascular shunts: the ductus arteriosus and the ductus venosus. The ductus arteriosus connects the pulmonary artery with the descending portion of the aortic arch, hence shunting most of the right ventricular output away from the unexpanded lungs. The ductus venosus connects instead the portal sinus with the inferior vena cava and allows well-oxygenated umbilical vein blood to bypass the liver and reach the central circulation rapidly. Both blood vessels cease their function after birth and undergo permanent closure. It is now well established that prenatal patency of the ductus arteriosus (PDA) is an active state sustained by a prostaglandin (PG). A similar mechanism has been recognized recently in fetal ductus venosus. Evidence has been presented indicating that PGE2 and PGI2 are natural relaxants for the ductus arteriosus and the ductus venosus, respectively. In addition, both vascular shunts share the dependence on an endogenous cytochrome P-450 mechanism to develop their contractile tone. This mechanism may be important in the normal process of shunt closure at birth 49.

In the fetus, the major function of the ductus arteriosus is to divert flow away from the lungs toward the placenta, thereby avoiding unnecessary circulation through the lungs and reducing the workload of the heart. Constriction of the ductus arteriosus is a clinical disorder produced by several mechanisms that may interact with one another in producing normal postnatal closure of the ductus arteriosus. The major mechanism is the constrictor effect of an increased O2 environment. This may directly affect the ductus arteriosus muscle or may work through the release of an intermediary substance. Other vasoactive substances circulating in the blood after birth may also play some role in constriction of the ductus arteriosus 50. Fetal ductus arteriosus constriction occurs because of inhibition of the PG synthesis pathway, and it has long been associated with maternal intake of NSAIDs in late pregnancy. Idiopathic intrauterine closure of the ductus arteriosus, distinct from intrauterine constriction associated with maternal NSAID ingestion or other secondary causes, is an uncommon event that often results in significant morbidity and mortality. In fact, because of an increased right ventricular pressure, with tricuspid regurgitation and heart failure, there is a risk for the development of neonatal pulmonary artery hypertension. Clinical and experimental evidence shows that maternal consumption of polyphenol-rich substances, such as herbal teas, orange and grape juice, chocolate, and others, may interfere with fetal ductus arteriosus dynamics. Preventive measures to avoid fetal ductal constriction in the third trimester of pregnancy include the possible need to change maternal dietary orientation, aiming to limit ingestion of foods with high concentrations of polyphenol-rich substances 51–54. The unique differentiation program of the ductus arteriosus is essential for its specific task during fetal life and for the adapting circulation after birth. Phenotypic changes occur in the ductus arteriosus during the normal maturation and definitive closure. Morphological abnormalities of the vessel wall characterize the PDA in older children. Genetic research has identified the cause of syndromic forms of PDA, such as the TFAP2B mutations in Char syndrome. Genes that interfere with the remodeling of vascular smooth muscle cells of the ductal media are affected in almost all of these anomalies 55.

In summary, during fetal life, PDA diverts placental oxygenated blood from the pulmonary artery into the aorta bypassing lungs. After birth, a decrease in prostacyclins and PG concentration usually causes arterial duct closure. This process may be delayed or may even completely fail in preterm infants, with the arterial duct still remaining patent. If this occurs, blood flow bypass of the systemic circulation through the arterial duct results in pulmonary overflow and systemic hypoperfusion. When pulmonary flow is 50% higher than systemic flow, a hemodynamic ‘paradox’ results, with an increase in left ventricular output without a subsequent increase in systemic output. Cardiac overload supports neurohumoral effects (activation of the sympathetic nervous system and the renin–angiotensin system) that finally promote heart failure. Moreover, increased pulmonary blood flow can cause vascular congestion and pulmonary edema. However, the most dangerous effect is cerebral underperfusion because of diastolic reverse flow, resulting in cerebral hypoxia. Finally, blood flow decreases through the abdominal aorta, reducing perfusion of the liver, gut, and kidneys and may cause hepatic failure, renal insufficiency, and necrotizing enterocolitis. Large PDA may cause life-threatening multiorgan effects. In preterm infants, early diagnosis and timely effective treatment are cornerstones in the prevention of cerebral damage and long-term multiorgan failure 56.

The ductus venosus, situated within the liver parenchyma, is a vascular shunt unique to fetal and neonatal circulations. In fetal life, the ductus venosus allows variable portions of the umbilical and portal venous blood flows to bypass the liver microcirculation. After birth, when the umbilical circulation ceases, blood flow through the ductus venosus decreases considerably. Most recent experiments indicate that mechanical factors exert a major influence on fetal ductus venosus shunt. In fetal sheep, for example, pressure and resistance differences across the liver are important determinants of the umbilical venous blood flow through the ductus venosus. Shortly after birth, blood flow and blood pressure in the umbilical sinus decrease abruptly. This causes the orifice of the ductus venosus to retract and narrow, resulting in functional closure of the vascular shunt. Permanent structural closure, consisting of connective tissue deposition within the entire ductus lumen, starts within days after birth and completes by 1–3 months of age 57.

The foramen ovale is a slit-like anatomical structure located in the interatrial wall of fetal heart that enables right-to-left shunting during fetal development. Therefore, the foramen ovale is an atrial septal defect that is essential in fetal circulation and is a frequent remnant from it. In fact, although this hole generally closes completely shortly after birth because of shifting pressures in the atrial chambers, it remains open, or patent, in about 25% of cases, thus representing the most common persistent abnormality of fetal origin and a potential substrate for right-to-left shunting during adult life. In these individuals, the patent foramen ovale (PFO) enables interatrial right-to-left shunting during those periods when right atrial exceeds left atrial pressure. A PFO is usually hemodynamically insignificant, even when large, but is the most common cause of right-to-left shunt. Large-diameter PFO may act as a pathway for the passage of thrombus, air, fat, vegetation, or vasoactive substances from the venous to the arterial circulation, potentially causing paradoxical emboli and stroke, inappropriate decompression sickness in divers, platypnea-orthodeoxia syndrome, and aural migraine. Over the past two decades, the association between PFO and the occurrence of migraine and cryptogenic stroke, particularly in younger adults, has been subject to considerable controversy and debate. Recently, the pathophysiological aspects of the PFO have been increasingly appreciated. Echocardiographic techniques have emerged as the principal means for the diagnosis and assessment of PFO. Currently, semi-invasive contrast-transesophageal echocardiography is accepted as the gold standard to detect right-to-left shunt across a PFO, but other imaging modalities utilizing contrast such as second-harmonic transthoracic echocardiogram, transcranial Doppler sonography, CT, and cardiac MRI have been shown to have similar sensitivity and specificity in detecting a PFO when compared with transesophageal echocardiography. Despite the growing recognition of the PFO, particularly when associated with an atrial septal aneurysm, as a risk factor for paradoxical embolism, the optimal treatment strategy for symptomatic patients remains undefined. Most patients with presumed paradoxical embolism are currently treated medically with antithrombotic medications, with a paucity of data on the efficacy of oral anticoagulant as opposed to antiplatelet therapy. Surgical PFO closure has proved feasible, but the procedure is associated with the complications of cardiac surgery, and the results have been mixed with respect to stroke prevention. The recent introduction of interatrial septal occlusion devices set the stage for a minimally invasive, percutaneous approach 58–63.

As we have seen before, considerable changes occur in the cardiovascular system at birth. The circulation changes from one characterized by the presence of central shunts, a relatively low CVO, right ventricular dominance, and pulmonary vasoconstriction, to a circulation in series with a high cardiac output equally divided between the two ventricles, and a considerably dilated pulmonary vascular bed 64. From animal studies, it is well known that during the first hours and weeks after birth, newborns are characterized by an extremely high cardiac output because of high metabolic demands. In order to meet this marked volume loading, already under resting conditions, the neonatal heart appears to be operating nearly at its full capacity without reserves in contractility, preload, and afterload. Consequently, the newborn heart has less ability to cope with additional acute afterload and/or preload stress 65. The transition from fetal to newborn to adult has previously been associated with a progressive increase in myocardial contractile function. The developing heart experiences a perinatal increase in the cellular quantity of the sarcoplasmic reticulum and the myofibrils, the organelles that regulate and utilize cytosolic calcium (Ca) to produce cardiac contraction. It also has become evident that the function of the available ion pump proteins is reduced in fetuses and newborns compared with adults of the same species. The resultant limited regulation of cytosolic Ca concentrations by the sarcoplasmic reticulum enhances the role of the sarcolemma in this process. Although it appears that perinatal maturation of sarcoplasmic reticular function is not under direct molecular regulation, alternative splicing may regulate its gene products. A great deal of perinatal maturation of myofibrillar protein function appears to be regulated by molecular processes. This has been best shown in detail for myosin. In some species, such as the rat, much of the perinatal increase in myocardial contractile function can be explained by a parallel change in myosin isoforms. This isoform shift alters the activity of its ion pump, thereby allowing it to utilize more Ca. In contrast, perinatal maturation of contractile function in several larger species cannot be explained fully by the extent of the molecular changes that have been identified currently in these species 66.

With birth, the function of gas exchange is transferred from the placenta to the lungs, and therefore from the systemic circulation to the pulmonary circulation. The venous and arterial circulations are separated, and not only are fetal shunts unnecessary, but their persistence may lead to circulatory compromise. The transition from fetal to neonatal circulation thus includes the following:

  • elimination of the placental circulation;
  • lung expansion and increase in lung blood flow, so that the entire cardiac output can be accommodated;
  • closure of the foramen ovale, ductus arteriosus, and ductus venosus.

For most congenital structural heart diseases, fetal shunt pathways allow redistribution of ventricular blood flows so that systemic blood flow is adequate and fetal growth and development are usually normal. Uncomplicated VSD do not alter the circulation significantly either in the fetal or in the immediate neonatal period, with the important exception of premature infants. With severe left heart obstruction, the burden of systemic and pulmonary blood flow is transferred to the fetal right ventricle, with reversal of blood flow at the foramen ovale, and systemic blood flow almost entirely transmitted through the ductus arteriosus. This ‘ductal-dependent’ systemic circulation is poorly tolerated in the newborn because normal closure of the ductus arteriosus progressively decreases systemic blood flow and progresses to circulatory failure and shock. Severe right heart obstruction is also well tolerated in the fetus because the combined fetal cardiac output can be transferred to the aorta, with the ductus arteriosus supplying predominantly lung blood flow. After birth, such ‘ductal-dependent’ pulmonary blood flow can lead to critically low levels of pulmonary blood flow and severe cyanosis with closure of the ductus arteriosus 35,67.

Although considerable information has accumulated over the past decade, many gaps remain in our understanding of the regulation of contractility and modulation of inotropic responsiveness in the developing heart. Investigators in the field of developmental cardiology are facing several important problems. Responses often differ among species and the human correlates to many of the animal studies remain to be defined. In many instances, the supply of tissues is limited and difficult to obtain consistently. Furthermore, comparable experiments may be nearly impossible to conduct in human fetal and neonatal myocardium. Interpretation of results from developmental studies using various animal species and a number of different experimental models is further complicated by the complexity of normal developmental processes. Numerous changes are occurring simultaneously in neurohumoral influences, cardiac ultrastructure, protein synthesis, gene expression, and metabolism. Comprehensive integration of the impact of these and other factors on overall contractile performance and inotropic responsiveness requires a multifaceted approach incorporating a variety of techniques. Results from pharmacological experiments must be placed into perspective with available knowledge of relevant morphological, physiological, and biochemical status at the precise age in the particular species in which the experiments are conducted. Basic knowledge of the regulation of contractile function during development will obviously have important therapeutic applications in the immature heart. Moreover, results from future developmental studies directed toward characterizing myocardial gene expression, modulation of specific effector systems, and regulation of excitation–contraction coupling are ultimately likely to contribute toward the design of therapeutic strategies for both congenital and acquired heart disease 68,69.

Normal fetal cardiac rhythm is characterized by a regular heart rate ranging between 100 and 160–180 beats/min, with a normal 1 : 1 AV electromechanical relationship during each cardiac cycle 70. The human fetal heart develops arrhythmias and conduction disturbances in response to ischemia, inflammation, electrolyte disturbances, altered load states, structural defects, inherited genetic conditions, and many other causes. Yet, sinus rhythm is present without altered rate or rhythm in some of the most serious electrophysiological diseases, which makes detection of diseases of the fetal conduction system challenging in the absence of MCG or ECG recording techniques. Life-threatening changes in QRS or QT intervals can be completely unrecognized if heart rate is the only feature to be altered. For many fetal arrhythmias, echocardiography alone can assess important clinical parameters for diagnosis. Appropriate treatment of the fetus requires awareness of arrhythmia characteristics, mechanisms, and potential associations. Criteria to define fetal bradycardia specific to gestational age are now available and may allow detection of ion channelopathies, which are associated with fetal and neonatal bradycardia. Ectopic beats, once considered to be entirely benign, are now recognized to have important pathologic associations. Fetal tachyarrhythmias can now be defined precisely for mechanism-specific therapy and for subsequent monitoring of response 71. AV re-entry is the most common type of supraventricular tachycardia in both the fetus and the newborn. It should be distinguished from other types of tachycardia, such as atrial flutter, atrial ectopic tachycardia, permanent junctional re-entry tachycardia, and ventricular tachycardia. Neonatal and fetal bradycardias are less common clinical problems. Sustained bradycardia is most often caused by complete AV block. It can be mimicked by the more common but benign occurrence of nonconducted atrial premature beats 72,73. In fact, intermittent extrasystoles, which are frequently encountered in clinical practice, do not require treatment. Sustained forms of bradyarrhythmias and tachyarrhythmias might require fetal intervention. Fetal echocardiography is essential not only to establish the diagnosis but also to monitor fetal response to therapy. In the last decade, improvements in ultrasound methodology and new diagnostic tools have contributed toward better diagnostic accuracy and toward a greater understanding of the electrophysiological mechanisms involved in fetal cardiac dysrhythmias. Ventricular tachycardia is rare in the fetus. Sustained tachycardias, intermittent or not, might be associated with the development of congestive heart failure and hydrops fetalis. Prompt treatment with either antiarrhythmic drugs or delivery must be considered. Persistent fetal bradycardias associated with CHB are also potentially dangerous, whereas bradyarrhythmia because of blocked ectopy is well tolerated in pregnancy. CHB can be associated with maternal anti-Ro/SS-A (anti-Ro)/anti-La/SS-B (anti-La) autoantibodies or develop in fetuses with left atrial isomerism or with malformations involving the AV junction 74,75.

Fetal tachycardia occurs in a∼0.5% of all pregnancies and is an important cause of fetal morbidity and mortality. A fetal tachycardia heart is at risk for developing low cardiac output, hydrops, and ultimately fetal death or significant neurological morbidity. Different conditions can play a role to determine the natural history of tachycardic fetus, such as:

  • gestational age;
  • underlying pathophysiology of the arrhythmia;
  • fetal heart rate (FHR);
  • duration of the tachyarrhythmia;
  • presence or absence of cardiac dysfunction.

As mentioned before, a reliable diagnosis of fetal arrhythmia in utero is possible by ultrasound examination of fetal heart. In fact, pulsed wave Doppler guided by 2-D echocardiography provides important information on cardiac rhythm as it studies the blood flow from different chambers (Fig. 1). With the introduction of the latest myocardial deformation methodology, fetal tachyarrhythmias can be diagnosed more accurately 75. Tachyarrhythmias can occur at any age from the developing fetus through adulthood. However, in deference to adult-onset ischemic cardiac issues, abnormal heart rhythms occurring in the young are often because of developmental alterations of the cardiac conduction tissue, genetically inherited changes in myocardial cellular ion membrane properties, and both presurgical and postsurgical repair of associated structural congenital heart anatomical defects. Moreover, different from adults, abnormal rhythms occurring in the young can disappear spontaneously with progressive patient growth. Both supraventricular and ventricular tachyarrhythmias occur in the young, although atrial rhythm abnormalities far exceed those of the ventricle. In both, pharmacologic therapies to alter tissue conduction and refractoriness remain the mainstay for initial intervention in the infant and young child, reserving more invasive and potentially harmful ablation therapies for drug-refractory cases 76. Despite major advances in the intrauterine pharmacologic treatment of these arrhythmias over the last few years, major uncertainties remain. Among these are controversies in the choice of agents in relation to arrhythmia type, and timing and duration of treatment. Currently, no evidence-based approach to the management of fetal tachyarrhythmias is available. An international registry has been proposed as an important step toward obtaining the necessary data to develop evidence-based management strategies 77. Flecainide appears to be safe (no deaths with usual oral dosing, <1% serious proarrhythmia) and effective (73–100% control, depending on the mechanism) in children with supraventricular tachycardia. The drug is very effective for the treatment of fetal tachyarrhythmias. Flecainide may not be safe for children who have structurally abnormal hearts and atrial flutter or ventricular arrhythmias. The safety of flecainide for patients with ventricular arrhythmias and normal hearts requires further investigation. Pharmacokinetic data show an age-dependent change in elimination half-life. Patients younger than 1 year of age have a plasma elimination half-life that is similar to that in children older than 12 years (i.e. 11 to 12 h). Children aged 1–12 years have a mean elimination half-life of 8 h. The effective flecainide dose is 100–200 mg/m2/day or 1–8 mg/kg/day. Toxicity may occur with doses in excess of these ranges, especially when high doses are accompanied by low serum trough levels. Milk blocks flecainide absorption and toxicity may become manifest when milk products are removed from the diet 78.

Figure 1:
(a, b) Fetal heart rate.

Complete CHB can be isolated or can occur in association with other structural heart diseases. Isolated CHB is because of transplacental transfer of autoantibodies reactive with the intracellular soluble ribonucleoproteins 48 kD anti-La, 52 kD anti-Ro, and 60 kD anti-Ro from mothers with connective tissue disease into fetal circulation. Varying degrees of heart block have been reported. CHB is usually complete, but incomplete blocks, sinus bradycardia, and QTc prolongation are also reported. Although second-degree block, on rare occasions, has reverted to normal sinus rhythm, complete AV block is irreversible. Anti-Ro and anti-La antibodies transferred from mothers have inflammatory and arrhythmogenic effects in the fetal conduction system. ‘Neonatal’ lupus erythematosus (NLE) describes the clinical spectrum of cardiac and noncardiac abnormalities observed. Of the cardiac abnormalities, congenital AV block is the most common cardiovascular abnormality found in affected fetuses and infants. Many other cardiovascular manifestations of NLE have been recognized more recently, including the following:

  • atrial and ventricular arrhythmias and other conduction abnormalities (low ventricular rate, QT prolongation);
  • myocarditis;
  • dilated cardiomyopathy often with endocardial fibroelastosis;
  • structural heart disease, particularly valvar lesions such as mitral insufficiency.

There is a significant risk of perinatal demise, particularly in association with fetal hydrops, poor ventricular function, and heart rates less than 55 beats/min. CHB has a mortality of 30%, and 60% of infants require pacemaker therapy. The recurrence rate exceeds, by at least two-fold, that of the first birth and is likely to influence the decision to have more children. Peculiarly, the mother’s heart is almost never affected (with complete heart block) despite exposure to identical circulating autoantibodies. As part of our continuing effort to understand the complex factors contributing toward the pathogenesis of CHB, an animal model of CHB has been established by immunizing female mice with recombinant proteins/antigens, reproducing the human complete AV block in an isolated Langendorff perfused fetal heart. These findings have been correlated with L-type Ca channel inhibition by maternal antibodies from mothers of children with CHB. In addition, a passive animal model has been established by directly injecting maternal antibodies into pregnant mice and significant sinus bradycardia has been reported, indicating that the spectrum of conduction abnormalities may extend beyond the AV node. Altogether, the data provided strong evidence supporting an etiologic role of antibody/Ca channel involvement in the pathogenesis of CHB. The autoantibodies most likely trigger the inflammation of the AV node and the myocardium in susceptible fetuses. The inflamed tissues may then heal with fibrosis that may cause the above-cited complications. However, other yet unknown factors seem necessary to explain the full expression of CHB, the most common cardiac complication, which typically develops between 18 and 24 gestational weeks. Fetal echocardiography is useful in early diagnosis. Untreated, the condition carries a significant risk of mortality as the fetus needs to overcome the sudden decrease in ventricular rate, the loss of normal atrial systolic contribution to ventricular filling, and perhaps concomitant myocardial inflammation and fibrosis. The rationale to treat a fetus at the stage of CHB is primarily to mitigate myocardial inflammation and to augment fetal cardiac output. A standardized treatment approach, including maternal dexamethasone at CHB diagnosis and β-stimulation for FHR less than 55 beats/min, used since 1997, reduces the morbidity and improves the outcome of isolated fetal CHB. Maternal dexamethasone administration has been shown to improve incomplete fetal AV block, myocardial dysfunction, and cavity effusions. β-Sympathomimetics may be useful to increase FHR and myocardial contractility. Published data suggest an improved survival greater than 90% if maternal high-dose dexamethasone was initiated at the time of CHB detection and maintained during the pregnancy and if a β-adrenergic drug was added at FHR less than 55 beats/min. Despite the improvement in outcome, there is an ongoing debate about treatment-related risks. Early pacemaker therapy is indicated in patients with symptomatic bradycardia and ventricular dysfunction. The indications for pacing in CHB continue to evolve with advances in techniques and most of these children will ultimately require permanent pacemakers by adulthood 79–84. The cardiac evaluation of these fetuses is difficult as the ventricular rate is low and the heart is dilated. A strategy has been implemented that includes the biophysical profile, which assesses fetal well-being, in combination with the cardiovascular profile score, which assesses cardiac function and the circulation. It is hypothesized that the management protocol initiates intervention before fetal compromise, hydrops, and myocardial damage occur. An evaluation of heart function is recommended in addition to assessment of fetal well-being in fetuses with CHB. Early delivery should be considered if there is evidence of distress and/or deteriorating cardiac function 86–88.

In conclusion, although fetal arrhythmias account for a small proportion of referrals to a fetal cardiologist, they may be associated with significant morbidity and mortality. Advances in echocardiography have resulted in significant improvements in our ability to elucidate the mechanism of arrhythmia at the bedside. At the same time, MCG is broadening our understanding of mechanisms of arrhythmia, especially as it pertains to ventricular arrhythmias and CHB. It provides a unique window to study the electrical properties of fetal heart, unlike what has been available to date. Recent reports of bedside use of fetal ECG make it a promising new technology. The underlying mechanisms resulting in immune-mediated CHB in a small subset of ‘at-risk’ fetuses is under investigation. There have been huge strides in the noninvasive diagnosis of fetal arrhythmias. However, we still need to improve our knowledge of the electromechanical properties of fetal heart as well as the mechanisms of arrhythmia to further improve outcomes. Multi-institutional collaborative studies are needed to help answer some of the questions on patient, drug selection, and management algorithms 89.

Prenatal diagnosis and screening of fetal cardiac abnormalities

Antenatal screening for fetal cardiac abnormalities was introduced over 25 years ago; yet, detection of CHD before birth remains a challenge. Although experienced tertiary centers report a high level of diagnostic accuracy, with most major forms of CHD being detectable before birth, the overall detection rate remains low. Pregnancies at an increased risk of having an affected baby are referred to tertiary centers for fetal ECG, but most cases of CHD will occur in low-risk pregnancies. These cases will only be detected by screening the low-risk population at the time of routine obstetric scanning. Many obstetric ultrasound units have learnt to successfully obtain, and correctly interpret, views of the heart, including the four-chamber view and outflow tract views. However, standards for doing this are not uniform, nationally or internationally; thus, there is a significant variation in detection rates across individual countries and between different countries. Early diagnosis of babies with lesions that can result in cardiovascular collapse and death could improve their survival as well as reduce morbidity. In addition, detection of a cardiac abnormality during pregnancy allows time to prepare parents for the likely course of events after birth. It also facilitates detection of other abnormalities in the baby and gives parents a choice, even if the choice is difficult and unwelcome. In addition to providing parents with accurate and up-to-date information on their baby’s abnormality, it is vital to provide continuing support to help them deal with the problem, irrespective of what decisions they make. Considerable work remains to establish a uniform standard for antenatal detection of cardiac abnormalities. National guidelines for examination of fetal heart along with formalized auditing processes should help to achieve this, although considerable time and effort will be required, particularly with respect to the teaching and training required 90,91.

CHD is the most frequent neonatal malformation, with an estimated prevalence between 0.8 and 1%. Echocardiography is an important tool for diagnosis and follow-up in cardiology because it is easy to use, inexpensive, and noninvasive (Fig. 2). The study of fetal heart by means of echocardiography allows early diagnosis and treatment of anomalies and dysfunction, and this technique is being used increasingly. This examination is often required after morphological fetal echography, when a CHD is suspected or when there is an increased risk of CHD. Fetal echocardiography allows evaluation of the cardiac anatomy and function or cardiac rhythm 92,93. Noninvasive ultrasound imaging is an ideal method for the detection and study of congenital heart malformations as it allows early recognition of abnormalities in the living fetus and the progression of disease can be followed in utero with longitudinal studies. Two platforms for fetal echocardiography exist: the clinical systems with 1–8 MHz phased array transducers and research systems with 2–15 MHz mechanical transducers. The clinical ultrasound system has limited 2-D resolution (axial resolution of 150 µm), but the availability of color and spectral Doppler allows quick interrogations of blood flows, facilitating the detection of structural abnormalities. M-mode imaging further provides important functional data, although the proper imaging planes are often difficult to obtain. In comparison, the research biomicroscope system has significantly improved 2-D resolution (axial resolution of 50 µm). Spectral Doppler imaging is also available, but in the absence of color Doppler, imaging times are increased and the detection of flow abnormalities is more difficult. M-mode imaging is available and equivalent to the clinical ultrasound system. Overall, the research system, given its higher 2-D resolution, is best suited for in-depth analysis of fetal cardiovascular structure and function, whereas the clinical ultrasound systems, equipped with phase array transducers and color Doppler imaging, are ideal for high-throughput fetal cardiovascular screens 94.

Figure 2:
(a, b) Fetal echocardiography.

Therefore, during the past 30 years, 2-D imaging of fetal heart has evolved into a sophisticated and widely practiced clinical tool, but most heart disease still goes undetected until sometime after birth, despite routine fetal ultrasound evaluations. Over the next 30 years, tremendous advances in fetal cardiac imaging, including 3-D imaging (Fig. 3), promise to revolutionize both the prenatal detection and diagnosis of CHD. Image resolution continues to improve year after year, allowing earlier (10–15 weeks) visualization of fetal heart, as well as the detection of subtle valvar abnormalities that may progress to serious forms of ventricular hypoplasia at term. However, fetal cardiac imaging remains constrained by limited sonographic windows. To improve prenatal detection of CHD, outflow tracts are increasingly included along with the routine screening four-chamber view (Fig. 4). However, although the four-chamber view resides within a single plane, lending itself to tomographic evaluation with 2-D ultrasound, the outflow tracts (and most forms of CHD) do not reside within a single plane (Figs 5–8). For these and other reasons, 3-D imaging of fetal heart ultimately may improve the detection of outflow tract abnormalities, and facilitate comprehension of complex forms of CHD. Finally, other imaging modalities, including but not limited to tissue Doppler imaging and MRI, continue to evolve and to complement 2-D and 3-D sonographic imaging of fetal heart 95. Progress has recently been made in implementing MRI techniques that can be used to obtain images in a fraction of a second rather than in minutes. Echoplanar imaging (EPI) uses only one nuclear spin excitation per image and lends itself to a variety of critical medical and scientific applications. Among these are:

Figure 3:
Three-dimensional fetal ultrasound machine [Voluson; General Electric (GE) Company Healthcare, Fairfield, Connecticut, USA)].
Figure 4:
(a–c) Four-chamber view.
Figure 5:
The ‘three vessels’.
Figure 6:
Outflow tracts.
Figure 7:
Left outflow.
Figure 8:
Right outflow.
  • evaluation of cardiac function in real time;
  • mapping of water diffusion and temperature in tissue;
  • mapping of organ blood pool and perfusion;
  • functional imaging of the central nervous system;
  • depiction of blood and cerebrospinal fluid flow dynamics; and
  • movie imaging of the mobile fetus in utero.

Through shortened patient examination times, higher patient throughput, and lower cost per MRI examination, EPI may become a powerful tool for early diagnosis of some common and potentially treatable diseases such as ischemic heart disease, stroke, and cancer 96,97. 3-D images are easier to achieve with CT because the scanning system of this technique is automatic and thus provides sequential slices. The same is true for MRI, which can acquire volumes directly. The problem with ultrasound lies in the fact that the scans are manual and therefore less precise. To obtain 3-D images, the following devices are commonly used:

  • manual scanning probes connected to spatial magnetic evidencers with remote processing;
  • manual scanning probes connected to spatial magnetic evidencers placed on the patient’s examination table with processing internal to the ultrasound unit;
  • mechanical probes that can provide volumetric scans;
  • ‘matrix’ probes.

This technique seems to be able to yield the best results in:

  • fetal malformations;
  • calculating the volumes of normal and diseased organs;
  • the follow-up of masses treated with irradiation/chemotherapy or with alcohol or chemoembolization;
  • the spatial reconstruction of extensive lesions;
  • the detection of small lesions (metastases);
  • the study of some complex functions such as cardiac valve dynamics 98.

Presenting volume data in a standard anatomic orientation aids both ultrasonographers and pregnant patients to recognize anatomy more readily. 3-D ultrasound is advantageous for the study of normal embryonic and/or fetal development as well as to provide information for families at risk for specific congenital anomalies by confirming normality. This method offers advantages in assessing the embryo in the first trimester as it is able to obtain multiplanar images through endovaginal volume acquisition. Rotation of the embryo and scrutiny of the volume allow the systematic review of anatomic structures, such as:

  • cord insertion;
  • limb buds;
  • cerebral cavities;
  • stomach; and
  • bladder.

Using this modality, one can easily obtain the volumes of the gestational sac and yolk sac and can evaluate their relationship with prediction of pregnancy outcome. 3-D power Doppler sonography has the potential to study the process of placentation and evaluate the development of embryonic and fetal cardiovascular systems. 3-D ultrasound imaging in-vivo complements pathologic and histologic evaluation of the developing embryo, giving rise to a new term: ‘3-D sonoembryology’. Rapid technological development will allow real-time 3-D ultrasound to provide improved and expanded patient care on the one hand and increased knowledge of developmental anatomy on the other 99.

In summary, fetal echocardiography has progressed to enable the diagnosis of many forms of CHD and to assess the prognosis of cardiac lesions on the basis of their anatomy and presentation in utero. Fetal echocardiography is for pregnancies at risk of structural, functional, and rhythm-related fetal heart disease. Routine obstetrical ultrasound screening is critical in prenatal detection of fetal heart disease and/or CHD. With or without CHD, fetal heart dysfunction defined as inadequate tissue perfusion may occur. Perinatal problems other than CHD can also be assessed, such as the effects of noncardiac malformations that affect hemodynamics, like twin–twin transfusion syndrome. Cardiac rhythm can affect cardiac function and outcome, and prenatal diagnosis can be lifesaving. A tool for the assessment of cardiac function is the cardiovascular profile score that combines ultrasonic markers of fetal cardiovascular unwellness on the basis of univariate parameters, which have been correlated with perinatal mortality. This ‘heart failure score’ could potentially be used in much the same way as and in combination with the biophysical profile score, as we have seen before 101.

A new technique for the examination of the fetal heart uses 4-D ultrasonography with spatiotemporal image correlation (STIC). Volume data sets of the fetal heart can be acquired with this new cardiac gating technique, which uses automated transverse and longitudinal sweeps of the anterior chest wall. Dynamic multiplanar slicing and surface rendering of cardiac structures can be performed. Volume data sets obtained with a transverse sweep can be utilized to show

  • the cardiac chambers;
  • moderator band;
  • interatrial and interventricular septae;
  • AV valves;
  • pulmonary veins;
  • outflow tracts.

With the use of a reference dot to navigate the four-chamber view, intracardiac structures can be studied simultaneously in three orthogonal planes. The same volume dataset can be used for surface rendering of the AV valves. The aortic and ductal arches are best visualized when the original plane of acquisition is sagittal (Figs 9 and 10). Volumes can be manipulated interactively to simultaneously visualize both outflow tracts, in addition to the aortic and ductal arches. Novel views of specific structures can be generated. For example, the location and extent of a VSD is imaged in a sagittal view of the interventricular septum (Fig. 11). Furthermore, surface-rendered images of the AV valves are used to distinguish between normal and pathologic conditions 102. In theory, STIC technology is able to compensate for the defects of previous traditional 2-D ultrasound and improve the diagnostic accuracy. In a study investigating the clinical application value of STIC technology combined with traditional 2-D ultrasound in the diagnosis of fetal cardiac abnormalities, fetuses were subjected to a sequential echocardiographic examination, during which STIC technology was used to collect heart volume data and carry out image postprocessing and off-line analysis. In addition, the prenatal and postnatal echocardiography results were compared with the pathology results following the induced labor of fetuses with cardiac abnormalities. The sensitivity, specificity, misdiagnosis rate, and rate of missed diagnosis for the STIC technology in the diagnosis of prenatal fetal cardiac abnormalities were 97.4, 99.6, 0.4, and 2.6%, respectively. The total coincidence rate was 99.2% and the positive and negative predictive values were 97.9 and 99.4%, respectively. The statistics for the consistency check of the STIC technology in the diagnosis of fetal cardiac abnormalities are κ=0.991, P=0.000. Thus, STIC technology combined with fetal echocardiography may be used for the definite diagnosis of fetal heart malformations, with high sensitivity and specificity 103.

Figure 9:
Aorta and epiaortic vessels.
Figure 10:
Figure 11:
(a, b) Ventricular septal defect.

Doppler ultrasound velocimetry of uteroplacental, umbilical, and fetal vessels provides the clinician with important information on the hemodynamics of respective vascular area and has therefore become one of the most dynamic areas of perinatal research. Gestational age-related reference values have been established for maternal uterine and arcuate artery (Fig. 12), umbilical artery, fetal descending aorta, and fetal cerebral, renal, and femoral arteries. Recently, velocimetry of the fetal central venous system has gained increasing attention. Velocimetry of the fetal middle cerebral artery provides important information on the redistribution of fetal blood flow in hypoxia. Examinations of umbilical artery velocity waveforms have gained recognition as a valuable clinical method of fetal surveillance in risk pregnancies (Fig. 13). In growth-retarded fetuses and fetuses developing intrauterine distress, the umbilical artery blood velocity waveform changes in a typical way: the diastolic velocity of the waveform decreases and eventually disappears. Pathological Doppler findings, especially the finding of absent or reverse end-diastolic (ARED) flow velocity, are associated with fetal hypoxia and adverse outcome of pregnancy with a high risk of intrauterine death. Follow-up studies indicate that abnormal Doppler findings are associated with impaired postnatal neurological development. When applied as a screening test in an unselected pregnant population, umbilical artery velocimetry has not been found to be useful. In a preselected population of high-risk pregnancies, especially pregnancies with small for gestational age fetuses, the method has a high predictive value with respect to diagnosing fetal compromise and can be used for monitoring fetal health. A meta-analysis of randomized clinical trials showed that including Doppler velocimetry in the management of high-risk pregnancies reduces perinatal mortality. Follow-up studies showed an association between the abnormal intrauterine umbilical and/or fetal blood flow and subsequent postnatal neurodevelopmental impairment. Doppler velocimetry of the umbilical artery applied in the management of high-risk pregnancies improves the perinatal outcome and can thus be considered a clinical method of fetal surveillance. More studies are needed to evaluate the use of Doppler velocimetry in labor. Possibly, the Doppler method may facilitate the interpretation of equivocal cardiotocography (CTG) tracings. New evidence has been collected on the correlation between hemodynamic findings and the morphology of the placenta and the placental bed. One of the very important applications of Doppler velocimetry is the evaluation of pharmacological effects on fetal circulation of drugs used for treatment in pregnancy and labor 104,105. In addition, the Doppler estimation of the blood flow in the descending aorta of the fetus and waveform analysis of the maximum aortic velocity provide valuable information on fetal circulation. When estimating fetal aortic flow, it is important to consider possible sources of error. Even when recording the maximum aortic velocity for waveform analysis, to obtain reproducible results, it is important to use a low high-pass filter, a well-defined angle of insonation, and a standardized site of measurement and to avoid periods of fetal breathing and activity. In normal pregnancy, the time-averaged mean velocity in the descending aorta is stable throughout the third trimester. The weight-related flow is stable until 37 weeks, after which it decreases slightly. The placental proportion of the flow in the thoracic descending aorta decreases toward term. In the aorta of normal fetuses, there is positive flow throughout the whole heart cycle, which is because of the low vascular resistance in the placental circulation. Pulsatility index (PI) can characterize the waveform of the aortic velocity, which is stable during the last trimester of gestation. Caution should be exercised when interpreting changes in the aortic PI as it is not only affected by the peripheral resistance but also by the heart’s performance. Furthermore, PI relates to FHR. Near term, different values of PI are found in different fetal behavioral states. In fetuses with retarded growth and in fetuses at distress, several researchers have reported characteristic changes of the aortic velocity waveform: the end-diastolic velocity reduces and disappears, and in extreme cases, a brief reversal of flow in diastole has been observed. Consequently, the PI increases in such cases. The absence of the end-diastolic aortic velocity can easily be determined and is the best indicator of fetal status: in fetuses with absent end-diastolic velocity, the incidence of perinatal mortality and morbidity is significantly higher than in fetuses with positive flow throughout the cycle. In pregnancies with hypertension or diabetes mellitus, normal aortic flow has been reported as long as the fetuses were not growth retarded. In cases of severe Rhesus (Rh)-isoimmunization, the mean aortic velocity correlates with fetal hematocrit. In hypoxic fetuses, the mean velocity was reported to correlate with the degree of hypoxia, hypercarbia, and acidosis 107.

Figure 12:
Uterine artery Doppler velocimetry.
Figure 13:
Umbilical artery Doppler velocimetry.

For a quantitative understanding of the venous Doppler sonograms, a model of the fetal cardiovascular system has been proposed that stresses the significance of flow. The model comprises three major components:

  • the heart, which provides constant power and dynamic capacitance;
  • peripheral fetal and placental vascular beds with flow-limiting conductances (1/resistance);
  • the resistance of the hepatoductal system.

As long as cardiac power is maintained, the conductances control the flow rate and, depending on hepatoductal and ventricular filling resistance, the umbilical venous as well as the central venous pressure. According to the model, the mean flow velocity of venous return is the total organ flow rate divided by cross-sectional areas in the cardiac input system, that is the central veins, both atria and both AV valves, respectively. The velocity pattern of venous return relates to cardiac performance and hepatoductal resistance as follows:

  • the E wave in early diastole describes the filling (driven by the central venous pressure) of the relaxed ventricle;
  • the time constant equals the ratio of elasticity over resistance in the ventricular wall;
  • the A wave mirrors the contractility of atrial myocardium that is related to central venous pressure;
  • the ratio of the forward A wave in the tricuspid valve to the backward A wave in the caval veins depends on ventricular capacitance;
  • the S wave is related to systolic valvular shift.

The velocity pulsations in the ductus venosus are transmitted backwards from the heart. The continuous velocity component in the ductus venosus and the nonpulsatile velocity in the umbilical vein are because of hepatoductal and placental vascular resistance 108.

Remarkable hemodynamics changes that occur in the maternal circulation and the continuous growth and development of fetoplacental circulation are now studied by transvaginal color Doppler. This seems to provide greater understanding of the pathophysiology of early pregnancy. There is no doubt that studies of maternal–fetal circulation in early pregnancy may lead to better understanding of physiological and pathological hemodynamic changes. Investigation of maternal (main uterine, arcuate, radial, and spiral), placental (umbilical, chorionic arterioles), and fetal (aorta and intracranial circulation) vessels’ flow patterns may aid diagnoses of abnormal implantation 109. Decrease in peripheral impedance, as well as increase in blood flow velocity, are found in all segments of the uteroplacental circulation with gestational age. The same finding is observed in the umbilical artery, fetal aorta, and intracranial blood vessels. A significant decrease in vascular impedance in cerebral blood vessels exists earlier than in the fetal aorta or umbilical artery, which could be attributed to the establishment of cerebral autoregulation mechanisms that ensure adequate O2 and glucose supply to the embryonic brain 110.

There is evidence for the paramount influence of the autonomic nervous system in the control of heart rate variability (HRV). The basic proposition underlying spectral analysis is that the two autonomic branches influence heart rate in a frequency-dependent manner, and their differential effects can be determined by power spectral analysis (PSA), which breaks down the heart rate trace into its component frequencies. The application of PSA to HRV data is an established tool in cardiology. The power spectrum is sensitive to the activity state of the fetus, particularly fetal breathing movements, which have a variable effect on short-term and long-term FHR variability. There are a variety of mathematical approaches to the construction of power spectra. Recent experimental evidence indicates a role for PSA as an indicator of fetal activity state. There are some problems with the technique of PSA, particularly in terms of accepted definitions and methods of analysis. Nevertheless, it is a powerful noninvasive tool in the elucidation of fetal cardiac control 111. The fetus with an arrhythmia may be at high risk both from the arrhythmia itself and from the condition that caused it. Incorrect diagnosis and inappropriate or delayed treatment may further compound the risk. As we have seen before, fetal echocardiography has proved to be a useful tool for prenatal detection and the diagnosis and, in some cases, the treatment of fetal arrhythmias. It is particularly indicated for mothers from high-risk groups. Although echocardiography can specifically identify the arrhythmia, this technique requires very skilled and careful examination by a physician who fully understands how to differentiate optimally between similar-appearing but mechanistically different arrhythmias. CHD may also be present and must be evaluated specifically 112,113.

Biomagnetism in the perinatal domain has been dominated by fetal cardiology, and early work pointed out the potential of both fetal cardiac time intervals (CTIs) and HRV for future clinical applications. Recent improvements in instrumentation have enabled numerous groups to investigate a considerable number of healthy fetuses in these two areas and to lay the groundwork for a delineation of normal ranges. With respect to fetal CTI, it is now clear that in particular the duration of P wave, PR interval, and QRS complex reflect fetal growth and development. Preliminary studies have shown that the age-adjusted CTI are shorter in growth-retarded fetuses and altered in cases of structural cardiac defects and in specific types of arrhythmia. Less work has been published on MCG-determined fetal HRV, although parameters from both the time and the frequency domains as well as complexity have been examined. Concomitant with the gradual change in heart rate during pregnancy, increases in time domain variables and complexity have been described for normal pregnancies. Furthermore, gestational age-related changes in specific spectral bands have been noted and increases in power have been documented at frequencies that are associated with fetal breathing movements. The fact that little has been reported to date on discriminatory power with respect to pathological states may be because of the lack of extended data acquisition in a clinical setting documenting acute states. Nonetheless, it may be expected that both fetal HRV and CTI will supplement standard fetal surveillance techniques in the near future 114. Fetal MCG can be recorded reliably from approximately the 15th week of gestation onward. The MCG has the ability to record CTIs accurately and to provide a real-time recording that reflects cardiac electrical activity. Standardization of the recording, signal processing, and measurement techniques can result in reproducible data that, when combined with the establishment of normal values for different gestational ages, can be useful for clinical application universally, particularly in selected groups of patients at risk of potentially lethal arrhythmias 115.

FHR monitoring has been the subject of many debates. The technique, in itself, can be considered accurate and reliable both in the antenatal period, when using the Doppler signal in combination with autocorrelation techniques, and during the intrapartum period, in particular when the FHR signal can be obtained from a fetal ECG electrode placed on the presenting part. The major problems with FHR monitoring relate to the reading and interpretation of the CTG tracings (Fig. 14). As the FHR pattern is primarily an expression of the activity of the control by the central and peripheral nervous system over cardiovascular hemodynamics, it is possible to indirect a signal. In other specialties such as neonatology, anesthesiology, and cardiology, monitoring and graphic display of heart rate patterns have not gained wide acceptance among clinicians. Digitized archiving, numerical analysis, and techniques that are even more advanced have primarily found a place in obstetrics. This can be easily explained as the obstetrician is fully dependent on indirectly collected information on fetal condition, such as:

Figure 14:
Cardiotocogram (
  • movements experienced by the mother, observed by ultrasound or recorded with kineto-CTG;
  • perfusion of various vessels, as assessed by Doppler velocimetry;
  • the amount of amniotic fluid or amniotic fluid index;
  • changes reflected in the condition of the mother, such as the development of pregnancy-induced hypertension;
  • the easily, continuously obtainable FHR signal.

It is of particular comfort to the obstetrician that a normal FHR tracing reliably predicts the birth of the infant in a good condition, which makes CTG so attractive for widespread application (Fig. 15). However, in the intrapartum period, many traces cannot fulfill the criteria of normality, especially in the second stage. In this respect, CTG remains primarily a screening and not so much a diagnostic method. As long as continuous monitoring of fetal acid–base balance has not been extensively tested in clinical practice, microblood sampling of the fetal presenting part is a useful adjunct. The problem with non-normal tracings is that their significance is very often unclear. They may indicate serious fetal distress, finally resulting in preventable destruction of critical areas in fetal brain and damage to various organs. In contrast, they may indicate temporary changes in cardiovascular control as a reaction to the intermittent effects on fetal hemodynamics of, for example, uterine contractions, whether or not in combination with partial or complete compression of umbilical cord vessels or the vessels on the chorionic plate. Many factors influence FHR and its variability, which further complicates the interpretation of FHR patterns. Undoubtedly, there is a need for quantitative and objective FHR analysis, as long as it does not lead to erroneous results. Close collaboration between engineers and clinicians is a prerequisite for further advances in this field. Decision support systems certainly have a future but only if they are able to take into account a large set of clinical data and can combine it with data obtained from FHR signals and other parameters referring to fetal condition, such as :

Figure 15:
(a, b) Cardiotocography.
  • fetal growth;
  • Doppler velocimetry;
  • amniotic fluid index (Fig. 16);
  • biochemical and biophysical data obtained from the mother.
Figure 16:
(a, b) Amniotic fluid index.

Basic technical concepts inherent in computerized CTG analysis, such as sampling rate, signal loss, artifact detection, further processing of intervals, archiving in digitized format, and monitor display, should receive considerable attention. There is still a long way to go before decision support systems find their way into obstetric practice. Further developments can only be achieved thanks to the efforts of many basic and clinical researchers 116–123.

Screening of the heart during routine obstetric ultrasound has become well established and is increasingly successful in the initial detection of major CHD. When the option of termination of pregnancy is available, the earlier the diagnosis of any major fetal malformation is made, the better it is for the patient. An important group that has recently been found to be at an increased risk of fetal heart malformation are fetuses with increased nuchal translucency (NT) measurements, who are identified between 11 and 14 weeks (Fig. 17). Thus, screening for fetal anomalies is being attempted much earlier in pregnancy, aided by advances in technology. However, some forms of cardiac malformations do not become evident until the third trimester of pregnancy. As a result, some of the late-developing lesions may go undetected during very early evaluation. The ideal timing for screening is a compromise between obtaining adequate images for diagnosis in the majority of routine patients, scanning sufficiently late not to miss late-developing lesions, and yet offering diagnosis as early as possible for parents to consider their options, if there are any applicable to their particular diagnosis. For low-risk patients, the best compromise appears to be at around 20 weeks of gestation. For patients at an increased risk of CHD, such as those found to have considerably increased NT or those with a family history of the disease, an initial scan to exclude major malformations should be performed by a fetal cardiology expert at 12–14 weeks, with follow-up at around 20 weeks to exclude more minor defects and those lesions that may become evident later 124. Fetuses with an increased NT have an increased risk for CHD with no particular bias for one form of CHD over another. This risk increases with increasing NT measurement. Although the NT measurement is only a modestly effective screening tool for all CHD when used alone, it may indeed be effective in identifying specific CHD ‘likely to benefit’ from a prenatal diagnosis. The combination of an increased NT, tricuspid regurgitation, and an abnormal ductus venosus Doppler flow profile is a strong marker for CHD. A fetal echocardiogram should be performed at 20 weeks’ gestation in fetuses with an NT of at least 95th percentile but less than 99th percentile. When the NT measurement is at least 99th percentile, or when tricuspid regurgitation and/or an abnormal ductus venosus flow pattern is found along with the increased NT, an earlier echocardiogram is indicated, followed by a repeat scan at around 20 weeks’ gestation. The resultant increased demand for early fetal echocardiography and sonographers with this special expertise needs to be planned and provided for 125–130.

Figure 17:
(a–c) Nuchal translucency.

Fetal cardiac surgery

The possibility of intervening in utero on certain cardiac malformations with the intent to prevent secondary major alterations in structure and function is becoming a reality. Central to progress in this area is the development of instrumentation specifically designed for minimally invasive cardiac surgery in the fetus. In meeting this objective, particular importance is assigned to the synergic contribution of diverse disciplines, both medical and nonmedical 131. In fact, performing successful fetal cardiac interventions requires multidisciplinary collaboration between perinatologists, cardiologists, fetal surgeons, and anesthesiologists. Each discipline has specific skills for providing safe access to the fetus, performing the procedure, and providing perioperative care. Techniques for safe access to the fetus must be improved and patient selection criteria must be developed. Most important is the early detection and referral of all patients who have CHD, enabling improved outcomes for infants 132.

Elucidation of the mechanisms of placental dysfunction after bypass and the negative effects of fetal stress has allowed these issues to be addressed effectively using indomethacin and appropriate fetal anesthesia. The effective management of these two major problems has made a huge difference in the ability of fetal animals to survive surgical intervention and extracorporeal circulation. Characterization of various aspects of placental vascular hemodynamics using the isolated placental preparation has also provided new insights into the behavior of the placental vasculature during extracorporeal circulation. These insights have been and will continue to be extremely useful in designing the ideal method of fetal extracorporeal circulatory support. Despite these advances, further work should be carried out before clinical application of these techniques can be applied reliably. Ideally, a specific blocker of the mediators of the placental response to cardiac bypass should be available before clinical studies are carried out. Indomethacin, although quite effective, may have secondary effects on other vascular beds that would be potentially detrimental. In addition, although fetal stress response can be blocked adequately using fetal total spinal anesthesia, with a marked improvement in cardiovascular stability, this technique of anesthesia would not only be cumbersome but also potentially dangerous in the human fetus. High-dose narcotic anesthesia has been shown to be very effective in neonates and infants undergoing cardiac procedures, with respect to both blockage of the stress response and maintenance of cardiac function. This technique may also be applicable in the human fetus as an effective method of blocking the stress response without causing myocardial depression or affecting peripheral vascular resistances. Unfortunately, sheep do not have opiate receptors and, therefore, are not an appropriate model for testing narcotic anesthesia in the fetus. Future studies in the primate model using high-dose narcotic anesthesia could provide important information about this problem. In addition, the ideal circuitry for fetal extracorporeal support has not been determined with certainty. Although a simplified circuit without an oxygenator is possible if the placenta is used as the oxygenator, this method has the disadvantages of high flow rates and placental stimulation. Extracorporeal circulation with the inclusion of an artificial oxygenator requires a somewhat more complex circuit. However, more manageable flow rates and less stimulation of placental vasculature are possible with this technique. All forms of fetal intervention for cardiovascular disease require an extensive understanding of fetal pathophysiologic responses to intervention, whether the intervention involves open techniques that necessitate extracorporeal circulatory support or closed interventional techniques 133.

Noninvasive and invasive fetal interventions in fetal cardiovascular disease are guided by observations at fetal echocardiography. Fetal cardiac lesions may be ameliorated by fetal intervention and, for noncardiac fetal pathologic findings, fetal echocardiography can provide important insights into the pathophysiology and aid in patient selection for and timing of intervention and postintervention surveillance 134. A trend toward the use of less invasive, nonsurgical approaches to the treatment of CHD has developed. Fetal catheter-based interventions are being developed for the treatment of severe CHD in utero135. Prenatal alleviation of severe fetal aortic valve obstructions by percutaneous ultrasound-guided BAV has been performed to improve the fate of affected fetuses. The early clinical experience of percutaneous ultrasound-guided fetal BAV in human fetuses with severe aortic valve obstruction has been poor because of the selection of severe cases, technical problems during the procedure, and high postnatal operative mortality in fetuses who survived gestation. Improved patient selection and technical modifications in interventional methods may hold promise to improve outcome in future cases 136. Because this trend toward catheter-mediated treatment is certain to continue, care must be taken to safely regulate the introduction of novel techniques and devices into clinical use in pediatric cardiology 135,137–140.


Fetal cardiology has been evolving as an exciting speciality over the last 20 years. Although much is because of technical advances in fetal echocardiographic techniques and the use of sophisticated ultrasound equipment, the partnership among fetal and pediatric cardiologists and a team of professionals working in fetal medicine unit should not be ignored. As a result, targeted fetal echocardiography allows CHD to be diagnosed in utero with a high degree of accuracy from as early as the end of the first trimester of pregnancy, that is from around 12 weeks. Conversely, prenatal detection rates in the general population remain suboptimal, with many congenital cardiac abnormalities being diagnosed postnatally. A recognized marker for chromosomal abnormalities, that is, the finding of an increased NT thickness at 11–14 weeks of gestation, has also emerged over the last few years as a novel and important marker for major cardiac abnormalities. This has further increased interest in imaging the fetal heart early in the pregnancy 141.

Prenatal treatment options for fetal heart disease are still limited but pharmacological treatment of fetal tachyarrhythmias is usually effective. Prenatal catheter interventions are likely to be an option in selected fetal cardiac defects in the future. Delivery should be at a tertiary care center if the need for immediate neonatal transport is anticipated. When a cardiac problem is diagnosed in a fetus, the parents should be counseled by a pediatric cardiologist specialized in fetal cardiology in close co-operation with the obstetric team. The rate of termination is influenced by gestational age at diagnosis, the severity of the heart defect, and the presence of associated malformations. In fetuses with isolated cardiac malformations who are in sinus rhythm with good myocardial function and no or trivial AV valve regurgitation, the risk of spontaneous intrauterine death is low. Prenatal echocardiography has the potential to improve postnatal survival in infants with critical heart defects, especially those with duct-dependent systemic or pulmonary circulations 142.

The fields of pediatric cardiology and CHD have achieved considerable progress in the last few years, with advances in new diagnostic and therapeutic techniques that can be applied at all stages of life from the fetus to the adult. In developed countries, CHD is becoming increasingly prevalent in nonpediatric patients, including pregnant women. Actions aimed at preventing coronary heart disease must be started early in infancy and should involve the promotion of a healthy diet and lifestyle. Recent developments in echocardiography include the introduction of 3-D echocardiography and of new techniques such as 2-D speckle tracking echocardiography, which can be used for both anatomical and functional investigations in patients with complex heart disease, including a univentricular heart. Progress has also occurred in fetal cardiology, with new data on prognosis and prognostic factors and developments in intrauterine interventions, although indications for these interventions are yet to be established. Heart transplantation has become a routine procedure, supplemented in some cases by circulatory support devices. In catheter interventions, new devices have become available for the closure of atrial septal defect or VSD and PDA as well as for percutaneous pulmonary valve implantation. Surgery is also advancing, in some cases with hybrid techniques, particularly for the treatment of hypoplastic left heart syndrome 143–146.

Advances in cardiac surgical techniques and intensive care have led to improved survival in babies with CHD. Although it is true that the majority of children with CHD today survive, many have impaired neurodevelopmental outcome. Although continuing to improve short-term morbidity and mortality are important goals, recent research has focused on defining the impact of CHD on brain development and brain injury in utero. Neurodevelopmental evaluation preoperatively and postoperatively in CHD patients should be standard practice, not only to identify those with impairments who would benefit from intervention services but also to identify risk factors and strategies to optimize outcome. Fetal management and intervention strategies for specific defects may ultimately play a role in improving in-utero hemodynamics and increasing cerebral O2 delivery to enhance brain development 147. The evolving field of stem cell therapy and its impact on the management of cardiac pathology, in particular CHD, has provided hope. To date, stem cell therapy has focused on cardiomyoplasty for heart muscle disease; stem cell therapies are already in clinical use for these disorders. Research is now also supporting the potential role of stem cell therapy in CHD. In the future, it may be possible to use stem cells to create cellular grafts and structures that may be implanted surgically into the disordered heart using bioengineering technology. Different types of stem cells have been evaluated and the identification of specific cardiac stem cells offers great potential. Preliminary animal studies investigating fetal cardiac therapies are also underway. These new directions for stem cell research provide exciting potential for the future management of CHD 148–150.


The authors thank the AMI Prato Onlus Association and the Service of Prenatal Diagnosis of the Division of Obstetrics and Gynecology of the Prato City Hospital for kindly making available the figures for publication.

Conflicts of interest

There are no conflicts of interest. In particular, they disclose professional relationships with companies or manufacturers who will eventually benefit from the present work, and they state that the conclusions of the present work do not constitute endorsement of any product by the Authors or the National Systems Contractors Association (NSCA).


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    congenital diseases; fetal heart; pregnancy; prenatal diagnosis; ultrasound

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