Functional echocardiography in the fetus with non-cardiac disease
Tim Van Mieghem1*, Ryan Hodges1
, Edgar Jaeggi2
indirect reflections of fetal cardiac function and that they are
strongly influenced by cardiac preload (venous return) and
directed to the placenta14
and hence a decreased return
through the umbilical vein. Overall however, cardiac output
is mai...
Vascular fetal or placental tumors such as solid sacr...
For now, assessment of cardiac output is used in adjunct to
other (non-cardiac) parameters to select patients for fetal
perfusion. This, in combination with less viscous blood, leads
to higher blood flow velocities in the middle cerebral arter...
fetus with extra cardiac disease. This would include at least
rough estimates of systolic (eyeballing ventricular contract...
35. Paek BW, Jennings RW, Harrison MR, et al. Radiofrequency ablation of
human fetal sacrococcygeal teratoma. Am J Obstet ...
alloimmunization. Collaborative group for Doppler assessment of the
blood velocity in anemic fetuses. N Engl J Med 2000;34...
Upcoming SlideShare
Loading in …5

Functional echocardiography in the fetus with non cardiac disease


Published on

Published in: Health & Medicine
  • Be the first to comment

Functional echocardiography in the fetus with non cardiac disease

  1. 1. REVIEW Functional echocardiography in the fetus with non-cardiac disease Tim Van Mieghem1*, Ryan Hodges1 , Edgar Jaeggi2 and Greg Ryan1 1 Fetal Medicine Unit, Mount Sinai Hospital, University of Toronto, Toronto, Canada 2 Fetal Cardiac Program, Pediatric Cardiology, Hospital for Sick Children, University of Toronto, Toronto, Canada *Correspondence to: Tim Van Mieghem. E-mail: ABSTRACT We describe the hemodynamic changes observed in fetuses with extra cardiac conditions such as intrauterine growth restriction, tumors, twin–twin transfusion syndrome, congenital infections, and in fetuses of mothers with diabetes. In most fetuses with mild extra cardiac disease, the alterations in fetal cardiac function remain subclinical. Cardiac function assessment has however helped us to achieve a better understanding of the pathophysiology of these diseases. In fetuses at the more severe end of the disease spectrum, functional echocardiography may help in guiding clinical decision-making regarding the need for either delivery or fetal therapy. The growth-restricted fetus represents a special indication for routine cardiac function assessment, as in utero hemodynamic changes may help optimize the timing of delivery. Moreover, in intrauterine growth restriction, the altered hemodynamics causes cardiovascular remodeling, which can result in an increased risk of postnatal cardiovascular disease. © 2013 John Wiley & Sons, Ltd. Funding sources: None Conflicts of interest: None declared INTRODUCTION Fetal cardiac function is routinely examined in the context of congenital heart disease. More recently, functional echocardiography has also been applied to fetuses with a structurally normal heart and hemodynamic challenges due to extra cardiac conditions. This experience has provided novel insights into fetal cardiac adaptation to a range of different fetal and maternal pathologies. Furthermore, novel imaging tools to assess disease progression, prognosis and fetal well-being have been proposed. The aim of this manuscript is (1) to review the literature regarding the more common pathologies seen in clinical practice (Table 1) and (2) to demonstrate how functional echocardiography can help guide clinical management decisions of some of these conditions. BASIC FETAL CARDIOVASCULAR PHYSIOLOGY In a healthy fetus, oxygenated blood returns from the placenta through the umbilical vein and the ductus venosus to the right atrium. The ductus venosus streams this blood preferentially through the foramen ovale toward the left atrium, where it mixes with the pulmonary venous return,1 and the left ventricle then ejects this blood into the aorta. A small percentage of the left ventricular output is distributed to the coronary arteries to perfuse the heart, whereas three quarters of the blood flows to the head and upper body. The remainder of the oxygenated blood is directed into the descending aorta and the lower body. The right ventricle on the other hand receives lower saturated blood from the systemic veins, which is forwarded into the main pulmonary artery. About one third of the right ventricular stroke volume passes via the lung circulation, whereas two thirds advances via the ductus arteriosus into the descending aorta, the lower body, and the placenta.2 It is important to note that the left and right heart circulations work in parallel and are connected at the level of the foramen ovale, the ductus arteriosus and the aortic isthmus. Although the cardiac chambers appear symmetrical in size, the right ventricle is dominant in a healthy fetus and provides about 60% of the combined fetal cardiac output, whereas the left ventricle contributes about 40%.3 Functional or anatomic changes that may occur at the level of these communications allow the fetus to favor one part of the circulation over another. The change in cardiac loading may then lead to a discrepancy in ventricular dimensions. HOW TO ASSESS FETAL CIRCULATION WITH ULTRASOUND? Multiple non-invasive, ultrasound-based, methods are available to assess the fetal circulation. Here, we will describe the basic tools required to understand the hemodynamic changes that occur in fetuses with extra cardiac disease. We direct the interested reader to recent review articles4,5 for a more in- depth discussion of the different indices of cardiac function and their specific application in individual pathologies. It is important to appreciate that most methods described are Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd. DOI: 10.1002/pd.4254
  2. 2. Table1Summaryofprenatalandlong-termcardiacfindingsinfetuseswithnon-cardiacdisease CardiacoutputCardiacsizeHypertrophyDiastolicfunctionSystolicfunctionArrhythmiaLong-termconsequences IUGRNormal,shift towardLV RelativecardiomegalyRV,lateRVdysfunction (increasedafterload) Normal—Globularheart,impaired relaxationandhypertension SCTandTRAPIncreasedCardiomegaly——Increased—Normalizationafterresection CCAMDecreasedDecreased—Poorfillingduetoextrinsic compression Normal—Normalizationafterresection Left-sidedCDHNormal,shift towardRV SmallLV——Normal—NormalafterCDHrepair TTTS(recipient)Normal/ decreased CardiomegalyRV>LVIntrinsicRV dysfunction>LV dysfunction Decreased,late—Fullrecoveryafterfetoscopiclaserandhigherarterial stiffnessindonorafteramniodrainage FetalanemiaIncreasedCardiomegaly—NormalIncreased—Partialcorrectionaftertransfusion,yetreducedLVmassin childhood PelvicmassesNormalNormal/increasedif pulmonaryhypoplasia RVRVdysfunctiondueto increasedafterload Normal—? MaternalGravesdiseaseIncreasedNormalRVNormalNormalSinustachycardiaNormalizationpostnatally MaternaldiabetesNormalCardiomegalyInterventricularseptum> freewall,RV=LV DecreasedDecreased(mild)—Normalizationpostnatally Myocarditis (SLE,infections) Normal/ decreased Cardiomegaly—VariableDecreasedHeartblockDilatedcardiomyopathy IUGR,intrauterinegrowthrestriction;LV,leftventricle;RV,rightventricular;SCT,sacrococcygealteratoma;TRAP,twinreversedarterialperfusion;CCAM,congenitalcysticadenomatoidmalformation;CDH,congenitaldiaphragmatichernia;TTTS, twin–twintransfusionsyndrome;SLE,systemiclupuserythematosus. T. V. Mieghem et al.24 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  3. 3. indirect reflections of fetal cardiac function and that they are strongly influenced by cardiac preload (venous return) and afterload (peripheral vascular resistance). Moreover, most methods are subject to large inter-observer and intra-observer variability, which, although acceptable in a research setting, limits application in clinical practice. Cardiac output measurements reflect the volume of blood flowing through the heart per unit of time. When measured using Doppler ultrasound of the outflow valves, combined left and right ventricular outputs per fetal weight stay stable throughout gestation at around 400–450 ml/kg/min6,7 Cardiac output is a crude estimate of the cardiac global ‘pump’ function and is influenced by heart rate, preload, afterload, ventricular volume, and myocardial contractility. Methods that look more specifically at myocardial function include the measurement of the shortening fraction8 (the percentage of radial narrowing of the ventricle during systole measured using M-mode echocardiography, which ranges around 32 ± 6%) or cardiac strain and strain rate (the relative myocardial shortening over time, which can be measured using speckle tracking or tissue Doppler9 ). Longitudinal ventricular contractility can be assessed by evaluating the atrioventricular annulus motion (tricuspid or mitral annular plane systolic excursion10,11 ). Eyeballing ventricular contractility, albeit less objective, is a valid clinical tool and commonly used. Although the aforementioned methods are more reflective of intrinsic myocardial function, they are still influenced by preload and afterload. Another commonly used tool in fetal cardiology is the myocardial performance index (MPI) or Tei index,12 which is the sum of the isovolumetric contraction and relaxation time (ICT + IRT) divided by the ejection time (Figure 1). These time intervals, during which the heart contracts to overcome the systemic pressure or relaxes in preparation for ventricular filling, can be measured using either combined Doppler sampling of blood flow through the atrioventricular and the outflow valves (Figures 1 and 2) or using tissue Doppler. The ICT reflects systolic function (contraction), with longer contraction times reflecting worse function. The IRT on the other hand reflects diastolic myocardial function (relaxation). As such, the complete MPI is a measure of global systolic and diastolic cardiac function, which is strongly dependent on intrinsic myocardial function. Finally, the E/A index is the ratio of early (E, passive ventricular filling) and late (A, atrial contraction) ventricular inflow through the atrioventricular valves. In the fetus, the E/A index is typically less than 1, and the normal inflow pattern is ‘biphasic’ (Figures 1 and 2) with distinct E and A peaks. In fetuses with diastolic myocardial dysfunction in whom the heart becomes less compliant and more dependent on atrial contraction for ventricular filling, the E/A index decreases. The E and A waves can also fuse, resulting in a ‘monophasic’ inflow pattern. With worsening diastolic function, the inflow duration, which usually makes up >35% of the total cardiac cycle length,13 will shorten. Poor atrioventricular valve function can also result in valvular regurgitation, which can be documented with color or pulsed Doppler. Mitral or tricuspid valve regurgitation can either be due to intrinsic valve abnormalities or can arise as a consequence of dilatation of the atrioventricular valve ring secondary to increased volume loading, myocardial dysfunction, or high ventricular pressures. In most situations, the cardiac sonographer will combine different indices to assess the different aspects of ventricular function or select a particular parameter, which is most for a specific disease process, as will be discussed later. INTRAUTERINE GROWTH RESTRICTION (IUGR) The fetus with progressive placental dysfunction and ensuing IUGR is probably the most comprehensively studied to date from a cardiovascular perspective, and this clinical scenario is one of the most common indications for fetal hemodynamic assessment. With advancing placental disease, the resistance in the umbilical artery rises, reflecting a reduction in patent downstream villous vessels. This can be imaged by Doppler ultrasound, initially as a decrease in end-diastolic velocity, which then progresses to absent and eventually reversed diastolic flow. The increased placental resistance (afterload) leads to a lower portion of the fetal cardiac output being Figure 1 Graphical representation of the Doppler waveform used to measure the myocardial performance index. This waveform is obtained by placing the Doppler sample volume over the mitral and aortic valve together in an apical or basal five-chamber view Fetal hemodynamics in non-cardiac disease 25 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  4. 4. directed to the placenta14 and hence a decreased return through the umbilical vein. Overall however, cardiac output is maintained because of an increased recirculation within the fetal body.14 Fetal hypoxia causes an increase in sympathetic tone and constriction of the portal hepatic vascular bed. This constriction is more pronounced in the portal vessels than in the ductus venosus and hence favors ductus venosus shunting at the cost of decreased liver perfusion.15 This effect is further augmented by a dilatation of the ductus venosus.16 As outlined earlier, the ductus venosus preferentially directs blood through the foramen ovale toward the left ventricle. The changes in hepatic and ductus venosus blood flow observed in IUGR therefore favor the left rather than the right ventricular venous return.17 The left ventricular output is further augmented by cerebral18 and coronary vasodilatation19 (heart and brain sparing effect), which decrease the left ventricular afterload. The biologic utility of this dominant left-sided circulation is that the oxygenated blood from the placenta is now preferentially shunted toward the heart and brain, which are essential for survival and metabolically the most demanding. The heart and brain sparing effect is clinically expressed as an increased head circumference relative to the abdominal circumference and a relative cardiomegaly in severe IUGR (normally grown heart in a small chest). Despite this protective redistribution of oxygenated blood toward the heart, subclinical myocardial impairment occurs as demonstrated by an abnormal MPI antenatally and evidence of myocardial cell damage at delivery.20 Moreover, the fetal heart remodels to a more globular configuration,21 the implications of which will be discussed later. Of clinical relevance, an abnormal MPI seems to predate decompensation or fetal death by 26 days.22 As placental resistance increases, and now with a vasodilated left-sided vascular bed, the blood expelled from the right ventricle takes the path of least resistance, and retrograde shunting occurs at the level of the aortic isthmus (Figure 3). This finding has been reported to become evident approximately 12 days prior to decompensation or fetal death.22 In the presence of retrograde aortic isthmus flow, poorly oxygenated right ventricular blood, intended for the placenta and lower body, mixes with oxygenated left ventricular blood and perfuses the brain, thereby reducing the mean oxygen tension in the cerebral vascular bed. The exact meaning of this finding is unknown, but some studies suggest that this may negatively affect long-term developmental outcomes of the affected offspring.23 If IUGR is allowed to progress even further, usually in the setting of extreme prematurity, where the clinician attempts to maximize gestational age before delivery, extensive diastolic cardiac dysfunction will result in impaired preload handling. This can be documented as a progressive increase in pulsatility index in the ductus venosus,22 manifested initially as deepening and ultimately reversal of the a-wave.24 A pulsatile flow pattern can occur in the umbilical vein. If the fetus remains in utero, the risk of demise is very high. A prospective multicenter study, which included more than 600 live-born growth-restricted infants, showed that the ductus venosus Doppler was a strong predictor of neonatal mortality and morbidity in infants born after 27 weeks gestation whose birth weight was over 600 g.25 In survivors, the cardiac changes observed antenatally may not resolve at birth. Cripsi et al. reported that these children maintain more globular hearts with impaired ventricular relaxation, whereas others documented decreased stroke volumes, early onset hypertension and increased intima-media thickness,21,26,27 resulting in a significantly increased risk for premature cardiovascular disease.28 Functional echocardiography has given us a better understanding of the sequence of events starting at placental failure and ending with postnatal cardiovascular disease. The challenge for clinicians and researchers now lies in identifying how to modulate the growth-restricted neonate’s primed phenotype to prevent adverse events later in life. This area must become a priority in perinatal research. Figure 2 Representative Doppler waveforms in a monochorionic twin pair affected by stage IV twin–twin transfusion syndrome. Legend: left pane: donor; right pane: recipient. Top line: myocardial performance index, middle line umbilical vein and ductus venosus; bottom line: tricuspid valve flow. ICT, isovolumetric contraction time; ET, ejection time and IRT, isovolumetric relaxation time. Note prolongation of ICT and IRT, biphasic umbilical vein pulsations, reversal of a-wave in ductus venosus, tricuspid regurgitation and decreased E/A ratio in the recipient fetus T. V. Mieghem et al.26 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  5. 5. VASCULAR TUMORS AND TWIN REVERSED ARTERIAL PERFUSION (TRAP) SEQUENCE Vascular fetal or placental tumors such as solid sacrococcygeal teratomas (SCT), cavernous hemangiomas or chorioangiomas are rare. These masses can function as large arteriovenous anastomoses leading to a hyperdynamic fetal circulation. A slightly different but similar situation is encountered in TRAP sequence, wherein a healthy ‘pump’ fetus perfuses its monochorionic acardiac parasitic co-twin through placental vascular anastomoses. The hemodynamic effects of volume load on the fetal heart largely depend on the size and vascularization of the tumor mass or acardiac twin. The typical echocardiographic image seen is a dilated heart with an increased cardiothoracic ratio.29 The cardiac output is increased and, in SCT, the inferior vena cava, which drains the blood from the tumor to the heart, is often widely dilated, suggesting an increased preload (Figure 4). Intrinsic myocardial function, as measured by the MPI, is typically preserved.29 In more advanced disease states, however, cardiac failure develops, leading to polyhydramnios, hydrops and placentamegaly. At that stage, reversal of the a- wave in the ductus venosus and atrioventricular valve regurgitation may be observed, and the risk of intrauterine fetal demise is high.30 Close surveillance during pregnancy and timely diagnosis of fast tumor growth with progression to high output failure are warranted as these predict a worse fetal outcome.29,31 In the presence of fetal decompensation (i.e. hydrops), delivery should be considered. In the previable period, fetal therapy directed at interrupting the blood supply toward the parasitic mass may be an option. In TRAP, this can be performed by occlusion of the acardiac twin’s umbilical cord (either by radiofrequency ablation or bipolar cautery), which results in 80% survival of the pump twin.32,33 In SCT, open fetal surgery or minimal invasive strategies aimed at interrupting the flow to the tumor may be attempted.34,35 Following successful fetal therapy, cardiac output typically normalizes, and the high output state resolves.36 Figure 4 Sagittal magnetic resonance image (left) and ultrasound (right) demonstrating a widely dilated inferior vena cava (arrow) in a fetus with a massive sacrococcygeal teratoma at 26 weeks gestation Figure 3 Graphical representation of the blood flow in the aortic isthmus in a normally grown fetus (A) and in severe growth restriction (B). (C) Clinical example of reversed aortic isthmus flow in a fetus with severe intrauterine growth restriction. Legend: red, oxygenated blood; blue, deoxygenated blood and purple, mixed oxygenated and deoxygenated blood Fetal hemodynamics in non-cardiac disease 27 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  6. 6. For now, assessment of cardiac output is used in adjunct to other (non-cardiac) parameters to select patients for fetal therapy.31 Decisions on prenatal intervention should not be taken on the basis of cardiac output alone, as in some fetuses’ high output states can be well tolerated for relatively long periods. INTRATHORACIC SPACE OCCUPYING LESIONS Large lung lesions such as bronchopulmonary sequestrations and congenital cystic adenomatoid malformations can compress the heart and thus extrinsically limit right ventricular filling. On echocardiography, this is evident as an increased right ventricular MPI,37 an increased E/A ratio38 or a short, monophasic inflow pattern, and decreased cardiac output.37 Moreover, cardiac tamponade increases ventricular filling pressure and the hydrostatic central venous pressure,39 which, if severe enough, will lead to hydrops. Similar hemodynamic changes are also seen in other intrathoracic space occupying lesions, such as congenital high airway obstruction, pleural or pericardial effusions, and pericardial teratomas.40–45 Although detection of hydrops in the previable period is an indication for fetal therapy,46 detailed monitoring of fetal hemodynamics has no role in the clinical management of fetuses with congenital cystic adenomatoid malformations, and changes in cardiac output or ventricular filling alone are not indications for intervention.47 Assessment of tumor size may be more indicative of the need for fetal therapy.48 The role of functional echocardiography may be more important in evaluating pericardial effusions. Indeed, small effusions with rapid onset (such as those seen after an intracardiac fetal procedure49 ) may sometimes be hemodynamically more challenging for the fetus than large, gradually appearing effusions, and echocardiography can help in guiding the need for therapy. In the left-sided congenital diaphragmatic hernia, the abdominal organs herniating into the chest cause mediastinal shift and result in altered ductus venosus streaming over the foramen ovale50 and a decreased left ventricular preload. Moreover, the hypoplastic lungs of diaphragmatic hernia fetuses have a more muscularized pulmonary vasculature, which is more resistant to blood flow. As a consequence, venous return from the lungs to the left atrium is reduced, again decreasing the left ventricular preload. This leads to an underfilled and thus smaller left ventricle51 and redistribution of the cardiac output toward the right ventricle.52 The opposite observations are true in the right-sided diaphragmatic hernia, where the right ventricle is smaller than in controls, and the right-sided cardiac output is reduced.53 Myocardial function is nevertheless preserved.51 The degree of prenatal ventricular hypoplasia is not related to postnatal survival in infants with congenital diaphragmatic hernia, but pulmonary blood flow may be a predictor of pulmonary hypertension.54,55 Fetal therapy for diaphragmatic hernia, which is aimed at promoting lung growth by temporarily occluding the fetal trachea, does not adversely affect cardiac function.51 Postnatally, with recovery of the preload and closure of the shunts between the left and right circulations, the ventricular volumes recover, and long-term cardiac outcomes are normal.56 TWIN–TWIN TRANSFUSION SYNDROME (TTTS) Twin–twin transfusion syndrome complicates 10–15% of all monochorionic twin pregnancies. Although its pathophysiology is poorly understood, vascular anastomoses in the placenta lead to a polyuric polyhydramnios in the recipient twin and oliguric oligohydramnios in the donor co- twin.57 In addition, the recipient fetus is hypertensive58 and, related to the high afterload, typically displays phenotypic signs of hypertrophic cardiomyopathy with biventricular hypertrophy, atrioventricular valve regurgitation, diastolic dysfunction and later also systolic dysfunction.59–63 These findings can be demonstrated both by ultrasound (ventricular wall thickening, mitral and tricuspid regurgitation, monophasic ventricular inflows, increased MPI, decreased ventricular strain63 and a-wave reversal in the ductus venosus; Figure 2) and biochemical markers of cardiac function in the amniotic fluid (natriuretic peptides and troponin).64 The typical TTTS phenotype predominantly affects the right ventricle and often precedes the picture of the full-blown clinical syndrome.65 Fetal cardiac function is worse in the more advanced Quintero stages66 of the disease, and, at least in stage I TTTS, worse cardiac function is predictive of disease progression.67 In more severe TTTS, high afterload can result in an acute right or less commonly, left ventricular failure with a picture of (reversible) functional pulmonary or aortic artresia with no antegrade flow over the cardiac outlets and retrograde flow in the ductus arteriosus or aortic arch.68,69 The echocardiographic findings in TTTS suggest that the disease process is not only mediated by interfetal volume shifts (which would result in a picture of volume overload rather than a hypertensive cardiopathy) but that intertwin exchange of vasoactive endocrine mediators such as endothelin-170 and the renin-angiotensin system71 probably also plays an important role. We find it interesting that, similar, but often milder, changes in cardiac function to those seen in TTTS can be observed in the larger fetus of monochorionic twin pregnancies affected by severe intertwin growth discordance,35,72,73 suggesting an overlap in pathophysiology between these conditions. Fetal therapy, that is, fetoscopic laser ablation of the culprit placental vascular anastomoses, has shown TTTS to be an excellent demonstration of the regenerative capacity and plasticity of the fetal heart. Fetoscopic laser ablation that is now the standard of care for severe TTTS74,75 does not only reverse the amniotic fluid discordance but after days to weeks also leads to a full recovery of fetal cardiac function.69,76–78 Despite this, however, recipient twins remain at a higher risk for congenital heart disease, including mainly pulmonary stenosis and septal defects78 and therefore, require close antenatal and postnatal echocardiographic follow-up. FETAL ANEMIA The moderately anemic fetus typically is in a hyperdynamic high output state as it tries to recirculate the available hemoglobin more rapidly to maintain adequate tissue T. V. Mieghem et al.28 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  7. 7. perfusion. This, in combination with less viscous blood, leads to higher blood flow velocities in the middle cerebral artery. Non-invasive Doppler measurement of these velocities can be used to accurately assess the degree of fetal anemia.79 In the heart, a hypercontractile state can be observed, with increased shortening fractions and strain,80 resulting in a higher cardiac output.81 Cardiomegaly seen in this ,setting is a sign of fetal compensation (increased ventricular volumes to achieve a higher output) rather than a sign of decompensation.82 Severe anemia may lead to cardiac ischemia, poor cardiac contractility and ultimately, fetal demise. Importantly, and unlike the middle cerebral artery Doppler, cardiac findings do not necessarily correlate with the severity of fetal anemia and are therefore not helpful in the clinical management of this condition.83 Intrauterine transfusion, which is the state-of-the-art therapy for severe fetal anemia, partially corrects the cardiac findings in utero.80 In childhood, however, reduced left ventricular mass and left atrial area have still been reported,84 the clinical implications of which are unclear as of yet. PELVIC MASSES Dilated intra-abdominal structures such as a megacystis due to lower urinary tract obstruction 85 or large ovarian cysts86 can compress the fetal abdominal and pelvic vessels and cause increased downstream resistance on the right ventricle. This can result in ventricular hypertrophy, altered ventricular filling (higher reliance on the atrial contraction as evidenced by a decreased E/A index and a higher pulsatility index in the ductus venosus), tricuspid regurgitation, cardiomegaly and pericardial effusions.85 These changes are however reversible after therapy87 and likely of little clinical significance. CONGENITAL INFECTIONS The most common infections causing fetal myocarditis are cytomegalovirus88 and human parvovirus B19.89 Although cytomegalovirus is most commonly present with other evidence of infection, such as ventriculomegaly and intracranial and abdominal calcifications or IUGR, the infection can also be present in dilated cardiomyopathy.90 The fetus with parvovirus B19 on the other hand, when symptomatic, almost always has cardiac signs, either due to severe fetal anemia (see previous discussion) or occasionally to acute myocarditis, which is present on ultrasound as cardiomegaly with variably abnormal diastolic and systolic function parameters, marked ascites or full- blown hydrops.91 Arrhythmias, due to inflammation of the electric conduction system, are very rare.89 MATERNAL CONDITIONS AFFECTING THE FETAL HEART Maternal Graves disease can cause fetal hyperthyroidism through transplacental passage of thyroid stimulating antibodies. Similar to experiments in lambs,92 fetal hyperthyroidism will cause sinus tachycardia in the range of 180–200 beats per minute with an ensuing increase in fetal cardiac output. In case of mild to moderate fetal hyperthyroidism, additional findings can include right ventricular hypertrophy with preserved ventricular function and pericardial effusions.93 These signs disappear after birth, when thyroid function normalizes.93 In more extreme cases, if the tachycardia is uncontrolled, fetal cardiac failure, hydrops and intrauterine death can occur. The cardiomyopathy observed in fetuses of diabetic mothers is the consequence of fetal hyperinsulinism94 and occurs both in well and poorly controlled diabetics.95,96 Severity of the disease, however, is dependent on glycemic control, and severe forms affecting cardiac function are almost exclusively seen in poorly controlled diabetes. Diabetic cardiopathy occurs both in pre-gestational and gestational diabetes. The myocardial hypertrophy predominantly affects the interventricular septum but may also involve the free walls symetrically.97 This myocardial hypertrophy resolves after birth, when insulin levels normalize, leaving no long-term consequences98,99 but may have severe implications antenatally when obstruction occurs at the level of the outflow tracts. Although usually only noticed by echocardiography in the third trimester of pregnancy, the myocardium of diabetic fetuses may already be abnormal from early pregnancy onwards, with decreased ventricular compliance (diastolic dysfunction), as evidenced by abnormal ventricular inflow patterns,100 atrial shortening fraction and isovolumetric relaxation time.101,102 Interestingly, some of these changes are also noted in diabetic fetuses without myocardial hypertrophy. Systolic function was typically thought to be preserved, yet use of more sensitive ultrasound techniques reveals that subtle changes in cardiac strain may be present in the hearts of fetuses of diabetic mothers.103 Similar to the observations in congenital infections, maternal systemic lupus erythematosus can cause a fetal myocarditis with ensuing endocardial fibroelastosis, dilated cardiomyopathy and complete heart block due to transplacental passage of anti-Ro antibodies.104 Although the incidence of neonatal heart block is low (less than 2% of infants of mothers with anti-Ro antibodies), the mortality and morbidity are significant and related to the life-long dependency on postnatal pacing.104 CONCLUSIONS We have described the alterations in fetal cardiac function that are seen in the more common non-cardiac fetal pathologies. In most cases, when the extra cardiac fetal disease is mild, these changes will remain subclinical, go unnoticed on routine obstetric ultrasound and reverse after treatment. In more severe cases, however, alterations in fetal cardiac function may become clinically apparent and lead to fetal decompensation (hydrops and death). In selected conditions, functional echocardiography may help in guiding clinical decision-making regarding a need for early delivery or offering antenatal therapeutic intervention. Obstetricians, sonographers and fetal medicine specialists should therefore be familiar with the (basic) fetal cardiac function assessment to evaluate the hemodynamic state in a Fetal hemodynamics in non-cardiac disease 29 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  8. 8. fetus with extra cardiac disease. This would include at least rough estimates of systolic (eyeballing ventricular contractility) and diastolic functions (ventricular inflow pattern, valvular regurgitation and ductus venosus Doppler). If function appears impaired, a more detailed assessment in a fetal cardiology unit is indicated. The growth-restricted fetus may represent a special indication for performing routine functional cardiac assessment. More research is needed to define which, if any, novel functional indices should become part of our clinical armamentarium when evaluating the fetus with IUGR antenatally and in following, the growth-restricted neonate. WHAT’S ALREADY KNOWN ABOUT THIS TOPIC? • Fetal cardiac function can be altered in fetuses with extra cardiac disease. WHAT DOES THIS STUDY ADD? • This article summarizes the changes in fetal hemodynamics seen in fetuses with non-cardiac disease and demonstrates how fetal cardiac function assessment can improve our understanding of the pathophysiology of these conditions. • The manuscript reviews how fetal hemodynamic assessment can help in guiding the clinical management of the sick fetus. REFERENCES 1. Kiserud T, Acharya G. The fetal circulation. Prenat Diagn 2004;24:1049–59. 2. Rasanen J, Wood DC, Weiner S, et al. Role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy. Circulation 1996;94:1068–73. 3. Seed M, van Amerom JF, Yoo SJ, et al. Feasibility of quantification of the distribution of blood flow in the normal human fetal circulation using CMR: a cross-sectional study. J Cardiovasc Magn Reson 2012;14:79, DOI: 10.1186/1532-429X-14-79. 4. Van Mieghem T, DeKoninck P, Steenhaut P, Deprest J. Methods for prenatal assessment of fetal cardiac function. Prenat Diagn 2009;29:1193–203. 5. Tutschek B, Schmidt KG. Techniques for assessing cardiac output and fetal cardiac function. Semin Fetal Neonatal Med 2011;16:13–21. 6. DeKoninck P, Steenhaut P, Van Mieghem T, et al. Comparison of Doppler-based and three-dimensional methods for fetal cardiac output measurement. Fetal Diagn Ther 2012;32:72–8. 7. Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001;103:1662–8. 8. Sikkel E, Klumper FJ, Oepkes D, et al. Fetal cardiac contractility before and after intrauterine transfusion. Ultrasound Obstet Gynecol 2005;26:611–7. 9. Teske AJ, De Boeck BW, Melman PG, et al. Echocardiographic quantification of myocardial function using tissue deformation imaging, a guide to image acquisition and analysis using tissue Doppler and speckle tracking. Cardiovasc Ultrasound 2007;5:27, DOI: 10.1186/1476-7120-5-27. 10. Cruz-Lemini M, Crispi F, Valenzuela-Alcaraz B, et al. Value of annular M-mode displacement vs tissue Doppler velocities to assess cardiac function in intrauterine growth restriction. Ultrasound Obstet Gynecol 2013;42:175–81. 11. Messing B, Gilboa Y, Lipschuetz M, et al. Fetal tricuspid annular plane systolic excursion (f-TAPSE): evaluation of fetal right heart systolic function with conventional M-mode ultrasound and spatiotemporal image correlation (STIC) M-mode. Ultrasound Obstet Gynecol 2013;42:182–8. 12. Hernandez-Andrade E, Lopez-Tenorio J, Figueroa-Diesel H, et al. A modified myocardial performance (Tei) index based on the use of valve clicks improves reproducibility of fetal left cardiac function assessment. Ultrasound Obstet Gynecol 2005;26:227–32. 13. Roman KS, Fouron JC, Nii M, et al. Determinants of outcome in fetal pulmonary valve stenosis or atresia with intact ventricular septum. Am J Cardiol 2007;99:699–703. 14. Kiserud T, Ebbing C, Kessler J, Rasmussen S. Fetal cardiac output, distribution to the placenta and impact of placental compromise. Ultrasound Obstet Gynecol 2006;28:126–36. 15. Ebbing C, Rasmussen S, Godfrey KM, et al. Redistribution pattern of fetal liver circulation in intrauterine growth restriction. Acta Obstet Gynecol Scand 2009;88:1118–23. 16. Bellotti M, Pennati G, De Gasperi C, et al. Simultaneous measurements of umbilical venous, fetal hepatic, and ductus venosus blood flow in growth-restricted human fetuses. Am J Obstet Gynecol 2004;190:1347–58. 17. al-Ghazali W, Chita SK, Chapman MG, Allan LD. Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obstet Gynaecol 1989;96:697–704. 18. Pearce W. Hypoxic regulation of the fetal cerebral circulation. J Appl Physiol 2006;100:731–8. 19. Baschat AA, Gembruch U, Reiss I, et al. Demonstration of fetal coronary blood flow by Doppler ultrasound in relation to arterial and venous flow velocity waveforms and perinatal outcome--the ‘heart- sparing effect’. Ultrasound Obstet Gynecol 1997;9:162–72. 20. Crispi F, Hernandez-Andrade E, Pelsers MM, et al. Cardiac dysfunction and cell damage across clinical stages of severity in growth-restricted fetuses. Am J Obstet Gynecol 2008;199:254 e1–8. 21. Crispi F, Bijnens B, Figueras F, et al. Fetal growth restriction results in remodeled and less efficient hearts in children. Circulation 2010;121:2427–36. 22. Cruz-Martinez R, Figueras F, Benavides-Serralde A, et al. Sequence of changes in myocardial performance index in relation to aortic isthmus and ductus venosus Doppler in fetuses with early-onset intrauterine growth restriction. Ultrasound Obstet Gynecol 2011;38:179–84. 23. Fouron JC, Gosselin J, Raboisson MJ, et al. The relationship between an aortic isthmus blood flow velocity index and the postnatal neurodevelopmental status of fetuses with placental circulatory insufficiency. Am J Obstet Gynecol 2005;192:497–503. 24. Turan OM, Turan S, Gungor S, et al. Progression of Doppler abnormalities in intrauterine growth restriction. Ultrasound Obstet Gynecol 2008;32:160–7. 25. Baschat AA, Cosmi E, Bilardo CM, et al. Predictors of neonatal outcome in early-onset placental dysfunction. Obstet Gynecol 2007;109:253–61. 26. Bjarnegard N, Morsing E, Cinthio M, et al. Cardiovascular function in adulthood following intrauterine growth restriction with abnormal fetal blood flow. Ultrasound Obstet Gynecol 2013;41:177–84. 27. Crispi F, Figueras F, Cruz-Lemini M, et al. Cardiovascular programming in children born small for gestational age and relationship with prenatal signs of severity. Am J Obstet Gynecol 2012;207:121.e1–9. 28. Barker DJ. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006;49:270–83. 29. Byrne FA, Lee H, Kipps AK, et al. Echocardiographic risk stratification of fetuses with sacrococcygeal teratoma and twin-reversed arterial perfusion. Fetal Diagn Ther 2011;30:280–8. 30. Rychik J. Fetal cardiovascular physiology. Pediatr Cardiol 2004;25:201–9. 31. Wilson RD, Hedrick H, Flake AW, et al. Sacrococcygeal teratomas: prenatal surveillance, growth and pregnancy outcome. Fetal Diagn Ther 2009;25:15–20. 32. Lee H, Bebbington M, Crombleholme TM. The North American Fetal Therapy Network Registry data on outcomes of radiofrequency ablation for twin-reversed arterial perfusion sequence. Fetal Diagn Ther 2013;33:224–9. 33. Hecher K, Lewi L, Gratacos E, et al. Twin reversed arterial perfusion: fetoscopic laser coagulation of placental anastomoses or the umbilical cord. Ultrasound Obstet Gynecol 2006;28:688–91. 34. Hedrick HL, Flake AW, Crombleholme TM, et al. Sacrococcygeal teratoma: prenatal assessment, fetal intervention, and outcome. J Pediatr Surg 2004;39:430–8. T. V. Mieghem et al.30 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  9. 9. 35. Paek BW, Jennings RW, Harrison MR, et al. Radiofrequency ablation of human fetal sacrococcygeal teratoma. Am J Obstet Gynecol 2001;184:503–7. 36. Langer JC, Harrison MR, Schmidt KG, et al. Fetal hydrops and death from sacrococcygeal teratoma: rationale for fetal surgery. Am J Obstet Gynecol 1989;160:1145–50. 37. Szwast A, Tian Z, McCann M, et al. Impact of altered loading conditions on ventricular performance in fetuses with congenital cystic adenomatoid malformation and twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2007;30:40–6. 38. Mahle WT, Rychik J, Tian ZY, et al. Echocardiographic evaluation of the fetus with congenital cystic adenomatoid malformation. Ultrasound Obstet Gynecol 2000;16:620–4. 39. Rice HE, Estes JM, Hedrick MH, et al. Congenital cystic adenomatoid malformation: a sheep model of fetal hydrops. J Pediatr Surg 1994;29:692–6. 40. Gonen R, Degani S, Shapiro I, et al. The effect of drainage of fetal chylothorax on cardiac and blood vessel hemodynamics. J Clin Ultrasound 1993;21:265–8. 41. Steffensen TS, Quintero RA, Kontopoulos EV, Gilbert-Barness E. Massive pericardial effusion treated with in utero pericardioamniotic shunt in a fetus with intrapericardial teratoma. Fetal Pediatr Pathol 2009;28:216–31. 42. Kamil D, Geipel A, Schmitz C, et al. Fetal pericardial teratoma causing cardiac insufficiency: prenatal diagnosis and therapy. Ultrasound Obstet Gynecol 2006;28:972–3. 43. Bader R, Hornberger LK, Nijmeh LJ, et al. Fetal pericardial teratoma: presentation of two cases and review of literature. Am J Perinatol 2006;23:53–8. 44. Bigras JL, Ryan G, Suda K, et al. Echocardiographic evaluation of fetal hydrothorax: the effusion ratio as a diagnostic tool. Ultrasound Obstet Gynecol 2003;21:37–40. 45. Yinon Y, Grisaru-Granovsky S, Chaddha V, et al. Perinatal outcome following fetal chest shunt insertion for pleural effusion. Ultrasound Obstet Gynecol 2010;36:58–64. 46. Coleman BG, Adzick NS, Crombleholme TM, et al. Fetal therapy: state of the art. J Ultrasound Med 2002;21:1257–88. 47. Schrey S, Kelly EN, Langer JC, et al. Fetal thoracoamniotic shunting for large macrocystic congenital cystic adenomatoid malformations of the lung. Ultrasound Obstet Gynecol 2012;39:515–20. 48. Crombleholme TM, Coleman B, Hedrick H, et al. Cystic adenomatoid malformation volume ratio predicts outcome in prenatally diagnosed cystic adenomatoid malformation of the lung. J Pediatr Surg 2002;37:331–8. 49. Arzt W, Tulzer G. Fetal surgery for cardiac lesions. Prenat Diagn 2011;31:695–8. 50. Stressig R, Fimmers R, Eising K, Gembruch U, Kohl T. Intrathoracic herniation of the liver (‘liver-up’) is associated with predominant left heart hypoplasia in human fetuses with left diaphragmatic hernia. Ultrasound Obstet Gynecol 2011;37:272–6. 51. Van Mieghem T, Gucciardo L, Done E, et al. Left ventricular cardiac function in fetuses with congenital diaphragmatic hernia and the effect of fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol 2009;34:424–9. 52. Allan LD, Irish MS, Glick PL. The fetal heart in diaphragmatic hernia. Clin Perinatol 1996;23:795–812. 53. Dekoninck P, Richter J, van Mieghem T, et al. Cardiac assessment in fetuses with right-sided congenital diaphragmatic hernia: a case-controlled study. Ultrasound Obstet Gynecol 2013, DOI: 10.1002/uog.12561. 54. Ruano R, Aubry MC, Barthe B, et al. Quantitative analysis of fetal pulmonary vasculature by 3-dimensional power Doppler ultrasonography in isolated congenital diaphragmatic hernia. Am J Obstet Gynecol 2006;195:1720–8. 55. Done E, Allegaert K, Lewi P, et al. Maternal hyperoxygenation test in fetuses undergoing FETO for severe isolated congenital diaphragmatic hernia. Ultrasound Obstet Gynecol 2011;37:264–71. 56. Stefanutti G, Filippone M, Tommasoni N, et al. Cardiopulmonary anatomy and function in long-term survivors of mild to moderate congenital diaphragmatic hernia. J Pediatr Surg 2004;39:526–31. 57. Fisk NM, Duncombe GJ, Sullivan MH. The basic and clinical science of twin-twin transfusion syndrome. Placenta 2009;30:379–90. 58. Mahieu-Caputo D, Salomon LJ, Le Bidois J, et al. Fetal hypertension: an insight into the pathogenesis of the twin-twin transfusion syndrome. Prenat Diagn 2003;23:640–5. 59. Barrea C, Alkazaleh F, Ryan G, et al. Prenatal cardiovascular manifestations in the twin-to-twin transfusion syndrome recipients and the impact of therapeutic amnioreduction. Am J Obstet Gynecol 2005;192:892–902. 60. Rychik J, Tian Z, Bebbington M, et al. The twin-twin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 2007;197:392 e1–8. 61. Van Mieghem T, Lewi L, Gucciardo L, et al. The fetal heart in twin-to-twin transfusion syndrome. Int J Pediatr 2010;2010, DOI: 10.1155/2010/379792. 62. Rychik J, Zeng S, Bebbington M, et al. Speckle tracking-derived myocardial tissue deformation imaging in twin-twin transfusion syndrome: differences in strain and strain rate between donor and recipient twins. Fetal Diagn Ther 2012;32:131–7. 63. Van Mieghem T, Giusca S, DeKoninck P, et al. Prospective assessment of fetal cardiac function with speckle tracking in healthy fetuses and recipient fetuses of twin-to-twin transfusion syndrome. J Am Soc Echocardiogr 2010;23:301–8. 64. Van Mieghem T, Done E, Gucciardo L, et al. Amniotic fluid markers of fetal cardiac dysfunction in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2010;202:48 e1–7. 65. Van Mieghem T, Eixarch E, Gucciardo L, et al. Outcome prediction in monochorionic diamniotic twin pregnancies with moderately discordant amniotic fluid. Ultrasound Obstet Gynecol 2011;37:15–21. 66. Michelfelder E, Gottliebson W, Border W, et al. Early manifestations and spectrum of recipient twin cardiomyopathy in twin-twin transfusion syndrome: relation to Quintero stage. Ultrasound Obstet Gynecol 2007;30:965–71. 67. Habli M, Michelfelder E, Cnota J, et al. Prevalence and progression of recipient-twin cardiomyopathy in early-stage twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2012;39:63–8. 68. Pruetz JD, Chmait RH, Sklansky MS. Complete right heart flow reversal: pathognomonic recipient twin circular shunt in twin-twin transfusion syndrome. J Ultrasound Med 2009;28:1101–6. 69. Van Mieghem T, Martin AM, Weber R, et al. Fetal cardiac function in recipient twins undergoing fetoscopic laser ablation of placental anastomoses for Stage IV twin-twin transfusion syndrome. Ultrasound Obstet Gynecol 2013;42:64–9. 70. Bajoria R, Ward S, Chatterjee R. Brain natriuretic peptide and endothelin-1 in the pathogenesis of polyhydramnios- oligohydramnios in monochorionic twins. Am J Obstet Gynecol 2003;189:189–94. 71. Mahieu-Caputo D, Meulemans A, Martinovic J, et al. Paradoxic activation of the renin-angiotensin system in twin-twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient. Pediatr Res 2005;58:685–8. 72. de Haseth SB, Haak MC, Roest AA, et al. Right ventricular outflow tract obstruction in monochorionic twins with selective intrauterine growth restriction. Case Rep Pediatr 2012;2012:426825. 73. Kondo Y, Hidaka N, Yumoto Y, et al. Cardiac hypertrophy of one fetus and selective growth restriction of the other fetus in a monochorionic twin pregnancy. J Obstet Gynaecol Res 2010;36:401–4. 74. Senat MV, Deprest J, Boulvain M, et al. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136–44. 75. Roberts D, Gates S, Kilby M, Neilson JP. Interventions for twin-twin transfusion syndrome: a Cochrane review. Ultrasound Obstet Gynecol 2008;31:701–11. 76. Van Mieghem T, Klaritsch P, Done E, et al. Assessment of fetal cardiac function before and after therapy for twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2009;200:400 e1–7. 77. Gardiner HM, Taylor MJ, Karatza A, et al. Twin-twin transfusion syndrome: the influence of intrauterine laser photocoagulation on arterial distensibility in childhood. Circulation 2003;107:1906–11. 78. Herberg U, Gross W, Bartmann P, et al. Long term cardiac follow up of severe twin to twin transfusion syndrome after intrauterine laser coagulation. Heart 2006;92:95–100. 79. Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell Fetal hemodynamics in non-cardiac disease 31 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.
  10. 10. alloimmunization. Collaborative group for Doppler assessment of the blood velocity in anemic fetuses. N Engl J Med 2000;342:9–14. 80. Michel M, Schmitz R, Kiesel L, Steinhard J. Fetal myocardial peak systolic strain before and after intrauterine red blood cell transfusion-- a tissue Doppler imaging study. J Perinat Med 2012;40:545–50. 81. Rizzo G, Nicolaides KH, Arduini D, Campbell S. Effects of intravascular fetal blood transfusion on fetal intracardiac Doppler velocity waveforms. Am J Obstet Gynecol 1990;163:1231–8. 82. Tongsong T, Tongprasert F, Srisupundit K, Luewan S. Venous Doppler studies in low-output and high-output hydrops fetalis. Am J Obstet Gynecol 2010;203:488.e1–6. 83. Bigras JL, Suda K, Dahdah NS, Fouron JC. Cardiovascular evaluation of fetal anemia due to alloimmunization. Fetal Diagn Ther 2008;24:197–202. 84. Dickinson JE, Sharpe J, Warner TM, et al. Childhood cardiac function after severe maternal red cell isoimmunization. Obstet Gynecol 2010;116:851–7. 85. Rychik J, McCann M, Tian Z, et al. Fetal cardiovascular effects of lower urinary tract obstruction with giant bladder. Ultrasound Obstet Gynecol 2010;36:682–6. 86. Slodki M, Janiak K, Szaflik K, et al. Fetal echocardiography in fetal ovarian cysts. Ginekol Pol 2008;79:347–51. 87. Slodki M, Janiak K, Szaflik K, Respondek-Liberska M. Fetal echocardiography before and after prenatal aspiration of a fetal ovarian cyst. Ginekol Pol 2009;80:629–31. 88. Barnett CP, Jaeggi E, Han RK, et al. Unusual cardiac presentation of congenital cytomegalovirus infection. Ultrasound Obstet Gynecol 2010;35:119–20. 89. Fishman SG, Pelaez LM, Baergen RN, Carroll SJ. Parvovirus-mediated fetal cardiomyopathy with atrioventricular nodal disease. Pediatr Cardiol 2011;32:84–6. 90. Sakaguchi H, Yamamoto T, Ono S, et al. An infant case of dilated cardiomyopathy associated with congenital cytomegalovirus infection. Pediatr Cardiol 2012;33:824–6. 91. Lamont RF, Sobel JD, Vaisbuch E, et al. Parvovirus B19 infection in human pregnancy. Bjog 2011;118:175–86. 92. Lorijn RH, Nelson JC, Longo LD. Induced fetal hyperthyroidism: cardiac output and oxygen consumption. Am J Physiol 1980;239: H302–7. 93. Kwon EN, Kambalapalli M, Francis G, Donofrio MT. Fetal right- ventricular hypertrophy with pericardial effusion and maternal untreated hyperthyroidism. Pediatr Cardiol 2012, DOI: 10.1007/ s00246-012-0580-5. 94. Huang T, Kelly A, Becker SA, et al. Hypertrophic cardiomyopathy in neonates with congenital hyperinsulinism. Arch Dis Child Fetal Neonatal Ed 2013;98:F351–4. 95. Weber HS, Copel JA, Reece EA, et al. Cardiac growth in fetuses of diabetic mothers with good metabolic control. J Pediatr 1991;118:103–7. 96. Jaeggi ET, Fouron JC, Proulx F. Fetal cardiac performance in uncomplicated and well-controlled maternal type I diabetes. Ultrasound Obstet Gynecol 2001;17:311–5. 97. Zielinsky P. Role of prenatal echocardiography in the study of hypertrophic cardiomyopathy in the fetus. Echocardiography 1991;8:661–8. 98. Stuart A, Amer-Wahlin I, Persson J, Kallen K. Long-term cardiovascular risk in relation to birth weight and exposure to maternal diabetes mellitus. Int J Cardiol 2013;168(3):2653–7. 99. Rijpert M, Breur JM, Evers IM, et al. Cardiac function in 7-8-year-old offspring of women with type 1 diabetes. Exp Diabetes Res 2011;2011:564316, DOI: 10.1155/2011/564316. 100. Rizzo G, Arduini D, Capponi A, Romanini C. Cardiac and venous blood flow in fetuses of insulin-dependent diabetic mothers: evidence of abnormal hemodynamics in early gestation. Am J Obstet Gynecol 1995;173:1775–81. 101. Turan S, Turan OM, Miller J, et al. Decreased fetal cardiac performance in the first trimester correlates with hyperglycemia in pregestational maternal diabetes. Ultrasound Obstet Gynecol 2011;38:325–31. 102. Zielinsky P, Piccoli AL, Jr. Myocardial hypertrophy and dysfunction in maternal diabetes. Early Hum Dev 2012;88:273–8. 103. Liu F, Liu S, Ma Z, et al. Assessment of left ventricular systolic function in fetuses without myocardial hypertrophy of gestational diabetes mellitus mothers using velocity vector imaging. J Obstet Gynaecol 2012;32:252–6. 104. Izmirly PM, Saxena A, Kim MY, et al. Maternal and fetal factors associated with mortality and morbidity in a multi-racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus. Circulation 2011;124:1927–35. T. V. Mieghem et al.32 Prenatal Diagnosis 2014, 34, 23–32 © 2013 John Wiley & Sons, Ltd.