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(BQ) Part 1 book “A practical guide to fetal echocardiography normal and abnormal hearts” has contents: Embryology of the heart, genetic aspects of congenital heart diseases, cardiac anatomy, fetal situs, systematic evaluation of the venous system,… and other contents.
Thank you for purchasing this e-book To receive special offers and news about our latest products, sign up below Or visit LWW.com A Practical Guide to Fetal Echocardiography Normal and Abnormal Hearts THIRD EDITION A Practical Guide to Fetal Echocardiography Normal and Abnormal Hearts THIRD EDITION Alfred Abuhamad, MD Professor of Obstetrics & Gynecology Professor of Radiology Chairman, Department of Obstetrics & Gynecology Vice Dean for Clinical Affairs Eastern Virginia Medical School Norfolk, Virginia Rabih Chaoui, MD Professor of Obstetrics & Gynecology Prenatal Diagnosis and Human Genetics Center Berlin, Germany Acquisitions Editor: Jamie M Elfrank Product Development Editor: Ashley Fischer Editorial Assistant: Brian Convery Marketing Manager: Stephanie Kindlick Senior Production Project Manager: Alicia Jackson Design Coordinator: Joan Wendt Artist/Illustrator: Patricia Gast Manufacturing Coordinator: Beth Welsh Prepress Vendor: S4Carlisle Publishing Services 3rd edition Copyright © 2016 Wolters Kluwer © 2010 by Lippincott Williams & Wilkins, a Wolters Kluwer business All rights reserved This book is protected by copyright No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the abovementioned copyright To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at lww.com (products and services) Library of Congress Cataloging-in-Publication Data Abuhamad, Alfred, author A practical guide to fetal echocardiography : normal and abnormal hearts / Alfred Abuhamad, Rabih Chaoui — 3rd edition p ; cm Includes bibliographical references and index ISBN 978-1-4511-7605-6 eISBN 978-1-4963-2640-9 I Chaoui, Rabih, author II Title [DNLM: 1.Fetal Heart—ultrasonography 2.Heart Defects, Congenital— ultrasonography 3.Ultrasonography, Prenatal—methods.WQ 209] RG628.3.E34 618.3’26107543—dc23 2015021079 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data, and other factors unique to the patient The publisher does not provide medical advice or guidance and this work is merely a reference tool Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work LWW.com This book is dedicated to all pregnant women who face the gutwrenching diagnosis of fetal congenital heart disease May the knowledge in this book provides for accurate diagnosis, compassionate counseling and optimal management We also dedicate this book to our parents for their unwavering support and commitment to excellence throughout the years, and to Sharon, Sami and Nicole Kathleen, Amin and Ella, With unconditional love I t is with great pleasure that we introduce this third edition of A Practical Guide to Fetal Echocardiography: Normal and Abnormal Hearts, a product of intense work and collaboration on the important and rapidly evolving field of fetal cardiology Given the major success that the second edition of this book received, and in keeping with the progress in fetal cardiac imaging, we decided to write this third edition in order to continue to provide the most up-to-date and comprehensive reference on this subject We strived to ensure that this third edition is written in the same easy-to-read style and illustrated with the most informative figures as the second edition Furthermore, as compared to the second edition, this third edition represents a substantive expansion on the subject with major chapter revisions and additions of several new relevant topics In order to maintain the widely successful systematic and methodical approach of the second edition of this book, we chose the difficult path of writing and illustrating this third edition in its entirety without outside collaboration The book is divided into two main parts, with part one covering the technical aspects of the cardiac exam and part two covering fetal cardiac abnormalities The first part of the book is totally revamped to include several new chapters on the following topics: risk factors for cardiac defects, national and international guidelines for fetal cardiac screening and fetal echocardiography, optimizing the cardiac examination, cardiac embryology, the three-vessel-trachea view, and the venous system An updated chapter on the genetics of cardiac malformations introduces the role of novel technologies in genetic screening and diagnosis Other chapters in part one underwent major revisions, including color and pulsed Doppler and the use of three-dimensional ultrasound in fetal echocardiography A comprehensive chapter on cardiac function completes the first part of the book Detailed discussion on fetal cardiac malformations is presented in the second part of the book in a uniform format that includes the definition, spectrum of disease and incidence, the use of gray scale, color Doppler, three-dimensional, and early gestation ultrasound in the diagnosis of each cardiac abnormality followed by the differential diagnosis, and prognosis and outcome New colored schematics, drawings, and figures illustrate cardiac anomalies and the book relies on the liberal use of tables outlining common and differentiating features of various cardiac malformations A comprehensive section on reference ranges of cardiac measurements is presented in a graphic and tabular format in the appendix Congenital heart disease is the most common congenital malformation with a significant impact on neonatal morbidity and mortality Prenatal diagnosis of congenital heart disease has been suboptimal over the years owing in large part to the complexity of cardiac anatomy and the inherent difficulty of the ultrasound examination of the fetal heart We feel that this third edition of this book provides a comprehensive reference to the practitioners involved in cardiac imaging, and we sincerely hope that this book enhances the detection rate of congenital heart disease, which should translate into improved outcome for our smallest patients This book would not have been a reality without the support of several people, first and foremost, our families who unselfishly allowed us to spend long evenings and weekends away from them in completing this task, the artistic talents of Ms Patricia Gast who performed all the superb drawings in this book in an efficient and accurate manner, Dr Elena Sinkovskaya (for Dr Abuhamad) and Dr Kai-Sven Heling (for Dr Chaoui) for the collegiality and close cooperation throughout the years, Drs Anna Klassen and Cornelia Tennsted for providing us with figures of anatomic specimens on the normal and abnormal hearts, and the professional editorial and production teams at Lippincott Williams and Wilkins In closing, we continue to owe a great debt of gratitude to two giants in the field of ultrasound, Dr John Hobbins (for Dr Abuhamad) and Dr Rainer Bollmann (for Dr Chaoui) who gave us our ultrasound roots and provided longlasting mentorship and guidance Alfred Abuhamad, MD Rabih Chaoui, MD 1 Congenital Heart Disease: Incidence,Risk Factors, and Prevention Strategies Guidelines for the Performance of the Sonographic Screening and Echocardiography Examination of the Fetal Heart Embryology of the Heart Genetic Aspects of Congenital Heart Diseases Cardiac Anatomy Fetal Situs Cardiac Chambers: The Four-Chamber and Short-Axis Views The Great Vessels: Axial, Oblique, and Sagittal Views The Three-Vessel-Trachea View and Upper Mediastinum 10 Systematic Evaluation of the Venous System 11 Optimization of the Two-Dimensional Grayscale Image in Fetal Cardiac Examination 12 Color Doppler in Fetal Echocardiography 13 Pulsed Doppler in Fetal Echocardiography 14 Fetal Cardiac Function 15 Three- and Four-Dimensional Ultrasound of the Fetal Heart 16 Fetal Cardiac Examination in Early Gestation 17 Fetal Cardiac Measurements and Reference Ranges 18 Atrial, Ventricular, and Atrioventricular Septal Defects 19 Univentricular Atrioventricular Connection, Double Inlet Ventricle, and Tricuspid Atresia with Ventricular Septal Defect 20 Ebstein Anomaly, Tricuspid Valve Dysplasia, and Tricuspid Regurgitation 21 Aortic Stenosis and Bicuspid Aortic Valve 22 Hypoplastic Left Heart Syndrome and Critical Aortic Stenosis 23 Coarctation of the Aorta and Interrupted Aortic Arch 24 Pulmonary Stenosis, Pulmonary Atresia with Intact Ventricular Septum, and Ductus Arteriosus Constriction 25 Tetralogy of Fallot, Pulmonary Atresia with Ventricular Septal Defect, and Absent Pulmonary Valve Syndrome 26 Common Arterial Trunk 27 Double Outlet Right Ventricle 28 Complete and Congenitally Corrected Transposition of the Great Arteries 29 Right Aortic Arch, Double Aortic Arch, and Aberrant Subclavian Artery 30 Fetal Heterotaxy and Situs Inversus 31 Anomalies of Systemic and Pulmonary Venous Connections 32 Fetal Cardiomyopathies and Fetal Heart Tumors 33 Fetal Arrhythmias Appendix: Graph Legends Index ● INCIDENCE OF CONGENITAL HEART DISEASE Congenital heart diseases (CHDs) are the most common severe congenital abnormalities (1) Half of the CHD cases are, however, minor and are easily corrected by surgery, the remainder accounting for over half of the deaths from congenital abnormalities in childhood (1) Moreover, CHD results in the most costly hospital admissions for birth defects in the United States (2) The incidence of CHD is dependent on the age at which the population is initially examined and the definition of CHD used Inclusion of a large number of premature neonates in a study may increase the incidence of CHD Both patent ductus arteriosus and ventricular septal defects are common in premature infants An incidence of 8 to 9 per 1,000 live births has been reported in large population studies (1) Of all cases of CHD, 46% are diagnosed by the first week of life, 88% by the first year of life, and 98% by the fourth year of life (1) The incidence of CHD is also influenced by the inclusion of bicuspid aortic valve, the incidence of which is estimated at 10 to 20 per 1,000 live births (3) Bicuspid aortic valve may be associated with considerable morbidity and mortality in affected persons (3) Furthermore, accounting for subtle anomalies such as persistent left superior vena cava (5–10 per 1,000 live births) and isolated aneurysm of the atrial septum (5–10 per 1,000 live births) results in an overall incidence of CHD approaching 50 per 1,000 live births (4) CHD remains the most common severe abnormality in the newborn; its prenatal diagnosis allows for better pregnancy counseling and improved neonatal outcome Table 1.1 lists the incidence of CHD by various subtypes (5) Several risk factors for CHD have been identified, including fetal and maternal risk factors, which are discussed in detail in the following sections ● FETAL RISK FACTORS Extracardiac Anatomic Abnormalities The presence of extracardiac abnormalities in a fetus is frequently associated with CHD and is thus an indication for fetal echocardiography The risk of CHD with fetal extracardiac abnormalities is increased even in the presence of normal karyotype (6) The risk of CHD is dependent on the specific type of fetal malformation Abnormalities detected in more than one organ system increase the risk of CHD and also of concomitant chromosomal abnormalities (7) Nonimmune hydrops in the fetus is frequently associated with CHD Incidence of abnormal cardiac anatomy is reported in about 10% to 20% of fetuses with nonimmune hydrops (8, 9) Table 1.2 lists associated extracardiac anomalies detected in fetuses with fetal cardiac anomalies (7) TABLE 1.1 Types and Incidence of Human Congenital Heart Disease Defect VSD PDA ASD AVSD PS AS CoA TOF D-TGA HRH Tricuspid atresia Incidence per 1,000 live births 3.570 0.799 0.941 0.348 0.729 0.401 0.409 0.421 0.315 0.222 0.079 Ebstein anomaly Pulmonary atresia 0.114 0.132 HLH Truncus DORV 0.266 0.107 0.157 SV TAPVC 0.106 0.094 VSD, ventricular septal defect; PDA, patent ductus arteriosus; ASD, atrial septal defect; AVSD, atrioventricular septal defect; PS, pulmonary stenosis; AS, aortic stenosis; CoA, coarctation of the aorta; TOF, tetralogy of Fallot; D-TGA, complete transposition of the great arteries; HRH, hypoplastic right heart; HLH, hypoplastic left heart; DORV, double outlet right ventricle; SV, single ventricle; TAPVC, total anomalous pulmonary venous connection Modified from Hoffman JI, Kaplan S The incidence of congenital heart disease J Am Coll Cardiol 2002;39:1890–1900, with permission TABLE Associated Extracardiac Anomalies in Fetal 1.2 Heart Defects according to Organ System Organ system Central nervous system Genitourinary Genital Renal Skeletal Respiratory Gastrointestinal Craniofacial TOTAL % 71.7 25 75 52.3 38.1 47.5 35.7 53.6 Modified from Song MS, Hu A, Dyamenahalli U, et al Extracardiac lesions and chromosomal abnormalities associated with major fetal heart defects: comparison of intrauterine, postnatal and postmortem diagnoses Ultrasound Obstet Gynecol 2009;33:552–559, with permission Fetal Cardiac Arrhythmia The presence of fetal cardiac rhythm disturbances may be associated with an underlying structural heart disease The association of CHD with fetal arrhythmia is dependent on the type of cardiac rhythm disturbances Overall, about 1% of fetal cardiac arrhythmias are associated with CHD (8) Fetal tachycardia and isolated extrasystoles are rarely associated with CHD Complete heart block, on the other hand, resulting from abnormal atrioventricular (AV) node conduction, is associated with structural cardiac abnormalities in about 50% of fetuses, with the remaining pregnancies associated with the presence of maternal Sjögren antibodies (10, 11) A fetal echocardiogram should be performed in all fetuses with suspected or confirmed arrhythmias to assess cardiac structure and function This includes fetuses with irregular fetal rhythm, such as that caused by frequent extrasystoles, as this may be the harbinger of more malignant arrhythmias if it is persistent (12) In fetuses with less frequent extrasystoles, a fetal echocardiogram is reasonable to perform, especially if the ectopic beats persist beyond to weeks (13) Diagnosis and management of fetal cardiac rhythm disturbances are discussed in detail in Chapter 33 Suspected Cardiac Anomaly on Routine Ultrasound A risk factor with one of the highest yields for CHD is the suspicion for the presence of a cardiac abnormality during routine ultrasound scanning Fetal echocardiogram should therefore be performed in all fetuses with a suspected cardiac abnormality noted on obstetric ultrasound CHD is confirmed in about 40% to 50% of pregnancies referred with this finding (8, 9) In view of this, and the fact that most infants born with CHD are born to pregnancies without risk factors, ultrasound evaluation of the fetal heart should not be limited to pregnant mothers with known risk factors Indeed, recent guidelines of cardiac screening have been expanded to include evaluation of the great vessels (14–16) The value of routine ultrasound in the screening for CHD is discussed in Chapter 2 Known or Suspected Chromosomal or Genetic Abnormality The presence of a fetal genetic or chromosomal abnormality is associated with a high risk of cardiac and extracardiac defects and thus a fetal echocardiogram should be performed Please refer to Chapter for a more comprehensive discussion on this topic Thickened Nuchal Translucency Measurement of fetal nuchal translucency (NT) thickness in the late first and early second trimesters of pregnancy is currently established as an effective method for individual risk assessment of fetal chromosomal abnormalities Several reports have noted an association between increased NT and genetic syndromes and major fetal malformations, including cardiac defects (17–19) The prevalence of major cardiac defects increases exponentially with fetal NT thickness, without an obvious predilection to a specific type of CHD (18) An NT thickness of greater than or equal to 3.5 mm in a chromosomally normal fetus has been correlated with a prevalence of CHD of 23 per 1,000 pregnancies, a rate that is higher than pregnancies with a family history of CHD (17, 20) In this setting of an NT that is greater than or equal to 3.5 mm, referral for fetal echocardiography is thus warranted Finding an NT thickness of greater than or equal to 3.5 mm may lead to an earlier diagnosis of all major types of CHD (21) Chapter 16 provides a more detailed discussion on the ultrasound examination of the fetal heart in early gestation Monochorionic Placentation The incidence of CHD in fetuses of monochorionic placentation is higher (22, 23) and is estimated at 2% to 9% (22, 24, 25) Twin–twin transfusion syndrome (TTTS), a complication of monochorionic twin placentation, has been reported to occur in about 10% of cases TTTS has been associated with acquired cardiac abnormalities, including right ventricular outflow tract obstruction, which occurs in about 10% of recipient twin fetuses (26) The increased risk of CHD in fetuses of monochorionic placentation is noted even after excluding cardiac effects of TTTS (23) In a cohort study of 165 sets of monochorionic twins, the overall risk of at least one of a twin pair having a structural CHD was 9.1% (23) This risk was 7% for monochorionic–diamniotic twins and 57.1% for at least one twin member of monochorionic– monoamniotic twins (23) If one twin member is affected, the risk that the other twin member is also affected is 26.7% (23) A systemic literature review of 830 fetuses from monochorionic–diamniotic twin pregnancies confirmed an increased risk of CHD independent of TTTS (22) Ventricular septal defects were the most common type of CHD in non-TTTS fetuses, and pulmonary stenosis and atrial septal defects were significantly more prevalent in fetuses of pregnancies complicated with TTTS (22) Fetal echocardiogram is therefore recommended in all monochorionic twin gestations ● MATERNAL RISK FACTORS Maternal Metabolic Disease Maternal metabolic disorders, primarily including pregestational diabetes mellitus and phenylketonuria, have a significant effect on the incidence of CHD In the presence of maternal metabolic disease, preconception counseling and tight metabolic control immediately prior to and during organogenesis are recommended in order to reduce the incidence of fetal CHD Diabetes Mellitus The incidence of CHD is fivefold higher in infants of pregestational diabetic mothers than in controls, with a higher relative risk noted for specific cardiac defects, including 6.22 for heterotaxy, 4.72 for truncus arteriosus, 2.85 for transposition of the great arteries, and 18.24 for single-ventricle defects (27) Poor glycemic control in the first trimester of gestation, as evidenced by an elevated glycohemoglobin level (HbA1c), has been strongly correlated with an increased risk of structural defects in infants of diabetic mothers (28, 29) Although some studies have identified a level of glycohemoglobin above which the risk of fetal structural abnormalities is increased (28), other studies have failed to identify a critical level of glycohemoglobin that provides an optimal predictive power for CHD screening (30) Therefore, it appears that although the risk may be highest in those with increased HbA1c levels (>8.5%), all pregnancies of pregestational diabetic women are at some increased risk Given this information, a fetal echocardiogram should be performed in all women with pregestational diabetes mellitus Gestational diabetes, which is diagnosed beyond the first trimester of pregnancy, does not increase the risk of CHD in the fetus, and thus a fetal echocardiogram is not indicated for these pregnancies Fetal ventricular hypertrophy in late gestation (third trimester) is a complication of poor glycemic control in pregestational and gestational diabetic pregnancies, and the degree of hypertrophy is related to the level of glycemic control Fetal echocardiogram in the third trimester to assess for ventricular hypertrophy is thus recommended for pregestational and gestational diabetic pregnancies if the HbA1c is greater than 6% in the second trimester (31) Phenylketonuria Another metabolic disorder that is associated with CHD is phenylketonuria Women with phenylketonuria should be aware of the association of fetal CHD with elevated maternal phenylalanine levels (32) This is particularly important as phenylketonurics usually follow unrestricted dietary regimens in adulthood Fetal exposure during organogenesis to maternal phenylalanine levels exceeding 15 mg/dL is associated with a 10- to 15-fold increase in CHD (33) Other fetal abnormalities in phenylketonurics include microcephaly and growth restriction (32) The risk of CHD in fetuses has been reported to be 12% if maternal dietary control is not achieved by 10 weeks of gestation (34) With maternal phenylalanine levels at 75%) of clinically significant chromosome abnormalities including trisomies 21, 18, and 13, triploidy, and aneuploidies involving the sex chromosomes, such as monosomy X (Turner syndrome) and XXY (Klinefelter syndrome) Some large balanced or unbalanced translocations can also be found in addition to rare mosaic trisomies and marker chromosomes Large chromosomal deletions can also be identified, such as the majority of deletions 4p- (Wolf–Hirschhorn syndrome) Small deletions, termed microdeletions, such as 22q11 (DiGeorge syndrome), are typically too small to be identified by this method Microdeletions can be detected by the use of selective fluorescence in situ hybridization (FISH) when such condition is suspected (e.g., FISH for deletion 22q11 in conotruncal anomalies) or by examining the complete chromosome using comparative genomic hybridization (CGH) (microarray) (discussed later) FISH Technique FISH is a cytogenetic technique using specific fluorescent probes, which are applied to detect and localize the presence or absence of specific DNA regions on chromosomes FISH uses a single DNA strand, called probe, corresponding to a specific locus and only binding to the corresponding complementary part on the chromosome Fluorescence with various colors is used to enable visualization under the fluorescence microscope FISH can be directly used on cells during cell division and as such it is called in situ interphase FISH, typically applied antenatally for a rapid diagnosis of trisomies FISH technique used for the identification of microdeletions is performed directly on interphase chromosomes with the addition of the FISH probes In general, two probes are used The first probe (green) is a control probe used for the identification of both copies of the target chromosome The second probe (red-magenta) hybridizes to the sequence of the region of interest on the target chromosome In the presence of a deletion, which is typically on one of the paired chromosomes, a lack of the red signal is noted, as the probe cannot bind to the target region on the chromosome When a specific cardiac anomaly is diagnosed in the fetus and an invasive procedure is performed, it has become customary to offer FISH for deletion 22q11.2 in addition to chromosome karyotyping Array Comparative Genomic Hybridization Array CGH, or microarray, is even more sensitive than the two previous techniques and compares the patient’s DNA in all chromosomes with a control DNA sample for the identification of variances between the two sets Imbalances in the patient’s DNA, such as deletions and duplications, can be identified with this technique Instead of examining one deletion, such as with FISH, all possible regions of the chromosomes are examined for deletions and duplications and other imbalances Explanation of the technical aspect of CGH is beyond the scope of this book, but it is important to state that CGH detects all DNA imbalances in chromosomes, some of which may have unclear clinical significance This new microarray technique has become popular in the last years despite its cost and limitations Some centers offer CGH as a first-line genetic testing after chorionic villus sampling or amniocentesis, while others restrict its use when DNA imbalance is suspected or as a second-line test following normal karyotypic analysis In a recent meta-analysis (3), it was shown that for fetal heart defects CGH detected additional 7% of chromosomal abnormalities after excluding aneuploidies and deletion 22q11.2 With this finding, it is reasonable to discuss the option for CGH with the patient when fetal malformations and particularly CHD is diagnosed The availability and cost of CGH should also factor into this decision As more information accumulates on the association of CHD with chromosomal imbalances, the role of CGH in the diagnosis and management of CHD will be more clarified Noninvasive Prenatal Testing Noninvasive prenatal testing (NIPT) is a relatively new genetic testing that is offered as a screening test in the first and second trimesters of pregnancy for trisomies 21, 13, and 18, monosomy X, and sex chromosomes abnormalities The test is based on the presence of fetal cell-free DNA (cfDNA) in the maternal circulation primarily from placental cell apoptosis (4) Placental cell apoptosis releases into the maternal circulation small DNA fragments that can be detected from about 4 to 7 weeks’ gestation (5) It is estimated that about 2% to 20% of circulating cfDNA in the maternal circulation is fetal in origin (5) The half-life of cfDNA is short and is typically undetectable within hours after delivery (6) Details of the technical aspect of NIPT are beyond the scope of this book but the various tests that are clinically available are based on the isolation and counting of cfDNA using sequencing methods NIPT has very good performance with regards to screening for trisomy 21 In published studies, the detection rate for trisomy 21 is at 99% for a false-positive rate of 0.16% (7) Detection rate for trisomy 18 is at 97% for a false-positive rate of 0.15% (7) To date, NIPT has been recommended as a screening test for the high-risk population Given a very small false-positive rate, incorporating NIPT for trisomy 21 screening in the high-risk population reduces the need for unnecessary invasive testing It should be emphasized that NIPT is a screening and not a diagnostic test and thus caution should be used when NIPT is incorporated in the genetic evaluation of CHD Given a relatively high association of CHD with chromosomal imbalance, the significance of a normal NIPT result in the setting of CHD should be explained to the patient and further invasive diagnostic testing should be recommended Undoubtedly, NIPT technology will expand over the next few years to allow for screening of chromosomal deletions and duplications As a new and emerging technology, the role of NIPT in CHD should be carefully evaluated before a change in management guidelines is adopted ● SONOGRAPHIC EVALUATION OF THE FETUS WITH CHD The antenatal detection of CHD in a fetus necessitates a detailed ultrasound evaluation given a high association with extracardiac anomalies, ranging between 30% and 50% in some series Establishing whether the CHD is isolated or part of a genetic syndrome is essential for patient counseling and for the assessment of long-term prognosis On rare occasions, the type of CHD by itself provides enough information about associations, or lack thereof, to allow for patient counseling For instance, this can be true for cardiac rhabdomyomas and their associations with tuberous sclerosis complex (TSC) or the commonly isolated simple transposition of the great arteries For most CHD, however, there is a wide range of possible associations and detailed fetal evaluation is therefore warranted Usually, the first step is to seek for the presence of additional soft markers and anomalies that suggest the presence of one of the common numerical chromosomal anomalies that can be detected by karyotyping Furthermore, a detailed sonographic evaluation of the fetus is essential with a thorough search for markers of associated genetic syndromes This can only be achieved if the examiner is aware of various associations and the phenotypic aspects of various syndromes In the presence of a normal fetal karyotype, a discussion on the benefit of additional genetic testing should be undertaken with the patient Tables on various associations of CHD with genetic abnormalities are available and have traditionally guided clinical management in such cases The presence of subtle signs on ultrasound can point the examiner to a genetic association that may not be clearly visible otherwise Tetralogy of Fallot is a typical example, where it can be isolated, but also is typically associated with trisomies 21 and 18, deletion 22q11.2, Alagille syndrome, CHARGE syndrome, and others Another example is the presence of atrioventricular septal defect (AVSD), since it is suggested that more than 50% of AVSDs are associated with either trisomy 21 or 18 AVSD can also be part of heterotaxy syndrome (see Chapter 30), either isolated or in the context of primary ciliary dyskinesia AVSDs were also observed in deletion 22q11.2 and other deletions as well as in CHARGE syndrome (13%) as has been recently reported (8) ● CHD AND NUMERICAL CHROMOSOMAL ANOMALIES The frequency of chromosomal abnormalities in infants with congenital heart defects has been estimated as 5% to 15% from postnatal data (9–11) In a population-based case-control study of 2,102 live-born infants, ascertained by their cardiovascular malformations, chromosomal abnormalities were found in 13% (10) In this study, Down syndrome occurred in 10.4% of infants with cardiovascular malformations, with the other trisomies each occurring in less than 1% of cases (10) Similar data were reported from three large registries of congenital malformations, involving 1.27 million births (11) The frequency of abnormal karyotype in fetuses with cardiac defects is higher and has been reported in the range of 30% to 40% by several studies (12–14) This higher rate of chromosomal abnormalities in fetuses with cardiac defects, when compared to their live-born counterparts, is mainly due to an increased prenatal mortality in fetuses with aneuploidy, which has been estimated at 30% for trisomy 21, 42% for trisomy 13, 68% for trisomy 18, and 75% for Turner syndrome (15) Not only is the association of congenital cardiac defects and chromosomal abnormalities lower in live-born infants than that in fetuses, but also is the distribution of chromosomal abnormalities more skewed toward Down syndrome in the neonatal population (10, 11), again probably due to the high prenatal mortality of trisomies 18 and 13 and monosomy X Certain specific cardiac diagnoses are more commonly associated with chromosomal abnormalities than others Prenatal and postnatal studies are concordant with regard to the specific cardiac diagnoses that are more likely to be associated with chromosomal abnormalities In general, malformations of the right side of the heart are less commonly associated with karyotype abnormalities Specific cardiac diagnoses, such as transposition of the great vessels and heterotaxy syndromes, are not usually associated with chromosomal abnormalities AVSD, ventricular (perimembranous) and atrial septal defects, tetralogy of Fallot, double outlet right ventricle, and hypoplastic left heart syndrome, on the other hand, are more commonly associated with chromosomal abnormalities in the fetus and newborn Table 4.1 lists specific cardiac diagnoses in infants with noncomplex cardiovascular defects from three large registries (11) and the corresponding incidence of associated numerical chromosomal abnormalities The majority of fetuses with cardiac defects and chromosomal abnormalities have other associated extracardiac abnormalities, in the order of 50% to 70% (12, 14) The distribution of extracardiac abnormalities usually follows the typical pattern noted within each chromosomal syndrome with no predominance of any specific abnormality In the fetus with an apparently isolated cardiac abnormality, the incidence of chromosomal abnormalities is still significantly increased (15%–30%), and thus appropriate genetic counseling is warranted (12, 14) TABLE Number of Infants with Identified Chromosomal 4.1 Anomalies according to Cardiac Defect Type (Noncomplex Cardiovascular Defects Only) When the diagnosis of a chromosomal abnormality is made in a fetus, an echocardiogram is indicated in view of the common association of cardiac malformations with karyotype abnormalities Data obtained from postnatal studies suggest that the incidence of cardiac defects is 40% to 50% in trisomy 21, 25% to 35% in Turner syndrome, and more than 80% in trisomies 13 and 18 (2, 16) Cardiac defects tend to be specific to the type of chromosomal abnormality Table 4.2 lists the most common numerical chromosomal abnormalities and their associated congenital cardiac defects TABLE Representative Numerical Chromosomal 4.2 Disorders and Their Association with Congenital Heart Defects ● CHD AND CHROMOSOMAL DELETION SYNDROMES DiGeorge Syndrome (Deletion 22q11.2) Definition of Disease DiGeorge syndrome, also known as monosomy 22q11.2 deletion syndrome, velocardiofacial syndrome, or CATCH-22, is the most common deletion in humans and is the second most common chromosomal anomaly in infants with CHD (second to trisomy 21) It has an estimated prevalence of 1:2,000 to 1:4,000 live births (17) DiGeorge syndrome results from a deletion in the region 11 on long arm of chromosome 22 The acronym CATCH-22 was used to describe features of DiGeorge syndrome to include cardiac anomalies (C), abnormal facies (A), thymus hypoplasia (T), cleft palate (C), hypocalcemia (H), and the microdeletion on chromosome 22 Phenotypic abnormalities include cardiac outflow tract abnormalities in combination with thymus hypoplasia or aplasia, cleft palate, velopharyngeal insufficiency, and dysmorphic facial features (18) The clinical feature of the 22q11.2 deletion is, however, highly variable Cardiovascular anomalies, which can be present in up to 85% of cases, immunodeficiency, and speech delay appear to be the most frequent phenotypic manifestations (18, 19) Other abnormalities include neonatal hypocalcemia due to parathyroid hypoplasia, feeding and behavioral disorders, learning disabilities, and cleft anomalies (2) Disorders of the skeleton can affect the limbs and the spine (20) Mental disorders are found in 30% of the adults with this deletion (17) Genetic Diagnosis Diagnosis of this microdeletion can be achieved by FISH technique or with microarray analysis FISH for 22q11.2 deletion must be specifically requested in addition to routine karyotyping when looking for this deletion The deleted region in this anomaly includes more than 40 genes, but one of these genes, namely the TBX1 gene, seems to be responsible for the cardiac and some other additional related anomalies Mutation in the TBX1 gene can explain the rare cases of a clinical suspicion of deletion 22q11.2, but with no microdeletion of chromosome 22 In an affected fetus or infant, the parental examination reveals in approximately 6% an affected parent with subtle signs of this syndrome with a 50% transmission to future offspring (19) Cardiac Findings Cardiac anomalies that are found in deletion 22q11.2 syndrome primarily include conotruncal anomalies, such as interrupted aortic arch, common arterial trunk, absent pulmonary valve syndrome, pulmonary atresia with ventricular septal defect, tetralogy of Fallot, and conoventricular septal defects (21–23) (see examples in corresponding chapters) The presence of a right aortic arch either isolated or in combination with a cardiac anomaly increases the risk of deletion 22q11.2 Other cardiac anomalies can be found but in less than 5% of cases Table 4.3 estimates the 22q11.2 deletion with various types of CHD Main Extracardiac Findings Once a cardiac anomaly is diagnosed prenatally, the additional demonstration of a hypoplastic or absent fetal thymus on an ultrasound examination increases the risk of an association with a deletion 22q11.2 (22, 23) The thymus is demonstrated in a transverse plane of the chest at the level of the upper sternum (three-vessel-trachea view) anterior to the three vessels (see Chapter 9) Thymic aplasia or hypoplasia may be suspected at this plane level Note that the presence of a thymus on ultrasound does not rule out a 22q11.2 deletion (23) Typical facies with bulbous nose, ear anomalies, polyhydramnios, skeletal findings including polydactyly, club foot, spinal anomalies (hemivertebra, spina bifida), renal anomalies, and others were reported (20, 24) Prenatal Reports Numerous reports on prenatal cardiac defects and features of deletion 22q11.2 in the fetus are available These reports highlight the cardiac defects found and the role of evaluating the thymus when deletion 22q11.2 is suspected Two recent studies report on the wide spectrum of anomalies in the fetus with DiGeorge on ultrasound and autopsy (20, 24) TABLE Estimated 22q11.2 Deletion Frequency in 4.3 Congenital Heart Defects Cardiac defect Estimated deletion frequency (%) Interrupted aortic arch 50–89 VSDs 10 With normal aortic archa With aortic arch anomalyb 45 Common arterial trunk 34–41 Tetralogy of Fallot (including pulmonary atresia with VSD and absent pulmonary valve syndrome) 10–40 Isolated aortic arch anomalies 24 Double outlet right ventricle 97.5th percentile), 19 fetuses in the case group with right deviation (cardiac axis, 2–3 mm) (Figs 18.14B, 18.17, and 18.18) They can be identified in the apical or transverse four-chamber views In such cases, the borders of the VSD commonly appear echogenic (Figs 18.17A and 18.18A), which can be an important hint in differentiating a true muscular VSD from artifact The majority of muscular VSDs are detected by the routine use of color Doppler (Figs 18.17 to 18.19) The shunt on color Doppler is typically bidirectional, and the most common location of VSDs is in the apical and midportion of the septum At many centers, muscular VSDs are the most common VSD type detected prenatally (19) The most common VSD detected on grayscale ultrasound is the perimembranous type, visualized in the five-chamber view The first clue to its presence is in the interruption of the continuity between the ventricular septum and the medial wall of the ascending aorta (Figs 18.20 and 18.21) When a perimembranous VSD is detected, detailed assessment of the great arteries is critical, given a strong association between perimembranous VSDs and conotruncal abnormalities (Table 18.2) Figure 18.17: Axial four-chamber views in gray scale (A) and color Doppler (B and C) in a fetus with a small muscular ventricular septal defect (VSD) in the middle part of the interventricular septum In A, the VSD is not clearly seen but suspected by the decrease in echogenicity of the septum (arrow) Color Doppler clearly demonstrates blood flow across the VSD in a bidirectional manner: from the left ventricle (LV) to the right ventricle (RV) in A and from the RV to the LV in B Figure 18.18: Axial four-chamber views in gray scale (A) and color (B) in a fetus with a muscular ventricular septal defect (VSD) Note that in A, the VSD is not visible Color Doppler in B demonstrates blood shunting (arrow) across the VSD thus confirming its presence LV, left ventricle; RV, right ventricle Color Doppler Large VSDs are detected on grayscale imaging at the level of the four- and fivechamber views When the VSD is small or when scanning is suboptimal, color Doppler can be of help in identifying the septal defect (Figs 18.17 to 18.19) When the insonating angle is perpendicular to the ventricular septum, motion and dropout artifacts are reduced and true shunting of blood is demonstrated at the septal defect level (Figs 18.17B,C and 18.18B) Despite near-equal ventricular pressures in the fetus, shunting across the septal defect occurs due to pressure changes during diastole and systole (Figs 18.17, 18.19, 18.21, and 18.22) Generally, shunting is bidirectional when interrogated with pulsed Doppler (Fig 18.22) unless a ventricular pressure gradient is present due to an outflow obstruction in one ventricle (e.g., left-to-right shunt in double outlet right ventricle or coarctation and right-to-left shunt in tetralogy of Fallot) Figure 18.19: Apical four-chamber views in color Doppler during systole (A) and diastole (B) in a fetus with two small muscular ventricular septal defects (VSDs) Color Doppler demonstrates left-to-right shunting in A (arrows) and right-to-left shunting in B (arrows) RV, right ventricle; LV, left ventricle Figure 18.20: Five-chamber view in a fetus with perimembranous ventricular septal defect (VSD) The ascending aorta (AO) is seen with an interruption in the septal-aortic continuity (arrow) at the VSD location LV, left ventricle; RV, right ventricle Early Gestation VSDs are generally too small to be reliably detected as isolated anomalies at 11 to 14 weeks’ gestation Caution should be made in diagnosing VSDs in early gestation given a significant false-positive diagnosis from echo dropout and color overlapping The presence of blood flow shunting across the VSD confirms its presence in early gestation (Fig 18.23) VSD can also be reliably demonstrated when it is associated with another cardiac anomaly or when the four-chamber view anatomy is abnormal (Fig 18.23) Figure 18.21: Five-chamber view in color Doppler in a fetus with perimembranous ventricular septal defect (VSD) Color Doppler shows the bidirectional blood shunting with left-to-right shunting during systole (Left figure) and right-to-left-shunting in diastole (Right figure) LV, left ventricle; RV, right ventricle; AO, aorta Figure 18.22: Color and pulsed Doppler in a fetus with a muscular ventricular septal defect (VSD) demonstrating bidirectional shunting on pulsed Doppler, confirming the presence of a VSD LV, left ventricle; RV, right ventricle Three-Dimensional Ultrasound Tomographic ultrasound imaging applied to a three-dimensional (3D) volume acquired at the level of the four-chamber view allows for the demonstration of the VSD in different adjacent planes of the septum rather than a single plane on conventional grayscale ultrasonography The orthogonal 3D display can be used in combination with color spatiotemporal image correlation (STIC) to demonstrate the presence of a VSD in all three planes, by placing the intersection dot on the shunting VSD (Fig 18.24) (20) The en face view of the interventricular septum in a 3D volume allows a direct view of the size of a large VSD on surface rendering (Fig 18.25) (21) as well as blood shunting when combined with color STIC (Fig 18.26) (22) Additional tools combined with STIC, such as Omniview (see Chapter 15), allow the selection of a section along the septum and the demonstration of shunting of VSD in color Doppler The recent introduction of electronic matrix probes allows for the use of biplane imaging in real time and in combination with color Doppler This approach confirms the presence of VSD by visualizing two orthogonal planes at the same time (Fig 18.27) Figure 18.23: The left figure represents a five-chamber view in a fetus with tetralogy of Fallot in early gestation Note the presence of a ventricular septal defect (VSD) The right figure represents a transverse four-chamber view in color Doppler at 12 weeks’ gestation in a different fetus with a muscular VSD Note the presence of blood flow across the VSD documented by color Doppler LV, left ventricle; RV, right ventricle; Ao, aorta Figure 18.24: Muscular ventricular septal defect (VSD) demonstrated in 3D ultrasound in orthogonal planes display The dot (shown in the circle) represents the intersection of the three planes The dot is placed on the VSD in A (transverse view at level of the four-chamber view) and is seen in B (short-axis view of the ventricles) and C (en face view of the interventricular septum) LV, left ventricle; RV, right ventricle Figure 18.25: Large perimembranous ventricular septal defect (VSD) shown in 3D ultrasound in the en face surface-rendering mode The 3D box is placed over the interventricular septum on 2D ultrasound as shown in A Surfacerendering mode shown in B demonstrates the VSD in an en face view from the right ventricle (RV) RA, right atrium Figure 18.26: 3D spatiotemporal image correlation (STIC) volume with color Doppler in surface-rendering mode showing a muscular ventricular septal defect (VSD) In A, the 3D box is placed over the interventricular septum (IVS) with the VSD seen on color Doppler In B and C, the VSD is imaged in surface view from the right ventricle (RV), showing left-to-right shunting (red color) in B and right-to-left shunting (blue color) in C LV, left ventricle Differential Diagnosis Dropout artifact, primarily in the perimembranous region of the septum, is a common false-positive diagnosis of VSD before 20 weeks’ gestation Harmonic and compound imaging designed to improve the grayscale image may result in reducing echo reflection from the thin perimembranous region and thus misdiagnose a VSD (see Chapters 7 and 11) The false-positive diagnosis of a VSD is more common in the apical approach to the ventricular septum The transverse approach to the septum and the use of sensitive color Doppler may be of help in confirming the diagnosis Figure 18.27: 4D ultrasound in biplane mode using an electronic matrix probe combined with color Doppler The muscular ventricular septal defect (VSD) is visualized in A and B simultaneously The orthogonal B-plane image shows the VSD shunting LV, left ventricle; RV, right ventricle Associated Cardiac and Extracardiac Findings Associated cardiac anomalies are common and are typically diagnosed prior to the diagnosis of the VSD When an apparently isolated large (>2–3 mm) VSD is detected in midgestation, careful attention should be given to the outflow tracts given a high association of VSD with conotruncal anomalies Table 18.2 summarizes the most common cardiac anomalies associated with VSD Extracardiac anomalies are associated with VSD and are not specific The association of an extracardiac abnormality with a VSD increases the risk of the presence of a syndrome or chromosomal aberration VSDs are the most common lesion in many chromosomal abnormalities, such as trisomies 21, 18, and 13 (10), and chromosomal abnormalities, such as trisomy 21, have been reported in more than 20% of fetuses with VSD, in association with major cardiac and extracardiac malformations (5, 19) In a large study involving 248 VSDs, of which 216 (87.1%) were muscular and 32 (12.9%) perimembranous, clinically relevant chromosomal anomalies were found in one (3.1%) perimembranous VSD compared with none in 216 muscular defects (17) Isolated muscular VSDs thus had a similar risk of chromosomal abnormalities to those of normal pregnancies (17, 19) Prognosis and Outcome The long-term outcome of fetuses with VSD is dependent on the size and location of the defect and the associated cardiac and extracardiac malformations Small muscular and perimembranous VSD detected by color Doppler have an excellent outcome and up to 80% close spontaneously before birth or by the first 2 years of life (10, 19, 23, 24) In a large study on isolated VSDs, spontaneous closure occurred prenatally in 5.2% of fetuses and postnatally in 76.3% of newborns who had an open VSD at birth (17) Closure was predicted by the size and location of VSDs (17) When a muscular VSD is diagnosed in the second trimester, the authors recommend follow-up in the third trimester to confirm its presence and to rule out additional small VSDs or other cardiac anomalies The prognosis is good for most patients with small VSDs (10) When the VSD is moderate or large, hemodynamic changes may necessitate surgical closure in order to reduce long-term morbidities Hemodynamic changes include left-toright shunting in the infant, which may lead to heart failure A perimembranous VSD is considered small when its diameter is