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Title: A Practical Guide to Fetal Echocardiography
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Begin Content
A Practical Guide to
Fetal Echocardiography
NORMAL AND ABNORMAL HEARTS
FOURTH EDITION
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Dedication
This book is dedicated in loving memory of
Zouheir Abuhamad
&
Nouhad Chaoui
Our parents whom we lost while preparing this 4th edition.
We owe our achievements and success to their unfailing lifelong direction, commitment, and sacrifices in our support.
Preface
It is with great pleasure that we bring to you this fourth edition of A Practical Guide to Fetal
Echocardiography: Normal and Abnormal Hearts , building on the great success of the third
edition, the winner of the 2016 Book of the Year Award by the British Medical Association. Big
thanks to our readers who complemented the third edition of this book and who informed us
consistently of the value that the book plays in their day-to-day practice. These statements were
indeed the primary stimulus that encouraged us to take on this daunting task of writing the fourth
edition and providing the most up-to-date and comprehensive reference on this subject.
We strived to ensure that this fourth edition is written in the same easy-to-read style and
illustrated with the most informative figures and schematic drawings. In order to maintain the
widely successful systematic, homogeneous, and methodical approach of the third edition of this
book, we chose again the difficult path of writing and illustrating this fourth edition in its entirety
without outside collaboration.
Now, how do we improve on an already very successful book? We did so by updating and
rewriting almost all chapters with the most up-to-date references; expanding the content from 33
chapters in the third edition to 47 chapters in this fourth edition; adding numerous schematic
drawings and ultrasound figures to illustrate key ultrasound findings; and including a highly
clinically relevant flow chart section that accompanies each chapter on cardiac malformation,
showing the step-by-step Approach to Diagnosis . We are hopeful that the readers will find these
31 new flow charts on the Approach to Diagnosis as highly useful aids in the ultrasound
diagnosis of complex cardiac malformations.
Overall, the book is divided into three main sections. Section one covers the general aspects
of fetal cardiac malformations with 4 chapters on epidemiology, genetic aspects of cardiac
malformations, cardiac embryology, and anatomy. Section two is composed of 14 chapters on
the guidelines for cardiac screening and echocardiography; the technical aspects of the fetal
cardiac examination; the detailed sonographic anatomy of the heart, great vessels, and venous
systems; and cardiac function. Section three includes 29 chapters on fetal cardiac malformations,
presented in a uniform format that includes the definition, spectrum of disease and incidence, the
use of grayscale, color Doppler, three-dimensional, and early gestation ultrasound in the
diagnosis of each cardiac abnormality, followed by the differential diagnosis, prognosis,
outcome, and Approach to Diagnosis . 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 fourth
edition 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.
We did most of the writing for this book during the COVID-19 pandemic and thus cannot but
reflect on the impact that the pandemic had on the world and on the millions of people who died
or were severely harmed from it. We stand in awe of the thousands of healthcare workers who
worked tirelessly and endangered their lives to support others. They are indeed our true heroes.
We owe many thanks to those who helped to support us in this endeavor. First and foremost,
our families who unselfishly allowed us to spend long evenings and most 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 cooperation
throughout the years, and the professional editorial and production teams at Wolters Kluwer.
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 believed in us, gave us our ultrasound roots, and provided long-lasting mentorship and
guidance. Finally, we sincerely hope that this fourth edition of A Practical Guide to Fetal
Echocardiography: Normal and Abnormal Hearts becomes your daily companion in the
ultrasound suite, providing you with the knowledge and necessary tools to expand your abilities
in screening for and diagnosing abnormal fetal cardiac conditions.
Alfred Abuhamad, MD
Rabih Chaoui, MD
Contents
SECTION one General Aspects
CHAPTER 1 •
CHAPTER 2 •
CHAPTER 3 •
CHAPTER 4 •
Epidemiology of Congenital Heart Disease
Genetic Aspects of Congenital Heart Disease
Embryology of the Heart
Cardiac Anatomy
SECTION two Technical Aspects
CHAPTER 5 •
CHAPTER 6 •
CHAPTER 7 •
CHAPTER 8 •
CHAPTER 9 •
CHAPTER 10 •
CHAPTER 11 •
CHAPTER 12 •
CHAPTER 13 •
CHAPTER 14 •
CHAPTER 15 •
CHAPTER 16 •
CHAPTER 17 •
CHAPTER 18 •
Guidelines for Fetal Cardiac Imaging
Fetal Situs
The Cardiac Chambers
The Great Vessels
The Three-Vessel-Trachea View
The Venous System
Fetal Heart in Early Gestation
Grayscale in Fetal Cardiac Imaging
Color Doppler in Fetal Cardiac Imaging
Spectral Doppler in Fetal Cardiac Imaging
M-Mode in Fetal Cardiac Imaging
Three- and Four-Dimensional Ultrasound in Fetal Cardiac Imaging
Biometry in Fetal Cardiac Imaging
Fetal Cardiac Function
SECTION three The Abnormal Heart
CHAPTER 19 • Atrial Septal Defects
CHAPTER 20 • Ventricular Septal Defects
CHAPTER 21 • Atrioventricular Septal Defects
CHAPTER 22 •
CHAPTER 23 •
CHAPTER 24 •
CHAPTER 25 •
CHAPTER 26 •
CHAPTER 27 •
CHAPTER 28 •
CHAPTER 29 •
CHAPTER 30 •
CHAPTER 31 •
CHAPTER 32 •
CHAPTER 33 •
CHAPTER 34 •
CHAPTER 35 •
CHAPTER 36 •
CHAPTER 37 •
CHAPTER 38 •
CHAPTER 39 •
CHAPTER 40 •
CHAPTER 41 •
CHAPTER 42 •
CHAPTER 43 •
CHAPTER 44 •
CHAPTER 45 •
CHAPTER 46 •
CHAPTER 47 •
Double Inlet Ventricle
Tricuspid Atresia
Ebstein Anomaly and Tricuspid Valve Dysplasia
Tricuspid Valve Regurgitation
Pulmonary Stenosis
Pulmonary Atresia with Intact Ventricular Septum
Tetralogy of Fallot
Pulmonary Atresia with Ventricular Septal Defect
Absent Pulmonary Valve Syndrome
Aortic Stenosis and Bicuspid Aortic Valve
Hypoplastic Left Heart Syndrome and Critical Aortic Stenosis
Coarctation of the Aorta
Interrupted Aortic Arch
Common Arterial Trunk
Double-Outlet Right Ventricle
Transposition of the Great Arteries
Corrected Transposition of the Great Arteries
Right Aortic Arch, Double Aortic Arch, and Aberrant Subclavian Artery
Abnormal Fetal Heart Position
Fetal Heterotaxy Syndrome
Anomalies of Systemic Venous Connections
Anomalies of Pulmonary Venous Connections
Fetal Cardiomyopathies
Fetal Cardiac Tumors
Fetal Arrhythmias
Rare Cardiac Anomalies
APPENDIX •
INDEX
Graph Legends
S E C T I O N
o n e
General Aspects
CHAPTER 1 • Epidemiology of Congenital Heart Disease
CHAPTER 2 • Genetic Aspects of Congenital Heart Disease
CHAPTER 3 • Embryology of the Heart
CHAPTER 4 • Cardiac Anatomy
C H A P T E R
1
Epidemiology of Congenital Heart Disease
INCIDENCE OF CONGENITAL HEART DISEASE
Congenital heart disease (CHD) is the most common severe congenital abnormality ( 1 ) as it
accounts for over half of 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 as both patent ductus arteriosus and ventricular septal defects are
common in premature infants. A representative incidence of CHD of 8 to 9 per 1000 live births
has been reported in large population studies ( 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 1000
live births ( 3 ). Furthermore, accounting for subtle anomalies such as persistent left superior
vena cava (5-10 per 1000 live births) and isolated aneurysm of the atrial septum (5-10 per 1000
live births) results in an overall incidence of CHD approaching 50 per 1000 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 and include
fetal and parental risk factors, which are discussed in detail in the following sections.
Table 1.1 • Types and Incidence of Human Congenital Heart Disease
Defect
Incidence per 1000 live births
VSD
3.570
PDA
0.799
ASD
0.941
AVSD
0.348
PS
0.729
AS
0.401
CoA
0.409
TOF
0.421
D-TGA
0.315
HRH
0.222
Tricuspid atresia
0.079
Ebstein anomaly
0.114
Pulmonary atresia
0.132
HLH
0.266
Truncus
0.107
DORV
0.157
SV
0.106
TAPVC
0.094
AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; CoA, coarctation of the aorta; DTGA, complete transposition of the great arteries; DORV, double-outlet right ventricle; HLH, hypoplastic left heart;
HRH, hypoplastic right heart; PDA, patent ductus arteriosus; PS, pulmonary stenosis; SV, single ventricle; TAPVC,
total anomalous pulmonary venous connection; TOF, tetralogy of Fallot; VSD, ventricular septal defect.
Modified from Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol . 2002;39:18901900, with permission from Elsevier.
RISK FACTORS FOR CHD
Fetal and parental risk factors and fetal echocardiography indications are determined when the
risk of CHD is elevated above that of the general population, taking into account the level of
risk, regional resources, and the availability of expert fetal echocardiographers. It is important to
note, however, that most cases of CHD are suspected on the fetal anatomic survey and in the
absence of apparent risk factors. When an abnormal fetal heart is suspected at the time of a basic
or detailed anatomic ultrasound examination, referral for fetal echocardiography is warranted as
the risk for CHD is increased in such setting. Fetal and parental risk factors for CHD are
discussed in detail in the following sections, and indications for fetal echocardiography and
detailed cardiac screening are shown in Tables 1.2 to 1.6 .
Table 1.2 • Fetal Factors in Which Fetal Echocardiography Is Indicated
Suspected cardiac structural anomaly
Suspected abnormality in cardiac function
Hydrops fetalis
Persistent fetal tachycardia (heart rate >180 beats/min)
Persistent fetal bradycardia (heart rate <120 beats/min) or a suspected heart block
Frequent episodes of a persistently irregular cardiac rhythm
Major fetal extracardiac anomaly
Nuchal translucency of 3.5 mm or greater or at or above the 99th percentile for
gestational age
Chromosomal abnormality by invasive genetic testing or with cell-free fetal DNA
screening
Monochorionic twinning
Modified from AIUM practice parameters for the performance of fetal echocardiography. J Ultrasound Med .
2020;39:E5-E16.
Table 1.3 • Fetal Factors in Which Fetal Echocardiography May Be Considered
Systemic venous anomaly (e.g., a persistent right umbilical vein, left superior vena
cava, or absent ductus venosus)
Greater-than-normal nuchal translucency measurement between 3.0 and 3.4 mm
Modified from AIUM practice parameters for the performance of fetal echocardiography. J Ultrasound Med .
2020;39:E5-E16.
Table 1.4 • Maternal/Familial Disease or Maternal Environmental Exposure Factors in Which Fetal
Echocardiography Is Indicated
Pregestational diabetes regardless of the hemoglobin A1c level
Gestational diabetes diagnosed in the first or early second trimester
In vitro fertilization, including intracytoplasmic sperm injection
Phenylketonuria (unknown status or a periconceptional phenylalanine level >10
mg/dL)
Autoimmune disease with anti-Sjögren syndrome–related antigen A antibodies and
with a prior affected fetus
First-degree relative of a fetus with congenital heart disease (parents, siblings, or
prior pregnancy)
First- or second-degree relative with disease of Mendelian inheritance and a
history of childhood cardiac manifestations
Retinoid exposure
First-trimester rubella infection
Modified from AIUM practice parameters for the performance of fetal echocardiography. J Ultrasound Med .
2020;39:E5-E16.
Table 1.5 • Maternal/Familial Disease or Maternal Environmental Exposure Factors in Which Fetal
Echocardiography May Be Considered
Selected teratogen exposure (e.g., paroxetine, carbamazepine, or lithium)
Antihypertensive medication limited to angiotensin-converting enzyme inhibitors
Autoimmune disease with Sjögren syndrome–related antigen A positivity and without
a prior affected fetus
Second-degree relative of a fetus with congenital heart disease
Modified from AIUM practice parameters for the performance of fetal echocardiography. J Ultrasound Med .
2020;39:E5-E16.
Table 1.6 • Maternal and Fetal Factors in Which a Detailed Second Trimester Ultrasound Examination Is
Indicated
Obesity (body mass index ≥ 30 kg/m 2 )
Selective serotonin reuptake inhibitor antidepressant exposure other than
paroxetine
Noncardiac “soft marker” for aneuploidy in the absence of karyotype information
Abnormal maternal serum analytes (e.g., α-fetoprotein level)
Isolated single umbilical artery
Gestational diabetes diagnosed after the second trimester
Warfarin exposure
Alcohol exposure
Echogenic intracardiac focus
Maternal fever or viral infection with seroconversion only
Isolated congenital heart disease in a relative further removed from second degree
to the fetus
Modified from AIUM practice parameters for the performance of fetal echocardiography. J Ultrasound Med .
2020;39:E5-E16.
FETAL RISK FACTORS AND INDICATIONS OF
ECHOCARDIOGRAPHY
Extracardiac Anatomic Abnormalities
The presence of a major extracardiac anatomic abnormality in a fetus is frequently associated
with CHD and is thus an indication for fetal echocardiography ( Table 1.2 ). 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 and thus
is an indication for fetal echocardiography ( Table 1.2 ). Incidence of abnormal cardiac anatomy
is reported in about 10% to 20% of fetuses with nonimmune hydrops ( 8 , 9 ).
The presence of a persistent left superior vena cava is associated with an increased risk for
associated cardiac and extracardiac abnormalities and thus fetal echocardiography may be
considered in such cases ( Table 1.3 ) ( 10 ). Other systemic venous anomalies such as a
persistent right umbilical vein or absent ductus venosus have also been shown to be associated
with a coexisting cardiac malformation, and therefore consideration should be given to fetal
echocardiography in such cases ( Table 1.3 ) ( 11 ).
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 ( 12 , 13 ). A
fetal echocardiogram should be performed in all fetuses with persistent fetal tachycardia (heart
rate >180 beats/min), persistent fetal bradycardia (heart rate <120 beats/min), or suspected heart
block in order to assess cardiac structure and function ( Table 1.2 ). The presence of frequent
episodes or a persistent pattern of irregular fetal rhythm, such as that caused by frequent
extrasystoles, is also an indication for fetal echocardiography, as this may be the harbinger of
more malignant arrhythmias if it is persistent ( Table 1.2 ) ( 14 ). In fetuses with less frequent
extrasystoles, a fetal echocardiogram is reasonable to perform, especially if the ectopic beats
persist beyond 1 to 2 weeks ( 15 ).
In pregnancies with autoimmune disease with anti-Sjögren syndrome–related antigen A
antibodies and with a prior affected fetus, fetal echocardiography is indicated given the increased
risk of fetal rhythm abnormalities ( Table 1.4 ). Fetal echocardiography may be indicated in the
presence of Sjögren syndrome–related antigen A positivity and without a prior affected fetus (
Table 1.5 ). Sjögren syndrome–related antigen B positivity is not an indication for fetal
echocardiography given the absence of associated fetal risk.
Diagnosis and management of fetal cardiac rhythm disturbances are discussed in detail in
Chapter 46 .
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 (
Table 1.2 ). 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 mothers 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 ( 16 - 19 ). The value of routine ultrasound in the
screening for CHD is discussed in Chapter 5 .
Known or Suspected Chromosomal or Genetic Abnormality
The presence of a fetal genetic or chromosomal abnormality by invasive genetic testing or with
cell-free DNA testing is associated with a high risk for cardiac and extracardiac defects and thus
a fetal echocardiogram is indicated ( Table 1.2 ). Please refer to Chapter 2 on the genetics of
CHD for a more comprehensive discussion on the 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 for fetal chromosomal abnormalities. Several reports have noted an association
between increased NT and genetic syndromes and major fetal malformations including cardiac
defects ( 20 - 23 ). The prevalence of major cardiac defects increases exponentially with fetal NT
thickness, without an obvious predilection to a specific type of CHD ( 21 ). An NT thickness of
greater than or equal to 3.5 mm or at or above the 99th percentile for gestational age in a
chromosomally normal fetus has been correlated with an increased risk of CHD, that is, higher
than pregnancies with a family history of CHD ( 20 , 21 , 23 , 24 ). In this setting of an NT that is
greater than or equal to 3.5 mm or at or above the 99th percentile for gestational age, referral for
fetal echocardiography is thus warranted ( Table 1.2 ), and this may also lead to an earlier
diagnosis of all major types of CHD ( 25 ). When the NT is increased and measures between 3.0
and 3.4 mm, fetal echocardiography may be considered in this setting given an increased risk of
CHD above the background population risk ( Table 1.3 ). Chapter 11 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 increased ( 26 , 27 ) and is
estimated at 2% to 9% ( 26 , 28 , 29 ). 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 to include right ventricular outflow tract
obstruction, which occurs in about 10% of recipient twin fetuses ( 30 ). The increased risk of
CHD in fetuses of monochorionic placentation is noted even after excluding cardiac effects of
TTTS ( 27 ). 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% ( 27 ). This risk was 7% for monochorionic–
diamniotic twins and 57.1% for at least one twin member of monochorionic–monoamniotic
twins ( 27 ). If one twin member is affected, the risk that the other twin member is also affected
is 26.7% ( 27 ). A systemic literature review of 830 fetuses from monochorionic–diamniotic twin
pregnancies confirmed an increased risk for CHD independent of TTTS ( 26 ). 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 ( 26 , 31 ). Fetal echocardiogram is therefore recommended in all monochorionic twin
gestations ( Table 1.2 ).
PARENTAL RISK FACTORS AND INDICATIONS OF
ECHOCARDIOGRAPHY
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 when
compared to 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 ( 32 ). Poor glycemic control in the first trimester of gestation, as
evidenced by an elevated glycohemoglobin (HbA1c) level, has been strongly correlated with an
increased risk of structural defects in infants of diabetic mothers ( 33 , 34 ). Although some
studies have identified a level of HbA1c above which the risk for fetal structural abnormalities is
increased ( 33 ), other studies have failed to identify a critical level of HbA1c that provides an
optimal predictive power for CHD screening ( 35 ). 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 is
indicated in all women with pregestational diabetes mellitus ( Table 1.4 ). Gestational diabetes
diagnosed in the first and early second trimesters of pregnancy is also an indication for fetal
echocardiography, as the presence of hyperglycemia during organogenesis cannot be ruled out (
Table 1.4 ). Gestational diabetes, which is diagnosed beyond the first or early second 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. Consideration should be
given for fetal echocardiogram in the third trimester to assess for ventricular hypertrophy for
pregestational and gestational diabetic pregnancies with elevated HbA1c in the second trimester
of pregnancy ( 36 ).
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 ( 37 ). 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 (
38 ). Other fetal abnormalities in phenylketonurics include microcephaly and growth restriction (
37 ). The risk for CHD in fetuses has been reported to be 12% if maternal dietary control is not
achieved by 10 weeks of gestation ( 39 ). With maternal phenylalanine levels at <6 mg/dL before
conception and during early organogenesis, the risk of CHD was noted to be no different than
that for controls in a large prospective study ( 40 ). Unless you have evidence of strict dietary
control in the periconceptional period with phenylalanine levels at <10 mg/dL, fetal
echocardiogram is recommended in phenylketonurics ( 15 ).
Pregnancies of Assisted Reproductive Technology
Infants born to pregnancies of assisted reproductive technology are more likely to be born
preterm, of low birth weight, and small for gestational age ( 41 ). This increased neonatal
morbidity applies to multiple and singleton births ( 42 ). The evidence relating to the risk of birth
defects is somewhat less clear. A report of systematically reviewed and pooled epidemiologic
data assessing the risk of birth defects suggests a 30% to 40% increase following assisted
reproductive technologies (in vitro fertilization [IVF] and/or intracytoplasmic sperm injection
[ICSI]) ( 43 ). Another population-based study on congenital malformations in children born
after IVF with matched controls noted a fourfold increase in CHD in the IVF population, with
the majority of cardiac anomalies representing atrial and ventricular septal defects ( 44 ). This
same rate of fourfold increase in CHD was also noted in pregnancies conceived through ICSI (
45 ). In a recent systematic review and meta-analysis of 41 studies including both singleton and
multiple gestations, total CHD events were noted in 1.30% of IVF/ICSI pregnancies as compared
to 0.68% in the spontaneous conception group, with a pooled odds ratio (OR) of 1.45 (95%
confidence interval [CI], 1.20-1.76) ( 46 ). In a recent cross-sectional analysis of live births in the
United States from 2011 to 2014, an increased risk of cyanotic CHD was noted for infants
conceived after all forms of infertility treatment when compared to natural conceptions ( 47 ).
Cyanotic CHD prevalence in assisted reproductive technology fertility treatments (IVF, ICSI),
nonassisted reproductive technology fertility treatments (medical treatment and intrauterine
insemination), and natural conception groups were 0.39%, 0.26% and 0.08%, respectively ( 47 ).
In view of these findings, fetal echocardiogram is currently indicated in pregnancies of
assisted reproductive technologies ( Table 1.3 ).
Familial Cardiac Disease
The risk of recurrence of CHD is increased in the presence of nonsyndromic or nonchromosomal
CHD in the family. It is twofold higher if the mother is affected versus a sibling or a father ( 48 ,
49 ). For the majority of maternal CHD, the risk of recurrence is in the range of 3% to 7%; for an
affected sibling, the risk of recurrence is at 2% to 6%; and for paternal CHD, the risk of
recurrence is at 2% to 3% ( 50 - 52 ). There is an increased risk, however, with some specific
cardiac malformations such as aortic stenosis or AV septal defect ( 48 , 52 ). Overall, the risk of
recurrence is low with isolated CHD in second- or third-degree relatives. The genetic aspect of
CHD is discussed in more detail in Chapter 2 . Fetal echocardiogram is indicated in the presence
of first-degree relative of a fetus with CHD (parents, siblings, or prior pregnancy) or first- or
second-degree relative with disease of Mendelian inheritance and a history of childhood cardiac
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manifestations ( Table 1.3 ). Fetal echocardiography may be considered in the presence of CHD
in a second-degree relative of a fetus ( Table 1.4 ).
Maternal Teratogen Exposure (Drug-Related CHD)
The effects of maternal exposure to drugs during cardiogenesis have been widely studied.
Numerous drugs have been implicated as cardiac teratogens. Evidence suggests that the overall
contribution of teratogens to CHD is small ( 53 ). Details on various maternal medication
exposures and associations with CHD are discussed in the following sections.
Lithium
Initial retrospective reports regarding the teratogenic risk of lithium treatment in pregnancy
showed a strong association between lithium use and Ebstein anomaly in the fetus ( 54 ). More
recent controlled studies, however, have consistently reported a lower risk for CHD in exposed
fetuses. Four case–control studies of Ebstein anomaly involving a total of 208 affected children
found no association with maternal lithium intake in pregnancy ( 55 - 57 ). A cohort study on the
effect of lithium exposure in pregnancy showed no significant risk to the fetus ( 58 ). These
findings suggest that the teratogenic risk of lithium exposure is significantly lower than
previously reported, and that the risk/benefit ratio of prescribing lithium in pregnancy should be
evaluated in light of this modified risk estimate. Fetal echocardiogram may be considered in
pregnancies exposed to lithium during embryogenesis, although its usefulness has not been
established given a very low likelihood of CHD ( Tables 1.5 and 1.6 ).
Anticonvulsants
Anticonvulsants, a class of drugs that includes hydantoin/phenytoin, carbamazepine,
trimethadione, and sodium valproate, among others, are occasionally used in the treatment of
epilepsy or pain management in pregnancy. An incidence of congenital defects varying from
2.2% to 26.1% has been noted in pregnancies exposed to phenytoin ( 59 ). Some evidence
suggests that the teratogenic effect of phenytoin is related to elevated amniotic fluid levels of
oxidative metabolites secondary to low activity of the clearing enzyme epoxide hydrolase ( 60 ).
A fetal hydantoin syndrome consisting of variable degrees of hypoplasia and ossification of
distal phalanges and craniofacial abnormalities has been described ( 61 ). CHD is often observed
in conjunction with this syndrome ( 62 ). Trimethadione, an anticonvulsant primarily used in the
treatment of petit mal seizures, is associated with a high incidence of congenital defects. Defects
include craniofacial deformities, growth abnormalities, mental retardation, limb abnormalities,
and genitourinary abnormalities ( 62 ). Cardiac abnormalities are common, with septal defects
occurring in about 20% of exposed fetuses ( 62 ). Sodium valproate has also been associated
with congenital defects, with the most serious abnormality being neural tube defects (1%-2%) (
62 ). Although some reports have suggested an increased risk of CHD in fetuses exposed to
valproate ( 63 ), others could not establish a causal relationship ( 64 ). Carbamazepine has been
associated with 1.8% risk for CHD in one study when compared to controls ( 65 ).
In a study of a large primary care database including 258,591 singleton live-born children of
mothers aged 15 to 44 years from 1990 to 2013, anticonvulsant exposure of mothers in the first
trimester of pregnancy was associated with a twofold increased risk of major congenital
anomalies compared to those unexposed, with the highest system-specific risks for heart
anomalies (adjusted OR 2.49, 1.47-4.21) ( 66 ). Compared with children of mothers without
anticonvulsant exposures, the adjusted ORs of overall congenital malformations were
statistically significant for valproate (2.63, 95% CI 1.46-4.73), lamotrigine (2.01, 1.12-3.59), and
other older anticonvulsants (2.67, 1.18-6.04) but not for carbamazepine (1.58, 0.86-2.89) and
other newer anticonvulsants (1.44, 0.57-3.65) ( 66 ). The study also found no evidence that
periconceptional high-dose folic acid, as was prescribed in this population, reduced the
malformation risk associated with anticonvulsants, although this may reflect late prescribing or
selective prescribing to women with severe conditions. The risk was not increased for
anticonvulsant exposure later in pregnancy ( 66 ).
In view of these findings, there appears to be a link between some anticonvulsant use in the
first trimester and an increased risk of CHD. Fetal echocardiogram may therefore be considered
in pregnancies exposed to anticonvulsants in early gestation ( Table 1.5 ).
Alcohol
The fetal alcohol syndrome, consisting of facial abnormalities, growth restriction, mental
retardation, and cardiac abnormalities, has been well described in women consuming heavy
amounts of alcohol in pregnancy ( 67 ). Cardioteratogenic effects of ethanol in the chick embryo
have been confirmed in concentrations comparable to human blood alcohol levels ( 68 ). CHD
has been identified in 25% to 30% of infants with fetal alcohol syndrome, with septal defects
representing the most common lesions ( 67 , 69 ). Fetal echocardiogram is recommended for
pregnancies with suspected fetal alcohol syndrome.
There have been conflicting results regarding maternal regular alcohol consumption before
and during pregnancy and the risk of CHD. The summary of 23 studies related to this topic
indicated an overall pooled relative risk of 1.13 (95% CI: 0.96, 1.29) among mothers drinking
before or during pregnancy with statistically significant heterogeneity in the data ( 70 ). This
meta-analysis provided no positive association between maternal alcohol consumption and the
risk of CHD ( 70 ), and therefore, a detailed ultrasound examination rather than fetal
echocardiography is indicated in this setting ( Table 1.6 ).
Retinoic Acid
Retinoic acid is a vitamin A derivative prescribed for the treatment of severe cystic acne. Since
its introduction, several reports have appeared in the literature describing the teratogenic effect of
this medication. A characteristic pattern of malformations is observed, which includes central
nervous system, craniofacial, branchial arch, and cardiovascular abnormalities ( 71 ). Cardiac
abnormalities are usually conotruncal defects and aortic arch abnormalities ( 62 , 72 ). The
mechanism of teratogenicity is probably related to free radical generation by metabolism with
prostaglandin synthase ( 73 ). Fetal echocardiogram is recommended for exposure to retinoic
acid in pregnancy ( Table 1.4 ).
Nonsteroidal Anti-inflammatory Agents
Nonsteroidal anti-inflammatory agents (NSAIDs) are used in the treatment of preterm labor or in
pain control in pregnancy. Indomethacin is an NSAID that is commonly used for tocolysis in the
second and third trimesters of pregnancy. In the fetus, indomethacin therapy may lead to
premature constriction of the ductus arteriosus. Doppler evidence of ductal constriction is
evident in up to 50% of fetuses exposed to indomethacin in late second and third trimesters of
pregnancy ( 74 , 75 ). Typically, the ductal constriction is mild and resolves with drug
discontinuation. Ductal constriction may also occur with the use of other NSAIDs ( 76 ). Several
neonatal complications, which appear to be limited to indomethacin exposure beyond 32 weeks
of gestation, include oliguria, necrotizing enterocolitis, and intracranial hemorrhage ( 77 ).
Cardiovascular complications include a higher risk for patent ductus arteriosus requiring surgical
ligation in indomethacin-exposed infants ( 77 ). Therefore, fetal echocardiogram is recommended
with extended NSAID use in the late second or third trimester of pregnancy.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme inhibitors (ACE inhibitors) are commonly used antihypertensive
medications. Fetal exposure to ACE inhibitors in the first trimester of pregnancy has been
associated with an increased risk of major congenital malformation that was 2.7 times greater
than the background risk or the risk of fetuses exposed to other antihypertensive medications ( 78
). The increase in major malformations primarily affects the cardiovascular (risk ratio, 3.72) and
central nervous systems (risk ratio, 4.39) ( 78 ). Atrial and ventricular septal defects represent the
most common cardiac abnormalities ( 78 ). Fetal exposure to ACE inhibitors in the second and
third trimesters of pregnancy is associated with “ACE inhibitor fetopathy,” which includes
oligohydramnios, intrauterine growth restriction, hypocalvaria, renal failure, and death ( 79 ).
Fetal echocardiogram may be considered for pregnancies exposed to ACE inhibitors ( Table 1.5
).
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) represent a class of antidepressants that has
gained wide acceptance for the treatment of depression and anxiety during pregnancy ( 80 ).
Specific SSRI medications include citalopram (Celexa), fluoxetine (Prozac), paroxetine (Paxil),
and sertraline (Zoloft). Pregnancies exposed to SSRIs in the first trimester have shown an
increased risk of congenital heart defects in some studies ( 81 - 83 ). Paroxetine has been singled
out as the SSRI with the greatest association with congenital heart malformations, primarily
atrial and ventricular septal defects ( 83 ). A meta-analysis of seven studies noted a significant
overall increased risk of 74% for cardiac malformations in women exposed to paroxetine in the
first trimester of pregnancy ( 84 ).
Large population studies have provided conflicting information with regard to the association
of other SSRIs with CHD. The risk of major CHD among infants born to women who took
antidepressants during the first trimester was compared to the risk among infants born to women
who did not use antidepressants in a large cohort of 949,504 pregnant women from Medicaid
data for the period of 2000 through 2007 ( 85 ). When the data were fully adjusted for
confounding variables, no substantial increase in the risk of cardiac malformations attributable to
antidepressant use during the first trimester was noted.
SSRI exposure after the 20th week of gestation has been associated with an increased risk of
persistent pulmonary hypertension of the newborn (PPHN) ( 86 ). PPHN occurs in 1 to 2 per
1000 live births and is associated with increased morbidity and mortality. SSRI exposure
increases this risk to about 6 to 12 per 1000 neonates, a sixfold increase over the background risk
( 86 ). Possible mechanisms of action include an accumulation of serotonin in the lung in
exposed fetuses ( 87 ). Serotonin has vasoconstrictor properties and a mitogenic effect on
pulmonary smooth muscle cells, which may result in the proliferation of smooth muscle cells, the
characteristic histologic pattern in PPHN ( 88 , 89 ).
In general, in women suffering from major depression and responding to a pharmacologic
treatment, introduction or continuation of an SSRI should be encouraged in order to prevent
maternal complications and to preserve maternal–infant bonding ( 90 ). Overall, it should be
recognized that the specific defects implicated are rare and the absolute risks are small ( 91 , 92 ).
Given the more consistent association of paroxetine use in the first trimester and CHD,
performing a fetal echocardiogram may be indicated in pregnant women exposed to paroxetine
in early gestation.
Maternal Obesity
The prevalence of obesity, which is defined as a body mass index (BMI) greater than or equal to
30 kg/m 2 , is increasing at an exponential rate. An established association between neural tube
defects and prepregnancy maternal obesity exists ( 55 ). Several studies have noted an increased
risk of congenital heart defects in obese pregnant mothers when compared to average-weight
mothers ( 93 , 94 ). This increased risk is relatively small: 1.18-fold for the obese mother and
1.40-fold for the morbidly obese mother (BMI > 35 kg/m 2 ). Atrial and ventricular septal defects
contribute to the majority of this increased risk ( 94 ). Given the small increased risk of CHD in
obese pregnant women, performing detailed cardiac screening rather than fetal echocardiogram
is considered reasonable ( Table 1.6 ).
PREVENTION OF CHD
Current evidence suggests that folic acid supplementation taken preconceptionally significantly
reduces the risk of CHD ( 95 - 98 ). Analysis of a randomized controlled trial evaluating the
efficacy of 0.8 mg of folic acid showed a 50% reduction in risk for a range of cardiac
malformations ( 95 ). Other studies have shown a significant reduction in conotruncal
abnormalities in newborns of pregnant women who took folic acid prenatally ( 96 , 97 ).
The mechanism of action of the effect of folic acid on the reduction in the risk of cardiac
malformations has not been elucidated. Methylenetetrahydrofolate reductase (MTHFR) enzyme
activity may be involved in this process ( 99 ). An association exists between homocysteine
elevations, MTHFR gene variants, and CHD ( 99 - 101 ). In a controlled study, fasting
homocysteine levels have been shown to be higher in mothers of infants affected by CHD ( 95 ).
Current data support folic acid as the active ingredient involved in fetal cardiac embryogenesis
and that periconceptional folic acid use may reduce the risk for congenital cardiac
malformations.
KEY POINTS ■ Epidemiology of CHD
The incidence of CHD is around 8 to 9 per 1000 live births. The overall incidence of CHD may be in the order
of 50 per 1000 live births if all subtle cardiac anomalies are counted including bicuspid aortic valve,
aneurysm of the atrial septum, and persistent superior vena cava.
The presence of extracardiac abnormalities in a fetus is frequently associated with CHD even in the
presence of normal karyotype.
The incidence of CHD is reported in 10% to 20% of fetuses with nonimmune hydrops.
Complete heart block in a fetus is associated with CHD in about 50% of cases and the overall risk for CHD
with fetal arrhythmia is about 1%.
The suspicion for CHD during a routine ultrasound is a risk factor with the highest yield for CHD (40%-50%).
The presence of a fetal genetic or chromosomal abnormality is associated with a high risk for cardiac and
extracardiac defects.
Most infants born with CHD are born to pregnancies without risk factors.
An NT thickness that is greater than or equal to 3.5 mm or at or above the 99th percentile for gestational age
warrants referral for fetal echocardiography.
The incidence of CHD in fetuses of monochorionic placentation is increased and is estimated at 2% to 9%.
TTTS has been associated with acquired cardiac abnormalities to include right ventricular outflow tract
obstruction, which occurs in about 10% of recipient twin fetuses.
The incidence of CHD is fivefold higher in infants of pregestational diabetic mothers with a higher relative risk
for heterotaxy, truncus arteriosus, transposition of the great arteries, and single ventricle defects.
Gestational diabetes diagnosed in the first and early second trimesters of pregnancy is an indication for fetal
echocardiography.
Fetal ventricular hypertrophy in late gestation (third trimester) is a complication of poor glycemic control in
pregestational and gestational diabetic pregnancies.
Fetal echocardiogram in the third trimester to assess for ventricular hypertrophy is recommended for
pregestational and gestational diabetic pregnancies if the HbA1c is greater than 6% in the second trimester.
Fetal exposure in the first trimester to maternal phenylalanine levels exceeding 15 mg/dL is associated with a
10- to 15-fold increase in CHD.
The risk of lithium exposure to the fetus is lower than previously reported.
Paroxetine exposure during the first trimester of pregnancy confers significant risk of CHD to the fetus.
CHD has been identified in 25% to 30% of infants with fetal alcohol syndrome, with septal defects
representing the most common lesions.
ACE inhibitor exposure to the fetus in the first trimester results in an increased risk of CHD. Exposure in the
second and third trimesters results in “ACE inhibitor fetopathy.”
A fourfold increase in CHD is noted in fetuses of IVF pregnancies.
Fetuses of obese mothers have a relatively small increased risk for CHD.
The risk of recurrence of CHD is increased in the presence of nonsyndromic or nonchromosomal CHD in the
family.
Folic acid supplementation taken preconceptionally reduces the risk for CHD.
REFERENCES
1 . Hoffman JI, Christianson R. Congenital heart disease in a cohort of 19,502 births with long-term follow-up. Am J Cardiol.
1978;42:641-647.
2 . Yoon PW, Olney RS, Khoury MJ, Sappenfield WM, Chavez GF, Taylor D. Contribution of birth defects and genetic
diseases to pediatric hospitalizations. A population-based study. Arch Pediatr Adolesc Med. 1997;151:1096-1103.
3 . Ward C. Clinical significance of the bicuspid aortic valve. Heart. 2000; 83:81-85.
4 . Benson DW. The genetics of congenital heart disease: a point in the revolution. Cardiol Clin. 2002;20:385-394, vi.
5 . Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890-1900.
6 . Fogel M, Copel JA, Cullen MT, Hobbins JC, Kleinman CS. Congenital heart disease and fetal thoracoabdominal anomalies:
associations in utero and the importance of cytogenetic analysis. Am J Perinatol. 1991;8:411-416.
7 . 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;33:552559.
8 . Friedman AH, Copel JA, Kleinman CS. Fetal echocardiography and fetal cardiology: indications, diagnosis and
management. Semin Perinatol. 1993;17:76-88.
9 . Crawford DC, Chita SK, Allan LD. Prenatal detection of congenital heart disease: factors affecting obstetric management
and survival. Am J Obstet Gynecol. 1988;159:352-356.
10 .Gustapane S, Leombroni M, Khalil A, et al. Systematic review and meta-analysis of persistent left superior vena cava on
prenatal ultrasound: associated anomalies, diagnostic accuracy and postnatal outcome. Ultrasound Obstet Gynecol.
2016;48:701-708.
11 .Lide B, Lindsley W, Foster MJ, Hale R, Haeri S. Intrahepatic persistent right umbilical vein and associated outcomes: a
systematic review of the literature. J Ultrasound Med. 2016;35:1-5.
12 .Crawford D, Chapman M, Allan L. The assessment of persistent bradycardia in prenatal life. Br J Obstet Gynaecol.
1985;92:941-944.
13 .Schmidt KG, Ulmer HE, Silverman NH, Kleinman CS, Copel JA. Perinatal outcome of fetal complete atrioventricular
block: a multicenter experience. J Am Coll Cardiol. 1991;17:1360-1366.
14 .Copel JA, Liang RI, Demasio K, Ozeren S, Kleinman CS. The clinical significance of the irregular fetal heart rhythm. Am J
Obstet Gynecol. 2000;182:813-817; discussion 817-819.
15 .Donofrio MT, Moon-Grady AJ, Hornberger LK, et al.; American Heart Association Adults With Congenital Heart Disease
Joint Committee of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology Council on
Cardiovascular Surgery and Anesthesia, Council on Cardiovascular and Stroke Nursing. Diagnosis and treatment of fetal
cardiac disease: a scientific statement from the American Heart Association. Circulation. 2014;129:2183-2242.
16 .American Institute of Ultrasound in Medicine. AIUM practice guideline for the performance of fetal echocardiography. J
Ultrasound Med. 2013;32:1067-1082.
17 .International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), Carvalho JS, Allan LD, Chaoui R, et al. ISUOG
Practice Guidelines (updated): sonographic screening examination of the fetal heart. Ultrasound Obstet Gynecol.
2013;41:348-359.
18 .American Institute of Ultrasound in Medicine. AIUM practice guideline for the performance of obstetric ultrasound
examinations. J Ultrasound Med. 2013;32:1083-1101.
19 .American Institute of Ultrasound in Medicine. AIUM practice parameter for the performance of fetal echocardiography. J
Ultrasound Med. 2020;39:E5-E16.
20 .Nicolaides KH. Nuchal translucency and other first-trimester sonographic markers of chromosomal abnormalities. Am J
Obstet Gynecol. 2004;191:45-67.
21 .Clur SA, Ottenkamp J, Bilardo CM. The nuchal translucency and the fetal heart: a literature review. Prenat Diagn.
2009;29:739-748.
22 .Khalil A, Nicolaides KH. Fetal heart defects: potential and pitfalls of first-trimester detection. Semin Fetal Neonatal Med.
2013;18: 251-260.
23 .Jelliffe-Pawlowski LL, Norton ME, Shaw GM, et al. Risk of critical congenital heart defects by nuchal translucency norms.
Am J Obstet Gynecol. 2015;212:518, e511-510.
24 .Bahado-Singh RO, Wapner R, Thom E, et al.; First Trimester Maternal Serum B, Fetal Nuchal Translucency Screening
Study Group. Elevated first-trimester nuchal translucency increases the risk of congenital heart defects. Am J Obstet
Gynecol. 2005;192:1357-1361.
25 .Makrydimas G, Sotiriadis A, Huggon IC, et al. Nuchal translucency and fetal cardiac defects: a pooled analysis of major
fetal echocardiography centers. Am J Obstet Gynecol. 2005;192:89-95.
26 .Bahtiyar MO, Dulay AT, Weeks BP, Friedman AH, Copel JA. Prevalence of congenital heart defects in
monochorionic/diamniotic twin gestations: a systematic literature review. J Ultrasound Med. 2007;26: 1491-1498.
27 .Manning N, Archer N. A study to determine the incidence of structural congenital heart disease in monochorionic twins.
Prenat Diagn. 2006;26:1062-1064.
28 .Karatza AA, Wolfenden JL, Taylor MJ, Wee L, Fisk NM, Gardiner HM. Influence of twin-twin transfusion syndrome on
fetal cardiovascular structure and function: prospective case-control study of 136 monochorionic twin pregnancies. Heart.
2002;88:271-277.
29 .Lopriore E, Bokenkamp R, Rijlaarsdam M, Sueters M, Vandenbussche FP, Walther FJ. Congenital heart disease in twin-totwin transfusion syndrome treated with fetoscopic laser surgery. Congenit Heart Dis. 2007;2:38-43.
30 .Herberg U, Gross W, Bartmann P, Banek CS, Hecher K, Breuer J. Long term cardiac follow up of severe twin to twin
transfusion syndrome after intrauterine laser coagulation. Heart. 2006;92:95-100.
31 .Stagnati V, Chalouhi GE, Essaoui M, et al. Pulmonary stenosis in complicated monochorionic twin pregnancies: prevalence,
management and outcome. Prenat Diagn. 2015;35:1085-1092.
32 .Lisowski LA, Verheijen PM, Copel JA, et al. Congenital heart disease in pregnancies complicated by maternal diabetes
mellitus. An international clinical collaboration, literature review, and meta-analysis. Herz. 2010;35:19-26.
33 .Miller E, Hare JW, Cloherty JP, et al. Elevated maternal hemoglobin A1c in early pregnancy and major congenital
anomalies in infants of diabetic mothers. N Engl J Med. 1981;304:1331-1334.
34 .Ylinen K, Aula P, Stenman UH, Kesaniemi-Kuokkanen T, Teramo K. Risk of minor and major fetal malformations in
diabetics with high haemoglobin A1c values in early pregnancy. Br Med J (Clin Res Ed). 1984;289:345-346. 5
35 .Shields LE, Gan EA, Murphy HF, Sahn DJ, Moore TR. The prognostic value of hemoglobin A1c in predicting fetal heart
disease in diabetic pregnancies. Obstet Gynecol. 1993;81:954-957.
36 .Jaeggi ET, Fouron JC, Proulx F. Fetal cardiac performance in uncomplicated and well-controlled maternal type I diabetes.
Ultrasound Obstet Gynecol. 2001;17:311-315.
37 .Levy HL, Waisbren SE. Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. N Engl J
Med. 1983;309:1269-1274.
38 .Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of
untreated and treated pregnancies. N Engl J Med. 1980;303:1202-1208.
39 .Koch R, Friedman E, Azen C, et al. The International Collaborative Study of Maternal Phenylketonuria: status report 1998.
Eur J Pediatr. 2000;159(suppl 2):S156-S160.
40 .Platt LD, Koch R, Hanley WB, et al. The international study of pregnancy outcome in women with maternal
phenylketonuria: report of a 12-year study. Am J Obstet Gynecol. 2000;182:326-333.
41 .Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a metaanalysis. Obstet Gynecol. 2004;103:551-563.
42 .Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a
systematic review of controlled studies. BMJ. 2004;328:261.
43 .Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects—a
systematic review. Hum Reprod. 2005;20:328-338.
44 .Koivurova S, Hartikainen AL, Gissler M, Hemminki E, Sovio U, Jarvelin MR. Neonatal outcome and congenital
malformations in children born after in-vitro fertilization. Hum Reprod. 2002;17:1391-1398.
45 .Kurinczuk JJ, Bower C. Birth defects in infants conceived by intracytoplasmic sperm injection: an alternative interpretation.
BMJ. 1997;315:1260-1265; discussion 1265-1266.
46 .Giorgione V, Parazzini F, Fesslova V, et al. Congenital heart defects in IVF/ICSI pregnancy: systematic review and metaanalysis. Ultrasound Obstet Gynecol. 2018;51:33-42.
47 .Shamshirsaz AA, Bateni ZH, Sangi-Haghpeykar H, et al. Cyanotic congenital heart disease following fertility treatments in
the United States from 2011 to 2014. Heart. 2018;104:945-948.
48 .Burn J, Brennan P, Little J, et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of
British collaborative study. Lancet. 1998;351:311-316.
49 .Oyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PK, Melbye M. Recurrence of congenital heart defects in families.
Circulation. 2009;120:295-301.
50 .Gill HK, Splitt M, Sharland GK, Simpson JM. Patterns of recurrence of congenital heart disease: an analysis of 6,640
consecutive pregnancies evaluated by detailed fetal echocardiography. J Am Coll Cardiol. 2003;42:923-929.
51 .Nora JJ, Nora AH. Maternal transmission of congenital heart diseases: new recurrence risk figures and the questions of
cytoplasmic inheritance and vulnerability to teratogens. Am J Cardiol. 1987;59:459-463.
52 .Rose V, Gold RJ, Lindsay G, Allen M. A possible increase in the incidence of congenital heart defects among the offspring
of affected parents. J Am Coll Cardiol. 1985;6:376-382.
53 .Tikkanen J, Heinonen OP. Maternal exposure to chemical and physical factors during pregnancy and cardiovascular
malformations in the offspring. Teratology. 1991;43:591-600.
54 .Schou M, Goldfield MD, Weinstein MR, Villeneuve A. Lithium and pregnancy. I. Report from the Register of Lithium
Babies. Br Med J. 1973;2:135-136.
55 .Kallen K. Maternal smoking, body mass index, and neural tube defects. Am J Epidemiol. 1998;147:1103-1111.
56 .Sipek A. Lithium and Ebstein’s anomaly. Cor Vasa. 1989;31:149-156.
57 .Zalzstein E, Koren G, Einarson T, Freedom RM. A case-control study on the association between first trimester exposure to
lithium and Ebstein’s anomaly. Am J Cardiol. 1990;65:817-818.
58 .Jacobson SJ, Jones K, Johnson K, et al. Prospective multicentre study of pregnancy outcome after lithium exposure during
first trimester. Lancet. 1992;339:530-533.
59 .Hanson JW, Buehler BA. Fetal hydantoin syndrome: current status. J Pediatr. 1982;101:816-818.
60 .Buehler BA, Delimont D, van Waes M, Finnell RH. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J
Med. 1990;322:1567-1572.
61 .Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet. 1968;2:1296.
62 .Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk .
10th ed. Lippincott Williams & Wilkins; 2014.
63 .Thisted E, Ebbesen F. Malformations, withdrawal manifestations, and hypoglycaemia after exposure to valproate in utero.
Arch Dis Child. 1993;69:288-291.
64 .Lindhout D, Meinardi H. Spina bifida and in-utero exposure to valproate. Lancet. 1984;2:396.
65 .Matalon S, Schechtman S, Goldzweig G, Ornoy A. The teratogenic effect of carbamazepine: a meta-analysis of 1255
exposures. Reprod Toxicol. 2002;16:9-17.
66 .Ban L, Fleming KM, Doyle P, et al. Congenital anomalies in children of mothers taking antiepileptic drugs with and without
periconceptional high dose folic acid use: a population-based cohort study. PLoS One. 2015;10:e0131130.
67 .Jones KL, Smith DW, Ulleland CN, Streissguth P. Pattern of malformation in offspring of chronic alcoholic mothers.
Lancet. 1973;1:1267-1271.
68 .Bruyere HJ Jr, Kapil RP. Cardioteratogenic dose of ethanol in the chick embryo results in egg white concentrations
comparable to human blood alcohol levels. J Appl Toxicol. 1990;10:69-71.
69 .Clarren SK, Smith DW. The fetal alcohol syndrome. Lamp. 1978;35:4-7.
70 .Sun J, Chen X, Chen H, Ma Z, Zhou J. Maternal alcohol consumption before and during pregnancy and the risks of
congenital heart defects in offspring: a systematic review and meta-analysis. Congenit Heart Dis. 2015;10:E216-E224.
71 .Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313:837-841.
72 .Rosa F. Isotretinoin dose and teratogenicity. Lancet. 1987;2:1154.
73 .Kubow S. Inhibition of isotretinoin teratogenicity by acetylsalicylic acid pretreatment in mice. Teratology. 1992;45:55-63.
74 .Huhta JC, Moise KJ, Fisher DJ, Sharif DS, Wasserstrum N, Martin C. Detection and quantitation of constriction of the fetal
ductus arteriosus by Doppler echocardiography. Circulation. 1987;75:406-412.
75 .Moise KJ Jr, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor. Effects on the fetal ductus
arteriosus. N Engl J Med. 1988;319:327-331.
76 .Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME. Nonsteroidal antiinflammatory drugs during third trimester and
the risk of premature closure of the ductus arteriosus: a meta-analysis. Ann Pharmacother. 2006;40:824-829.
77 .Norton ME, Merrill J, Cooper BA, Kuller JA, Clyman RI. Neonatal complications after the administration of indomethacin
for preterm labor. N Engl J Med. 1993;329:1602-1607.
78 .Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE
inhibitors. N Engl J Med. 2006;354:2443-2451.
79 .Tabacova S, Little R, Tsong Y, Vega A, Kimmel CA. Adverse pregnancy outcomes associated with maternal enalapril
antihypertensive treatment. Pharmacoepidemiol Drug Saf. 2003;12:633-646.
80 .Mann JJ. The medical management of depression. N Engl J Med. 2005;353:1819-1834.
81 .Cole JA, Ephross SA, Cosmatos IS, Walker AM. Paroxetine in the first trimester and the prevalence of congenital
malformations. Pharmacoepidemiol Drug Saf. 2007;16:1075-1085.
82 .Kallen B, Otterblad Olausson P. Antidepressant drugs during pregnancy and infant congenital heart defect. Reprod Toxicol.
2006;21:221-222.
83 .Anonymous. SSRI antidepressants and birth defects. Prescrire Int. 2006;15:222-223.
84 .Bar-Oz B, Einarson T, Einarson A, et al. Paroxetine and congenital malformations: meta-Analysis and consideration of
potential confounding factors. Clin Ther. 2007;29:918-926.
85 .Huybrechts KF, Palmsten K, Avorn J, et al. Antidepressant use in pregnancy and the risk of cardiac defects. N Engl J Med.
2014;370:2397-2407.
86 .Chambers CD, Hernandez-Diaz S, Van Marter LJ, et al. Selective serotonin-reuptake inhibitors and risk of persistent
pulmonary hypertension of the newborn. N Engl J Med. 2006;354:579-587.
87 .Suhara T, Sudo Y, Yoshida K, et al. Lung as reservoir for antidepressants in pharmacokinetic drug interactions. Lancet.
1998;351:332-335.
88 .McMahon TJ, Hood JS, Nossaman BD, Kadowitz PJ. Analysis of responses to serotonin in the pulmonary vascular bed of
the cat. J Appl Physiol. 1993;75:93-102.
89 .Runo JR, Loyd JE. Primary pulmonary hypertension. Lancet. 2003;361:1533-1544.
90 .Weisskopf E, Fischer CJ, Bickle Graz M, et al. Risk-benefit balance assessment of SSRI antidepressant use during
pregnancy and lactation based on best available evidence. Expert Opin Drug Saf. 2015;14:413-427
91 .Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors
and the risk of birth defects. N Engl J Med. 2007;356:2675-2683.
92 .Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM. Use of selective serotonin-reuptake inhibitors in pregnancy
and the risk of birth defects. N Engl J Med. 2007;356:2684-2692.
93 .Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA. Maternal obesity and risk for birth defects. Pediatrics.
2003;111: 1152-1158.
94 .Cedergren MI, Kallen BA. Maternal obesity and infant heart defects. Obes Res. 2003;11:1065-1071.
95 .Czeizel AE. Periconceptional folic acid-containing multivitamin supplementation for the prevention of neural tube defects
and cardiovascular malformations. Ann Nutr Metab. 2011;59:38-40.
96 .Shaw GM, O’Malley CD, Wasserman CR, Tolarova MM, Lammer EJ. Maternal periconceptional use of multivitamins and
reduced risk for conotruncal heart defects and limb deficiencies among offspring. Am J Med Genet. 1995;59:536-545.
97 .Scanlon KS, Ferencz C, Loffredo CA, et al. Preconceptional folate intake and malformations of the cardiac outflow tract.
Baltimore-Washington Infant Study Group. Epidemiology. 1998;9:95-98.
98 .Botto LD, Mulinare J, Erickson JD. Occurrence of congenital heart defects in relation to maternal mulitivitamin use. Am J
Epidemiol. 2000;151:878-884.
99 .Junker R, Kotthoff S, Vielhaber H, et al. Infant methylenetetrahydrofolate reductase 677TT genotype is a risk factor for
congenital heart disease. Cardiovasc Res. 2001;51:251-254.
100 .Kapusta L, Haagmans ML, Steegers EA, Cuypers MH, Blom HJ, Eskes TK. Congenital heart defects and maternal
derangement of homocysteine metabolism. J Pediatr. 1999;135:773-774.
101 .Wenstrom KD, Johanning GL, Johnston KE, DuBard M. Association of the C677T methylenetetrahydrofolate reductase
mutation and elevated homocysteine levels with congenital cardiac malformations. Am J Obstet Gynecol. 2001;184:806-812;
discussion 812-807.
C H A P T E R
2
Genetic Aspects of Congenital Heart Disease
INTRODUCTION
For almost four decades, genetic evaluation of congenital heart disease (CHD) could only be
assessed by conventional karyotyping, primarily revealing numeric chromosomal abnormalities
(e.g., trisomy 21), and by the description of syndromic conditions in infants with CHD and
associated extracardiac anomalies (e.g., Holt–Oram syndrome, DiGeorge syndrome).
Furthermore, the association of CHD with genetic abnormalities was underestimated, and was
assumed to be around 10% to 15% ( 1 ), with the majority of defects thought to result from
multifactorial causes. The rapid advent of new genetic technologies in the last two decades has
enabled the decoding of the human genome and has afforded a better understanding and
classification of many anomalies. Microarray techniques have allowed for the evaluation of
submicroscopic copy number variants (CNV). In addition to microarray, the increasing use of
targeted sequencing (cardiac panels) and the sequencing of whole exome sequencing (WES) or
whole genome sequencing (WGS) has shown a much higher association of CHD with genetic
abnormalities, in the order of 30% of cases ( 2 ). In the last decade, several genetic studies have
been performed on large cohorts of children with CHD that have identified a host of new genes
responsible for nonsyndromic cardiac malformations ( 3 , 4 ). These discoveries are enabling the
ability to fine-tune genetic testing with a better understanding of the genes responsible for
cardiac anomalies, thus enhancing patient counseling. The field of human cardiovascular
genetics is progressing at a rapid pace, and novel genetic tests for various forms of cardiac
abnormalities are regularly being introduced to clinical medicine. In this chapter, we will first
discuss the principles of currently available genetic techniques and then expand on the following
three main groups of genetic anomalies: ( 1 ) chromosomal aneuploidies detected with
conventional karyotype, ( 2 ) deletions and duplications detected on microarray analysis, and ( 3
) single-gene defects detected via cardiac panels or exome sequencing.
Conventional Karyotyping and Chromosomal Analysis
Chromosomal analysis is done on cell cultures that are treated to arrest growth in the metaphase
when the chromosomes are visible. Special banding techniques (usually G-banding) are used to
identify individual chromosomes by their specific pattern of light and dark bands. The analysis is
performed under the microscope and the chromosomes are classified into seven groups, A to G,
based on their length and centromere position. Nomenclature designates the centromere as “cen”
and the telomere (terminal structure) as “ter.” The short arm of each chromosome is designated
as “p” (petit) and the long arm as “q” (queue). Each arm is subdivided into a number of bands
and sub-bands.
This traditional karyotyping technique identifies the majority (>75%) of clinically significant
chromosomal abnormalities including trisomies 21, 18, and 13, triploidy, and aneuploidies
involving the sex chromosomes, such as monosomy X (Turner syndrome) and XXY (Klinefelter
syndrome). With light microscopy, large balanced or unbalanced translocations can also be
diagnosed in addition to rare mosaic trisomies and structurally abnormal chromosomes. Large
chromosomal deletions (>5-10 million base [MB] pairs) can also be identified, such as the
majority of deletions 4p- (Wolf–Hirschhorn syndrome) or deletions 5p- (Cri-du-Chat syndrome).
Small deletions, termed microdeletions, such as microdeletion 22q11.2 (DiGeorge syndrome;
discussed later), 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 conditions
are suspected (e.g., FISH for deletion 22q11.2 in conotruncal anomalies) or by examining the
complete set of chromosomes using comparative genomic hybridization (CGH) (microarray;
discussed later).
FISH Technique
FISH is a cytogenetic technique that uses 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 a 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 is typically applied antenatally for a rapid diagnosis of trisomies. The
FISH technique used for the identification of microdeletions is also performed directly on
metaphase chromosomes with the addition of 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 to check for
microdeletion 22q11.2 in addition to chromosome karyotyping.
Array CGH (Microarray) and CNV
Array CGH, or microarray, is a sensitive technique that compares the patient’s DNA (comprising
all the chromosomes) with a control DNA sample, for the identification of variances between the
two sets. Imbalances in the patient’s DNA, called CNV include losses (deletions) and gains
(duplications) and 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. An explanation of the technical aspects of CGH is beyond the scope of this book,
but it is important to state that CGH detects DNA imbalances in chromosomes above a certain
size (e.g., a cutoff of 50 Kb), some of which may have unclear clinical significance. This
microarray technique has become popular in the last few years despite its high cost and
limitations. Some centers offer CGH as a first-line option for genetic testing after chorionic villus
sampling or amniocentesis, while others restrict its use to when DNA imbalance is suspected, or
as a second-line test following normal karyotype analysis. In one meta-analysis of Jansen et al. (
5 ), it was shown that for fetal heart defects, CGH detected an additional 7% of chromosomal
abnormalities after excluding aneuploidies and deletion 22q11.2. With this finding, it has
become reasonable to discuss the option for CGH with patients when fetal malformations, and
particularly CHD, is diagnosed. The availability and cost of CGH should also be factored into
this decision.
Next-Generation Sequencing, Exome Sequencing, and Single-Gene
Defects
Until recently, seeking genetic mapping for a single-gene defect was limited to families that had
several siblings affected with a known gene defect. With rapid evolution in genetic testing,
especially with advances in DNA sequencing, the gene defect(s) in many clinical genetic
diseases have been identified and now can be tested within days. The technique is generally
called next-generation sequencing (NGS) or massively parallel sequencing to emphasize that it is
new and rapid, in comparison to the earlier Sanger sequencing (first-generation sequencing),
which allows the analysis of only one specific gene region and is more time-consuming. The
advent of affordable and rapid NGS has revolutionized genetics of human malformations and has
led to a better understanding of the pathways of many diseases. Some anomalies that were earlier
being considered as separate entities have now been reclassified into groups of anomalies with
common clinical and genetic features. For instance, Noonan syndrome (discussed later in this
chapter), which was considered a distinct genetic syndrome, now belongs to a group of genetic
syndromes known as RASopathies, and includes defects in 17 genes. Another group of genetic
syndromes are now known as ciliopathies and have in common the mutations of genes involved
in cilia development and function. Over the past decade, genetic studies on children and fetuses
with CHD have elucidated the etiology of CHD in many conditions.
Noninvasive Prenatal Testing
Noninvasive prenatal testing (NIPT) is a genetic test 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 ( 6 ). Placental cell apoptosis
releases into the maternal circulation small DNA fragments that can be detected from about 4 to
7 gestation of weeks ( 7 ). It is estimated that about 2% to 20% of circulating cfDNA in the
maternal circulation is fetal in origin ( 7 ). The half-life of cfDNA is short and is typically
undetectable within hours after delivery ( 8 ). Details of the technical aspects 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 regard 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% ( 9 ). The
detection rate for trisomy 18 is at 97% for a false-positive rate of 0.15% ( 9 ). To date, NIPT is
recommended as a screening test for high-risk populations. Given a very small false-positive
rate, incorporating NIPT for screening for trisomy 21 in high-risk populations reduces the need
for unnecessary invasive testing. Recently, testing for deletion 22q11.2 has been included in
NIPT and shows a sensitivity of 70% to 75% with a specificity of 99.5% ( 10 ).
It should be emphasized that NIPT is a screening test and not a diagnostic test, and, thus,
caution should be used when NIPT is incorporated in the genetic evaluation of CHD. Given the
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. NIPT technology is now expanding to allow for the
screening of chromosomal deletions and duplications. The authors believe that invasive
diagnostic testing is more appropriate in the setting of CHD given the high association with
genetic malformations. Nondirective genetic counseling is important in this setting in order to
provide a comprehensive menu of options to the family faced with the prenatal diagnosis of
CHD.
SONOGRAPHIC EVALUATION OF THE FETUS WITH CHD
IN SUSPECTING GENETIC DISEASE
The antenatal detection of CHD in a fetus necessitates a detailed ultrasound evaluation, given a
high association of CHD 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 is for cardiac rhabdomyomas and their associations with
tuberous sclerosis complex (TSC) or the commonly isolated simple transposition of the great
arteries. For most CHDs, however, there is a wide range of possible associations and detailed
fetal evaluation is therefore warranted. Usually, the first step in the ultrasound evaluation is to
look for the presence of additional soft markers and/or extracardiac malformations 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
case 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 an ultrasound can point the examiner to a genetic association that
may not be clearly visible otherwise. Tetralogy of Fallot (TOF) is a typical example as it can be
isolated, but also 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), which is associated with either trisomy 21 or 18 in more than 50% of
cases, but also can be part of heterotaxy syndrome ( Chapter 41 ), either isolated or in the context
of primary ciliary dyskinesia. AVSDs are also observed in deletion 22q11.2 and other deletions,
as well as in CHARGE syndrome (13%) ( 11 ).
CHD AND NUMERICAL CHROMOSOMAL ANOMALIES
The frequency of chromosomal abnormalities in infants with CHD has been estimated at 5% to
15% from postnatal data ( 1 , 12 , 13 ). In a population-based case-control study of 2102 liveborn infants, ascertained by their cardiovascular malformations, chromosomal abnormalities
were found in 13% ( 1 ). 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 (
1 ). Similar data was reported from three large registries of congenital malformations, involving
1.27 million births ( 13 ). The frequency of abnormal karyotypes in fetuses with cardiac defects
is higher and has been reported to be in the range of 30% to 40% by several studies ( 14 - 16 ).
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 ( 17 ). Keep in mind that earlier studies reported more
CHD cases with multiple structural anomalies, which may increase the genetic association. Not
only is the association of congenital cardiac defects and chromosomal abnormalities lower in
live-born infants than in fetuses, but the distribution of chromosomal abnormalities is also more
skewed toward Down syndrome in the neonatal population ( 1 , 13 ), 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. AVSD, ventricular (perimembranous) septal defect (VSD) and atrial
septal defect (ASD), TOF, double outlet right ventricle (DORV), and hypoplastic left heart
syndrome (HLHS), on the other hand, are more commonly associated with chromosomal
abnormalities in the fetus and newborn. Table 2.1 lists specific cardiac diagnoses in infants with
noncomplex cardiovascular defects from three large registries ( 13 ) and the corresponding
incidence of associated numerical chromosomal abnormalities.
Table 2.1 • Number of Infants with Identified Chromosomal Anomalies According to Cardiac Defect Type
(Noncomplex Cardiovascular Defects Only)
Chromosomal anomaly
Cardiovascular defect
Corrected transposition
No
Yes
Percentage
16
0
0.0
D-TGA
969
9
0.9
Pulmonary atresia without VSD
195
4
2.0
TAPVC
287
6
2.0
ASD + pulmonary valve stenosis
117
5
4.1
HLHS
799
35
4.2
Tricuspid valve atresia
132
6
4.3
Pulmonary valve stenosis
374
17
4.3
Common arterial trunk
217
10
4.4
Aortic valve stenosis
235
11
4.5
Interrupted aortic arch
179
11
5.8
Ebstein anomaly
110
8
6.8
Coarctation of aorta
403
32
7.4
91
9
9.0
207
21
9.2
1077
123
10.3
174
25
12.6
VSD
2134
474
18.2
ASD
868
319
26.9
VSD + ASD
447
207
31.7
AVSD
317
687
68.4
Single ventricle
VSD + coarctation of aorta
Tetralogy of Fallot
DORV
ASD, atrial septal defect; AVSD, atrioventricular septal defect; DORV, double outlet right ventricle; D-TGA, Dtransposition of great arteries; HLHS, hypoplastic left heart syndrome; TAPVR, total anomalous pulmonary venous
connection; VSD, ventricular septal defect.
Modified by permission from Springer Nature: Harris JA, Francannet C, Pradat P, Robert E. The epidemiology of
cardiovascular defects, part 2: a study based on data from three large registries of congenital malformations.
Pediatr Cardiol . 2003;24:222-235. Copyright 2003.
The majority of fetuses with cardiac defects and chromosomal abnormalities have other
associated extracardiac abnormalities, in the order of 50% to 70% ( 14 , 16 ). 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 CHD, the incidence of chromosomal abnormalities is still significantly increased
(15%-30%) and thus appropriate genetic counseling is warranted ( 14 , 16 ). When the diagnosis
of any abnormality in genetic testing is made in a fetus, an echocardiogram is indicated in view
of the possible association of cardiac malformations.
In the following sections, we will discuss the more common aneuploidies detected in
association with CHD in the fetus.
Down Syndrome (Trisomy 21)
Definition of Disease
Down syndrome is caused by the presence of three copies of chromosome 21. It is the most
common chromosomal aberration in humans with a mean occurrence of 1:500 in the general
population. Since 30% of the fetuses with trisomy 21 die in utero, the prevalence during
gestation is higher than at birth. In 95% of cases, trisomy 21 is due to an error in maternal
meiosis, which increases with maternal age, while in the remaining 5%, it is due to an
unbalanced translocation, which is independent of parental age and can be of maternal or
paternal origin. Persons with trisomy 21 have distinctive clinical features associated with mental
challenge of variable degree. Structural and immunologic anomalies can also be present.
Genetic Diagnosis
The genetic diagnosis can be achieved prenatally on fetal tissue collected from an amniocentesis,
chorionic villous sampling, or fetal blood sampling. The genetic diagnosis is achieved on
karyotyping with G-banding technique. The FISH technique is often used to rapidly confirm the
diagnosis. Trisomy 21 can also be suspected on NIPT screening with high accuracy (99%). On
prenatal ultrasound, the presence of distinct cardiac and extracardiac structural anomalies, as
well as soft markers, can highly suggest the presence of trisomy 21 ( Table 2.1 ) ( Figs. 2.1 to 2.4
).
Figure 2.1: First trimester markers of trisomy 21 include thickened nuchal translucency (NT) (A-short arrow) and
absent or hypoplastic nasal bone (NB) (A-long arrow), generalized edema (B and C-arrows), cardiac anomaly (Cstar), most commonly an atrioventricular septal defect (AVSD), abnormal course of the umbilical vein (UV) with an
absent or abnormal connection of the ductus venosus (DV), here connecting to the inferior vena cava (IVC) (D-arrow),
reverse flow in the DV (E-arrows), and tricuspid regurgitation (F-arrows).
Figure 2.2: Cardiovascular abnormalities in trisomy 21 fetuses typically include an atrioventricular septal defect
(AVSD) (A-star), ventricular septal defect (VSD) (B-arrow), linear insertion of the AV valves with a cardiac defect (Carrows), aberrant right subclavian artery (ARSA) (D-arrows), with the course of the artery behind the trachea,
intracardiac echogenic focus (E-arrow), abnormal course of the umbilical vein (UV) with an absent or abnormal
connection of the ductus venosus (DV) (F-arrow). The thymus gland (G-arrows) can be small in fetuses with trisomy
21 with a small thymic–thoracic ratio. Pericardial fluid (H-arrow) can also be found in trisomy 21 fetuses in
combination with a cardiac anomaly.
Figure 2.3: Trisomy 21 fetuses can show diverse abnormalities including skeletal, such as short femur (A), wide
pelvic angle (B-arrows), short hands and fingers with clinodactyly (C), and 11-pair ribs (D). Other anomalies
occasionally found include duodenal obstruction as double bubble (E), hydrops (F-arrows), shown here as scalp
edema, pyelectasis (G-arrows), and occasionally (H) increased pulsatility index (PI) in the umbilical artery (UA)
Doppler with a normal uterine Doppler (not shown).
Figure 2.4: Cranial and facial markers in trisomy 21 fetuses including absent nasal bone (A-circle), protruding tongue
with an open mouth (A-arrow), prenasal thickness (B-arrow), brachycephaly (C), dilated cavum septi pellucidi (CSP)
(C-arrow), nuchal edema (D-arrows), as seen in sagittal (D-left) or axial (D-right) view. The midfacial hypoplasia in
trisomy 21 is associated with a short maxilla (E) and small mouth, as microstoma (F). Facial features of trisomy 21
can be recognized on 3D ultrasound and are shown in panel G. A small ear (H) can also be found but is not very
specific.
Cardiac Findings
Cardiac findings in trisomy 21 fetuses are present in more than 50% of cases and include
AVSDs, VSDs (inlet or perimembranous), TOF, and other less common anomalies (Ebstein,
DORV, coarctation of the aorta [CoA] etc.) ( Fig. 2.2 ). In addition, anatomic variants/markers in
the chest can be present in association with trisomy 21 and include an aberrant right subclavian
artery, a hyperechogenic intracardiac focus, linear insertion of the atrioventricular valves,
pericardial effusion, tricuspid regurgitation, and others. Figure 2.2 shows examples of cardiac
findings in several fetuses with trisomy 21.
Extracardiac Findings
Structural anomalies such as duodenal or esophageal atresia in trisomy 21 are occasionally found
( Fig. 2.3 ), but are much less common than anatomic variants ( Fig. 2.4 ). Anatomic markers
associated with trisomy 21 are common and can be seen in several organ systems, including
lymphatic, skeletal, cerebral, facial, renal, abdominal, and placental/amniotic fluid. Table 2.2
lists common ultrasound markers associated with trisomy 21. The majority of fetuses with
trisomy 21 (>90% of cases) can be detected in early gestation, by the first trimester genetic
screening test ( Fig. 2.1 ), which includes maternal age, nuchal translucency (NT) measurement,
and biochemical markers. A detailed first trimester anatomy survey can also improve detection
of trisomy 21. For more details refer to the authors’ book on first trimester ultrasound ( 18 ).
Table 2.2 • Physical Abnormalities in Fetuses with Trisomy 21 Organized by Organ System
Organ system
Abnormalities in trisomy 21
Cardiac
AVSD, VSD, TOF, ARSA, EIF, TR, pericardial effusion,
right aortic arch
Skeletal
Short femur, short humerus, absent or short nasal bone,
short head, wide pelvic angle, short maxilla, clinodactyly,
short hands, sandal gap
Facial
Prefrontal skin edema, absent or short nasal bone, flat
face, small mouth (microstoma), open mouth with
protruding tongue, small ears
Lymphatic
Thickened nuchal translucency, nuchal edema, ascites
Gastrointestinal and
renal
Esophageal, duodenal and other bowel obstruction, renal
pelvis dilation, small omphalocele, echogenic bowel
Cerebral
Short head (brachycephaly), ventriculomegaly, dilated
cisterns magna, dilated CSP, abnormal corpus callosum
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