In the past quarter century, two population studies, the New England Regional Infant Cardiac Program ²⁹⁰ and the Baltimore-Washington Infant Study,^263,²⁶⁴ increased understanding of the incidence and etiology of CHD. Recent years have brought the human genome project, advances in molecular biology, and expanded capabilities for chromosomal analysis. Small chromosome deletions and duplications can be identified through fluorescence in situ hybridization (FISH) and, more recently, array comparative genomic hybridization (A-CGH), which opens the door to identification of a greater number of genetic diagnoses. All of these factors combined with the epidemiologic results of the population studies mentioned above are contributing to the identification of genes that cause syndromes as well as isolated congenital heart defects, classification of the pathologic processes of embryology that are triggered by genetic abnormalities, and correlation between genotypes and various phenotypes (the characteristic features).^265,^657,⁶⁹⁹ These methods are enabling identification of chromosome anomalies and gene abnormalities that are a result of new or inherited mutations. These and other new developments are leading to better genetic testing, improved diagnostic and prognostic capabilities, future research opportunities, and enhanced care planning and counseling.⁹³²

Findings about noninherited risk factors for congenital heart disease have also expanded. Knowledge about prescription and nonprescription drugs, environmental influences (chemical, physical, and biologic agents/teratogens), and parental diseases have enhanced our understanding about the etiologies of CHD.

Whether the triggering event is a teratogen, a genetic abnormality, or unknown, the pathogenesis of congenital heart defects follow six mechanisms as proposed by Clark ^181,^182,^506,⁷⁴⁷:

I. Ectomesenchymal tissue migration or neural crest abnormalities, resulting in conotruncal (ventricular outflow) and aortic arch anomalies;

II. Abnormalities of intracardiac blood flow, resulting in hypoplasia of structures through which flow was diminished or absent;

III. Cell death abnormalities, resulting in Ebstein malformation and muscular ventricular septal defects;

IV. Extracellular matrix abnormalities, resulting in anomalous formation of the endocardial cushions (atrioventricular septal and canal defects);

V. Abnormal targeted growth, resulting in anomalies of pulmonary venous and left atrium formation; and

VI. Abnormal situs and looping, resulting in malposition of organs, structures, and vascular connections.

An etiologic event triggers abnormal pathogenesis and each of the preceding pathogenetic mechanisms can cause a spectrum of disorders.

Exploration of anomalies in terms of a common pathogenetic mechanism allows researchers to learn more about familial patterns. As more information about the interaction of genes, environment, and proteins involved in developmental pathways is available, our understanding of the biologic basis of normal and abnormal cardiovascular embryologic development (morphogenesis) will be refined.⁵⁰⁶ Further information on cardiovascular morphogenesis is provided in the section, Fetal Development of the Heart and Great Vessels.

Although most congenital heart disease was previously believed to be of multifactorial etiology (a combination of a number of genetic factors from both parents, environmental influences, and random events), new information has led to the belief that most human CHDs result from single gene defects ⁵⁰⁶ and some from exposure to teratogens. Nevertheless, at this point, for most patients with CHD there is not a precise identifiable cause.⁵⁰⁶ Congenital heart defects are thought to be related to teratogens in 2% to 4%, genetics in 10% (although this is probably underestimated), and unknown in 85% to 90%.^190,²⁷⁷ As discoveries continue, the percentage with unknown cause should decrease.

This section further describes the teratogens and genetics associated with CHDs as an isolated defect or in association with extracardiac anomalies. These are divided into noninherited and inherited risk factors that lead to CHD.

Noninherited Risk Factors for CHD (Many Potentially Modifiable)

Maternal Disorders or Biologic Teratogens

Maternal disorders or biologic teratogens associated with increased incidence of CHD include phenylketonuria (PKU), diabetes, infections, obesity, systemic lupus erythematosus, and epilepsy.²⁷⁷ When a mother has untreated PKU during pregnancy, the fetus may have growth and mental retardation and has a 20% to 25% incidence of CHD. Maternal control of blood phenylalanine concentration and adequate maternal nutrition before and throughout the pregnancy must occur to reduce the risk. All babies conceived when the mother was receiving inadequate nutrition should have an echocardiogram.⁵⁵⁸ The most frequently associated defects are tetralogy of Fallot, ventricular septal defect (VSDs), patent ductus arteriosus (PDA), and single ventricle.⁴¹⁴

Maternal pregestational insulin dependent diabetes increases fetal risk of CHD. The most common defects are malformations with laterality or embryologic heart tube looping defects, transposition of the great arteries, conotruncal defects (e.g., tetralogy of Fallot, interrupted aortic arch, truncus arteriosus), VSDs, atrioventricular septal (AV canal) defects, hypoplastic left heart syndrome, outflow tract defects, PDA, and hypertrophic cardiomyopathy (which may resolve).⁴¹⁴ Less frequently, gestational diabetes also has been associated with CHDs, and these cases may represent women who have undetected type 2 diabetes. Adequate blood sugar control before and during pregnancy does reduce the risk.^414,⁷⁹⁵

Maternal infections have long been associated with CHD. Maternal rubella has been associated with PDA, pulmonary valve abnormalities, peripheral pulmonary stenosis, and VSDs. Immunization of women against rubella can eliminate this risk. More recently other maternal febrile illnesses (such as influenza) in the first trimester have been associated with a variety of heart defects, but it is unknown whether the fever, infectious agent, or medication to treat the fever and infection cause the effect.^190,⁴¹⁴ Although HIV infection in utero increases the risk of dilated cardiomyopathy and left ventricular hypertrophy, it has not been associated with structural cardiac defects.⁴¹⁴

Maternal obesity before pregnancy has been associated with CHD, but findings are inconsistent. The many complex variables with obesity and nutrition make this a difficult area for drawing conclusions.⁴¹⁴ Connective tissue disorders such as systemic lupus erythematosus in women are associated with congenital heart block in infant offspring. Maternal connective tissue disorders have not been associated with structural cardiac malformations.⁴¹⁴

Maternal epilepsy is associated with increased incidence of CHD. The therapy of anticonvulsant drugs and their potential impact on folate metabolism—rather than the seizures themselves—may increase the risk.⁴¹⁴

Maternal Drug Exposure (Chemical Teratogens)

Of note, use of maternal multivitamins and folic acid in the periconceptual period may reduce the risk of CHDs, but the evidence is not yet conclusive. These supplements may reduce the risk of CHD when used with some other agents that are associated with an increased risk of CHD, for example maternal febrile illness. Further studies are needed.⁴¹⁴

Exposure to chemical agents can alter cellular development, and the timing of such exposure can influence the effect on risk. Identification of timing related to fetal vulnerability could help ensure counseling about treatment options to avoid critical exposures for a susceptible embryo.^190,^277,⁴¹⁴ Many therapeutic drugs used preconceptually or during pregnancy have been linked with possible associated risk of congenital heart disease. (The interested reader can find a list on the Evolve Website. Please see Evolve Box 8-1 in the Chapter 8 Supplement on the Evolve Website.) Because much of the evidence is inconclusive and there are always reports from new studies, research and caution is urged before use of any therapeutic drugs during the periconceptual period and pregnancy.

Nontherapeutic drugs used preconceptually and/or during pregnancy that have been associated with increased risk of CHD include: alcohol, cocaine, marijuana, cigarette smoking, and vitamin A in high doses. Again, the evidence is often inconclusive, so actual risks can be difficult to determine. Many other agents have been studied but the data are insufficient to determine risks for cardiac defects.^414,⁷⁵⁴

Environmental Exposures (Chemical, Biologic, and Physical Teratogens) and Influences

Increased risk of a variety of CHDs has been associated with maternal occupational exposure to organic solvents (compositions of solvents can include degreasers, dyes, lacquers, paints, glycol ethers, and mineral oil products); heavy metals; herbicides, pesticides, and rodenticides associated with maternal employment in the agriculture industry; air quality (increased levels of ambient carbon monoxide, ozone, and dioxide); and parental exposure to groundwater contamination with trichloroethylene. There are other environmental exposures, such as hazardous waste sites and occupational exposure to ionized radiation, but no consistent association with CHD has been found.^414,⁸⁶⁶

Evaluation of maternal sociodemographic characteristics has shown that maternal age is not associated with nongenetic CHDs as a group. Some specific defects are more likely with advanced maternal age, and young maternal age is associated with tricuspid atresia.⁴¹⁴ Some studies have shown disparity of incidence between white and black infants, with many defects being more prevalent in white infants, whereas pulmonary stenosis is more prevalent in black infants. Other studies have not shown variations in prevalence of birth defects in general among white, black, and Hispanic infants.⁴¹⁴ Reproductive problems (miscarriage, stillbirth, or preterm birth) have been associated with increased incidence of tetralogy of Fallot, nonchromosomal atrioventricular canal defects, ASDs, and Ebstein’s anomaly, where the association could represent exposure to teratogens or an inherent susceptibility.⁴¹⁴ Maternal stress associated with job loss, divorce, separation, or death of a close relative or friend, especially in mothers who were not high school graduates, was found to be associated with a greater prevalence of conotruncal heart defects.⁴¹⁴

Paternal exposures and factors may also play a role in noninherited cardiac defects. Older fathers have been associated with Marfan syndrome. Studies have suggested that increasing paternal age is associated with ASDs, VSDs, PDA, and tetralogy of Fallot, whereas children of men less than 20 years of age were also at higher risk for septal defects.⁴¹⁴ Other paternal exposures have been investigated in a limited number of studies, with the suggestion or trend toward increased risk of CHD associated with paternal exposure to marijuana, cocaine, cigarette smoking, and alcohol.⁴¹⁴

A unique environmental influence may be present for some monochorionic twins. The smaller twin is more often affected with CHD, which may result from abnormal cord insertion.³⁷³

Prevention of some CHDs may be accomplished by following these recommendations for mothers who wish to become pregnant: Take a multivitamin with folic acid daily, obtain prenatal and preconceptual care for management of maternal disorders associated with increased risk of CHD, discuss use of any drugs with the healthcare provider, avoid contact with people who have the flu or other febrile illnesses, avoid exposure to organic solvents,⁴¹⁴ and follow any employer guidelines established to avoid exposures that may increase risks.

Genetic Factors Associated with CHD

New findings with molecular genetic studies indicate that the genetic contribution to the etiology of CHD has been underestimated. With the rapid changes in this field it is certain that our understanding will be evolving and the identifiable genetic etiologies of CHD will continue to expand.⁷⁰⁰ Review of current literature will always be necessary to have an accurate understanding of these factors.

Humans normally have 46 chromosomes (23 pairs). The first 22 pairs are autosomal (non-sex) chromosomes and the 23rd pair determines gender (XX = female, XY = male). Each chromosome has two arms held together by a centromere—a short arm (p) and a long arm (q). There are more than 35,000 pairs of genes on our chromosomes,¹⁹⁰ and each gene is composed of hundreds or thousands of base pairs. An abnormality in a single base pair can cause a malfunction. Changes in the deoxyribonucleic acid (DNA) sequence (a mutation) in a single gene changes the path of a protein, which is like changing one part of a recipe. (The results can range from asymptomatic to disastrous malformations.) Mutations may occur de novo (a new mutation that is not inherited from a parent) or may result from autosomal-dominant or -negative inheritance. Many gene mutations associated with cardiovascular malformations are now being identified.^190,^277,⁷⁰⁰

Before advanced cytogenetic tests were available, chromosome abnormalities were found in approximately 8% to 13% of neonates with CHD,²⁶³ but with new testing the prevalence of chromosome aberrations is now estimated to be much higher.⁷⁰⁰ These abnormalities can be aneuploidies (abnormal number of chromosomes) such as trisomies (an extra chromosome), or tetrasomies. Other chromosome abnormalities are caused by deletions (a missing piece), duplications (extra genetic material on chromosome), or translocations (genetic material transferred from one chromosome to another).^190,²⁷⁷ Single gene defects have been thought to account for about 3% to 5% of those CHDs with a genetic etiology, but new findings indicate that this range substantially underestimated the problem. Any genetic defect can start an embryonic chain reaction, which can create mild to severe phenotypic expression of the abnormality.⁸⁰³

Inheritance of genetic abnormalities associated with CHD can occur in several ways. Deletions, duplications, and single gene defects can all be the result of a mutation (a sporadic change in DNA sequence triggering abnormalities) or Mendelian inheritance from parents with the same gene anomaly. If both parents must contribute the abnormality it is autosomal recessive—both parents carry the genetic difference, but the parents will only have the disorder if they, too, have two genes with the difference. If the anomaly is inherited when only a single parent is a carrier, the inheritance is autosomal dominant, and in this situation that parent also has the condition.

Cardiovascular malformations can occur as a part of a group or pattern of anomalies. A syndrome, a combination of multiple anomalies occurring together resulting from a single cause (the cause is often a genetic error but the cause may be unknown), is thought to cause about 5% of the CHD. More than 400 genetic syndromes list CHD as a possible manifestation.^651,⁸⁰³ Associations, a group of anomalies that occur in a recurrent pattern, may also involve CHDs. There may be no known genetic basis for an association. Inherited metabolic diseases have a variety of genetic etiologies and may include cardiovascular problems.

For more information on characteristics and etiologies of specific defects and conditions see Tables 8-1 and 8-2. There are hundreds of syndromes and conditions with multiple manifestations that involve cardiovascular malformations. Table 8-2 includes an abbreviated table, and a more comprehensive table with genetic associations is provided in Evolve Table 8-1 in the Chapter 8 Supplement on the Evolve Website.

Table 8-1 Cardiac Defects and Associated Genetics, Teratogens, and Exposures ³²⁸^,⁴¹⁴^,⁷⁰⁰^,⁸⁷¹^,⁹³²

Cardiac Defect	Associated Genetics, Teratogens, and Exposures
Any congenital heart defect	Maternal PKU, pregestational diabetes, febrile illness, influenza, rubella, epilepsy, anticonvulsants, NSAIDS/Ibuprofen, sulfasalazine (antiinflammatory), thalidomide, trimethoprim-sulfonamide, and vitamin A congeners/retinoids. Many illnesses, medical and substance exposures, as well as sociodemographic factors have been studied, but there have been insufficient data to determine risks for CHD with these. Somatic mutations (occur after fertilization and therefore only affect some cells or tissues) are hypothesized to be an important cause of isolated CHDs.
Aortic atresia	See HLHS
Coarctation of the aorta	Turner syndrome. Familial left-sided obstructive heart defects. Deletion of chromosome locus 18p. Duplications in chromosome 4p, 4q, 6q, or 10p. Trisomy 8 or 9. Maternal exposure to organic solvents.
Supravalvular aortic stenosis	Williams-Beuren syndrome. Deletion or translocation (rare) in chromosome locus 7q11. Elastin gene mutations.
Aortic valve or LV outflow tract obstruction	Deletion of chromosome locus 11q or 10q. Trisomy 13 or 18. Duplications of chromosome locus 1q, 2p, 2q, 6q, or 11q. NOTCH 1 gene mutations. Noonan, Turner, or Jacobsen syndromes. Pregestational diabetes. Maternal vitamin A exposure.
Atrial septal abnormalities	Holt Oram, Ellis-van Creveld, Noonan, Rubinstein-Taybi, Kabuki, Williams, Goldenhar, thrombocytopenia-absent radius, Klinefelter, or (rare) Marfan syndrome. Mutations of TBX5 gene on chromosome 12q24.1, NKX2.5 gene on chromosome 5, EVC gene on chromosome 4p16.1, MYH6 gene, or GATA 4 gene. Deletions on chromosome 1, 4, 4p, 5p, 6, 10p, 11,13,17,18, or 22. Trisomy 18 or 21. Pregestational diabetes. Familial ASDs with AV conduction disturbances without extracardiac manifestations (may also have VSD, TOF, and others) has been associated with mutations of NKX2.5 on chromosome 5. Familial ASD without AV conduction disturbances without extracardiac manifestations (may also have VSD and/or PS) has been associated with mutations of GATA 4 gene with variable expression and autosomal dominant inheritance. This condition has also been associated with mutations of NKX2.5 on chromosome 5.
Atrioventricular septal abnormalities/atrioventricular canal/endocardial cushion defects	Trisomy 21, 13 or 18. Deletions of chromosome 3p25, 8p2, or 22q. Duplications of chromosome 10q, 11q, 22q. Holt-Oram, Noonan, Smith-Lemli-Opitz, or Ellis-van Creveld syndrome. Mutation of gene on chromosome 1p21-p31. CRELD1 gene mutations. Chondrodysplasias. Pregestational diabetes. Maternal exposure to organic solvents. Familial AVSD (partial or complete) without extracardiac manifestations has been associated with gene locus on 1p21-p31 mutation with autosomal dominant inheritance.
Bicuspid aortic valve	Turner syndrome. Familial left-sided obstructive heart defects. Deletion of chromosome locus 10p. Duplications in chromosome 6q. Trisomy 13 or 18. BAV without extracardiac manifestations may be associated with other CHDs (especially CoA) and ascending aortic aneurysm is associated with Notch1 gene mutations with autosomal dominant inheritance.
Conotruncal defects (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch and others)	Deletion of chromosome 22q11.2. Mutations of NKX2.5 and 2.6. Pregestational diabetes. Maternal exposure to organic solvents.
Double-outlet right ventricle	Trisomy 9, 13, or 18. Duplications on chromosome 2p or 12p. Deletion of 22q11 (rare).
Ebstein anomaly	Most cases are sporadic. Chromosome abnormalities are rare. Has been reported with Trisomy 21, abnormalities of 11q with renal malformation, and Pierre Robin sequence. Familial occurrences are rare but are associated with family members with mitral valve abnormalities or with familial atrial conduction problems. Animal studies are suggestive of a genetic connection with genes on chromosome 17q. Maternal marijuana. Maternal exposure to organic solvents.
Heterotaxy syndromes with complex CHD—laterality and looping abnormalities	Chromosome locus 2 (CFC1 gene encoding CRYPTIC protein), 6q (HTX3 gene), LEFTY A gene, or X-linked q26.2 or Xq24-47 (ZIC3 gene). Pregestational diabetes.
Hypoplastic left heart syndrome	Deletion of chromosome locus 11q (Jacobsen syndrome). Turner or Wolf-Hirschhorn (deletion of 4p) syndromes. Trisomy 13 or 18. Familial left-sided obstructive heart defects. Pregestational diabetes. Maternal exposure to organic solvents.
Interrupted aortic arch	Deletion 22q11.
Left-sided obstructive heart disease—familial—CoA, aortic atresia/HLHS, BAV	Increased occurrence of these lesions in first-degree relatives. Inheritance patterns may be multifactorial, autosomal dominant with reduced penetrance, or autosomal recessive.
Left superior vena cava persistence	60% have other anomalies, 87% have other CHD, and 42% syndromes or other conditions (VACTERL, Down’s syndrome, CHARGE).
Patent ductus arteriosus	Char syndrome. Mutations of TFAP2B. Pregestational diabetes. Indomethacin tocolysis.
PA branch stenosis	Alagille, congenital rubella, Ehlers-Danlos, Noonan, Costello, Cardiofaciocutaneous, LEOPARD, or Williams-Beuren syndromes. Deletions in chromosome locus 20p12. JAG1 gene mutation. Pregestational diabetes. Maternal vitamin A exposure. Maternal exposure to organic solvents.
Pulmonary Valve Obstruction	Noonan, Alagille, Costello, or LEOPARD syndromes. Mutations of PTPN11, KRAS, SOS1, and HRAS genes. Chromosome deletions of 1p, 8p, 10p, or 22q. Chromosome duplications of 6q, 15q, or 19q. Trisomy 8. Maternal vitamin A exposure. Maternal exposure to organic solvents. Maternal rubella.
Tetralogy of Fallot	Deletion of 22q11, 5p or many other chromosomes. Duplication on chromosome 22 and many other chromosomes. Alagille (JAG1 gene), Noonan (PTNP11), Cat-eye, and nearly 50 other syndromes. Trisomy 18 or 21. Partial trisomy 8q. Translocation 1p36. Maternal exposure to organic solvents. Isolated TOF is associated with NKX2.5 mutations.
Total anomalous pulmonary venous return	Most cases are sporadic. Trisomy 8. Familial cases have been reported with familial scimitar syndrome and a chromosome 4p13-q12 abnormality with autosomal dominant inheritance and variable expression (a large Utah-Idaho family). Maternal exposure to organic solvents.
Transposition of great arteries	Rarely associated with chromosome abnormalities or syndromes. Pregestational diabetes. Maternal exposure to organic solvents.
Tricuspid atresia	Most cases are sporadic. Chromosome abnormalities are rare with tricuspid atresia, but deletions of 22q11 and 4p and duplications of chromosome 22 have been reported. Familial occurrences are rare but have been reported. A gene mutation has been associated in mice, which suggests a genetic basis for this disease.
Truncus arteriosus	Deletion on chromosome 22q11 or 10p. Trisomy 8. An autosomal recessive form has been mapped to chromosome 8p21.
Ventricular septal abnormalities	Holt Oram, Rubinstein-Taybi, Goldenhar, Costello, Williams, Kabuki, Cornelia de Lange, Apert, or Carpenter syndrome. VACTERL association. Familial ASD with or without AV conduction disturbances. TBX5 or GATA 4 mutation. Deletions or duplications of many chromosomes. Trisomy 13, 18, or 21. Pregestational diabetes. Maternal marijuana. Maternal exposure to organic solvents. Septal defects without extracardiac manifestations are associated with mutations in MYH6 and CITED2 genes.

ADD, Attention deficit disorder; AS, aortic stenosis; ASD, atrial septal defect; AV, atrioventricular; AVC, atrioventricular canal; AVSD, atrioventricular septal defect; BAV, bicuspid aortic valve; CA, coronary artery; CHD, congenital heart defect; CNS, central nervous system; CoA, coarctation of aorta; CV, cardiovascular; DCM, dilated cardiomyopathy; DORV, double-outlet right ventricle; GI, gastrointestinal; GU, genitourinary; HCM, hypertrophic cardiomyopathy; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; IVC, inferior vena cava; LSVC, persistent left superior vena cava; LV, left ventricular; LVOTO, left ventricular outflow tract obstruction; MV, mitral valve; NSAIDs, nonsteroidal antiinflammatory drugs; PA, pulmonary artery; PAPVR, partial anomalous pulmonary venous return; PAtresia, pulmonary atresia; PDA, patent ductus arteriosus; PKU, phenylketonuria; PPS, peripheral pulmonary stenosis; PS, pulmonary stenosis; RVOTO, right ventricular outflow tract obstruction; SVC, superior vena cava; SVT, supraventricular tachycardia; TAPVR, total anomalous pulmonary venous return; TEF, tracheoesophageal fistula; TGA, transposition of great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

See Table 8-2 for more information on specific genes, syndromes, and conditions.

Table 8-2 Conditions, Cardiac Manifestations, and Genetics

Genetic Testing, Counseling, and Nursing Implications

Genetic testing can reveal important genetic patterns that are critical for identifying other important organ system involvement; gaining prognostic information; learning important reproductive risks for the family; and considering the appropriate testing of other family members.⁷⁰⁰ Genetic testing can be performed on blood lymphocytes, cord blood, skin, amniotic fluid, chorionic villi, and bone marrow. Current genetic tests available to be used in assessing CHD include:

• Standard chromosome analysis—reveals standard karyotype and is used to identify many chromosomal disorders, especially those in which there is an abnormal number of chromosomes.⁷⁰⁰

• High resolution banding—better defines chromosomal structure abnormalities such as duplications, deletions, and translocations of genetic material.⁷⁰⁰

• Fluorescence in situ hybridization (FISH)—specific DNA probes can be used to diagnose more subtle structural abnormalities such as microdeletions, tiny duplications, and/or subtle translocations.⁷⁰⁰

• Array comparative genomic hybridization (A-CGH)—even more sensitive than FISH for testing for tiny structural abnormalities of chromosomes.⁸⁶⁸

• Gene discovery—cloning techniques are used to identify genes that produce a protein associated with cardiogenic gene mutations.⁷⁰⁰

• DNA mutation analysis—identifies changes in the coding sequence of a gene to find small deletions, duplications, or substitutions that alter the resulting protein structure. Once a change is found, it must be determined if it constitutes a disease-causing mutation.⁷⁰⁰

As more etiologic genes are identified, progress can be made in determining mechanisms and interactions that cause various phenotypes. That may lead to the development of targeted therapies for patients and fetuses.⁸⁷¹

Genetic counseling is warranted when there is one major or two minor birth defects and may be employed to attempt to determine exact causes of anomalies in individual situations. Testing must be accurately ordered to direct the proper studies to obtain complete results. Simply ordering a karyotype will not achieve the targeted exploration that can be achieved with FISH or A-CGH studies. Information gathered enables practitioners to counsel the family on problems associated with a condition, allowing them to be proactive in their child’s care. Discussions with the family should be informative but not directive so that parents may make their own decisions.^190,⁶⁵¹

At the very least, preconceptual and prenatal counseling of all women of child-bearing age is important to encourage the use of multivitamins and folic acid supplements, avoiding contact with people with flu or other febrile illnesses, and avoiding exposure to organic solvents during pregnancy. Targeted counseling should be done with women who have specific risk factors to discuss any medications that must be considered with pregnancy. Prenatal testing is also available for some conditions, and early diagnoses can affect care management, morbidity, mortality, and family well-being.

Another feature of genetic counseling is providing recurrence risks. With the exception of possibly teratogen exposures, parents can be counseled that their actions did not cause the condition. For chromosomal deletions, duplications, translocations, and gene anomalies, parental testing may be recommended to determine recurrence risks. In cases of gene anomalies, commercial testing is available for some mutations. Testing capabilities continue to expand so follow-up genetic consultation may be warranted to realize the advantages of new technologies.

Recurrence risks for chromosomal trisomies are low if there are no other birth defects in the family and maternal age is not advanced. For a parent with an autosomal dominant genetic anomaly, there is a 50% risk of recurrence. In parents who have an autosomal negative genetic anomaly (without the evidence of the problem), both parents must have the anomaly to cause the resulting disorder. In these cases the recurrence risk for the couple is 25%. In X-linked recessive anomalies, the risk is 50% for a male to be affected and 50% for a female to be a carrier. In cases of unknown etiology (possibly multifactorial inheritance), if no other child in the family is affected the recurrence risk is presumed to be 3% to 5%, but this changes if a subsequent sibling is affected.^190,⁶⁵¹

Information about genetic conditions is widely available via websites and targeted support groups and associations (e.g., Online Mendelian Inheritance in Man, www.ncbi.nlm.nih.gov/Omim/). Web-based databases and support groups that provide valuable information are provided in the Chapter 8 Supplement on the Evolve Website.

The nursing implications of genetics involvement in congenital heart defects are significant. Nurses who are familiar with the patterns of anomalies can have a heightened index of suspicion when a single malformation is noted and findings can be unmasked. Nursing knowledge can be enhanced by familiarity with the most current scientific statements from the American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young on both the genetic basis and the noninherited risk factors for congenital heart disease.^414,⁷⁰⁰

Nurses are in a unique position to gather information from families and communicate those findings. Facts about previous pregnancies, parents’ siblings, childhood deaths, other birth defects, exposures, and much more can be revealing. Nurses are also in a unique position to support families through these challenging situations. Nurses must be prepared to provide families with appropriate resources and encourage referrals.

This quote from Joey’s Journey: Our Life with Lissencephaly, at http://lfurlotte.tripod.com expresses how parents may feel when they begin a journey with a child affected by anomalies and the support others can provide: “Life will never be the same again. However, with a little different perspective, life does go on and happiness does return.”⁴¹⁵

Fetal development of the heart and great vessels

Mary Rummell

Formation of the Heart Tube: Day 22

The cardiovascular system is the first system to function in the embryo. The critical period of cardiovascular growth begins at 15 to 18 days of gestation and is initiated by a period of rapid cell proliferation. During this period, the developing heart is most susceptible to teratogens (factors that can be harmful). Early development of the cardiovascular system is necessary because of the increasing need for nutritional and oxygen requirements by the rapidly growing embryo and for elimination of carbon dioxide and waste products. Moore et al.,⁶²⁷ Ransom and Srivastava,⁷²³ and Sander et al.,⁷⁶⁴ describe heart development as involving five primary steps:

1. Migration of precardiac cells from the primitive streak and assembly of paired cardiac crescents at the myocardial plate

2. Coalescence of the cardiac crescents to form the primitive heart tube, an event that establishes the definitive heart

3. Cardiac looping, a complex process that assures proper alignment of the future cardiac chambers

4. Septation and heart chamber formation

5. Development of the cardiac conduction system and coronary vasculature

The primordial heart and vascular system appear in the middle of the third week. The cardiovascular system is primarily derived from embryonic mesoderm and neural crest cells. The precardiac stem cells (mesoderm) migrate to form the cardiac crescents that fuse to form the single heart tube at 22 days (Fig. 8-1).^627,^723,^764,⁹⁰²

Fig. 8-1 Cardiac embryologic development—coiling of the heart tube. At approximately the 21st to 22nd day of fetal life, the two lateral endothelial heart tubes fuse to form a single endocardial tube. A, Between the 22nd and 28th days of life, the heart tube thickens. B, and C, the tube then coils to the right. D, By approximately the 28th day of fetal life, the tube is completely coiled, and major chambers can be identified. At this time, blood is flowing through the heart, and septation of the heart and great vessels can occur.

(Illustration by Marilou Kundemueller.)

At this time (22 days), circulation begins with ebb-and-flow blood flow from the venous to arterial poles. Premyocardial cells and neural crest cells continue to migrate into the region of the heart tube. The regulation of the mesoderm is partially controlled by retinoids, isoforms of vitamin A, that bind to specific nuclear receptors and regulate gene transcription and by extracellular matrix proteins, such as fibronectin, that direct cellular migration. The teratogenic effects caused by interaction of retinoid-like drugs on cell receptors are seen clinically (see Noninherited Risk Factors).⁷⁹

Formation of the Heart Loop: Day 22 to 28

Before and during the looping process, sections of the single heart tube begin to develop specialized cells that will ultimately become the chambers of the mature heart. A cascade of genes is expressed in the anterior (ventricular) and the posterior (atrial) portions of the tube. These genes regulate the cellular processes that transform the heart tube into a four-chambered heart. This transformation occurs through a balance of cell growth, cell differentiation, and cell death (apoptosis). Disruptions in these genetic mechanisms and specific cellular signaling processes result in cardiac malformations seen in congenital heart disease. Problems include defects in cardiac looping, septation, and chamber formation.⁷⁶⁴

The endocardial heart tube begins to expand and elongate and develops areas of dilation: the bulbus cordis (including the truncus arteriosus, conus arteriosus, and conus cordis), ventricle, atrium, and sinus venosus. This expansion and elongation results in coiling of the heart tube anteriorly and to the right (this is referred to as “dextral,” or “D-looping”), with creation of a bulboventricular loop (see Fig. 8-1, B and C).

Because the venous and arterial poles of the heart tube are fixed during this time of coiling, torsion occurs within the anterior portion of the loop, the truncus arteriosus. This torsion will later contribute to the formation of a spiral septum within the truncus. By the 26th day of gestation, a truncus arteriosus is visible in the center of the anterior portion of the heart, and a common atrium and ventricle are recognizable (see Fig. 8-1, D). By day 28 the looping process is complete.

The embryonic heart begins to contract by day 26 to 28, with cycles that are similar to those in mature hearts.⁷² In this “in-series circulation,” blood flows from the morphologically right atrium to the morphologically left atrium, left ventricle, right ventricle and then the truncus arteriosus.⁹⁰²

As the common atrium and ventricle divide into the chambers of the right and left heart, individual chambers are identified by their structure and appearance, or morphology. Structures should be identified by morphology rather than location because the location of the ventricles and great vessels may be abnormal when congenital heart disease is present.

When the ventricles rotate or loop normally to the right, a D-bulboventricular loop has occurred. The anatomic (i.e., morphologic) right ventricle is anterior (and to the right), and the anatomic (i.e., morphologic) left ventricle is posterior (and to the left). Later, normal division of the great vessels will result in location of the aorta posterior and to the right of the pulmonary artery. When the great vessels are in normal position and relationship, they are labeled “d-related great vessels” because the aorta is located to the right (dextral) of the pulmonary artery.

Malrotation during the formation of the ventricular loop may cause various cardiac malpositions (such as dextrocardia) and malformations. As noted, the normal direction for the ventricular loop is to the right, or D-looping. If the ventricles loop to the left instead, L-looping has occurred, so the morphologic left ventricle is located to the right, and the morphologic right ventricle is on the left (Fig. 8-2).

Fig. 8-2 Cardiac loop formation, The primordial heart tube during the fourth week. A, Normal looping (bending) to the right. B, Abnormal looping (bending) to the left.

(From Moore KL, Persaud TVN, Torchia MG: The cardiovascular system. The developing human: clinically oriented embryology, ed 8. Philadelphia, 2008, Saunders Elsevier.)

L-looping of the ventricles frequently is associated with transposed great vessels; this combination commonly is referred to as “corrected transposition of the great arteries.” It is a type of “transposition,” because the aorta lies to the left of the pulmonary artery. The great vessels are transposed: the ascending aorta is anterior and arises from an anatomic (morphologic or structural) right ventricle, sweeping to the left, and the pulmonary artery is posterior and arises from the anatomic (or morphologic or structural) left ventricle. The term “corrected” is appropriate because the hemodynamic pathways are not altered; systemic venous return ultimately enters the pulmonary circulation, and pulmonary venous return enters the systemic circulation. The systemic venous return enters the right atrium, flows through a mitral valve into a morphologic left ventricle, and is then ejected into a posterior pulmonary artery. The pulmonary venous return flows into the left atrium, exits through a tricuspid valve into a structural right ventricle and is then ejected into an anterior aorta. Although the heart is not normal, the child will be asymptomatic unless a complicating heart lesion is present.

Complete congenital heart block, ventricular septal defect, tricuspid valve anomalies, and cardiac malpositions are common among children with l-transposition. It is important to remember that the mitral valve is located with the morphologic left ventricle in corrected transposition, and that these structures receive systemic venous return; the tricuspid valve is associated with the morphologic right ventricle, receiving pulmonary venous return. Therefore if tricuspid atresia is present, obstruction to pulmonary venous return occurs (because the tricuspid valve is located abnormally on the left side). Ebstein’s malformation, an abnormality of the tricuspid valve, produces signs associated with mitral insufficiency (e.g., pulmonary edema). The use of the phrase “ventricular inversion with transposed great vessels” probably would be less confusing than “corrected transposition.”

Formation of Cardiovascular Septation: Day 26 to 49

Cardiac septation occurs after the looping process is complete. During the septation process, septae are formed that ultimately close the ostium primum, the central atrioventricular canal, and the interventricular foramen. At the end of this period, the in-series circulation becomes two parallel circulations.⁹⁰²

Endocardial Cushion Development: Day 26 to 40

Septation begins on day 26 with the ingrowth of large tissue masses, the endocardial cushions. These cushions form on the dorsal and ventral walls of the atrioventricular (AV) canal separating the primordial atrium from the primordial ventricle.⁶²⁷ These cushions contain mesenchymal cells, derived from endocardium, and cardiac jelly, derived from endothelium. The endothelial cells line the atrioventricular canal and conotruncal segments. Neural crest cells migrate into the pharyngeal arches and then to the endocardial cushions, where they play a role in the septation of the cardiac chambers, outflow tracts, and heart valves. From the endocardial cushions, the neural crest cells then invade the myocardium.

Genetic disruptions in neural crest cell development are not fully understood, but patients with DiGeorge, Alagille, and Noonan syndrome have congenital heart defects that are influenced by cardiac neural crest cells.⁷⁶⁴

Defects in the formation of the endocardial cushions can result in an ostium primum atrial septal defect, a ventricular septal defect (that may allow an interventricular shunt, or simply may result in a deficiency of ventricular septal tissue), anomalies of the tricuspid and mitral valves (including tricuspid atresia), or in a complete atrioventricular septal defect (AVSD, also referred to as AV canal).

Atrial Septation: Day 30 to 35

Septation of the atria begins around day 30. Two septae develop and are modified to form a flapped orifice, the foramen ovale as illustrated in Fig. 8-3. The first septum to form is the septum primum, which grows from the anterior, superior portion of the atrium and extends toward the center of the heart. The development of the septum primum leaves a gap, the ostium primum, in the inferior portion of the atrial wall; this gap normally is closed by the fusion of the endocardial cushions. As the ostium primum is closing, perforations produced by apoptosis begin to form in the central portion of the septum primum. These perforations coalesce to create the ostium secundum (see Fig. 8-3, C and D).⁶²⁷

Fig. 8-3 Atrial and ventricular septation. (A-E) Drawings of the developing heart showing partitioning of the atrioventricular canal, primordial atrium and ventricle. A, Sketch showing the plane of the sections. B, Frontal section of the heart during the fourth week (approximately 28 days) showing the early appearance of the septum primum, interventricular septum, and dorsal endocardial cushion. C, Similar section of the heart (approximately 32 days) showing perforations in the dorsal part of the septum primum. D, Section of the heart (approximately 35 days) showing the foramen secundum. E, At approximately 8 weeks, showing the heart after it is partitioned into four chambers. The arrow indicates the flow of well-oxygenated blood from the right to the left atrium. F, Sonogram of a second trimester fetus showing the four chambers of the heart. Note the septum secundum (arrow) and the descending aorta.

(Courtesy of Dr. G. J. Reid, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Manitoba, Women’s Hospital, Winnipeg, Manitoba, Canada.) (From Moore KL, Persaud TVN, Torchia MG: The cardiovascular system. The developing human: clinically oriented embryology, ed 8. Philadelphia, 2008, Saunders Elsevier.)

The septum secundum is the second septum to form within the atria. It is a thick crescent-shaped muscular fold that grows immediately adjacent to the septum primum. As it grows, it overlaps the foramen secundum in the septum primum. The atrial partition is incomplete, forming an oval foramen (in Latin, the foramen ovale).⁶²⁷

The portion of the septum primum that is attached to the cranial portion of the atrium gradually disappears. The remaining portion of the primum septum that is attached to the fused endocardial cushions forms the flap of tissue called the valve of the oval foramen.⁶²⁷

Before birth the foramen ovale allows the oxygenated blood from the placenta entering the right atrium via the inferior vena cava to flow to the left atrium and to the fetal brain. (See section, Fetal Circulation that follows.) The flap of the oval foramen normally prevents flow in the opposite direction.⁶²⁷

Atrial septal defects occur when the primum septum or the secundum septum or both do not completely form. Atrial septal defects include an ostium primum, secundum atrial septal defect, or common atrium. An ostium primum atrial septal defect is located near the atrioventricular valves. This defect will not close spontaneously. An ostium secundum atrial septal defect is thought to result from excessive apoptosis of the septum primum, so that a large defect is present in the area of the foramen ovale. Some secundum defects decrease in size and some undergo spontaneous closure.⁷²³

Ventricular Septation: Day 25 to 49

Septation of the ventricles begins around day 25 with protrusions from the inlet (primitive ventricle) and outlet (bulbus cordis) segments of the primordial heart. The muscular intraventricular septum initially grows from the apex of the ventricle and increases with dilation of both ventricles. With rapid proliferation of the myoblasts in the septum, the muscular septum extends toward the center of the heart.^79,⁶²⁷ At first there is a crescent-shaped intraventricular foramen between the septum and endocardial cushions. The right and left bulbar ridges and the fused endocardial cushions join with the intraventricular muscular septum to form the membranous septum, obliterating the intraventricular foramen (refer again to Fig. 8-3, B-E).

As the ventricular cavities develop, the walls form a sponge work of muscular bundles. Some of the bundles become the papillary muscles and the tendinous cords (Latin, chordae tendineae) of the atrioventricular valves.⁶²⁷ Ventricular septal defects can occur in any location in the developing ventricular septum. Some muscular defects will close spontaneously.⁷²³

Septation of the Truncus Arteriosus: Day 26 to 42

Active proliferation of the mesenchymal cells in the walls of the bulbus cordis form the conotruncal or bulbar ridges. Similar ridges form in the truncus arteriosus (Fig. 8-4).

Fig. 8-4 Division of truncus arteriosus into pulmonary artery and aorta. Partitioning of the bulbus cordis and truncus arteriosus. A, Ventral aspect of heart at 5 weeks. The broken lines and arrows indicate the levels of the sections shown in B. B, Transverse sections of the truncus arteriosus and bulbus cordis, illustrating the truncal and bulbar ridges. C, The ventral wall of the heart and truncus arteriosus has been removed to demonstrate these ridges. D, Ventral aspect of heart after partitioning of the truncus arteriosus. The broken lines and arrows indicate the levels of the sections shown in E. E, Sections through the newly formed aorta (A) and pulmonary trunk (PT), showing the aorticopulmonary septum. F, 6 Weeks. The ventral wall of the heart and pulmonary trunk has been removed to show the aorticopulmonary septum. G, Diagram illustrating the spiral form of the aorticopulmonary septum. H, Drawing showing the great arteries (ascending aorta and pulmonary trunk) twisting around each other as they leave the heart.

(From Moore KL, Persaud TVN, Torchia MG: The cardiovascular system. The developing human: clinically oriented embryology, ed 8. Philadelphia, 2008, Saunders Elsevier.)

The mesenchymal cells in these ridges are primarily from neural crest cells. As cell proliferation occurs, the truncal and bulbar ridges create a 180-degree spiraling. This spiraling may be enhanced by the streaming of blood from the ventricles, as illustrated, or may result from passive untwisting as the pulmonary artery passes from the anterior pulmonary valve to the posterior pulmonary bifurcation.⁹⁰²

The spiraling of the conotruncal septum aligns the future pulmonary artery to the anterior and rightward right ventricle, where it joins with the outflow tract (infundibulum) created by incorporation of the bulbus cordis into the right ventricle. The future aorta communicates with the posterior and leftward left ventricle at the aortic vestibule created by incorporation of the bulbus cordis below the aortic valve.⁶²⁷ Differences in cell growth create a separation between the tricuspid and pulmonary valve. Disappearance of this segment below the aortic valve provides fibrous continuity between the mitral and aortic valve.⁷⁹

Defects in the conotruncal and aortic arch development do not close spontaneously. Congenital heart defects that result from defective conotruncal development include: truncus arteriosus, tetralogy of Fallot, pulmonary atresia, double-outlet right ventricle, interrupted aortic arch, and aortopulmonary window. These defects are often associated with genetic deletions of chromosome 22q11 (see section, Genetic Factors Associated with CHD).^627,⁷²³ Failure of appropriate conal reabsorption of the subaortic conus is thought to produce improper truncal rotation and result in d-transposition of the great vessels.

Formation of the Cardiac Valves: Day 34 to 42

The semilunar valves form when truncal septation is nearly complete. They develop from three swellings of subendocardial tissue around the openings of both the aortic and pulmonary trunks. The signaled transformation of endocardial cells to mesenchymal cells creates the differentiation of fibrous valve tissue.³⁰ This fibrous tissue is hollowed out and reshaped to form three thin-walled cusps for each valve.⁶²⁷ Congenital heart defects that result during valve formation include pulmonary valve stenosis or atresia, pulmonary infundibular stenosis, a bicuspid aortic valve, and aortic stenosis.

The atrioventricular valves develop from localized proliferation of tissue around the atrioventricular canals.⁶²⁷ Most of the atrioventricular valve tissue comes from the ventricular myocardium in a process that involves undermining the ventricular walls. This process is asymmetric and positions the tricuspid valve annulus closer to the apex of the heart than the mitral valve annulus. Physical separation of these two valves creates the atrioventricular septum. Absence of this septum is the common defect in children with atrioventricular septal defects. Ebstein anomaly is thought to result from incomplete undermining of the ventricular wall.⁷⁹

Classification of Complex Cardiac Malpositions and Malformations

Complex cardiac malformations and malpositions can be described according to a labeling system proposed by Van Praagh.⁹⁰² This classification included 10 cardiac segments, but three were used most often. The positions of the viscera, the ventricular loop, and the great arteries are all labeled separately, using three letters within curved brackets, such as {A, B, C}.

The cardiac chambers and organ segments are identified by morphology (i.e., structure and appearance); the segments then can be referred to as concordant (consistent in position), or discordant (inconsistent in position). Although this segmental description of congenital heart defects is not used for the most common forms of defects, it is used in the classification of cardiac malpositions (e.g., dextrocardia or dextroversion) and complex transpositions. A variation of the Van Praagh segmental classification has been published recently ³⁴³ using six segments (systemic and pulmonary veins, atrial situs, atrioventricular connection, ventricles and infundibulum, ventricle to artery connection, and great arteries and the ductus arteriosus). The following section identifies the three most commonly used segments for identification.