Potential risk factors

Genetic factors Therapeutic drugs Infections and maternal disorders Toxic exposures

• Familial occurrence of congenital heart disease
  In the Baltimore Washington Infant Study (BWIS) there was a two-fold excess of familial congenital heart disease in the total group of cases in comparison to controls. However there was considerable variation between the anatomic types of the cardiac anomalies. The family history of congenital cardiac disease was statistically associated with 11 of the 18 diagnostic subgroups.This association was present for patients with mild as well as for patients with severe cardiac defects. Additionally there was evidence of a complex etiology since the family history was only one of several potential risk factors.
  
  The BWIS provided a unique opportunity to evaluate the concordance of sibling malformations by the enrollment over the 9-year study period of a second affected child. Among 20 such sibling pairs there was high concordance of the cardiac defects and non-cardiac defects. Genes known to be associated with cardiac abnormalities appeared in the infants and their families.
  There was a single family with transmission of an atrial septal defect across three generations with a conduction defect in the older siblings and adults. This represents a well known special type of atrial septal defect which was recently explained by a mutation in a transcription factor which controls early cardiac development (Schott, 1998)

  It is now known that the same malformation may result from mutations in different genes and that various forms of an anomaly may represent different manifestations of the same gene. The BWIS found this to be true for the various forms of left heart obstruction that were present in relatives of infants with hypoplastic left heart syndrome, coarctation of the aorta or aortic valve abnormalities.Such genetic liability was also evident among cases of atrioventricular septal defects among whom 3 infants with Down syndrome had families in which a partial form of the defect was present: 2 in mothers and one in a sister (Ferencz, 1989).

  Similarly in infants with ventricular septal defect the familial expression of congenital heart disease included severe anomalies of the outflow tract of the heart such as tetralogy of Fallot, transposition of the great vessels or common arterial trunk.
  

• Chromosomal Abnormalities

  Numerical Excesses or Deficiencies

  Major genetic defects such as chromosomal abnormalities were recognized as a causal association with congenital heart disease 50 years ago with the identification of numerical excesses or deficiencies. Trisomy 21, which is responsible for Down syndrome, is characteristically associated with an atrioventricular septal defect as well as other cardiac abnormalities. The same is true for trisomy18. Absence of the Y chromosome, causes Turner's syndrome with coarctation and other left-sided heart anomalies.

  In the Baltimore Washington Infant Study (BWIS), 12 % of the cases had a chromosome anomaly. There was a distinctive distribution of cardiac diagnoses in the three major types of trisomy: atrioventricular septal defect was present in 59% of trisomy 21 cases, 24% of trisomy 18 cases, and none of the trisomy 13 cases. In contrast outflow tract defects, made up 50% of Trisomy13-15 cases, 18% of trisomy 18 cases, and only 6% of trisomy 21 cases.These findings suggest specific developmental relationships.

  Structural Abnormalities

  Since the BWIS was completed there has been a rapid expansion of information on deletions within chromosomes associated with specific cardiac and non-cardiac defects. This is a rapidly advancing field of knowledge. (Goldmuntz, 2001)
  

  Structural abnormalities of chromosomes, such as deletions of a small segment, as of chromosome 22q11, occur among patients with tetralogy of Fallot and persistent arterial trunk. A common arterial trunk in association with thymus and facial abnormalities constitutes the DiGeorge syndrome, which is also found with other forms of congenital heart disease including aortic arch defects (Goldmuntz, 2001, McElhinney, 2001). Deletions of chromosome 22 have also been found in families in which both congenital heart disease and neural tube defects have occurred (Kousseff Syndrome) (Forrester, 2002).

• Genetic Complexes
  Embryologic disturbances that may be due to gene mutations may lead to congenital heart disease and also to abnormalities in other organ systems. Combinations of these abnormalities define specific entities that may be expressed in various members of the family. Recognition of even mild abnormalities may indicate an increased genetic risk for the offspring of adults with congenital heart disease.
  
  Complexes of multisystem malformations are of a great variety. In the Baltimore-Washington Infant Study about 5% of the patients were so diagnosed. In the Study's report, Dr. I.W. Lurie discussed the various syndromes. His table of 55 syndromes that occurred in the study shows the combinations of abnormalities, frequency of associated heart disease, presumed etiology and references to the Birth Defects Encyclopedia. (Lurie, 1997)
  
  Common associations included the Noonan and the Holt-Oram syndrome as well as the Williams syndrome, which has now been demonstrated to represent a microdeletion of chromosome 7q11. With advancing knowledge in chromosome structure other syndromes are likely to be more precisely identified.

• Heritable coagulation disorders
  An important finding of the Baltimore Washington Infant Study (BWIS) was the recognition that familial clotting abnormalities, such as hemophilia and Von Willebrand's disease were confined to case families and did not occur in controls. This suggested the hypothesis that coagulation defects may play a role in cardiac development. (Ferencz 1984) This proposal was further evaluated coincidentally with the dramatic advances in Vascular Biology which followed the successful culture of endothelial cells and the determination of their manifold biologic functions.(Ferencz, 2000) The hypothesis has found support in the work of cell biologists (English, 2002) and in clinical observations (DiGiglio 2001) of severe congenital heart disease, notably transposition of the great arteries, in hemophiliac families. (Ferencz, 2002)
  

Current advances in molecular genetics explore the mechanisms of protein formation and cellular signals with an explosive extension of our understanding of heredity and development. These will become the new horizons representing the "closed doors" referred to by Nora.

Selected References

Selected Web Resources

• GeneTests - By providing current, authoritative information on genetic testing and its use in diagnosis, management, and genetic counseling, GeneTests promotes the appropriate use of genetic services in patient care and personal decision making.
  It is funded by the National Institutes of Health.
  
  
• HuGENet™ - Human Genome Epidemiology Network from the CDC is a global collaboration of individuals and organizations committed to the assessment of the impact of human genome variation on population health and how genetic information can be used to improve health and prevent disease.
  
  
• National Society of Genetic Counselors - The mission of the society is to promote the genetic counseling profession as a recognized and integral part of health care delivery, education, research and public policy.
  

• Rubella
  The recognition that the live virus of German measles persists in the fetus as a cause of permanent abnormalities opened up a new chapter in the study and prevention of birth defects. The association was brought to light by an Australian ophthalmologist, who recognized an unusual frequency of congenital cataracts in newborns during a time of an epidemic of rubella (Gregg, 1941). Soon the additional cardiac defects of patent arterial duct and peripheral pulmonic stenosis were also found to be linked to this infection (Rose 1972, Rowe 1978). The development of immunization programs to include rubella immunity has virtually eliminated this major teratogen in developed countries. No case occurred in the BWIS.
  
  
• Influenza
  A maternal history of possible influenza in the earliest weeks of pregnancy would be difficult to evaluate but was searched for in the Baltimore Washington Infant Study (BWIS). Only a single defect, transposition of the great arteries with intact ventricular septum, revealed a 2-fold statistical excess of such a history, but the odds were increased to 5-fold in the presence of ibuprofen treatment. These findings are based on small numbers, but are worthy of further attention, as this is a unique malformation with very few other associations.
  
  
• Maternal diabetes
  In pre-insulin days women with diabetes were seldom able to bear children but with insulin control they have achieved a normal life course, and successful pregnancies. However their infants are at risk for malformations of the cardiovascular, renal and central nervous systems. Recent advances in the care of high-risk mothers with better control of blood sugar levels has reduced the risk to population levels under close obstetrical care. A major problem remains in women, who are not aware of their diabetic status and present for maternity care too late to institute an adequate level of blood sugar control during the earliest susceptible period of pregnancy (Reece EA 1996, 1998).
  
  In the Baltimore Washington Infant Study (BWIS), maternal diabetes was found to be specifically associated with certain cardiac defects: a 3-fold risk for all cases (excluding chromosomal and other genetic conditions) was increased to 4.7- fold for early CVM , and to 23-fold for cases with complete, but not partial, atrioventricular septal defects (Loffredo 2001). There was also a 12-fold increase in the risk of maternal diabetes for cases of early CVM with associated non-cardiac abnormalities . Low birthweight and prematurity were responsible for an increased mortality in the first year of life (Loffredo 2001).
  
  
• Maternal phenylketonuria
  No infant in the BWIS had a history of maternal phenylketonuria but the occurrence of severe cardiac defects has been reported in infants whose mothers had phenylketonuria and had been raised on low phenylalanine diets. These mothers had relaxed their attention to their diets prior to pregnancy. This is a remarkable story of the success of a public health program with failure of its long-tem completion (Pass, 2000).

Selected References

A wide range of drugs has been shown to have adverse effects on the developing fetus and such a possibility has formed the basis of strict evaluation of every new therapeutic agent. The licensing for distribution and the surveillance of adverse effects is the responsibility of the Food and Drug Administration.

The Baltimore Washington Infant Study (BWIS) gave great attention to the recall of drug intake of the study mothers. Rubin (1993) found that more than half of the mothers used at least one medication during early pregnancy. In the analyses of all cardiac defects as a group only three drugs appeared as possible risk factors: diazepam, metronidazole and ibuprofen. In the diagnosis-specific analyses possible associations were also found for antitussives, chlomiphene, corticosteroids and benzodiazepines as a category of psychotropic, tranquilizing drugs. Early CVM were associated with the latter agents, but the number of exposed mothers was small .

Selected References

Although experimental studies have well established the adverse effects of toxic agents on fetal development, the list of agents affecting human development has been quite short ( Schardein, 2000, Shepard, 2004). The difficulty of defining adequate research methods includes the certainty and measures of exposures, the timing of exposures during pregnancy and the possibility of differing genetic susceptibility of the study subjects.

In the Baltimore Washington Infant Study (BWIS) potentially harmful environmental exposures were considered as substances used in parental life style, such as alcohol, cigarette and recreational drugs, and environmental agents encountered in occupations, home use, or vocational activities. The three major suspected potential teratogens were organic solvents, pesticides and lead and other heavy metals.

Organic solvent exposure was derived from the use of lacquers, paints, varnishes and degreasing agents. Associations with a 2 to 6-fold excess were found for several anatomic diagnostic groups. This is consistent with the reports of other investigators. Additionally the search for genetic variations has revealed possible alterations in the genotypes of solvent metabolizing enzymes (Loffredo,1996).

Selected References