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Congenital heart disease (CHD) is the most common major birth defect, and yet its etiology remains poorly understood. It is generally accepted that both genetic and environmental factors contribute to abnormal cardiac development. With rapid advances in the field of genetics, specific gene alterations underlying named syndromes or groups of cardiac malformations continue to be identified. Our understanding of both positive and negative environmental influences also continues to evolve. Identifying the etiology of cardiac malformations is important, as environmental changes can aid normal development and information on inheritance patterns and recurrence rates aids early identification of at-risk individuals and informs future plans for individuals and families.

In this chapter, we briefly summarize the current knowledge of environmental and genetic causes of CHD.1,2,3 A brief guide to clinical screening by history, examination, and testing for genetic causes is also presented.

CHD is the most common major birth defect. Estimates of the birth prevalence of CHD range from 4 to 50 cases per 1000 live births depending on the epidemiologic study.1 The variation in estimates is explained in part by differences in study design, case ascertainment, and disease classification. In addition, the advent of ultrasound in the 1980s has resulted in identification of milder abnormalities1 and more accurate classification and prenatal diagnosis. The latter may in fact have led to an increase in pregnancy termination and a decline in birth prevalence.

Multiple environmental risk factors have been implicated in the development of CHD. Although unproven, some occurrences of CHD are potentially preventable through changes in the fetal environment. A select group of environmental risk factors are briefly reviewed in this section, although a growing body of epidemiologic literature is dedicated to this topic (Figure 4-1).

Figure 4-1

Currently the vast majority of congenital heart disease does not have an identified underlying etiology. An as-of-yet undefined percentage is likely attributable to unknown environmental effects and single-gene defects. However, newer diagnostic techniques suggest that congenital heart disease is frequently a complex trait arising from a combination of environmental and heterogeneous genetic effects. (Adapted with permission from van der Born et al. Nat Rev Cardiol. 2011.)


Pregestational diabetes is a known risk factor for CHD as well as abnormal development of other organ systems. Heart defects most often associated with maternal diabetes include conotruncal defects, laterality defects and, less commonly, left ventricular outflow obstructive defects (Table 4-1).3 Hypertrophic cardiomyopathy is commonly associated with maternal diabetes but typically resolves after birth, once exposure to the hyperglycemic fetal environment ceases. The risk of birth defects secondary to diabetes can be reduced with strict glycemic control prior to conception and throughout pregnancy.3 Identification of this risk factor is crucial because the prevalence of type 2 diabetes increases in women of childbearing ...

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