In a more recent evaluation, Nelson and Holmes (1989; also see Holmes 1997) collected data on 69,277 infants, of which 2.24% had at least one major congenital anomaly. The infants were in a surveillance program at a university hospital and were not from the population at large and, therefore, these percent-ages should be viewed cautiously. Nelson and Holmes estimated the causes of congenital anomalies to be genetic, 28%; multifactorial inheritance, 23%; uterine factors and twinning, 3%; toxicants, 3%; and unknown, 43%.

Multifactorial inheritance (23%), which is a category not distinguished by Wilson, has a genetic and an environmental component. The term is used when geneological studies indicate that a physical trait, disease, or developmental defect occurs at a higher rate within families than expected in the general population, but the patterns of inheritance do not follow strict Mendelian segregation rules. To explain the departure from Mendelian rules, the genetic variant of a gene is said to predispose the individual, but further circumstances, either environmental or other genetic factors, are needed for the production of the disease. An example of multifactorial inheritance is the relationship between maternal smoking, transforming growth factor (TGF) polymorphisms, and oral cleft (Hwang et al. 1995). This example is described in detail in Chapter 5.

Such a departure from Mendelian rules might be attributable to environmental factors, but the departure could as well be due to the requirement for a combination of particular alleles of two or more genes to produce the trait (a polygenic trait) or to genomic imprinting. Specific genes and environmental exposures have been associated in multifactorial inheritance in only a few instances, but increased information is becoming available. With the identification of the multifactorial inheritance category in the Nelson and Holmes study, Wilson’s unknown-cause category of 65-75% is reduced to 42-52%, equaling the 43% unknown-cause category of Nelson and Holmes. As the Nelson and Holmes figures indicate, however, the knowledge about the causes and prevention of developmental defects continues to be limited (Mattison 1997).

Today, about 3% of the major developmental defects are estimated to be attributable to toxicant exposure (Oakley 1986; Kimmel 1997; March of Dimes 1999), but that figure is a rough approximation. It is generally recognized that 40-50 extrinsic agents probably have acted as human developmental toxicants and that more than 1,200 chemical and physical agents produce developmental defects in experimental animals (Shepard 1998; Schardein 2000). It should be noted that much of the developmental toxicity testing on experimental animals was conducted at up to maternally toxic doses and, therefore, observed effects at those doses might not be the same as effects observed after exposure to environmentally relevant doses. It is not known how many of the 1,200 agents actually produce developmental defects in humans, and the figure is not obtainable by direct testing in humans. In light of the experimental animal results, many of the agents have never entered the marketplace or environment, and others are handled with great caution according to preventive public-health and workplace-safety guidelines.

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