Nongenetic Risk Factors and Congenital Heart Defects

Abstract

Advances have been made in identifying genetic etiologies of congenital heart defects. Through this knowledge, preventive strategies have been designed and instituted, and prospective parents are counseled regarding their risk of having an affected child. Great strides have been made in genetic variant identification, and genetic susceptibility to environmental exposures has been hypothesized as an etiology for congenital heart defects. Unfortunately, similar advances in understanding have not been made regarding strategies to prevent nongenetic risk factors. Less information is available regarding the potential adverse effect of modifiable risk factors on the fetal heart. This review summarizes the available literature on these modifiable exposures that may alter the risk for congenital heart disease. Information regarding paternal characteristics and conditions, maternal therapeutic drug exposures, parental nontherapeutic drug exposures, and parental environmental exposures are presented. Factors are presented in terms of risk for congenital heart defects as a group. These factors also are broken down by specific defect type. Although additional investigations are needed in this area, many of the discussed risk factors present an opportunity for prevention of potential disease.

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

“…The importance of gene dosage for the occurrence of cardiac malformations has been shown, along with the concept of an oligogenic etiology for CHD, supporting the concept that mild alterations in gene expression levels may lead disease phenotypes (10)(11)(12)(13). Similarly, numerous environmental risk factors for CHD have been reported, each of which increases the risk of having a child with CHD (14). For the majority of these, exposure to a single teratogen raises the risk by only 2-to 10-fold, suggesting that additional factors, i.e., underlying genetic susceptibility, may be involved.…”

“…The cardiac phenotypes include looping, conotruncal, and septation defects (14,16,17). MatDM constitutes an unfavorable environment for embryonic development, characterized by fetal exposure to elevated blood glucose levels, which is the proposed Birth defects are the leading cause of infant mortality, and they are caused by a combination of genetic and environmental factors.…”

Identification of Copy Number Variations in Isolated Tetralogy of Fallot

“…ToF is a multifactorial congenital defect that has been associated with rubella embryopathy, maternal diabetes, anticonvulsant ingestion during pregnancy, and other maternal exposures such as metronidazole [11]. ToF occurs during the first 8 weeks of human embryogenesis.…”

Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice

“…It is generally believed that both environmental and genetic factors based on variations in many different genes contribute to CHD. Environmental or nongenetic risk factors include diabetes mellitus, obesity, and hypoxic responses, but the molecular events driving CHD have remained enigmatic (3)(4)(5)(6). Small observational groups and potential confounding effects have complicated analysis of the contribution of specific environmental effects in human beings.…”