As a woman of child-bearing age, I am acutely aware that the longer I postpone having children, the greater the risk that my future offspring may have a medical or developmental disorder. It seems like every few weeks, a new study makes it into the news cycle linking advanced maternal age to disease X or condition Y. (Men don’t get off scotch free – recent studies have linked advanced paternal age to autism.) A study published in Nature this week has shed light on maternal age-associated risk of congenital heart disease and risk-modifying factors.

Despite advances in diagnoses and treatment, congenital heart disease remains one of the leading causes of childhood illness and mortality. Roughly one in 100 children will have minor congenital heart disease whereas one in 1000 will require heart surgery. The risk factors for congenital heart disease include genetics, infections, maternal diabetes and advanced maternal age. A team of researchers led by Dr. Patrick Jay at Washington University School of Medicine asked whether the maternal age effect was based on the age of the mother’s eggs or the mother herself.

To tease apart these scenarios, the researchers carried out reciprocal ovarian transplants where the ovaries of young mice were transplanted into older mice and vice versa. Young mice were less than 100 days old whereas old mice were on average 318 days old (lab mice live on average two and a half years or roughly 850 days). They compared what proportion of the offspring of these two groups of mice had congenital heart disease by looking for ventricular septal defects (VSD). Ventricular septal defects are a common birth defect of the heart where there is a hole in the wall separating the lower chambers of the heart. The offspring of older mothers with young ovaries developed VSD significantly more frequently than the offspring of young mothers with old ovaries. This result provides compelling evidence that the risk of congenital heart disease is associated with the increased age of the mother and not of her eggs.

The researchers next asked whether the risk associated with advanced maternal age could be modified by environmental or genetic factors. Since maternal diabetes and body weight are known risk factors for congenital heart disease in humans, the researchers tested the effect of a high-fat diet on the risk of VSD in young mothers versus older mothers. Surprisingly, although a high-fat diet led to dramatic weight gain and impaired glucose tolerance, the offspring of young mothers fed a high-fat diet were no more likely to develop VSD than those of young mothers fed a normal diet. In older mothers, a high-fat diet led to an increase in the incidence of VSD although this result was not statistically significant.

When they compared risk of VSD between different strains of mice, the researchers found that genetic factors can also act to mitigate or enhance the risk of advanced maternal age. In one strain of mice, offspring of older mothers were no more likely to develop VSD than offspring of younger mothers. In another strain with a different genetic background, the age of the mother was a significant risk factor in development of VSD.

Finally, the researchers looked at the effect of exercise on VSD risk in both young and older mothers. While exercise had no impact on the risk of VSD in young mothers, it reduced the incidence of VSD in offspring of older mothers. Ninety days or more of exercise led to a dramatic reduction in the VSD risk in older mothers, even though it had no obvious effects on the weight, body composition, or glucose metabolism of the mothers.

The cool factor of this study comes from its innovative approach in using reciprocal ovarian transplants to determine that the maternal age-associated risk of VSD is due to physical traits in the mother and not her eggs. There are, however, a few caveats to this study.

The first is that the researchers used mice with a genetic mutation in a gene called Nkx2-5, which puts them at a high risk of developing VSD. The Nkx2-5 gene was first discovered in humans where mutations in the gene were found to cause congenital heart defects. It will be important to determine if maternal-based, and not egg-based, risk for VSD holds true for populations that are not genetically predisposed to congenital heart defects. In this study, body weight was not correlated with VSD risk in either the young or old mothers. This finding directly contradicts data from human studies that have identified maternal obesity as a risk factor for congenital heart disease. Discrepancies like this highlight an important caveat of animal studies: humans and mice are inherently different species with different genetics and physiologies. These differences can sometimes be a confounding factor in interpreting results from animal studies and hinder translation of basic research to clinical impact.

One outstanding question is what maternal factor or factors convey the risk for congenital heart disease? These factors could contribute to the growth environment within the womb through changes in the uterus or placenta. Further complicating matters is the finding that these factors interact with a myriad of genetic and environmental factors to establish risk. A thorough understanding of these maternal factors and their complex interactions is needed to translate these findings to improved tools and intervention strategies for the clinic.

Reference:
Schulkey C.E., Rachel A. Magnan, Megan T. Danzo, Herman Luther, Alayna K. Hutchinson, Adam A. Panzer, Mary M. Grady, David B. Wilson & Patrick Y. Jay (2015). The maternal-age-associated risk of congenital heart disease is modifiable, Nature, DOI: http://dx.doi.org/10.1038/nature14361