Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn 1, 2, 3, 4, 5, 6, 7 . Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8 ). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease.
This is a preview of subscription content
Subscription info for Chinese customers
We have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Forrester, M. B. & Merz, R. D. Descriptive epidemiology of selected congenital heart defects, Hawaii, 1986–1999. Paediatr. Perinat. Epidemiol. 18, 415–424 (2004).
Hollier, L. M., Leveno, K. J., Kelly, M. A., McIntire, D. D. & Cunningham, F. G. Maternal age and malformations in singleton births. Obstet. Gynecol. 96, 701–706 (2000).
Kidd, S. A., Lancaster, P. A. & McCredie, R. M. The incidence of congenital heart defects in the first year of life. J. Paediatr. Child Health 29, 344–349 (1993).
Materna-Kiryluk, A. et al. Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatr. Perinat. Epidemiol. 23, 29–40 (2009).
Miller, A., Riehle-Colarusso, T., Siffel, C., Frias, J. L. & Correa, A. Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States. Am. J. Med. Genet. A 155, 2137–2145 (2011).
Pradat, P., Francannet, C., Harris, J. A. & Robert, E. The epidemiology of cardiovascular defects, part I: a study based on data from three large registries of congenital malformations. Pediatr. Cardiol. 24, 195–221 (2003).
Reefhuis, J. & Honein, M. A. Maternal age and non-chromosomal birth defects, Atlanta—1968–2000: teenager or thirty-something, who is at risk? Birth Defects Res. A Clin. Mol. Teratol. 70, 572–579 (2004).
Winston, J. B. et al. Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation. Circ Cardiovasc Genet 5, 293–300 (2012).
MRC Vitamin Study Research Group . Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131–137 (1991).
Winston, J. B. et al. Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation 121, 1313–1321 (2010).
Schott, J. J. et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281, 108–111 (1998).
Benson, D. W. et al. Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways. J. Clin. Invest. 104, 1567–1573 (1999).
Nadeau, J. H. Modifier genes in mice and humans. Nature Rev. Genet. 2, 165–174 (2001).
Jenkins, K. J. et al. Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 115, 2995–3014 (2007).
Baird, P. A., Sadovnick, A. D. & Yee, I. M. Maternal age and birth defects: a population study. Lancet 337, 527–530 (1991).
Loane, M., Dolk, H. & Morris, J. K. Maternal age-specific risk of non-chromosomal anomalies. BJOG 116, 1111–1119 (2009).
Burrage, L. C. et al. Genetic resistance to diet-induced obesity in chromosome substitution strains of mice. Mamm. Genome 21, 115–129 (2010).
Singer, J. B. et al. Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304, 445–448 (2004).
Allen, D. L. et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J. Appl. Physiol. 90, 1900–1908 (2001).
Li, M. et al. Detecting maternal–fetal genotype interactions associated with conotruncal heart defects: a haplotype-based analysis with penalized logistic regression. Genet. Epidemiol. 38, 198–208 (2014).
Bye, A. et al. Serum levels of choline-containing compounds are associated with aerobic fitness level: the HUNT-study. PLoS ONE 7, e42330 (2012).
Chorell, E., Svensson, M. B., Moritz, T. & Antti, H. Physical fitness level is reflected by alterations in the human plasma metabolome. Mol. Biosyst. 8, 1187–1196 (2012).
Krug, S. et al. The dynamic range of the human metabolome revealed by challenges. FASEB J. 26, 2607–2619 (2012).
Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33ra37 (2010).
Lustgarten, M. S. et al. Identification of serum analytes and metabolites associated with aerobic capacity. Eur. J. Appl. Physiol. 113, 1311–1320 (2013).
Mukherjee, K. et al. Whole blood transcriptomics and urinary metabolomics to define adaptive biochemical pathways of high-intensity exercise in 50–60 year old masters athletes. PLoS ONE 9, e92031 (2014).
Tanaka, M., Chen, Z., Bartunkova, S., Yamasaki, N. & Izumo, S. The cardiac homeobox gene Csx/Nkx2.5 lies genetically upstream of multiple genes essential for heart development. Development 126, 1269–1280 (1999).
C.E.S. was supported by a Ruth L. Kirschstein National Research Service Award from the Developmental Cardiology and Pulmonary Training Program (National Institutes of Health (NIH) T32 HL007873). P.Y.J. is an Established Investigator of the American Heart Association and the Lawrence J. & Florence A. DeGeorge Charitable Trust. This work was supported by the Children's Discovery Institute of Washington University and St Louis Children's Hospital, the Children's Heart Foundation, and the NIH (R01 HL105857). The Washington University Digestive Diseases Research Core Center provided histology services and is supported by the NIH (P30 DK52574). MRI studies were performed in the Washington University Diabetes Research Center, which is supported by the NIH (P30 DK020579). We thank J. Magee, J. Rubin, D. Rudnick and A. Schwartz for comments.
The authors declare no competing financial interests.
Extended data figures and tables
Nkx2-5+/− offspring from several maternal genetic backgrounds and experimental conditions were phenotyped. Nkx2-5+/− C57BL/6N males were crossed to FVB/N or A/J females to produce F1 hybrids. The cross to a C57BL/6N female maintains the inbred strain. Nkx2-5+/− F1 hybrids were intercrossed to produce the F2 progeny. The hearts of newborn Nkx2-5+/− F2 pups were phenotyped to calculate the incidence of a defect and the effect of maternal age. C57BL/6N × FVB/N F1 hybrid mothers were bred in either sedentary/chow, high-fat diet, early or late onset exercise conditions. C57BL/6N × A/J F1 hybrid and C57BL/6N inbred mothers were studied only in the sedentary/chow condition. The number of mothers in each cross and experimental condition that were used to produce pups in this study are shown.
The relative incidences of ASD in the reciprocal ovarian transplant experiment are consistent with a maternal basis of the age-associated effect. The differences that were significant in the VSD data, however, are not significant here because of the lower incidence of ASD, as depicted by the y-axis drawn on a scale comparable to that for VSD. The total number of pups in each group is shown.
Extended Data Figure 3 Growth charts for C57BL/6N × FVB/N F1 mothers under sedentary, early onset exercise and high-fat diet conditions.
C57BL/6N × FVB/N F1 mothers on a high-fat diet develop marked obesity as they age. They weigh substantially more than mothers in the sedentary or early onset exercise groups. Mothers in the latter two groups weigh the same.
Maternal age may affect the risk of ASD, but the lower incidence of ASD and other defects that are less common than VSD preclude firm statistical conclusions. For example, the incidences of ASD are shown for the Nkx2-5+/− offspring of young and old C57BL/6N × FVB/N mothers in the sedentary, early onset exercise, and high-fat diet conditions. The y-axis is drawn on a scale comparable to that for VSD incidence. ASD incidences are higher, but not significantly, among the offspring of old mothers compared to young mothers. The incidences are not significantly different between experimental conditions. The total number of pups in each group is shown.
About this article
Cite this article
Schulkey, C., Regmi, S., Magnan, R. et al. The maternal-age-associated risk of congenital heart disease is modifiable. Nature 520, 230–233 (2015). https://doi.org/10.1038/nature14361
Egyptian Journal of Medical Human Genetics (2020)
Scientific Reports (2019)
Associations of trace elements in blood with the risk of isolated ventricular septum defects and abnormal cardiac structure in children
Environmental Science and Pollution Research (2019)
Nature Communications (2017)
Reproductive Biology and Endocrinology (2016)