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The maternal-age-associated risk of congenital heart disease is modifiable


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.

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Figure 1: Reciprocal ovarian transplants between young and old mothers localize the basis of the maternal-age-associated risk to the mother.
Figure 2: A high-fat diet does not accelerate the onset of the maternal age effect.
Figure 3: The maternal-age-associated risk of VSD is a quantitative genetic trait.
Figure 4: Exercise can mitigate the risk associated with maternal ageing.


  1. 1

    Forrester, M. B. & Merz, R. D. Descriptive epidemiology of selected congenital heart defects, Hawaii, 1986–1999. Paediatr. Perinat. Epidemiol. 18, 415–424 (2004).

    Article  Google Scholar 

  2. 2

    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).

    CAS  PubMed  Google Scholar 

  3. 3

    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).

    CAS  Article  Google Scholar 

  4. 4

    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).

    Article  Google Scholar 

  5. 5

    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).

    Article  Google Scholar 

  6. 6

    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).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    Winston, J. B. et al. Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation. Circ Cardiovasc Genet 5, 293–300 (2012).

    CAS  Article  Google Scholar 

  9. 9

    MRC Vitamin Study Research Group . Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131–137 (1991).

    Article  Google Scholar 

  10. 10

    Winston, J. B. et al. Heterogeneity of genetic modifiers ensures normal cardiac development. Circulation 121, 1313–1321 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Schott, J. J. et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281, 108–111 (1998).

    ADS  CAS  Article  Google Scholar 

  12. 12

    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).

    CAS  Article  Google Scholar 

  13. 13

    Nadeau, J. H. Modifier genes in mice and humans. Nature Rev. Genet. 2, 165–174 (2001).

    CAS  Article  Google Scholar 

  14. 14

    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).

    Article  Google Scholar 

  15. 15

    Baird, P. A., Sadovnick, A. D. & Yee, I. M. Maternal age and birth defects: a population study. Lancet 337, 527–530 (1991).

    CAS  Article  Google Scholar 

  16. 16

    Loane, M., Dolk, H. & Morris, J. K. Maternal age-specific risk of non-chromosomal anomalies. BJOG 116, 1111–1119 (2009).

    CAS  Article  Google Scholar 

  17. 17

    Burrage, L. C. et al. Genetic resistance to diet-induced obesity in chromosome substitution strains of mice. Mamm. Genome 21, 115–129 (2010).

    CAS  Article  Google Scholar 

  18. 18

    Singer, J. B. et al. Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304, 445–448 (2004).

    ADS  CAS  Article  Google Scholar 

  19. 19

    Allen, D. L. et al. Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J. Appl. Physiol. 90, 1900–1908 (2001).

    ADS  CAS  Article  Google Scholar 

  20. 20

    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).

    Article  Google Scholar 

  21. 21

    Bye, A. et al. Serum levels of choline-containing compounds are associated with aerobic fitness level: the HUNT-study. PLoS ONE 7, e42330 (2012).

    ADS  CAS  Article  Google Scholar 

  22. 22

    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).

    CAS  Article  Google Scholar 

  23. 23

    Krug, S. et al. The dynamic range of the human metabolome revealed by challenges. FASEB J. 26, 2607–2619 (2012).

    CAS  Article  Google Scholar 

  24. 24

    Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33ra37 (2010).

    Article  Google Scholar 

  25. 25

    Lustgarten, M. S. et al. Identification of serum analytes and metabolites associated with aerobic capacity. Eur. J. Appl. Physiol. 113, 1311–1320 (2013).

    CAS  Article  Google Scholar 

  26. 26

    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).

    ADS  Article  Google Scholar 

  27. 27

    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).

    CAS  PubMed  Google Scholar 

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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.

Author information




C.E.S., D.B.W. and P.Y.J. designed experiments. C.E.S., S.D.R., R.A.M., M.T.D., H.L., A.K.H., A.A.P., M.M.G. and P.Y.J. executed experiments. C.E.S. and P.Y.J. interpreted experiments. C.E.S. and P.Y.J. wrote the manuscript. D.B.W. critically reviewed the paper.

Corresponding author

Correspondence to Patrick Y. Jay.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Breeding scheme and experimental conditions.

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.

Extended Data Figure 2 Incidences of ASD in the reciprocal ovarian transplant experiment.

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.

Extended Data Figure 4 Incidences of ASD in the offspring of C57BL/6N × FVB/N mothers.

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.

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Schulkey, C., Regmi, S., Magnan, R. et al. The maternal-age-associated risk of congenital heart disease is modifiable. Nature 520, 230–233 (2015).

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