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Infertility and Risk of Heart Failure in the Women’s Health InitiativeFree Access

Original Investigation

J Am Coll Cardiol, 79 (16) 1594–1603
Sections

Central Illustration

Abstract

Background

There is growing recognition that reproductive factors are associated with increased risk of future cardiovascular disease. Infertility has been less well studied, although emerging data support its association with increased risk of cardiovascular disease. Whether infertility is associated with future risk of heart failure (HF) is not known.

Objectives

This study sought to examine the development of HF and HF subtypes in women with and without history of infertility.

Methods

We followed postmenopausal women from the Women’s Health Initiative prospectively for the development of HF. Infertility was self-reported at study baseline. Multivariable cause-specific Cox models were used to evaluate the association of infertility with incident overall HF and HF subtypes (heart failure with preserved ejection fraction [HFpEF]: left ventricular ejection fraction of ≥50% vs heart failure with reduced ejection fraction [HFrEF]: left ventricular ejection fraction of <50%]).

Results

Among 38,528 postmenopausal women (mean age: 63 ± 7 years), 5,399 (14%) participants reported a history of infertility. Over a median follow-up of 15 years, 2,373 developed incident HF, including 807 with HFrEF and 1,133 with HFpEF. Infertility was independently associated with future risk of overall HF (HR: 1.16; 95% CI: 1.04-1.30; P = 0.006). Notably, when examining HF subtypes, infertility was associated with future risk of HFpEF (HR: 1.27; 95% CI: 1.09-1.48; P = 0.002) but not HFrEF (HR: 0.97; 95% CI: 0.80-1.18).

Conclusions

Infertility was significantly associated with incident HF. This was driven by increased risk of HFpEF, but not HFrEF, and appeared independent of traditional cardiovascular risk factors and other infertility-related conditions. Future research should investigate mechanisms that underlie the link between infertility and HFpEF.

References

  • 1. Arnett D.K., Blumenthal R.S., Albert M.A., et al. "2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". J Am Coll Cardiol 2019;74:e177-e232.

    View ArticleGoogle Scholar
  • 2. Honigberg M.C., Zekavat S.M., Aragam K., et al. "Association of premature natural and surgical menopause with incident cardiovascular disease". JAMA 2019;322:2411-2421.

    CrossrefMedlineGoogle Scholar
  • 3. Tooher J., Thornton C., Makris A., Ogle R., Korda A., Hennessy A. "All hypertensive disorders of pregnancy increase the risk of future cardiovascular disease". Hypertension 2017;70:798-803.

    CrossrefMedlineGoogle Scholar
  • 4. Søndergaard M.M., Hlatky M.A., Stefanick M.L., et al. "Association of adverse pregnancy outcomes with risk of atherosclerotic cardiovascular disease in postmenopausal women". JAMA Cardiol 2020;5:1390-1398.

    CrossrefMedlineGoogle Scholar
  • 5. "Infertility workup for the women’s health specialist: ACOG committee opinion, number 781". Obstet Gynecol 2019;133:e377-e384.

    CrossrefMedlineGoogle Scholar
  • 6. Parikh N.I., Cnattingius S., Mittleman M.A., Ludvigsson J.F., Ingelsson E. "Subfertility and risk of later life maternal cardiovascular disease". Hum Reprod 2012;27:568-575.

    CrossrefMedlineGoogle Scholar
  • 7. Parikh N.I., Jeppson R.P., Berger J.S., et al. "Reproductive risk factors and coronary heart disease in the Women’s Health Initiative Observational Study". Circulation 2016;133:2149-2158.

    CrossrefMedlineGoogle Scholar
  • 8. Cairncross Z.F., Ahmed S.B., Dumanski S.M., Nerenberg K.A., Metcalfe A. "Infertility and the risk of cardiovascular disease: findings from the Study of Women’s Health Across the Nation (SWAN)". CJC Open 2021;3:400-408.

    CrossrefMedlineGoogle Scholar
  • 9. Farland L.V., Grodstein F., Srouji S.S., et al. "Infertility, fertility treatment, and risk of hypertension". Fertil Steril 2015;104:391-397.

    CrossrefMedlineGoogle Scholar
  • 10. Heidenreich P.A., Albert N.M., Allen L.A., et al. "Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association". Circ Heart Fail 2013;6:606-619.

    CrossrefMedlineGoogle Scholar
  • 11. Dewan P., Rørth R., Raparelli V., et al. "Sex-related differences in heart failure with preserved ejection fraction". Circ Heart Fail 2019;12: e006539.

    CrossrefMedlineGoogle Scholar
  • 12. Lam C.S.P., Arnott C., Beale A.L., et al. "Sex differences in heart failure". Eur Heart J 2019;40:3859-3868c.

    CrossrefMedlineGoogle Scholar
  • 13. Hall P.S., Nah G., Howard B.V., et al. "Reproductive factors and incidence of heart failure hospitalization in the Women's Health Initiative". J Am Coll Cardiol 2017;69:2517-2526.

    View ArticleGoogle Scholar
  • 14. Curb J.D., McTiernan A., Heckbert S.R., et al. "Outcomes ascertainment and adjudication methods in the women's health initiative". Ann Epidemiol 2003;13:S122-S128.

    CrossrefMedlineGoogle Scholar
  • 15. "Design of the Women’s Health Initiative Clinical Trial and Observational Study". Control Clin Trials 1998;19:61-109.

    CrossrefMedlineGoogle Scholar
  • 16. Practice Committee of the American Society for Reproductive Medicine. "Definitions of infertility and recurrent pregnancy loss: a committee opinion". Fertil Steril 2020;113:533-535.

    CrossrefMedlineGoogle Scholar
  • 17. Rosamond W.D., Chang P.P., Baggett C., et al. "Classification of heart failure in the atherosclerosis risk in communities (ARIC) study: a comparison of diagnostic criteria". Circ Heart Fail 2012;5:152-159.

    CrossrefMedlineGoogle Scholar
  • 18. Parikh N.I., Kapphahn K., Hedlin H., et al. "Effects of reproductive period duration and number of pregnancies on midlife ECG indices: a secondary analysis from the Women’s Health Initiative Clinical Trial". BMJ Open 2018;8: e019129.

    CrossrefMedlineGoogle Scholar
  • 19. Gleason J.L., Shenassa E.D., Thoma M.E. "Self-reported infertility, metabolic dysfunction, and cardiovascular events: a cross-sectional analysis among U.S. women". Fertil Steril 2019;111:138-146.

    CrossrefMedlineGoogle Scholar
  • 20. Honigberg M.C., Riise H.K.R., Daltveit A.K., et al. "Heart failure in women with hypertensive disorders of pregnancy: insights from the cardiovascular disease in Norway Project". Hypertension 2020;76:1506-1513.

    CrossrefMedlineGoogle Scholar
  • 21. Solomon C.G., Hu F.B., Dunaif A., et al. "Menstrual cycle irregularity and risk for future cardiovascular disease". J Clin Endocrinol Metab 2002;87:2013-2017.

    CrossrefMedlineGoogle Scholar
  • 22. Redmond G.P. "Thyroid dysfunction and women’s reproductive health". Thyroid 2004;14:suppl 1: S5–15.

    MedlineGoogle Scholar
  • 23. Flynn R.W., Macdonald T.M., Jung R.T., Morris A.D., Leese G.P. "Mortality and vascular outcomes in patients treated for thyroid dysfunction". J Clin Endocrinol Metab 2006;91:2159-2164.

    CrossrefMedlineGoogle Scholar
  • 24. Savji N., Meijers W.C., Bartz T.M., et al. "the association of obesity and cardiometabolic traits with incident HFpEF and HFrEF". J Am Coll Cardiol HF 2018;6:701-709.

    Google Scholar
  • 25. Eaton C.B., Pettinger M., Rossouw J., et al. "Risk factors for incident hospitalized heart failure with preserved versus reduced ejection fraction in a multiracial cohort of postmenopausal women". Circ Heart Fail 2016;9.

    CrossrefGoogle Scholar
  • 26. Takefuji M., Murohara T. "Corticotropin-releasing hormone family and their receptors in the cardiovascular system". Circ J 2019;83:261-266.

    CrossrefMedlineGoogle Scholar
  • 27. Murphy E. "Estrogen signaling and cardiovascular disease". Circ Res 2011;109:687-696.

    CrossrefMedlineGoogle Scholar
  • 28. Zhao Z., Wang H., Jessup J.A., Lindsey S.H., Chappell M.C., Groban L. "Role of estrogen in diastolic dysfunction". Am J Physiol Heart Circ Physiol 2014;306:H628-H640.

    CrossrefMedlineGoogle Scholar
  • 29. Beale A.L., Meyer P., Marwick T.H., Lam C.S.P., Kaye D.M. "Sex differences in cardiovascular pathophysiology: why women are overrepresented in heart failure with preserved ejection fraction". Circulation 2018;138:198-205.

    CrossrefMedlineGoogle Scholar
  • 30. Zhao D., Guallar E., Ouyang P., et al. "Endogenous sex hormones and incident cardiovascular disease in post-menopausal women". J Am Coll Cardiol 2018;71:2555-2566.

    View ArticleGoogle Scholar
  • 31. Lindenfeld J., Ghali J.K., Krause-Steinrauf H.J., et al. "Hormone replacement therapy is associated with improved survival in women with advanced heart failure". J Am Coll Cardiol 2003;42:1238-1245.

    View ArticleGoogle Scholar
  • 32. Manson J.E., Hsia J., Johnson K.C., et al. "Estrogen plus progestin and the risk of coronary heart disease". N Engl J Med 2003;349:523-534.

    CrossrefMedlineGoogle Scholar
  • 33. Anderson G.L., Limacher M., Assaf A.R., et al. "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial". JAMA 2004;291:1701-1712.

    CrossrefMedlineGoogle Scholar
  • 34. Osibogun O., Ogunmoroti O., Michos E.D. "Polycystic ovary syndrome and cardiometabolic risk: opportunities for cardiovascular disease prevention". Trends Cardiovasc Med 2020;30:399-404.

    CrossrefMedlineGoogle Scholar
  • 35. Mahalingaiah S., Sun F., Cheng J.J., Chow E.T., Lunetta K.L., Murabito J.M. "Cardiovascular risk factors among women with self-reported infertility". Fertil Res Pract 2017;3:1-7.

    CrossrefGoogle Scholar
  • 36. Verit F.F., Yildiz Zeyrek F., Zebitay A.G., Akyol H. "Cardiovascular risk may be increased in women with unexplained infertility". Clin Exp Reprod Med 2017;44:28-32.

    CrossrefMedlineGoogle Scholar
  • 37. Dick M.L., Bain C.J., Purdie D.M., Siskind V., Molloy D., Green A.C. "Self-reported difficulty in conceiving as a measure of infertility". Hum Reprod 2003;18:2711-2717.

    CrossrefMedlineGoogle Scholar