Association between oral contraceptive use and incident heart failure
Dongling Luo
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
These authors contributed equally to this work.
Search for more papers by this authorHezhi Li
Department of Echocardiography, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China
These authors contributed equally to this work.
Search for more papers by this authorPengyuan Chen
Department of Cardiology, Guangdong General Hospital's Nanhai Hospital, The Second Hospital of Nanhai District Foshan City, Foshan, China
These authors contributed equally to this work.
Search for more papers by this authorNanshan Xie
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Search for more papers by this authorZiyang Yang
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Search for more papers by this authorCorresponding Author
Caojin Zhang
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Correspondence to: Caojin Zhang, Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou 510080, China. Tel: 86-020-83827812; Fax: 020-83827712. Email: [email protected]Search for more papers by this authorDongling Luo
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
These authors contributed equally to this work.
Search for more papers by this authorHezhi Li
Department of Echocardiography, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, Guangzhou, China
These authors contributed equally to this work.
Search for more papers by this authorPengyuan Chen
Department of Cardiology, Guangdong General Hospital's Nanhai Hospital, The Second Hospital of Nanhai District Foshan City, Foshan, China
These authors contributed equally to this work.
Search for more papers by this authorNanshan Xie
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Search for more papers by this authorZiyang Yang
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Search for more papers by this authorCorresponding Author
Caojin Zhang
Department of Cardiology, Guangdong Provincial People's Hospital, Guangdong Cardiovascular Institute, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou, 510080 China
Correspondence to: Caojin Zhang, Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan 2nd Road, Guangzhou 510080, China. Tel: 86-020-83827812; Fax: 020-83827712. Email: [email protected]Search for more papers by this authorAbstract
Aims
Oral contraceptives (OCs) are widely used in women of reproductive age, but their influences on heart failure (HF) development have yet to be reported. This study was performed to assess HF risk associated with OC use.
Methods and results
We studied women participating in the Multi-Ethnic Study of Atherosclerosis with available data on OC use. Inverse probability of treatment weighting analyses were used to reduce baseline imbalances. Cox proportional hazards models were applied to evaluate the associations of OC use and HF risk. The primary analysis comprised a total of 3594 participants [average age 62.10 (10.24) years]. During an average follow-up of 12.45 (3.75) years, 138 incident HF occurred. In unadjusted Cox model, OC use was associated with a decreased risk of HF [hazard ratio (HR) = 0.45, 95% confidence interval (CI) 0.31–0.64, P < 0.001]. However, in multivariable-adjusted and inverse probability of treatment weighting models, the results were attenuated and became non-significant (HR = 0.96, 95% CI 0.63–1.48, P = 0.86 and HR = 0.79, 95% CI 0.45–1.40, P = 0.43, respectively). Duration of OC use was not related to increased risks of HF. When stratifying HF into subtypes, similar associations were observed. In multivariable–adjusted regression models, OC use was positively associated with left ventricular end-diastolic mass [coefficient (β) = 3.04, P = 0.006] and stroke volume (β = 1.76, P = 0.01 for the left ventricle; β = 2.17, P = 0.005 for the right ventricle) but had no impact on left ventricular ejection fraction (β = 0.09, P = 0.75) and right ventricular ejection fraction (β = 0.33, P = 0.25).
Conclusions
Oral contraceptive use in women of reproductive age does not portend increased risk of HF. However, whether the formulations or dosages differently impact this association should be further investigated.
Conflict of interest
None declared.
Supporting Information
| Filename | Description |
|---|---|
| ehf2_13328-sup-0001-DataS1.docxWord 2007 document , 2.3 MB |
Table S1. Baseline characteristics of oral contraceptives users and non-users after inverse probability of treatment weighting (IPTW). Table S2. Hazard ratios (HR) and 95% confidence intervals (95%CI) of incident heart failure (HF) and HF subtypes with use of oral contraceptives across a serious of sensitivity analysis using multivariable-adjusted models. Table S3. Comparison of cardiac structural parameters between oral contraceptive (OC) users and non-users. Figure S1. The log(−log (survival)) versus log (survival time) plots. No violation was found in the proportional hazards assumption. Figure S2. Standardized mean biases comparing the full unmatched cohort with the inverse probability of treatment weighting (IPTW) matched cohort. SBP = systolic blood pressure. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Cignarella A, Kratz M, Bolego C. Emerging role of estrogen in the control of cardiometabolic disease. Trends Pharmacol Sci 2010; 31: 183–189.
- 2Vitale C, Mendelsohn ME, Rosano GM. Gender differences in the cardiovascular effect of sex hormones. Nat Rev Cardiol 2009; 6: 532–542.
- 3Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Kober L, Jensen JEB. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.
- 4Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK. Cardiovascular disease outcomes during 6.8 years of hormone therapy. JAMA 2002; 288: 49.
- 5Hulley S. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605–613.
- 6Reis SE, Holubkov R, Young JB, White BG, Cohn JN, Feldman AM. Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies. J Am Coll Cardiol 2000; 36: 529–533.
- 7Carlton C, Banks M, Sundararajan S. Oral contraceptives and ischemic stroke risk. Stroke 2018; 49: e157–e159.
- 8Dunn N, Thorogood M, Faragher B, de Caestecker L, MacDonald TM, McCollum C, Thomas S, Mann R, Lidegaard O. Oral contraceptives and myocardial infarction: results of the MICA case-control study. Commentary: oral contraceptives and myocardial infarction: reassuring new findings. BMJ 1999; 318: 1579–1584.
- 9Lewis MA, Heinemann LAJ, Spitzer WO, MacRae KD, Bruppacher R. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Contraception 1997; 56: 129–140.
- 10Thorneycroft IH. Oral contraceptives and myocardial infarction. Am J Obstet Gynecol 1990; 163: 1393–1397.
- 11 Compiled by Earth Policy Institute from U.N. Population Division. World Contraceptive Use 2011, wall chart, February 2011. https://www.google.fr/url?sa=t%26rct=j%26q=%26esrc=s%26source=web%26cd=1%26cad=rja%26uact=8%26ved=0CCMQFjAA%26url=http%3A%2F%2Fwww.earth-policy.org%2Fdatacenter%2Fxls%2Fhighlights26_all.xls%26ei=FZ0WVKPMOdTvaKXzgqgP%26usg=AFQjCNF10wNQtG2aoPUgkK9YRymHRxb5cw%26sig2=ZpqOHEY2CTVVkIA9WUrS4Q%26bvm=bv.75097201,d.d2s. Assessed on 9 December, 2020.
- 12Bousser MG, Conard J, Kittner S, de Lignières B, MacGregor EA, Massiou H, Silberstein SD, Tzourio C. Recommendations on the risk of ischaemic stroke associated with use of combined oral contraceptives and hormone replacement therapy in women with migraine. The International Headache Society Task Force on Combined Oral Contraceptives & Hormone Replacement Therapy. Cephalalgia 2000; 20: 155–156.
- 13Liu H, Yao J, Wang W, Zhang D. Association between duration of oral contraceptive use and risk of hypertension: a meta-analysis. J Clin Hypertens 2017; 19: 1032–1041.
- 14Smals AG. Fluid retention with oral contraceptives. Gynecol Endocrinol 2000; 14: 476–478.
- 15Borges LE, Andrade RP, Aldrighi JM, Guazelli C, Yazlle MEHD, Isaia CF, Petracco A, Peixoto FC, Camargos AF. Effect of a combination of ethinylestradiol 30 μg and drospirenone 3 mg on tolerance, cycle control, general well-being and fluid-related symptoms in women with premenstrual disorders requesting contraception. Contraception 2006; 74: 446–450.
- 16Momeni Z, Dehghani A, Fallahzadeh H, Koohgardi M, Dafei M, Hekmatimoghaddam SH, Mohammadi M. The impacts of pill contraceptive low-dose on plasma levels of nitric oxide, homocysteine, and lipid profiles in the exposed vs. non exposed women: as the risk factor for cardiovascular diseases. Contracept Reprod Med 2020; 5: 1–6.
- 17Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA 2000; 284: 72–78.
- 18Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011; 342: d2151.
- 19Stampfer MJ, Willett WC, Colditz GA, Speizer FE, Hennekens CH. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl J Med 1988; 319: 1313–1317.
- 20Weill A, Dalichampt M, Raguideau F, Ricordeau P, Blotière PO, Rudant J, Alla F, Zureik M. Low dose oestrogen combined oral contraception and risk of pulmonary embolism, stroke, and myocardial infarction in five million French women: cohort study. BMJ 2016; 353: i2002.
- 21Kessler KM, Warde DA, Ledis JE, Kessler RM. Left ventricular size and function in women receiving oral contraceptives. Obstet Gynecol 1980; 55: 211–214.
- 22Bild DE, Bluemke DA, Burke GL, Detrano R, Diez Roux AV, Folsom AR, Greenland P, Jacob DR Jr, Kronmal R, Liu K, Nelson JC, O'Leary D, Saad MF, Shea S, Szklo M, Tracy RP. Multi-Ethnic Study of Atherosclerosis: objectives and design. Am J Epidemiol 2002; 156: 871–881.
- 23Iversen L, Fielding S, Lidegaard O, Morch LS, Skovlund CW, Hannaford PC. Association between contemporary hormonal contraception and ovarian cancer in women of reproductive age in Denmark: prospective, nationwide cohort study. BMJ 2018; 362: k3609.
- 24Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med 2012; 366: 2257–2266.
- 25Eng J, McClellandm RL, Gomes AS, Hundley WG, Cheng S, Wu CO, Carr JJ, Shea S, Bluemke DA, Lima JA. Adverse left ventricular remodeling and age assessed with cardiac MR imaging: the Multi-Ethnic Study of Atherosclerosis. Radiology 2016; 3: 714–722.
- 26Chang PP, Wruck LM, Shahar E, Rossi JS, Loehr LR, Russell SD, Agarwal SK, Konety SH, Rodriguez CJ, Rosamond WD. Trends in hospitalizations and survival of acute decompensated heart failure in four US communities (2005–2014): ARIC study community surveillance. Circulation 2018; 138: 12–24.
- 27Zhao D, Guallar E, Ballantyne CM, Post WS, Ouyang P, Vaidya D, Jia X, Ying W, Subramanya V, Ndumele CE, Hoogeveen RC. Sex hormones and incident heart failure in men and postmenopausal women: the atherosclerosis risk in communities study. J Clin Endocrinol Metab 2020; 105: e3798–e3807.
- 28Natori S, Lai S, Finn JP, Gomes AS, Hundley WG, Jerosch-Herold M, Pearson G, Sinha S, Arai A, Lima JA, Bluemke DA. Cardiovascular function in multi-ethnic study of atherosclerosis: normal values by age, sex, and ethnicity. Am J Roentgenol 2006; 186: S357–S365.
- 29Schulte PJ, Mascha EJ. Propensity score methods: theory and practice for anesthesia research. Anesth Analg 2018; 127: 1074–1084.
- 30Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med 2009; 28: 3083–3107.
- 31Charlton BM, Rich-Edwards JW, Colditz GA, Missmer SA, Rosner BA, Hankinson SE, Speizer FE, Michels KB. Oral contraceptive use and mortality after 36 years of follow-up in the Nurses' Health Study: prospective cohort study. BMJ 2014; 349: g6356.
- 32Petersen SE, Sanghvi MM, Aung N, Cooper JA, Paiva JM, Zemrak F, Fung K, Lukaschuk E, Lee AM, Carapella V, Kim YJ, Piechnik SK, Neubauer S. The impact of cardiovascular risk factors on cardiac structure and function: insights from the UK Biobank imaging enhancement study. PLoS One 2017; 12: e0185114.
- 33Mosher WD, Jones J. Use of contraception in the United States: 1982–2008. Vital Health Stat 2010; 29: 1–44.
- 34Bhupathiraju SN, Grodstein F, Stampfer MJ, Willett WC, Hu FB, Manson JE. Exogenous hormone use: oral contraceptives, postmenopausal hormone therapy, and health outcomes in the Nurses' Health Study. Am J Public Health 2016; 106: 1631–1637.
- 35Roach RE, Helmerhorst FM, Lijfering WM, Stijnen T, Algra A, Dekkers OM. Combined oral contraceptives: the risk of myocardial infarction and ischemic stroke. Cochrane Database Syst Rev 2015; 8: CD011054.
- 36Peragallo Urrutia R, Coeytaux RR, McBroom AJ, Gierisch JM, Havrilesky LJ, Moorman PG, Lowery WJ, Dinan M, Hasselblad V, Sanders GD, Myers ER. Risk of acute thromboembolic events with oral contraceptive use. Obstet Gynecol 2013; 122: 380–389.
- 37Engel HJ, Engel E, Lichtlen PR. Coronary atherosclerosis and myocardial infarction in young women—role of oral contraceptives. Eur Heart J 1983; 4: 1–6.
- 38Dragoman M, Curtis KM, Gaffield ME. Combined hormonal contraceptive use among women with known dyslipidemias: a systematic review of critical safety outcomes. Contraception 2016; 94: 280–287.
- 39Horton LG, Simmons KB, Curtis KM. Combined hormonal contraceptive use among obese women and risk for cardiovascular events: a systematic review. Contraception 2016; 94: 590–604.
- 40Okoth K, Chandan JS, Marshall T, Thangaratinam S, Thomas GN, Nirantharakumar K, Adderley NJ. Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review. BMJ 2020; 371: m3502.
- 41Hall PS, Nah G, Howard BV, Lewis CE, Allison MA, Sarto GE, Waring ME, Jacobson LT, Manson JAE, Klein L, Parikh NI. Reproductive factors and incidence of heart failure hospitalization in the Women's Health Initiative. J Am Coll Cardiol 2017; 69: 2517–2526.
- 42Walters W. Cardiovascular dynamics in women receiving oral contraceptive therapy. Lancet 1969; 294: 879–881.
10.1016/S0140-6736(69)92332-0 Google Scholar
- 43Donaldson C, Eder S, Baker C, Aronovitz MJ, Weiss AD, Hall-Porter M, Wang F, Ackerman A, Karas RH, Molkentin JD, Patten RD. Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. Circ Res 2009; 104: 265–275 11p following 75.
- 44Satoh M, Matter CM, Ogita H, Takeshita K, Wang CY, Dorn GW II, Liao JK. Inhibition of apoptosis-regulated signaling kinase-1 and prevention of congestive heart failure by estrogen. Circulation 2007; 115: 3197–3204.
- 45Finlay GA, York B, Karas RH, Fanburg BL, Zhang H, Kwiatkowski DJ, Noonan DJ. Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-β and ERK-1/2. J Biol Chem 2004; 279: 23114–23122.
- 46Stachenfeld NS, Keefe DL. Estrogen effects on osmotic regulation of AVP and fluid balance. Am J Physiol Endocrinol Metab 2002; 283: E711–E721.
Citing Literature
