Association between infertility and all-cause mortality: analysis of US claims data

Published:February 09, 2021DOI:


      The consequences of an infertility diagnosis extend beyond the pursuit of family building, because women with infertility also face increased risks for severe maternal morbidity, cancer, and chronic disease.


      This study aimed to examine the association between female infertility and all-cause mortality.

      Study Design

      This retrospective analysis compared 72,786 women with infertility, identified in the Optum Clinformatics Datamart from 2003 to 2019 by infertility diagnosis, testing, and treatment codes, with 3,845,790 women without infertility seeking routine gynecologic care. The baseline comorbidities were assessed using the presence of ≥1 metabolic syndrome diagnoses and the Charlson Comorbidity Index. The primary outcome, which was all-cause mortality, was identified by linkage to the Social Security Administration Death Master File outcomes and medical claims. The association between infertility and mortality was examined using a Cox proportional hazard regression by adjusting for age, hypertension, hyperlipidemia, type II diabetes, year of evaluation, smoking, number of visits per year, nulliparity, obesity, region of the country, and race.


      Among 16,473,458 person-years of follow-ups, 13,934 women died. Women with infertility had a 32% higher relative risk for death from any cause (0.42% vs 0.35%, adjusted hazard ratio, 1.32; 95% confidence interval, 1.18–1.48) than women without infertility. The mean follow-up time per patient was 4.0±3.7 years vs 4.2±3.8 years for women with and without infertility, respectively. When stratified by age of <35 or ≥35 years or baseline medical comorbidity, the association between infertility and mortality remained. Women with infertility who delivered a child during the follow-up period faced a similar increased risk for mortality than the overall infertile group. Finally, receiving fertility treatment was not associated with a higher risk for death than receiving an infertility diagnosis or testing alone.


      Although the absolute risk for death was low in both groups, women with infertility faced a higher relative risk for mortality than women without infertility. The association remained across all age, race and ethnicity groups, morbidities, and delivery strata. Importantly, infertility treatment was not associated with an increased risk for death. These findings reinforce the disease burden associated with infertility and its potential for long-term sequelae.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • 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
        • Niederberger C.
        • Pellicer A.
        • Cohen J.
        • et al.
        Forty years of IVF.
        Fertil Steril. 2018; 110: 185-324.e5
        • Murugappan G.
        • Li S.
        • Lathi R.B.
        • Baker V.L.
        • Eisenberg M.L.
        Risk of cancer in infertile women: analysis of US claims data.
        Hum Reprod. 2019; 34: 894-902
        • Murugappan G.
        • Li S.
        • Lathi R.B.
        • Baker V.L.
        • Eisenberg M.L.
        Increased risk of incident chronic medical conditions in infertile women: analysis of US claims data.
        Am J Obstet Gynecol. 2019; 220: 473.e1-473.e14
        • Glazer C.H.
        • Bonde J.P.
        • Eisenberg M.L.
        • et al.
        Male infertility and risk of nonmalignant chronic diseases: a systematic review of the epidemiological evidence.
        Semin Reprod Med. 2017; 35: 282-290
        • Eisenberg M.L.
        • Li S.
        • Cullen M.R.
        • Baker L.C.
        Increased risk of incident chronic medical conditions in infertile men: analysis of United States claims data.
        Fertil Steril. 2016; 105: 629-636
        • Eisenberg M.L.
        • Li S.
        • Brooks J.D.
        • Cullen M.R.
        • Baker L.C.
        Increased risk of cancer in infertile men: analysis of U.S. claims data.
        J Urol. 2015; 193: 1596-1601
        • Kurabayashi T.
        • Mizunuma H.
        • Kubota T.
        • Hayashi K.
        Ovarian infertility is associated with cardiovascular disease risk factors in later life: a Japanese cross-sectional study.
        Maturitas. 2016; 83: 33-39
        • 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
        • Udell J.A.
        • Lu H.
        • Redelmeier D.A.
        Long-term cardiovascular risk in women prescribed fertility therapy.
        J Am Coll Cardiol. 2013; 62: 1704-1712
        • Eisenberg M.L.
        Risks beyond reproduction for infertile men.
        Fertil Steril. 2016; 105: 300-301
        • Choy J.T.
        • Eisenberg M.L.
        Male infertility as a window to health.
        Fertil Steril. 2018; 110: 810-814
        • Coleman P.K.
        • Reardon D.C.
        • Calhoun B.C.
        Reproductive history patterns and long-term mortality rates: a Danish, population-based record linkage study.
        Eur J Public Health. 2013; 23: 569-574
        • Barclay K.
        • Keenan K.
        • Grundy E.
        • Kolk M.
        • Myrskylä M.
        Reproductive history and post-reproductive mortality: a sibling comparison analysis using Swedish register data.
        Soc Sci Med. 2016; 155: 82-92
        • Stentz N.C.
        • Koelper N.
        • Barnhart K.T.
        • Sammel M.D.
        • Senapati S.
        Infertility and mortality.
        Am J Obstet Gynecol. 2020; 222: 251.e1-251.e10
        • Salonia A.
        • Matloob R.
        • Gallina A.
        • et al.
        Are infertile men less healthy than fertile men? Results of a prospective case-control survey.
        Eur Urol. 2009; 56: 1025-1031
        • Sundararajan V.
        • Henderson T.
        • Perry C.
        • Muggivan A.
        • Quan H.
        • Ghali W.A.
        New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.
        J Clin Epidemiol. 2004; 57: 1288-1294
        • Quan H.
        • Li B.
        • Couris C.M.
        • et al.
        Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data From 6 countries.
        Am J Epidemiol. 2011; 173: 676-682
        • Ailes E.C.
        • Simeone R.M.
        • Dawson A.L.
        • Petersen E.E.
        • Gilboa S.M.
        Using insurance claims data to identify and estimate critical periods in pregnancy: an application to antidepressants.
        Birth Defects Res A Clin Mol Teratol. 2016; 106: 927-934
        • Bennett W.L.
        • Chang H.Y.
        • Levine D.M.
        • et al.
        Utilization of primary and obstetric care After medically complicated pregnancies: an analysis of medical claims data.
        J Gen Intern Med. 2014; 29: 636-645
        • Laurent S.L.
        • Thompson S.J.
        • Addy C.
        • Garrison C.Z.
        • Moore E.E.
        An epidemiologic study of smoking and primary infertility in women.
        Fertil Steril. 1992; 57: 565-572
        • Murugappan G.
        • Li S.
        • Lathi R.B.
        • Baker V.L.
        • Luke B.
        • Eisenberg M.L.
        Increased risk of severe maternal morbidity among infertile women: analysis of US claims data.
        Am J Obstet Gynecol. 2020; 223: 404.e1-404.e20
        • Practice Committee of the American Society for Reproductive Medicine. Electronic address: [email protected], Practice Committee of the American Society for Reproductive Medicine
        Evidence-based treatments for couples with unexplained infertility: a guideline.
        Fertil Steril. 2020; 113: 305-322
        • Luke B.
        • Stern J.E.
        • Hornstein M.D.
        • et al.
        Is the wrong question being asked in infertility research?.
        J Assist Reprod Genet. 2016; 33: 3-8
        • Glazer C.H.
        • Eisenberg M.L.
        • Tøttenborg S.S.
        • et al.
        Male factor infertility and risk of death: a nationwide record-linkage study.
        Hum Reprod. 2019; 34: 2266-2273
        • Murshidi M.M.
        • Choy J.T.
        • Eisenberg M.L.
        Male infertility and somatic health.
        Urol Clin North Am. 2020; 47: 211-217
        • 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
        • Lund E.
        • Arnesen E.
        • Borgan J.K.
        Pattern of childbearing and mortality in married women—a national prospective study from Norway.
        J Epidemiol Community Health. 1990; 44: 237-240
        • Vassard D.
        • Schmidt L.
        • Pinborg A.
        • et al.
        Mortality in women treated With assisted reproductive technology-addressing the healthy patient effect.
        Am J Epidemiol. 2018; 187: 1889-1895
        • Venn A.
        • Hemminki E.
        • Watson L.
        • Bruinsma F.
        • Healy D.
        Mortality in a cohort of IVF patients.
        Hum Reprod. 2001; 16: 2691-2696
        • Braat D.D.
        • Schutte J.M.
        • Bernardus R.E.
        • Mooij T.M.
        • van Leeuwen F.E.
        Maternal death related to IVF in the Netherlands 1984-2008.
        Hum Reprod. 2010; 25: 1782-1786
        • Chandra A.
        • Copen C.E.
        • Stephen E.H.
        Infertility service use in the United States: data from the National Survey of Family Growth, 1982-2010.
        Natl Health Stat Report. 2014; 73: 1-21
        • Domar A.
        • Gordon K.
        • Garcia-Velasco J.
        • La Marca A.
        • Barriere P.
        • Beligotti F.
        Understanding the perceptions of and emotional barriers to infertility treatment: a survey in four European countries.
        Hum Reprod. 2012; 27: 1073-1079
        • Lepkowski J.M.
        • Mosher W.D.
        • Davis K.E.
        • Groves R.M.
        • van Hoewyk J.
        The 2006-2010 National Survey of Family Growth: Sample design and analysis of a continuous survey.
        Vital Health Stat. 2010; 150: 1-36