{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T23:03:53Z","timestamp":1789427033446,"version":"build-2803163510"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Faculty of Health and Medical Sciences"},{"DOI":"10.13039\/501100001734","name":"University of Copenhagen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001734","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Is there an increased risk of breast cancer among women after ART treatment including ovarian hormone stimulation?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>The risk of breast cancer was slightly increased among women after ART treatment compared to age-matched, untreated women in the background population, and the risk was further increased among women initiating ART treatment when aged 40+ years.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>The majority of breast cancer cases are sensitive to oestrogen, and ovarian hormone stimulation has been suggested to increase the risk of breast cancer by influencing endogenous oestrogen levels. Previous studies on ART treatment and breast cancer have varied in their findings, but several studies have small sample sizes or lack follow-up time and\/or confounder adjustment. Recent childbirth, nulliparity and higher socio-economic status are breast cancer risk factors and the latter two are also associated with initiating ART treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>The Danish National ART-Couple II (DANAC II) cohort includes women treated with ART at public and private fertility clinics in 1994\u20132016.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>Women with no cancer prior to ART treatment were included (n\u2009=\u200961 579). Women from the background population with similar age and no prior history of ART treatment were randomly selected as comparisons (n\u2009=\u2009579 760). The baseline mean age was 33.1\u2009years (range 18\u201346\u2009years). Results are presented as hazard ratios (HRs) with corresponding CIs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>During follow-up (median 9.69\u2009years among ART-treated and 9.28\u2009years among untreated), 5861 women were diagnosed with breast cancer, 695 among ART-treated and 5166 among untreated women (1.1% versus 0.9%, P &amp;lt; 0.0001). Using Cox regression analyses adjusted for nulliparity, educational level, partnership status, year, maternal breast cancer and age, the risk of breast cancer was slightly increased among women treated with ART (HR 1.14, 95% CI 1.12\u20131.16). All causes of infertility were slightly associated with breast cancer risk after ART treatment. The risk of breast cancer increased with higher age at ART treatment initiation and was highest among women initiating treatment at age 40+ years (HR 1.37, 95% CI 1.29\u20131.45). When comparing women with a first birth at age 40+ years with or without ART treatment, the increased risk among women treated with ART persisted (HR 1.51, 95% CI 1.09\u20132.08).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>Although this study is based on a large, national cohort of women, more research with sufficient power and confounder adjustment is needed, particularly in cohorts with a broad age representation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>An increased risk of breast cancer associated with a higher age at ART treatment initiation has been shown. Ovarian stimulation may increase the risk of breast cancer among women initiating ART treatment when aged 40+ years. Age-related vulnerability to hormone exposure or higher hormone doses during ART treatment may explain the increased risk.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This work was supported by a PhD grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen, Denmark. Funding for establishing the DANAC II cohort was received from the Ebba Rosa Hansen Foundation. The authors report no conflict of interest.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                  <jats:p>N\/A.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/humrep\/deab219","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T03:06:01Z","timestamp":1631502361000},"page":"3152-3160","source":"Crossref","is-referenced-by-count":14,"title":["Assisted reproductive technology treatment and risk of breast cancer: a population-based cohort study"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-4146","authenticated-orcid":false,"given":"D","family":"Vassard","sequence":"first","affiliation":[{"name":"Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8340-104X","authenticated-orcid":false,"given":"A","family":"Pinborg","sequence":"additional","affiliation":[{"name":"Fertility Clinic, Rigshospitalet, Copenhagen University Hospital, Copenhagen \u00d8, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Kamper-J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Section of Epidemiology, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Lyng Forman","sequence":"additional","affiliation":[{"name":"Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C H","family":"Glazer","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, Copenhagen NV, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Kroman","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Copenhagen University Hospital Herlev, Copenhagen \u00d8, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9518-1734","authenticated-orcid":false,"given":"L","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Section of Social Medicine, Department of Public Health, University of Copenhagen, Copenhagen K, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"2021111812101752300_deab219-B1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/sj.bjc.6602302","article-title":"Breast cancer risk by age at birth, time since birth and time intervals between births: exploring interaction effects","volume":"92","author":"Albrektsen","year":"2005","journal-title":"Br J Cancer"},{"key":"2021111812101752300_deab219-B2","first-page":"357","article-title":"The Danish in vitro fertilisation (IVF) register","volume":"46","author":"Andersen","year":"1999","journal-title":"Dan Med Bull"},{"key":"2021111812101752300_deab219-B3","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1093\/humrep\/deaa293","article-title":"Fertility treatment and cancers\u2014the eternal conundrum: a systematic review and meta-analysis","volume":"36","author":"Barcroft","year":"2021","journal-title":"Hum Reprod"},{"key":"2021111812101752300_deab219-B4","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1093\/humrep\/deq080","article-title":"Maternal death related to IVF in the Netherlands 1984-2008","volume":"25","author":"Braat","year":"2010","journal-title":"Hum Reprod"},{"key":"2021111812101752300_deab219-B5","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/humrep\/dey242","article-title":"ART in Europe, 2014: results generated from European registries by ESHRE","volume":"33","author":"De Geyter","year":"2018","journal-title":"Hum Reprod"},{"key":"2021111812101752300_deab219-B6","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1056\/NEJM198202183060712","article-title":"Female fecundity and age","volume":"306","author":"DeCherney","year":"1982","journal-title":"N Engl J Med"},{"key":"2021111812101752300_deab219-B7","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/humrep\/des016","article-title":"Understanding the perceptions of and emotional barriers to infertility treatment: a survey in four European countries","volume":"27","author":"Domar","year":"2012","journal-title":"Hum Reprod"},{"key":"2021111812101752300_deab219-B8","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1158\/1055-9965.EPI-19-0652","article-title":"A cohort study of breast cancer risk after 20 years of follow-up of women treated with fertility drugs","volume":"28","author":"Guleria","year":"2019","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"2021111812101752300_deab219-B9","doi-asserted-by":"crossref","first-page":"e78690","DOI":"10.1371\/journal.pone.0078690","article-title":"Educational differences in postmenopausal breast cancer\u2014quantifying indirect effects through health behaviors, body mass index and reproductive patterns","volume":"8","author":"Hvidtfeldt","year":"2013","journal-title":"PLoS One"},{"key":"2021111812101752300_deab219-B10","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1093\/humrep\/deq307","article-title":"Malignancies among women who gave birth after in vitro fertilization","volume":"26","author":"K\u00e4ll\u00e9n","year":"2011","journal-title":"Hum Reprod"},{"key":"2021111812101752300_deab219-B11","doi-asserted-by":"crossref","first-page":"djv048","DOI":"10.1093\/jnci\/djv048","article-title":"Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race\/ethnicity, poverty, and state","volume":"107","author":"Kohler","year":"2015","journal-title":"J Natl Cancer Inst"},{"key":"2021111812101752300_deab219-B12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1056\/NEJM199407073310102","article-title":"Transient increase in the risk of breast cancer after giving birth","volume":"331","author":"Lambe","year":"1994","journal-title":"N Engl J Med"},{"key":"2021111812101752300_deab219-B13","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.canep.2010.12.005","article-title":"Socioeconomic position and lifestyle in relation to breast cancer incidence among postmenopausal women: A prospective cohort study, Denmark, 1993\u20132006","volume":"35","author":"Larsen","year":"2011","journal-title":"Cancer Epidemiol"},{"key":"2021111812101752300_deab219-B14","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1023\/A:1015287208222","article-title":"Transient increase in breast cancer risk after giving birth: postpartum period with the highest risk (Sweden)","volume":"13","author":"Liu","year":"2002","journal-title":"Cancer Causes Control"},{"key":"2021111812101752300_deab219-B15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.fertnstert.2017.05.010","article-title":"Ovarian stimulation and risk of breast cancer in Swedish women","volume":"108","author":"Lundberg","year":"2017","journal-title":"Fertil Steril"},{"key":"2021111812101752300_deab219-B16","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1245\/s10434-007-9800-2","article-title":"The possible association between IVF and breast cancer incidence","volume":"15","author":"Pappo","year":"2008","journal-title":"Ann Surg Oncol"},{"key":"2021111812101752300_deab219-B17","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/s10815-016-0844-8","article-title":"Couples\u2019 discontinuation of fertility treatments: a longitudinal study on demographic, biomedical, and psychosocial risk factors","volume":"34","author":"Pedro","year":"2017","journal-title":"J Assist Reprod Genet"},{"key":"2021111812101752300_deab219-B18","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1002\/ijc.29069","article-title":"Risk of breast cancer following fertility treatment\u2014a registry based cohort study of parous women in Norway","volume":"136","author":"Reigstad","year":"2015","journal-title":"Int J Cancer"},{"key":"2021111812101752300_deab219-B19","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1158\/1055-9965.EPI-16-0809","article-title":"Cancer risk in women treated with fertility drugs according to parity status\u2014a registry-based cohort study","volume":"26","author":"Reigstad","year":"2017","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"2021111812101752300_deab219-B20","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1742-5573-5-7","article-title":"Methods for stratification of person-time and events\u2014a prerequisite for Poisson regression and SIR estimation","volume":"5","author":"Rostgaard","year":"2008","journal-title":"Epidemiol Perspect Innov"},{"key":"2021111812101752300_deab219-B21","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1056\/NEJM198202183060706","article-title":"Female fecundity as a function of age","volume":"306","author":"Schwartz","year":"1982","journal-title":"N Engl J Med"},{"key":"2021111812101752300_deab219-B22","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/aogs.12705","article-title":"Are repeated assisted reproductive technology treatments and an unsuccessful outcome risk factors for unipolar depression in infertile women?","volume":"94","author":"Sejbaek","year":"2015","journal-title":"Acta Obstet Gynecol Scand"},{"key":"2021111812101752300_deab219-B23","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/humupd\/dmt034","article-title":"IVF and breast cancer: a systematic review and meta-analysis","volume":"20","author":"Sergentanis","year":"2014","journal-title":"Hum Reprod Update"},{"key":"2021111812101752300_deab219-B24","first-page":"535","article-title":"The Danish Cancer Registry\u2014history, content, quality and use","volume":"44","author":"Storm","year":"1997","journal-title":"Dan Med Bull"},{"key":"2021111812101752300_deab219-B25","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.rbmo.2019.11.015","article-title":"Cancer in IVF patients treated at age 40 years and older: long term follow-up","volume":"40","author":"Tsafrir","year":"2020","journal-title":"Reprod Biomed Online"},{"key":"2021111812101752300_deab219-B26","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1001\/jama.2016.9389","article-title":"Ovarian stimulation for in vitro fertilization and long-term risk of breast cancer","volume":"316","author":"van den Belt-Dusebout","year":"2016","journal-title":"JAMA"},{"key":"2021111812101752300_deab219-B27","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1136\/bmj.302.6789.1361","article-title":"Delaying childbearing: effect of age on fecundity and outcome of pregnancy","volume":"302","author":"van Noord-Zaadstra","year":"1991","journal-title":"BMJ"},{"key":"2021111812101752300_deab219-B28","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1093\/aje\/kwy085","article-title":"Mortality in women treated with assisted reproductive technology\u2014addressing the healthy patient effect","volume":"187","author":"Vassard","year":"2018","journal-title":"Am J Epidemiol"},{"key":"2021111812101752300_deab219-B29","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1093\/humrep\/16.12.2691","article-title":"Mortality in a cohort of IVF patients","volume":"16","author":"Venn","year":"2001","journal-title":"Hum Reprod"},{"key":"2021111812101752300_deab219-B30","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/S0140-6736(99)05203-4","article-title":"Risk of cancer after use of fertility drugs with in-vitro fertilisation","volume":"354","author":"Venn","year":"1999","journal-title":"Lancet"},{"key":"2021111812101752300_deab219-B31","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S0140-6736(95)91687-3","article-title":"Breast and ovarian cancer incidence after infertility and in vitro fertilisation","volume":"346","author":"Venn","year":"1995","journal-title":"Lancet"},{"key":"2021111812101752300_deab219-B32","doi-asserted-by":"crossref","first-page":"k2644","DOI":"10.1136\/bmj.k2644","article-title":"Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991-2010: data linkage study including 2.2 million person years of observation","volume":"362","author":"Williams","year":"2018","journal-title":"BMJ"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/36\/12\/3152\/41172389\/deab219.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/36\/12\/3152\/41172389\/deab219.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T12:12:07Z","timestamp":1637237527000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/36\/12\/3152\/6377225"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,9,28]]},"published-print":{"date-parts":[[2021,11,18]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deab219","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,12,1]]},"published":{"date-parts":[[2021,9,28]]}}}