{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:38:03Z","timestamp":1787503083842,"version":"build-2736575974"},"reference-count":37,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"unspecified","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"crossref","award":["APP1147683"],"award-info":[{"award-number":["APP1147683"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"crossref","award":["NHMRC APP1147872"],"award-info":[{"award-number":["NHMRC APP1147872"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2026,7,28]]},"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The relationship between clomiphene citrate (CC) dosing regimens and adverse reproductive outcomes has not been fully elucidated, both with and without use of in vitro fertilisation (IVF). We aimed to study the association between cumulative CC dose and perinatal outcomes among fresh autologous IVF cycles.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>Retrospective cohort study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>We included all fresh autologous IVF embryo transfer cycles performed in the US fertility clinics during 2004\u20132021 using CC for ovulation induction. We used robust Poisson regression models to estimate adjusted risk ratios (aRRs) and 95% CIs for associations between four categories of CC dose (&lt;500 mg, 500\u2013749\u2009mg, 750\u2013999\u2009mg and \u22651000\u2009mg) and perinatal outcomes of interest.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>21\u2009004 fresh autologous embryo transfer cycles using CC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary outcome measures<\/jats:title>\n                    <jats:p>The primary outcome measures included biochemical pregnancy, clinical pregnancy, spontaneous abortion, stillbirth, live birth, multiple birth and preterm delivery.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among fresh autologous embryo transfer cycles using CC, 21.3% used &lt;500\u2009mg, 67.8% used 500\u2013749\u2009mg, 7.2% used 750\u2013999\u2009mg and 3.7% used \u22651000\u2009mg. After adjustment, rates of spontaneous abortion were higher for patients using 500\u2013749\u2009mg (11.8%; aRR, 1.12; 95%\u2009CI 1.02 to 1.25)\u2009and 750\u2013999\u2009mg of CC (14.4%; aRR, 1.38; 95%\u2009CI 1.18 to 1.62) than for those using &lt;500\u2009mg (10.3%). The \u22651000\u2009mg group had a three-fold higher rate of stillbirth than the &lt;500\u2009mg group, but these estimates were imprecise (0.7% vs 0.2%; aRR, 3.31; 95%\u2009CI 0.88 to 12.40). Multiple birth risk was significantly higher among all CC dosage categories compared with the &lt;500\u2009mg group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings extend previous findings on the association between CC exposure and adverse perinatal outcomes by demonstrating a dose-dependent relationship.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-115285","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:40:22Z","timestamp":1786110022000},"page":"e115285","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Dose-dependent perinatal risks of clomiphene citrate in US IVF cycles: a national cohort study, 2004\u20132021"],"prefix":"10.1136","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7638-7374","authenticated-orcid":false,"given":"Sheree","family":"Boulet","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA"},{"name":"Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Kissin","sequence":"additional","affiliation":[{"name":"Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Davies","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide, Adelaide, South Australia, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"2026080706401758000_16.8.e115285.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2013.05.033"},{"key":"2026080706401758000_16.8.e115285.2","doi-asserted-by":"crossref","unstructured":"Kamath MS , Maheshwari A , Bhattacharya S , et al . Oral medications including clomiphene citrate or aromatase inhibitors with gonadotropins for controlled ovarian stimulation in women undergoing in vitro fertilisation. Cochrane Database Syst Rev 2017;11. doi:10.1002\/14651858.CD008528.pub3","DOI":"10.1002\/14651858.CD008528.pub3"},{"key":"2026080706401758000_16.8.e115285.3","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1016\/j.fertnstert.2017.08.017","article-title":"In vitro fertilization treatments with the use of clomiphene citrate or letrozole","volume":"108","author":"Haas","year":"2017","journal-title":"Fertil Steril"},{"key":"2026080706401758000_16.8.e115285.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2008.02.092"},{"key":"2026080706401758000_16.8.e115285.5","doi-asserted-by":"publisher","DOI":"10.2174\/092986707780598023"},{"key":"2026080706401758000_16.8.e115285.6","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000450757.18294.cf"},{"key":"2026080706401758000_16.8.e115285.7","doi-asserted-by":"crossref","unstructured":"Ryu K-J , Kim MS , Lee JY , et al . Risk of endometrial polyps, hyperplasia, carcinoma, and uterine cancer after tamoxifen treatment in premenopausal women with breast cancer. JAMA Netw Open 2022;5. doi:10.1001\/jamanetworkopen.2022.43951","DOI":"10.1001\/jamanetworkopen.2022.43951"},{"key":"2026080706401758000_16.8.e115285.8","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.fertnstert.2024.03.026","article-title":"Fertility drugs and cancer: a guideline","volume":"122","year":"2024","journal-title":"Fertil Steril"},{"key":"2026080706401758000_16.8.e115285.9","first-page":"1","article-title":"Fertility drugs associated with thyroid cancer risk: a systematic review and meta-analysis","volume":"2018","author":"Yu","year":"2018","journal-title":"Biomed Res Int"},{"key":"2026080706401758000_16.8.e115285.10","doi-asserted-by":"crossref","unstructured":"Skalkidou A , Sergentanis TN , Gialamas SP , et al . Risk of endometrial cancer in women treated with ovary-stimulating drugs for subfertility. Cochrane Database Syst Rev 2017;3. doi:10.1002\/14651858.CD010931.pub2","DOI":"10.1002\/14651858.CD010931.pub2"},{"key":"2026080706401758000_16.8.e115285.11","doi-asserted-by":"crossref","unstructured":"Rizzuto I , Behrens RF , Smith LA . Risk of ovarian cancer in women treated with ovarian stimulating drugs for infertility. Cochrane Database Syst Rev 2019;6. doi:10.1002\/14651858.CD008215.pub3","DOI":"10.1002\/14651858.CD008215.pub3"},{"key":"2026080706401758000_16.8.e115285.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1008095"},{"key":"2026080706401758000_16.8.e115285.13","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/2.6.483"},{"key":"2026080706401758000_16.8.e115285.14","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1111\/1471-0528.15800","article-title":"Clomiphene citrate and neural tube defects: a meta-analysis of controlled observational studies","volume":"126","author":"Auffret","year":"2019","journal-title":"BJOG"},{"key":"2026080706401758000_16.8.e115285.15","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deq313"},{"key":"2026080706401758000_16.8.e115285.16","doi-asserted-by":"crossref","unstructured":"Chin PY , Chan HY , Kieffer TEC , et al . Clomiphene citrate administered in periconception phase causes fetal loss and developmental impairment in mice. Endocrinology 2024;165. doi:10.1210\/endocr\/bqae047","DOI":"10.1210\/endocr\/bqae047"},{"key":"2026080706401758000_16.8.e115285.17","doi-asserted-by":"publisher","DOI":"10.1001\/JAMA.2021.4788"},{"key":"2026080706401758000_16.8.e115285.18","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0015-0282(16)49574-9","article-title":"Single-dose pharmacokinetics of clomiphene citrate in normal volunteers","volume":"46","author":"Mikkelson","year":"1986","journal-title":"Fertil Steril"},{"key":"2026080706401758000_16.8.e115285.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(98)00537-8"},{"key":"2026080706401758000_16.8.e115285.20","unstructured":"Centers for Disease Control and Prevention . 2021 Assisted Reproductive Technology Fertility Clinic and National Summary Report. Atlanta: U.S. Department of Health and Human Services, 2021."},{"key":"2026080706401758000_16.8.e115285.21","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1089\/jwh.2023.0267","article-title":"Multiple imputation of missing race\/ethnicity information in the national assisted reproductive technology surveillance system","volume":"33","author":"Zhang","year":"2024","journal-title":"J Womens Health (Larchmt)"},{"key":"2026080706401758000_16.8.e115285.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2005.08.034"},{"key":"2026080706401758000_16.8.e115285.23","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.fertnstert.2010.04.001","article-title":"Monozygotic pregnancies conceived by in vitro fertilization: understanding their prognosis","volume":"95","author":"Vela","year":"2011","journal-title":"Fertil Steril"},{"key":"2026080706401758000_16.8.e115285.24","doi-asserted-by":"crossref","unstructured":"Isaksson J , Ruchkin V , Ljungstr\u00f6m T , et al . Evaluation of birth weight and neurodevelopmental conditions among monozygotic and dizygotic twins. JAMA Netw Open 2023;6. doi:10.1001\/jamanetworkopen.2023.21165","DOI":"10.1001\/jamanetworkopen.2023.21165"},{"key":"2026080706401758000_16.8.e115285.25","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.fertnstert.2016.06.017","article-title":"Elective single embryo transfer in women less than age 38 years reduces multiple birth rates, but not live birth rates, in United States fertility clinics","volume":"106","author":"Mancuso","year":"2016","journal-title":"Fertil Steril"},{"key":"2026080706401758000_16.8.e115285.26","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1093\/humrep\/deae010","article-title":"ESHRE guideline: number of embryos to transfer during IVF\/ICSI\u2020","volume":"39","author":"Alteri","year":"2024","journal-title":"Hum Reprod"},{"key":"2026080706401758000_16.8.e115285.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2012.11.023"},{"key":"2026080706401758000_16.8.e115285.28","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.fertnstert.2021.08.030","article-title":"Dispensing of clomiphene citrate to treat infertility: medication supplied and population prevalence of assisted pregnancies and multiple births","volume":"117","author":"Moore","year":"2022","journal-title":"Fertil Steril"},{"key":"2026080706401758000_16.8.e115285.29","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1093\/humupd\/dmae002","article-title":"Maternal and perinatal outcomes in twin pregnancies following assisted reproduction: a systematic review and meta-analysis involving 802 462 pregnancies","volume":"30","author":"Marleen","year":"2024","journal-title":"Hum Reprod Update"},{"key":"2026080706401758000_16.8.e115285.30","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1001\/jamapediatrics.2019.6096","article-title":"Associations of assisted reproductive technology and twin pregnancy with risk of congenital heart defects","volume":"174","author":"Wen","year":"2020","journal-title":"JAMA Pediatr"},{"key":"2026080706401758000_16.8.e115285.31","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41372-018-0273-x","article-title":"Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age","volume":"39","author":"Logan","year":"2019","journal-title":"J Perinatol"},{"key":"2026080706401758000_16.8.e115285.32","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.rbmo.2014.04.012","article-title":"On the cost and prevention of iatrogenic multiple pregnancies","volume":"29","author":"Allen","year":"2014","journal-title":"Reprod Biomed Online"},{"key":"2026080706401758000_16.8.e115285.33","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1210\/clinem\/dgae741","article-title":"Clomiphene citrate medication for infertility and risk of stillbirth or neonatal death: a population-based cohort study","volume":"110","author":"Moore","year":"2025","journal-title":"J Clin Endocrinol Metab"},{"key":"2026080706401758000_16.8.e115285.34","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/"},{"key":"2026080706401758000_16.8.e115285.35","doi-asserted-by":"crossref","unstructured":"Marino JL , Moore VM , Willson KJ , et al . Perinatal outcomes by mode of assisted conception and sub-fertility in an Australian data linkage cohort. PLoS ONE 2014;9. doi:10.1371\/journal.pone.0080398","DOI":"10.1371\/journal.pone.0080398"},{"key":"2026080706401758000_16.8.e115285.36","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1093\/humrep\/deac113","article-title":"Increased versus standard gonadotrophin dosing in predicted poor responders of IVF: an open-label randomized controlled trial","volume":"37","author":"Liu","year":"2022","journal-title":"Hum Reprod"},{"key":"2026080706401758000_16.8.e115285.37","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr543"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-115285","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:40:27Z","timestamp":1786110027000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-115285"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,7]]},"published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1136\/bmjopen-2025-115285"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-115285","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]}}}