{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T06:36:52Z","timestamp":1789799812947,"version":"4.0.1"},"reference-count":76,"publisher":"The Endocrine Society","issue":"7","license":[{"start":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T00:00:00Z","timestamp":1712880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"NHMRC","doi-asserted-by":"publisher","award":["APP1041335"],"award-info":[{"award-number":["APP1041335"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75\u2005mg\/kg sufficient to cause altered reproductive outcomes in 3 independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and \u223c30% of fetuses exhibited delayed development and\/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30-hour average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed postweaning growth and development similar to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can compromise implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the periconception phase unless its use is well-supervised.<\/jats:p>","DOI":"10.1210\/endocr\/bqae047","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T13:01:11Z","timestamp":1712754071000},"source":"Crossref","is-referenced-by-count":6,"title":["Clomiphene Citrate Administered in Periconception Phase Causes Fetal Loss and Developmental Impairment in Mice"],"prefix":"10.1210","volume":"165","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0923-0553","authenticated-orcid":false,"given":"Peck Y","family":"Chin","sequence":"first","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide , Adelaide, SA 5005 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9841-2094","authenticated-orcid":false,"given":"Hon Yeung","family":"Chan","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide , Adelaide, SA 5005 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0375-5022","authenticated-orcid":false,"given":"Tom E C","family":"Kieffer","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide , Adelaide, SA 5005 , Australia"},{"name":"Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen , 9713 GZ Groningen , The Netherlands"},{"name":"Amsterdam University Medical Center , Meibergdreef 9, 1105 AZ Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3984-2163","authenticated-orcid":false,"given":"Jelmer R","family":"Prins","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen , 9713 GZ Groningen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4930-7658","authenticated-orcid":false,"given":"Darryl L","family":"Russell","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide , Adelaide, SA 5005 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1526-0801","authenticated-orcid":false,"given":"Michael J","family":"Davies","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide , Adelaide, SA 5005 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-0084","authenticated-orcid":false,"given":"Sarah A","family":"Robertson","sequence":"additional","affiliation":[{"name":"Robinson Research Institute and School of Biomedicine, University of Adelaide , Adelaide, SA 5005 , Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2024,4,12]]},"reference":[{"issue":"6","key":"2024070101470995100_bqae047-B1","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1093\/humupd\/dmw025","article-title":"The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance","volume":"22","author":"Balen","year":"2016","journal-title":"Hum Reprod Update"},{"issue":"6","key":"2024070101470995100_bqae047-B2","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1056\/NEJMoa063971","article-title":"Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome","volume":"356","author":"Legro","year":"2007","journal-title":"N Engl J Med"},{"issue":"7","key":"2024070101470995100_bqae047-B3","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/0002-9378(62)90067-4","article-title":"Induction of ovulation","volume":"84","author":"Greenblatt","year":"1962","journal-title":"Am J Obstet Gynecol"},{"issue":"1","key":"2024070101470995100_bqae047-B4","first-page":"3","article-title":"Serendipity in the search for \u201cmorning-after pills\u201d led to clomiphene for the induction of ovulation","volume":"1","author":"Jordan","year":"2020","journal-title":"F S Sci"},{"issue":"8","key":"2024070101470995100_bqae047-B5","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1093\/humrep\/dei042","article-title":"Clomiphene citrate\u2013end of an era? 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