{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:32:39Z","timestamp":1790775159192,"version":"4.1.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T00:00:00Z","timestamp":1655942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Does maternal exposure to first trimester corticosteroids in IVF\/ICSI treatment result in an increased risk of congenital anomalies?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>Children born with the aid of IVF\/ICSI whose mothers were treated with adjuvant corticosteroids during the first trimester had an increased risk of cryptorchidism, hypospadias and talipes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>Maternal exposure to corticosteroids may increase the risk of congenital anomalies such as cleft palate and neural tube defects. However, the existing studies have conflicting outcomes, are underpowered, and do not study a population undergoing IVF\/ICSI, a group known to be at increased risk of abnormalities.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>This retrospective cohort analysis covering Monash IVF fertility clinics in Melbourne, Australia assessed the outcomes of 12\u200a426 live births from both fresh and frozen embryo transfers between 2010 and 2016.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>There were 618 live births included in our study group of mothers exposed to corticosteroids (oral prednisolone or dexamethasone) during their IVF\/ICSI treatment, with the remainder of births not exposed to steroids (control, n\u2009=\u200911\u200a808). The primary outcome measured was the presence of congenital anomalies and secondary outcomes were birth weight and gestation length. Multivariate binary logistic regression was used to assess the independent effects of corticosteroid exposure and the freezing of embryos, with adjustment for maternal age at oocyte retrieval, smoking status, number of cycles taken, BMI, etiology of the infertility and the use of ICSI. Results are presented as incidence rate ratios (IRRs) with 95% CIs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>Amongst 12\u200a426 live births, and 597 birth defects, multivariate logistic regression demonstrated there was an increased incidence in talipes equinovarus (1.33% vs 0.32%, adjusted IRR\u2009=\u20094.30, 95% CI\u2009=\u20091.93, 9.58; P\u2009&amp;lt;\u20090.001), hypospadias (0.66% vs 0.18%, adjusted IRR\u2009=\u20095.90, 95% CI\u2009=\u20092.09, 16.69; P\u2009=\u20090.001) and cryptorchidism (0.83% vs 0.19%, adjusted IRR\u2009=\u20095.53, 95% CI\u2009=\u20091.91, 15.42; P\u2009=\u20090.001) in the offspring of mothers exposed to corticosteroids compared to those who were unexposed. The incidence of neither neural tube defects nor cleft palate were significantly increased in babies exposed to corticosteroids. The sex ratio of infants exposed to corticosteroids during a fresh embryo transfer cycle significantly favored males but reverted to the normal sex ratio in infants conceived in frozen embryo transfer cycles.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>This was a retrospective observational cohort study using administrative datasets with the potential for measurement error and unobserved confounding. Missing outcome data were obtained from patients using self-report leading to possible ascertainment bias. Given the rare incidence of some of the anomalies assessed, the study was underpowered to identify differences in abnormality rates for some specific anomalies.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>The findings of this study, the largest of its kind, suggest that caution should be heeded when prescribing corticosteroids to women undergoing IVF\/ICSI, given that this study has now identified three previously unassociated serious neonatal complications (talipes, hypospadias and cryptorchidism), plus a potential alteration in sex ratio. Physicians should be careful in using corticosteroids in the critical first trimester and should counsel patients regarding the potential risks of this treatment<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>There was no funding sought or obtained for this study. K.T., V.T., B.V. and D.Z.-F. are employees or contractors to Monash IVF and hold a minority stock position in Monash IVF. R.J.W. reports 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\/deac142","type":"journal-article","created":{"date-parts":[[2022,6,23]],"date-time":"2022-06-23T07:41:19Z","timestamp":1655970079000},"page":"2167-2174","source":"Crossref","is-referenced-by-count":17,"title":["Exposure to corticosteroids in the first trimester is associated with an increased risk of urogenital congenital anomalies"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1677-5639","authenticated-orcid":false,"given":"V","family":"Thalluri","sequence":"first","affiliation":[{"name":"Repromed , Adelaide, Australia"},{"name":"Department of Obstetrics & Gynaecology, University of Adelaide , Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R J","family":"Woodman","sequence":"additional","affiliation":[{"name":"Flinders Centre for Epidemiology and Biostatistics, College of Medicine and Public Health, Flinders University , Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Vollenhoven","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynaecology, Flinders University , Adelaide, Australia"},{"name":"Monash IVF , Melbourne, Australia"},{"name":"Department of Obstetrics & Gynaecology, Monash University , Melbourne, Australia"},{"name":"Monash Health , Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Tremellen","sequence":"additional","affiliation":[{"name":"Repromed , Adelaide, Australia"},{"name":"Department of Obstetrics & Gynaecology, Flinders University , Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Zander-Fox","sequence":"additional","affiliation":[{"name":"Monash IVF , Melbourne, Australia"},{"name":"University of South Australia , Adelaide, Australia"},{"name":"Monash University , Adelaide, Australia"},{"name":"Department of Obstetrics and Gynaecology, University of Adelaide , Adelaide, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,6,23]]},"reference":[{"key":"2022090106003409300_deac142-B1","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/S0022-3476(72)80547-X","article-title":"The transplacental passage of prednisone and prednisolone in pregnancy near term","volume":"81","author":"Beitins","year":"1972","journal-title":"J Pediatr"},{"key":"2022090106003409300_deac142-B2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.jpeds.2009.01.039","article-title":"Maternal corticosteroid use and hypospadias","volume":"155","author":"Carmichael","year":"2009","journal-title":"J Pediatr"},{"key":"2022090106003409300_deac142-B3","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1002\/(SICI)1096-8628(19990917)86:3<242::AID-AJMG9>3.0.CO;2-U","article-title":"Maternal corticosteroid use and risk of selected congenital anomalies","volume":"86","author":"Carmichael","year":"1999","journal-title":"Am J Med Genet"},{"key":"2022090106003409300_deac142-B4","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.ajog.2007.05.046","article-title":"Maternal corticosteroid use and orofacial clefts","volume":"197","author":"Carmichael","year":"2007","journal-title":"Am J Obstet Gynecol"},{"key":"2022090106003409300_deac142-B5","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.ajog.2017.09.010","article-title":"Measurement of uterine natural killer cell percentage in the periimplantation endometrium from fertile women and women with recurrent reproductive failure: establishment of a reference range","volume":"217","author":"Chen","year":"2017","journal-title":"Am J Obstet Gynecol"},{"key":"2022090106003409300_deac142-B6","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3109\/10253890.2011.585188","article-title":"Stress induces glucocorticoid-mediated apoptosis of rat Leydig cells in vivo","volume":"15","author":"Chen","year":"2012","journal-title":"Stress"},{"key":"2022090106003409300_deac142-B8","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/(SICI)1096-9926(199711)56:5<335::AID-TERA7>3.0.CO;2-W","article-title":"Population based case-control study of teratogenic potential of corticosteroids","volume":"56","author":"Czeizel","year":"1997","journal-title":"Teratology"},{"key":"2022090106003409300_deac142-B9","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1008095","article-title":"Reproductive technologies and the risk of birth defects","volume":"366","author":"Davies","year":"2012","journal-title":"N Engl J Med"},{"key":"2022090106003409300_deac142-B10","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/ajmg.a.20130","article-title":"Case control study of cleft lip or palate after maternal use of topical corticosteroids during pregnancy","volume":"120A","author":"Edwards","year":"2003","journal-title":"Am J Med Genet"},{"key":"2022090106003409300_deac142-B11","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0303-7207(02)00290-3","article-title":"Mechanisms of glucocorticoid-induced Leydig cell apoptosis","volume":"199","author":"Gao","year":"2003","journal-title":"Mol Cell Endocrinol"},{"key":"2022090106003409300_deac142-B12","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/molehr\/gaq042","article-title":"Sex-related physiology of the preimplantation embryo","volume":"16","author":"Gardner","year":"2010","journal-title":"Mol Hum Reprod"},{"key":"2022090106003409300_deac142-B15","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.reprotox.2003.10.007","article-title":"Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study","volume":"18","author":"Gur","year":"2004","journal-title":"Reprod Toxicol"},{"key":"2022090106003409300_deac142-B16","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1210\/endo-124-5-2099","article-title":"Glucocorticoid-mediated repression of P450scc mRNA and de novo synthesis in cultured leydig cells","volume":"124","author":"Hales","year":"1989","journal-title":"Endocrinology"},{"key":"2022090106003409300_deac142-B18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0022-3468(86)80830-2","article-title":"Testicular feminization: a model for testicular descent in mice and men","volume":"21","author":"Hutson","year":"1986","journal-title":"J Pediatr Surg"},{"key":"2022090106003409300_deac142-B19","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/s00441-005-1126-4","article-title":"Abnormalities of testicular descent","volume":"322","author":"Hutson","year":"2005","journal-title":"Cell Tissue Res"},{"key":"2022090106003409300_deac142-B20","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/molehr\/gal032","article-title":"Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue","volume":"12","author":"Jasper","year":"2006","journal-title":"Mol Hum Reprod"},{"key":"2022090106003409300_deac142-B21","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/j.1365-2605.2009.01050.x","article-title":"Testicular dysgenesis syndrome comprises some but not all cases of hypospadias and impaired spermatogenesis","volume":"33","author":"J\u00f8rgensen","year":"2010","journal-title":"Int J Androl"},{"key":"2022090106003409300_deac142-B22","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1597\/02-077","article-title":"Maternal drug use and infant cleft lip\/palate with special reference to corticoids","volume":"40","author":"Kall\u00e9n","year":"2003","journal-title":"Cleft Palate Craniofac J"},{"key":"2022090106003409300_deac142-B23","doi-asserted-by":"crossref","first-page":"518","DOI":"10.3109\/01443615.2012.693988","article-title":"Prednisolone for repeated implantation failure associated with high natural killer cell levels","volume":"32","author":"Krigstein","year":"2012","journal-title":"J Obstet Gynaecol"},{"key":"2022090106003409300_deac142-B24","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/(SICI)1097-0185(19990701)255:3<306::AID-AR6>3.0.CO;2-B","article-title":"Effect of androgens on the cranial suspensory ligament and ovarian position","volume":"255","author":"Lee","year":"1999","journal-title":"Anat Rec"},{"key":"2022090106003409300_deac142-B25","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1007\/s00360-010-0483-9","article-title":"Programming of offspring sex ratios by maternal stress in humans: assessment of physiological mechanisms using a comparative approach","volume":"180","author":"Navara","year":"2010","journal-title":"J Comp Physiol B"},{"key":"2022090106003409300_deac142-B26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/1096-9926(200012)62:6<385::AID-TERA5>3.0.CO;2-Z","article-title":"Birth defects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies","volume":"62","author":"Park-Wyllie","year":"2000","journal-title":"Teratology"},{"key":"2022090106003409300_deac142-B27","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1210\/endo-129-3-1429","article-title":"Multiple mechanisms for regulation of 3 beta-hydroxysteroid dehydrogenase\/delta 5\u2014delta 4-isomerase, 17 alpha-hydroxylase\/C17-20 lyase cytochrome P450, and cholesterol side-chain cleavage cytochrome P450 messenger ribonucleic acid levels in primary cultures of mouse leydig cells","volume":"129","author":"Payne","year":"1991","journal-title":"Endocrinology"},{"key":"2022090106003409300_deac142-B28","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1002\/bdra.10134","article-title":"First trimester exposure to corticosteroids and oral clefts","volume":"67","author":"Pradat","year":"2003","journal-title":"Birth Defects Res Clin Mol Teratol"},{"key":"2022090106003409300_deac142-B29","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/S1472-6483(10)62012-3","article-title":"Uterine natural killer cells, implantation failure and recurrent miscarriage","volume":"13","author":"Quenby","year":"2006","journal-title":"Reprod Biomed Online"},{"key":"2022090106003409300_deac142-B31","first-page":"78","article-title":"Malformation surveillance and maternal drug exposure:the MADRE project","volume":"6","author":"Robert","year":"1994","journal-title":"Risk Safety Med"},{"key":"2022090106003409300_deac142-B32","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1093\/humrep\/dew186","article-title":"Corticosteroid therapy in assisted reproduction-immune suppression is a faulty premise","volume":"31","author":"Robertson","year":"2016","journal-title":"Hum Reprod"},{"key":"2022090106003409300_deac142-B33","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/(SICI)1096-9926(199807)58:1<2::AID-TERA2>3.0.CO;2-4","article-title":"Corticosteroids during pregnancy and oral clefts: a case-control study","volume":"58","author":"Rodr\u00edguez-Pinilla","year":"1998","journal-title":"Teratology"},{"key":"2022090106003409300_deac142-B34","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1093\/humrep\/dev096","article-title":"Enough! Stop with the arguments and get on with the science of natural killer cell testing","volume":"30","author":"Sacks","year":"2015","journal-title":"Hum Reprod"},{"key":"2022090106003409300_deac142-B35","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1152\/physrev.00017.2015","article-title":"Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility","volume":"96","author":"Skakkebaek","year":"2016","journal-title":"Physiol Rev"},{"key":"2022090106003409300_deac142-B36","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1093\/humrep\/16.5.972","article-title":"Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects","volume":"16","author":"Skakkebaek","year":"2001","journal-title":"Hum Reprod"},{"key":"2022090106003409300_deac142-B38","doi-asserted-by":"crossref","first-page":"231","DOI":"10.3181\/00379727-204-43658","article-title":"Effect of immobilization stress on plasma luteinizing hormone, testosterone, and corticosterone concentrations and on 3 beta-hydroxysteroid dehydrogenase activity in the testes of adult rats","volume":"204","author":"Srivastava","year":"1993","journal-title":"Proc Soc Exp Biol Med"},{"key":"2022090106003409300_deac142-B39","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1210\/er.2008-0014","article-title":"Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn and infant hypothalamic-pituitary-adrenal axis function in humans: a systemic review","volume":"30","author":"Tegethoff","year":"2009","journal-title":"Endocr Rev"},{"key":"2022090106003409300_deac142-B40","volume-title":"Congenital anomalies in Victoria 2013\u20132014","author":"Victorian Congenital Anomalies Register","year":"2017"},{"key":"2022090106003409300_deac142-B41","doi-asserted-by":"crossref","first-page":"23996","DOI":"10.1073\/pnas.1905890116","article-title":"Maternal prenatal stress phenotypes associate with fetal neurodevelopment and birth outcomes","volume":"116","author":"Walsh","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022090106003409300_deac142-B42","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.bbrc.2016.01.161","article-title":"Prenatal exposure to dexamethasone disturbs sex-determining gene expression and fetal testosterone production in male embryos","volume":"471","author":"Yun","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"key":"2022090106003409300_deac142-B43","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1210\/mend.13.5.0272","article-title":"Targeted disruption of the Insl3 gene causes bilateral cryptorchidism","volume":"13","author":"Zimmermann","year":"1999","journal-title":"Mol Endocrinol"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/37\/9\/2167\/45537085\/deac142.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/37\/9\/2167\/45537085\/deac142.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T06:08:40Z","timestamp":1662012520000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/37\/9\/2167\/6613499"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,23]]},"references-count":37,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,6,23]]},"published-print":{"date-parts":[[2022,8,25]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deac142","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,9,1]]},"published":{"date-parts":[[2022,6,23]]}}}