{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:30:26Z","timestamp":1784043026688,"version":"3.55.0"},"reference-count":52,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"unspecified","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Foght\u2019s Fund"},{"name":"Svend Andersen Fund"},{"DOI":"10.13039\/501100009898","name":"Beckett Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009898","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,10,23]]},"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate whether treatment with oral corticosteroids and intravenous immunoglobulin (IVIg) improves pregnancy outcomes in women with unexplained recurrent pregnancy loss (RPL) following assisted reproduction technology (ART) treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>A randomised, double-blinded, parallel-group, placebo-controlled trial conducted from January 2021 to February 2024.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Setting<\/jats:title>\n                    <jats:p>A single-centre trial at a Danish tertiary clinic for RPL management.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Participants<\/jats:title>\n                    <jats:p>80 women with at least two consecutive early pregnancy losses following ART, age 18\u201341 years, body mass index below 35, and no identified cause of RPL. Forty participants were allocated to each group, with 37 fulfilling the protocol criteria in each group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interventions<\/jats:title>\n                    <jats:p>Participants were randomised to receive either a combination of low-dose oral prednisolone starting on the first day of menstruation and IVIg given the first time around the time of embryo transfer; or matching placebo tablets and albumin infusions. Treatment continued until gestational week 8+4 in those who conceived with a total of four infusions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Primary and secondary outcome measures<\/jats:title>\n                    <jats:p>The primary outcomes were the ongoing pregnancy rate (OPR) defined as a living fetus in gestational week 13 among all randomised participants and in those who conceived after embryo transfer, respectively, based on intention-to-treat (ITT) and per-protocol (PP) analyses. Secondary outcomes included safety outcomes related to pregnancy complications and neonatal health.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OPR was equal to live birth rate. Among all randomised participants (ITT), the OPR was 25.0% in the treatment group and 15.0% in the placebo group (relative risk 1.67; 95% CI 0.67 to 4.15; p=0.26). Among participants without major protocol deviations (PP), OPRs were 21.6% and 16.2%, respectively (relative risk 1.33; 95% CI 0.51 to 3.47; p=0.55). Among participants who became pregnant following embryo transfer, ongoing pregnancy occurred in 83.3% of the treatment group and 42.9% of the placebo group (relative risk 1.94; 95% CI 1.01 to 3.75; p=0.05). No differences in adverse events or neonatal outcomes were observed between the two groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The combination of oral corticosteroids and IVIg did not improve overall pregnancy rates in women with RPL after ART. However, among those who achieved pregnancy after embryo transfer, the risk of pregnancy loss appeared reduced. Larger randomised trials are needed to confirm these findings.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      ClinicalTrials.Gov:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04701034\">NCT04701034<\/jats:ext-link>\n                      . Registration date: 5 January 2021\n                    <\/jats:p>\n                    <jats:p>EudraCT number: 2020-000256-35; Registration date: 11 November 2020<\/jats:p>\n                    <jats:p>The North Denmark Region Committee on Health Research Ethics: N-20200066, Registration date: 16 December 2020<\/jats:p>\n                    <jats:p>The Data Protection Agency: 2020-156; Registration date: 4 November 2020<\/jats:p>\n                    <jats:p>WHO universal trial number: U1111-1273-8585<\/jats:p>\n                    <jats:p>Date of first patient\u2019s enrolment: 28 January 2021.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-106024","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T08:51:50Z","timestamp":1763628710000},"page":"e106024","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a randomised, double-blind, placebo-controlled trial"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"nct04701034","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04701034","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9609-8396","authenticated-orcid":false,"given":"Caroline","family":"N\u00f8rgaard-Pedersen","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University, Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrik Schi\u00f8ler","family":"Kesmodel","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University, Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malene M","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5000-8516","authenticated-orcid":false,"given":"Ole","family":"Christiansen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Aalborg University Hospital, Aalborg, Denmark"},{"name":"Department of Clinical Medicine, Aalborg University, Aalborg, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"2025112000504810000_15.11.e106024.1","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.13210"},{"key":"2025112000504810000_15.11.e106024.2","first-page":"1","article-title":"ESHRE guideline: recurrent pregnancy loss: an update in 2022","volume":"2023","author":"Bender Atik","year":"2022","journal-title":"Human Reproduction Open"},{"key":"2025112000504810000_15.11.e106024.3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00415-008-3002-0","article-title":"Advances in the understanding of the mechanism of action of IVIg","volume":"255 Suppl 3","author":"Hartung","year":"2008","journal-title":"J Neurol"},{"key":"2025112000504810000_15.11.e106024.4","doi-asserted-by":"crossref","first-page":"103977","DOI":"10.1016\/j.jri.2023.103977","article-title":"High doses of intravenous immunoglobulin stimulate regulatory T cell and suppress natural killer cell in women with recurrent pregnancy loss","volume":"158","author":"Yamada","year":"2023","journal-title":"J Reprod Immunol"},{"key":"2025112000504810000_15.11.e106024.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2007.00574.x"},{"key":"2025112000504810000_15.11.e106024.6","doi-asserted-by":"publisher","DOI":"10.1177\/00912700122012733"},{"key":"2025112000504810000_15.11.e106024.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2005.05.012"},{"key":"2025112000504810000_15.11.e106024.8","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1321.009"},{"key":"2025112000504810000_15.11.e106024.9","doi-asserted-by":"crossref","first-page":"647496","DOI":"10.3389\/fcell.2021.647496","article-title":"Prednisolone alters endometrial decidual cells and affects decidual-trophoblast interactions","volume":"9","author":"Grbac","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"2025112000504810000_15.11.e106024.10","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1097\/00007890-198903000-00019","article-title":"The effect of steroids on the regulation of major histocompatibility complex-class II expression on nonlymphoid tissue","volume":"47","author":"Ruers","year":"1989","journal-title":"Transplantation"},{"key":"2025112000504810000_15.11.e106024.11","doi-asserted-by":"crossref","unstructured":"Kalampokas T , Pandian Z , Sd K , et al . Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI (Review). Cochrane Database Syst Rev 2017. doi:10.1002\/14651858","DOI":"10.1002\/14651858.CD004752.pub2"},{"key":"2025112000504810000_15.11.e106024.12","doi-asserted-by":"crossref","first-page":"101527","DOI":"10.1016\/j.eclinm.2022.101527","article-title":"Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: A double-blind, randomised, placebo-controlled trial","volume":"50","author":"Yamada","year":"2022","journal-title":"eClinicalMedicine"},{"key":"2025112000504810000_15.11.e106024.13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jdermsci.2016.11.003","article-title":"A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid","volume":"85","author":"Amagai","year":"2017","journal-title":"J Dermatol Sci"},{"key":"2025112000504810000_15.11.e106024.14","doi-asserted-by":"crossref","unstructured":"Zhang F , Wang Z , Lian R , et al . Intrauterine perfusion of dexamethasone improves pregnancy outcomes in recurrent reproductive failure patients with elevated uterine natural killer cells. A retrospective cohort study. Am J Reprod Immunol 2023;90. doi:10.1111\/aji.13796","DOI":"10.1111\/aji.13796"},{"key":"2025112000504810000_15.11.e106024.15","doi-asserted-by":"crossref","unstructured":"Ae R , Abrams JY , Maddox RA , et al . Corticosteroids added to initial intravenous immunoglobulin treatment for the prevention of coronary artery abnormalities in high-risk patients with Kawasaki disease. J Am Heart Assoc 2020;9. doi:10.1161\/JAHA.119.015308","DOI":"10.1161\/JAHA.119.015308"},{"key":"2025112000504810000_15.11.e106024.16","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)15324-X"},{"key":"2025112000504810000_15.11.e106024.17","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2012-302126"},{"key":"2025112000504810000_15.11.e106024.18","doi-asserted-by":"crossref","unstructured":"Egerup P , Lindschou J , Gluud C , et al . The effects of intravenous immunoglobulins in women with recurrent miscarriages: a systematic review of randomised trials with meta-analyses and trial sequential analyses including individual patient data. PLoS One 2015;10. doi:10.1371\/journal.pone.0141588","DOI":"10.1371\/journal.pone.0141588"},{"key":"2025112000504810000_15.11.e106024.19","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.rbmo.2016.08.025","article-title":"The effect of intravenous immunoglobulin passive immunotherapy on unexplained recurrent spontaneous abortion: a meta-analysis","volume":"33","author":"Wang","year":"2016","journal-title":"Reprod Biomed Online"},{"key":"2025112000504810000_15.11.e106024.20","doi-asserted-by":"crossref","unstructured":"Yamada H , Deguchi M , Saito S , et al . Intravenous immunoglobulin treatment in women with four or more recurrent pregnancy losses: a double-blind, randomised, placebo-controlled trial. EClinicalMedicine 2022;50. doi:10.1016\/j.eclinm.2022.101527","DOI":"10.1016\/j.eclinm.2022.101527"},{"key":"2025112000504810000_15.11.e106024.21","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/aji.12373","article-title":"Effect of prednisolone administration on patients with unexplained recurrent miscarriage and in routine intracytoplasmic sperm injection: a meta-analysis","volume":"74","author":"Dan","year":"2015","journal-title":"Am J Reprod Immunol"},{"key":"2025112000504810000_15.11.e106024.22","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1111\/jcpt.13629","article-title":"Oral immunosuppressants improve pregnancy outcomes in women with idiopathic recurrent miscarriage: A meta-analysis","volume":"47","author":"Ma","year":"2022","journal-title":"J Clin Pharm Ther"},{"key":"2025112000504810000_15.11.e106024.23","doi-asserted-by":"crossref","unstructured":"Boomsma CM , Keay SD , Macklon NS . Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev 2012. doi:10.1002\/14651858.CD005996.pub3","DOI":"10.1002\/14651858.CD005996.pub3"},{"key":"2025112000504810000_15.11.e106024.24","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.fertnstert.2014.08.029","article-title":"Immunomodulatory treatment with intravenous immunoglobulin and prednisone in patients with recurrent miscarriage and implantation failure after in vitro fertilization\/intracytoplasmic sperm injection","volume":"102","author":"Nyborg","year":"2014","journal-title":"Fertil Steril"},{"key":"2025112000504810000_15.11.e106024.25","doi-asserted-by":"crossref","unstructured":"N\u00f8rgaard-Pedersen C , Nielsen K , Steffensen R , et al . Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a protocol for a randomised, double-blind, placebo-controlled trial. BMJ Open 2022;12. doi:10.1136\/bmjopen-2022-064780","DOI":"10.1136\/bmjopen-2022-064780"},{"key":"2025112000504810000_15.11.e106024.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2019.103208"},{"key":"2025112000504810000_15.11.e106024.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2008.08.010"},{"key":"2025112000504810000_15.11.e106024.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(00)01622-8"},{"key":"2025112000504810000_15.11.e106024.29","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s42003-020-0763-1","article-title":"Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window","volume":"3","author":"Lucas","year":"2020","journal-title":"Commun Biol"},{"key":"2025112000504810000_15.11.e106024.30","doi-asserted-by":"publisher","DOI":"10.1210\/er.2014-1045"},{"key":"2025112000504810000_15.11.e106024.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00777-2"},{"key":"2025112000504810000_15.11.e106024.32","doi-asserted-by":"crossref","first-page":"656701","DOI":"10.3389\/fimmu.2021.656701","article-title":"The endometrial immune profiling may positively affect the management of recurrent pregnancy loss","volume":"12","author":"Cheloufi","year":"2021","journal-title":"Front Immunol"},{"key":"2025112000504810000_15.11.e106024.33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ejogrb.2021.12.024","article-title":"Understanding human immunity in idiopathic recurrent pregnancy loss","volume":"270","author":"Bagkou Dimakou","year":"2022","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2025112000504810000_15.11.e106024.34","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/"},{"key":"2025112000504810000_15.11.e106024.35","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1600-0897.1995.tb00960.x","article-title":"Intravenous immunoglobulin for treatment of recurrent pregnancy loss","volume":"34","author":"Coulam","year":"1995","journal-title":"American J Rep Immunol"},{"key":"2025112000504810000_15.11.e106024.36","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1111\/j.1471-0528.1994.tb13584.x","article-title":"Intravenous immunoglobulin in the prevention of recurrent miscarriage","volume":"101","year":"1994","journal-title":"BJOG"},{"key":"2025112000504810000_15.11.e106024.37","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/12.11.2388"},{"key":"2025112000504810000_15.11.e106024.38","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/14.3.838"},{"key":"2025112000504810000_15.11.e106024.39","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/17.3.809"},{"key":"2025112000504810000_15.11.e106024.40","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.13192"},{"key":"2025112000504810000_15.11.e106024.41","doi-asserted-by":"publisher","DOI":"10.1159\/000078154"},{"key":"2025112000504810000_15.11.e106024.42","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2022-325274"},{"key":"2025112000504810000_15.11.e106024.43","doi-asserted-by":"crossref","unstructured":"Cornelisse S , Zagers M , Kostova E , et al . Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev 2020;9. doi:10.1002\/14651858.CD005291.pub3","DOI":"10.1002\/14651858.CD005291.pub3"},{"key":"2025112000504810000_15.11.e106024.44","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103613"},{"key":"2025112000504810000_15.11.e106024.45","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1111\/aogs.13821","article-title":"Preimplantation genetic testing practices in the Nordic countries","volume":"99","author":"Hreinsson","year":"2020","journal-title":"Acta Obstet Gynecol Scand"},{"key":"2025112000504810000_15.11.e106024.46","unstructured":"Sundhedsstyrelsens IVF register . Dansk fertilitetsselvskab - \u00e5rsrapport 2018. 2018. Available: https:\/\/fertilitetsselskab.dk\/wp-content\/uploads\/2024\/04\/dfs2018-til-hjemmesiden_revideret-jan-2020.pdf [Accessed 11 Apr 2023]."},{"key":"2025112000504810000_15.11.e106024.47","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/16.9.1861"},{"key":"2025112000504810000_15.11.e106024.48","doi-asserted-by":"crossref","first-page":"295","DOI":"10.5653\/cerm.2021.04819","article-title":"Glucocorticoid therapy in assisted reproduction","volume":"48","author":"Kim","year":"2021","journal-title":"Clin Exp Reprod Med"},{"key":"2025112000504810000_15.11.e106024.49","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-014-3262-0"},{"key":"2025112000504810000_15.11.e106024.50","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/det117"},{"key":"2025112000504810000_15.11.e106024.51","doi-asserted-by":"crossref","unstructured":"Salker M , Teklenburg G , Molokhia M , et al . Natural selection of human embryos: impaired decidualization of endometrium disables embryo-maternal interactions and causes recurrent pregnancy loss. PLoS One 2010;5. doi:10.1371\/journal.pone.0010287","DOI":"10.1371\/journal.pone.0010287"},{"key":"2025112000504810000_15.11.e106024.52","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deq179"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-106024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T08:52:00Z","timestamp":1763628720000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-106024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11,19]]},"published-print":{"date-parts":[[2025,11]]}},"alternative-id":["10.1136\/bmjopen-2025-106024"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-106024","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11]]}}}