1 Nørgaard-Pedersen C, et al. BMJ Open 2022;12:e064780. doi:10.1136/bmjopen-2022-064780 Open access 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 Caroline Nørgaard-Pedersen , 1,2 Kaspar Nielsen, 3 Rudi Steffensen, 3 Line Eriksen, 3 Malene Møller Jørgensen, 2,3 Ulrik Schiøler Kesmodel, 1,2 Ole Bjarne Christiansen 1,2 To cite: Nørgaard-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:e064780. doi:10.1136/ bmjopen-2022-064780 ► Prepublication history and additional supplemental material for this paper are available online. To view these fles, please visit the journal online (http://dx.doi.org/10.1136/ bmjopen-2022-064780). Received 16 May 2022 Accepted 08 September 2022 For numbered affliations see end of article. Correspondence to Caroline Nørgaard-Pedersen; c.noergaardpedersen@rn.dk Protocol © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. ABSTRACT Introduction Recurrent pregnancy loss (RPL), defned as two or more consecutive pregnancy losses in the frst trimester, affects around 5% of fertile women. The underlying causes remain unknown in up to 60% of patients; however, most studies point at an immunological pathology in unexplained RPL, and therefore, an effective treatment may be immunomodulatory. This study aims to evaluate the effect of intravenous immunoglobulin (IVIg) and prednisolone on reproductive outcome and the immune system in women with unexplained RPL undergoing assisted reproductive technology treatment. Methods and analysis This randomised, placebo-controlled trial with double-blinded randomisation to two parallel arms evaluate if immunomodulatory (active) treatment is superior to placebo in increasing the chance of ongoing pregnancy assessed at nuchal translucency scan in gestational weeks (GW) 11–13 after embryo transfer (ET) in 74 RPL patients with ≥2 pregnancy losses as its primary objective. The active treatment consists of IVIg (one infusion preferably 1–5 days before ET and in GW 5, 6 and 7) and prednisolone (5 mg/ day from frst day of menstrual bleeding until ET and 10 mg/ day from ET to GW 8+0) while the comparator consists of intravenous human albumin (5%) and placebo tablets. Allocation is concealed for participants, caregivers, and investigators until trial termination and is performed in a 1:1 ratio. The secondary objective is to evaluate treatment safety, and the tertiary objective is exploration of the association between treatment, reproductive outcome after ET, and the lymphocyte subset distribution in peripheral blood collected before and after intravenous infusion(s). Excess biological material is stored in a biobank for future research. Ethics and dissemination The North Denmark Region Committee on Health Research Ethics (N-20200066) approved this trial. The results will be published in peer- reviewed scientifc journals and presented to relevant patient associations, at relevant academic conferences and to key stakeholders. Trial registration number NCT04701034. INTRODUCTION Background Recurrent pregnancy loss (RPL) defined as ≥2 consecutive pregnancy losses (PLs) 1 affects around 5% of women in reproduc- tive age. 2 In Denmark, >25% of all RPL cases happens after assisted reproductive technologies (ART) including in-vitro fertili- sation (IVF), intracytoplasmatic sperm injec- tion (ICSI) and frozen embryo/blastocyst transfer (FET) and >10% children born after 2019 in Denmark are conceived using ART. In up to 60% of RPL patients, no risk factor is found, and for unexplained RPL (uRPL), STRENGTHS AND LIMITATIONS OF THIS STUDY ⇒ The pragmatic, randomised, double-blinded study design refecting the contemporary practice strengthens the study results’ external validity. ⇒ The combination of clinical and immunochemical outcome measures evaluated by blinded clinicians and the randomised study-settings strengthen the current research that evaluate how the immune sys- tem is changed during early pregnancy and whether it is related to the reproductive outcome. ⇒ The combination of two active drugs in the active treatment group does not allow differentiation of whether one of the active drugs or only the com- bination possesses the effect on reproductive out- come observed in the study. ⇒ Participants are not selected based on a biomarker associated with an aberrant immune function, which was done in some of the previous studies reporting a signifcant effect of intravenous immunoglobulin on unexplained recurrent pregnancy loss; however, since the evidence of such an association is still sparse, further elaboration on this topic is needed. on October 29, 2022 by guest. 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