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

Abstract

IntroductionRecurrent pregnancy loss (RPL), defined as two or more consecutive pregnancy losses in the first 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 analysisThis 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 first 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 disseminationThe North Denmark Region Committee on Health Research Ethics (N-20200066) approved this trial. The results will be published in peer-reviewed scientific journals and presented to relevant patient associations, at relevant academic conferences and to key stakeholders.Trial registration numberNCT04701034.

Intravenous immunoglobulin use in patients with unexplained recurrent pregnancy loss

“…Indeed, secondary RPL occurs after a pregnancy was carried for ≥24 weeks implicating that the maternal immune system was exposed to a higher fetal antigen load. It is possible that secondary RPL is due to a much stronger adaptive immune response against the fetus, requiring higher doses of IVIg or co‐therapy with another molecules 35 …”

Recurrent Pregnancy Loss: immunological risk factors and immunomodulatory treatments

“…Thus, this study will aid our understanding of immune mechanisms that occur during the window of implantation, the action of the immunomodulatory treatment on the immune system concerning the pregnancy outcome, and which immunological biomarker(s) may select patients eligible for the treatment. The full statistical analysis plan was published with the protocol to increase transparency and validity of the results that will be published when the study inclusion is complete [5].…”

“…Således vil dette studie kunne bidrage til vores forståelse af immunologiske mekanismer, der opstår på tidspunktet for embryonets implantation i livmoderen, virkningen af den immunmodulerende behandling på immunsystemet i forhold til resultatet af behandlingen med kunstig befrugtning, og hvilke immunologiske biomarkører der kan identificere patienter, som kan forventes at have gavn af behandlingen. Den fulde statistiske analyseplan blev publiceret sammen med protokollen for at øge gennemsigtigheden og validiteten af de resultater, der vil blive offentliggjort, når undersøgelsen er gennemført på alle projektdeltagere [5].…”

“…We hypothesize that the treatment combination increases the chance of an ongoing pregnancy after embryo transfer in RPL patients [5].…”

“…In continuation of our pilot study [406,407] and the presented knowledge gap, we decided to combine IVIG with prednisolone in the present trial and to accompany the trial with a comprehensive analysis of a wide range of immune biomarkers in peripheral blood, including the level of several leukocyte subsets before and after treatment [5].…”