A combination of the HLA-DRB1*03 phenotype and low plasma mannose-binding lectin predisposes to autoantibody formation in women with recurrent pregnancy loss.

Introduction: It is documented that a series of autoantibodies can be detected with increased frequency in women with recurrent pregnancy loss (RPL) and they may impact the pregnancy prognosis negatively. It is unknown whether the autoantibodies per se or the basic immune disturbances underlying autoantibody production, are the reason for this association. Our group has previously found that some genetically determined immunological biomarkers are associated with RPL and the same biomarkers are also in various degrees known to predispose to autoantibody production. The aim of this study was to clarify whether the RPL-associated immunogenetic biomarkers are associated with positivity for three major classes of autoantibodies associated with RPL. Methods: In 663 patients with RPL in whom we had results for HLA-DRB1 typing and plasma mannose-binding lectin (p-MBL) measurement, it was investigated whether there is a correlation between positivity for the autoantibodies: anticardiolipin antibodies, ß2 glycoprotein I antibodies, and lupus anticoagulant (jointly called antiphospholipid antibodies), thyroid-peroxidase antibodies, and antinuclear antibodies and each of the HLA-DRB1 alleles HLA-DRB1*03 or HLA-DRB1*07 either alone or in combination with low p-MBL defined as ≤500 µg/l. Results: Although slightly higher frequencies of positivity of two or more autoantibodies were seen in patients with either p-MBL ≤500 µg/l or being positive for HLA-DRB1*03, none were significantly associated. However, in patients with the combination of low p-MBL and HLA-DRB1*03, presence of at least one autoantibody was significantly more frequent than in patients with no such combination (OR= 2.4; 95% CI 1.2-5.0, p = 0.01). In an analysis of which autoantibodies were most strongly associated with the low p-MBL/HLA-DRB1*03 combination, antinuclear antibodies were significantly more frequent in these patients (OR 2.0; 95% CI 1.0-3.9, p=0.05) whereas the other autoantibodies were also positively but more weakly associated with this combination. Discussion: In conclusion, to clarify the pathogenetic background, underlying immunogenetic factors should be examined in autoantibody positive RPL patients (as well as other patients with autoimmune diseases) but the genetic background may be complex.

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.

INTRODUCTION: Recurrent 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 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 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 DISSEMINATION: The 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 NUMBER: NCT04701034.

Women with Recurrent Pregnancy Loss More Often Have an Older Brother and a Previous Birth of a Boy: Is Male Microchimerism a Risk Factor?

Known etiologic factors can only be found in about 50% of patients with recurrent pregnancy loss (RPL). We hypothesized that male microchimerism is a risk factor for RPL and aimed to explore whether information on family tree and reproductive history, obtained from 383 patients with unexplained RPL, was supportive of this hypothesis. The male:female sex ratio of older siblings was 1.49 (97:65) in all RPL patients and 1.79 (52:29) in secondary RPL (sRPL) patients, which differed significantly from the expected 1.04 ratio (p = 0.027 and p = 0.019, respectively). In contrast, the sex ratio of younger siblings was close to the expected ratio. Sex ratio of the firstborn child before sRPL was 1.51 (p = 0.026). When combined, 79.1% of sRPL patients had at least one older brother, a firstborn boy, or both. This differed significantly from what we expected based on the distribution of younger siblings and a general 1.04 sex ratio of newborns (p = 0.040). We speculate whether (s)RPL patients possibly acquired male microchimerism from older brother(s) and/or previous birth of boy(s) by transplacental cell trafficking. This could potentially have a detrimental impact on their immune system, causing a harmful response against the fetus or trophoblast, resulting in RPL.