Special issue recurrent pregnancy loss:Etiology, diagnosis, and therapy

The definition of recurrent pregnancy losses (RPL) varies between guidelines from different national and international scientific societies, but overall, a history of two or more (or alternatively, three or more) confirmed pregnancy losses is required for the diagnosis [...

Women with a History of Recurrent Pregnancy Loss Are a High-Risk Population for Adverse Obstetrical Outcome:A Retrospective Cohort Study

Recurrent pregnancy loss (RPL), defined as three or more consecutive miscarriages, is hypothesized to share some of the same pathogenic factors as placenta-associated disorders. It has been hypothesized that a defect implantation causes pregnancy loss, while a partially impaired implantation may lead to late pregnancy complications. The aim of this retrospective register-based cohort study was to study the association between RPL and such disorders including pre-eclampsia, stillbirth, small for gestational age (SGA) birth, preterm birth and placental abruption. Women registered with childbirth(s) in the Swedish Medical Birth Register (MFR) were included in the cohort. Pregnancies of women diagnosed with RPL (exposed) in the National Patient Register (NPR), were compared with pregnancies of women without RPL (unexposed/reference). Obstetrical outcomes, in the first pregnancy subsequent to the diagnosis of RPL (n = 4971), were compared with outcomes in reference-pregnancies (n = 57,410). Associations between RPL and placental dysfunctional disorders were estimated by odds ratios (AORs) adjusting for confounders, with logistic regression. RPL women had an increased risk for pre-eclampsia (AOR 1.45; 95% CI; 1.24– 1.69), stillbirth <37 gestational weeks (GWs) (AOR 1.92; 95% CI; 1.22–3.02), SGA birth (AOR 1.97; 95% CI; 1.42–2.74), preterm birth (AOR 1.46; 95% CI; 1.20–1.77), and placental abruption <37 GWs (AOR 2.47; 95% CI; 1.62–3.76) compared with pregnancies by women without RPL. Women with RPL had an increased risk of pregnancy complications associated with placental dysfunction. This risk population is, therefore, in need of improved antenatal surveillance

Live Birth Rate in Women with Recurrent Pregnancy Loss after In Vitro Fertilization with Concomitant Intravenous Immunoglobulin and Prednisone

Pregnancy loss after in vitro fertilization (IVF) is at least as common as after spontaneous conception. Recurrent pregnancy loss (RPL) may often have an immunological background, and it is therefore relevant to test immune-based interventions in these patients. The objective was to investigate the effect of immunotherapy with intravenous immunoglobulin (IvIg) and prednisone (PRS) as concomitant therapy to IVF in women with RPL after earlier IVF treatments. In a cohort study conducted at The Danish RPL Clinic, 41 women with three or more consecutive pregnancy losses after IVF underwent at least one further IVF cycle with concomitant immunotherapy from 2012 to 2017. The immunotherapy with IvIg and PRS was given before embryo transfer and repeatedly in the first trimester when pregnancy was achieved. Fourteen women (34.2%) achieved a live birth after the first embryo transfer with immunotherapy, and a total of 32/41 (78%) achieved a live birth after up to 4 embryo transfers. Baseline characteristics and the presence of autoantibodies were not significantly different among women achieving live birth or not. The observed 34% birth rate in women with RPL after IVF receiving immunotherapy appears higher than the expected 16–19% birth rate without immunotherapy and is similar to findings in a previous cohort from our clinic. Concomitant immunotherapy as described may be a promising intervention for women with RPL after IVF; however, the effect must be tested in a randomized controlled trial

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