Search

Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40-60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.

Problem While there are several known causes for recurrent pregnancy loss (RPL), about 50% are unexplained (uRPL), and in these cases, an aberrant immune regulation seems to be involved. Although fetally derived trophoblast cells have a key role in immune regulation, it is difficult to study their immune function during pregnancy, and it is not known whether trophoblast function may be an inherent aberration in uRPL or whether it is associated with the outcome of the current pregnancy. Method of study Chorionic villus sampling (CVS) was performed for clinical indications at 12 weeks of gestation. Superfluous materials, divided in small explants, were cultured for 20-24 hours, and supernatants (conditioned medium) were collected from 36 women with singleton normal pregnancies, of whom 9 women had a history of RPL. The secreted immune protein profile was measured by proximity extension assay, and the conditioned medium was further used in functional ex vivo models to assess ability to polarize blood monocytes and CD4(+)T cells into immune regulatory phenotypes, as detected by flow cytometry. Results Conditioned medium from chorionic villi, human fetally derived placental tissue, was able to induce a decidual-type of M2-like macrophages, as well as an expansion of Treg cells ex vivo, both in women with uRPL and in control women. The preserved immunological properties were confirmed by a maintained immune protein profile in RPL compared with controls. Conclusion Trophoblasts in an ex vivo model maintain tolerogenic and proteomic profile features in successful pregnancies, despite a previous history of RPL., Funding Agencies|Swedish Research CouncilSwedish Research Council [2018-02776]; Linkoping University; Tor Vergata University; ALF Grants

The aim of this prospective cohort study was to determine whether women with recurrent pregnancy loss (RPL) have an increased risk of pregnancy complications compared to normal pregnant women. A total of 1092 singleton pregnancies were followed, 431 in women with RPL and 661 in normal healthy women. The prevalence of the following complications was observed: threatened miscarriage, miscarriage, cervical insuciency, chromosomal/genetic abnormalities, fetal anomalies, oligohydramnios, polyhydramnios, fetal growth restriction, intrauterine fetal death, gestational diabetes mellitus (GDM), preeclampsia, placenta previa, abruptio placentae, pregnancy-related liver disorders, and preterm premature rupture of the membranes. The odds ratio and 95% CI for each pregnancy complication considered were determined by comparing women with RPL and normal healthy women. Women with RPL had an overall rate of pregnancy complications higher than normal women (OR = 4.37; 95% CI: 3.353–5.714; p < 0.0001). Their risk was increased for nearly all the conditions considered. They also had an increased risk of multiple concomitant pregnancy complications (OR = 4.64; 95% CI: 3.10–6.94, p < 0.0001). Considering only women with RPL, women with 3 losses had a higher risk of pregnancy complications than women with two losses (OR = 1.269; 95% CI: 1.112–2.386, p < 0.02). No dierences were found in the overall risk of pregnancy complications according to the type, explained or unexplained, of RPL. Women with secondary RPL had an increased risk of GDM than women with primary RPL. Pregnancy in women with RPL should be considered at high risk.

In the present manuscript, we review the recent research investigating the pathogenic association between most studied autoantibodies and recurrent pregnancy loss. Pregnancy loss represents a common obstetric complication occurring in about 15%‐25% of all clinically recognized pregnancies. The recurrence of pregnancy loss identifies a distinct clinical entity, that is recurrent pregnancy loss (RPL), affecting about 2%‐4% of couples. Several factors, including age, chromosomal abnormalities, uterine anomalies, thrombophilic disorders, endocrinopathies, hormonal and metabolic disorders, infections, sperm quality, and lifestyle issues, are involved in RPL. The role of autoantibodies in RPL is only partially determined. In some cases (antiphospholipid antibodies [aPL]), their involvement is well established. In other cases (anti‐thyroid autoantibodies, antinuclear, anti‐transglutaminase, and anti‐endomysial antibodies), it is still debated, despite multiple, although not fully conclusive, evidences strongly suggest a possible involvement in RPL. Further extensive research is needed to definitively confirm or exclude their actual role.