Understanding recurrent pregnancy loss: recent advances on its etiology, clinical diagnosis, and management

Abstract

Recurrent pregnancy loss (RPL) has become an important reproductive health issue worldwide. RPL affects about 2%-3% of reproductive-aged women, and makes serious threats to women's physical and mental health. However, the etiology of approximately 50% of RPL cases remains unknown (unexplained RPL), which poses a big challenge for clinical management of these patients. RPL has been widely regarded as a complex disease where its etiology has been attributed to numerous factors. Heretofore, various risk factors for RPL have been identified, such as maternal ages, genetic factors, anatomical structural abnormalities, endocrine dysfunction, prethrombotic state, immunological factors, and infection. More importantly, development and applications of next generation sequencing technology have significantly expanded opportunities to discover chromosomal aberrations and single gene variants responsible for RPL, which provides new insight into its pathogenic mechanisms. Furthermore, based upon patients' diagnostic evaluation and etiologic diagnosis, specific therapeutic recommendations have been established. This review will highlight current understanding and recent advances on RPL, with a special focus on the immunological and genetic etiologies, clinical diagnosis and therapeutic management.

Keywords: etiologic diagnosis; genetic etiology; next generation sequencing; recurrent pregnancy loss; therapeutic recommendations.

Figure 1:

Dysregulation of immune and coagulation systems at the maternal-fetal interface in RPL patients. Decidual lymphocytes modulate immune response via interacting with each other and also regulate invaded trophoblasts and decidual cells by secreting various cytokines and chemokines. Notably, disturbance of immune regulation at the interface, which leads to impaired immune tolerance, is frequently associated with RPL. dNK cells are the dominant immune cells at the interface, and they induce immune tolerance by recognizing different kinds of HLA molecules on EVTs by encoding various types of inhibitory KIR. Recent single-cell transcriptomics analyses show that reduction of specific dNK subsets such as CD27⁻CD11b⁻, pregnancy trained dNK, and CSF1⁺ CD59⁺ KIRs⁻may be related to RPL. Furthermore, increased Th1/Th2 and M1/M2 ratios, reduced immunosuppressive Treg cells and DC, and increased pro-inflammatory Th17 cells, have also been identified as risk factors for RPL. In addition, aPLs interacts with open form of β2GP I in endothelial and placental cells, and can activate the complement system, which inhibits angiogenesis and the development of spiral arteries, as well as proliferation and differentiation of trophoblast cells. RPL, recurrent pregnancy loss; EVTs, extravillous trophoblast cells; KIR, killer cell immunoglobulin like receptors; DC, dendritic cells.

Figure 2:

The genetic factors of maternal and paternal origins contribute to RPL. Studies have identified many RPL associated genetic factors, including maternally and paternally derived chromosomal abnormalities, maternal aneuploidy mosaicism, sperm DNA fragmentation, Y chromosome microdeletions and variants of functional genes involved in coagulation, immune response, ECM remodeling, and so on. ECM, extracellular matrix; RPL, recurrent pregnancy loss.