It is important to conclude this in-depth discussion of the immune-mediated mechanisms of isolated and recurrent pregnancy loss by suggesting that pregnancy may not require an intact maternal immune system. Supporting this concept are data showing that agammaglobulinemic animals and women can successfully reproduce (282). Further, viable births also occur among women with severe immune deficiencies and in murine models that lack T and B cells (severe combined immunodeficiency [SCID] mice) and those that display a congenital absence of their thymus (nude mice). Still, immune factors may play important roles in a significant proportion of patients with recurrent pregnancy loss, and their presence is the subject of abundant research. Until this role is better defined, an understanding of contemporary immunologic hypotheses fosters the informed consideration of novel findings.
Male Factors Most publications that review testing and treatment for recurrent pregnancy loss couples, including this chapter, recommend only a single test for the male partner in the couple—a peripheral blood karyotype. The role of the male partner in the etiology of recurrent pregnancy loss is understudied, but there is a growing body of literature suggesting that the development and validation of novel testing and treatment regimens for the male may prove beneficial (283,284). Detailed peripheral chromosomal testing of men whose partners experienced recurrent pregnancy loss revealed an increased incidence of Y chromosome microdeletions when compared to male partners in fertile and infertile couples (285). Small studies demonstrated that male partners in couples experiencing recurrent pregnancy loss have an increased incidence of sperm chromosomal aneuploidy, particularly sex chromosome disomy, when compared to fertile men (16,286). The addition of specialized testing to a standard semen analysis among men in couples with recurrent loss revealed reductions in sperm functional testing (hypo-osmotic swelling, acrosome status, nuclear chromatin decondensation) and increased DNA fragmentation and lipid peroxidation when compared to fertile men or historical controls (287–289). The latter results suggest that these men may have abnormal levels of reactive oxygen species in their semen or that their sperm cells are particularly sensitive to these compounds. To this point, paternal carriage of the MTHFR C677T mutation and hyperhomocysteinemia were associated with both DNA damage and recurrent pregnancy loss (290). A single, small, uncontrolled treatment study using antioxidants among male partners in recurrent pregnancy loss couples who had high levels of sperm DNA damage or semen lipid peroxidation suggested favorable treatment outcomes (288).
Other Factors It is increasingly evident that the implantation of the blastocyst within the uterine decidua involves an exquisitely scripted crosstalk between embryo and mother. Alterations in this dialogue often result in improper implantation and placental development. For instance, recurrent pregnancy loss has been linked to a dysregulation in the expression patterns of vascular endothelial growth factors (VEGFs) on the developing placenta and their requisite receptors within the maternal decidua (291). Cellular and extracellular matrix adhesion properties may also be involved in this dialogue. The concept of uterine receptivity has been emboldened by the description of endometrial integrins and the timing of integrin switching during implantation (292). Others have reported decreased levels of endometrial mucin secretion and reductions in the endometrial release of soluble intercellular adhesion molecule I among women with histories of recurrent pregnancy loss (293,294). Programmed cell death (apoptosis) may also play an essential role in normal placental development. Alterations in two important apoptotic pathways—Fas-Fas ligand and bcl2—have both been linked to recurrent pregnancy loss and poor pregnancy outcome (121,295).