The etiologic mechanism linking specific organisms to either isolated or recurrent pregnancy loss remains unclear and must certainly differ among infectious organisms. Certain viral organisms, such as herpes simplex virus (HSV) and human cytomegalovirus (HCMV) can directly infect the placenta and fetus (116,117). The resulting villitis and related tissue destruction may lead to pregnancy disruption. Another theoretic possibility warranting study is that infection-associated early pregnancy loss may result from immunologic activation in response to pathologic organisms. A large body of evidence supports the role of this mechanism in adverse events later in gestation, such as intrauterine growth restriction, premature rupture of membranes, and preterm birth (118,119). Alternatively, mechanisms that protect the fetus from autoimmune rejection also may protect virally infected placental cells from recognition and clearance. This could potentially promote periods of unfettered infectious growth for some of the pathogenic organisms gaining entry to the reproductive tract (120).
During the past decade, there has been extensive information published concerning the possible immunologic causes and treatments of recurrent pregnancy loss. There is a lack of consensus as to the mechanisms and the impact of therapeutic intervention because the detection of a therapeutic effect is difficult in the absence of very large studies. This situation reﬂects the fact that many recurrent pregnancy loss patients present after their index pregnancy has expired but prior to its being expelled. In these cases, the physiologic immune reaction to the presence of nonviable tissue may mask any alternative, underlying immune causes for the demise itself. Finally, it is very likely that there are a wide variety of immune alterations that may result in the same end point—isolated or recurrent pregnancy loss. This latter theory is certainly supported by a now classic review article that lists 10 fairly well-supported immune mechanisms that are each potentially important in pregnancy maintenance (121) (Tables 33.1 and 33.2).
Before launching into the most commonly accepted causes of immune-mediated pregnancy loss, a brief review of some of the important concepts in basic immunology is warranted. Although these descriptions are presented in general terms, and are further defined in Chapter 6, they should serve as useful reference for the ensuing information.
Immune responses classically are divided into innate and acquired responses. Innate responses represent the body’s first line of defense against pathogenic invasion. They are
Table 33.2 Concepts in Reproductive Immunology 1. Resident endometrial/decidual cells a.
b.
TCRαβ+ and TCRγδ+ cells are present, TCRγδ+ cells increase in early pregnancy c.
NK-like, large granular lymphocytes (decidual NK cells) accumulate at sites of implantation d.
e.
2. Immune cell education and homing a.
b.
c.
3. Antigen presentation a.
MHC class II molecules are not expressed in the placenta b.
Classical MHC class I molecules HLA-A and HLA-B are not expressed in the placenta c.
Extravillous cytotrophoblast cells express HLA-C, HLA-E, and HLA-G 4. In situ immunoregulation a.
b.
1.
2.
3.
4.
5.
6.
c.
Tryptophan metabolism and indolamine 2,3 dioxygenase (IDO) d.
1.
Fetal antigens are recognized by the maternal immune system and humoral responses are mounted 2.
a.
b.
c. Anti-β2 glycoprotein-1 (anti-beta2GP-1) antibodies d. Antiphosphatidly serine antibodies 3. Organ specific autoantibodies a.
b.
c.
1.
2.
3.
Treg, regulatory T cells; TH, T helper; NK, natural killer; NKT, natural killer T; MHC, major histocompatibility complex.