One additional regulatory mechanism proposed for the induction of maternal tolerance to the fetal allograft involves the amino acid tryptophan and its catabolizing enzyme indolamine 2,3 dioxygenase (IDO). The IDO hypothesis of tolerance in pregnancy rests on data that indicate that T cells need tryptophan for activation and proliferation (234), and that local alterations in tryptophan metabolism at the maternal–fetal interface could either activate or fail to suppress maternal antifetal immunoreactivity (235). Studies in mice have shown that the inhibition of IDO leads to loss of allogeneic, but not syngeneic, fetuses, and that this effect is mediated by lymphocytes (236). Further support lies in studies demonstrating that hamsters fed diets high in tryptophan have increased rates of fetal wastage (237). Extending this theory to humans requires further investigation. However, the demonstration of IDO expression in human uterine decidua, and the documentation of alterations in serum tryptophan levels with increasing gestational age during human pregnancy both support further interest in this potential local immunoregulatory mechanism (238,239).
Endometriosis is the growth of both endometrial glands and stroma outside of the intrauterine cavity. Although associations between the development of endometriosis and immunologic abnormalities are now being defined, the link between endometriosis and recurrent pregnancy loss remains contentious (240,241). The occurrence of recurrent pregnancy loss in the presence of endometriosis certainly would involve the interaction of complex mechanisms, some of which may involve cellular or humoral immune dysfunction (242,243).
Humoral responses to pregnancy-specific antigens exist, and patients with recurrent pregnancy loss can display altered humoral responses to endometrial and trophoblast antigens (Table 33.2) (199,244). Nevertheless, most literature surrounding humoral immune responses and recurrent pregnancy loss focus on organ nonspecific autoantibodies associated with the antiphospholipid antibody syndrome (APS). Historically, these immunoglobulin-G (IgG) and IgM antibodies were considered as directed against negatively charged phospholipids. Those phospholipids most often implicated in recurrent pregnancy loss are cardiolipin and phosphatidylserine. However, antiphospholipid antibodies often are directed against a protein cofactor, β2 glycoprotein 1, which assists antibody association with the phospholipid (245–249). Antiphospholipid antibodies were originally characterized by prolonged phospholipid-dependent coagulation tests in vitro (activated partial thromboplastin time [aPTT], Russell Viper Venom time) and by thrombosis in vivo. The association of these antiphospholipid antibodies with thrombotic complications has been termed the antiphospholipid syndrome, and although many of these complications are systemic, some are pregnancy specific—spontaneous abortion, stillbirth, intrauterine growth retardation, and preeclampsia (250,251). A reassessment of the criteria used to diagnose APS resulted in additions to the prior Sapporo criteria for diagnosis of APS and continues to include adverse pregnancy outcomes. These criteria, which have been validated clinically, are as follows (251–253).
For a patient to be diagnosed with antiphospholipid antibody syndrome, one or more clinical and one or more laboratory criteria must be present: 1.
One or more confirmed episode of vascular thrombosis of any type: Venous  Arterial  Small vessel 2.
Pregnancy complications: of gestation with exclusion of maternal anatomic and hormonal abnormalities and exclusion of paternal and maternal chromosomal abnormalities