br Acknowledgments Denise Fernandes acknowledges a postdoc f
Acknowledgments Denise Fernandes acknowledges a postdoc fellowship (SFRH/BPD/34289/2006) from the Portuguese Fundação para a Ciência e Tecnologia (FCT) of the Ministry of Science and Technology of Portugal. This work was supported by the Spanish National Plan for Research (Project Ref. CGL2011-24538).
Introduction A fact that is not appreciated by most laypersons, and even by doctors who are not in the field of obstetrics and gynaecology, is that pregnancy is not nearly as successful as one might assume. Numerous potential complications may arise between the long period of gestation from conception to delivery; these include threatened abortion, spontaneous miscarriage, pre-eclampsia, preterm rupture of membranes and preterm labour and delivery. As much as 30% of pregnancies result in miscarriage within two weeks of Ki16198 and another 15–20% of conceptions fail within 14 weeks of gestation.
Spontaneous miscarriage Spontaneous miscarriage, defined as a clinically detectable pregnancy loss prior to 20 weeks of gestation, occurs in one out of every four pregnant women. Recurrent spontaneous miscarriage (RSM) is defined as the occurrence of three or more pregnancy losses before the 20th week of gestation and is one of the most challenging complications of pregnancy. Interestingly, despite years of research, only about 40–50% of the cases of RSM are attributable to the so called “known” causes such as chromosomal anomalies, endocrinologic abnormalities, infections, anatomic problems and humoral factors, and as much as 60% consigned conveniently (and inevitably) to the mysterious “black box” designated as “unknown” or “unexplained” aetiology (Fig. 1).1, 2, 3 Thus, the causes of RSM remain “unexplained” in the majority of women; the fact that the aetiology is unexplained in such a large proportion of cases of RSM has inspired the exploration of possible immunologic etiologies of RSM. As is true for many fields such as rheumatology, nephrology, and pulmonology, immunologists have been very active in field of obstetrics and gynaecology, ascertaining whether immunologic factors are responsible for complications which are unexplained in terms of genetic, infectious and endocrinologic factors.
Immune etiologic factors in recurrent spontaneous miscarriage While humoral and cell-mediated etiologic factors have been investigated, interestingly the conceptus appears to be resistant to attack by humoral immunity except for anti-phospholipid antibodies which are clearly implicated in a proportion of RSM. Anti-phospholipid antibodies appear to cause pregnancy loss by interfering with the anti-thrombotic role of phospholipids.
Modulation of cytokine profiles The observation of an association between RSM and maternal pro-inflammatory cytokine dominance, has spurred research on manipulating the cytokine balance with the objective of downregulating pro-inflammatory cytokines such as IFNγ and TNFα, thereby creating a milieu that is more conducive to the success of pregnancy. A similar rationale for inhibiting inflammatory cytokines exists in autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease.31, 32 This has been achieved by the administration of antibodies to cytokines and/or cytokine receptors. Another approach would be to use a hormone such as progesterone, which fascinatingly enough has been shown, in early pioneering studies, to have anti-inflammatory and immunosuppressive properties. Progesterone has long been known to be absolutely indispensable for the establishment of the receptive endometrium, but is now being recognized as possibly also contributing immunologically to the sustenance of pregnancy by interacting with the maternal immune system. Almost 40 years ago Stites referred to progesterone as “Nature's immunosuppressant” based on studies that demonstrated immunosuppressive properties of progesterone. Indeed, progesterone has been shown to suppress the activation and proliferation of lymphocytes, to decrease the oxidative burst of monocytes and to prolong the survival of allografts when administered locally.35, 36