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Systemic inflammatory responsiveness was studied in normal human pregnancy and its specific inflammatory disorder, pre-eclampsia. Compared with nonpregnancy, monocytes were primed to produce more TNF-α throughout normal pregnancy, more IL-12p70 in the first and second trimesters, and more IL-18 in the first trimester only. Intracellular cytokine measurements (TNF-α and IL12p70) showed little change by comparison. IFN-γ production was suppressed in all three trimesters. In pre-eclampsia, IL-18 secretion was increased. Secreted but not intracellular measures of TNF-α and IL-12p70 were also further enhanced compared with normal pregnancy. Inhibition of IFN-γ production was lost and involved both CD56+ NK and CD56− lymphocyte subsets. We determined whether circulating syncytiotrophoblast microparticles (STBM) could contribute to these inflammatory changes. Unbound STBM could be detected in normal pregnancy by the second trimester and increased significantly in the third. They were also bound in vivo to circulating monocytes. Women with pre-eclampsia had significantly more circulating free but not cell-bound STBMs. STBMs prepared by perfusion of normal placental lobules stimulated production of inflammatory cytokines (TNF-α, IL12p70, and IL-18 but not IFN-γ) when cultured with PBMCs from healthy nonpregnant women. Inflammatory priming of PBMCs during pregnancy is confirmed and is established by the first trimester. It is associated with early inhibition of IFN-γ production. The inflammatory response is enhanced in pre-eclampsia with loss of the IFN-γ suppression. Circulating STBMs bind to monocytes and stimulate the production of inflammatory cytokines. It is concluded that they are potential contributors to altered systemic inflammatory responsiveness in pregnancy and pre-eclampsia.

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Women with RM have altered peripheral blood NK parameters. NK cells as a percentage of lymphocytes best discriminated RM and control populations. Women with RM and high NK levels may have an immunological disorder.

With the exception of aspirin and heparin for the prevention of recurrent miscarriage in women with the antiphospholipid syndrome, no other suggested therapies for this heterogeneous group of patients have been evaluated in randomized controlled trials. These include thromboprophylaxis for inherited thrombophilias and use of insulin sensitizers in women with insulin resistance and/or polycystic ovarian syndrome. The role of the innate immune system in pregnancy was recently highlighted, and use of nonspecific therapies to suppress the maternal immune response to pregnancy should be reassessed.

SUMMARYThis paper considers both monocytes and peripheral blood lymphocytes as potential targets for maternal immunological modulation in pregnancy. Peripheral blood mononuclear cells (PBMCs) from nonpregnant and normal pregnant donors were stimulated in vitro , and cytokine production detected intracellularly by flow cytometry. It was found that monocyte production of TNF-a was unaltered in pregnancy, while production of IL-12 was significantly enhanced. In contrast, production of the Th1 type cytokine IFN-g was suppressed in the lymphocyte subsets: CD4 + T helper cells and CD56 + NK cells. Production of the Th2 type cytokine IL-4 in CD4 + cells was not significantly altered in pregnancy. These data suggest that the concept that pregnancy is a 'Th2 phenomenon' cannot be generalized to the function of all aspects of maternal cellular immunity as, paradoxically, circulating monocytes are 'primed' to produce the Th1 cytokine IL-12. Furthermore, these data support the hypothesis that components of maternal innate immunity are activated in normal pregnancy.Keywords human pregnancy interleukin 12 monocytes Th1/Th2