Immunological Basis for Recurrent Fetal Loss and Pregnancy Complications

Abstract

Pregnancy stimulates an elaborate assortment of dynamic changes, allowing intimate approximation of genetically discordant maternal and fetal tissues. Although the cellular and molecular details about how this works remain largely undefined, important clues arise from evaluating how a prior pregnancy influences the outcome of a future pregnancy. The risk of complications is consistently increased when complications occurred in a prior pregnancy. Reciprocally, a prior successful pregnancy protects against complications in a future pregnancy. Here, we summarize immunological perturbations associated with fetal loss, with particular focus on how both harmful and protective adaptations may persist in mothers. Immunological aberrancy as a root cause of pregnancy complications is also considered, given their shared overlapping risk factors and the sustained requirement for averting maternal-fetal conflict throughout pregnancy. Understanding pregnancy-induced immunological changes may expose not only new therapeutic strategies for improving pregnancy outcomes but also new facets of how immune tolerance works that may be applicable to other physiological and pathological contexts.

Keywords: microchimerism; preeclampsia; prematurity; regulatory T cells; spontaneous abortion; stillbirth.

Figure 1.. Expanded maternal tolerance to fetal expressed antigens is essential for averting complications throughout pregnancy.

Peripheral immune tolerance expands to encompass fetal expressed paternal antigens during uncomplicated healthy pregnancy. Fractured fetal tolerance at any time during pregnancy can cause gestational time specific complications such as spontaneous abortion, stillbirth, preeclampsia and prematurity.

Figure 2.. Fetal specific adaptive immune components retained in mothers after pregnancy influence susceptibility to complications in future pregnancies.

Harmful adaptive immune components with fetal specificity primed with pregnancy complications are retained in mothers after parturition, and cause increased partner-specific risk of complications in subsequent pregnancies (top). Protective fetal specific adaptive immune components retained in mothers after healthy pregnancy enforce fetal tolerance and confer partner-specific protection against complications in subsequent pregnancies (bottom).