Risks associated with viral infections during pregnancy

Abstract

Despite the prevalence of viral infections in the American population, we still have a limited understanding of how they affect pregnancy and fetal development. Viruses can gain access to the decidua and placenta by ascending from the lower reproductive tract or via hematogenous transmission. Viral tropism for the decidua and placenta is then dependent on viral entry receptor expression in these tissues as well as on the maternal immune response to the virus. These factors vary by cell type and gestational age and can be affected by changes to the in utero environment and maternal immunity. Some viruses can directly infect the fetus at specific times during gestation, while some only infect the placenta. Both scenarios can result in severe birth defects or pregnancy loss. Systemic maternal viral infections can also affect the pregnancy, and these can be especially dangerous, because pregnant women suffer higher virus-associated morbidity and mortality than do nonpregnant counterparts. In this Review, we discuss the potential contributions of maternal, placental, and fetal viral infection to pregnancy outcome, fetal development, and maternal well-being.

Figure 1. Cell types at the maternal-fetal interface.

Maternal and fetal cells make up the maternal-fetal interface. The maternal decidua consists of pregnancy-specific differentiated stromal cells that house the maternal blood vessels and maternal immune cells including T cells, uterine NK (uNK) cells, macrophages, and DCs. Extravillous cytotrophoblasts (evCYTs) invade the decidua and reach the maternal spiral arteries, establishing nutrient circulation between the embryo and the mother. The placental villus is in direct contact with the maternal blood and thus facilitates gas, nutrient, and communication exchange between the mother and developing fetus. It is formed by a double cell layer consisting of syncytiotrophoblasts and cytotrophoblasts. The villus contains the fetal blood vessels that are surrounded by fibroblasts and fetal macrophages (termed Hofbauer cells).

Figure 2. Mouse models of viral infection during pregnancy.

Herpesviruses target the pregnant cervix and induce dramatic molecular and functional changes. (A) High sex hormone levels associated with pregnancy enhance cervical susceptibility to infection by causing upregulation in the cervix of integrins and HA, receptors for herpes infection. (B) Infection of cervical epithelial cells results in activated SRC kinase, which stabilizes the ER. These changes are also associated with reduced expression of innate immune factors such as TLRs and defensins, as well as tissue remodeling in the stroma that is reminiscent of cervical ripening.

Figure 3. Maternal viral infections and associated outcomes.

Viral infection at the maternal-fetal interface can affect the mother as well as fetal development. The placenta functions as a physiologic and immunologic barrier to prevent viral transfer from the mother to the fetus. However, the immunologic response to infection might reach the fetal circulation or predispose the mother to abnormal responses to other microorganisms, with potential pregnancy complications such as IUGR, PTB, or even early pregnancy loss. Fetal infection can cause pregnancy loss and is associated with hearing loss, cataract, microcephaly, and psychiatric disorders in the fetus.