Fetal viral infections: predisposing factors

the relative importance of each varies with species. The relative contributions of the corpus luteum and placenta as sources of progesterone can also change as gestation advances, thus placental production of progesterone can, by itself, sustain pregnancy in Ž . the ewe and mare late in gestation Casida and Warwick, 1945; Holtan et al., 1979 . This is important because disruption of placental progesterone production in these species, as occurs with death of the fetus, will quickly lead to fetal expulsion in the latter half of pregnancy. In contrast, fetal expulsion is delayed in those species, that depend on the corpus luteum as the principal source of progesterone throughout gestation. The balance between placental production and metabolism of progesterone is of considerable importance to the maintenance of pregnancy and induction of parturition, and this Ž . balance may differ between species Conley and Mason, 1990 and so influence occurrence of abortion. Estrogen is also an important modulator of uterine activity through its influence on Ž . prostaglandin synthesis and levels of oxytocin receptors Zeeman et al., 1997 . Thus, an increase in estrogen or a decrease in the ratio of progesterone to estrogen at the level of the myometrium signals maternal preparation for parturition. In contrast, fetal prepara- tion involves an activation of the pituitary–adrenal axis and an increase in fetal cortisol Ž . synthesis Wood and Cudd, 1997 . The fetal cortisol surge precedes birth in both the ovine and equine fetus, and the secretion of cortisol by the sheep fetus appears to initiate Ž . the parturition cascade Norwitz et al., 1999 . A sharp rise in the secretion of fetal cortisol induces the expression of placental enzymes in the sheep, both 17a-hydroxylase Ž . and aromatase cytochromes P450 France et al., 1988 , which promote a pre-partum Ž . burst in placental estrogen synthesis Liggins, 1989 . The process of parturition is less clear in the mare. Like the sheep, the perinatal equine fetus experiences activation of the adrenal cortex with increased secretion of cortisol, and recent evidence indicates that Ž . progesterone levels decline immediately prior to birth Silver, 1994 . Fetal administra- Ž . tion of ACTH can induce parturition in the pregnant mare Ousey et al., 1998 , whereas maternal dexamethasone administration is relatively ineffective. Much remains to be determined regarding the initiation of parturition in the mare, and the interaction and metabolism of progesterone and estrogen, but it is clear that there is an increase in Ž uterine responsiveness to certain agents that precedes fetal expulsion Leadon et al., . 1982 . The influence of fetal viral infections on levels of these various modulators is virtually uncharacterized.

3. Fetal viral infections: predisposing factors

3.1. Maternal immunity The fetus is afforded protection by the host defense mechanisms of its dam and by the placenta, because viruses first must infect the pregnant dam before they gain access Ž . to the fetus Arvin, 1997 . Maternal viremia is a critical prerequisite to fetal infection, and the risk of transplacental transmission of some viral infections is proportional to Ž . maternal viral load Garcia et al., 1999 . Immunologically naive dams tend to be most predisposed to transmission of viruses to their fetuses because prior infection or immunization usually confers protective immunity. Thus, females undergoing their first pregnancy are most at risk to infection with endemic viruses, whereas pregnant animals of all ages usually are susceptible to epizootic virus infections that periodically spread through the population. 3.2. Ontogeny of fetal immunity The placenta of the large domestic species does not allow the passage of maternal immunoglobulins to the fetus, whereas the fetal membranes of small domestic carnivores allow such transfer of maternal antibody to the fetus. The fetus is clearly capable of Ž . mounting an active acquired immune response humoral and cellular to a variety of agents thus, in the absence of significant placental injury, immunoglobulins, found in fetal fluids of the large domestic species, are produced by the fetus itself. Immunity, Ž . Ž both innate cytokines, complement, phagocytic function, etc. and acquired humoral . and cellular , develops sequentially in the fetus during gestation so domestic animals are born with functional, if not fully mature, innate and acquired immune defense mecha- Ž . nisms Arvin, 1997; Osburn et al., 1982 . The pregnant uterus usually allows the fetus to develop in a sterile environment, but the fetus is at considerable risk to in utero virus infections when they occur because of the inherent slowness of the acquired immune response. Thus, a virus that is able to cross the placenta to infect the fetus can cause extensive damage before immune clearance occurs. 3.3. Stage of gestation Susceptibility of the conceptus to the deleterious effects of virus infections often is inversely proportional to fetal age, although a number of viruses cause fetal death and abortion regardless of fetal age. Teratogenic agents typically exert their effect only Ž . during a narrow ‘‘window’’ of susceptibility Schofield and Cotran, 1994 , and the fetus is especially susceptible to teratogenic agents during the period when organogenesis occurs. Rapidly dividing populations of stem cells are present at this time, which are both fragile and highly susceptible to selected virus infections.

4. BTV infection of the fetal ruminant