Physiological and regulatory roles of activin A in late pregnancy

Unexplained fetal death in utero in late pregnancy represents an increasing proportion of perinatal deaths. It has been assumed that critical hypoxia is the likely mechanism underlying these losses, but the lack of a physiological marker has hampered both confirmation and prediction which could lead to timely intervention. In this paper, we report studies on hypoxia that we have performed in chronically cannulated late pregnant sheep, complemented by parallel investigations undertaken in human pregnancies. Our initial studies were directed towards determining activin secretion in the fetus and mother during late gestation, and immediately after fetal surgery using a sheep model. This led us to propose that there may be a relationship between hypoxia and activin A, follistatin and prostaglandin (PG) release from the feto-placental unit. Subsequent studies have been directed towards examining this potential relationship in sheep and in humans with compromised pregnancies. As a result of these studies, we have identified a potential mechanism by which activin A may be involved in regulating the response of the fetus to hypoxic insult. Activin A and follistatin concentrations increased in late gestation in ovine maternal plasma and in fetal fluids. Feto-placental hypoxemia or maternal isocapnic hypoxemia, leading to fetal hypoxia, were specific triggers for an acute increase in fetal activin A and follistatin concentrations during late gestation. The source and secretion of activin A, follistatin, and the associated release of PGE(2,) from within the feto-placental unit varied according to the site of the insult. The concomitant secretion of activin A and PGE(2) into the fetal circulation and amniotic fluid during reduced uterine blood flow provides an insight into the physiological regulatory mechanisms that might be involved. Changes observed in maternal activin A concentrations in mid and late gestation in the human may also be associated with fetal compromise. In human pregnancies, elevated activin A concentrations were observed in maternal plasma in mid and late gestation, in association with severe pre-eclampsia and with severe fetal growth restriction, compared to those observed in pregnancies with constitutionally small, healthy fetuses. Activin A was also elevated in maternal and arterial cord plasma in women at term during labour and immediately prior to undergoing emergency Caesarean section for failure to progress. These findings offer exciting new possibilities to gain insights into the mechanisms that underlie the maintenance of fetal wellbeing and provide a rationale for the potential that activin A may prove to be a useful clinical marker of fetal distress.