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 physiolo gical marker has hampered both confirmation and prediction which could lead to timely intervention. In this paper. we report studies on hypoxia that w e have performed in chronically cannulated late pregnant sheep, complemente d by parallel investigations undertaken in human pregnancies. Our initial s tudies 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 betwee n hypoxia and activin A. follistatin and prostaglandin (PG) release from th e feto-placental unit. Subsequent studies have been directed towards examin ing this potential relationship in sheep and in humans with compromised pre gnancies. As a result of these studies, we have identified a potential mech anism 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-place ntal hypoxemia or maternal isocapnic hypoxemia, leading to fetal hypoxia, w ere specific triggers for an acute increase in fetal activin A and follista tin concentrations during late gestation. The source and secretion of activ in A, follistatin. and the associated release of PGE,, from within the feto -placental unit varied according to the site of the insult. The concomitant secretion of activin A and PGE, into the fetal circulation and amniotic fl uid during reduced uterine blood flow provides an insight into the physiolo gical regulatory mechanisms that might be involved. Changes observed in mat ernal activin A concentrations in mid and late gestation in the human may a lso be associated with fetal compromise. In human pregnancies, elevated act ivin A concentrations were observed in maternal plasma in mid and late gest ation. in association with severe pre-eclampsia and with severe fetal growt h restriction. compared to those observed in pregnancies with constitutiona lly small, healthy fetuses. Activin A was also elevated in maternal and art erial cord plasma in women at term during labour and immediately prior to u ndergoing emergency Caesarean section for failure to progress. These findin gs offer exciting new possibilities to gain insights into the mechanisms th at 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 fe tal distress. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.