Altered fetal pituitary-adrenal function in the ovine fetus treated with RU486 and meloxicam, an inhibitor of prostaglandin synthase-II

Term and preterm labor are associated with increased fetal hypothalamic-pit uitary-adrenal (HPA) activation and synthesis of prostaglandins (PGs) gener ated through the increased expression of prostaglandin Fl synthase-ll (PGHS -II) in the placenta. Inhibition of PGHS-II has been advocated as a means o f producing uterine tocolysis, but the effects of such treatment on fetal e ndocrine functions have not been thoroughly examined. Because PGE(2) is kno wn to activate the fetal HPA axis, we hypothesized that administration of m eloxicam, a PGHS-II inhibitor, to sheep in induced labor would suppress fet al HPA function. Chronically catheterized pregnant ewes were treated with R U486, a progesterone receptor antagonist, to produce active labor, and then treated with either high-maintenance-dose meloxicam, graded-maintenance-do se meloxicam, or a saline infusion. Maternal uterine contraction frequency increased 24 h after the RU486 injection and the animals were in active lab or by 48 +/- 4 h. RU486 injection led to increased concentrations of PGE(2) , ACTH, and cortisol in the fetal circulation, and increased concentrations of 13,14 dihydro 15-ketoprostaglandin F-2 alpha (PGFM) in the maternal cir culation. Uterine activity was inhibited within 12 h of beginning meloxicam infusion at both infusion regimes. During meloxicam infusion there were si gnificant decreases in fetal plasma PGE,, ACTH, and cortisol concentrations , and PGFM concentrations in maternal plasma. In control animals, frequency of uterine contractions, maternal plasma PGFM, fetal plasma PGE,, ACTH, an d cortisol concentrations increased after RU486 administration, and continu ed to rise during saline infusion until delivery occurred. We conclude that RU486-provoked labor in sheep is associated with activation of fetal HPA f unction, and that this is attenuated during meloxicam treatment to a level considered compatible with pregnancy maintenance.