Prostaglandins (PGs) have been recently proven essential for parturition in mice. To dissect the contributions of the two cyclooxygenase (COX) isoforms to the synthesis of PGs during pregnancy, we have characterized the parturition phenotype of COX-1-deficient mice. We find that mice with targeted disruption of the COX-1 gene have delayed parturition resulting in neonatal death. Results of matings of COX-1-deficient females with COX-1 intact males, and blastocyst transfer of COX-1-deficient or -intact embryos into wild-type foster mothers, proved necessity and sufficiency of maternal COX-1 for the normal onset of labor. COX-1 expression is induced in gravid murine uterus and by in situ hybridization; this induction is localized to the decidua. Measurement of uterine PGs further confirmed that COX-1 accounted for the majority of PGF2␣ production. To evaluate the interaction of PGs with oxytocin during murine labor, we generated mice deficient in both oxytocin and COX-1. Surprisingly, the combined oxytocin and COX-1-deficient mice initiated labor at the normal time. COX-1-deficient mice demonstrated impaired luteolysis, as evidenced by elevated serum progesterone concentration and ovarian histology late in gestation, and delayed induction of uterine oxytocin receptors. In contrast, simultaneous oxytocin and COX-1 deficiency restored the normal onset of labor by allowing luteolysis in the absence of elevated PGF2␣ production. These findings demonstrate that COX-1 is essential for normal labor in the mouse, with a critical function being to overcome the luteotrophic action of oxytocin in late gestation.

Prostaglandins (PGs) have proven important during parturition, but inhibition of PG production treating preterm labor (PTL) results in significant maternal and fetal side effects. We hypothesize that specific inhibition of either cyclooxygenase (COX)-1 or -2 may result in separation of therapeutic and toxic effects. We demonstrate that COX-2, but not COX-1, is induced during inflammation-mediated PTL caused by lipopolysaccharide (LPS) administration. A two- to threefold increase in uterine and ovarian PG concentrations coincides with this induction of COX-2. The COX-2-selective inhibitor SC-236 proved effective in stopping preterm delivery and the increases in PGs. The COX-1-selective inhibitor SC-560 also attenuated uterine and ovarian PG production after LPS but did not inhibit PTL as efficiently as SC-236. COX-1-deficient mice, which show delay in the onset of term labor, exhibited no delay in onset of PTL after LPS. These findings suggest that the mechanisms for initiation of inflammation-mediated PTL and term labor differ and that selective COX-2 inhibition may provide a means of stopping inflammation-induced PTL in humans.

Leptin plays an important role in regulating body composition through modulation of appetite and energy expenditure. We hypothesized that leptin levels in umbilical cord blood correlate with newborn body weight and habitus. We also hypothesized that infants of diabetic mothers would demonstrate altered leptin metabolism. Venous blood was sampled at birth from the umbilical cords of 105 infants (74 infants of nondiabetic mothers, and 31 infants of diabetic mothers). Thirty-nine mothers had plasma leptin concentrations measured. Analysis was done using Student's t-test, Pearson's correlation, and Spearman's correlation. Univariate/multivariate regression was used for analysis of factors associated with leptin concentration in umbilical cord plasma. Maternal and newborn characteristics were correlated with log leptin levels in umbilical venous plasma. Leptin concentration in umbilical cord plasma correlated best with birth weight for newborns of both nondiabetic and diabetic mothers (p < 0.01 for either). Umbilical cord plasma concentration of leptin was higher in infants of diabetic mothers than in infants of nondiabetic mothers (2.53 +/- 1.09 vs. 1.76 +/- 0.82; p < 0.001). Multiple regression analysis revealed a significant (p < 0.01) relationship between umbilical cord leptin level and newborn birth weight, as well as maternal DM, but not with gestational age. Similarly, there was no significant correlation with maternal plasma leptin concentration. The strong correlation of leptin concentration in umbilical cord plasma with newborn birth weight, and the lack of significant correlation with maternal leptin plasma levels, suggest that normal fetal leptin metabolism reflects fetal size and/or body habitus independent of maternal leptin metabolism. On the other hand, the higher umbilical plasma levels in infants of diabetic mothers may reflect an influence of altered fetal insulin homeostasis on fetal leptin metabolism, and suggests that maternal diabetes may influence fetal leptin metabolism.

This fetal overgrowth index that incorporates five clinical factors provides a means of predicting fetal overgrowth and thereby serves as a tool for targeting the allocation of healthcare resources and treatment individualization.

Prostaglandins are essential for the initiation of parturition in mice. The peak in uterine prostaglandin F(2)(alpha) levels occurs at d 19.0 of gestation, just before the onset of labor. Our studies set out to determine the important regulatory step(s) involved in this increase of prostaglandin F(2)(alpha). We show that cytosolic phospholipase A(2) mRNA, protein, and activity do not significantly vary during mouse gestation. Rather, our studies demonstrate that cyclooxygenase-1 mRNA is abruptly induced at d 15.5 of gestation, but cyclooxygenase-1 protein levels only gradually increase throughout gestation. In contrast, cyclooxygenase-2 protein remains constant during gestation. We find that prostaglandin F synthase protein increases significantly during gestation reaching peak levels between d 15.5 and d 17.5 of gestation. We also find that the level of prostaglandin dehydrogenase, responsible for degradation of prostaglandins, decreases during late gestation. Taken together these results suggest that the regulation of prostaglandin F(2)(alpha) is a complex process involving the coordinate induction of synthetic enzymes along with a decrease in degradative enzymes involved in prostaglandin metabolism.