Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus.
Preterm delivery is the leading cause of neonatal mortality and contributes significantly to infant morbidity. Classical cyclooxygenase (COX) inhibitors, such as indomethacin, which inhibit both COX-1 and COX-2, are effective for delaying premature labor, but their use is limited by serious complications to the fetus and neonate, including adverse effects on the ductus arteriosus (DA). Using isoform-selective inhibitors, we characterized the roles of the COX isoforms in the initiation of labor and the regulation of fetal and neonatal DA closure in mice. Chronic inhibition of COX-2 during pregnancy (gestation days 15-18) significantly increased neonatal mortality by preventing closure of the DA after birth, whereas acute COX-2 inhibition near the end of term (gestation day 18) constricted the fetal DA. In contrast, the inhibition of COX-1 during pregnancy lacked these prenatal and postnatal adverse effects on the DA and effectively delayed the initiation of full-term labor and LPS-induced preterm labor. These findings suggest that premature fetal DA closure or neonatal patent DA observed following indomethacin tocolysis in women may result from the inhibition of COX-2. Therefore, COX-1-selective inhibitors may provide effective treatment to delay preterm labor with fewer adverse effects on fetal or neonatal health than nonselective or COX-2-selective inhibitors.
Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. langenbach@niehs.nih.gov
Charles D
CD
Loftin
Darshini B
DB
Trivedi
Robert
R
Langenbach
D000818:Animals; D000831:Animals, Newborn; D003251:Constriction, Pathologic / Q000139:chemically induced / Q000473:pathology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000473:pathology; D004374:Ductus Arteriosus, Patent / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000201:enzymology; D005865:Gestational Age; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D007700:Kinetics; D007743:Labor, Obstetric / Q000187:drug effects*; D008431:Maternal-Fetal Exchange; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology* / Q000633:toxicity; D017482:Receptors, Thromboxane / Q000819:agonists; D016019:Survival Analysis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D017482:Receptors, Thromboxane; C115461:SC 560; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse