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J Clin Invest. 2002 Aug;110(4):549-57.

Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus.

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1
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

Abstract

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.

PMID:
12189249
PMCID:
PMC150416
DOI:
10.1172/JCI14924
[Indexed for MEDLINE]
Free PMC Article
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