Delayed Neonatal Closure of the Ductus Arteriosus Following Early in utero Exposure to Indomethacin in the Rat

Abstract

Background: Indomethacin is used to close the patent ductus arteriosus in premature infants and for tocolysis of preterm labor. Clinically and experimentally, early in utero exposure to indomethacin induces the paradoxical delay of postnatal closure of the ductus arteriosus. Objectives: To clarify the pharmacological nature of the delay of closure of the ductus arteriosus in the rat. Methods: We studied early in utero exposure to indomethacin (dose and timing) in addition to other drugs, inducing a delay in postnatal ductal closure. Pregnant rats at near term were studied by cesarean section on gestational day 21 (D21), incubated in room air at 33°C, followed by rapid whole-body freezing. Results: The delay in closure of the ductus arteriosus was dose dependent. A large dose of indomethacin (10 mg/kg) 1 or 2 days before birth induced a delay of 3–4 times. A timing study revealed maximum delay with administration of indomethacin 2 days before birth and minimum delay with administration 5 days before. Aspirin, ibuprofen, the selective COX1 inhibitor SC 560, the selective COX2 inhibitor rofecoxib and a prostaglandin EP₄ receptor blocker, ONO-208, all delayed neonatal ductal closure following maternal administration on D19 and D20. Conclusions: The delay by indomethacin was dose dependent. The maximum delay was induced by 2 doses of 10 mg/kg indomethacin on D19 and D20. The delay was induced by a decreased stimulus to the prostaglandin EP₄ receptor system in the last 2 days in utero. The delay was temporary with recovery 3 days or more after exposure.

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

“…Conversely, vasodilatation could result from interference with some factor, such as the Rho/Rho kinase complex, that is critical for the contractile tension of blood vessels, DA included [12,29] . Whatever the explanation, an additional question is whether pre-and postnatal MF63-induced dilatation share the same mechanism since there are experimental data, although at variance with ours [4][5][6] , showing that PGE 2 suppression in utero may cause by itself a persistent DA after birth [30,31] . MF63 needs to be tested directly in the newborn to settle this issue.…”

Selective COX-1 Inhibition: A Therapeutic Target to be Reconsidered

“…However, according to Momma results, not only indomethacin but also aspirin, ibuprofen, rofecoxib (selective COX-2 inhibitor), SC-560 (selective COX-1 inhibitor), and ONO-208 (EP 4 receptor antagonist) delay rat neonatal ductal closure following maternal administration on day19 and day20 (rat gestation period: 21.5 days) [86].…”

Indomethacin in Pregnancy: Applications and Safety

“…124 It is important to note that the relation between antenatal indomethacin exposure and postnatal failure of medical therapy for PDA has been shown to be time dependent 121 and, in animal studies, dose dependent. 135 In the various meta-analyses, there is agreement that indomethacin treatment at less than 34 weeks of gestation for tocolysis does not increase the risk of PDA. 94,95…”