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Indomethacin in Pregnancy: Applications and Safety

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Indomethacin in Pregnancy: Applications and Safety Original Article 175 Indomethacin in Pregnancy: Applications and Safety Gael Abou-Ghannam, M.D. 1 Ihab M. Usta, M.D. 1 Anwar H. Nassar, M.D. 1 1 Department of Obstetrics and Gynecology, American University of Address for correspondence and reprint requests Anwar H. Nassar, Beirut Medical Center, Hamra, Beirut, Lebanon M.D., American University of Beirut Medical Center, P.O. Box 113-6044/B36, Hamra 110 32090, Beirut, Lebanon (e-mail: [email protected]). Am J Perinatol 2012;29:175–186. Abstract Preterm labor (PTL) is a major cause of neonatal morbidity and mortality worldwide. Among the available tocolytics, indomethacin, a prostaglandin synthetase inhibitor, has been in use since the 1970s. Recent studies have suggested that prostaglandin synthetase inhibitors are superior to other tocolytics in delaying delivery for 48 hours and 7 days. However, increased neonatal complications including oligohydramnios, Keywords renal failure, necrotizing enterocolitis, intraventricular hemorrhage, and closure of the ► indomethacin patent ductus arteriosus have been reported with the use of indomethacin. Indometh- ► tocolysis acin has been also used in women with short cervices as well as in those with idiopathic ► preterm labor polyhydramnios. This article describes the mechanism of action of indomethacin and its ► short cervix clinical applications as a tocolytic agent in women with PTL and cerclage and its use in ► polyhydramnios the context of polyhydramnios. The fetal and neonatal side effects of this drug are also ► fetal side effects summarized and guidelines for its use are proposed. Preterm labor (PTL) is a major cause of neonatal morbidity in women with PTL and cerclage and its use in the context of and mortality worldwide.1 Care of premature infants has polyhydramnios. The fetal and neonatal side effects of this dramatically improved over the years but the progress in drug are also summarized and guidelines for its use are decreasing the incidence of preterm birth (PTB) has not been proposed. remarkable.2 A multitude of tocolytic agents have been tried to prolong Mechanism of Action labor including β-agonists, calcium channel blockers, prosta- glandin synthetase inhibitors, magnesium sulfate, and oxyto- It is well documented that prostaglandins are involved in cin receptor antagonists. However, no clear-cut first-line PTL.7 By enhancing myometrial gap junctions and stimulating treatment has been identified.3 In addition, there is limited calcium intracellular influx as well as its release from the Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. evidence supporting the role of tocolytics in improving sarcoplasmic reticulum, prostaglandins result in activation of perinatal outcomes despite some success in prolonging myosin light-chain kinase and muscular contraction.7 Prosta- pregnancy.3 glandin levels increase in the plasma and amniotic fluid of Indomethacin, a prostaglandin synthetase inhibitor, has women in labor, and prostaglandin metabolites have also been used as a tocolytic since the 1970s4 and recently as a been shown to be higher in women who deliver preterm.7 first-line agent in Canada.5 On the other hand, maternal–fetal Indomethacin is a prostaglandin inhibitor that acts by medicine specialists in the United States would choose mag- competing with arachidonic acid for cyclooxygenase (COX). nesium sulfate first, then prostaglandin synthetase inhibitors This mechanism of action was confirmed by Niebyl et al,8 who as first-line tocolytic agents.6 showed that when treated with indomethacin for tocolysis, In this article, we describe the mechanism of action of the maternal serum level of prostaglandin F2α metabolite indomethacin and its clinical applications as a tocolytic agent decreases. received Copyright © 2012 by Thieme Medical DOI http://dx.doi.org/ March 17, 2011 Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0031-1284227. accepted after revision New York, NY 10001, USA. ISSN 0735-1631. May 6, 2011 Tel: +1(212) 584-4662. published online July 22, 2011 176 Indomethacin for Tocolysis, Short Cervix, and Polyhydramnios Abou-Ghannam et al. Uterine contractility is influenced by other mechanisms, ing pregnancy. Abramov et al38 compared the efficacy of and the effect of nonsteroidal anti-inflammatory drugs 200 mg intravaginal or intrarectal plus oral indomethacin (NSAIDs) is not due to inhibition of prostaglandin synthesis in delaying PTL in singleton pregnancies with idiopathic PTL alone. Using myometrial strips collected at the time of (< 33 weeks of gestation). Twenty-three women were ran- cesarean delivery, Sawdy et al9 showed almost complete domized to each arm. Intravaginal indomethacin was more and immediate inhibition of spontaneous contractions effective in delaying delivery for more than 7 days (78% versus when using indomethacin. Inhibition of prostaglandins alone 43%, p ¼ 0.03) and was associated with a longer interval from cannot explain this finding because time is needed for initiation of treatment to delivery (26.5 Æ 5.7 versus accumulated prostaglandin to decrease and COX activity to 12.6 Æ 3.7 days, p ¼ 0.007). In addition, birth weights were stop. This can rather be explained by the indomethacin- significantly higher in the intravaginal group with shorter mediated inhibition of calcium channel currents.9 duration of mechanical ventilation and neonatal intensive Another mechanism of tocolysis by indomethacin involves care unit stay.38 The incidence of respiratory distress syn- the nuclear factor kappa β (NFkB) protein. These proteins are drome (RDS), neonatal septicemia, necrotizing enterocolitis involved in COX-2 and prolabor genes, such as interleukin (NEC), and intraventricular hemorrhage (IVH) was also lower (IL)-8 expression. NFkB activity is increased during labor and in the intravaginal group, without reaching statistical signifi- acts as an antiprogesterone.10 In addition, both COX-2 and IL- cance. Transient fetal and maternal side effects were similar in 8 genes are up-regulated before labor.11,12 It has been shown both groups. that NFkB activity is reduced by NSAIDs.13 Use of indomethacin for the treatment of PTL, therefore, NSAID Use in PTL not only would reduce prostaglandin synthesis but also potentially would reduce the antiprogesterone effect of Multiple NSAIDs such as indomethacin, nimesulide, sulindac, NFkB on the other prolabor genes such as IL-8 and IL-1β.14 and celecoxib have been used for treatment of PTL. COX-2 is the isoform of COX mostly involved in PTL.14 Therefore, the Route of Administration and latter three drugs, being COX-2-selective inhibitors, were Pharmacokinetics expected to gain more popularity than indomethacin, which is a nonselective COX inhibitor. However, when compared Although the exact site of action of indomethacin has never with indomethacin, nimesulide resulted in the same pro- been confirmed, the most likely target for prostaglandin longation of labor and had similar side effects.39 On the other synthesis inhibition seems to be the cervix and fetal mem- hand, sulindac and celecoxib decreased the amniotic fluid to a – brane.15 21 Because placing prostaglandins into the cervix or lesser extent than indomethacin and were equally effective in vagina can induce labor, it seems logical that indomethacin delaying delivery.26,40 Even with those promising results, could be applied vaginally to induce tocolysis.15 Clinically, indomethacin is still the most commonly used NSAID in the however, oral and rectal routes are more commonly used. In treatment of PTL. most reports, treatment is usually initiated by a loading dose – of either 50 mg22 or 100 mg9,22 27 rectal suppositories. Oral Indomethacin versus Placebo loading dose of 50 mg has also been reported in several Although indomethacin tocolysis has been investigated since studies.8,28,29 In some protocols, if tocolysis was judged the mid-1970s, only three randomized, placebo-controlled, suboptimal after the loading dose, a repeat dose 100 mg double-blind trials with a total of 100 women have compared indomethacin rectally would be used 1 to 2 hours after the it with placebo.8,23,28 Niebyl et al,8 in a prospective, random- initial dose.30 Concerning maintenance treatment, most ized, double-blind trial, showed that compared with placebo Downloaded by: Koebenhavns Universitetsbibliotek. Copyrighted material. – studies agree on the oral route of either 25 mg22,25 27 or (n ¼ 15), treatment with indomethacin (n ¼ 15) for 24 hours – – 50 mg8,22 24,27 29 every 4 to 6 hours for 24 to 48 hours. But was significantly more effective in inhibition of PTL with 50 mg indomethacin rectally for maintenance every 6 hours is treatment failure occurring in nine placebo-treated women also reported.31 versus only one in the indomethacin group (p < 0.01). There Peak maternal plasma concentrations are achieved within was no difference with respect to delivery rate 48 hours after 2 hours of initiation of treatment, although rectal adminis- treatment, gestational age at delivery, birth weight, and tration achieves a peak level somewhat faster than oral neonatal morbidity and deaths. administration.32 Indomethacin readily crosses the placenta Zuckerman et al,23 in a prospective, randomized, double- with fetal umbilical artery serum concentrations equilibrat- blind study, examined the effect of 200 to 300 mg indometh- ing with the maternal serum levels within 5 hours of dosing.33 acin in women with PTL between 24 and 34 weeks Metabolism of the drug is primarily done by the liver, but ~10 of gestation. In 15 of 18 indomethacin-treated women to 20% is excreted unchanged in the urine.34 The half-life of (83.3%), PTL was arrested compared with 4 of 18 (22.2%) in indomethacin in premature infants is at least double the placebo group. The mean gestational age at delivery was (63 hours) that in adults.35 The immature liver accounts for significantly greater in the indomethacin group (36.4 versus the prolonged half-life in the fetus.8,36 31.2 weeks, p < 0.001). It is important to note that these Regarding efficacy, the vaginal and oral routes have been studies were not entirely placebo controlled.
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