Using indomethacin as a tocolytic

By Stephen T. Vermillion, MD, and James A. Scardo, MD

There's little doubt that this nonsteroidal anti-inflammatory agent can inhibit labor. But for clinicians to use it effectively, they need to be cognizant of several potential adverse effects.

Indomethacin, a potent prostaglandin synthetase inhibitor, gained popularity several decades ago as a potential tocolytic agent. This popularity was tempered by concerns over fetal and neonatal complications. With better recognition of its safety limitations, however, there has been renewed interest in using indomethacin for acute tocolysis.

LEARNING OBJECTIVES

Upon completion of this article, participants will be able to:

Explain how to prevent complications during indomethacin tocolysis with proper fetal surveillance studies.

This article will review the pharmacology and efficacy of indomethacin, and discuss the potential adverse fetal and neonatal effects associated with its use. We will also present guidelines that will assist the clinician in using indomethacin as an effective tocolytic while avoiding untoward effects.

The pharmacology of indomethacin

Indomethacin nonspecifically inhibits the cyclooxygenase enzymes that are essential for the conversion of arachidonic acid and fatty acids into prostaglandin endoperoxides.¹ This inhibition is readily reversible once serum drug levels decline after discontinuation of therapy.

The role of prostaglandins in the initiation and maintenance of human labor has been widely accepted: Prostaglandins stimulate the influx of calcium ions into the uterine smooth muscle cell. Calcium then facilitates the interaction of the myosin-actin complex, resulting in myocyte contraction. Additionally, prostaglandins enhance the development of gap junctions within the myometrium that coordinate myometrial activity, allowing synchronized contractions.² The ability of the drug to suppress the production of prostaglandins, therefore, is the basis of its ability to inhibit preterm labor.

Prostaglandins have many other functions in maintaining the normal physiology of the fetus and newborn, however. They include potent vasodilatory and vasoconstrictive effects that are particularly important for the preservation of adequate blood flow through the developing fetal circulation.^3,4 Animal studies also indicate that prostaglandins inhibit the effect of antidiuretic hormone on the collecting duct of the fetal kidney.⁵

With that in mind, indomethacin's suppression of circulating prostaglandins may not only lead to cessation of uterine activity, but vasoconstriction and reduction in the effective blood flow to various fetal organs. This vasoconstriction is reversible, but prolonged exposure to indomethacin may result in persistent changes in the fetal ductus arteriosus and the developing fetal cerebral and mesenteric circulation. These changes have the potential to place the preterm neonate at increased risk for intraventricular hemorrhage (IVH) or bowel ischemia. Furthermore, prolonged suppression of endogenous prostaglandins may decrease the production of fetal urine and ultimately lead to oligohydramnios. Short courses of less than 72 hours of indomethacin therapy do not, however, appear to promote such significant risks.

Indomethacin can be administered via oral, rectal, or vaginal routes. Depending on the administration route, peak maternal plasma concentrations are achieved within 2 hours after dosing, with a mean half-life in the maternal serum of approximately 4.5 hours.⁶ The drug readily crosses the placenta with fetal umbilical artery serum concentrations equilibrating with maternal serum levels within 5 hours of dosing.⁷ The half-life in preterm neonates is approximately five times longer than that seen in an adult. Most reports have used a 50- to 100-mg loading dose, usually via rectal suppository, followed by 25 mg orally every 6 to 8 hours. Identifying the lowest effective dose is important to decrease the risk of side effects. The drug is contraindicated in patients with a history of peptic ulcer disease, kidney or liver disease, and hematologic abnormalities. It should also be avoided by anyone with a hypersensitivity to nonsteroidal anti-inflammatory agents (NSAIDs). And finally, indomethacin has antipyretic properties so it should be shunned in cases of suspected chorioamnionitis.

How effective is the drug?

Despite the lack of large randomized trials, the efficacy of indomethacin as a tocolytic has generally been acknowledged. Two studies have compared the NSAID to placebo for the treatment of preterm labor. Both trials were limited by small sample sizes, however, and by the use of rescue tocolysis in those patients considered to be tocolytic failures.^8,9 Niebyl demonstrated that patients treated for 24 hours with indomethacin had significantly fewer deliveries within 48 hours of treatment, when compared with the placebo group. Success was short-lived, however, as no difference in the overall delivery rate was detected after 48 hours.

Zuckerman reported slightly better success in delaying preterm delivery in a group of patients treated for 24 hours with indomethacin. The women in the treatment group had fewer deliveries within 1 week of treatment compared to placebo. Ultimately, both investigations were unable to demonstrate a difference in neonatal outcomes between the treatment and control groups.

Interpreting the efficacy of tocolytic agents in preterm labor trials is difficult due to the heterogenous definitions used to describe success. Prolonging pregnancy for at least 48 hours may allow for the benefit of corticosteroid administration. However, if neonatal outcomes are unchanged, it is difficult to claim success. Other trials have reported similar efficacy and fewer maternal side effects when comparing indomethacin with betamimetics.^10,11

Examining indomethacin's safety profile

As a tocolytic, indomethacin has been associated with several potentially significant fetal and neonatal complications in a number of reports. Most of these complications were associated with prolonged administration and with little or no fetal surveillance.

Constriction of the fetal ductus arteriosus. The most widely reported complication associated with antenatal exposure to indomethacin is constriction of the fetal ductus arteriosus. The association was suspected due to the ability of indomethacin to close the persistently patent ductus arteriosus in the newborn period. Animal studies have specifically identified cyclooxygenase-1 (COX-1)-dependent prostaglandins as the predominant mediators of ductal patency in utero.¹²

Because of its nonselective nature, the drug inhibits both COX-1 and cyclooxygenase-2 (COX-2) enzymes. A few early investigations reported isolated cases of primary pulmonary hypertension in the newborn after prolonged in utero exposure to indomethacin. Presumably it was due to prolonged constriction of the fetal ductus arteriosus.^10,13,14 Prolonged shunting of blood away from the constricted ductus arteriosus and through the pulmonary vasculature is believed to lead to hypertrophy of the muscular walls of the pulmonary vessels.

Closer evaluation of the effect of extended indomethacin tocolysis on the developing fetal ductus arteriosus shows that, as gestation progresses, there is an increased sensitivity of the ductus to indomethacin. Moise and colleagues were the first to evaluate the developing fetal ductus arteriosus with serial fetal echocardiography.¹⁵

They demonstrated that fetuses exposed to indomethacin had a significant increase in the frequency of ductal constriction around 32 weeks' gestation. Using a similar study protocol at our institution, we followed 72 fetuses exposed in utero to prolonged courses (>48 to 72 hours) of indomethacin.¹⁶ While 70% of the fetuses that developed ductal constriction in our study did so around 32 weeks, there were several cases of ductal constriction occurring at earlier gestational ages; even as early as 25 weeks.

The protocols used in the two studies described above are the basis for the current recommendations for monitoring patients receiving antenatal indomethacin (Tables 1 and 2). Indomethacin should initially be limited to gestations less than 32 weeks because of the increasing likelihood of ductal constriction after this gestational age. After 48 to72 hours of therapy, if the decision is made to continue indomethacin, then you should perform fetal echocardiography to detect any evidence of ductal constriction. The complication is evidenced by increasing ductal blood flow velocities (systolic >1.4 m/sec, diastolic >0.35 m/sec) and in some cases by the appearance of tricuspid valve regurgitation.^11,16

TABLE 2
Fetal surveillance recommendations

Perform fetal echocardiography for the detection of ductal constriction:

All fetuses should be individually evaluated in the case of multiple gestations because variations in ductal flow velocities can exist between fetuses of the same pregnancy. If ductal flow velocities are normal, echocardiographic evaluations should be repeated weekly for the duration of therapy. Fetal echocardiography is not necessary, however, if the decision has been made to discontinue therapy.

About 50% of the fetuses exposed to maintenance indomethacin tocolysis developed mild ductal constriction at some point during our study. However, in all of these cases, the constriction completely resolved when therapy was promptly discontinued!⁶

Therapy should be discontinued in all cases of constriction. If you detect increasing but not abnormal ductal flow velocities, dosing may be tapered from every 6 hours to every 8 or 12 hours, with repeat echocardiography performed within 24 to 48 hours. Patients receiving only a short course (<72 hours) of indomethacin do not need echocardiographic evaluation due to inherent reversibility of fetal ductal constriction.

It is less clear whether to maintain surveillance for intermittent short courses of indomethacin. Based on pharmacologic data, it seems reasonable to defer ductal evaluation if the interval between treatment courses is greater than 48 hours. Indomethacin should be avoided in pregnancies complicated by intrauterine growth restriction because there is the potential for ductal constriction and possible perfusion abnormalities.

Oligohydramnios. Indomethacin has also been used to treat symptomatic polyhydramnios because it decreases amniotic fluid volume within a few days.¹⁷ Recognizing this effect, you should evaluate amniotic fluid volume measurements twice weekly for evidence of oligohydramnios. In fact, the drug should be discontinued or tapered with any trend toward oligohydramnios. In our study of maintenance tocolysis, oligohydramnios developed in about 10% of pregnancies.¹⁶ Fortunately, in all of these cases, amniotic fluid volume normalized after the drug was promptly discontinued.

Intraventicular hemorrhage. In a retrospective review, Norton and colleagues reported an increase in the frequency of advanced-grade intraventricular hemorrhage (IVH) in preterm infants after indomethacin tocolysis.¹⁸ The study was limited, however, by the fact that there was marked variation in the medication dosing and surveillance procedures. Additionally, the increased risk of advanced-grade IVH reported in the trial was the result of the inclusion of grade II IVH along with the more clinically significant grades III and IV. Only grade II IVH was significantly associated with indomethacin exposure; the frequency of grades III and IV is similar between the treatment and control groups.

Some have hypothesized that the development of IVH after indomethacin tocolysis may actually be associated with prolonged constriction of the ductus. Ductal constriction increases the shunting of blood through the fetal carotids, resulting in alterations in cerebral perfusion; that in turn may predispose the premature infant to IVH. Since echocardiographic evaluation of the fetal ductus arteriosus was not routinely incorporated into the Norton study, it is not possible to specifically comment on the potential association of IVH with ductal constriction.

To further evaluate the potential risks associated with antenatal exposure to indomethacin, we performed a case­control study of 75 infants exposed to at least 24 hours of indomethacin within 72 hours of a delivery occurring before 32 weeks' gestation.¹⁹ The neonatal outcomes of these infants were compared with 150 infants matched for gestational age, mode of delivery, fetal sex, and race. Overall, the indomethacin-exposed neonates experienced no increase on any measure of neonatal morbidity. Interestingly, we found a trend towards a reduction in advanced-grade IVH in those neonates who were recently exposed to a short course of antenatal indomethacin. Similarly a separate trial has reported a protective effect of low-dose indomethacin against IVH; in this investigation, the drug was administered during the first 72 hours of life to very-low-birthweight infants.²⁰ Further studies are needed to explore the possibility that limited doses of indomethacin, administered shortly before delivery, may provide similar prophylactic effects.

Two additional studies have focused on the possibility of an increased risk for neonatal complications if delivery occurs within 48 hours of indomethacin exposure. Souter reported that neonates delivered after recent tocolysis with indomethacin were at an increased risk for developing IVH.²¹ Many patients in this study received prolonged indomethacin therapy with limited fetal surveillance. Also, patients with premature rupture of the membranes were included in the cohort, which may have increased the overall frequency of infection-induced IVH. No increased neonatal risks were identified in those infants delivered more than 48 hours after the last dose of indomethacin.

Persistent patent ductus arteriosus. Several studies have demonstrated that premature newborns have an increased frequency of persistent patent ductus arteriosus that is unresponsive to medical management after antenatal indomethacin tocolysis.^18,21 It's logical that suppression of vasodilatory prostaglandins with indomethacin could constrict the fetal ductus arteriosus. Less convincing, however, is the association of persistent patent ductus in the newborn with antenatal indomethacin exposure. The theory is that a secondary compensatory surge in prostaglandin production occurs after indomethacin is discontinued. This surge results in supranormal prostaglandin concentrations after delivery, causing protracted vasodilation of the ductus. Recent antenatal exposure appears to be the most significant risk factor in these studies, although our recent study has not shown this association.¹⁹

Necrotizing enterocolitis. Major and colleagues demonstrated that neonates delivered within 24 to 48 hours of antenatal indomethacin exposure were more likely to be diagnosed with necrotizing enterocolitis.²² Similar to the Souter study, patients who received prolonged treatment with indomethacin were included. Recognizing the concern for recent indomethacin exposure and subsequent neonatal complications, we evaluated the effect of short-term indomethacin tocolysis in those neonates who ultimately failed tocolysis and delivered within 72 hours of exposure.¹⁹ As previously noted, we were unable to demonstrate a significant difference in the frequency of either necrotizing enterocolitis, persistent patent ductus arteriosus, or IVH after recent indomethacin exposure compared with matched controls. Perhaps the duration of therapy with indomethacin is a more significant risk factor than is the timing of exposure.

Reasonable recommendations

As long as one recognizes the drug's limitations, indomethacin appears to be an acceptable tocolytic. While the potential complications associated with indomethacin tocolysis are primarily associated with longer durations of therapy, acute tocolysis for less than 72 hours does not appear to produce significant risks. Of course, larger randomized trials incorporating appropriate fetal surveillance and follow up are needed to further evaluate both the efficacy and safety of the tocolytic.

REFERENCES

1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231:232-235.

2. Huszar G. Physiology of the myometrium. In: Creasy RK, Resnik R, eds. Maternal-Fetal Medicine Principles and Practice. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1994:133-139.

3. Cassin S. Role of prostaglandins and thromboxanes in the control of the pulmonary circulation in the fetus and newborn. Semin Perinatol. 1980;4:101-107.

4. Clyman RL Ontogeny of the ductus arteriosus response to prostaglandins and inhibitors of their synthesis. Semin Perinatol. 1980;4:115-124.

5. Anderson RJ, Berl T, McDonald D, et al. Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney. J Clin Invest. 1975;56:420-426.

6 Alvan G, Orme M, Bertilsson L, et al. Pharmacokinetics of indomethacin. Clin Pharmacol Ther. 1975;18;364-373.

7. Bhat R, Vidyasagar D, Vadapalli M, et al. Disposition of indomethacin in preterm infants. J Pediatr. 1979; 95:313-316.

8. Niebyl JR, Blake DA, White RD, et al. The inhibition of premature labor with indomethacin. Am J Obstet Gynecol. 1980;136:1014-1019.

9. Zuckerman H, Shalev E, Gilad G, et al. Further study of the inhibition of premature labor by indomethacin. Part II double-blind study. J Perinat Med. 1984;12:25-29.

10. Besinger RE, Niebyl JR, Keyes WG, et al. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Am J Obstet Gynecol. 1991;164:981-986; discussion 986-988.

11. Morales WJ, Smith SG, Angel JL, et al. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. Obstet Gynecol. 1989;74:567-572.

12. Guerguerian AM, Hardy P, Bhattacharya M, et al. Expression of cyclooxygenases in ductus arteriosus of fetal and newborn pigs. Am J Obstet Gynecol. 1998;179:1618-1626.

13. Manchester D, Margolis HS, Sheldon RE. Possible association between maternal indomethacin therapy and primary pulmonary hypertension of the newborn. Am J Obstet Gynecol. 1967;126:467-469.

14. Eronen M, Pesonen E, Kurki T, et al. The effects of indomethacin and a beta-sympathomimetic agent on the fetal ductus arteriosus during treatment for premature labor: a randomized double-blind study. Am J Obstet Gynecol. 1991;164:141-146.

15. Moise KJ Jr. Effect of advancing gestational age on the frequency of fetal ductal constriction in the association with maternal indomethacin use. Am J Obstet Gynecol. 1993;168:1350-1353.

16. Vermillion ST, Scardo JA, Lashus AG, et al. The effect of indomethacin tocolysis on fetal ductus arteriosus constriction with advancing gestational age. Am J Obstet Gynecol. 1997;177:256-269; discussion 259-261.

17. Moise KJ Jr. Indomethacin therapy in the treatment of symptomatic polyhydramnios. Clin Obstet Gynecol. 1991;34:310-318.

18. Norton ME, Merrill J, Cooper BA, et al. Neonatal complications after the administration of indomethacin for preterm labor. N Engl J Med. 1993;329:1602-1607.

19. Vermillion ST, Newman RB. Recent indomethacin tocolysis is not associated with neonatal complications in preterm infants. Am J Obstet Gynecol. 1999;181:1083-1086.

20. Ment LR, Duncan CC, Ehrenkranz RA, et al. Randomized low-dose indomethacin trial for prevention of intraventricular hemorrhage in very-low-birthweight neonates. J Pediatr. 1988;112:948-955.

21. Souter D, Harding J, McCowan L, et al. Antenatal indomethacin - adverse fetal effects confirmed. Aust N Z J Obstet Gynaecol. 1998;38:11-6.

22. Major CA, Lewis DF, Harding JA, et al. Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low-birthweight neonate. Am J Obstet Gynecol. 1994;170:102-106.

Dr. Vermillion is Assistant Professor in the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, S.C.

Dr. Scardo id Director of Obstetrics and Gynecology Medical Education in the Division of Maternal-Fetal Medicine, Spartanburg Regional Medical Center, Spartanburg, S.C.

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This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Jefferson Medical College and Medical Economics, Inc.

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Jefferson Medical College, in accordance with accreditation requirements, asks the authors of CME articles to disclose any affiliations or financial interests they may have in any organization that may have an interest in any part of their article. The following information was received from the authors of "Using indomethacin as a tocolytic."

Stephen T. Vermillion, MD, and James A. Scardo, MD, have no information to disclose.

 

Stephen Vermillion, James Scardo. CME: Using indomethacin as a tocolytic. Contemporary Ob/Gyn 2000;7:102-110.