The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. A comparative study of ketorolac (Toradol) and magnesium sulfate for arrest of preterm labor. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. A double-blind randomized study of fetal side effects during and after the short-term maternal administration of indomethacin, sulindac, and nimesulide for the treatment of preterm labor. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. Lack of effect of antenatal indomethacin on fetal cerebral blood flow. The inhibition of premature labor with indomethacin. Further study of the inhibition of premature labor by indomethacin. Part II double-blind study. A prospective randomized safety trial of celecoxib for treatment of preterm labor. A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor. A randomized double-blind study comparing the fetal effects of sulindac to terbutaline during the management of preterm labor.
To determine whether indomethacin tocolysis in preterm labour is associated with a better perinatal outcome than placebo.
                A randomised placebo-controlled trial.
                Two university teaching hospitals with level three neonatal intensive care units.
                Women in preterm labour with intact membranes between 23 and 30 weeks of gestation.
                Random allocation to tocolysis with indomethacin (50 mg followed by 25 mg 6 hourly for 48 hours) or placebo in a double-blind fashion.
                The primary outcome, perinatal mortality or severe neonatal morbidity, was defined as perinatal death, necrotising enterocolitis, bronchopulmonary dysplasia, intraventricular haemorrhage or peri-ventricular leucomalacia. Data were analysed using odds ratios (OR) and 95% confidence intervals (95% CI).
                Between March 1995 and February 1996, 34 women (39 babies) were recruited. The baseline characteristics of the two groups were similar. No patient was lost to follow up. In the indomethacin group, gestation was prolonged by > 48 hours in 13/16 (81%) of women vs 10/18 (56%) in the placebo group. The incidence of perinatal mortality or severe neonatal morbidity was not significantly different between the groups, but occurred in twice as many babies in the indomethacin group as in the placebo group--6/19 (32%) vs 3/20 (15%) OR (95% CI) 2.62 (0.44-18.8). There was one perinatal death, of a baby delivered at 24 weeks of gestation. This occurred in the indomethacin group.
                There is no evidence that indomethacin tocolysis is beneficial, and further trials are needed to assess the impact of indomethacin tocolysis in preterm labour. One hundred six patients in preterm labor with intact amniotic membranes and gestational age less than or equal to 32 weeks were randomized to receive either ritodrine hydrochloride or a 48-hour course of indomethacin for tocolysis. The relative efficacy, maternal and neonatal safety, and costs were evaluated to determine which may be the more appropriate first-line pharmacologic agent used to manage preterm labor. Fifty-four patients and 52 patients were randomized to receive ritodrine hydrochloride or indomethacin, respectively. Ritodrine hydrochloride and indomethacin were equally effective in inhibiting uterine contractions and delaying delivery. Delivery was delayed for at least 48 hours in 83 and 94%, and for at least 7 days in 70 and 75% of patients receiving ritodrine or indomethacin, respectively. Tocolysis with indomethacin was associated with no maternal side effects, whereas tocolysis with ritodrine hydrochloride was associated with a 24% incidence of serious cardiovascular and metabolic adverse effects prompting discontinuation of the drug. There were no differences in outcome between the infants exposed to indomethacin versus ritodrine hydrochloride when delivered either remote from therapy or during therapy, except for a statistically higher serum glucose in the infants exposed to ritodrine hydrochloride when delivered during tocolytic therapy. There were no cases of premature closure of the ductus arteriosus or pulmonary hypertension. Tocolysis with indomethacin was 17 times less costly than tocolysis with ritodrine hydrochloride. For gestations less than or equal to 32 weeks complicated by preterm labor, indomethacin may be an appropriate alternative as a first-line tocolytic agent. We evaluated the efficacy and safety of ketorolac (Toradol).
                In this prospective trial, 88 women in confirmed preterm labor at < or =32 weeks' gestation were randomized to receive magnesium sulfate given as an initial 6 g intravenous bolus followed by continuous infusion therapy (2 to 6 g/hr) or intramuscularly administered ketorolac (60 mg loading dose) followed by 30 mg every 6 hours for a maximum of 24 hours.
                The study groups were similar with respect to age, parity, cervical status, and gestational age on admission. Ketorolac was more rapid (2.71 hr+/-2.16) in the arrest of preterm labor than was magnesium sulfate (6.22 hr+/-5.65). No patient required discontinuance of either drug due to adverse effects. There was no difference in the incidence of neonatal complications between the two groups.
                In gestations with preterm labor at <32 weeks, ketorolac appears to be an appropriate first-line tocolytic agent. Our purpose was to evaluate the relative efficacy and safety of indomethacin versus magnesium sulfate in the management of preterm labor in pregnancies < 32 weeks of gestation.
                Eligible patients admitted with singleton pregnancies and idiopathic preterm labor between August 1988 and October 1989 were randomized by sealed envelopes to receive either indomethacin or intravenous magnesium sulfate.
                Of 101 eligible patients 49 were randomized to receive indomethacin. The two study groups were similar in regard to a number of entry variables, including gestational age, cervical examination, and contraction frequency. Indomethacin was as effective as magnesium sulfate in delaying delivery > 48 hours, 90% versus 85%, and together with oral terbutaline in extending the gestation, 22.9 versus 22.7 days. Tocolysis with magnesium sulfate was discontinued in eight (15%) patients because of maternal side effects, in contrast to none in the indomethacin group, p < 0.05.
                For gestations < 32 weeks indomethacin may be considered an appropriate alternative to magnesium sulfate as a first-time tocolytic agent. The purpose of this study was to establish whether nimesulide causes fewer fetal side effects than indomethacin or sulindac after short-term maternal exposure for tocolysis.
                This was a double-blind, double-dummy prospective randomized study with three drug treatment groups (n = 10 per group) that were comprised of subjects who were at 28 to 32 weeks of gestation with preterm contractions. The subjects were treated in the delivery suites of two busy inner-city teaching hospitals; the intervention consisted of 48 hours of treatment and with 72 hours of follow-up observation with indomethacin 100 mg (twice daily), sulindac 200 mg (twice daily), or nimesulide 200 mg (twice daily). The amniotic fluid index, hourly fetal urine production, and ductal Doppler pulsatility index observations were monitored before the treatment and at 4, 24, 48, 72, and 120 hours after the treatment was started. The statistical analysis used repeated measures analysis of variance, Bonferroni test, and Bland-Altman agreement. Significance assumed when the probability value was <.05.
                Each drug caused a significant reduction in all three observations over the 48-hour treatment period, which recovered to pretreatment levels by 72 hours after treatment. There were no significant differences among drugs for any of these effects.
                Nimesulide causes similar short-term fetal side effects to indomethacin and sulindac. A randomized prospective trial was performed to compare the efficacy and safety of ritodrine and indomethacin in the long-term treatment of preterm labor. Forty patients with intact membranes in preterm labor at 23 to 34 weeks' gestation were randomized to receive either intravenous ritodrine or oral indomethacin as the first-line tocolytic agent. Successful intravenous ritodrine therapy was followed by oral terbutaline therapy, and indomethacin-treated patients continued to receive oral indomethacin. Treatment failures were defined as progressive preterm labor or patient intolerance, and these patients were treated with intravenous magnesium sulfate. Ritodrine and indomethacin were equally successful in delaying preterm birth as defined by interval to delivery, gestational age at delivery, delivery delayed greater than 7 days, attainment of 35 weeks of gestation, percentage of patients who required magnesium sulfate therapy, percentage of patients who were readmitted with premature rupture of membranes, absence of recurrent preterm labor, and infant birth weight. More than 80% of mothers who received ritodrine voiced complaints of beta-sympathomimetic side effects, and one patient discontinued treatment as the result of intolerance. There were minimal patient complaints with indomethacin use. No statistically significant differences were noted in neonatal outcome as defined by Apgar scores, umbilical cord pH, intensive care days, ventilator days, or neonatal deaths. However, three cases of primary pulmonary hypertension were observed in the indomethacin group. We had not previously observed this problem with short-term (24 to 48 hours) indomethacin therapy. Our purpose was to investigate fetal cerebral blood flow and the incidence of intraventricular hemorrhage in patients undergoing tocolysis with either indomethacin or magnesium sulfate at < 30 weeks' gestation.
                Consenting patients at < 30 weeks' gestation with preterm labor were randomized to receive indomethacin or magnesium sulfate tocolysis. Magnesium sulfate was administered intravenously with an 8 gm loading dose given over the first hour, 4 gm over the second hour, and then a maintenance infusion of 2.5 gm per hour. The infusion was continued for approximately 12 hours after the cessation of uterine contractions. Patients randomized to receive indomethacin were given an initial dose of 50 to 100 mg orally or per rectum, followed by 25 to 50 mg orally every 4 to 6 hours for 24 to 48 hours. Oral tocolytic agents were not used after successful tocolysis. Betamethasone was administered to all patients. Patients underwent fetal cerebral Doppler studies during tocolytic therapy and at least 24 hours after completion of the treatment.
                Twelve patients were randomized to receive indomethacin and twelve patients were randomized to receive magnesium sulfate. Twenty-one fetuses underwent cerebral Doppler studies in triplicate during and after therapy. The mean gestational age at tocolysis was 27.5 +/- 1.9 weeks for the indomethacin group and 26.4 +/- 1.6 weeks for the magnesium sulfate group (p = 0.14). The middle cerebral artery resistance index for fetuses during indomethacin treatment was 0.73 +/- 0.09, whereas the resistance index after therapy was 0.75 +/- 0.05 (p = 0.49). The resistance index during magnesium sulfate tocolysis was 0.79 +/- 0.04 and after therapy it was 0.76 +/- 0.04 (p = 0.18). There was no significant difference in the resistance index between the groups on or off therapy. In addition, the incidence of intraventricular hemorrhage was similar in both groups.
                These results suggest that indomethacin does not significantly affect fetal cerebral blood flow. If antenatal indomethacin in the preterm fetus increases the risk of intraventricular hemorrhage, it would appear to be by another mechanism. We administered indomethacin orally for the treatment of premature labor in a prospective, randomized, double-blind fashion, and all infants were followed up. Indomethacin was significantly more effective than placebo in inhibition of premature labor during a 24-hour course of therapy, with treatment failure during therapy occurring in only one of 15 indomethacin-treated patients compared to nine of 15 placebo-treated patients (p less than 0.01). Mean plasma concentrations of indomethacin were approximately 0.8 micrograms/ml at both 4 and 12 hours after administration. Mean plasma levels of 15-oxo-13,14-dihydroprostaglandin F2 alpha (PGFM) were similar in the two groups before treatment, decreased markedly in the indomethacin group by 4 hours, and were not detected at 12 hours in all but the one indomethacin-treated patient who was delivered within 24 hours. Patients in the placebo group who were delivered prematurely had higher pretreatment PGFM levels (mean +/- SE, 83 +/- 18 pg/ml, n = 9) than the patients who responded to placebo (25 +/- 6 pg/ml, n = 6) (p less than 0.05). There was no difference between the indomethacin and placebo groups with respect to gestational age at delivery, birth weight, and neonatal morbidity and deaths. In particular, we found no evidence of premature closure of the ductus arteriosus, pulmonary hypertension, or increase in bleeding problems among the infants exposed to indomethacin in utero. Although no difference in neonatal outcome was observed in this small number of patients, it would seem prudent still to consider indomethacin as an experimental therapy. In the etiology of premature labor prostaglandins fulfill a significant role. It is known that indomethacin is a strong inhibitor of prostaglandin synthesis. The effect of indomethacin on premature labor was studied in a prospective randomized double-blind study in 36 patients. Eighteen patients received indomethacin and eighteen received placebo. 200-300 mg of indomethacin was the total dosage in a 24 hours period. The activity of the uterus was monitored with a cardiotocograph. The mean duration of pregnancy and the mean birth weight in indomethacin group (36.4 weeks, 2833 g) were both significantly greater (p less than 0.001) than that in placebo group (31.2 weeks, 2028 g). In the indomethacin group 3 children weighted less than 2500 g compared with 14 in placebo group. In 15 of 18 indomethacin treated patients (83.3%) premature labor was arrested after indomethacin treatment compared with 4 of 18 in the placebo group (22.2%). The indomethacin group had a mean 1 minute APGAR score of 9.3 +/- 0.2 whereas the placebo group showed a score of 7.8 +/- 0.5 (p less than 0.01). Three infants died from respiratory distress syndrome; one in the indomethacin group (1810 g) and two in the placebo group (600 and 1450 g). Autopsies in the infants demonstrated a typical picture of pulmonary atelectasis and hyaline membranes. There was no evidence of premature closure of the ductus arteriosus or pulmonary hypertension. 2 mothers in the indomethacin group suffered minor discomfort i.e. nausea, vomiting and vertigo.(ABSTRACT TRUNCATED AT 250 WORDS) We compared the safety of celecoxib, a selective cyclo-oxygenase-2 inhibitor, with the safety of the nonselective cyclo-oxygenase inhibitor indomethacin, when it was administered for treatment of preterm labor.
                In a randomized, double-blind, placebo-controlled trial, 24 pregnant women in preterm labor at 24 to 34 weeks of gestation received either indomethacin or celecoxib for 48 hours. Clinical assessment, fetal sonography, and Doppler blood flow studies of the fetal ductus arteriosus were performed daily.
                Mean maximum ductal flow velocity was significantly elevated over baseline (82.9 +/- 4.6 cm/s vs 111.14 +/- 14.3 cm/s; P =.02) after 24 hours of indomethacin, but not celecoxib. Both medications were associated with a transient decrease in amniotic fluid volume, with a greater effect by indomethacin. The medications were equally effective in the maintenance of tocolysis. There were no significant maternal or neonatal adverse events.
                In this initial evaluation, the safety of short-term celecoxib in women with preterm labor was superior to that of indomethacin. We compared the tocolytic effect of indomethacin and nylidrin in a prospective double-blind trial in which the appearance of the tocolytic treatment (always intravenous infusion and rectal suppositories/oral capsules) was identical to the subjects. Sixty healthy women in imminent preterm labor between 25-34 weeks of singleton gestation were included. Thirty of these women received indomethacin (concomitantly with placebo infusion), with doses as follows: day 1, 100-mg rectal suppository followed by two oral capsules (50 mg) at 8-hour intervals; days 2 and 3, three 50-mg oral capsules each day. Thirty women received intravenous nylidrin (concomitantly with rectal/oral placebo), initiated with the dose of 50 micrograms/minute and continued at the dose of 100-150 micrograms/minute for a maximum of 3 days. Preterm labor was arrested for 24, 48, and 72 hours in 100, 96, and 90%, respectively, of subjects in the indomethacin group, compared with 100, 76, and 73% of women in the nylidrin group; the difference was significant (P less than .05) at 48 hours. Women progressed beyond 37 gestational weeks more commonly (P less than .05) with indomethacin (21 of 30, 70%) than with nylidrin (13 of 30, 43%). Indomethacin treatment was accompanied by maternal side effects 20% of the time, significantly less commonly (P less than .001) than with nylidrin (83%). The neonatal outcome was similar in the two study groups. We conclude from this double-dummy technique trial that indomethacin is more effective and better tolerated than nylidrin in arresting imminent preterm labor. The object of this study was to compare the fetal effects of sulindac and terbutaline used in the management of preterm labor on the ductus arteriosus, middle cerebral artery, renal artery, umbilical artery, fetal urine production, and amniotic fluid index.
                In a randomized, double-blind study 20 patients with preterm labor and no evidence of fetal structural anomalies or intra-amniotic infection received either sulindac (200 mg orally every 12 hours for 6 doses) or terbutaline (5 mg orally every 4 hours) for 72 hours of therapy. All medications were administered from identical blister packs. Opaque glucose base tablets were given at 4-hour intervals in the sulindac treatment arm to mimic the dosing interval in the terbutaline arm of the study. The Doppler pulsatility indices for the ductus arteriosus, middle cerebral artery, renal artery and umbilical artery and also the fetal urinary output were obtained at baseline and 5, 12, 24, 48, and 72 hours after the medication was started. Doppler data were analyzed within each group with raw data and between groups with the change in pulsatility indices from baseline. Statistical analysis was performed with the Kolmogorov-Smirnov test for normality, repeated measures analysis of variance, Mann-Whitney rank sum test, and Student t test as appropriate. P <.05 (2-tailed) was used to denote statistical significance.
                There were 10 patients in each group, with no difference in gestational age between the 2 groups (32.3 vs 31.7 weeks). Sulindac was stopped in 2 patients after severe ductal constriction was noted, in 1 at 12 hours and in the other at 24 hours. One patient at 33 weeks' gestation was delivered because of fetal distress after 46 hours of sulindac therapy. When analyzed across time within groups, the pulsatility index in the ductus arteriosus decreased significantly at 12 and 24 hours in the sulindac group but not the terbutaline group. No significant differences were noted in the middle cerebral artery, umbilical artery, renal artery, or fetal urinary output within either group over time. Significant differences in the change from baseline in pulsatility index of the ductus arteriosus between the sulindac and terbutaline groups were noted at 5, 12, 24, and 48 hours. A similar effect was noted in the change from baseline in pulsatility index of the middle cerebral artery at 48 and 72 hours. There was a significant decrease in the amniotic fluid index in both groups at 24, 48, and 72 hours. The amniotic fluid index in the sulindac group was significantly lower than that in the terbutaline group at 48 and 72 hours of therapy.
                Sulindac constricted the fetal ductus arteriosus, with an effect noted within 5 hours of starting therapy. The constriction, which resolved in all cases within 48 hours of discontinuing therapy, had minimal effects on the pulsatility index of the middle cerebral artery, renal artery, and umbilical artery. Sulindac and terbutaline both resulted in a significant reduction in the amniotic fluid index, with sulindac having a greater effect.
There is insufficient information on which to base decisions about the role of COX inhibition for women in preterm labour. Further well designed trials are needed.
[Note: The 11 citations in the awaiting classification section of the review may alter the conclusions of the review once assessed.]