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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Arnold Palmer Hospital for Children and Women, Orlando, Florida, Department of Obstetrics and Gynecology, University of South Florida, Tampa, Florida.
Address reprint requests to: S. J. Carlan, MD, Department of Obstetrics and Gynecology, Orlando Regional Healthcare, 105 West Miller Street, Orlando, Florida 32806; E-mail scarlan{at}orhs.org.
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ABSTRACT |
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METHODS: This was a randomized, double-blind, placebo-controlled study of patients between 24 and 34 weeks’ gestation with preterm labor treated with intravenous magnesium sulfate. After successful tocolysis, patients were randomized by the pharmacy to receive either oral sulindac (100 mg) or placebo orally every 12 hours until 34 weeks’ gestation. A power analysis required 43 patients in each group.
RESULTS: Ninety-five patients were enrolled (46 in the sulindac group, 49 controls). No significant differences were found with respect to time gained in utero (39 ± 25 versus 45 ± 26 days, P = .29), delivery at more than 35 weeks’ gestation (61% versus 74%, P = .29), recurrent preterm labor (20% versus 18%, P = .86), birth weight (2562 ± 623 versus 2624 ± 543 g, P =.62), or time spent in the neonatal intensive care unit (2.8 ± 9.2 versus 2.4 ± 8.6 days, P =.83) for the sulindac and control groups, respectively.
CONCLUSION: The use of oral sulindac until 34 weeks’ gestation after successful parenteral tocolysis failed to reduce the incidence of readmission for preterm labor.
The recorded rate of preterm birth has increased more than 20% in the United States since 1981, and it now accounts for 11.4% of all births.1 Approximately 65% of non-anomalous fetal and neonatal deaths are attributed to complications of prematurity,2 and those infants that survive a preterm birth have a higher incidence of both acute and long-term health sequelae.3 Pharmacologic therapy with a variety of drugs of different categories has been the primary method of treating acute preterm labor in the United States.4 Although possibly effective in delaying delivery for a short period of time,5 the benefit of follow-up oral tocolytic maintenance is questionable.6
Sulindac is a prostaglandin synthetase inhibitor closely related to indomethacin in structure and mechanism of action.7 An earlier double-blind, placebo-controlled study of sulindac demonstrated that a 1-week course of 200 mg twice a day after successful arrest of acute preterm labor resulted in a significantly longer interval between start of therapy and failure in the group of women that either delivered preterm or required readmission for parenteral tocolycis.8 Sulindac, however, is known to cross the placenta9 and is associated with a dose-related reduction of amniotic fluid and fetal urine production,10 and possibly a reversible constriction of the fetal ductus arteriosis.11 It may be that lower doses of sulindac for prolonged periods of time would be safer for the fetus and result in prolongation of pregnancy in patients that have had successful arrest of acute preterm labor. The purpose of this study was to determine if sulindac maintenance therapy after a successfully treated episode of acute preterm labor could decrease the risk of recurrent preterm labor and preterm delivery.
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MATERIALS AND METHODS |
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The women were initially hydrated with 500 mL of Ringer’s lactate over a 30-minute period; in some cases, a subcutaneous 0.25-mg dose of terbutaline was used at the discretion of the attending physician. No patient received more than one dose of terbutaline. All patients were given IV magnesium sulfate, with an initial bolus of 4–6 g followed by continuous infusion at a rate of 2–4 g per hour.
After arrested preterm labor was diagnosed, the patient was counseled about the study and offered an institutional review board–approved informed consent document. All patients included in the study were randomized within 48 hours of arrest of labor. Each participant in the study was randomized by means of opaque sealed envelopes containing computer-generated random numbers supplied by the pharmacy to receive either placebo (for the control group) or sulindac in identically appearing hard gelatin capsules. The hospital pharmacy supplied the patient with the medications, and the investigators were blinded as to which preparation the patient was taking. At no time before data analysis did any clinical investigator have access to or knowledge of the identity of assigned drug. The sulindac group received 100 mg orally every 12 hours until 34 weeks’ gestation, and the control group took the placebo every 12 hours until 34 weeks’ gestation. The subjects were offered pharmacologic acceleration of fetal pulmonary maturation, which consisted of 12 mg of intramuscular beta-methasone every 24 hours for two doses. If the subjects were stable and undelivered after a total of 48 hours, they were discharged for observation in the high-risk obstetric clinic.
Those women who resumed preterm labor and required readmission for repeat parenteral tocolysis, delivered before completion of the study medication (34 weeks), or discontinued the medication for any reason (including any adverse effects), were considered failures and were removed from the study, their condition was managed at the discretion of the attending physician.
During the study period, no patient received aspirin or other oral tocolytics other than the study agent. All patients were observed weekly in the high-risk obstetrics clinic; if the patient complained of subjectively increased uterine activity, a digital exam was performed by the physician.
An ultrasound examination was scheduled before the start of treatment, at 1 week, and then every 2 weeks thereafter. All scans were performed by a single investigator (SJC) with either an Ultramark IX or ATL 3000 ultrasound unit (Advanced Technology Laboratories, Bothell, WA). The investigator was blinded to the group assignment. Pulsed Doppler examinations at the ductus were performed using the image-directed transducer. All women were studied with left uterine displacement, except during vaginal probe examinations.
In addition to initial fetal biometric indices, at each examination we attempted to evaluate the deepest pocket of amniotic fluid (AF), the amniotic fluid index (AFI), the hourly fetal urine production, systolic and diastolic ductal arteriosis velocities, systolic/diastolic (S/D) ratios of the umbilical artery, and cervical length, along with internal cervical os dilatation. The ductal arch was obtained either in the longitudinal or short axis, depending on fetal orientation, and the maximum velocity was marked with a cursor.12,13 The angle between the Doppler cursor and the blood flow direction was always less than 15° and sample volume was 1–3 mm. Manual on-screen calculations at peak velocity (systolic and diastolic) were performed using the standard vascular examination package included in the ultrasound software. At least five acceptable waveform measurements were required for a successful study, and the mean of these values was recorded. All measurements were performed during fetal apnea. We measured hourly fetal urine production using the method of Rabinowitz et al14 by obtaining serial bladder volumes and plotting against time. For each study, at least 10 measurements were obtained 2–4 minutes apart. Umbilical artery S/D ratios were obtained using the pulsed Doppler image–directed probe and insonating an area of the umbilical artery as close to the placental insertion as possible. All measurements were made during fetal apnea, and the ratio was determined on-screen by the calculation package.
Throughout the treatment, the investigators reviewed nursing notes and conducted patient interviews to assess the incidence of adverse maternal effects.
All neonates were examined within 24 hours of birth by a pediatrician. The diagnosis of persistent pulmonary hypertension, patent ductus arteriosis, and intracranial hemorrhage was based on clinical imaging and laboratory criteria when necessary.
Comparisons between the groups for AF glucose; systolic ductal velocities after 7 days of treatment in fetuses exceeding 30 weeks’ gestation; time from start of medication to delivery or readmission; and gestational age at delivery in those patients readmitted for repeat tocolysis were analyzed using Student t test (Statistical Package for the Social Sciences, v.6, SPSS Inc., Chicago, IL). Comparison between the groups for numbers of patients completing the study, undergoing amniocentesis, receiving betamethasone, failing, delivering before 37 weeks or readmitted for parenteral tocolysis, readmitted for tocolysis in patients at high risk for recurrence of preterm labor, and incidence of neonatal respiratory distress syndrome (RDS) were analyzed with the 
2. Comparisons between groups for cervical length and hourly fetal urine production over the course of the study were analyzed with repeated measures analysis of variance. Determination of sample size was based on a previous report showing8 that 71% of patients returned for tocolysis or preterm delivery. To reduce this by 45% would require 43 patients in each group, which would yield a power of 80% at a 95% confidence level. Statistical significance was defined as P < .05. All patients were included in the analysis.
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RESULTS |
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). In addition, risk factors for failed tocolysis were similar (Table 2).
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The overall response was comparable in the two groups (Table 3). Twenty (44%) and 17 (35%) patients in the sulindac and control groups, respectively, failed (P = .57) (Figure 1). Seventeen (37%) and 13 (27%) patients in the sulindac and control groups, respectively, failed because of either a delivery before 34 weeks or a readmission for repeat tocolysis (P = .55). Two (4%) and three (6%) patients in the sulindac and control groups, respectively, were noncompliant with the study protocol (P = .54), and one patient in the control group did not take her medication home because of technical error. One sulindac patient was removed by the physician at 32 weeks when the AFI was noted to be 8.6, and hourly fetal urine production was 1.3 mL per hour. Thirty-seven (70%) versus 26 (53%) patients in the sulindac and control groups, respectively, were either delivered before 37 weeks or had at least one readmission for parenteral tocolysis before 34 weeks (P = .10). In this group of patients, the days from start of medication to delivery was 30 ± 22 versus 36 ± 28 in the sulindac and control groups, respectively ([-19.07, 7.25] P = .37), and the gestational age at delivery was 34.2 ± 2.7 versus 34.6 ± 2.6, in the sulindac and control groups, respectively ([-1.81, 1.01] P = .57). In those patients readmitted for tocolysis before 34 weeks, the days from start to readmission was similar at 14 ± 16 versus 10 ± 9, sulindac versus control group, respectively ([-9.24, 17.24] P = .53). There was no difference between the groups in days to delivery or incidence of readmission in specific groups thought to be high risk for recurrence of preterm labor (estimated gestational age on admission, at most 30 weeks, and cervical dilatation at start of medication, at least 3 cm).
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and 3). There was no difference in umbilical artery S/D ratio between the groups at any time interval. With the exception of measurements at 14 days, there were no significant differences between the groups in the depth of deepest AF pocket and the AFI (Table 4). Ductal velocities were not significantly different between the groups (Table 5). No fetus in either group showed evidence of ductal constriction (defined as velocities greater than 140 cm per second systolic and more than 35 cm per second diastolic) on Doppler examination. There were no maternal complaints, adverse effects, or complications in either group believed to be related to the study medications. There was no significant difference between the sulindac and control groups, respectively, in important neonatal variables. Three (6.5%) and two (4.1%) of the sulindac and control groups, respectively, had neonates with respiratory distress syndrome (P = .56). There were no cases of neonatal necrotizing enterocolitis or persistent pulmonary hypertension in either group. Neonatal sepsis occurred in two patients in both groups (P = .63), and one neonate (2.2%) in the sulindac group had a patent ductus arteriosus (P = .33).
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DISCUSSION |
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The present study suggests that lower doses may decrease the incidence but will not eliminate adverse effects. None of our sulindac-treated patients had ductal systolic velocities exceeding 140 cm per second (ductal constriction). However, when we evaluated systolic ductal velocities after 7 days of treatment in fetuses exceeding 30 weeks’ gestation, we found a significantly higher mean value in the sulindac group (91 ± 10 versus 77 ± 11 cm per second, [4.13, 23.3] P =. 007). This finding is similar to that of Kramer et al,11 wherein 20% of sulindac-treated patients had ductal constriction, and all were at gestational ages over 30 weeks. It appears that like indomethacin-treated patients, patients receiving sulindac also showed more pronounced ductal constriction with advancing gestational age.28
Decreased AF has also been reported as an adverse effect of prolonged sulindac treatment at doses of 200 mg twice daily.10 Although we did not find any sulindac-treated patient at any gestational age with an AFI over 5.0, we did note significantly lower AF measurements at 14 days, and one fetus developed a calculated hourly fetal urine production of less than 2 mL per hour, and she was removed from the study.
All known fetal adverse effects appear to be reversible, and no study to this point has confirmed any permanent maternal or neonatal health sequelae from prenatal sulindac use, regardless of the dose or duration of exposure. The results of this study suggest there is no benefit to the pregnancy to prolonged sulindac at 100 mg twice a day. Thus, even though any potential adverse effects are temporary, the risk-versus-benefit ratio does not support the routine use of sulindac to prevent the recurrence of preterm labor and prolong gestation. Several reasons could explain its apparent lack of efficacy. First, compliance with extended oral therapy is much lower than with some other drug delivery methods. In fact, it appears that compliance in our patients was compromised after 2 weeks. Considering the known effect of the drug on AF, we would expect a differential between the groups that would increase with advancing gestation. However, even though there was a decrease in AF measurements at 7 days and significant difference between the groups at 14 days, there was no difference in AF after the 14-day measurement, suggesting that there was compromised patient compliance. This possible incomplete compliance over the study’s duration might be one explanation of why these results are different from the previous sulindac investigation.8 Second, we may have over-diagnosed preterm labor and treated some women in both groups unnecessarily. When preterm labor is diagnosed on the basis of contractions alone, between 30% and 70% of women will resolve without treatment.29–31 In this circumstance, many more patients would be required to determine a benefit of sulindac. Third, preterm labor may be episodic rather than a continuous process that does not require continuous therapy to prevent recurrence. Finally, the drug at these doses may not be effective. In fact, even when we evaluated subgroups of patients at high risk for preterm labor recurrence (those with early gestation and cervical dilatation of at least 3 cm on admission), there was no apparent benefit of the medication.
Patients with arrested preterm labor are at increased risk for recurrence,32,33 but to this point, continued tocolytic treatment with any agent after arrest of acute preterm labor is of questionable value in extending gestation or improving outcome.34 The results of the current study also suggest that antiprostaglandin sulindac in doses of 100 mg twice a day to 34 weeks’ gestation does not extend gestation or improve outcome.
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Footnotes |
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Received January 18, 2001. Received in revised form April 10, 2001. Accepted May 24, 2001.
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REFERENCES |
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