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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Texas Tech University Health Sciences Center at El Paso, El Paso, Texas; and School of Allied Health, The University of Texas at El Paso, El Paso, Texas.
Address reprint requests to: Frederick Harlass, MD, Texas Tech University Health Sciences Center, Department of Obstetrics and Gynecology, 4800 Alberta Avenue, El Paso, TX 79905; E-mail: fharlass{at}ttmcelp.ttuhsc.edu.
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ABSTRACT |
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METHODS: A total of 107 women with clinical indication for induction were randomly assigned to receive oral or vaginal misoprostol. Doses of 100 µg of oral or 25 µg of vaginal misoprostol were given every 3–4 hours. If cervical ripening or active labor did not occur, repeated doses of oral (100–200 µg) or vaginal (25–50 µg) were given until labor was established.
RESULTS: Fifty-nine women received oral misoprostol, and 48 received vaginal administration. Delivery time was similar for the vaginal and oral arms (1074 ± 488 minutes versus 930 ± 454 minutes, P = .11). Parity was significantly different (P = .04) for the vaginal and oral groups. The cesarean delivery rate was similar for the vaginal and oral arms (17% versus 15%, P = .72). The number of medication administrations was consistent between groups. Birth weight was not different for patients in the control and treatment groups (vaginal 3281 ± 507 g versus oral 3359 ± 541 g, P = .44). Chorioamnionitis and tachysystole were comparable for the oral and vaginal groups. There was no statistical difference in neonatal outcomes. Similar proportions of infants were admitted to the well baby nursery and intermediate care nursery.
CONCLUSION: These findings indicate that, in a closely supervised hospital setting with adequate monitoring, oral misoprostol has the potential to induce labor as safely and effectively as its vaginal analogue.
The search for the ideal agent, timing, and dosage interval to convert an unfavorable cervix to one receptive to delivery is an ongoing process. Attention has focused on prostaglandins as effective pharmacologic adjuncts to induction. Prostaglandin estradiol (PGE2) is an agent that has been shown to have utility in promoting cervical ripening and labor initiation. Dinosprone is currently the only medication specifically approved by the Food and Drug Administration for this purpose. Although effective, these agents are expensive and require refrigeration. Because of these issues, the search for alternatives of more cost-effective cervical ripening has continued. One agent that has become intensely investigated is misoprostol, a PGE1 analogue. Misoprostol has been approved for the treatment of pepetic ulcers. Initial studies attested to misoprostol’s uterotonic abilities, and intravaginal application was successfully used to terminate first- and second-trimester pregnancies.1,2 The first investigations using misoprostol in cervical ripening and cervical induction came from South America. Subsequent studies showed intravaginal misoprostol comparing favorably with other commonly used induction agents, including prostaglandins and oxytocin.3–13 Misoprostol compares favorably with the currently approved agent dinoprostone in expense and storage requirements. The optimal dosing regimen, timing, and route of administration remain the focus of ongoing research.14–16 Although vaginal application of misoprostol has been validated as a reasonable means of induction, there is patient resistance to the digital exams necessary for placement of the agent. We designed this randomized trial to compare the safety and effectiveness of vaginal misoprostol with oral misoprostol for induction of labor.
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MATERIALS AND METHODS |
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Patients were eligible for inclusion if they presented with indications for induction and a single live fetus older than 37 weeks’ gestation in cephalic presentation and no contraindication to vaginal delivery. Patients with previous uterine surgery, known prostaglandin hypersensitivity, three or more contractions per 10 minutes, nonreassuring fetal heart tracings, and those with vaginal birth contraindications were excluded from participation.
Before the initiation of the study, computer randomization was performed. A series of consecutively numbered opaque envelopes with each envelope containing an even or odd number was generated. Even numbers indicated oral treatment, and odd numbers indicated vaginal assignment. Sealed envelopes were available to the attending physician at the labor and delivery unit. After the rationale for induction was reviewed and approved and cervical examination confirmed a Bishop score of less than 5,17 consent was obtained. The sealed envelope in turn indicating oral or vaginal treatment was then opened. Patients in the oral group were initially given 100 µg of misoprostol orally. This was repeated every 3–4 hours until the occurrence of progressive labor (as evidenced by a Bishop score of 7 or more), a contraction pattern of three every 10 minutes, and evidence of fetal intolerance or delivery. If an insufficient response was noted with the first application, the physician managing labor had the discretion to increase subsequent doses to 200 µg. The physician made decisions regarding pain amelioration, rupture of membranes, and the need for oxytocin augmentation once active labor was achieved. All study inductions were done with continuous monitoring of uterine contractility and fetal heart rate. Fetal heart rate tracing was according to the caregiver’s interpretation. Patients in the vaginal group received 25 µg of misoprostol placed at the posterior fornix using water as a lubricant. The need for repeated dosing in this group was managed by the same considerations as with the study group. The physician managing labor had the option of increasing subsequent vaginal doses to 50 µg.
The primary outcome measurement was the time from induction initiation to vaginal delivery. Secondary outcome variables included fetal status (as evidenced by Apgar scores, presence of meconium, or admission to a neonatal intensive care unit) and the mode of delivery. Cord artery acid-base values were not measured. Data were analyzed using SPSS-PC+ (Statistical Package for the Social Sciences, Chicago, IL) programs. Differences for continuous and categoric variables were analyzed using the t and 
2 tests. Because parity was different between groups, the Mantel-Haenszel 2 test was conducted. Assuming an induction interval mean from onset to delivery of 12 ± 4 hours, 45 women were required in each arm to detect with 80% power a 20% difference in means between groups given a significance level of 0.05.10
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RESULTS |
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displays induction indication for the oral and vaginal groups. Parity was significantly different (P = .04) for the vaginal and oral groups. After adjusting for parity, no significant difference between groups was found in mode of delivery (Table 2). The cesarean delivery rate for the vaginal and oral arms (17% versus 15%, P = 72) was consistent with the institutional rate of 17%.
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A reversal pattern was seen when multiparous patients were evaluated: a vaginal birth was three times more likely with the oral study arm of the investigation. Outcomes of labor including the number of administrations did not show a significant difference. The number of medication administration was similar in the vaginal and oral groups (1.8 ± 1.0 versus 1.5 ± 1.5, P = .17); however, multiple doses of misoprostol to produce desired effects in cervical ripening were used in some patients. A cumulative maximum of 225 µg intravaginally and 800 µg orally was used in patients who were especially refractory to labor induction. Although greater levels of misoprostol demonstrated an increased tendency to uterine tachysystole, no difference was seen between the oral and vaginal study arms. Meconium was reported to be higher in the oral arm when compared with the vaginal treatment (15% versus 6%, P = .07). However, this difference did not approach statistical significance (Table 3). Other neonatal outcomes including Apgar scores, birth weight, and neonatal infection did not show a significant difference. Similar proportions of infants in both groups were admitted to the well baby nursery and intermediate care nursery (Table 4). The study was well tolerated by the maternal participants.
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DISCUSSION |
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Because of the documented differences in bioavailability in oral versus vaginal misoprostol, a larger dose was used to compensate for the first-pass effects. It may be that an initial 100-µg dose of oral misoprostol effectively skirts the Scylla of ineffective induction and the Charybdis of tachysystole. Unlike other studies using smaller oral doses, the time from induction initiation to vaginal delivery was not prolonged compared with controls. This regimen detected no tendency towards the uterine tachysystole associated with larger misoprostol doses. There were no significant differences in outcomes between the oral and vaginal arms of the study. The perceived difference in delivery modes between nulliparous and multiparous participants in the respective arms was mentioned for the sake of completeness, and after statistical analyses the proportions in question did not approach statistical significance. Potential differences in rates of choriamnionitis were not seen in this study, presumably because of the relatively small numbers. Our findings indicate that, in a closely supervised hospital setting with adequate monitoring, oral misoprostol has the potential to induce labor as safely and effectively as its vaginal analogue. Additional research is needed to categorically determine the most effective dosing regimens and intervals.
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Footnotes |
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Received August 7, 2001. Received in revised form December 12, 2001. Accepted January 17, 2002.
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REFERENCES |
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2. El-Rafaey H, Templeton A. Early induction of abortion by a combination of oral mifepristone and misoprostol administered by the vaginal route. Contraception 1994;49: 111–4.[Medline]
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4. Fletcher H, Mitchell S, Simeon D, Frederick J, Brown D. Intravaginal misoprostol versus dinoprostone as cervical ripening and labor-inducing agents. Obstet Gynecol 1994; 83:244–7.
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17. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266–8.
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