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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University Hospital of Puerto Real, Puerto Real, Cadiz, Spain.
Address reprint requests to: Jose L. Bartha, MD Department of Obstetrics and Gynecology Hospital Universitario de Puerto Real Carretera Nacional IV, KM 665 Puerto Real, Cadiz Spain E-mail: jbarthar{at}sego.es
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Abstract |
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Methods: Two hundred women were randomized to receive single doses of oral misoprostol 200 µg or 0.5 mg of dinoprostone intracervically every 6 hours for a maximum four doses.
Results: The intervals from administration of the drug to active phase of labor (11.1 hours [7–24] versus 15.8 hours [7.5–29.62], P = .01), to delivery (14.0 hours [8.42–27.61] versus 20.2 hours [16.7–32.8], P = .01), and to rupture of membranes (10.0 hours [4.95–24.7] versus 15.6 hours [8.2–29.2], P = .003) were significantly shorter in the misoprostol group. All those variables were not distributed normally, so results are presented as median and interquartile range. The rates of women who needed oxytocin (68% versus 52%, P = .03) and cesarean for failed induction (9% versus 1%, P = .01) were higher in the dinoprostone group.
Conclusion: A single dose of 200 µg oral misoprostol was more effective for cervical ripening and labor induction than 0.5 mg of dinoprostone intracervically every 6 hours, with a maximum of four doses.
Dinoprostone has been widely effective for cervical ripening and labor induction and is available as an intravaginal preparation in many countries. However, it is expensive, needs refrigeration for storage, requires endocervical administration, and in most cases oxytocin is needed with it to augment labor.1 When given intravaginally, misoprostol, a synthetic prostaglandin (PG) E1 analog, also has been successful for cervical ripening and labor induction. It is inexpensive, is stable at room temperature, and is as effective intravaginally, if not more so, than intracervical dinoprostone.2,3 Misoprostol is also active by oral administration but, in spite of its obvious consumer acceptability, that route has been evaluated less for labor induction4–12 compared with intravaginally, and only two series6,7 compared it with dinoprostone. Both included women with premature rupture of membranes. In one of them,6 almost half the women had ripe cervices (Bishop score at least 6), and in the other,7 misoprostol was given by oral and vaginal routes.
The aim of this study was to compare effectiveness, safety, and tolerance of a 200-µg single dose of oral misoprostol with our traditional protocol for cervical ripening and induction of labor with repeated intracervical dinoprostone in women with unfavorable cervices and intact membranes.
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Subjects and Methods |
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Active phase was defined as complete cervical effacement and dilatation of at least 3 cm. Once in labor, women were cared for according to current obstetric practices. In cases in which cervical ripening was not reached, oxytocin was given after the fourth dose in the dinoprostone group, and after 24 hours in the misoprostol group (to equalize the intervals to oxytocin induction), depending on the pattern of uterine contractility. Oxytocin was given for a maximum 12 hours. After that, if women did not reach active phase, cesarean for failed induction was done. In both groups, labor was augmented with oxytocin in the active phase if progress was arrested for longer than 1 hour. No further induction agents were administered when uterine contractions reached a frequency of three in 10 minutes. No other indications of oxytocin were considered. Membranes were ruptured when the cervix was at least 80% effaced and dilated at least 3 cm. Continuous electronic fetal heart rate (FHR) monitoring and tocodynamometry were used with all women. Internal monitors were used at the discretion of obstetricians. Tachysystole was defined as more than five uterine contractions per 10 minutes for two consecutive 10-minute periods. Hypertonus was defined as uterine contraction for at least 2 minutes. Hyperstimulation syndrome was defined as tachysystole or hypertonus associated with fetal tachycardia, late decelerations, or loss of beat-to-beat variability. The FHR tracings were reviewed for the first author, who was not aware of subject assignment.
The primary outcome measure was the interval from start of induction to vaginal delivery. Other measures were 1) need for oxytocin augmentation; 2) interval from start of induction to beginning of active phase; 3) number of women with Bishop scores of at least 6 at 6, 12, and 24 hours from start of induction; 4) number of women with spontaneous rupture of membranes and interval from start of induction to this event; 5) success of induction defined as a delivery within 24 hours of administration of study drugs; 6) route of delivery; and 7) cesarean for failed induction. Fever, gastrointestinal symptoms, hyperstimulation, cesarean for abnormal FHR patterns, Apgar scores, and admission to neonatal intensive care unit (NICU) also were evaluated.
Statistical analysis was done by using the Statistical Package for Social Sciences (SPSS); (SPSS Inc., Chicago, IL) program. Distributions were checked with histogram and Kolmogorov-Smirnov test. When a variable was distributed normally, the results were presented as mean and standard deviation (SD); otherwise, results were shown as median and interquartile range. Qualitative variables are expressed as number and percentage. Groups were compared by using unpaired Student t test; when a variable was not distributed normally, Mann-Whitney U test was used. To compare proportions (qualitative variables), 
2 and Fisher exact tests (when expected numbers were fewer than 5) were used.
Using experience from the pilot study with the interval from start of induction to vaginal delivery as the primary outcome, with a difference between means of 4.5 hours, and a standard deviation of 14.8 hours, we calculated that a sample of 190 would be needed to show a difference with a two-tailed 
level of .05 and a power (1 - ß) of 80%. We enrolled 200 women to account for deviations from study protocol and withdrawals. Statistical significance was set at the 95% level (P < .05). With multiple significance testing, analyses of secondary outcomes should be considered exploratory and a higher level of statistical significance should be required.
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Results |
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. Baseline data included maternal age, gravidity, parity, previous abortions, previous cesareans, estimated gestational age, initial Bishop score, and indication for induction. Initial Bishop scores were assessed by a consultant, and when possible, subjects were reexamined by the same person. The median preinduction Bishop scores did not differ between groups (Table 1). The median (range) gestational age was identical (40.5 [39–42] weeks), and the rate of nulliparas was analogous (60% versus 68%) in both groups. Indications for labor induction did not differ significantly between groups (Table 2).
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). Among those who needed oxytocin, the median (range) cervical dilatation before oxytocin was started was greater with misoprostol than with dinoprostone (3 [2–4] versus 2 [2–3], P = .04).
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The rate of patients with ripe cervices at 6 hours from the start of induction was higher in the misoprostol group (43% versus 27%), (P = .02). There were no significant differences in rate of vaginal delivery before 24 hours (67% versus 55%) or in the rate of mature cervices at 12 and 24 hours (66% versus 53% and 76% versus 64%), even though the percentages were always favorable for misoprostol-treated women. Thirty-six women needed at least two doses of PGE2 for cervical ripening and induction of labor in the dinoprostone group.
There was no significant difference in incidence of cesarean delivery between groups (14% with misoprostol versus 20% with dinoprostone). However, the indications for cesarean delivery were significantly different. Only one cesarean in the misoprostol group was for failed induction compared with nine (9%) in the dinoprostone group. More cesareans were done in the misoprostol group for abnormal FHR patterns than in the dinoprostone group (3% versus 1%); however, that did not reach statistical significance. The rest of the indications for cesarean were failure of progression (suspected cephalopelvic disproportion) (9 in the misprostol and 10 in the dinoprostone group) and one case of worsening maternal conditions (in a case of severe preeclampsia) in the misoprostol group. There was no significant difference in the rate of tachysystole (20% versus 13%), hypertonus (20% versus 15%), and hyperstimulation (6% versus 2%) between groups (Table 4). There were no cases of disruption of previous uterine incisions in either group.
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). The number of neonates with 1-minute Apgar scores less than 7 was small, and none had a 5-minute Apgar score less than 7. Meconium passage was similar between groups (20% in the misoprostol versus 14% in the dinoprostone group). Hyperstimulation did not cause any cesareans for abnormal FHR patterns. No infants required intubation or prolonged resuscitation. The rate of neonates who needed NICU admission was similar between groups (12% versus 11%), and none presented with neurologic damage. |
Discussion |
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Ngai et al4 compared 200 µg oral misoprostol with placebo before intravenous (IV) oxytocin infusion for cervical ripening in women with PROM at term. They found that dose effective for improving Bishop score, reducing incidence of oxytocin infusion for labor induction, and decreasing leaking-to-delivery intervals, with no increase in maternal side effects or perinatal morbidity. To our knowledge, only one other study used 200 µg of oral misoprostol for labor induction.9 Adair et al,9 in a randomized, double-masked trial of 178 women, found similar efficacy between 200-µg oral and 50-µg vaginal administration, but the oral route was associated with more frequent abnormal uterine contractility, including an unexpectedly high rate of hyperstimulation syndrome (44.1%).
To decrease that high rate, other studies used lower doses of oral misoprostol, but the effectiveness was lower also. The protocol used most widely was oral misoprostol, 50 µg every 4 hours, with which oral misoprostol was less effective than dinoprostone plus oxytocin,6 vaginal misoprostol,10 Foley catheter plus oxytocin,11 and oxytocin alone.12 Only one study7 that compared oral with vaginal misoprostol recommended the oral route using that scheme. Toppozada et al5 found a shorter interval from start of induction to delivery with the vaginal route when using 100 µg. Kadanali et al7 found 100 µg intravaginal followed by 100 µg oral misoprostol every 2 hours more effective for labor induction than oxytocin and PGE2.
Ngai et al,4 using 200 µg, did not report incidence of hyperstimulation syndrome, but one woman among 39 in the misoprostol group had late decelerations on external cardiotocography when uterine contractions were at 2-minute intervals. Adair et al9 found a considerably high rate of hyperstimulation syndrome and they suggested prescribing that dose only for nonviable pregnancies. When their article was published, we had already finished our study and our results were completely different on that point because our hyperstimulation rate was only 6%. Differences in rates of hyperstimulation syndrome with Adair et al could be explained by the fact that they used a repetitive dose of 200 µg. Therefore, their cumulative dose was much higher than ours.
Safety in terms of perinatal outcome was confirmed in our study by similar rates of meconium passage, cesarean owing to abnormal FHR patterns, low Apgar scores, need of intubation in delivery room, and admission to NICU. However, because it was reported that peak concentration could be as soon as 12 minutes after oral administration,13 we recommend using continuous electronic FHR and uterine contraction monitoring from the onset of induction. In our study, oral misoprostol was well tolerated at the dose used. The rates of gastrointestinal dysfunction or other adverse effects were very low and similar to those in the dinoprostone group. A higher frequency of disruption in prior uterine incisions was reported with intravaginal misoprostol.14 Although we had no such complications in the three women who had cesareans and were given misoprostol, we believe that oral dose could be avoided for those women.
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Footnotes |
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Received January 11, 2000. Received in revised form April 17, 2000. Accepted May 11, 2000.
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References |
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2. Sánchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E1 methyl analogue misoprostol versus oxytocin: A randomized trial. Obstet Gynecol 1993;81:332–6.
3. Wing DA, Jones MM, Rahall A, Goodwin TM, Paul RH. A comparison of misoprostol and prostaglandin E2 gel for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1995;172:1804–10.[Medline]
4. Ngai SW, To WK, Lao T, Ho PC. Cervical priming with oral misoprostol in pre-labor rupture of membranes at term. Obstet Gynecol 1996;87:923–6.[Abstract]
5. Toppozada MK, Anwar MY, Hassan HA, el-Gazaerly WS. Oral or vaginal misoprostol for induction of labor. Int J Gynaecol Obstet 1997;56:135–9.[Medline]
6. Windrim R, Bennett K, Mundle W, Young DC. Oral administration of misoprostol for labor induction: A randomized controlled trial. Obstet Gynecol 1997;89:392–7.[Abstract]
7. Kadanali S, Kuücuükozkan T, Zor N, Kumtepe Y. Comparison of labor induction with misoprostol vs. oxytocin/prostaglandin E2 in term pregnancy. Int J Gynaecol Obstet 1996;55:99–104.[Medline]
8. Bennett KA, Butt K, Crane JMG, Hutchens D, Young DC. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction. Obstet Gynecol 1998;92: 481–6.[Abstract]
9. Adair CD, Weeks JW, Barrilleaux S, Edwards M, Burlison K, Lewis DF. Oral or vaginal misoprostol administration for induction of labor: A randomized, double-blind trial. Obstet Gynecol 1998;92: 810–3.[Abstract]
10. Wing DA, Ham D, Paul RH. A comparison of orally administered misoprostol with vaginally administered misoprostol for cervical ripening and labor induction. Am J Obstet Gynecol 1999;180:1155–60.[Medline]
11. Abramovici D, Goldwasser S, Mabie BC, Mercer BM, Goldwasser R, Sibai BM. A randomized comparison for oral misoprostol versus Foley catheter and oxytocin for induction of labor at term. Am J Obstet Gynecol 1999;181:1108–12.[Medline]
12. Butt KD, Bennett KA, Crane JM, Hutchens D, Young DC. Randomized comparison of oral misoprostol and oxytocin for labor induction in term prelabor membrane rupture. Obstet Gynecol 1999;94: 994–9.
13. Karim A. Antiulcer prostaglandin misoprostol: Single and multiple dose pharmacokinetic profile. Prostaglandins 1987;33:40–50.
14. Wing DA, Lovett K, Paul RH. Disruption of prior uterine incision following misoprostol for labor induction in women with previous cesarean delivery. Obstet Gynecol 1998;91:828–30.[Abstract]
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