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ORIGINAL RESEARCH |
From the Department of Obstetrics-Gynecology, Division of Maternal-Fetal Medicine, Women’s & Children’s Hospital, Keck School of Medicine of the University of Southern California, Los Angeles, California.
Address reprint requests to: Deborah A. Wing, MD University of Southern California Women’s and Children’s Hospital 1240 North Mission Road, Room 5K40 Los Angeles, CA 90033 E-mail: dwing{at}hsc.usc.edu
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Abstract |
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Methods: One hundred eighty women with pregnancies beyond 41 weeks and undilated, uneffaced cervices were assigned randomly to receive mifepristone 200 mg or placebo and observed for 24 hours. We then gave intravaginal misoprostol 25 µg every 4 hours or intravenous oxytocin. We expected 60% of placebo-treated and 80% of mifepristone-treated women to deliver vaginally within 48 hours.
Results: Among 180 subjects, 97 received mifepristone and 83 received placebo. The mean interval (± standard deviation [SD]) from start of induction to delivery was 2209 ± 698 minutes for mifepristone-treated subjects and 2671 ± 884 minutes for placebo-treated subjects (P < .001, log-transformed data). Twelve (13.6%) mifepristone-treated women and seven (10.8%) placebo-treated women delivered vaginally on day 1 (P = .60). After 24 hours, the median Bishop score for both groups was 3 (0–11) (P = .51). One hundred thirty-one subjects required misoprostol, 65 (67.0%) were mifepristone-treated women, and 66 (79.5%) placebo-treated women (P = .06). The median (range) oxytocin dose was 871.5 (0–22,174) mU for mifepristone-treated women and 2021.0 (0–24,750) mU for placebo-treated women (P = .02). Seventy-seven (87.5%) mifepristone-treated women and 46 (70.8%) placebo-treated women delivered vaginally 48 hours after the start of treatment (P = .01). There were nine cesareans in the mifepristone group and 18 in the placebo group (P = .02). More nonreassuring fetal heart rate patterns and uterine contractile abnormalities occurred in mifepristone-treated subjects. There were no statistically significant differences in neonatal outcomes between groups.
Conclusion: Mifepristone had a modest effect on cervical ripening when given 24 hours before labor induction, appearing to reduce the need for misoprostol and oxytocin compared with placebo.
One of the most common indications for labor induction is prolonged pregnancy. Between 3.5% and 12% of pregnant women have not delivered more than 2 weeks beyond estimated delivery dates.1 Increased perinatal mortality, higher rate of cesarean delivery, nonreassuring fetal heart rate (FHR) patterns, fetal macrosomia, and neonatal meconium aspiration syndrome are complications of prolonged gestations.2,3 To avoid those problems, labor is often induced when pregnancy duration exceeds 287 days.4 In one large multicenter study of post-term pregnancies, labor induction was associated with fewer cesarean deliveries and no significant differences between neonatal morbidity and mortality compared with expectant management with serial antenatal monitoring.5
Mifepristone is a steroid compound that has antiglucocorticoid and antiprogesterone properties. It increases uterine activity and causes cervical effacement and dilation for pregnancy termination.6–11 There are few studies on mifepristone for cervical ripening and labor induction in term pregnancies.12–15 Frydman et al12 studied 120 women at term who received 200 mg mifepristone or placebo for 2 consecutive days of a 4-day observation period. More women had spontaneous labor and fewer needed cervical ripening with prostaglandin in the mifepristone-treated group than in the placebo group. Similar results were reported in 93 women with post-term pregnancies who were given mifepristone or placebo. Mifepristone produced greater cervical ripening and reduced time to delivery compared with placebo.14
We investigated the safety and efficacy of a single dose of 200 mg of mifepristone for preinduction cervical ripening and labor induction in women with prolonged gestations.
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Materials and Methods |
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Inclusion criteria were singleton gestation, cephalic presentation, reactive FHR pattern, intact membranes, gestational age more than 41 weeks, and maternal age greater than 18 years. Exclusion criteria were Bishop score at least 7 or cervical dilatation greater than 3 cm, more than nine uterine contractions per hour, ultrasonographically estimated fetal weight greater than 4500 g or evidence of cephalopelvic disproportion, ultrasonographically estimated fetal weight less than 2000 g, placenta previa or unexplained vaginal bleeding, active genital herpes simplex infection, previous cesarean or history of uterine surgery, chorioamnionitis evidenced by maternal temperature of 38C or more and uterine tenderness or foul-smelling amniotic fluid (AF), parity of six or more, pre-existing moderate or severe disease, and contraindications to prostaglandins (PGs).
The trial was double-masked, and subjects were assigned by a computer-generated random number sequence to receive 200 mg mifepristone (Population Council-Center for Biomedical Research, New York, New York, and Exelgyn, Paris, France) or placebo (vitamin C, Sundown Vitamins, Boca Raton, FL) by mouth. An Investigational New Drug Application (52,415) was filed with the Food and Drug Administration. Medications were packaged by an independent third party in sequentially numbered envelopes. Subjects were assigned sequential study numbers and given medications in accordance with the numbers. Participants were observed to ensure they took the medication. One hundred thirty of 180 subjects (72.2%) received study medications between 8 AM and 5 PM.
Senior obstetrics-gynecology residents assigned initial Bishop scores, and when possible, subjects were re-examined by the same individuals after 24 hours. If Bishop scores were at least 7, labor was induced with oxytocin. If Bishop scores were less than 7, FHR patterns were reactive, and uterine activity minimal, participants received 25 µg misoprostol intravaginally. If contraction frequencies were less than three in 10 minutes, additional doses of 25 µg misoprostol were given at 4-hour intervals until labor was adequate or 24 hours elapsed (maximum six doses or 150 µg). Bishop scores were assigned again before each misoprostol dose and before oxytocin. A Bishop score of 13 was assigned to subjects who entered the active phase of labor. Once in active labor, patients were managed routinely.
Oxytocin also was given for failure to enter the active phase of labor after maximum misoprostol dosage, augmentation after adequate cervical ripening (dilatation of 3 cm or more or Bishop score of 7 or more), or failure to progress in the active phase of labor (less than 1 cm progression over 2 hours). Oxytocin was infused by pump with the use of a standardized protocol, with an initial dose of 1 mU/minute and incremental increases every 30 minutes to a maximum of 22 mU/minute.
Continuous external FHR monitoring and tocodynamometry were used. Fetal heart rate patterns were classified according to Kubli et al.16 Abnormal FHR patterns were defined as either fetal tachycardia or bradycardia, late decelerations, or moderate-severe decelerations. Uterine activity patterns were evaluated for frequency and duration of tachysystole, hypertonus, and hyperstimulation syndrome.17 Uterine hypertonus was defined as a single uterine contraction that lasted 2 or more minutes, tachysystole as at least 12 uterine contractions in 20 minutes, and hyperstimulation as either hypertonus or tachysystole associated with abnormal FHR pattern. Terbutaline 0.25 mg given intravenously (IV) or subcutaneously, or IV magnesium sulfate, was used to treat contraction abnormalities.
Chorioamnionitis was defined as maternal temperature of at least 38C, foul-smelling amniotic fluid, fundal tenderness, or persistent elevation of FHR baseline of 160 or more beats per minute. It was treated with antipyretics and antimicrobial agents. Neonatal blood glucose was monitored on the first and second days of life by heel-prick samples. Neonatal vital signs, including blood pressure (BP), were recorded within 24 and 48 hours of life. Standard observations were recorded, and adverse events were noted.
The primary outcome measure was the time from start of treatment-to-delivery. We also tabulated frequency of vaginal delivery 24 hours and 48 hours from administration of study medication, and change in Bishop score after 24 hours of study medication. Other outcome variables were route of delivery, need for misoprostol, number of misoprostol doses, need for oxytocin, and neonatal outcome measures such as Apgar scores, need for resuscitative measures beyond routine warming and drying, and number of neonatal intensive care unit admissions (NICU).
Sample calculations were based on the assumption that 60% of women would deliver vaginally within 48 hours of treatment. Using an estimate that a 33% increase in that number to 80% would be clinically important, and assuming a type I error of 0.05 and a type II error of 0.2, we calculated that 80 women in each group were necessary. The test was one-sided. We assumed a 10% withdrawal rate. Differences in age, height, weight, estimated gestational age, parity, gravidity, total doses of misoprostol, and average intervals, such as induction-to-delivery, were analyzed using t tests; differences in route of delivery, frequency of complications, need for misoprostol, and need for oxytocin were analyzed with the use of 
2 tests or Fisher exact tests when appropriate. Intervals were analyzed after log transformation. Apgar and Bishop scores and median oxytocin dose, were analyzed with the use of the Mann-Whitney U test. Tests were two-sided, with P < .05 statistically significant.
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Results |
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). Twenty-six percent of mifepristone-treated women were nulliparous, compared with 34 (41.0%) of placebo-treated women (P = .045). Median Bishop scores at the start of induction in each group were similar (Table 2).
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). Among those undelivered by the beginning of day 2, the median Bishop scores before administration of oxytocin or misoprostol were similar (Table 2). However, more women in the mifepristone group had Bishop scores greater than 7 than the placebo group (12 of 80 [15.0%] versus four of 73 [5.5%], P = .05). One hundred thirty-one women needed misoprostol for cervical ripening, 65 (67.0%) mifepristone- and 66 (79.5%) placebo-treated (P = .06). The mean number of misoprostol doses required by mifepristone-treated subjects was less than that of placebo-treated women, 1.7 ± 0.8 versus 2.0 ± 1.0 (P = .11). Whereas similar numbers of subjects from each group required oxytocin for induction or augmentation (P = .48), the median dose of oxytocin for mifepristone-treated women was less than for placebo-treated women (Table 2).
The mean interval from treatment-to-delivery was shorter for mifepristone-treated subjects than for those receiving placebo (Table 3). The difference between groups in mean time to delivery was approximately 7 hours. Among women who delivered vaginally, the mean interval from treatment to delivery was 2194 ± 697 minutes for mifepristone-treated women, and 2504 ± 852 minutes for placebo-treated women (P = 0.03). Few women delivered vaginally within the initial 24 hours (Table 3).
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Parity influenced the likelihood of vaginal delivery within 48 hours, regardless of medication. In the mifepristone group, 15 (15.5%) nulliparas and 62 (63.9%) multiparas delivered vaginally within 48 hours of initiation of treatment, and in the placebo group, ten (12.0%) nulliparas and 36 (43.3%) multiparas delivered in that period. Among nulliparas, the mean interval from start of treatment to delivery was 2426 ± 804 minutes in the mifepristone group, and 3169 ± 875 minutes in the placebo group (P = .002, log-transformed data). Among multiparas, that interval was 2129 ± 644 minutes in the mifepristone women and 2326 ± 714 minutes in the placebo-treated women (P = .16, log-transformed data). Among nulliparas, six from the mifepristone group and 14 from the placebo group, respectively, had cesareans (P = .34) for nonreassuring FHR (one versus zero), arrest of labor (four versus ten), failed induction (zero versus three), and other indications (one each).
The types and frequencies of uterine contractile abnormalities are shown in Table 2. Most episodes of tachysystole were many hours after administration of misoprostol and in the active phase of labor. The mean interval from last dose of misoprostol to onset of tachysystole was 322 ± 257 minutes in mifepristone women, and 239 ± 169 minutes in placebo-treated women (P = .83, log-transformed data). There was more active-phase hypertonus and hyperstimulation in the mifepristone group.
Chorioamnionitis occurred in 15 (15.5%) mifepristone women and 18 (21.7%) placebo women (P = .28). Sixteen (16.5%) infants from the mifepristone group and 14 (16.9%) from the placebo group had meconium-stained AF (P = .95). Thick meconium was reported in 11 mifepristone- and eight placebo-treated women (P = .51). Abnormal FHR patterns were found in 18 (18.6%) mifepristone and six placebo women (7.2%) (P = .03).
Birth outcomes did not differ between groups (Table 4). The numbers of infants who needed resuscitation beyond usual warming and drying were 26 (26.8%) and 15 (18.1%) in the mifepristone and placebo groups, respectively (P = .16). Admissions to the NICU, most of which were for clinically suspected sepsis, were similar between groups. Among 104 infants who had daily capillary blood glucose testing and 98 who had BP monitoring before discharge, no differences were seen between groups.
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Discussion |
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We did not meet our expectations for statistical power. Fewer mifepristone- and fewer placebo-treated women delivered vaginally by the end of the second day than expected. We had approximately 65% power to detect a significant difference in vaginal delivery rates by 48 hours at an 
level of .05.
Longer exposure to mifepristone might be required to show significant clinical differences in cervical ripening and labor induction. We hypothesize that the action of mifepristone is mediated locally after it triggers a decline in the systemic level of progesterone. Our lack of efficacy might be the result of the 24-hour interval from administration of mifepristone to re-evaluation and induction of labor compared with other trials in which 48 to 96 hours elapsed before induction.12,14,15 With 24-hour intervals, we could continuously observe our subjects after mifepristone. Our results after the first 24 hours of exposure were similar to those reported by Frydmann et al,12 ie, 13 subjects (3%) went into labor within 24 hours after receiving mifepristone. The dose used in our study was selected arbitrarily with consideration of maternal safety. In one three-armed trial in Scotland, 50 mg mifepristone was compared with 200 mg mifepristone and with placebo. Women were evaluated every 24 hours until 72 hours, when labor was induced. The larger dose of mifepristone resulted in favorable cervices in more women than placebo, and the degree of ripening effected by 50 mg was less than the 200 mg dose.15 Our results were consistent with the literature that shows decreased PG requirements and heightened oxytocin sensitivity when mifepristone is given either for second-trimester pregnancy termination or term induction.19–21
Although not statistically different, more uterine contractile abnormalities and nonreassuring FHR patterns were observed in mifepristone- than placebo-treated women, most of which were during active-phase labor, and in most cases after intravaginal misoprostol. That might indicate an increase in sustained uterine activity from mifepristone22 or synergy between antiprogestational agents and the PG compound.19
There were fewer cesareans in the mifepristone than the placebo group, particularly for dysfunctional labor and failed inductions, similar to another study15 that showed mifepristone administration in humans might decrease the likelihood of dystotic labor, unlike in monkeys.23
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Footnotes |
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Received February 2, 2000. Received in revised form April 13, 2000. Accepted May 3, 2000.
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References |
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2. Naeye RL. Causes of perinatal mortality excess in prolonged gestations. Am J Epidemiol 1978;108:429–33.
3. Usher RH, Boyd ME, McLean FH, Kramer MS. Assessment of fetal risk in postdate pregnancies. Am J Obstet Gynecol 1988;158:259–64.[Medline]
4. Racker D, Burgress GH, Manly G. The management of postmaturity. Lancet 1953;2:953–6.
5. Hannah ME, Hannah WJ, Hellman J, Hewson S, Milner R, Willan A. Induction of labor as compared with serial antenatal monitoring in post-term pregnancy. A randomized controlled trial. The Canadian Multicenter Post-term Pregnancy Trial group. N Engl J Med 1992;326:1587–92.[Abstract]
6. Swahn ML, Bygdeman M. The effect of the antiprogestin RU 486 on uterine contractility and sensitivity to prostaglandin and oxytocin. Br J Obstet Gynaecol 1988;95:126–34.[Medline]
7. Johnson N, Bryce FC. Could antiprogesterones be used as alternative cervical ripening agents? Am J Obstet Gynecol 1990;162:688–90.[Medline]
8. Norman JE, Thong KJ, Baird DT. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet 1991;338:1233–6.[Medline]
9. Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet Gynaecol 1992;99: 1004–7.[Medline]
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12. Frydman R, Lelaidier C, Baton-Saint-Mleux C, Fernandez H, Vial M, Bourget P. Labour induction in women at term with mifepristone (RU 486): A double-blind, randomized, placebo-controlled study. Obstet Gynecol 1992;80:972–5.
13. Lelaidier C, Baton C, Benifla JL, Fernandez H, Bourget P, Frydman R. Mifepristone for labour induction after previous caesarean section. Br J Obstet Gynaecol 1994;101:501–3.[Medline]
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15. Elliott CL, Brennand JE, Calder AA. The effects of mifepristone on cervical ripening and labor induction in primigravidae. Obstet Gynecol 1998;92:804–9.[Abstract]
16. Kubli FW, Hon EH, Khazin AF, Takemura H. Observations on heart rate and pH in the human fetus during labor. Am J Obstet Gynecol 1969;104:1190–206.[Medline]
17. Stookey RA, Sokol RJ, Rosen MG. Abnormal contraction patterns in patients monitored during labor. Obstet Gynecol 1973;42:359–67.
18. Li L, Gao W, Chen S. Labour induction in women at term with mifepristone and misoprostol. Chung Hua Fu Chan Ko Tsa Chih 1996;31:681–4.
19. Rodger MW, Baird DT. Pretreatment with mifepristone (RU 486) reduces the interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41–5.[Medline]
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23. Haluska GJ, Stanczyk FZ, Cook MJ, Novy MJ. Temporal changes in uterine activity and prostaglandin response to RU486 in rhesus macaques in late gestation. Am J Obstet Gynecol 1987;157:1487–95.[Medline]
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