(continued from Part III)
A Summary of Articles Published in English about Misoprostol (Cytotec) for Cervical Ripening or Induction of Labor
By Ina May Gaskin, CPM
Originally published by www.inamay.com, 2005-09-05
They go on, “Use of both 25- and 50-microgram dosing for cervical ripening seems to be associated with a relatively increased incidence of uterine rupture in patients with an early cesarean delivery.”
40. Gerstenfeld TS and Wing DA. Rectal misoprostol versus intravenous oxytocin for the prevention of postpartum hemorrhage after vaginal delivery, Am J Obstet Gynecol 185 (2001):878-82.
The purpose of this study was to compare rectally administered misoprostol to intravenously administered oxytocin for the management of third-stage labor. Three hundred twenty-five Los Angeles women were randomized into two groups. Group 1 was given two, 200 microgram misoprostol tablets rectally (the study medication) plus 2 mL saline in Ringer’s lactate intravenously, while group 2 was given two lactose tablets rectally plus 20 units oxytocin in Ringer’s lactate intravenously.
The conclusion was that rectal misoprostol was no more effective than intravenous oxytocin in preventing postpartum hemorrhage. Thirty-six of 159 women (23%) in the misoprostol group and 18 of 166 (11%) women in the oxytocin group needed at least one additional medication to control bleeding after vaginal birth.
The authors show a table indicating that 42% of the women in the misoprostol group had induced labors, while 35% “required labor augmentation.” Of the oxytocin group, 37% had induced labors, and 33% “required labor augmentation.” The authors appear not to have considered the possibility that induction or augmentation of labor with prostaglandins or oxytocin might negatively affect the efficacy of these drugs to halt postpartum hemorrhage in these same labors.
41. Fisher SA, Mackenzie VP, et al. Oral versus vaginal misoprostol for induction of labor: a double-blind randomized controlled trial, Am J Obstet Gynecol 185 (2001):906-10.
This Ontario study was designed to determine the efficacy of oral misoprostol (50 microgram doses) given every 3 hours compared to vaginal misoprostol (50 micrograms) given every 6 hours for induction of labor. Women with prior uterine scars were excluded.
The interval between start of induction to birth was shorter in the vaginal misoprostol arm of the study than in the oral arm. There was an increased incidence of tachysystole in the vaginal group (26.5% vs 9.7%).
The authors comment: “Of interest in the current study is that of 23 adverse events (tachysystole, hypertonus {contractions lasting longer than 2 minutes}, or hyperstimulation) that occurred in the vaginal group, all but 1 woman experienced this complication after receiving only a single dose of misoprostol.”
And this. “Despite its increased efficacy compared with oral misoprostol, high rates of tachysystole and hyperstimulation associated with vaginal misoprostol in the current study are cause for concern.”
42. Incerpi MH, Fassett MJ, et al. Vaginally administered misoprostol for outpatient cervical ripening in pregnancies complicated by diabetes mellitus, Am J Obstet Gynecol 185 (2001):916-9
The authors undertook a study that compared the use of intravaginal misoprostol to a placebo for outpatient labor induction in women with diabetes. They write in their introduction: “Although inpatient cervical ripening and labor induction is a well-recognized obstetric procedure that has proven to be safe and effective, there are few studies and limited data regarding the safety and effectiveness of outpatient cervical ripening and labor induction. The advantages of outpatient labor induction include patient convenience, improved staffing in labor and delivery units, and reduced hospitalization costs.” (Remember, the authors are talking about diabetic mothers).
The study itself was small, with 57 women in the misoprostol and 63 in the placebo arm. Women with prior uterine surgery were excluded.
The conclusion of the study was that vaginally placed misoprostol was no more effective than a placebo in reducing the need for in-hospital labor induction of the interval between the beginning of induction and birth.
The authors remark: “Although we did not demonstrate a statistically significant difference between groups in our primary outcome measures, we did demonstrate that 25 micrograms of misoprostol administered vaginally in our established study protocol was well tolerated.” They call for a multicenter trial to evaluate the use of outpatient misoprostol. They do recognize that there is controversy regarding whether pregnant women with diabetes should be induced at all, but they do not consider that the use of misoprostol itself is controversial.
By the way, one of the researchers (Wing) headed the study that included one maternal death and two emergency hysterectomies, all of which complications occurred after only one 25 microgram dose of misoprostol. (See Note 12).
I found it odd that the researchers considered their study size too small to come to a strong conclusion about the apparent lack of efficacy of misoprostol inductions at 38 – 39 weeks but that they apparently considered it big enough to satisfy safety concerns. Certainly, a large multicenter trial could expose many more women to a potential danger of uterine rupture if such a study were undertaken (if we look at the results of all of the misoprostol studies, not just those cherry-picked to bolster the view that “inpatient labor induction in women with diabetes at term is a common practice that has gained support and widespread clinical practice”) and [misoprostol] “has proven to be safe, efficacious, and cost-effective,” as the authors maintain.
43. How HY, Leaseburge L, et al. A comparison of various routes and dosages of misoprostol for cervical ripening and the induction of labor, Am J Obstet Gynecol 185 (2001):911-5.
Cincinnati, Ohio was the site of this study, which compared the efficacy of different routes of misoprostol administration for cervical ripening and induction of labor. The authors comment in the first paragraph of this paper: “Only a few studies have examined the efficacy and safety of orally administered misoprostol.” They reference six such studies that had been published by that time, but leave out two others, one of which was a case study of uterine rupture in a woman whose labor was induced with oral misoprostol (see Note 36).
Three hundred thirty-three women were randomly divided into three groups. Group 1 was given 25 micrograms of oral misoprostol plus 25 micrograms of intravaginal misoprostol. Group 2 got an oral placebo plus 25 micrograms of intravaginal misoprostol. Group 3 got 25 micrograms of oral misoprostol plus an intravaginal placebo. Doses in each group were repeated every 4 hours until labor began or a maximum of 12 doses had been given.
The primary outcome for the researchers was vaginal birth within 24 hours of the start of the induction. Secondarily, they were interested in time from induction to birth, need for oxytocin augmentation, mode of birth, incidence of side effects and maternal and infant outcomes.
Results: The vaginal misoprostol only group ranked highest in the incidence of birth within 24 hours: 67% compared with 53% in the oral-plus-vaginal misoprostol group.
The cesarean rates were highest in the oral group (32%) and the oral-plus-vaginal group (30%), compared with 17% in the vaginal group.
The authors comment: “The rate of tachysystole and hyperstimulation were higher than expected in the group that received vaginally administered misoprostol.”
My comment: I was puzzled by a couple of points in the following paragraph from the “Materials and methods” section following the introductory paragraph of this paper. It reads:
“Inclusion criteria included (1) singleton pregnancy, (2) cephalic presentation, (3) gestational age between 32 and 42 weeks with our , without rupture of membranes, (4) Bishop score of < or = to 6, (5) reassuring fetal heart pattern, and (6) fewer than 8 contractions per hour.”
Does this mean that a woman who was already having 7 contractions per hour could be included in this study and be given misoprostol if she was randomized to that group? Having that many contractions per hour fits the definition of tachysystole, before the women were given misoprostol. For what purpose could the drug be given in such cases?
The very next sentence in the paper is this one: “Exclusion criteria were (1) nonreassuring fetal heart rate pattern, (2) contraindications to labor (such as placenta previa, active herpes simplex virus, and prior vertical uterine scar), (3) more than 1 low transverse uterine scar, and (4) known allergy to prostaglandins.” These researchers apparently felt comfortable inducing labor in women with a scarred uterus even after the well- documented reports of a 28-fold increase in uterine rupture and fetal death in such cases by the time this study was initiated (see Notes 28, 30 and 32). Several uterine ruptures had also occurred in women with no uterine scars. One wonders whether these facts were made clear to the women in this study before they signed the informed consent documents required for their participation.
44. Carlan SJ, Blust D et al. Buccal versus intravaginal misoprostol administration for cervical ripening, Am J Obstet Gynecol 186 (2001):229-33
This South Florida study employed some of the same inclusion and exclusion criteria as the How et al study summarized above (Note 43). “Patients with a previous cesarean delivery were not excluded. Patients were required to sign informed consent to participate.”
Now to explain the main elements of the study design. One hundred fifty-seven women were randomly divided into two groups. The buccal group (77) got 2 doses of 200 micrograms of misoprostol 6 hours apart, followed by 300 microgram doses at 6 hour interval to a maximum dose of 1600 micrograms. The intravaginal group got 50 microgram doses twice, followed by an increase in dosage to 100 micrograms (!), to a maximum dosage of 500 micrograms. These doses were also given at 6 hour intervals.
Results:
Five women were found to be in labor and weren’t given misoprostol. I couldn’t find to which group these 5 cases belonged.
“The most common reason for intervention of the ripening process was abnormal fetal heart rate with 5 patients (7%) and 4 patients (5%) in the buccal and vaginal group, respectively (P = .64 x2). Three patients (4%) and 0 patients of the buccal and vaginal groups, respectively, had the tablet removed for abnormal fetal heart rate patterns (P = .06, x2). The median time from insertion to removal was 28 minutes; despite removal, 2 of the 3 patients had immediate cesarean deliveries for a persistent abnormal fetal heart rate pattern. Four patients (6%) and 2 patients (3%) of the buccal and vaginal groups, respectively, required urgent cesarean delivery during the ripening process (P = .35, x2).”
One wonders how these results would have compared with a third group receiving a placebo.
The authors conclude that the hours from drug administration to birth were similar between the two groups they studied. There was significantly more tachysystole in the buccal group (38%) than in the intravaginal group (19%).
From the final paragraph of this paper: “Buccal administration of misoprostol has a rapid onset, avoids the need for repeated examinations, can be used in patients who are unable to eat, and is highly effective as a cervical ripening agent. It may be an ideal method of cervical ripening in women with unripe cervices and premature rupture of membranes. This study supports the use of misoprostol administration in the buccal pouch.”
No mention is made of the need for comparison between groups of women whose cervices are left to ripen on their own.
A noteworthy sentence from “Materials and methods”:
“Episodes of uterine activity that were deemed excessive by the physician were treated with a standard combination of maneuvers that included a change in maternal position, oxygen administration, and terbutaline 250 micrograms subcutaneously. Persistent abnormal fetal heart rate patterns resulted in intervention by removing the patient from the study and transferring her to the labor suite.” Nothing further is said about how many women were removed from the study on this account. Two paragraphs later we are told: “All randomized subjects were included in the statistical analysis unless otherwise noted.”
It would seem that removal of the women from the study would mask an unknown number of negative results, lowering the value of this study.
45. Shetty A, Danielian P et al. Sublingual misoprostol for the induction of labor at term, Am J Obstet Gynecol 186 (2002):72-6.
This study was carried out at Aberdeen Maternity Hospital, Aberdeen, Scotland. One hundred women with medical or obstetric indications for induction of labor after 37 weeks and unfavorable cervices were randomized into two groups. The first received 50 micrograms of misoprostol orally and the second received the same dose sublingually. Doses were given at 4 hours intervals to a maximum of 5 doses.
No women were included in the study who had had prior cesareans.
Significantly more women in the sublingual group had their babies within 24 hours of the initiation of induction than in the oral group (73.8% versus 45.7%).
There were no significant differences in mode of birth, interventions for fetal distress or neonatal outcomes in the 2 groups.
One woman in the oral group had an emergency cesarean for suspected placental abruption.
One first-time mother in the sublingual group had an emergency cesarean and abnormal fetal heart tracing 4 hours after the first dose of misoprostol.
The researchers comment that they decided to try the sublingual method of administration because of “issues relating to patient preference.” Women in the United Kingdom are apparently less tolerant of repeated vaginal probes than are women in the United States. The authors remark that sublingual misoprostol appeared to be more efficacious than oral misoprostol. “Our sample size was not large enough to address issues of safety,” they write.
46. Wing DA, Tran S, et al. Factors affecting the likelihood of successful induction after intravaginal misoprostol application for cervical ripening and labor induction, Am J Obstet Gynecol 186 (2002):1237-43.
The first two sentences of this paper read as if the safety of misoprostol induction were a foregone conclusion:
“Cervical ripening and labor induction is common practice in modern obstetrics. The use of intravaginally administered misoprostol has become a standard of practice.”
The paper retrospectively reviews a computerized database of 1373 pregnancies in which intravaginal misoprostol was given for cervical ripening and labor induction. Most of the women were handled according to protocols providing for 25 to 50 microgram doses of intravaginal misoprostol, with dosing intervals from 3 to 6 hours. No more than 24 hours of administration was permitted.
Women with unfavorable cervices were included (Bishop scores of 4 or less) and without spontaneous labor or ruptured membranes.
Forty-eight percent of the women had successful induction, defined by birth within 24 hours. Favorable Bishop scores, greater gestational age, and initial cervical dilation were significantly correlated with successful induction. However, the authors write: “In conclusion, knowledge of cervical dilatation, gestational age, or parity provides little practice predictive advantage in determining the dose response to misoprostol for cervical ripening and labor induction.”
Selected comments from the “Discussion” section
Dr. Michael Nageotte, Long Beach, California: Would you comment on the fact that we are only about 13 months after the infamous letter from Searle and only about 8 months after ACOG’s position in the New England Journal of Medicine regarding the safety and efficacy of what I, as well as, I hope, everyone else in this room, considers the most important drug for women of this generation? There was no comment on safety in your paper.”
Dr. Wing: “Overall, our biggest concerns with regard to safety are those of uterine contractile abnormalities and fetal heart rate tracing abnormalities. . . A number of my colleagues have researched oral misoprostol administration in women with rupture of membranes at term. Acceptable effectiveness is seen. There are safety concerns, though, across the board, with orally applied misoprostol for labor induction. . . Basically, misoprostol appears to have an accumulative (sic) effect. Mimi Zieman’s data on the pharmacokinetics of vaginally applied misoprostol indicate there is a rapid uptake of this medication and a long half-life, a long degradation period.”
Women with uterine scars were apparently included in this study.
47. Hall R, Duarte-Gardea, et al. Oral versus vaginal misoprostol for labor induction, Obstet Gynecol 99 (2002): 1044-8.
This west Texas investigation involved a population of predominantly Spanish-speaking women living in the border city of El Paso. Women with previous uterine surgery were excluded.
A total of 107 women with clinical indications for induction were randomly assigned to receive either oral or vaginal misoprostol. The women in the oral arm got 100 micrograms of misoprostol and the women in the vaginal arm 25 micrograms every 3 – 4 hours. If cervical ripening or active labor did not take place, repeated doses were given. These repeated doses could be doubled after the first, according to the discretion of the individual physician.
There were 48 women in the vaginal group and 59 women in the oral group.
Parity was significantly different (P = .04) for the vaginal and oral groups. More of the vaginal group were first-time mothers.
Cesarean rates were similar (17% for the vaginal group versus 15% for the oral).
The authors concluded that oral misoprostol “has the potential to induce labor as safely and effectively as its vaginal analogue.” They remark that they have found “patient resistance to digital exams necessary for the placement of the agent.”
One woman in the oral arm had an atonic uterus (which responded to methergine), while another woman in that group had a retained placenta. In the vaginal group, one woman had a wound seroma at the cesarean incision site. “None of these sequelae can be attributed to the use of misoprostol,” say the authors, without offering evidence for this statement. Certainly, there have been previous reports of uterine atony associated with misoprostol. (Note 12)
48. Sanchez-Ramos, Danner CJ, et al. The effect of tablet moistening on labor induction with intravaginal misoprostol: a randomized trial, Obstet Gynecol 99 (2002): 1080-4.
Sanchez-Ramos and colleagues begin their article with statements pointing to the popularity, “safety and efficacy” of the drug for labor induction: “Misoprostol has become one of the most important medications for labor induction in the United States and other parts of the world. . .However, misoprostol’s optimal dose and route of administration remain uncertain.”
The authors wanted to find out whether a dosage of 50 micrograms of misoprostol moistened with 3% acetic acid and administered intravaginally every 4 hours is more efficacious for labor induction than a similar dosage regimen using dry tablets.
Of the 162 women in the study, 80 were in the dry group and 82 in the moist group. There was no significance between the groups in interval to vaginal birth. Besides this, there were no statistical differences with respect to need for oxytocin, number of women giving birth after a single dose, labor complications, mode of birth or perinatal outcomes.
49. Carlan SJ, Blust D, et al. Buccal versus intravaginal misoprostol administration for cervical ripening, Am J Obstet Gynecol 186 (2002): 229-33.
The study was planned to compare the efficacy of misoprostol administered in the mouth to the intravaginal route. One hundred fifty-seven women were randomized into two groups. The mouth group was given two first doses of 200 micrograms; the third and subsequent doses were increased to 300 micrograms, to a maximum of 1600 micrograms. The vaginal group received 50 micrograms for 2 doses, with the dose being increased to 100 micrograms for the rest of the study (up to a total of 500 micrograms). The dosage interval was 6 hours.
Sixty-three percent versus 67% gave birth vaginally within 24 hours. Tachysystole was higher in the mouth group (38%) than in the vaginal group (19%; P = .01.
Six percent of the women in the mouth group needed urgent cesarean section, compared to 3 percent of the vaginal group.
50. Barrilleaux, PS, Bofill JA, et al. Cervical ripening and induction of labor with misoprostol, dinoprostone gel, and a Foley catheter: a randomized trial of 3 techniques, Am J Obstet Gynecol 186 (2002): 1124-9.
This study was designed to compare the efficacy of three different techniques of cervical ripening and induction. Three hundred thirty-nine women were randomized into three groups. Group one got the supracervical Foley catheter with intravaginal dinoprostone gel. Group two got the supracervical Foley catheter with 100 microgram doses of misoprostol. Group three got serial 100 microgram oral doses of misoprostol.
Women were included in this study only if they had an unscarred uterus.
No significant differences were found in the time from initiation of induction to birth among the 3 groups. Likewise, similar percentages of women from each group required oxytocin. Cesarean rates were also roughly equivalent, ranging from 29 – 32%. Fifty to 68% of women had epidurals, with the Foley/gel group requiring the highest percentage. The highest cesarean rate (32%) was in the Foley/misoprostol group.
The authors comment: “It should be noted that our goals in providing cervical ripening and induction of labor may differ considerably from that of many other venues of care. In most units, including ours, a premium is placed on obtaining the highest rate of vaginal delivery in the shortest possible period of time. This avoids potential problems with labor unit congestion and also negates the increased risks of a prolonged induction (such as chorioamnionitis or uterine atony with hemorrhage).” Actually, Wing et al’s 1996 study (Note 12) demonstrates well that one of the risks of misoprostol induction is uterine atony with profuse hemorrhage.
In light of the authors’ comments, it is interesting to note that the chorioamniotis rates in this study were 7.9% in the Foley/gel group, 11% in the Foley/misoprostol group, and 4.2% in the oral misoprostol group.
51. Frohn WE, Simmons, S, et al. Prostaglandin E2 gel versus misoprostol for cervical ripening in patients with premature rupture of membranes after 34 weeks, Obstet Gynecol 99 (2002): 206-10.
This study compared intravaginal misoprostol to dinoprostone for cervical ripening in women with premature rupture of membranes after 34 weeks of gestation.
One hundred nine women were randomized into two groups. Group one got 2.5 milligrams of dinoprostone gel intravaginally, while group two got 50 micrograms of misoprostol intravaginally. The dose was repeated 6 hours later if deemed necessary. If another 6 hours passed without satisfactory results, the women were treated with intravenous oxytocin.
