The Misoprostol/Cytotec Controversy (Part I)
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
Ina May Gaskin, 2005-09-05
For those readers who are curious as to what the medical literature in English has published about the use of the drug misoprostol (brand name: Cytotec) for cervical ripening or induction, I offer the following brief summary of the articles I was able to obtain. For your convenience, I have listed these articles in chronological order of their publication.
Definitions to keep in mind:
Tachsystole (polysystole): Abnormally frequent contractions, more than 5 per 10 minutes.
Hypertonus – A contraction with a duration of more than 90 seconds.
Exaggerated uterine response – Hypertonic or tachysystolic contractions.
Hyperstimulation – Exaggerated uterine response with late fetal heart rate decelerations or fetal tachycardia (more than 160 beats per minute).
1. Margulies M et al. Misoprostol to induce labor [letter], Lancet 339 (1992):64.
This letter is the first mention in English of the use of misoprostol to induce labor. Its Argentinean authors mention two studies published in 1991 in Spanish “that corroborate the efficacy of vaginal misoprostol in inducing uterine contractions during the third trimester of pregnancy,” using an initial dose of 50 micrograms in the posterior vaginal fornix, followed by increasing doses of 50 micrograms every 2 hours until the desired level of uterine activity is reached or a maximum of 600 micrograms of the drug is reached.
We are not told the number of participants in the first study, nor are we told anything about the group with which the misoprostol group was compared. We are told that more than half of the women in the misoprostol group responded to a single 100-microgram dose of the drug.
The authors do tell us there were 64 women in the second study they mention in their letter to Lancet. Slightly more than half were given misoprostol, while the rest were given intravenous oxytocin.
Findings: “Side effects were not observed, but polysystole (more than 5 contractions in 10 min.) was more frequent in the misoprostol group (17%) than in the oxytocin group (12%); however, no fetal distress was associated with this condition in either group.”
However, this last statement appears in contradiction to another statement appearing in their letter. The sentence: “In the misoprostol group, induction was successful in 26 (79%) patients; 1 patient was delivered by caesarean section because of fetal distress.” [My italics] No explanation is given for this discrepancy.
Three women in the oxytocin group also had caesareans because of fetal distress.
2. Fletcher HM, Mitchell S et al. Intravaginal misoprostol as a cervical ripening agent, British J of Obstet Gynaec 100 (1993): 641-4.
This Jamaican study illustrates how little thought was given to dosage in the earlier trials of misoprostol for induction of labor. Participants in this double-blind clinical trial were given 100 microgram doses of misoprostol inserted vaginally (twice the amount given in the Jamaican study). The misoprostol group was compared with a group of women given a placebo that looked similar to the misoprostol white powder which was used.
Incidentally, this study is one of the few I found which involved the use of a placebo; most comparison groups in studies which followed this one were given some other induction drug.
24 women were given misoprostol.
21 were given the placebo.
If the women in either group hadn’t started labor within 12 hours, they were sent to the labour ward for oxytocin induction.
Results: the women in the misoprostol group began labor sooner than in the placebo group (15.6 hours, compared with 43.2 hours).
Fewer women in the misoprostol group required oxytocin under the standard mentioned above.
One woman in the misoprostol group had tachysystole (hyperstimulation of the uterus).
Two babies in the misoprostol group had meconium staining, compared with no babies in the placebo group.
Caesarean and forceps rates were similar in both groups.
The authors stress that uterine activity should be closely monitored following use of misoprostol.
3. Fletcher H, Mitchell S et al. Intravaginal misoprostol versus dinoprostone as cervical ripening and labor-inducing agents, Obstet Gynecol 83 (1994): 244-7.
Here we have the same Jamaican authors studying 45 women, 32 of whom were given misoprostol, with an additional 31 women being given dinoprostone to ripen the cervix and induce labor. Again, the dose was 100 micrograms of misoprostol, inserted vaginally. According to the authors, “There were no significant differences in induction-to-delivery interval, spontaneous labor rates, type of delivery, fetal outcome, or maternal complications” between the two groups of women.
Women with previous scars on their uteri were excluded from this study, a precaution, as we will see, which was not observed in many later studies. The authors say that they obtained informed consent from all of the women, but we are given no details as to whether the women were told that the drug had not yet been tested on anyone in the English-speaking world by 1992, the date of this study.
Findings: The authors concluded that misoprostol was effective in cervical ripening, as the mean change in the Bishop score of the misoprostol group was significantly higher than in the dinoprostone group. They decided that misoprostol was as effective as dinoprostone for ripening the cervix and inducing labor. (At the time, neither drug was approved for this use by the U.S. Food and Drug Administration, but by 1995, dinoprostone’s manufacturer had received FDA approval). Misoprostol’s manufacturer has never applied for US FDA approval and says that it never will.
The authors mentioned how cheap misoprostol is in both of their articles, adding that misoprostol does not require refrigeration.
“Based on this study,” they write, “it is tempting to conclude that misoprostol is as safe as dinoprostone, but the number of patients was too small and Apgar scores too crude to establish safety conclusively. One of the greatest drawbacks of misoprostol is our limited knowledge about its safety, especially in regard to uterine hyperstimulation with fetal distress, a known complication of all PGs [prostaglandins], including dinoprostone.”
4. Sanchez-Ramos L, Kaunitz AM et al. Labor induction with the prostaglandin E1 methyl analogue misoprostol versus oxytocin: A randomized trial, Obstet Gynecol 81 (1993):332-36.
Sixty-four women were given 50 micrograms of misoprostol every 4 hours, to a maximum dose of 600 micrograms. Five of the women in the misoprostol group had had prior cesareans, compared with ten women in the dinoprostone group.
Nearly 11% of the women in the misoprostol group experienced hyperstimulation, compared with 4.6% in the oxytocin group.
5. Chuck FJ, Huffaker, BJ. Labor induction with intravaginal misoprostol versus intracervical prostaglandin E2 gel (Prepidil gel): Randomized comparison, Am J Obstet Gynecol 173 (1995):1137-42.
In this Los Angeles study, 49 women were given 50 micrograms vaginally and compared with 50 women who received prostaglandin E2 gel (Prepidil).
The authors found that their misoprostol group had shorter times from the start of induction to vaginal delivery (11.4 vs 18.9 hours).
Cesarean rates were high for both groups: 20%.
The authors mention the 2% risk of hyperstimulation that their study showed for misoprostol and add: “Although hyperstimulation remains a concern, these series suggest that hyperstimulation does not appear to translate into increased risk of operative delivery or low Apgar scores at birth.”
“No uterine ruptures occurred in our series, nor have any been reported by others. We allowed patients with prior low-transverse cesarean section to participate in the study, but no generalization can be drawn regarding the safety of misoprostol in patients with prior cesarean section because of the limited sample size.”
My comment on this statement: The first reports of uterine rupture in women given misoprostol for the induction of labor were published in 1997. (See Notes 13 and 14) Several more followed in subsequent studies, especially in women with prior cesareans. (See Notes 28,30,32,35,36.)
6. Wing DA, Jones MM et al. A comparison of misoprostol and prostaglandin E2 gel for preinduction cervical ripening and labor induction, Am J Obstet Gynecol 172 (1995):1804-10.
This Los Angeles study involved 68 women given misoprostol, compared with 67 given dinoprostone. No women with prior scars were included in either group. The women in the misoprostol group were given 50 micrograms of the drug every 3 hours, to a maximum of 300 micrograms.
“Tachysystole occurred significantly more in the misoprostol-treated patients (36.7%) than in the dinoprostone-treated patients (11.9%) (p <0.001) Forty percent (10/25) of the misoprostol-treated patients who experienced tachysystole did so after receiving their first dose of this medication. An additional 11 patients exhibited tachysystole after the second dose.”
Approximately one quarter of the women in both groups had abnormal FHR patterns during labor after being medicated.
“Meconium passage occurred significantly more in the misoprostol treated group—27.9% versus 10.5% (p <0.05). The occurrence of thick meconium passage was 13 of 68 (19.1%) in the misoprostol-treated group versus five of 67 (7.5%) in the dinoprostone-treated group.”
I found the authors’ comments in the last section of this article interesting:
“Bothersome was a significant incidence of uterine contractile abnormalities in the misoprostol arm of this study. Although we found no significant differences between the two study groups in intervention for abnormal FHR patterns, tachysystole occurred three times more frequently in the misoprostol-treated group. Although 10 of the 25 misoprostol-treated patients who experienced tachysystole did so after the first dose of the medication, an additional 11 patients had tachysystole after the second dose. This finding suggests that the medication may have a cumulative effect and suggests the need for an altered dosing regimen,” say the authors.
They conclude their article with this cautionary note: “Because of these untoward side effects, this dosage of misoprostol is not recommended for preinduction cervical ripening and induction of labor.”
This dosage, by the way, is half that used in the two Fletcher studies. (Notes 2 and 3)
7. Wing DA, Rahall A, et al. Misoprostol: An effective agent for cervical ripening and labor induction. Am J Obstet Gynecol 172 (1995)1811-6.
The same group of researchers as in the study reported just above reported on this trial which compared intravaginal misoprostol to intracervical dinoprostone. One hundred thirty-eight women were given misoprostol and 137 the dinoprostone. No women with prior uterine scars were included in the study. A dosage of 25 micrograms of misoprostol was given every 3 hours with a maximum of 8 doses.
The cesarean rate for the misoprostol group was 20.3%; for the dinoprostone group the rate was 27.7%.
The authors comment that when they previously used misoprostol in 50 micrograms every 3 hours (see Note 2), they “found an unacceptable higher frequency of uterine tachysystole and thick meconium passage in patients treated with this medication compared with those treated with prostaglandin E2 gel.”
Later oxytocin augmentation was considered necessary more often in the misoprostol-treated group than the dinoprostone-treated group (45.7% vs 72.6%).
As to the time difference from the start of induction to birth, the misoprostol group was approximately 5 hours quicker than the dinoprostone group.
Twice as many cesareans were performed for abnormal fetal heart tracings in the misoprostol group as in the dinoprostone group.
Nearly 1/4 of the women in the misoprostol group had labors in which abnormal fetal heart rate patterns occurred.
Meconium-stained fluid was more frequent (17.4%) in the misoprostol group than in the dinoprostone group (13.9%).
The authors add an interesting statement under the “Comment” section at the end of their article:
“Some patients appear to be quite sensitive to misoprostol, demonstrating prolonged contraction responses after a dose of the agent, sometimes in excess of 20 hours after the drug.” [Italics mine]
8. Ngai SW, Wing KT et al. Cervical priming with oral misoprostol in pre-labor rupture of membranes at term, Obstet Gynecol 87 (1996);923-6.
This Hong Kong study included 39 women treated with 200 micrograms of misoprostol given orally, compared with 41 women given a placebo of 50 micrograms of vitamin B6. This was the first randomized, double-blind, placebo-controlled study on the effect of oral misoprostol in women with pre-labor rupture of membranes. Women who had had prior cesareans were excluded from this study. All of the women had had spontaneous rupture of membranes and singleton pregnancies.
One of the 39 women in the misoprostol arm of the study showed late decelerations in the fetal heart rate 15 minutes after ingesting the medication, with contractions taking place every 2 minutes. The cervix was still closed, and an emergency cesarean was performed. The authors found that misoprostol was effective for cervical ripening. “In this study, the use of misoprostol did not lead to a reduction in cesarean delivery rate.” The main outcome measures tracked in this study were induction rate, duration of labor, mode of delivery, and leaking-to-delivery interval.
Cesarean rates in this study were lower than would generally be found in U.S. practices during the same period: 8% in the misoprostol group and 7% in the placebo group.
9. Varaklis K, Gumina R et al. Randomized controlled trial of vaginal misoprostol and intracervical prostaglandin E2 gel for induction of labor at term, Obstet Gynecol 86 (1995):541-4.
Thirty-six women were given 25 micrograms of misoprostol vaginally every 2 hours and were compared with 33 women given dinoprostone gel (0.5 micrograms) at 6-hour intervals.
The misoprostol group tended to go into labor more quickly. Three women had hypertonus of the uterus in the misoprostol group. “In our study,” the authors remark, “excessive uterine activity was seen only in the misoprostol group.” The contractions in these cases occurred at 1-minute intervals.
In the discussion at the end of the article, the authors write: “If all three [cases] are considered to be excessive uterine activity, our incidence of three of 36 (8.3%) cases appears to improve on the 34% incidence reported by Sanchez-Ramos et al [see note 4.] but sufficient to raise concerns that our dosing interval is not ideal. Excessive uterine activity was never seen until after a second 25-microgram dose of vaginal misoprostol. The drug is long-lasting and very potent when administered vaginally in late pregnancy.” [Italics mine]
10. Mundle WR and Young DC. Vaginal misoprostol for induction of labor: A randomized controlled trial, Obstet Gynecol 88 (1996):521-5.
This Newfoundland study involved 111 women given 50 micrograms of misoprostol vaginally, compared to 111 women given dinoprostone every 6 hours with artificial rupture of membranes and intravenous oxytocin. Women with prior uterine surgery were excluded from the study.
There was no blinding in this study, since the method of induction was apparent to the staff in each case.
Misoprostol resulted in shorter time to vaginal birth.
There were more 3rd and 4th-degree lacerations in the misoprostol group, as well as more lacerations generally.
More women in the misoprostol group had meconium staining (35 of 111 women).
11. Wing DA, Rahall A et al. Misoprostol: An effective agent for cervical ripening and labor induction. Am J Obstet Gynecol 172 (1995):1811-6.
This paper describes a study that randomized women into two groups. Group one (138 women) got 25 micrograms of misoprostol (vaginally) given in 3-hour intervals, and group two (137 women) got intracervical dinoprostone. The misoprostol group tended to go into labor about 90 minutes more quickly. More cesareans were necessary in the misoprostol group for abnormal fetal heart rates than in the dinoprostone group. There was more meconium staining in the misoprostol group (17.4%) than in the dinoprostone group (13.9%).
The next-to-last paragraph of the paper is a warning: “Some patients appear to be quite sensitive to misoprostol, demonstrating prolonged contraction responses after a dose of the agent, sometimes in excess of 20 hours after the drug.”
12. Wing, D, Paul RH. A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 1996;175:158-64.
In this study, Dr. Wing and colleagues looked at 25 micrograms of misoprostol given every 3 hours compared with the same dosage given every 6 hours.
None of the 520 women in this study had had previous uterine surgery.
Here we have the first study to report some major bad results from the use of misoprostol for labor induction.
There was one maternal death from amniotic fluid embolism (AFE). The first-time mother was given a single 25-microgram dose 9 hours before her collapse. No reason was given to explain why subsequent doses were withheld. Just before her death, her amniotic sac was ruptured, an intrauterine pressure catheter had been placed, and an epidural administered. An emergency cesarean was then performed for fetal distress. During the operation, the woman suffered cardiopulmonary arrest and was resuscitated. Soon afterward, she had a second, this time fatal cardiopulmonary arrest. Incidentally, I found no references to this woman’s death in the text of the many studies that followed publication of this one. While no more cases of AFE have appeared in misoprostol studies published in English since this one, the Food and Drug Administration has collected at least 19 such reports. (See Note 56)
Two other cases in this series involved serious maternal complications. Two women had cesarean hysterectomies to treat hemorrhage because of uterine atony. Each of these women had been given a single 25-microgram dose of misoprostol. No explanation is given why subsequent doses were withheld, but the authors do say that one of the 2 cases of uterine atony took place 13 hours after the single dose and the other 30 hours after that dose. Neither woman’s hemorrhage responded to “aggressive medical, including therapy for atony, including oxytocin, methergine, and prostaglandin F.”
The authors also reported a high rate of FHR abnormality—about 1/3 of group had this problem.
The authors write: “We were unable to identify any characteristics of the patients who demonstrated tachysystole after the initial dose, which may have predisposed them to the development of the excessive uterine activity. This may suggest that some patients are sensitive to the effects of the medication and therefore demonstrate this abnormal response.”
“Bothersome was the higher number of patients who had tachysystole in the 3-hour regimen with a second dose (n=15) versus those in the 6-hour regimen (n=5),” they add.
“Disappointing is the 20% cesarean delivery rate in subjects enrolled. In spite of the positive findings associated with administration of misoprostol for labor induction in patients with unfavorable cervices, we have not diminished the overall cesarean delivery rate compared with the national average, and a higher abdominal delivery rate remains inherent when labor induction is undertaken.”
“Additionally, the maternal death occurring in this study deserves further discussion. It appears unlikely that misoprostol had a role in the etiology of this catastrophic event because it had been given 9 hours before.”
Remember that this study is the one that includes the two atonic uteri, complications that also took place many hours after the drug was administered.
13. Bennett B. Uterine rupture during induction of labor at term with intravaginal misoprostol, Obstet Gynecol 89 (1997):832-3.
This case study was reported by Dr. Bennett, from the University of Florida College of Medicine, Gainesville, Florida. The mother was a 34-year-old multigravida, induced at 39 weeks with intravaginal misoprostol. The woman had had three term vaginal births followed by a D&C for spontaneous first-trimester abortion. On vaginal exam, she had a closed, uneffaced cervix and an unengaged fetal head. Fetal growth was judged poor, a reason given for the induction. Five hours after she was given a second 25-microgram dose after a 3-hour interval, the FHR suddenly dropped and an emergency cesarean was performed. Terbutaline administration was ineffective.“Hysterectomy and left salpingo-oophorectomy were necessary to control bleeding from a 15-cm posterior uterine wall rupture.” According to the author, “Even using the lower misoprostol dose, hyperstimulation syndrome (uterine hyperactivity associated with fetal distress) and uterine rupture may occur.”
Three hours after the second dose of misoprostol, the woman was experiencing intermittent tachysystole, so a third dose was withheld. She complained of an urge to push. Two hours later, fetal bradycardia developed, which was unchanged despite position changes and oxygen administration. Vaginal exam revealed a cervix at 2 cm dilation, blood in the vagina and a floating fetal head. The decision was made for an emergency cesarean.
After delivery of the baby and the placenta, the large rent in the posterior wall of the uterus was discovered, bleeding profusely. Patient’s post-op hematocrit 14.5%. Blood loss 2000 mL.
14. Farah L, Sanchez-Ramos L, et al. Randomized trial of two doses of the prostaglandin E1 analog misoprostol for labor induction. Am J Obstet Gynecol 1997;177:364-71.
This study was based in Jacksonville and Gainesville, Florida. The two comparison groups were both given misoprostol—the first getting 25 micrograms every 3 hours and the second 50 micrograms every 3 hours. There were 192 women in the first group and 207 in the second.
Women with scarred uteri were excluded from the study.
As you might expect, the group with the larger dosage had a shorter time from the start of induction to birth (approximately a 1 1/2 hour difference).
There was a higher cesarean rate in the higher dose group: 15.9%, compared with 12%.
Women in the lower dose group were more likely to be given oxytocin augmentation than the higher dose group (27.1% vs 16.9%).
Both groups had relatively high operative delivery rates (vacuum extraction or forceps): 26% in the lower dose group and 28.5% in the higher dose group.
Comments from physicians attending the meeting at which this paper was first presented:
• Dr. Ernest H. Brown, Lumberton, North Carolina. “I recently saw misoprostol used in third-world countries in 50 microgram doses by family practitioners. There was no monitoring and there were no intravenous fluids. We followed up tachysystole by palpating the abdomen. We saw some ruptured uteri.”
Dr. Farah: The only major adverse outcome that I am aware of during our institution’s use of misoprostol for labor induction occurred in a patient who was not in the study protocol. The unfortunate incident occurred when three repeated doses of misoprostol were given when the patient was already having three contractions in 10 minutes by external monitor. This caused uterine hyperstimulation. An emergency cesarean section was performed, at which time uterine rupture was noted.”
The Misoprostol/Cytotec Controversy, Part II
