(continued from Part I)
A Summary of Articles Published in English about Misoprostol (Cytotec) for Cervical Ripening or Induction of Labor, Part II
By Ina May Gaskin, CPM
Originally published by www.inamay.com, 2005-09-05
15. Toppozada MK, Anwar MYM et al. Oral or vaginal misoprostol for induction of labor, International J Gynecol Obstet 56 (1997):135-9.
The study was carried out in Alexandria, Egypt. Twenty women received 100 micrograms of vaginal misoprostol every 3 hours, while the other 20 were given the same dose orally. If labor of sufficient strength did not follow, the dose was doubled! [Exclamation point mine.]
All the women in this study were pregnant with their first through their fourth pregnancies at gestations between 37 and 42 weeks. Those with prior uterine scars may have been included, but we are not given a number.
The authors write: “Oral administration is easier and more convenient for the patients than the vaginal route and when safety is documented it may be developed for self-administration at home prior to arrival at hospital.” They go on, “It seems that we have to pay a little more in terms of slightly increased abnormal CTG tracings if we want to get a higher success rate in a shorter induction time.”
Little information is given regarding maternal complications, but six women experienced hypertonus during labor.
16. Buser D, Mora G et al. A randomized comparison between misoprostol and dinoprostone for cervical ripening and labor induction in patients with unfavorable cervices, Obstet Gynecol 89 (1997):581-5.
Still another dosage regimen was used in this study, carried out in St. Louis, Missouri. Seventy-six women were given intravaginal misoprostol in 50 microgram doses every 4 hours. They were compared to a group given dinoprostone intracervically every 6 hours. No women with prior cesareans were included.
Misoprostol was found to be more effective than dinoprostone for cervical ripening, but there were also more abnormal heart tracings and a higher incidence of cesareans in the misoprostol group.
The authors comment: “It would be a mistake to dismiss the high incidence of cesarean delivery secondary to FHR alterations associated with hyperstimulation as an event particular to this study. We believe that our results are representative of what may happen if the use of misoprostol expands rapidly in this country, where the largest proportion of obstetric care is provided by private obstetricians in community hospitals.”
17. Carlan SJ, Bouldin S et al. Extemporaneous preparation of misoprostol gel for cervical ripening: a randomized trial. Obstet Gynecol 90 (1997) 911-5.
Tampa, Florida was the site for this study, which compared 234 women given misoprostol tablets intravaginally (50 micrograms every 8 hours) to 233 women given the misoprostol in gel form (50 microgram doses). In both groups, after two doses with an 8-hour interval, the amount of the dose was doubled to 100 micrograms. No woman was to receive more than 500 micrograms. Women with prior cesareans (apparently, no matter how many) were included in the study, as long as their scars were low transverse ones and their membranes were ruptured.
The researchers concluded that intravaginal misoprostol gel is associated with fewer uterine contractile abnormalities than the tablet form of the drug but results in a slower time to labor or delivery.
Fifteen percent of the women receiving misoprostol in tablet form required terbutaline to correct hyperstimulation, while 7.3% of those in the misoprostol gel group received terbutaline.
One curious sentence that caught my attention—the last in the “Results” section of the article. “There were no uterine ruptures or maternal complications believed to be related solely to misoprostol.” Hmmm. How many ruptures in all were there? We aren’t told. One wonders why the editorial committee of this journal failed to ask this question.
18. Surbek DV, Boesinger H et al. A double-blind comparison of the safety and efficacy of intravaginal misoprostol and prostaglandin E2 to induce labor, Am J Obstet Gynecol 177 (1997):1-18-23.
This Swiss study compared women given 50 micrograms of intravaginal misoprostol with those given 3 milligrams of intravaginal dinoprostone. The doses were repeated at 6, 24 and 30 hours after the first dose if active labor had not begun. There were approximately 50 women in each group. Women with prior uterine surgery were excluded.
Results: More women in the misoprostol group gave birth within 24 hours (70% vs 46%). Cesarean rates were similar, as were rates of fetal heart rate problems, tachysystole, hyperstimulation syndrome, fetal outcome, and meconium staining. The authors say that drug-induced maternal side effects were rare and that intravaginal misoprostol is “a safe drug for labor induction with superior effectiveness compared with intravaginal prostaglandin E2.” He add that “the somewhat higher incidence of meconium staining in the misoprostol group could be a point of concern, but the difference was not statistically significant and all other fetal outcome parameters favored misoprostol.”
19. Wing DA, Ortiz-Omphroy G. A comparison of intermittent vaginal administration of misoprostol with continuous dinoprostone for cervical ripening and labor induction, Am J Obstet Gynecol 177 (1997):612-8
Another Los Angeles study. Ninety-nine women were randomized into the misoprostol group (which received 25 micrograms every 4 hours), with 101 going to the dinoprostone group. The researchers found similar incidences of meconium passage, Apgar scores, and admissions to the neonatal intensive care unit. There were no women with scarred uteri in either arm of this study.
The authors concluded that vaginally administered misoprostol is as effective as dinoprostone for cervical ripening and induction of labor. “Incidence of uterine tachysystole with misoprostol every 4 hours was significantly less than with dinoprostone,” they wrote.
20. Windrim R, Bennett K et al. Oral administration of misoprostol for labor induction: A randomized controlled trial. Obstet Gynecol 89 (1997):392-7.
This Newfoundland study assigned 275 women randomly into two groups: one received 50 micrograms orally every 4 hours, while the other was treated according to established protocol (physician-chosen combinations of intracervical or vaginal prostaglandins every 4-6 hours, artificial rupture of membranes and intravenous oxytocin). Women with prior uterine surgery were excluded from the study.
No significant differences were noted between the two arms of the study.
21. Kramer FL, Gilson GJ et al. A randomized trial of misoprostol and oxytocin for induction of labor: safety and efficacy. Obstet Gynecol 89 (1997):387-91.
New Mexico was the site of this study. One hundred thirty women requiring induction were randomized to receive either intravenous oxytocin or 100 micrograms of misoprostol, given intravaginally every four hours until the woman was judged to be in active labor. “The 100-microgram dose was selected because of the ease of accurately obtaining such a dose.”
Apparently, the researchers in this study did not take into account the possibility that a 100-microgram dose might be harmful to some women or their babies. (Here, it is relevant to mention that the 100-microgram dose was decided upon by G.D. Searle, the drug’s manufacturer, in conjunction with its testing of the drug for its use to prevent peptic ulcers in non-pregnant patients taking non-steroidal anti-inflammatory drugs, while seeking FDA approval for the drug in the late 1980s. Those who advocate using the drug in smaller doses are forced to cut the small white tablets into halves, quarters or into powder, which is hardly the ideal way to obtain an appropriate dose of any drug).
The most significant findings of this study were that, compared with oxytocin, misoprostol resulted in a shorter induction-to-birth interval, less frequent use of epidural analgesia, and less expense to the hospital. On the other hand, misoprostol was significantly more likely to result in overstimulation of the uterus. Terbutaline was used in one of every five of the misoprostol-induced labors, compared with only three of every hundred of the oxytocin-induced labors. Seventy percent of the women in the misoprostol group experienced uterine tachysystole.
The authors give some discussion to the additional costs that might be associated with misoprostol use by noting differences between the costs of vaginal birth and cesareans, and those for normal newborn nurseries compared to intensive care nurseries.
Women who had had prior uterine surgery were excluded from the study.
22. Sanchez-Ramos L, Chen AH et al. Labor induction with intravaginal misoprostol in term premature rupture of membranes: a randomized study, Obstet Gynecol 89 (1997):909-12.
Here we have another study from Jacksonville, Florida, in which 141 women with term premature rupture of membranes were assigned randomly to either a group receiving intravaginal misoprostol or one receiving intravenous oxytocin.
Women with prior cesareans were excluded from the study.
“Uterine tachysystole occurred more frequently with misoprostol than with oxytocin (28.6% compared with 14.0%; P < .04).”
23. Gottschall DS, Borgida AF, et al. A randomized clinical trial comparing misoprostol with prostaglandin E2 gel for preinduction cervical ripening, Amer J Obstet Gynecol 177 (1997):1067-70.
This Connecticut study involved 75 women allocated either to receive 100 micrograms of intravaginal misoprostol or 5 milligrams of intravaginal dinoprostone gel. Women with a prior uterine scar was excluded from the study.
In both arms of the study, those women who did not go into labor with one dose within 6 hours were given oxytocin. “The mean time to delivery and the need for oxytocin was significantly less for subjects receiving misoprostol.”
The authors write: “In our series, with use of a single 100 microgram dose of intravaginal misoprostol, we had a uterine tachysystole/hypertonus rate of 15.7%. The accumulated effect of multiple doses of misoprostol, as reported in other series, may have a resulting increase in uterine tone. . . Although repetitive dosing may reduce the need for oxytocin, we felt a cumulative drug effect could result in a dangerous degree of uterine hyperactivity.”
24. Bennett KA, Butt K, et al. A masked randomized comparison of oral and vaginal administration of misoprostol for labor induction, Obstet Gynecol 92 (1998):481-6.
Back to Newfoundland. This study featured 206 women randomly divided into two groups. One group received 50 micrograms of intravaginally administered misoprostol every 4 hours, while the other got the same dose orally with the same dosage interval.
Differences between the two groups weren’t significant in cesarean rate, epidural use or neonatal outcomes. The vaginal group had more frequent tachysystole and hyperstimulation.
Women with prior uterine scars were not included in this study. The hospital where the study was carried out had an induction rate of just over 20% during the study period.
25. Wing DA and Paul RH. Induction of labor with misoprostol for premature rupture of membranes beyond thirty-six weeks’ gestation, Amer J Obstet Gynecol 179 (1998):94-9.
One hundred ninety-seven women slated to give birth at Women’s and Children’s Hospital in Los Angeles took part in this study. Ninety-eight received intravaginal misoprostol in 25 microgram doses and ninety-nine received intravenous oxytocin. Women who got misoprostol and didn’t have a contraction pattern of more than 3 contractions in a 10-minute period within 6 hours received a second dose, for a maximum of 50 micrograms. Each of the women in the study had premature rupture of membranes beyond 36 weeks’ gestation. Women with prior uterine scars were excluded.
The authors comment: “We were unable to reduce the cesarean delivery rate in women with premature rupture of membranes by administering misoprostol rather than oxytocin for labor induction. . . We were also unable to reduce the numbers of women receiving antimicrobial therapy for the diagnosis of chorioamnionitis by administering misoprostol rather than oxytocin. Intravaginal misoprostol administration may have contributed to the relatively high frequency of chorioamnionitis in this treatment arm.” Slightly more than 1/4 of the babies in the misoprostol arm were sent to the neonatal intensive care nursery.
26. Sanchez-Ramos L, Peterson DE, et al. Labor induction with prostaglandin E1 misoprostol compared with dinoprostone vaginal insert: a randomized trial, Obstet Gynecol 91 (1998):401-5.
Two hundred twenty-three women from northern Florida were assigned randomly to one of two treatment groups. The first group received 50 micrograms of intravaginal misoprostol every 3 hours, and the second received 10 milligrams of dinoprostone in a single intravaginal insert for 12 hours. Women with prior uterine surgery were not included in the study.
There were no statistical differences between the two groups with regard to vaginal birth within 24 hours, complications in labor, and bad neonatal or maternal outcomes, say the authors. The interval between the start of induction and birth was significantly shorter in the misoprostol group. There was significantly more uterine tachysystole in the misoprostol group than in the dinoprostone group (21.3% vs 7.0%).
27. Adair CD, Weeks JW et al. Oral or vaginal misoprostol administration for induction of labor: a randomized, double-blind trial, Obstet Gynecol 92 (1998):810-3.
This study took place in Shreveport, Louisiana, under the auspices of the Louisiana State University School of Medicine. In their introductory paragraph, the authors make the following rather misleading statement about the use of misoprostol for labor induction: “Doses of 50 micrograms to 200 micrograms have been reported to be efficacious and safe,” citing the studies summarized in my Notes 8 (39 women who received 200 micrograms orally), 14 (20 women, who received 100 micrograms, not 200), and 19 (137 women who received 50 micrograms). Efficacious, maybe, but how can a study of 39 women be cited as indicative of safety?
The study design allocated women randomly to one of two groups: one receiving 200 micrograms of oral misoprostol and the other receiving half a tablet of 100 microgram intravaginal misoprostol. Placebos were given women in both groups to blind the study. Doses were repeated every 6 hours until labor was well established.
The authors’ main conclusion was that oral administration of 200 micrograms of misoprostol (the largest dose tablet provided by the manufacturer) was no more efficacious in inducing labor but was associated with more frequent abnormal uterine contractions.
No mention was made in this paper of whether the patients involved in the study were informed that misoprostol has never been approved by the FDA for use in pregnant women. Women with scarred uteri were excluded from the study.
The authors write: “However, oral administration was associated with a significantly higher occurrence of the hyperstimulation syndrome. While no neonatal or maternal compromise was observed, this high rate of hyperstimulation indicates that a 200 microgram oral dose should be prescribed for nonviable pregnancies. The only other report utilizing an oral 200 microgram dose approach for indicated inductions (Ngai et al, Note 
reported favorable neonatal outcomes, but failed to report the incidence of tachysystole and/or hyperstimulation syndrome.”
28. Sciscione AC, Nguyen L, et al. Uterine rupture during preinduction cervical ripening with misoprostol in a patient with a previous caesarean delivery, Aust NZ J Obstet Gynaecol 38 (1998):96-7.
This important paper begins with the following editorial comment: “We accepted this case for publication because it indicates that misoprostol can cause uterine rupture. It is our understanding that a number of trials of misoprostol for induction of labour include patients with a prior Caesarean section which is a further reason for heeding this case report. In the past 40 years or so the introduction of each new oxytocic agent to induce labour, whatever the route of administration, ranging from intramuscular, intravenous, sublingual, intranasal spray, intraamniotic, extraamniotic, vaginal and oral has subsequently been followed by reports of rupture of the uterus. It would seem that misoprostol is no exception to former preparations.”
This case study was submitted by a U.S. physician from Delaware. We might wonder why it was the Australian-New Zealand Journal of Obstetrics and Gynaecologists that published this report, not a U. S. journal. Was it submitted and refused? It’s not possible to answer this question from the information given in this paper.
The 26-year-old woman had had 3 previous pregnancies and 2 previous low transverse caesareans. She wanted to give birth vaginally to this baby. She was given 50 micrograms of misoprostol every 4 hours to a maximum of 3 doses. Within 1 hour of the second dose, she experienced uterine hyperstimulation, which resolved after 20-30 minutes. Eight hours later, the baby experienced a prolonged heart rate deceleration lasting 4 minutes “after resuscitative manoeuvres” (what might these have been?). The FHR recovered for approximately an hour, then went through a period of “occasional, moderate variable decelerations, with good variability in between.” At full dilation, there was a dramatic loss of station (the head had been at +2 station) and fetal bradycardia. An emergency caesarean was performed, revealing that the baby had been extruded through a large uterine perforation at the site of the previous caesarean delivery scar.
The baby survived and the woman’s uterus was repaired.
The authors write that they began a randomized prospective trial at their hospital (it’s unclear whether the hospital was in Pennsylvania or Delaware), hoping to find out whether misoprostol or the Foley bulb would be more efficacious for preinduction cervical ripening. They cite two studies published in German that reassured them about the safety of using dinoprostone (a prostaglandin E2 preparation) in women who had had prior cesareans, extrapolating that this “safety factor” would also apply to misoprostol (prostaglandin E1 analogue). They also cited Chuck et al’s study (Note 5) and that of Bugalho et al (Gynecol Obstet Invest 1995;39;252-6) for reassurance given that women with prior cesareans need not be excluded from studies of this kind.(Five women in the misoprostol arm of the Chuck study had prior cesareans). Incidentally, the Bugalho study included a woman in her third pregnancy who experienced a posterior uterine rupture. This study made no mention of the number of women with previous uterine surgery.
No mention is made of why the prospective study mentioned in the first paragraph has not been published.
29. Perry KG, Larmon JE, et al. Cervical ripening: a randomized comparison between intravaginal misoprostol and an intracervical balloon catheter combined with intravaginal dinoprostone, Am J Obstet Gynecol 178 (1998):1333-40.
This study took place in Vicksburg, Mississippi. Sixty-two women who were given 25 micrograms of intravaginal misoprostol every 4 hours were compared to 75 women treated with Foley catheter/dinoprostone gel. The Foley/gel group had more rapid cervical ripening, shorter induction to vaginal birth interval, and more vaginal births within 24 hours than the misoprostol group.
Both arms of the study included women with prior cesarean scars (14% in the Foley group and 16% in the misoprostol group). Cesarean rates were similar in both groups: gel, 25%, and misoprostol, 32%.
After commenting that complications were generally similar between the two groups, the authors write,” However tachysystole occurred significantly more often in the misoprostol group than the catheter/gel group (26% vs 6%, p = 0.002). There was also more hyperstimulation and meconium passage in the misoprostol group, with the difference in these areas not quite reaching statistical significance.
Selected comments from the “Discussion” section that follows this formal report in this paper:
Dr. Fredrik F. Broekhuizen, Milwaukee, Wisconsin: “Many recent studies are blurring the distinction between ripening and induction by repeated dosages of the agents or continuous release of the agents.”
“I am wondering if [the authors’] study design did not introduce a bias. In the catheter/gel group the time to achieve “ripening” dosage was limited to 12 hours, whereas in the misoprostol group that time was limited to 24 hours.”
“Unusual in this study of ripening/induction is the absence of “failed” inductions or multiple day inductions. Cesarean section occurred before the active phase of labor in this study in both groups. Is this a reflection of solid indications for induction, need for timely delivery, and a justification for the 25% cesarean section rate?”
“This study did not attempt to address the appropriateness of induction and indications in general. It appears that across the country, induction of labor is performed for broader and less stringent indications. Postdatism and presumed macrosomia [large babies] are questionable indications for induction.”
Dr. Richard Perkins, Las Vegas, Nevada:
“Everybody wants labor to be efficient, and certainly the consumer deserves a short yet safe parturition. The difference may be that the active management of labor is predicated on the patient’s being in labor. I am not sure that we can apply the same urgent agenda to those initiating the process from ground zero. Rockets take much less thrust for course corrections than to lift off. Being delivered by tea time is not a standard of performance in the United States. The extraordinary rates of oxytocin use in the two populations suggests that the average patient finds it hard to satisfy the expectations of these providers.”
“Other questions surround the use of a 25 microgram use dose of misoprostol and that obtained by the quartering of a small 100 microgram tablet by pharmacy personnel. It is equivalent to the attempt we used to make to divide a 20 milligram dinoprostone suppository into four equal parts—it was slippery science at best. If this is the right dose, we should ask for a different preparation from the maker and be glad and surprised if we get it.”
“Finally, it is disturbing that so many neonates went to the neonatal intensive care unit. It is not stated why, though data would seem to exclude depression or acidosis as indications.”
Dr. James R. Scott, Salt Lake City, Utah:
“The question I have is that one of the outcome measures that I did not see was the incidence of infection. I ask this because we looked at this a few years ago and started a study that we discontinued because of a couple of very bothersome infections; a couple of very serious sepsis patients, one diabetic . . .”
30. Wing DA, Lovett K, et al. Disruption of prior uterine incision following misoprostol for labor induction in women with previous cesarean delivery, Obstet Gynecol 91 (1998):828-30.
The authors describe the randomized controlled trial they planned to compare the safety and efficacy of vaginally administered misoprostol with the use of intravenous oxytocin for cervical ripening and labor induction in women with prior cesareans. Each woman to be included in the study had a history of one immediate prior cesarean with no subsequent vaginal birth after cesarean. The women were to be randomly assigned to one of two groups: one being given 25 micrograms of intravaginal misoprostol every 6 hours to a maximum of 4 doses, and one given intravenous oxytocin.
The Misoprostol/Cytotec Controversy, Part III
