A Summary of Articles Published in English about Misoprostol (Cytotec) for Cervical Ripening or Induction of Labor

 

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

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 Argentinian 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 Set 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 mlsoprostol 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 been approved by the Food and Drug Administration for use in pregnancy. "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 E 1 methyl analogue misoprostol versus oxytocin: A randomized trial, Obstet Gynecol 81(1993):33236.

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 misoorostol 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 OA, 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 misoprostoltreated 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, Rahal! 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 prelabor 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. Mundie 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 Gynecol172 (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-Iast 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.” [Italics mine]

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)

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-cmposterior 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.”

15. Toppozada M K, 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 hiah incidence of cesarean delivery secondarv 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.” The authors 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 OS, Borgida AF, et al. A randomized clinical trial comparing misoprostol with prostaglandin E2 gel for preinduction cervical ripening, Arner JObstet Gynecol177 (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, Arner 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 10minute 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 ai, Note 8) 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.

Seventeen women went through the misoprostol side of the study and 21 through the oxytocin side. After a uterine dehiscence in the ninth participant and a uterine rupture in the 38th, the study was cancelled because of safety concerns.

The rupture took place in a healthy 25-year-old woman at 42 weeks’ gestation. After 2 25-microgram doses of misoprostol, she appeared to be in active labor. There were occasional later decelerations. Eighteen hours after her first dose of misoprostol, she was treated with intravenous oxytocin.

Full dilation took place 23 hours after the beginning of induction, She was unable to push her baby out after 2 hours of pushing. With a fetal heart rate of 180 with late decelerations and a maternal temperature of 1 02F, the decision was made to perform a cesarean. Inspection of the uterus showed a 10-cm laceration of the anterior surface of the uterus, along with a laceration of the bladder. “Repair was difficult and required retroperitoneal dissection. The estimated blood loss was 2500 mL.”

The second woman’s dehiscence took place also within the group given misoprostol. She, too, was given 2 doses and entered active labor. Her cervix began to dilate a bit about 21 hours after the first dose. With minimal uterine activity, she was given a third dose. After 6 more hours, her cervix progress to 4 cm. An amnioinfusion was begun, and epidural analgesia administered. This precipitated a sudden drop in the fetal heart rate and a change in the contour of the woman’s abdomen. After emergency cesarean, it became apparent that there had been an 8 cm “transverse uterine defect”, “through which no fetal parts had been extruded.”

According to the authors, “Although neither of the two women with disruption of the prior uterine incision experienced uterine tachysystole with misoprostol in this investigation, the presence of any uterine contractile abnormality in a woman undergoing cervical ripening or labor induction with any medication demands vigilance. Regardless of the agent used, the same clinical guidelines should be applied to patients with and without prior uterine incisions. These include avoidance of uterine hyperstimulation and prompt recognition and treatment of labor abnormalities. Although oxytocin use has been associated with uterine rupture in patients with previous cesarean deliveries, these reports are rare.”

31. Vengalil SR, Guinn DA, et al. A randomized trial of misoprostol and extra-amniotic saline infusion for cervical ripening and labor induction, Obstet Gynecol 91 (1998):7749.

This was the first study I found which mentions a 30% induction rate as normal for “either maternal or fetal reasons.” The two groups compared in this study, which was conducted in Chicago and Birmingham, Alabama, got either 50 micrograms of intravaginal misoprostol or extra-amniotic saline infusion and oxytocin. One hundred twenty women were in the misoprostol arm and 128 in the other arm. Women with prior uterine surgery were excluded.

The authors state that the overall cesarean rate was “only 23%”, “as a result of comparing two effective methods of cervical ripening and labor induction.” They attribute the popularity of misoprostol to its inexpensiveness (36 cents per tablet retail). “However,” they write, “the frequency of tachysystole and hyperstimulation is not inconsequential.”

They continue, “Some women might be inherently more sensitive to misoprostol, thus making it necessary to titrate the individual dose.”

32. Plaut M, Schwartz ML, et al. Uterine rupture associated with the use of misoprostol in the gravid patient with a previous cesarean section, Am J Obstet Gynecol 1999;180:1535-42.

This important article reported on 7 cases of uterine rupture in women with a prior cesarean. The paper includes 4 case reports and brief summaries of the other 3 women. The first 3 women were each given 25 micrograms intravaginally. In case 1, emergency cesarean was performed when the FHR dropped to 60 beats per minute at full dilation. The baby was found outside the uterus. Both her uterus and bladder were torn and repaired. Mother and baby survived.

In case 2, the woman had 2 25 microgram doses and was given an epidural. Rapid progress followed, and the woman reached full dilation, at which time the fetal heart dropped to 60 beats per minute. An emergency cesarean followed and revealed complete separation of the previous uterine incision. The rupture and a large cervical tear were repaired.

Mother and baby survived.

In case 3, the insulin-dependent diabetic mother was given a single 25 microgram dose of misoprostol. One hour after oxytocin was administered to augment labor resulting in cervical dilation, the woman experienced severe abdominal pain. Emergency laparotomy was performed, which revealed a complete separation of the uterine scar, with both the baby and the placenta floating free outside the uterus. The mother’s uterus was repaired, but the baby died in the intensive care unit.

In case 4, the uterine rupture occurred after a single 25 microgram dose of misoprostol. There were no decelerations in the fetal heart rate, no tachysystole and no cervical dilation. At 1 cm of dilation (after 12 hours of oxytocin augmentation), the woman reported extreme pain, and the fetal heart rate plummeted to 60 beats per minute.

Emergency cesarean followed. The baby’s arm was found extending through the uterine laceration. Mother and baby survived.

The authors tell us that chart review at their institution (in Vancouver, Washington) turned up 3 more cases of uterine rupture associated with misoprostol use in women attempting vaginal birth following prior cesarean.

The seven cases took place over a course of 15 months (April 1997 to June 30, 1998). Uterine rupture occurred in 5 (5.6%) of the 89 patients with a trial of labor who received misoprostol.

By contrast, rupture took place in 1 (0.2%) of the 423 women with a trial of labor who were not given misoprostol.

In other words, the women given misoprostol faced a 28-fold increase in risk of uterine rupture.

Even so, the authors remark, “It is essential to recognize, however, that this report does not definitively prove that the use of misoprostol in the setting of a previous low transverse cesarean section is inappropriate.” They speculate that perhaps the individual women whose uteri ruptured possibly represented “a subgroup at much higher relative risk for uterine rupture,” and possibly should have been scheduled for repeat cesareans.

Despite this puzzling statement, the authors remark, “As the result of the one tragic outcome and the other near-misses that have occurred in the institutions where we practice and of our literature review, we have recommended to our colleagues that a moratorium be placed on the use of misoprostol in the setting of a scarred uterus until the relative risks of this agent have been thoroughly investigated in appropriately controlled trials.”

Selected comments from the “Discussion” section following this paper:

Dr. Hampton W. Irwin, Spokane, Washington:

“What I have learned about misoprostol in preparation for these comments suggests that there may be some underrated dangers with the use of this drug.”

“If misoprostol or any widely used induction system can be shown to favor uterine scar dehiscence, a notice of alarm is justified regardless of the consequences that go along with criticizing a popular drug. Misoprostol is very popular.”

“Bad press for misoprostol will likely be a big disappointment to obstetricians around the world who have flooded the literature for the past 3 years with largely favorable reports for the use of misoprostol to induce labor and for other uses as well.”

Dr. T. Murphy Goodwin, Los Angeles, California:

“The only established benefit of misoprostol is a shortening of a few hours in the time of labor; that is it. There may be a reduction in the cesarean section rate, but by no means is that consistently found or statistically significant in most reports. Any reports of possible complications should be evaluated in this light.”

Dr. George F. Lee, San Francisco, California:

“At our hospital we do about 5000 deliveries a year and approximately 175 to 200 VBACs per year. It has been our experience over the last 4 years that the rate of uterine rupture at our institution exceeds that which has been previously reported ‘in the literature. It appears to be a sustained phenomenon that is a greater risk than initially anticipated. We converted to misoprostol this year, and the uterine rupture rate does not seem to have been further increased. However, there are very serious concerns about misoprostol being voiced by our labor staff.”

Dr. Roger B. Rowles, Yakima, Washington:

“What possible mechanism might account for the uterine rupture occurring several hours after the last dose of misoprostol?”

33. Wing DA, Ham D, et al. A comparison of orally administered misoprostol with vaginally administered misoprostol for cervical ripening and labor induction, Am J Obstet Gynecol 180 (1999) 1155-60.

Back to Los Angeles. This paper reviews a study that randomized 220 women into 2 groups: those who were given 50 micrograms of oral misoprostol every 4 hours and those who were given 25 micrograms of intravaginal misoprostol every 4 hours.

Women with previous uterine surgery were excluded.

The orally treated women required significantly more doses than the women treated intravaginally and took more time before entering effective labor.

34. Kolderup L, McLean L, et al. Misoprostol is more efficacious for labor induction than prostaglandin E2, but is it associated with more risk? Am J Obstet Gynecol 180 (1999):1543-50.

No grand multiparas or women with prior cesareans or uterine scars were included in this California study. One hundred fifty-nine women did participate in the study, and 56 were given 50 micrograms of intravaginal misoprostol, with 54 women receiving intracervical prostaglandin E2 (Prepidil).

The misoprostol group was associated with significantly fewer hours from the start of induction to birth, with significantly less oxytocin use. These results came at the price of more frequent occurrence of tachysystole, a significantly higher incidence of late decelerations or bradycardias in the misoprostol group than in the Prepidil group. (Prepidil, by the way, was approved by the FDA for use in cervical ripening and labor induction.)

Interesting finding:

“Of the 16 deliveries for fetal distress in the misoprostol group, only 5 (31%) occurred within 8 hours of a misoprostol dose and were thus possibly related to the use of the drug.” [Notice that the authors apparently cannot conceive of a situation in which there could be an unexplained delayed response related to this drug.]

“There were significantly more babies admitted to the intensive care nursery in the misoprostol group, even after exclusion of admissions exclusively for fetal anomalies or gestational age <34 weeks (P = .02).”

“. . . the 3 babies with asphyxia were all in the misoprostol group.”

Selected comments from the “Discussion” section of this paper

Dr. Roger B. Rowles, Yakima, Washington:

“Misoprostol is now widely used in nonacademic settings, often without firm protocols, consistent dosing, or tracking of complications.”

Dr. Mark D. Nichols, Portland, Oregon:

“What are your thoughts on ways of handling the tablets? I have difficulty in cutting these tablets into fourths, and I would be interested in your thoughts on a better way of administering a more exact dose of this medication.”

Dr. T. Murphy Goodwin, Los Angeles, California:

“It has already been indicated that the possibly dangerous dosage of this medication is very close to the dosage that is safe and efficacious. There are published reports in the literature suggesting that 50 micrograms is safe—which alone is shocking. Thirty-five percent of the patients have more than 6 contractions in 10 minutes with that dose. That is a lot of smoke, and where there is that much smoke, there is going to be fire.”

Dr. Paul W. Schroeder, Medford, Oregon:

“. . .in our institution I have observed what seems to be an increased risk or at least an increased occurrence rate of intrapartum abruptio placentae with the use of misoprostol when labor is induced in the setting of pregnancy-induced hypertension. ”

Dr. Kilpatrick:

“How can we explain the actual effect of misoprostol on these outcomes? It may have something to do with the medication itself and some type of cumulative effect in terms of absorption. I do not have a good explanation regarding how to understand the mechanism of morbidity.”

“Frankly, it is difficult to cut the 25 microgram dose.”

“I have received many telephone calls about how great it is to use misoprostol.”

“. . .I feel very, very strongly that anyone with a prior cesarean delivery should not have misoprostol.”

35. Blanchette HA. Nayak S, et al. Comparison of the safety and efficacy of intravaginal misoprostol (prostaglandin E 1) with those of dinoprostone (prostaglandin E2) for cervical ripening and induction of labor in a community labor, Am J Obstet Gynecol 180 (1999):1551-9.

This paper is a retrospective analysis of 81 women given cervical ripening and labor induction with dinoprostone over a year’s period. A comparison analysis of 145 women given misoprostol over the following year completed the study.

Mean time from the beginning of induction to birth was significantly shorter with misoprostol than with dinoprostone.

Birth within 24 hours of induction was significantly more frequent with misoprostol.

There was no difference in the cesarean rates (25.6% vs 22.2%).

The incidence of uterine hyperstimulation was higher with dinoprostone.

However, there were no uterine ruptures with dinoprostone, while there were three uterine ruptures in misoprostol group of women undergoing trial of vaginal birth after cesarean. In addition, there was another rupture in the misoprostol group, this time to a multipara. One of the ruptures was massive and resulted in a fetal death and hysterectomy. The stillbirth occurred 10 hours after the last insertion. This bears repeating, I think: the misoprostol group had 3 ruptures among 16 patients (18.8%).

Selected remarks from the “Comment” section of the paper

Dr. Donald Barford of Spokane, WA: I think that you have appropriately raised our concern about the use of an induction and indeed mortality among the fetuses.

Dr. Julian T. Parer, Stan Francisco, California: “I have no objection to using misoprostol in a study situation, and I have yet to hear any evidence that misoprostol is any worse than the other prostaglandin substances, or even oxytocin, at appropriate doses.”

Dr. Clyde V. Von der Ahe, Los Angeles, California: “. . .I am concerned about the number of babies that seem to end up in the neonatal intensive care unit, particularly after the misoprostol induction.”

Dr. Simon Henderson, San Francisco, CA, said: “I am really impressed with these studies on misoprostol, an agent that is really designed for cervical ripening [?] and whose subsequent effect lasts some time after what one would expect the half-life of the medication to be.”

Dr. Howard Blanchette, Framingham, Massachusetts: “It was disturbing, however, that of the 16 patients in our study undergoing trial of labor after cesarean birth 3 did have a rupture, for an incidence of 20%. We must look at the evidence and ask what is the natural rupture rate among women in spontaneous labor undergoing trials of vaginal birth after previous cesarean delivery. There is a sense that this figure is underreported and that indeed the reports of 0.7% to 0.8% may be understated, that we may be looking at higher rupture rates of 2% to 3% or even more.”

36. Mathews JE, Mathai M, et al. Uterine rupture in a multiparous woman during labor induction with oral misoprostol, International J Obstet Gynecol 68 (2000):43-4.

This report from India details the case of a multipara with gestational diabetes and mild pregnancy-induced hypertension. She was given 3 doses of 100 micrograms of oral misoprostol at three hourly intervals. Active labor began, but a fourth dose was given because contractions were considered too infrequent and the cervix was 1 cm long and just 2 cm dilated. The baby was born in less than an hour, followed immediately by “expulsion of the placenta, bloody hindwaters and clots.”

The hemorrhage that followed was so severe that the mother’s uterus had to be removed and her left uterine artery ligated. The baby had a cephalohematoma that had not resolved by day 12.

The authors remark: “It would therefore seem judicious to use a lower dose of misoprostol especially in multiparous women and those at risk of uterine rupture.”

Even though this journal was published in English, it has received little to no attention within the U. S. (I didn’t find it on anyone’s reference list.)

37. Oyelese Y, Landy HJ, et al. Cervical laceration associated with misoprostol induction, International J Gynecol Obstet 73 (2001):161-2.

This case report from Washington, D.C., tells of a 33-year-old woman, whose labor was induced at 38 weeks gestation for severe oligohydramnios. Her cervix was long and closed, with the baby’s head at -4 station. She was given 425 microgram misoprostol tablets vaginally at 3 hours intervals.

Twelve hours after the first dose, her cervix was 70% effaced and 1 cm dilated. Spontaneous rupture of the membranes occurred one hour later. Three more hours passed, and the woman gave birth to a live 6 pound 8 ounce baby girl. There was an extensive midline tear of the posterior lip of her cervix, “extending up to, but not into, the cul-de-sac.” Estimated blood loss was 800 cc. The authors write that this case is the first to their knowledge of an extensive cervical laceration associated with misoprostol use. “Cervical lacerations,” they write, “are rare following a normal vaginal delivery, and usually occur when the cervix is not fully dilated or as a consequence of obstetric maneuvers. However, cervical laceration may result from the very rapid dilation of the cervix. We can only attribute this complication, in this case, to the extremely rapid cervical dilation accompanying the usage of misoprostol.”

They quote the American College of Obstetricians and Gynecologists Practice Bulletin Number 10, Induction of Labor, stating that tachysystole and hyperstimulation are more frequent when a dose of 50 micrograms or greater of misoprostol is used. “We used the lower 25-microgram dose; there was no tachysystole or hyperstimulation. Despite this, the patient’s active phase of labor was extremely short, presumably resulting in this extensive cervical laceration. While there is continued enthusiasm for using misoprostol for labor induction, we urge caution in its use, advocating the lowest effect dose, until more data are available regarding potential side effects of this promising new drug.”

38. Buccellato CA, Stika CS, et al. A randomized trial of misoprostol versus extra-amniotic sodium chloride infusion with oxytocin for induction of labor, Am J Obstet Gynecol 182 (2000):1039-44.

This randomized trial originates from Evanston, Illinois. One hundred twenty-three women were randomly selected to a group getting either 50 micrograms of misoprostol intravaginally every 4 hours or extra-amniotic sodium chloride infusion. Those with a history of prior uterine surgery were excluded.

There was no significant difference in the interval between the start of induction and birth between the two groups. The infusion group had a 32.8% cesarean rate versus a 19.4% rate for the misoprostol group. The dosage interval was changed from 25 micrograms every 3 hours to 50 micrograms every 4 hours mid-study, after it appeared that the misoprostol group was showing significantly less success than the infusion group. Only those patients enrolled after the protocol modification were included in this study.

Rates of uterine contraction abnormalities was high in both groups. In addition, terbutaline was necessary for the treatment of hyperstimulation in 16% of the misoprostol group.

39. Hill DA, Chez RA, et al. Uterine rupture and dehiscence associated with intravaginal misoprostol cervical ripening, J Reprod Med 45 (2000):823-6.

This paper reports on a 2-year retrospective chart review from Florida. The goal was to determine the incidence of uterine rupture in women with a prior cesarean who underwent cervical ripening or induction of labor.

Results: There were 3 uterine ruptures and one uterine dehiscence out of the 48 women with prior cesareans treated with 50 micrograms of intravaginal misoprostol.

Another case of uterine rupture occurred within the group of 89 women who had oxytocin induction of labor and none among the 24 women who had Prepidil placed for cervical ripening.

Case 1 involved a 36-year-old woman with one previous cesarean. She was induced at 38 weeks because she has genital herpes and she had an outbreak-free interval at that time. After a single 50 microgram dose of misoprostol and the onset of labor, she developed acute shoulder pain and severe decelerations of the fetal heart. At emergency cesarean, a baby’s limb was sticking out through a 10 cm rupture of the previous cesarean incision.

Case 2 involved a 38-year-old women with three vaginal births preceding a cesarean in her pregnancy just before this one. Seven hours after one 50-microgram dose of misoprostol, intravenous oxytocin was begun. Severe fetal heart decelerations began approximately 12 hours after she was admitted. A 12-cm rupture of her uterus was discovered during the emergency cesarean that was performed. The wound also involved extension into the left broad ligament as well.

Case 3 involved a 30-year-old woman with a history of one vag’inal birth followed by a cesarean for a footling breech. Eleven hours after one 50-microgram dose of misoprostol, there was a prolonged fetal heart deceleration, and an emergency cesarean was performed. There was a 90% placental abruption, and the baby’s head and shoulders were presenting through a 1 O-centimeter rupture of the previous scar.

Case 4 involved a 29-year-old woman with one previous cesarean. She was given 2 50-microgram doses of intravaginal misoprostol 4 hours apart. There were severe decelerations of the fetal heart, which prompted the obstetrician to deliver the baby with low forceps. An 8-cm separation of the uterine scar on vaginal intrauterine examination. She was observed, without further treatment, as she appeared not to be in pain, was not bleeding and her uterus contracted well.

The authors write: “The ruptures occurred with an apparent delay of 7.5 – 13 hours after the last dose of misoprostol. No patient demonstrated tachysystole or an accelerated labor curve; there is no evidence that intense or frequent contractions were contributors. Other confounders, such as cephalopelvic disproportion and the medical and obstetric indication for delivery per se, cannot be indicted. Further, the dictated descriptions of the previous low transverse incisions all included two-layer closures without extensions.”

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 misbprostol 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 a 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 cherrypicked 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 costeffective,” 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 Gynecol185 (2001):911-5.

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 misbprostol had a role in the etiology of this catastrophic event because it had been given 9 hours before.”

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 Gynecol186 (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 a!. Sublingual misoprostol for the induction of labor at term, Am J Obstet Gynecol186 (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 modem 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 col1)ment 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 concems 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 EI 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 regiment 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): /206-1 O.

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.

Women who had a previous low transverse cesarean were included, despite warnings published during the latter period of the study of the increased rupture rate associated with misoprostol use in women with uterine scars. Were the women who entered this study after November 1999 told in their informed consent that the ACOG Committee on Obstetric Practice on Induction of Labor with Misoprostol (November 1999) explicitly recommended against its use in patients with prior uterine surgery? Apparently not.

Hyperstimulation occurred in 9% of the misoprostol group; there were no instances of hyperstimulation in the gel group. There was a trend toward longer hospitalizations in the newborns in the misoprostol group.

52. Ie Roux PA, Olarogun JO, et al. Oral and vaginal misoprostol compared with dinoprostone for induction of labor: a randomized controlled trial, Obstet Gynecol 99 (2002): 201-5.

This South African study evaluated the efficacy of oral and vaginal misoprostol compared with dinoprostone for induction of labor. Women with prior cesareans were included in the study.

Four hundred eighty women were randomized into three groups. Groups one and two were given 50 micrograms of misoprostol orally or vaginally every 6 hours, to a maximum of four doses. Group three got 1 milligram of dinoprostone in the posterior fornix of the cervix, with the dose repeated after 6 hours, to a maximum of two doses.

The authors followed other studies in making the primary outcome the incidence of vaginal birth within 24 hours. Physicians’ discretion was followed if this result was not achieved.

“The overall cesarean section rate was 33% with no differences between the treatment and control groups. There was a higher proportion of cesarean sections for fetal distress (27.5%) in the vaginal misoprostol group compared with the dinoprostone group (13.7%).

In the first paragraph of this paper, the authors quote Hofmeyr et al on safety-that “if sufficient numbers are studied, an unacceptably high number of serious adverse events including uterine rupture and asphyxial deaths may occur.” However, they begin their last paragraph with this statement: “The conclusion that misoprostol was not more effective should not necessarily be seen as a negative result.”

53. Mozurkewich E, Horrocks J, et al. The MisoPROM study: a multicenter randomized comparison of oral misoprostol and oxytocin for premature rupture of membranes at term, Am J Obstet Gynecol189(4) (2003): 1026-30.

This study aimed to find out whether induction of labor with oral misoprostol would result in fewer cesareans than intravenous oxytocin in first-time mothers with premature rupture of membranes at term.

Three hundred five women at 10 centers around the United States were randomly assigned to receive 100 micrograms of oral misoprostol every 6 hours to a maximum of two doses or intravenous oxytocin.

Results: The study was stopped prematurely because of recruitment difficulties. This was likely due in part to bad publicity the drug had received through media reports. The authors explain that they experienced increasing difficulty in recruiting research subjects after publication of the August 23, 2000, Searle letter warning against the use of misoprostol for induction of labor. . . Unsuccessful efforts were made to bolster recruitment over the ensuing 8 months. In January 2002, this trial’s steering committee advised that the study be terminated on the basis of recruitment difficulties and the lack of a trend toward meaningful differences in the primary outcome measure.”

One woman who was supposed to get misoprostol left the hospital against medical advice before being treated. She was not included in the study.

This paper reports on the 305 women who did participate in the study. Cesarean rates were very similar in both arms (20.1 % in the misoprostol group and 19.9% in the oxytocin group).

Time intervals between induction start and birth were similar, as were maternal and neonatal safety outcomes.

More babies in the misoprostol group needed intravenous anttbiotics during the neonatal period (16.4% vs 6.9%).

There was a lower incidence of postpartum hemorrhage if the misoprostol group compared with the oxytocin group (1.9% vs 6.2%).

The conclusion: “Oral misoprostol does not offer any advantage in time from induction to vaginal delivery or risk of cesarean section.”

54. Chung JH, Huang WH, et al. A prospective randomized controlled trial that compared misoprostol, Foley catheter, and combination misoprostol-Foley catheter for labor induction, Am J Obstet Gynecol 189(4) (2003): 1031-35.

This southern California study was designed to test the efficacy of combination intravaginal misoprostol and intracervical Foley catheter for prelabor cervical ripening.

One hundred forty-six women were randomly divided into three groups. Group one (49 women) got misoprostol in 25 microgram doses intravaginally every 3 hours. Group two (54 women) got the Foley catheter, which was kept in place for 12 hours. Group three (43 women) got the combination of Foley catheter with concurrent intravaginal administration of 25 micrograms every 3 hours, for a maximum of 6 doses.

‘There was no difference in the use of oxytocin or epidural anesthesia during labor. However, tachysystole, hyperstimulation, and the use of terbutaline occurred more frequently in the misoprostol group compared with the Foley group and the combination group.”

There was a higher rate of chorioamnionitis in the combination group—probably, the authors say, due to ascending infection via the catheter and multiple cervical examinations to administer the misoprostol in the presence of the catheter. There was no difference in the rate of meconium-stained amniotic fluid or endometritis. Other outcomes, as well, were similar.