(continued from Part II)
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
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 102F, 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):774-9.
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.
in uterine tachysystole and fetal heart rate changes. 5.6% rupture rate for VBACs with misoprostol compared to 0.2% with the no misoprostol VBACs.
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 E1) 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 4 25 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 vaginal 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 10-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.”
The Misoprostol/Cytotec Controvery, Part IV
