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
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. le 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 Gynecol 189(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 antibiotics 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.
One of the most striking findings from the study was the 47% cesarean rate in the first-time mothers, regardless of group. The authors suggest that this “should be taken into consideration before choosing to induce such a patient.”
55. Crane J, Delaney T, et al. Oral misoprostol for premature rupture of membranes at term, Am J Obstet Gynecol 189(3) (2003): 720-4.
Another study from Newfoundland. It was designed to compare the efficacy, safety and maternal satisfaction of oral misoprostol and intravenous oxytocin for labor induction in women with premature rupture of membranes at term.
One hundred five women were randomly assigned to oral misoprostol at 75 micrograms every 4 hours as needed to establish labor or to intravenous oxytocin.
“Oral misoprostol resulted in a longer induction to vaginal birth interval but increased maternal satisfaction and less hyperstimulation compared with intravenous oxytocin.”
Eighty-four women completed the maternal satisfaction questionnaire—the first of its kind mentioned in any of the papers summarized on this review of the medical literature in English on misoprostol. Thirty-seven of the 43 women in the misoprostol group and 26 of the 41 in the oxytocin group were very satisfied with the care they got, giving the highest rating possible. The authors correctly point out that very few studies have evaluated patient satisfaction with labor induction with misoprostol.
56. Wagner M Adverse events following misoprostol induction of labor, Midwifery Today, Autumn 2004, Number 71, pg 9 – 12
This is not a trial but a review of 16 cases of misoprostol induction with adverse outcomes.
57. Sachs BP, A 38-year-old woman with fetal loss and hysterectomy, Journal of the American Medical Association 294, No 7 (August 17, 2005): 833-840
In this last paper, there are references specific to it (1-5), which can be found just below.
This highly unusual paper is a case study of a misoprostol induction that ended in disaster at the Beth Israel Deaconess Medical Center in Boston, Massachusetts, in late 2000. What is uncommon about the paper is that it involves physicians apologizing and admitting to multiple errors in what the Boston Globe labeled a “remarkable example of public disclosure.” Just as unusual is the inclusion of the statements made by the injured family.
My guess is that the settlement reached with the family in this case called for this unprecedented level of public disclosure. Usually, in such settlements, there is a provision that requires the injured parties to be silent about what happened. This is one reason why the media have rarely reported on fatal outcomes following misoprostol inductions.
At any rate, the mother, a Mrs. W., was 38 years old at the time (November 2000) her baby was due. She was self-employed, healthy and able to afford private health insurance. This, her first pregnancy, ended tragically with a stillbirth, hysterectomy, and a long period of hospitalization and physical therapy. ( By the way, it is safe to say that most of the U. S. women given misoprostol in the studies summarized above did not have private health insurance).
This paper is quite revealing, as it contains comments and descriptions of what happened to Mrs. W. and her baby, first, from the point of view of Dr. Sachs, department head, as well as from Mrs. and Mr. W. This format gives the paper a Rashomon-like quality.
According to one of the physicians involved in her case, Mrs. W. was healthy at the end of her pregnancy. At 41 weeks, her obstetrician, Dr. F., decided to admit her to hospital for a misoprostol induction. Dr. F. was not on call the night Mrs. W. was admitted.
With her cervix closed and 50% effaced and blood pressure at 125/90, she was given 25 micrograms of misoprostol vaginally and sent home. Contractions began in a rapid pattern on the way home, so Mrs. W. returned to the hospital, arriving there at midnight in active labor.
By this time, she was vomiting and her blood pressure had risen sharply to 174/104; her cervix was still closed. An hour and a half later, her contractions were coming every one to two minutes. (This is severe tachysystole, so this previously healthy woman was already exhibiting two worrisome symptoms.)
At 3:30 a.m. she was given a test dose for epidural anesthesia, and her blood pressure immediately dropped to 53/33, returning to 107/53 with ephedrine.
By 4:30 the baby’s heart rate was showing some occasional late decelerations, with the cervix dilated to 4 to 5 centimeters. Mrs. W. was fully dilated an hour later and asked to push.
Half an hour later the baby’s heart rate was dipping to 115 per minute with late decelerations. Soon the decelerations became more pronounced, dipping to 90 beats per minute for 3 minutes.
A low forceps delivery was attempted at 6:20, but failed. Mrs. W. was transferred to the operating room for an emergency cesarean. The lower segment of Mrs. W’s uterus was ruptured, and both baby and placenta were loose in her abdominal cavity. Her 10-pound baby did not respond to resuscitation efforts.
Mrs. W’s uterus was repaired, and she was given 4 units of blood, along with misoprostol for uterine atony. (There have been many anecdotal reports, by the way, that when hemorrhage occurs after a misoprostol-induced labor, misoprostol is not effective at stopping it). A hysterectomy was performed at 10:00 a.m., when Mrs. W.’s uterine atony was unresponsive to massage, intravenous oxytocin, and Hemabate. This episode was followed by “numerous complications, including bleeding with disseminated intravascular coagulation requiring the transfusion of 38 units of packed red blood cells, 42 units of fresh frozen plasma, 60 units of cryoprecipitate, and 111 bags of platelets. She required 3 weeks of hospital care thereafter, including 18 days in the intensive care unit. She encountered and overcame complex medical issues including prolonged disseminated intravascular coagulopathy, acute respiratory distress syndrome, sepsis, and a wound infection. She recovered steadily, was transferred to a rehabilitation hospital for further care for a few days, and then returned home where she received intensive physical therapy, occupational therapy, and other supportive care. Now, 3 years after her disastrous hospitalization, she reports she has almost fully recovered physically. She has mild generalized weakness and labile emotional symptoms that she ascribes to hormonal imbalance. She and her husband have recently adopted a healthy, happy child,” Dr. Del Banco writes.
The article continues with Mrs. W.’s words. She remarks that she had chosen what she and her husband thought was the best hospital possible in their area. She seems to have changed this assessment and comments that the risks of taking Cytotec (misoprostol) to bring on labor quickly were never explained to her. “We trusted a lot,” she remarked.
“It was about 6 AM when the attending physician came into my room and pretty much panicked, and we all felt that sense of panic in the room.”
Mrs. W’s husband’s comments are especially disturbing: “How are mothers, patients, being informed of the use of misoprostol, or any drug that may be used on them? You know it is important to make the ultimate decision as a patient. The only way to do that is with knowledge. The trust is already there, because they would not be a patient with that particular doctor if they didn’t trust the doctor . . . especially with pregnant women. So my question is: How are things changing so that every pregnant woman is informed and able to make her own decision? We had a nurse who was dealing with 2 or 3 rooms, including ours. Is that type of coverage standard, or are you now limiting a nurse to one particular pregnant woman? Has the communication between residents and the doctor on duty assigned to the particular case improved? That night, I saw residents who were afraid. They were either unable or unwilling to get the doctor, when clearly things weren’t going the right way.”
Dr. F, Mrs. W’s primary obstetrician, talks about the factors that led her to recommend the misoprostol induction: Mrs. W.’s being “a bit older” and a slight elevation in her blood pressure (though still in the normal range). (Of course, the misoprostol seems not to have helped the blood pressure problem; it apparently caused it, along with the too frequent contractions.) Even though tests showed that all was well and Mrs. W’s cervix wasn’t “favorable” for labor, “we decided there was no benefit to be gained in waiting” and the induction was scheduled.
According to Dr. F., she reviewed “with Mrs. W. that the risk of an induction is that it might fail and necessitate a cesarean delivery. However, as misoprostol is viewed as a safe medication, I did not discuss any specific complications.” In essence, then, she corroborates Mrs. W.’s story that she wasn’t told that there could be any serious risks to accepting the misoprostol induction.
It would have been far more accurate if Dr. F. had said that “misoprostol is viewed by some as a safe medication.” There were certainly strenuous efforts made before Mrs. W. reached 41 weeks of pregnancy to warn women, physicians and midwives about the known dangers of misoprostol. (References 1-5, below)
As department chair, Dr. Sachs discusses his opinions of the mistakes made in the care of Mrs. W., the lessons learned at Beth Israel Deaconess Medical Center and the reorganization of care that has taken place since then. In the course of his discussion, he mentions that the incidence of uterine rupture in an unscarred uterus is between 1:17 000 and 1:20 000. This reference is rather misleading, since these figures are not derived from women whose labors were chemically induced.
Besides, as we can see from the studies summarized above, there were several that involved women with unscarred uteri that were published before November, 2000 that indicated that misoprostol usage for induction could be risky. (Notes 11, 12, 13, 35, above) Had these studies been read and taken seriously by the attending physicians and the residents at Beth Israel around the time of their publication, there might have been more caution about inducing labor in a healthy woman who would likely have gone into labor on her own within a few days. After all, the evidence about the risks of “prolonged pregnancy” (all published before the misoprostol studies of the late 1990s) shows that there is nothing to be gained by chemical induction before 41.5 weeks. Even after 41.5 weeks, the few studies we have show that about 500 women must be induced in order to prevent one perinatal death. Among 500 misoprostol inductions, it is quite possible for the perinatal death rate to exceed what it would have been without induction, and this doesn’t take into account the risks to the mothers.
As noted above, in 1996 (Note 12), Wing reported a maternal death from amniotic fluid embolism and two near maternal deaths from severe uterine atony, warning that some women are “quite sensitive” to misoprostol, as long as 20-30 hours after the last dose. Each of the three women in her study had been given only 1 25-microgram dose of misoprostol. In 1997 Bennett reported a rupture requiring hysterectomy in a woman with an unscarred uterus after two 25-microgram doses. In addition, a physician who commented on Farah’s 1997 study mentioned his knowledge of several uterine ruptures following misoprostol induction, without mentioning what happened to the women or their babies. All of these physicians warned their colleagues about some women’s extreme sensitivity to misoprostol and its long-lasting effects. Mrs. W. should have been told of these risks before being given the drug.
Dr. Sachs writes that the 25 micrograms of misoprostol that Mrs. W. was given at 8:45 the previous evening was “unlikely to have caused the uterine rupture 9 hours later, although she did have uterine hyperstimulation.” He maintains that “uterine rupture has only been reported at much higher doses and nearly always in women who had prior uterine surgery.” Had he not read Dr. Wing’s 1996 study and the other studies mentioning its long-lasting effects in some women?
Another case of uterine rupture of an unscarred uterus that Dr. Sachs could have studied (and made sure that his attending physicians and residents had read) was described in Mathew’s paper published in January, 2000. One has to wonder why no one at this prestigious Boston hospital appeared to be aware of Mathew’s misoprostol case report. A simply Medline search would have found it. Mathews himself cites three other cases of uterine rupture following misoprostol use.
As department head, Dr. Sachs is certain to have known about another warning about misprostol’s potential adverse effects. On August 23, 2000, Michael Cullen, MD, Medical Director for the United States for Searle Company, issued a letter to all health care providers in the country that off-label use of Cytotec in pregnant women had resulted in “serious adverse events,” such as “maternal or fetal death; uterine hyperstimulation, rupture or perforation requiring uterine surgical repair, hysterectomy or salpingo-oophorectomy; amniotic fluid embolism; severe vaginal bleeding, retained placenta, shock, fetal bradycardia and pelvic pain.”
If the physicians at Beth Israel Deaconess had heeded Searle’s warning while Mrs. W. was still in her second trimester of pregnancy, her baby could be alive today and her uterus still in her body. Instead, they chose to follow the path laid out by the American College of Obstetricians and Gynecologists, which in October, 2000, issued a news release, called the “ACOG Issues Letter on Safety of Misoprostol.” This news release was written out of “concerns” raised by Searle’s letter of August 23 and states that , “. . . misoprostol has been used for many years to induce labor in women ready, but unable, to deliver healthy babies without assistance. Misoprostol, in these cases, helps ensure the delivery of healthy babies and helps ensure the health and the life of the mother, both by bringing the pregnancy to a safe conclusion and by helping to prevent post-delivery hemorrhaging.”
This letter refers the reader to the ACOG Committee on Obstetric Practice Opinion Number 228, issued in 1999, which states, “The American College of Obstetricians and Gynecologists supports induction of labor as a worthwhile therapeutic option when the benefits of expeditious delivery outweigh the risks of continuing the pregnancy.” Was this standard met in Mrs. W.’s case? Apparently not. Neither Dr. Sachs nor Dr. Del Banco has gone so far as to claim in this paper that either Mrs. W. or her baby would have been in danger if her labor hadn’t been induced with misoprostol when it was.
Even if she had needed induction, there were better options. I quote now from ACOG Practice Bulletin Number 10, November 1999, which states: “Stripping the membranes is commonly practiced to induce labor. . .In a randomized trial of 195 normal pregnancies beyond 40 weeks of gestation, two thirds of the patients who underwent membrane stripping labored spontaneously within 72 hours, compared with one third of the patients who underwent examination only.”
Dr. Sachs remarks that the hospital bore the expense of the family’s stay at a local hotel throughout the period of crisis, adding that a financial settlement was made with the W’s without a suit being filed, which “included an annual lectureship devoted to enhancing patient safety in the memory of Mrs W’s child.”
Dr. Sachs points to six errors (without mentioning those I have already pointed out). He writes:
“First, communication was poor. During Mrs W’s last 5+ hours of labor, despite 12 personal assessments by attending physicians and residents in obstetrics and anesthesiology, no clear clinical plan was effectively communicated to all the health care staff and the patient, and little was documented. The plan should have addressed the management of Mrs W’s pain and vomiting, elevated blood pressure, and the changes in the fetal heart rate tracing from about 4:30 AM. Second, mutual performance cross-monitoring, the concept of a team approach in which another physician or nurse identifies issues and informs the attending physician, was not in place.
The nurse caring for Mrs. W. was relatively new to labor and delivery and was not being supervised by other nurses due to the number of patients in labor and delivery. (Apparently, Dr. F. didn’t pick a good night to add another labor case to an already busy caseload.) The fetal heart rate tracing changes were unusual and so noted but not fully appreciated by the nurse or the resident. The attending physician was very experienced but was focused on another patient and therefore did not address the issues in Mrs. W.’s case. Third, there was inadequate conflict resolution. Although the resident believed that the patient’s baby should have been delivered, she did not seek additional help. Both attending physicians were on the unit that night. Furthermore, the department’s conflict resolution policy instructs the chief resident, in cases such as this, to call the director of obstetrics at home. Fourth, the team displayed poor situational awareness, in that they did not comprehend the essential elements in Mrs W’s case and anticipate future events based on this understanding.
“The already overstressed unit was further challenged by Mrs. W’s emergency cesarean delivery and affected the overall safety on the unit. No one was anticipating the needs or prioritizing the care of all the patients in labor and delivery. Fifth, the physician workload was too high and there was no contingency plan in place to deal with the overload such as calling for backup and reassigning patients. Sixth, the attending physician had been on call for 21 hours, which may have impaired the physician’s judgment. In this case, the physician displayed ‘vigilance fatigue,’ or sticking to a diagnosis despite evidence to the contrary, between 5:30 AM and 6 AM and remained convinced by the fetus’s caput and molding that the patient would deliver spontaneously in a short period of time.” Elsewhere he mentions that it had also been a mistake to give Mrs. W. misoprostol and to send her home.
Could the tragedy that befell the W. family have been prevented or alleviated by the midwifery model, an unnamed physician asked Dr. Sachs (apparently, this paper was transcribed from some sort of forum). The physician added, “We have turned obstetrics into a medical illness and not an event that’s about the making of a family. If we could take care of low-risk women with a midwifery model, then we could have more alert doctors to care for patients at high risk.”
Dr. Sachs dismissed this idea: “I am very supportive of the midwifery model for low-risk obstetrical patients. However, I do not believe that midwives are any less susceptible to making medical errors. Most of the serious adverse events we have seen in the last few years occurred to patients that started out being low-risk.” (Of course, it could be argued that Mrs. W. was low-risk until she was given misoprostol.)
One of Mrs. W.’s comments is particularly poignant, as it demonstrates the degree to which she faults herself, as well as the hospital staff at Beth Israel Deaconess. ”Looking back, had I just gotten up and yelled out in the hallway, right outside the door,” she remarked, “I feel like that would have made something different happen.”
References
1. Cullen M. Letter to health care practitioners: Important drug warning concerning unapproved use of intravaginal or oral misoprostol in pregnant women for induction of labor or abortion. Skokie (IL): Searle, August 23, 2000.
2. Wing DA, Paul RH. A comparison of differing dosing regimens of vaginally administered misoprostol for preinduction cervical ripening and labor induction. Am J Obstet Gynecol 175 (1996):158-64.
3. Bennett BB. Uterine rupture during induction of labor at term with intravaginal misoprostol. Obstet Gynecol 89 (1997):832-3.
4. 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.
5. Gaskin IM. Cytotec: Dangerous experiment or panacea? Salon.com, July 11, 2000.
Copyright 2005 Ina May Gaskin
midwifeim@earthlink.net
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