Part II: 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

55. Thomas, A, Jophy, R, et al. Uterine rupture with misoprostol used for induction of labour. BJOG 110 (February 2003): 217-218.

This case report comes from St. John’s Medical College Hospital, India. A 19 year old primigravid woman had regular prenatal care between 11 and 32 weeks of gestation. Her tests were normal except for hemoglobin concentration of 9.6 g/dL. She attended no more prenatal clinics until she was seen again at 39 weeks with a lower hemoglobin concentration (7.6 g/dL), edema of the ankles, blood pressure of 160/100 and pale color.

Induction was started because of pregnancy-induced hypertension at 39 weeks, despite her unfavorable cervix. The first dose of 50 mg of misoprostol was inserted into the posterior fornix. Eight hours later, her cervix was 2 cm dilated, uneffaced and anterior. A second dose of 50 mg of misoprostol was inserted.

Four hours later, the fetal heart tracing showed decelerations to 110 beats per minute. Dilation was 3 cm. Artificial rupture of membranes was done and thick meconium-stained amniotic fluid was drained. A cesarean section was quickly performed (just before it, the cervix was 8 cm dilated and the fetal heart rate 80-100 beats per minute). A tear of the uterus 15 cm long was found, from the right corner of the uterus to the right lateral fornix. “This case report shows that misoprostol can cause rupture of the uterus in primigravidae.”

56. 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 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. Ws 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. Ws 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 how we 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. Ws 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. Ws 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 :20000. 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 Ws 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 Ws 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 Ws case and anticipate future events based on this understanding.

“The already overstressed unit was further challenged by Mrs. Ws 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 (lL): 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

57. Rydahl E, Clausen JA. An unreported uterine rupture in an unscarred uterus after induced labor with 25 mg misoprostol vaginally. Case Reports in Women’s Health I (2014) 8-10. This is an open access article under the CC By-MC-SA license. (http://creativecommons.org/licenses/by-nc-sa/3.0/)

This case report comes from the Department of Midwifery, Metropolitan University College, Copenhagen, Denmark.

The authors note that misoprostol is recommended by the Danish Association of Obstetricians and Gynecologists for induction of labor. They note that misoprostol, even when used in small doses on an unscarred uterus, might cause uterine rupture. They believe that side effects in the setting of off-label use should be reported to national reporting systems, where such systems are available.

This case involved a woman whose first baby was born via umcomplicated vaginal delivery. Her second was induced at 42 weeks gestation, a routine procedure in a Danish hospital in 2009. Her pregnancy was normal. There was no Bishops Score recorded, but her cervix was described as no cervical dilatation, 2 cm in length, posterior location. At 11:53 am 25 mg misoprostol was placed in the posterior fornix of her vagina. About 1 hour later, at 1:00 pm, after a normal fetal heart tracing, she left the hospital, according to hospital policy. She returned home to await contractions and received no further treatment with misoprostol. Seven hours later, at 8:00 pm, she phoned the hospital, reporting increasing labor pains. She was encouraged to stay home. Thirteen hours after the misoprostol was inserted (10 minutes past midnight), she returned to the hospital with strong contractions coming every 2-3 minutes. She was 3-4 cm dilated, her cervix at ½-1 cm open, posterior location and soft with the fetal head present at the pelvic brim.

In pain, she asked for an epidural block, which was done. An external CTG was applied, classified as normal and disconnected after 13 minutes. Her labor progressed rapidly, and 25 minutes after arrival to the hospital, she had the urge to push. Ten minutes later, the amniotic sac broke, the fluid was meconium-stained, and her cervix was dilated to 9 cm. There were minor decelerations at this point. Mother was receiving oxygen via mask and was encouraged to push.

The baby’s head descended normally as she pushed, but it retracted between contractions. After 20 minutes of pushing, there was no further sign of descent, and the midwife called for an obstetrician. He ordered oxytocin via an intravenous line. This was administered at a cautious rate (6 ml/h), at half the standard dose. The mother was encouraged to push again, but after 20 minutes (when the drip had been slowly increased to 24 ml/h), the fetal heart decelerated to 75-80 beats per minute and the fetal head detracts significantly. The mother complained about unremitting abdominal pain and turned pale. An emergency cesarean was performed.

The baby’s Apgar scores at 5/10 minutes were 1/1, with pH 6.68, SBE – 19 and weight 5800 g. She received 72 hours of hypothermal treatment in an intensive care unit at another hospital. At age 3, she was diagnosed with cerebral palsy.

The uterus was severely damaged. There was a full, posterior rupture extending from the fundus down, with almost a complete separation between the uterus and the vagina. The uterus was restored, but the mother bled 5500 ml during the operation. Two hours after the operation was finished, she bled heavily again and was re-operated. The bleeding was located at the lower part of the uterine rare side and in the left side of the cervix and after several insertions, hemostasis was obtained. However, there was more bleeding from the fundal part. A double B-lynch suture was applied. It was estimated that the mother’s total blood loss was 10 l. She received 27 product with 245 ml erythrocites, 18 product was 279 ml plasma and 9 products with 350 ml thrombocytes. She also received approximately 2.4 l NaCl solution which indicates that her blood loss might have been underestimated (total amount of IV products = 14.6 l + 2.4 l NaCl).

After the second operation she was sedated for approximately 14 hours. She was discharged with the newborn 14 days after delivery.

The authors criticize that the mother was never informed that she was treated with an off-label product, nor was her family informed about their right to complain to the National Patient Complaint System. This case was not reported as an adverse incident report.