If Guidelines for Northern Ireland do not advise physicians regarding which patients are at higher risk and must be excluded, then they must expect a higher rate of serious adverse effects than that seen in the U.S. where the exclusions are required and where serious adverse events have nevertheless occurred. Without the exclusions, there is much greater potential for greater numbers of more serious complications, including death.
Recommendation 22 of the RCOG Guideline says ultrasounds are not essential, however ultrasounds must be required for dating of pregnancies and to detect possible ectopic pregnancies. Gary and Harrison, reviewing FDA adverse events reports, found 17 cases of ectopic pregnancies (11 ruptured; 1 death).93 They state, "Ectopic pregnancy is an absolute contraindication to use of mifepristone,"94 (also stated in FDA mandated product labeling).95 Ultrasound documentation of intrauterine pregnancy before medical abortion would prevent this complication. This is essential because, "When an ectopic pregnancy ruptures, the women will rapidly bleed to death . . . unless she undergoes immediate surgery."96 However, "The signs and symptoms of ectopic pregnancy (e.g., cramping and bleeding) resemble those experienced by a woman undergoing a medical abortion. [A] . . . patient might delay treatment thinking her symptoms were due to the [medical abortion]-- not an ectopic pregnancy."97
The Guideline encourages use of mifepristone in combination with vaginal misoprostol but does not discuss multiple serious issues concerning use of misoprostol, particularly when given by the vaginal route, which has been associated with serious complications such as sepsis, uterine rupture, and death.
Use of vaginal misoprostol for medical abortion is not approved by the FDA.98 The Mifeprex (mifepristone) product label specifies the FDA-approved medical abortion protocol which includes 400 mg. of misoprostol taken orally at one time.99 However, following FDA approval, a number of U.S. abortion providers adopted an unapproved regimen which involved use of misoprostol vaginally.
Some women developed fatal infections following medical abortion using this unapproved regimen which included both oral mifepristone (200 mg.) and vaginal misoprostol (800 mcg.).100 To date, there have been six reported North American deaths by C. sordellii sepsis following medical abortion. Each of these deaths involved use of mifepristone with vaginal misoprostol.101
After the third and fourth septic shock deaths were made public, the FDA published "FDA public health advisory: sepsis and medical abortion" on July 19, 2005. In this document they gave several cautions related to possible serious infection and death after medical abortion, and they repeated that the approved dose of misoprostol was 400 mcg. taken orally (not vaginally).102 The FDA emphasized, "The safety and effectiveness of other Mifeprex dosing regimens, including use of oral misoprostol tablets intravaginally has not been established by the FDA."103
According to Dr. McDonald at the CDC workshop, an additional death has been reported which used only misoprostol but no mifepristone. This additional death was still under investigation at the time of the CDC-FDA workshop but involved a uterine infection by Clostridium perfringens, closely related to C. sordellii.104
Use of vaginal misoprostol has been prohibited in France according to Dr. McGregor105 and Dr. Didier Sicard, Professor of Infectious Disease, Paris,106 speaking at the CDC-FDA workshop.
Misoprostol causes uterine contractions and has been used to start labor in pregnant women.107,108 FDA cautions that obstetrical uses of misoprostol are "not approved by the FDA. No company has sent the FDA scientific proof that misoprostol is safe and effective for these uses."109 FDA mandated label information for misoprostol (trade name Cytotec) states in a boxed warning, "Uterine rupture has been reported when Cytotec was administered in pregnant women to induce labor or to induce abortion beyond the eight week of pregnancy."110 FDA explains that "a torn uterus may result in severe bleeding, having the uterus removed (hysterectomy), and death of the mother. . ."111
FDA's Dr. Sandra Kweder stated out that vaginal misoprostol, in general obstetric use, has a "high rate of uterine rupture" which is "well reported."112 Kweder also stated that the oral misoprostol tablets have a "very unpredictable pharmacokinetic profile" when used vaginally.113 She suggested that misoprostol through vigorous uterine contractions, may have a role in setting the stage for Clostridial infections by deoxygenating the uterine tissue as well as by thrusting vaginal bacteria into the uterus.114
Dr. McGregor reported, "In our own work and others, we've shown that when the uterus contracts, that actually substances from the vagina are normally transported up inside the uterus so that would include Clostridia sordellii spores or other microorganisms. . . . . "115 Thus misoprostol may play a role in facilitating transfer of the bacteria into the uterus. Dr. McGregor also stated misoprostol and the prostaglandins both primary and secondary roles in regard to innate immunity.116
The Cytotec (misoprostol) label states that congenital anomalies have been reported when misoprostol has been used unsuccessfully for medical abortion. "Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with skull defects, cranial nerve palsies, facial malformations, and limb defects."117 Spitz also states says that misoprostol has been teratogenic in humans, citing two reports.118
In the study by Spitz et al. 5 percent of the women did not return for their final visit, and previously five of the women had ongoing pregnancies when last seen. The final visit which could provide for surgical intervention if necessary is important in order to avoid ongoing pregnancy and the risk of birth defects due to misoprostol.119 A report by Ashok et al. also states, "It is imperative to interrupt the pregnancy because of the possibility of birth defects following the administration of misoprostol."120
The Report of the International Inquiry Commission on RU 486 stated that "known side effects" of prostaglandins (such as misoprostol) include diarrhea, nausea, vomiting, severe pain, and also cardiovascular and respiratory risks. The report also cautioned on the lack of study of side effects when RU 486 and prostaglandins are used together.121
Misoprostol is used as an integral part of the approved RU486 abortion regimen in the U.S. and is also part of the "optimal" protocol recommended by the RCOG. However, the FDA has approved only the oral misoprostol, while the RCOG Guideline recommends at least the first dose should be vaginal, with subsequent doses in most cases being vaginal or oral depending on circumstances.122 The FDA approved only the 400 mg. dose, but RCOG recommends higher doses, starting with 800 mcg.123 Additionally, FDA recommends one dose only, while the RCOG Guideline recommends multiple doses (depending on gestation and circumstances, 800 mg. initially and up to four doses of 400 mcg. subsequently).124
A medical abortion is counted as a "failure" if surgery is needed afterward to remove retained tissue or to remove an intact ongoing pregnancy. The Guideline cites the work of Ashok et al.125 whose 2002 study claimed, "The ongoing pregnancy rates in this series is the lowest reported to date," which was attributed as possibly due to both the route of administration (vaginal) and the number of doses of misoprostol given.126
However, even though the pregnancy has been successfully terminated, that is no guarantee against the complications that have been reported with use of mifepristone and misoprostol. The same vigorous contractions that successfully empty the uterus produce high risk of uterine rupture as stated by FDA's Dr. Kweder.127
Additionally, a successfully emptied uterus is no guarantee of protection against sepsis. At the CDC-FDA workshop, Dr. Fischer, discussed the first four U.S. deaths from C. sordellii sepsis following medical abortion. He stated that at autopsy, "none of the patients had retained fetal or placental tissue."128 The abortions were successful, their uteri were empty, and these young women were dead nevertheless. Based on an extensive investigation which included genetic testing of the bacteria for precise diagnosis, the four deaths were attributed to C. sordellii endometritis and toxic shock syndrome.129
Dr. Fischer also made the point there may have been other deaths that have gone unrecognized. "Additional cases of pregnancy-associated C. sordellii infection in which the organism was not cultured or speciated may exist, but may not have been pursued because they did not receive the scrutiny afforded these four cases."130 Since the first four reported deaths all occurred in California, Dr. Fischer suggests that "local and regional attention around the first two cases in California may have increased the awareness of both the public and healthcare providers to this possible connection and stimulated reports of additional cases that may have not. . .been detected in other states. In addition, the laboratory confirmation of C. sordellii in these cases resulted from extraordinary efforts at a national reference laboratory."131
In short, deaths could occur in young women sent home following a "successful" abortion - young women from Derry or Belfast, for example - and these deaths might never be recognized as being related to the abortion. The empty uterus won't give a clue about the abortion and there may be no fever or other signs of infection. In fact, it is possible a post-abortive young woman with a serious infection won't make it to the hospital in time to give her medical history. Dr. Fischer stated that one of the California women "collapsed and died before reaching medical care."132
Dr. McGregor, after suggesting that eliminating mifepristone should be a consideration, also acknowledged that misoprostol, especially the vaginal use of misoprostol, was part of the problem. He stated that "certainly I would agree with practitioners, such as Planned Parenthood who've already gone to the oral only - oral only administration, which is actually what was approved by the FDA."133 By this time, following several deaths and the publication of the FDA Advisory, Planned Parenthood Federation of America, the largest U.S. abortion provider, had reportedly shifted from the unapproved regimen previously used to a more cautious unapproved regimen which used oral misoprostol in place of vaginal.
RCOG Guideline supports medical abortion for up to 24 weeks (168 days)134 while the FDA has approved only to 7 weeks (Day 49).135 The study by Spitz et al. containing the mifepristone data submitted to the FDA, was able to support an approved use of mifepristone with oral misoprostol only to Day 49.136 The failure rate increased from 8% in less than 49-days, to 17% in the 50-to-56-days group, to 23% in the 57-to-63-days group. Spitz et al. concluded the regimen was safe and effective only through Day 49. "With longer durations of pregnancy, the regimen is less effective and the incidence of adverse events is higher."137
Following U.S. approval of mifepristone, Planned Parenthood Federation of America, the largest U.S. abortion provider, had adopted an unapproved protocol allowing for medical abortion use up to 9 weeks (63 days). However, after several of the septic shock deaths had occurred and the second FDA Advisory had been published, Planned Parenthood adopted a new (also unapproved regimen) which used only oral (not vaginal) misoprostol, and limited medical abortion to starting no later than Day 56 after last menstrual period.
Their website, in an article first published on May 1, 2006, which references the FDA Advisory of March 17, 2006, states, "Planned Parenthood currently provides medication abortion up to 56 days' gestation." 138
To use medical abortion beyond the 9th week is completely beyond American experience, which has demonstrated sufficient complications as well as the known deaths that a U.S. Congressional report, following hearings, concluded that approval of mifepristone should be withdrawn. The reports conclusion states that mifepristone is a "dangerous and fatal product" which must be withdrawn "before more women suffer the known and anticipated consequences or fatalities. RU-486 is a hazardous drug for women. . . and its withdrawal from the market is justified and necessary to protect the public's health."139 Several different U.S. physician groups have joined in litigation to require the FDA to withdraw approval of RU-486.
The RCOG Guideline specifically discusses abortion beyond 15 weeks (referring to the 15 to 24 week period), presenting evidence that at this stage, women undergoing medical abortion were "significantly more likely to have a complication" than women undergoing a D & E (dilatation and evacuation) surgical abortion (29% complications for medical vs. 4% for D & E).140
Because of this, the RCOG recommends the D & E as method of choice for 15 weeks and beyond if the practitioner has the necessary instruments and sufficient skill.141 However, "for gynaecologists lacking the necessary expertise" use of mifepristone plus prostaglandin is appropriate" for an abortion at 15 to 24 weeks.142
Here the RCOG has acknowledged that medical abortion has much higher rate of complications beyond 15 weeks, 29% in the study by Autry et al. which they reference. Nevertheless, the RCOG considers it appropriate for less skilled abortion providers to use this method. Of note, the Guideline states that "the most common complication of medical abortion was retained products of conception requiring surgical evacuation," but even excluding these, women undergoing "medical abortions still had more complications, including one case of uterine rupture."143 Thus, the less skilled providers for whom medical abortion methods are deemed more appropriate are then in many cases faced with managing a surgical procedure for the complications that arise.
The Guideline does not discuss whether the high complication rate for medical abortion at this stage, or the skill of the provider, are considered appropriate to include in the informed consent process. Autrey et al. do recommend that patients considering a second trimester medical abortion "should be advised that they have a significant risk (21%) of requiring surgery for retained products of conception."144
Autrey et al. also caution that the true rate of complications may be higher than reported. "Because these abortions were performed in referral centers, complications may have occurred that were treated by the referring physicians without our knowledge."145 In this study of less than 300 patients, some of the complications were quite serious including hemorrhage with transfusion, patients with cervical laceration, "organ damage," and infections requiring intravenous antibiotics.146
However, overall in the literature there seems to be a grave lack of data on medical abortion at the later gestational ages and it is unclear from the Guideline at the referenced studies how the RCOG was able to conclude that medical abortion to 24 weeks could be considered as "safe and effective."
The RCOG Guideline cites a meta-analysis by Kahn et al. which showed clearly that "efficacy decreases with increasing gestational age"147 with a rate of complete abortion being 91% at 50-56 days148 (meaning, a 9% failure rate), and only 85% "success" for 57 days or greater149 (meaning, a 15% failure rate at 57 days and onward). However, this meta-analysis did not clearly identify any abortions approaching 24 weeks. A few of the studies included had cases up to 63 days, in one case, 63+ days, and two that specifically included up to 70 days, but many of the studies included went up to 49 days or 56 days only. Some of the reports considered did not specify gestational age at all, but there was no evidence that they included cases in the 15 to 24 week range.
Assuming the true failure rate of medical abortion is 15% at 57 days as Kahn found, and also assuming it is true as Kahn concluded that "efficacy decreases with increasing gestational age," then what might be expected for failure rates even beyond 70 days, much less 24 weeks? Data for both safety and efficacy of medical abortion during the second trimester seem to be quite limited but what little is available should be sufficient to raise grave concern about this method at this gestational period.
In regard to failure rates of medical abortion in general, Recommendation 16.5 states that the failure rate for medical abortion is between 1 and 14 per thousand (from 0.1% to 1.4%),150 but studies from U.S. and throughout the world have shown a much higher failure rate for medical abortion.151,152,153,154,155 The RCOG Guideline is able to demonstrate this lower failure rate by citing two studies of consecutive cases (one a continuation of the other) by Ashok et. al.156,157 in which vaginal misoprostol was used, and in the half of the cases, the protocol was altered to allow for a second dose of vaginal misoprostol.
Vaginal misoprostol, and with repeated, multiple doses, as we have already seen, is more effective at emptying the uterus. However, as we have shown above, it is also much more dangerous for the woman. Vaginal misoprostol was abandoned by Planned Parenthood in the U.S. following deaths of several North American young women after abortions using mifepristone along with vaginal misoprostol. Indeed, as we have seen, these deaths occurred after "successful" complete abortion, with no retained products. Vaginal misoprostol is prohibited in France. There has been at least one death reported from vaginal misoprostol without mifepristone.
In any event, Ashok et al. only included cases up through Day 63 so their efficacy data does not in any way address the efficacy of later medical abortions.158
Limitations of current research: Kahn et al. state, in their report on 54 studies of medical abortion: "Data on complications were very difficult to interpret because of the lack of standardized clinical protocols (eg. when surgical hemostasis is indicated for bleeding) and even shifting practices during the study period."159
In some reports, there are limitations on follow up data. For example, Ashok et al. concluded that 70% of women undergoing medical abortion would opt for the same procedure in the future,160 though recognizing that only one third of all women who underwent medical abortion returned the questionnaire.161
Conclusion: The U.S. experience continues to demonstrate an increasing number of adverse events reported to the FDA, with multiple physician groups litigating for withdrawal of this product. A U.S. Congressional committee report, following Congressional committee hearings, has concluded that mifepristone is a hazard to women's health, and that this product should be withdrawn, as we have seen above. The information we have presented here is only a small portion of the extensive evidence on the extreme health hazards associated with mifepristone.
The FDA Medical Officer Review162 as well as the Congressional report "The FDA and RU-486: lowering the standard for women's health"163 give a very different picture of the safety and efficacy of RU-486 compared to what is suggested in the RCOG Guideline. These two U.S. reports which include information from the French and U.S. clinical trials, from world wide studies and from recent U.S. experience, all bear reading and study. The actual transcript of the 2006 CDC-FDA workshop164 also is well worth study before action is taken to make mifepristone abortion readily available to the women of Northern Ireland, particularly under the specifications of the RCOG Guideline.
The State of Tennessee Senate Judiciary Committee has just recently (April, 2007) held hearings regarding the information which physicians should be required to disclose to women considering medical abortion. Although we believe the evidence would strongly recommend against moving forward with use of RU-486 in Northern Ireland, nevertheless, if it is to be used it is a necessity that detailed, accurate informed consent be provided to anyone consideration use of this dangerous drug.
Many young women, including the young teens who will be able to access medical abortion without their parents knowledge under the draft Guideline, will be led to believe that medical abortion is easy and safe, as easy and safe as taking a tablet. Yet if women were given accurate information about what they could expect to experience, they might well choose differently.
In the U.K., are most young women informed about bleeding that may go on for a month (as we have seen above) or that research demonstrates more pain with medical than with surgical abortion (according to a number of head to head comparison studies165,166,167,168,169,170,171)? Is she cautioned about less frequent but more serious complications that may occur, the immune suppression, the risk of death from sepsis or hemorrhage (as discussed above)? Are those women considering a second trimester medical abortion informed of the complication rate at that stage, or of the relative lack of data at the higher gestational stages? The literature is limited on what information women are actually receiving in the informed consent process. In the U.S., there has been reason for concern that it is not sufficient, which is the reason for the Tennessee Senate hearings.
Did this young woman, quoted in the New York Times, have any idea of the experience she was in for when she took her tablets? "I felt like I was dying...it hurt so much. I had contractions coming so fast, and I was sick to my stomach and dry heaving. I couldn't stop trembling and I felt so hot."172
If the people of Northern Ireland were acquainted with the information presented in the Congressional hearing, very likely few would want this legally available for their daughters, and very few would choose it themselves.
The authors have consistently opposed abortion and continue to do so; however, a careful examination of the claims made in this submission should alert people of conscience on either side of this contentious issue to the safety problems experienced by those who use mifepristone as an abortifacient.
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