|
July/August, 1998 Volume XIII Number 1
By: Lawrence F. Roberge, M.S.
c 1998: Lawrence F. Roberge
Editor's note: Lawrence Roberge M.S. was on the scientific advisory group that investigated RU486 for Americans United for Life (AUL) in 1994-1995. As a result of their research, AUL filed a complaint letter against the Food and Drug Administration (FDA) blocking the FDA attempt to put RU486 on fast track approval. Also as a result of this research, the FDA required the adverse effects information to be incorporated into the drug warning literature. The following article is based on some of that research.
RU486 (also known as Mifepristone) has been a drug with a great deal of controversy surrounding it. Early research was directed at the drug as a glucocorticoid receptor blocker for possible anti-cancer applications, (1). But the drug's most promising application was as an abortifacient. There in lies the true controversy.
This article will only briefly mention the application and avoids the longer political, social, and marketing morass that has encircled RU486 in the 1990's (SEE 2). Rather, the true purpose of this paper is to review the data surrounding the problems and complications of RU486 as an abortifacient. As pro-abortion advocates chant a mantra of "safe legal abortion"; the final conclusion from the following research is more likely, "It maybe legal, but its' not safe!"
Mechanism
RU486 acts as an abortifacient. The drug's actions are effective for the first 49 days after conception. The mechanism of action is as follows.
RU486 blocks progesterone receptors in the uterine lining. Progesterone is necessary in the woman to maintain the lining of the uterus, which, during pregnancy is loaded with blood vessels, acts as a life support system for the developing embryo (life). (Note: the developing life for the first 60 days post conception is medically referred to as an embryo, whereas after 2 months it is referred to as a fetus.) As the embryo implants into the uterine lining, the embryo grows dependent upon the mother's uterine blood supply for nutrients, oxygen, and waste removal. Thus, any cut off of the blood supply would lead to the rapid death of the developing life.
RU486 acts to block the effects of progesterone to maintain the uterine lining. As the progesterone signal is cut off in the uterus, the uterine blood vessel lining begins to breakdown and subsequently the embryo dies (1).
Now as the embryo is dead, the uterus may try to expel the embryo and its surrounding tissues. But, using RU486 alone results in only about a 60-65% (3,4) success rate. Therefore many doctors give a second very powerful drug-prostaglandins (the best known is Misoprostol-also known as Cytotec TM ), which causes very strong (and sometimes very painful) uterine contractions to expel the dead embryo. Using the dual drug system, RU486 and Cytotec TM, the success rate rises to 84 to 95% (5). In small cases, 5 to 15% of patients, the patient is required to undergo a surgical procedure called a dilation and curettage (D&C) to remove any remaining embryonic tissue (6). In some reports (7), the women report discharging the embryo into the toilet under great pain due in part to the powerful uterine contractions.
RU486 pharmacology basics
Several important points must be observed at this point. Use of RU486 to induce an abortion is not like a surgical abortion. The most widely used technique for surgical abortion (8) is a D&C, whereby the embryo is scraped off the uterine wall. A surgical abortion occurs at a certain moment of time and the patient then returns home. The process using RU486 requires that the woman be given the drug at the clinic and then return back to the clinic within 24 to 48 hours for the second drug (the prostaglandin-usually Cytotec TM ), where upon within 12 to 24 hours the woman will, via strong uterine contractions, expel the embryo.
What this means is that the process requires more time for the action to occur (the abortion) as well as less monitoring by medical authorities for any complications. The patient must decide on her own if complications warrant a return visit to the clinic or to the emergency room. This decision making could be hampered by guilt, desire to maintain the abortion as a secret, or problems of obtaining transportation to the clinic or hospital. Each delay factor increases the risk of death or further trauma. We will discuss this shortly.
Also the drug process (RU486) is different as the drug remains in the woman for a prolonged period of time. A drug "half life" is a pharmaceutical term to describe the time period by which « (one half) of the active drug is broken down by the body and/or removed from the body. Also, a drug "metabolite" is the drug by-product, produced by the body's metabolic enzymes (usually from the liver) acting to breakdown or chemically alter the active drug. It must be noted that drug metabolites can still retain some of the original drug's properties!
With regard to RU486, the half-life is 25.5 to 47.8 (9) hours, depending if the drug is given in a single or multiple dose. Also, one study has shown that the active drug may linger in the woman's blood stream up to 10 days after taking the drug (10). Finally, the RU486 metabolites are partly active (they also will bind to progesterone and glucocorticoid receptors) and the metabolites can linger up to 5 days after administration (11, 12). This is important to remember as some effects of the drug RU486 may last well past (10 to 15 days) after administration and the time of the actual abortion. This writer questions whether women are properly informed of these aspects of the drug. The actions of having the drug last so long in the body may play a role in the following complications.
Adverse effects
Immunosuppression
In many of the studies with RU486, a common side effect is infections, usually in the pelvic or genital tract (13, 14). One medical study stated that patients required a 6-week follow up treatment of antibiotics (15). Whenever the RU486 treatment led to an incomplete abortion (thus, requiring a D&C for a follow-up), up to 29.4% of the women reported an infection requiring antibiotic treatment (15).
Why?
Several factors are now understood. RU486 will itself suppress the immune system by causing the patient's cortisol to rise (16). Cortisol, a glucocorticoid hormone, acts to suppress the immune system by diminishing the ability of certain white blood cells (leukocytes) to migrate to sites of tissue infection; acts to suppress lymphocyte (another type of white blood cell) gene expression; and acts on the capacity of neutrophils (another type of white blood cell) to kill ingested bacteria cells (thus blocking this white blood cells' capacity to stop infection). All of these effects hinder the immune systems capacity to fight off bacterial infection (17).
Also, a study by Van Voorhis et al (18) demonstrated that RU486 alone acted to hinder white cell activity, but, the effect of suppressing white cells is magnified greatly by the combined presence of cortisol and RU486!
Finally, one study by Moran et al (19) mentioned unpublished data that Cytotec TM (the prostaglandin given to enhance the uterine expulsion of the embryonic remains) can work in a synergistic manner with steroids (like cortisol) to suppress immune function.
This may explain the persistence of infections in RU486 patients. The scenario is that first RU486 acts to damp down immune function, while cortisol levels rise, then cortisol and RU486 act together and further magnify immune system suppression, and finally, as Cytotec TM is given to the patient, the presence of Cytotec TM and high cortisol levels render the immune system incapable of defending against infection, especially an infection brought on by the ensuing abortion and subsequent uterine bleeding. This allows bacterial infections to gain a significant foothold in the pelvic or genital region, and would require strong antibiotics to fight off and finally defeat the infection.
Since the risk of infection is so prevalent, all users of RU486 need to be warned of the infection hazard. The problem is further complicated if the woman using RU486 has AIDS/HIV or other immunosuppressive diseases, since any infection would almost certainly run rampant in the patient and become a cause for a possible patient death.
One final note on this topic. Margie Profet produced a study examining (20) menstruation as a defense factor against the development of female reproductive infection. In her work, she notes the dynamic microbiological activity within the female reproductive tract and lists various methods that infection can be introduced. Should the immune system weaken (as via RU486) any infection from a hostile microorganism could cultivate in the female reproductive tract. Also, beyond the natural microbiological activity within the female reproductive tract, microorganisms can be transported into the tract by either seminal fluid or via attachment to sperm. These various pathogens that "hitch a ride" in seminal fluid or on sperm, include E. Coli, Chlamydia, N. Gonorrhea (pathogen that causes Gonorrhea), Trichomonad (which causes Vaginitis), or even Cytomegalovirus (21, 22, 23, 24, 25, 26, 27). With the immune system suppressed via RU486 (as well as elevated cortisol levels and Cytotec TM) and with the half life of the active drug and its partly active metabolites lasting as a long as 10 to 15 days after administration, any RU486 patient may have to refrain from active sexual relations for a significant period after receiving the drug to avoid a serious infection. Again, this writer wonders how many doctors will inform their patients of this point!
Pain
During use of RU486 and Cytotec TM, medical studies cited patients reporting pain (79.1%, see 28) or severe uterine cramps (80.5%, see 7) to such a degree that many required opiate based painkillers. The percentage of patients in the studies reporting pain ranged from 57.1% to as high as 79.1%. Many patients required and were treated with injections of very strong analgesics (13).
The problem with this issue is that many patients go home after receiving RU486 and may not have easy access to powerful narcotic painkillers (which require a doctor's prescription). Furthermore, in this pill popping, "self medicating", instant pain relief nation; use of over the counter medications would be dangerous, if not fatal.
How?
Use of nonsteroid anti-inflammatory drugs (NSAIDs) will not relieve pain, but due to the NSAIDs capacity to block blood clotting, these drugs could enhance bleeding (See Chart 1). One case was reported in January 1996 (29) of a near death due to massive hemorrhaging (bleeding) by a patient using RU486. It must be noted that by the very nature of the RU486 abortion, the woman will bleed significantly during the process of expelling the embryo and associated tissues.
NSAIDs will only enhance the blood loss incited by an RU486 abortion and will only increase the risk of death to the woman.
One other curious research paper reported in 1990 (30) that women who use RU486 to abort their first pregnancy and then used the pain reliever acetaminophen (commonly know by its trade name TYLENOL TM) has an increase in reported pain. Scientists do not know why, but acetaminophen increased painful suffering in the presence of RU486.
Bleeding
As previously mentioned, bleeding is a serious issue when dealing with RU486 abortions. A series of studies (13, 15, 31, 32) demonstrates that 1 to 11% of the women using RU486 suffered profuse bleeding. Some cases even required blood transfusions! (15, 29, 31, 32)
If a woman is not told to avoid over the counter pain medications, like NSAIDs, this could clearly increase the incidence of severe bleeding and possible death.
Sleep
Sleep is a necessary component for the maintenance of health of any individual. But more so, it is the various components of sleep that are important to both physical and mental well being of a person.
With that much in mind, one study (33) by Wiedemann et al demonstrated how RU486 disrupts sleep: including total sleep time, slow wave sleep, and REM (Rapid Eye Movement) sleep. RU486 diminished total sleep time, reduced both slow wave and REM sleep, and caused increased sleep time re-awakenings (i.e. "kept waking up in the middle of the night").
REM sleep is referred to as "dream sleep." This is the stage of sleep when most dreaming occurs. There are various theories as to why we sleep, but many psychologists believe dream sleep is useful in helping the individual cope with stress and stressful events of life (34).
As undergoing an abortion will put the woman under psychological stress and tension, it is sad to note that the very same drug used to induce the abortion will also suppress the woman's dream mechanisms (in the brain) which are needed to help the individual cope with the psychological stresses (e.g. guilt, shame, remorse, grief, etc.) of the event. It may be interesting to note that after several days of REM sleep suppression (which could occur since RU486 may linger up to 10 days in the woman's blood stream), the brain then increases the amount of REM sleep each night. This is referred to as REM REBOUND (35). This may help to explain (in part) any incidents where RU486 patients have extended periods of dreams or nightmares.
One must wonder that since RU486 induced the abortion and its subsequent physical and psychological stress, how many women suffered further physical or psychological harm due to sleep reduction, REM sleep (dream) deprivation, and the subsequent REM rebound (as the RU486 drug blood levels have dissipated)?
The future pathway
One other important point must be noted regarding RU 486 and its marketing. It will become much more freely available in the not so distant future. How?
Note that many pharmaceutical manufacturers convert over their products from prescription only (RX) to over the counter (OTC) products after a decade or so. This is called RX to OTC conversion. These conversions have been demonstrated by the successful marketing of such products as Aleve TM (sodium naproxen), Rogaine TM , Motrin TM (ibuprofen), and Tagamet TM. This process occurs when the pharmaceutical manufacturer's patent is about to expire. With the RX to OTC conversion, the pharmaceutical manufacturer gets a new lease on the life of the drug product. The FDA has banned RX to OTC conversions on only narcotic drugs. Therefore, when the RU486 patient approaches expiration (in 2002, See 36), it is conceivable that somewhere in the near future, RU486 will be as easy to buy at the discount drug store as aspirin, condoms, and mouthwash. At that time, how many abortions will occur? Only God may know.
Rather than surgical abortion, RU486 has been a herald towards a new method of abortion-pharmaceuticals. This method can reduce the need for clinics, allowing doctors to shield patients from surgical procedures, and yet allow women the expulsion of pregnancies in the privacy of their home bathrooms. Although this may appear efficient, the murder of the unborn life and the physical and psychological harm to the mothers are certainly unconscionable.
But, this technology has its risks. Patients must know any and all warning signs of complications to allow time for the woman to take the necessary steps (e.g. emergency room treatment, blood transfusion, antibiotics, etc.); steps necessary to prevent injury or death. In light of the paucity of information regarding complications, both physical and psychological, pro-life forces at present have a strategic advantage avenue to warn women from not just the point of saving the unborn life (some unfortunately will not listen to this avenue), but provide information to warn women about the complications of almost certain hemorrhaging, infection, intense pain, sleep disruption, and psychological trauma.
The challenge to pro-life is clear. It is necessary to become quite familiar with this technology and its complications as the drug RU86 enters US and foreign markets. Pro-life forces with the necessary technical, medical and psychological knowledge could save unborn children from death and save their mothers from tremendous agony (both physical and mental) or even death.
Lawrence Roberge is a member of the New York Academy of Science, Catholic Association of Scientists and Engineers, Society of Catholic Social Scientists, and Center for Bioethics and Human Dignity. Mr. Roberge teaches at Elms College (Chicopee, MA) and Lesley College (Cambridge, MA), He has researched issues of reproductive medicine, genetics, neuroscience, and biotechnology. He is the author of the booklet, The Cost of Abortion (1995, Four Winds Publications).
BIBLIOGRAPHY:
Ulman, et al. RU486, Scientific American. 262, 6, June 1990, 42-48.
Glasow, Richard D., With Key RU486 Lawsuit Settled, Proponents Aim for US Sales by year's end. The RU486 Report, Life Issue Institute, Feb-Mar 1998, 1-4.
Sitruk-Ware et al, The Use of the Antiprogestin RU486 (Mifepristone) as an Abortifacient in Early Pregnancy-Clinical and Pathological Findings: predictive Factors for Efficacy. Contraception, 41, 1990, 221-243.
The RU486 Collaborative Group, Termination of Early Pregnancy by RU486 Alone or in Combination with Prostaglandin, Chinese J. Obst. & Gyn., 25, 62, 1990, 31-34.
McKinley et al, The Effect of Dose of Mifepristone and Gestation on the Efficacy of medical Abortion with Mifepristone and Misoprostol, Human Reproduction, 8, 1993, 1502-1505. Chan et al, Blood Loss in Termination of early Pregnancy by Vacuum Aspiration and by combination of Mifepristone and Gemeprost, Contraception, 47,85,1993, 85-95. Peyron et al, Early termination of Pregnancy with Mifepristone (RU486) and the Orally Active Prostaglandin Misoprostol, N. Eng. J. Med., 328, 1993, 1509-1513.
Henshaw et al, Characteristics of US Women Having Abortions 1987, Fam. Plann. Perspect., 23, 2, 1991, 75-81.
Heikinheimo, O., Pharmacokinetics of Antiprogesterone RU486 in women During Multiple Dose Administration, J. Steroid Biochem., 32, 1A, 1989, 21-25.
Lahteenmaki et al, Pharmacokinetics and Metabolism of RU486, J. Steroid Biochem., 27, 4-6, 1987, 859-863.
Heikinheimo, O., Antiprogesterone Steroid RU486: Pharmacokinetics and Receptor Binding in Humans, Acta Obstet. Gyncol. Scand., 69, 4, 1990, 357-358. Heikinheimo et al, Pharmacokinetics of the Antiprogesterone RU486: No Correlation to Clinical Performance of RU486, Acta Endocrinol., 123, 3, 1990, 298-304.
Hill et al, The Efficacy of Oral Mifepristone (RU 38, 486) with a Prostaglandin E1 Analog Vaginal Pessary for the Termination of Early Pregnancy: Complications and Patient Acceptability, Am. J. Obstet & Gyn., 162, 1990, 414-417.
Rodger et al, Induction of Therapeutic Abortion in Early Pregnancy with Mifepristone in Combination with Prostaglandin Pessary, Lancet, ii, 1987, 1415-1418.
World Health Organization, Pregnancy Termination with Mifepristone and Gemeprost: A Multicenter Comparison Between Repeated Doses and a Single Dose of mifepristone, Fertil. Steril., 56, 1, 1990, 32-40.
Bertagna et al, The new Steroid Analog RU486 Inhibits Glucocorticoid Action in Man, J. Clin. Endocrinol. Metab., 59, 1, 1984, 25-28.
Schulster et al, Molecular Endocrinology of the Steroid Hormones, 1976, New York, John Wiley & Sons, 282.
Van Voorhis et al, The Effects of RU486 on Immune Function and Steroid-Induced Immunosuppression IN VITRO, J. Clin. Endocrinol. Metab., 69, 1989, 1195-1199. Moran et al, Prevention of Acute Graft Rejection by the Prostaglandin E1 Analogue
Misoprostol in Renal-Transplant Recipients Treated with Cyclosporine and Prednisone, N. End. J. Med., 322, 1990, 1183-1188.
Profet, M., Menstruation as a Defense Against Pathogens Transported by Sperm, Quart. Review Biol., 68, 3, 1993, 335-386.
Keith et al, On the Causation of Pelvic Inflammatory Disease, Am. J. Obstet. Gynecol., 149,1984, 215-224.
Friberg et al, Attachment of Escherichia coli to Human Spermatozoa, Am. J. Obstet. Gynecol., 146, 1983, 465-467.
James-Holmquest et al, Differential Attachment by Piliated and Nonpiliated Neisseria gonorrhoeae to Human Sperm, Infect. Immun., 9, 5, 1974, 897-902.
Toth et al, Asymptomatic Bacteriospermia in Fertile and Infertile Men. Fertil. Steril., 36, 1, 1981, 88-91.
Friberg et al, Chlamydia Attached to Spermatozoa, J. Infect. Dis., 152, 1985, 854.
Toth et al, Evidence for Microbial Transfer by Spermatozoa, Obstet. Gynecol., 59, 1982, 556-559. Lang et al, Demonstration of Cytomegalovirus in Semen, N. Eng. J. Med., 287, 1972, 756-758. Norman et al, Uterine Contractility and Induction of Abortion in Early Pregnancy by Misoprostol and Mifepristone, Lancet, 338, 1991, 1233-1236.
Glasow, Richard D., RU486 "Near-Death" Accident in Iowa Raises Safety Questions, The RU486 Report, Jan 1996, 1-4.
Weber, B. and Fontan, J.B., Acetaminophen as a Pain Enhancer During Voluntary Interruption of Pregnancy with Mifepristone and Sulprostone, Eur. J. Clin. Pharmacol., 34, 1990, 609.
Rodger et al, Induction of Early Abortion with Mifepristone (RU486) and Two Different Doses of Prostaglandin Pessary (Gemeprost), Contraception, 39, 1989, 497-502.
WHO Task Force on Post-Ovulatory Methods of Fertility Regulation, Termination of Pregnancy with Reduced Doses of Mifepristone, BMJ, 307, 1993, 532-537.
Wiedmann et al, Antiglucocorticoid Treatment Disrupts Endocrine Cycle and Nocturnal Sleep Pattern, Eur. Arch. Psychiatry Clin. Neurosci., 241, 6, 1992, 372-375.
Lefrancois, G. R., 1980, Psychology, Belmont, Ca, Wadsworth, pg. 83.
Wortman, C. B., Loftus, E. F., and Marshall, M., 1981, Psychology, New York, NY, Alfred A. Knopf, pg. 379.
Glasow, Richard, D., New Contract Dispute Delays US RU486 Marketing, The RU486 Report, Life Issues Institute, July 1997, Pg. 1-3.
OTHER
FEATURE
ARTICALS
Dump dating?
RU486: The hidden effects
|
|
