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August 18, 2005

On That RU-486 Matter

Topics: Medicine

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Two of my favorite fellow bloggers are in a bit of a discussion about the safety of RU-486 being a real concern or a case of ""shoehorning science and medicine in order to fit an ideological agenda, misrepresenting risk and utilizing hyperbole."

Michelle Malken writes:

"Bill at INDC Journal, accuses me of "shoehorning science and medicine in order to fit an ideological agenda, misrepresenting risk and utilizing hyperbole" because I "hyped" the deaths of four Californian women who used RU-486, the abortion pill.

Bill implies that RU-486 is safe because only a small number of deaths have been linked to it. He notes (correctly) that plenty of other drugs are on the market despite being linked to far more than four deaths.

This is a good point, and I should have noted it in my post.

On the other hand, Bill cautions Michelle:
... and anyone else that writes about science or medicine in the context of politics, to use a bit of perspective when working backwards from an ideological presumption. We're all prone to making these mistakes, especially in the context of a political issue that commands our passion.
Although I hate to sound like a politician by seeing a middle ground here, but I do see both bloggers as having valid points of few. As Bill writes, we're all prone to make mistakes when "working backwards from an ideological presumption," especially in medicine or science. So let's take a look at the science, not the statistics, for just a moment.

In July 2005, Stanley J. Lloyd, PharmD,proposed a mechanism for the link between RU-486 and fatal infections. The abortion drug mifepristone (Mifeprex,TM RU-486) has been linked to rare cases of fatal bacterial infections, but until now the connection has not been clearly understood.

In "Pathophysiology of mifepristone-induced septic shock due to Clostridium sordellii(a gram-positive, toxin-forming anaerobic bacteria)," author and Brown University professor Ralph P. Miech, MD, PhD, proposed two models of how this devastating reaction may occur. The article appeared in The Annals of Pharmacotherapy Online and in the journal's September print issue(info here).

During an abortion, mifepristone works by blocking the effects of progesterone, shutting off nutrition to the placenta and fetus. However, as Miech points out, the antiprogesterone effects of mifepristone also cause changes in the cervix that allow Clostridium sordellii, a common vaginal bacteria (part of the normal vaginal flora in about 10% of women), to enter the cervical canal. Clostridium sordellii thrives in this low-oxygen environment and derives nutrition from the decaying fetal tissue. Meanwhile, other hormonal effects of mifepristone, known as antiglucocorticoid actions, are taking place throughout the body. Through two models proposed by Miech, these antiglucocorticoid effects may interfere with chemical regulators known as cytokines, offsetting the delicate balance between over- and under-activation of the immune system. This disruption impairs the body's ability to fight off C. sordellii and may help spread the bacteria's toxic by-products, a combination that sometimes results in widespread septic shock.

A little more detail on Dr. Miech's two possible theoretical mechanisms for how RU-486 could lead to runaway infection and septic shock from Clostridium sordellii help to make this somewhat clearer:

In the first proposed mechanism, RU-486 interferes with the hypothalamo-pituitary-adrenal axis, which is the system responsible for producing corticosteroid hormones. This interference leads to excessive production of cortisol from the adrenal cortex which, in turn, causes excessive levels of the cytokine IL-10. Finally, the high levels of IL-10 inhibit the production of proinflammatory cytokines such as IL-1 and IL-6. Without these cytokines, C. sordellii grows unchecked.

In the second proposed mechanism, RU-486 blocks glucocorticoid receptors on immune system cells such as macrophages, monocytes, and neutrophils. With these receptors blocked, the cells cannot produce IL-10. This leads to uncontrolled production of proinflammatory cytokines such as IL-1 and IL-6 which, in turn, can contribute to septic shock by causing systemic vasodilation and a critical fall in blood pressure.

It is possible that one, both, or neither of the mechanisms are involved, but I believe it more likely that both mechanisms are involved. A controlled clinical study in a laboratory model has not been published (that I could find), and such a study should have been conducted prior to approval by regulatory agencies.

At least 5 women in the US and Canada have died from septic shock after taking mifepristone. C. sordellii has been linked to 3 of those cases, while the bacteria remains unidentified in the others. C. sordellii infections are rare outside of mifepristone use and have proven particularly dangerous because they often lack the usual warning signs, such as fever and tenderness on examination.

In 2004, the labeling of mifepristone was amended to include a black box warning about bacterial infections, sepsis, and death that may occur after use. A citizen petition for withdrawal of mifepristone from the US market has been submitted to the FDA. It cites numerous safety concerns as well as procedural violations that occurred during the drug's approval process.

Clinicians, including a spokesman for the American College of Obstetricians and Gynecologists (ACOG), have said that the abortion drug appeared to present no special infection risk.

A little more detail on Dr. Miech's two possible theoretical mechanisms for how RU-486 could lead to runaway infection and septic shock from Clostridium sordellii helps to make this somewhat clearer:

In the first proposed mechanism, RU-486 interferes with the hypothalamo-pituitary-adrenal axis, which is the system responsible for producing corticosteroid hormones. This interference leads to excessive production of cortisol from the adrenal cortex which, in turn, causes excessive levels of the cytokine IL-10. Finally, the high levels of IL-10 inhibit the production of proinflammatory cytokines such as IL-1 and IL-6. Without these cytokines, C. sordellii grows unchecked.

In the second proposed mechanism, RU-486 blocks glucocorticoid receptors on immune system cells such as macrophages, monocytes, and neutrophils. With these receptors blocked, the cells cannot produce IL-10. This leads to uncontrolled production of proinflammatory cytokines such as IL-1 and IL-6 which, in turn, can contribute to septic shock by causing systemic vasodilation and a critical fall in blood pressure.

It is possible that one, both, or neither of the mechanisms are involved, but I believe it more likely that both mechanisms are involved. A controlled clinical study in a laboratory model has not been published (that I could find), and such a study should have been conducted prior to approval by regulatory agencies.

At least 5 women in the US and Canada have died from septic shock after taking mifepristone. C. sordellii has been linked to 3 of those cases, while the bacteria remains unidentified in the others. C. sordellii infections are rare outside of mifepristone use and have proven particularly dangerous because they often lack the usual warning signs, such as fever and tenderness on examination.

In 2004, the labeling of mifepristone was amended to include a black box warning about bacterial infections, sepsis, and death that may occur after use. A citizen petition for withdrawal of mifepristone from the US market has been submitted to the FDA. It cites numerous safety concerns as well as procedural violations that occurred during the drug's approval process.

Clinicians, including a spokesman for the American College of Obstetricians and Gynecologists (ACOG), have said that the abortion drug appeared to present no special infection risk.

Noting that 460,000 U.S. women have used the drug since the FDA approved it in 2000, Steven Sondheimer, M.D., a professor of obstetrics and gynecology at the University of Pennsylvania Medical School, said "it appears to be safe."

The rates of uterine infection after medical abortion are so low that ACOG does not recommend prophylactic antibiotics before the procedure in its practice guidelines(an important point but not very good for the patient if she has a latent Clostridium infection and a normal blood count - and a physician wouldn't expect a young, seemingly healthy woman, to be susceptable to a C.s instigated reaction - ergo dangerous).

">No data support such treatment with medical abortion," the guidelines state. In clinical trials involving more than 500 participants, the infection rate typically varied from 0.09% to 0.5%, the guidelines said.

In the way of a summation I'd like to make a couple of points. First of all, idealogically, I believe that abortion by any means is the murder of an unborn child, and that it is wrong, immoral and should be unlawful. Having gotten that matter out in the way of a disclaimer, if you are one of ten percent of women that have Clostridium sordellii in your vaginal flora, I believe that with what little we know now about the possible mechanisms involved in possible fatal side effects, using RU-486 is a risk. If you are one of the ninety percent of women who don't have Clostridium sordellii in your vaginal flora, taking RU-486 is less a risk. On the other hand, if one or both of the proposed mechanisms are not involved in fatal side effects resulting from the use of RU-486, a possibility, then both camps may be equally at risk. Does it look like the just the "tip of the iceberg?" From what we know as we speak, we don't know! Do I think it's the tip of the iceberg? From what I've read about the pharmacology and what I know about the immunoendocrinology, I don't believe that anyone at this time believes it to be the tip of the iceberg. And as Bill offers in his post, the regulatory agencies are fulfilling their mandate to look out for public safety, but the jury is still out on their conclusions.

So far, the risk seems small - unless you become one of the chosen few!

However, I still believe that it's a murder pill, and nobody can say that taking RU-486 is without any risk. There are five women, so far, that know better. And there may be more.

Other coverage
OMFSerge at Imago Dei writes "RU-486: Unsafe Regardless of Ideology"

Steve at Outside The Beltway writes, "Calling Michelle Malkin on Her Nonsense"

Righteous Indignation writes: "Collateral Damage and RU-486"

Related:
FDA ALERT
Press release - Annals of Pharmacology article

Rapid activation of JNK and p38 by glucocorticoids in primary cultured hippocampal cells.
Causal Relationship Between RU-486 and Deaths Explored
Safety of mifepristone abortions in clinical use.

Home self-administration of misoprostol for medical abortion up to 56 days' gestation.

RU-486 Files(mostly pro-life view)

RU-486: The Uncontrolled Birth Control Pill
Mifepristone Questions and Answers

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Posted by Richard at August 18, 2005 4:31 PM



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