Plan B, again

Here is a link to a summary of the two papers that describe the clinical studies of the active ingredient in Plan B: http://www.obgyn.net/contraception/contraception.asp?page=/news/popcoun…. Two letters to the editor in the NYTimes on Saturday got it wrong as well. It does not help that the FDA website offers what appears to be a politically motivated description of the effect of Plan B here: http://www.fda.gov/cder/drug/infopage/planB/planBQandA.htm.

LM Wanderer

Heh. When we went through IVF, we were given Plan B (well, progesterone, actually) to help maintain the receptivity of the uterine lining to pregnancy. Seems that some women don't respond well enough to the progesterone signal from the implanting embryo and thus wind up shedding that lining (and the pregnancy). The result of this process turned five earlier this year.
This whole disinformation campaign is based on confusion in the public's (and some physicians') minds between Plan B and RU-486.

The same mistake was repeated on the ABC nightly news broadcast tonight.

There is the naive assumption that this misrepresentation was a mistake.

And it keeps on happening - and it is still a mistake.

ummmm ....

Oh, the "confusion" on the part of the more sophisticated anti-Plan B folks is undoubtedly intentional. But I'll bet that many of those disseminating that confusion are indeed naively mistaken, which isn't surprising since few have the background to understand the reproductive hormone cycle, and so must trust the "experts."

Just another example how expertise is debased for political purposes.

Maybe the poor reporters were getting their information from Physicians and Surgeons for Scientific Integrity.

http://www.pssiinternational.com/

This illustrious group was recently mentioned in a posting titled Poor Orac on Panda's Thumb. Pretty scary that it is possible to become a medical doctor in this country and have no understanding at all about biology. I guess "Biology" must be all greek to some of them...the only problem with that is I thought they were also supposed to understand Greek.

So given that, maybe you can forgive the journalists' lack of comprehension of the fact that plan B prevents ovulation so there can be no fertilized egg. Then again if it weren't for Monthy Python I wouldn't know that every sperm was sacred either...

So, I guess this means there's also a chance that if I take it, I'll get the proportional strength of a spider, too. Cool!

The subscription medical resource for clinicians, UpToDate, lists prevention of implantation as one mechanism of action for Plan B. Note that I'm far from pro-life, and I agree with you on the principle here, but this is what the medical literature says. I'm working on looking up the references listed on the UpToDate writeup now.

Lots of sources say that. Try tracking down the primary literature, though, and you won't find any supporting evidence, other than general statements that progesterone thickens the endometrium (which is not necessarily a bad thing for implantation...). What you really have is a recognition that you are tinkering with the normal progression of hormones in the woman, and maybe it does something else, but there's no good reason given for it.

Now what has happened is that this vague possibility is canonized in the secondary literature, and everyone feels the need to cautiously echo it.

Paul wrote:

"Look, it prevents ovulation, OK? Not implantation."

Wrong. It definitely can affect implantation after fertilization.

http://ec.princeton.edu/questions/ecabt.html

"Medical authorities such as the United States Food and Drug Administration/National Institutes of Health and the American College of Obstetricians and Gynecologists define the beginning of pregnancy as the implantation of a fertilized egg in the lining of a woman's uterus. Implantation begins five to seven days after fertilization (and is completed several days later). Emergency contraceptives work before implantation and not after a woman is already pregnant. Depending on the time during the menstrual cycle that they are taken, ECPs may inhibit or delay ovulation, inhibit tubal transport of the egg or sperm, interfere with fertilization, or alter the endometrium (the lining of the uterus), thereby inhibiting implantation of a fertilized egg.
They work before implantation, but not necessarily before fertilization.

I was halfway listening to the stupid ABC piece and caught their statement on implantation. Because I had read your post, I immediately recognized that they were wrong. Thanks, PZ.

(I hope someday they fix the commenting problems on SB.)

The ABC News report stated:

"Plan B, the brand name for emergency contraception, can prevent a fertilized egg from implanting in the uterus after a woman has unprotected sex or experiences contraceptive failure (like a condom breaking). It has to be taken within 72 hours of having sex and is made of the same hormones used in birth control pills."

This is an absolutely correct statement.

Charlie, the quote you provided was talking about emergency contraception in general, and not specifically about Plan B. Also, note the use of the word "may" before the list of possible modes of action of emergency contraceptives. To make your interpretation correct, that word would have to be removed from the quote.

Anyway, Charlie, who gives a shit? Do you know how many worthless zygotes are flushed down the toilet every day because they fail to implant? Maybe I should have a funeral for my underpants because there might occassionally be some poor little zygote in there at the end of the day.

This is an absolutely correct statement.

To a wingnut, it is. In reality it's at best misleading, since the primary effect -- suppressing ovulation -- is completely neglected. There could be a grain of truth in the statement -- altering the endometrium is going to have an effect on fertility. But as I mention in an earlier comment, this may in some cases enhance fertility where a not-yet-implanted embryo is present.
Most lies have a grain of truth in them. "Prevent a fertilized egg from implanting in the uterus" doesn't, in a strict sense, contradict "prevent an egg from being released to be fertilized" -- preventing release most definitely has the effect of preventing implantation. In politics, this form of lying is called "spin."

Charlie,

The claim repeated by ABC has been debunked by several peer-reviewed papers in the last few years. See the previous Plan B and RU486 threads, or the Wikipedia article on Emergency Contraception for discussion and citations.

Basic qualitative reasoning suggests that Plan B would not inhibit implantation; if anything, it might promote it. Emprical results in animal models and in humans seem to show that it does neither---it fails an eighth of the time or so precisely because it does NOT inhibit an already-fertilized egg from implanting.

That's good news or bad news, depending on your point of view. If you consider simple contraception OK, but don't want to prevent implantation of fertilized eggs, it's good.

If you want to avoid the 1-in-8-or-so failure rate, it's good to have RU486 or something else available as a backup.

Paul W wrote:

"The claim repeated by ABC has been debunked by several peer-reviewed papers in the last few years. "

I would use the word "inconclusive" rather than "debunked".
The Wikipedia article that you refer to says:

""Emergency contraception may, however, prevent the implantation of an embryo in cases where it fails to prevent fertilization in the first place. Although the United States Food and Drug Administration, National Institutes of Health, the American College of Obstetricians and Gynecologists and other health agencies define pregnancy as beginning with implantation, some pro-life medical professionals, embryology texts, and activists argue that preventing implantation is unethical, as the blastocyst (early-stage embryo) then dies instead of growing into a fetus and, ultimately, being carried to term...Recent medical studies in animals (the rat and the monkey) were inconclusive as to how often or whether emergency contraception prevents implantation; however, this mechanism of action cannot be ruled out in all cases, as it is impossible to prove a negative. Therefore, women who believe it is immoral to prevent a fertilized egg from implanting may wish to avoid use of this drug."

I have no problems with Plan B and I would recommend it, even to my own children. I think it's a valuable and worthwhile addition to medicine.
On the other hand, I also recognize that there are some people who sincerely believe that life begins at conception (fertilization) and those persons who choose to believe this should not be lied to and should be given all the available information so they can make informed choices based on their own ethical and religious beliefs.

Hmmm, my trackback didn't seem to work - I started writing such a long comment that I figured, well, I might as well put it on my blog! Here is the link:
http://www.inoculatedmind.com/?p=40

Charlie, your quotes are all talking about ALL "emergency contraception" in toto, not specifically/only about Plan B. Some emergency contraception *does* work by preventing implantation. There is no evidence that Plan B itself, on it's own, independent of any other emergency contraception does.

Capice?

Charlie, I understand and appreciate what you're trying to say. Nevertheless, you're effectively wrong. Plan B "can prevent a fertilized egg from implanting in the uterus" is NOT an absolutely correct statement, and indeed is a quite misleading one.

Please do some more thorough digging, most especially using the links and citations provided in this posting and PZ's other posts on the subject. Most of what you've been providing has been of the "oh yeah, well all these people say it prevents implantation or may prevent it" variety, without solid data backing the claim. As PZ and others point out in this post and the linked resources, this was prevailing conventional wisdom despite an utter lack of evidence. There is NO evidence backing that claim, recent studies looking for it have failed to find it, and some evidence contradicts it (as noted within the wikipedia article, within the philosophical limitations of proving a negative).

The data thus far shows no reason to think that Plan B affects anything but ovulation, in terms of contraceptive effects, and some reason to think it does not. If it has any other mode of action, given the statistics of its success and failure, it is likely to be negligible.

I appreciate your concern, but I would not call "Plan B does not prevent implantation" a lie. I would call it a sound conclusion based on good scientific evidence. At most, I would offer the qualification that there is a tiny chance that in a tiny number of cases it may discourage OR encourage implantation. I recognize that for some people, that may be enough to discourage its use, and of course you and I have already established our disagreement with their opinions.

At most, I would offer the qualification that there is a tiny chance that in a tiny number of cases it may discourage OR encourage implantation.

And this is true of many other drugs, as well. There are lots of drugs out there that might, unbeknownst to us, affect implantation sometimes by some unknown mechanism. (And non-drug influences as well.)

Charlie---

I would say that the claim about Plan B has been "debunked"; even if the tests are "inconclusive" in this minor sense.

debunk: tr.v. To expose or ridicule the falseness, sham, or exaggerated claims of: debunk a supposed miracle drug.

I'd say the medical claim that Plan B inhibits implantation has been exposed as probably false and certainly exaggerated; it is basically untrue.

Nobody seems to be worried about the potential for rare implantion prevention by other drugs, which happen not to be contraceptives.

For those drugs, it's sufficient that (a) there's no reason why they should and (b) maybe a little empirical testing doesn't show that they do.

We don't generally hold up drug approvals because a drug has not been conclusively shown to never interfere with implantation. It's sufficient that they shouldn't, especially if there's evidence that they generally don't.

(Imagine the testing required for conclusive proof for each drug, especially if you required actual human studies...)

Plan B is in essentially the same situation; the fact that it was once thought that it might inhibit implantation shouldn't matter, because that reasoning has been shown to be wrong---if it had an effect, it should go the other way.

This article

http://www.popcouncil.org/publications/popbriefs/pb11(2)_3.html

discusses several pieces including tests of Plan B's effectiveness for inhibiting ovulation in humans---not just rats or monkeys---and how well that correlates with overall effectiveness at preventing pregnancy.

If Plan B has any anti-implantation effect, it's unexpected (based on current knowledge) and hard to measure.

And even if by some chance, Plan B does rarely inhibit the implantation of a fertilized egg,

(a) it more likely does the opposite more often, and

(b) it clearly reduces the frequency of failed implantations or abortions dramatically, by preventing ovulation and thus fertilization. This avoids most natural failures of implantation and spontaneous abortions, which are quite commmon. (Thanks to Amanda Marcotte and Matt McIrvin for pointing that out.) Plan B clearly reduces the chance of abortion dramatically. Unless you're anti-contraception, that should be great news; it's an anti-abortion drug.

I really doubt there'd be opposition on these kinds of grounds if Plan B wasn't a contraceptive. Do we really know for sure that an aspirin or a Sudafed or a cheeseburger or an aerobic workout won't occasionally inhibit implantation of a fertilized egg? Should we stop selling those things over the counter until we have conclusive proof?

If people are worried about off-chances of things inhibiting implantation, or causing spontaneous abortions, we have a lot of other things to worry about.

I don't think most people are worried about that, including most who are anti-abortion but not anti-contraception. If the risk of something causing an abortion is low enough, they figure "that's the breaks." (We all take very minor risks all the time, e.g. by driving a car. It matters whether you're taking a minor, justified risk or a big, unjustified one---the latter is negligence, which is too close to doing it on purpose.)

The anti-Plan B people are pretty clearly trying to make it sound like the risk of an "abortion" (actually, failed implantation) is substantial enough that if it happens, it's intentional or at least negligent, rather than a fluke.

I'd say that's like saying we shouldn't be allowed to sell cars, or drive buses, just because there's always a risk that somebody might get accidentally run over. (And hey, that might kill a zygote or fetus, too; does that make cars "abortion machines"?)

The relevant standard can't be conclusive proof that there's no risk. Plan B is being singled out for deceptive talk about the risks, because its staunchest critics don't like easily-available contraception, and they're willfully confusing everybody else.

Correct me if I'm wrong, but isn't this confusion partly the fault of manufacturers of emergency contraception, because they thought it made better marketing to make EC sound more effective if you throw around that it may prevent implantation? Although I thoroughly combed the packaging and information inserts of a pack of plan B recently and couldn't find one word suggesting that it might do that. So they definitely aren't saying so any more.

rtt wrote:

"Charlie, I understand and appreciate what you're trying to say. Nevertheless, you're effectively wrong."

"Many orthodox people speak as though it were the business of sceptics to disprove received dogmas rather than of dogmatists to prove them. This is, of course, a mistake. If I were to suggest that between the Earth and Mars there is a china teapot revolving about the sun in an elliptical orbit, nobody would be able to disprove my assertion provided I were careful to add that the teapot is too small to be revealed even by our most powerful telescopes. But if I were to go on to say that, since my assertion cannot be disproved, it is intolerable presumption on the part of human reason to doubt it, I should rightly be thought to be talking nonsense. If, however, the existence of such a teapot were affirmed in ancient books, taught as the sacred truth every Sunday, and instilled into the minds of children at school, hesitation to believe in its existence would become a mark of eccentricity and entitle the doubter to the attentions of the psychiatrist in an enlightened age or of the Inquisitor in an earlier time."
-- Bertrand Russell, "Is There a God?" commissioned by, but never published in, Illustrated Magazine (1952: repr. The Collected Papers of Bertrand Russell, Volume 11: Last Philosophical Testament, 1943-68, ed. John G. Slater and Peter Köllner (London: Routledge, 1997), pp. 543-48, quoted from S. T. Joshi, Atheism: A Reader

Correct me if I'm wrong, but isn't this confusion partly the fault of manufacturers of emergency contraception, because they thought it made better marketing to make EC sound more effective if you throw around that it may prevent implantation?

I think it's mostly the fault of manufacturers of conventional birth control pills, which also use progesterone, who spread the idea that they worked in three ways. The effect on implantation wasn't ever established, doesn't really make sense, and became "truth by repetition," but has recently been debunked.

Check out the Wikipedia article on Emergency Contraception at http://en.wikipedia.org/wiki/Emergency_contraception and particularly the section titled Controversy over post-fertilization effects of EC.

Charlie, you're being an idiot again.

Your Russell quote has NOTHING to do with the matter at hand; it's just an excuse to cover up your mental laziness towards looking up the primary literature yourself.

Somebody's looked up the primary literature. You haven't. I'd sure as hell trust them over you.

Roger Tang wrote:

"Your Russell quote has NOTHING to do with the matter at hand; it's just an excuse to cover up your mental laziness towards looking up the primary literature yourself."

Yeah, but it's a cool quote, is it not?
Hopefully neo-darwinian evolutionists will take note ;-)

As for the primary literature, I read a paper by :
Croxatto HB, Ortiz ME, Müller AL. Mechanisms of action of emergency contraception. Steroids 2003;68:1095-98.

In this paper they claim that:

(Roughly translated from Spanish)

"In the present debate, some have made reference to the existence of a third mechanism of the hormonal contraception of emergency (method of Yuzpe and levonorgestrel), through as would prevent the fixation (implantation) of an ovum already fertilized by means of the alteration of the endometrium (the internal coating of uterine cavity). On the matter, it is important to mention that during the decades of the seventies and eighties some studies argued the saying existence mechanism. Nevertheless, later it has been verified that those studies they were made with a weak methodology and slanted and, therefore, they lack value. From 2000 investigations have been published on the post-coital effect of both regimes (Yuzpe and levonorgestrel), based on solid designs and methodologies of investigation and falsified, which have not demonstrated differences endometrial between treated and not treated women, nor they have found effects direct on the implantation associated to these methods. That is to say, recent solid investigations they have demonstrated that evidences do not exist, direct nor indirect, of effects post-fertilization on the endometrium that interfere with the implantation. One has not either demonstrated that the methods of Contraception of Emergency contemplated in the Mexican Official Norm they act for "coming off the endometrium" an ovum fertilized already implanted, which would be considered under all the criteria as abortion."

This would seem to support the position that Plan B only affects ovulation, not implantation but one must remember that there are political agendas at work here and I still maintain that the issue is not definitively resolved.

"Charlie, you're being an idiot again."

Sad that you feel it necessary to make such statements.

"We are a link in Amida's golden chain of love that stretches around the world, we will keep our link bright and strong.

We will be kind and gentle to every living thing and protect all who are weaker than ourselves.

We will think pure and beautiful thoughts, say pure and beautiful words, and do pure and beautiful deeds.

May every link in Amida's chain of love be bright and strong, and may we all attain perfect peace."

Namo Amida Buddha.

*sigh* Looks like Charlie's hit counter has tapered off again.

This would seem to support the position that Plan B only affects ovulation, not implantation but one must remember that there are political agendas at work here and I still maintain that the issue is not definitively resolved.

Right. And I'm sure you won't mind telling us just what the political agenda is that would cause someone to try to conceal any evidence regarding Plan B's prevention of implantation of an embryo.

Before blaming the reporters for their incompetance, think about what obligations they have in reporting. It may be all fine and good that the claim that Plan B may interfere in implantation has no basis, but their primary source and who they have to answer to for an article informing about Plan B, would be the manufacturers of Plan B, and here is what they say: http://go2planb.com/ForConsumers/AboutPlanB/HowItWorks.aspx 3rd sentence: "Plan B may also work by preventing it from attaching to the uterus (womb)." If journalists reported otherwise, they might be obligated to issue a retraction and look like bad reporters. Its hard to defend plan B's lack of implantation effect when they won't even do it themselves.

Respectfully, Karey, I disagree. I don't think a journalist is stuck with the position or definition of a Plan B company itself any more than they are stuck with the historic stance of tobacco companies on the health consequences of smoking, or the "natural remedy" purveyors on the benefits of their products.

Dustin wrote:

"Right. And I'm sure you won't mind telling us just what the political agenda is that would cause someone to try to conceal any evidence regarding Plan B's prevention of implantation of an embryo."

Is this a trick question?

Clearly, if you want to sell an emergency contraceptive in a country like Mexico, which is mostly Catholic, or to people who believe that life begins at conception, you must convince them that this does not affect implantation and that it is not an abortion pill. If certain consumers believe that there is a chance, no matter how small, that this pill prevents implantation of an already fertilized egg, they will not use it.

Exposing a company's coverup of harmful side effects is not the same as this situation though. Plan B's position is more like the opposite of what tobacco companies did, and disclose more warnings than necessary. This is like if tobacco companies had warned that they may cause birth defects, before it had been proven, and journalists had reported that there was no proof of birth defects but only proof of lung cancer. Journalists would get in a lot more trouble for that. I guess I'm just more upset with the Plan B people than I am with reporters, I see their hands being somewhat tied due to the companies own stance, Plan B should make at least some effort to ay, we've tested our product for this effect and there's no evidence to substantiate it at this time. but its like they side with the implantation effect people. They won't say anything other than this may have an effect.

I think I disagree with some of that, but that really wasn't my point anyway. My point was that a journalist is not obligated to say "well, the company says it prevents implantation, so that's what I have to say." A good journalist should, in my opinion, dig deep enough into a topic like this one to uncover the truth. And I have no problem if they report that their remains an unproven, small, outside chance.

My point with the analogy had nothing to do with exposing coverups, but rather disagreeing with the concept that they somehow have to stick to and answer to the company's official position on Plan B's mode of action, when the real story is different and pretty easy to find. Under certain circumstances, such as the present situation with new data, or the cases of pseudoscience as I offered with tobacco or natural remedies, the manufacturer doesn't necessarily have to be the definitive authority. I'm assuming in this case that they simply didn't find the new information (probably barely looked), and that's technically fine, I chalk it up to error or shallow reporting (thus far).

Nor, at present, am I sure that the companies' statements on Plan B are meant to disclose warnings. I'd certainly defer to someone who knows a lot more what their thinking was and is, but I've been under the impression the original stance was taken because it simply wasn't known what the mode of action was for sure, and to rule out any one mode without a lot of data would have been a legally pointless risk. The fact that they haven't changed it today YET doesn't surprise me, as much of the medical community itself doesn't understand this yet. We're right in the middle of the "sea change" based on the new data we have. I'd expect them to be slow in changing. Again, that's no defense of the companies for their own sake, and if anyone has better info regarding their motives I'd welcome it.

I've ocassionally lectured med and grad students on reproductive hormones and the pharmacology of contraception.

Preparing for this material forces one to wade through the textbooks and the primary literature, and try to keep an eye on it. I do not conduct primary research in the field.

Suffice it to say that the mechanism of action of progestin- only contraceptives are complex, and always have been.

What we do know is that plan B is reasonably effective as an emergency contraceptive, ~85% effective. This, IMO, is surprising given the findings that levonorgestrel does not suppress ovulation in women when given in the late follicular phase or during the LH surge. It only suppresses ovulation if given well before the follicle has matured.

In other words, it suppresses ovulation in women who are in their cycle at a point where they are at low risk for pregnancy.

Its reasonable to conclude from these and other observations that mechanisms other than anovulation likely contribute to the efficacy of "PlanB", but those mechanisms are far from known with any certainty at this time.

Thats the truth and I'm sticking to it.

I guess i didn't explain well enough why I think that analogy is relevant and why it does highlight a differential motivation for reporters to either side with or investigate the manufacturers claims depending. This situation is different because the reporters are trying to promote plan-b. Or at the least, are writing about people who are promoting it. If you want to convince people, first and foremost, that plan-b is not an embryo-expulsion pill like ru-486 you need a more unified attack. Thats another reason why the article is in an exempt situation I think, you guys think its shallow reporting to go with standard opinion on the implantation prevention, but the article is not even about that. Its frying one fish at a time here. You guys are farther down the road in the debate while the article is still trying to deal with people who are hung up going "did they call plan-b a morning after pill? Doesn't that expel already-implanted embryos?" When convincing people that implantation-prevention is different from embryo expulsion, it isn't yet relevant whether implantation-prevention occurs and it doesn't help to leave your detractors with a loophole big enough for them to dismiss your whole article with. Because people who don't want to believe plan b is safe are gonna do what I did and go straight to the manufacturers site and say you don't know what you're talking about. Rather than listen to the important point at this juncture, which is that even if it does prevent implantation, that still isn't RU-486.

Ah, yes Karey, that does make more sense to me. I dunno if that was their approach or not, but I could see it. Although I suppose they technically shouldn't be trying to promote Plan B themselves, as journalists.

Blader: I KNOW I saw a discussion of that particular claim...somewhere...and no clue where now. Grr. :/

rrt-I'm aware of what you wrote and I wrote what I wrote to disagree. What you wrote, quoted below, is not supportable by the evidence in the current primary literature of studies in women on the mechanism of plan B action.

In point of fact, the most recent data strongly suggest that the anovulatory effect of plan B cannot explain the drug's efficacy in women who use it in late follicular stage. That is to say, in the women who are most likely to be ovulating around the time of coitus, plan B appears not to suppress ovulation. Yet, the drug is still remarkably effective. Therefore, something other than an effect on ovulation explains the contraceptive efficacy.

"The data thus far shows no reason to think that Plan B affects anything but ovulation, in terms of contraceptive effects, and some reason to think it does not. If it has any other mode of action, given the statistics of its success and failure, it is likely to be negligible."

What we do know is that plan B is reasonably effective as an emergency contraceptive, ~85% effective. This, IMO, is surprising given the findings that levonorgestrel does not suppress ovulation in women when given in the late follicular phase or during the LH surge. It only suppresses ovulation if given well before the follicle has matured.

Blader, what is your source for this claim?

From what I've read, it sounded like Plan B suppressed ovulation if given before the LH surge, with no mention of it failing if the follicle has matured. (What's the relative timing of those events?)

Contraception 2006 Jan;73(1):107

Contraception 2005 June 71(6):451

Even if there were some post fertilization effect (which there is not), it would be statistically impossible to prove because the control group in any formal study who took a placebo, already has a 50 to 80% chance of implantation failure naturally occurring.

It doesn't matter anyway. Wingnuts will believe what they want to believe no matter what.