Thursday, August 24, 2006

The Murky Moral Waters of Embryonic Science

There has been a burst of news relating to embryonic science in the last two days, raising some very interesting (and difficult) moral questions.

First, there was the report in the journal Nature that a group of scientists had found a way to generate new embryonic stem cell lines for research without harming the embryo in the process. The procedure used is similar to what is currently performed in fertility clinics to screen pre-implanted embryos for genetic defects.

Then today, the Plan B contraceptive debate hit the front burners again, as the FDA approved it for over-the-counter use in America. Many are up in arms, saying that President Bush has gone against his pro-life principles by approving the use of an abortion drug. Others are up in arms (or have been), saying that the delay in approval was an example of religious conviction overriding science.

Is the Plan B contraceptive an abortifacient? Specifically, does it inhibit implantation of a fertilized embryo? We had a discussion closely related to this previously on this blog, comparing breastfeeding with other forms of contraception such as the pill, arguing that both had the possibility of inhibiting implantation and therefore being abortifacient. I also came across (via RedBlueChristian) a seemingly well-researched opinion on the Ales Rarus blog, arguing that there is no solid evidence that either breastfeeding or Plan B inhibits implantation at all (the post is in two parts, and due to bizarre web formatting, you'll want to read the printable versions of the posts here and here).

I confess that I'm confused. The citations on the Ales Rarus blog sound very convincing... but are they comprehensive? According to the Washington Post article, "Some research suggests Plan B also may keep a fertilized egg from attaching to the womb". What research is that? Does anyone know? The quote on Ales Rarus from Joe DeCook (VP of American Association of Pro-Life Obstetricians and Gynecologists) seems to suggest that there is no such research: "The post-fertilization effect was purely a speculation that became truth by repetition". Also, as cited on Ales Rarus, the results of the testing in Chile that showed that "when [Plan B] was given [to monkeys] after mating—at a time when fertilization was believed to have occurred (on the basis of previous monitoring)—the pregnancy rates observed were identical in cycles treated with levonorgestrel or with a placebo". In other words, if ovulation had already occurred, Plan B had no effect in that study on the fertilized embryo.

So what are the studies that show that Plan B does affect implantation, or that it has any effect on a fertilized embryo? Are there any such studies? Or are people opposed to Plan B simply because it might affect embryos, even if there's no evidence to show that it does?

This focus on preserving embryonic life also is central to the importance of new process developed to extract embryonic stem cell lines for research without harming the embryo itself. It's fascinating, and could be significant... but I have one pressing question.

14 embryos were used by the research firm that developed the method. Those 14 embryos each had a single cell extracted, and were then still healthy and able to develop. What happened to those 14 embryos? I can easily guess... they were probably treated like countless other results of IVF procedures, and destroyed.

If we, as a society, are OK with intentionally destroying embryos that are "left over" from IVF... then why exactly again are we so concerned about not using those embryos for research? There is a large sector of our society that is opposed to embryonic stem cell research (somewhere between 40% and 50%, I think, from most polls I've seen). There is nothing near that type of movement in opposition to IVF, with consequent embryo destruction.

So how is it that such a significant percentage of the American population is OK with destroying embryos intentionally for convenience, but is not OK with destroying embryos intentionally for research purposes? This, for me, is a conundrum.

Personally, I have significant concerns about IVF in general, though I can see its value in very limited circumstances, and carried out in very specific ways. We've had discussions on that topic on this blog in the past, here and here.

These topics bring up so many potential interesting questions, I won't even try to suggest a subset of them here. :)

Mark

34 comments:

purple_kangaroo said...

OK, so there are two things I'm wondering if I'm getting clear:

First, this PGD method of testing for genetic defects in an embryo with IFV . . . it actually lowers the chances of having a healthy baby? There's a big difference between a success rate of 20% vs. 28.3%.

They're making themselves as much as 17% less likely to end up with a healthy baby by doing a procedure with the goal of deciding to kill the embryo if it's not perfect enough? Plenty of moral problems with that already, IMHO, even without using the procedure to generate cells for research.

And, am I understanding correctly that Plan B supposedly only works if ovulation has not taken place before the pill is taken? Plan B says you can take it up to 72 hours after having unprotected sex. So it works ONLY if a woman hasn't ovulated within the 2-3 days before having sex or the 2-3 days after having sex? If that's truly the case, then how could it be effective at all?

If so, the only case it would possibly be useful to take the Plan B pill 72 hours after having sex would be in what must be a very rare case where the sperm stays alive and active for more than 72 hours, and at the same time the woman ovulates sometime after the 72 hours have passed, but before the sperm become ineffective.

If it only does anything to prevent pregnancy if both of those factors are present, what's the point of taking it anyway? According to various articles I've read, sperm usually only live 24-48 hours after intercourse, although if they get into the fallopian tubes there's a possibility they could survive up to 7 days. If the average is 24-48 hours, as most sources seem to state, then most people aren't going to have much of a chance of getting pregnant more than 72 hours after having sex anyway.

We're talking maybe a 1 to 24-hour time period in most cases during which the Plan B might actually make a difference if the woman happened to ovulate during that time?

I can't see that something like Plan B would prevent a significant number of pregnancies if taken 72 hours after intercourse, if it truly does nothing but prevent ovulation.

In order to get the effectiveness rates quoted by the manufaturer (lowering chance of pregnancy by 75%), it seems it would have to be taken sooner and/or work by a different mechanism as well.

Something doesn't seem right with the information being stated. Either Plan B would have to work by some additional mechanism after ovulation has taken place, or the efficacy rate would have to be extremely low, it seems to me. If it depends on ovulation having not yet taken place by the time the pill is swallowed, it's not really going to do much to prevent pregnancy.

Kevin said...

purple_kangaroo,

From the LA Times article: "Between 20% and 25% of couples who use PGD end up with healthy babies, compared with a success rate of 28.3% for all in vitro fertilization patients"

That does make PGD seem counter-productive. :) My best guess is that they should not have included the word "healthy". i.e. perhaps the PGD procedure reduces the likelihood of having a baby by 3-8%.

Here's an excerpt from the Pharmaceutical company that probably makes Plan B (levonorgestrel):
"""
How does Plan B work (mechanism of action)?

Plan B is believed to act as an emergency contraceptive principally by preventing ovulation or fertilization (by altering tubal transport of sperm and/or ova). In addition, it may inhibit implantation by altering the endometrium. Plan B is not effective if a woman is pregnant. Plan B is a contraceptive and cannot terminate an established pregnancy.

Will Plan B harm an unborn fetus?

There is no evidence that Plan B would harm a pregnant woman or a developing fetus if the product were accidentally taken during early pregnancy. Studies involving women who have inadvertently taken combined oral contraceptives containing levonorgestrel during early pregnancy suggest that these drugs do not have an adverse effect on the fetus.
"""

According to babycenter.com, it takes 45 minutes to 12 hours for sperm to reach the egg, and about 3 days for the embryo to travel to the uterus. Planned Parenthood Golden Gate states that "After 2 or 3 days in the uterus, the fertilized egg begins to implant in the uterine lining." I imagine that this accounts for the 3 to 5 days maximum for levonorgestrel.

Google links to some information about levonorgestrel studies regarding fetuses, including a Safety Review at fda.gov and an article from 2005 Study: 'Morning After' Pill Not Harmful to Fetus at foxnews.com:

"""
This form of emergency contraception is about 85 percent effective at preventing pregnancy and is believed to work in one of three ways: temporarily blocking eggs from being produced, preventing the formation of hormones within the ovaries that maintain a pregnancy, or keeping a fertilized egg from becoming implanted in the uterus.

A possible association between prepregnancy exposure to progestins and congenital abnormalities has been debated, they write. These abnormalities tend to arise from long-term use of levonorgestrel rather than short-term, low-dose preparations used in emergency contraception pills, they add.

In the study, which appears in the August issue of Fertility and Sterility, researchers looked at whether failed use of the morning-after pill was associated with any increased risk to the mother or fetus.

Researchers compared the number of stillbirths, birth defects, and pregnancy complications among a group of 36 pregnant women who had used the morning-after pill and a comparison group of 80 pregnant women who did not use emergency contraception. There were 25 births among the women who used the morning-after pill and 69 among the comparison group.

The results showed that babies born to women who used emergency contraception were similar in weight and length to other babies. There were no differences in the number of stillbirths, birth defects, or pregnancy complications between the two groups.

Based on these results, researchers say that unsuccessful use of the morning-after pill should not warrant a voluntary abortion due to fears of potentially adverse effects of hormonal emergency contraception.
"""

Perhaps the title of the article is a bit misleading, considering that they're not exactly sure how levonorgestrel works and that it did cause the rate of successful birth to drop from 86% (69/80) to 70% (25/36). Of course, with such a small sample size, perhaps that is within the margin of error?

Douglas_Coombs said...

PK put things well. If Plan B can be taken with the effectiveness rates quoted up to 72 hours after intercourse, it has to be preventing implantation on a regular basis.

M said,
"So how is it that such a significant percentage of the American population is OK with destroying embryos intentionally for convenience, but is not OK with destroying embryos intentionally for research purposes? This, for me, is a conundrum."

I would have to agree with your conclusion here. It is a conundrum. Most people also oppose mid to late term abortions, but still vehemently support the status quo regarding abortion law and policy. What are they thinking?

In mulling this over myself, I've come up with a couple hypothoses as to why this may be. 1) Ignorance. People just don't understand what they are saying when they say they support one thing and not another. 2) Poeple, even with understanding the contradictions, still strongly identify with emotional images of those suffering distress (e.g., the childless, the single pregnant woman).

2) can easily be argued to be on the researchers side in the case of stem cell research, but I think there are a couple things working against it. A) There are scientists acting on behalf of the suffering to formulate a future cure. Supporting scientists is not like supporting victims directly. The pain of the suffering will not be removed immediately, nor is this necessarily the only way to ease their suffering. At least one scientist in this field has been shown to be greedy liar. He got away with it for a relatively long time. B) There are competing emotional images in this case. Many people are strongly repulsed by cloning and other things of that nature. There are scary images in popular culture of this sort of thing that people identify with on an emotional level.

That's all I have time for right now. Anybody else have their own hypothoses or want to poke holes in mine?

Doug

Kevin said...

Doug's reasoning makes sense.

I also think there is a concern that researching potential uses for embryo stem cells may lead to a market for embryos that is not directly associated with the potential life of that embryo, and that it would be better to first research other sources for stem cells which do not have the same moral or emotional dilemmas.

In addition, the immediate purpose of IVF is conception, so IVF is more readily associated with aiding fertility and conception, even though many more embryos are destroyed than by more natural means.

Mark Congdon said...

PK,

Great point. How could it be effective at all past 12 hours if it doesn't affect the fertilized egg? That just makes no sense... so it must affect the embryo. I wonder why they're not able to do studies to confirm that type of behavior...?

Doug and Kevin,

Your picture of a society that makes moral decisions based primarily on emotion is the scariest thing I've heard in a long time.

But I'm sure you're right.

Mark

steviepinhead said...

Plan B is a progesterone-only pill. Its primary method of action is to temporarily suppress any impending ovulation. Despite speculation that progesterone somehow also interferes with implantation, I know of no research that suggests that as one of its modes of action.

In fact, progesterone is used as a pregnancy-maintaining hormone, once a pregnancy has become established (that is, once a fertilized egg has implanted).

PK is right that Plan B is ineffective where an already-released egg has already been fertilized. At that point it's too late to either delay the release of the egg or to interfere with the up-fallopian motility of the sperm.

(Likewise, though, at that point, there's been no showing that Plan B interferes with implantation or with the healthy progress of any resulting pregnancy.)

Over-nice analysis of the 85% effectiveness claim may be misleading. While it may well be true that no pregnancy results in 85% of the cases where Plan B is correctly taken within the correct timeframe, that's not the same thing as saying--at least as I understand it--that Plan B is responsible for all those non-occurences. Any more than the 90% plus "effective" rates of regular birth control pills are all correctly attributable to something accomplished by The Pill (although presumably those "effective" rates are averaged over longer time periods and multiple, um, potential opportunities for conception, whereas the effectiveness of Plan B is presumably premised on a much shorter time period and a one-time event, though I see several "data control" problems buried in that shorthand).

Pregnancy is a pretty iffy event in the first place. As we've discussed here (and in Mark's own blog) on several occasions, timing is critical. Even if the egg is released at the appropriate time, and intercourse takes place, and healthy sperm are dispatched, the odds are still against fertilization and implantation for a host of reasons. The environment in question is decidedly hostile to sperm from the get-go (for, biologists would argue, evolutionary reasons having to do with selecting out all but the most robust and high-quality sperm). Implantation is highly iffy (and its low success rate--even when all the upstream processes have gone well or been artificially finessed--is one of the main reasons that "assisted" reproductive efforts fail), and spontaneous/natural failures of early-pregnancy also occur at high rates, most of them likely occurring in the very early stages well before pregnancy can be reliably detected.

I would expect that, for any given, um, random session of intercourse--even without admininistration of Plan B--the chances of a timely release, effective fertilization, fortuitous fallopian transport, successful implantation, and a well-maintained early-stage pregnancy (through to the time of effective pregnancy detection) are not great.

It's my assumption, though I'd be happy to be corrected, that the "effectiveness" rates of both regular birth-control pills and Plan B must to some large extent "piggy-back" on the natural odds against any one intercourse session resulting in pregnancy (I assume this, again, because it's difficult to imagine the "data control" problems that would filter out these background effects)...

Mark Congdon said...

Stevie,

Thanks for joining in! You've pushed me to do a little more research and clarify some things.

First, Plan B does not contain progesterone, but a progesterone-like synthetic progestin called levonorgestrel. Not all progestins are the same, and I have not heard of levonorgestrel being used to maintain healthy pregnancies, though I guess it is possible.

In fine Wikipedia style, here's a good overview of the controversy and research, indecisive as it is.

Your critique of the "85% effective" claim is well taken. I've been trying to track down the origin of that claim, but I'm having a hard time. Here's a quote from the manufacturer's website:

"Plan B® works better the sooner you take it. If it is taken within 3 days (72 hours) after sex, it will significantly decrease the chance that you will get pregnant. Seven out of every 8 women who would have gotten pregnant will not become pregnant. Plan B® works even better if you take it within the first 24 hours after sex."

There are clearly making the claim there that, taken up to 72 hours after sex, it increases the chance of not getting pregnant over any other natural causes by a very large percent. More details (though still not very many) about the study used to determine those numbers can be found on the Prescribing Information PDF.

It appears that those studies do not (at least in the public summaries available to me) break down the results by how soon after intercourse the contraceptive was taken. They say that results are much better within 12 hours... but how bad are the results if the contraceptive is taken after 48 hours, for example? If the overall of the "0-72 hours" group is roughly 80% reduction in pregnancy, how much of that is attributable to the "0-24 hours" group, and how much to the "48-72 hours" group? That is information I'd love to have, but can't find.

A small number of pregnancies do result from an ovulation or fertilization occurring 72 hours or more after intercourse... but it's a very small number, from what I can tell. If the effectiveness of Plan B when initiated during that time period is anything close to the 80% that the manufacturer is claiming, then it undoubtedly has a detrimental affect on already-fertilized embryos.

I wonder... are there any third-party confirmations of the effectiveness of emergency contraception, particularly focusing on the late-application (48-72 hours) situations? I haven't been able to find them yet, but if any of you come across such a study, I'd love to see it. Thanks!

Mark

steviepinhead said...

Thanks, Mark. I would doubt here that the synthetic progesterone makes a difference in the respects we're concerned about, but--as always--I'm open to correction.

I agree with you that the manufacturer appears to be claiming that they have somehow compared groups of women who would otherwise have gotten pregnant with otherwise-comparably, um, "exposed" women who have taken Plan B within the appropriate time window.

Now, based on the information I've seen to date, I'm actually in favor of the FDA's latest action wrt Plan B--that is, I am so far persuaded that it acts as a contraceptive rather than an abortifacient.

But, I'm having a little trouble visualizing the design of the study that would demonstrate that they have comparable groups of equally-fertile men and women (for all those up- and down-stream fertility factors that we've discussed), being "caught" at comparable times in the women's cycles, with comparable motivations to either become pregnant or to avoid pregnancy (and is that even a valid comparable? maybe it's the opposite?), etc. And then that, for every 8 times the (statistically-averaged) "control" group women become pregnant, only one of the Plan B-taking women does. It would certainly seem to require a whole lot of consenting couples, going to a whole lot of trouble (reporting--fairly precisely--on when they did it, where the woman was in her cycle, etc., all the things that couples aren't very good at while remaining appropriately, er, spontaneous), just to average out the various fertility factors...

Not saying, on reflection, that they couldn't have managed it or that the claim is inaccurate, but it sure sounds like an ethical nightmare of a study to design and administer, a giant cat-herding exercise.

Maybe there's a simpler answer and the data come, not from a carefully-controlled study, but from--in effect--some kind of "real life" tracking or polling of consumers in one or more of the countries in which (as I understand) Plan B has been available a good deal longer.

I suppose that if it's the latter, that that would be good news, in some respects, as regards the safety of the product (for the women and any pregnancies that slip through the gaps in the effectiveness): we'd be dealing with data on substantial real-world populations using Plan B in real-world ways.

Though I'm not sure my ethical scruples are entirely assuaged, contemplating that our long-term drug-safety data is being obtained at the potential risk of foreign nationals. (Or, flipping that around, that the approval of reasonably-safe drugs is being unreasonably delayed in the U.S. for non-scientific reasons, while being made available at appropriately-earlier times for the rest of the First World...).

Kevin said...

Stevie,

Here's a portion of the abstracts of a couple of WHO studies that are often cited, including their basic methods.

1) Using levonorgestrel within 72h. This might be where the oft quoted 85% comes from. Working backwards, it seems that the expected rate of pregnancies without treatment is about 7.5% (vs. 1.1% if levonorgestrel is taken within 72h):

Title: Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception
("
METHODS: We enrolled in the double-blind, randomised trial 1998 women at 21 centres worldwide. Women with regular menses, not using hormonal contraception, and requesting emergency contraception after one unprotected coitus, received levonorgestrel (0.75 mg, repeated 12 h later) or the Yuzpe regimen (ethinyloestradiol 100 mu g plus levonorgestrel 0.5 mg, repeated 12 h later).

FINDINGS: Outcome was unknown for 43 women (25 assigned levonorgestrel, 18 assigned Yuzpe regimen). Among the remaining 1955 women, the crude pregnancy rate was 1.1% (11/976) in the levonorgestrel group compared with 3.2% (31/979) in the Yuzpe regimen group. The crude relative risk of pregnancy for levonorgestrel compared with the Yuzpe regimen was 0.36 (95% CI 0.18-0.70). The proportion of pregnancies prevented (compared with the expected number without treatment) was 85% (74-93) with the levonorgestrel regimen and 57% (39-71) with the Yuzpe regimen. Nausea (23.1 vs 50.5%) and vomiting (5.6 vs 18.8%) were significantly less frequent with the levonorgestrel regimen than with the Yuzpe regimen (p<0.01). The efficacy of both treatments declined with increasing time since unprotected coitus (p=0.01).
")

2) Using levonorgestrel within 120h:

Title: Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial
("
METHODS: We did a randomised, double-blind trial in 15 family-planning clinics in 10 countries. We randomly assigned 4136 healthy women with regular menstrual cycles, who requested emergency contraception within 120 h of one unprotected coitus, to one of three regimens: 10 mg single-dose mifepristone; 1.5 mg single-dose levonorgestrel; or two doses of 0.75 mg levonorgestrel given 12 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Analysis was by intention to treat, but we did exclude some patients from the final analyses.

FINDINGS: Of 4071 women with known outcome, pregnancy rates were 1.5% (21/1359) in those given mifepristone, 1.5% (20/1356) in those assigned single-dose levonorgestrel, and 1.8% (24/1356) in women assigned two-dose levonorgestrel.
")

Mark,

I haven't been able to verify it, but this site suggests that:
("
- If taken correctly in the first 24 hours, the pills are 97-99% effective.
- The earlier they are taken the better. If taken more than 3 to 5 days after unprotected sex they are around 70% effective.
- They may be less effective if taken more than once in any one menstrual cycle.
")

Note that although the References section includes the WHO levonorgestrel 120h study, the preceding text does not mention levonorgestrel specifically.

I haven't found an actual study that segments and compares the first 72 hours, but here's a study that explicitly compares the 0-72h and 72-120h segments:
Effectiveness of emergency contraceptive pills between 72 and 120 hours after unprotected sexual intercourse.
("
Study Design: We conducted an observational study comparing 2 groups of women for whom the regimen of Yuzpe and Lancee was administered after unprotected sexual intercourse. One group (usual time frame treatment group) sought consultation within 72 hours (n = 131), and the other (extended time frame treatment group) after 72 to 120 hours (n = 169).

RESULTS: The pregnancy rate was 0.8% for the <72-hour group and 1.8% for the 72- to 120-hour group. The effectiveness rate varied from 87% to 90% for the <72-hour group and from 72% to 87% for the 72- to 120-hour group. In both groups the chi(2) tests showed that emergency contraceptive pills significantly reduced the risk of pregnancy.
")

Kevin

Mark Congdon said...

Kevin,

Wow... thanks for doing all that research.

I'm uncertain how much the last study applies, because it refers to Yuzpe instead of Plan B. My understanding of Yuzpe is that it includes estrogen, and so could possibly have additional methods of action that levonorgestrel by itself does not have. That's all speculation on my part...

The statement on the Australian site is really surprising:

"If taken more than 3 to 5 days after unprotected sex they are around 70% effective."

If that is true of Plan B (that it prevents pregnancy roughly 70% of the time when statistically we would expect pregnancy to occur), then it is inconceivable that Plan B affects only ovulation. If emergency contraception is actually 70% effective "more than 3 to 5 days" after coitus, then it seems to me that it must be able to affect an already-implanted embryo as well... at least, that is, if my information is correct that implantation normally happens between 3 and 5 days after coitus.

Something just isn't adding up, in my mind. If Plan B affects only ovulation, then how can it be so effective taken so long after intercourse?

Mark

Kevin said...

Mark,

You're right that the last study is not directly applicable to Plan B. Sorry I missed that.

Mark said: "at least, that is, if my information is correct that implantation normally happens between 3 and 5 days after coitus."

I haven't found a study or anything official, but I've read that the typical embryo implants 6-12 days after ovulation.

I also linked a couple of pages in my response to PK, for example Planned Parenthood Golden Gate states that "In a normal pregnancy, the fertilized egg travels down the fallopian tube. On about the third day of travel, the fertilized egg arrives in the woman's uterus. After 2 or 3 days in the uterus, the fertilized egg begins to implant in the uterine lining."

So, implantation occurs about 5-6 days after fertilization, which itself might be about 1-5 days after coitus.

Here is a review of many studies regarding the Mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception, which they thoughtfully provide for free online. Unfortunately, they seem to spend more time on mifepristone.

Here's a nice introduction: "Unprotected intercourse may occur, and emergency contraception may be used, at any time during the menstrual cycle but it is only during a limited period, from 5 days before to 1 day after ovulation that unprotected intercourse may result in a pregnancy (Wilcox et al., 1995). To be effective, postcoital treatment could theoretically target one or several of the following events: sperm transport and function, follicular development, ovulation, fertilization, embryo development and transport, endometrial receptivity and implantation and corpus luteum function (Table I). In the following we address the effects of mifepristone and levonorgestrel on each of these reproductive processes"

Apparently, levonorgestrel might actually be more effective than appears in the WHO studies: "In all WHO studies, efficacy was calculated as ‘intention-to-treat’ which means that all pregnancies were included, even those resulting from intercourse after treatment but before follow-up."

They also assume somewhat similarly to Stevie that "An adverse effect of levonorgestrel seems unlikely since gestagens are commonly administered to facilitate implantation following assisted reproduction such as IVF."

"In conclusion, emergency contraception with 10 mg of mifpristone as a single dose or 1.5 mg of levonorgestrel acts mainly to inhibit or delay ovulation but does not prevent fertilization or implantation."

Working backwards, if their conclusion is correct and if the efficacy of levonorgestrel at 72-120h is above 50%, then wouldn't that suggest that the majority of pregnancies are the result of fertilization in that 72-120h (4-5 day) timeframe? Is this reasonable, given that most sperm are dead by then?

Alas, perhaps I'm missing something; simplistic reasoning and statistics don't always correlate. But one thing is certain: I'll do just about anything to avoid doing my work, even discussing and researching emergency contraception. :)

Kevin

steviepinhead said...

Yes, Kevin, thanks for the research. As you'll see, you even stimulated me to do some of my own (which, as regular readers will know, I'm usually loath to undertake).

Understanding the concerns that are being expressed (though recall that the manufacturer also suggests that Plan B may work by inhibiting sperm, as well as by delaying ovulation, so that a conclusion that there is also an effect upon fertilized eggs or implantation is not necessarily compelled), it initially seemed to me that, if there were good studies verifying substantial Plan B impacts on fertilized eggs and implantation, then opponents of making Plan B available would have widely publicized these.

This echoes Mark's original "show me the research" remark in his initial post.

Somewhat to my surprise, therefore, it is easy to locate such studies (though, note that they are still speculative in attempting to attribute the hypothesized loss of maybe-fertilized, maybe-not post-ovulatory eggs among several possible factors); here's a representative example, though also note that it is primarily directed at the potential "post-fertilization effects" of birth control pills: http://archfami.ama-assn.org/cgi/content/full/9/2/126 (and not all birth control pills are composed only of synthetic progesterone, as has been noted).

I googled "post-fertilization effects progesterone," though I'm sure other variations will occur to those of you who are interested (substituting "Plan B" for "progesterone" pulls up a somewhat different mix of studies reaching what seemed to me to be similar conclusions).

It remains unclear to me whether the primary problematic mechanism whereby this post-fertilization effect is postulated to take place--that is, thinning or disruption of the endometrial lining--is a short-term or long-term effect of progesterone-like substances. If longer-term, then it would tend to show up in the review of birth-control studies, but might be less applicable to the very short-term use of Plan B that "emergency contraception" involves.

Even by those who acknowledge the theoretical possibility of these post-fertilization effects, however, it has been argued that, "Intervention within 72 hours after intercourse cannot possibly amount to abortion, because implantation is not achieved until at least seven days after ovulation and the egg is capable of being fertilized for only about 24 hours." In other words, it's being argued that--even if we assume that an egg is released just before (or despite) the use of Plan B, and is then fertilized within the first 24 hours following the, um, sperm-intoduction event, and Plan B is also (properly) taken within 72 hours of the same event--then whatever the possible effects of Plan B may be, they can't--at least in the above hypothetical, actually involve the failure of a fertilized egg to implant.

The validity of this reasoning might, it seems to me, be diluted if there is in fact a short-term impact of the synthetic progesterone on the endometrial lining and, particularly, if the spike of progesterone received within the first 72 hours persists at the necessary effective level for several days following administration.

I have also come across the claim that, "Bunches of animal studies [were reported] in 2004, monkeys, cows, rats, go forth and Google! There's no fertilization effect. Contraception prevents ovulation only. Even with a major dose of hormones, the baby...I mean zygote...will still implant, if it's viable in the first place, that is." This individual apparently googled using some combination of the terms "fertilization effect," rather than using post-fertilization.

In any event, whatever this hypothesized effect may be, it appears to have been most clearly demonstrated with respect to long-term use of birth control pills. So whatever moral and ethical issues may arise with regard to Plan B, they exist even more strongly wrt to the use of birth control pills.

And, of course, IUDs are conceded to work in at least im part through interference with implantation.

Without necessarily wanting to instigate yet another debate before we've finished working through this one, I'm nonetheless constrained to wonder whether the pregnancy-suppressing effects of nursing may be related, in any part, to some similar post-fertilization effect, in addition to ovulation-suppressing (or other purely contraceptive) effects.

Mark Congdon said...

Kevin,

I stand corrected about 3-5 days comment... thanks for setting me straight.

Stevie,

The postfertilization affects of standard birth control pills have been well known for a long time. Those affects are the primary reason my wife and I won't consider using the pills.

[rabbit trail...]

It is another conundrum to me that so many people (hard to quantify, but it must be sizable) are opposed to embryonic stem cell research purportedly because they value embryonic life, but are at the same time willing to take pills that cause embryonic death in their own bodies on a regular basis. I can't quite figure it out, myself.

I guess it comes down to the unhappy observation that lots of people are willing to have principles, as long as those principles only affect others.

[end rabbit trail]

Plan B intrigues me because it is being promoted in many circles as being of a different nature than birth control pills, and having no postfertilization affect at all. I'd love to be convinced of that... it would make Plan B an option for my family, and an option I would be willing to recommend to others, unlike other contraceptive pills on the market.

Mark

purple_kangaroo said...

Steviepinhead, it sounds like you may be mixing up two different issues. Prevention of pregnancy after fertilization but before implantation is a very different thing than prevention of pregnancy before ovulation, or even before fertilization.

The claim is that Plan B only works in the latter way, and does not affect an already-fertilized egg, before or after implantation.

The only way I can think of that Plan B would have a 75% effectiveness rate if it truly didn't inhibit implantation is if the researchers purposely (and successfully) made the study participants have intercourse 72 hours or more before ovulation happened, while at the same time somehow making the sperm survive more than 72 hours.

That would be a really ineffective and dishonest way to prove the efficacy of a birth control method, since most women taking Plan B won’t be timing intercourse to take place exactly 72 hours or more before ovulation.

For Plan B to work only by inhibiting ovulation and/or fertilization, the act of intercourse would always have to happen 72 hours or more before egg and sperm actually met. I'd have a really hard time believing that's true in that large a percentage.

The group taking Plan B starting 72 hours after intercourse supposedly had a 75% lower rate of pregnancy than the control group. It seems nothing short of ridiculous to suggest that upwards of 75% of all pregnancies are not fertilized until 72 hours or more after the act of intercourse resulting in the pregnancy.

The claim that Plan B does not inhibit implantation would require that fully 75% of the expected pregnancies were not fertilized until 72 hours or more after the act of intercourse. Sperm don’t usually live that long, for one thing, and an egg can only be fertilized for up to 24 hours after ovulation.

For a 75% success rate of birth control initiated 72 hours after intercourse, either Plan B would have to work by some method other than simply inhibiting ovulation/fertilization, or the statistics would seem to have been skewed or misrepresented somehow to make Plan B look more effective than it really is.

I'd really like to see a copy of the study, not just a summary.

purple_kangaroo said...

Mark, another thing about Plan B is that it's not meant to be taken regularly. It's emergency contraception designed to be taken after a single, rare act of unprotected se or a broken condom, etc--not a substitute for other forms of contraception. It would not be a safe alternative to the pill or IUD or a substitute for barrier methods or NFP.

One of my big concerns with having Plan B available OTC is that people are likely to use it on a regular basis instead of just an emergency basis. Nobody really knows what effect that would have, and it's not researched or approved for such use.

purple_kangaroo said...

Another point that I think has been missed is that fertilization only takes a few seconds, or minutes at most, when both egg and sperm are present and viable.

steviepinhead said...
This comment has been removed by a blog administrator.
steviepinhead said...

Hmmm. While I agree with Mark that the possible "post-fertilization effects" of standard birth-control pills seem to have been known by specialists--and perhaps by the interested and motivated public--for quite some time (that is, the information has been available), the point of several of the studies that I read was that these effects seem not to have been well-communicated to the current generation of OB/gyns and primary care physicians, and that they often aren't, therefore, explicitly communicated to recipients via informed consent.

Thus, people who might very strongly object to taking a drug that potentially acted via "post-fertilization" effects might never be effectively presented with that information (see also my reference to the kindly small-town pharmacist, below).

I didn't imagine that I was communicating anything new to most of our participants here, but thought that it was important to be as explicit as possible for any interested on-lookers (and while I doubt we're competing for traffic with the better-known "issue" blogs, we have already had several "new" folks comment on various threads...).

I'm not quite sure to respond to the always-delightful purple kangaroo. It's almost as if she didn't read my second post of yesterday, even though her posts appear below it. Near simul-posting, perhaps?

pk: certainly I began with the information that Plan B was a "true" contraceptive, and did not detrimentally affect fertilized eggs or interfere with implantation. That's a little different than "mixing up" pre- and post-fertilization effects. Based in part on the doubts expressed by several of you, specifically including the questions raised by pk's careful explanation of the sequence of events, and by Mark and Kevin's further research, I went looking for info that might contradict my starting position.

Our Plan B discussion has been directly aimed at the issue of how it works, whether by delaying ovulation and inhibiting fertilization (contraception) or (in addition, since it seems clear that progesterone variants do suppress ovulation) whether by one or more post-fertilization effects. pk describes that distinction well: "prevention of pregnancy after fertilization but before implantation is a very different thing than prevention of pregnancy before ovulation, or even before fertilization." Mark is even more direct: "caus[ing] embryonic death."

Our debate hasn't been about whether there are significant differences between these modes of action, but about which modes of action Plan B utilizes.

As I said, I went looking for information that might change my understanding of those modes of action. And I found it: the effectiveness of Plan B may indeed, in some part, be attributable to "post-fertilization effects." Or, perhaps more precisely expressed, "post-fertilization effects" as a mode of action of Plan B--while not easily studied or quantified--are reasonably suspected and cannot be ruled out.

And let me be clear, again, since apparently I failed to communicate before. By this term, I mean just what pk and Mark mean: interference with pregnancy after fertilization but before implantation. Or, for some of you, embryonic death (I think the technical term prior to implantation is pre-embryo, just as "pregnancy" may also not technically refer to the pre-implantation period, but retreating to the technical jargon would not, for our purposes, serve to honestly confront the moral and ethical implications).

So, based upon the suspicions, concerns, and research from the rest of you, I've changed my position on how Plan B may act. Kind of that basic "risk" that we run on this blog, by opening ourselves up to new attitudes and information.

Yikes!

In fact, there was a front-page article in the Seattle P.I. yesterday about a "genial" 65-year-old pharmacist in the small community of Covington, who is refusing to stock Plan B, precisely because he believes that, "if a person's purpose is to kill a fertilized egg, then I disagree with that."

(Unlike some of you here, this pharmacist somehow has never figured out that birth control pills work by these same problematic methods, leading one to question his professional qualifications.)

Before coming here yesterday, I was inclined to write a letter--critical both of the pharmacist for failing to understand the science and of the P-I for failing to prominently present the correct science. Obviously, if I were to now write any letter at all, it would be to make an entirely different point.

Link to original article:
http://seattlepi.nwsource.com/local/283106_planb30.html.

steviepinhead said...

Last dratted comment posted twice (the first time I was sent to "can't find the page" limbo, so I assumed it hadn't posted). The second version is the intended one. I can't figure out how to delete the first comment (Blogger.com only seems to allow the deletion of the original posts, or at least that's all I could figure out...). Sorry about any extra reading! Stevie

Mark Congdon said...

Stevie,

I removed the double-posted comment for you.

Thanks for setting me straight... I was obviously wrong about the degree to which the method of operation of birth control pills was generally known. It's always been generally known to me, and I don't talk about such topics generally with, say, coworkers or casual acquaintances... so I guess I just didn't realize.

Your story about the pharmacist is amazing... either he is a very underqualified pharmacist (which, in my experience, wouldn't be a great surprise), or he applies his principles very inconsistently (which, in my experience, would be even less of a surprise).

This discussion has been very helpful for me. Trying to sort through medical research in an area that I don't understand very well, and in a politicized environment where disinformation on both sides is rampant, is a tedious and difficult task. Having other people work through the process with me is amazingly helpful.

I wish the answers were a little more clear, but at least I feel that I have a reliable handle on what we currently know, and probably all we can expect to know in the near future.

Thanks, stevie, kevin, doug, and pk!

Mark

purple_kangaroo said...

I'm sorry, Stevie. I guess I didn't explain myself clearly or didn't read your post carefully enough or something. It took me a long time to write that post yesterday, so I think your second comment was posted while I was writing my reply.

I do understand that you grasp the difference between post-fertilization but pre-implantation action versus post-implantation action.

What I was primarily responding to, though, is that at least once or twice you quoted a scientist saying that Plan B could not be abortificatient because it did not affect the pregnancy post-implantation, and extrapolated that to mean that Plan B was "a true contraceptive" because it did not affect the pregnancy between fertilization and implantation.

For instance, you quoted this article from the New England Journal of Medicine saying: "Intervention within 72 hours after intercourse cannot possibly amount to abortion, because implantation is not achieved until at least seven days after ovulation and the egg is capable of being fertilized for only about 24 hours."

You commented: "In other words, it's being argued that--even if we assume that an egg is released just before (or despite) the use of Plan B, and is then fertilized within the first 24 hours following the, um, sperm-intoduction event, and Plan B is also (properly) taken within 72 hours of the same event--then whatever the possible effects of Plan B may be, they can't--at least in the above hypothetical, actually involve the failure of a fertilized egg to implant."

Actually, the author of the article wasn't saying that it "can't . . . actually involve the failure of a fertilized egg to implant." The context was in discussing a known abortificatient drug taken post-fertilization but pre-implantation.

The doctor is arguing not that it doesn't interfere with implantation, but that any intervention that takes place before implantation is not an abortion but a contraception. Like many others, the author of that article has redefined conception to being the moment of implantation rather than the moment of fertilization.

Here's a more extensive quote I found from the same article, giving a little more of the context: "Use of emergency contraception is limited largely by ignorance. Although it seems likely that the strogen/progestin regimen works mainly by interfering with ovulation, it is nevertheless regarded by many as an abortifacient because it is taken after, rather than before, intercourse. This confusion is compounded when mifepristone is advocated for emergency contraception since, when taken after pregnancy is established, it can be and is used for the induction of abortion. The prevention of pregnancy before implantation is contraception and not abortion. Intervention within 72 hours after intercourse cannot possibly amount to abortion, because implantation is not achieved until at least seven days after ovulation and the egg is capable of being fertilized for only about 24 hours."

So what I particularly wanted to point out is that just because someone is saying that something "can't possibly amount to abortion" doesn't mean it doesn't have an effect post-fertilization. Quite often it really means they've redefined the term conception so that they don't consider a woman to be pregnant until after implantation, so something that disrupts implantation of course can't (in their eyes) be considered abortion-inducing.

steviepinhead said...

Well, I think pk is still to some degree misunderstanding who I was quoting, how I intended to handle the quotes, and so forth. I won't go into great detail--since I'm now pretty sure that pk and I at least understand each other--except to say that neither of the later quotes in my referenced comment were from the article in the Archives of Family Medicine (not the New England Journal of Medicine, to which pk's link leads) that I linked to, nor did I claim that they were.

(I'm not sure how pk got to her NEJM article--maybe from something cited by Mark or Kevin? Or by using my suggested google terms, which of course lead to lots of articles, not just the one I linked to...?)

However, upon re-reading, I see I could have been clearer in attributing the quotes. I attributed the quote pk discusses not to my AFM scientist, not to pk's NEJM scientist, and indeed not to any scientist, but merely to an anonymous someone who I said "acknowledge[s] the theoretical possibility of these post-fertilization effects..."

I then quoted the relevant portion of what that person had to say (actually an unknown contributor to a science blog I also follow), largely for the purpose of then questioning that person's claim in my next paragraph (which started out, "The validity of this reasoning might, it seems to me, be diluted if...").

My use of "diluted" was intended to be a signal of doubt, but perhaps--like my failure to clearly attribute the quote to someone distinct in the first instance--that phraseology was also misleading to pk.

Likewise, my second quote (which I led into by saying, "I have also come across the claim that...") did not come from any particular scientific research article. And, again, it was my intent to critique the point made in the quote.

Thus, while neither of my quotes was attributed to a scientific journal author, they weren't very clearly attributed to anyone. I'll try to do better, and be less confusing, n the future.

Please just understand for now that--on those rare occasions when I actually do the work of researching something!--just because I have quoted someone, does not necessarily mean that I'm going to then be agreeing with them--though I'll try to use "stronger" signals for how I do intend to treat them!

steviepinhead said...

Perhaps I should add that, in saying:

"I think the technical term prior to implantation is pre-embryo, just as "pregnancy" may also not technically refer to the pre-implantation period, but retreating to the technical jargon would not, for our purposes, serve to honestly confront the moral and ethical implications."

--it was my intent to make the same general point that I think pk is also making when she says:

"Quite often it really means they've redefined the term conception so that they don't consider a woman to be pregnant until after implantation, so something that disrupts implantation of course can't (in their eyes) be considered abortion-inducing."

In other words--while it will often be helpful to "define our terms," to be sure we're talking about the same thing--on this blog our intent is to honestly confront whatever issue we are dealing with, and not to merely "define" our way around an honest meeting of the issue.

Mark Congdon said...

Stevie,

It looks to me like PK reached the NEJM article by Googling the exact quote. I tried it, and even though the full text of that article requires registration, I was able to find pertinent extracts from the article quoted elsewhere. I'd gues PK did the same thing.

Your anonymous poster on the other blog must have been quoting from the NEJM article as well... the wording is too precise for it to be otherwise.

Mark

purple_kangaroo said...

In other words--while it will often be helpful to "define our terms," to be sure we're talking about the same thing--on this blog our intent is to honestly confront whatever issue we are dealing with, and not to merely "define" our way around an honest meeting of the issue.

Very well-said. Another quote worthy of the blog header, Steviepinhead. :) I love the intellectual honesty in the discussions here.

I was looking for the source of the quote you included in your post, and according to all the sources I found it comes from the NEJM article I linked to. As Mark said, I'm sure whoever said it on your forum must have been quoting the NEJM author, because the wording of the entire quote is exactly the same.

steviepinhead said...

Weird.

Well, unless my anonymous (they do have a screen name, of course) blogster WAS the lead author of the article, then they utilized that direct quote without acknowledgment or attribution...

Mark Congdon said...

Thanks to something PK forwarded me today, I came across a series of posts on a blog (LTI Blog)dedicated to "Abortion, Stem Cell Research, and Beyond". These posts do an excellent job of evaluating the evidence of post-fertilization effects of Plan B.

The series is in six parts. Here are links:

Part 1 - Overview
Part 2 - Info from Manufacturer
Part 3 - Evidence for Post-Fertilization Effects
Part 4 - Do Studies show post-ovulatory effectiveness?
Part 5 - Morphological changes?
Part 6 - Plan B Effectiveness

The most pertinent post to the discussion we had here is Part 6, where the author questions the effectiveness ratings cited by the manufacturer and determined in various studies. Stevie, he echos some of your doubts about the possible effectiveness of those studies. He also cites two other studies that I had not previously heard of, which found little to no real-world effectiveness of Plan B.

It's definitely worth the read...

Mark

steviepinhead said...

Interesting.

Boy, reaching some kind of moral-ethical decision is certainly getting more nuanced and complex. First, you have to do your best to set aside your political-moral-ethical pre-commitments and stances (not to abandon them permanently, but just to temporarily hold them in abeyance), and try to decide--as objectively as possible--what the evidence and the science is actually telling us with regard to some of these prickly questions.

Not an easy task (and, of course, it might be argued that the first step is to have enough of an informed ethical-moral compass to decide what prickly edges, boundaries, and slopes need to be informed by science--or other factual, evidence-based information-gathering)...

And, once you've done your best to try to figure out what the evidence is actually saying, you may then need to take a deep breath and re-don your ethical-moral-political viewpoint and decide WHAT TO DO--as citizen, voter, individual, church-goer, environmental organization member--with your best read of the best evidence you could lay hands on.

I'm sure some of us here will, at that point, reach different conscience-driven decisions. But it's invigorating to learn of the commitment that the folks here--and hopefully many other relatively-"silent" mostly-moderate folks out there--have to digging out the best information in the first place.

If only we could have confidence that MOST folks were doing that.

At least, with the resources of the internet, there's less and less excuse NOT to have done it.

Kevin said...

Mark,

I skimmed Part 6 - Plan B Effectiveness. Serge apparently has access to the full texts, so perhaps he has studied the details. I don't really know what to make of it.

The article: "Direct Access to Emergency Contraception Through Pharmacies and Effect on Unintended Pregnancy and STIs" apparently studied various forms of access to EC, so I'm not sure it lends itself to analyzing isolated EC effectiveness per incident.

For example, the use of EC ranged from 21.0% to 37.4% and the abstract does not mention how many within that subset became pregnant despite their use of EC in each incident. Furthermore, it is not clear to me what the regimen of EC was in each case... how often was EC used?

I did find an abstract of a study on the Minimum effectiveness of the levonorgestrel regimen of emergency contraception which suggests that levonorgestrel is 49% more effective than the Yuzpe regimen, which they in turn call the "minimum" effectiveness.

Perhaps the effectiveness studies should at least compare an EC group to a statistically similar group that wants to have a child. It's not double blind, but with a large enough sample size, the findings might be more relevant than just estimating the pregnancy rate. It might also be helpful to see the individual correlation between a woman's cycle and her use of EC.

Kevin

Funky Dung said...

"due to bizarre web formatting, you'll want to read the printable versions of the posts"

1. I think it only looked bizarre for IE users. IE sucks and I gave up on coding html and css for it.
2. I've changed themes. The newer one is cleaner and may be more aesthetically pleasing to you.

"I confess that I'm confused. The citations on the Ales Rarus blog sound very convincing... but are they comprehensive?'

Comprehensiveness is something I've started working on.

Anonymous said...

It is impossible to have a viable pregnancy without implantation. That is why IVF has only a 30% success rate. And, the majority of old time theologians (pre 1800s) believed life began with the quickening - when the baby could first be felt.

The truth is that if this drug only has a 70 to 75% rate of prevention it is no better than nature in "preventing" pregnancy since even in the most fertile of couples there is only a 20% chance of conception each month with well-timed intercourse.

Anon.

MarkC said...

Hi Anonymous!

Welcome to our archives. :)

even in the most fertile of couples there is only a 20% chance of conception each month with well-timed intercourse

I'm fascinated by that assertion. My experience and the experience of other people that I know would, from an anecdotal standpoint, contradict those numbers. I'm fascinated to learn where they came from, and to understand them better. Can you point me toward a source?

Thanks,
Mark

Anonymous said...

Inference from this study is only slightly higher than 20% for fecund couples:

http://humrep.oxfordjournals.org/cgi/content/abstract/17/2/503

This article even talks about which days are best for getting pregnant:

http://171.66.123.143/cgi/content/extract/334/19/1266

I know one of the researchers and have confidence in his methodologies.

The truth of the matter is that most people (including the specialists) have very little understanding of everything that is involved to make a pregnancy happen each month. A viable pregnancy is a miracle no matter how it happens.

Remember, due to ART technologies and more sensitive, we are now seeing positive pregnancy tests for pregnancies that were never viable and would have been rejected by the woman's body well before she knew she was pregnant.

I am well aware of the arguments that life begins at conception but thoroughly reject this idea because of my understanding of things like chemical pregnancy, chromosomal abnormalities, ectopic pregnancies, early (non-chemical) miscarriage. If a fetus cannot exist outside a womb-like environment, I cannot think of it as a fully formed human.

I understand and respect that others have a different viewpoint. However, I cannot respect the idea that they should in any way infringe on my or other's rights in regards to reproduction.

Of course, with egg vitrification this might become a moot point in the near future. Some of the most exciting research is being done in ovarian tissue and egg freezing, and a technology known as IVM that is being pioneered in Israel, Denmark, and Japan. (Only St. Louis has a group doing research in the USA.) Due to the stranglehold some very conservative people have on research dollars, there is actual encouragement for overstimulation of ovaries which leads to having more eggs than necessary.

Many women never get more than one egg to transfer. It is relatively uncommon to have many viable fertilized embryos. New studies - worldwide - are showing that as many as 85% of embryos are not viable. (This is usually blamed on the woman's egg vs. sperm, but even men are beginning to see that their sperm has a limited shelf life for healthy children.)

To me, it is not murky. An embryo is only a potential, not a human being. A human being has been "quickened" and can survive outside the womb. Perhaps my own family's experience with miscarriages and stillborns has colored my viewpoint on this.

MamasBoy said...

"So how is it that such a significant percentage of the American population is OK with destroying embryos intentionally for convenience, but is not OK with destroying embryos intentionally for research purposes?"

My best guess is that they are forming opinions based on emotional connections and not on facts. Nobody wants another couple to undergo the pain of infertility. People are also uncomfortable with using humans for experimentation. It reminds them of too many uncomfortable historical facts.

The widespread acceptance of homosexuality in this country follows a similar trend. People who see images they can identify with and feel sorry for portrayed in the media are much more likely to accept things like gay marriage than those who have formed their opinions on the topic other ways. I figure all that is needed for acceptance of polygamy and incest to become common are 1) for gay marriage to pass and 2) for Hollywood to embrace the cause.

MB