Plan B: Is the FDA Using Outdated, Inaccurate Information? [Serge]

An e-mailer recently asked about the fact that the FDA does list prevention of implantation as a potential mechanism of action of Plan B. You can see that in the FDA Q&A here as well as the package insert here. Does the FDA know something that we don't?

The FDA relies on information provided by the manufacturer for the mechanism of action of any medication (they do not do their own research). I responded to the information provided by the manufacturer in this post here. In short, the manufacturer has a responsibility to list any possible mechanisms of action for any medications. Since there is an open question in the literature regarding the mechanism of Plan B, and since post-fertilization events are listed as one possible mechanism, it is not surprising (nor particularly helpful) that interruption of implantation is included as a possible mechanism of action.

In other words, the fact that the manufacturer mentions this as a possible mechanism is evidence that the question is an open one that we have no definitive answers to. Therefore, the presence of this information by the FDA does not trump the most recent literature on the topic. In fact, the opposite is true.

I can illustrate this in another way that does not directly address the mechanism of action of Plan B. The manufacturer makes this claim in its literature, and its repeated on the packaging of Plan B that the FDA agreed to:

A double-blind, controlled clinical trial in 1,955 evaluable women compared the efficacy and safety of Plan B (one 0.75 mg tablet of levonorgestrel taken within 72 hours of intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets of 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two tablets taken 12 hours later). Plan B was at least as effective as the Yuzpe regimen in preventing pregnancy. After a single act of intercourse, the expected pregnancy rate of 8% (with no contraception) was reduced to approximately 1% with Plan B. Thus, Plan B reduced the expected number of pregnancies by 89%.

The exact citation isn't listed, but clearly they were citing this study from 1998 (both studies had 1955 women enrolled), Lancet 1998 Aug 8;352(9126):428-33. This is the same study that I posted about here. They used a crude method of determining ovulation: they added 14 days to the last period. The primary author for this paper was H Von Hertzen.

In other words, the FDA is allowing data 8 years old that used a very inaccurate way of determining ovulation, which is essential in determining effectiveness in stopping pregnancy. In fact, the author of that study has more recently contributed to an article which acknowledges the inaccuracy of their data in estimating the expected rate of pregnancy(Contraception 2003 Apr;67(4):259-65.)

This article, in which Von Hertzen is an author, states in the abstract:

The expected pregnancy rate among typical users was 6.2% in the Population Council trial and 7.4% in the WHO trial based on conception probabilities by cycle day relative to the day of ovulation. Based on conception probabilities by cycle day relative to the first day of bleeding, the expected pregnancy rates dropped to 5.4% and 5.2%, respectively. The two trials yield conflicting evidence regarding whether effectiveness declines with treatment delay. CONCLUSIONS: Our results suggest that the absolute levels of effectiveness for the Yuzpe regimen of emergency contraception and the cost-effectiveness of this regimen have probably been overstated when based on conception probabilities by cycle day relative to day of ovulation.

Although the authors only mention the Yuzpe regimen the same pregnancy estimation was also used to determine the efficacy of Plan B. If the effectiveness of the Yuzpe regimen had been overstated, then the same can be inferred with Plan B. It should also be noted that even with the "more accurate" method of determining ovulation, there is a significant chance for error in determining the actual date of ovulation.

I hope I haven't lost anyone. Here's the bottom line: the FDA is allowing the manufacturer of Plan B to claim that it can be almost 90% effective based on a study from 1998. This study has been shown to be inaccurate due to its crude way of estimating ovulation. This fact was pointed out by none other than the author of the original study. Yet there it is on the packaging being readied for OTC sale.

Still confident in the FDA information now? There is significant reason why we should not be. In any event, it should be clear that the information given by the FTC does not refute more recent scientific studies.

Plan B EC: No Morphological Changes Found in Endometrium [Serge]

Fifth in a series.

In this post, I spoke of three evidences that have been presented to support a post-fertilization mechanism of action from Plan B EC. I promised to challenge each one, and this was #2:

2. Since EC has the same types of hormones found in regular oral contraceptives, and there is evidence that regular OCs can have a post-fertilization event, then it stands to reason that EC would also have a post-fertilization mechanism of action.

I believe this point is the easiest one to refute, and my research in this area has turned up some surprises.

First, this point implies that there is a known post-fertilization effect from regular OCs. There is no consensus on that issue, and there is no direct evidence that OCs cause a "hostile endometrium." However, even if you believe that regular OCs do cause abortions, that does not indicate that Plan B EC does work via a post-fertilization event. This was a surprising aspect of this research: if Plan B acts after fertilization, the evidence states argues that it must do so by a mechanism that is different than regular OCs. I will show why.

Most who believe that regular OCs can act as an abortifacient use what I call the "hostile endometrium" theory". The theory is that continued use of OCs create a thinner, less vascular endometrium that would be less likely to accept an embryo attempting to implant. Randy Alcorn, who has written extensively on this topic, explains it this way:

When the Pill thins the endometrium, it seems self-evident a zygote attempting to implant has a smaller likelihood of survival. A woman taking the Pill puts any conceived child at greater risk of being aborted than if the Pill were not being taken...

First, after a woman stops taking the Pill, it usually takes several cycles for her menstrual flow to increase to the volume of women who are not on the Pill. This suggests to most objective researchers that the endometrium is slow to recover from its Pill-induced thinning

Now if the effect of regular OCs take months to for a woman's body to "undo", then how does Plan B EC create a hostile environment in a matter of hours? It seems that if EC works via a post-fertilization event, it must use some different mechanism than regular OCs, which appears to be based on a chronic thinning of the endometrium.

However, I did not have to depend on the argument of the last paragraph. There is actually experimental evidence that shows that Plan B taken after ovulation does not have any significant change in the morphology of the endometrium. Take a look at the abstract here and the full article here that presents this evidence. (Contraception. 2001 Oct;64(4):227-34.) They performed endometrial biopsies on women who took Plan B EC and control groups and found no difference in the morphology between the two. The paper states:

No significant changes were observed between treated and control specimens in any of the studied parameters. No significant differences among groups were observed. Of particular importance was the finding that the predecidual changes as evaluated by the presence of prominent spiral arteries, which are considered crucial for implantation [24], were not altered by LNG.

Remember, the proposed mechanism of regular OCs is to create a significantly thinner endometrium. This does not occur when a woman takes Plan B.

Although the medications are the same, if Plan B acts to cause abortions, it seems to have to do so via a different mechanism than does regular OCs. Instead of being evidence for a post-fertilization mechanism of action, this actually gives support to the theory that Plan B does not act after ovulation.

Plan B: The Evidence So Far [Serge]

Its been a while since I posted on Plan B, so I'll summarize my thoughts so far:

1) an analysis of the most recent literature supports the theory that Plan B works predominately, if not exclusively, prior to the fertilization event. In other words its effectiveness is primarily associated with its ability to impair ovulation, and not effect implantation.

2) If Plan B does not work after fertilization, the reported effectiveness of the medication must be less than the 85% or 91% that has been reported in the literature and on the package insert.

These two posts address the effectiveness issue of Plan B. If I am right here, we would expect the data that uses a more accurate measure for predicted pregnancy rates to show decreased effectiveness for EC. I have detailed four studies which showed that real world usage of Plan B does not effect pregnancy rates. However, one could argue that factors outside of medication effectiveness were responsible for the number of pregnancies in the Plan B groups. When I wrote the original posts, there was no studies out which showed a decrease in the effectiveness of Plan B using a more accurate way of estimating pregnancy risk. As I will detail in the next post, that is no longer the case.

What about the FDA Information? [Serge]

Note: This is a post that I made over seven years ago.  A number of readers recently emailed me the same question.  I have updated the post with some new information and added a bit to the end.  The original post is here.

An e-mailer recently asked about the fact that the FDA does list prevention of implantation as a potential mechanism of action of Plan B. You can see that in the FDA certified package insert here. Does the FDA know something that we don't?

The FDA relies on information provided by the manufacturer for the mechanism of action of any medication (they do not do their own research).  In short, the manufacturer has a responsibility to list any possible mechanisms of action for any medications. Since there is an open question in the literature regarding the mechanism of Plan B, and since post-fertilization events are listed as one possible mechanism, it is not surprising (nor particularly helpful) that interruption of implantation is included as a possible mechanism of action.

In other words, the fact that the manufacturer mentions this as a possible mechanism is evidence that the question is an open one that we have no definitive answers to. Therefore, the presence of this information by the FDA does not trump the most recent literature on the topic. In fact, the opposite is true.

I can illustrate this in another way that does not directly address the mechanism of action of PlanB. The manufacturer makes this claim on the packaging of Plan B that the FDA agreed to:

How effective is Plan B® One-Step?
The sooner you take Plan B® One-Step, the better it will work. Take Plan B®
One-Step as soon as possible after unprotected sex. If it is taken as soon as
possible within 72 hours (3 days) after unprotected 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. 

I have noted in a number of posts beginning over 7 years ago that this claim is completely wrong.  There is no one aware of the research on Plan B who believes that it is over 87% effective.  In fact, recently we have discovered that for many, many women the effectiveness is essentially zero.  This is not new information - the FDA has very little incentive to stay current with the most recent research once a drug is on the market.

Here's the bottom line: the FDA is allowing the manufacturer of Plan B to claim that it can be almost 90% effective based very old data. These studies have been shown to be inaccurate due to its crude way of estimating ovulation.  Yet there it is on the packaging being readied for OTC sale.

Still confident in the FDA information now? There is significant reason why we should not be. In any event, it should be clear that the information given by the FTC does not refute more recent scientific studies.

Lastly, I wish to mention that the FDA really does not concern itself with mechanism of action.  Essentially, when a drug seeks FDA approval, it has to show that it is both safe and efficacious.  In other words, it does what it claims to do and doesn't do anything else too dangerous.  (As we can see, it sometimes fails in either one or both of these goals).  If a drug can show these two things, it is unimportant to indicate its mechanism of action.  In fact, for many drugs that we use, including the majority of the anesthetic drugs we use, we do not know the exact mechanism of action.  

Ella: the Anti-Plan B [Serge]

Elizabeth and Scott have awakened me from my slumber (thanks guys). There is a lot of confusion regarding the new "emergency contraceptive" Ella (ulipristal), and hopefully I'll be able to provide some clarification in the next few posts.

Let me contrast Plan B and Ella. Plan B is basically synthetic progesterone, and is merely a larger dose of a form of oral contraceptive that has been used for years. Ella is a progesterone antagonist, which means that it works by blocking the effect of progesterone. The only other progesterone antagonist on the market at this time is mifepristone, otherwise known as RU-486, the abortion pill.

Its seems a bit strange that the proposed mechanism for both of these drugs is to suppress ovulation, and the evidence is clear that both of them do that. The concern is with any other effects the medications may have on a developing embryo and its ability to attach to the uterine lining.

Since human beings are intrinsically valuable from the moment they become human beings, any medication that serves to end the life of a human being after fertilization is morally wrong. This is true whether or not the medication has a direct effect on an implanted embryo or if it adversely effects that uterine lining to make implantation more difficult. I would oppose any medication that has been shown to have either effect.

In the case of Plan B - there is no direct evidence that it decreases the receptivity of the uterine lining to an embryo that is attempting to implant. There is some indirect evidence that has concerned many in our movement, but there is also evidence from both animal studies and human studies that indicate no post-fertilization effects from Plan B. In the absence of clear evidence, I urge caution, but cannot state that using Plan B is wrong because of its post-fertilization effects. Lots of my older posts on this topic can be found here.

This may seem like a win for the pro-EC crowd, but in truth it is an epic fail. If EC only works before fertilization, than its effectiveness will be far less than the stated 90%. In fact, the evidence now supports this. There have been over 14 studies that have tried to show that taking EC will decrease pregnancies within a certain group. The number of the studies that showed a decrease in pregnancies for those taking Plan B have been a whopping zero.

What about Ella? I will show in following posts that just about everything that I stated about Plan B is completely different than Ella. Ella has been shown conclusively to have an adverse effect on the uterine lining. Investigators admit that if taken in higher doses, Ella will cause an abortion just like her sister RU-486. This is not an emergency contraceptive drug - it is a low dose abortifacient.

Plan B EC: What is its Real Effectiveness? [Serge]

Sixth in a series.

I wish to challenge the most compelling line of evidence that Plan B works at least some if the time via a post-fertilization mechanism. In this post, I believe those who are very pro-emergency contraception will be quite disappointed.

The most common evidence used to support a post-fertilization effect of Plan B is its proposed effectiveness. Quoting from this post:

1. The reported effectiveness of EC cannot be fully explained by a suppression of ovulation. In other words, if EC worked through non-fertilization events, we would not expect it to be as effective as it appears to be. Therefore there must be some post-fertilization event that is responsible for at least part of its effectiveness.

The effectiveness of Plan B is reported to be somewhere between 90 and 75% in stopping an unintended pregnancy. If this is true, it seems impossible that it could work via a purely anti-ovulatory action. As Steve states here, the most important question to ask would be when did a woman ovulate. If Plan B is taken after a woman ovulates, and it contributes to the 75% effectiveness, then it must work at least part of the time via a post-fertilization event.

If, on the other hand, Plan B works through predominantly anti-ovulatory actions, its effectiveness would be expected to be less than 75%. What does the data support? If one looks at some of the more recent studies, it is reasonable to conclude that the effectiveness of EC is significantly less than 75%.

First, it is a known fact that studying the effectiveness of EC is quite challenging. The main reason is that in order to have a comparison group, an accurate determination of the date of ovulation is essential. An ideal study would use a placebo control group - but that would entail giving a woman who is seeking to prevent a pregnancy a placebo, which is considered unethical. For that reason, estimates of ovulation are used. It has been shown that these estimations are often very inaccurate, as shown by this article: (Contraception 2003 Apr;67(4):259-65)

Calculations of the efficacy of EC depend on knowing the timing of intercourse in relation to the estimated day of ovulation. The results of this study suggest that these calculations are likely to be inaccurate for a significant minority of women.

Is there evidence that EC may not be effective as advertised? Absolutely. I will cite two very recent studies. In this article about EC in JAMA (JAMA 2005;293:54-62), the authors specifically choose a number of women that would have direct access to EC vs pharmacy access in order to show a difference in pregnancy rate between the two groups (they choose about 890 women in each group). They say so in the article, and this was not a small study. As it was, the group who had to go to the pharmacy to get EC used it 197 times, while the group who had direct access used it 309 times. The result on pregnancy: absolutely nothing! The pregnancy rate for the first group was identical despite the fact that they used EC one third more often. This caused the authors of the study to state:

While we set out to demonstrate a large reduction in pregnancy rates, even a10% or 20% reduction in unintended pregnancy rates would be a significant and desirable public health achievement.

What ever happened to 75%? They set out to demonstrate a large reduction in pregnancies, and got zero despite the fact that so many more women took EC. Now they would be happy to see a 10-20% reduction. This is solid evidence that in the "real world", EC doesn't work nearly as often as stated.

Here's one more (Contraception 69 (2004) 361-366). These researchers showed that having EC at home did not reduce pregnancy or abortion rates in that population. Lest anyone think that my reasoning is novel here, the authors seem to agree with me:

Finally, it is possible that EC may be less effective than we belief. Estimates of efficacy are unsubstantiated by randomized trials. Efficacy is based on rather unreliable data and a great many assumptions [28] and have been questioned both in the past [29] and more recently [30].

In conclusion, I believe there is an increasing amount of evidence that the proposed efficacy of EC is not nearly what was originally thought. There is no doubt in my mind that those who support increased access of EC as a public policy issue are not in any hurry to publicize this data. On the other hand, the decreased efficacy of EC is also key evidence that Plan B works predominately prior to ovulation.

Plan B Not Effective for Majority of Women [Serge]

I have been making the claim for many years that the evidence is clear that Plan B emergency contraception is less effective than frequently advertised.  When first made available, the manufacturer claimed that Plan B EC was about 90% effective in reducing unwanted pregnancy when taken after unprotected sex.  Later on, and very quietly, researchers admitted that the effectiveness is not even close to 90%.  In fact, here is the quote from researcher and senior fellow of the Guttmacher Institute James Trussell:

The risk of pregnancy for women requesting ECPs appears to be lower than assumed in the
estimates  of  ECP  efficacy,  which  are  consequently  likely to  be  overestimates.  Yet,  precise estimates of efficacy may not be highly relevant to many women who have had unprotected intercourse, since ECPs are often the only available treatment. A more important consideration for most ECP clients may be the fact that data from both clinical trials and mechanism of action studies clearly show that at least the levonorgestrel regimen of ECPs is more effective than nothing.

It turns out that Dr. Trussell was far too optimistic even in this assessment.  Now, it turns out that for many women, Plan B EC is not actually better than nothing! 

The European manufacturer of an emergency contraceptive pill identical to Plan B, also known as the morning-after pill, will warn women that the drug is completely ineffective for women who weigh more than 176 pounds and begins to lose effectiveness in women who weigh more than 165 pounds... 

 These pills, which use a compound called levonorgestrel to prevent pregnancies, are the most effective morning-after pills available without a prescription. Other pills sold in the United States require a prescription, are less effective at preventing pregnancy, or cause side effects such as nausea or vomiting. Plan B One-Step, which retails for $50, is the only emergency contraceptive drug in the United States available to women of all ages without a prescription.
Emergency contraception advocates reacted to the news about Norlevo with dismay. "There's a whole swath of American women for whom [these pills] are not effective," says James Trussell, a professor of public affairs at Princeton and a senior fellow with the Guttmacher Institute, a think tank for reproductive health issues. 

Data for the years 2007 to 2010 show the average weight of American women 20 years and older is 166.2 pounds—greater than the weight at which emergency contraceptive pills that use levonorgestrel begin to lose their effectiveness. The average weight of non-Hispanic black women aged 20 to 39 is 186 pounds, well above the weight at which these pills are completely ineffective. A CDC survey published in February found that 5.8 million American women used emergency contraceptive pills from 2006 to 2010.

The advocates of Emergency Contraception have been pushing this medication women of all ages without prescription despite the fact that the evidence has been available for quite a while that it was not effective.  This is shameful.

Plan C

NOTE! Please accept my apologies for any confusion the original post below may have caused. In fairness to Elizabeth, I failed to communicate to her the LTI position on Plan B (Emergency Contraception) and the Pill in general. Elizabeth, noting what many pro-life groups have said about Plan B, understandably concluded that our position was similar. The burden was on me to explain why we differed from those other groups and I overlooked doing that in her case. Thus, any confusion her post caused is my fault not hers. To clarify, LTI takes a cautious view on Plan B and the Pill in general while we await further evidence. That is, while we don’t think there is sufficient evidence to say for certain that Plan B (or the Pill) functions as an abortifacient in the event of breakthrough ovulation, we do think there’s sufficient evidence to indicate it may function that way. Thus, we should err on the side of caution while we await further evidence, meaning we do not endorse its use. Ella (Plan C), however, appears to function much like RU 486 abortion, thus Elizabeth is correct to raise concern. I have taken the liberty of modifying the post to reflect our position. Again, I apologize for the confusion, which is fully my fault.
--Scott Klusendorf


The Food and Drug Administration has approved a new form of "emergency contraceptive" pill that works as many as five days after unprotected intercourse. Plan B worked up to three days following intercourse.

Read all about the prescription "ella" in Friday's New York Times.

The company manufacturing the drug insists that it does not cause abortion, but this so-called birth control method appears to function much like the abortifacient RU-48; therefore, LTI does not endorse its use.

On a side note, I found it interesting that the article points out that some "religious groups" are opposed to the pill because of the perception that it causes abortion. I think the author here has overlooked groups like the Life Training Institute that base their arguments on science and philosophy. It's insulting to imply that opponents who espouse religious beliefs are incapable of reaching a logical conclusion.

Be Careful Out There (When Discussing Emergency Contraception) [Serge]

It is very important when discussing important and controversial issues to do everything in our power to find the truth and not overstate the evidence that we have supporting our conclusions.  This can be challenging when dealing with an issue such as emergency contraception, where the data and evidence is frequently either missing, confusing, or difficult to understand.  To this point, I believe that the evidence shows that Ella and IUDs have some sort of mechanism of action post-fertilization.  I believe that the evidence does not support a post-fertilization mechanism for Plan B, but its efficacy has been greatly overstated.  Overstating our case is a frequent problem in the pro-life community, and one that we should be careful to avoid.  So lets look at the headline of this post at LifeNews:

New Studies Show All Emergency Contraceptives Can Cause Early Abortion

I need a second here...

When you can't get through the headline without overstated conclusions it is not a good start.  First, the "New studies" that the post speaks of are actually not studies at all, but reviews.  The authors of these reviews looked at research done by others in the past and come to different conclusions.  There is nothing wrong with that, of course, but to state that "new studies" have concluded something certainly implies that there is new data and evidence that has settled this question.  As it turns out, the "new studies" are simply an alternate conclusion to what the original authors wrote.

The main review that is mentioned is this one from Peck and Velez from the National Catholic Bioethics Center.  It is not an easy read, but they posit that Plan B may have an effect when given prior to ovulation on the future developing embryo.  This conclusion is based on these two papers that have the exact opposite conclusion.  They are from Noe et al and the abstracts can be found here and here.  The abstract of that last paper states:

The efficacy of LNG-EC has been overestimated in studies using presumptive menstrual cycle data. Our results confirm previous similar studies and demonstrate that LNG-EC does not prevent embryo implantation and therefore cannot be labeled as abortifacient.

So how does Peck and Velez come to a completely different conclusion by looking at the same evidence?   They posit an interesting theory.  They believe that although Plan B is not effective if given after ovulation, its lingering effects on the pituitary axis and the corpus luteum hormones may still have an effect on the developing embryo.  This may be from an effect on the endometrium or another deleterious effect on the embryo (like being unable to transport an embryo to the uterus in time for implantation.)

Although this is an interesting theory, I do not believe there is adequate evidence to support it at this time.  I do believe however that we may be able to investigate this further, although it may be a moot point now that Ella and the copper IUDs are being pushed as the most effective emergency contraceptives.

So do new studies show that all forms of EC can cause early abortions?  In a word, NO.  There has been an interesting look at data published 3-4 years ago that contradicts the original author's conclusions.  If the future evidence supports this theory, then it may be possible that Plan B effects a developing embryo even though it is not effective when given after ovulation.  I plan on being very careful to look at this data before overstating possible conclusions.  I hope others will do the same.

"Depressed" about Emergency Contraception [Serge]

Wow. I just finished listening to a web seminar about the efficacy of emergency contraception by Dr. James Trussell, who is one of the most well reknown researchers in the field of contraception. I haven't been putting a while lot of time in studying EC lately, but essentially what Dr. Trussell had to say supports all of my previous postings on the subject, which can be found here. Here are some of the high (low) lights according to the Powerpoint slides that he presented.

1. Trussell previously hoped (published in 1992) that EC would reduce unintended pregnancies and abortion by half.

2. 15 years later 11 studies have consistently showed no decrease of pregnancy rates from use of ECs.

3. Trussell also stated that a future decrease in pregnancy rates from EC use is highly unlikely - an astounding admission.

4. He then quoted TH Huxley when he stated "The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact."

5. Due to difficulties in estimating the expected pregnancy rates, the published efficacy in the package insert of EC is almost certainly too high.

6. The only thing he could say about the actual efficacy of Plan B was that it was "more effective than nothing".

7. According to the latest research, the efficacy of Plan B can be fully explained via a pre-fertilization mechanism. Research continues to lead away from a post-fertilization mechanism.

This is amazing stuff. Since there was extensive news coverage of the effort to get Plan B to OTC status, why the silence in the wake of information that Plan B will not effect pregnancy or abortion rates? Imagine the outcry if a heart medication was thought to reduce heart attacks by 95% - and was made over-the-counter in order to increase its availability to reduce heart disease. A year later evidence comes out that no study had ever found that it had any effect on heart attack rates, and that the only thing that could be said about it is that it is "probably better than nothing". There would be a great outcry, congressional hearings, and accusations that the evil pharmaceutical companies were gouging unsuspecting patients. However, so far there has not been a peep among those concerned about "women's health" that they could be promoting an expensive medication that may not be effective.

Lastly, at the end of the seminar there was a pause before participants asked questions. Dr. Trussell commented that everyone must be too depressed.

More Evidence that Plan B is Not Effective After Ovulation [Serge]

This is only a pilot study, and I will be very interested to see the results when more patients are studied. However, the preliminary results seem to support the theory that Plan B is not effective after ovulation. Of course, if this is true, it means that Plan B does not effect implantation of an embryo.

Background

Although widely used, the mechanisms of action of the levonorgestrel emergency contraceptive pill (LNG ECP) are still unclear. There are increasing data to indicate that LNG is particularly effective as an ECP by interrupting follicular development and ovulation. An important outstanding question is whether it has any effect on fertilization or implantation.

Method

Ninety-nine women participated; they were recruited at the time they presented with a request for emergency contraception. All women took LNG 1.5 mg in a single dose during the clinic consultation. A blood sample was taken immediately prior to ingestion of the ECP for estimation of serum LH, estradiol and progesterone levels to calculate the day of ovulation. The specimens were analyzed in a single batch. Based on these endocrine data, we estimated the timing of ovulation to be within a ±24-h period with an accuracy of around 80%. Women were followed up 4–6 weeks later to ascertain pregnancy status. The effectiveness of ECP when taken before and after ovulation was determined.

Results

Three women became pregnant despite taking the ECP (pregnancy rate, 3.0%). All three women who became pregnant had unprotected intercourse between Days −1 and 0 and took the ECP on Day +2, based on endocrine data. Day 0 was taken as ovulation day. Among 17 women who had intercourse in the fertile period of the cycle and took the ECP after ovulation occurred (on Days +1 to +2), we could have expected three or four pregnancies; three were observed. Among 34 women who had intercourse on Days −5 to −2 of the fertile period and took ECP before or on the day of ovulation, four pregnancies could have been expected, but none were observed. We found major discrepancies between women's self-report of stage of the cycle and the dating calculation based on endocrine data.

Conclusion

These data are supportive of the concept that the LNG ECP has little or no effect on postovulation events but is highly effective when taken before ovulation.

Evidence that the Emergency Contraceptive Ella May Cause Abortions [Serge]

I had a great time speaking with Josh Brahm on Life Report last week on the subject of contraception.  I have constantly maintained that the available evidence reveals that Plan B doesn't work after fertilization because, well, Plan B really doesn't work.  I have also claimed that there is evidence that Ella has a post fertilization effect, and in fact may cause abortions when ovulation is not stopped.  A recent tweet by Jessica Valenti suggests that this idea that certain EC's may cause abortions received the typical treatment - a change of subject and an insult.  Ramesh Ponnuru makes the same claim as I.

Well I've taken a few science classes in my day, but that doesn't make me right.  It would be nice if we had some study that investigated whether or not there was an effect on the endometrium if a woman took a single dose of Ella after ovulation.  Well, in fact, there is...

I have the full text, and what is reveals is pretty clear.  The investigators gave women a single dose of ulipristal (labelled cdb-2914 in the study) after they had ovulated.  They then measured the effect of the medication on the endometrial lining, both histologically and with ultrasound.  They measured 3 doses, 10mg, 50mg, and 100mg (the dose of Ella is 30mg).  Did these doses have any effect on an embryo's ability to implant?  Clearly, the answer is yes:

CDB-2914 also was associated with decreased expression of peripheral node addressins (PNAds), which are important L-selectin ligands found on the surface of endothelial cells. Recent studies have shown that L-selectin ligands are up-regulated during the implantation window, making the uterus more receptive to the trophoblast (17,18).

In other words, there is direct evidence that Ella decreased the action of endometrial cells that are known to be important for implantation.

 Although a thicker endometrium might be expected in those with continued endometrial proliferation after an antiprogestin, in this study, women with proliferative endometrium on mid-luteal biopsy did not have a thicker endometrium. Either effect of CDB-2914, endometrial atrophy or continued proliferation,however, may hamper implantation.

 Here the authors acknowledge directly that Ella may hamper iplantation if taken after ovulation has occurred.  Its hard to get any clearer.  Even the summary acknowledges this:

In summary, decreased endometrial thickness and decreased L-selectin ligands expression may be the earliest features of the antiprogestational effect of CDB-2914 in the luteal phase, heralding other endometrial changes. In our studies, endometrial maturation appeared to be more vulnerable to a small, single dose given in the follicular phase than with a single dose given either in early or mid-luteal phase. Whether this is a direct endometrial effect or secondary to an ovarian effect is not known. Taken together, these endometrial effects in the absence of ovarian and menstrual cycle effects suggest mechanisms by which CDB-2914 might be effective as an emergency contraceptive (28).

Science is a stubborn thing.  We now have experimental evidence that Ella has an effect on the endometrium that can act to prevent an embryo from implanting.  The burden of proof is now on the other side to give evidence that this is wrong - which almost certainly they will not do.  Its far easier to insult us.

This is especially important considering the latest news about Plan B.  Because of its ineffectiveness, more and more women will be encouraged to take Ella (especially since cost is no longer an issue).

Clarifying Confusion about OCPs [Serge]

Over at Soulation (a great site, btw), a commenter named Marie has responded to some of my writing here as well as a recent interview that I had with Life Report regarding the mechanism of action of certain contraceptives.  I thought I would respond here in order to help others who may also be confused regarding this, well, complex and confusing issue.  Marie's response is very long, so I will be responding to specific quotes.  Her entire response can be found here.  I wish to remind everyone that we are discussing the ethical implications of contraception, but the medical mechanism of action.

 and since we know that the progestin in the pill is a synthetic form of progesterone which does not act like natural progesterone to prepare the uterus for implantation, it ends up working like a slower, low dose mifepristone. Yes, mifepristone has double the binding site affinity as normal progesterone and progestins and therefore it works much more harshly and quickly, but they are both "progesterone Narcan" as far as filling progesterone receptors but yet blocking the function of the woman's natural progesterone to prepare the uterus for implantation. A woman's own progesterone works best to prepare the uterus and maintain a pregnancy, that's why so many doctors and others have switched to bioidentical progesterone for treating infertility/miscarriage/menopause.

The assertion here is that LNG, the progestin found in Plan B, works as a competitive antagonist for progesterone receptors like Narcan works for opioid receptors.  She doesn't provide evidence for this, and I believe there are at least three reasons why it is very unlikely.

First, the amount of progesterone secreted by the corpus luteum after ovulation is far greater than that exogenous progestin absorbed by taking Plan B.  The notion that the small amount of oral progestin that effects the endometrium would overcome the huge surge of natural progesterone secreted in the luteal phase of the cycle is highly unlikely and would need evidence to be compelling.

Second, if LNG acts as a "weak" mifipristone (RU-486), then it should also have the effect of exhausting the progesterone receptors after inplantation has occurred.  In all studies, LNG has had no effect on pregnancies after implantation.  Why not?

Third, and I believe most compelling, is that other progestins are used in order to treat luteal insufficiency.  When a women does not produce enough progesterone during the luteal phase of her cycle it has been shown that progestins have had a positive effect on preventing spontaneous miscarriage.  It is true that bioidentical progesterone has been shown to be the best supplement for the insufficient natural progesterone in these patients (not surprisingly), but synthetic progestins did not have a negative effect, but a positive one.

In short, the assertion that the LNG in Plan B acts as a competitive antagonist is not only not supported in the literature, there is a number of reasons see that the evidence shows it is highly unlikely.

I'll respond to Marie's other comments in a future post.

Crunchin' Some EC Numbers [Serge]

JivinJ asks in the comments:

I'm trying to crunch the numbers to figure out what the effectiveness of EC would have been estimated at if the WHO used the pregnancy risk number from the Canadian study.

Correct me if I'm wrong but my estimations from trying to decipher how they figured out the effectiveness (is it percentage of pregnancies divided by pregnancy risk?) show that if the WHO study used the pregnancy risk number (4.12) from the Canadian study instead of the 7.7 garnered from the traditional method of estimating pregnancy risk and then took the percentage of women who became pregnant from the WHO study then the effectiveness of EC would be somewhere around 75% and not the 85% cited for the WHO.

I actually believe its worse than that. James Trussell, who I believe was an author in the WHO study, uses a meta analysis of all of the studies about plan B when discussing its efficacy. The 1.1% crude pregnancy rate found in that study has not been reproduced. Trussel states:

Therefore, the chance that pregnancy would occur in the absence of emergency contraception is estimated indirectly using published data on the probability of pregnancy on each day of the menstrual cycle.14,15 This estimate is compared to the actual number of pregnancies observed after treatment in observational treatment trials. Effectiveness is calculated as 1-O/E, where O and E are the observed and expected number of pregnancies, respectively...

Eight studies of the levonorgestrel regimen that included a total of more than 9,500 women reported estimates of effectiveness (a reduction in a woman’s chance of pregnancy) between 59% and 94%.7,8,9,17,18,19,20,21 A meta-analysis of eight studies of the combined regimen including more than 3,800 women concluded that the regimen prevents about 74% of expected pregnancies; the proportion ranged from 56% to 89% in the different studies.

Using the 7.7% rate for the traditional method of estimating pregnancies, Trussel's numbers are about a 2% rate of pregnancy when a woman is using Plan B EC (from the 74% number). This translates to an effectiveness of 51%.

One more thing. As the authors of the Canadian study state, even the revised method of estimating pregnancy may not be very accurate. This study of using ultrasound techniques to determine ovulation time was far more accurate than the calender method.

Bottom line: if the Canadian study is accurate, and the data from the meta-analysis of Plan B is used, then its maximum effectiveness is 51%. I believe further data will show that it is actually less than that.

Bad Reporting from Our Side [Serge]

It frustrates me greatly when pro-abortion choicers misrepresent scientific data in order to support their ideology. It frustrates me even more when those on our side do the same thing. Here is a report from Catholic News Agency that claims this about Plan B emergency contraception:

The most recent scientific study on Levonorgestrel, the essential component of the “morning-after pill” or “emergency contraceptive,” confirms that the drug does indeed have a third effect on users, which consists in preventing the implantation of a fertilized ovum in the womb of the mother.

Here is another post from prolifeblogs that mirrors this thought:

A study published in the journal Fertility and Sterility found that levonorgestrel, the drug contained in Plan B emergency contraception, does inhibit implantation after all, at least some of the time. (Preventing implantation interrupts an existing pregnancy and is an abortive mechanism.)

Interesting stuff, until you realize that both claims are completely untrue. Here is the abstract of the study in question. The investigators used computer models to determine the effectiveness of LNG as contraception if it acted via a pre-fertilization mechanism and compared it to the effectiveness if it also had a post-fertilization mechanism. The results were this:

With disruption of ovulation alone, the potential effectiveness of levonorgestrel EC ranged from 49% (no delay) to 8% (72-hour delay). With complete inhibition of fertilization before the day of ovulation, the potential effectiveness of levonorgestrel EC ranged from 90% (no delay) to 16% (72-hour delay).

This is not surprising at all, although it may very well be helpful if real experimental data ever come out that confirms the actual effectiveness of LNG. In fact, this post of mine essentially predicts these numbers. In the meantime, the authors do note that the projected effectiveness of LNG if it acts via a pre-fertilization mechanism is lower than the effectiveness rates reported in the literature. However, it is precisely those rates that have been previously reported that are under question not only by me, but by a number of pro-EC researchers. This study does nothing to shed light on the true effectiveness of LNG EC, and thus cannot confirm its actual mechanism at all. The authors understand this when they conclude:

The gap between effectiveness of levonorgestrel EC estimated from clinical studies and what can be attributed to disruption of ovulation may be explained by overestimation of actual effectiveness and supplementary mechanisms of action, including postfertilization effects.

Reporting that this paper confirms a post-fertilization mechanism for Plan B is completely irresponsible. Reporting the results of scientific papers using your ideology to cloud what they actually say is simply wrong.

Post-Fertlization Effects of the IUD Mirena [Serge]

There has been a recent emphasis among reproductive health professionals to strongly encourage women away from traditional oral contraceptives to long acting reversible contraception (LARC).  This fact, in conjunction with the changes to contraceptive coverage implemented in Obamacare, will result in an increase in the use of both IUDs and implantable contraceptives.  As a result, many speakers here at LTI have been asked about the most commonly used IUD in the USA, an IUD with the hormone progestin marketed here by the trade name Mirena.  Mirena has the same hormonal component as Plan B emergency contraception.  I have argued that Plan B most likely does not involve via a post-fertilization mechanism.  Does that indicate that Mirena also works exclusively before fertilization?  Well, in a word, no.

IUDs have actually been around for quite a long time.  Their effectiveness has never really been questioned - they were always found to be highly effective contraceptives.  Originally, it was thought that IUDs work almost exclusively by a local inflammatory response in a woman's endometrium.  In other words, we used to believe that IUDs work almost exclusively post-fertilization.

About 20 years ago, data began to emerge that questioned that theory.  It was found that IUDs also had effects on the local environment of the uterus that could result in some of its contraceptive efficacy.  An increase in the thickness of the cervical mucous may result in inhibition of sperm motility.  Likewise, the copper released form certain IUDs (not Mirena) may have a toxic effect on sperm.  There is also some research that shows a possible effect of the IUD on ovulation.  Remember, Mirena uses the same progestin analogue as Plan B (LNG).  If these mechanisms are totally responsible for the contraceptive effect of Mirena, then we could confidently state that Mirena does not act after fertilization and would not have an effect on a developing human embryo.

Unfortunately, the evidence does not support this.  The LNG that was added to the Mirena only has a local effect within the endometrium, and its blood levels never rise enough to have an effect on ovulation.  In fact, this LNG was added primarily to decrease the amount of bleeding sometimes seen amongst copper IUD users.  Furthermore, this study shows deleterious effects of this LNG dose on the endometrium, resulting in the conclusion that these changes may have "a pivotal role in the contraceptive effect of the LNG-IUS".  This is clear evidence that the changes in the uterine lining not only can cause an embryo not to implant, but may also be a primary mechanism for the contraceptive effect of Mirena.

This is supported in many other places.  Here is an article about various forms of IUDs.  Its conclusions are clear:

In women with the LNG-IUS, the endometrium is abnormally thin and contains areas of superficial fragile vessels (Guttinger and Critchley, 2007). These features suggest that the uterus would be hostile to implantation. 

In conclusion, IUDs may exert their contraceptive action at different levels. Potentially, they interfere with sperm function and transport within the uterus and tubes. It is difficult to determine whether fertilization of the oocyte is impaired by these compromised sperm. There is sufficient evidence to suggest that IUDs can prevent and disrupt implantation. The extent to which this interference contributes to its contraceptive action is unknown. The data are scanty and the political consequences of resolving this issue interfere with comprehensive research.

As usual, this data come from peer-reviewed sources that are otherwise very hostile to the pro-life view.  There is very little evidence that Mirena acts exclusively before fertilization and significant evidence that it effects the endometrium to an extent that implantation impairment may be an important mechanism to explain its efficacy.  If one believes in the inherent value of human beings from the moment they become human beings, the use of Mirena is very much ethically problematic.

Plan B: More Evidence That Its Effectiveness is "Markedly Lower" Than Previously Thought [Serge]

This study from the Journal of OB-GYN: Canada was the first population based study that used a more accurate method of measuring the risk of pregnancy. The full study is available here. The results are as I would expect: the effectiveness of Plan B is "markedly lower" than previously reported. I'll let the study speak for itself:

When the data for all women are combined, the mean risk of pregnancy is estimated to be 4.12% (95% CI 3.77–4.49). This risk of pregnancy is substantially lower than that estimated in studies comparing the effectiveness of the levonorgestrel and Yuzpe regimens.3,4

This is the first report of risk of pregnancy among a population-based cohort of women requesting EC from pharmacists under conditions of routine use. Overall, in the two groups combined, the estimated risk of pregnancy was 4.12%, which is markedly lower than that reported when effectiveness of EC has been estimated in clinical trials.2–5

If the estimates of risk of pregnancy from the present study and related studies are reasonably accurate, the effectiveness of EC among women in the general population may be markedly lower than is currently believed by professionals and advocates for wider EC use. In light of these observations, consideration should be given to revising the information on effectiveness that physicians, pharmacists and other health care professionals provide to women seeking EC.

Plan B EC: Others Question its Effectiveness [Serge]

Here is a very recent letter to the editor in the Journal Pediatrics that poses some of the same questions that I have regarding the efficacy of emergency contraception (Pediatrics 117:4 April 2006, p1448).

To the Editor.-

The American Academy of Pediatrics Committee on Adolescence policy statement on emergency contraception1 reports the effectiveness of the Yuzpe regimen (ethinyl estradiol and levonorgestrel) in terms of a pregnancy reduction of 70% to 80% and of levonorgestrel-only emergency contraception of 85%. These estimates are outdated. Using current methods for estimating effectiveness, the effectiveness rates seem to be in the range of 50% to 66% and 72% to 80%, respectively.2-5 Because there are no randomized trials with a placebo arm, considerable uncertainty remains about the effectiveness of emergency contraception.3,5

The policy statement also proposes that "[e]mergency contraception has tremendous potential to reduce unintended pregnancy rates in teens and adults." This statement remains, as yet, a hypothesis that is unsupported by empirical evidence. Several studies have failed to document a decrease in rates of unintended pregnancy or abortion in populations that are provided with advance access to emergency contraception.6-8 This suggests that the studies that have demonstrated no changes in sexual behavior with advance access (other than increased use of emergency contraception) have used inadequate surrogate end points or have failed to detect small changes in sexual behavior that were nevertheless sufficient to negate any decrease in unintended pregnancy.

Joseph B. Stanford, MD, MSPH

Department of Family and Preventive Medicine

University of Utah

Salt Lake City, UT 84108

Rafael T. Mikolajczyk, MD

Department of Public Health Medicine

School of Public Health

University of Bielefeld

D-33501 Bielefeld, Germany

A Question about Emergency Contraception [Serge]

I'm too busy to make a long post today, but I have a question to ask about the introduction of the new "EC" Ella. Supposedly, Plan B is 90% effective if taken within 48 hours of intercourse, and is available over the counter. Ella is twice as expensive and will never be available without a prescription. What is the market for this new drug? Who is supposed to buy it? What problem is it supposed to solve? Is it really for those unfortunate women who have had unprotected sex and have been unable to reach any of our nation's pharmacies for over 48 hours - so now they can go to their physician first, then the pharmacist to pay twice as much for a medication so they can use it up to 90 hours after sex? How many women does this accurately describe?

Or is there another reason that we can speculate about... Stay tuned.

LTI Podcast #30 - Free Plan B in New York HIgh Schools [Serge]

We're back again!  Jay, Rich and Megan discuss the new policy in New York public schools that enables children as young as 14 to obtain emergency contraception as well as long term contraception in school without parental consent or notification.  Is this the best we can do to train and protect our children?

Direct link is 
http://traffic.libsyn.com/serge13102/LTI_Podcast_30.mp3

or you can subscribe via ITunes right here.