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Acupuncture for IVF Revisited – More Tooth Fairy Science?

I read this Reuters Health article on MedlinePlus, and then I read the study the article referred to (The impact of acupuncture on in vitro fertilization) and now my head hurts. The study found that acupuncture was not effective in increasing the pregnancy rate (PR) during in vitro fertilization (IVF). As quoted on MedlinePlus, the lead author, Alice Domar, seems to blame her patients (the presumably poor quality of their embryos) rather than acupuncture for the lack of success, and then she recommends using acupuncture even if it doesn’t work. That was bad enough, but “poor quality embryos” is a hypothesis that was actually tested and rejected in the study itself. Has Domar forgotten?

The headline of the MedlinePlus article says “acupuncture doesn’t boost IVF success for all” – suggesting that it boosts success for some? Then the first sentence says the study suggested that acupuncture doesn’t work, period. But wait…

The lead researcher says acupuncture may not have worked in her study because, unlike past research, her investigation wasn’t limited to women who had good quality embryos available for transfer. “I’m wondering if my sample was just not a good sample, in that most of the patients in my study were probably not the best-prognosis patients,”
Domar and her team say the most likely explanation for the lack of an acupuncture effect in their study was the fact that they included many women who didn’t have good quality embryos available for transfer. While acupuncture may help a woman become pregnant after the transfer of a healthy embryo, the researcher noted in an interview, it can’t repair an embryo with chromosomal defects or other abnormalities.

Hold the boat!! In the Discussion section of the paper itself, Domar et al point out that previous research has included mostly patients with good quality embryos. They ask if perhaps acupuncture only works for good quality embryos? They test that hypothesis by separately analyzing the subjects in this study who had good quality embryos. There was no increase in PR with acupuncture in this sub-group; the results were the same as for the entire sample.

This study not only had an objective endpoint (pregnancy) but it also had several subjective psychological endpoints (optimism, confidence, and anxiety as measured by perceived relaxation). The women who received acupuncture felt more relaxed and enjoyed the IVF procedure more, the researchers found. They were also more optimistic about getting pregnant, but not more confident that they would get pregnant.”

Despite the results of my own study, I still recommend acupuncture to women going through IVF because there’s no downside,” Domar added, aside from the $150 an acupuncturist would typically charge — a small fraction of the $12,000 to $14,000 couples typically spent on a single round of IVF.

It seems to me this translates as: Acupuncture works. It didn’t work in this study, but that can’t be the fault of acupuncture, because acupuncture works. So it must be the fault of the patients for producing poor quality embryos, (our data don’t support that hypothesis, but let’s just ignore that). Acupuncture is harmless and people like it, so let’s use it on every patient whether it works or not. Patients will have to pay $150 extra, but I’m willing to decide for them that the expense is worth it. What?!

Domar’s study was intended to replicate an earlier study by Paulus from 2002, the first randomized, controlled, prospective study on the impact of acupuncture in 160 IVF patients with good quality embryos. The treatment group got 25 minutes of acupuncture before and after the IVF procedure, and the control group rested for 25 minutes. The pregnancy rate was significantly higher in the acupuncture group.

Domar also mentions a subsequent study that the Paulus’ group did with the same protocol but using sham acupuncture as a control. There was no significant difference. They proposed an “acupressure” effect of sham acupuncture, assuming that both groups achieved a greater pregnancy rate than they would have with no treatment; but the data don’t support that hypothesis since there was no comparable control group of untreated patients selected for good quality embryos. For some reason, they opted not to publish this second, negative study. It was only presented orally at a conference in Madrid in June 2003. (Paulus WE, Zhang M, Strehler E, Seybold B, Sterzik K. Placebo-controlled trial of acupuncture effects in assisted reproduction therapy. 2003: Oral presentation, ESHRE, Madrid, Spain, June 2003;18(Suppl1): xviii18.)

Domar’s intent was to repeat Paulus’ study and also investigate the potential of a placebo effect. Double blind acupuncture studies are impossible: the patients know they are getting acupuncture and the acupuncturist knows he’s giving it. But for the first time Domar tried to blind the rest of the IVF treatment team so no one else knew which group a patient was in. She expected the acupuncture patients not only to have a higher pregnancy rate (PR), but also to be more optimistic and confident that their cycle would be successful, thus demonstrating a placebo effect. The acupuncture patients were indeed less anxious and more optimistic, but they were not more confident, and the PR was not higher.

They were asked “how optimistic do you feel” and “how confident do you feel” about the outcome of the current cycle of IVF. I’m not sure where I would draw the line between optimism and confidence; the whole thing is a bit nebulous. And one could argue that false optimism may not be a good thing. If a patient is confident that the IVF will work this time, she will have to deal with greater disappointment when it doesn’t work.

They can’t understand why they got negative results when previous studies got positive results; but to my mind if acupuncture is no better than placebo, the very fact that the IVF treatment team was blinded would tend to reduce part of the apparent placebo effect. They point out that this is the first study from the United States. In R. Barker Bausell’s book Snake Oil Science, he shows why studies from other countries are more likely to get positive results. (Anecdotally, I recently heard from a friend with contacts in China that a political officer in at least one Chinese research institution reviews all studies before they are submitted for publication and routinely vetoes any studies with negative results.) It is common for a new study in the US to contradict previous studies from elsewhere. And it is common for a well-designed study to contradict results of previous studies.

Now here’s the part that really blew my mind. In 2005, Alice Domar wrote “Acupuncture and infertility: we need to stick to good science.”   She pointed out flaws in existing IVF/acupuncture research and mentioned several studies that got negative results (studies that are not mentioned in the review of the literature in the introduction to the current study). She also mentioned one where the acupuncture group had greater pregnancy loss after a second session. She clearly postulated that the apparent effects of acupuncture might be only a placebo effect, and she suggested that there could even be harmful effects. Then she recommended that future studies include a sham treatment. Why, oh why, did she ignore her own advice and do this new study without a sham treatment? She offers no explanation. Even her psychological findings are suspect because she compared a relaxing acupuncture treatment (“how relaxed did you feel during the sessions?”) to an inadequate control: no treatment at all. Would a relaxing massage have produced even better psychological results than acupuncture?

The whole thing smells of “I want to use acupuncture no matter what.” Indeed, Domar heads the Domar Center for Mind/Body Health, where acupuncture and other kinds of “mind/body medicine” are offered.

She does not question the choice of acupuncture points. They were chosen for their sedative effect as well as to increase uterine blood flow. How can she be sure they have these effects? She offers no references to support those claims. If they do have these effects, is there any evidence that sedation and increased uterine blood flow increase fertility? How would that work? Do we have any evidence that anxiety or deficient uterine blood flow impair IVF? (In fact, this study found that the patients in the acupuncture group report reported less anxiety but did not have better outcome).

Isn’t this an example of what I have called Tooth Fairy Science? We can study the amount of money left by the Tooth Fairy in different settings, but since we haven’t determined that there is really a Tooth Fairy, any conclusions we reach will be falsely attributed to an imaginary being rather than to the real cause (parental behavior). In acupuncture studies, the acupuncture points/meridians/qi may be imaginary and we may be studying an elaborate placebo rather than a real physiologic phenomenon.

This study fits a pattern. The original study by Paulus showed an effect of acupuncture on PR but only compared to a no-treatment control group. When he repeated the study with a sham acupuncture control group, there was no difference between the “real” acupuncture and the sham acupuncture groups. When Domar improved on the methodology by blinding the treatment team, acupuncture had no effect on PR. As controls are tightened, the effect disappears.

If this same pattern appeared in successive studies of a prescription drug, I doubt if Domar would be recommending it for all patients, even if the drug had no reported side effects and the patients felt better when they took it – and even if it “only” cost $150. Of course, if the same pattern appeared in drug studies, the drug would not even be on the market.

Domar et al have tried to do good science and have contributed to the evidence against acupuncture. Unfortunately, they seem not to want to accept the implications of their own results; and the poor reporting in the MedlinePlus article only muddied the waters further.

Posted in: Acupuncture, Clinical Trials

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17 thoughts on “Acupuncture for IVF Revisited – More Tooth Fairy Science?

  1. Dr Benway says:

    Despite the results of my own study, I still recommend acupuncture to women going through IVF because there’s no downside,” Domar added, aside from the $150 an acupuncturist would typically charge — a small fraction of the $12,000 to $14,000 couples typically spent on a single round of IVF.

    And hey, it’s nothing compared to the average mortgage or cost of a new car. Or the national debt.

    /snark

    A salesman often compares apples to oranges. Doctors are supposed to think more clearly.

    So in 2005, Alice Domar had an interest in acupuncture but found it didn’t work and couldn’t recommend it. Then in 2009 she’s indulging in wooly rationalizations justifying its use. Wah happen? Fell in love with a Reiki master? Stumbled upon a woo friendly wealthy patron?

    Humans –all of ‘em, I suspect– will distort reality to accommodate their wishes and fears. Most only bend when the stakes are high – i.e., when reality means death or career-ending public humiliation or loss of a loved one. But some sell out for less.

    Oh look what I found: The Domar Foundation was created in 2007 with a mission of furthering the application and knowledge of mind/body approaches to women’s health.

    In the alt med world, it seems a common practice to set up a 501 charity to receive donations which can be funneled into the practice via subsidies to patients who can’t afford the full cost of the services. Maybe that’s a reasonable solution to the problem of helping inadequately insured patients. But it troubles me that these charities basically support a single doctor’s practice.

    I’d appreciate it if someone with more business-fu than me would explain the ethical boundaries of these little 501s.

  2. Dr Benway says:

    My link-fu sucks. Try again: The Domar Foundation.

  3. DrBadger says:

    Wow can’t believe that it got published. What kind of peer reviewers does Fertility and Sterility have? Remind me to send them the manuscript I have about jumping up and down after sex being a good method of contraception. My results show that it doesn’t really help any, but since it’s free and I’m sure it works I don’t see why people shouldn’t do it.

  4. daedalus2u says:

    Low nitric oxide and the placebo effect (as I understand it) explain both the initial infertility and the (possible) effects of acupuncture. Becoming pregnant is one of the most important physiological events. As such, it has to be done “right”, and evolution has configured human physiology to (within the limits of our evolutionary history) get it “right”. “Right” in this sense relates to reproductive success in an evolutionary sense, not what a particular woman desires.

    A time of very high stress is a bad time to get pregnant. Pregnant women have increased metabolic and physiologic demands, and so are more susceptible to having their physiological capacity exceeded during an acute stress.

    Stress invokes the “fight or flight” state, where resources are mobilized for immediate use, as for running from a bear. While running from a bear (or the equivalent) would be a bad time to devote metabolic resources to becoming pregnant. Stress is a low NO state, NO is lowered to maximize aerobic ATP production by mitochondria. Low NO also lowers ATP concentration and shifts myriad physiological pathways to cope with the stress. Relatively little of this is well understood. The placebo effect is the standing down of physiology from the “fight or flight” state to the state where resources are no longer needed to be held in reserve for immediate use (such as for running from a bear).

    Oocytes require NO to sustain the capacity to be fertilized. The length of time this “window” of capacity to be fertilized remains open depends on the ambient NO level. If that level is high (as in a low stress state) the time is longer than when the NO level is low (as in a state of stress). No doubt there are many other pathways involved too, likely many of them mediated through the final common pathway of low NO.

    Many instances of reduced fertility are associated with high levels of androgens as in polycystic ovarian syndrome and hyperandrogenic anovulatory syndrome. It turns out that the rate limiting enzyme for androgen synthesis is inhibited by NO, so low NO causes high levels of androgens. Those high levels of androgens also cause people to become hirsute, to have increased hair growth. That hair is the niche where the bacteria I am working with live, so by expanding that niche, the amount of NO/NOx they can produce is increased. That is one (of many) feedback mechanism to regulate NO/NOx levels.

    Any positive effect of acupuncture on infertility can be completely explained by the placebo effect. How effective a placebo acupuncture is on a particular woman will depend on many things. $150 is a high price to pay for a placebo, but the higher the price of a placebo the more effective it tends to be. Tooth Fairy science or Cargo Cult science, they are pretty much the same, going through the motions without enough intellectual integrity to recognize and abandon wrong ideas.

  5. Versus says:

    Dr. Benway:
    The Domar website does state that it is a 501(c)(3) tax exempt organization but its not on the IRS list of tax exempt organizations. For more info on tax exempt charitable organizations go to http://www.irs.gov/charities/index.html.

  6. DVMKurmes says:

    I really like the term “Tooth Fairy Science”. I have seen the same phenomenon in some of the veterinary proponents of acupuncture. One of the most prominent is actually pretty good at applying science and critical thinking to other modalities like herbal medicine, but then insists that acupuncture is backed by strong scientific evidence. The only problem is that she never produces said evidence. It is rather entertaining though-she seems to irritate most of the true believers even more than the skeptics. I can’t forgive her for teaching veterinary students her inconsistent “science” though.

  7. SF Mom and Scientist says:

    I am very reluctant to make this comment, but here goes.

    First let me say that I do not believe that acupuncture works. I live in a city that has many acupuncture clinics, and I am amazed at how much money people spend on this.

    However, if women having acupuncture are indeed more optimistic and less anxious, it would be great to find a cheaper way to duplicate this result. I know this is anecdotal, but I have seen many women try to get pregnant through IVF, and it wrecks havoc on their emotions and state of mind. I’m not sure if it is the hormones or the anxiety at wanting to get pregnant so badly. (Or the anxiety of all that money being spent!) I don’t think we should underestimate the benefit of reducing anxiety, if only for the benefit to mental health.

    Also, I do not agree with your comment,

    “If a patient is confident that the IVF will work this time, she will have to deal with greater disappointment when it doesn’t work.”

    One will be disappointed no matter what the initial level of confidence was. I have had several miscarriages, and personally I felt it was worse when I went into the pregnancy thinking that something might go wrong. When I was less anxious I was better able to deal with the result.

    I apologize for giving so much anecdotal information, but I do wish we had a better method to help women reduce their anxiety so they can deal with the very likely result that IVF won’t work for them.

  8. adomar says:

    Since I am the one being criticized here, I think it is only fair to hear both sides of the story.

    What was omitted from the Reuters story was my explanation as to why my clinical recommendations are different from the study I just published. There was a meta-analysis published last year by Eric Manheimer, and it included all of the RCT’s on acupuncture and infertility, including mine. The results strongly supported the use of acupuncture for pre and post embryo transfer to increase pregnancy rates. So my interpretation is that in fact, although I got negative results from my own research, what we know from current research from around the world is that acupuncture might well increase pregnancy rates pre and post ET. More research must be done. But in the meantime, since the vast majority of the research supports its use, I do recommend acupuncture pre and post. According to Manheimer’s results, for every 9-10 patients who do acupuncture, there is an “extra baby”. Given the extremely high cost of IVF compared to the cost of acupuncture, until we know more it does seem to make financial sense.

  9. Dr Benway says:

    I have a hunch the decrease in anxiety is related to the expectation that the acupuncture is helping the uterus make a baby somehow, just a little. Remove that expectation, and the benefit will probably vanish.

  10. pmoran says:

    “I do recommend acupuncture pre and post. ”

    Why post-implantation? According to the Cochrane review pf this subject the results were not as good and not statistically significant in those studies where acupuncture was repeated after 2-3 days.

    (Cheong YC, Hung Yu Ng E, Ledger WL. Acupuncture and assisted conception. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006920.)

  11. daedalus2u says:

    SF mom and scientist, it isn’t “anxiety” per se; it is the physiological pathways triggered by anxiety that evolved to reduce fertility while living under conditions that cause anxiety. Those pathways are not under conscious control or awareness and patient reports may have no relation to whether they are triggered or not.

    In the use of acupuncture to treat a variety of different things, it is not uncommon for “sham” acupuncture to achieve better results than does “real” acupuncture. This includes IVF.

    http://www.ncbi.nlm.nih.gov/pubmed/18940896

    My explanation of why sham acupuncture not infrequently works better than real acupuncture is because sham acupuncture is a better placebo. A placebo is the opposite of something that triggers the fight or flight state. Any injury, even a very slight one as being pricked by a tiny needle during acupuncture, will trigger the fight or flight state more than the same stimulus without an injury.

    The meta analysis by Manheimer lumped sham acupuncture and no treatment together. They were not RCTs (in my judgment) because they were not placebo controlled. 4 of 7 of the studies were not even blinded (!) because no needles of any type were used. I suggest reading the online comments to the Manheimer meta analysis.

    http://www.bmj.com/cgi/eletters/336/7643/545

    The comment by Ernst is particularly relevant. I think that Manheimer’s comment that:

    “Furthermore, when a sham has effects that are part and parcel of the working mechanism of acupuncture (e.g. increased expectations, reduced anxiety), but without being a feasible alternative in clinical practice, you can learn little from sham- controlled trials. For clinically relevant conclusions, we need to compare realistic alternatives, like adjuvant acupuncture versus no adjuvant to IVF.”

    is disingenuous. Why is “sham” acupuncture not a feasible alternative? If sham acupuncture works better than real acupuncture (as some studies have shown), shouldn’t the most effective treatment be used?

    It is not a surprise to me that placebos are effective at increasing fertility. The appropriate response of a treating physician is then to use the most effective placebo. The only way to determine which placebo treatment is most effective is by understanding the physiology of the placebo effect, so that physiology can be effectively evoked. It is my understanding that the physiology of the placebo effect involves nitric oxide, and my hypothesis is that the placebo effect can be invoked pharmacologically by increasing the basal NO level. Once the placebo effect is maximally invoked, there is nothing more that any other placebo can do.

  12. wertys says:

    That Manheimer meta-analysis is a complete mess ! They included three out of their seven studies which were only in ABSTRACT form !! They were admittedly not peer-reviewed and properly published. However we are meant to accept that because the authors told them they were OK results that we should take their word for it !?!?!?

    They also had the integrity to discuss what they term ‘orientation bias’ which they admit can be a problem in preliminary studies where the proponents of a new treatment may overinterpret the data to be unduly favourable. They then dismiss this by saying acupuncture ‘is a non-proprietary treatment’, the implication being that unlike big nasty drug companies there is nobody with a financial stake in proving acupuncture to be effective.

    Nobody, that is, except the thousands of small business people who (and some not-so-small) who make most if not all of their living from doing acupuncture. Apart from the academics whose living depends on teaching it, and the Government-appointed bodies who are charged with regulating it…..do I need to go on ?
    This is the problem when you let adoption of a practice get ahead of the evidence.

    The BMJ should be embarrassed that they let this shoddy, confused and sub-standard meta-analysis get through.

  13. Karl Withakay says:

    “Given the extremely high cost of IVF compared to the cost of acupuncture…”

    I don’t agree with this wording. I think, “given the marginal extra cost of acupuncture relative to the cost of IVF…” would be a better way to phrase it.

    Of course the cost of hiring a witch doctor to cast a fertility spell is also a marginal extra cost relative to the cost if IVF. Throwing coins in a wishing well literally costs pennies. Standing on your head is free, as is crossing your fingers or sacrificing a cat you get from the pound.

    Why don’t we stick to recommending practices scientifically shown to be effective rather than recommending anything that someone claims will help as long as it doesn’t add too much of an extra cost?

    “More research must be done. But in the meantime, since the vast majority of the research supports its use, I do recommend acupuncture pre and post.”

    Why do the study if there is already sufficient support for recommending acupuncture for IVF? Surely the point of doing the study is that the jury is still out, and more research is needed before a general recommendation can be made?

    If you’re going to disregard the results of your study if they don’t turn out the way you anticipate, what’s the point of doing the study?

    Why not take the position that this study raises a question about the efficacy of acupuncture with IVF, and further research must be done to determine if this study was an aberration or not.

  14. Dr Benway says:

    “More research must be done. But in the meantime, since the vast majority of the research supports its use, I do recommend acupuncture pre and post.”

    Why do the study if there is already sufficient support for recommending acupuncture for IVF? Surely the point of doing the study is that the jury is still out, and more research is needed before a general recommendation can be made?

    In the alt med world, “more research must be done,” justifies any promoted practice in spite of decades of study resulting in merely equivocal or unimpressive evidence of efficacy. The research *must* continue until the practice is proven to work. Then the research can stop.

    In the alt med world, simply saying the above makes me a bad person who hates Jesus and is probably mean to puppies.

  15. hatch_xanadu says:

    “It seems to me this translates as: Acupuncture works. It didn’t work in this study, but that can’t be the fault of acupuncture, because acupuncture works. So it must be the fault of the patients for producing poor quality embryos, (our data don’t support that hypothesis, but let’s just ignore that). Acupuncture is harmless and people like it, so let’s use it on every patient whether it works or not. Patients will have to pay $150 extra, but I’m willing to decide for them that the expense is worth it.”

    Exactly. That’s exactly what it translates to.

  16. PTsickofBS says:

    “(Anecdotally, I recently heard from a friend with contacts in China that a political officer in at least one Chinese research institution reviews all studies before they are submitted for publication and routinely vetoes any studies with negative results.)”

    backed up by this study –

    http://www.ncbi.nlm.nih.gov/pubmed/9551280

    which concludes -
    Some countries publish unusually high proportions of positive results. Publication bias is a possible explanation. Researchers undertaking systematic reviews should consider carefully how to manage data from these countries.

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