Surprise! Surprise! (Well, actually, no.) Acupuncture does not work for in vitro fertilization

I didn’t think I’d be writing about acupuncture again so soon after my discussion of a howlingly bad acupuncture meta-analysis, but here we are. Of course, as I note from time to time, I do tened to write about acupuncture a lot because it is the most “respectable” form of quackery. After all, Harvard Medical School even teaches a large online course in acupuncture worth over 300 continuing medical education credits, a course I first noted nearly a decade ago and wrote about again last year. It doesn’t matter that rigorous science shows that acupuncture is no more than a theatrical placebo. It seems to be the “gateway woo” that leads many physicians into the “integration” of quackery with medicine in the specialty known as “integrative medicine.” (Another gateway woo is functional medicine.) Once that woo is accepted, all manner of pseudoscience, quackery, and outright nonsense seem to follow into academic medical centers, up to and including the finding of new “organs” to “explain” how acupuncture “works.” Other times, it leads the National Center for Complementary and Integrative Health (NCCIH) to try to use it as a potential answer to the opioid addiction crisis. it leads to studies trying to demonstrate that acupuncture improves pregnancy rates after in vitro fertilization (IVF).

Yes, earlier this week, JAMA published the results of a randomized clinical trial of acupuncture on IVF success rates. Amazingly, this was, unlike most acupuncture trials, large and well designed. Not surprisingly, it was negative. Before I discuss the study itself, let me just discuss the biological plausibility of acupuncture as an intervention to improve the success rates of IVF. Basically, there is none, as far as science has been able to tell. Certainly, science has not been able to detect the “life energy” or “life force” that supposedly travels down the various acupuncture meridians and whose flow sticking thin needles into the skin is supposed to “unblock” to healing effect. Indeed, no anatomic correlate has ever been convincingly demonstrated for acupuncture meridians.

But, say acupuncture advocates, you don’t have to accept the vitalistic prescientific view in traditional Chinese medicine as to how acupuncture works. It works through adenosine! It stimulates nerves! it does other things! We can mix it up, too. After all, it involves sticking needles into the body; so surely it isn’t so implausible that it does…something. Maybe. But what? After all, remember that acupuncture enthusiasts claim that it’s good for almost anything that ails you, for conditions including back pain, insomnia, weight loss, menopausal hot flashes, battlefield injuries, Parkinson’s disease, headache, gastroesophageal reflux, and, well, IVF and many other conditions with unrelated physiology.

Indeed, this is not the first time that I’ve written about acupuncture for IVF. For instance, ten years ago, a dubious meta-analysis didn’t convince me. Neither did another meta-analysis from 2013. This brings us to reinventing the crappy wheel, 2018 edition, in the form of this study. It’s an Australian study, from the NICM Health Research Institute, Flinders University, University of New South Wale, University of South Australia, Greenslopes Private Hospital, and Western Sydney University.

It’s also a pretty big study with reasonably good design. It’s biggest flaw is that it was single blind such that study participants, fertility specialists and nurses, and the analysts were blinded to group allocation. However, the clinical trial coordinator and acupuncturists were not blinded to group allocation. Still, it might not have been so critical in a study like this, because pregnancy after IVF is a “hard” outcome. IVF either results in pregnancy and a live birth, or it doesn’t. As for the rest of the study design, it’s a randomized, sham acupuncture placebo-controlled trial. Subjects were recruited from 16 IVF centers in Australia and New Zealand. Inclusion criteria included women aged 18 to 42 years undergoing IVF or intracytoplasmic sperm injection (ICSI) (IVF in which a sperm is injected into the egg). Exclusion criteria included women undergoing a frozen embryo transfer, previous randomization to the study, planning preimplantation genetic diagnosis, or receiving donor eggs. One change was made to the protocol and was approved by all ethics committees. Initially, only women with recurrent IVF failure and unsuccessful clinical pregnancies from 4 IVF centers were included. However, these women turned out to be high users of acupuncture. So, in June 2013, following a review by the data and safety monitoring committee, a decision was made to revise the inclusion criteria to increase eligibility to the trial by removing the requirement that women must have previous failed IVF cycles and poor treatment outcomes, and to increase the number of recruitment sites.

The protocol, it turns out, was developed by the Delphi method. (Lovely.) Women were recruited at the time of their decision to undergo IVF or ICSI, and randomization occurred before the the beginning of the follicle stimulation protocol. IVF or ICSI treatment protocol was determined by each subject’s treating clinician. After randomization, women underwent either acupuncture or sham acupuncture treatment beginning between days 6 and 8 of ovarian stimulation and two treatments were given on the day of embryo transfer. In this particular study, non-penetrating sham needles were placed in non-acupuncture points.

Reading the article and the protocol, I was amazed at how much handwaving was necessary to produce a facsimile of biological plausibility. From Supplement 1:

Mechanisms underlying acupuncture have been widely researched in relation to pain. Acupuncture analgesia research suggests acupuncture triggers a sequence of events involving the release of endogenous opioid like substances, for example β-endorphin, and enkephalin that modulate pain signals. Further, imaging technology studies show the hypothalamus-limbic system plays a role with acupuncture analgesia by modulating sensory and emotional aspects of pain processing. Mechanisms underlying other health conditions may involve modulation of the autonomic nervous system, as seen in patients with irritable bowel syndrome and major depression. Electroacupuncture has been shown to release ß-endorphin a neurotransmitter and neuro hormone via two systems. One system involves the hypothalamus and neuronal network which results in an inhibitory effect on the vasomotor centre resulting in decreased sympathetic tone. Secondly, ß-endorphin released into the blood may exert an effect on both the hypothalamicpituitary axis and hypothalamic-pituitary-gonadal axis and may have an effect on gonadotropinreleasing hormone (GnRH) and pituitary gonadotrophin secretion. Acupuncture may exert a sympatho-inhibitory effect reducing uterine artery impedance and increase uterine and ovarian blood flow. Improved blood flow in women undergoing the down regulation phase of IVF from acupuncture has been reported26. This improved blood flow could hypothetically improve the growth and thickness of the endometrium and endometrial receptivity. To date these findings have not been confirmed in controlled studies.

This is, as I said, major handwaving. It’s what I like to refer to as “woo babble,” which is like Star Trek technobabble, only with woo and science-y sounding sentences that sound impressive to lay people but are clearly nothing more than wild speculation.

But lets get to the results. Among 848 women randomized, 24 withdrew consent, leaving 824 women. Of these 809 had data available on live birth outcomes, 405 receiving acupuncture and 404 receiving sham control acupuncture, whose live birth outcome rates were 18.3% and 17.8%, respectively. The difference was not statistically significant. A clinical pregnancy was achieved in 25.7% of the acupuncture group and 21.7% in the sham control group, which was also not a statistically significant difference.

In other words, acupuncture doesn’t work to improve IVF.

Not that the authors didn’t try really hard to salvage some result from their data. They did some post hoc analyses. They did some exploratory analyses. They didn’t find much of anything. Here’s where I ask you to guess what the authors said in their conclusion to excuse their lack of any sort of positive effect due to acupuncture. Yes, they admit that they found no difference between the acupuncture and sham groups and admitted that their results support a recent guideline from the American Society for Reproductive Medicine and 2 high-quality meta-analyses that found that acupuncture compared with a sham control performed around the time of ovarian stimulation and embryo transfer does not improve live birth rates in IVF.

But:

The study addressed whether acupuncture was more efficacious than a placebo and specifically examined whether any effect was mediated through the point-specific needle insertion. To do this, a noninsertive needle was used. A recent meta-analysis examining placebo devices as effective control methods in acupuncture clinical trials found that these devices are not necessarily inert control interventions. These findings therefore may be explained by potential activity from the sham control. To determine whether any treatment effect in clinical outcomes arises from point-specific needle insertion or from other nonspecific effects, such as the placebo or time and attention from a therapist, would require the inclusion of a no-adjuvant treatment group in the trial design. A usual care–alone group was not included in the RCT due to findings from a previous pilot study that women would decline randomization to this design. Therefore, it remains unclear whether there are nonspecific effects from acupuncture or a sham control.

Yep. They’re saying that the sham control had an effect, and that could be why there was no difference between the acupuncture and sham acupuncture groups. Of course, if they had included a regular treatment group and there had been no difference between the two acupuncture groups but even a slight improvement in one of the two groups over the regular treatment group, the authors would be saying that acupuncture works. Heads, I win, tales you lose. Of course, as I’ve said many times before, it doesn’t matter where you stick the needles. It doesn’t even matter if the needles are inserted. There is no specific effect attributable to acupuncture. It’s a theatrical placebo.

At least the authors stopped there with that bit of speculation, which was actually fairly restrained for believers in acupuncture whose large multicenter acupuncture study had been negative. What surprised me, however, is that I found myself a little bit disappointed by the commentary on Medscape by F. Perry Wilson MD, MSCE on its Methods Man blog. He goes beyond even the authors’ speculation. First, here he is on biological plausibility:

As always, we should start with biologic plausibility. Is it biologically plausible that acupuncture should increase the live birth rate in women undergoing IVF? Well, it depends what you mean by acupuncture. If, by acupuncture, you mean the insertion of needles in very specific locations to alter the flow of an immeasurable energy force within the body, then no, there is no biologic plausibility there.

OK, so far, there’s nothing objectionable here—or even anything that I wouldn’t have written myself. However, notice the framing (“it depends what you mean by acupuncture”). Now read what comes later:

But acupuncture may not be totally without physiologic effect. Perhaps the local stimulation of nerve endings can release endorphins or promote blood flow (though these claims are actually a bit controversial). But of course, if that’s the case, sham acupuncture (where the needles are placed randomly) should work just as well as “real” acupuncture for IVF.

And indeed, that is what was found.

Yes, it’s the same speculative excuse invoked by the authors. He builds on this:

The use of a rigorous sham control here demonstrates what we know deep down – there is nothing magical about acupuncture.

This is not to say it is without value. As a clinical researcher, when I look at an acupuncture study the first thing I think of is “co-intervention bias.” Acupuncture is so much more than the sticking of needles into specific locations. It’s a quiet room, soft music, a compassionate therapist, and human touch.

These are all things that might be really beneficial.

Maybe. Or maybe not. They probably wouldn’t hurt, at least. Look, I agree that there’s nothing magic about acupuncture. I also used to think there might be something to it. After close to 15 years of delving into the nitty gritty of acupuncture studies, I’ve become convinced that acupuncture really is nothing more than a theatrical placebo.

Here’s the problem. You can’t say that about acupuncture based on this study. You just can’t. Why? Because there’s no regular care control group to compare the acupuncture and sham acupuncture to! Only if there had been such a group and it had had lower live birth rates than the acupuncture groups would such speculation be (barely) justifiable on a scientific basis, given the extreme lack of biological plausibility of acupuncture as a treatment to increase IVF success rates. What we have here is a resoundingly negative study.

Maybe I shouldn’t be too hard on Dr. Wilson, though. Amusingly, even his mild commentary provoked pushback from an acupuncturist:

I gave some commentary on a (negative) acupuncture study. A deeply ironic response (from an acupuncturist):
"This article is disingenuous and the author should be ashamed at his biased, unscientific ignorance." #hmm https://t.co/zfd1ft9nCQ

— F. Perry Wilson, MD (@methodsmanmd) May 16, 2018

That’s because no one can make excuses for negative studies like acupuncturists. Check out the comments after Dr. Wilson’s article. There are several to choose from. Some point to other, less rigorous studies. Others claim that acupuncture done outside of the TCM diagnosis of infertility is pointless. Never mind that TCM diagnosis methods were based on prescientific mystical beliefs. Two question the skill of the acupuncturists used. For instance, here’s Geoffrey Levins:

My comment is in line with Mr. Levens, above. Who did the “real” acupuncture and how were they trained? Was each patient subject evaluated as an individual? Or was everyone given the identical treatment protocol? Additionally it is written clearly in the Chinese medicine literature that acupuncture can create a strong potential for miscarriage, if used incorrectly. If it was doing nothing much, as proposed by the author here, then why the increase in miscarriages with the “real” vs the “sham” or perhaps the “sham” had a preventive effect on miscarriage? Yes, many many unanswered questions.

And Geoffrey Levins:

“Rigorous sham acupuncture”. I don’t have access to article but how rigorous was the “real” acupuncture? After practicing as a professional for 25+ years and having hundreds at least treatments myself, I know that there is a very wide variety of skill levels between various practitioners. Also, there several, very different from each other, approaches to acupuncture for example Traditional Chinese vs Japanese vs Korean, etc. Lots of unanswered questions so far as I am concerned.

How much money does the Tooth Fairy leave per tooth? How soon after the tooth is put under the pillow does the Tooth Fairy come? Is there a lifetime limit to what the Tooth Fairy will give? Yes, Levins is asking Tooth Fairy research questions, because this study was Tooth Fairy science. As for the skill of acupuncturists, how does that matter when there is no scientific basis to acupuncture and it doesn’t matter where you stick the needles?

What really bothers me is how unethical this study was. There was no plausible scientific basis for it. Existing evidence for IVF and acupuncture was, by and large, negative. Worse, this was a decent-sized study that likely cost millions of dollars to carry out, money that could have been used to study real medical questions whose answers might actually lead to improvement in patient care and improved outcomes.