Acupuncture and IVF

– no clear effect on live birth rate

This blog was first published on 18th June 2018 on https://blogs.bmj.com/aim/

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Acupuncture has become very popular within the field of assisted reproduction, and particularly as an intervention within IVF (In-Vitro Fertilisation). In an editorial from 2015 in Acupuncture in Medicine, David Carr lists 12 meta-analyses on the subject in just 6 years, including a total of 34 RCTs.[1] There was no clear conclusion from the reviews – most outcomes showed no benefit for acupuncture, but some did. In general we see quite large benefits over control in open studies, and no effects in blinded sham control studies.

It is worth noting that in one high quality double blind study (n=370), the sham acupuncture group had a significantly better outcome than the real acupuncture group (live birth rate 38.4% versus 29.7% respectively).[2] The research team from Hong Kong went on to test the same protocol (treatment before and after embryo transfer – ET) in frozen-thawed cycles (FET; n=226). The results were very similar (live birth rate 35.4% with sham versus 29.2% with real), significantly favouring sham in all outcomes.[3] Following directly on from this the team decided, logically but rather surprisingly, to test sham versus sham: a single session of sham acupuncture after ET with sham before and after ET, as in the original protocol. This trial was presented in a meeting at The Hague in 2011, where it won a research prize (I was part of the awarding committee), and I remember discussing the topic with the first author of the paper – Emily So. There was no significant difference in pregnancy outcomes, but the two-session protocol conferred a significant benefit in terms of anxiolysis (details from the abstract submitted to the meeting, 2011).

So where am I going with this? Well it seems likely that acupuncture or sham acupuncture confer a context-related benefit in terms of supportive care mediating anxiolysis. But beyond this, it seems possible that real acupuncture has some potential disadvantages when performed around embryo transfer. In brief, strong somatic stimulation in the segments related to the uterus, or indeed outside those segments, may influence contractile behaviour of the uterus. This is mostly harmless of course, but increasing contractions after ET in an otherwise quiescent uterus may expel the embryo. Equally, contractions initiated by the instrumentation during ET may be suppressed by acupuncture, which might prevent expulsion of the embryo. It was on the latter basis that Paulus first used the technique around ET (personal communication, Irina Szmelskyj).[4] A panel of experts presenting at the BMAS Spring meeting in Newcastle (2015) concluded that acupuncture should be avoided around ET and implantation unless the woman had symptoms that might be ameliorated with acupuncture – abdominal cramps for example.

…it seems possible that real acupuncture has some potential disadvantages when performed around embryo transfer.

The paper that stimulated this blog was published in JAMA in May 2018.[5] I heard the results presented in a meeting in Berlin a year before, and discussed them with the lead author Caroline Smith. Essentially it is the largest sham controlled trial of acupuncture within IVF to date (n=824), and it failed to demonstrate any benefit of acupuncture over sham. The live birth rate was 18.3% in the acupuncture group versus 17.8% in the sham group. The clinical pregnancy rate was marginally higher in the acupuncture group at 25.7% versus 21.7%, but this was negatively offset by an increased rate of pregnancy loss.

Given what I said above about Emily So’s research, the results are not particularly surprising. The rates of live birth appear much lower, but that is likely related to the fact that nearly half of the women in Caroline Smith’s study had already failed 2 or more cycles of IVF, whereas the majority in Emily So’s research were on their first cycle.

I was particularly interested to see in the supplementary data of Caroline Smith’s huge multicentre trial that in two of the 15 sites there was a significant benefit of sham over real acupuncture, and at no site was there a significant benefit for real over sham. Data was pooled from 4 sites, leaving 12 comparisons in the forest plot (see figure below). Using 95% confidence intervals we would only expect a type I statistical error (a significant difference in the sample data when there is no real difference between the populations sampled) to occur 5% of the time ie 1:20. So 2 occurrences in 12 comparisons does not seem likely by chance alone. This adds some weight to my comments above regarding potential risks associated with the somatovisceral reflex effects of real acupuncture.

Smith-et-al-JAMA-2018-eFigure-2-1002x1024

Does acupuncture have a role in fertility or not? The majority of the clinical trial data comes from within IVF cycles, and more specifically either side of ET. I have always thought this was a long shot from a physiological point of view, since acupuncture generally requires a course of regular treatments to mediate measurable effects in clinically relevant outcomes. So I am pleased that this trial will probably place the last nail in the coffin for this very limited technique. But is there any role for acupuncture in fertility? Well we have also seen a very large negative trial from China on segmental electroacupuncture (EA) versus clomiphene for ovulation induction in PCOS: the subject of a previous blog. I still hold out some hope that we will find a useful place for the technique since Elisabet Stener-Victorin first opened the whole chapter in 1996 with her trial on the influence of segmental EA on uterine artery impedance.[6]

In terms of acupuncture research and practice I think the focus should be outside IVF.

Either for couples with unexplained infertility and no male factor (unless treatment is aimed at the man of course – that’s another topic entirely), or in the weeks and months prior to an IVF cycle. This phase, theoretically at least, has always held the greatest promise, but because of the trial by Paulus in 2002,[4] the research, in my opinion, went on a very loud and frantic wild goose chase.

Postscript

After posting this blog I decided to email the team to ask about the live birth rate in the third of Emily So’s studies – the one comparing sham with sham. I emailed the senior author Ernest Hung Yu Ng, and to my surprise he answered with a further abstract describing more unpublished research from his team. They had gone on to test sham acupuncture either side of ET in an open pragmatic trial against no additional acupuncture in 800 women undergoing IVF! Live birth rate was not included in the abstract, but the on-going pregnancy rate was 32.3% in the sham acupuncture group and 33.3% in the no acupuncture group.

This is very useful addition data that clearly now points to the fact that sham acupuncture around ET is not beneficial, and therefore implies that real acupuncture may sometimes confer risks when applied at ET. This does not apply to acupuncture performed at other times, and further encourages me to promote the testing of acupuncture performed in the lead up to IVF rather than during the process.

References

  1. Carr D. Somatosensory stimulation and assisted reproduction. Acupunct Med 2015;33:2–6. doi:10.1136/acupmed-2014-010739
  2. So EWS, Ng EHY, Wong YY, et al. A randomized double blind comparison of real and placebo acupuncture in IVF treatment. Hum Reprod 2009;24:341–8. doi:10.1093/humrep/den380
  3. So EWS, Ng EHY, Wong YY, et al. Acupuncture for frozen-thawed embryo transfer cycles: a double-blind randomized controlled trial. Reprod Biomed Online 2010;20:814–21. doi:10.1016/j.rbmo.2010.02.024
  4. Paulus WE, Zhang M, Strehler E, et al. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril 2002;77:721–4.
  5. Smith CA, de Lacey S, Chapman M, et al. Effect of Acupuncture vs Sham Acupuncture on Live Births Among Women Undergoing In Vitro Fertilization: A Randomized Clinical Trial. JAMA 2018;319:1990–8. doi:10.1001/jama.2018.5336
  6. Stener-Victorin E, Waldenström U, Andersson SA, et al. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314–7.

Declaration of interests MC

Segmental EA falls short in ovulation induction

…in women with polycystic ovarian syndrome (PCOS)

This blog was first published on 18th November 2017 on https://blogs.bmj.com/aim/

affection beautiful blur couple
Photo by Pixabay on Pexels.com

Finally I have come to address this topic, some months following publication of an eagerly awaited (at least by me) large clinical trial.[1] I have been a colleague and friend of the second author (ES-V) since proofreading her PhD thesis over 20 years ago. In those days I focussed solely on muscle so any suggestion of acupuncture being used to influence visceral function or blood flow was a bit of a conceptual stretch for me. After all my needles were going directly into the target that I wanted to influence, and I was just about comfortable with the idea that the needle alone actually did something useful without the need for injecting a drug. So the idea that acupuncture or electroacupuncture could have any useful effect through indirect influences only really arose when I read Lisa’s thesis.

Her early work stimulated interest in the use of acupuncture in fertility and augmented reproduction,[2,3] although the subsequent plume of clinical research that occurred in this field seemed to go a little off course from a basic science perspective, with an unwarranted focus on embryo transfer as part of IVF.[4] Lisa observed this, but continued with her research path, which was by then on PCOS. She clearly showed that segmental electroacupuncture (EA) could have positive influences on the condition, both in terms of hormonal and metabolic markers, and apparently in terms of ovulation rates.[5,6]

Lisa regularly runs research updates for the BMAS, and we were all excited to hear of her involvement in this huge clinical trial in China on women with PCOS. With 1000 women to be randomised and treated the trial was a considerable undertaking, and several years passed with no news. Then on the 27th June 2017 the results were out… clomiphene was nearly twice as good as segmental EA, and segmental EA was no better than a very minimal non-segmental sham.

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Figure from Wu et al JAMA 2017 [1]

It did not seem to make sense from the basic science perspective! The numbers were big enough to power the comparison with sham (assuming similar size effects to those we see in clinical trials of chronic pain). The intervention appeared sufficient in neurophysiological terms, to generate the effects that had been demonstrated in the basic science experiments that had led up to this trial. Yes it was a penetrating sham, but the physiological stimulus of the sham intervention would not have generated any effect in the laboratory in terms of somatovisceral reflexes. In the clinical realm, with conscious humans, sham always seems to have a substantial context effect, but still I would have expected some physiological effect from the segmental EA.

Well there was a difference between real and sham EA in terms of adverse events. In the segmental EA group the rate of diarrhoea was 3 times that in the sham EA group, perhaps indicating an excess effect in somatovisceral reflexes in a small proportion of women. It should be noted that the absolute rate of diarrhoea was low at 1.6 and 5%, in sham and real segmental EA respectively.

The primary outcome was live birth rate. This is the most valid outcome for trials of this nature, but it is not the same as ovulation induction of course, so it is not a direct measure of the putative physiological effect of segmental EA. This could add noise to the statistics, but even so, there was not even a trend in favour of segmental EA.

The slightly curious thing is that both acupuncture groups seemed to substantially outperform metformin, which, in a large comparative trial with clomiphene resulted in a live birth rate of just 7.2%.[7] The populations are not easily comparable though as there were notable differences in BMI that would favour acupuncture. The Chinese women were normal weight compared with an average BMI of about 35 in the metformin group in the prior comparative trial, and BMI is inversely related to outcome.[8] Could that explain the difference between 7.2 and 15.4%? Well frankly, I’m afraid it probably can!

So where does that leave the acupuncture in the fertility arena? There is little or no high quality clinical data to support its use, just a lot of experimental data that did seem encouraging, although the results of this trial should give pause to the assumptions of advocates that anything demonstrated at the bench should automatically imply useful effects at the bedside.

For now at least we must encourage women with PCOS to consider clomiphene before acupuncture for ovulation induction.

References

  1. Wu X-K, Stener-Victorin E, Kuang H-Y, et al. Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome. JAMA 2017;317:2502. doi:10.1001/jama.2017.7217
  2. Stener-Victorin E, Waldenström U, Andersson SA, et al. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314–7.
  3. Stener-Victorin E. Reproductive medicine: Research projects in acupuncture. Acupunct Med 1998;16:80–2.http://dx.doi.org/10.1136/aim.16.2.80
  4. Carr D. Somatosensory stimulation and assisted reproduction. Acupunct Med 2015;33:2–6. doi:10.1136/acupmed-2014-010739
  5. Stener-Victorin E, Maliqueo M, Soligo M, et al. Changes in HbA1c and circulating and adipose tissue androgen levels in overweight-obese women with polycystic ovary syndrome in response to electroacupuncture. Obes Sci Pract 2016;2:426–35. doi:10.1002/osp4.78
  6. Johansson J, Redman L, Veldhuis PP, et al. Acupuncture for ovulation induction in polycystic ovary syndrome: a randomized controlled trial. Am J Physiol Endocrinol Metab 2013;304:E934-43. doi:10.1152/ajpendo.00039.2013
  7. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007;356:551–66. doi:10.1056/NEJMoa063971
  8. Legro RS, Zhang H, Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole or clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med 2014;371:1463–4. doi:10.1056/NEJMc1409550

Declaration of interests MC