Tuesday, February 19, 2008

On Acupuncture and Infertility (an in depth analysis)

Below you will find an in depth analysis of the available science on acupuncture and IVF. As you probably know i am a fertility specialist with a decade of experience. I use acupuncture daily as part of my practice and my professional experience with it has been very positive . Nevertheless since i have done some reading to see what info was available online on this topic most of what i found was complete junk, advertising ,false promises and unscientific information. This makes me sad because very valuable alternative treatment options often end up on websites like quackwatch because of the misinformation that is spread around online.
Consequently I attemped to fix this problem by reading all the literature currently available on the topic and summarize it in a scientific way, as if i was presenting it to some of my colleagues. So i am sorry if the content at times appears heavy.

What is Acupuncture?

The term "acupuncture" describes a family of procedures involving the stimulation of anatomical points on the body using a variety of techniques. The acupuncture technique that has been most often studied scientifically involves penetrating the skin with thin, solid, metallic needles that are manipulated by the hands or by electrical stimulation.

Practiced in China and other Asian countries for thousands of years, acupuncture is one of the key components of traditional Chinese medicine. In TCM, the body is seen as a delicate balance of two opposing and inseparable forces: yin and yang. The concept of two opposing yet complementary forces described in traditional Chinese medicine. Yin represents cold, slow, or passive aspects of the person, while yang represents hot, excited, or active aspects. A major theory is that health is achieved through balancing yin and yang and disease is caused by an imbalance leading to a blockage in the flow of qi. Yin represents the cold, slow, or passive principle, while yang represents the hot, excited, or active principle. According to TCM, health is achieved by maintaining the body in a "balanced state"; disease is due to an internal imbalance of yin and yang. This imbalance leads to blockage in the flow of qi. In traditional Chinese medicine, the vital energy or life force proposed to regulate a person's spiritual, emotional, mental, and physical health and to be influenced by the opposing forces of yin and yang(vital energy) along pathways known as meridians. Qi can be unblocked, according to TCM, by using acupuncture at certain points on the body that connect with these meridians. Sources vary on the number of meridians, with numbers ranging from 14 to 20. One commonly cited source describes meridians as 14 main channels "connecting the body in a weblike interconnecting matrix" of at least 2,000 acupuncture points.

Source : NIH

Do I Believe In Acupuncture ?

I get asked frequently by patients if I believe in Acupuncture or other alternative treatments. My standard answer to the question is that as a scientist i have no beliefs, i just look at the evidence. Of course as a very open minded person i understand there are different levels of evidence. I also understand that absence of evidence of any treatment's efficacy is not the same thing as proven evidence that it is not efficacious. Therefore i do not discard a treatment option a priori just because there are no randomized double blind prospective studies on the topic published in the New England Journal of Medicine.

So far there have been 6 Prospective Randomized Studies on the role of acupuncture in infertility

These studies do not focus on acupuncture and fertility in general since this kind of study would be very difficult if not impossible to do. Most of the studies have focus a simple question: does acupuncture performed during IVF (In Vitro Fertilization) treatments around the time of embryo transfer (usually one session thirty minutes before and after embryo transfer) increase the chance of pregnancy?

1) The Original Study ("Paulus Study")

This research originated from an original study performed by a German group (Paulus et al.) which is cited pretty much in every website that advertises acupuncture services. In the study (the first randomized, controlled, prospective trial of acupuncture with IVF patients), published in 2002, 165 women undergoing embryo transfer were randomized to receive either 25 minutes of acupuncture or were assigned to a control group, that consisted of resting quietly for the same amount of time both before and after embryo transfer. In this study a significant increase was observed in the clinical pregnancy rate for the acupuncture arm when compared with the control arm (42.5% vs. 26.3%).

As exciting as the study was, there was an important source of criticism in it: the control group was no treatment (rest) rather than placebo (sham acupuncture). Now I do not want to spend much time here explaining what a placebo is but in a nutshell a placebo is a "sham" treatment that has no known effect on a disease, but the receiver of the treatment believes that the placebo is efficacious and thanks to the power of suggestion a treatment effect is observed.

2) The follow up study of the Paulus Group ("Second Paulus study")

Interestingly enough the same group was aware of the fact that a no treatment control group might have constituted a problem and one year later carried out a follow up study with with the placebo control. The study was presented at the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). In the follow up study 200 patients were randomized to receive either real or sham acupuncture for 25 minutes before and after the IVF Embryo Transfer. The study concluded that there was no statistical difference between the two groups ( 43% vs 37% , p=0.39 ). It is important to note that in this study good quality embryos were used.

It is important to note that the authors of the study hypothesized that the control group may have had higher than expected pregnancy rates due to a possible acupressure effect of the sham acupuncture. This is pure hypothesis though since there was no third group without therapy to compare the outcomes with.

The authors opted never to publish this study with negative outcome as full paper, this is a bit concerning because it may signal bias in favour of acupuncture.

3) The Dieterle Study

This is the third randomized prospective study, the lead author is Stefan Dieterle in Dortmund, Germany. The study included 225 patients.

The protocol consisted of 30 minutes of acupuncture after Embryo Transfer and 3 days later and the addition of a special Chinese medical drug (the seed of Caryophyllaceae) was placed on the patient’s ear at the same time. The control group received different acupuncture points, specifically designed not to influence fertility and making sure that equal numbers of needles were applied to the study and control groups.

The clinical pregnancy rate was 34% in the treatment group vs. 16% in the control group (P<.01). This astounding difference in pregnancy was noticed by the authors. More specifically in the paper they note that "according to the German IVF/ICSI register (2003), the average clinical pregnancy rates for this age are 24.6% for IVF and 22.6% for ICSI". I am quite surprised that the study was not controlled for embryo quality (in fact the words "embryo quality" are not ever mentioned in the paper) although all other major parameters such as age, weight, cause of infertility, type of stimulation, number of ampules etc.., were not statistically different. The authors do not highlight this fact although they mention that thanks to the German Embryo Protection Law, clinics are not allowed to perform embryo selection. Nevertheless this observation leaves the door open to the possibility that the treatment group could have just had better embryos by pure chance.

So rather than looking into the obvious, control for embryo quality, the authors look elsewhere to explain these discrepancies suggesting that the the sham acupuncture group could have had an adverse effect on the pregnancy rate.

4) The Danish Study

This is probably the largest randomized perspective study to date it was conducted by Dr. Lars Westergaard in Denmark and it was sponsored by the Danish government.

Dr. Westergaard randomized 300 IVF patients so that 100 received acupuncture on the day of Embryo Transfer according to the original Paulus protocol, 100 received acupuncture on the day of Embryo Transfer and again 2 days later, and a control group of 100 subjects received no acupuncture at all. The control subjects had 1 hour of bed rest after Embryo Transfer.

It is interesting to note that unlike the previous studies where acupuncture was administered by licensed acupuncturists (and often the same practitioner) in this study, 9 nurses were trained and administered the acupuncture.

Pregnancy rates: both acupuncture groups had statistically significant greater pregnancy rates with( 39% for the single-session acupuncture, 36% for the two-session) the control group that had a clinical pregnancy rate of 24%.

The ongoing pregnancy/delivery rate was statistically significantly higher in the one-session group than in the control group, but there were no differences between the two-acupuncture-session and control group. This observation, along with the observation that pregnancy loss rates were much greater in the 2 session group vs the 1 session group (although not statistically significant) brought up again the question on weather acupuncture days after transfer could potentially have adverse effects.

What I found to be really interesting about this study was the fact that the authors found no difference in implantation rates (gestational sacs/no. of transferred embryos) which is a bit surprising because the theory behind acupuncture is that it may increase implantation.

So again no mention about embryo quality in any of the groups.

Why do I think mentioning embryo quality is important? Because Acupuncture is administered after the embryos are created and therefore it is a key element in determining whether the groups of subjects being compared are really similar.

The Australian Study

228 women were randomized in two groups: acupuncture and sham acupuncture (that means not on acupuncture points known to affect fertility) with placebo needles, these newly developed needles are retractable, so the subjects are not aware of whether they are receiving real acupuncture treatment.

All subjects had three treatment sessions. The first took place on day 9 of stimulating injections, and the second and third were immediately before and after Embryo Transfer.

Although the pregnancy rate was 31% in the acupuncture group and 23% in the control group the difference did not reach statistical significance. The ongoing pregnancy rate at 18 weeks was higher in the treatment group (28% vs. 18%), but the difference was not statistically significant either.

This study also reported embryo quality, no difference of embryo quality being reported in the 2 groups.

This was a well designed and executed study that was designed after the original Paulus study (with some differences such as the day 7 acupuncture). The authors hypothesize that if they had done a study with more subjects and therefore a greater power t detect smalled differences acupuncture may have proven efficacious.

The Harvard Study

This very recent study was conducted by Dr. Alice Domar. Dr Domar is well known worldwide for heading the Mind Body Center for Women's Health at Harvard's affiliated Boston IVF. Dr. Domar was interested in trying to figure out a way to do a good acupuncture study that mimicked a well designed study using a pill. In order to do this blinding was essential so that it would be possible to rule out if the placebo effect was on the part of the patient, the health care team, or a combination of the two.

Dr Domar went about replicating the original Paulus study and to "assess the potential contribution of a placebo effect on the part of the patient, but to control for the placebo effect on the part of the health care team." For this reason all members of the health care team, not only the doctor the doctor performing the transfer(as in prior studies), were blinded to the treatment.

As per Dr. Domar's paper :

In both the Paulus and Dieterle studies the physician performing the embryo transfer was blind but the remainder of the health care team was apparently not. There was no information on staff blinding in the Smith study and in the Westergaard study , blinding could not have taken place as the actual acupuncture sessions were conducted by the clinic nurses themselves. Thus it is possible that there could have been a placebo effect on the part of members of the health care team. This is somewhat doubtful, as one would think that the member of the team who has the greatest potential impact on the results of the embryo transfer would be the physician and this was controlled for in at least two of the studies.

There were no significant differences between the two groups in terms of clinical pregnancy rates with 30.8% ultrasound-confirmed clinical pregnancy for the acupuncture compared to a 33.8% rate in the controls (P=.69).

No difference in early miscarriage rates was noted as well.

On the topic of embryo quality: "Because the Paulus study used only subjects with good quality embryos, a separate analysis was performed on subjects who had at least one good quality embryo transferred. The acupuncture patients in this subgroup had a 42% clinical PR and the control subjects had a 47% rate (P=not significant [NS])".

I was very impressed by Dr. Domar's study, mostly because she is not a member of the alternative medicine denier's gang like the people on Quackwatch. On the contrary she is the kind of person who carries out studies with titles like "Impact of group psychological interventions on pregnancy rates in infertile women", in which she proved that 10 months of psychological intervention increased pregnancy rates in infertile patients. She is the kind of researcher that you would imagine being biased towards an alternative regimen rather than against; however, she is also a good scientist who has written about the need of sticking to good science.

Final Considerations

I think that the existing evidence is suggestive that an acupuncture session at the time of embryo transfer may increase pregnancy rates in IVF. Given the quality of the studies and the fact that they appear to have some methodological limitations, such as selection bias which may have influenced the study findings, it can be argued that the existing evidence is inconclusive.

What is the mechanism of action of acupuncture in IVF?

Based on the existing science we do not really know. Various possibilities have been hypothesized: increased blood flow to the uterus, uterine relaxation (although a large ultrasound study of 163 subjects by the Paulus group confirmed acupuncture treatment does not inhibit uterine motility, interestingly this negative study was also not published and left languishing as an oral presentation at ASRM) or increased release of endorphins, and finally placebo effect.

Lets say that the effect of acupuncture on IVF is due to placebo, if i am a patient should I care?

I say that if it works for you .....you shouldn't care why it works! In fact the more you question the less it is likely to work.

I think that the issue is more relevant for practitioners and it deals more with the ethics of medicine and the philosophy of science.

My good friend Dr. Pati suggested a way to approach this: even if it is placebo effect-if it
works-use it -the power of the mind is limited only by our preconceptions-

Is there any good scientific evidence that Acupuncture may help me even if i am not doing IVF?

All of the evidence currently available at this time is anecdotal, which means that all of the claims that you read on all promotional websites are pretty much unverified claims. As I stated at the beginning of this article, this does not exclude that an effect may be present: it's just not been proven by rigorous scientific methodology (the kind of methodology and rigorous work that you expect and demand your infertility specialists to go by).

What About the Study on the British Medical Journal?

In February 2008 an Article from British Medical Journal presented a meta analysis of the existing studies (excluding the domar study) and concluded that " current estimates of the effects of adjuvant acupuncture on in vitro fertilisation are significant and clinically relevant" .

Since this article is nothing but a cumulative analysis of the above trials and overall does not contradict their outcomes i would argue that id does not add much to the discourse: ultimately if there are methodological flows in the original study a meta-analisys is not going to correct any errors.

Why has Acupuncture become so popular?

Because of the evolving nature of medicine from humanistic to science we have witnessed major change in the role of doctors. Doctors are not healers anymore, they operate according to algorithms. Because of this they are viewed as detached and not caring. So there is an enormous interest in ancient healing practices whose practitioners actually seem to "care" and "listen".

One of the major arguments in favour of acupuncture is that it has been around for thousands of years.

Most alternative treatments and especially the ones which are ancient and have survived to our times have almost no side or adverse effects: this makes a lot of sense if you think about it. Throughout the centuries many other medical treatments in use (application of leeches for example) had major side effects ,and some actually killed people. Therefore any treatments that may have had no effect or minimal effect on whichever ailment ended up appearing much more efficacious just by virtue of contrast.


Paulus WE, Zhang M, Strehler E, El-Danasouri I, Sterzik K. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril.

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.

Dieterle S, Ying G, Hatzmann W, Neuer A. Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmic sperm injection: a randomized, prospective, controlled study. Fertil Steril. 2006;85:1347–1351.

Smith C, Coyle M, Norman RJ. Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006;85:1352–1358.

Westergaard LG, Mao Q, Krogslund M, Sandrini S, Lenz S, Grinsted J. Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective randomized trial. Fertil Steril. 2006;85:1341–1346.

Domar a., Meshay I, Kelliher J, Alper M, Powers D. The impact of acupuncture on in vitro fertilization outcome. Fertil Steril. 2008; march

Gleicher n. , et al. Background pregnancy rates in an infertile population. Hum Reprod. 1996 May;11(5):1011-2.

Copyright © 2008 Andrea Vidali  All rights reserved.

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