Acupuncture Improves IVF Success Rates & Patient Experience

Introduction

In this post we will be going through;

• Overview of acupuncture mechanisms influencing reproductive health
• Review of most current quality research on acupuncture & IVF and other fertility treatments

Acupuncture is understood to affect several mechanisms associated with reproduction

• Acupuncture is thought to induce neurotransmitter secretion, which activates the release of gonadotropin-releasing hormone (i.e. FSH & LH), and thereby increases ovulation, promotes menstrual regularity and regulates overall fertility.
• Acupuncture is also thought to inhibit central sympathetic nerve activity (fight-flight-freeze), and thereby increase parasympathetic activity (feed & breed) resulting in increased blood circulation to uterine and ovarian tissue.
• Finally, through its effects on increasing endogenous opioid production (b-endorphins), acupuncture appears to downregulate various stress responses that are known to inhibit fertility and regulate cytokine activity known to impact implantation and early loss

Research on Acupuncture used in conjunction with IVF & other fertility treatments

Main issues with Acupuncture & IVF research

Despite the issues outlined below, acupuncture and Chinese medicine are proving to be very beneficial in optimizing peoples chances of IVF success, and should be considered as adjunctive therapy to those undergoing assisted reproductive technology. As research in this area improves by addressing the following issues, I am certain we will see even more positive results.

1. Strict non-individualized protocols 

A major issue with some of the studies is that never-before-tested acupuncture protocols are used and then, rather than stating: “These findings do not support the use of this acupuncture protocol in the improvement of IVF outcomes”, they generalized their findings in the conclusion as if they applied to all acupuncture protocols. A colleague and researcher Brandon Horn put it best when he stated “This is somewhat analogous to conducting a clinical trial on the efficacy of pharmaceuticals against Staphylococcus areas (bacteria) using acyclovir (anti-viral) as the pharmaceutical and then stating that pharmaceuticals are ineffective at treating S. aureus infections. There are indeed acupuncture protocols that were found in clinical trials to improve IVF outcomes. There are also other acupuncture protocols that were found to have no effect and one protocol that seemed to negatively impact IVF outcomes.”

2. Inappropriate and unverified controls (sham)

Many studies done to date on the topic of acupuncture and IVF involve inappropriate or unvalidated controls, or ‘sham’ treatments. In scientific research, a ‘control’ or a ‘sham’ arm of a study needs to be verified to be  completely inert, or in other words, have no treatment effect on the subjects. As we already know from years of medical research using placebos (typically sugar pills), they end up having treatment effect due to the patient manifesting the desired results. Obviously the sugar is doing nothing, this is clear and verified. Applying this thinking to acupuncture studies with fake spring sham needles, or actual needles being inserted in locations that are not the intended point protocol, without verifying these ‘controls’ or ‘sham’ treatments to be without their own treatment effect (like a sugar pill), the results of the comparison between the real acupuncture and the control create a scenario that is more challenging for the acupuncture to outperform the sham, since the sham is often showing favorable results itself! I hope that makes sense. Bottom line, I am just pointing out that this model of researching acupuncture effects is flawed, not in its favor, so when we see acupuncture improving live birth rates, we can be assured that it is doing just that. 🙂

3. Dose (# of acupuncture treatments)

Another colleague and researcher, Lee Hullender-Rubin, concluded in her own research and stated the following in regards to dose; “It is my opinion that the pre and post embryo transfer treatments are insufficient to increase IVF birth outcomes alone, but is very helpful in supporting women on the day of ET and helps them to relax (become more receptive). However, when the two sessions on day of ET combined with a larger dose of acupuncture similar to what we saw in other studies, i.e. 9-12 sessions prior to transfer day, we see a significant association with improving IVF birth outcomes. Basically, a fundamental flaw is the dose.”

In other words, in regards to treatment leading up to an IVF, we can easily see the importance of health in the timeline and explanation below; 

Bias

As with almost any meta-analysis there is potential for bias within the studies examined, which can affect the accuracy of the results. The inclusion of large numbers of studies and subjects helps minimize this issue, as does the absence of financial motivation in obtaining specific results. Since these meta-analyses contain significant numbers, and there are no financial conflicts, the results from these studies I will discuss are more trustworthy.

STUDY

Smith, Caroline A. et al.. Acupuncture performed around the time of embryo transfer: a systematic review and meta-analysis. Reproductive BioMedicine Online, 2019 Volume 38 , Issue 3 , 364 – 379

Meta-Analysis to evaluate the safety and effectiveness of acupuncture as an adjunct to embryo transfer when compared to controls or no adjuvant treatment. Acupuncture administered within 1 day of embryo transfer. Most include 2 treatments on day of ET, before and after procedure.

• 20 trials – 5130 women included in review, all primarily from the U.S., South America, and Europe (Andersen et al., 2010; Arnoldi et al., 2010; Craig et al., 2014; Dieterle et al., 2006; Domar et al., 2009; Feliciani et al., 2011; Gillerman et al., 2016; Madaschi et al., 2010; Morin et al., 2017; Moy et al., 2011; Omodei et al., 2010; Paulus et al., 2002, 2003; Rashidi et al., 2013; Smith et al., 2006, 2018; So et al., 2009, 2010; Villahermosa et al., 2013; Westergaard et al., 2006).

Conclusions

32% increase in pregnancy rate 

• • 12 trials, 2230 women, [RR] 1.32, 95% confidence interval [CI] 1.07–1.62

30% increase in live births 

• • 9 trials, 1980 women, [RR] 1.30, 95% CI 1.00–1.68

43% reduction of miscarriage 

• • 10 trials, 2042 women, [RR] 1.43, 95% CI 1.03–1.98

*The above data is based on [RR] risk ratio and [CI] confidence interval. [RR] >1 means there is an increased risk of the measured outcome, <1 suggests a reduced risk of the measured outcome, so if RR is 1.30 there is a 30% increased risk of live birth rate when compared to controls. [CI] meaning how confident the researchers are in the result. If the numbers are close together then it means a large sample size and greater degree of accuracy of results.

Sub-group analysis

• Significant effect on clinical pregnancy rates when used in women who have had multiple previous IVF cycles, or where there was a low baseline pregnancy rate, including women who may have a poor prognosis of IVF success (Manheimer et al., 2013 – meta-analysis).
• Previous subgroup analyses have found higher pregnancy rates from acupuncture trials administered during ovarian stimulation (Qian et al., 2017), and an increased number of treatment sessions performed prior to and including the day of embryo transfer (Hullender Rubin et al., 2015; Magarelli et al., 2009). Therefore, dose is important to consider in future research.

Review

The following conclusions are from a review article done by Hullender Rubin LE, Anderson BJ, Craig LB. Acupuncture and in vitro fertilisation research: current and future directions. Acupunct Med. 2018;36(2):117-122. These point to strengths and weaknesses in the current literature, and ideas for improving both treatment efficacy and research in the future.

• Two to three acupuncture sessions performed on or around the day of embryo transfer are insufficient interventions to improve IVF birth outcomes but provide significant IVF-related stress reduction. 
• Evidence suggests several acupuncture sessions improve endometrial thickness, reduce stress, and improve patient satisfaction. 
• Observational studies suggest more sessions are associated with increases in clinical pregnancy and live birth rates. 
• An optimized acupuncture intervention with evidence-based guidance on number of sessions (i.e. 9-12) are needed for future studies to further clarify acupuncture’s role in supporting IVF cycles.

STUDY

Yun L, Liqun W, Shuqi Y, Chunxiao W, Liming L, Wei Y. Acupuncture for infertile women without undergoing assisted reproductive techniques (ART): A systematic review and meta-analysis. Medicine (Baltimore). 2019;98(29):e16463.

Studies of randomized controlled trials (RCTs) on women with infertility treated by acupuncture or its combined therapy were included. The experimental group received acupuncture or its combined therapy, and the control group received other standard therapies, such as injected Western drugs and oral Western medication. Control groups all included placebo.

Western medication used as controls in these studies consisted primarily of clomiphene citrate (clomid). Metformin, HCG, and bromocriptine were also used.

• 22 trials with a total of 2591 participants were included. Women 20-40 years of age. All sperm samples normal
• All studies were conducted in China

Primary outcomes included pregnancy rate, which was confirmed with a pregnancy test and ultrasound. Secondary outcomes included ovulation rate, endometrial thickness, endocrine indexes (i.e. LH).

Conclusions

Our findings provide the first clear evidence that acupuncture might be an effective intervention for infertile women without undergoing ART. Evidence of significant effectiveness in the acupuncture group was observed in pregnancy rate, ovulation rate, LH, and endometrial thickness compared to that in the control group. In addition, subgroup analyses of different types of intervention suggested that acupuncture alone or combined with other therapies is more beneficial in terms of pregnancy rate compared to the benefits of standard therapies.

• The pregnancy rate increased 84% with acupuncture treatment (RR = 1.84, 95% CI 1.62 to 2.10, P < .00001), compared to that in the control groups

Subgroup analysis showed that comparing with pure western medicine intervention, no matter intervention with acupuncture alone, with acupuncture plus western medicine, with acupuncture plus Chinese medicine, or acupuncture plus Chinese medicine and western medicine, all of these subgroups exhibited significant improvement.

• PCOS groups showed very significant improvement in pregnancy rates with the addition of acupuncture (RR = 1.70, 95% CI 1.47–1.97, P < .00001)
• Ovulation rate showed significant improvement with the addition of acupuncture, 15 trials, 1702 women (RR = 1.29, 95% CI 1.21–1.37, P < .00001)
• Endometrial thickness was significantly improved with the addition of acupuncture, 9 trials, 786 women (MD=1.39, 95% CI 0.51–2.27, P = .002)
• LH levels were significantly improved with the addition of acupuncture (MD = −1.93, 95% CI −2.43 to −1.44, P < .00001)

STUDY

Smith CA, de Lacey S, Chapman M, et al. The effects of acupuncture on the secondary outcomes of anxiety and quality of life for women undergoing IVF: A randomized controlled trial. Acta Obstet Gynecol Scand. 2019 ;98:460‐469

Double-blind RCT – acupuncture vs. sham acupuncture control

• • 16 IVF centers in Australia / New Zealand, only fresh cycles (no FET, donor, or PGD)
  • 526 participants all received 3 acupuncture treatments and completed IVF cycle
  • *One during injections (stim day 6-8), then 2 on ET day (before and after)
  • Participants were not using acupuncture prior to study

Note: original sample size was over 5000. This number declined significantly largely due to the fact that so many women were using acupuncture already and didn’t want risk being randomized into a non-acupuncture (sham) group

Anxiety scores taken on Embryo Transfer day

Conclusions

Women that received acupuncture reported reduced anxiety after embryo transfer when compared to sham control 

• mean difference [MD] −1.1, 95% CI −2.2 to −0.1, P = 0.03
• This effect was not sustained at 14 days post ET
• Neither group showed improved quality of life

*In this study the P value and the Mean difference are important to understand. P value (probability value) is the statistical probability of the results being wrong. A P value of less than 0.05 is considered significant. Mean difference [MD] closer to 1 expresses similarity of the different groups being researched.

Considerations

• Anxiety and low quality of life are experienced by women during and following an IVF cycle
• Acupuncture continued through the 2 week wait post ET may be beneficial for anxiety
• Increased acupuncture dose may benefit quality of life throughout IVF cycles

STUDY

Sutton C, Pentland S, Roberts J.  A Comparison of Stress Levels in Women Undergoing Single Versus Multiple Acupuncture Session Prior to Embryo Transfer.  Fertility and Sterility, Volume 103, Issue 2, e36 – e37

• This retrospective cohort study included 87 women undergoing IVF at a private fertility clinic
• All women completed validated questionnaire, the perceived stress scale (PSS), on embryo transfer day

Conclusions

Stress is lower for women receiving >1 month of regular acupuncture before embryo transfer, demonstrating a dose-dependent effect. Acupuncture appears to be a promising stress-lowering tool for women undergoing IVF.

In our clinical experience, infertility-related or IVF treatment-related stress and/or anxiety may be the primary reason a physician/nurse refers a patient for acupuncture. 

The psychological burden associated with infertility can be a barrier to continuing treatment. 

If acupuncture can help reduce stress throughout the IVF process, people will choose more treatment cycles, resulting in more babies.

STUDY

Hullender Rubin LE, Opsahl MS, Wiemer KE, Mist SD, Caughey AB. Impact of whole systems traditional Chinese medicine on in-vitro fertilization outcomes. Reprod Biomed Online. 2015;30(6):602-612.

Retrospective cohort study, 1231 IVF patient records were reviewed. Patients undergoing IVF patients may receive either acupuncture or whole-systems traditional Chinese medicine (WS-TCM) as an adjuvant IVF treatment. WS-TCM is a complex intervention that can include acupuncture, Chinese herbal medicine, dietary, lifestyle recommendations

• Outcomes compared among three groups: 
  1. IVF with no additional treatment
  2. IVF and elective acupuncture on day of embryo transfer
  3. IVF and elective WS-TCM.

The primary outcome was live birth

Conclusions

Overall, IVF with adjuvant WS-TCM was associated with greater odds of live birth in donor and non-donor cycles.

• Of 1069 non-donor cycles, WS-TCM was associated with greater odds of live birth compared with IVF alone (adjusted odds ratio [AOR] 2.09; 95% confidence interval [CI] 1.36 to 3.21), or embryo transfer with acupuncture only (AOR 1.62; 95% CI 1.04 to 2.52). 
• Of 162 donor cycles, WS-TCM was associated with increased live births compared with all groups (odds Ratio [OR] 3.72; 95% CI 1.05 to 13.24, unadjusted] or embryo transfer with acupuncture only (OR 4.09; 95% CI: 1.02 to 16.38, unadjusted). 

*Odds Ratio – An odds ratio of exactly 1 means that exposure to property A does not affect the odds of property B. An odds ratio of more than 1 means that there is a higher odds of property B happening with exposure to property A. An odds ratio is less than 1 is associated with lower odds.

Traditional Chinese Medicine (TCM)

 “A mediocre doctor treats disease, a good doctor prevents disease, and a master doctor teaches his community to be well.”

~ Huang Di Nei Jing Su Wen

“The easiest method to improve the outcomes for pregnancy and child is keeping mom healthy.”
~ Dr. Jeff Roberts, MD, FRCSC
Pacific Centre for Reproductive Medicine

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13. Yun L, Liqun W, Shuqi Y, Chunxiao W, Liming L, Wei Y. Acupuncture for infertile women without undergoing assisted reproductive techniques (ART): A systematic review and meta-analysis. Medicine (Baltimore). 2019;98(29):e16463
14. Smith CA, de Lacey S, Chapman M, et al. The effects of acupuncture on the secondary outcomes of anxiety and quality of life for women undergoing IVF: A randomized controlled trial. Acta Obstet Gynecol Scand. 2019 ;98:460‐469
15. Sutton C, Pentland S, Roberts J.  A Comparison of Stress Levels in Women Undergoing Single Versus Multiple Acupuncture Session Prior to Embryo Transfer.  Fertility and Sterility, Volume 103, Issue 2, e36 – e37
16. Hullender Rubin LE, Opsahl MS, Wiemer KE, Mist SD, Caughey AB. Impact of whole systems traditional Chinese medicine on in-vitro fertilization outcomes. Reprod Biomed Online. 2015;30(6):602-612