Acupuncture and IVF: New Evidence for an Unlikely Duo

By Brandon Horn, PhD, JD, LAc, Board Certified Acupuncture and Oriental Medicine Practitioners, Eastern Center for Complementary Medicine, PC. Dr. Horn reports no financial relationships relevant to this field of study.

What happens when you mix one of the most technologically advanced medical technologies with one of the oldest medical techniques? According to some studies, you get higher pregnancy rates, and according to others, you don't.

This article analyzes recent studies in the growing field of IVF acupuncture and addresses discrepancies in the available data to suggest a clinical "bottom line." In doing so, common misconceptions about acupuncture will be discussed, and acupuncture's role in a modern IVF setting will be elucidated.

Literature Summary

An excellent review of the pre-2005 literature was featured in the October 2005 issue of Alternative Therapies in Women's Health; therefore, we will only touch briefly on the pre-2005 literature. The seminal study on acupuncture and IVF was conducted by Paulus colleagues in 2002.1 Paulus demonstrated a 62% increase in clinical pregnancies (P = .03), which were defined as the presence of a fetal sac at 6 weeks. Paulus repeated the study the following year using a sham acupuncture treatment as the control instead of a non-treatment group.2 This time the increase was only 16% (P = .39). In commenting on the study, Paulus realized that they had made an assumption that the sham treatment was inert, when in fact it may not have been. Therefore, they concluded that the sham points they chose may have actually had some real effects. Indeed, when comparing the sham pregnancy rates (37%) with the non-treatment control group of Paulus' prior study (26.3%), we see substantial differences. The appropriateness of placebo controls in acupuncture studies is highly problematic, and researchers have suggested that more valuable information is attained through non-placebo control groups.3

Following the Paulus study, Quintero and colleagues designed a pilot study to see if they could reproduce the results with an even more rigorous study design.4 They used a randomized, sham-controlled, crossover study. They found a trend toward higher implantation rates (180% increase in the treatment group) and a trend toward higher ongoing pregnancy rates (60% increase in the treatment group). Though neither of these was statistically significant, it is clinically interesting that the percentage increase in ongoing pregnancies was similar to that of the Paulus study. Quintero did, however, find a statistically significant reduction in the amount of gonadotropins used in the treatment group, indicating that acupuncture may have direct effects on ovarian function.

In the same year, Magarelli and colleagues performed a retrospective study where they found a statistically significant 42% increase in ongoing pregnancies.5 They also found a statistically significant reduction in the number of miscarriages and ectopic pregnancies. Wang and colleagues used a completely different acupuncture protocol from Paulus, Magarelli, and Quintero.6 Contrary to the other studies, Wang demonstrated a trend toward a reduction in pregnancy rates (though not statistically significant). This was the first study showing a possible negative effect of acupuncture on IVF pregnancies, indicating that acupuncture's effects on reproductive physiology are not simply generalized effects irrespective of the acupuncture protocol.

Three very interesting studies were published in 2006. Smith and colleagues randomized 228 IVF patients to receive true or non-invasive sham acupuncture.7 Smith used a modified Paulus protocol and added a treatment on day 9 of stimulation. The day 9 treatment varied from person to person depending on their "Traditional Chinese Medicine diagnosis." The actual treatments given were not revealed. The true acupuncture group had a 28% pregnancy rate at week 18, whereas the sham group had an 18% pregnancy rate (P = .08). This difference, though statistically non-significant, is very significant clinically when read together with the Paulus and Quintero studies, which achieved very similar increases.

Dieterle and colleagues randomized 225 patients to receive true acupuncture or a sham. The true acupuncture group received a modified Paulus protocol with only one treatment done after embryo transfer and another three days later. The sham acupuncture was actually a real acupuncture treatment using points, not thought, to influence fertility. As with Paulus' second study, Dieterle et al did not validate their sham treatment. The true acupuncture group had a 115% increase in clinical pregnancies (33.6% vs 15.6%, P < .01) and a 106% increase in ongoing pregnancies compared to the sham group (28.4% vs 18%, P < .01). At first glance, this seems astonishing. However, the researchers did not indicate the average pregnancy rates for their clinic without acupuncture. Instead, they provided the national average for clinical pregnancies in Germany, which is 24.6% for IVF and 22.6% for ICSI.8 Although the pregnancy rate for the true acupuncture group is still approximately 40% higher than the national average, the sham acupuncture group is approximately 30% lower than the national average.

Despite the shortcomings of the study design, it is a very interesting and important study for 2 reasons. First, it adds evidence that true acupuncture, administered appropriately, can substantially increase pregnancy rates. Second, together with the Wang study, it adds evidence that improperly chosen acupuncture points may have detrimental effects on pregnancy outcomes.

Westergaard and colleagues randomized 273 patients to one of three groups: control group, ACU 1, or ACU 2. In the ACU 1 group, patients received acupuncture in the form of a modified Paulus protocol, where the auricular points were excluded. There is no indication why the researchers removed the auricular points, since auricular acupuncture has been shown to improve reproductive outcomes.9 The ACU 2 group received the same treatment as ACU 1 except that they received an additional treatment 2 days post embryo transfer. Both the ACU 1 and ACU 2 groups had significantly higher clinical pregnancy rates (P < .05) compared to controls (39%, 36%, and 24%, respectively).10

The increases in pregnancy rates were consistent with most of the prior studies. However, interestingly, the ACU 2 group had double the number of pregnancy losses when compared to the ACU 1 and control groups (12, 6, and 5, respectively). This was not statistically significant, but again, when read together with the Wang and Dieterle studies, the trend is certainly of high clinical significance. Westergaard commented, "In our study, an additional session of acupuncture on ET day + 2 (ie, closer to the day of implantation) did not significantly affect the outcome, but showed an insignificant increase in the rate of early pregnancy loss. Whether this implies a possible harmful effect of repeated acupuncture sessions (3) remains unanswered by the present study, but might deserve further investigation."11

Though highly significant, Westergaard and colleagues did not mention the fact that, although used successfully during embryo transfer, the acupuncture points they chose for the ET day + 2 treatment were traditionally contraindicated during pregnancy due to their potential abortifacient effects.12 If the traditional contraindications are correct, their use after embryo transfer could theoretically reduce the number of pregnancies.

In addition, Westergaard and many other researchers erroneously generalize the results of their particular methodology to all of acupuncture. This is a crucial mistake. While there is clearly evidence of generalized effects of acupuncture, there is a substantial body of literature demonstrating that various acupuncture points have relatively unique and site specific effects as well.

For example, fMRI studies have shown that stimulation of a point traditionally used to treat visual problems causes visual cortical activations, where stimulation of control points did not.13,14 In rat studies, C-FOS expression in the visual cortex was also increased when using similar points, whereas non-relevant acupuncture points produced no increase.15 Although acupuncture fMRI studies have yet to be conducted in reproductive medicine, Doppler studies investigating pulsatility indices have shown site-specific increases in blood flow in the uterine (P < .0001) and ovarian arteries.16,17

Mechanistic Studies

Having established a very strong trend toward increases in pregnancy rates, several studies have begun looking at mechanisms of action. In light of studies such as Richter and colleagues,18 demonstrating that endometrial thickness may be one factor in pregnancy outcomes, Yu and colleagues conducted a study to examine acupuncture's effects on the uterine lining when combined with Sildenafil.19 Inclusion criteria were women who had never achieved a lining of > 8 mm or greater in prior cycles. Although only a pilot study of 4 patients, Yu et al reported that, "All 4 subjects achieved endometrial lining thickness of > 10 mm following the administration of the combination of acupuncture and Sildenafil; this included one patient whose lining did not exceed 5 mm in a previous cycle. Another patient, who had not responded to Sildenafil alone in a prior IVF cycle, responded to the combination of Sildenafil and acupuncture."

Yu et al concluded that acupuncture's seeming effects on the endometrium could be mediated by affecting nitric oxide synthase.

Liu and colleagues conducted a very interesting study on rats to investigate acupuncture's role on implantation. The researchers took 3 groups of rats: a control group and 2 other groups treated with Mifepristone. Half of the Mifepristone rats received acupuncture (the Acupuncture Group), the other half did not. The rats that received Mifepristone and acupuncture had the same implantation rates as normal rats. The Mifepristone only group had significantly less pregnancies (P < .01).20 This was fascinating evidence of acupuncture's ability to reverse certain chemotoxic agents that may be blocking fertility.

Liu et al then followed up with another similarly designed study, this time measuring a number of serum parameters. Liu et al found that the pregnancy rate and average number of blastocysts were significantly higher in the acupuncture group than those in the control group respectively (P <0.01). They also found that acupuncture was able to maintain serum levels of progesterone and prolactin, as well as the protein and mRNA expression levels of progesterone receptors and prolactin receptors (P < 0.05).21

This study suggests that acupuncture may have the ability to help maintain progesterone levels despite hormonally-adverse environmental factors. In our world of xenosteroids, this is an important consideration. This study also suggests that research should be done on acupuncture's ability to help maintain a pregnancy in groups at high risk for xenosteroid exposure.

Magarelli et al investigated prolactin and cortisol levels in patients receiving a particular acupuncture protocol during an IVF cycle. Given traditional uses of acupuncture points to increase lactation, the potential of acupuncture to elevate prolactin levels was anticipated. Surprisingly, however, cortisol levels also increased significantly in part of the cycle. The Magarelli study, therefore, suggests that, contrary to popular belief, acupuncture's beneficial effects on fertility are probably not secondary to a relaxation response. In commenting on the results, Magarelli noted that elevated hydrocortisone levels in follicular fluid has been shown to improve ongoing pregnancy rates, and surmised that this may be another avenue by which acupuncture is helping to improve pregnancy rates.22

Conclusion

The clinical "bottom line" is that with proper point selection, timing, and administration, acupuncture substantially and consistently improves pregnancy outcomes. Because of the potential for negative effects of improper acupuncture administration, it is prudent to utilize acupuncturists that have demonstrated competency in reproductive medicine, such as by passing the oriental reproductive medicine board exams.23 Lastly, although traditional contraindications have not been proven to be valid, it may be prudent to have traditionally trained acupuncturists on IRBs to ensure that any such contraindications are taken into consideration as part of the risk/benefit analysis.

References

1. Paulus WE, et al. Influence of acupuncture on the pregnancy rate in patients who undergo assisted reproduction therapy. Fertil Steril. 2002;77:721-724.

2. Paulus WE, et al. Placebo controlled trial of acupuncture effects in assisted reproductive therapy. Fertil Steril. 2003;18:xviii18.

3. Paterson C, Dieppe P. Characteristic and incidental (placebo) effects in complex interventions such as acupuncture. BMJ. 2005;330:1202-1205.

4. Quintero R. A randomized, controlled, double-blind, cross-over study evaluating acupuncture as an adjunct to IVF. Fertil Steril. 2004;81:11-12.

5. Magarelli P, Cridennda D. Acupuncture & IVF poor responders: A cure? Fertil Steril. 2004;81:20.

6. Wang W, et al. A matched controlled study to evaluate the efficacy of acupuncture for improving pregnancy rates following in vitro fertilization-embryo transfer. Fertil Steril. 2005;83:S24.

7. Smith C, et al. Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006;85:1352-1358.

8. Dieterle S, et al. Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmic sperm injection: A randomized, prospective, controlled clinical study. Fertil Steril. 2006;85:1347-1351.

9. Gerhard I, Postneek F. Auricular acupuncture in the treatment of female infertility. Gynecol Endocrinol. 1992;6:171-181.

10. Westergaard LG, et al. 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.

11. Westergaard LG, et al. Positive effects of acupuncture in assisted reproductive technologies are not mediated by changes in ovarian and endometrial production of estradiol, progesterone, and placental protein 14. Fertil Steril. 2006;85:1368-1369.

12. Deadman, Peter. A manual of acupuncture (Second Edition). East Sussex: Journal of Chinese Medicine Publications, 2007.

13. Li G, et al. Visual cortical activations on fMRI upon stimulation of the vision-implicated acupoints. Neuroreport. 2003;14:669-673.

14. Cho ZH, et al. New findings of the correlation between acupoints and corresponding brain cortices using functional MRI. Proc Natl Acad Sci U S A. 1998;95:2670-2673. Note half of the authors retracted the conclusions of this study in 2006 based upon reasons that had nothing to do with the study itself (which is probably why the other half did not retract the conclusions).

15. Lee H, et al. Acupuncture stimulation of the vision-related acupoint (Bl-67) increases c-Fos expression in the visual cortex of binocularly deprived rat pups. Am J Chin Med. 2002;30:379-385.

16. Stener-Victorin E, et al. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod. 1996;11:1314-1317.

17. Stener-Victorin E, et al. Ovarian blood flow responses to electroacupuncture stimulation depend on estrous cycle and on site and frequency of stimulation in anesthetized rats. J Appl Physiol. 2006; 101:84-91.

18. Richter K, et al. Relationship between endometrial thickness and embryo implantation, based on 1294 cycles of in vitro with transfer of two blastocyst-stage embryos. Fertil Steril. 2006;87:53-59.

19. Yu W, et al. A pilot study evaluating the combination of acupuncture with sildenafil on endometrial thickness. Fertil Steril. 2007;87:S23.

20. Liu XY, et al Effects of acupuncture promoting embryo implantation and development in the rat with dysfunctional embryo implantation. Zhongguo Zhen Jiu. 2007;27:439-442.

21. Liu XY, et al Preliminary study on the mechanisms of acupuncture in promoting embryo implantation in rats. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007; 27:633-636.

22. Magarelli PC, et al. Proposed mechanism of action of acupuncture on IVF outcomes. Program and abstracts of the American Society for Reproductive Medicine 62nd Annual Conference; October 21-25, 2006; New Orleans, LA. Session P-118.

23. The first Board exam is scheduled in March of 2008. A list of practitioners who have passed their board exams and demonstrated competency in oriental reproductive medicine will be listed on the ABORM website (www.aborm.org).