Randomized controlled trial: effects of acupuncture on pregnancy rates in women undergoing in vitro fertilization

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1 Randomized controlled trial: effects of on pregnancy rates in women undergoing in vitro fertilization Irene Moy, M.D., Magdy P. Milad, M.D., Randall Barnes, M.D., Edmond Confino, M.D., Ralph R. Kazer, M.D., and Xingqi Zhang, Ph.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Northwestern Feinberg School of Medicine, Chicago, Illinois Objective: To evaluate the influence of true versus sham on pregnancy rates (PRs) in women undergoing IVF. Design: Randomized controlled trial, double-blinded with independent observer. Setting: Academic infertility clinic. Patient(s): One hundred sixty patients <38 years old undergoing IVF with or without intracytoplasmic sperm injection. Intervention(s): Subjects were randomly allocated to the true or sham group and underwent 25 minutes before and after ET. Subjects completed a McGill Pain Questionnaire regarding their clinical symptoms during ET. Main Outcome Measure(s): Clinical PR and clinical symptoms during ET. Result(s): While the overall clinical PR was 51.25%, there was no significant difference between the arms of the study (true ¼ 45.3% vs. sham ¼ 52.7%); 33.1% of the patients had ultrasound-documented singleton pregnancy, and 15% of patients had twin gestations, while one patient in the true arm had a triplet gestation. There were significant differences in the subjective, affective, and total pain experience between both arms. The subjects in the true arm described their session as being more tiring and fearful and experienced more achiness compared with their sham counterparts. Conclusion(s): There was no statistically significant difference in the clinical or chemical PRs between both groups. Patients undergoing true had differing sensory experiences compared with patients in the sham arm. There were no significant adverse effects observed during the study, suggesting that is safe for women undergoing ET. (Fertil Steril Ò 2011;95: Ó2011 by American Society for Reproductive Medicine.) Key Words: Acupuncture, in vitro fertilization, pregnancy, complementary and alternative medicine Received February 27, 2010; revised May 3, 2010; accepted May 10, 2010; published online June 20, I.M. has nothing to disclose, M.P.M has nothing to disclose, R.B. has nothing to disclose, E.C. has nothing to disclose, R.R.K. has nothing to disclose. X.Z. has nothing to disclose. Supported by a grant from the Northwestern Memorial Faculty Foundation. Presented at the American Society for Reproductive Medicine, which was held in San Francisco on November 8 12, Reprint requests: Irene Moy, M.D., 676 North Street Clair, Suite 1845, Chicago, Illinois (FAX: ; imoy004@md. northwestern.edu). Infertility is a significant public health issue affecting approximately 6.1 million women and their partners in the United States per year. Since 1978, assisted reproductive technology (ART) procedures have been used to overcome infertility. In 2007, 142,415 ART procedures were reported to the Centers for Disease Control, resulting in 43,408 live births and 57,564 infants, with IVF being the most successful treatment (1). Acupuncture is one of the oldest, most commonly used medical procedures in the world. Its theory is based on the energy flow of qi. Imbalances are believed to cause diseases, which can be treated by stimulating specific points (qi points) on the body surface. Acupuncture has been used for obstetrical and gynecological problems and is one form of complementary and alternative medicine considered by women seeking assistance for their fertility treatments (2 9). Before the initiation of the current trial in 2006, there were only two randomized controlled trials investigating the influence of on pregnancy rates (PRs) in women undergoing ART (5, 6). Stener-Victorin et al. demonstrated a higher PR (45.9% vs. 28.3%; P<.05) in the electro group compared with intravenous alfentanil during oocyte aspiration (5). Paulus et al. reported on 160 patients randomized to IVF alone versus IVF with (6). A higher PR was found in the group compared with the control group (42.5% vs. 26.3%; P<.03). Although both studies demonstrated a statistically significant improvement in pregnancy outcomes, investigators from both studies could not distinguish this effect from placebo or other nonspecific treatment effects. Since 2002, several studies have been published demonstrating higher PRs in those receiving during the time of ET (7 9). The aim of this study was designed to answer the question of whether true in classical meridians (qi lines) is superior to sham needling in non sites. We hypothesized that in particular sites along classical meridians would have a stronger influence on PRs than the same manipulation at sites not located on a meridian. Both groups underwent during the time of day 3 ET. Outcome measurements included PR /$36.00 Fertility and Sterility â Vol. 95, No. 2, February doi: /j.fertnstert Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 FIGURE 1 Flow diagram of study participants. Total number of patients < 38 years old (n=304) Oocyte retrievals (n=276) Excluded (n=68) Prior (n=46) Day 5 ET (n= 22) Declined participation (n=47) Randomized eligible patients (n=161) Allocated to true (n=87) Received intervention (n=87) Allocated to sham (n=74) Received intervention (n=74) Lost to follow-up (n=0) Discontinued intervention (n=1) Lost to follow-up (n=0) Discontinued intervention (n=0) Available for analysis (n=86) Completed (n=86) Completed questionnaire (n=86) Available for analysis (n=74) Completed (n=74) Completed questionnaire (n=73) and pain scale during ET. The risks of undergoing have been widely investigated and have been found to be minimal (10 13). Thus, we did not expect to observe any major adverse events from our study. MATERIALS AND METHODS Setting and Design This prospective randomized controlled trial was conducted at the Northwestern Memorial Faculty Foundation s Division of Reproductive Endocrinology and Infertility, an academic fertility clinic in Chicago, from August 2006 until February The inclusion criteria were infertile women ages undergoing fresh cycle IVF with or without intracytoplasmic sperm injection (ICSI) who were na ıve. Women with a planned day 3 ETwere eligible for inclusion. Women excluded from the study were R38 years old, were undergoing day 5 ET, had prior experience with, or had previously participated in the trial. Information and consent forms regarding the study were provided to all patients during their initial IVF consultation. Eligible women were identified and recruited on the day of their retrieval. Informed consent was obtained from all study participants. This study was approved by Northwestern University s Institutional Review Board. Subjects were randomly allocated to a study group via a random number generator with the use of sealed, sequentially numbered, opaque envelopes. The physician and patient were blinded to the randomization until the conclusion of the study. Details of our controlled ovarian stimulation regimen, gamete handling, ICSI, ET, and luteal support were described elsewhere (14, 15). All participants underwent day 3 ET. The number of embryos transferred was based on the 2004 guidelines set by the Practice Committee of the Society of Assisted Reproductive Technologies and the American Society of Reproductive Medicine. Acupuncture for all subjects was performed in the procedure room by licensed hospital-employed acupuncturists. Careful attention to verbal and nonverbal communication was paid in an attempt to preserve patient blinding. Study participants received two 25-minute sessions (in qi lines vs. non-qi lines), one before and one after ET. Sterile disposable stainless steel needles were inserted into predetermined point locations. Selection of true and sham points was reviewed and agreed upon by the acupuncturists involved in the study. Before ET, subjects in the true arm had needles placed in the following recognized traditional Chinese medicine locations: CV 6 (qi hai), SP 8 (di ji), LIV 3 (tai chong), ST 29 (gui lai), DU 20 (bai hui). After transfer, these 584 Moy et al. Acupuncture and IVF Vol. 95, No. 2, February 2011

3 TABLE 1 Participant demographics. Characteristic True Sham (n [ 74) P value Age No. of cycles a Parity (no. of patients) G 0 P G n P G n P n Body mass index Reason for infertility (no. of patients) Male factor Ovarian dysfunction Tubal factor Endometriosis Uterine Unexplained Other Eggs retrieved Embryos transferred E 2 (pg/ml) 2, , Note: Values reported as mean standard error of the mean, unless otherwise stated. a Total no. of cycles patient has undertaken, including current cycle with intervention. subjects had needles placed in the following locations: ST 36 (zu san li), SP 6 (san yin jiao), SP 10 (xue hai), LI 4 (he gu). Auricular was also performed in the true subjects at the following points: shenmen, sympathetic, uterus, endocrine. The side of the auricular was changed after ET. The true points were consistent with those used in prior studies (16). The patients undergoing needling in non-qi lines also had needles placed before and after ET in the predetermined locations. Auricular in the sham arm was performed at the following points: knee, heel, allergic area, mouth. The side of the auricular was changed after ET. To assess treatment outcome, serum beta-hcg was measured 14 days after retrieval in all patients and repeated 2 days later if the first result was positive. The primary outcome measurement was clinical pregnancy confirmed by ultrasound observation of fetal cardiac activity 5 6 weeks after retrieval. Secondary outcome measurements included chemical PR and comparison of clinical discomfort/pain during ET as assessed by the McGill Pain Questionnaire. Participants impression of whether they received true versus sham was also assessed. All patients were asked to complete a McGill Pain Questionnaire after their post-et treatment to evaluate their subjective experience. Subjects were asked to provide information regarding their sensory pain rating index (S-PRI), affective pain rating index (A-PRI), present pain intensity via visual analog (PPI-VAS), total pain rating index (sum of S-PRI and A-PRI), and overall intensity of total pain experience. S-PRI and A-PRI indices were on a scale of 0 3, where 0 ¼ no pain, 1 ¼ mild pain, 2 ¼ moderate pain, and 3 ¼ severe pain. In the PPI-VAS, subjects were asked to select a rating between the values of 0 10, where 0 ¼ no pain and 10 ¼ worst possible pain. Lastly, in the overall intensity of total pain intensity, patients were asked to select from a scale of 0 5, where 0 ¼ no pain, 1 ¼ mild pain, 2 ¼ discomforting, 3 ¼ distressing, 4 ¼ horrible, and 5 ¼ excruciating pain. Statistical Methods The power analysis was based on data presented by Paulus et al., which reported a PR of 42.5% in the treatment group and 26.3% in the control group (6). For women undergoing IVF at Northwestern, the PR for women aged <38 years old was 32%. A trial of 109 women per group would detect a difference between study arms, assuming a power of 80% and two-sided testing at the 5% significance level. We used Student s t-test and c 2 analysis when appropriate. Data were analyzed with commercial software SPSS (Chicago, IL). Funding was provided by an unrestricted research grant from the Northwestern Memorial Faculty Foundation. RESULTS Between August 2006 and February 2009, a total of 161 women were randomized. One patient discontinued intervention, leading to a total of 160 women analyzed (Fig. 1). As demonstrated in Table 1, there were no significant differences in patient demographics or infertility diagnosis between the two groups. Male factor infertility was found to be the most common cause of infertility in both arms of the study. Additionally, true and sham study groups did not differ in the mean number of eggs retrieved ( vs ) or number of embryos transferred ( vs ). Table 2 presents the primary outcomes. The clinical PR was 45.3% in the true arm and 52.7% in the sham arm (P¼.353). The chemical PR was 7% in the true arm and 8.1% in the sham arm (P ¼.786). There was also no significant difference in the number of multiple pregnancies observed in the two groups. Subjects were asked which group they thought they were randomized to. Of the patients in the true arm, 81.4% of subjects correctly guessed their group allocation, compared with 23.3% in the sham arm. Results of the McGill survey of pain and discomfort revealed a significant difference between the two groups. Compared with the sham group, subjects in the true arm reported their sessions as more tiring (P<.005) or fearful (P<.001) and felt more achiness (P<.018). In all, the true arm participants experienced a significant difference in their affective pain rating index, sensory pain rating index, total pain rating index, and overall intensity of total pain experience (Table 3). Fertility and Sterility â 585

4 TABLE 2 Pregnancy outcomes by group. TABLE 3 McGill Pain Questionnaire. Pregnancy outcome True Sham (n [ 74) P value Category True Sham (n [ 73) a P value Chemical 6 (7) 6 (8.1).786 pregnancy (%) Clinical 39 (45.3) 39 (52.7).353 pregnancy (%) Multiple gestation Twins Triplets 1 0 DISCUSSION In 2002, Paulus et al. published the results of the first randomized controlled trial investigating the effects of on PRs of IVF patients. The study demonstrated an increase in the clinical PR for those in the arm when compared with those in the IVF alone control arm (42.5% vs. 26.3%; P<.03). Since that time, several trials and case reports have been published suggesting a possible benefit of in ART. In 2008, three meta-analyses were published on the effects of on pregnancy and live birth rates among women undergoing IVF (16 18). The meta-analyses by the Cochrane Collaboration (16) and Manheimer et al. (17) both reported increased PRs in women undergoing on the day of ET, while El- Toukhy et al. (18) found no difference. Although most studies consistently report higher PRs, two recent trials dispute this claim. So et al. (19) conducted a randomized double-blinded comparison between real and placebo on IVF outcomes and found that the placebo group achieved significantly higher overall PRs (55.1% vs. 43.8%; P<.038). Domar et al. replicated the Paulus et al. study and did not find increased PRs in patients who received before and after ET (20). We identified a growing interest in the use of by our patients. As such, we designed our study to investigate the effects of on pregnancy outcomes in our patient population. Like the Paulus et al. study, our patients received two sessions of : one 25-minute session before and one immediately after a day 3 ET. To take into account a possible placebo effect, we opted to have a sham arm with penetrating needles placed near, but not on, true points. The results from this study demonstrate a higher clinical PR in the sham arm when compared with the true arm (52.7% vs. 45.3%). Differences in both the clinical PR and chemical PR outcomes did not achieve significance in the study. Enrollment in the study was discontinued before achieving the a priori calculated sample size. This decision was made based on the diminishing number of eligible patients who are na ıve to therapy and a change in the availability of acupuncturists within the IVF clinic. A post hoc analysis of our data revealed that a sample size of 1,400 would be required to detect a clinically significant difference between both groups. Developed by Melzack, the McGill pain scale is widely used to provide a generic instrument for all painful health problems (21). We observed a significant difference between the two groups in all main categories of our pain scale. Results suggest that the patients in the true arm experienced affective perception of being tired and Sensory Pain Rating Index (S-PRI) b Throbbing Shooting Stabbing Sharp Cramping Gnawing Hot burning Aching Heavy Tender Splitting S-PRI total score Affective Pain Rating Index (A-PRI) b Tiring Sickening Fearful Punishing A-PRI total score Total Pain Rating Index (T-PRI): S-PRI þ A-PRI, mean score Overall intensity of total pain experience, b mean score a McGill survey was not successfully obtained from one of the sham patients. b Reported as mean scores. See text for scale values. fearful. Additionally, patients in the true arm reported more achiness compared with their sham counterparts. One of the fundamental characteristics of is obtaining de qi. De qi are sensations that occur after an needle has been properly placed in the body. According to MacPherson et al., the feeling of achiness, dullness, heaviness, numbness, radiation, spreading, and tingling are common de qi sensations (22). The sensation of being tired is also a side effect of, with up to 3% of patients experiencing this phenomenon after a session (10 13, 23). It may be that the differences in sensory perceptions reported by the patients in the true arm are due to de qi arriving at the point, which can be expected in true sessions. The optimal control group for studies of is not obvious (24 28). Like Dieterle et al., we opted to use penetrating needles in our sham arm. In the Dieterle et al. study (8), patients in the control arm received active but not infertility-related, whereas we placed our needles in non points. Our overall observed PR during this study was 51.25%. We found a lower PR in our true arm when compared with sham and nonstudy 586 Moy et al. Acupuncture and IVF Vol. 95, No. 2, February 2011

5 patients. Only 23.3% of the patients in the sham arm correctly guessed their group allocation. Interestingly, the sham arm achieved a higher, although not statistically significant, clinical PR (52.7% vs. 45.3%). The observed increased PR in the sham arm could be due to either expectation or placebo effects. When one considers the placebo effect, there are two potential sources belief on the part of the patient and/or belief on the part of the practitioner. The ideal study would include a design such that all parties are blinded to the subject assignment. With, it is impossible for the acupuncturist to be blinded to whether the patient is receiving true or sham. Keeping this in mind, everyone else on the health care team was blinded to the subject assignment, including the physician who was performing the transfer. With regard to patient blinding and expectations, approximately the same percentage of patients from each arm thought they received true (81.4% in the true arm vs. 76.7% in the sham arm). Of note, we only recruited -na ıve patients into the study to eliminate prior experience as a confounding factor. No significant adverse events occurred during the study period. One patient refused to continue with treatment secondary to pain at the needle sites. Standard clinical practices used by acupuncturists usually occur over a period of weeks to months in which the imbalances and deficiencies leading up to infertility are treated on an individual basis with multiple sessions and herbal medications. Our study was designed with the same treatment protocol given to all subjects regardless of the basis of their infertility. This creates a fixed-protocol bias, and we acknowledge that this may reduce the likelihood that the treatment plan would be appropriate and effective for individual subjects. To the best of our knowledge, this is first randomized controlled trial published in the United States comparing fertility outcomes of sham and true completed on the day 3 ETs. Future research should be conducted with the use of standardized methods to enhance comparability between studies. The use of alternative controls, such as placebo needles, may be useful to better investigate possible nonspecific effects of. Studies with an treatment protocol that is consistent with traditional Chinese medicine principles would also provide valuable insight into the effect of in a more individualized setting. Acknowledgments: The authors thank Theri G. Raby, M.D., for her assistance in fundraising. We wish to extend our appreciation to Ania Grimone L.Ac., M.S., and Janice S. Staron L.Ac., M.S.O.M., for providing services to our study participants. 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