Medical Research Article #3

Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial

Lars G. Westergaard, M.D., Ph.D.,a Qunhui Mao, M.D.,b Marianne Krogslund,a Steen Sandrini,cSuzan Lenz, M.D., Ph.D.,a and Jørgen Grinsted, M.D., Ph.D.a

Fertility Clinic Trianglen, Hellerup; b Holistic Acupuncture Clinic, Frederiksberg C; and c Sandrini Acupuncture I/S, Varde,Denmark

Objective: To evaluate the effect of acupuncture on reproductive outcome in patients treated with IVF/intracytoplasmic sperm injection (ICSI). One group of patients received acupuncture on the day of ET, another group on ET day and again 2 days later (i.e., closer to implantation day), and both groups were compared with a control group that did not receive acupuncture.

Design: Prospective, randomized trial.

Setting: Private fertility center.

Patient(s): During the study period all patients receiving IVF or ICSI treatment were offered participation in the study. On the day of oocyte retrieval, patients were randomly allocated (with sealed envelopes) to receive acupuncture on the day of ET (ACU 1 group, n 95), on that day and again 2 days later (ACU 2 group, n 91), or no acupuncture (control group, n 87).

Intervention(s): Acupuncture was performed immediately before and after ET (ACU 1 and 2 groups), with each session lasting 25 minutes; and one 25-minute session was performed 2 days later in the ACU 2 group.

Main Outcome Measure(s): Clinical pregnancy and ongoing pregnancy rates in the three groups.

Result(s): Clinical and ongoing pregnancy rates were significantly higher in the ACU 1 group as compared with controls (37 of 95 [39%] vs. 21 of 87 [26%] and 34 of 95 [36%] vs. 19 of 87 [22%]). The clinical and ongoing pregnancy rates in the ACU 2 group (36% and 26%) were higher than in controls, but the difference did not reach statistical difference.

Conclusion(s): Acupuncture on the day of ET significantly improves the reproductive outcome of IVF/ICSI,compared with no acupuncture. Repeating acupuncture on ET day 2 provided no additional beneficial effect.

(Fertil Steril 2006;85:1341– 6. ©2006 by American Society for Reproductive Medicine.)

Key Words: Acupuncture, ET day, IVF, pregnancy

Acupuncture is an ancient therapeutic art, which has been given renewed attention in light of recent scientific research and current integration with modern medical practice in the treatment of a wide range of diseases, including infertility. The mechanisms through which acupuncture influence female fertility are believed to involve [1] central stimulation of -endorphin secretion (1), which in turn impacts on the GnRH pulse generator and thereby on gonadotrophin and steroid secretion (2, 3), and [2] a general sympathoinhibitory effect through increased blood flow to the uterus and ovaries (4), resulting in uterine conditions favoring implantation (for a recent review, see Chang et al. [5]).

Many reports in the literature claim positive effects of acupuncture in the treatment of female infertility, but only a few of them satisfy the requirements of rigorously conducted prospective, randomized trials (6). In a prospective, randomized study comparing electro-acupuncture and alfentanil as anesthesia during oocyte aspiration in IVF, Stener-Victorin et al. (7) found, unexpectedly, a significantly higher implantation rate and “take-home baby” rate per ET in the electro-acupuncture group. Later and larger studies using electro-acupuncture on the day of oocyte retrieval, however, did not confirm these positive effects on reproductive outcome (8, 9). Using conventional manual acupuncture on the day of ET, Paulus et al. (10) demonstrated a significantly increased clinical pregnancy rate in a group receiving acupuncture (n 80) as compared with a control group (n 80) not receiving acupuncture.

Accepting the above notion that the positive effects of acupuncture on the day of oocyte retrieval and on the day of ET might be mediated through effects on local ovarian and uterine blood flow, enhancing the quality of the endometrium, we hypothesized that applying acupuncture 5 days after oocyte retrieval (i.e. closer to the day of implantation, (6 –12 days after oocyte retrieval) might further optimize endometrial conditions for the embryo to implant. In the present prospective study, women undergoing IVF/ intracytoplasmic sperm injection (ICSI) treatment were randomly allocated to one of three groups: [1] no acupuncture (control group), [2] acupuncture on the day of ET (i.e., 3 days after oocyte retrieval) (ACU 1 group), and [3] acupuncture on the ET day as above and again 2 days later (i.e., 5 days after oocyte retrieval) (ACU 2 group).

The aims of the study were to evaluate the effects of acupuncture on the reproductive outcome of IVF/ICSI treatment by comparing the rates of positive pregnancy tests, clinical pregnancy, and ongoing pregnancy/delivery in these three groups.

MATERIALS AND METHODS

Setting and Design

This prospective, randomized trial was carried out in a large, private IVF clinic in Copenhagen, Denmark from March 1, 2003 to June 30, 2004. During that period, all couples admitted to the clinic for IVF or ICSI treatment of infertility were consecutively invited to participate. At the start of hormonal stimulation for IVF/ICSI, all patients were in formed orally and in writing about the aims and practical details of the project, and willingness to participate was confirmed in writing. The study was approved by the institutional review board of the cities of Copenhagen and Frederiksberg (no. 01-203/02).

By design, the study population comprised an unselected average of couples seeking infertility treatment in our clinic. The only inclusion criterion for participation in the study was the couples’ consent to be randomized to one of three groups (see below), independent of infertility diagnosis, number of previous ART attempts, and hormonal treatment in the actual cycle. Patients who after randomization did not achieve ET or who for personal reasons did not want to participate further were excluded from the study (Table 1).

On the basis of the data previously published by Paulus et al. (9), combined with an average 25% clinical pregnancy rate per ET in our clinic during the previous 5 years, power calculations (Medcalc software, Mariakerke, Belgium) anticipated that a significant difference in clinical pregnancy rate of 11% between no acupuncture and acupuncture would require approximately 100 patients in the control group and 200 patients in the acupuncture groups.

Randomization

During the study period of 16 months, a total of approximately 1000 couples underwent IVF or ICSI treatment in our clinic. Of these, a total of 300 couples accepted participation in the study and were randomized to one of three groups by the drawing of a sealed envelope on the day of oocyte retrieval. After randomization, 27 patients were excluded for various reasons (Table 1). Of the remaining 273 patients, 87 were allocated to no acupuncture (control group), 95 to acupuncture on the day of ET (ACU 1 group), and 91 to receive acupuncture on the day of ET and 2 days later.

Acupuncture

The acupuncture points used in the present study were, as in the study by Paulus et al. (10), chosen in agreement with the concepts of traditional Chinese medicine. According to these, the kidney system dominates the reproductive system, the liver (LR) regulates Qi (vital force and energy), and spleen (SP) and stomach (ST) are sources of Qi and blood.

Spleen 6 (SP6) is the crossing point of the spleen, kidney, and liver meridians and is considered the key point in treating infertility. Needling SP6, SP8, SP10, ST36, and ST29 aims to provide improved blood perfusion and more energy to the uterus.

Large intestine 4 (LI4) and LR3 are the so-called “four gates points,” which are commonly used to open relevant meridians and calm the mind. Combining them with pericardium 6 (PC6) and DU20 would relax the patient. In the ACU 1 group, acupuncture was given on the day of ET (i.e., 3 days after oocyte retrieval) in two sessions lasting 25 minutes immediately before and after ET. Acupoints before ET included DU20 (Baihui), ST29, SP8, PC6, and LR3. Acupoints after ET were ST36, SP6, SP10, and LI 4.

Needles were inserted into the above points and manipulated until needle-sensation was obtained, (i.e., Deqi—a feeling of, for example, soreness or numbness, distension or pain). After 10 minutes of retention, the needles were again manipulated to maintain Deqi. Fifteen minutes later, the needles were removed.

For the ACU 2 group, the same acupuncture protocol as for the ACU 1 group was applied on the day of ET. In addition, this group received one acupuncture session of 25 minutes’ duration 2 days after ET (i.e., 5 days after oocyte retrieval), to the following acupoints: DU20, Ren 3, ST29, SP10, SP6, ST36, and LI 4. The acupoints chosen for this session aimed at general relaxation and improvement of uterine blood perfusion, to further enhance endometrial receptivity for implantation. Manipulation and retention was the same as in the previously described procedure.

The patients in the control group followed the clinic’s routine procedure (i.e., had bed rest for 1 hour after ET before leaving the clinic).

All acupuncture procedures in the present study were administered by nurses who, before the initiation of the project, were instructed carefully by two professional acupuncture practitioners (Q.M. and S.S.), who supervised the procedures by frequent visits throughout the study period.

One of the nurses (M.K.), who was working daily in the clinic, performed approximately half of all acupunctures (94 of 186), whereas the other eight nurses, assisting during weekends and holidays, performed from 3 to 24 acupunctures each.

Hormone Treatments and IVF/ICSI Procedures

Apart from the acupuncture, all patients were treated according to well-established standard regimens of the clinic. These included [1] long protocol GnRH agonist down-regulation from the midluteal phase, followed by gonadotropin stimulation after down-regulation had been ascertained by ultra sound and serum E2 levels