We will conduct a parallel randomized controlled trial of acupuncture compared with a placebo control using a non-invasive placebo needle. A non-randomized group will receive standard care to allow comparisons with the baseline pregnancy rate. The rationale for a non-randomized arm includes the need to provide a baseline pregnancy rate, and acknowledgement from our previous research experience that women would not accept randomization to this group [17]. We acknowledge this group of women may have different outcomes, and incorporating a usual care group to provide baseline pregnancy rate is problematic. The analysis of the usual care only group will be treated as an observational study with known confounding factors adjusted for in the analysis. The study will recruit participants from IVF centers in Australia (IVF Australia, Assisted Conception and Fertility South Australia, Flinders Reproductive) and one center in New Zealand (Fertility Plus).
Eligibility criteria
We will recruit women aged <43 years, undergoing a fresh IVF or intracytoplasmic sperm injection (ICSI) cycle, and restricted to women with the potential for a lower live birth rate defined as two or more previous unsuccessful ETs (fresh or frozen), and unsuccessful clinical pregnancies of quality embryos deemed by the embryologist to have been suitable for freezing by standard criteria. The rationale for our inclusion criteria is based on a possibility that where the baseline pregnancy rates are high for some IVF settings, the added value of acupuncture maybe reduced. We have identified a group of women were the pregnancy rates are lower, and for whom adding acupuncture may improve their clinical outcomes. The characteristics of age <43 years, undergoing a fresh IVF or intracytoplasmic sperm injection (ICSI) cycle, reflect the characteristics of majority of women undergoing fresh IVF cycle in Australia and New Zealand. IVF units outside of Australia and New Zealand may have lower age restrictions.
Women will be excluded if they are undergoing a frozen ET, have been previously randomized to the study, planning pre-implantation genetic diagnosis, or receiving donor eggs, or are currently having acupuncture.
Randomization and blinding
Women will be allocated to a study group by a research nurse phoning the randomization service, prepared and based at the National Health and Medical Research Council Clinical Trials Centre, Sydney, Australia. The randomization sequence is computer generated and concealed via central allocation. There will be stratification by the number of ET cycles (2 to 6 and 6+), woman’s age (<38 years, and 38 to 42 years), and collaborating center. Randomization will be into two study groups, acupuncture and a placebo control using the non-invasive Park needle [18]. Study participants, care providers, the outcome assessors, and the analyst will be blind to study group allocation.
Interventions
Following randomization women in the intervention groups will see the study acupuncturist based at the IVF centers, or at close proximity to the IVF centers. The acupuncturists are registered with national professional associations, and with a minimum of 2 years clinical experience. Training will be provided to all study acupuncturists on the treatment protocol, practitioner intent or treatment aspirations, recording of treatments administered, the acupuncturists’ duty and an explanation of proposed future monitoring. The treatment protocol was based on two rounds of a Delphi process, with consensus achieved on a treatment protocol for the study. Nineteen acupuncturists participated in this process, with practitioners from Australia (6), China (2), Denmark (1), Sweden (1), the United States (4), and the United Kingdom (1). All women will undergo a traditional Chinese medicine (TCM) diagnosis. The initial diagnosis and treatment will take 60 to 90 minutes undertaken on days 6 to 8 of the stimulated IVF cycle. Two treatments will be administered immediately before and after ET.
Group 1: Acupuncture treatment based on the traditional Chinese medicine (TCM) style of acupuncture. For women randomized to receive acupuncture the initial treatment includes core points Guilai ST-29, Guanyuan Ren-4, Qihai Ren-6, Sanyinjiao SP-6, Xuehai SP-10, plus up to five additional points based on a TCM pattern differentiation. Two subsequent treatments will be administered on the day of ET pre and post transfer. Points administered on the day of ET include Diji SP-8, Xuehai SP-10, Taichong LR-3, Guanyuan Ren-4, one point from Shenmen HT-7, Neiguan PC-6, or YinTang, Baihui DU-20, Taixi KD-3, Zusanli ST-36, Sanyinjiao SP-6, and auricular points Shenmen and Zhigong. Manual acupuncture will be performed with needles inserted using the Park device [18], a supporting tube that facilitates maintenance of blinding for the participant. Needles will be inserted to a depth of not greater than 2 cm and retained for 25 min. The insertion of the acupuncture needle into an acupuncture point typically generates a range of sensations called ‘de qi’, this sensation will be maintained during the initial treatment on days 6 to 8, and during the pre-embryo treatment only. Points will be inserted bilaterally except for acupuncture points located on the Ren and Du points and YinTang point.
Group 2: Placebo control. This group will receive placement of non-invasive Park sham needles [18]. The Park needle has been shown to be an effective device for blinding in RCT [18]. These needles have a retractable needle shaft, a blunt tip, and skin penetration does not occur, and the needles have a supporting device. The acupuncturist will hold the ‘needle’ in place with one hand, while moving the handle of the needle with the other hand, so the shaft disappears into the handle. The needle is inserted through Park supporting device. The location of sham non-acupuncture points are away from real points and are described in relation to anatomical landmarks and relationship to acupuncture channels. Thirteen sham points are described: three on the abdomen, four on the arm, two on the leg, one on the back, one on the forehead, one on the foot, and one on the ear. The duration of needling and treatment session is the same as for the acupuncture group.
Study group 3: Usual care only. For women who decline to be randomized and were not planning to have acupuncture, they will be invited to participate in a non-randomized group receiving standard care only group, and provide consent to participate in all data collection.
Outcome measures
Our primary study endpoint will be the proportion of women reporting a live birth defined as the delivery of one or more living infants, >20 weeks gestation or 400 g or more birth weight. Our secondary endpoints will be the proportion of women reporting a clinical pregnancy defined as demonstration of fetal heart activity on ultrasound scan, measured at 7 to 8 weeks, miscarriage defined as a non-viable pregnancy prior to 12 weeks, quality of life using the MOS Short Form 36 (SF36) [19], anxiety using the Stait Trait Anxiety Inventory [20] and infertility self-efficacy measured by the Infertility Self-Efficacy Scale [21] at trial entry, 2 and 14 weeks from trial entry. We will also collect data on expectations, and the therapeutic alliance. Clinical data will be collected from the IVF center database. Other outcomes will be collected by postal questionnaires. Data on the safety of acupuncture and any adverse events will be collected from practitioner treatment notes (Figure 1)
Sample size
Our pilot data [17] were suggestive of a larger treatment difference; however we have chosen a more conservative 7% estimate of the clinical effect from acupuncture compared with the placebo control group. The proportion of women with a live birth for women with multiple cycle failures in the placebo control group in our previous study was 12.1% [17]. To detect a 7% increase in the proportion of women that report a live birth between the treatment and placebo control, with 80% power at the 5% significance level will require 449 women per group. We have allowed for a loss of 30% due to cancelled cycles, or no ET. A total sample size of 1,168 women is required.
We expect a larger treatment effect (10%) when comparing acupuncture and standard care. To detect a 10% increase in the proportion of women that report a live birth between the treatment and standard care, with 80% power at the 5% significance level will require 193 women in the non-randomized group. Allowing for a 30% loss, due to cancelled cycles, or no ET, 251 women in the non-randomized group are required.
Data analysis
Data will be analyzed by a statistician based at UWS blind to study group. Analyses of the endpoints will undertake an ‘intention to treat’ approach and compare differences in the primary and secondary endpoints between groups. The primary analysis will compare the proportions of patients with live births. Logistic regression will be used to identify baseline variables which are associated with outcomes. Linear models will be used to test for between group differences in the continuous outcome measures (for example, health status).
Subgroup analyses will be stated a priori, for example influence of stimulation doses, long- or short-acting stimulation cycle. Levels of significance will be reported at P < 0.05.
Qualitative study
A qualitative study using in-depth interviews is nested within the RCT. The purpose of the interviews is: to investigate how women perceive the study intervention and how they think about their use and experience of it, and its effects; and to provide evidence of the process by which the outcomes of the RCT may have been achieved. A sample of 50 women will be recruited through theoretical and purposive sampling to ensure equal numbers of participants from both the intervention and placebo control groups, and a socially diverse sample of women across demographic background, treatment outcome and coping outcomes (as determined by the self-efficacy scores). It is anticipated that 50 interviews will lead to data saturation. The interview will cover topics such as the women’s experience of IVF treatment and its impact on personal wellbeing and social and family relationships, and women’s perception of the impact of acupuncture. Interviews will examine their experience during the period following ET and the pregnancy test. Their beliefs about the impact of acupuncture on their bodies and health, and its potential impact on the reproductive outcome of their treatment will be explored in conversation. Analysis of qualitative interview data will be iterative and the interview schedule will be modified to include emerging themes.
Economic analysis
An economic analysis will be conducted alongside the RCT. The primary measure of outcome for the economic analysis will be the cost per live birth. Resource use collected within the study will include costs associated with the provision of the proposed acupuncture intervention plus the direct costs of IVF based on expected average clinic fees, the frequency and duration of GP visits, the frequency and duration of antenatal visits and inpatient admissions, for example miscarriage loss or antenatal complications. Mean costs and effectiveness between the intervention and control groups will be compared and incremental cost-effectiveness ratios (ICERs) presented in terms of the cost per unit improvement in clinical outcome as measured by the live birth rate. An assessment of the sensitivity of the results obtained to variation in measured resource use, effectiveness and/or unit costs will be undertaken using appropriate one-way and multi-way sensitivity analysis [22]. Data will be collected from Medicare, a national database of health utilization, activity and resource use, and completion of data forms by women reporting health utilization not captured by Medicare.
Ethics
Approval to conduct this study has been obtained from the following research and ethics committees: University of Western Sydney (New South Wales), Greenslopes Private Hospital (Brisbane, Queensland), IVF Australia (Sydney, New South Wales), St Andrews Hospital (Adelaide, South Australia), and the Southern Adelaide Clinical Human Research Ethics Committee (South Australia).
