Effects of Acupuncture on the Outcomes of In Vitro Fertilization: A Systematic Review and Meta-Analysis

Abstract

Objectives:

The objective of this article was to conduct a systematic review with meta-analysis of the trials of acupuncture during in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment on the outcomes of clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, and miscarriage.

Search strategy:

The search was conducted by using MEDLINE^®, SCISEARCH, the Cochrane Menstrual Disorders and Subfertility Group trials register, AMED, Cumulative Index to Nursing and Allied Health Literature, EMBASE, Wanfang Database, China Academic Journal Electronic full text Database in China National Knowledge Infrastructure, Index to Chinese Periodical Literature, ISI Proceedings for conference abstracts, and ISRCTN Register and Meta-register for randomized controlled trials.

Data collection and analysis:

Study selection, quality appraisal, and data extraction were performed independently and in duplicate. The measures of treatment effect were the pooled relative risks (RR) of achieving clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, or miscarriage for women in the acupuncture group compared with women in the control group.

Results:

Using the random-effects model, pooling of the effect estimates from all of the 17 trials showed no significant difference in the clinical pregnancy outcome between the acupuncture and the control groups (RR=1.09, 95% confidence interval (CI) 0.94–1.26, p=0.25). No significant differences in the biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, or miscarriage outcomes were found between the acupuncture and the control groups (biochemical pregnancy: RR=1.01, 95% CI 0.84–1.20, p=0.95; ongoing pregnancy: RR=1.20, 95% CI 0.93–1.56, p=0.16; implantation rate: RR=1.22, 95% CI 0.93–1.62, p=0.16; live birth: RR=1.42, 95% CI 0.92–2.20, p=0.11; miscarriage outcomes: RR=0.94, 95% CI 0.67–1.33, p=0.74).

Conclusions:

No significant benefits of acupuncture are found to improve the outcomes of IVF or ICSI.

Introduction

I n vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) is linked to over 3,500,000 babies worldwide.¹ Children conceived through IVF or ICSI comprise as many as 2%–3% of total births in the United States.² More than 300,000 treatment cycles of IVF and ICSI are performed each year in Europe.³ However, no significant increase in the implantation rates of cleaving embryos has been obtained in recent years, although there have been many relevant techniques emerging to improve the IVF outcomes.⁴ Complementary and alternative medicines, especially acupuncture, have been chosen by many couples as an adjunct when they undergo IVF or ICSI.^5

–9

Acupuncture has been used for treating numerous medical and psychologic conditions in some Asian countries for thousands of years. As early as in 2006, it was recommended to establish an international multicenter study group to evaluate the effects of acupuncture on IVF and ICSI outcomes.¹⁰ More than 70 clinical studies have been conducted in recent years to explore the effects of acupuncture on IVF outcomes. However, as there existed variance on the study design, intervention, and sample size, the conclusions of these studies were inconsistent. Consequently, it is difficult for clinical practitioners and patients to make the final decision on whether to choose acupuncture in IVF treatment.¹¹ Five (5) systematic reviews or meta-analyses^5

–9 designed to explore the effects of acupuncture on IVF outcomes were published in 2008 and 2009. Three (3) of them^5,7,8 showed that acupuncture improved rates of pregnancy in women undergoing IVF treatment. The other one meta-analysis⁶ together with its updated version⁹ did not find any improvement in IVF outcomes following acupuncture. In these meta-analyses, clinical pregnancy and live birth were selected as the parameters to evaluate the IVF outcomes.

With some new clinical studies emerging in 2009 and 2010 to evaluate the effects of acupuncture on IVF outcomes, it is necessary to generate a more precise and complete estimate of the effects of acupuncture on IVF outcomes. A randomized, multicenter, double-blinded and placebo-controlled trial including 635 women undergoing IVF or ICSI (twice as many as in the largest randomized controlled trial included in the previous meta-analysis) was published in 2010.¹² The IVF outcomes in the present systematic review with meta-analysis include the indicators of clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, and miscarriage. Seventeen (17) randomized trials involving the use of acupuncture during IVF or ICSI treatment were covered in the systematic review with meta-analysis.

Materials and Methods

The objective of the systematic review with meta-analysis is to explore whether acupuncture can improve the outcomes of IVF or ICSI. We searched MEDLINE^® (1966–October 2010), SCISEARCH (1974–October 2010), the Cochrane Menstrual Disorders and Subfertility Group trials register (October 2010), AMED (Allied and Complementary Medicine) (1985–October 2010), Cumulative Index to Nursing and Allied Health Literature (1982–October 2010), EMBASE (1974–October 2010), and reference lists for the relevant studies. Chinese studies were also searched from the Wanfang Database (1982–October 2010), China Academic Journal Electronic full text Database in China National Knowledge Infrastructure (1982–October 2010), and Index to Chinese Periodical Literature (1978–October 2010). ISI Proceedings for conference abstracts, and International Standard Randomized Controlled Trial Number Register and meta-register for randomized controlled trials were also searched for the randomized controlled trials. The reference lists of relevant primary and review articles were examined to identify cited articles not captured by electronic searches. The corresponding authors were contacted to obtain missing information. No restrictions of language or publication type were placed in any of the searches.

The following terms were searched as free text terms and Medical Subject Headings terms: (acupuncture, acupressure, moxibustion, electroacupuncture, auricular-acupuncture, auriculotherapy, acupuncture therapy and Traditional Chinese Medicine) and ( in vitro fertilization, fertilization in vitro , intracytoplasmic-sperm-injection, assisted reproductive techniques, oocytes, egg collection, embryo transfer, and embryo implantation).

Study selection

The randomized controlled trials that compared acupuncture with no or sham (placebo) acupuncture in IVF or ICSI treatment were selected. The therapeutic intervention was any accepted regimen of acupuncture including traditional needling acupuncture, auricular acupuncture, electro-acupuncture, and laser acupuncture. Studies with a crossover design were excluded. For trials to be eligible, data had to be able to be extracted on at least one of the following outcomes: clinical pregnancy (that is, presence of at least one gestational sac or fetal heartbeat, confirmed by transvaginal ultrasound); biochemical pregnancy (that is, presence of a positive urine pregnancy test or a positive serum human chorionic gonadotrophin test); ongoing pregnancy (that is, pregnancy beyond 10 weeks of gestation, as confirmed by fetal heart activity on ultrasound); implantation rate (that is, number of gestational sacs per number of transferred embryos); live birth (that is, presence of a baby born alive after 24 weeks gestation); miscarriage (that is, presence of miscarriage before the 16th week of pregnancy).

The titles and abstracts from the electronic searches were scrutinized by 2 reviewers independently (FQ and JZ), and full manuscripts of all citations that were likely to meet the predefined selection criteria were obtained. The final inclusion or exclusion decisions were made on examination of the full manuscripts. In cases of duplicate publication, the most recent and complete versions were selected. Any disagreements about inclusion were resolved by discussion or arbitration by a third reviewer (RXR).

The methodological quality of the selected studies was assessed with the internal validity criteria from the checklist created by the Cochrane menstrual disorders and subfertility group.¹³ Information on the adequacy of randomization, concealment of allocation, blinding, comparability at baseline, the use of sham (or placebo) acupuncture, intention-to-treat analysis, adherence to STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) and power analysis were sought by examining the full-text articles and by contacting the corresponding authors if clarification was needed. Any standard method of delivering sham acupuncture was accepted, including application of true acupuncture in the points that is not designed for treating the medical conditions, superficial needling of the true acupoints, or use of blunt (placebo) needles or use of sham laser acupuncture.

Data extraction

The measures of treatment effect were the pooled relative risks (RR) of achieving clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, or miscarriage for women in the acupuncture group compared with women in the control group. The time of acupuncture in the selected trials included around the time of ovulation induction, around the time of transvaginal oocyte retrieval (TVOR), and around the time of embryo transfer (ET). Study characteristics such as population features and interventions were extracted from each study. Outcome data from each study were extracted using an intention-to-treat approach.

Statistical analysis

The results were pooled and expressed as RR with 95% confidence interval (CI). Heterogeneity of treatment effects was evaluated graphically using forest plot and statistically using the χ² test. Meta-analysis was then performed. An attempt was also made to do a sensitivity analysis based on whether the acupuncture was applied around the time of TVOR or around the time of ET. In the meta-analysis, a random-effects model was used for the encountered heterogeneity of the trials' characteristics and populations studied. The funnel plot was used to evaluate the publication bias. All statistical analysis was performed with RevMan 4.2.7 (Cochrane Collaboration, Oxford, UK) software.

Results

Main study characteristics

A total number of 129 citations was obtained from the electronic searches and examination of the reference lists of primary and review articles, of which 62 were selected for retrieval. The whole process of literature identification and selection is shown in Figure 1. Of the 62 full manuscripts examined, 17 articles^{12,14

–29} including a total of 3744 women were included, among which, 31 women were excluded from analysis for various reasons in five studies.^{14,15,18,27,29} A total of 3713 women met the selection criteria. The quality and the characteristics of the included trials are respectively summarized in Table 1 and Table 2.

FIG. 1.

The process of study selection for the systematic review with meta-analysis of the effects of acupuncture on outcomes of in vitro fertilization (IVF) or intracytoplasmic sperm injection treatment.

Table 1.

Quality of the 17 Randomized Trials Involving the Use of Acupuncture During In Vitro Fertilization or Intracytoplasmic Sperm Injection Treatment Included in the Systematic Review with Meta-Analysis

Study	Single-/multi center	Randomization method	Concealment of allocation	Comparability at baseline	Blinding	ITT	Adherence to STRICTA	Power analysis	Administered acupuncture
Stener-Victorin et al. (1999)	Multicenter	Not mentioned	Adequate	Unclear	No	Yes	No	No	Trained midwives
Paulus et al. (2002)	Single-center	Computerized randomization	Adequate	Yes	Single blind	Yes	No	No	Trained examiner
Stener-Victorin et al. (2003)	Multicenter	Not mentioned	Adequate	Unclear	No	No	Yes	Yes	Trained nurses
Paulus et al. (2003)	Single-center	Not mentioned	Adequate	Unclear	No	Yes	No	No	Not mentioned
Humaidan and Stener-Victorin (2004)	Single-center	Not mentioned	Adequate	Yes	No	Yes	Yes	Yes	Trained nurses
Gejervall et al. (2005)	Single-center	Computerized randomization	Unclear	Unclear	No	No	Yes	Yes	Four midwives
Dieterle et al. (2006)	Single-center	Not mentioned	Adequate	Yes	Double blind	Yes	No	Yes	Physician
Westergaard et al. (2006)	Single-center	Unclear	Adequate	Yes	No	No	Yes	Yes	Nurse
Smith et al. (2006)	Single-center	Block randomization	Adequate	Yes	Single blind	Yes	Yes	Yes	Acupuncturist
Sator-Katzenschlager et al. (2006)	Single-center	Computerized randomization	Unclear	Yes	Double blind	Yes	Yes	Yes	Trained gynaecologist
Benson et al. (2006)	Single-center	Not mentioned	Unclear	Yes	No (except Laser groups)	Yes	No	No	Acupuncturist
Craig et al. (2007)	Multicenter	Computerized randomization	Adequate	Yes	Single blind	No	No	No	Acupuncturist
Domar et al. (2009)	Single-center	Computerized randomization	Adequate	Yes	Single blind	Yes	No	No	Acupuncturist
Chen et al. (2009)	Single-center	Computerized randomization	Unclear	Yes	No	Yes	No	No	Unclear
So et al. (2009)	Single-center	Computerized randomization	Adequate	Yes	Double blind	Yes	Yes	Yes	Acupuncturist
Andersen et al. (2010)	Multicenter	Computerized randomization	Adequate	Yes	Double blind	Yes	Yes	Yes	Nurses who were authorized professional acupuncturists
Moy et al. (2011)	Single-center	Computerized randomization	Adequate	Yes	Double blind	Yes	Yes	Yes	Acupuncturist

ITT, intention-to-treat analysis; STRICTA, STandards for Reporting Interventions in Clinical Trials of Acupuncture.

Table 2.

Characteristics of the 17 Randomized Trials Involving the Use of Acupuncture During In Vitro Fertilization (IVF) or Intracytoplasmic Sperm Injection (ICSI) Treatment Included in the Systematic Review with Meta-Analysis

Study	Participants	Country	Intervention	Control	Placebo intervention	IVF outcomes
Stener-Victorin et al. (1999)	150 randomized—no inclusion criteria	Sweden	PCB and EA	Alfentanil + PCB	No	CP, IR, M
Paulus et al. (2002)	160 randomized—only women with good-quality embryos included	Gemany	TA and AA for 25 minutes before and after ET	Lying still for 25 minutes before and after ET	No	CP, OP, LB
Stener-Victorin et al. (2003)	286 randomized—eligible women aged <38 years, BMI <28 kg/m², had four or more follicles of size 18 mm or more and no more than three previous IVF attempts	Sweden	PCB and EA	Alfentanil + PCB	No	CP, OP, IR, M
Paulus et al. (2003)	200 randomized—only women with good-quality embryos included	Germany	TA for 25 minutes before and after ET	Sham (noninvasive) acupuncture	Yes	CP, OP, LB
Humaidan and Stener-Victorin (2004)	200 randomized—no inclusion criteria	Denmark	PCB and EA	Alfentanil + PCB	No	CPR, BCP, IR
Gejervall et al. (2005)	160 randomized—no inclusion criteria	Sweden	PCB and EA	Premedication + alfentanil + PCB	No	CP
Dieterle et al. (2006)	225 randomized—no inclusion criteria	Germany	TA for 30 minutes after ET and 3 days later + Chinese medical drug	Placebo needling at points designed not to influence fertility	Yes	CP, BCP, OP, IR, LB, M
Westergaard et al. (2006)	300 randomized—no inclusion criteria	Denmark	TA for 25 minutes before and after ET with or without a third session for 25 minutes 2 days after ET	Bed rest for 1 hour after ET	No	CP, BCP, OP, IR LB
Smith et al. (2006)	228 randomized—women with a planned ET were eligible	Australia	TA	Placebo needling at points close to the real acupuncture points	Yes	CP, OP
Sator-Katzenschlager et al. (2006)	94 randomized—women aged <43 years, BMI <28 kg/m², had four or more follicles of size >18 mm	Austria	AA with or without electrical stimulation + PCA	PCA + placebo AA	Yes	CP
Benson et al. (2006)	258 randomized—women scheduled to have ET were eligible	United States	Traditional needle or laser acupuncture for 25 minutes before and after ET	Sham laser acupuncture, relaxation or no intervention	No (except laser group)	CP, BCP
Craig et al. (2007)	107 randomized—women undergoing IVF who have not had acupuncture within 3 months	United States	TA for 25 minutes before and after ET	No intervention	No	CP, BCP
Domar et al. (2009)	150 randomized—women scheduled to have ET using non-donor eggs were eligible	United States	TA for 25 minutes before and after ET	Lie quietly for same amounts of time	No	CP, BCP
Chen et al. (2009)	60 randomized—women with poor ovarian response or decreased reserve	China	TA around ovulation induction	No intervention	No	CP, IR, M
So et al. (2009)	370 randomized—women who had a normal uterine cavity shown on ultrasound scanning on the day of TVOR	China	TA for 25 minutes before and after ET	Placebo needling for 25 minutes before and after ET	Yes	CP, BCP, OP, IR, LB, M
Andersen et al. (2010)	635 randomized—<37 years of age, treatment with IVF/ICSI and transfer of one or two embryos in the first, second, or third stimulated cycle	Denmark	TA accompanying ET	Placebo needling accompanying ET	Yes	CP, BCP, OP, LB
Moy et al. (2010)	161 randomized—women <38 years old undergoing IVF with or without ICSI	United States	TA and AA for 25 minutes before and after ET	Placebo needling in non-qi lines in the predetermined locations. AA was performed at the following points: knee, heel, allergic area, mouth.	Yes	CP, BCP

PCB, paracervical block; EA, electroacupuncture; CP, clinical pregnancy; IR, implantation rate; M, miscarriage; TA, traditional acupuncture; AA, auricular acupuncture; ET, embryo transfer; OP, ongoing pregnancy; LB, live birth; BMI, body–mass index; CPR, clinical pregnancy rate; BCP, biochemical pregnancy; PCA, patient-controlled analgesia (remifentanil pump); TVOR, time of transvaginal oocyte retrieval.

All of the 17 included trials (n=3713) provided clinical pregnancy outcome.^{12,14

–29} Nine (9) of the 17 included trials (n=2388) provided biochemical pregnancy outcome.^{12,14,19,21,22,25,27
–29} Eight (8) of the 17 included trials (n=2392) provided ongoing pregnancy outcome.^{12,16
–18,22,24,25,28} Seven (7) of the 17 included trials (n=2864) provided implantation rate outcome.^{15,18,19,22,25,26,28} Six (6) of the 17 included trials (n=1990) provided live-birth outcomes.^{12,16,17,22,25,28} Five (5) of the 17 included trials (n=373) provided miscarriage outcomes.^{15,18,22,26,28} The items of randomization methods, concealment of allocation, comparability at baseline, blinding type, and adherence to STRICTA are all key factors affecting the quality of trials. As shown in Table 1, randomization methods were used in 10 trials.^{12,14,16,20,23,24,26

–29} Most of the trials reported adequate concealment of allocation, except four trials^20,21,23,26 that failed to clearly describe the concealment of allocation. Comparability at baseline was clearly stated in 13 included studies.^{12,14,16,19,21

–29} Single blinding was applied in four trials^16,24,27,29 and double blinding in five trials.^{12,14,22,23,28} Nine (9) studies^{12,14,18
–20,23
–25,28} adhered to STRICTA. In two of the selected studies,^15,20 acupuncture was administered by midwives. Nurses administered acupuncture in 4 studies,^12,18,19,25 and an acupuncturist administered the acupuncture treatment in six studies.^{14,21,24,27
–29}

Ten (10) of the selected studies were performed in Europe: three were conducted in Germany^16,17,22; three in Sweden^15,18,20; three in Denmark^12,19,25; and one in Austria.²³ Four (4) trials were performed in the United States.^14,21,27,29 One (1) trial was conducted in Australia.²⁴ The other two were conducted in China.^26,28 Four (4) of these were multicenter trials,^12,15,18,29 while all of the others were single-center trials.

Acupuncture was applied around the time of TVOR in five of the selected trials,^{15,18
–20,23} and they were mainly designed to assess the pain-relieving effects of acupuncture used at the time of TVOR compared with conventional analgesia. In only one of the trials, acupuncture was applied around the time of ovulation induction.²⁶ In all of the remaining trials, acupuncture was applied around the time of ET.

IVF outcome

For the clinical pregnancy outcome, data were available from all of the 17 included trials (n=3713). ^{12,14

–29} There was significant statistical heterogeneity between the studies (test for heterogeneity, p=0.0004). Using the random-effects model, pooling of the effect estimates from all of the 17 trials showed no significant difference in the clinical pregnancy outcome between the acupuncture and the control groups (RR=1.09, 95% CI 0.94–1.26, p=0.25; Fig. 2). There also was no significant difference found in the clinical pregnancy outcome between the acupuncture and the control groups when pooling of the effect estimates from 5 trials was done^{15,18
–20,23} in which acupuncture was performed around the time of TVOR (RR=1.06, 95% CI 0.82–1.37, p=0.65), nor was a significant difference found when pooling of the effect estimates from 11 trials was done^{12,14,16,17,19,21,22,25,27
–29} in which acupuncture was performed around the time of ET (RR=1.09, 95% CI 0.90–1.32, p=0.37).

FIG. 2.

Meta-analysis of the studies evaluating the effects of acupuncture on the clinical pregnancy outcome. IVF, in vitro fertilization; RR, relative risk; CI, confidence interval.

For the biochemical pregnancy outcome, data were available from 9 of the 17 included trials (n=2388).^{12,14,19,21,22,25,27
–29} There was significant statistical heterogeneity between the studies (test for heterogeneity, p=0.0002). Using the random-effects model, pooling of the results from all nine trials showed no significant difference in the biochemical pregnancy outcome between the acupuncture and the control groups (RR=1.01, 95% CI 0.84–1.20, p=0.95; Fig. 3). Acupuncture was performed around the time of TVOR in one¹⁹ of the nine studies, and for all of the others, acupuncture was performed around the time of ET. Exclusion of the study¹⁹ did not change the meta-analysis result (RR=1.02, 95% CI 0.83–1.25, p=0.84).

FIG. 3.

Meta-analysis of the studies evaluating the effects of acupuncture on the biochemical pregnancy outcome. IVF, in vitro fertilization; RR, relative risk; CI, confidence interval.

For the ongoing pregnancy outcome, data were available from 8 of the 17 included trials (n=2392).^{12,16
–18,22,24,25,28} There was significant statistical heterogeneity between the studies (test for heterogeneity, p=0.001). Using the random-effects model, pooling of the results from all of the eight trials showed no significant difference in the ongoing pregnancy outcome between the acupuncture and the control groups (RR=1.20, 95% CI 0.93–1.56, p=0.16; Fig. 4). Acupuncture was performed around the time of TVOR in one¹⁸ of the eight studies, and for all of the others, acupuncture was performed around the time of ET. Exclusion of the study¹⁸ did not change the meta-analysis result (RR=1.27, 95% CI 0.95–1.71, p=0.11).

FIG. 4.

Meta-analysis of the studies evaluating the effects of acupuncture on the ongoing pregnancy outcome. IVF, in vitro fertilization; RR, relative risk; CI, confidence interval.

For the implantation rate, data were available from 7 of the 17 included trials (n=2864).^{15,18,19,22,25,26,28} There was significant statistical heterogeneity between the studies (test for heterogeneity, p=0.003). Using the random-effects model, pooling of the results from all the 7 trials showed no significant difference in the implantation rate between the acupuncture and the control groups (RR=1.22, 95% CI 0.93–1.62, p=0.16; Fig. 5). No significant difference in the implantation rate outcome between the acupuncture and the control groups was found when pooling the effect estimates from three trials^15,18,19 in which acupuncture was performed around the time of TVOR (RR=1.11, 95% CI 0.79–1.55, p=0.55), nor was a significant difference found when pooling the effect estimates from three trials^22,25,28 in which acupuncture was performed around the time of ET (RR=1.25, 95% CI 0.74–2.11, p=0.41).

FIG. 5.

Meta-analysis of the studies evaluating the effects of acupuncture on the implantation rate outcome. IVF, in vitro fertilization; RR, relative risk; CI, confidence interval.

For the live-birth outcome, data were only available from 6 of the 17 included trials (n=1990).^{12,16,17,22,25,28} There was significant statistical heterogeneity between the studies (test for heterogeneity, p<0.00001). Using the random-effects model, pooling of the results from the six trials showed no significant difference in the live-birth outcome between the acupuncture and the control groups (RR=1.42, 95% CI 0.92–2.20, p=0.11; Fig. 6).

FIG. 6.

Meta-analysis of the studies evaluating the effects of acupuncture on the live-birth outcome. IVF, in vitro fertilization; RR, relative risk; CI, confidence interval.

For the miscarriage outcome, data were available from 5 of the 17 included trials (n=373).^{15,18,22,26,28} There was no significant statistical heterogeneity between the studies (test for heterogeneity, p=0.49). Using the random-effects model, pooling of the results from the five trials showed no significant difference in the miscarriage outcome between the acupuncture and the control groups (RR=0.94, 95% CI 0.67–1.33, p=0.74; Fig. 7). No significant difference in the miscarriage outcome between the acupuncture and the control groups was found when pooling the effect estimates from two trials^15,18 in which acupuncture was performed around the time of TVOR (RR=0.65, 95% CI 0.20–2.13, p=0.48), nor was a significant difference was found when pooling the effect estimates from two trials^22,28 in which acupuncture was performed around the time of ET (RR=1.08, 95% CI 0.72–1.61, p=0.72).

FIG. 7.

Meta-analysis of the studies evaluating the effects of acupuncture on the miscarriage outcome. IVF, in vitro fertilization; RR, relative risk; CI, confidence interval.

Discussion

A growing number of studies examining the effectiveness of acupuncture as an adjunct to IVF or ICSI have emerged since the first relevant clinical research was published in 1999.¹⁵ Five (5) systematic reviews and meta-analysis^5

–9 designed to explore the effects of acupuncture on IVF outcomes were published in 2008 and 2009. Manheimer et al.⁷ found that complementing the ET process with acupuncture was associated with significant improvements in clinical pregnancy (odds ratio [OR]=1.65, 95% CI 1.27–2.14), ongoing pregnancy (OR=1.87, 95% CI 1.40–2.49), and live birth (OR=1.91, 95% CI 1.39–2.64). A recent Cochrane review also reported the evidence of benefit on the live-birth rate when acupuncture is performed on the day of ET (OR=1.89, 95% CI 1.29–2.77).⁵ Similarly, a meta-analysis of 10 randomized studies by Ng et al.⁸ revealed a significant improvement in the pregnancy rate for acupuncture treatment (OR=1.42, 95% CI 1.17–1.72). Subgroup analysis based on the day of acupuncture detected a significant improvement in pregnancy rate for acupuncture treatment when acupuncture was administered on the day of ET (OR=1.83, 95% CI 1.40–2.39). However, there was no improvement in pregnancy rate when acupuncture was given on the day of TVOR only (OR=1.07, 95% CI 0.81–1.42). They then concluded that the positive effect of acupuncture during IVF treatment might be related to the changes in uterine blood flow and uterine contractility, as well as relaxation of stress.⁸ However, in the systematic review by El-Toukhy et al.,⁶ meta-analysis of five studies of acupuncture around the time of egg collection did not show a significant difference in clinical pregnancy (RR=1.06, 95% CI 0.82–1.37), and meta-analysis of eight studies of acupuncture around the time of ET showed no difference in the clinical pregnancy rate (RR=1.23, 95% CI 0.96–1.58). Their updated meta-analysis⁹ showed no improvement in clinical pregnancy rates with acupuncture at the time of ET (RR=1.16, 95% CI 0.92–1.48). A restricted meta-analysis⁹ using high-quality studies that employed sham acupuncture in the control group also failed to show improvement in live birth rates (RR=1.25, 95% CI 0.70–2.20). The finding difference between these systematic reviews with meta-analysis may be caused by the variation in the inclusion criteria, the inclusion of new trials in subsequent meta-analysis, and variations in the quality of the acupuncture intervention, which may have contributed to clinical heterogeneity. Similar to these published systematic reviews and meta-analysis,^5

–9 the randomized controlled trials that compared acupuncture with no or sham (placebo) acupuncture in IVF or ICSI treatment were selected in the present systematic review with meta-analysis. The different sources of controls may lead to the extreme heterogeneity. However, none has been widely recognized as a standard control or sham acupuncture administration so far.

Since the publication of the 5 systematic reviews, more than 10 new randomized, controlled, and blinded trials have been published, among which, 4 met the inclusion criteria of this review.^12,14,26,27 To replicate previous research on the efficacy of acupuncture in increasing pregnancy rates in patients undergoing IVF and to determine whether such an increase was due to a placebo effect, Domar et al.²⁷ conducted a prospective, randomized, controlled and single-blinded trial. They found that there were no significant differences in pregnancy rates between the acupuncture and the control groups, and that acupuncture patients reported being more optimistic about their cycle. Moy et al.¹⁴ found there was no significant difference in the clinical or biochemical pregnancy rates between acupuncture and sham-acupuncture groups. The patients undergoing true acupuncture had differing sensory experiences compared with patients in the sham arm. A new prospective, randomized, and controlled trial²⁶ from China was also included in the present meta-analysis. In the research, 60 women who had undergone IVF with poor ovarian response were randomly divided into an acupuncture group (n=30) and a control group (n=30). Acupuncture treatment was administered beginning at the time of the last natural menstrual cycle of the controlled ovarian hyperstimulation and continued until the day of the TVOR. No acupuncture treatment was administered post-TVOR. Guanyuan (CV4), Taixi (KI3), and Sanyinjiao (SP6) were selected as the main acupoints. The acupuncture treatment was performed once a day for 30 minutes. Although the results showed that acupuncture improved the outcomes of clinical pregnancy and implantation rate, there was no statistically significant difference between the two groups. Exclusion of the study²⁶ did not change the present review's meta-analysis results of clinical pregnancy (RR=1.08, 95% CI 0.93–1.26, p=0.30), implantation rate (RR=1.10, 95% CI 0.91–1.33, p=0.31), or miscarriage outcomes (RR=0.95, 95% CI 0.58–1.58, p=0.85). A large, randomized, multicenter, double-blinded, placebo-controlled trial included 635 women undergoing IVF or ICSI was completed in Denmark in 2009 and was published in 2010.¹² The size of the study was almost twice as large as any earlier conducted study. The investigators achieved complete follow-up of all pregnancies and obtained the number of live births, which is considered to be the optimal endpoint for assisted reproduction treatment. In the study, optimal design including a placebo procedure was used. The researchers found that there were no significant differences between the acupuncture group and the placebo group on ongoing pregnancy rates or live-birth rates, indicating that acupuncture administered in relation to embryo transfer has no effect on the outcomes of IVF or ICSI.

In the present meta-analysis, a random-effects model was used for the encountered heterogeneity of the trials' characteristics and populations studied. A random-effects meta-analysis model involves an assumption that the effects being estimated in the different studies are not identical, but follow some distribution. The sources of the significant heterogeneity between the studies included in the present systematic review with meta-analysis may be from the following factors: (1) difference on population of the studies: Ten (10) of the selected studies were performed in Europe—three were conducted in Germany^16,17,22; three in Sweden^15,18,20; three in Denmark^12,19,25; and one in Austria.²³ Four (4) trials were performed in the United States.^14,21,27,29 One (1) trial was conducted in Australia.²⁴ The other two were conducted in China.^26,28 The different backgrounds of acupuncture in the population may lead to the heterogeneity; (2) difference on details of the inclusion criteria of these studies; (3) difference on size of the studies; (4) difference on places of the studies: Four (4) of these were multicenter trials,^12,15,18,29 while all of the others were single-center trials; (5) difference on the interventions of controls in these studies; (6) difference on types of blindness in the studies; (7) difference on the main aims of the studies: five trials^{15,18
–20,23} were mainly designed to assess the pain-relieving effects of acupuncture used at the time of TVOR compared with conventional analgesia, while all the others were designed to evaluate the effects of acupuncture on the outcomes of IVF or ICSI; (8) difference on the selection of acupoints in the studies; (9) difference on type of acupuncture in the studies; (10) difference on the acupuncture practitioners of the studies; (11) difference on location of acupuncture treatment; (12) difference on definition of indicators of IVF outcomes in these studies; and (13) difference on IVF outcomes among IVF centers, specifically, the baseline pregnancy rates, live birth rates, and so on.

In the present meta-analysis, six IVF outcomes indicators including clinical pregnancy, biochemical pregnancy, ongoing pregnancy, implantation rate, live birth, and miscarriage were selected in order to generate a more precise and complete estimate of the effects of acupuncture on IVF outcomes. The present systematic review with meta-analysis failed to show any significant benefits of acupuncture in improving the outcomes of IVF or ICSI, either acupuncture around the time of TVOR or ET. However, the outcome indicators of clinical pregnancy, ongoing pregnancy, implantation rate, and live birth favored acupuncture, although no statistical significance was achieved.

As an important part of Traditional Chinese Medicine (TCM), acupuncture is based on the classic theory of TCM. The effects of acupuncture on IVF or ICSI outcomes depend on many various factors, such as diagnosis of patient's conditions based on TCM theory, selection of the acupoints, skills of the acupuncturist, performance type of acupuncture (traditional needling acupuncture, electro-acupuncture, laser acupuncture, or auricular acupuncture). Pinborg et al.³⁰ considered that the effects of acupuncture are most likely to involve uterine contractility instead of uterine receptivity, and acupuncture is unlikely to have exerted a central effect by mediating the release of neurotransmitters because the hypothalamic secretion of gonadotrophin-releasing hormone would be “switched off” by the gonadotrophin-releasing hormone analogues used during IVF. Acupuncture may act by reducing the contractility of the uterus, thereby avoiding expulsion of embryos after transfer.³¹ Consequently, the following items may be useful for the design of further studies aiming to evaluate the effects of acupuncture on IVF or ICSI outcomes: (1) selection of the acupoints should be based on the correct diagnosis of a patient's conditions according to TCM theory; (2) standardized acupuncture methods should be applied to enhance comparability among studies; (3) clinical pregnancy and live birth should be used as the primary outcomes; (4) data of the hormones and psychologic index during the treatment should be collected. To minimize the significant heterogeneity among studies, standard acupuncture protocols and a standard control or sham acupuncture administration should be established on the basis of consensus.

Conclusions

Although no significant benefits of acupuncture have been found to improve the outcomes of IVF or ICSI in the present meta-analysis, the authors believe that more TCM theory-based, large-size, randomized and multicenter trials should be conducted before a final decision is made on whether to chose acupuncture to improve IVF outcomes.

Footnotes

Acknowledgments

The authors would like to express their deep thanks to Elisabeth C. Larsen for providing study data.

Disclosure Statement

No competing financial interests exist.

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