Acupuncture-assisted embryo transfer techniques: Research frontiers and future directions

Abstract

BACKGROUND

Acupuncture, an ancient practice, is gaining recognition as a complementary and alternative medicine, especially in assisted reproductive technology. It plays a crucial role in enhancing embryo transfer success rates. Research indicates that acupuncture can improve blood flow, increase endometrial receptivity regulate pressure, and affect neuroendocrine activities in the ovaries and uterus during embryo implantation, therefore improving pregnancy outcomes.

AIM

To highlight recent developments related to acupuncture's influence on embryo transfer and elucidating the precise mechanisms by which acupuncture influences embryo transfer.

METHODS

We searched database including PubMed, Cochrane Library up to September 2024 for relevant studies and patents to evaluate the effects of acupuncture on women undergoing in vitro fertilization (IVF). The experimental design included an intervention group using needling, and a control group consisting of no needling or sham needling. The main outcome is clinical pregnancy rate (CPR), while secondary includes live birth rate (LBR) and biochemical pregnancy rate (BPR). We examined the influence of adjunctive needling on pregnancy outcomes by analyzing variations in the main outcomes.

RESULTS

A total of 145 randomized controlled trials involving 27748 participants were analyzed. Data revealed that the overall CPR was significantly elevated in all acupuncture cohorts compared to the control group [relative risk (RR): 1.21, 95%CI: 1.07-1.38, P = 0.01]. In contrast, the aggregated LBR did not exhibit a corresponding increase, and notable statistical heterogeneity was observed among the studies. Acupuncture-assisted frozen-thawed embryo transfer enhanced the BPR (RR: 1.51, 95%CI: 1.21-1.89, P = 0.03) and improved endometrial morphology (RR: 1.41, 95%CI: 1.13-1.75, P = 0.01). Furthermore, IVF outcomes were significantly superior in the acupuncture group when acupuncture was administered during controlled ovarian hyperstimulation (RR: 1.71, 95%CI: 1.08-2.13, 95%CI: 1.08-4.21, P = 0.03).

CONCLUSION

We find that acupuncture positively influences pregnancy rates in women receiving IVF treatment. Nonetheless, there are no established guidelines for optimal acupuncture protocols. Considering the methodological limitations identified in current research, there is a need for larger, methodologically rigorous studies.

Key Words: Acupuncture; In vitro fertilization; Embryo transfer; Assisted reproductive technology; Clinical pregnancy rate; Fertility treatment; Acupuncture therapy; Surface stimulation

Core Tip: In vitro fertilization and embryo transfer is one of the most common treatments for couples of childbearing age facing infertility. The correlation among acupuncture locations, treatment frequency, and improved pregnancy rates requires additional research.

INTRODUCTION

Infertility has become more common worldwide, with a global average incidence of 8%-12%. In China, approximately 25% of couples of reproductive age experience infertility issues[1]. Around 10%-15% of these couples pursue specialized fertility services, and one of the most common treatments is in vitro fertilization and embryo transfer (IVF-ET) and its outreach treatments. Nonetheless, despite advancements in reproductive technologies leading to increased live birth rates (LBRs), the clinical pregnancy rate (CPR) for IVF-ET remains relatively low at 58.7%, based on the existing data[2]. It is a common occurrence for women undergoing IVF-ET cycles to require multiple attempts before achieving a successful outcome. While the extended duration and high financial cost associated with IVF-ET cycles highlight the necessity to improve the success rate of this procedure[3].

Acupuncture constitutes an essential element of traditional Chinese medicine (TCM). Since the publication of the first report of acupuncture improving pregnancy outcomes in IVF in 1999, the use of acupuncture in IVF-ET has garnered growing attention as an adjunct therapy[4]. At present, there is no consensus among the experts regarding the efficacy and safety of acupuncture in the realm of IVF-ET. Some systematic reviews suggest that acupuncture may effectively improve reproductive outcomes. However, other studies have not found statistically significant differences in CPR or LBR when compared to the control group.

Conclusively, in this review, we aim to evaluate the effectiveness of acupuncture-assisted embryo transfer for patients by examining current clinical studies, elucidate the underlying mechanisms and theoretical advancements of this treatment through foundational research, and conduct a quantitative analysis and synthesis of the literature from existing systematic reviews and meta-analyses to furnish additional evidence for future clinical applications and to guide subsequent experimental design.

MATERIALS AND METHODS

Journal literature retrieval

The electronic literature was searched in English in international electronic databases including PubMed, EMBASE, Cochrane Library and Web of Science from inception to Sep 10 2024, using the MeSH items and free words: ("acupuncture" OR "acupuncture therapy" OR "acupuncture points") AND ("embryo transfer" OR "fertility treatment" OR "in vitro fertilization" OR "assisted reproductive techniques"). The inclusion criteria for literature were restricted to randomized controlled trials (RCTs), meta-analyses and systematic reviews. Non-empirical literature such as non-RCT systematic reviews, review comments, conference abstracts, editorials and guidelines were excluded, as were duplicate publications or those irrelevant to the research topic. The search strategy involved the identification of key thematic terms in titles, abstracts and keywords. Regarding the exclusion criteria, duplicate entries and articles that lacked relevance to the subject matter were firstly eliminated. Then refine the full-text evaluation by excluding non-English publications and those with incomplete data. The manuscripts were meticulously evaluated by Wang AL and Zhao Y based on the predetermined inclusion and exclusion criteria. Additionally, Mao RY participated as a third reviewer and rendered a decision in instances where the two primary authors had differing viewpoints. A total of 1333 publications met the inclusion criteria and were subjected to a comprehensive data extraction process using EndNote.

Search strategy for patents

Patents serve as research indicators of clinical translatability. Numerous patents concerning acupuncture feature extensive body surface stimulation. Consequently, we performed a systematic search in Google Patents for assisted reproductive technology (ART)-related body surface stimulation patents. Between January 1, 2004, and September 10, 2024, a comprehensive patent search was conducted in Google Patents, focusing on the application of acupuncture and related techniques in the field of ART, specifically in the context of embryo transfer. The search strategy employed a combination of subject-specific terms such as "acupuncture", "electroacupuncture", "moxibustion", "auricular acupuncture", "scalp acupuncture", "transcutaneous electrical nerve stimulation", "laser stimulation", "embryo transfer", "fertility treatment", "in vitro fertilization", "assisted reproductive techniques" and "endometrial receptivity".

Inclusion criteria focused on patents that specifically addressed the application of acupuncture or alternative surface stimulation techniques in embryo transfer within ART. Eligible patents described technical implementation methods and relevant application scenarios, and were classified as invention or utility model patents with active legal status and full-text availability. Exclusion criteria ruled out patents unrelated to acupuncture, ART, or the specific topic of interest, as well as those that had been invalidated, revoked, or contained incomplete information that hindered detailed analysis. Duplicate patent records were consolidated based on the most recent filing date.

For literature screening and data normalization, the retrieved patent documents were imported into Excel for preliminary deduplication. Titles and abstracts were reviewed to exclude documents not meeting the inclusion criteria, followed by a full-text assessment of the remaining documents. Technical terminology and classifications were standardized according to relevant international standards.

The final dataset of included patent documents was compiled into an Excel table, with extracted data comprising patent number, title, abstract, filing date, patent type, technical field, and patent status. Python 3.10.11 was employed for descriptive analysis, statistical distribution of technology types, and correlation analysis, identifying technological hotspots and trends in development.

RESULTS

Findings and analyses of journal literature

Following the initial publication of pertinent clinical studies in 1999, researchers have progressively concentrated on the effectiveness of acupuncture as an adjunctive method to enhance pregnancy outcomes, with the body of literature in this domain steadily expanding since 2004. We searched electronic databases for 1333 publications from 2004 to 2024. The studies included in this review were classified into the following 3 categories.

Characteristics of participants: Participants were women undergoing IVF-ET and those receiving intracytoplasmic sperm injection (ICSI). Most participants in these studies were aged between 25 years and 35 years, with one exception where the average age exceeded 35 years. The frequency of acupuncture sessions varied across treatment protocols, with some studies administering treatments two times to three times weekly, while others conducted sessions every other day. Each treatment lasted between 25 minutes to 30 minutes and was carried out over two to three consecutive menstrual cycles.

Clinical research: To thoroughly evaluate the specific impacts of acupuncture within the framework of ART and embryo transfer, we conducted an extensive search of clinical trials on PubMed and Web of Science. In our literature review, 61 studies were totally synthesized. The specific screening process is shown in Figure 1A.

Figure 1 The screening process. A: The screening process of the clinical studies; B: The screening process of the fundamental researches.

By reading all the articles included, we analyzed what they had in common. Most clinical studies examining acupuncture in ART for embryo transfer, exhibit certain common characteristics. The study population includes female patients diagnosed with infertility who are undergoing IVF-ET. These patients receive acupuncture as a supplemental approach to embryo transfer, with no age limitations. The scope of inquiry is restricted to RCTs, while non-randomized studies and crossover trials are excluded. Acupuncture often targets points related to the reproductive system, such as Guan Yuan (CV4), Zu San Li (ST36), and San Yin Jiao (SP6). Each session lasts 20-30 minutes and occurs 2-3 times weekly. The overall treatment duration spans 2-4 weeks[5].

The main indicators of the chosen tests are encapsulated in the Table 1 below: Various acupoints exhibit distinct therapeutic effects[5-9]. Acupuncture at the Guan Yuan (CV4) and Zhong Ji (RN3) points significantly enhances blood circulation. This method can increase local blood flow to the uterus, thereby improving embryo implantation rates. Furthermore, stimulating the Shen Que (RN8) point during ovulation can enhance endometrial receptivity. The Zu San Li (ST36), Xue Hai (SP10) and San Yin Jiao (SP6) primarily regulate internal organ functions. Targeting these points post-transplantation aids in stabilizing the fetal element.

Table 1 Key indicators and analysis of clinical studies.

Index	Unit	Sample size	Trial population	Acupoint selection	Controls	Results
Pregnancy rate	Ataturk University of Erzurum, Turkey	72	The mean age of infertile women undergoing IVF was 30.9 years ± 3.7 years	First stage: H7, GV20. Second stage: CV3, GV20, 1IV3, ST30, SP8. Third stage: LI4, SP6, ST36	Insert the needle to a depth of 1 to 2 inches. Keep it for 30 minutes	CPR increased. The pregnancy rate was 63.9% in the acupuncture group and 33.3% in the control group
Success rate of IVF	Medical University of Shiraz, Iran	186	Women undergoing IVF treatment	HT7, PC6, RN6, DU20, SP6, RN4	Electroacupuncture	Significantly increase the success rate of IVF and improve the CPR
Oocyte quality	Shandong University of Chinese Medicine	60	Elderly women undergoing IVF	RN12, RN4, DU20, KI3, BL23, SP6, LR3, ST25, BL32	Insert the needle 10-30 mm, once every ten minutes, and stay for 30 minutes before each removal	Effectively improve the quality of female oocytes and improve the pregnancy outcome of IVF-embryo transfer
Planting rate	Faculty of Medicine of ABC, Clinic for Human Reproduction, Santo André, São Paulo, Brazil	84	Infertile patients who have had at least two failed IVF treatment	BL18, BL22, BL23, BL52, CV3, CV4, CV5, CV7, GV4	Combine acupuncture with moxibustion	The pregnancy rate in the acupuncture group was 35.7%, significantly higher than the 71% in the control group and 10.7% in the sham acupuncture group
Mental state	Ataturk University of Erzurum, Turkey	72	Infertile women with an average age of 30.9 years ± 3.7 years who underwent IVF	First stage: H7, GV20. Second stage: CV3, GV20, 1IV3, ST30, SP-8. Third stage: LI4, SP6, ST-36	Insert the needle to a depth of 1 to 2 inches. Allow it to remain in place for 30 minutes	Relieve anxiety and stress before embryo transfer and improve the probability of embryo transfer success

CPR: Clinical pregnancy rate; IVF: In vitro fertilization.

Different stimulation methods have different curative effects. Traditional acupuncture uses twisting, lifting and thrusting to treat acupoints. A large number of studies have consistently shown that traditional acupuncture has significant effects on enhancing endometrial receptivity, improving egg quality and improving embryo implantation rate. Studies by Li Jing and other scholars have shown that spindle is positively correlated with oocyte quality, and electroacupuncture (EA) can improve oocyte quality and CPR in polycystic ovarian syndrome (PCOS) patients receiving IVF-ET. For improving pregnancy rates, research by Qu et al[6] suggests that transcutaneous electrical acupoint stimulation can help improve IVF outcomes in part by increasing neuropeptide Y levels in follicular fluid. EA combines traditional acupuncture with micro-current stimulation to increase stimulation intensity and promote local blood circulation. EA before and after embryo transfer can reduce endometrial blood flow index and resistance, improve local uterine blood supply, increase endometrial thickness, and thus increase embryo implantation rate. Ear acupuncture stimulates specific points in the ear, affecting the function of the viscera and meridians throughout the body. This method is easy to use and has few side effects. Although its application in ART is limited, studies have shown that it can reduce patients' anxiety, pain, and support embryo implantation[6,7].

Different interventions also affect the results of the experiment. Among the included literatures, 15 studies using acupuncture and sham acupuncture showed that acupuncture had certain effects on enhancing endometrial receptivity, improving egg quality, and promoting embryo implantation, but the difference was not significant compared with sham acupuncture[8]. Studies have shown that even fake acupuncture can elicit a certain effect, which is often attributed to the psychological comfort it provides, the natural response of the nervous system, or the body's inherent self-repair capabilities[10]. Acupuncture can assist the reproductive process by regulating the neuroendocrine system, enhancing blood supply to the ovaries and uterus, and regulating uterine movement[9,11]. But some of these mechanisms may also be present in fake acupuncture. Contrary to the negligible differences observed between acupuncture and sham acupuncture approaches, the outcomes of acupuncture versus unassisted treatment revealed significant disparities. Specifically, when compared to unassisted treatment, acupuncture has demonstrated more pronounced benefits within the realm of ART. The majority of the trials lacked sufficient documentation of adverse effects, or reported adverse effects[12].

Fundamental research: Based on the pre-defined inclusion and exclusion criteria, we thoroughly searched the electronic databases of PubMed and Web of Science for relevant literatures.

Figure 1B provides a visual representation of the trial screening process.

Table 2 summarizes the main information of the fundamental researches included in this review[8,13-16].

Table 2 Basic information of included fundamental researches.

Nature of acupuncture	Number of participants (intervention/control)	Age (intervention/control)	Control	Acupuncture points	Time of acupuncture/frequencies/cycles	Outcomes	Ref.
TA	40 (20/20)	32.65/31.20	No adjuvant treatment	LR3, SP6, CV4, SP10, ST36	30 minutes/2 days/between the time of menstruation and the simulated transplantation day	Endometrial thickness, ndometrial typing, Pulsatility index, Resistance index, Peak systolic velocity/diastolic velocity, expression of endometrial receptor-related factors, expression of key molecules and gene expression of the AMP-activated protein kinase/mammalian target of rapamycin pathway, CPR, embryo implantation rate	Qi et al[13]
TA	12 (6/6)	31/27.5	No adjuvant treatment	CV4, ST36, SP6, BL23, BL32	30 minutes/2 days/two menstrual cycles during in vitro fertilization and embryo transfer	CPR, endometrium thickness, identification, functional analysis and validation of differentially expressed genes, competing endogenous RNA network	Cheng et al[14]
TA	62 (20/20/22 in the young control group)	37.70/37.27/29.83	Routine ovulation induction combined with sham acupuncture	RN4, SP6, EX-CA1	30 minutes/3 times a week until the day of human chorionic gonadotropin injection	The score of kidney qi deficiency syndrome, the 2 pronuclei fertilization rate, HQER and CPR	Xia et al[8]
EA	76 (38/38)	28.4/29.2	Pseudo-acupuncture	RN12, ST25, SP15, GB26, CV6, CV4, SP10, ST40, ST36, SP9	25 minutes/twice a week until the day of oocyte collection/3 menstrual cycles	The phlegm-dampness syndrome. Score, the index of rigidity scores, the number of oocytes retrieved, CPR, transplantable embryo rate;, HQER, live birth rate, expression of insulin receptor substrate-1, PI3K and GLUT4 mRNA	Xiang et al[15]
EA	66 (33/33)	31.76/33.73	Placebo needle puncture	CV3, CV6, ST29, SP6, LI4/Th12–L2, S2–S4	25 minutes duration/2days/3 menstrual cycles	CPR, oocyte retrieval, Fertilization, HQER, expression of PI3K, protein kinase B, Forkhead box o3 mRNA	Wu et al[16]

CPR: Clinical pregnancy rates; EA: Electroacupuncture; HQER: High-quality embryo rate; PI3K: Phosphatidylinositol-3-kinase; TA: Traditional acupuncture.

In particular, with the exception of one solitary study in which participants with an average age of more than 35 years were enrolled, the majority of the studies involved subjects in the age range of 25 years to 35 years. All trials employed acupuncture as a therapeutic intervention for embryo transfer in women undergoing IVF-ET. Regarding the control mechanisms, 2 trials refrained from incorporating adjuvant treatment controls[13,14], whereas the remaining 3 trials used sham acupuncture as the control method[8,15,16]. Additionally, 2 trials administered EA[15,16], while 3 trials opted for traditional acupuncture techniques[8,13,14]. The frequency of acupuncture sessions varied, with some trials providing treatment two times or three times a week or on alternate days. The duration of each session ranged from 25 minutes[15,16] to 30 minutes[8,13,14], and the intervention was applied continuously for 2 menstrual cycles to 3 menstrual cycles. In contrast to the clinical trials, the fundamental trials included in this analysis delved deeper into specific mechanisms underlying the clinical efficacy. Specifically, three trials centered on elucidating expression pathways, one investigated the whole transcriptome[14], and another explored metabolomics[8]. Moreover, no significant adverse effects were noted during all the study periods.

Studies reveal that EA enhances embryo quality and pregnancy rates due to its intricate mechanisms. EA stimulates the central secretion of β-endorphin, impacting the gonadotropins (Gn) RH pulse generator and promoting the release of Gn and steroid hormones. It also downregulates the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box o3 (Foxo3a) signaling pathway in ovarian granulosa cells, creating a more favorable environment for oocyte maturation and minimizing abnormal follicular development, thus increasing pregnancy success rates[16]. In contrast, pharmacological interventions typically employ ovulation-stimulating agents, such as Gn, to enhance follicular development. Additionally, they utilize human chorionic gonadotropin to facilitate ovulation and boost conception rates. While these medications are effective in promoting follicular maturation and increasing the likelihood of pregnancy, they may also give rise to certain side effects, such as ovarian hyperstimulation syndrome (OHSS).

In PCOS patients, EA upregulates insulin receptor substrate-1 and PI3K gene expression, enhancing glucose metabolism and improving insulin sensitivity in the ovaries, which elevates oocyte and embryo quality[8]. This personalized treatment approach for insulin resistance patients effectively enhances insulin sensitivity while minimizing medication use.

Acupuncture therapy also significantly impacts mRNA and non-coding RNA expression, regulating various biological processes and augmenting pregnancy rates in IVF-ET patients[14]. By targeting specific acupoints, acupuncture fine-tunes oocyte quality by adjusting metabolic pathways, benefiting patients with age-related kidney energy deficiencies[8]. When combined with intrauterine physiotherapy, acupuncture at key acupoints enhances energy metabolism, promotes autophagy, and improves endometrial health. This upregulation of endometrial receptivity-related genes further boosts embryo implantation and CPRs, highlighting the significant potential of EA and acupuncture in assisted reproduction. While, pharmacological interventions typically enhance endometrial receptivity through hormone supplementation, such as estrogen and progesterone. While these medications are effective in increasing endometrial thickness and improving blood flow, prolonged use may lead to potential side effects, such as thrombosis.

Systematic review and meta-analysis: To systematically assess the impact of acupuncture on ART regarding embryo transfer, we conducted a comprehensive search of PubMed and Web of Science.

The main characteristics of included reviews and meta-analysis are presented in Table 3[5,17-22].

Table 3 Characteristics of included reviews and meta-analysis.

Ref.	Number of studies (total sample)	Nature of acupuncture	Control	Time of acupuncture	Outcomes
Manheimer et al[17]	16 (4012)	TA/EA	No adjuvant treatment or sham acupuncture	Before and after ET	CPR/LBR
Wang et al[18]	7 (516)	MA/AA/TEAS/EA	No adjuvant treatment	During COH, during ET	CPR/ET
Gu et al[5]	31 (4450)	TA/EA/AA/TEAS/LA	No adjuvant treatment or sham acupuncture	During COH, during ET	CPR/BRP/OPR/MR
Zhu et al[19]	14 (1130)	TA/EA/TEAS	No adjuvant treatment or sham acupuncture	Before and after frozen-thawed embryo transfer	CPR/BRP/LBR/ET/endometrial pattern
Qian et al[20]	30 (6344)	TA/EA/LA/AA	No adjuvant treatment or sham acupuncture	During COH, during ET	BPR/CPR/LBR/OPR
Xie et al[21]	27 (6166)	MA/EA/AA/TA	No adjuvant treatment or sham acupuncture	Before and after ET	CPR/LBR
Smith et al[22]	20 (5130)	MA/EA/LA/TEAS/dry needling	No adjuvant treatment or sham acupuncture	Before and after ET	CPR/LBR/OPR/MR

AA: Auricular acupuncture; BRP: Biochemical pregnancy rate; CPR: Clinical pregnancy rate; COH: Controlled ovarian hyperstimulation; EA: Electrical acupuncture; ET: Endometrial thickness; LA: Laser acupuncture; LBR: Live birth rate; MA: Manual acupuncture; MR: Miscarriage rate; OPR: Ongoing pregnancy rate; TA: Traditional acupuncture; TEAS: Transcutaneous electrical acupoint stimulation.

The six included reviews were published in English, span from 2013 to 2023[17-22]. This review analyzed 145 original RCTs involving 27748 participants. The cohort comprised women undergoing IVF-ET and those utilizing ICSI as part of their IVF protocols. We focused exclusively on RCTs applying acupuncture interventions administered before and after IVF, specifically including sessions on the day of embryo transfer, aiming to enhance assisted conception outcomes and improve IVF success rates. Women in the intervention group received acupuncture alongside IVF-ET. In contrast, the control group received IVF without acupuncture or underwent sham (placebo) acupuncture.

In regard to study design, we excluded non-randomized studies and crossover studies because of limitations in the duration of the intervention.

In respect of interventions, 3 reviews used traditional acupuncture as the primary intervention[17,19,20], all reviews used EA[17-22], 3 reviews used transcutaneous electrical stimulation interventions[18,19,22], and the remaining reviews also used hand acupuncture, auricular acupuncture, laser acupuncture and other interventions. Wang et al[18] used no treatment as a control group, while other reviews used sham acupuncture or no adjuvant treatment.

The primary outcome measure for evaluating the role of acupuncture in assisted embryo transfer is the CPR, and secondary measures include LBR, ongoing pregnancy rate (OPR) and biochemical pregnancy rate (BPR).

The analysis of the included articles revealed no statistically significant advantage of acupuncture treatment in terms of OPR and LBR when compared to the control group. Nevertheless, four studies indicated that the intervention group exhibited significantly elevated rates of high-quality embryos in comparison to the control group, accompanied by elevated implantation rates. A meta-analysis comparing the fertilization rate of the acupuncture plus controlled ovarian hyperstimulation (COH) treatment group with that of the COH treatment group alone revealed a significantly higher fertilization rate in the former. Furthermore, 31 included trials yielded clinical pregnancy outcomes, and 11 trials reported live birth outcomes. Acupuncture was observed to have a positive effect on LBRs. The extent to which acupuncture enhanced CPR and improved endometrial tolerance varied according to the length of treatment. A total of 3 reviews referenced adverse events, including mild allergy, nausea, somnolence, dizziness, and fatigue. While the remaining reviews did not report any serious adverse events[18,19,22].

The data analysis revealed that the overall CPR was markedly elevated in all acupuncture cohorts compared to the control group [relative risk (RR): 1.21, 95%CI: 1.07-1.38, P = 0.01]. However, the combined LBR did not exhibit a similar increase, with notable statistical heterogeneity observed across the studies. Furthermore, acupuncture-assisted frozen-thawed embryo transfer (FET) demonstrated a significant enhancement in the outcomes related to BPR (RR: 1.51, 95%CI: 1.21-1.89, P = 0.03) and endometrial pattern (RR: 1.41, 95%CI: 1.13-1.75, P = 0.01). Meta-regression subgroup analyses indicated that the efficacy of acupuncture was particularly pronounced in groups where the proportion of repeat IVF cycles was ≥ 50%, a covariate that may account for some of the observed heterogeneity.

Meanwhile, compared with other acupuncture time, the IVF outcome results were significantly superior in the acupuncture group when acupuncture was conducted during COH (RR: 1.71, 95%CI: 1.27–2.29, P = 0.0004). The integration of acupuncture with COH therapy significantly elevated implantation rates (RR: 2.13, 95%CI: 1.08-4.21, P = 0.03) and increased endometrial thickness (RR: 0.54, 95%CI: 0.13-0.96, P = 0.01). The findings of this study indicate that acupuncture may enhance the CPR in contrast to the absence of adjunctive therapy. Nonetheless, no significant benefit of acupuncture was observed when compared to the sham control group. Furthermore, the quality of evidence presented in this review varied from low to moderate, generally reflecting low quality.

Patent search results

We have systematically examined 37514 patents from the inception of the database to the present (Figure 2). Applying strict inclusion and exclusion criteria, 65 patents were ultimately selected for analysis. Notably, Han et al’s research team from Peking University made the most significant contributions[23]. The included patents can be categorized according to their technical fields and applications into: (1) Acupuncture stimulation device category; (2) Implantable acupuncture system category; (3) Non-invasive neural stimulation category; (4) Wearable stimulation equipment category; (5) Electrical stimulation treatment equipment category; (6) TCM drug combination category; and (7) Acupoint pressure stimulation patch category, etc.

Figure 2  Date distribution.

Acupuncture prescriptions: As a traditional Chinese medical practice, acupuncture has demonstrated its unique value and potential in the field of ART. By promoting local blood circulation and regulating the endocrine system, acupuncture helps create a more favorable uterine environment for embryo implantation. It contributes to enhancing uterine blood flow and endometrial thickness, thereby increasing the success rate of embryo implantation[24]. Acupuncture prescription devices, as described in specific patents, typically involve the intelligent input of electrical pulse parameters or transcutaneous stimulation via a motor, using Bluetooth communication to stimulate particular acupoints before and after embryo transfer[25].

Studies have shown that stimulation of specific acupoints can improve endometrial receptivity, enhance embryo implantation rates, and increase CPRs[23]. Furthermore, from the perspective of modern medicine, acupuncture has the advantages of being non-invasive and having fewer side effects. However, the precise mechanisms through which acupuncture influences embryo transfer still require further scientific investigation. More research is needed to explore the effects of different acupoints and acupuncture methods on embryo transfer interventions, in order to determine the most effective treatments and provide patients with more personalized and effective therapeutic options.

Other intervention strategies for embryo transfer: During the process of embryo transfer, the scientific validity and efficacy of various stimulation methods for intervention have been substantiated. Based on the standard inclusion of patent-related data, the commonly used stimulation methods can be categorized as follows. Acupoint electrostimulation is a method that uses electrical stimulation of acupoints to reduce discomfort during oocyte retrieval and improve the outcome of embryo transfer[26]. This method has been shown to effectively alleviate discomfort during oocyte retrieval and enhance the success of embryo transfer. The mechanism primarily involves improving endometrial receptivity, regulating the endocrine system, reducing stress responses and pain, and promoting local blood circulation. According to current experimental data, patients undergoing acupoint electrostimulation have a significantly higher number of pinopodes compared to the control group, though the subjectivity in selecting the electrical current frequency introduces some risk factors. Additionally, mild ovarian stimulation protocols have gradually gained acceptance in recent years, particularly for infertile patients of advanced age or those with poor ovarian response. These protocols use low doses of Gn to stimulate ovulation, and case studies of live births achieved through mild stimulation and natural cycle FET suggest that reducing the dosage of Gn to improve embryo quality may be one of the contributing factors to success[27]. With the development of embryo culture and freezing techniques, frozen embryo transfer is gradually being used in routine ART regimens. It has been found that frozen embryo transfer not only reduces the risk of severe OHSS, but may also increase pregnancy rates and improve neonatal outcome[28,29].

Conclusively, while various stimulation methods show potential for boosting embryo transfer success, further investigation is crucial to clarify optimal conditions and underlying mechanisms. This work will ultimately aid in creating tailored and effective treatment protocols.

DISCUSSION

Acupuncture and associated therapeutic modalities: Key attributes of treatment

Acupuncture serves as a non-invasive, supplementary treatment method with minimal side effects and has demonstrated efficacy in enhancing pregnancy rates during IVF-ET. Traditional acupuncture stimulates specific acupuncture points to access meridians, thereby raising endometrial tolerance. In contrast, EA employs a micro-electric current to intensify stimulation at these acupoints, promoting the release of hormones like Gn and steroid hormones. While auricular acupuncture is less frequently utilized in assisted reproduction, it is user-friendly, well-accepted by patients, and effectively modulates the body's internal organs and meridians. This technique has been shown to relieve stress, anxiety, and depression by suppressing sympathetic nerve activity in the uterine center.

In conclusion, acupuncture enhances pregnancy success rates by increasing local blood flow, moderating the neuroendocrine system, and establishing a uterine environment more conducive to embryo implantation.

Clinical and foundational studies based on acupuncture-assisted therapy

Preliminary experimental findings indicate that acupuncture enhances embryo quality and increases pregnancy rates to some extent. The underlying mechanisms are intricate. Acupuncture triggers the central release of β-endorphin, influencing the GnRH pulse generator and thereby modulating gonadotropin and steroid hormone levels. Specifically, concerning sex hormones, evidence shows that acupuncture notably lowers FSH levels[30]. Clinical research found that decreased FSH levels and active regulation of baseline endocrine levels in patients with POR can enhance pregnancy rates. While this effect may also occur with some sham acupuncture, since the nervous system response does not rely solely on acupoint stimulation.

Available research indicates that ovarian reserve and uterine conditions significantly influence pregnancy outcomes. EA can downregulate the PI3K/Akt/Foxo3a signaling pathway in ovarian granulosa cells. This downregulation fosters a more conducive environment for oocyte maturation and reduces abnormal follicular development. Furthermore, acupuncture stimulates aromatase activity, positively modulates the reproductive axis, enhances neuropeptide Y production, and improves local ovarian blood flow. A total analysis of 72 RCTs reveals that acupuncture enhances endometrial receptivity, egg quality, and embryo implantation rates in participants, thereby substantiating acupuncture's efficacy in increasing pregnancy rates[31,32].

In addition, different acupuncture strategies, timing and frequency of acupuncture may be important factors influencing efficacy. It has been suggested that increasing the frequency of acupuncture improves uterine blood flow, increases serum cortisol and prolactin, and improves IVF pregnancy outcomes[33]. Current studies regarding this assertion primarily present correlation analyses (Figure 3). Further clinical trials remain necessary to validate these findings.

Figure 3  Correlation.

Applications of patents relevant to acupuncture: ART

Acupuncture plays a pivotal role in enhancing reproductive outcomes by influencing the neuroendocrine system, particularly the hypothalamus-pituitary-ovarian axis. It improves blood flow to the ovaries and uterus while modulating uterine contractions. Recent patents highlight a refined ovarian stimulation protocol, demonstrating acupuncture's significance in assisted reproductive techniques, particularly for older infertile individuals or those exhibiting diminished ovarian response. Furthermore, evidence suggests that minimizing discomfort during oocyte retrieval may correlate with higher rates of successful embryo transfers. The underlying mechanisms of acupuncture's efficacy, as noted in these patents, involve enhancing endometrial receptivity, increasing localized blood flow, and mitigating stress responses and pain (Table 4).

Table 4 Patents relating to acupuncture treatment for embryo transfer.

Category	Patent ID	Title	Assignee	Inventor	Priority date	Publication date	Grant date
Non-invasive Neurostimulation Category	US-11534600-B2	Non-invasive nerve stimulation to treat or prevent autism spectrum disorders and other disorders of psychological development	Electrovore, Inc	Simon BJ, Errico JP, Raffle JT	2009-03-20	2022-12-27	2022-12-27
Wearable Stimulation Device Category	US-11413294-B2	Monolithic intravaginal rings comprising progesterone and methods of making and uses thereof	Ferring BV	Ahmed SU, Tsao JX, Mahashabde A, Harrison DD	2020-01-31	2020-12-31	2022-08-16
Implantable Acupuncture Electrostimulation System Category	US-8965511-B2	Implantable electroacupuncture system and method for reducing hypertension	Valencia Technologies Corporation	Greiner JH, Peterson DKL, Thenuwara C	2011-08-30	2015-02-24	2015-02-24
Acupuncture Stimulation Device Category	CN-202376635-U	Acupoint stimulation apparatus used for increasing extracorporeal fertilization-embryo transplantation pregnancy rate	Han JS, Sun W, Zhang R	Han JS, Sun W, Zhang R, Ma XJ	2011-11-03	2012-08-15	2012-08-15

Different acupuncture techniques, timings, and frequencies yield varying influences on pregnancy outcomes. Therefore, it is essential to evaluate each patient’s circumstances to design a treatment strategy effectively. The acupuncture prescription device detailed in the patents allows for intelligent input of electrical stimulation parameters, thereby supporting the creation of customized protocols. The ability to accurately identify acupuncture points through Bluetooth technology exemplifies the harmonious integration of contemporary medical practices with technological advancements, holding promise for further evolution within the healthcare landscape.

Limitations

The primary limitation of this review lies in the considerable heterogeneity observed across the studies, the underlying causes of which remain unclear. There are currently no universally accepted therapeutic reference standards for acupuncture treatment protocols or for the selection of acupuncture points. Both ancient and contemporary literature on acupuncture distinctly highlight that the needling of specific points can potentially lead to miscarriage. Furthermore, the frequency, duration, and modality of stimulation during acupuncture treatment may influence its efficacy, an aspect we have not investigated in depth. Additionally, variations in acupuncture techniques may result in differing clinical outcomes and subtleties, contributing to the observed heterogeneity. These discrepancies persisted even with the application of a random-effects model. Another notable limitation is the omission of non-English language databases in our search, which may have resulted in the exclusion of relevant studies. The paucity of specifically targeted works of literature could be another limitation. Moreover, some types of reporting bias cannot be excluded in this review, such as publication bias, language and regional bias, which may lead to limitations, making it difficult to obtain accurate results.

Implications for future research

Future research should delve deeper into the correlation between pregnancy rates and the effectiveness of adjunctive acupuncture, as well as investigate the variables that contribute to varying outcomes. From a TCM standpoint, the selection of acupuncture points ought to be tailored to the unique signs and symptoms presented by each individual. With additional clinical studies anticipated in the future, we aim to establish the parameters for optimal acupuncture practices and further clarify the impact of acupuncture on IVF results. Our analysis indicates that acupuncture is advantageous for women with a history of IVF failure, and conducting long-term follow-ups with patients, along with a comprehensive analysis of aggregated patient data, will be instrumental in uncovering the true influence of these parameters on the effectiveness of acupuncture in relation to IVF outcomes.

CONCLUSION

The quality of evidence regarding the effects of acupuncture on pregnancy outcomes in IVF-ET varies. Existing patents and literature indicate that acupuncture holds considerable promise within ART, especially during embryo transfer, while the likelihood of severe adverse effects remains minimal. Nonetheless, additional clinical trials are essential to evaluate the efficacy of acupuncture in enhancing embryo transfer success.

ACKNOWLEDGEMENTS

The authors would like to express their profound gratitude to all contributors included in the RCTs for their efforts in identifying and supplying pertinent data related to their respective studies.