DOI: https://doi.org/10.21203/rs.3.rs-2059117/v1
Background: Tubal obstruction is the leading cause of infertility. Acupuncture and Chinese herbal medicine (CHM) are widely used in treating tubal obstruction infertility (TOI), and clinical research is increasing. However, there is still controversy about its efficacy and safety. This systematic review aimed to assess the efficacy and safety of acupuncture and CHM in treating TOI.
Methods: We searched eight databases to collect randomized controlled trials comparing Hydrotubation with Acupuncture combined with CHM from inception to July 31, 2022. A total of 1580 papers were collected, and the methodological quality of the included trials was assessed in line with the criteria of the Cochrane risk of the bias assessment tool. In the end, only 18 randomized clinical trials met the requirements and were included.
Results: Meta-analysis showed that acupuncture and CHM was associated with a higher pregnancy rate [RR 1.74, 95% CI (1.54, 1.95), P < 0.00001] and a lower ectopic pregnancy rate [OR 0.61, 95 % CI (0.19, 1.92), P＜0.0001]. The success rate of tubal recanalization was significantly improved with acupuncture combined with CHM treatment[RR 1.37, 95 % CI (1.20, 1.57), P＜0.0001], and signs and symptoms were better relieved [OR 3.44, 95 % CI (2.22, 5.33), P＜0.00001].
Conclusions: This meta-analysis suggests that acupuncture and CHM can be used as complementary therapies to treat tubal obstructive infertility with better outcomes than Hydrotubation.
Common causes of female infertility include ovulatory dysfunction (e.g., PCOS), damaged or blocked fallopian tubes, endometriosis, and uterine fibroids [1], among which tubal patency is abnormal due to tubal blockage, adhesions, etc. The resulting infertility is called Tubal Obstructive Infertility(TOI) [2], accounting for 11–67% of female infertility.[3][4]
As the primary infertility factor, tubal infertility seriously affects women's reproductive health and quality of life. Western medicine mainly adopts surgical methods to treat TOI, such as hysteroscopy, laparoscopy, and other minimally invasive techniques to mechanically dredge the fallopian tubes, to achieve the effect of loosening adhesions. Although the minimally invasive technique has an apparent curative effect, minor trauma, and short treatment time, once the fresh wound of the fallopian tube mucosa is infected, it will easily lead to re-adhesion, obstruction, and the possibility of inflammatory lesions. Although Assisted Reproductive Technologies(ART) have primarily solved the problem of tubal infertility, the pregnancy rate has not improved clinically, from about 29–35% [5]. There are also adverse reactions such as miscarriage, ectopic pregnancy, and ovarian hyperstimulation, which are unsuitable for promotion.
Given the above phenomenon, there have been a large number of clinical research reports that Traditional Chinese Medicine has significant curative effects in the treatment of tubal obstructive infertility, such as eliminating chronic inflammation, reducing edema, restoring tubal function, and improving pregnancy rate, and has the advantages of less trauma, low cost, and high patient compliance[6]. Although there are many reports on controlled clinical trials of acupuncture combined with Chinese herbal medicine (CHM) in the treatment of tubal obstructive infertility, there is no systematic review of these trials in China and abroad, and it is difficult to determine an appropriate evidence-based treatment plan. Therefore, we conducted this study to evaluate the potential therapeutic effect of acupuncture combined with CHM in treating tubal obstructive infertility.
This study was conducted by the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement.[7]
Databases including the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), VIP information database, Wanfang Data Information Site, and Chinese Biomedical Database (CBM) were searched from inception to July 31, 2022. We also manually searched conference proceedings, reference lists of relevant articles, and reviewed articles to obtain additional relevant data. The following search terms were used for searching databases: ("infertility, female" or "female infertility" or "subfertility") and ("fallopian tube diseases" or "tubal obstruction" or "fallopian tubal obstruction") and ("Chinese herbal drugs" or "Chinese herbal medicines" or "oriental herbal medicine" or "medicine, East Asian traditional" or "traditional Chinese medicine" or "medicine, Kampo") and ("acupuncture" or "moxibustion" or "point, acupuncture" or "acupoints" or "electroacupuncture" or "warming needle" or "auricular acupressure" or "auricular points") and ("randomized controlled trial" or "randomized" or "Placebo" or "RCT" ).
In this review, only RCTs were eligible for inclusion, comparing the efficacy and safety of acupuncture and CHM versus fallopian tube hydrotubation for TOI.
A woman diagnosed with TOI was eligible for this research. (1) At least one year of regular sexual intercourse without contraception and male infertility;(2) The woman has not become pregnant, or a woman fails to conceive one year or more after a previous pregnancy; (3) infertility caused by oviduct obstruction can be identified with congested Oviduct under hysterosalpingogram (HSG), hysteroscopy, laparoscopy, or liquid flow under ultrasound hysterosalpingography.
This study compares acupuncture combined with CHM and hydrotubation. In this review, Chinese medicine includes herbal decoctions, powder, and capsules. Acupuncture included body acupuncture and a warming needle. Interventions of the specific herbs and acupoints in the prescriptions should be provided. The control group interventions were Hydrotubation, which includes conventional hydrotubation, hysteroscopic hydrotubation, laparoscopic tubal correction with hydrotubation, and intervention therapy with hydrotubation and antibiotic drugs, with or without TCM treatment.
The Primary outcome was the pregnancy rate. It is a positive urine or blood pregnancy test. Intrauterine pregnancy should be identified with intrauterine gestational sac Or fetal heartbeat by ultrasound. The Secondary outcome was tubal recanalization, and we defined the effectiveness of treatment as successful tubal recanalization or improvements detected by hysterosalpingography, hysteroscope, laparoscope, or ultrasound. The tertiary outcome was Relief of clinical symptoms and signs. The integration method was applied to determine the total effects in alleviating the signs and symptoms.
We conducted the selection process through EndNote X7 software, a tool that allows multiple people to log in simultaneously. Thus, two review authors (HTT, XHM) independently screened studies by title and abstract to evaluate whether a study met the inclusion and exclusion criteria. We resolved disagreements by involving a third review author (LYX). We drew a PRISMA flow diagram to show the search results and the numbers of included and excluded trials. For all included trials, two review authors (HTT, XHM) independently extracted data using a data abstraction form and summarized trial characteristics in tables. From each included study, two review authors (HTT, XHM) derived baseline characteristics of TOI females, types of interventions (acupoints, drugs, doses), and outcomes. We intended to contact the study investigators for further data on methods and results if required. The criteria of Cochrane’s risk of bias assessment tool[8] evaluated the bias risks of included articles. Two evaluators were designated to assess the reports in terms of the following items by giving the results of “high," “low," and “unclear" independently: (1) Generation of random sequence; (2) Allocation concealment; (3) Blind method implementation to the researchers and subjects; (4) Blind method implementation to the outcome index evaluation; (5) Data integrity; (6) Selective report of study results; (7) Other bias sources.
Analyses were performed using Revman 5 statistical software provided by Cochrane collaboration. We used the relative risk (RR) for enumeration data. If the incidences were low, we used the odds ratio (OR) and estimated the corresponding 95% confidence interval (CI). The Chi-square test was used to measure heterogeneity. We used the fixed effects meta-analysis modeling if between-study heterogeneity was not observed. In the presence of between-study heterogeneity, we analyzed the quality of the methodology, the age of patients, the time of follow-up visits, and the sample size of the trial to find the factors affecting heterogeneity, excluded trials of statistically significant differences, and did sensitivity analyses. If no factors were identified, we used the random effects meta-analysis modeling.
In this review, 1580 relevant articles were retrieved. After importing all the studies into EndNote X7 software, 863 duplicate studies were excluded. By screening, titles, and abstracts of the remaining 33 records, 830 articles were excluded because of ineligibility, such as case reports, case series, traditional reviews, commentary articles, animal experiments, or not rigorously designed RCTs. Fifteen of the remaining 33 studies were excluded by examining the body texts. Among them, two articles had no relevant outcome; 13 studies didn't meet the inclusion of Intervention. Finally, 18 studies were selected for meta-analysis. (Fig. 1)
This review included 18 RCTs.[9–26]All of them were single-center studies, including women, 837 in trial groups and 786 in control groups. All the available data compared acupuncture and CHM versus hydrotubation for TOI(table-1).
All the incorporated documents were randomly allocated, and all the trials were considered a low risk of selection bias. All the included trials did not mention allocation concealment and were rated as unclear risk of bias. Ten studies provided information on blind methods and were assessed as having a “high” risk of bias. [9–11, 13–16, 22–23, 25–26]. During treatment and follow-up, 18 trials did not report exclusion or loss and were rated low risk. The protocols of included studies have not been published, and all experiments have not been registered, which we judged as an unclear risk of bias. We found no potential within-study bias in the 18 documents and rated them low risk (Fig. 2 and Fig. 3).
Eighteen trials[9–26] reported pregnancy rates which were categorical data. Between-study heterogeneity was tested (X² = 10.80, P = 0.87). No factors that cause heterogeneity were found through analysis. We then used fixed effects modeling for meta-analysis. The results indicated that compared with hydrotubation (with or without TCM treatment), Acupuncture combined with CHM was associated with higher pregnancy rates [RR 1.74, 95% CI (1.54, 1.95), P༜0.00001] (Fig. 4). The asymmetry funnel plot(Fig. 5) showed publication bias.
Sixteen trials[9–10, 12–14, 16–26] reported the conditions of tubal recanalization. Heterogeneity was observed (x² = 21.76, P = 0.11). No factors that cause heterogeneity were found through analysis. We then used fixed effects modeling for meta-analysis. The results indicated that Acupuncture combined with CHM is more effective than hydrotubation. [RR 1.37, 95% CI (1.20, 1.57), P༜0.00001] (Fig. 4).
Six trials[17, 19, 20, 22, 25–26] reported the relief of signs and symptoms, which were categorical data. No significant heterogeneity was observed (x² = 5.54, P = 0.35), we then used fixed effects modeling for meta-analysis. The results suggested that Acupuncture combined with CHM can better relieve the signs and symptoms than hydrotubation. [OR 3.44, 95% CI (2.22, 5.33), P༜0.00001] (Fig. 4).
Among the 18 trials mentioned above, three reported cases of ectopic pregnancy [11, 21, 23], which were categorical data. No significant heterogeneity was observed (x² = 0.04, P = 0.98); we therefore used fixed effects modeling for meta-analysis. The results showed that hydrotubation was associated with a higher incidence of ectopic pregnancy compared with Acupuncture combined with CHM [OR 0.61, 95% CI (0.19, 1.92), P = 0.40] (Fig. 4).
In this study, we searched all the data about acupuncture combined with Chinese medicine for infertility caused by tubal obstructive and retrieved 33 relevant studies. Eighteen randomized controlled trials were included, involving 1623 patients. The results indicated that:(1) Compared with hydrotubation, acupuncture combined with CHM for tubal obstructive infertility was associated with a higher pregnancy rate, better tubal recanalization, and better relief of signs and symptoms. (2) The incidence of ectopic pregnancy was lower using acupuncture combined with CHM than with hydrotubation for infertility caused by tubal obstruction. This study suggests that there is a prospect for acupuncture combined with CHM in the treatment of infertility caused by tubal obstruction. Slight abdominal pain was observed during and after the operation, and recovery from the pain was achieved in a week without special treatment. No noticeable side effects were detected after drinking decoction, applying Chinese medicine externally, or by enema. Slight allergies in local areas were alleviated without any treatment. No abnormal changes were seen on lab test indexes (blood and urine routine examination) or type-B ultrasonic probe with pelvic cavity before and after the administration.
Although the Acupuncture points and CHM selected in these 18 articles are not the same, we can still find more commonly used herbs and acupoints in them. The following twelve acupoints have been used in more than five (including five) studies, including Zigong(EX-CA1), Zhongji(RN3), Qihai(RN6), Sanyinjiao(SP6), Guanyuan(RN4), Shenshu(BL23), Zusanli(ST36), Xuehai(SP10), Taichong(LR3), Ganshu(BL18), Ciliao(BL32), Mingmen(DU4). The following eight herbs had been most frequently used in more than five (including five) studies, including Danggui(Angelica Sinensis), Chishao(Radix Paeoniae Rubra), Baizhu(Atractylodes macrocephala), Dangshen(Codonopsis pilosula), Gancao(liquorice), Danshen(Salvia miltiorrhiza), Lulutong(Fructus liquidambaris), Baijiangcao(Herbal patriniae).
The evidence of Acupuncture and CHM for TOI includes the following aspects: (1)Improving the hemodynamics of the ovary and uterus. A study showed that Chinese herbal medicine treating salpingitis obstructive infertility could effectively improve the hemodynamic rheological indicators of the uterus and ovary. In this study, the hemorheological indexes of the rats in the tubal obstructive infertility model in the experimental group were significantly lower than those in the western medicine group treated with cefuroxime and metronidazole. Another study showed that acupuncture combined with traditional Chinese medicine in treating salpingitis obstructive infertility could inhibit the expression of sICAM-1 protein, effectively improve hemorheological indicators, and promote the absorption and dissipation of inflammation. [27][28](2)Regulating immunity. A study confirmed that acupuncture could effectively increase the levels of β-endorphins in rats' peripheral blood and hypothalamus[29]. In regulating the female gonadal axis, β-endorphin, an endogenous opioid peptide, is a universal messenger of the nervous, endocrine, and immune systems and plays a crucial role in neuromodulation and maintaining the stability of the body's internal environment[30]. Domestic studies have also shown that acupuncture can regulate the endocrine system, stimulate ovarian function, and acupuncture can promote the absorption of inflammation. It has incomparable advantages for dredging the fallopian tubes, promoting the combination of sperm and egg, and improving the pregnancy rate[31]. (3)Regulates the hypothalamic-pituitary-ovarian axis. It has been reported at home and abroad that traditional Chinese medicine treatment can effectively improve women's ovarian function and increase the natural conception rate[32] [33]. A meta-analysis showed that treatment with CHM significantly reduced FSH levels in women[34], and another study showed that Danggui Buxue decoction had estradiol activity in vitro[35].
The limitations of the included studies in this meta-analysis are as follows: Firstly, the methodological quality was low due to the lack of description of blinding in most of the included studies. Blinding is necessary to prevent study results from being influenced by placebo effects or observer bias[36]. However, in the related research on acupuncture, it is difficult to apply the blind method to the patient because acupuncture needs to be implemented on the patient. In addition, traditional Chinese medicine formulations are mainly decoctions, which can be better differentiated from clinical drug capsules or placebos. In conclusion, it is challenging to achieve double-blindness in the clinical application of acupuncture combined with traditional Chinese medicine. Secondly, pregnancy and live birth rates are clinical trials' most reliable efficacy indicators for infertility. These two indicators are closely related to patients and have tremendous clinical significance. However, the live birth rate requires long-term follow-up of all patients. Unfortunately, none of these articles have data on live birth rates. Thirdly, most of the studies included in this meta-analysis used inconsistent acupuncture points and herbal decoctions. In traditional Chinese medicine, combining different acupoints and herbs will lead to other effects, and factors such as the preparation of the herbs and the method of decoction will affect the therapeutic effect. Therefore, we did not select specific acupoints or traditional Chinese medicines, and we believe that the review's conclusions are general. Finally, there are irregularities in the evaluation criteria for symptom relief, and the results largely depend on the patient's subjective evaluation. Therefore, a larger, high-quality, multicenter RCT should be performed.
The data included are published reports, excluding any grey literature (workshop proceedings, unpublished reports, presentations, and evidence from unconventional sources) and ongoing research. We only analyzed published studies, so unpublished studies with negative results may be missed. Therefore, the efficacy indicators may not reflect the actual situation. All included RCTs were conducted in China, which may lead to publication bias and affect the validity and reliability of this systematic review.
JAMA recommends that HSG (Hysterosalpingography) be used in diagnosing TOI to identify the site of obstruction, followed by surgical repair (e.g., hysteroscopy with tubal cannulation for proximal tubal obstruction, tubal re-anastomosis, or fimbrioplasty for distal obstruction) or IVF. Although surgical treatment can restore tubal patency in the short term and increase the odds of pregnancy in women with TOI, it also increases the risk of infection and lumen adhesions postoperatively[37].
In some Asian countries, acupuncture and CHM are commonly used in TOI as a complementary and alternative therapy. Although acupuncture and traditional Chinese medicine can increase the pregnancy rate and improve the degree of tubal blockage, there is a lack of high-level evidence-based medical research. Therefore, further studies on the efficacy and safety of acupuncture and CHM in treating TOI are encouraging and promising. However, doctors tend to choose acupoints and herbs based on the syndrome differentiation theory (a key concept in TCM), which leads to subjectivity in selecting acupoints and herbs. At the same time, the non-uniform diagnosis and treatment standards will also affect the objective evaluation of the curative effect. Therefore, in the future, it is necessary to urge standardized diagnosis and treatment, explore more appropriate treatment methods, and establish a standardized TOI treatment system in traditional Chinese medicine.
Based on the current clinical data, we can confirm that acupuncture combined with traditional Chinese medicine is an effective alternative therapy for the treatment of tubal obstructive infertility and has good results in improving pregnancy rate, tubal recanalization rate, and symptom relief. In particular, the occurrence of ectopic pregnancy is also relatively rare. However, an evaluation of the literature according to strict randomization, double-blind, and follow-up found that the quality of the evidence was low, and the evidence for the therapeutic effect of acupuncture combined with traditional Chinese medicine was insufficient. Therefore, future research may consider focusing on well-designed authoritative studies with rigorously conceived, randomized, and controlled trials to provide conclusive evidence and re-evaluate effects.
Competing interests
The authors declare that they have no conflict of interests.
Authors' contributions
Funding
not applicable
Availability of data and materials
The authors declare that all the meta-analysis data supporting the findings of this study are available within the article.
Table 1 is available in the Supplementary Files section