| BackgroundPoor Ovarian response(POR)is a pathological condition in which the ovaries are unresponsive to gonadotropin(Gn)stimulation.Decreased ovarian responsiveness to Gn is an important aspect of clinical pregnancy rates.POR usually leads to poorer pregnancy outcomes,severely affecting the physical and psychological health of patients and threatens the stability of the family and social harmony.POR is currently a therapeutic challenge in the field of assisted reproduction at present.In order to improve the reproductive outcome of in vitro fertilization(IVF)of POR patients,western medicine usually uses drugs for pretreatment before ovulation promotion,but there is no sufficient evidence to prove that a drug intervention can improve the treatment outcomes of POR patients.In recent years,some studies have shown the efficacy of acupuncture in increasing the number of sinus follicles,the number of retrieved oocytes,the number of high-quality embryos,and improving ovarian reserve function in POR patients,but the number of relevant modern studies is small,the quality of studies is variable,and there is no systematic compilation of the current state of clinical research in this area.To sum up,this study first conducted a scoping review on acupuncture treatment of POR to fully evaluate the progress of clinical research status on acupuncture for POR and to find the value and direction of clinical research or systematic of acupuncture and moxibustion treatment of POR.On this basis,a multi center case registry study on acupuncture for POR was carried out to analyze the clinical characteristics of POR patients and evaluate the clinical efficacy of acupuncture treatment of POR in the real world.At the same time,a multi-center randomized controlled study on acupuncture treatment of POR was carried out to evaluate the effectiveness and safety of acupuncture treatment of POR.Literature research evidence,real-world research evidence and RCT evidence were complementary to each other,in order to provide detailed and reliable evidence-based medical evidence for acupuncture treatment of POR.Objective1 To systematically sort out the current status of research on acupuncture for POR.2 To analyze the clinical characteristics of POR patients in the real world,and preliminarily explore the effect of acupuncture alone in the real world on ovarian function and pregnancy outcome of POR patients.3 To evaluate the effect of acupuncture on the number of eggs retrieved in the ART cycle,and further explore the effect of acupuncture in improving ovarian function and pregnancy outcome of POR patients.Method1 The scoping review of clinical studies on the treatment of acupuncture for patients with poor ovarian responseGuided by the methodological framework proposed by Arksey and O’Malley and 2021 update version of the Australian Joanna Briggs Institute’s handbook,this study collected clinical research literature on acupuncture and moxibustion treatment of POR through computer system retrieval of relevant databases.The articles were screened and data were extracted according to the inclusion criteria.The clinical studies on acupuncture and moxibustion treatment of POR were qualitatively summarized by using statistical description methods.The descriptive analysis was carried out by using statistical charts and tables combined with frequency,rate and composition ratio.The clinical research status of acupuncture and moxibustion treatment of POR was generally described,and the quality of the systematic evaluation and randomized controlled trials was evaluated.Finally,according to the PRISMA ScR statement issued by the PRISMA working group in 2018,the clinical research evidence of acupuncture and moxibustion treatment of POR was reported.2 A Patient registry study of acupuncture for poor ovarian responseThis study was a case series study based on real world multi-center case registry data.Based on the international acupuncture case registration data collection system,this study has set broad inclusion and exclusion criteria.The acupuncture protocol recommended by the World Federation of acupuncture and moxibustion Societies and the Premature Ovarian Failure Project Team of the Case Registration Research Alliance of the Chinese acupuncture and moxibustion Society was the basic scheme.At the same time,doctors can add or subtract treatment protocols according to clinical practice,and collect diagnosis and treatment data of real world POR patients,The effect of acupuncture alone on ovarian function and pregnancy outcomes in POR patients were evaluated.The primary outcome was the number of retrieved oocytes in COH cycle,and the secondary outcomes were ovarian function index\ART-related outcomes,ART-related index,SAS score and kuppermann score.3 A multicenter randomized controlled trial on acupuncture for poor ovarian responseAll the participants were recruited in 9 sub-centers from March 2018 to October 2022.The eligible participants were randomly assigned to acupuncture group and control group in a ratio of 1:1 using the central randomization system.The patients in the acupuncture group were treated with acupuncture for 12 weeks before COH.Patients in the control group waited for 12 weeks before COH.The efficacy evaluators and statistical analysts were blinded.The primary outcome was number of retrieved oocytes,and the secondary outcomes was the number/rate of fertilization,the number/rate of cleavage,the number/rate of available embryos,the number/rate of high-quality embryos,clinical pregnancy rate,abortion rate,live birth rate,and the SAS score.Results1 The scoping review of clinical studies on the treatment of acupuncture for patients with poor ovarian response(1)Literature search resultsA preliminary search of the Chinese and English databases yielded 536 studies,and 28 papers were finally included for analysis.(2)Basic study informationThe research type of acupuncture and moxibustion for POR is mainly randomized controlled trials(21 articles).27 are studies conducted in China,and 1 in South Korea.The first study of acupuncture for POR was published in 2009.The funding source is mainly from national level funds(11 articles),and there are also 6 articles that do not mention whether there is funding.The total sample size included in the study was 1891,with a randomized controlled trial sample size ranging from 23 to 120 cases.Single center studies accounted for 80.95%;The sample size of the observational study was 30-158 cases,all of which were single center studies.(3)Specific information of 24 clinical studies(RCT+observational studies)Of the 24 clinical studies included,23 focused on the effectiveness and safety of acupuncture in improving ovarian function,pregnancy outcome and assisted reproduction related indicators in patients with POR,and the remaining one was a non-efficacy study.Twenty-one studies reported the average age of the patients with POR,61.90%of the patients were over 35 years old.Sixteen studies reported the infertile years of patients with POR,62.50%reported that the infertile years of patients were between 3-5 years.21 studies reported the basal FSH level of POR patients before treatment,and 76.19%reported that the basal FSH level of patients before treatment was greater than 10mIU/ml.Twelve studies adopted the Bologna consensus as the diagnostic criteria.Seven studies reported TCM syndrome types,of which 5 included patients with kidney deficiency.Of the 24 clinical studies included,45.83%were treated with TEAS or TEAS combined with traditional Chinese medicine or western medicine;33.33%of the research treatment protocol were acupuncture alone,including 4 hand acupuncture and 4 electric acupuncture.At the time of intervention,8 research started acupuncture in the natural menstrual period before COH,5 research started after the end of the natural menstrual period before COH,9 reports only started before COH.In the course of intervention,58.33%of the study courses were 3 menstrual cycles.In the selection of acupoints,22 studies reported specific acupoints,of which Sanyinjiao,Guanyuan,Zigong,Shenshu,Tianshu were the most frequently used.22 studies set up controls,90.48%of which were single controls,of which 14 were blank controls.The outcome measures mainly included ovarian reserve function indicators,endometrial receptivity indicators,ART-related indicators,improvement of traditional Chinese medicine syndromes,follicular fluid related indicators,negative emotion scale scores,menstrual status and VAS scores.A total of 8 studies reported safety indicators and there are no economic indicators for evaluation.(4)Risk assessment of bias in randomized controlled trialsThe risk bias of 21 randomized controlled trials included was evaluated.The results showed that 12 studies used the random number table method as the generation method of random sequence,8 studies only mentioned random grouping but did not describe the specific generation method of random sequence,and 1 study used random lottery.The 4 items report the distribution concealment method,and all use sealed opaque envelopes.One study was blinded to researchers and subjects during the experiment.Two studies blinded the outcome evaluators.Nine studies reported the number of subjects dropped off or lost in each group during the treatment.There was no significant difference in the number of missing cases between the two groups,and the other studies did not report data loss.All studies reported the pre-determined outcome indicators.2 A Patient registry study of acupuncture for poor ovarian response(1)Study completion and physician informationFrom October 2017 to January 2023,a total of 299 cases of POR were recorded.After screening,268 cases were included,including 268 cases of clinical symptom characteristics analysis,and 124 cases of effective cases whose intervention measures were acupuncture alone.A total of 31 doctors participated,distributed in 24 hospitals in 17 cities and 14 provinces across the country,with an average age of 39.94 ± 8.87 years,and an average length of service of 9.32 ± 4.32 years.The proportion of master’s degree and attending doctor is relatively large,and the participating hospitals are mainly public tertiary hospitals.(2)Demographic characteristics of POR patientsThe average age of 268 patients included in the study was 41.81 ± 5.61 years old.70.15%of the patients were over 40 years old and were married.The proportion of Han nationality is the largest and the proportion of people with bachelor’s degree or above is 50.37%.(3)Clinical characteristicsOf the patients who came to the clinic,58.21%(156/268)came for infertility.The average age of menarche is 13.08 ± 2.03 years old,the overall menstrual cycle is 28.00[5.00]days,and the average menstrual period is 4.72±1.58 days.56.72%of patients had normal menstruation,and 49.80%of patients had low menstrual volume.Of the 268 patients with POR,191 had a history of pregnancy and childbirth,with an average number of pregnancies of 2.31±1.41.Among the pregnant POR patients,47.12%had a history of abortion,The basic FSH level of 268 patients with POR was 15.94[17.56]IU/L,and the FSH level of 50%patients was between 10 IU/L-25 IU/L;FSH/LH was 2.68[1.70],and 80.53%of patients had FSH/LH greater than 2;AMH was 0.33[0.48]ng/ml,and 92.62%of patients had AMH less than 1.10 ng/ml;AFCs were 2.00[2.00],and 64.05%of patients had AFCs between 1-3.(4)Analysis of therapeutic effect of acupuncture alone on the treatment outcome of patients with POROf the 124 effective cases in which the intervention was acupuncture alone,a total of 71 cases had recorded assisted reproduction-related indicators.Three POR patients with a 1-month course of treatment received more than 3 eggs after treatment,of which one was clinically pregnant and had no live birth.Four POR patients with a 2-month course of treatment had more than 3 eggs obtained after treatment,including 2 clinical pregnancies and 1 live birth.Eight POR patients with a 3-month course of treatment had more than 3 retrieved eggs,including 2 clinical pregnancies and 1 live birth.One POR patient with a course of treatment of 4 months and a number of retrieved eggs greater than 3 after treatment,including one clinically pregnant and without live birth.The overall mean number of available embryos and high-quality embryos in 124 POR patients were 1.66±1.22 and 1.07±1.10,respectively.With the increase of the course of treatment,the number of available embryos and high-quality embryos had an increasing trend.After the treatment,the pregnancy rate of 124 patients with POR was 19.35%(24/124),of which the natural pregnancy rate was 7.26%(9/124),the IVF pregnancy rate was 12.10%(15/124),and the live birth rate was 8.06%.The overall basal FSH level at the end of treatment in the 1-month POR patients was 11.23[11.78]IU/L,which was not statistically significant compared with that before treatment(P>0.05).The overall basal FSH level at the end of treatment in the 2-month POR patients was 11.41[6.61]IU/L,which was significantly different from that before treatment(P<0.05).The overall basal FSH level at the end of treatment in the 3-month POR patients was 10.25[5.19]IU/L,which was significantly different from that before treatment(P<0.05).The overall basal FSH level at the end of treatment in POR patients with 4 months of treatment was 15.5[6.33]IU/L,which was significantly different from that before treatment(P<0.05).The percentage of FSH reduction to normal(10 IU/L)after different courses of treatment was 10.81%,13.89%,19.57%,and 20.00%,respectively.The overall basal LH level at the end of treatment in POR patients with a 1-month course of treatment was 4.28[5.50]IU/L,which was not statistically significant compared with the pre-treatment level(P>0.05).The overall basal LH level of POR patients with 2 months of treatment was 4.88[2.72]IU/L at the end of treatment,which was significantly different from that before treatment(P<0.05).The overall basal LH level of POR patients with a 3-month course of treatment at the end of treatment was 4.22[3.00]IU/L,which was significantly different from that before treatment(P<0.05).The overall basal LH level of POR patients with a course of 4 months at the end of treatment was 6.22[27.35]IU/L,which had no significant difference compared with that before treatment(P>0.05).The total FSH/LH of POR patients with a course of treatment of 1 month was 2.29[0.01]at the end of treatment,and there was no statistically significant difference compared with that before treatment(P>0.05).At the end of treatment,the total FSH/LH of POR patients with 2 months of treatment was 2.63[1.66],and there was no statistically significant difference compared with that before treatment(P>0.05).The total FSH/LH of POR patients with a 3-month course of treatment was 2.64[1.33]at the end of treatment,and there was no statistically significant difference compared with that before treatment(P>0.05).The total FSH/LH of POR patients with a 4-month course of treatment was 2.00[1.72]at the end of treatment,which was significantly different from that before treatment(P<0.05).After different courses of treatment,the proportion of FSH/LH decreased to normal(<2)was 10.81%,13.89%,19.57%and 20.00%respectively.The overall basal E2 level at the end of treatment in POR patients with a 1-month course was 157.30[164.91]pmol/L,which was significantly different from that before treatment(P<0.05).The overall basal E2 level at the end of treatment in POR patients with a 2-month course of treatment was 157.30[164.91]pmol/L,which was significantly different from that before treatment(P<0.05).The overall basal E2 level at the end of treatment in POR patients with a 3-month course was 157.30[164.91]pmol/L,which was significantly different from that before treatment(P<0.05).The overall basal E2 level at the end of treatment in the POR patients with a 4-month course was 227.54[273.84]pmol/L,which was not statistically significant compared with the pre-treatment level(P>0.05).The overall number of AFCs at the end of treatment in POR patients with a 1-month course was 2.00[3.00],which was significantly different from that before treatment(P<0.05).The overall basal E2 level at the end of treatment in POR patients with a 2-month course of treatment was 3.00[2.00],awhich was significantly different from that before treatment(P<0.05).The overall basal E2 level at the end of treatment in POR patients with a 3-month course was 3.00[2.00],which was significantly different from that before treatment(P<0.05).The overall basal E2 level at the end of treatment in POR patients with a 4-month course of treatment was 4.00[3.00],which was significantly different from that before treatment(P>0.05).The percentage of increase in AFC after different courses of treatment compared to pre-treatment was 56.77%,58.33%,73.91%,and 60.00%,respectively.The average SAS score of POR patients with a course of treatment of 1 month at the end of treatment was 41.8 1 ± 6.44,which was significantly different from that before treatment(P<0.05).The average SAS score at the end of treatment of POR patients with a course of 2 months was 41.14±4.99,which was significantly different from that before treatment(P<0.05).The average SAS score of POR patients with a 3-month course of treatment at the end of treatment was 41.91 ± 3.01,which was significantly different from that before treatment(P<0.05).The average SAS score of POR patients with a course of treatment of 4 months at the end of treatment was 41.91± 3.01,which had no significant difference compared with that before treatment(P>0.05).As the course of treatment increases,the proportion of Kupperman scores returning to normal shows an increasing trend.The average Kupperman score at the end of treatment for POR patients with a course of treatment of 1 month was 11.00[14.00],which was significantly different from that before treatment(P<0.05).The average Kupperman score at the end of treatment for POR patients with 2 months of treatment was 8.00[7.00],which was significantly different from that before treatment(P<0.05).The Kupperman score of POR patients with a 3-month course of treatment was 8.00[7.00]at the end of treatment,which was significantly different from that before treatment(P<0.05).The Kupperman score of POR patients with 4 months of treatment was 3.50[5.00]at the end of treatment,and there was no statistically significant difference compared with that before treatment(P>0.05).As the course of treatment increases,the proportion of Kupperman scores returning to normal shows an increasing trend..(5)Safety analysisAmong the 124 patients included in the analysis,3 patients reported subcutaneous hematoma after acupuncture,and 1 patient reported foreign body sensation after acupuncture,all of which were related to acupuncture.The symptoms were relieved after hot compress and rest,and no serious adverse events occurred.3 A multicenter randomized controlled trial on acupuncture for poor ovarian response(1)Research completionA total of 148 subjects meeting the criteria were included in this study,of which 6 were not returned to the hospital after randomization,and there was no relevant information.13 patients had no data after baseline or did not receive acupuncture treatment in the acupuncture group.Therefore,129 patients were finally included in the mITT set,including 65 in the acupuncture group and 64 in the control group.6 cases fell off in the acupuncture group(1 case changed the ovulation promotion plan,1 case lost the follow-up,4 cases abandoned the tube treatment),and 16 cases fell off in the control group(1 case developed other diseases,2 cases lost the follow-up,2 cases changed the ovulation promotion plan,3 cases withdrew the informed consent,3 cases directly transplanted without taking the eggs,5 cases abandoned the IVF).(2)BaselineThere was no significant difference between the two groups in terms of age,height,weight and other demographic characteristics,as well as age at menarche,number of pregnancies,number of abortions,family history,surgery history,treatment history,comorbidities and previous pregnancy assistance(P>0.05).(3)Number of retrieved oocytesAt baseline,there was no significant difference in the number of retrieved oocytes between the two groups(P>0.05),which was comparable.The difference between acupuncture group and control group before and after treatment was statistically significant(P<0.05).At the end of treatment,there was no significant difference between the two groups(P>0.05).The proportion of the number of retrieved oocytes in the acupuncture group increased from the baseline was 47.54%(29/61),which was higher than the proportion of the number of eggs captured in the blank group was 37.5%(23/59).There was no statistical difference between the two groups(P>0.05).(4)Ovarian functionAt baseline,there was no significant difference between the two groups in the basic FSH,LH and E2 levels(P>0.05),which was comparable.There was no significant difference between acupuncture group and control group before and after treatment(P>0.05).At the end of treatment,there was no significant difference between the acupuncture group and the control group in the basic FSH,LH and E2 levels(P>0.05).At baseline,there was no significant difference in the number of basic AFCs between the two groups(P>0.05),which was comparable.There was no significant difference between the acupuncture group and the blank group before and after treatment(P>0.05).After treatment,there was no significant difference in the number of AFC between the two groups(P>0.05).After 3 months of treatment,the number and proportion of AFC increased in the acupuncture group was 27 cases(41.54%),higher than that in the blank group(18 cases(28.13%).There was no statistically significant difference between the groups(P>0.05).(5)IVF-related indicatorsAfter treatment,there was no significant difference between the two groups in he clinical pregnancy rate and live birth rate(P>0.05).After treatment,there was no significant difference in the number of fertilization,fertilization rate,cleavage number,the number/rate of available embryos and the number/rate of high-quality embryos between the two groups(P>0.05).After treatment,the cleavage rate of the acupuncture group was 100%,higher than that of the control group(87.29%),and the difference between the two groups was statistically significant(P<0.05).(6)SAS scoreAt baseline,there was no significant difference in SAS scores between the two groups(P>0.05),which was comparable.The difference before and after treatment was statistically significant in the acupuncture group(P<0.05),and no significant difference was seen before and after treatment in the control group(P>0.05).At the end of treatment,there was no significant difference in SAS scores between the two groups(P>0.05).(7)Adverse eventsThe acupuncture group reported 3 adverse events,including 1 participant with infection after tooth extraction,1 participant with new herpes zoster during the study,and 1 participant with hysteroscopy and polypectomy during the study,which were not related to acupuncture.No adverse events were reported in the control group.Conclusions1 The scoping review showed that clinical studies of acupuncture for POR started late and the number of studies was small,but the overall trend was on the rise,with a variety of acupuncture treatment protocols and greater heterogeneity in the timing and duration of interventions.The research quality was not high,which affected the credibility of the research results and limited the dissemination and use of evidence.And there was a lack of basic research on acupuncture for POR.2 The case registry study showed that POR patients were older and came to the hospital mainly due to infertility.Most of them had a history of pregnancy,childbirth,and previous treatment.The ovarian reserve function was low,and the actual acupuncture treatment protocols were diverse.3 The case registry study showed that acupuncture could reduce the abnormal FSH,LH level and FSH/LH ratio of POR patients,increased E2 level and AFC number,and improved the adverse mood and menopausal symptoms.4 The randomized controlled study showed that acupuncture improved the cleavage rate and dysphoria in POR patients.Compared with the control group,there was no significant difference in improving the number of oocytes retrieved,basic sex hormone level,sinus follicle count,clinical pregnancy rate,live birth rate,abortion rate,fertilization number/rate,cleavage number,available embryos number/rate,and high-quality embryos number/rate.However,the number of oocytes increased from the baseline,the number of AFC increased from the baseline,clinical pregnancy rate,live birth rate and high-quality embryo rate in acupuncture group had an increasing trend compared with the control group,suggesting that acupuncture might have potential therapeutic effects. |
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