| BackgroundDiminished Ovarian Reserve(DOR)refers to a decrease in the number or quality of eggs retained in the ovary,clinically manifested by a decrease in Antral Follicle Count(AFC),elevated Follicle Stimulating Hormone(FSH)levels and Anti-Mullerian Hormone(AMH).FSH levels are elevated and Anti-Mullerian Hormone(AMH)is reduced.Epidemiological evidence shows that the prevalence of DOR has increased from 19%in 2004 to 26%in 2014 and is increasing,placing an emotional and financial burden on infertility patients and families.For patients with DOR who have a need for fertility,active fertility testing or assisted reproductive technology(ART)is often encouraged,with different ovulation regimens and pretreatment medications such as dehydroepiandrosterone and growth hormone used during the treatment cycle.The use of different ovulation regimens and pretreatment drugs such as dehydroandrosterone and growth hormone during the treatment cycle is often encouraged,but the efficacy of these methods is inconclusive.Clinical practice and research on the treatment of DOR with TCM has been increasing year by year in recent years,especially with acupuncture,which has a diverse range of therapeutic approaches and significant efficacy in improving clinical symptoms of DOR,but the level of evidence from clinical studies is insufficient and has not been widely promoted.Although Randomized Controlled Trials(RCTs)are the accepted standard for evaluating interventions,the ideal conditions for such clinical trials are far removed from the real-world medical environment due to the more restricted population included in RCTs,resulting in higher internal veracity of study results but poorer external veracity and limited promotion of clinical applications.Compared to RCTs,Real World Studies(RWS)are more likely to yield evidence-based evidence that is close to clinical reality.In this study,to assess the clinical efficacy of acupuncture in the treatment of DOR,an RCT was used to confirm the ’efficacy’ of acupuncture in the treatment of DOR,combined with an ’ffectiveness study’ of acupuncture in the treatment of DOR in a real-world medical setting to form a sufficient A "chain of evidence" is used to confirm and validate the pregnancy outcomes,clinical efficacy and associated influences of acupuncture for DOR.Finally,a pregnancy prognosis model for patients with DOR treated with acupuncture will be constructed based on real-world treatment information to assist physicians in making personalised clinical decisions for their patients.Study objectivesTo assess the clinical efficacy of acupuncture for the treatment of patients with DOR by regulating menstruation and promoting pregnancy;and to construct a predictive model of clinical pregnancy to provide evidence to support clinical application and clinical decision making.Study methods1 Menstrual regulation and promotion of pregnancy by acupuncture for the treatment of hypovarian reserve function:a randomised controlled studyUsing a prospective,parallel,randomised,blinded clinical study design,120 patients with DOR were recruited and subjects were randomised into the acupuncture group(treated with the Menstrual Regulating and Promoting Pregnancy method of acupuncture)and the sham acupuncture group(treated with superficial sham acupuncture)in a 1:1 ratio via a central randomisation system.Subjects in both groups were treated for a total of 36 sessions and the treatment lasted for a total of 3 months.The primary outcome indicators were the change in AFC at the end of treatment and the secondary outcome indicators were the change in AMH levels,FSH,LH,FSH/LH ratio,E2 and the clinical pregnancy rate,live birth rate and miscarriage rate.2 Evaluation of the efficacy of acupuncture in regulating menstruation and promoting pregnancy in the treatment of hypovarian reserve function:a multicentre case registry study(1)Based on multicentre case registry data,combined with data mining techniques,the clinical characteristics of DOR patients were analysed:demographic,etiological characteristics,menstrual characteristics,core symptoms and treatment protocols.(2)Based on a multicentre case registry study,the patients were divided into acupuncture and acupuncture-drug groups according to whether the exposure factors were combined with drugs.The primary efficacy index was clinical pregnancy rate,and secondary efficacy indexes were live birth rate,miscarriage rate,AFC,AMH,FSH,LH,FSH/LH ratio,E2.Influencing factors were screened by group,number of acupuncture sessions(12 sessions/unit),cumulative acupuncture time(1 month/unit),and age,and Beta values and 95%confidence intervals were calculated.3 Prediction model development and validation of acupuncture for pregnancy prediction in hypovarian reserve functionA comprehensive statistical and computational model of the data was constructed by a supervised machine learning algorithm,selecting logistic regression,random forest,plain Bayesian and neural network,to construct a DOR acupuncture pregnancy prediction model and perform comparative performance analysis.ROC curve and P-R curve tests were used to assess the calibration of the prediction models,and discriminant accuracy was reported by AUC values as well as specificity,sensitivity and positive predictive values.Study results1 Menstrual regulation and promotion of pregnancy method of acupuncture for hypovarian reserve function:a randomised controlled studyA total of 120 patients with DOR were included in this study,and 12 cases were shed during treatment,representing a shed rate of 10.0%.Of these,2 patients withdrew informed consent after randomization,so that 118 patients with DOR were finally included in the ITT set:59 in the acupuncture group and 59 in the sham acupuncture group.1.1 Baseline characteristicsThere was no statistical difference between the two groups in terms of demographic information such as age,body mass index,menstrual history,past history,treatment history and ovarian function assessment(P>0.05).1.2 Main efficacy indicatorsAFC levels changed from baseline by 2.20(1.52,2.87)in the acupuncture group and 1.54(0.76,2.33)in the sham acupuncture group after treatment,with both groups of DOR subjects having significantly higher AFC levels after treatment compared to baseline(P<0.0001);the difference between the two groups was 2(-1.5,3.5),with the acupuncture group having a better improvement in AFC after treatment than the sham acupuncture group(P=0.019).1.3 Secondary efficacy indicatorsEffect of acupuncture on AMH in patients with DOR:AMH levels changed by 0.13(0.00,0.38)in the acupuncture group and 0.07(-0.04,0.36)in the sham acupuncture group after treatment compared to baseline,and AMH levels improved in both DOR groups after treatment compared to baseline(P<0.0001,P=0.002),but the difference between groups was not statistically significant(P=0.721).Effect of acupuncture on FSH in DOR patients:FSH levels changed by 4.39(-5.58,-3.20)from baseline in the acupuncture group and 0.07(-0.04,0.36)in the control group after treatment,with a significant reduction in FSH levels from baseline in both groups of DOR subjects after treatment(P<0.0001,P=0.008).The difference between the two groups was-0.46(-4.98,2.59),with better improvement in FSH after treatment in the acupuncture group than in the sham acupuncture group(P=0.046).Effect of acupuncture on LH in patients with DOR:LH levels changed 0.74(-0.13,1.50)from baseline in the acupuncture group and 0.17(-0.50,0.86)in the control group after treatment,with both groups of DOR subjects showing an improvement in LH levels from baseline after treatment(P<0.0001);the difference between the two groups was 0.46(-1,73,2.35),and the between-group The difference between the two groups was 0.46(-1,73,2.35),with no statistically significant difference between the groups(P=0.759).Effect of acupuncture on FSH/LH in DOR patients:FSH/LH levels changed-1.69(-1.74,-0.11)in the acupuncture group and-0.76(-1.75,-0.11)in the sham acupuncture group after treatment compared to baseline;FSH/LH levels improved in both DOR subjects after treatment compared to baseline(P<0.0001,P=0.026),but the difference between the two The difference between the two groups was not statistically significant(P>0.05).Effect of acupuncture on E2 in DOR patients:E2 levels changed-1.69(-1.74,-0.11)in the acupuncture group and-0.76(-1.75,-0.11)in the sham acupuncture group after treatment compared to baseline.statistically significant(P>0.05).Effect of acupuncture on pregnancy outcomes in patients with DOR:Pregnancies in patients with DOR were statistically analysed using Poseidon age stratification.For women aged≥35 years,there was a significant difference in the clinical pregnancy rate between the acupuncture and sham acupuncture groups(21.82%vs 7.55%,P=0.033)and no difference in the live birth and miscarriage rates(P=0.060,P=0.970);for women aged<35 years,there was no significant difference in the clinical pregnancy,live birth and miscarriage rates between the two groups(7.27%vs 7.55%,P=0.476;7.27%vs 7.55%,P=0.476;7.27%vs 5.66%,P=0.735).1.4 Safety evaluationOne case of haematoma and one case of dizziness occurred in the acupuncture group during treatment;the haematoma resolved on its own after 3 days;the dizzy patient improved the next day after rest.There were no adverse reactions in the sham acupuncture group.There were no serious adverse reactions such as infection,organ damage and nerve damage in both groups.2 Evaluation of the efficacy of acupuncture in regulating menstruation and promoting pregnancy in the treatment of hypovarian reserve function:a multicentre case registry study2.1 Clinical characteristics of patients with DORThe RWS study showed that patients with DOR are clinically insidious,diverse and progressive in development;DOR patients are predominantly elderly,married women;idiopathic factors account for 84.8%of DOR pathogenesis,followed by medical factors;59.6%of patients have normal menstrual cycles,followed by premenstruation(15.8%)and amenorrhoea only accounts for 5.7%;in terms of menstrual flow,it is mainly menstrual flow The core symptoms of DOR patients are night sweats-hot flushes-fatigue-chilliness-poor sleep-depression-infertility;the treatment plan is based on complex interventions,with acupuncture The treatment plan is based on complex interventions,with acupuncture points highly focused on the points that regulate menstruation and promote pregnancy.2.2 Evaluation of the efficacy of acupuncture for regulating menstruation and promoting pregnancy in patients with DOR:a multicentre case registry study(1)Baseline situationThe mean age of DOR patients was 39.0 ± 5.9 years,98.1%of patients were married,60.5%of patients had university or higher education,the mean age of menarche was 13±1 years,and the mean duration of disease was 30[12,61]months;55%of DOR patients had a history of pregnancy and childbirth,47.6%had a history of miscarriage;8.1%of patients had a history of acupuncture treatment,29.9%of patients had a history of herbal treatment,12.4%had a history of HRT treatment,and 29.7%had a history of ART treatment;patients had a mean FSH of 13.3[9.9,15.4]IU/L,a mean LH of 4.7[3.2,6.2]IU/L,a mean FSH/LH ratio of 2.56[2.0,3.5],a mean E2 of 36[24,58]pg/ml,mean AMH of 0.57[0.26,0.90]ng/ml and mean AFC of 4[2,5].There was no difference in age,marriage,education,ethnicity,occupation,age at menarche,duration of illness,history of pregnancy and delivery,and history of miscarriage between the acupuncture and acupuncture-medicine groups(P>0.05).(4)InterventionsThe median frequency of acupuncture in DOR patients was 8(3,11)acupuncture sessions/month,the median number of acupuncture sessions was 17(12,34),the duration of acupuncture was 31-60 minutes in 59%of the patients,82%of the patients did not adjust the acupuncture points for regulating menstruation and promoting pregnancy,26.3%of the patients received moxibustion and 1.3%of the patients received auricular pressure bean treatment.There was no difference between the acupuncture group and the acupuncture and medicine group in terms of frequency/month and number of acupuncture sessions(P>0.05).In terms of frequency/month,the acupuncture and medicine group had more frequent acupuncture sessions than the acupuncture group(P=0.006).(5)Clinical pregnancy,live birth and miscarriage ratesThe overall clinical pregnancy rate in this study was 36.9%(139/377),with a spontaneous pregnancy rate of 13.5%(51/377)and an in vitro pregnancy rate of 23.3%(88/377);a live birth rate of 20.4%(77/377),with a spontaneous live birth rate of 6.6%(25/377)and an in vitro live birth rate of 13.8%(52/377);and an abortion rate of The miscarriage rate was 13.8%(52/377),of which 6.9%(26/377)were spontaneous abortions and 6.9%(26/377)were in vitro abortions.In the acupuncture group,the clinical pregnancy rate was 36.7%(99/270),the live birth rate was 21.9%(59/270)and the miscarriage rate was 13.0%(35/270);in the acupuncture group,the clinical pregnancy rate was 37.4%(40/107),the live birth rate was 16.8%(18/107)and the miscarriage rate was 15.9%(17/107).There was no difference in the clinical pregnancy rate,live birth rate and miscarriage rate between the two groups(P>0.05).However,the in vitro pregnancy rate and in vitro live birth rate were higher in the acupuncture group than in the acupuncture-medicine group(P=0.031,P=0.025),and the spontaneous pregnancy rate and spontaneous miscarriage rate were higher in the acupuncture-medicine group than in the acupuncture group(P=0.002,P=0.005).Factors influencing the clinical pregnancy rate of DOR treated with acupuncture were further explored:age was independently negatively correlated with patient pregnancy(P<0.001)and AFC was independently positively correlated with patient pregnancy(P<0.001).(4)Efficacy of ovarian function-related indicatorsFSH,E2 and AFC were statistically significant(P<0.05)compared with those before treatment,suggesting that the menstrual regulation and promotion method was able to improve the FSH,E2 and AFC levels of the patients.Subgroup analysis showed that the efficacy of the needle and medicine group on FSH,LH and FSH/LH was better than that of the acupuncture group at 1 month of treatment or≥12 months of treatment.Further analysis of the effect of acupuncture on ovarian function revealed that the intervention method(acupuncture,acupuncture and medicine)and the number of acupuncture sessions(12 sessions/unit)were independent influencing factors for FSH and AFC(P<0.05),and the cumulative duration of acupuncture(1 month/unit)was positively correlated with FSH(β=0.28,P<0.001),suggesting that for every 12 sessions increase in the number of acupuncture sessions,FSH decreased by 0.3 mIU/mL;1.20(0.58,1.83)AFCs were gained after acupuncture or acupuncture-medicine treatment;0.21(0.04,0.38)AFCs were gained for every 12 additional acupuncture sessions.3 Prediction model development and validation of acupuncture for pregnancy with reduced ovarian reserve function(1)Selection of predictor variablesThe predictor variables were identified by Spearman correlation test and feature engineering:age,history of herbal treatment,history of acupuncture treatment,baseline FSH,baseline AMH,baseline AFC,post-treatment FSH,post-treatment LH,post-treatment FSH/LH,post-treatment AFC.(2)Training set,validation set divisionThe 377 included DOR subjects were randomly divided into training set,validation set according to 7:3.Age,history of acupuncture treatment,baseline AMH,baseline AFC,post-treatment LH,post-treatment FSH/LH ratio,and post-treatment AFC were statistically significant(P<0.05)when comparing the two groups of DOR patients.In the validation cohort,age,acupuncture treatment history,and post-treatment AFC were statistically significant(P<0.05)when comparing the two groups of DOR patients.(3)Model construction and validationThe random forest model had the highest AUC of 0.99,ACC value of 0.95,and the best F β value of 0.93,with the lowest Logloss value of 0.30,achieving the highest accuracy and precision for the overall model variables.the KNN algorithm was the second highest performing model overall after the RF algorithm,with AUC:0.95,ACC:0.86,Fβ:0.80,and Logloss:0.35.The LR algorithm,NB algorithm,MLNN algorithm,SVM algorithm and LDA algorithm are basically comparable in performance in all aspects,with AUC and ACC coefficients maintaining between 0.69 and 0.80;Fβ values are lower,with coefficients maintaining between 0.5 and 0.54,and Logloss values are higher,between 0.56 and 0.63.XGboost with AUC(0.86),ACC(0.79)and Fβ(0.71),had a better overall performance,but a higher Logloss of 0.59.The predictive characteristic variables contributing to the prediction model were:post-treatment AFC,age,post-treatment LH,post-treatment FSH/LH ratio,post-treatment FSH,and history of acupuncture treatment.Study findings1 The RCT study showed that acupuncture with the method of regulating menstruation and promoting pregnancy improved ovarian function in DOR patients,especially in terms of improving AFC and FSH levels;acupuncture showed a significant improvement in clinical pregnancy rates in women ≥ 35 years of age.2 The RWS study showed that patients with DOR tend to be clinically insidious,diverse and progressive in their development.Acupuncture or acupuncture-medicine interventions for DOR can increase clinical pregnancy and live birth rates,reduce miscarriage rates,improve ovarian function in DOR patients,especially FSH and AFC levels,and delay DOR disease progression.Needle medicine has the advantage of long-term efficacy.3 The model for clinical pregnancy in patients with DOR treated with acupuncture had the best overall performance with the random forest algorithm model(AUC=0.99,ACC=0.95,Fβ=0.93,Logloss=0.30),followed by the KNN algorithm(AUC=0.95,ACC=0.86,Fβ=0.80,Logloss=0.35).The predictive model independent variables contributions in order of magnitude were:post-treatment AFC,age,post-treatment LH,post-treatment FSH/LH ratio,post-treatment FSH,and acupuncture treatment history. |
PDF Full Text Request