Effetcts Of Acu-point Stimulation On The Outcomes Of In Vitro Fertilization And Embryo Transfer (IVF-ET):the Meta-analysis And Its Rule Of Application

The first human offspring by IVF-ET born in 1978 in the UK.In vitro fertilizaion and embryo transfer(IVF-ET),as the representative of assisted reproductive technology(ART),was widely used in the treatment of infertility among the next twenty years,and became the hope for infertile couples.However,the pregnancy rate of IVF-ET is still about thirty percents,and descends significantly after 35 years old of female.With the constantly updated of the randomized clinical trials(RCTs),the effect of acu-point stimulation(like acupuncture,electroacupuncture,etc.)on the outcomes of IVF-ET may bring different conclusions.Conducting Meta-analysis of the RCTs,a method of evidence-based medicine(EBM),the effect of acu-point stimulations on the outcomes of IVF-ET can be evaluated.The rule of acu-points and meridians selection and other applicating parameters can also be concluded,which can instruct the clinical applications and provide references for further research.Objectives(1)To review the quality of the randomized clinical trials(RCTs)of acu-point stimulation on the treatment of female subfertility by assisted reproductive technology(ART),including in vitro fertilization and embryo transfer(IVF-ET)and intra-cytoplasmic sperm injection(ICSI);(2)to evaluate whether acu-point stimulation could improve rates of clinical pregnancy when used as adjuvant treatment in women undergoing IVF-ET(and ICSI);(3)to explore the rule of selecting acu-points and the meridians and find out the indicating syndromes of using auc-point stimulation as an adjuvant in women undergoing IVF-ET(and ICSI),by using the principle of "predicting meridian by its acu-point" and "predicting syndrome by its organ-related-meridian".MethodsAll reports which described RCTs of acu-point stimulation in assisted conception were obtained through data searches of the China National Knowledge Infrastructure(CNKI),Cochrane Library,Ovid Medline,Embase,Web of Science,APC Journal Club and AMED(Allied and Complementary Medicine)(all from inception to December 2015).The including and excluding criteria of the selected trial and the literature searching strategy were developed,before full text document were obtained.The qualities of the included studies then were evaluated by using the modified JADAD scoring.Meta-analyses of the high-quality included studies(with modified JADAD score ≥4)and further subgroup analyses were processed by using Review Manager 5.3.The effectiveness and safety of acu-point stimulation as an adjuvant to IVF-ET cycle for female subfertility were then determined and discussed.The frequency statistics of the selected acu-points,meridians and treatment parameters in all RCTs(with modified JADAD score 1-7)were also conducted and discussed.ResultsAccording to the literature searching strategy,3273 articles published in formal academic journals were collected.By reading the titles and abstracts and removing the repeated documents,320 articles left.After reading the full text,53 articles were obtained,in which 33 articles with modified JADAD score ≤3,thus eventually 20 articles were included in the meta-analysis.A total of 4118 participants contained treatment group 2138 cases,sham control group 1127 cases and control group 853 cases.All included studies used appropriate allocation concealment methods and mentioned baseline comparability between treatment group and controls.Only 15 articles mentioned sample size and power calculation in details.3 studies(15%)applied single-blinled methods,8 articles(40%)applied double-blinded methods and 9 articles(45%)had not mentioned blinding.Statistical results mentioned with concepts of intent to treat(ITT)analysis in 11 studies.Regarding modified JADAD scoring,8 studies got 7scores,5studies got 5scores and 7studies got 4 pointsThis updated meta-analysis showed the higher clinical pregnancy rate(CPR)in the acu-point stimulation treatment group than both control groups(sham and no intervention control)with statistical significance[RR = 1.20,95%CI(1.02,1.41),P = 0.02(P<.0.05)].Comparing with sham control group only,which complied blinding and even more ensuring the quality,CPR in treatment group was also higher than that in the control[RR=1.29,95%CI(1.01,1.65),P=0.05(P≤0.05)].This implied that acu-point stimulation could improve the pregnancy outcome in women undergoing IVF-ET for subfertility.In the aspects in biochemical clinical rate,ongoing pregnancy rate,live birth rate and miscarriage rate,the difference between the treatment group and control groups in each individual study did not show any statistical significance.Subgroup analyses were conducted in different aspects like aims of the study,intervention phases,forms of treatment group intervention,sham control designs,etc.When designing the intervention in RCTs,the intervention method and acu-points selected were decised according to the aims of the studies,and would indeed affect the results like CPR.Treatment group in the studies aimed at improving IVF-ET pregnancy outcomes had higher CPR than both control groups[RR=1.26,95%CI(1.03,1.54),P=0.03(P<0.05)].No significant difference was found between treatment and control groups in the studies aimed at oocyte aspiration analgnesia.On the basis of different intervention phases,the combined effects of acu-point stimulation were evaluated separately.All of the three intervention phase sub-group including "acu-point stimulation performed only around the time of embryo transfer(ET)","acu-point stimulation performed only around the time of oocyte aspiration(OA)" and "acu-point stimulation performed only during and before controlled ovarian hyperstimulation(COH)"did not show elevation in CPR in treatment group,but found positive result when acu-point stimulation performed in more than one of above intervention phases[RR=1.65,95%CI(1.32,2.06),P<0.00001(P<0.01)].This indicated acu-point stimulation performed in more than one intervention phases may have decisive signifiant effect,further studies are worthy in exploration.Further comparsions were made in sub-groups "acu-point stimulation performed involved phase around the time of ET","acu-point stimulation performed involved phase around the time of OA" and "acu-point stimulation performed involved phase during and before COH".The comparsions found that"acu-point stimulation performed involved phase around the time of OA" and"acu-point stimulation performed involved phase during COH" could significantly promote the pregnancy outcome of IVF-ET[RR=1.31,95%CI(1.01,1.69,P=0.04(P<0.05);RR=1.79,95%CI(1.10,2.91.),P=0.02(P<0.05)].However,the CPR did not elevate in the comparsion "acu-point stimulation performed involved phase around the time of ET".For the treatment group interventions,the treatment group of intervention involving electrical stimulation had higher CPR that the controls[RR=1.25,95%CI(1.00,1.57),P=0.05(P<0.05)].This prompted that electrical stimulation has positive impact on the efficacy of IVF-ET outcome."Minimal acu-point stimulation or superficial needling of true acu-points" and"non-specific acu-point stimulation" were contrasted in subgroup analyses for different designs of sham control,the treatment groups showed significant positive effect on CPR[RR=1.79,95%CI(1.34,2.39),P<0.0001(P<0.01);RR=1.56,95%CI(1.00,2.43),P=0.05(P<.0.05)].Conversely,sham control of Streitberger’s needle showed higher CPR than in the treatment group.In the 53 articles with modified JADAD score 1 to 7,a total of 44 articles reported RCTs with acu-point stimualation used as an adjuvant in IVF-ET aimed at improving the pregnancy outcome.Frequency statistics of the acu-points and its meridians selection,and other treatment parameters were conducted.The result found that the most commonly used meridian acu-points and extra acu-points as an adjuvant in IVF-ET were Sanyinjiao(SP6),Zusanli(ST36),Zigong(Ex-CA1),Taichong(LR3),Guanyuan(CV4),Xuehai(SP10),Neiguan(PC6),Hegu(LI4),Guilai(ST29),Taixi(KI3),Diji(SP8),Zhongji(CV3)and Baihui(GV20).The most frequently used auricular acu-ponts were Internal genitals(TF2),Shenmen(TF4)and Endocrine(C018).And the most frequently used meridians or body regions were Spleen Channel of Foot-Taiyin(SP),Stomach Channel of Foot-Yangming(ST),Conception Vessel(CV),Ear Point(GB),Liver Channel of Foot-Jueyin(LR)and Extra Point(EX).And specific acu-points were used in high rate.Manipulations of acu-point stimulation intervention included pure hand-stimulation,electrical stimulation and ear point stimulation.Studies"only involved pure hand-stimulation" and "only involved ear point stimulation"more got use of 25minutes of intervention time,while studies" only involved electrical stimulation" commonly applied 30 minutes.Majority of the included studies instructed acu-point stimulation should achieved "de-qi"sensation.In studies with interventions involved electrical stimulation,the most currently used parameters were:waveform was sparse-dense form,electrical frequency was 2-60Hz and more imploded in 10-20Hz,and the intensity achieved "comfort" or within 15-30V.The rules of acu-point and its meridians selected were summerized:(i)around the affected region-"local therapeutic effect"(ii)far from the affected region-"remote therapeutic effect",and(iii)along the meridians/channels-"specific therapeutic effect",meaned that acu-point stimulation focusing on the Spleen,Stomach and Conception Channels coordinating with Liver and Kidney Channels,and also(iv)making good use of ear point.According to the principle of "predicting meridian by its acu-point" and"predicting syndromes by its organ-related-meridian",this study concluded that the main indication syndromes of acu-point stimulation as an adjuvant in women undergoing IVF-ET for subfertility was:blood deficiency with weak speleen and stomach,liver qi stagnation and disorder between Conception and Governor Vessels;apart from kidney deficiency syndrome.The corresponding treatment guidelines were:adjusting functions of spleen and stomach,coordinating with dredging liver qi and nourishing kidney yin and yang,and also regulating Conception and Governor Vessel’ functions.ConclusionsIt was found that acu-point stimulations as an adjuvant cound improve the pregnancy outcome of IVF-ET like clinical pregnancy rate.This study summarized the most commonly used meridian acu-points,extra acu-points,auricular acu-points and the most frequently used meridians or body regions in IVF-ET in the included RCTs.It also generalized the principles of acu-points selection,which provided the reference for clinical manipulation of acu-point stimulations and indicating syndromes women undergoing IVF-ET.