Analysis Of Clinical Outcomes Of Different Ovulation Stimulation Protocols In Elderly Patients With Diminished Ovarian Reserve

Background and ObjectivesWith the advancement of the national"two-child"policy and the change in people’s fertility attitudes,the number of elderly women with childbearing needs is gradually increasing,and more and more elderly infertile women are seeking Assisted reproductive technology（ART）to help them get pregnant.The continuous developments of ART have brought hope for some elderly infertile women to give birth to offspring.However,the success rate of elderly infertile women in ART is significantly lower than that of younger women.The main reason is the decline of the number and quality in oocytes in elderly women.Relevant data show that among women over the age of 35 undergoing in vitro fertilization and embryo transfer（IVF-ET）treatment,the cumulative pregnancy rate and fetal live birth rate decrease by about 10%and the abortion rate increases by about 10%for each increase in age by 1 to 2 years.Therefore,the fertility problem of elderly infertile women has become a hot and difficult issue in the field of reproduction.In 2016,the POSEIDON（Patient-Oriented Strategies Encompassing Individualize D Oocyte Number,POSEIDON）standard was put forward,providing new reference opinions for clinicians to manage patients with"low prognosis".It clarified the classification of different patients through more detailed and reasonable classification.According to the standard,patients with age over 35 years old,AMH<1.2 ng/ml and bilateral AFC<5 were defined as POSEIDON group 4,which means the elderly women with diminished ovarian reserve group.According to the classification standards of POSEIDON,this article retrospectively analyzes the laboratory indicators and relevant clinical outcomes of the luteal phase ovarian stimulation proticol,follicular phase progestin primed ovarian stimulation protocol,Gn RH antagonist protocol and micro-stimulation protocol in the elderly patients with diminished ovarian reserve in our center to provide a reference for choosing a effective and economical ovulation stimulation protocol for elderly patients with diminished ovarian reserve.Materials and Methods1.Research subjects and groupsClinical data of 517 cycles of patients over the age of 35 with diminished ovarian reserve who underwent IVF/ICSI treatment at the Reproductive Center of the Second Affiliated Hospital of Zhengzhou University from January 2018 to August2020 were retrospectively analyzed.According to different ovulation stimulation protocols,they were divided into three groups:group A was progestin primed ovarian stimulation group（310 cases）,group B was micro-stimulation group（155 cases）and group C was Gn RH antagonist group（52 cases）.According to different drug regimens,the progestin primed ovarian stimulation group was divided into two subgroups,namely,follicular phase progestin primed ovarian stimulation protocol（PPOS group,132 cases）and luteal phase ovarian stimulation proticol（LPOS group,178 cases）.2.Inclusion and exclusion criteriaInclusion criteria:age≥35 years old;according to POSEIDON standard,the criteria for diminished ovarian reserve are:bilateral ovarian AFC<5 and AMH<1.2 ng/ml.Exclusion criteria:1.contraindications for IVF/ICSI;2.chromosomal abnormalities of either spouse;3.endocrine metabolic diseases,such as uncontrolled thyroid dysfunction,diabetes,hyperandrogenemia,etc;4.diseases affecting the outcomes of IVF pregnancy,such as severe adenomyosis,untreated hydrosalpinx,untreated endometrial lesions,myoma of uterus≥4 cm,etc.3.MethodsCollect the patients’age,years of infertility,BMI,AFC,AMH and other general data;gonadotropin（Gn）days,dosages of Gn used,the number of obtained oocytes,the number of available embryos,clinical pregnancy outcomes,other related indicators and IVF costs4 Statistical methodSPSS 23.0 software was used for statistical analysis.Measurement data conforming to normal distribution were expressed as the mean±standard deviation（Mean±SD）,independent sample t test was used for the comparison between two groups,and one-way analysis of variance was used for the comparison between multiple groups.When comparing multiple groups in pairs,LSD method was used if the variances were homogeneous,and Tamhanes’T2 method was used if variances were not homogeneous.Measurement data that didn’t conform to the normal distribution were expressed as M(P₂₅,P₇₅),and non-parametric Mann-Whitney U test and Kruskal-Wallis H test were used for comparison between groups.The enumeration data was expressed as rate（%）,and the comparison between groups adoptedχ²test or fisher test.P<0.05 indicated that the difference was statistically significant.Results1.There were no significant differences in age,years of infertility,AMH,BMI,AFC,basal FSH and basal LH in the progestin primed ovarian stimulation group,the micro-stimulation group and the Gn RH antagonist group（P>0.05）.2.Days of Gn[（8.35±3.71）d]and the dosages of Gn used[（1626.12±1006.85）U]in the micro-stimulation group were lower than those in the progestin primed ovarian stimulation group[（9.31±2.83）d,（2195.08±862.15）)U]（P=0.014,P<0.001）and the Gn RH antagonist group[（9.67±3.29）d,（2354.16±1022.90）U]（P=0.035,P<0.001）;the level of LH on HCG days in progestin primed ovarian stimulation group[（4.38±3.64）U/L]was lower than that in micro-stimulation group[（9.41±7.32）U/L]（P<0.001）and Gn RH antagonist group[（6.85±6.81）U/L]（P=0.04）,the rate of early ovulation（0.64%）,no obtained oocytes rate（14.83%）and no available embryos rate（24.19%）in progestin primed ovarian stimulation group were lower than those in micro-stimulation group,the differences were statistically significant（P<0.05）;There were no significant differences in the level of E₂ on HCG day among the three groups（P>0.05）.3.The number of obtained oocytes[（2.42±1.65）n],the number of available embryos[1（1,2）n]and MII oocyte rate（92.38%）in the progestin primed ovarian stimulation group were higher than those in the micro-stimulation group[（1.83±1.91）n,1（1,1）n,87.63%]（P=0.001,P=0.007,P=0.017）;There were no statistically significant differences in the normal fertilization rate,normal fertilization cleavage rate and the excellent embryo rate among the three groups（P>0.05）.4.In frozen-Frozen-thawed embryo transfer cycles,there were no significant differences in the proportion of D3 embryos transfer cycles,clinical pregnancy rate,embryo implantation rate and early abortion rate among the three groups（P>0.05）,but compared with the other two groups,the clinical pregnancy rate in progestin primed ovarian stimulation group increased and the early abortion rate decreased.5.The total cost for each cycle:Gn RH antagonist group[（11843.52±2626.95）yuan]>progestin primed ovarian stimulation group[（9639.05±2165.95）yuan]>micro-stimulation group[（8023.31±2766.39）yuan]（P<0.001）;the cost for each oocyte obtained and each available embryo available:Gn RH antagonist group[（6443.41±3576.55）yuan,（9641.98±3233.94）yuan]were higher than progestin primed ovarian stimulation group[（4672.42±2844.28）yuan,（7517.20±3226.96）yuan]（P=0.007,P=0.001）and micro-stimulation group[（4545.54±2519.95）yuan,（7068.71±2731.16）yuan]（P=0.005,P<0.001）.6.In the two subgroups of progestin primed ovarian stimulation group,there were no significant differences in age,AMH,BMI,years of infertility,AFC,basal FSH,and basal LH between PPOS group and LPOS group（P>0.05）.7.The level of progestin on HCG days in LPOS group[0.97（0.62,1.49）ng/ml]was higher than that in PPOS group[0.75（0.53,0.97）ng/ml]（P<0.05）;there were no significant differences in Gn days,dosages of Gn,the level of LH and E2 on HCG days,premature ovulation rate,no obtained oocytes rate,no available embryos rate,the numbers of oocytes obtained and available embryos,MII oocyte rate,normal fertilization rate,normal fertilization cleavage rate,the excellent embryo rate,and clinical pregnancy rate,embryo implantation rate and early abortion rate in the frozen-thawed embryo transfer cycles between the two groups（P>0.05）.Conclusions1.The progestin primed ovarian stimulation protocol,which is more economical and affordable,can effectively suppress the premature LH surge,get more oocytes and available embryos,and the quality of oocyte is higher,.2.Both PPOS protocol and LPOS protocol can be used as the preferred protocol for elderly patients with diminished ovarian reserve.