| BACKGROUNDAs human life style and the rapidly changing levels of economic development, female education and the ability to participate in social activities significantly increased, which lead to marriage and fertility of women showing significant trend after the implementation.Thus the requirement of procreation advanced age of the women are significantly increased the proportion of the total women of reproductive life. Reproductive physiology research has already found that female reproductive capacity decreased sharply after the age of 35, showIng significantly accelerated loss of follicles and ovarian reserve decreases rapidly, at the same time oocytes easy to aging, the risk of chromosomal abnormalities of ovums and embryos appears significantly increased. Accordingly, the assisted reproductive of woman with advanced age becoming the difficulty of in vitro fertilization - embryo transfer (in vitro fertilization-embryo transfer, IVF-ET) and its derivative technology. Actually, women of these age groups want to got the pregnancy opportunity is not an easy thing extremely whether natural or accept ART. Moreover, they got more chance of abortion. Nonetheless, ART is still regarded as the top way to pregnant for women in that age.Follicles in ovarian cortex will growth, development, to form fertilized egg, all of above are called ovarian reserve. There are many indicators to evaluate ovarian reserve, including the basal follicle stimulating hormone (bFSH) in serum and baseline antral follicle count (bAFC), which have been widely used in clinical practice. Clinical study shows both of them have a certain relevance with age, and they may predictable the ovarian reaction to controlled ovarian hyperstimulation (COH) and the pregnancy probability to some extent.Patients of these age groups undertake COH often use the classical mid-luteal long protocol or GnRH antagonist protocol. The optimal protocol (ie, patients could get more good quality embryos and probability of pregnancy) for these patients, however, have not reached a consensus. For this reason, it becomes the focus of attention of clinical reproductive medicine practitioners. At the same time, as majority of developing countries with limited health resources, high medical costs (especially for high medical expenses) has become the component element of most concerned. Clinicians are also confronted with how to reduce the treatment costs reasonably.Health Economics is one of the branchs of economics with a wide range of study. Cost, benefit, effectiveness and utility were compared between multifarious technologies or projects by the application of economic theories, which provided the necessary decision-making informations to clinicians and the best options for patients to counseling or treatment. Currently, the method has been widely used to evaluate medical technology and medicine and health. This study combines knowledge of health economics, committed to addressing COH for women with advanced age by using relevant theories (such as cost effectiveness analysis and decision tree). Not only provide scientific basis for patients'treatment, and make some contributions to the rational allocation of limited medical resources.PART-ⅠThe ovarian reserve of patients over the age of 35 and the outcomes of IVF-ETOBJECTIVETo investigate the correlation among age, bFSH, bAFC and ovarian reserve in patients with advanced age undergoing IVF-ET..METHODS1. Patients:Female patients over 35 years old who underwent in vitro fertilization -embryo transfer between January-2007 and May-2010. All 415 ART transfer procedures that used freshly fertilized embryos in the Assisted Reproduction Unit of the Department of Obsterics and Gynaecology, the Nanfang Hostipal.1.1 The inclusion criteria:(to meet all of these)(1) age≥35 years old;(2) Mid-luteal phase long protocol or GnRH antagonist protocol(3) Complete bilateral annex(4) Clinical information was available(5) transfer procedures that used freshly fertilized embryos1.2 The exclusion criteria:(to meet one of the following)(1) have contraindications of COH(2) medical history with-recurrent spontaneous abortion(3) use steroids or drugs that affect the endocrine before the first 3 months included in this study(4) two-step transplantation, blastula transplantation or costing protocol (5) uterine malformation,endometrial organic disease and tuberculosis in pelvic cavity(6) triplets2. Grouping:All patients were were divided into 3 groups according to age:35 years≤group A1﹤38 years,38 years≤group A2<40 years, group A3≥40 years. They were divided into 2 groups according to bFSH:group B1≤10mIU/ml and group B2>10mIU/ml. And all patients were divided into 3 groups according to bAFC:group C1< 6,6≤group C2< 10 and group C3≥10.3. Measurement of hormone:Basal hormone were measurement after serum sample was collected in the early follicular phase (usually on the morning of day 3 of the last natual menstrual period). E2,LH and P were measurement on the day of hCG admistration.4. Measurement of bAFC:Aloka SSD-4000 transvaginal ultrasound was used to count the numbers of AFC on the third day of nutral cycle. bAFC= the AFC numbers of the left ovary+the AFC numbers of the right ovary. The observation were done by the specialists. Both interobserver and intraobserver differences were not significantly different.5. Protocol:Both mid-luteal long protocol and GnRH antagonist protocol were adopted. The details were best seen by reference to the conventional methods of our center.6. Laboratory processing, luteal support and pregnancy diagnosis:Fertilized though IVF. Then based on the patient's age, datas of previous transplant situation and numbers of embryos after 72h, the highest scores of 1 to 3 embryos were selected and transplanted. Luteal support and clinical pregnancy diagnosis were best seen by reference to the conventional methods of our center. After clinical pregnancy was identified, periodic telephone follow-up during pregnancy period and obstetric outcome.7. Statistical analysis:We used SPSS 13.0 software package for statistical analysis. Results were showed by mean±standard deviation. When data satisfy the conditions of homogeneity of variance, independent sample t test (Independent-samples t test) or ANOVA (one-way ANOVA) were be used; otherwise, the nonparametric Kruskal-Wallis test was been choiced.χ2 test or Fisher exact test were applied to rate comparison. When data satisfy the conditions of bivariate normal distribution, Pearson correlation coefficient and partial correlation analysis were be adopted for the bivariate correlation analysis; or Spearman correlation coefficient was been applied. All P values reported are two-tailed, and values≤0.05 were considered to be statistically significant.RESULTS:1. A total 365 patients were meet the above inclusion-exclusion criteria. There were 435 started cycles,20 cycles were cancellated, cancellation rate was 4.60% (20/435); mean age of 37.88±2.37 (years) and the average numbers of embryo transfer were 2.58±0.60, clinical pregnancy rate was 32.77%(136/415).2. The basic conditions and ovulation induction for patients in various age groups:bFSH, bAFC, the starting doses of gonadotropin, total IU of Gn, and the serum E2 levels on the day of hCG administration were significantly different (P< 0.05). The bFSH levels, starting doses of gonadotropin and Gn applied becoming increased with age increasing, meanwhile, bAFC and the serum E2 levels on the day of hCG administration were decreasing significantly. The No. of oocytes retrieved, No. of normally fertilized oocytes (2PN), No. of matured oocytes, No. of gradeⅠand gradeⅡembryos, clinical PR, implantation rate and live birth rate were reducing significantly with the age to go up, the abortion rate is rising gradually.3. The basic conditions and ovulation induction for patients in various bFSH groups:When comparied with bFSH> 10mIU/ml group, the age, bAFC, the starting doses of gonadotropin and total IU of Gn were lower, which were significantly different (P<0.05). Embryos in different bFSH groups and pregnancy outcome:No. of oocytes retrieved, No. of normally fertilized oocytes (2PN), No. of matured oocytes, No. of gradeⅠand gradeⅡembryos, clinical PR, implantation rate were higher in group A1 (P<0.001). No statistically significant differences in the other details4. The basic conditions and ovulation induction for patients in various bAFC groups:Age, bFSH, the starting doses of gonadotropin and Gn applied becoming diminished with bAFC increasing, meanwhile, endomentrial thickness on the day of hCG administration and the serum E2 levels on the day of hCG administration were increasing.Embryos in different bAFC groups and pregnancy outcome:No. of oocytes retrieved, No. of normally fertilized oocytes (2PN), No. of matured oocytes, No. of gradeⅠand gradeⅡembryos, clinical PR, implantation rate and live birth rate were higher with bAFC increasing, which were statistically different(P<0.05). And the abortion rate is lower. The No. of embryos transferred were similar among the three groups(P=0.293).5. Relative analysis among age, bFSH and bAFC:Age was positively correlated to the bFSH (R=0.149, P=0.002) and negatively related to the bAFC (R= 0.312, P<0.001)Correlation equations were:bFSH=-1.13+0.24age;bAFC=38.81-0.75age.6. Relative analysis among age, bFSH, bAFC and the total IU of Gn and mature oocyes:Age was positively correlated to the total IU of Gn (R=0,323, P<0.001) and negatively related to the number of mature oocytes (R= -0.296, P<0.001) bFSH was positively correlated to the total IU of Gn (R=0.381, P<0.001) and negatively related to the number of mature oocytes (R= -0.273, P<0.001) bAFC was negatively correlated to the total IU of Gn (R= -0.591, P<0.001) and positively related to the number of mature oocytes (R= 0.531, P< 0.001)Correlation equations were:The total IU of Gn=-2179.74+151.90age;The number of mature oocytes= 34.10 - 0.65age.The total IU of Gn= 2519.76+131.59bFSH;The number of mature oocytes=13.55 - 0.53 bFSH.The total IU of Gn= 4860.36-120.13bAFC;The number of mature oocytes= 5.38+0.37 bAFC.7. The values of bFSH and bAFC with clinical parameters:In both bFSH≤10mIU/ml group and bFSH> 10mIU/ml group, the average age in various bAFC groups were (38.40±2.61) years and (38.86±2.71) years; (37.13+1.76) years and (38.30±2.46) years, respectively. No differences were found (P>0.05). In both bAFC groups, women with bFSH≤10mIU/ml group and bFSH> 10mIU/ml group with lower the initial doses of Gn and total IU of Gn. At the same time, the clinical PR and the implantation rate were elevated. BMI, duration of infertility, number of days of Gn, oestradiol on hCG day, thickness of endometrium on hCG day and number of embryos transferred were similar(P>0.05). Meanwhile, in group of bAFC < 10 group, the oocyte recrieves were more than bFSH>10mIU/ml.CONCLUSIONS1. Age, bFSH and bAFC are all predictors of ovarian reserve in patients with adnanced age undergoing IVF-ET.2. Age was positively correlated to bFSH, and negatively related to bAFC. Age was positively correlated to the total IU of Gn and negatively related to the number of mature oocytes. bFSH was positively correlated to the total IU of Gn and negatively related to the number of mature oocytes. bAFC was negatively correlated to the total IU of Gn and positively related to the number of mature oocytes.3. The patients who got clinical pregnancy were younger than others, with low bFSH level and more bAFC.PART-ⅡHealth economic analysis parameters of IVF-ET in women with advanced ageOBJECTIVEIn an attempt to evaluate the correlations between pregnancy outcomes and the direct medical costs in patients, who undergoing IVF-ET with advanced age. Not only provide scientific basis for patients'treatment, but also contribute to the rational allocation of limited medical resources.METHODS1. Patients:Female patients over 35 years old who underwent in vitro fertilization -embryo transfer between January-2007 and May-2010. All 173 ART transfer procedures that used freshly fertilized embryos in the Assisted Reproduction Unit of the Department of Obsterics and Gynaecology, the Nanfang Hostipal.1.1 The inclusion criteria:(to meet all of these)(1) 35 years old≤age< 44 years old;(2) Mid-luteal phase long protocol or GnRH antagonist protocol(3) Complete bilateral annex(4) Clinical information was available(5) transfer procedures that used freshly fertilized embryosThe inclusion criteria and the exclusion criteria:(the same to partⅠ)2. The hormone measurements, protocols of ovarian stimulation, procedures in the laboratory, luteal-phase support, pregnancy test were identical with part-Ⅰ.3. The direct medical costs:In the study cases, only the first transfer cycle used freshly fertilized embryos were been choosed. The types of direct medical costs usually considered include those of TVS, injections, withdrawal, drugs, laboratory tests, operations, embryo culture and other fees(registration, physician's fees, assisted hatch and so on).4. Both of the two protocols were compared:the clinical results and medical costs in the two protocols were compared by the cost effectiveness analysis. And both of the down regulation drugs were compared by this method.5. Statistical analysis:We used SPSS 13.0 software package for statistical analysis. Results were showed by mean±standard deviation. When data satisfy the conditions of homogeneity of variance, independent sample t test (Independent-samples t test) or ANOVA (one-way ANOVA) were be used; otherwise, the nonparametric Kruskal-Wallis test was been choiced.χ2 test or Fisher exact test were applied to rate comparison. Logistic regression was used to predict the probolity of achieving a clinical pregnancy. All P values reported are two-tailed, and values≤0.05 were considered to be statistically significant.RESULTS:1. In both protocols, no differences were found in patients with age, duration of infertility, bFSH, bAFC, BMI and the total IU of Gn. Compared to the GnRH antagonist protocol, the starting doses of Gn were lower, No. of days of Gn, oestradiol on hCG day, thickness of endometrium on hCG day, No. of oocytes retrieved, No. of normally fertilized oocytes (2PN), No. of matured oocytes, No. of fertilized oocytes, No. of gradeⅠand gradeⅡembryos, number of embryos transferred, clinical PR, the implantation rate and live birth rate were increasing significantly(P<0.05). the abortion rate is lower(P<0.001). 2.. In both dosage forms, compared with short-acting preparation, No. of days of Gn were longer, No. of oocytes retrieved, No. of normally fertilized oocytes (2PN), No. of matured oocytes, No. of fertilized oocytes and clinical PR were higher in the long acting preparation group, and the treatment costs was lower.3. Pregnancy outcomes was negatively correlated to the patients'age and positively related to the leves of bAFC.CONCLUSIONS1. The long luteal down-regulation protocol was recommended when women with advanced age experienced COH, for better clinical outcomes and the relatively cheap costs.2. The long acting preparations was recommended when women with advanced age experienced COH, for better clinical outcomes and the relatively cheap costs.3. Analysis though clinical therapeutics and health economics, is more beneficial for patients to develop individualized treatment programs and to optimize the allocation of health resources.BRIEF SUMMARY1. Age, bFSH and bAFC are predictors of ovarian reserve and clinical outcomes in patients with adnanced age.2. Age was positively correlated to the bFSH and negatively related to the bAFC. Age, bFSH were positively correlated to the total IU of Gn and negatively related to the number of mature oocytes. bAFC was negatively correlated to the total IU of Gn and positively related to the number of mature oocytes3. From the perspective of both the treatment and economics, the long luteal down-regulation protocol and the long acting preparations were recommended when patients with advanced age experienced COH. |
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