All the raw data and analysis have been included as Supplementary Files. Table 1 presents the demographic characteristics of both groups. As shown in Table 2 , Cetrorelix consumption was significantly lower 0. Furthermore, the LH, E 2 , and progesterone levels on the trigger day showed no significant difference between the two groups. Meanwhile, the number of retrieved oocytes, fertilized oocytes, and available embryos did not significantly differ between the two groups, and the number of cycles canceled due to pre-ovulation did not significantly differ between groups 1 and 2 1.
As shown in Table 3 , there was a total of fresh embryo transfer cycles: in Group 1 and in Group 2. There was no statistically significant difference in the average number 1. The implantation rate Of the patients in Group 1, 30 Patients from subgroup 1 had significantly higher basal serum FSH 8. Furthermore, the average age, BMI and the basal serum LH and E 2 levels did not significantly differ between the two subgroups.
Meanwhile, patients from subgroup 1 were administered higher doses of gonadotropin The progesterone and LH levels on the trigger day did not significantly differ between the two subgroups, but the E 2 level on the trigger day was significantly lower in subgroup 1 than in subgroup 2 Table 4. Demographic characteristics and ovarian stimulating parameters between subgroup. During COS in IVF, premature LH surge is harmful to ovum development, causing luteinization and untimely ovulation, leading to poor outcomes, even requiring cancellation of the cycle 3.
Although it is still controversial, the pregnancy rate achieved with GnRH-ant protocol has been considered to be lower than that achieved with GnRH-agonist protocol, and the impaired endometrial receptivity has been thought of the main cause for this difference. Doctors in reproductive health services have attempted to achieve satisfactory pregnancy outcomes by reducing the GnRH-ant dose. However, the minimum suitable daily dose of GnRH-ant remains controversial.
Currently, 0. Some other studies have reported that reducing the GnRH-ant dose to 0. Therefore, we attempted to reduce the initial daily Cetrorelix dose to 0. First, we found there were no differences in the LH, E 2 , and progesterone levels on the trigger day, neither in terms of the number of retrieved oocytes, fertilized oocytes, and available embryos between the two groups. These results demonstrated that the initial 0. Compared with the previous study 14 , our study showed that adjusting the GnRH-ant dose from 0.
Furthermore, Group 1 had a notable reduction in GnRH-ant consumption and reduced duration of stimulation compared with Group 2; this might result in improved pregnancy outcomes in Group 1. Furthermore, prolonged ovarian stimulation was associated with a decreased rate of superior-quality embryos and lower implantation, and live birth rates 23 — In this present study, the implantation rate, clinical pregnancy rate, and ongoing pregnancy rate were all higher in Group 1 than in Group 2, although this difference was not statistically significant.
We assumed that this may be because the reduction in the GnRH-ant dose to 0. In addition, insufficient number of cases of this retrospective study could be another reason. A multicenter randomized controlled study will be performed in the next step. Second, there was no significant difference in the BMI between subgroups 1 and 2, suggesting that the BMI might not be an important impact factor for the selection of the GnRH-ant dose.
Although a few studies have suggested that it is appropriate to reduce the GnRH-ant dose for slim patients 12 , Engel et al. Hsieh et al. In addition, compared with subgroup 2, patients in subgroup 1 had significantly higher basal serum FSH level and lower AFCs. Furthermore, patients in subgroup 1 had a higher gonadotropin requirement, higher LH level, and lower E 2 level at the start of the Cetrorelix treatment, indicating that subgroup 1 patients had lower ovarian reserve than subgroup 2 patients.
The patients in subgroup 1 were slightly older than those in subgroup 2, but the difference was not statistically significant. Meanwhile, more gonadotropin was consumed in subgroup 1 than in subgroup 2.
Together, these results indicated that the ovarian response was lower in subgroup 1 than in subgroup 2. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome OHSS. Pre-planned subgroup analyses were performed for various antagonist treatment schedules.
We included 50 studies. In general IVF patients, ongoing pregnancy rate was significantly lower in the antagonist group compared with the agonist group RR 0. In women with PCOS and in women with poor ovarian response, there was no evidence of a difference in ongoing pregnancy between the antagonist and agonist groups RR 0.
Subgroup analyses for various antagonist treatment schedules compared to the long protocol GnRH agonist showed a significantly lower ongoing pregnancy rate when the oral hormonal programming pill OHP pretreatment was combined with a flexible protocol RR 0. Subgroup analysis for the fixed antagonist schedule demonstrated no evidence of a significant difference with or without OHP RR 0. No data on OHSS was available from trials in poor responders. Within this population, antagonist treatment prevents one case of OHSS in 40 patients but results in one less ongoing pregnancy out of every 28 women treated.
Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. The two approaches for this are pituitary desensitization with prolonged daily administration of a gonadotrophin releasing hormone GnRH agonist or an instant blockade of the pituitary luteinizing hormone LH secretion with a GnRH antagonist Huirne and Lambalk, ; Huirne et al.
Both procedures are effective in blocking premature LH surges The ganirelix dose-finding group, ; Janssens et al. Advantages of antagonists are the shorter duration of the analog treatment, the shorter duration of stimulation with FSH and the lower risk of developing ovarian hyperstimulation syndrome OHSS Al-Inany et al. One particular advantage in the context of preventing OHSS may be the possiblity of triggering ovulation with a short endogenous LH surge induced with a GnRH agonist instead of the prolonged exogenous LH action induced by the administration of hCG Youssef et al.
A number of systematic reviews have appeared over the past decade Kolibianakis et al. Most reviews have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome PCOS or women with poor ovarian response. This is likely to be of relevance since these women strongly differ with regard to ovarian responsiveness particularly in relation to the long agonist and antagonist protocols Huirne et al.
All of the previous reviews have included a number of studies in which the agonist or antagonist was not the only variable between the compared study arms and, by doing so, analysis of the specific effect of the type of analog used is not feasible.
In some studies, the applied FSH dose was lower in the antagonist arm in comparison to the agonist regimen, which could affect oocyte yield, pregnancy rate and OHSS Serafini et al. In other studies, there were differences in stimulation strategies between the study arms which could serve as uncontrolled confounders Kiochi et al.
An important matter with regard to application of the GnRH antagonist is the inability to plan the start of an IVF treatment. Therefore many clinics apply some sort of sex-hormonal pretreatment in order to program the start of stimulation.
This is a widely spread approach when antagonists are applied and it occurs prior to start of stimulation. Because of this universally wide spread application and the need to examine actual clinical practice, we decided to include the 22 studies that applied this strategy.
Thus we conducted a systematic review and meta-analysis evaluating the effect of the type of GnRH analog used in IVF to prevent the premature LH surge, with regard to pregnancy outcomes and OHSS rates, with special attention to differences in patient populations and interventions. Only published randomized controlled studies RCTs were included in this review. Reported quasi randomized trials were not included.
We compared a standard long GnRH agonist protocol versus various flexible and fixed protocols of GnRH antagonists with or without oral hormonal programming OHP pretreatment. Secondary outcomes were live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety outcome with regard to OHSS.
The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception in through June using the following search terms: gonadorelin agonist, gonadorelin antagonist, infertility therapy, buserelin, triptorelin, goserelin, leuprorelin, nafarelin, cetrorelix, ganirelix and teverelix.
We excluded studies that compared more than one variable, for instance studies that, in addition to comparing a GnRH antagonist with a GnRH agonist, also compared agonist versus hCG triggering and studies in which not only the type of analog for prevention of premature luteinization but also dosage or type of gonadotrophins varied between compared groups.
We assessed all eligible studies for appropriateness for inclusion and methodological quality. Methodological criteria were trial characteristics, population characteristics, interventions and outcomes. Study selection was performed independently by two reviewers F. Authors of trials were contacted to request additional information if the papers contained insufficient information. We received replies from 15 of the 43 authors we contacted.
The primary outcome was ongoing pregnancy defined as an intact pregnancy at 12 weeks of amenorrhea. Secondary outcomes were OHSS per woman randomized, live birth, clinical pregnancy, defined as intrauterine pregnancy with a positive heartbeat at 6 weeks of gestation, and number of oocytes retrieved.
We performed the meta-analysis according to the intention-to-treat ITT principle. Heterogeneity between the results of different studies was determined using the inconsistency measure I 2 Higgins et al. The absolute risk reduction was calculated by subtracting event rates in the antagonist group from that in the agonist group. For numbers needed to harm and numbers needed to treat, we calculated the reciprocal of the absolute risk difference.
We performed separate analyses for three populations: the general IVF population, women with PCOS and women with poor ovarian response.
An IVF patient was categorized as belonging to the general IVF population, if reported as being ovulatory or with a regular menstrual cycle or when not specified.
Women with PCOS and women with poor response were considered as such when categorized in the relevant publication accordingly. A pre-planned subgroup analysis was performed based on the type of antagonist protocol used, i.
We assessed the likelihood of publication bias by constructing a funnel plot Higgins et al. In total, studies were retrieved. After checking for relevance of the comparisons and the truly randomized nature of the trials, 50 randomized RCTs were included in the systematic review Fig.
The excluded studies are shown in Table II. The included studies randomized a total of women. We subdivided these women into three subcategories: women belonging to the general IVF population 34 studies , women with PCOS 10 studies and women with poor ovarian response 6 studies. Flow chart showing the selection of publications identified in the literature search. In the general IVF population, from 21 studies using a flexible protocol, six were pretreated with OHP and from the 13 studies with a fixed protocol, four were pretreated with OHP.
In PCOS patients, seven trials used the flexible protocol and three used the fixed protocol. All of these trials applied OHP pretreatment. Of the poor responder population, three studies used a flexible protocol, one study combined the flexible protocol with OHP and two studies used the fixed protocol and OHP. Types of antagonist used were cetrorelix 32 studies , ganirelix 15 studies , one did not report type of antagonist and in two studies both cetrorelix or ganirelix were used.
Types of agonist used were buserelin 17 studies , leuprorelin 12 studies , triptrorelin 16 studies and nafarelin 5 studies. All studies used a long multiple dose MD agonist protocol 50 studies.
The gonadotropin starting dose varied from to IU of recombinant follicle stimulating hormone rFSH or human menopausal gonadotropin hMG. All of the included trials had a parallel study design. Studies were multicentre 11 studies or single center 38 studies and in one case, it was unclear. Inclusion and exclusion criteria were available in all studies, but differently specified especially in the 34 studies with a general IVF population. Of these studies, 19 described a required regular menstrual cycle in the inclusion criteria, four studies described the exclusion of PCOS and three described exclusion of endocrine disorders, while eight studies did not adequately specify menstrual cycle regularity.
The method of randomization was computerized in 28 studies; an interactive voice response was used in four studies; five studies used sealed envelopes without further details regarding the randomization method; number tables were used in threee studies; a randomization list sequentially numbered and a centralized telephone was used in three studies and the method of randomization was not available in seven studies.
Allocation concealment was adequate in 32 studies, not concealed in one and unclear in 17 studies. The randomization ratio was: 38 studies , 5 studies , 6 studies , or unclear 1 study. The duration of the studies varied from three months to five years and two months and was not available for 11 studies.
ITT analysis was performed in 17 studies, not performed in 26 studies, inadequate in six studies and unclear in one study. Financial support was declared in 25 studies and none was declared in 25 studies. There were 26 trials, entailing couples from a general IVF population, that provided the primary outcome of ongoing pregnancy Fig. In these couples, the ongoing pregnancy rate was significantly lower after the use of antagonists than after the long agonist protocol RR 0.
The ongoing pregnancy rate after antagonist use was Ongoing pregnancy rates in the general population per prespecified antagonist treatment protocol are summarized in Fig. Ongoing pregnancy rates were lower when a flexible antagonist protocol was used with OHP 5 trials, couples; RR 0. The RR was 0. There was no evidence of a difference in ongoing pregnancy rate between antagonist and agonist when a fixed antagonist protocol was used without OHP 9 trials, couples; RR 0.
A fixed protocol with OHP pretreatment also did not yield a significant difference 3 trials, couples; RR 0. Ongoing pregnancy rate per antagonist per flexible or fixed protocol with or without oral hormonal programming OHP in a general IVF population.
In the general population clinical pregnancy rate was lower with antagonist 34 trials, couples; RR 0. In the general population the RR for live birth with use of antagonist was 0. Due to the high statistical heterogeneity, this finding should be considered with care. Antagonist treatment in this general population resulted in a significantly lower OHSS rate than agonist 22 trials, couples; RR 0. Compared to a control OHSS rate of 6.
Nine trials including couples from a PCOS population provided the primary outcome of ongoing pregnancy. When subgrouping the antagonist protocol, no evidence for a difference was found for antagonist versus agonist, either when a fixed protocol after OHP pretreatment was used 3 trials, couples; RR 0. There was also no difference in clinical pregnancy rate between antagonist and a long agonist protocol 10 trials, couples; RR 1.
There were no differences in oocyte yield Fig. Six trials including couples from a poor responder population provided the primary outcome of ongoing pregnancy Fig. No evidence of a difference in ongoing pregnancy rate was found in poor responders RR 0.
In view of the low number of trials, no further subgrouping of the antagonist protocol group was done. In the poor response patients, the RR for live birth with use of antagonist compared to agonist was 0. There was also no evidence of a difference in clinical pregnancy rate 6 trials, couples; RR 0. Sensitivity analysis on the primary endpoint, namely ongoing pregnancy, leaving out studies not reporting mode of randomization and studies that used steroid programming by oral hormonal treatment OHP in the general population, the RR for ongoing pregnancy rate was not changed at 0.
Leaving out one such study in the poor responder group resulted in a slightly lower RR of 0. This meta-analysis showed that with regard to the chance of an ongoing pregnancy in general IVF patients, when evident ovarian dysfunction such as PCOS or poor response are excluded explicitly, there is an absolute risk reduction of 3. The number needed to harm was 28, i. On the other hand, use of antagonist instead of agonist reduced the absolute rate of OHSS by 2.
Sub-analyses suggest that the use of a fixed protocol may at least partly resolve the difference in clinical effectiveness with GnRH antagonist. Based on its 3. It should be noted that a recent study employing a so-called discrete choice analysis evaluating patients preferences, the respondents were willing to trade-off 0. In couples with PCOS, we found no evidence for a difference in ongoing pregnancy or clinical pregnancy rate, but again there was a significantly lower OHSS rate in the antagonist group.
In poor responders, we also found no statistical differences with regard to pregnancy rates although the power seems too low to make solid statements for this group. Statistical analysis All statistical analyses were performed using Revman 5. Results Eligible studies The initial literature search yielded 1, studies. Download: PPT. Main outcome measures of effectiveness The clinical pregnancy rate.
Fig 2. Forest plot comparing the clinical pregnancy rate per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group. The ongoing pregnancy rate. Fig 3. Forest plot comparing the ongoing pregnancy rate per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group.
The live birth rate. Fig 4. Forest plot comparing the live birth rate per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group. Secondary outcome measures of effectiveness The number of stimulation days. Fig 5. Forest plot comparing the number of stimulation days per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group. Gn dosage. Fig 6. The endometrial thickness on the day of HCG administration. Fig 7. The E2 level on the day of HCG administration.
Fig 8. The number of oocytes retrieved. Fig 9. Forest plot comparing the number of oocytes retrieved per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group. The number of embryos obtained. Fig Forest plot comparing the number of embryos obtained per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group.
The miscarriage rate. Forest plot comparing the miscarriage rate per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group. The cycle cancellation rate. Forest plot comparing the cycle cancellation rate per woman randomized between the GnRH-ant group and the GnRH-a long-protocol group. Sensitivity analysis and publication bias The sensitivity analysis was performed by excluding the maximum weight studies [ 8 , 17 , 31 , 36 , 37 , 41 ] in each outcome.
Discussion Summary of main results Ovarian reserve can be tested by biochemical measures, such as basal follicle stimulating hormone bFSH , anti-Mullerian hormone AMH , and inhibin B level, as well as imaging measures, such as antral follicle count AFC.
Limitations of this study First of all, this meta-analysis lacked a uniform definition of normal ovarian reserve, which made it difficult to define inclusion and exclusion criteria, and the studies included may be not strict enough. Implications The GnRH-ant protocol is a short, convenient, and cost-effective protocol in COH among patients with normal ovarian reserve, which can also reduce the incidence of OHSS without affecting the live birth rate when compared to GnRH-a long protocol.
Conclusion In conclusion, our meta-analysis demonstrated that GnRH antagonist protocol substantially decreased the incidence of OHSS without influencing the pregnancy rate and live birth rate compared to GnRH agonist long protocol among patients with normal ovarian reserve. Supporting information. S1 Table. Quality assessment of studies. S1 Fig. S2 Fig. S3 Fig. S4 Fig. S5 Fig. S6 Fig. S7 Fig. S8 Fig. S9 Fig. S10 Fig. S11 Fig.
S12 Fig. However, no previous study directly compares the two protocols for those patients who are predicted as high ovarian responders without PCOS. A non-blind randomized controlled trial conducted at the Genetic and Reproductive Institution of Chongqing, China, from January to July Two hundred four infertile women were enrolled into the study only once after the Informed consent form was signed.
The recruited women were allocated randomly into two groups when Gonadotropin was started on menstrual cycle days 3.
Randomization was performed using sealed opaque envelopes prepared by a third party. In group A the fixed regimen , women received daily 0. Women in Group B the flexible regimen received daily 0. ICSI would be performed only in cases with severe male factor or previous fertilization failure. Embryo quality was evaluated for all available embryos on day 3 of culture by the experienced embryologist.
One or two Day3 good quality embryos transferred, and other remaining embryos vitrified for frozen-thawed embryo transfer cycle. An artificial cycle was used for endometrial preparation in the next menstrual cycle. Hormonal assessment and ultrasound monitoring were performed on the menstrual cycle day 3 both groups , stimulation day 4 and then daily up to initiation of the antagonist flexible , initiation day of the antagonist both groups , the day after antagonist starting both groups and the day of hCG trigger both groups and additional monitoring decided by investigator as ovarian stimulation response.
All blood samples were drawn in the morning before antagonist injection. The primary endpoint was to assess a difference in the total number of retrieved oocytes between the two groups. The CLBRs were calculated by including the first live birth generated during the complete first IVF cycle as the numerator and all women allocated to treatment as the denominator. The estimates of the CLBR assumed that women who did not return for treatment would not have a live birth. The true difference between the means was assumed to be 0.
For the primary endpoint, mean and SD on the number of oocytes were presented. For the secondary endpoints, the number and percentage of the event were calculated and displayed on categorical variables. Clinical and ongoing pregnancy rates were separately calculated and presented. Mean and SD were summarized for continuous variables in terms of secondary outcome measures. A treatment difference between study groups was made by using two-sample t-test or nonparametric test whenever appropriate.
A total of patients participated in the study and were randomized to each two treatment groups. Three patients were discontinued prior to oocyte aspiration due to personal reasons.
One hundred patients in fixed protocol group and patients in the flexible protocol group were adhere to the ovarian stimulation protocol and complete the oocyte aspiration. Forty-six in fixed group and 47 in flexible group received fresh embryo transfer Fig. Finally, 91 patients both in fixed group and flexible group completed all embryo transfer. The baseline population characteristics of two groups are summarized in Table 1.
Results of the endpoint analyses are presented in Table 2. The mean SD number of oocytes retrieved in the fixed group was No significant differences were observed between the two groups on the dose of rFSH and duration of stimulation.
No premature LH surges were occurred. Treatment duration of GnRH antagonist in fixed protocol group was significantly longer than in flexible group 6. Table 3 shows that implantation rate, clinical pregnancy rate, ongoing pregnancy rate per fresh embryo transfer and cumulative live birth rate per patients were comparable in two groups.
Nine patients in flexible group developed the moderate and severe OHSS and 7 patients were observed in fixed group. Except the treatment duration of GnRH antagonist in the flexible protocol group was shorter than that in the fixed protocol group, no significant differences were between the two protocols in term of the treatment duration and total dose of rFSH, premature LH surges, implantation, clinical pregnancy, ongoing pregnancy, and cumulative live birth rate.
Previous published studies focused on ovulatory women arrived at the similar outcomes.
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