Bologna Criteria Research Articles

Cumulative Live Birth Rates Following Stimulation With Corifollitropin Alfa Compared With hp-hMG in a GnRH Antagonist Protocol in Poor Ovarian Responders.

Background: Bologna criteria poor ovarian responders have a very low prognosis. Although, it has been proposed that LH supplementation could be beneficial in women with previous hypo-response to FSH. There are no studies comparing the cumulative live birth rates (LBRs) between corifollitropin alfa (CFA) and highly purified human menopausal gonadotrophin (hp-hMG).Objective: To compare cumulative LBRs in Bologna poor ovarian responders undergoing ovarian stimulation with CFA followed by hp-hMG vs. hp-hMG alone in a GnRH antagonist protocol.Design: This is a retrospective cohort study. We included in total 917 poor responders fulfilling the Bologna criteria for poor ovarian response (POR) at a university-affiliated tertiary center from January 2011 until March 2017. Patients were administered either fixed daily doses of 300–450 IU of hp-hMG (group A) or a single dose of 150 μg of CFA followed by daily injections of ≥300 IU of hp-hMG from Day 8 of stimulation until the day of ovulation trigger (group B), in a fixed GnRH antagonist protocol.Results: LBRs after fresh embryo transfer (ET) were similar in group A 71/510 (14%) and B 42/407 (10%). Cumulative LBR per cycle was significantly higher in group A (16.9%) compared to group B (11.8%); (P = 0.03). However, logistic regression analysis showed no association between the type of gonadotropin administered and cumulative LBR. Only age was significantly associated with cumulative LBR (OR = 0.93, P = 0.007).Conclusion: Cumulative LBRs are similar in Bologna poor responders stimulated with CFA followed by hp-hMG compared to hp-hMG monotreatment in an antagonist protocol.

Evaluation of the Second Follicular Wave Phenomenon in Natural Cycle Assisted Reproduction: A Key Option for Poor Responders through Luteal Phase Oocyte Retrieval.

Background: Emergence of Luteal Phase Oocyte Retrieval (LuPOR) may revolutionize the practice regarding the time-sensitive nature of poor responders ascertaining a higher number of oocytes, in a shorter amount of time. This may be especially important in view of employing the approach of natural cycles for Poor Responders. We suggest the acronym LuPOR describing the clinical practice of luteal phase oocyte retrieval. The aim of the study is to offer insight regarding the identity of LuPOR, and highlight how this practice may improve management of the special subgroup of poor responders. Materials and Methods: The present retrospective observational clinical study includes the collection and statistical analysis of data from 136 poor responders who underwent follicular oocyte retrieval (FoPOR) and subsequent LuPOR in natural cycles, during their In Vitro Fertilization (IVF) treatment, from the time period of 2015 to 2018. All 136 participants were diagnosed with poor ovarian reserve (POR) according to Bologna criteria. The 272 cycles were categorized as follows: 136 natural cycles with only FoPORs (Control Group) and 136 natural cycles including both FoPORs and LuPORs. Results: Our primary results indicate no statistically significant differences with regards to the mean number of oocytes, the maturation status, and fertilization rate between FoPOR and LuPOR in natural cycles. Secondarily, we demonstrate a statistically significant higher yield of oocytes (2.50 ± 0.78 vs. 1.25 ± 0.53), better oocyte maturity status (1.93 ± 0.69 vs. 0.95 ± 0.59) and higher fertilization rate (1.31 ± 0.87 vs. 0.61 ± 0.60) in natural cycles including both FoPOR and LuPOR, when compared to cycles including only FoPOR. Conclusion: Our study may contribute towards the establishment of an efficient poor responders’ management through the natural cycle approach, paving a novel clinical practice and ascertaining the opportunity to employ oocytes and embryos originating from a luteal phase follicular wave.

Does double trigger (GnRH-agonist + hCG) improve outcome in poor responders undergoing IVF-ET cycle? A pilot study

Many strategies are offered for the treatment of poor responders. However, no compelling advantage for one stimulation protocol over another has been hitherto established. In this study, we aimed to evaluate the role of different modes and timings of final follicular maturation trigger, on in vitro fertilization (IVF) cycle outcome of poor responder patients. In the present randomized controlled study, poor responder patients, according to the Bologna criteria, undergoing controlled ovarian hyperstimulation (COH) using the gonadotropin-releasing hormone (GnRH) antagonist protocol were randomly assigned to three different final follicular maturation trigger modes and timings: hCG 36 h before oocyte pick-up (OPU) (hCG trigger); GnRH agonist (GnRHag) 36 h before (OPU) and hCG on day of OPU (GnRHag trigger); and GnRHag and hCG, 40 and 34 h prior to OPU, respectively (double trigger). Pregnancy rate, number of oocytes, and top quality embryos (TQEs). Thirty-three poor responder patients were recruited and randomized to the different study groups. While there were no in-between groups’ differences in patients’ demographics and stimulation variables, patients in the double trigger group had a significantly higher number of TQE (1.1 ± 0.9 vs. 0.3 ± 0.8 and 0.5 + 0.7; p<.02) as compared to the hCG trigger and the GnRH-ag trigger groups, respectively, with an acceptable pregnancy rate. Double trigger offers an additional benefit to poor responder patients. Larger studies are required to support this new concept prior to its implementation to IVF practice.Trial registration: ClinicalTrials.gov identifier: NCT02144818.

Medically Assisted Reproduction in Natural Cycle: Outcome Evaluation of a Reproductive Medicine Department

Medically assisted reproduction in natural cycle has been investigated, especially in women with poor response to conventional ovarian stimulation, with endometrial receptivity improvement, lower cost and possibility of successive cycles. The disadvantages are: lower profitability per treatment cycle and higher cancellation rate. The aim of this study was to determine the rate of clinical pregnancy in infertile women subjected to medically assisted reproduction in natural cycle. Retrospective study of 149 medically assisted reproduction without ovarian stimulation of 50 infertile women, between January/2011 and October/2014. The mean age of women undergoing medically assisted reproduction in natural cycle was 36.1 years. Approximately half (46.0%) of the cycles were performed in poor responders. On the day of ovulation trigger, the mean diameter of the follicle was 17.5 mm. Twenty-three cycles (15.4%) were canceled prior to ovulation trigger. In 8 cycles (5.3%), ovulation occurred between ovulation trigger and oocyte retrieval. In the majority of cycles (n = 118; 79.2%) oocyte retrieval was executed, a medically assisted reproduction technique was performed in 71 (47.6%), mostly intracytoplasmic injection. The overall fertilization rate was 77.5%. In 40 cycles (26.8%) there was embryo transfer. The implantation rate and the clinical pregnancy rate by embryo transfer was 35.0% and 25.0%, respectively. Most pregnancies occurred in poor responders, according to Bologna criteria. Although the pregnancy rate per cycle started was 6.7%, the rate of clinical pregnancy per embryo transfer is quite satisfactory, being a group of women with unfavorable responses in previous treatments. The relatively high rates of cycle cancellation are mitigated by the greater simplicity and lower cost of these cycles. The results obtained in this study demonstrate that Medically Assisted Reproduction in natural cycle may be an alternative treatment for ovarian stimulation in patients with poor prognosis, whose only alternative would be oocyte donation.

Dual stimulation using corifollitropin alfa in 54 Bologna criteria poor ovarian responders – a case series

What are the reproductive outcomes of Bologna criteria poor responders undergoing dual stimulation (DuoStim) and subsequent cryopreserved embryo transfer? Case series of patients treated during the period August 2015 to March 2018 in a public fertility clinic. The study included 54 Bologna criteria poor responder IVF patients younger than 42 years receiving a follicular stimulation (DuoStim 1) followed by a luteal phase stimulation (DuoStim 2) within the same cycle, both stimulations being performed with corifollitropin alfa followed by a subsequent cryopreserved embryo transfer cycle. The primary endpoint was the number of oocytes retrieved in DuoStim 1 compared with DuoStim 2. The secondary endpoint was ongoing pregnancy rate (OPR) at 12 weeks of gestation. The mean number of oocytes retrieved in DuoStim 1 and DuoStim 2 was 2.4±2.1 versus 3.7±2.6, respectively; thus, a total of 1.2 (95% CI, 0.46-1.96) more oocytes was retrieved in DuoStim 2 compared with DuoStim 1 (P=0.002). The OPR at 12 weeks was 20% (11/54) in this poor ovarian response population with a mean age of 36.7 years. Luteal phase stimulation results in more oocytes in poor responders compared with follicular phase stimulation. DuoStim, using corifollitropin alfa followed by individualized FSH dosing, appears to be an alternative to conventional follicular phase stimulation, decreasing the risk of cycle cancellation.

Assisted reproductive technology outcome in poor responders classified by patient-oriented strategies encompassing individualized oocyte number stratification

Aim: This study aims to evaluate the assisted reproductive technology (ART) outcome among various subgroups of poor responders classified by Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria. Successful end point of any ART treatment is live birth, which depends on various factors including adequate number of follicles being stimulated, adequate number of oocytes retrieved, and quality of oocytes, which in turn depends on ovarian response. Usually, success rate is low in women who respond poorly to controlled ovarian stimulation. Bologna criteria have been used in the past to identify poor responders. Heterogeneity of subgroups using the Bologna criteria makes it difficult to manage the poor ovarian responder group. Moreover, specific profiles of abnormal ovarian response like hypo and suboptimal and the age-related embryo/blastocyst aneuploidy rate, which could dramatically change the prognosis in women that have the same oocyte yield were not included in Bologna criteria. The main goal of this study was to evaluate the ART outcome among various subgroups of poor responders defined by the POSEIDON stratification. Materials and Methods: In this retrospective cohort study, the clinical and laboratory records of 260 poor responder women undergoing their first ovarian stimulation and fresh embryo transfer cycle were reviewed. Patients were categorized into 4 groups according to the POSEIDON classification. Results: There was no difference in the fertilization and cleavage rate across the groups, but the blastocyst formation rate was higher in younger patients and reached statistical significance (P Conclusions: Poor responders are a heterogeneous group and not homogenous for pregnancy prospects. Apart from oocytes retrieved, age and ovarian reserve will also modulate the chance of pregnancy which is higher in women

Comparison of GnRH agonist versus luteal estradiol GnRH antagonist protocol using transdermal testosterone in poor responders.

Objective:Transdermal testosterone has been used in different doses and in different stimulation protocols in poor responders. The aim of the present study is to compare the luteal estradiol/GnRH antagonists protocol versus long GnRH agonists in poor responder patients according to the Bologna criteria, in which transdermal testosterone has been used prior to the stimulation with gonadotropins.Methods:In this retrospective analysis, a total of 141 poor responder patients according to the Bologna criteria were recruited. All patients were treated with transdermal testosterone preceding ovarian stimulation with gonadotropins during 5 days. In 53 patients we used the conventional antagonist protocol (Group 1). In 88 patients (GrH pituitary suppression was achieved by leuprolide acetate according to the conventional long protocol (Group 2). We analyzed the ovarian stimulation parameters and IVF outcomes.Results:Comparing groups 1 and 2, there were no significant differences between cancellation rates and number of oocytes retrieved. However the total gonadotropin dose used and the mean length of stimulation were significantly lower in group 1 when compared to group 2. There were no significant differences in pregnancy outcomes; however, there was a slight increase in the implantation rate in group 1 vis-a-vis group 2, although statistical significance was not achieved.Conclusion:TT in poor responder patients can be effective both with the conventional agonist's long protocol and with the conventional antagonist's protocol. However, short regimes with previous estradiol antagonists in the luteal phase facilitate ovarian stimulation by shortening the days of treatment and the consumption of gonadotropins

Pituitary suppression protocol among Bologna poor responders undergoing ovarian stimulation using corifollitropin alfa: does it play any role?

Does the type of pituitary suppression protocol influence cumulative live birth rate (LBR) in Bologna poor responders treated with corifollitropin alfa (CFA)? Retrospective cohort analysis including poor responder patients fulfilling the Bologna criteria who underwent their first intracytoplasmic sperm injection cycle using a CFA-based ovarian stimulation protocol between 2011 and 2017. The starting dose of CFA was 150µg. The primary outcome was cumulative LBR, defined as the first delivery of a live born resulting from the fresh and all the subsequent frozen embryo transfers. A total of 717 cycles were divided into three groups: A (gonadotrophin-releasing hormone [GnRH] antagonist protocol, n=407), B (long GnRH agonist protocol, n=224) and C (short GnRH agonist protocol, n=86). Cumulative LBR did not significantly differ between groups (20.1% versus 17.4% versus 14.0%; P = 0.35). Significantly more patients in Group A had supernumerary embryos cryopreserved (28.3% versus 18.4% versus 11.6%; P<0.001). Days of additional highly purified human menopausal gonadotrophin 300IU injections following CFA were significantly different between Groups A, B and C (3 versus 5 versus 3 days; P<0.001). Multivariate logistic regression analysis showed that the number of oocytes retrieved remained an independent predictive factor (odds ratio 1.23, 95% confidence interval 1.16-1.31) for cumulative LBR. Poor responders according to the Bologna criteria in whom CFA is used for ovarian stimulation had comparable cumulative LBR, irrespective of the type of pituitary suppression. An increase in number of oocytes retrieved is an independent variable related to cumulative LBR.

Double mild stimulation and egg collection in the same cycle for management of poor ovarian responders

PurposeTo evaluate the effect of double stimulations during the follicular and luteal phases in women with poor ovarian response (POR) in in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles. Basic proceduresThis prospective clinical study was performed in Royan Institute from October 2014 to January 2016. 121 patients were diagnosed as POR on the basis of Bologna criteria were included. Double stimulations were performed during the follicular and luteal phases by Letrozole, Clomid, hMG and GnRH-agonist. The patients’ present cycle outcomes were compared with those of the previous cycle results using appropriate statistical tests. Main findingThe total of 104 (85.9%) patients completed the stimulation stages. The analysis revealed the number of retrieved oocytes after the first and second stimulations did not differ (P = 0.2); however, the fertilization rate and the number of frozen embryos after the first stimulation were significantly higher than those of in the second stimulation (P < 0.001 and P = 0.03), indicating the better quality of retrieved oocytes after the first stimulation. The mean number of MII oocytes and the fertilization rate after Shanghai protocol were higher than those of the previous antagonist protocol with a substantial trend toward significance (P = 0.06), which can be clinically important. The cancellation rate (33%) due to no ovarian response and no embryo formation was still high in these patients. Principal conclusionSince the intensity of stimulation in both stages was mild, this protocol can be considered a time-efficient and patient friendly regime; however, more studies are required with emphasis on its cost-effectiveness.

Does the \u201cdelayed start\u201d protocol with gonadotropin-releasing hormone antagonist improve the pregnancy outcome in Bologna poor responders? a randomized clinical trial

BackgroundRecently, a novel approach with delaying the start of controlled ovarian stimulation along with gonadotropin-releasing hormone (GnRH) antagonist pretreatment for 7 days after estrogen priming for further suppression of endogenous follicle stimulating hormone (FSH) during the early follicular phase, resulting in more FSH-responsive follicles and thus improving synchronous follicular development was introduced. Two clinical trials have examined this strategy and reported controversial results. This study aimed to compare the effect of delayed-start GnRH antagonist protocol and standard GnRH antagonist in patients with poor ovarian response (POR) undergoing in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI).MethodsThis randomized clinical trial was conducted at infertility department of Royan Institute from January 2017 to June 2018. Poor ovarian response was defined according to the Bologna criteria. The eligible women were randomly allocated into an experimental and control groups. In experimental group, patients received delayed-start GnRH antagonist protocol with estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin and in control group, patients treated with estrogen priming antagonist protocol. IVF/ICSI outcomes were compared between groups.ResultsAmong all the 250 patients examined 156 women were eligible for study and finally 120 patients were allocated to intervention (n = 60) and control (n = 60) groups. Demographic characteristics and hormonal profiles of the patients did not differ between groups. The statistical analysis showed that there were significant differences between groups regarding the total dose of used gonadotropins (P < 0.001), stimulation duration (P < 0.001), number of retrieved oocytes (P = 0.01) and top quality embryo (P < 0.001) and also cancellation (P = 0.002) and fertilization rates (P = 0.002).ConclusionOn the basis of present results the delayed-start protocol in poor responders can improve the fertilization rate and quality of embryos and reduce the cycle cancellation but have no significant effect on clinical pregnancy rate; however, larger randomized clinical trials are required to compare it with other protocols.Trial registrationNCT, NCT03134690. Registered 1 May 2017 - Retrospectively registered, http://www.clinicaltrial.gov/ NCT03134690.

Bologna criteria are predictive for ovarian response and live birth in subsequent ovarian stimulation cycles

The ESHRE Working Group on Poor Ovarian Response defined a set of variables to define poor responders, named as the Bologna Criteria, but several concerns have been raised regarding their applicability and prognostic significance. In order to evaluate the clinical relevance of the criteria, we retrospectively analyzed the ovarian response and live birth rates in women who had consecutive IVF attempts, according to their fulfillment of the criteria. The study group comprised 1153 and 288 women who had two and three consecutive ovarian stimulation (OS) cycles between May 2010 and January 2017, respectively. We compared the ovarian response and live birth rates in subsequent IVF attempts of Bologna criteria-defined poor responder women and women who did not fulfill the Bologna criteria. Women who fulfilled the criteria achieved higher rates of poor ovarian response (76.2% vs 14.3% and 60.3% vs 13.4%) and lower live birth rates (14.6% vs 33.3% and 12.9% vs 34.3%) in their second and third OS cycles, respectively (both p < 0.001) compared to women who did not fulfill the criteria. The former group also had lower number of oocytes and lower likelihood of having embryo transfer in their subsequent OS cycles. The criteria were able to predict both ovarian response and clinical outcome in the subsequent cycle in < 40-year-old women, whereas they were predictive only for the ovarian response but not for the clinical outcome in women over 40years of age, who exhibited very low live birth rates regardless of the fulfillment of the criteria. The results of this study show that the Bologna criteria are clinically relevant in terms of prediction of ovarian response and clinical outcome in subsequent OS cycles.

Could polymorphisms of some hormonal receptor genes, involved in folliculogenesis help in predicting patient response to controlled ovarian stimulation?

PurposeThe aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in selected genes, responsible for hormonal regulation of folliculogenesis, are associated with response to controlled ovarian hyperstimulation (COH) and clinical characteristics of women enrolled in in vitro fertilization (IVF) programs.MethodsIn a cross-sectional study, 60 (IVF) patients underwent COH by using gonadotropin-releasing hormone (GnRH) antagonist and recombinant follicle-stimulating hormone (rFSH) protocol. Patients were classified into three groups: poor-responders (according to Bologna criteria), normo-responders (≤ 15 oocytes), and hyper-responders (> 15 oocytes). Genotyping of SNPs AMH rs10407022, AMHR rs3741664, FSHR rs1394205 and rs6166, and ESR1 rs2234693 was performed using high-resolution melting analysis (HRMA). Basal FSH (bFSH), estradiol (E2), and anti-Müllerian hormone (AMH) were measured by enzyme-linked immunosorbent assay (ELISA).ResultsPatients with GG genotype of FSHR rs1394205 had significantly lower AMH level (P = 0.016) and required higher rFSH dose per oocyte compared to women with AA or AG genotype (P = 0.036). We also found higher frequency of GG genotype of FSHR rs1394205 in poor- (76.5%) than in hyper-responders (37.5%, P = 0.002). Patients with AA genotype of FSHR rs6166 had higher level of measured bFSH compared to those with AG or GG genotypes (P = 0.043). Women with GG genotype of AMHR rs3741664 required higher rFSH dose in comparison with patients carrying genotypes AA or AG (P = 0.028).ConclusionsThe GG genotype at position rs1394205 is associated with poor ovarian response to COH. Patients with this genotype may require higher doses of rFSH for ovulation induction.

Does the empty follicle syndrome occur in cases of low number of maturing follicles in assisted reproduction?

The pathophysiology of the genuine empty follicle syndrome (EFS) is still debated. Ovarian aging has been contested as a cause of this condition. Our aim was to investigate the occurrence of the genuine EFS in cases of a low number of mature follicles in a prospective manner. Ninety-five infertile women were recruited and evaluated following conventional controlled ovarian stimulation (COS) with ≤ six follicles of ≥14 mm diameter on the day of hCG administration. Enrolled women were 37.5 ± 5.2 years of age with basal FSH level of 9.1 ± 3.7 mIU/L, antral follicle count (AFC) of 6.9 ± 4.6, and number of ≥14 mm follicles (on the day of hCG) of 3.4 ± 1.5. Among the 95 women, four were complicated by the genuine EFS (4.2%) with features of the depleted ovarian reserve. Comparison between these four cases and the 91 controls revealed significant differences between age, AFC, number of ≥14 mm follicles, and serum E2 level corresponding to 41.8 ± 1.7 versus 37.4 ± 5.2 years, 1.7 ± 0.6 versus 7.1 ± 4.5, 2.0 ± 0.8 versus 3.4 ± 1.5 follicles, and 356 ± 200 versus 975 ± 557 pg/mL, respectively. Post hoc analysis revealed that 56 among the 95 women fulfilled the Bologna criteria for poor ovarian response and all four cases matched the definition of the genuine EFS raising its incidence to 7.1% in this group. A logistic regression analysis showed that AFC was a significant factor in the development of the genuine EFS. We conclude that the genuine EFS complicates infertile women characterized by a low number of mature follicles. Our findings suggest that the mechanism behind this occurrence is associated with a more exhausted ovarian reserve.

Should corifollitropin alfa be offered to patients with “genuine” poor response to controlled ovarian hyperstimulation?

Objective: To examine whether poor ovarian response (POR) patients during conventional IVF/ intracytoplasmic sperm injection (ICSI) cycle, may benefit from multiple-dose GnRH-antagonist protocol with 150 mg of corifollitropin alfa via a cohort historical study. at a Tertiary, University affiliated Medical Center. Materials and Methods: Eighteen POR patients, defined according to the Bologna criteria, who underwent a subsequent 150 mg corifollitropin alfa cycle, within three months of the previous failed conventional IVF/ICSI cycle were included. The elimination of bias in this selection, for the purposes of this study, was achieved by including only a subgroup of “genuine” poor responder patients, those who yielded up to three oocytes following COH with a minimal gonadotropin daily dose of 300 IU. One hundred fifty mg corifollitropin alfa, administered on day 2-3 of the menstrual cycle, followed highly purified human menotropin (HP-hMG) or rFSH + rLH from stimulation day 5-6, within a flexible multiple-dose GnRH-antagonist COH cycle. Pregnancy rate, number of oocytes retrieved, number of embryos transferred, and COH variables were assessed. Results: The corifollitropin alfa COH protocol provided a non-significant one more oocyte, with no pregnancies. Considering the equivalence of 150 mg corifollitropin alfa to 2,100 IU of FSH, offering corifollitropin has no cost-effective advantages. Discussion: The corifollitropin alfa COH is of no benefit for “genuine” POR and alternative strategies, such as increasing the daily FSH dose or proceeding to egg-donation, should be seriously considered for this population.

Evaluation of in vitro fertilization outcomes using the FMR1 CGG repeat level and genotypes as a potential marker

Introduction: The correlation between FMR1 and ovarian function is a relatively new field of research. It has been stated that premutation carriers present with higher rates of premature ovarian failure, compared to the general population. In the present study, we attempted to correlate the distribution of FMR1 CGG level and genotypes with the outcome of in vitro fertilization protocol between good and poor responders. Materials and Methods: Sixty-two infertile women were enrolled in the study and subdivided into two groups; one group of 36 good responders and one of 26 poor responders, according to the Bologna criteria. Good responders presented with ≥ 8 oocytes retrieved, basal FSH levels ≤ 10 mIU/ml and peak estradiol (E2) levels of ≥ 1500 pg/ml. Patients in both groups presented with tubal, male and unexplained infertility. Results: The most prevalent genotype in both good and poor responders was the normal type; 46.2% and 52.8%, respectively. The distribution of genotypes between good and poor responders did not statistically differ (p-value 0.256). Regarding the FMR1 genetic background, infertile women carrying a normal genotype had statistically significant higher mean oocyte maturation rates (p=0.026). In the whole study population women not carrying a Low Allele in their Genotype had less mean number of days of stimulation, compared to those carrying a low allele (p-value=0.033). Conclusions: The relative small size of the study population allows for only preliminary results. The random X-inactivation could act as a possible modifier of the impact of FMR1 genotypes in the ovary.

Whether poor responses have worse perinatal prognosis (retrospective analysis of assisted reproductive technologies cycle)

The prevalence of poor ovarian response is 5.6–35.1% in women undergoing controlled ovarian stimulation in ART cycles. The frequency of delivery of poor responders after ART is on average from 9.9% to 23.8%. In clinical practice, the vast majority of poor responders are older women, which may have an effect on perinatal outcomes, respectively. Although numerous studies have reported that the fertility rate after ART in women of this age group is quite low, data on perinatal outcomes in this group of women is limited. Therefore, the aim of our study was to retrospectively analyze and compare perinatal outcomes in women with poor ovarian response to stimulation compared to control group (normal response to stimulation) in assisted reproductive technology programs. 278 women with infertility with a reduced response to stimulation (poor responders), who were the main group, were screened. Indications for the inclusion of women in the main group were the presence of at least two of the following criteria for a poor ovarian response according to the 2011 Bologna criteria and 93 infertile patients with a normal ovarian response to stimulation of the control group. Subsequently, retrospective study of perinatal effects such as preterm labor, low birth weight, gestational diabetes, preeclampsia in 50 women with infertility with reduced response to stimulation and 37 controls with normal response to stimulation in which pregnancy was diagnosed was performed. Variational-statistical processing of the results of the study was performed using the program “Statistica 6.0”. The study demonstrated a significantly lower pregnancy rate in poor responders compared with women from the control group — 50 (17.9%) vs. 37 (39.8%), respectively. Perinatal outcome were similar only to the statistically significant difference in the percentage of spontaneous abortions before 12 weeks of gestation — 9 (18%) vs. 4 (10.8%), respectively, in groups with no significant difference in the preterm labor frequency — 10 (20.8%) and 6 (18.1%) of the low weight of the child at birth — 9 (18.7%) versus 5 (15.1%), respectively, in poor responders patients and in women with normal ovarian response. The frequency of complications such as gestational diabetes and high blood pressure were not significantly different in both clinical groups — 3 (6.25%) versus 2 (6.1%) and 5 (10.4%) versus 3 (9.1%) respectively. Thus, he poor responders in ART programs have a significantly lower pregnancy rate and a higher incidence of pregnancy loss up to 12 weeks compared with women who had a normal response to ovarian stimulation without a significant difference in the rates of various complications of pregnancy and perinatal outcomes. Wide randomized multicentric trials are needed to find out the causal relationships with regard to the effect on pregnancy, miscarriage, perinatal effects of controlled ovarian stimulation regimens, embryotransfers in fresh or cryo cycles etc.

Dehydroepiandrosterone (DHEA) supplementation improves in vitro fertilization outcomes of poor ovarian responders, especially in women with low serum concentration of DHEA-S: a retrospective cohort study

BackgroundDehydroepiandrosterone (DHEA) is now widely used as an adjuvant for in vitro fertilization (IVF) cycles in poor ovarian responders (PORs). Several studies showed that DHEA supplementation could improve IVF outcomes of PORs. However, most of the PORs do not respond to DHEA clinically. Therefore, the aim of this study is to confirm the beneficial effects of DHEA on IVF outcomes of PORs and to investigate which subgroups of PORs can best benefit from DHEA supplementation.MethodsThis retrospective cohort study was performed between January 2015 and December 2017. A total of 151 PORs who fulfilled the Bologna criteria and underwent IVF cycles with the gonadotropin-releasing hormone antagonist protocol were identified. The study group (n = 67) received 90 mg of DHEA daily for an average of 3 months before the IVF cycles. The control group (n = 84) underwent the IVF cycles without DHEA pretreatment. The basic and cycle characteristics and IVF outcomes between the two groups were compared using independent t-tests, Chi-Square tests and binary logistic regression.ResultsThe study and control groups did not show significant differences in terms of basic characteristics. The study group demonstrated a significantly greater number of retrieved oocytes, metaphase II oocytes, fertilized oocytes, day 3 embryos and top-quality embryos at day 3 and a higher clinical pregnancy rate, ongoing pregnancy rate and live birth rate than those measures in the control group. The multivariate analysis revealed that DHEA supplementation was positively associated with clinical pregnancy rate (OR = 4.93, 95% CI 1.68–14.43, p = 0.004). Additionally, in the study group, the multivariate analysis showed that serum dehydroepiandrosterone-sulfate (DHEA-S) levels < 180 μg/dl were significantly associated with a rate of retrieved oocytes > 3 (OR = 5.92, 95% CI 1.48–23.26, p = 0.012).ConclusionsDHEA supplementation improves IVF outcomes of PORs. In PORs with DHEA pretreatment, women with lower DHEA-S level may have greater possibility of attaining more than 3 oocytes.

Does freeze-all policy affect IVF outcome in poor ovarian responders?

To evaluate whether the freeze-all strategy affects in-vitro fertilization (IVF) outcome in poor ovarian responders (POR) defined according to the Bologna criteria. This was a retrospective cohort study of patients undergoing IVF treatment between January 2012 and December 2016 at a single center. A total of 433 POR (as defined by the Bologna criteria) fulfilled criteria and were included in the study; of these, 277 patients underwent fresh embryo transfer (ET) and 156 followed the freeze-all policy. All patients underwent controlled ovarian stimulation (COS) following a gonadotropin-releasing hormone antagonist protocol, and cleavage-stage ET. Main outcome measure was ongoing pregnancy rate. Secondary outcomes included implantation and clinical pregnancy rates. The freeze-all strategy was implemented when the progesterone serum level was > 1.5 ng/mL or the endometrium was < 7 mm on the trigger day, or as per patient preference. Patients with previous failed fresh ET also underwent fresh ET or freeze-all strategy considering the indications mentioned above. Mean maternal age in the freeze-all group was 39.5 ± 3.6 years and in the fresh ET group was 39.7 ± 3.8 years (P = 0.54). Mean number of embryos transferred (nET) was 1.53 ± 0.6 and 1.60 ± 0.6 (P = 0.12) in the freeze-all and fresh ET groups, respectively. Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh ET groups (9.6% vs 10.1%, respectively; relative risk (RR), 0.95; 95% CI, 0.52-1.73), nor did the clinical pregnancy rate (14.1% vs 13.7%, respectively; RR, 1.03; 95% CI, 0.63-1.67). Implantation rate was 9.6% and 9.8% (P = 0.82) in the freeze-all and fresh ET groups, respectively. Logistic regression analysis (including maternal age, antral follicle count, number of retrieved and mature oocytes, nET, and fresh ET vs freeze-all strategy) indicated that maternal age (P < 0.001) and nET (P = 0.039) were the only independent variables associated with ongoing pregnancy rate. The freeze-all strategy, compared with fresh ET, had no impact on IVF outcomes in POR patients as defined according to the Bologna criteria. Multicenter studies including large numbers of patients should be carried out to confirm the results of this study and reach conclusions about the potential benefits of the freeze-all policy for poor responders. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Circulating 25-hydroxyvitamind concentrations among infertile couples and associations with IVF /ICSI outcome

Through examining the level of serum vitamin D in couples undergoing IVF/ICSI, the study was aimed to investigate whether serum vitamin D correlated with fertilization, embryo development and endometrial receptivity in IVF/ICSI. Between March 2016 and March 2017, we performed a large retrospective, non-interventional, single-center cohort study and measured 25OHD plasma levels prior to controlled ovarian stimulation in couples who underwent IVF/ICSI(including 3055 couples). The inclusive criteria were:1) female age between 20 and 42 years old without poor ovarian response according to Bologna criteria; 2) serum basal FSH≤10 mIU/ml. In this study, sperm or egg donation, ovum frozen, no oocyte for fertilization, chromosome abnormalities, congenital dysplasia of gonadal were excluded from this study.We excluded the couples if the time break between serum 25(OH)D measurement and ovum pick-up was over a season. Several statistical methods were employed in this study, including Pearson correlation coefficient, multiple linear regression and regression of binary logistic. The primary outcome were normal fertilization rates, top-quality embryo rates, implantation rates, clinical pregnancy rates and abortion rates. Women were grouped by serum 25OHD quartiles:≦14.8 ng/ml (Q1), 14.9-19.6 ng/ml (Q2), 19.7-24.7 ng/ml (Q3), ≧24.8 ng/ml (Q4). In women undergoing IVF, the baseline characteristics between groups were comparable and normal fertilization rates were 60.06%,62.55%,62.90% and 65.53%, respectively(P=0.003). There was a positive correlation between maternal serum 25OHD conditions and normal fertilization rates (r=0.09, P<0.001). Binary logistic regression was employed to assess whether 25(OH)D groups correlated with low fertilization rate(LFR), in which LFR was set as dependent variable and 25 (OH)D groups as independent variable. Unadjusted odds ratio(OR)was 2.78 (P=0.022) comparing patients with 25OHD in the Q1 versus Q4. After adjusting for confounders, 25OHD ≦14.8 ng/mL (Q1) was associated with 1.86 times more than levels ≧24.8 ng/mL (Q4) of suffering low fertilization rate (OR =2.86, P=0.031). The adjusted ORs for the Q2 and Q3 were indistinguishable from OR = 2.79 (P=0.035) and OR = 1.68 (P=0.318). What’s more, top-quality embryos rates, implantation rates, clinical pregnancy rate, abortion rates and vitamin D levels in women were not correlated. In men, we could not find significant differences in fertilization rates, embryo development and clinical pregnancy rates according to vitamin D status. Maternal vitamin D mainly may have an effect on fertilization process in IVF, but not on embryo development and endometrial receptivity. Besides, fertilization, embryo development and endometrial receptivity were not correlated with serum 25 OHD levels in men. Further randomized controlled trials about vitamin D supplementation and fertilization process were merited.

Conventional versus minimal ovarian stimulation: an intra-patient comparison of ovarian response in poor-responder women according to Bologna Criteria.

Is minimal ovarian stimulation (MOS) as effective as conventional ovarian stimulation (COS) in ovarian response and embryo quality in the same 46 poor-responder patients according to the Bologna criteria? An intra-patient comparison of patients undergoing both protocols. Ovaries were stimulated with either a gonadotrophin-releasing hormone antagonist protocol and a combination of recombinant FSH and highly purifiedhuman menotrophin(HP-HMG) daily (COS), or with the use of clomiphene citrate 50 mg daily and 150 IU of HP-HMG or recombinant FSH every other day from simulation day 4 (MOS). After MOS, significantly more good-quality embryos (1.0 ± 1.2 versus 0.3 ± 0.6) (P = 0.002), oocytes (3.2 ± 1.9 versus 2.0 ± 1.8) (P = 0.002), and mature (metaphase II) oocytes (2.6 ± 1.7 versus 1.6 ± 1.7) (P = 0.001) were obtained. In COS cycles, a significantly higher total gonadotrophin dose was needed per good-quality embryo (+2194 IU; 95% CI 618 to 3170). In poor responder patients, MOS is a good alternative when COS has failed, or even as a first-line treatment. It offered a significantly greater number of good-quality embryos as well as a higher number of oocytes, using significantly lower doses of gonadotrophins per oocyte and embryo obtained.