Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger and freeze-all strategy in GnRH antagonist protocol; case report and literature review.

Ovarian hyperstimulation syndrome (OHSS) is characterized by increased vascular permeability, hemoconcentration and fluid leakage to the third space. The vast majority of OHSS cases occur following ovarian stimulation for IVF. This potentially lethal iatrogenic condition is one of the most serious complications of assisted reproductive technologies. We report one case of severe early OHSS after GnRH agonist trigger in a GnRH antagonist protocol and freeze-all approach without the administration of any hCG for luteal-phase support in a 34-year-old case of PCO with 7 years primary infertility. After oocyte retrieval the patient was seen at the emergency unit of the hospital with abdominal distension, pain, anuria, dyspnea, and OHSS symptoms. The diagnosis was OHSS with severe ascitis. She was admitted to the Intensive care unit (ICU). She was managed with oxygen by mask, intravenous fluids, anticoagulant and albumen, we performed a two-time vaginal ascites puncture, resulting in the removal of 7800mL of clear fluid in Intensive Care Unit with full recovery. This case study presents the clinical manifestations, investigation, progress, management, outcome and preventive measures. The patient was managed with no complications. Clinicians have to be aware that even the sequential approach to ovarian stimulation with a freeze-all approach and GNRH analog triggering does not completely eliminate OHSS in all patients.

Three successful births after three consecutive embryo transfers.

In the last decade, frozen embryo transfer (FET) has become the preferred option for certain groups of patients rather than fresh embryo transfer. The apparent superiority of FET may be explained by improved endometrial receptivity outside stimulated cycles. In this context, our study seeks to contribute to this discussion by reporting a case involving a certain degree of originality and a success rate not commonly seen in ART. This case demonstrates that both fresh and frozen embryo transfer are good treatment options.

Fresh versus elective frozen embryo transfer: Cumulative live birth rates of 7,236 IVF cycles.

OBJECTIVE: To determine whether elective frozen embryo transfer (eFET), or the 'freeze-all' strategy, associated with better cumulative clinical outcomes compared with fresh embryo transfer (ET). METHODS: A total of 7,236 IVF cycles that were followed by a fresh ET or eFET between 2013 and 2017. The patients were subjected to controlled ovarian stimulation (COS) with a gonadotropin-releasing hormone (GnRH) antagonist protocol and cleavage-stage ET. Embryo cryopreservation was performed on day 3 by vitrification using an open system. A comparison of cumulative outcomes between the eFET (n=4,065cycles) and the fresh ET groups (n=3,171cycles) were performed. The analysis was performed in four groups of patients based on the number of retrieved oocytes: Group 1: poor responders (1-3 oocytes); Group 2: suboptimal responders (4-9 oocytes); Group 3: normal responders (10-15 oocytes); and Group 4: hyper-responders (>15 oocytes). The primary outcome was the cumulative live birth rate (CLBR) per stimulated cycle. RESULTS: There were a total of 10,283 ETs (n=5,639 eFET group; n=4,644 fresh group). The freeze-all strategy is associated with improved CLBRs in normal and hyper-responders, but not in suboptimal and poor responders. In Group 1, there were 351 IVF cycles and 387 ETs in total, and the CLBR was 14.3% and 17.7% (p=0.584) for the eFET and fresh group, respectively. In Group 2, there were 2,074 IVF cycles and 2,465 ET in total, and the CLBR was 25.1% and 23.3% (p=0.083) in the eFET and fresh group, respectively. There was a significant difference in the CLBR in Groups 3 and 4, favouring the eFET strategy. In Group 3, 2226 IVF cycles and 3243 ET were performed. The CLBR was 40.5% in the eFET and 36.6% in the fresh group (p<0.001). In Group 4, there were 2547 IVF cycles and 3,188 ET in total, and the CLBR was 52.2% and 47.7% (p<0.001) in the eFET and fresh group, respectively. The number needed to treat to achieve one additional live birth was 25.9 in Group 3 and 22.3 in Group 4. CONCLUSIONS: The implementation of the freeze-all strategy should be individualized. The freeze-all strategy is associated with improved CLBRs in normal and hyper-responders, but not in suboptimal and poor responders.

Freeze-all en reproducción asistida

Los avances en los protocolos de vitrificación y los resultados obtenidos tras la transferencia de embriones congelados han dado lugar a una versión distinta de los ciclos estándar de reproducción asistida: los ciclos freeze-all. Independientemente de su uso frente a las indicaciones más comunes (progesterona elevada, riesgo de hiperestimulación, entre otros), este nuevo concepto hoy representa una práctica habitual en muchas clínicas siendo aplicado a todas las pacientes. En este artículo analizaremos los distintos factores que pudieron haber contribuido a este cambio de política y la evidencia científica en relación al tema. Basados en esta evidencia concluiremos si las clínicas deberían cambiar su forma de trabajo pasando de transferencias de embriones frescos a solo transferencia de embriones congelados o si deberíamos mantener el protocolo estándar.

Breakthroughs in vitrification protocols and the results obtained after frozen embryo transfer have resulted in a different version of the assisted reproduction standard cycles: the "freeze-all" cycles. Regardless of their use beyond the usual indications (elevated progesterone, risk of hyperstimulation, among others), this new concept currently represents a common practice in many institutions and is applied to all patients. In this article, we will discuss the various factors that may have contributed to this change in policy and the scientific evidence for this topic. Based on this evidence, we will conclude if clinics should change their way of working from fresh embryo transfers to only transfer frozen embryos, or if we should maintain the standard protocol.

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

OBJECTIVE: To evaluate whether the freeze-all strategy affects in-vitro fertilization (IVF) outcome in poor ovarian responders (POR) defined according to the Bologna criteria. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Fresh embryos versus freeze-all embryos - transfer strategies: Nuances of a meta-analysis.

OBJECTIVE: The present meta-analysis aimed to evaluate whether the freeze-all strategy (Freeze/All-ET) could bring about improvements in the clinical assisted reproductive technique (ART) outcomes when compared with the fresh embryo transfer strategy (Fresh-ET) in patients undergoing an ART cycle in accordance with the mean number of oocytes collected. METHODS: A systematic review based on electronic searches in databases (PubMed, EMBASE, Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials) was carried out to identify randomized controlled trails (RCTs) comparing ART outcomes between fresh-embryo transfers versus elective frozen-embryo transfers up to February of 2017. Four reviewers independently evaluated abstracts, validity assessment and data extraction. Odds Ratio (OR) values with a 95% confidence interval (CI), and heterogeneity were evaluated. RESULTS: Five RCTs were included as targets for data extraction and meta-analysis purposes. The results of this meta-analysis were divided into two parts (Freeze/All-ET versus Fresh-ET): Part I- All trials in which the mean number of collected oocytes was >12 and <21 for ongoing pregnancy rate (OR=1.24; 95%CI=1.06-1.44), clinical pregnancy rate (OR=1.19; 95%CI=0.98-1.43), live birth rate (OR= 1.39; 95%CI=0.99-1.95), and miscarriage rate (OR=0.68; 95%CI=0.46-1.00); Part II- Three studies where the mean number of oocytes retrieved was >12 and <15 for ongoing pregnancy rate (OR=1.17; 95%CI=1.00-1.38), clinical pregnancy rate (OR=1.34; 95%CI=0.79-2.28), live birth rate (OR= 1.24; 95%CI=1.00-1.55), and miscarriage rate (RR=0.68; 95%CI=0.46-1.02). CONCLUSIONS: The freeze-all strategy could be favorable when high numbers of oocytes are collected, signaling an association between higher ovarian stimulation and consequent impairment of endometrial receptivity. However, when the mean number of oocytes collected is <15, the freeze-all strategy does not appear to be advantageous.

Freeze-all cycle in reproductive medicine: current perspectives.

The freeze-all strategy has emerged as an alternative to fresh embryo transfer (ET) during in vitro fertilization (IVF) cycles. Although fresh ET is the norm during assisted reproductive therapies (ART), there are many concerns about the possible adverse effects of controlled ovarian stimulation (COS) over the endometrium. The supra-physiologic hormonal levels that occur during a conventional COS are associated with modifications in the peri-implantation endometrium, which may be related to a decrease in pregnancy rates and poorer obstetric and perinatal outcomes when comparing fresh to frozen-thawed embryo transfers. The main objective of this study was to assess the available literature regarding the freeze-all strategy in IVF cycles, in regards to effectiveness and safety. Although there are many potential advantages in performing a freeze-all cycle over a fresh ET, it seems that the freeze-all strategy is not designed for all IVF patients. There is a need to develop a non-invasive clinical tool to evaluate the endometrial receptivity during a fresh cycle, which enables the selection of patients that would benefit from this strategy. Today, it is reasonable to perform elective cryopreservation of all oocytes/embryos in cases with a risk of OHSS development, and in patients with supra-physiologic hormonal levels during the follicular phase of COS. It is not clear if all normal responders and poor responders may benefit from this strategy.

Freeze-all cycle for all normal responders?

PURPOSE: The purpose of this study is to evaluate the freeze-all strategy in subgroups of normal responders, to assess whether this strategy is beneficial regardless of ovarian response, and to evaluate the possibility of implementing an individualized embryo transfer (iET) based on ovarian response. METHODS: This was an observational, cohort study performed in a private IVF center. A total of 938 IVF cycles were included in this study. The patients were submitted to controlled ovarian stimulation (COS) with a gonadotropin-releasing hormone (GnRH) antagonist protocol and a cleavage-stage day 3 embryo transfer. We performed a comparison of outcomes between the fresh embryo transfer (n = 523) and the freeze-all cycles (n = 415). The analysis was performed in two subgroups of patients based on the number of retrieved oocytes: Group 1 (4-9 oocytes) and Group 2 (10-15 oocytes). RESULT(S): In Group 1 (4-9 retrieved oocytes), the implantation rates (IR) were 17.9 and 20.5% (P = 0.259) in the fresh and freeze-all group, respectively; the ongoing pregnancy rates (OPR) were 31 and 33% (P = 0.577) in the fresh and freeze-all group, respectively. In Group 2 (10-15 oocytes), the IR were 22.1 and 30.1% (P = 0.028) and the OPR were 34 and 47% (P = 0.021) in the fresh and freeze-all groups, respectively. CONCLUSION(S): Although the freeze-all policy may be related to better in vitro fertilization (IVF) outcomes in normal responders, these potential advantages decrease with worsening ovarian response. Patients with poorer ovarian response do not benefit from the freeze-all strategy.

Comparación de la tasa de embarazo con embriones desvitrificados transferidos por ciclo natural vs ciclo con preparación endometrial / Comparison of pregnancy rate for embryos transferred in natural cycle vs cycles with endometrial preparation

Resumen OBJETIVO: comparar la tasa de embarazo en ciclos de transferencia de embriones vitrificados versus ciclos naturales y con preparación endometrial. MATERIALES Y MÉTODOS: estudio comparativo, observacional y retrospectivo efectuado mediante la revisión de expedientes clínicos de procedimientos de fertilización in vitro efectuados entre enero de 2010 y diciembre de 2013. Los casos se dividieron en dos grupos: ciclo natural y preparación endometrial. Se analizaron las variables de edad, IMC, FSH, LH y estradiol al inicio del ciclo, progesterona el día del inicio del soporte lúteo, LH, y estradiol el día de transferencia, supervivencia embrionaria, número de embriones transferidos, calidad embrionaria y tasa de embarazo. Posterior al análisis principal los grupos se dividieron, nuevamente, de acuerdo con la calidad embrionaria. RESULTADOS: se revisaron 951 expedientes clínicos en los que se identificaron y analizaron 75 ciclos que reunieron los criterios de inclusión. No se encontraron diferencias en porcentaje de supervivencia embrionaria o número de embriones transferidos, ni en la tasa de embarazo entre los grupos. En el grupo con embriones de calidad regular se observó una diferencia significativa en las tasas de embarazo en transferencia en ciclo natural (15%) versus ciclos con preparación endometrial (33.3%) con una p significativa de 0.02. CONCLUSIONES: cuando la calidad embrionaria es regular, la tasa de embarazo es mayor que cuando la transferencia se efectúa en un ciclo con preparación endometrial.

Abstract OBJECTIVE: Compare pregnancy rates of thawed embryo transfer between natural cycle and endometrial preparation. MATERIALS AND METHODS: This is a comparative, retrospective, observational study. 951 medical files where reviewed in the from January 2010 to January 2014. 75 files met with the inclusion criteria. The cycle where divided into two groups. The first group, thawed embryos where transferred during a natural cycle without any hormonal therapy. The second group, thawed embryos where transferred to a prepared endometrium with GnRH agonist and exogenous estrogen. Two embryos where transferred if the patient had two or more viable thawed embryos and one in all other cases. Variables analyzed in both groups where, age, body mass index, FSH, LH, and estrogen at the beginning of the cycle, progesterone on the day of initiating luteal support, LH and estradiol the day of embryo transfer, post-thaw embryo survival rate, number of embryos transferred, embryo quality and pregnancy rate. Groups where then divided according to the embryo quality forming a good quality cohort and a regular quality cohort. In both groups transfers during a natural cycle where compared with embryo transfer to a prepared endometrium. RESULTS: There was no difference observed in embryo survival or number of embryos transferred between both groups. Embryo quality was statistically better in the group with prepared endometrium. There was no statistical significant difference in pregnancy rate between the two groups. In cycles with good quality embryos there was no statistical difference in pregnancy rate when embryos where transferred during a natural cycle versus those transferred to a prepared endometrium. In cycles with regular quality embryos there was a statistical significant difference in pregnancy rate. Pregnancy rate for thawed-embryo transfer during a natural cycle was 15% and 33.3% when the transfer was to a prepared endometrium (p = 0.02). CONCLUSION: Endometrial preparation increases de pregnancy rate when regular quality thawed-embryos are transferred.

Freeze-all, oocyte vitrification, or fresh embryo transfer? Lessons from an egg-sharing donation program.

OBJECTIVE: To compare the outcomes of ETs using cryopreserved embryos, cryopreserved oocytes, or fresh embryos. DESIGN: Observational, cohort study. SETTING: Private university-affiliated fertility center. PATIENT(S): This study included 8,210 mature oocytes obtained from 425 oocyte donors. Of those, 5,440 were used for the donors' own cycles (Fresh Oocyte Cycles Group), and 2,770 were cryobanked for 425 recipients (Banked Donor Egg Group). All of the oocytes were sperm injected, resulting in 4,585 embryos from the donors' own cycles and 2,128 embryos from the recipients' cycles. For the donor cycles, embryos were either cryopreserved and transferred during a subsequent cycle (Thaw Cycles Group, 3,209 embryos), or they were transferred during a fresh cycle (Fresh Cycles Group, 1,307 embryos). For the recipient cycles, embryos derived from vitrified oocytes were transferred (Vitrified Oocytes Group, n = 425 cycles, 2,128 embryos). INTERVENTION(S): Oocyte/embryo vitrification and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Embryo quality, pregnancy, and implantation rates. RESULT(S): Decreased embryo quality and lower rates of blastocyst formation were observed among embryos derived from vitrified oocytes. The highest pregnancy and implantation rates were noted for the Thaw Cycles Group, followed by the Banked Donor Egg Group; the Fresh Cycles Group had the lowest rates. CONCLUSION(S): Oocyte vitrification followed by intracytoplasmic sperm injection leads to lower embryo developmental competence compared with when fresh insemination methods are used. However, pregnancy and implantation rates are higher when embryos are transferred into a "more receptive" endometrium, free of the adverse effects of gonadotropin. Moreover, the freeze-all method leads to exceptional clinical outcomes.

Cost-Effectiveness of the Freeze-All Policy.

OBJECTIVE: To evaluate the cost-effectiveness of freeze-all cycles when compared to fresh embryo transfer. METHODS: This was an observational study with a cost-effectiveness analysis. The analysis consisted of 530 intracytoplasmic sperm injection (ICSI) cycles in a private center in Brazil between January 2012 and December 2013. A total of 530 intracytoplasmic sperm injection (ICSI) cycles - 351 fresh embryo transfers and 179 freeze-all cycles - with a gonadotropin-releasing hormone (GnRH) antagonist protocol and day 3 embryo transfers. RESULTS: The pregnancy rate was 31.1% in the fresh group and 39.7% in the freeze-all group. We performed two scenario analyses for costs. In scenario 1, we included those costs associated with the ICSI cycle (monitoring during controlled ovarian stimulation [COS], oocyte retrieval, embryo transfer, IVF laboratory, and medical costs), embryo cryopreservation of supernumerary embryos, hormone measurements during COS and endometrial priming, medication use (during COS, endometrial priming, and luteal phase support), ultrasound scan for frozen- thawed embryo transfer (FET), obstetric ultrasounds, and miscarriage. The total cost (in USD) per pregnancy was statistically lower in the freeze-all cycles (19,156.73 ± 1,732.99) when compared to the fresh cycles (23,059.72 ± 2,347.02). Even in Scenario 2, when charging all of the patients in the freeze-all group for cryopreservation (regardless of supernumerary embryos) and for FET, the fresh cycles had a statistically significant increase in treatment costs per ongoing pregnancy. CONCLUSIONS: The results presented in this study suggest that the freeze-all policy is a cost-effective strategy when compared to fresh embryo transfer.