Risk Of Ovarian Hyperstimulation Syndrome Research Articles

Gonadotropin versus Follicle-Stimulating Hormone for Ovarian Response in Patients Undergoing in vitro Fertilization: A Retrospective Cohort Comparison

Poor ovarian responders generally refer to patients who respond poorly to ovarian stimulation for assisted reproductive techniques (ART) such as in-vitro fertilization (IVF) and hence experience low live birth rate. Various controlled ovarian stimulation (COS) protocols have been developed during the past 3 decades for IVF/ICSI to improve oocyte quality and ultimately live birth rate, to increase ovarian response in POR patients, and to reduce the risk of ovarian hyperstimulation syndrome. Both highly puri?ed human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) have been widely used for COS during IVF/ICSI. Their in?uence on treatment outcome in women undergoing IVF/ICSI hasbeen actively debated. To compare highly purified human menopausal gonadotropin (hp-hMG) and recombinant follicle-stimulating hormone (rFSH) in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. This retrospective cohort study included 60 patients with poor ovarian response (30 received hp-hMG and 30 received rFSH) undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol. Pregnancy-related outcomes, ovarian response, oocyte, and embryo parameters were compared between the 2 groups. Additionally, serum insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels on the day of oocyte retrieval were compared between the 2 groups. The 2 treatments resulted in comparable numbers of oocytes retrieved and embryos, comparable oocyte retrieval rate, mature oocyte rate, and fertilization rate, and also comparable clinical pregnancy rates, implantation rates, and miscarriage rate. However, hp-hMG led to statistically insignificant higher viable embryo rate (54.0% vs 44.8%; P = 0.174) and live birth rate per pregnancy (16.7% vs 10%) versus rFSH. Finally, statistically significantly higher serum insulin-like growth factor-1 level (178.53 [13.70] ng/mL vs 164.93 [12.17] ng/mL; P = 0.01) and statistically insignificantly lower serum insulin-like growth factor binding protein-1 level (19.53 [3.56] ng/mL vs the lower insulin-like growth factor binding protein-1 level SD is (2.76 [20.83] ng/mL; P > 0.05) on the day of oocyte retrieval were associated with hp-hMG versus rFSH. hp-HMG and rFSH did not lead to significantly different treatment outcomes in patients with poor ovarian response undergoing in vitro fertilization/intracytoplasmic sperm injection with a gonadotropin-releasing hormone antagonist protocol, although significantly higher serum insulin-like growth factor-1 level and insignificantly lower serum insulin-like growth factor binding protein-1 level on the day of oocyte retrieval associated with hp-HMG might suggest a beneficial endocrine environment. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Reproductive Outcomes of Women with Polycystic Ovarian Syndrome Following In-Vitro Fertilization — A Meta-Analysis and Systematic Review

Background: Polycystic ovarian syndrome (PCOS) is a common cause of infertility in women. In-vitro fertilization (IVF) is required in 20–30% of women with PCOS trying to conceive. This is associated with increased risk of multiple gestation and ovarian hyperstimulation syndrome. Improvements in IVF techniques, safety standards, and the increased use of frozen embryos in recent years have lead to improved outcomes for women with PCOS. We performed a systematic review and meta-analysis to compare these outcomes with women without PCOS. Search Methods: A search of PubMed, EMBASE, the Cochrane Central Register of clinical trials, and Scopus databases for all articles published until November 16th, 2017 identified 21 studies comparing IVF outcomes in PCOS and non-PCOS women. Inclusion criteria were Rotterdam criteria PCOS, comparable IVF regimes, immediate IVF outcomes, and pregnancy outcomes. Studies were excluded if the control group included any PCOS criteria, donor oocytes, or in-vitro maturation. Outcomes: No difference was observed in live birth rate per cycle in women with vs. without PCOS (RR [Formula: see text] 1.01 [0.89, 1.16]; [Formula: see text] 82%), but the live birth rate per first cycle in PCOS cycles (RR [Formula: see text] 0.93 [0.88, 0.99]) was slightly lower. There was also no difference in the clinical pregnancy rate (RR 1.02 [0.89, 1.17]) or biochemical pregnancy rate (RR 1.03 [0.99, 1.08]) observed between the two groups. PCOS was associated with a significantly higher number of oocytes retrieved (mean difference [Formula: see text] 3.6; 95% CI [2.8, 4.4]), risk of miscarriage (RR 2.90 [2.09, 4.02]), and risk of ovarian hyperstimulation syndrome (RR 3.42 [2.28, 5.13]) per cycle. Conclusion: Despite a widespread perception of poor reproductive potential, women with PCOS experience IVF outcomes similar to those without PCOS. Although there is a slightly lower live birth rate during their first stimulation cycle, success rates are similar after multiple cycles. PCOS is associated with a higher risk of ovarian hyperstimulation syndrome. Further studies are required to mitigate this risk.

Effects of pre-pregnancy body mass index on pregnancy and perinatal outcomes in women with PCOS undergoing frozen embryo transfer

BackgroundPrevious studies have shown that among women with polycystic ovary syndrome who have difficulties conceiving, frozen-embryo transfer resulted in increased live birth rates and decreased ovarian hyperstimulation syndrome risk than did fresh-embryo transfer. In the present retrospective analysis, we sought to determine the effect of body mass index (BMI) on pregnancy and perinatal outcomes in women with PCOS undergoing FET.MethodsWomen with PCOS (n = 1556) undergoing FET were divided into groups based on weight, with those with normal weight having a BMI of 18.5–24.9 kg/m2,those who were overweight having a BMI of 25–29.9 kg/m2, and those who were obese having a BMI ≥30 kg/m2. Both pregnancy and perinatal outcomes were compared among these groups.ResultsThe normal-weight, overweight, or obese groups exhibited similar pregnancy outcomes, including clinical pregnancy rate, miscarriage rate, ongoing pregnancy rate and live birth rate. In singletons, birth characteristics regarding newborn gender, gestational age, birthweight and length at birth were comparable between the three groups. For adverse neonatal outcomes, the three groups showed no significant differences on the rates of low birthweight, very low birthweight, preterm birth, and very preterm birth after adjustment. In addition, the obstetric complications and the frequencies of live-birth defects were also comparable between the three groups except that overweight and obese women were more likely than women of normal weight to have delivered via cesarean section.ConclusionBMI did not affect the pregnancy or perinatal outcomes in women with PCOS undergoing FET.

Perinatal and maternal outcome after vitrification of blastocysts: a Nordic study in singletons from the CoNARTaS group.

Is transfer of vitrified blastocysts associated with higher perinatal and maternal risks compared with slow-frozen cleavage stage embryos and fresh blastocysts? Transfer of vitrified blastocysts is associated with a higher risk of preterm birth (PTB) when compared with slow-frozen cleavage stage embryos and with a higher risk of a large baby, hypertensive disorders in pregnancy (HDPs) and postpartum hemorrhage (PPH) but a lower risk of placenta previa when compared with fresh blastocysts. Transfer of frozen-thawed embryos (FETs) plays a central role in modern fertility treatment, limiting the risk of ovarian hyperstimulation syndrome and multiple pregnancies. Following FET, several studies report a lower risk of PTB, low birth weight (LBW) and small for gestational age (SGA) yet a higher risk of fetal macrosomia and large for gestational age (LGA) compared with fresh embryos. In recent years, the introduction of new freezing techniques has increased treatment success. The slow-freeze technique combined with cleavage stage transfer has been replaced by vitrification and blastocyst transfer. Only few studies have compared perinatal and maternal outcomes after vitrification and slow-freeze and mainly in cleavage stage embryos, with most studies indicating similar outcomes in the two groups. Studies on perinatal and maternal outcomes following vitrified blastocysts are limited. This registry-based cohort study includes singletons born after frozen-thawed and fresh transfers following the introduction of vitrification in Sweden and Denmark, in 2002 and 2009, respectively. The study includes 3650 children born after transfer of vitrified blastocysts, 8123 children born after transfer of slow-frozen cleavage stage embryos and 4469 children born after transfer of fresh blastocysts during 2002-2015. Perinatal and maternal outcomes in singletons born after vitrified blastocyst transfer were compared with singletons born after slow-frozen cleavage stage transfer and singletons born after fresh blastocyst transfer. Main outcomes included PTB, LBW, macrosomia, HDP and placenta previa. Data were obtained from the CoNARTaS (Committee of Nordic ART and Safety) group. Based on national registries in Sweden, Finland, Denmark and Norway, the CoNARTaS cohort includes all children born after ART treatment in public and private clinics 1984-2015. Outcomes were assessed with logistic multivariable regression analysis, adjusting for the country and year of birth, maternal age, body mass index, parity, smoking, parental educational level, fertilisation method (IVF/ICSI), single embryo transfer, number of gestational sacs and the child's sex. A higher risk of PTB (<37weeks) was noted in the vitrified blastocyst group compared with the slow-frozen cleavage stage group (adjusted odds ratio, aOR [95% CI], 1.33 [1.09-1.62]). No significant differences were observed for LBW (<2500g), SGA, macrosomia (≥4500g) and LGA when comparing the vitrified blastocyst with the slow-frozen cleavage stage group. For maternal outcomes, no significant difference was seen in the risk of HDP, placenta previa, placental abruption and PPH in the vitrified blastocyst versus the slow frozen cleavage stage group, although the precision was limited.When comparing vitrified and fresh blastocysts, we found higher risks of macrosomia (≥4500g) aOR 1.77 [1.35-2.31] and LGA aOR 1.48 [1.18-1.84]. Further, the risks of HDP aOR 1.47 [1.19-1.81] and PPH aOR 1.68 [1.39-2.03] were higher in singletons born after vitrified compared with fresh blastocyst transfer while the risks of SGA aOR 0.58 [0.44-0.78] and placenta previa aOR 0.35 [0.25-0.48] were lower. Since vitrification was introduced simultaneously with blastocyst transfer in Sweden and Denmark, it was not possible to explore the effect of vitrification per se in this study. The results from the change of strategy to vitrification of blastocysts are reassuring, indicating that the freezing technique per se has no major influence on the perinatal and maternal outcomes. The higher risk of PTB may be related to the extended embryo culture rather than vitrification. The study is part of the ReproUnion Collaborative study, co-financed by the European Union, Interreg V ÖKS. The study was also financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (LUA/ALF 70940), Hjalmar Svensson Research Foundation and NordForsk (project 71 450). There are no conflicts of interest to declare. ISRCTN11780826.

Association between body mass index and oocyte maturation in patients triggered with GnRH agonist who are at high risk for severe ovarian hyperstimulation syndrome: an observational cohort study.

Is body-mass index (BMI) associated with oocyte maturation in women at high risk for developing severe ovarian hyperstimulation syndrome (OHSS) who are triggered with gonadotrophin releasing hormone (GnRH) agonist? Prospective observational cohort study. A total of 113 patients at high risk for severe OHSS (presence of at least 19 follicles ≥11 mm) pre-treated with gonadotrophin releasing hormone (GnRH) antagonists and recombinant FSH were administered 0.2 mg triptorelin to trigger final oocyte maturation. Patients were classified in two groups depending on their BMI: ΒΜΙ less than 25 kg/m2 (n = 72) and ΒΜΙ 25 kg/m2 or over (n = 41). Baseline, ovarian stimulation and embryological characteristics, as well as luteal-phase hormone profiles, were compared in patients classified into the two BMI groups. The main outcome measure was the number of mature oocytes. A significantly higher number of mature (metaphase II) oocytes (19 [18-21] versus 16 [13-20], P = 0.029) was present in women with BMI less than 25 kg/m2 compared with those with BMI 25 kg/m2 or greater. The number of retrieved oocytes, the number of fertilized oocytes, oocyte retrieval, maturation and fertilization rates were similar in the two groups. A significantly higher dose of recombinant FSH was required for patients with BMI 25 kg/m2 or greater compared with patients with BMI less than 25 kg/m2 (1875 [1650-2150] IU versus 1650 [1600-1750] IU, P = 0.003) and the two groups displayed different luteal phase hormonal profiles. Among women at high risk for developing severe OHSS who are triggered with a standard dose (0.2 mg) of the GnRH agonist triptorelin, women with BMI 25 kg/m2 or greater had significantly fewer mature oocytes, required a higher total dose of recombinant FSH compared with women with BMI less than 25 kg/m2.

Serum Anti-Mullerian Hormone, Follicle Stimulating Hormone and Antral Follicle Count Measurement as a Prediction for Pregnancy Rates in IVF/ICSI cycle

Background: A successful in vitro fertilization treatment depends on the ability of the ovary to respond to gonadotrophin stimulation. This response reflects the ovarian function or ‘ovarian reserve’. Poor ovarian response may be associated with reduced number of oocytes and embryos and may lead to cycle cancellation in severe cases. On the other hand, exaggerated response leads to increased risk of ovarian hyper-stimulation syndrome. Objective: The aim of this study is to assess role of serum AMH, FSH and AFC measurement as a prediction of pregnancy rates in IVF/intracytoplasmic sperm injection (ICSI) cycle. Patients and Methods: A prospective cross sectional study was conducted at Specialized Air Forced Hospital in the period between January 2018 and December 2018. The study included 100 unexplained infertility patients undergoing IVF/ICSI treatment cycles. They were 82 patients primary infertility and 18 patients secondary infertility. Results: Type of infertility showed insignificant difference between the 2 groups while menstrual history and gonadotrophins type showed significant difference. Age and duration of infertility were significantly higher in nonpregnant group than pregnant. The mean value of FSH, day 3 E2 levels did not have any significant difference between the 2 group while the mean value of serum E2 the day of HCG injection, serum AMH day 3, AFC were significantly higher in pregnant group than non-pregnant. Conclusion: No test can predict pregnancy in high accuracy as it is multifactorial however, mean levels of FSH, E2, a day HCG injection and AFC showed significant difference between pregnant and non-pregnant.

Is oocyte maturity influenced by ovulation trigger type in oocyte donation cycles?

The aim of this study was to compare clinical and laboratory outcomes between GnRHa, dual and HCG triggers in altruistic oocyte donation cycles. Normal or high responders were given either gonadotropin releasing hormone agonist (GnRHa) or a dual trigger of GnRHa and a low dose of human chorionic gonadotropin (HCG). Low responders were given HCG trigger. In 333 cycles, 232 (69.7%) received GnRHa trigger, 59 (17.7%) received dual trigger and 42 (12.6%) had HCG trigger. The total number of mature oocytes retrieved and cryopreserved were significantly higher in the GnRHa and dual trigger groups, compared to the HCG group (p < 0.001). However, the ovarian hyperstimulation syndrome (OHSS) rate was significantly higher in the dual trigger group (n = 5 (8.5%)), compared to the GnRH agonist (n = 1 (0.4%)) and HCG groups (n = 0 (0%)) (p = 0.001). GnRHa trigger maximises mature oocyte yields in oocyte donors suspected of normal and high response but offers a significant reduction in OHSS risk compared to dual trigger. As such, dual trigger should not be used in oocyte donation. HCG trigger can also be used with a very low risk of OHSS at low risk of OHSS in carefully selected donors where GnRHa is unlikely to be effective.

The role of Letrozole (LE) in controlled ovarian stimulation (COS) in patients at high risk to develop ovarian hyper stimulation syndrome (OHSS). A prospective randomized controlled pilot study

BackgroundRecently, it has been shown that PCOS patients with extremely high anti-Mullerian hormone (AMH) level are more likely to experience OHSS during IVF, compared to PCOS patients with lower AMH level. While recent data questioned the effect of Letrozole (LE) on the occurrence of OHSS in non-PCOS patients, it role in PCOS patients with very high AMH level was never investigated in a prospective manners. Hence, our main objective was to evaluate the clinical outcome of PCOS patients at very high risk for OHSS undergoing two different COS protocols (with or without LE). MethodsA prospective randomized controlled study (RCT) of 51 patients with specifically high levels of AMH undergoing one of two COS protocols. The control group (group A) consisted of 24 PCOS women who received low-dose gonadotropins using the multiple-dose GnRH-antagonist protocol, GnRH agonist-triggered and “freeze all”. The study group (group B) consisted of 24 women with PCOS who received the same protocol combined with LE. High risk criteria for OHSS were: PCOS patients with low BMI, young age, and extremely high level of serum AMH (inclusion criteria for AMH > 50 pmol/L). ResultsCumulative live birth rates per retrieval were similar in both groups. While no single case of severe OHSS was observed in, in the study group (group B), the rate of moderate and mild OHSS was 5 times lower compared to the control group (P < 0.05). ConclusionIn PCOS patients with extremely high AMH levels the LE co-administration to GnRH-Ant protocols results in reduced incidence of OHSS than conventional GnRH-Ant protocols. LE co-administration may prove to be highly effective in preventing OHSS, even in the women who are at high risk to these dangerous complications.

New Twists in Ovarian Stimulation and Their Practical Implications.

Ovarian stimulation (OS) has for objective to induce multiple ovulation in order to yield a multiple oocyte harvest and offer multiple embryos available for transfer thereby increasing the efficacy of ART. Originally, the primary risk associated with OS was the occurrence of frank ovarian hyperstimulation syndrome (OHSS), a possibly dreadful—sometime fatal—complication of ART. These fears limited the number of oocytes aimed for during OS in order to curb the risk of OHSS. On the contrary, the meager implantation rates of the early days of ART led to easily transfer multiple embryos in order to achieve acceptable pregnancy rates. Today the perspectives have changed. The advent of antagonist-based OS protocol and the possibility to trigger the ultimate phase of oocyte maturation with GnRH-a has allowed to reduce the risk of OHHS. Conversely, the markedly increased implantation rates of today's ART makes multiple pregnancy a worry that has come in the limelight worldwide, pushing the practice of single embryo transfer (SET).

Fresh versus freeze-all strategy in assisted reproductive technology – a cochrane review

In vitro fertilisation (IVF) treatments imply a fresh embryo transfer, possibly followed by one or more frozen-thawed embryo transfers in subsequent cycles. Alternatively, one can opt to freeze all suitable embryos and transfer frozen-thawed embryos in subsequent cycles only, which is also known as the freeze-all strategy. We compared the effectiveness and safety of these treatment strategies. We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in February 2019 for relevant studies, and checked references and contacted study authors in the field to obtain additional data. We used standard methodological procedures as recommended by Cochrane for our search, data extraction, and analyses. The primary outcome was cumulative live birth rate (cLBR). Secondary outcomes included ovarian hyper stimulation syndrome (OHSS), pregnancy complications, and time to pregnancy. We included six RCTs in our meta-analyses, that together reported on 4324 women. The studies compared the freeze-all strategy to IVF with fresh transfer in women with a high risk of OHSS, in ‘good prognosis' women based on the number of follicles, in women with PCOS, and in young women without PCOS. The evidence was of moderate to low quality due to serious risk of bias, serious imprecision for four studies, and serious unexplained heterogeneity for one study. For cLBR we found an OR of 1.10 (95% CI 0.97 to 1.24; 6 RCTs; 4324 women; I2 = 0%, moderate quality of evidence) for the freeze-all strategy versus IVF with fresh transfer of embryos. These data suggest that for a cLBR of 63% following IVF with fresh transfer of embryos, the cLBR following the freeze-all strategy would be between 62% and 67%. Women developed less OHSS after the freeze-all strategy compared to IVF with fresh transfer of embryos (OR 0.29, 95% CI 0.19 to 0.44; 4 RCTs; 4065 women; I2 = 5%, low quality evidence). These data suggest that for an OHSS rate of 4% following the conventional strategy, the rate following the freeze-all strategy would be between 1% and 2%. The risk of maternal hypertensive disorders and having a large for gestational age baby was increased following the freeze-all strategy (OR 2.15, 95% CI 1.42 to 3.25; 3 trials; 3940 women; I2 = 29% and OR 1.87, 95% CI 1.43 to 2.44; 3 trials; 3119 women; I2 = 0%, respectively, both low-quality evidence). The risk of having a small for gestational age baby was lowered following the freeze-all strategy (OR 0.68, 95% CI 0.53 to 0.89; 3 trials; 3119 women; I2 = 56%, low-quality evidence). One trial reported on time to conception and one trial reported on time to live birth which were both longer in the freeze all strategy. We did not find a clear difference in cLBR between the two strategies. The freeze-all strategy lowered the risk of OHSS, increased the risk of maternal hypertensive disorders of pregnancy, increased the risk of a large for gestational age baby, and lowered the risk of a small for gestational age baby. The time to pregnancy was longer in the freeze-all strategy.

Analysis of the effect of a delayed second dose of gonadotropin releasing hormone-agonist (GnRH-a) on oocyte and blastocyst quality and risk of ovarian hyperstimulation syndrome (OHSS)

Analysis of the effect of a delayed second dose of gonadotropin releasing hormone-agonist (GnRH-a) on oocyte and blastocyst quality and risk of ovarian hyperstimulation syndrome (OHSS)

A novel GnRH antagonist protocol by switching antagonist to provera to prevent premature luteinizing hormone surge when patients turned out to be at high risk of ovarian hyperstimulation syndrome during ovarian stimulation

A novel GnRH antagonist protocol by switching antagonist to provera to prevent premature luteinizing hormone surge when patients turned out to be at high risk of ovarian hyperstimulation syndrome during ovarian stimulation

HCG trigger versus GnRH agonist trigger in PCOS undergoing IVF cycles: frozen embryo transfer outcome

The use of Gonadotrophin releasing hormone agonist (GnRHa), with freeze-all strategy followed by frozen embryo transfer (FET) has been found to eliminate the risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovarian syndrome (PCOS) undergoing IVF cycles. However, there still has been hesitations with the use of GnRHa as a routine trigger replacing Human chorionic gonadotrophin (hCG), for concerns of compromised cycle outcome. We aimed to evaluate the outcome following transfer of embryos in FET cycles obtained from GnRHa trigger in comparison with hCG trigger in PCOS of Asian origin. Prospective observational cohort study. 210 PCOS undergoing IVF in an antagonist protocol who were randomized in the previous study (to evaluate if GnRHa trigger is a better alternative than hCG in PCOS for prevention of OHSS; Group A: GnRHa trigger (n=92)] and Group B: hCG trigger (n=101)], were followed up in FET cycles to assess the outcome. A prospective, observational study was conducted in a tertiary care center- Milann, The fertility center, Bangalore to assess the frozen- thawed embryo transfer cycle outcome following GnRHa trigger and hCG trigger in PCOS. In the previous randomized controlled trial conducted between May 2013 and November 2015, [comparing GnRH agonist with hCG trigger in an antagonist protocol for prevention of OHSS with freeze-all strategy; 210 PCOS patients were randomized; 92 subjects in Group A: GnRHa trigger (n=92) and Group B: hCG trigger (n=101) included for the final analysis (Deepika et al., 2016)], were followed up prospectively over a period of three years. All participants underwent subsequent frozen-thawed embryo transfer cycles and the treatment outcome of these subjects is reported herein. The odds of cumulative live birth rate per stimulation cycle favours GnRHa trigger as against hCG trigger [OR= 2.15; (CI 1.2–3.83); P=0.008]. A significantly higher number of mature oocytes (19.1±11.7 versus 14.1±4.3; P<0.001) and blastocysts (4.2±1.63 versus 3.26±1.22; P<0.001) were available in GnRHa group as compared to hCG group. The cumulative live birth rate is better following transfer of frozen-thawed embryos generated from GnRHa triggered cycles compared to hCG trigger. Hence, in PCOS undergoing IVF, as a good practice point, hCG trigger should be replaced by GnRHa trigger with vitrification of all embryos followed by FET later.

Withholding luteal hcg is associated with decreased live birth (LB) in women at high risk for ovarian hyperstimulation syndrome (OHSS) despite "intensive" luteal support with intramuscular progesterone (IMP)

Withholding luteal hcg is associated with decreased live birth (LB) in women at high risk for ovarian hyperstimulation syndrome (OHSS) despite "intensive" luteal support with intramuscular progesterone (IMP)

Is oocyte maturation rate associated with triptorelin dose used for triggering final oocyte maturation in patients at high risk for severe ovarian hyperstimulation syndrome?

Are oocyte maturation rates different among 0.1, 0.2 and 0.4mg triptorelin used for triggering final oocyte maturation in patients at high risk for ovarian hyperstimulation syndrome (OHSS) undergoing ICSI? A dose of 0.1mg triptorelin results in similar oocyte maturation rates compared to higher doses of 0.2 and 0.4mg in patients at high risk for OHSS undergoing ICSI. The GnRH agonist triptorelin is widely used instead of hCG for triggering final oocyte maturation, in order to eliminate the risk of severe OHSS in patients undergoing ovarian stimulation for IVF/ICSI. However, limited data are currently available regarding its optimal dose use for this purpose in patients at high risk for OHSS. A retrospective study was performed between November 2015 and July 2017 in 131 infertile patients at high risk for severe OHSS undergoing ovarian stimulation for ICSI. High risk for severe OHSS was defined as the presence of at least 19 follicles ≥11mm in diameter on the day of triggering final oocyte maturation. Ovarian stimulation was performed with recombinant FSH and GnRH antagonists. Patients received 0.1 (n = 42), 0.2 (n = 46) or 0.4mg (n = 43) triptorelin for triggering final oocyte maturation. Hormonal evaluation of FSH, LH, estradiol (E2) and progesterone (PRG) was carried out on the day of triggering final oocyte maturation, 8 and 36hours post triggering and 3, 5, 7, and 10days after triptorelin administration. During this period, all patients were assessed for symptoms and signs indicative of severe OHSS development. Primary outcome measure was oocyte maturation rate, defined as the number of metaphase II (MII) oocytes divided by the number of cumulus-oocyte-complexes retrieved per patient. Results are expressed as median (interquartile range). No significant differences in patient baseline characteristics were observed among the 0.1mg, the 0.2mg and the 0.4mg groups. Regarding the primary outcome measure, no differences were observed in oocyte maturation rate among the three groups compared [82.6% (17.8%) versus 83.3% (18.8%) versus 85.1% (17.2%), respectively, P = 0.686].In addition, no significant differences were present among the 0.1mg, 0.2mg and 0.4mg groups, regarding the number of mature (MII) oocytes [21 (13) versus 20 (6) versus 20 (11), respectively; P = 0.582], the number of oocytes retrieved [25.5 (13) versus 24.5 (11) versus 23 (12), respectively; P = 0.452], oocyte retrieval rate [81.0% (17.7%) versus 76.5% (23.5%) versus 75.0% (22.5), respectively; P = 0.088], the number of fertilized (two pronuclei) oocytes [12.5 (9) versus 14.5 (7) versus 14.0 (8), respectively; P = 0.985], fertilization rate [71.7% (22%) versus 77.1% (19.1%) versus 76.6% (23.3%), respectively; P = 0.525] and duration of luteal phase [7 (1) versus 8 (2) versus 7 (1) days, respectively; P = 0.632]. Moreover, no significant differences were present among the three triptorelin groups regarding serum levels of LH, FSH, E2 and PRG at any of the time points assessed following triggering of final oocyte maturation. This is a retrospective study, and although there were no differences in the baseline characteristics of the three groups compared, the presence of bias cannot be excluded. Based on the results of the current study, it appears that triggering final oocyte maturation with a lower (0.1mg) or a higher dose (0.4mg) of triptorelin, as compared to the most commonly used dose of 0.2mg, does not confer any benefit in terms of oocyte maturation rate in patients at high risk for severe OHSS. No external funding was obtained for this study. There are no conflicts of interest.

In Freeze-All Strategy, Cumulative Live Birth Rate (CLBR) Is Increasing According to the Number of Blastocysts Formed in Women

Background: Elective freezing of all embryos, followed by frozen-thawed ET cycles emerged to prevent risk of Ovarian Hyperstimulation Syndrome and to allow endometrium recovery after Controlled Ovarian Stimulation, leading to better IVF outcomes. Blastocyst Freeze-all policy can minimize the number of abnormal embryos and consequently failed ETs, but its efficacy in terms of cumulative rates has not been studied yet.Methods: A prospective cohort observational study was carried out in Assisting Nature, Center of Assisted Reproduction and Genetics, in Thessaloniki, Greece from January 2014 until December 2017. 244 patients- normal or high responders- underwent COS with recFSH and Freeze-all policy with blastocyst culture. The included patients were 18-39 years and achieved clinical pregnancy and/or live birth or had all their vitrified blastocysts transferred in subsequent frozen-thawed cycles. Women were divided into four groups (group A: 1–2 blastocysts frozen; group B: 3–4; group C: 5–6; group D ≥7 blastocysts frozen) or seven groups (group I: 1–2 blastocysts frozen, group II: 3, group III: 4, group IV: 5, group V: 6, group VI: 7; group VII: ≥8 blastocysts frozen), according to the numerical range or to the absolute number of vitrified blastocysts, respectively.Results: The main outcome of the study was the CLBR achieved by frozen-thawed ETs, according to the number of the vitrified blastocysts. Higher CLBR are expected, when at least 3 blastocysts are formed (group B: 65.2%) and at least 2 frozen-thawed ETs are performed, reaching highest rates (88%) by group D (≥7 vitrified blastocysts). Similarly, CLBR is significantly increasing with the absolute number of the vitrified blastocysts, ranging from 20%, when 1–2 blastocysts are vitrified (group I) to 82.4% when ≥8 blastocysts are available.Conclusions: A higher number of vitrified blastocysts is associated with higher CLBR in women <40 years old- normal/high responders- following Freeze-all policy. Adopting Freeze-all strategy after blastocyst culture can contribute to improve delivery outcome after IVF, in terms of CLBR. The number of the total cryopreserved blastocysts produced might reflect the quality of the oocyte and can successfully predict the pregnancy outcome. The blastulation rate can be a robust criterion to segment or not an IVF cycle.

Independent serum markers of corpora lutea function after gonadotropin-releasing hormone agonist trigger and adjuvant low dose human chorionic gonadotropin in in vitro fertilization

To characterize corpora lutea (CL) function after gonadotropin-releasing hormone agonist (GnRHa) trigger with the use of adjuvant human chorionic gonadotropin (hCG). Secondary analysis of serum from prospective randomized clinical trial. University-based fertility center. Women under 40years of age at risk of ovarian hyperstimulation syndrome (OHSS) with serum E2 level <4,000 pg/mL. All subjects underwent ovarian stimulation with the use of a GnRH antagonist protocol. Within a larger study, subjects were randomized to receive 1,000 IU hCG at the time of GnRHa trigger and placebo at the time of vaginal oocyte retrieval (VOR) or placebo at the time of GnRHa trigger and 1,500 IU hCG at the time of VOR. Luteal phase and early pregnancy curves of serum prorenin and 17α-hydroxyprogesterone (17OH-P). Thirty subjects enrolled in this secondary analysis. Serum 17OH-P peaked in the early luteal phase, 5days after GnRHa trigger, with a nadir in the mid-luteal phase 9days after trigger. Serum prorenin peaked in the luteal phase 2days after GnRHa trigger, independently from adjuvant hCG timing, and reached a nadir at 9days after trigger. CL function appears higher when adjuvant hCG is given at VOR compared with adjuvant hCG given at the time of trigger. CL function, as interpreted by proxy measures of serum prorenin and 17OH-P with pregnancy, continues despite GnRHa trigger. Both options for adjuvant hCG timing are sufficient for CL rescue and successful pregnancy, so the potential for OHSS risk with increased CL activity after hCG at VOR should be considered. NCT01815138.

Study protocol: E-freeze - freezing of embryos in assisted conception: a randomised controlled trial evaluating the clinical and cost effectiveness of a policy of freezing embryos followed by thawed frozen embryo transfer compared with a policy of fresh embryo transfer, in women undergoing in vitro fertilisation

BackgroundInfertility affects one in seven couples; many of these need in vitro fertilisation (IVF). IVF involves external hormones to stimulate a woman’s ovaries to produce eggs which are harvested surgically. Embryos, created in the laboratory by mixing eggs with sperm, are grown in culture for a few days before being replaced within the uterus (fresh embryo transfer). Spare embryos are usually frozen with a view to transfer at a later point in time – especially if the initial fresh transfer does not result in a pregnancy. Despite improvements in technology, IVF success rates remain low with an overall live birth rate of 25–30% per treatment. Additionally, there are concerns about health outcomes for mothers and babies conceived through IVF, particularly after fresh embryo transfer, including maternal ovarian hyperstimulation syndrome (OHSS) and preterm delivery. It is believed that high levels of hormones during ovarian stimulation could create a relatively hostile environment for embryo implantation whilst increasing the risk of OHSS. It has been suggested that freezing all embryos with the intention of thawing and replacing them within the uterus at a later stage (thawed frozen embryo transfer) instead of fresh embryo transfer, may lead to improved pregnancy rates and fewer complications. We aim to compare the clinical and cost effectiveness of fresh and thawed frozen embryo transfer, with the primary aim of identifying any difference in the chance of having a healthy baby.MethodsE-Freeze is a pragmatic, multicentre two-arm parallel group randomised controlled trial where women aged ≥18 and < 42 years, with at least three good quality embryos are randomly allocated to receive either a fresh or thawed frozen embryo transfer. The primary outcome is a healthy baby, defined as a term, singleton, live birth with appropriate weight for gestation. Cost effectiveness will be calculated from a healthcare and societal perspective.DiscussionE-Freeze will determine the relative benefits of fresh and thawed frozen embryo transfer in terms of improving the chance of having a healthy baby. The results of this pragmatic study have the potential to be directly transferred to clinical practice.Trial registrationISRCTN registry: ISRCTN61225414. Date assigned 29/12/2015.

The N680S variant in the follicle-stimulating hormone receptor gene identifies hyperresponders to controlled ovarian stimulation.

ObjectiveTo study if the follicle-stimulating hormone receptor (FSHR) variant asparagine/serine in amino acid 680 (N680S) can predict hypersensitivity to gonadotropins in women undergoing assisted reproduction.Patients and methodsIn this retrospective study, 586 women undergoing their first in-vitro fertilisation treatment were enroled, and their FSHR N680S genetic variant was analysed. The main outcome measures were number of retrieved oocytes and any grade of ovarian hyperstimulation syndrome (OHSS). Experimental studies were performed on FSHR variants transfected into eukaryotic cells treated with 1–90 IU recombinant follicle-stimulating hormone. The receptors’ ability to induce a second messenger 3′,5′-cyclic AMP was measured.ResultsThe proportion of women who developed OHSS was 6% (n=36). None of the women who developed this condition had the homozygous serine variant. The N680S polymorphism in the FSHR was associated with the condition, Ptrend (genotype)=0.004 and Pallelic (alleles)=0.04. Mean oocyte number was 11±6 in women without OHSS and 16±8 in women who developed OHSS (P=0.001), despite exposure to lower total hormonal dose in the latter group. The odds ratio for developing OHSS in carriers of the asparagine allele was 1.7 (95% confidence interval: 1.025–2.839, P=0.04). A higher receptor activity in cells expressing asparagine compared with the serine was also evident at all concentrations of recombinant follicle-stimulating hormone used (P<0.05 for all).ConclusionThis study confirms previous findings regarding higher hormonal sensitivity in carriers of asparagine in the N680S position. These women are at higher risk for OHSS during in-vitro fertilisation. Genetic testing could identify those at highest risk to develop this adverse effect.

Individualized luteal phase support.

The aim of this review is to summarize the different aspects of luteal phase deficiency in IVF treatment and the possibilities of individualized luteal phase support. After the application of human chorionic gonadotrophin (hCG) for final oocyte maturation, the vaginal route for progesterone administration is sufficient to maintain an adequate luteal phase support. New data point toward the possibility of oral medication; however, those data have yet to be confirmed in larger studies. Luteolysis after gonadotropinrealzing hormone (GnRH) agonist trigger is patient specific and not always severe. According to the progesterone level, individualized low dosages of hCG can be applied as luteal phase support without the risk of ovarian hyperstimulation syndrome (OHSS) development. It is the task of the reproductive medicine specialist to individualize luteal phase support according to the patient's specific characteristics, needs and desires and the type of treatment performed. The greatest indication for individualization of the luteal phase is following GnRH agonist trigger in high responder patients in order to tailor luteal phase support to the patient-specific pattern of luteolysis and minimize the risk of causing OHSS with unnecessary high hCG dosages.