Fertility and pregnancy complications following chorioamnionitis.

Acute chorioamnionitis complicates 1-2% of all pregnancies and might increase the prevalence of endometritis that can cause Asherman syndrome or adhesions, but little is known about the direct effects of chorioamnionitis on future fertility. We aimed to evaluate the effect of chorioamnionitis on future fertility and obstetrics complications in patients diagnosed with chorioamnionitis during their pregnancy. We performed an observational, case-control retrospective study of pregnant women aged 18-40 years old, hospitalized with a diagnosis of chorioamnionitis between January 2013 and December 2017. The control group consisted of patients with similar demographic/obstetrics characteristics, matched with a ratio of 1:2 without chorioamnionitis. The prevalence of post gestational diagnostic hysteroscopy was significantly higher in the study group as compared to the control group (22.9% versus 9.0%, respectively; p = 0.005). Moreover, the study group underwent significantly more operative hysteroscopy compared to the control group (10.8% versus 3.6%, respectively; p = 0.04). The patients in the study group had significantly higher prevalence of miscarriages (27% versus 13.2%, respectively; p < 0.01). We conclude that chorioamnionitis may cause endometritis with the consequent impaired fertility, necessitating comprehensive evaluations for secondary infertility, including hysteroscopy aiming to treat intrauterine adhesions that may affect and impair fertility.

Elective egg freezing patients may benefit from increasing the maximal daily gonadotropin dose above 300IU.

OBJECTIVE: Nowadays, patients attempting social/elective egg freezing has spread globally. Ovarian stimulation (OS) with high daily gonatotropin doses, are commonly offered to this group of patients, aiming to achieve the maximal oocytes cohort with minimum IVF cycle attempts. We aim to assess the IVF-ET outcome, and specifically the oocyte yield, of patients undergoing two successive IVF cycle attempts for elective egg freezing (EEF), and whether changing the daily gonadotropin dose in the second IVF cycle attempt, affect the outcome. PATIENTS AND METHODS: All women admitted to our IVF unit for social/EEF, who underwent 2 consecutive IVF cycle attempts, with only those who used in the first attempt a starting daily gonadotropin dose of 300 IU were included. Ovarian stimulation characteristics, duration of OS, number of retrieved oocytes, number of mature oocytes were assessed and compared between the 1st and the 2nd IVF cycle attempts, and between the different daily gonadotropin doses and the oocyte yields in the 2nd cycle attempt (increase, decrease or no change). MAIN OUTCOME MEASURES: Oocytes and mature oocytes yield in the 2nd as compared to the 1st IVF cycle attempt. RESULTS: A reduced oocyte yield in the 2nd cycle attempt was observed in those who highly responded in the 1st attempt, regardless the daily dose in the 2nd cycle attempt (whether it was increased, no change and decreased). Moreover, the proportion of patients with same or more oocytes in the 2nd IVF cycle attempt was significantly lower in patients with high peak E2 levels, compared to those with peak E2 levels < 9175 pmol/L. Among patients with high peak E2 (> 9175 pmol/L), those who achieved a lower oocytes yield in the 2nd IVF cycle attempt had lower basal Day-3 FSH/LH ratio (1.5 + 0.5 vs 1.8 + 0.8, p < 0.03) and higher oocyte (range: 7-28, median:10; vs range: 2-15, median:7) and mature oocytes yields. With a cut-off of 9 oocytes, 78.8% of those with > 9 oocytes and 61.8% of those with < 9 oocytes will achieve lower/higher oocytes yield in the 2nd IVF cycle attempt, respectively. CONCLUSIONS: Ovarian stimulation with high daily gonatotropin doses (300 IU) should be offered to patients attempting social/EEF. Moreover, in their 2nd IVF cycle attempt, those with high peak E2 (> 9175 pmol/L) in the 1st attempt, and basal Day-3 FSH/LH ratio < 1.5 and/or more than 9 oocytes retrieved, should receive same OS protocol with no change in the daily gonadotropin dose.

Predicting IVF outcome in poor ovarian responders.

BACKGROUND: Poor responders to ovarian stimulation are one of the most challenging populations to treat. As a failed cycle can cause a considerable emotional and economical loss, adequate fertility counseling addressing patients' expectations are highly important when facing patients with poor ovarian response. The study aimed to evaluate reproductive outcomes and to identify factors associated with live birth (LB) after fresh autologous IVF/intracytoplasmic sperm injection (ICSI) cycles of patients fulfilling the Bologna criteria for poor ovarian response (POR). METHODS: A retrospective study included 751 IVF/ICSI treatment cycles which yielded up to three retrieved oocytes, at a tertiary referral hospital between January 2016 and February 2020. A logistic regression analysis was used to adjust for confounders. RESULTS: Clinical pregnancy and LB rate per cycle were significantly higher among women younger versus older than 40 years (9.8% and 6.8% vs 4.5% and 2.1%, p < 0.01, respectively). Patients who achieved LB were significantly younger, had higher number of oocytes retrieved, fertilization rate and top-quality embryos (p < 0.05). Multivariable regression analysis identified patient's age (OR 0.90; 95% CI 0.845-0.97; p = 0.005) and mean number retrieved oocytes (OR 1.95; 95% CI 1.20-3.16; p = 0.007) as factors significantly associated with the probability of a LB. CONCLUSIONS: The woman's age and the number of retrieved oocytes are both independent predicting factors of live birth in poor ovarian responders. Considering the risks, the high financial investment and poor reproductive outcomes involved in IVF treatments, raises questions regarding the adequacy of providing treatments in these patients' population. POR younger than 40 years may represent a possible exception due to acceptable probability for a LB.

Embryos derived from delayed mature oocyte should be cryopreserved and are favourable to transfer in a following endometrium synchronize frozen-thawed cycle.

Oocytes eligible for intracytoplasmic sperm injection (ICSI) are those that have progressed through meiosis to metaphase 2 (MII). The remaining delayed mature oocytes can be injected, aiming to achieve more embryos and a better chance to conceive. We aimed to assess the outcome of delayed matured oocytes, derived from either germinal vesicles or metaphase 1 (MI), that reached maturity (MII) 24 h following retrieval. The study population consisted of 362 women who underwent 476 IVF cycles. While fertilization rates were comparable between the sibling delayed mature oocyte group compared with injection on day 0 group (58.4% vs 62%, respectively, P = 0.07), the top-quality embryo rate per injected MII day 0 oocyte was significantly higher compared with day 1 injected oocyte (57.5% vs 43.9% respectively, P < 0.001). Moreover, following fresh transfer of embryos derived from delayed mature oocytes, implantation rate and the clinical pregnancy (CPR) and live-birth rates (LBR) per transfer were 3.9%, 3.3% and 1.6% respectively. When considering the following thawed embryo transfer cycles, implantation, pregnancy and LBR were non-significantly higher (10%, 8.3% and 8.3%, respectively). Although clinical outcomes are significantly lower when using embryos derived from delayed mature oocyte to mature day 0 oocytes, the additional embryos derived from delayed mature oocytes might contribute to the embryo cohort and increase the cumulative live-birth rate per retrieval. Moreover, the embryos derived from delayed mature oocyte favour a transfer in a frozen-thawed cycle rather than in a fresh cycle.

The effect of coronavirus disease 2019 immunity on frozen-thawed embryo transfer cycles outcome.

OBJECTIVE: To study the effect of patients' immunization after coronavirus disease 2019 (COVID-19) infection or messenger ribonucleic acid (mRNA) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine on frozen-thawed embryo transfer (FET). DESIGN: Cohort retrospective study. SETTING: Tertiary university affiliated medical center. PATIENT(S): All consecutive patients undergoing FET cycles in our center. The study group (immune group) consisted of patients treated during the COVID-19 pandemic (between January 2021 and August 2021) who either recovered from COVID-19 infection or received the mRNA SARS-CoV-2 vaccine. The control groups consisted of patients treated during the COVID-19 pandemic (between January 2021 and August 2021) but were not infected or did not receive the mRNA SARS-CoV-2 vaccine (not-immune2021 group) and those treated between January 2019 and August 2019 (before the pandemic) (not-immune2019 group). INTERVENTION(S): Frozen-thawed embryo transfer cycles. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rates and FET cycles' characteristics. Data on patient age and variables related to infertility treatment were collected from the patient records. RESULT(S): During the study periods, 428 patients underwent 672 FET cycles. The immune group consisted of 141 patients who underwent 264 FET cycles (44 in postinfection and 220 in postvaccination), whereas the not-immune2021 and not-immune2019 groups consisted of 93 and 194 patients undergoing 125 and 283 FET cycles, respectively. Patients' characteristics and the types of endometrial preparations were comparable between the study groups. The implantation rate and clinical and ongoing pregnancy rates per transfer were similar between the study groups (immune group, postinfection and postvaccination; not-immune2021 group; not-immune2019 group). CONCLUSION(S): Coronavirus disease 2019 infection or vaccination did not affect patients' performance or implantation in their subsequent FET cycle.

GnRH-Agonist Ovulation Trigger in Patients Undergoing Controlled Ovarian Hyperstimulation for IVF with Stop GnRH-Agonist Combined with Multidose GnRH-Antagonist Protocol.

OBJECTIVE: This study aimed to characterize those patients undergoing the stop gonadotropin-releasing hormone (GnRH)-agonist combined with multidose GnRH-antagonist protocol, with suboptimal response to GnRH-agonist trigger in in vitro fertilization (IVF) cycles. DESIGN: This is a cohort study. SETTING: The study was conducted in a university hospital. PATIENTS: All consecutive women admitted to our IVF unit from February 2020 through November 2020 who reached the ovum pick-up stage were reviewed. INTERVENTIONS: Triggering final oocyte maturation by GnRH-ag alone (GnRH-ag trigger group), or combined with hCG (dual trigger group), in patients undergoing the stop GnRH-agonist combined with multidose GnRH-antagonist protocol was performed. MAIN OUTCOME MEASURE: The main outcome measure was LH level 12 h after the trigger. RESULTS: Five out of the 32 patients (15.6%) demonstrated suboptimal response as reflected by LH levels <15 IU/L 12 h after GnRH-agonist trigger. Moreover, while no differences were observed in oocyte recovery rate, maturity, or embryo quality between the different study groups (GnRH-ag trigger and dual trigger groups), those achieving a suboptimal response to the GnRH-agonist trigger (post-trigger LH <15 mIU/mL) demonstrated significantly higher number of follicles and peak estradiol levels at the day of trigger, compared to those with optimal response (post-trigger LH >15 mIU/mL). CONCLUSIONS: The stop GnRH-agonist combined with GnRH-antagonist protocol enables the substitution of hCG with GnRH-ag for final oocyte maturation. However, caution should be taken in high responders, where the dual trigger with small doses of hCG (1,000-1,500 IU) should be considered, aiming to avoid suboptimal response (post-trigger LH levels <15 IU/L).

"Add-Ons" for Assisted Reproductive Technology: Do Patients Get Honest Information from Fertility Clinics' Websites?

"Add-on" procedures are actively promoted on some fertility clinic websites as proven means to improve IVF success rates, especially for couples with repeated implantation/IVF failures. However, the actual contribution of these interventions to live birth rates remains inconclusive. At present, little is known about the type and quality of the information provided on the IVF clinics' websites regarding the merits of "add-ons." A systematic evaluation of the quality of information on "add-on" procedures in fertility clinic websites was performed using 10-criteria structured questionnaire. We included English language websites that presented in the Google.com search engine after typing the following key-words:"endometrial scratching"(ES), "intralipid infusions"(ILI), "assisted hatching"(AHA), "PGT-A," or "PGS". In total, 254 websites were evaluated. In most cases, an accurate description of the "add-on" procedures was provided (78.8%). However, only a minority (12%) reported their undetermined effectiveness. The use of PGT-A was more often encouraged (52.8%) than ES (23.6%) and AHA (16%). The cost was infrequently presented (6.9%). Scientific references were only rarely provided for ILI, versus 12.7% for ES, 4.0% for AHA, and 5.6% for PGT-A. The information entry date was often missing. None of the websites reported the clinic's pregnancy-rate following the "add-on" procedures. Information on "add-ons" available to patients from IVF clinic websites is often inaccurate. This could perpetuate false myths among infertile patients about these procedures and raises concern regarding possible commercial bias. It is imperative that IVF clinic websites will better communicate the associated risks and uncertainties of "add-ons" to prospective patients.

Does mRNA SARS-CoV-2 vaccine influence patients' performance during IVF-ET cycle?

OBJECTIVE: No information exists in the literature regarding the effect of mRNA SARS-CoV-2 vaccine on subsequent IVF cycle attempt. We therefore aim to assess the influence of mRNA SARS-CoV-2 vaccine on IVF treatments. DESIGN: An observational study. SETTING: A tertiary, university-affiliated medical center. PATIENTS AND METHODS: All couples undergoing consecutive ovarian stimulation cycles for IVF before and after receiving mRNA SARS-CoV-2 vaccine, and reached the ovum pick-up (OPU) stage. The stimulation characteristics and embryological variables of couples undergoing IVF treatments after receiving mRNA SARS-CoV-2 vaccine were assessed and compared to their IVF cycles prior to vaccination. MAIN OUTCOME MEASURES: Stimulation characteristics and embryological variables. RESULTS: Thirty-six couples resumed IVF treatment 7-85 days after receiving mRNA SARS-CoV-2 vaccine. No in-between cycles differences were observed in ovarian stimulation and embryological variables before and after receiving mRNA SARS-CoV-2 vaccination. CONCLUSIONS: mRNA SARS-CoV-2 vaccine did not affect patients' performance or ovarian reserve in their immediate subsequent IVF cycle. Future larger studies with longer follow-up will be needed to validate our observations.

A Novel Stimulation Protocol for Poor-Responder Patients: Combining the Stop GnRH-ag Protocol with Letrozole Priming and Multiple-Dose GnRH-ant: A Proof of Concept.

OBJECTIVE: The objective of this study was to examine whether the combined Stop GnRH-agonist (GnRH-ag), letrozole priming, and multiple-dose GnRH-antagonist (GnRH-ant) protocol may improve in vitro fertilization/intracytoplasmic sperm injection cycle in poor ovarian responders (PORs). DESIGN: This was a historical cohort, proof of concept study under tertiary setting at University affiliated Medical Center. PATIENTS: Five PORs fulfilling the POSEIDON Group 4 criteria were included. MAIN OUTCOME MEASURES: Number of oocytes retrieved, number of top-quality embryos (TQEs), and controlled ovarian hyperstimulation (COH) variables were the main outcome measures. RESULTS: The combined Stop GnRH-ag, letrozole priming, and multiple-dose GnRH-ant COH protocol revealed significantly higher number of follicles >13 mm on the day of hCG administration and higher number of oocytes retrieved, with non-significantly more TQEs and a reasonable clinical pregnancy rate. CONCLUSIONS: The combined Stop GnRH-ag, letrozole priming, and multiple-dose GnRH-ant COH protocol is a valuable tool in the armamentarium for treating POSEIDON Group 4 patients. Further large prospective studies are needed to elucidate its role in POR and to identify the specific characteristics of women (before initiating ovarian stimulation) that will aid both fertility specialists' counseling and their patients in adjusting the appropriate COH protocol.

Future fertility of patients with zero oocytes yield in their first IVF cycle attempt.

PURPOSE: We aim to estimate the future fertility of patient undergoing their first IVF cycle attempt with no oocyte retrieved, and to identify factors that might predict those who will conceive in subsequent IVF cycle attempt. METHODS: A cohort retrospective study of all consecutive women attending our IVF unit, for their first IVF cycle attempt, between January 2013 to December 2019, who reached the ovum pick-up (OPU) stage with zero oocyte retrieved. Patients' characteristics and infertility-treatment-related variables in the first IVF cycle attempt were compared between those who conceived in a subsequent cycle and those who did not. Moreover, infertility-treatment-related variables during successful cycles resulting in pregnancy were compared to those without. RESULTS: 59 met the study inclusion criteria, yielding zero oocytes. During the follow-up period, 12 (20.3%) women conceived (one conceived twice), and 8 (14%) gave birth to a live infant. Cumulative live-birth rate per OPU and per patients were 4% and 14%, respectively. Clinical pregnancies were achieved after 3.61+1.4 cycle attempts (range: 1-6), with no live-births following the fifth IVF cycle attempt. No in-between group differences were observed in ovarian stimulation variables of their first IVF cycle attempt. Moreover, in those cycles resulting in pregnancy, patients achieved a significantly higher number of fertilized oocytes (2.15+1.5 vs 0.94+1.5, respectively; p<0.01) and a higher mean top-quality embryos (TQE) (1.76+0.9 vs 0.73+1.2, respectively; p<0.003). CONCLUSION: Women yielding zero oocytes at their first IVF cycle attempt, may achieve 14% cumulative live-birth rate after 5 IVF cycle attempts. Moreover, those who conceived in subsequent IVF cycle attempts were those achieving 2 or more fertilized oocytes/TQE.

The role of ICSI vs. conventional IVF for patients with advanced maternal age-a randomized controlled trial.

OBJECTIVES: This study aimed to evaluate the role of intracytoplasmic sperm injection (ICSI) in the treatment of non-male factor infertile patients aged ≥ 39. METHODS: This is a single-center, prospective, randomized controlled clinical trial, between March 2018 and December 2019. Sixty-nine patients were recruited, and sixty patients participated in the study. Their ovaries were randomized prior to the beginning of the ovarian stimulation: the oocytes from one side (n = 257) were allocated to the ICSI (ICSI arm), while those of the contralateral side (n = 258) were allocated to conventional insemination (IVF arm). The fertilization rate per oocyte retrieved, number of zygotes (2PN), and cleavage-stage embryos were assessed and compared between the two study groups. RESULTS: The average number of zygotes (3.1 vs. 2.7 p = 0.45), the fertilization rate (72.4% vs. 65.1% p = 0.38), the average number of cleavage-stage (2.8 vs. 2.4 p = 0.29), and the average top-quality embryos (TQE) cleavage-stage embryos (1.7 vs. 1.6 p = 0.94) were comparable between the two groups. The TQE rate per randomized oocyte (41.2% vs. 41% p = 0.8) was also similar in both groups. CONCLUSIONS: ICSI does not improve the reproductive outcomes of advanced-age patients undergoing conventional insemination for non-male factor infertility. TRIAL REGISTRATION: NCT03370068.

The Effect of Ovarian Stimulation on Endothelial Function-A Prospective Cohort Study using Peripheral Artery Tonometry.

CONTEXT: Gonadotropin-releasing hormone agonist (GnRH-a) serves as an alternative to human chorionic gonadotropin (hCG) to trigger final oocyte maturation, while it significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS), probably by attenuating vascular/endothelial activation. OBJECTIVES: The objectives of this work are to compare the effect of different modes of final follicular maturation (hCG vs GnRH-a) following ovarian stimulation (OS) for in vitro fertilization (IVF) on endothelial function. DESIGN AND SETTING: A prospective cohort study was conducted at a tertiary medical center. PARTICIPANTS: Patients age 37 years or younger, undergoing OS for IVF, were allocated into 2 groups according to the type of final follicle maturation: the hCG group (n = 7) or the GnRH-a group (n = 8). INTERVENTION: Endothelial function was assessed by measurement of the peripheral arterial tonometry in reaction to temporary ischemia at 3 study points: day 3 of menstrual cycle (day 0), day of hCG/GnRH-a administration (day trigger) and day of oocyte pick-up (day OPU). The ratio of arterial tonometry readings before and after ischemia is called the reactive hyperemia index (RHI). Decreased RHI (< 1.67) indicates endothelial dysfunction. MAIN OUTCOME MEASURES: The main outcomes measures of this study included endothelial function at 3 study points during OS with different modes of triggering final follicular maturation. RESULTS: The mean RHI values at day 0 were within the normal range for all patients and comparable between both groups (hCG: 1.7 ±â€…0.3 vs GnRH-a: 1.79 ±â€…0.4, P = .6). All patients presented a decrease in RHI values on day trigger, which did not differ between the 2 groups (1.62 ±â€…0.3 vs 1.4 ±â€…0.2, respectively, P = .2). However, the hCG group demonstrated a further decrease in RHI on day OPU, whereas patients who received GnRH-a had restored normal endothelial function reflected by increased RHI values (1.4 ±â€…0.2 vs 1.75 ±â€…0.2, respectively, P = .03). CONCLUSIONS: Triggering final follicular maturation with GnRH-a restored normal endothelial function, whereas hCG trigger resulted in a decrease in endothelial function.

Does a Large (>24 mm) Follicle Yield a Competent Oocyte/Embryo?

AIM: To evaluate the effect of large follicular size (≥24 mm) at day of oocyte retrieval on oocyte/embryo quality. PATIENTS AND METHODS: A cohort study was conducted in a single tertiary medical center between July 2018 and May 2019. Before ultrasound-guided follicular aspiration, follicles were measured and divided into 2 groups according to their maximal dimensional size: large: ≥24 mm and normal: <24 mm. Microscopic examination of the follicular aspirates was performed by an embryologist. Each follicle aspirated was evaluated for oocyte maturation, oocyte fertilization, and embryo quality. RESULTS: 428 follicles were measured, including 383 (62.81%) in the normal and 45 (14.06%) in the large follicle groups. Oocytes were achieved during aspiration from 297 (75.5%) and 29 (64.4%) of the normal and large follicle groups, respectively (p = 0.05). No in-between group differences were observed in mature oocyte (MII), fertilization, and top-quality embryo (TQE) rates. Nevertheless, once a zygote (2PN) was achieved, a trend toward a higher TQE rate/2PN was found in the large follicle group (16/19 [84.2%] vs. 115/171 [67.3%]; p = 0.062). CONCLUSION: While a nonsignificant decrease in oocyte recovery rate was found in follicles ≥24 mm, the zygote and TQE per follicle were comparable.

Does daily co administration of gonadotropins and letrozole during the ovarian stimulation improve IVF outcome for poor and sub optimal responders?

BACKGROUND: Co-administration of letrozole during the first 5 days of ovarian stimulation was suggested to improve IVF outcomes in poor responders. We aimed to determine whether poor/sub-optimal responders might benefit from Letrozole co-treatment throughout the entire stimulation course. METHODS: We retrospectively reviewed the medical files of women who demonstrated poor (oocyte yield ≤3) and sub-optimal (4 ≤ oocyte yield ≤9) ovarian response during conventional multiple-dose antagonist stimulation protocols and were co-treated in a subsequent cycle with 5 mg Letrozole from the first day of stimulation until trigger day. A self-paired comparison between gonadotropins-only and gonadotropins-letrozole cycles was performed. RESULTS: Twenty-four patients were included. Mean patients' age was 39.83 ± 4.60 and mean day-3-FSH was 12.77 ± 4.49 IU/m. Duration of stimulation and total gonadotropins dose were comparable between the two cycle groups. Peak estradiol levels were significantly lower in gonadotropins-letrozole cycles (2786.74 ± 2118.53 vs 1200.13 ± 535.98, p < 0.05). Number of retrieved oocytes (3.29 ± 2.15 vs 6.46 ± 3.20, p < 0.05), MII-oocytes (2.47 ± 1.65 vs 5.59 ± 3.20, p < 0.05), 2PN-embryos (1.78 ± 1.50, 4.04 ± 2.74, p < 0.05) and top-quality embryos (0.91 ± 0.97 vs. 2.35 ± 1.66, p < 0.05) were significantly higher in the gonadotropins-letrozole cycles. Clinical pregnancy rate in gonadotropins-letrozole cycles was 31.5%. CONCLUSION: Letrozole co-treatment during the entire stimulation course improves ovarian response and IVF outcomes in poor/sub-optimal responders.

Stop GnRH-Agonist Combined With Multiple-Dose GnRH-Antagonist Protocol for Patients With "Genuine" Poor Response Undergoing Controlled Ovarian Hyperstimulation for IVF.

Objective: To examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may improve conventional IVF/intracytoplasmic sperm injection (ICSI) cycle in poor ovarian response (POR) patients. Design: Cohort historical, proof of concept study. Setting: Tertiary, University affiliated Medical Center. Patient(s): Thirty POR patients, defined according to the Bologna criteria, who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist controlled ovarian hyperstimulation (COH) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle, were included. For the purposes of this study, we eliminated a bias in this selection by including only "genuine" poor responder patients, defined as those who yielded up to 3 oocytes following COH with a minimal gonadotropin daily dose of 300 IU. Main Outcome Measure(s): Number of oocytes retrieved, number of top-quality embryos, COH variables. Result(s): The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly higher numbers of follicles >13 mm on the day of hCG administration, higher numbers of oocytes retrieved, and top-quality embryos (TQE) with an acceptable clinical pregnancy rate (16.6%). Moreover, as expected, patients undergoing the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol required significantly higher doses and a longer duration of gonadotropins stimulation. Conclusion(s): The combined Stop GnRH-ag/GnRH-ant COH protocol is a valuable tool in the armamentarium for treating "genuine" poor ovarian responders. Further, large prospective studies are needed to elucidate its role in POR and to characterize the appropriate patients subgroup (before initiating ovarian stimulation) that may benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol.

Stop GnRH-Agonist Combined with Multiple-Dose GnRH-Antagonist for Patients with Elevated Peak Serum Progesterone Levels Undergoing Ovarian Stimulation for IVF: A Proof of Concept.

AIM: The aim of the study was to examine whether the Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol may overcome progesterone elevation during the late follicular phase. PATIENTS AND METHODS: A cohort historical, proof of concept study consisting of 11 patients with progesterone elevation (>3.1 nmol/L) during conventional IVF/intracytoplasmic sperm injection (ICSI), who underwent a subsequent Stop GnRH-agonist combined with multiple-dose GnRH-antagonist ovarian stimulation (OS) protocol, within 3 months of the previous failed conventional IVF/ICSI cycle. RESULTS: The Stop GnRH-agonist combined with multiple-dose GnRH-antagonist COH protocol revealed significantly lower peak progesterone levels, with significantly higher numbers of follicles >13 mm in diameter on the day of hCG administration, oocytes retrieved, mature oocytes, and top-quality embryos, with an acceptable clinical pregnancy rate (18.2%). CONCLUSIONS: The combined Stop GnRH-ag/GnRH-ant OS protocol is a valuable tool in the armamentarium for treating patients with progesterone elevation during the late follicular phase. Further large prospective studies are needed to validate our observation and to characterize the appropriate patients' subgroup, which might benefit from the combined Stop GnRH-ag/GnRH-ant COH protocol.

Do Follicles of Obese Patients Yield Competent Oocytes/Embryos?

AIM: This study evaluated the competency of oocytes/embryos derived from follicles >15 mm in diameter from obese patients, compared with nonobese patients. PATIENTS AND METHODS: A cohort study was conducted in a single tertiary medical center between July 2018 and May 2019. Before ultrasound-guided follicular aspiration, follicles were measured and those with maximal dimensional size >15 mm were tracked. Microscopic examination of the follicular aspirates was performed by an embryologist. Each follicle aspirated was evaluated for oocyte maturation, oocyte fertilization, and embryo quality. RESULTS: 457 follicles were measured: 380 (83.2%) in nonobese and 77 (16.8%) in obese patients. No in-between group differences were observed in the causes of infertility, patients' demographics, or ovarian stimulation characteristics. Oocytes were achieved during aspiration from 277 (72.8%) and 54 (70.0%) of the nonobese and obese groups, respectively (p = 0.67). No in-between group differences were observed in fertilization (2PN/oocyte), top quality embryo (TQE) per zygote (2PN), and TQE per follicle. CONCLUSION: Oocyte recovery rate from follicles >15 mm is unrelated to patients' BMI. Moreover, the oocytes recovered from obese patients are competent yielding comparable zygote and TQE per follicle/oocyte, compared with nonobese patients. Further investigation is required to strengthen this finding.

Do poor-responder patients undergoing IVF benefit from splitting and increasing the daily gonadotropin dose?

We aim to retrospectively evaluate the role of increasing the gonadotropin daily dose from 450 IU/day to 300 IU twice a day on IVF-ET outcome in poor responder patients. All consecutive women admitted to our IVF unit and underwent COH consisting of daily gonadotropin dose of 450 IU, followed by an IVF cycle using 300 IU twice a day, were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate was assessed. Twenty-three patients undergoing both cycles were evaluated. While there was no between-group difference in the duration of COH, number of 2PN embryos, fertilization rate and number of embryos transferred, patients receiving daily gonadotropin 300 IU twice a day achieved a significantly higher peak estradiol levels (3350.39 ± 2364.26 vs. 2223.74 ± 1299.91; p < .03, respectively), and yielded significantly higher number of follicles >15 mm in diameter on day of hCG administration (3.2 ± 2.4 vs 1.8 ± 1; p < .03, respectively) and higher number of oocytes retrieved (3.48 ± 2.54 vs 1.87 ± 1.1; p < .02, respectively) with an acceptable live birth rate (5%). To conclude, in poor responders undergoing COH a daily gonadotropin dose of 450 IU, increasing the dose to 300 IU twice daily may result in higher oocyte yield, with the possible improvement in IVF outcome.

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.

Maternal Phthalate and Personal Care Products Exposure Alters Extracellular Placental miRNA Profile in Twin Pregnancies.

Prenatal exposure to endocrine-disrupting chemicals (EDCs) exerts both short- and long-term adverse effects on the developing fetus. However, the mechanisms underlying these effects have yet to be uncovered. Maternal-fetal signaling is mediated in part by signaling molecules (eg, microRNAs [miRNAs]) contained in extracellular vesicles (EVs) that are released by the placenta into the maternal circulation. We investigated whether maternal exposure to the EDCs phthalates and personal care products alters the miRNA profile of placental-derived EVs circulating in maternal blood. Blood and urine samples from pregnant women with uncomplicated term dichorionic, diamniotic twin pregnancies were analyzed as part of a larger study investigating correlations between exposure of phthalate and personal care products and epigenetic alterations in twin pregnancies. We explored correlations between maternal urinary levels of 13 phthalate and 12 personal care products metabolites and the miRNA profile of placental EVs (EV-miRNAs) circulating in maternal blood. The expression of miR-518e was highest among women with high urinary levels of monobenzyl phthalate and methyl paraben. miR-373-3p was the least expressed in women exposed to high levels of methyl paraben, and miR-543 was significantly downregulated in women exposed to high levels of paraben metabolites, dichlorophenol metabolites, and triclosan. In conclusion, this pilot study reveals that prenatal exposure to EDCs is associated with altered profile of circulating placenta-derived EV-miRNAs. Further studies are needed to generalize these results to singleton pregnancies and to assess whether these alterations are associated with pregnancy complications.