How far is too far? Does time interval between GnRH antagonist and GnRH agonist trigger in GnRH antagonist cycles matter?

RESEARCH QUESTION: What is a suitable time interval between the last GnRH antagonist exposure and GnRH agonist (GnRHa) triggering for final follicular maturation? DESIGN: A retrospective cohort study including 413 patients undergoing GnRH antagonist cycles in which GnRHa trigger was used, either solely or as a dual trigger. The primary outcome measure was the follicle/mature oocyte ratio. Cycles were analysed according to the time interval between the last GnRH antagonist exposure and the GnRHa triggering: Group 1 included patients with a 12-14 h interval; Group 2: 7-10 h interval; Group 3: 5-6 h interval and Group 4: 2-4 h interval. LH concentration was measured 11-13 h post-GnRHa injection. RESULTS: Median LH value was 65 IU/l. There was a weak but significant correlation between basal LH and the LH surge (R2 = 0.137, P < 0.001). Although square root LH values differed significantly between study groups (P < 0.001; higher in Groups 2 and 3), the follicle/mature oocyte ratio was not different across the four antagonist-agonist interval groups and no correlation was detected between the post-trigger LH concentration and the follicle/oocyte ratio (R2 = 0.011). In a model integrating age, day 3 FSH concentration, maximal oestradiol and body mass index along with the study groups, none of these factors was significantly related to the follicle/mature oocyte outcome ratio. Insufficient surge (LH < 15 IU/l) occurred in 14 (3.4%) cases. Rates of insufficient LH surge did not differ significantly between the groups (2.4%, 3.2%, 3.4% and 7.1% in Groups 1 to 4, respectively; P = 0.5). CONCLUSIONS: LH concentrations post-GnRHa trigger differ in regard to antagonist-agonist intervals, but the follicle/mature oocyte ratio achieved was not affected.

High ovarian response to ovarian stimulation: effect on morphokinetic milestones and cycle outcomes.

PURPOSE: To assess the effect of high ovarian response on oocyte quality and ovarian stimulation cycle outcomes. METHODS: A retrospective cohort study conducted at three IVF units. The high ovarian response (HOR) and polycystic ovary syndrome (PCOS) with HOR (PCOS HOR) groups included 151 and 13 women who underwent controlled ovarian stimulation (COS) resulting in more than 15 retrieved oocytes, for a total of 1863 and 116 cultured embryos, respectively. The normal ovarian response (NOR) group comprised 741 women with 6-15 retrieved oocytes, resulting in 4907 cultured embryos. Data collected included fresh cycle data and pregnancy rates, in addition to annotation of morphokinetic events from time of pronuclei fading to time of initiation of blastocyst formation of embryos cultured in a time lapse incubator, including occurrence of direct unequal cleavage at first cleavage (DUC-1) (less than 5 h from two to three blastomeres). Comparison was made between morphokinetic parameters between the 3 groups. Cycle outcomes were compared in the high vs. normal ovarian response groups. RESULTS: Oocyte maturation rate was significantly lower in the HOR vs. NOR groups (56.5% vs. 90.0%, p < 0.001), while the fertilization rates were similar (60.2% vs. 58.1%, p = 0.397). The prevalence of DUC-1 embryos was higher in the PCOS HOR and the HOR groups as compared to the NOR group (22.7% vs. 16.2% and 12.0%, respectively, p < 0.001). After exclusion of DUC-1 embryos, remaining embryos from the NOR and HOR groups reached the morphokinetic milestones at similar rates, with comparable implantation and clinical pregnancy rates, while the PCOS HOR showed shorter time to 5 blastomeres compared to the NOR and HOR groups. CONCLUSIONS: High ovarian response might be associated with decreased oocyte quality, manifested as a higher proportion of immature oocytes and higher rate of direct uneven cleavage embryos, while embryos exhibiting normal first cleavage have similar temporal milestones and implantation potential.

Prevalence and Characteristics of Postpartum Vulvovaginal Atrophy and Lack of Association With Postpartum Dyspareunia.

OBJECTIVE: Breastfeeding-related hypoestrogenic state has been reported as a possible risk factor for postpartum dyspareunia. This study aimed to evaluate the prevalence and characteristics of postpartum vulvovaginal atrophy according to 3 different diagnostic methods and to estimate its association with postpartum dyspareunia and daily vulvovaginal symptoms. METHODS: This is a prospective cohort study of puerperal women attending a routine postpartum checkup. Participants completed a questionnaire and underwent a gynecological examination. Atrophy was diagnosed separately according to gynecologist impression, vaginal pH measurement (≥5.1), and cytologic vaginal maturation index. Patients were followed up with a telephone survey 2-3 months later, inquiring about symptoms possibly associated with atrophy. RESULTS: Of 117 participants, vaginal atrophy was diagnosed in 48% by gynecological examination, 62% by a pH level of 5.1 or greater, and 40.2% had cytological atrophy. Of the 35.9% of women who had resumed sexual intercourse (42/117), 69% reported dyspareunia. No significant association was found between dyspareunia and atrophy parameters. There was no difference in the rates of dyspareunia among women who were exclusively breastfeeding (21/27 = 78%), partially breastfeeding (4/7 = 57%), or not breastfeeding (4/8, 50%). Atrophy was more common in breastfeeding women according to the 3 criteria (gynecological examination: 57.6% vs 16.7%, p = .006; pH: 70% vs 22%, p < .001; vaginal maturation index: 51.1% vs 0%, p < .001). Of the 117 participants, 47% reported daily vulvovaginal symptoms. Those with daily symptoms reported more dyspareunia as compared with those without daily symptoms (85% vs 52%, p = .025). CONCLUSIONS: A high prevalence of atrophy was observed in puerperal women in association with breastfeeding. There was no significant association between atrophy and dyspareunia or daily vulvovaginal symptoms.

Predictive value of serum HCG concentrations in pregnancies achieved after single fresh or vitrified-warmed blastocyst transfer.

Possible differences between serum HCG levels in pregnancies achieved after transfer of a single fresh or a vitrified-warmed blastocyst were evaluated. Out of 1130 single blastocyst transfers resulting in positive HCG results, 789 were single fresh blastocyst transfers and 341 single vitrified-warmed blastocyst transfers. The initial serum HCG levels of 869 clinical intrauterine pregnancies were evaluated, 638 after the transfer of a single fresh blastocysts and 231 after the transfer of a single vitrified-warmed blastocysts. The HCG levels from cycles resulting in a clinical intrauterine pregnancy were significantly higher after the transfer of a single vitrified-warmed blastocyst (383 ± 230 IU/l) versus a fresh transfer (334 ± 192 IU/l; P = 0.01). Threshold values for predicting a clinical pregnancy for a fresh blastocyst were 111 IU/l and for a vitrified-warmed blastocyst 137 IU/l. Our study shows that the overall beta-HCG levels are comparable after the transfer of a fresh or vitrified-warmed blastocyst, suggesting that vitrification most probably does not affect the ability of the embryos to produce beta-HCG. This study further shows that when clinicians counsel patients, they should take into account that higher HCG levels are needed after a vitrified-warmed blastocyst transfer to predict a clinical intrauterine pregnancy.

Early maternal serum ß-human chorionic gonadotropin (ß-hCG) levels and sex-related growth difference of IVF embryos.

PURPOSE: Maternal serum ß-human chorionic gonadotropin (ß-hCG) represents the trophoblastic cell mass and is an indirect measurement of embryo development at early implantation stage. Studies in animals and human embryos detected sex-related growth differences (SRGD) in favour of male embryos during the pre-implantation period. The purpose of our study was to correlate SRGD and maternal serum ß-hCG at 16 days after embryo transfer. METHODS: We retrospectively analysed all (fresh and frozen) non-donor, single embryo transfers (SET), elective and not elective, that were performed between December 2008 and December 2013. We included ß-hCG values from day 16 after oocyte collection of pregnancies resulting in live birth. Neonatal gender was retrieved from patient files. Male and female embryos were further grouped to cleavage and blastocyst stage transfers. Regression analysis for confounding variables included maternal age, maternal body mass index (BMI), use of micromanipulation (ICSI), embryo quality (grade), assisted hatching, day of transfer and fresh or frozen embryo transfer. RESULTS: Seven hundred eighty-six non-donor SETs resulted in live birth. After including only day 16 serum ß-hCG results, 525 SETs were analysed. Neonatal gender was available for 522 cases. Mean maternal serum ß-hCG levels were similar, 347 ± 191 IU/L in the male newborn group and 371 ± 200 IU/L in the female group. The difference between ß-hCG levels remained insignificant after adjusting for confounding variables. CONCLUSIONS: Early maternal ß-hCG levels after embryo transfers did not represent SRGD in our study.

Prediction of the degree of abnormal invasive placentation by obstetric history.

BACKGROUND: Diagnosis of placenta accrete spectrum (PAS) disorders is of utmost importance and mostly relies on high index of suspicion and sonographic criteria. The degree of abnormal invasive placentation is strongly associated with patients' outcomes. We aimed to determine the association between prior obstetric characteristics and the degree of PAS. METHODS: A retrospective cohort study. The study cohort comprised all women who delivered by cesarean delivery with a histopathological diagnosis of PAS during 2005-2019. We divided the cohort into 2 groups: severe PAS (increta/percreta) and mild PAS (accrete). Obstetrical characteristics and last delivery and cesarean characteristics were compared. RESULTS: Overall, 130 cases of histopathologically proven PAS were included. Of those 104 (80.0%) were mild PAS and 26 (20.0%) severe PAS. Both groups did not differ in terms of age and obstetric history. Mean parity of both study groups was 4. Intrapartum fever as noticed in 2.9-3.8% of primary cesarean (P=1.0). Cervical dilation at time of primary cesarean delivery was similar between the groups (mean 5 vs. 6 centimeters, P=0.73). Urgent cesarean delivery rate did not differ between groups (69.2% vs. 50.%, P=0.07). Method of hysterotomy closure was comparable as well. The only different variable found between groups was the rate of cephalic presentation at previous cesarean was higher in mild PAS group 69 (66.3%) vs. 11 (42.3%), P=0.024. odds ratio 2.68, 95% confidence interval 1.11-6.45. CONCLUSIONS: Discrimination of PAS severity by obstetric and previous surgical history is questionable. Our findings might be limited by sample size. Future prospective studies are warranted.

Ovarian reserve in women with cystic fibrosis: is this a cause of sub-fertility?

BACKGROUND: Over the past two decades, increasing number of people with cystic fibrosis (CF) survive into adulthood. Compared to the general population, sub-fertility is an obstacle for many women with CF (wwCF). Decreased ovarian reserve has been proposed as a possible cause, but limited data is available to support this. The aim of this study was to evaluate the ovarian reserve in wwCF and to correlate this with patients' demographic and clinical data. METHODS: Reproductive-aged wwCF were enrolled during their routine medical appointments. Assessment included Anti-Mullerian hormone (AMH) levels, routine blood tests and antral follicular count (AFC) evaluation. Additionally, demographic, and clinical information were collected. RESULTS: A total of wenty-three wwCF were enrolled, with ages ranging from 19 to 40 years (median 27 years). Among the fourteen wwCF who were considering pregnancy, five (35.7%) disclosed undergoing an infertility assessment and receiving fertility treatments. All but one patient had an Anti-Mullerian hormone (AMH) level between the 5th and 95th % for age. Measurement of the antral follicular count (AFC) was possible in 12 of the 23 patients and was ranging 8-40 with a median of 17. The proportion of wwCF presenting below median AMH values was not different in sub-fertile as compared to fertile wwCF (P value 0.54). There were no correlations between AMH levels and disease severity parameters. AMH seemed to be relatively higher in wwCF with mild class mutations, but this was not shown to have statistical significance. CONCLUSIONS: Our results, in contrast with the limited available published data, do not support the hypothesis that decreased ovarian reserve plays a major role in infertility in wwCF.

Boosting Dose of Pfizer-BioNtech mRNA Vaccine Against SARS-CoV-2 Does Not Affect Reproductive Outcomes in In-Vitro Fertilization Patients: A Cohort Study.

Background: Since the introduction of anti-COVID-19 mRNA vaccination, few studies have shown that reproductive outcomes in artificial reproductive technology (ART) treatments are not impaired, after receiving the two-dose regimen. Our aim was to investigate whether a boosting dose of the Pfizer-BioNtech mRNA vaccine affects reproductive outcomes in ART patients. Materials and Methods: This is a prospective observational study, including 157 consecutive in-vitro fertilization (IVF) cycles between October 1, 2021, and November 24, 2021, in a single university affiliated IVF unit. We included female patients going through an ART procedure and male partners in cases of utilization of a fresh sperm sample. The study population was divided into four groups according to exposure status: vaccinated and boosted patients (three total doses of Pfizer-BioNtech mRNA vaccine), patients who were vaccinated without the booster dose (one or two vaccine doses), PCR-confirmed convalescent COVID-19 patients, and unvaccinated nonconvalescent patients. Main outcome measure was clinical pregnancy rate. Results: In total, 99 (63%) female patients were vaccinated three times, 24 (15.3%) were vaccinated without the booster dose, 21 (13.4%) were convalescent, and 13 were (8.3%) unexposed. Although age differed between study groups, vaccination exposure status did not affect treatment outcome: clinical pregnancy rates, maximal estradiol levels, and number of oocytes retrieved did not differ significantly between study groups (p = 0.78, 0.50, and 0.97, respectively). Vaccinated patients who received a boosting vaccine dose were treated within 43.3 ± 30.9 days after receiving the last dose, whereas vaccinated, nonboosted, or convalescent patients were treated 168.7 ± 53 and 209.6 ± 85.1 days after their last exposure, respectively. We stratified the male cohort according to boosting vaccine dose status. Sperm concentration and motility did not differ significantly after boosting (p = 0.49 and 0.49, respectively). Conclusions: Our results provide further reassurance that IVF outcomes are not affected by the anti-SARS-CoV-2 Pfizer-BioNtech mRNA vaccine, in particular the three-dose regimen.

Mild COVID-19 Was Not Associated with Impaired IVF Outcomes or Early Pregnancy Loss in IVF Patients.

Data collection regarding the effects of COVID-19 on reproduction is ongoing. This study examined the effect of COVID-19 on IVF cycle parameters and early pregnancy outcomes. It included two arms: the first compared non-exposed cycles to post-SARS-CoV-2 IVF cycles. Sperm parameters were also compared. The second, prospective arm compared pregnancy outcomes among IVF patients who contracted COVID-19 during early pregnancy to those who did not. None of the patients were vaccinated against SARS-CoV-2. The first arm included 60 treatment cycles of women with confirmed COVID-19, compared to 60 non-exposed cycles (either the same patient before exposure or matched non-exposed patients). The outcomes of the treatment cycles did not differ significantly between exposed and non-exposed groups, including number of oocytes, endometrial thickness, fertilization rate and number of top-quality embryos. In 11 cycles, the male partner had also recently recovered: sperm concentration was lower post-exposure: 6.27 million/mL vs. 16.5 pre-exposure (p = 0.008). In 189 patients with IVF-achieved pregnancies, pregnancy loss and hospital admissions did not differ between exposed and non-exposed groups. IVF treatment outcomes and the rate of early pregnancy loss appears to be unaffected by SARS-CoV-2 disease, despite a minor decline in sperm concentration among recent recoverees.

Conventional ICSI vs. physiological selection of spermatozoa for ICSI (picsi) in sibling oocytes.

BACKGROUND: Physiological selection of spermatozoa for ICSI (PICSI) is a sperm selection method based on sperm binding to hyaluronic acid. Previous studies on the effect of hyaluronic acid binding assays on fertilization and embryo quality have shown inconsistent results. Previous sibling oocyte studies have not found a significant improvement in fertilization or embryo development with hyaluronic acid binding assays. OBJECTIVE: To compare fertilization and embryo development between standard intracytoplasmic sperm injection (ICSI) and PICSI in sibling oocytes. MATERIALS AND METHODS: This is a retrospective analysis of all in vitro fertilization (IVF) cycles between January 2017 and April 2020 in which sibling oocytes were randomly fertilized by both ICSI and PICSI. Fertilization rate and the rate of embryos eligible for transfer were compared. RESULTS: Forty-five IVF cycles, in which 257 oocytes were fertilized with PICSI and 294 with standard ICSI, were compared. Most of the patients included in the study had previous failures of fertilization, poor embryonic development, implantation failure, or miscarriage. All but two of the patients had at least one previous unsuccessful IVF cycle. Both fertilization rates (71% vs. 83%) and transfer eligible embryo rates (38% vs. 51%) were significantly higher in PICSI fertilized oocytes (p = 0.008 and p = 0.01 respectively). DISCUSSION: Our study is the largest sibling oocyte study comparing ICSI and PICSI, and the first to find a significant improvement in fertilization and embryo quality with PICSI using sibling oocytes. The fact our cohort included almost exclusively couples with previous unsuccessful IVF cycles might suggest that PICSI should be used in selected cases. CONCLUSION: PICSI improves fertilization rates and transfer eligible embryo rates in sibling oocytes in a selected study group.

Predictive value of maternal serum human chorionic gonadotropin levels in pregnancies achieved by in vitro fertilization with single cleavage and single blastocyst embryo transfers.

OBJECTIVE: To compare serum hCG levels after transfer of a single fresh cleavage embryo and of a single fresh blastocyst embryo and to determine the predictive value of serum hCG levels for pregnancy outcomes. DESIGN: A single center retrospective cohort study. SETTING: Tertiary university health center. PATIENT(S): All fresh single ETs between December 2008 and December 2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mean serum hCG levels on day 16 after oocyte collection, after the transfer of a fresh single cleavage embryo and a fresh single blastocyst embryo were compared. Multivariable regression analysis was performed to determine the association of potential factors on hCG value and a clinical pregnancy. RESULT(S): One thousand twenty-six fresh single ETs were analyzed, 801 (638 pregnancies) from a single blastocyst transfer and 225 (167 pregnancies) from a single cleavage ET. The mean hCG levels resulting from a single fresh blastocyst transfer (299 ± 204 IU/L) were significantly higher than those from a cleavage transfer (245 ± 204 IU/L). This difference remained after adjusting for confounding variables. The threshold value predicting a clinical pregnancy for a cleavage embryo was 100 IU/L, and for a blastocyst transfer, 133 IU/L. CONCLUSION(S): Our study suggests that initial serum hCG values are higher after the transfer of a single fresh blastocyst embryo compared with after a single fresh cleavage ET, even after adjusting for confounding variables.