The effect of ovarian follicle size on oocyte and embryology outcomes.

OBJECTIVE: To identify relationships between the size of punctured ovarian follicles and subsequent embryology outcomes. DESIGN: Prospective observational cohort study. SETTING: Private fertility center. PATIENTS: One hundred fifty-seven oocyte retrievals performed during the study period. INTERVENTIONS: The diameter of punctured follicles was ultrasonically measured during routine oocyte collection. The resulting embryos were group-cultured to the blastocyst stage and classified into 8 groups according to follicle size (≤9.5, 10-12.5, 13-15.5, 16-18.5, 19-21.5, 22-24.5, 25-27.5, and ≥28 mm). MAIN OUTCOME MEASURE: Rate of good-quality blastocysts per follicle puncture. RESULTS: This study included 4,539 follicle punctures, 2,348 oocytes, 1,772 mature oocytes, 1,258 bipronuclear (2pn) oocytes, and 571 good-quality blastocysts derived from 157 oocyte retrievals. The per-puncture yields of oocytes, mature oocytes, 2pn oocytes, and good-quality blastocysts were associated with the size of the punctured follicle. The rates of good-quality blastocysts per punctured follicle were 2.2% (≤9.5 mm), 6.2% (10-12.5 mm), 11.9% (13-15.5 mm), 14.5% (16-18.5 mm), 18.9% (19-21.5 mm), 17.5% (22-24.5 mm), 15.9% (25-27.5 mm), and 16.0% (≥28 mm). When compared with the overall average, punctures of follicles in groups ≤12.5 mm in diameter had significantly inferior yields of good-quality blastocysts, whereas punctures of follicles in groups 19-24.5 mm in diameter were associated with significantly greater than average yields of good-quality blastocysts. Other groups did not differ significantly from average. No correlation was observed between follicle diameter and ploidy of biopsied blastocysts. CONCLUSIONS: Punctures of follicles ≤12.5 mm in diameter rarely result in good-quality blastocysts. The yield of good-quality blastocysts progressively increases with follicle size up to approximately 19 mm in diameter, with no substantial decline above that size. The ploidy of the blastocysts that form appears to be unaffected by follicle size.

The change in endometrial thickness following progesterone exposure correlates with in vitro fertilization outcome after transfer of vitrified-warmed blastocysts.

PURPOSE: To determine if the change in endometrial thickness following exogenous progesterone (P) initiation correlates with outcome following autologous transfer of a single thawed blastocyst. METHODS: The study is a retrospective observational cohort study conducted at a private fertility center. Patients scheduled for thawed blastocyst transfer received artificial endometrial preparation (artificial cycle FET) and underwent serial ultrasonography. The main outcomes were the rate of ongoing pregnancy (fetal heart motion at 12 weeks of gestation) and early pregnancy loss. Logistic regression was used to test for correlations between these outcomes and the change in endometrial thickness while adjusting for potential confounders (patient age, embryo quality, and the use of genetic testing). RESULTS: There were 232 qualifying autologous single-blastocyst transfers in the 20-month study period ending 31 December 2019. Mean endometrial thicknesses were 3.8 mm, 10.0 mm, and 11.2 mm at baseline, P initiation, and at transfer, respectively. The change in endometrial thickness after exogenous P exposure ranged from - 5 to + 9 mm and negatively correlated with ongoing pregnancy in logistic regression analyses. Specifically, ongoing pregnancy rates per transfer were 63.2% in 19 cases where endometria compacted by 10% or more, 64.2% in 95 cases where there was unchanged endometrial thickness, and 52.5% in 118 cases where endometria expanded. CONCLUSIONS: The change in endometrial thickness after P initiation was associated with the probability of ongoing pregnancy but not with early pregnancy loss. Ongoing pregnancy rates were greater in endometria with negative growth (compaction) when compared to endometria that grew (expanded) after P exposure.

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

OBJECTIVE: To characterize corpora lutea (CL) function after gonadotropin-releasing hormone agonist (GnRHa) trigger with the use of adjuvant human chorionic gonadotropin (hCG). DESIGN: Secondary analysis of serum from prospective randomized clinical trial. SETTING: University-based fertility center. PATIENT(S): Women under 40 years of age at risk of ovarian hyperstimulation syndrome (OHSS) with serum E2 level <4,000 pg/mL. INTERVENTIONS(S): 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. MAIN OUTCOME MEASURE(S): Luteal phase and early pregnancy curves of serum prorenin and 17α-hydroxyprogesterone (17OH-P). RESULT(S): Thirty subjects enrolled in this secondary analysis. Serum 17OH-P peaked in the early luteal phase, 5 days after GnRHa trigger, with a nadir in the mid-luteal phase 9 days after trigger. Serum prorenin peaked in the luteal phase 2 days after GnRHa trigger, independently from adjuvant hCG timing, and reached a nadir at 9 days after trigger. CL function appears higher when adjuvant hCG is given at VOR compared with adjuvant hCG given at the time of trigger. CONCLUSION(S): 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT01815138.

Euploidy rates between cycles triggered with gonadotropin-releasing hormone agonist and human chorionic gonadotropin.

OBJECTIVE: To evaluate differences in euploidy rates between IVF cycles triggered with either GnRH agonist (GnRHa) or hCG. DESIGN: Retrospective cohort study. SETTING: University-affiliated fertility center. PATIENT(S): A total of 366 patients performing 539 IVF cycles utilizing preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTION(S): Gonadotropin-releasing hormone agonist or hCG trigger of oocyte maturation during IVF cycles. MAIN OUTCOME MEASURE(S): Rate of euploid embryos. RESULT(S): Patients in the GnRHa trigger arm were younger, with a lower body mass index and higher antimüllerian hormone level, and they had a higher number of oocytes retrieved and embryos biopsied. Euploid rate per embryo biopsied was higher after GnRHa trigger than after hCG trigger (37.8% ± 2.1% vs. 30.3% ± 1.8%), but multivariate regression analysis controlling for potential confounding factors did not show any differences between the two groups. Moreover, the euploid rate per oocyte retrieved was not significantly different overall (GnRHa vs. hCG: 33.9% ± 2.2% vs. 28.0% ± 1.9%). The anticipated decline in the rate of euploid embryos per oocyte retrieved went from 15.8% ± 1.2% for age <35 years to 4.3% ± 0.9% for patients aged ≥41 years. There were no significant differences between the two groups after stratifying by age and controlling for PGT-A testing modality. CONCLUSION(S): Both GnRHa and hCG trigger result in comparable euploid rates. Trigger with GnRHa should therefore be considered a valid option for trigger modality in freeze-all PGT-A cycles, in view of its demonstrated effectiveness and known safety enhancement.

Frozen blastocyst transfer outcomes in immediate versus delayed subsequent cycles following GnRH agonist or hCG triggers.

PURPOSE: The aim of this study is to analyze clinical pregnancy rates (CPR) and ongoing pregnancy rates (OPR) for frozen embryo transfers (FET) performed with blastocysts in the cycle immediately after GnRH agonist (GnRHa) versus human chorionic gonadotropin (hCG) triggers, with outcomes of delayed FET for comparison. METHODS: Retrospective cohort study at a university-affiliated in vitro fertilization (IVF) clinic, including patients undergoing IVF between 2013-16 with a blastocyst FET performed within two menstrual cycles of a previous stimulation cycle and vaginal oocyte retrieval (VOR). FETs included programmed and natural endometrial preparation. Outcome measures were clinical and ongoing pregnancy rates. RESULTS: CPR and OPR for 344 FET cycles were similar when comparing immediate and delayed transfer overall (crude CPR 67.5 versus 76.5%, p = 0.11; OPR 57.5 versus 66.7%, p = 0.13), and after stratifying by cycles following hCG trigger (OPR 62.5 versus 66.3%, p = 0.61) and GnRHa trigger (OPR 55.6 versus 64.5%, p = 0.17). When considering a number of predictors for OPR, an adjusted odds ratio (OR) of 1.74 [95% CI 1.00-3.03] approached significance in favor of delayed FET. CONCLUSIONS: Regardless of trigger modality, patients can be reassured that pregnancy rates with FET are high in immediate and delayed cycles. However, our study suggests a potential benefit in delaying a cycle before proceeding with FET.

Does the Difference in Fascial Closure Technique Affect Postoperative Pain?

STUDY OBJECTIVE: To compare postoperative incisional pain on postoperative days (PODs) 1 and 14 when using a fascial closure device (FCD) versus a traditional fascial closure (TFC) of the 12-mm upper quadrant port during robotic surgery. Time required to close the incision was also compared. DESIGN: Randomized controlled trial (Canadian Task Force classification I). SETTING: Two academic affiliated hospitals, The Hospital of Central Connecticut and The University of Connecticut. PATIENTS: Women undergoing robotic surgery for benign indications by minimally invasive gynecologists at our institutions between November 2012 and October 2014 were enrolled in the study at their preoperative visit. INTERVENTIONS: Patients were randomized to either an FCD or TFC immediately before closure of the fascial incision. Pain score using a 10-point analog pain scale was recorded on POD 1 and POD 14. Time to close the fascial incision, length of surgery, and body mass index were also recorded. MEASUREMENTS AND MAIN RESULTS: Sixty-seven patients were enrolled, and 65 were randomized at the time of the fascial closure, whereas 2 enrolled patients converted to laparotomy. Statistical analysis demonstrated that pain scores differed by fascial closure technique. Mean pain scores on POD 1 were 3.43 ± 2.48 and 2.06 ± 2.03 for the FCD and TFC, respectively (p = .028). On POD 14 the mean pain scores were 1.97 ± 2.48 and .83 ± 1.42 for the FCD and TFC, respectively (p = .102). Times to close fascia were 106.5 ± 102.28 seconds and 141.97 ± 102.85 seconds for the FCD and TFC, respectively (p = .138). CONCLUSION: Our study demonstrates that at POD 1 the use of the fascia closure device results in higher pain scores without a significant difference in closure time.

Pregnancy rates for single embryo transfer (SET) of day 5 and day 6 blastocysts after cryopreservation by vitrification and slow freeze.

PURPOSE: The purpose of this study was to compare clinical and ongoing pregnancy rates in cycles with single embryo transfer (SET) of blastocysts cryopreserved on day 5 or day 6. Our aim was to determine whether day 6 blastocysts perform adequately to recommend SET. METHODS: Retrospective cohort study including 468 transfer cycles for 392 women younger than age 38 undergoing SET at a university-affiliated IVF clinic in the USA. A total of 261 day 5 blastocysts and 207 day 6 blastocysts for frozen-thawed SET between 2010 and 2016 were analyzed. Data included cryopreservation by both a slow freeze method and vitrification. RESULTS: In total, 59.0% of day 5 SET cycles resulted in a clinical pregnancy compared to 54.1% of day 6 blastocysts (p = 0.54). Ongoing pregnancy rates from day 5 frozen-thawed blastocysts (51.7%) were comparable to day 6 (44.9%, p = 0.14). When looking at vitrified blastocysts only, there were no significant differences between day 5 and day 6 blastocysts, with a clinical pregnancy rate of 69.2% for day 5 and 72.5% for day 6 (p = 0.68). CONCLUSIONS: SETs of day 6 cryopreserved blastocysts resulted in similar clinical and ongoing pregnancy rates compared to day 5, particularly after vitrification.

Old habits die hard: retrospective analysis of outcomes with use of corticosteroids and antibiotics before embryo transfer.

OBJECTIVE: To evaluate clinical pregnancy rates in embryo transfer (ET) cycles with and without peri-implantation corticosteroid and oral antibiotic administration. DESIGN: Retrospective cohort study. SETTING: University-affiliated in vitro fertilization (IVF) clinic. PATIENT(S): Eight hundred and seventy-six ETs with or without the routine use of methylprednisolone and doxycycline. INTERVENTION(S): Embryo transfer procedures. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates (CPR). RESULT(S): The CPR with the routine use of methylprednisolone and doxycycline was 56.1% compared with 61.5% after discontinuation of these medications. Ongoing pregnancy rates were 49.5% with medications versus 53.2% without medications. Of the cleavage-stage embryos, 79% underwent assisted hatching; among these, the CPR was 28.7% when treated with corticosteroids and antibiotics compared with 47.4% without medications. CONCLUSION(S): No statistically significant difference in overall IVF outcomes was noted after the discontinuation of routine peri-implantation corticosteroids and antibiotics. The use of these medications varies across the country and may be a result of habit rather than evidence-based medicine.

Increasing awareness of age-related fertility and elective fertility preservation among medical students and house staff: a pre- and post-intervention analysis.

OBJECTIVE: To assess medical students' and house staff's knowledge and personal and professional perceptions of age-related fertility and fertility preservation before and after an educational intervention. DESIGN: Pre-/post intervention survey. SETTING: University-based medical center. PATIENT(S): Medical students and house staff. INTERVENTION(S): An educational session on age-related fertility decline and elective fertility preservation. MAIN OUTCOME MEASURE(S): Knowledge scores and perceptions assessed immediately before and after the intervention. RESULT(S): Sixty-five surveys were administered. Of the 53 respondents, 71.7% were married or in a committed relationship; 89.4% reported that they were delaying childbearing, with career and/or education being the most frequently listed reason (85.7%); 39.5% indicated that they had both personal and professional interest in fertility preservation but identified finances (62.5%) and time (59.4%) as barriers; 86.9% indicated previous exposure, with formal education (80.0%) and social media (40.0%) being the most common sources. Mean scores on a six-question knowledge-based assessment improved significantly following the presentation (54.6 ± 19.0% vs. 78.1 ± 16.0%), as did the number of participants who indicated that they might now recommend elective oocyte cryopreservation to others (71.1% vs. 54.3%). After the intervention, 97.8% thought that it was important for medical professionals to be informed about age-related fertility decline and elective oocyte cryopreservation. CONCLUSION(S): Despite professional and personal interest, knowledge of age-related fertility decline and elective fertility preservation is limited among medical students and house staff. This study highlights the need for formal education across all levels of training and specialties, with even brief interventions being of potential benefit.

Survey assessing obesity policies for assisted reproductive technology in the United States.

OBJECTIVE: To determine what assisted reproductive technologies (ART) policies, if any, have been instituted in response to an increasingly overweight and obese patient population. DESIGN: Cross-sectional survey. SETTING: University-affiliated IVF clinic. PATIENT(S): Women in the overweight and obese body mass index (BMI) categories seeking ART treatments. INTERVENTION(S): Anonymous survey sent to medical directors at 395 IVF centers listed in Society for Assisted Reproductive Technology database. MAIN OUTCOME MEASURE(S): Assessment of recommendations, policies, and restrictions for patients who are overweight/obese and who desire treatment for infertility, including in IVF, IUI, and donor egg cycles. RESULT(S): Seventy-seven anonymous responses were received (19.5% response rate): 64.9% of centers have a formal policy for obesity, and 84% of those have a maximum BMI at which they will perform IVF, while 38% of those have a maximum BMI for performing IUI; 64.6% of respondents reported anesthesia requirements/concerns as the primary criteria for patient exclusion. Other primary considerations included safety during ongoing pregnancy and ART outcomes. CONCLUSION(S): Centers that have policies regarding obesity and access to ART consider efficacy, procedural safety, safety in pregnancy, and overall health status. Policies vary widely. The patient's autonomy must be balanced with nonmaleficence and the avoidance of interventions that may be unsafe both immediately and long term.

Gaze maintenance and autism spectrum disorder.

CASE: Chase is a 5½-year-old boy whom you have followed in your primary care practice since age 26 months. He was born full-term vaginal delivery weighing 6 pounds 15 ounces. His biological mother used heroin, tobacco, and cocaine during pregnancy. From 8 weeks to 18 months, he spent time in a foster home where he was provided limited attention and nurturing. At age 18 months, he entered a loving foster home; at 26 months, he was adopted. There is maternal history of attention-deficit hyperactivity disorder, learning disability, depression, bipolar disorder, and substance abuse but no history of autism or cognitive disability. Chase received early intervention before adoption. Specific concerns are unknown. At the time of his adoption, he had delays in gross motor and fine motor skills, nonverbal communication, and speech production. Familiar listeners find Chase to be 100% intelligible but unfamiliar listeners understand about 70% of what Chase says. He enjoys being with his adopted mother and imitating her. He has demonstrated significant anxiety during his play therapy. He has difficulty in paying attention to multistep directions. Chase can point and wave but has difficulty following someone's eyes to see where another person is looking. Chase enjoys a variety of interests but has a special fixation on Toy Story characters. Chase does initiate social interactions but can be aggressive toward his siblings and oppositional toward his parents. He is not aggressive at school. Teachers note hyperactivity and impulsivity. Chase is bothered by bright lights and by others making loud noises but has no difficulty with crowds. Chase is reported to have difficulty in transitioning between activities. At his 5-year-old visit, you as well as his mother and therapists note that he has trouble following with his eyes so he is referred to a neuro-ophthalmologist. Evaluation showed Chase was able to fix on and follow objects and light, his peripheral vision was normal, his pupils were equal and reactive without afferent pupillary defect, and normal visual tracking as assessed through pursuit and saccades. There were some head jerking motions observed which were not thought to be part of Chase's attempts to view objects. Gaze impersistence was noted, although it was not clear if this was due to a lack of attention or a true inability to maintain a gaze in the direction instructed. On review of the school's speech and language report, they state that he is >90% intelligible. He has occasional lip trills. Testing with the Clinical Evaluation of Language Fundamentals shows mild delays in receptive language, especially those that require visual attention. Verbal Motor Production Assessment for Children reveals focal oromotor control and sequencing skills that are below average, with groping when asked to imitate single oromotor nonspeech movements and sequenced double oromotor nonspeech movements. At 5½ years, he returns for follow-up, and he is outgoing and imaginative, eager to play and socialize. He makes eye contact but does not always maintain it. He asks and responds to questions appropriately, and he is able to follow verbal directions and verbal redirection. He is very interested in Toy Story characters but willing to share them and plays with other toys. Chase's speech has predictable, easy to decode sound substitutions. On interview with him, you feel that he has borderline cognitive abilities. He also demonstrates good eye contact but lack of visual gaze maintenance; this is the opposite of the pattern you are accustomed to in patients with autism spectrum disorder. What do you do next?