Assisted gamete treatment to pinpoint acquired meiotic maturity and overcome oocyte activation deficiency contributed by both gametes.

Objective: To treat couples with total fertilization failure (TFF) based on a combined oocyte- and sperm-related oocyte activation deficiency by optimizing oocyte response to chemical activation with calcium ionophore. Design: Case report. Setting: Tertiary Hospital. Patients: Two couples with a history of TFF after intracytoplasmic sperm injection intracytoplasmic sperm injection (ICSI). Interventions: To overcome oocyte-related oocyte activation deficiency (OAD), extended in vivo/in vitro oocyte maturation was performed to enhance ooplasmic maturity; to address sperm-related OAD, assisted gamete treatment (AGT) was performed to trigger oocyte activation. Main outcome measures: Treatment cycle outcomes for the 2 couples undergoing ICSI with extended oocyte maturation (EOM) and AGT. Results: We identified 2 couples with TFF after ICSI because of a combined factor of OAD confirmed by phospholipase C zeta expression and genomic assessment. Initial AGT treatment alone failed to enhance fertilization, suggesting superimposed oocyte dysmaturity prohibiting oocytes from responding to chemical stimuli. To address this complex form of OAD, in couple 1, 27 oocytes out of 34 retrieved presented normal metaphase II spindles after EOM; ICSI with AGT yielded a fertilization rate of 63.0% (17/27). All 17 zygotes were cryopreserved initially. Two embryos were thawed and transferred, yielding a monochorionic diamniotic twin pregnancy. Couple 2 underwent 3 ICSI cycles with EOM and AGT; 91.4% (32/35) of oocytes displayed normal metaphase II spindle and achieved an overall fertilization rate of 43.8% (14/32). A total of 12 blastocysts were cryopreserved. A single 46XY blastocyst was thawed and transferred, resulting in a singleton pregnancy. Conclusions: Our study has demonstrated the usefulness of EOM by targeting spindle presence to enhance chemical responses to AGT.

The use of fertility preservation services for cancer patients: a single institution experience.

Objective: To analyze the use of services regarding fertility preservation (FP) in cancer patients at a single institution. Design: A retrospective cohort study. Setting: Academic medical center. Patients: A total of 208 FP referrals. Interventions: None. Main Outcome Measures: Method of FP; time from referral to FP intervention. Results: A total of 553 patients were referred to a reproductive specialist for FP in the setting of a medical diagnosis from 2011 to 2016. Of these, 208 patients satisfied the inclusion criteria and met with a reproductive specialist. Ninety patients underwent FP services. The average age at referral was 30.9 ± 7.9 years. Breast cancer (n=94, 45%) and leukemia/lymphoma (n=62, 30%) were the most prevalent cancer diagnoses. A 68.9% of patients underwent oocyte cryopreservation (n=62), 26.7% underwent embryo cryopreservation (n=24) and 4.4% underwent ovarian tissue preservation (n=4). The time interval from the referral to the FP intervention ranged from 1 to 810 days, with a median of 17 days. Conclusions: In the setting of a cancer diagnosis, most patients undergoing FP intervention underwent oocyte cryopreservation, were <35 years old, and underwent FP intervention in <30 days from referral. Whereas FP should ideally be initiated at the time of cancer diagnosis, all patients with a cancer diagnosis should be referred to a reproductive specialist and counseled on options for FP to preserve the optionality for the reproductive future they desire.

PCOS and the risk of pre-eclampsia.

RESEARCH QUESTION: What is the association between polycystic ovary syndrome (PCOS) and pre-eclampsia? Data suggest that patients with PCOS are at increased risk of developing pre-eclampsia; however, several studies have not found an independent association between the two. DESIGN: A retrospective case-control study of singleton deliveries at a tertiary care hospital from 2011 to 2015. Patients with pre-eclampsia (cases) were matched to the next delivery without pre-eclampsia (controls) on gestational age week. Medical history data, a diagnosis or clinical features of PCOS and obstetric data, including pre-eclampsia, were abstracted from the medical record. Groups were compared with the chi-squared test, and conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (95% CI). OR were adjusted for maternal age at delivery and race/ethnicity. RESULTS: This study included 435 cases and 435 controls. Cases were more likely to be Black compared with controls. Age, comorbidities, features of PCOS and use of IVF were similar between groups. Patients with pre-eclampsia were not more likely to have PCOS (8.3%) than those without pre-eclampsia (6.2%, adjusted OR 1.40, 95% CI 0.81-2.30). Sensitivity analyses for body mass index and parity suggested an increased pre-eclampsia risk for patients with PCOS and these additional factors, however no group showed a statistically significant association between PCOS and pre-eclampsia. CONCLUSIONS: In this study, a history of PCOS was not associated with the risk of pre-eclampsia. Further investigation is necessary to determine whether there are subgroups of PCOS patients who are at increased risk of pre-eclampsia.

Age-specific blastocyst conversion rates in embryo cryopreservation cycles.

RESEARCH QUESTION: What is the blastocyst conversion rate in embryo cryopreservation cycles, per year of female age? DESIGN: Retrospective cohort study including patients undergoing their first ovarian stimulation cycle at our center with planned freeze-all strategy January 1st, 2014-June 30th, 2020. Primary outcome was blastocyst conversion rate. Secondary outcomes included mature oocyte and fertilization rates. Patients were stratified by year of age to assess oocyte yield and embryo development outcomes. RESULTS: 3,362 patients were included. The median blastocyst conversion rate in patients ≤30 was 66.7% (interquartile range 50.0-86.6) and remained statistically comparable through age 40 with a significant decline among ages ≥41 (41-years: marginal effect (ME) -5.2% (-9.7 to -0.7); 42-years: ME -9.6% (-14.3 to -4.8); 43-years: ME -7.7% (-12.8 to -2.6); ≥44-years: ME -20.8% (-26.5 to -15.1)). For the entire cohort, the median mature oocyte rate was 81.8% and the median fertilization rate was 81.8%. The mature oocyte and fertilization rates remained statistically comparable for each year of age except age ≥44 which had a statistically significantly increased mature oocyte rate (ME 4.4% (1.3 to 7.5)) and statistically significantly decreased fertilization rate (ME -5.8% (-9.8 to -1.9)) CONCLUSIONS: In embryo cryopreservation cycles, the blastocyst conversion rate remained statistically comparable through age 40 followed by a statistically significant decline for patients ≥41; however, the mature oocyte and fertilization rates were not impacted by increasing age until age ≥44. Even in women ≥44, over 40% of fertilized oocytes developed to blastocyst. Overall, this information is useful when counseling patients during the embryo culture stage regarding predicted blastocyst yield.

Aqueous vaginal contrast and scheduled hematocolpos with magnetic resonance imaging to delineate complex müllerian anomalies.

OBJECTIVE: To demonstrate the advantage of using aqueous vaginal contrast and scheduled hematocolpos with magnetic resonance imaging (MRI) to improve the delineation of gynecologic anatomy and to recommend that this modality be considered in patients with complex müllerian anomalies. DESIGN: Video demonstration of MRI adjuncts to improve visualization of gynecologic anatomy. SETTING: Academic Hospital. PATIENT(S): A patient with obstructed hemivagina and ipsilateral renal agenesis (OHVIRA) who presented for definitive surgical management. INTERVENTION(S): OHVIRA is a unilateral obstructed müllerian anomaly that presents typically after menarche with progressively worsening dysmenorrhea caused by progressive distension of the obstructed hemivagina and uterine horn. The definitive treatment for this anomaly is resection of the unilateral obstruction. When the obstructed hemivagina is within close proximity to the patent hemivagina, vaginal septum resection should be performed to relieve the obstruction successfully. However, when the obstructed hemivagina and uterine horn are not adjacent to the patent hemivagina, a simple septum resection is not feasible and there is a high rate of restenosis if anastomosis is attempted. In this case, laparoscopic removal of the obstructed uterine horn, fallopian tube, cervix, and vagina should be considered as an alternative approach to resolving the obstruction. A surgical approach can be recommended only once the surgeon has a clear understanding of the patient's pelvic anatomy and the magnitude of the obstruction. In the presented case, a 17-year-old patient with OHVIRA presented for definitive surgical management. While on hormonal suppression, a pelvic MRI was performed that identified a uterus didelphys with a left hemiuterus and cervix communicating with a patent vagina. The right hemiuterus and cervix were measured 2.5 cm from the patent vagina. However, because of hormonal suppression, the vaginal cavity was decompressed, making it very difficult to discern the relationship between the two uteri and vaginas. To better determine whether vaginal septum resection to relieve the obstruction was feasible, norethindrone was discontinued to allow menstrual blood to fill the obstructed hemivagina followed by a subsequent pelvic MRI with aqueous vaginal contrast to fill the patent vagina with contrast gel to improve the visualization of the decompressed vaginal cavities. MAIN OUTCOME MEASURE(S): Advantage of aqueous vaginal contrast and scheduled hematocolpos with MRI to image pelvic anatomy in a patient with a complex müllerian anomaly to guide surgical decision-making. RESULT(S): The addition of vaginal aqueous contrast clearly delineated the course and caliber of the patent vagina and its relationship to the obstructed hemivagina, now filled with blood. The inferior margin was in closer proximity to the patent vagina, but with only a very narrow segment (<1 cm) adjacent to the patent vagina and the obstructed cervix was displaced superiorly, now measuring 3.5 cm above the patent vagina. Surgical management options were discussed with the patient, and given the superior location of the obstructed uterus and cervix with only a narrow border of the vagina in continuity with the patent vagina, the risk of postoperative stenosis after vaginal septum resection was determined to be too high. The decision was made to proceed with a laparoscopic resection of the obstructed right side, and the patient underwent laparoscopic resection of the right hemiuterus, fallopian tube, cervix, and vagina. Intraoperatively, a survey of the pelvis again confirmed that the two vaginas were too far to reconnect safely without a high risk of stenosis. The patient recovered without complications postoperatively and her menses resumed without any pain. CONCLUSION(S): We highlight the use of two techniques to optimize MRI imaging of pelvic anatomy in a patient with a complex müllerian anomaly. First, the use of aqueous vaginal contrast with MRI is advantageous to clearly delineate the course and caliber of the patent vagina in patients with complex gynecologic anatomy. Second, cessation of hormonal suppression to allow menstruation to cause hematocolpos helped delineate the relationship between the obstructed vagina and patent vagina. In the presented case, these MRI adjuncts provided necessary detail that could not be appreciated with standard MRI to confirm that vaginal septum resection to preserve the right uterus would be too high a risk for postoperative stenosis in this patient. Aqueous vaginal contrast and scheduled hematocolpos should be considered as adjuncts to MRI when standard imaging modalities are unable to clearly describe the relationship between pelvic structures in cases of complex müllerian anomalies to help guide treatment recommendations.

Elevated serum progesterone during in vitro fertilization treatment and the risk of ischemic placental disease.

BACKGROUND: Elevated progesterone on the day of human chorionic gonadotropin (hCG) administration is associated with decreased live birth rates in IVF cycles. The association with adverse pregnancy outcomes is unknown. OBJECTIVES: Assess the association between serum progesterone on the day of hCG administration and the risk of ischemic placental disease [IPD; preeclampsia, placental abruption, and/or small for gestational age (SGA)]. METHODS: We conducted a retrospective cohort study of autologous fresh IVF cycles resulting in delivery between 2005 and 2018. All IVF procedures were conducted at a large, university-affiliated infertility center. Patients were divided into tertiles based on their serum progesterone level on the day of hCG administration; the lowest tertile served as the reference group. We identified pregnancies complicated by preeclampsia and placental abruption using ICD-9/10 codes and medical record review. We defined SGA as < 10th percentile using U.S. growth curves. RESULTS: The cohort included 166 deliveries in the lowest tertile of progesterone (0.2-0.73 ng/ml), 166 deliveries in the middle (0.64-1.05 ng/ml) and 167 deliveries in the highest tertile (1.05-5.6 ng/ml). Compared with the lowest tertile, the risk of IPD was greater in the middle (RR 1.6; 95% CI 1.1-2.5) tertile after adjustment for age, parity, number of oocytes retrieved, and estradiol. The highest tertile was also not associated with an increased risk of IPD. CONCLUSION: In an IVF population, elevated serum progesterone in the range of 0.64-1.05 ng/mL on the day of hCG administration was associated with a small increased risk of IPD.

Multiple cryopreservation-warming cycles, coupled with blastocyst biopsy, negatively affect IVF outcomes.

RESEARCH QUESTION: Do multiple cryopreservation-warming cycles, coupled with blastocyst biopsy, negatively affect IVF outcomes? DESIGN: Patients undergoing IVF with homologous single embryo transfer, and who underwent trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) between 2013 and 2017, were divided into three groups based on degree of embryonic micromanipulation: once-biopsied, once-cryopreserved (group BC, n = 2603), once-biopsied, twice-cryopreserved (group CBC, n = 95) and twice-biopsied, twice-cryopreserved (group BCBC, n = 15). The primary outcome was live birth; secondary outcomes included positive serum pregnancy test, clinical pregnancy and miscarriage. RESULTS: Group CBC had a significantly lower chance of live birth (adjusted RR 0.57, 95% CI 0.41 to 0.79) and clinical pregnancy (adjusted RR 0.67, 95% CI 0.53 to 0.85) compared with group BC. Miscarriage rates were similar between groups BC and CBC (adjusted RR 1.3, 95% CI 0.64 to 2.7). CONCLUSIONS: Multiple cryopreservation-warming cycles, coupled with blastocyst biopsy, negatively affect IVF outcomes. Although PGT-A is thought to improve reproductive outcomes on a per transfer basis, caution must be exercised in counselling patients on the possibility of diminishing returns owing to further embryonic micromanipulation after an embryo has been cryopreserved.

Prepregnancy Genetic Carrier Screening in Recipients of Hematopoietic Stem Cell Transplants.

BACKGROUND: Genetic carrier screening of individuals with a history of hematopoietic stem cell (HSC) transplant is not always straightforward. CASE: We present the case of a couple who underwent prepregnancy genetic screening before fertility treatment. The genetics laboratory flagged the male partner's blood sample because there was a discrepancy between the sex of the patient and the sex chromosome markers, ultimately leading to the discovery of a prior HSC transplant. CONCLUSION: A history of HSC transplant may confound results of serum-based genetic carrier screening. Hematopoietic stem cell transplant recipients are at risk for misinterpreted genetic carrier screening because the results of such screening may not actually be reflective of their own DNA.

Basal cell carcinoma of the vulva: a case report and systematic review of the literature.

The vulva is an unusual site for basal cell carcinoma (BCC). Vulvar BCC accounts for <1% of all BCCs and <5% of all vulvar malignancies. We report the case of an 83 year-old woman who presented with a 2-month history of a tender labial growth, with histopathology confirming nodular BCC. We conducted a systematic literature review of the characteristics of reported cases of vulvar BCCs. A comprehensive systematic review of articles indexed for MEDLINE and Embase yielded 96 reports describing 437 patients with 446 BCCs of the vulva. The mean age at presentation was 70 (range 20-100). Most women had no underlying vulvar disease. Approximately 60% of cases were of the nodular subtype. Treatment approach varied widely with over half of cases treated with wide local or local excision. Mohs micrographic surgery (MMS) for vulvar BCC was first reported in 1988 with seven total MMS cases reported. Twenty-three cases of recurrence have been reported; 21 of these cases after local excision but none following MMS. Vulvar BCC is a rarely reported cancer that affects older women predominantly. MMS represents a promising treatment for BCC in this anatomic location.

Teaching & Learning Tips 9: Case-based teaching with patients.

Challenge: "Case-based teaching" is a buzzword for engaging clinical teaching through cases, but how can it be implemented effectively in practice? We review popular case-based teaching methods (i.e., one-minute preceptor, SNAPPS, and the "Aunt Minnie method") for use during traditional one-on-one clinical preceptorships in the ambulatory dermatological setting.

Teaching & Learning Tips 8: Preparing to teach in ambulatory settings.

Challenge: Clinical teaching in dermatology largely occurs in the outpatient setting. Herein, we review common barriers to teaching in the ambulatory setting and discuss strategies preceptors can take to "teach on the run" during clinic sessions.

Effects of a Short Video-Based Resident-as-Teacher Training Toolkit on Resident Teaching.

OBJECTIVE: To pilot a short video-based resident-as-teacher training toolkit and assess its effect on resident teaching skills in clinical settings. METHODS: A video-based resident-as-teacher training toolkit was previously developed by educational experts at Beth Israel Deaconess Medical Center, Harvard Medical School. Residents were recruited from two academic hospitals, watched two videos from the toolkit ("Clinical Teaching Skills" and "Effective Clinical Supervision"), and completed an accompanying self-study guide. A novel assessment instrument for evaluating the effect of the toolkit on teaching was created through a modified Delphi process. Before and after the intervention, residents were observed leading a clinical teaching encounter and scored using the 15-item assessment instrument. The primary outcome of interest was the change in number of skills exhibited, which was assessed using the Wilcoxon signed-rank test. RESULTS: Twenty-eight residents from two academic hospitals were enrolled, and 20 (71%) completed all phases of the study. More than one third of residents who volunteered to participate reported no prior formal teacher training. After completing two training modules, residents demonstrated a significant increase in the median number of teaching skills exhibited in a clinical teaching encounter, from 7.5 (interquartile range 6.5-9.5) to 10.0 (interquartile range 9.0-11.5; P<.001). Of the 15 teaching skills assessed, there were significant improvements in asking for the learner's perspective (P=.01), providing feedback (P=.005), and encouraging questions (P=.046). CONCLUSION: Using a resident-as-teacher video-based toolkit was associated with improvements in teaching skills in residents from multiple specialties.

Geographic Comparison of Women in Academic Obstetrics and Gynecology Department-Based Leadership Roles.

OBJECTIVE: To describe and compare geographic representation of women in obstetrics and gynecology department-based leadership roles across American Congress of Obstetricians and Gynecologists (ACOG) districts and U.S. Census Bureau regions while accounting for the proportion of women practicing in each area. METHODS: We conducted a cross-sectional observational study. To more meaningfully quantify representation of women as leaders in ACOG districts and U.S. Census Bureau regions, we calculated representation ratios-the proportion of department-based leaders who were women divided by the proportion of obstetrician-gynecologists who were women. A ratio of 1.0 indicates proportionate representation and less than 1.0 indicates underrepresentation. We calculated 95% CIs to compare representation of women in leadership roles across geographic areas. The gender of major department-based leaders (chair, vice chair, division director) and educational leaders (fellowship, residency, associate residency, medical student clerkship director) was determined from websites. RESULTS: The proportion of department chairs who were women was highest in the West and lowest in the South Census Bureau regions. Representation ratios for women in major department-based leadership roles demonstrated underrepresentation relative to the practicing base nationally and in all four regions. Although women were underrepresented in major department-based leadership throughout the country, there was significantly higher women's representation in major department-based leadership roles in the West (ratio 0.82, 95% CI 0.68-0.99) compared with the Northeast (ratio 0.50, 95% CI 0.42-0.59) and the South (ratio 0.45, 95% CI 0.36-0.57). Similarly, in the division director role, the West (ratio 0.85, 95% CI 0.68-1.1) had significantly higher representation of women compared with the Northeast (ratio 0.50, 95% CI 0.40-0.62). Nationally, women were underrepresented as fellowship directors, proportionately represented as residency program directors, and overrepresented as medical student clerkship directors. CONCLUSION: Representation ratios of women in major department-based leadership roles, which account for the proportion of women practicing in each geographic area, suggest that women were more likely to advance to the department-based leadership roles of chair, vice chair, or division director in the western United States.

Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation.

BACKGROUND: The occurrence of a congenital heart defect has long been thought to have a multifactorial basis, but the evidence is indirect. Complex trait analysis could provide a more nuanced understanding of congenital heart disease. METHODS AND RESULTS: We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects (VSDs) caused by a heterozygous Nkx2-5 knockout mutation. We phenotyped >3100 hearts from a second-generation intercross of the inbred mouse strains C57BL/6 and FVB/N. Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5(+/-) animals. The chromosome 6 locus overlaps one for muscular VSD susceptibility. Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5(+/-) but not wild-type animals. The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals. The risk of a VSD is not only complex but dynamic. Whereas the effect of genetic modifiers on risk remains constant, the effect of maternal aging increases over time. CONCLUSIONS: Enumerable factors contribute to the presentation of a congenital heart defect. The factors that modify rather than cause congenital heart disease substantially affect risk in predisposed individuals. Their characterization in a mouse model offers the potential to narrow the search space in human studies and to develop alternative strategies for prevention.

Heterogeneity of genetic modifiers ensures normal cardiac development.

BACKGROUND: Mutations of the transcription factor Nkx2-5 cause pleiotropic heart defects with incomplete penetrance. This variability suggests that additional factors can affect or prevent the mutant phenotype. We assess here the role of genetic modifiers and their interactions. METHODS AND RESULTS: Heterozygous Nkx2-5 knockout mice in the inbred strain background C57Bl/6 frequently have atrial and ventricular septal defects. The incidences are substantially reduced in the Nkx2-5(+/-) progeny of first-generation (F1) outcrosses to the strains FVB/N or A/J. Defects recur in the second generation (F2) of the F1 X F1 intercross or backcrosses to the parental strains. Analysis of >3000 Nkx2-5(+/-) hearts from 5 F2 crosses demonstrates the profound influence of genetic modifiers on disease presentation. On the basis of their incidences and coincidences, anatomically distinct malformations have shared and unique modifiers. All 3 strains carry susceptibility alleles at different loci for atrial and ventricular septal defects. Relative to the other 2 strains, A/J carries polymorphisms that confer greater susceptibility to atrial septal defect and atrioventricular septal defects and C57Bl/6 to muscular ventricular septal defects. Segregation analyses reveal that > or = 2 loci influence membranous ventricular septal defect susceptibility, whereas > or = loci and at least 1 epistatic interaction affect muscular ventricular and atrial septal defects. CONCLUSIONS: Alleles of modifier genes can either buffer perturbations on cardiac development or direct the manifestation of a defect. In a genetically heterogeneous population, the predominant effect of modifier genes is health. (Circulation. 2010;121:1313-1321.)