The use of GnRH-agonist trigger for the final maturation of oocytes in normal and low responders undergoing planned oocyte cryopreservation.

STUDY QUESTION: Does GnRH-agonist trigger offer similar maturity rate (MR) in low and normal responders compared to high responders in women undergoing planned oocyte cryopreservation, for whom even a small risk of ovarian hyperstimulation syndrome (OHSS) may not be acceptable? SUMMARY ANSWER: GnRH-agonist is an appropriate choice for final maturation of oocytes in planned oocyte cryopreservation, regardless of response to stimulation or risk of ovarian hyperstimulation syndrome. WHAT IS KNOWN ALREADY: Numerous studies have demonstrated the utility of GnRH-agonist trigger for the prevention of ovarian hyperstimulation in high-responder in vitro fertilization cycles. Limited data exist supporting its use in normal or low responders, or in non-infertile women undergoing planned oocyte cryopreservation. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study of 1189 subjects including all planned oocyte cryopreservation cycles performed at a large, single center, oocyte cryopreservation program from April 2016 to December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1680 cycles were included in the study. A total of 57.1% (959/1680) utilized GnRH-agonist for trigger. Demographic and clinical data were collected from the medical record. Maturation rate was calculated for the entire cohort, and by trigger type, using the quotient of Metaphase II (MII) oocytes and retrieved oocytes. A sub-cohort of GnRH-agonist trigger cycles were categorized by peak estradiol (E2) levels and maturation rates compared between groups. Associations were made using Student's t test, ANOVA, Mann-Whitney U and Kruskal-Wallis, where appropriate. A sample size calculation for 90% power with a significance of 5% to detect non-inferiority of <0.05 from a 0.75 maturity rate between subjects with E2 > 3000 pg/mL and E2 < 3000 pg/mL demonstrated the need for at least 116 cycles per group. MAIN RESULTS AND THE ROLE OF CHANCE: Mean MR was 0.71 ± 0.19 overall, and 0.73 ± 0.18 in the sub-cohort of GnRH-agonist trigger cycles. A total of 611 cycles (63.7%) had peak E2 < 3000, and 331 (34.5%) had E2 > 3000. No significant difference in maturity rate was noted between cycles with E2 levels >3000 pg/mL and <3000 pg/mL (0.72 ± 0.19 vs. 0.74 ± 0.14, P = 0.18), confirming the non-inferiority of maturity rates with GnRH-agonist triggers in cycles with peak E2 < 3000 pg/mL. While lower mean oocytes retrieved and mean MII oocytes were associated with lower peak E2 levels, maturity rate did not significantly differ amongst E2 level groups. Cycles with E2 < 1000 pg/mL had lower MR irrespective of trigger type. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature cannot entirely exclude selection biases, confounding factors or additional variables that could not be accounted for or were not collected by the electronic medical record. Given the nature of planned oocyte cryopreservation, studies of ongoing pregnancy rates and birth outcomes will naturally be delayed. Lastly, the study population was limited to women undergoing planned oocyte cryopreservation; therefore, the results may not be generalizable to women undergoing in vitro fertilization. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study specifically comparing the efficacy of GnRH-agonist in patients at lower risk for OHSS to those at high risk, as well the first study evaluating GnRH-agonist's efficacy specifically in planned oocyte cryopreservation cycles. STUDY FUNDING/COMPETING INTEREST(S): Study support provided by departmental funds from the Center for Fertility Research and Education-Extend Fertility Medical Practice. BLM discloses personal fees from Ferring Pharmaceuticals and Merck KgAA, unrelated to the submitted work. C.S., M.G., L.R. and J.K. have nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Likelihood of achieving a 50%, 60%, or 70% estimated live birth rate threshold with 1 or 2 cycles of planned oocyte cryopreservation.

PURPOSE: To characterize the likelihood of cryopreserving enough oocytes for 50%, 60%, or 70% estimated live birth rate (eLBR) with 1-2 planned oocyte cryopreservation (Pl-OC) cycles. METHODS: We performed a retrospective cohort study utilizing all patients completing ≥ 1 Pl-OC cycle from 2016 to 2018 at a large single-center OC program. Subjects were categorized by age at retrieval and number of cycles. We extrapolated age-based oocyte thresholds for 50%, 60%, or 70% eLBR from previously published data. We calculated the proportion of subjects overall, and for each age group, whose number of frozen oocytes was greater than or equal to their age-based threshold for a 50%, 60%, or 70% eLBR after 1 and 2 cycles. OR for 60% eLBR with one cycle was calculated for age and AMH cutoff values and corroborated with logistic regression. RESULTS: A total of 1241 subjects, completing 1799 Pl-OC cycles, were included. With one cycle, 66% (819/1241) achieved ≥ 50% eLBR and 51% (634/1241) achieved 70% eLBR. With two cycles, 79.6% (988/1241) attained ≥ 50% eLBR and 65.5% (813/1241) achieved 70% eLBR. Achieving 50%, 60%, or 70% eLBR with 1-2 cycles was significantly associated with both age (p < 0.001) and AMH (p < 0.001). Age < 37.5 and AMH > 1.995 were independently associated with attaining 60% eLBR with one cycle (age: OR 13.73; 95%CI 9.16-20.57, p < 0.001; AMH: OR 7.32; 95% CI 5.50-9.76, p < 0.001). CONCLUSIONS: Younger age and higher AMH were associated with achieving 50%, 60%, or 70% eLBR thresholds with Pl-OC. Nevertheless, almost all subjects were successfully able to preserve enough oocytes for ≥ 50% eLBR in 1-2 cycles.

Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy.

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.

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.

Correlation of normal-range FMR1 repeat length or genotypes and reproductive parameters.

PURPOSE: This study aims to ascertain whether the length of normal-ranged CGG repeats on the FMR1 gene correlates with abnormal reproductive parameters. METHODS: We performed a retrospective, cross-sectional study of all FMR1 carrier screening performed as part of routine care at a large university-based fertility center from January 2011 to March 2014. Correlations were performed between normal-range FMR1 length and baseline serum anti-Müllerian hormone (AMH), cycle day 3 follicle stimulating hormone (FSH), ovarian volumes (OV), antral follicle counts (AFC), and incidence of diminished ovarian reserve (DOR), while controlling for the effect of age. RESULTS: Six hundred three FMR1 screening results were collected. One subject was found to be a pre-mutation carrier and was excluded from the study. Baseline serum AMH, cycle day 3 FSH, OV, and AFC data were collected for the 602 subjects with normal-ranged CGG repeats. No significant difference in median age was noted amongst any of the FMR1 repeat genotypes. No significant correlation or association was found between any allele length or genotype, with any of the reproductive parameters or with incidence of DOR at any age (p > 0.05). However, subjects who were less than 35 years old with low/low genotype were significantly more likely to have below average AMH levels compared to those with normal/normal genotype (RR 3.82; 95 % CI 1.38-10.56). CONCLUSIONS: This large study did not demonstrate any substantial association between normal-range FMR1 repeat lengths and reproductive parameters.

Occult abnormal pregnancies after first post-embryo transfer serum beta-human chorionic gonadotropin levels of 1.0-5.0 mIU/mL.

OBJECTIVE: To assess the occult pregnancy rate after "negative" first post-embryo transfer (ET) serum ß-hCG results. DESIGN: Two-part retrospective cohort study and nested case series. SETTING: University-based fertility center. PATIENT(S): A total of 1,571 negative first post-ET serum ß-hCG results were included in the study; 1,326 results (primary cohort, June 2009-December 2013) were initially reported as <5 mIU/mL and 245 results (secondary cohort, January 2014-March 2015) were reported as discrete values from 1.0 to 5.0 mIU/mL. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of occult pregnancy, ectopic pregnancy, and complications after negative first post-ET serum ß-hCG results. RESULT(S): A total of 88.8% (1,178/1,326) of the negative first post-ET results reported as <5 were actually <1.0 mIU/mL. Occult pregnancy was incidentally identified in 1.2% (12/1,041) of subjects with follow-up. Six had ectopic pregnancies, and seven experienced serious complications; 11 (91.7%) of the 12 occult pregnancies had a first post-ET serum ß-hCG level of 1.0-5.0 mIU/mL and 1 (8.3%) <1.0 mIU/mL. All pregnancies with serious complications had initial ß-hCG levels of 1.0-5.0 mIU/mL. Of the 245 results reported as discreet values, occult pregnancies were diagnosed in 5.5% (9/163) of subjects with follow-up. One had an ectopic pregnancy, which was treated with methotrexate. There were no serious complications in the secondary cohort. CONCLUSION(S): The majority of negative first post-ET serum ß-hCG levels are <1.0 mIU/mL. Results from 1.0 to 5.0 mIU/mL may fail to exclude abnormal pregnancy and are associated with poor outcomes compared with ß-hCG levels <1.0 mIU/mL. Serial serum ß-hCG may be warranted in this population.

Single-Nucleotide Polymorphism-Microarray Ploidy Analysis of Paraffin-Embedded Products of Conception in Recurrent Pregnancy Loss Evaluations.

OBJECTIVE: To compare the analysis of chromosome number from paraffin-embedded products of conception using single-nucleotide polymorphism (SNP) microarray with the recommended screening for the evaluation of couples presenting with recurrent pregnancy loss who do not have previous fetal cytogenetic data. METHODS: We performed a retrospective cohort study including all women who presented for a new evaluation of recurrent pregnancy loss over a 2-year period (January 1, 2012, to December 31, 2013). All participants had at least two documented first-trimester losses and both the recommended screening tests and SNP microarray performed on at least one paraffin-embedded products of conception sample. Single-nucleotide polymorphism microarray identifies all 24 chromosomes (22 autosomes, X, and Y). RESULTS: Forty-two women with a total of 178 losses were included in the study. Paraffin-embedded products of conception from 62 losses were sent for SNP microarray. Single-nucleotide polymorphism microarray successfully diagnosed fetal chromosome number in 71% (44/62) of samples, of which 43% (19/44) were euploid and 57% (25/44) were noneuploid. Seven of 42 (17%) participants had abnormalities on recurrent pregnancy loss screening. The per-person detection rate for a cause of pregnancy loss was significantly higher in the SNP microarray (0.50; 95% confidence interval [CI] 0.36-0.64) compared with recurrent pregnancy loss evaluation (0.17; 95% CI 0.08-0.31) (P=.002). Participants with one or more euploid loss identified on paraffin-embedded products of conception were significantly more likely to have an abnormality on recurrent pregnancy loss screening than those with only noneuploid results (P=.028). The significance remained when controlling for age, number of losses, number of samples, and total pregnancies. CONCLUSION: These results suggest that SNP microarray testing of paraffin-embedded products of conception is a valuable tool for the evaluation of recurrent pregnancy loss in patients without prior fetal cytogenetic results. Recommended recurrent pregnancy loss screening was unnecessary in almost half the patients in our study. LEVEL OF EVIDENCE: II.

Contraceptive use and the role of contraceptive counseling in reproductive-aged women with cancer.

OBJECTIVE: Few data on contraceptive choices in women with cancer exist. Contraception is challenging for women with cancer, particularly those with breast cancer, who are limited to nonhormonal methods. This study characterized contraceptive use during cancer treatment in a group of reproductive-aged women with a recent cancer diagnosis and assessed the impact of contraceptive counseling on the methods they selected. STUDY DESIGN: Cross-sectional, survey study of reproductive-aged women at a large tertiary care health system with a recent cancer diagnosis. RESULTS: A total of 107 women completed the survey. Eighty-two women reported 101 contraceptive choices. Twenty-seven percent (27/101) of all methods selected were Tier I/II, and 35% (35/101) were Tier III/IV. Only 4 used an intrauterine device (IUD). Among women reporting sexual activity after diagnosis, 19 (27%) of 71 reported using Tier I/II methods, 21 (30%) of 71 reported using Tier III/IV methods, 16 (23%) of 71 reported abstinence and 10 (14%) of 71 reported using no method. Factors significantly associated with Tier I/II use in the multivariable model included not having a college degree [odds ratio (OR) 0.21, 95% confidence interval (CI) 0.05-0.92, p=.038], intercourse during treatment (OR 5.92, 95% CI 1.48-23.66, p=.012) and non-breast cancer (OR 3.60, 95% CI 1.03-12.64, p=.046). Report of contraceptive counseling was positively associated with Tier I/II contraceptive use during cancer treatment (OR 6.92, 95% CI 1.14-42.11, p=.036). CONCLUSION: Reproductive-aged women diagnosed with cancer underutilized Tier I/II contraceptive agents, especially IUDs. Contraceptive counseling by physicians increases contraceptive use, particularly methods most effective at preventing pregnancy. IMPLICATIONS: The study uniquely described the contraceptive practices of over 100 women with cancer. The study sample commonly reported abstinence and use of contraceptive methods with high failure rates. Our data suggest that contraceptive counseling from a health care provider may increase use of more effective methods among women with cancer.

The "muffin test"--an alternative to the oral glucose tolerance test for detecting impaired glucose tolerance.

OBJECTIVE: The aim of this study was to compare the effectiveness of the "muffin test" (MT) with that of the oral glucose tolerance test (OGTT) in diagnosing impaired glucose tolerance (IGT). METHODS: This is a cross-sectional study in a single academic institution. The participants were 73 women aged 42 to 58 years, less than 36 months after menopause, recruited for the Kronos Early Estrogen Prevention Study Trial. After a 10-hour fasting blood draw, the participants were provided a muffin and a beverage. Two-hour glucose levels were assessed. A subset underwent metabolic testing consisting of an OGTT (n = 12) and a mixed-meal tolerance test (n = 10). The main outcome measures were the prevalence of IGT and 2-hour glucose measurements after each testing method. RESULTS: Two-hour glucose levels were linearly related to fasting values by multivariable linear regression. This association was exaggerated in overweight (body mass index, 25 kg/m2) women (coefficient, 1.43; P < 0.001). Two-hour OGTT and MT glucose levels were comparable (P > 0.05); 2-hour glucose levels after OGTT were slightly lower than after the mixed-meal tolerance test (P < 0.05). CONCLUSIONS: The prevalence of IGT was 11% (8 of 73). Fasting plasma glucose alone would have missed 63% of cases (five of eight cases). The MT demonstrated 100% sensitivity and specificity for diagnosing IGT compared with the gold standard OGTT. This small pilot study should be confirmed in a larger prospective group of participants.

Women and HIV infection: the makings of a midlife crisis.

With the advent of highly active antiretroviral agents, women with HIV infection can expect to live longer than ever before. This increased survival has led to concerns about the long-term implications of HIV disease and its treatment. Women with HIV infection appear to lose ovarian function earlier in life than women without HIV infection. They also have evidence of reduced bone mineral density and increased cardiovascular risk. Moreover, many of these increases in risk factors are present even prior to the menopausal transition. All of these risks, present at midlife, augur poorly for future health and describe a substantially increased burden of disease likely to accrue to HIV-infected women as they enter older age groups. Further compounding the adversity faced by the HIV infected, the demographics of women most vulnerable to this disease include adverse social and economic influences, both of which worsen their long-term prognosis. For example, drug use and poverty are related to more severe menopausal symptoms and chronic stress is related to worse psychological and cardiovascular risk. An understanding of how menopause interacts with HIV infection is therefore most important to alert the clinician to perform surveillance for common health problems in postmenopausal women, and to address directly and appropriately symptomatology during the menopausal transition.

HIV and the menopause.

Dramatic improvement in the survival of the HIV population has occurred with the ascendance of highly active antiretroviral therapy (HAART). In the foreseeable future, HIV-infected women who acquired disease during the peak years of the epidemic are expected to survive to experience menopause and even years beyond. The HIV epidemic may be viewed as 'mature', as its earlier victims become part of the geriatric population. Research about the process of menopause in HIV-infected women and, conversely, about HIV infection in women undergoing menopause is currently limited. Existing research suggests that the process of menopause is affected by HIV infection, inasmuch as infected women appear to experience menopause at an earlier age, with greater symptomatology, and with different reproductive hormone profiles compared with HIV-uninfected women. HIV infection also appears to affect bone mineral density, cardiovascular disease and cognition, with some age-related interactions. Lifestyle and demographic factors have pervasive importance for both HIV infection and the menopause in women. This article reviews the current state of knowledge about the menopausal process in HIV-infected women, and the common conditions in postmenopausal women that are likely to be affected by HIV infection. Clinicians should appreciate the potential role of HIV infection in caring for menopause-aged women.