First PGT-A using human in vivo blastocysts recovered by uterine lavage: comparison with matched IVF embryo controls†.

STUDY QUESTION: After controlled ovarian stimulation (COS) and IUI, is it clinically feasible to recover in vivo conceived and matured human blastocysts by uterine lavage from fertile women for preimplantation genetic testing for aneuploidy (PGT-A) and compare their PGT-A and Gardner scale morphology scores with paired blastocysts from IVF control cycles? SUMMARY ANSWER: In a consecutive series of 134 COS cycles using gonadotrophin stimulation followed by IUI, uterine lavage recovered 136 embryos in 42% (56/134) of study cycles, with comparable in vivo and in vitro euploidy rates but better morphology in in vivo embryos. WHAT IS KNOWN ALREADY: In vivo developed embryos studied in animal models possess different characteristics compared to in vitro developed embryos of similar species. Such comparative studies between in vivo and in vitro human embryos have not been reported owing to lack of a reliable method to recover human embryos. STUDY DESIGN, SIZE, DURATION: We performed a single-site, prospective controlled trial in women (n = 81) to evaluate the safety, efficacy and feasibility of a novel uterine lavage catheter and fluid recovery device. All lavages were performed in a private facility with a specialized fertility unit, from August 2017 to June 2018. Subjects were followed for 30 days post-lavage to monitor for clinical outcomes and delayed complications. In 20 lavage subjects, a single IVF cycle (control group) with the same ovarian stimulation protocol was performed for a comparison of in vivo to in vitro blastocysts. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Women were stimulated with gonadotrophins for COS. The ovulation trigger was given when there were at least two dominant follicles ≥18 mm, followed by IUI of sperm. Uterine lavage occurred 4-6 days after the IUI. A subset of 20 women had a lavage cycle procedure followed by an IVF cycle (control IVF group). Recovered embryos were characterized morphologically, underwent trophectoderm (TE) biopsy, vitrified and stored in liquid nitrogen. Biopsies were analyzed using the next-generation sequencing technique. After lavage, GnRH antagonist injections were administered to induce menstruation. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 134 lavage cycles were performed in 81 women. Uterine lavage recovered 136 embryos in 56 (42%) cycles. At the time of cryopreservation, there were 40 (30%) multi-cell embryos and 96 (70%) blastocysts. Blastocysts were of good quality, with 74% (70/95) being Gardener grade 3BB or higher grade. Lavage blastocysts had significantly higher morphology scores than the control IVF embryos as determined by chi-square analysis (P < 0.05). This is the first study to recover in vivo derived human blastocysts following ovarian stimulation for embryo genetic characterization. Recovered blastocysts showed rates of chromosome euploidy similar to the rates found in the control IVF embryos. In 11 cycles (8.2%), detectable levels of hCG were present 13 days after IUI, which regressed spontaneously in two cases and declined after an endometrial curettage in two cases. Persistent hCG levels were resolved after methotrexate in three cases and four cases received both curettage and methotrexate. LIMITATIONS, REASON FOR CAUTION: The first objective was to evaluate the feasibility of uterine lavage following ovarian stimulation to recover blastocysts for analysis, and that goal was achieved. However, the uterine lavage system was not completely optimized in our earlier experience to levels that were achieved late in the clinical study and will be expected in clinical service. The frequency of chromosome abnormalities of in vivo and IVF control embryos was similar, but this was a small-size study. However, compared to larger historical datasets of in vitro embryos, the in vivo genetic results are within the range of high-quality in vitro embryos. WIDER IMPLICATIONS OF THE FINDINGS: Uterine lavage offers a nonsurgical, minimally invasive strategy for recovery of embryos from fertile women who do not want or need IVF and who desire PGT, fertility preservation of embryos or reciprocal IVF for lesbian couples. From a research and potential clinical perspective, this technique provides a novel platform for the use of in vivo conceived human embryos as the ultimate benchmark standard for future and current ART methods. STUDY FUNDING/COMPETING INTEREST(S): Previvo Genetics, Inc., is the sole sponsor for the Punta Mita, Mexico, clinical study. S.M. performs consulting for CooperGenomics. J.E.B. and S.A.C. are co-inventors on issued patents and patents owned by Previvo and ownshares of Previvo. S.N. is a co-author on a non-provisional patent application owned by Previvo and holds stock options in Previvo. S.T.N. and M.J.A. report consulting fees from Previvo. S.T.N., S.M., M.V.S., M.J.A., C.N. and J.E.B. are members of the Previvo Scientific Advisory Board (SAB) and hold stock options in Previvo. J.E.B and S. M are members of the Previvo Board of Directors. A.N. and K.C. are employees of Previvo Genetics. L.V.M, T.M.M, J.L.R and S. S have no conflicts to disclose. TRIAL REGISTRATION NUMBER: Protocol Registration and Results System (PRS) Trial Registration Number and Name: Punta Mita Study TD-2104: Clinical Trials NCT03426007.

Smoking in infertile women with polycystic ovary syndrome: baseline validation of self-report and effects on phenotype.

STUDY QUESTION: Do women with polycystic ovary syndrome (PCOS) seeking fertility treatment report smoking accurately and does participation in infertility treatment alter smoking? SUMMARY ANSWER: Self-report of smoking in infertile women with PCOS is accurate (based on serum cotinine levels) and smoking is unlikely to change over time with infertility treatment. WHAT IS KNOWN ALREADY: Women with PCOS have high rates of smoking and it is associated with worse insulin resistance and metabolic dysfunction. STUDY DESIGN, SIZE, DURATION: Secondary study of smoking history from a large randomized controlled trial of infertility treatments in women with PCOS (N = 626) including a nested case-control study (N = 148) of serum cotinine levels within this cohort to validate self-report of smoking. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with PCOS, age 18-40, seeking fertility who participated in a multi-center clinical trial testing first-line ovulation induction agents conducted at academic health centers in the USA. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, self-report of smoking in the nested case-control study agreed well with smoking status as determined by measure of serum cotinine levels, at 90% or better for each of the groups at baseline (98% of never smokers had cotinine levels <15 ng/ml compared with 90% of past smokers and 6% of current smokers). There were minor changes in smoking status as determined by serum cotinine levels over time, with the greatest change found in the smoking groups (past or current smokers). In the larger cohort, hirsutism scores at baseline were lower in the never smokers compared with past smokers. Total testosterone levels at baseline were also lower in the never smokers compared with current smokers. At end of study follow-up insulin levels and homeostatic index of insulin resistance increased in the current smokers (P < 0.01 for both) compared with baseline and with non-smokers. The chance for ovulation was not associated with smoking status, but live birth rates were increased (non-significantly) in never or past smokers. LIMITATIONS, REASONS FOR CAUTION: The limitations include the selection bias involved in our nested case-control study, the possibility of misclassifying exposure to second hand smoke as smoking and our failure to capture self-reported changes in smoking status after enrollment in the trial. WIDER IMPLICATIONS OF THE FINDINGS: Because self-report of smoking is accurate, further testing of smoking status is not necessary in women with PCOS. Because smoking status is unlikely to change during infertility treatment, extra attention should be focused on smoking cessation in current or recent smokers who seek or who are receiving infertility treatment. STUDY FUNDING/COMPETING INTERESTS: Sponsored by the Eugene Kennedy Shriver National Institute of Child Health and Human Development of the U.S. National Institutes of Health. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov numbers, NCT00068861 and NCT00719186.

Human Uterine Lavage: First Live Births from In Vivo Conceived Genetically Screened Blastocysts.

INTRODUCTION: We wish to report the first live births from genetically screened human euploid blastocysts obtained by uterine lavage. The embryos transferred to infertile women were previously obtained using a novel fully automated uterine lavage catheter and fluid recovery device developed for this indication. The objective of this portion of the research was to confirm embryo implantation and live births with these unique in vivo conceived blastocysts obtained by uterine lavage. METHODS: In vivo conceived embryos recovered by uterine lavage 5 days after intrauterine insemination were available for embryo donation. In vivo embryos were the result of prior controlled ovarian stimulation cycles in oocyte donors and intrauterine insemination with donor sperm. An observational case series of nine embryo transfer procedures was performed at an outpatient fertility center. One to two embryos were transferred to eight infertile women since one woman had two separate embryo transfer procedures. RESULTS: Nine embryo transfer procedures were performed with 14 blastocysts in eight women resulting in a blastocyst implantation rate of 36% (5/14) and live birth rate of 44% (4/9). Five infants have been born from the four delivered pregnancies with one set of twins. CONCLUSIONS: This is the first report of live births from genetically screened human euploid blastocysts obtained by uterine lavage. The nonsurgical uterine lavage office procedure represents the only current approach to obtain in vivo conceived embryos and can provide a benchmark for comparison to standard in vitro cultured blastocysts. Live births of in vivo conceived blastocysts represent the validation that the nonsurgical uterine lavage procedure allows simplified access to naturally conceived embryos without performing the surgical procedure of an oocyte aspiration. Owing to its simplicity, uterine lavage may be useful in screening embryos for preimplantation genetic testing for aneuploidy in fertile and infertile couples. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (Identifier NCT03426007).

The overall goal of this research was to develop a procedure that would allow collection of naturally conceived human embryos and compare them to embryos that result from the standard process of in vitro fertilization (IVF). IVF is a procedure where eggs are surgically removed from the ovaries and fertilized with sperm in a laboratory. Embryos from IVF are cultured for 3­7 days before they are placed back into a woman's uterus to establish a pregnancy. Uterine lavage is a different procedure where the sperm fertilizes an egg in the normal process of conception and the uterus is rinsed with fluid to recover the embryo before implantation. The embryos reported in this study were the first to be obtained in over 30 years owing to many improvements in the overall uterine lavage procedure. Until our initial study findings reported in 2020, the vast majority of information on embryo development was based on embryos fertilized and cultured in a laboratory. Our prior report of embryos obtained by uterine lavage compared with IVF embryos from the same women demonstrated a significantly better appearance of the embryos recovered by lavage. This current report documents the first live births from these genetically screened naturally conceived human embryos. The live births provide evidence that uterine lavage allows ready access to normal embryos without performing the surgical procedure IVF. Owing to the simplicity of uterine lavage, the procedure may improve access to genetic testing of embryos before pregnancy.

High throughput, cell type-specific analysis of key proteins in human endometrial biopsies of women from fertile and infertile couples.

BACKGROUND: Although histological dating of endometrial biopsies provides little help for prediction or diagnosis of infertility, analysis of individual endometrial proteins, proteomic profiling and transcriptome analysis have suggested several biomarkers with altered expression arising from intrinsic abnormalities, inadequate stimulation by or in response to gonadal steroids or altered function due to systemic disorders. The objective of this study was to delineate the developmental dynamics of potentially important proteins in the secretory phase of the menstrual cycle, utilizing a collection of endometrial biopsies from women of fertile (n = 89) and infertile (n = 89) couples. METHODS AND RESULTS: Progesterone receptor-B (PGR-B), leukemia inhibitory factor, glycodelin/progestagen-associated endometrial protein (PAEP), homeobox A10, heparin-binding EGF-like growth factor, calcitonin and chemokine ligand 14 (CXCL14) were measured using a high-throughput, quantitative immunohistochemical method. Significant cyclic and tissue-specific regulation was documented for each protein, as well as their dysregulation in women of infertile couples. Infertile patients demonstrated a delay early in the secretory phase in the decline of PGR-B (P < 0.05) and premature mid-secretory increases in PAEP (P < 0.05) and CXCL14 (P < 0.05), suggesting that the implantation interval could be closing early. Correlation analysis identified potential interactions among certain proteins that were disrupted by infertility. CONCLUSIONS: This approach overcomes the limitations of a small sample number. Protein expression and localization provided important insights into the potential roles of these proteins in normal and pathological development of the endometrium that is not attainable from transcriptome analysis, establishing a basis for biomarker, diagnostic and targeted drug development for women with infertility.

Ovulation induction in women with polycystic ovary syndrome: an update.

Infertility is frequently caused by anovulation. The affected women present with irregular menstrual cycles and the most common diagnosis is polycystic ovary syndrome. Ovulation induction is commonly used to treat these women. Clomiphene citrate (a selective estrogen receptor modulator or SERM) remains the most used medication for treating this condition. Alternatives that have been used include other SERMs such as tamoxifen, aromatase inhibitors, insulin sensitizing agents, and ovarian drilling. Evidence for and against the effectiveness of these agents has fluctuated over the last decade. Controversies surrounding the use of ovulation induction such as development of functional cysts, high-order multiple births, and development of ovarian cancer have been further studied and some controversies have almost been laid to rest in the last decade.

Phthalates and bisphenol do not accumulate in human follicular fluid.

OBJECTIVE: To determine if phthalates and bisphenol A accumulate in human follicular fluid after brief exposure to medical plastics during an IVF cycle STUDY DESIGN: Prospective collection of follicular fluid from five infertile women undergoing oocyte retrieval at a University IVF laboratory and analysis of Phthalate & Bisphenol A levels. RESULTS: All phthalate levels were detected at levels less than 15 ng/mL and Bisphenol A levels were undetectable in all five samples. The concentrations of phthalates are 200-1000 fold less than the minimum levels reported to cause reproductive toxicity in vitro to cumulus-oocyte complexes of laboratory animals. CONCLUSIONS: In reproductive age women undergoing infertility treatments there is little transfer or accumulation of phthalates, phthalate metabolites or bisphenol A into the microenvironment of the human preovulatory oocyte and the levels are not clinically significant. Further investigation of phthalate and bisphenol A accumulation in vivo in human follicular fluid may not be productive.

Use of in-cycle antimüllerian hormone levels to predict cycle outcome.

OBJECTIVE: The goal of this work is to expand the usefulness of antimüllerian hormone (AMH) in predicting in vitro fertilization cycle outcome by demonstrating that AMH concentration obtained in an ongoing treatment cycle predicts both oocyte number and pregnancy. STUDY DESIGN: Serum samples were obtained from 190 in vitro fertilization patients at onset of follicle-stimulating hormone stimulation. These were analyzed retrospectively during a single cycle in which clinicians were blinded to the results. Our major outcome measures were the number of oocytes obtained and ongoing pregnancy. RESULTS: Patients with an initial AMH concentration of >3 ng/mL were found to produce a mean of 19.8 oocytes and had an ongoing pregnancy rate of 60.3%. In contrast, those with AMH values of ≤1 ng/mL yielded a mean of 6.2 oocytes and had an ongoing pregnancy rate of 23.4% (P < .0001 for both). CONCLUSION: Greater AMH serum concentration strongly predicts an increased number of oocytes and ongoing pregnancy (P ≤ .0001).

Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.

BACKGROUND: The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. METHODS: We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. RESULTS: The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. CONCLUSIONS: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861 [ClinicalTrials.gov].).

Detection and quantification of mRNA in single human polar bodies: a minimally invasive test of gene expression during oogenesis.

Proteins and mRNA produced in oogenesis support embryonic development until the zygotic transition, 3 days after fertilization. Since polar bodies can be biopsied with little if any harm to the oocyte, we tested the hypothesis that mRNA originating from expression in the meiotic oocyte is present and detectable in a single polar body prior to insemination. Human oocytes were obtained from patients undergoing controlled ovarian hyperstimulation and intracytoplasmic sperm injection. Immature oocytes were cultured overnight and inspected the following day for maturation. Metaphase II oocytes underwent polar body biopsy followed by reverse transcription without RNA isolation. Sibling oocytes were similarly prepared. Complementary DNA from all samples were pre-amplified over 15 cycles for candidate genes using selective primers. Real-time PCR was performed to detect and quantify relative single-cell gene expression. Polar body mRNA was detected in 11 of 12 candidate genes. Transcripts that were present in greater abundance in the oocyte were more likely to be detected in qPCR replicates from single polar bodies. Pre-amplification of cDNA synthesized without RNA isolation can facilitate the quantitative detection of mRNA in single human polar bodies.

Moral attitudes and beliefs among couples pursuing PGD for sex selection.

This article reports the results from a study of couples participating in a research protocol in which IVF/preimplantation genetic diagnosis (PGD) was available for non-medical sex selection. The study sought to characterize the moral attitudes and beliefs of couples actively pursuing IVF/PGD solely for purposes related to sex selection. Eighteen couples participated in ethnographic interviews from November 2005 to April 2006. These interviews explored couples' motivations for pursuing sex selection, moral beliefs and attitudes regarding sex selection and sources of moral ambivalence about the use of IVF/PGD for sex selection. Couples reported a combination of motivations for pursuing sex selection, including a desire to limit family size, concerns about parental age and financial concerns about multiple pregnancies. Many couples compared their decision to choices about abortion, maintaining that individuals have a right to make such decisions privately. Couples frequently expressed anxiety about telling their other children and family members about their plans to use IVF/PGD for sex selection. Few couples cited concerns about the physical or emotional burdens of IVF/PGD. The study's findings suggest that couples pursuing IVF/PGD for sex selection view this as an ethically complex decision and express considerable uncertainty about the ethical acceptability of this practice.

Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome.

CONTEXT: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene-resistant anovulators with polycystic ovary syndrome (PCOS). OBJECTIVE: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. DESIGN: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed. SETTING: Study volunteers at multiple academic medical centers were included. PARTICIPANTS: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study. INTERVENTIONS: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy. MAIN OUTCOME MEASURES: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1-2 wk. RESULTS: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. CONCLUSION: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.

Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene.

CONTEXT: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome (PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood. OBJECTIVE: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response. DESIGN: This was a substudy of a multicenter randomized clinical trial. SETTING: This study was performed at academic medical centers and their affiliates. PARTICIPANTS: A total of 312 women with PCOS were included in the study. MAIN OUTCOME MEASURES: Historical, biometric, biochemical, and genetic parameters were performed. RESULTS: We found that the C allele of a single nucleotide polymorphism in the STK11 gene (expressed in liver; also known as LKB1) was associated with a significantly decreased chance of ovulation in PCOS women treated with metformin. In an analysis of ovulation per cycle, the adjusted odds ratio (OR) comparing the C/C genotype to the G/G genotype was 0.30 [95% confidence interval (CI) 0.14, 0.66], and the OR for the C/G genotype vs. the G/G genotype was also 0.30 (95% CI 0.14, 0.66). In an analysis of metformin-treated subjects, we found that the percentage of women who ovulated increased with the number of G alleles present: 48% (10 of 21) of C/C women, 67% (32 of 48) of C/G women, and 79% (15 of 19) of G/G women ovulated. We also found that increased frequency of ovulation was associated with lower body mass index (BMI) [adjusted OR of 2.36 (95% CI 1.65, 3.36) and 2.05 (95% CI 1.46, 2.88), respectively, for comparisons of BMI less than 30 vs. BMI equal to or more than 35, BMI 30-34 vs. BMI equal to or more than 35, in the analysis of ovulation per cycle], a lower free androgen index (FAI) [adjusted OR of 1.59 (95% CI 1.17, 2.18) for FAI<10 vs. FAI>or=10], and a shorter duration of attempting conception [adjusted OR of 1.63 (95% CI 1.20, 2.21) for<1.5 vs.>or=1.5 yr]. CONCLUSIONS: We have demonstrated that a polymorphism in STK11, a kinase gene expressed in liver and implicated in metformin action, is associated with ovulatory response to treatment with metformin alone in a prospective randomized trial. The interaction with the effects of changes in modifiable factors (e.g. BMI or FAI) requires further study.

Female fertility: what every urologist must understand.

This article provides an overview of the evaluation and treatment of female factor infertility. It reviews the physiology of female reproduction and subsequently discusses pertinent findings in the evaluation and treatment of female infertility that are relevant to a urologist treating the male partner. Finally, it provides an overview of current treatment modalities.

The First National Summit on Women's Health: The Future of Obstetrics and Gynecology Training.

OBJECTIVE: To identify the current challenges in obstetrics and gynecology residency education and propose solutions to overcome these obstacles. METHODS: The American College of Obstetricians and Gynecologists (ACOG) hosted the first National Summit on Women's Health on May 31 and June 1, 2017, with a follow-up meeting December 20-21, 2017, at ACOG headquarters in Washington, DC. Invitees from 20 related societies briefly presented their organizations' perspectives and discussed focused questions about specific challenges, proposed solutions, and anticipated obstacles. Finally, participants summarized their top two recommendations to improve current residency training. RESULTS: Summit participants identified four primary areas of focus: 1) align curriculum with relevant topics to practice, 2) ensure faculty have the necessary resources and time to teach effectively, 3) consider using the final months of medical school to get a jump start on residency fund of knowledge and skills, and 4) use better assessments during the course of residency. CONCLUSION: Representatives of the Council on Resident Education in Obstetrics and Gynecology, the American Board of Obstetrics and Gynecology, and the Accreditation Council for Graduate Medical Education must work together to address these priorities and reach consensus on the curricular content of core training in obstetrics and gynecology.

Obstetrics and Gynecology Resident Interest and Participation in Global Health.

OBJECTIVE: To evaluate obstetrics and gynecology resident interest and participation in global health experiences and elucidate factors associated with resident expectation for involvement. METHODS: A voluntary, anonymous survey was administered to U.S. obstetrics and gynecology residents before the 2015 Council on Resident Education in Obstetrics and Gynecology in-training examination. The 23-item survey gathered demographic data and queried resident interest and participation in global health. Factors associated with resident expectation for participation in global health were analyzed by Pearson χ tests. RESULTS: Of the 5,005 eligible examinees administered the survey, 4,929 completed at least a portion of the survey for a response rate of 98.5%. Global health was rated as "somewhat important" or "very important" by 96.3% (3,761/3,904) of residents. "Educational opportunity" (69.2%) and "humanitarian effort" (17.7%) were cited as the two most important aspects of a global health experience. Residents with prior global health experience rated the importance of global health more highly and had an increased expectation for future participation. Global health electives were arranged by residency programs for 18.0% (747/4,155) of respondents, by residents themselves as an elective for 44.0% (1,828/4,155), and as a noncredit experience during vacation time for 36.4% (1,514/4,155) of respondents. Female gender, nonpartnered status, no children, prior global health experience, and intention to incorporate global health in future practice were associated with expectations for a global health experience. CONCLUSION: Most obstetrics and gynecology residents rate a global health experience as somewhat or very important, and participation before or during residency increases the perceived importance of global health and the likelihood of expectation for future participation. A majority of residents report arranging their own elective or using vacation time to participate, suggesting that residency programs have limited structured opportunities.

Vitamin D Status Relates to Reproductive Outcome in Women With Polycystic Ovary Syndrome: Secondary Analysis of a Multicenter Randomized Controlled Trial.

CONTEXT: Experimental evidence supports a relevance of vitamin D (VitD) for reproduction; however, data in humans are sparse and inconsistent. OBJECTIVE: To assess the relationship of VitD status with ovulation induction (OI) outcomes in women with polycystic ovary syndrome (PCOS). DESIGN: A retrospective cohort. SETTING: Secondary analysis of randomized controlled trial data. PARTICIPANTS: Participants in the Pregnancy in PCOS I (PPCOS I) randomized controlled trial (n = 540) met the National Institutes of Health diagnostic criteria for PCOS. INTERVENTIONS: Serum 25OHD levels were measured in stored sera. MAIN OUTCOME MEASURES: Primary, live birth (LB); secondary, ovulation and pregnancy loss after OI. RESULTS: Likelihood for LB was reduced by 44% for women if the 25OHD level was < 30 ng/mL (<75 nmol/L; odds ratio [OR], 0.58 [0.35-0.92]). Progressive improvement in the odds for LB was noted at thresholds of ≥38 ng/mL (≥95 nmol/L; OR, 1.42 [1.08-1.8]), ≥40 ng/mL (≥100 nmol/L; OR, 1.51 [1.05-2.17]), and ≥45 ng/mL (≥112.5 nmol/L; OR, 4.46 [1.27-15.72]). On adjusted analyses, VitD status was an independent predictor of LB and ovulation after OI. CONCLUSIONS: In women with PCOS, serum 25OHD was an independent predictor of measures of reproductive success after OI. Our data identify reproductive thresholds for serum 25OHD that are higher than recommended for the nonpregnant population.

Preimplantation genetic diagnosis (PGD) for heritable neoplasia.

UNLABELLED: Especially applicable for heritable neoplasia, preimplantation genetic diagnosis (PGD) is possible for any Mendelian disorder whose gene has been localized, whether the molecular basis is known or not. METHODS AND RESULTS: PGD requires DNA from gametes (oocytes) or embryos before 6 days postconception, when implantation occurs. Approaches include 1) polar body biopsy, 2) blastomere biopsy (aspiration of one or two cells from the six- to eight-cell embryos at 2 or 3 days), and 3) trophectoderm biopsy, which allows recovery of 20 or more cells (20-50) from 125- to 150-cell, 5- to 6-day blastocysts. Of some 6000 PGD cycles worldwide, approximately 1500 have been performed for Mendelian indications. The approximately 25% live birth rates following PGD parallel the general U.S. experience for assisted reproductive technology. PGD has been accomplished for both cancer-specific disorders like adenomatous polyposis coli (APC), BRCA1, retinoblastoma, Li-Fraumeni syndrome, and von Hippel-Lindau syndrome (VHL), as well as disorders predisposing to neoplasia (Fanconi anemia, Wiskott-Aldrich syndrome). PGD also makes possible the identification and, hence, transfer of embryos of specific HLA genotypes. This allows cord blood harvesting for stem cell implantation into a moribund child, often an older sibling of the fetus. CONCLUSIONS: PGD is a complex, but achievable, approach especially applicable to Mendelian forms of neoplasia. PGD is an attractive addition to the prenatal diagnostic armamentarium, especially relevant to heritable neoplasia. PGD also makes possible novel indications having special relevance to heritable neoplasia.