The impact of ovarian stimulation on the human endometrial microenvironment.

STUDY QUESTION: How does ovarian stimulation (OS), which is used to mature multiple oocytes for ART procedures, impact the principal cellular compartments and transcriptome of the human endometrium in the periovulatory and mid-secretory phases? SUMMARY ANSWER: During the mid-secretory window of implantation, OS alters the abundance of endometrial immune cells, whereas during the periovulatory period, OS substantially changes the endometrial transcriptome and impacts both endometrial glandular and immune cells. WHAT IS KNOWN ALREADY: Pregnancies conceived in an OS cycle are at risk of complications reflective of abnormal placentation and placental function. OS can alter endometrial gene expression and immune cell populations. How OS impacts the glandular, stromal, immune, and vascular compartments of the endometrium, in the periovulatory period as compared to the window of implantation, is unknown. STUDY DESIGN, SIZE, DURATION: This prospective cohort study carried out between 2020 and 2022 included 25 subjects undergoing OS and 25 subjects in natural menstrual cycles. Endometrial biopsies were performed in the proliferative, periovulatory, and mid-secretory phases. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were processed to determine serum estradiol and progesterone levels. Both the endometrial transcriptome and the principal cellular compartments of the endometrium, including glands, stroma, immune, and vasculature, were evaluated by examining endometrial dating, differential gene expression, protein expression, cell populations, and the three-dimensional structure in endometrial tissue. Mann-Whitney U tests, unpaired t-tests or one-way ANOVA and pairwise multiple comparison tests were used to statistically evaluate differences. MAIN RESULTS AND THE ROLE OF CHANCE: In the periovulatory period, OS induced high levels of differential gene expression, glandular-stromal dyssynchrony, and an increase in both glandular epithelial volume and the frequency of endometrial monocytes/macrophages. In the window of implantation during the mid-secretory phase, OS induced changes in endometrial immune cells, with a greater frequency of B cells and a lower frequency of CD4 effector T cells. LARGE SCALE DATA: The data underlying this article have been uploaded to the Genome Expression Omnibus/National Center for Biotechnology Information with accession number GSE220044. LIMITATIONS, REASONS FOR CAUTION: A limited number of subjects were included in this study, although the subjects within each group, natural cycle or OS, were homogenous in their clinical characteristics. The number of subjects utilized was sufficient to identify significant differences; however, with a larger number of subjects and additional power, we may detect additional differences. Another limitation of the study is that proliferative phase biopsies were collected in natural cycles, but not in OS cycles. Given that the OS cycle subjects did not have known endometrial factor infertility, and the comparisons involved subjects who had a similar and robust response to stimulation, the findings are generalizable to women with a normal response to OS. WIDER IMPLICATIONS OF THE FINDINGS: OS substantially altered the periovulatory phase endometrium, with fewer transcriptomic and cell type-specific changes in the mid-secretory phase. Our findings show that after OS, the endometrial microenvironment in the window of implantation possesses many more similarities to that of a natural cycle than does the periovulatory endometrium. Further investigation of the immune compartment and the functional significance of this cellular compartment under OS conditions is warranted. STUDY FUNDING/COMPETING INTERESTS: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (R01AI148695 to A.M.B. and N.C.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD109152 to R.A.), and the March of Dimes (5-FY20-209 to R.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or March of Dimes. All authors declare no conflict of interest.

Metabolic screening in patients with polycystic ovary syndrome is largely underutilized among obstetrician-gynecologists.

Women with polycystic ovary syndrome have substantially higher rates of insulin resistance, impaired glucose tolerance, type 2 diabetes, dyslipidemia, and metabolic syndrome when compared with women without the disease. Given the high prevalence of these comorbidities, guidelines issued by the American College of Obstetricians and Gynecologists and the Endocrine Society recommend that all women with polycystic ovary syndrome undergo screening for impaired glucose tolerance and dyslipidemia with a 2 hour 75 g oral glucose tolerance test and fasting lipid profile upon diagnosis and also undergo repeat screening every 2-5 years and every 2 years, respectively. Although a hemoglobin A1C and/or fasting glucose are widely used screening tests for diabetes, both the American College of Obstetricians and Gynecologists and the Endocrine Society preferentially recommend the 2 hour oral glucose tolerance test in women with polycystic ovary syndrome as a superior indicator of impaired glucose tolerance/diabetes mellitus. However, we found that gynecologists underutilize current recommendations for metabolic screening in women with polycystic ovary syndrome. In an online survey study targeting American College of Obstetricians and Gynecologists fellows and junior fellows, 22.3% of respondents would not order any screening test at the initial visit for at least 50% of their patients with polycystic ovary syndrome. The most common tests used to screen for impaired glucose tolerance in women with polycystic ovary syndrome were hemoglobin A1C (51.0%) and fasting glucose (42.7%). Whereas 54.1% would order a fasting lipid profile in at least 50% of their polycystic ovary syndrome patients, only 7% of respondents order a 2 hour oral glucose tolerance test. We therefore call for increased efforts to encourage obstetrician-gynecologists to address metabolic abnormalities in their patients with polycystic ovary syndrome. Such efforts should include education of physicians early in their careers, at the medical student and resident level. Efforts should also include implementation of continuing medical education activities, both locally and at the national level, to improve understanding of the metabolic implications of polycystic ovary syndrome. Electronic medical record systems should be utilized to generate prompts for appropriate screening tests in patients with a diagnosis of polycystic ovary syndrome. Because obstetrician-gynecologists may be the only physicians seen by many polycystic ovary syndrome patients, particularly those in their young reproductive years, such interventions could effectively promote optimal preventative health care and early diagnosis of metabolic comorbidities in these at-risk women.

Effect of single embryo transfer on the risk of preterm birth associated with in vitro fertilization.

PURPOSE: To determine whether elective single embryo transfer (eSET) reduces the risk of preterm delivery associated with in vitro fertilization (IVF). METHODS: This is an observational study of 3125 eSET cycles performed from 2008 to 2009 and reported to the Society for Assisted Reproductive Technology (SART) database. Preterm delivery rates were compared to the overall preterm delivery rate among all patients undergoing IVF over the same time period. RESULTS: The 3125 eSET cycles resulted in 1507 live births (live birth rate 48.2 %) Among these deliveries were 27 twins (1.8 %) and one set of triplets (0.07 %). The overall preterm delivery rate (20-37 weeks gestation) following eSET was 17.6 % (269/1527). This is significantly greater than the preterm birth rate for all patients undergoing IVF over the same time period (12 %, P < 0.001). CONCLUSIONS: Elective single embryo transfer does not reduce the risk of preterm delivery associated with in vitro fertilization (IVF).

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.

Blastocyst expansion score and trophectoderm morphology strongly predict successful clinical pregnancy and live birth following elective single embryo blastocyst transfer (eSET): a national study.

PURPOSE: To determine which characteristics of blastocyst embryo morphology may predict clinical pregnancy and live birth rates. METHODS: A retrospective analysis of data from 3,151 cycles of fresh, non-donor eSET cycles from 2008 to 2009 was performed. Data were obtained from the Society for Assisted Reproductive Technologies (SART) underwent. All eSET were performed at the blastocyst stage. Main outcome measures were clinical pregnancy and live birth rates. RESULTS: Trophectoderm morphology, embryo stage and patient age are highly significant independent predictors of both clinical pregnancy and live birth. Neither inner cell mass morphology nor embryo grade predicted clinical pregnancy or live birth. CONCLUSIONS: Better trophectoderm morphology, younger patient age and further blastocyst progression all result in higher clinical pregnancy and live birth rates. Therefore, trophectoderm morphology and blastocyst stage should preferentially be used as the most important factors in choosing the best embryo for transfer.

Endocrine disruptors and female fertility: a review of pesticide and plasticizer effects.

An ongoing interest in environmental exposures and female fertility has led to an increasing number of studies focusing on endocrine-disrupting chemicals (EDCs). Both natural and synthetic compounds have the ability to impact reproductive health by altering the structure and/or function of genes and proteins that facilitate normal ovarian and endometrial functions. This mini-review aims to summarize the effects of some of the most common EDCs on female fertility, including the effects of pesticides and plasticizer alternatives (phthalates, bisphenol A), based on available data in human studies. A literature search was performed using the key words "pesticides, fertility, reproduction, plasticizers, bisphenol A, phthalate, miscarriage, and in vitro fertilization." The data supporting EDCs' role in female infertility remain limited, but existing evidence suggests that exposure may have an adverse impact. Accumulating evidence in animal studies provides important insights into the mechanisms underlying EDC effects. As dose-response dynamics are better elucidated, understanding the effects of EDCs on female fertility will help in the development of guidelines for both industry and individuals.

Increased male live-birth rates after blastocyst-stage frozen-thawed embryo transfers compared with cleavage-stage frozen-thawed embryo transfers: a SART registry study.

OBJECTIVE: To investigate whether there is a difference in live-birth gender rates in blastocyst-stage frozen-thawed embryo transfers (FETs) compared with those in cleavage-stage FETs. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: All women with recorded live births who underwent FET at either the blastocyst or cleavage stage, reported to the Society for Assisted Reproductive Technology during 2004-2013. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The primary outcome was live-birth gender rates. Demographic criteria were also collected. The chi-square analyses were used for bivariate associations, and multiple logistic regression models were used for adjusted associations, with all two-sided P<.05 considered statistically significant. RESULTS: A statistically significant increase was noted in the number of live male births after blastocyst-stage FET compared with that after cleavage-stage FET (51.9% vs. 50.5%). After controlling for potential confounders including age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.03, 1.08), body mass index (OR, 1.08; 95% CI, 1.04, 1.12), and male factor infertility (OR, 1.06; 95% CI, 1.03, 1.08), the increase in male live births after blastocyst-stage FET remained statistically significant. CONCLUSIONS: In patients undergoing FETs, blastocyst-stage transfers are associated with higher male gender live-birth rates compared with cleavage-stage transfers.

The incidence of ectopic/heterotopic pregnancies after blastocyst-stage frozen-thawed embryo transfers compared with that after cleavage-stage: a Society for Assisted Reproductive Technologies Clinical Outcomes Reporting System study.

OBJECTIVE: To investigate whether there is a difference in the ectopic/heterotopic pregnancy rate of blastocyst-stage frozen-thawed embryo transfers (FETs) compared with that of cleavage-stage FETs. DESIGN: A retrospective cohort study. SETTING: Not applicable. PATIENTS: Women undergoing autologous FETs at either the blastocyst stage (n = 118,572) or the cleavage stage (n = 117,619), as reported to the Society for Assisted Reproductive Technology from 2004 to 2013. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Pregnancy outcomes, specifically ectopic pregnancy rates and heterotopic pregnancy rates. RESULTS: Among those who became pregnant, there was a significantly lower incidence of ectopic/heterotopic pregnancies in blastocyst-stage FETs versus that in cleavage-stage FETs (0.8% vs. 1.1%). The differences in ectopic/heterotopic pregnancy rates remained statistically significant after controlling for confounders such as tubal factor infertility and number of embryos transferred. CONCLUSIONS: Blastocyst-stage FET was associated with a lower ectopic/heterotopic pregnancy rate compared with cleavage-stage FET.

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].).

Comparison of 2-Hour Oral Glucose Tolerance Test and Hemoglobin A1C in the Identification of Pre-Diabetes in Women with Infertility and Recurrent Pregnancy Loss.

RESEARCH QUESTION: Does hemoglobin A1C (HbA1C) predict pre-diabetes (pre-DM) in a population of women with infertility and/or recurrent pregnancy loss (RPL), when considering the 75 g, 2-hour oral glucose tolerance test (2h GTT) as the gold standard? DESIGN: Retrospective study of 242 patients with infertility or RPL presenting to a university-affiliated reproductive endocrinology and infertility clinic between January 2012 and December 2016 who underwent screening for disorders of glucose metabolism with a 2h GTT. The prevalence of pre-DM as defined by HbA1C 5.7% to 6.4% and 2h GTT values of 140-199 mg/dL, and predictive values of HbA1C for the identification of pre-DM when compared with 2h GTT, were calculated and compared. RESULTS: Of 242 patients, 188 (77.7%) women had both HbA1C and 2h GTT performed. Of these, 89 (47.3%) tested positive for pre-DM by one or both methods. Of 89 patients, 14 (15.7%) had both an abnormal 2h GTT and an abnormal HbA1C. Only 6 out of 89 (6.7%) patients tested positive for pre-DM by an abnormal 2h GTT in the setting of a normal HbA1C result. Conversely, 69 of these 89 patients (77.5%) tested positive for pre-DM by an abnormal HbA1C in the setting of a normal 2h GTT. The prevalence of pre-DM, as defined by 2h GTT, was 10.6% (20/188) (95% CI, 6.6-16.0), compared with a prevalence of 44.1% (83/188) (95% CI, 36.9-51.6) when pre-DM was defined by HbA1C alone. When the 2h GTT was considered the gold standard for the identification of pre-DM, the negative predictive value (NPV) of HbA1C compared with 2h GTT was 94.3% (95% CI, 88.0-97.9), whereas the positive predictive value (PPV) of HbA1C compared with 2h GTT was only 16.9% (95% CI, 9.5-26.7). CONCLUSIONS: Although a normal HbA1C was highly predictive of a normal 2h GTT, the two tests demonstrate poor agreement in the identification of pre-DM in women with infertility and/or RPL. Hemoglobin A1C is superior to the 2h GTT as an initial screening test for pre-DM in this population, since it identified a substantial number of women who would otherwise remain undiagnosed in the setting for a normal 2h GTT alone. However, the long-term clinical relevance of an elevated HbA1C in this population needs to be better defined.

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.

Ongoing barriers to immediate postpartum long-acting reversible contraception: a physician survey.

BACKGROUND: Postpartum women are at risk for unintended pregnancy. Access to immediate long-acting reversible contraception (LARC) may help decrease this risk, but it is unclear how many providers in the United States routinely offer this to their patients and what obstacles they face. Our primary objective was to determine the proportion of United States obstetric providers that offer immediate postpartum LARC to their obstetric patients. METHODS: We surveyed practicing Fellows and Junior Fellows of the American College of Obstetricians and Gynecologists (ACOG) about their use of immediate postpartum LARC. These members are demographically representative of ACOG members as a whole and represent all of the ACOG districts. Half of these Fellows were also part of the Collaborative Ambulatory Research Network (CARN), a group of ACOG members who voluntarily participate in research. We asked about their experience with and barriers to immediate placement of intrauterine devices and contraceptive implants after delivery. RESULTS: There were a total of 108 out of 600 responses (18%). Participants practiced in a total of 36 states and/or US territories and their median age was 52 years. Only 26.9% of providers surveyed offered their patients immediate postpartum LARC, and of these providers, 60.7% work in a university-based practice. There was a statistically significant association between offering immediate postpartum LARC and practice type, with the majority of providers working at a university-based practice (p < 0.001). Multiple obstacles were identified, including cost or reimbursement, device availability, and provider training on device placement in the immediate postpartum period. CONCLUSION: The majority of obstetricians surveyed do not offer immediate postpartum long-acting reversible contraception to patients in the United States. This is secondary to multiple obstacles faced by providers.

Improved outcomes after blastocyst-stage frozen-thawed embryo transfers compared with cleavage stage: a Society for Assisted Reproductive Technologies Clinical Outcomes Reporting System study.

OBJECTIVE: To investigate whether there is a difference in obstetrical and perinatal outcomes in blastocyst frozen-thawed embryo transfers (FETs) compared with cleavage-stage FET. DESIGN: A retrospective cohort study. SETTING: Not applicable. PATIENT(S): Women undergoing autologous FETs at either the blastocyst stage (n = 118,572) or the cleavage stage (n = 117,619) reported to the Society for Assisted Reproductive Technology in the years 2004-2013. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth, gestational age, birth weight, miscarriage. RESULT(S): After controlling for confounders, there were a 49% increased odds of live birth after blastocyst-stage FET compared with cleavage-stage FET (odds ratio [OR] = 1.49; 95% confidence interval [CI], 1.44, 1.54). Additionally, blastocyst FET was associated with a 68% (OR = 1.68; 95% CI, 1.63, 1.74) increased odds of clinical pregnancy and an 7% (OR = 0.93; 95% CI, 0.88, 0.92) decreased odds of miscarriage. There was also a 16% increased odds of preterm delivery (OR = 1.16; 95% CI, 1.06, 1.27) after blastocyst FET but no difference in birth weights. CONCLUSION(S): In patients undergoing FET, blastocyst-stage transfer is associated with higher live-birth rates when compared with cleavage-stage transfers. Furthermore, perinatal outcomes are similar between the groups.

Reporting in vitro fertilization cycles to the Society for Assisted Reproductive Technology database: where have all the cycles gone?

OBJECTIVE: To assess the relationship between live birth rates (LBRs) and the incidence of under-reported cycles by IVF clinics. DESIGN: Cohort study. SETTING: Not applicable. PATIENT(S): All patients undergoing IVF cycles in the aforementioned clinics. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): The reporting percentage (RP), defined as number of cycles with reported pregnancy rates divided by total cycles performed. Results from cryopreservation cycles are only presented by SART if an embryo transfer occurs. Thus, RP decreases as incidence of embryo or oocyte banking cycles increases. The LBRs in women aged <35 years were compared between clinics. RESULT(S): The median RP of all clinics was 93%-97%. Clinics with RP <80% increased from 2 in 2004 to 30 in 2012. Twenty-one clinics had an RP that fell 2 standard deviations below the mean in any year. Over the 9 years, there was a negative correlation between RP and LBR of -0.17, but for the 21 outlier clinics the correlation increased to -0.26. In 2012 alone, in outlier clinics, for every 10% drop in RP there was an associated rise in LBR of 4.3%; some clinics reported 40% fewer cycles than the median. CONCLUSION(S): In clinics with very low RP, the cycles that are reported have higher success rates. Regardless of intent, the reduction of reported data to SART makes it increasingly difficult for clinicians and patients to accurately assess a clinic's success rates.

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.

Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women's Health Initiative.

OBJECTIVE: To estimate the effects of estrogen plus progestin (E+P) therapy on menopausal symptoms, vaginal bleeding, gynecologic surgery rates, and treatment-related adverse effects in postmenopausal women. METHODS: Randomized, double-blind, placebo-controlled trial of 16,608 postmenopausal women, ages 50-79 (mean +/- standard deviation 63.3 +/- 7.1) years, with intact uterus, randomized to one tablet per day containing 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone acetate (n = 8,506) or placebo (n = 8,102), and followed for a mean of 5.6 years. Change in symptoms and treatment-related effects were analyzed at year 1 in all participants. Bleeding and gynecologic surgery rates were analyzed through study close-out. RESULTS: Baseline symptoms did not differ between the treatment groups. More women assigned to E+P than placebo reported relief of hot flushes (85.7% versus 57.7%, respectively; odds ratio 4.40; 95% confidence interval 3.40-5.71), night sweats (77.6% versus 57.4%; 2.58; 2.04-3.26), vaginal or genital dryness (74.1% versus 54.6%; 2.40; 1.90-3.02), joint pain or stiffness (47.1% versus 38.4%; 1.43; 1.24-1.64), and general aches or pains (49.3% versus 43.7%; 1.25; 1.08-1.44). Women asymptomatic at baseline who were assigned to E+P more often developed breast tenderness (9.3% versus 2.4%, respectively; 4.26; 3.59-5.04), vaginal or genital discharge (4.1% versus 1.0%; 4.47; 3.44-5.81), vaginal or genital irritation (4.2% versus 2.8%; 1.52; 1.27-1.81), and headaches (5.8% versus 4.7%; 1.26; 1.08-1.46) than women on placebo. Estrogen plus progestin treatment prevented the onset of new musculoskeletal symptoms. Vaginal bleeding was reported by 51% of women on E+P and 5% of women on placebo at 6 months; most bleeding was reported as spotting. Gynecologic surgeries (hysterectomy and dilation and curettage) were performed more frequently in women assigned to E+P (3.1% versus 2.5% for hysterectomy, hazard ratio = 1.23, P = .026; 5.4% versus 2.4% for dilation and curettage, hazard ratio = 2.23, P < .001). CONCLUSION: Estrogen plus progestin relieved some menopausal symptoms, such as vasomotor symptoms and vaginal or genital dryness, but contributed to treatment-related effects, such as bleeding, breast tenderness, and an increased likelihood of gynecologic surgery.

Successful Pregnancy in a Couple with Severe Male Factor Infertility after Selection of Sperm with Cytoplasmic Droplets.

We present live births resulting from two separate IVF cycles in a couple in which ICSI was performed with sperm specifically selected for presence of small cytoplasmic droplets. These cycles followed previous cycles using standard sperm selection methods in which very poor embryo development and no pregnancies ensued. The male partner was diagnosed with severe male factor infertility including elevated DNA fragmentation.

In vitro maturation and its role in clinical assisted reproductive technology.

IMPORTANCE: In vitro maturation (IVM) refers to maturation in culture of immature oocytes that may or may not have been exposed to short courses of gonadotropins. Approximately 5000 live births have occurred as a result of IVM since the 1970s. Currently, IVM is reserved for carefully selected patients at risk for ovarian hyperstimulation syndrome and for those with contraindications to hormone administration. The technology is still considered experimental. OBJECTIVE: The objective of this study was to identify a role for IVM and discuss clinical practices based on the current literature. EVIDENCE ACQUISITION: We conducted a literature review of all available and published data. Relevant studies were identified using PubMed and MEDLINE. Search parameters included "in vitro maturation or IVM" and "oocyte maturation." Multiple case-control studies were identified comparing reproductive outcomes between conventional in vitro fertilization (IVF) and IVM, but no randomized controlled trials have been reported to date comparing IVF and IVM. RESULTS: Results from retrospective and prospective observational studies have shown decreased live birth and implantation rates in comparison to conventional IVF/intracytoplasmic sperm injection for patients with various indications for IVM. However, rates of ovarian hyperstimulation syndrome were significantly reduced in studies with patients with polycystic ovary syndrome. CONCLUSIONS: Although the pregnancy rate is lower than conventional IVF, IVM is a safer and simpler alternative to conventional IVF. Future research needs to focus on improving implantation and live birth rates before universal implementation.