A spatially resolved timeline of the human maternal-fetal interface.

Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR)1-3. However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.

Miscarriage risk assessment: a bioinformatic approach to identifying candidate lethal genes and variants.

PURPOSE: Miscarriage, often resulting from a variety of genetic factors, is a common pregnancy outcome. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. In this study, we evaluated the potential impact of both known and candidate genes on prenatal lethality and the effectiveness of PGCS in diverse populations. METHODS: We analyzed 125,748 human exome sequences and mouse and human gene function databases. Our goals were to identify genes crucial for human fetal survival (lethal genes), to find variants not present in a homozygous state in healthy humans, and to estimate carrier rates of known and candidate lethal genes in various populations and ethnic groups. RESULTS: This study identified 138 genes in which heterozygous lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these 138 genes could identify 4.6% (in the Finnish population) to 39.8% (in the East Asian population) of couples at risk of miscarriage. This explains the cause of pregnancy loss in approximately 1.1-10% of cases affected by biallelic lethal variants. CONCLUSION: This study has identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The variation of these genes across ethnic groups underscores the need for a comprehensive, pan-ethnic PGCS panel that includes genes related to miscarriage.

Decision regret, and other mental health outcomes, following fertility preservation in the transgender individual compared to the cisgender woman.

PURPOSE: This study aimed to (1) determine differences in depression, anxiety, body image, quality-of-life (QOL), and decision regret scale (DRS) scores in transgender individuals undergoing fertility preservation (FP) compared to those who decline and (2) determine if DRS score following FP varies between transgender individuals and cisgender women. METHODS: Sixteen transgender birth-assigned (BA) females and 13 BA males, undergoing FP consultation at an academic center between January 2016 and November 2019, were compared to each other and cisgender cohorts with pre-existing data: 201 women undergoing elective oocyte cryopreservation (EOC) between 2012 and 2016 and 44 women with cancer undergoing FP between 1993 and 2007. Outcomes included demographics; validated scales for depression, anxiety, body image, QOL (see below) in the trans cohort; DRS score in all three cohorts. RESULTS: Of 29 transgender individuals participating, 10 BA females (62%) and 12 BA males (92%) underwent FP. Beck Depression Inventory II, Hospital Anxiety and Depression Scale, Body Image Scale for Transsexuals, Satisfaction with Life Scale, Short Form Health Survey-36, and DRS scores were not significantly different between trans individuals who underwent FP and those who declined. On univariate modeling, regret was significantly lower in transpeople undergoing FP compared to those who did not (OR 0.118, p = 0.03). BA female and BA male transpatients undergoing FP reported DRS median scores 5 (mean 9) and 7.5 (mean 15), respectively, both were not significantly different from cisgender women (p = 0.97, p = 0.25) nor from each other (p = 0.43). CONCLUSIONS: Depression, anxiety, body image, and QOL, in a group of individuals presenting for FP consultation, appear similar between transpeople undergoing FP and not, while regret is significantly lower in those choosing FP. FP is an option for transgender individuals without significant differences in regret compared to cisgender women.

Decision regret among women considering planned oocyte cryopreservation: a prospective cohort study.

PURPOSE: To (1) prospectively characterize the incidence of decision regret among women considering planned oocyte cryopreservation (planned OC), comparing those who pursued treatment vs those who did not freeze eggs, and (2) to identify baseline predictors for future decision regret. METHODS: A total of 173 women seen in consultation for planned OC were followed prospectively. Surveys were administered at (1) baseline (< 1 week after initial consultation) and (2) follow-up, 6 months after planned OC among participants who froze eggs or 6 months following consultation in the absence of further communication to pursue treatment. The primary outcome was the incidence of moderate-to-severe decision regret, indicated by a Decision Regret Scale score > 25. We also examined predictors of regret. RESULTS: The incidence of moderate-to-severe regret over the decision to freeze eggs was 9% compared to 51% over the decision not to pursue treatment. Among women who froze eggs, adequacy of information at baseline to decide about treatment (aOR 0.16, 95% CI 0.03, 0.87) and emphasis on future parenthood (aOR 0.80, 95% CI 0.66, 0.99) were associated with reduced odds of regret. Forty-six percent of women who froze eggs regretted not doing so earlier. Among women who did not freeze eggs, the primary reasons were financial and time constraints, correlating with increased odds of decision regret in an exploratory analysis. CONCLUSIONS: Among women undergoing planned OC, the incidence of decision regret is low compared to the regret confronting women seen in consultation for planned OC but who do not pursue treatment. Provider counseling is key to offset the regret risk.

Early pregnancy anxiety during the COVID-19 pandemic: preliminary findings from the UCSF ASPIRE study.

BACKGROUND: Antenatal anxiety has been linked to adverse obstetric outcomes, including miscarriage and preterm birth. However, most studies investigating anxiety during pregnancy, particularly during the COVID-19 pandemic, have focused on symptoms during the second and third trimester. This study aims to describe the prevalence of anxiety symptoms early in pregnancy and identify predictors of early pregnancy anxiety during the COVID-19 pandemic. METHODS: We assessed baseline moderate-to-severe anxiety symptoms after enrollment in the UCSF ASPIRE (Assessing the Safety of Pregnancy in the Coronavirus Pandemic) Prospective Cohort from May 2020 through February 2021. Pregnant persons < 10 weeks' gestation completed questions regarding sociodemographic characteristics, obstetric/medical history, and pandemic-related experiences. Univariate and multivariate hierarchical logistic regression analyses determined predictors of moderate or severe anxiety symptoms (Generalized Anxiety Disorder-7 questionnaire score ≥ 10). All analyses performed with Statistical Analysis Software (SAS®) version 9.4. RESULTS: A total of 4,303 persons completed the questionnaire. The mean age of this nationwide sample was 33 years of age and 25.7% of participants received care through a fertility clinic. Over twelve percent of pregnant persons reported moderate-to-severe anxiety symptoms. In univariate analysis, less than a college education (p < 0.0001), a pre-existing history of anxiety (p < 0.0001), and a history of prior miscarriage (p = 0.0143) were strong predictors of moderate-to-severe anxiety symptoms. Conversely, having received care at a fertility center was protective (26.6% vs. 25.7%, p = 0.0009). COVID-19 related stressors including job loss, reduced work hours during the pandemic, inability to pay rent, very or extreme worry about COVID-19, and perceived stress were strongly predictive of anxiety in pregnancy (p < 0.0001). In the hierarchical logistic regression model, pre-existing history of anxiety remained associated with anxiety during pregnancy, while the significance of the effect of education was attenuated. CONCLUSION(S): Pre-existing history of anxiety and socioeconomic factors likely exacerbated the impact of pandemic-related stressors on early pregnancy anxiety symptoms during the COVID-19 pandemic. Despite on-going limitations for in-person prenatal care administration, continued emotional health support should remain an important focus for providers, particularly when caring for less privileged pregnant persons or those with a pre-existing history of anxiety.

Predictors of adequate physical activity within a multiethnic polycystic ovary syndrome patient population: a cross-sectional assessment.

BACKGROUND: Physical activity is a cornerstone for treatment of women with polycystic ovary syndrome (PCOS), but there are limited data on their exercise behaviors. A previous study identified PCOS patients of non-White ethnicity to be at higher risk for inadequate physical activity. Further data is needed to identify groups that would benefit from additional counseling in achieving adequate physical activity (APA). Therefore, this study examined correlates of APA within a multiethnic PCOS patient population. METHODS: Cross-sectional assessment of exercise behaviors within a multiethnic PCOS patient population was performed using the International Physical Activity Questionnaire (IPAQ). Kruskal-Wallis test was used to compare metabolic equivalents from physical activity among racial/ethnic groups. APA was defined as at least 150 min of moderate-intensity, or 75 min of vigorous-intensity, or an equivalent combination of moderate- and vigorous-intensity activity per week. Logistic regression analyses were performed to identify correlates of APA. RESULTS: Four hundred and sixty-five women of various racial/ethnic backgrounds were included in analysis: 62% (n = 287) self-identified as White, 15% (n = 71) as Hispanic, 11% (n = 52) as East/Southeast Asian, 7% (n = 32) as South Asian, and 5% (n = 23) as Black/African American. Significant differences were observed in metabolic equivalents (METs) from vigorous-intensity and total (moderate plus vigorous-intensity) exercise across racial/ethnic groups (p < 0.01); South Asian patients had the lowest metabolic expenditure in moderate-intensity, vigorous-intensity, and total exercise. Overall prevalence of APA was 66%; South Asian patients exhibited the lowest prevalence (46.9%). Ethnicity was a predictor for APA when controlled for age (p = 0.01); this finding was attenuated in logistic regression models that also controlled for age and body mass index (p = 0.05) as well as education level and parity (p = 0.16). CONCLUSIONS: South Asian patients with PCOS exhibited the lowest metabolic expenditure and frequency of APA in our cohort. Differences in frequency of APA across racial/ethnic groups appear to be influenced by anthropometric and sociodemographic factors. Our findings present an opportunity for women's health providers to be cognizant and provide additional counseling regarding physical exercise to at-risk PCOS patients to improve their known higher risk for adverse long-term metabolic outcomes.

Associations of Polycystic Ovary Syndrome With Indicators of Brain Health at Midlife in the CARDIA Cohort.

BACKGROUND AND OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common reproductive disorder associated with an adverse cardiometabolic profile early in life. Increasing evidence links cardiovascular risk factors, such as diabetes and hypertension, to accelerated cognitive aging. However, less is known about PCOS and its relationship to brain health, particularly at midlife. Our goal was to investigate possible associations between PCOS and midlife cognitive function and brain MRI findings in an ongoing prospective study. METHODS: We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a geographically diverse prospective cohort study of individuals who were 18-30 years at baseline (1985-1986) and followed for 30 years. We identified women with PCOS from an ancillary study (CARDIA Women's study (CWS); n = 1,163) as those with elevated androgen levels and/or hirsutism in conjunction with symptoms of oligomenorrhea. At year 30, participants completed cognitive testing, including the Montreal Cognitive Assessment, Rey Auditory Verbal Learning Test (RAVLT) (verbal learning and memory), Digit Symbol Substitution Test (processing speed and executive function), Stroop test (attention and cognitive control), and category and letter fluency tests (semantics and attention). A subset completed brain MRI to assess brain structure and white matter integrity. Multivariable linear regression models estimated the association between PCOS and outcomes, adjusting for age, race, education, and study center. RESULTS: Of the 1163 women in CWS, 907 completed cognitive testing, and of these, 66 (7.1%) met criteria for PCOS (age 54.7 years). Women with and without PCOS were similar for age, BMI, smoking/drinking status, and income. At year 30, participants with PCOS performed lower (mean z score; 95% CI) on Stroop (-0.323 (-0.69 to -7.37); p = 0.008), RAVLT (-0.254 (-0.473 to -0.034); p = 0.002), and category fluency (-0.267 (-0.480 to -0.040); p = 0.02) tests. Of the 291 participants with MRI, 25 (8.5%) met PCOS criteria and demonstrated lower total white matter fractional anisotropy, a measure of white matter integrity (coefficient (95% CI) -0.013 (-0.021 to -0.005); p = 0.002), though not abnormal white matter. DISCUSSION: Our results suggest that women with PCOS have lower cognitive performance and lower white matter integrity at midlife. Additional research is needed to confirm these findings and to determine potential mechanistic pathways including potential modifiable factors.

In Utero Exposure to Maternal COVID-19 and Offspring Neurodevelopment Through Age 24 Months.

Importance: In utero exposure to maternal infections has been associated with abnormal neurodevelopment among offspring. The emergence of a new, now endemic infection (SARS-CoV-2) warrants investigating developmental implications for exposed offspring. Objective: To assess whether in utero exposure to maternal COVID-19 is associated with abnormal neurodevelopmental scores among children ages 12, 18, and 24 months. Design, Setting, and Participants: Data were ascertained from the ASPIRE (Assessing the Safety of Pregnancy in the Coronavirus Pandemic) trial, a prospective cohort of pregnant individuals aged 18 years or older who were enrolled before 10 weeks' gestation and their children. Individuals were recruited online from May 14, 2020, to August 23, 2021, using the Society for Assisted Reproductive Technology and BabyCenter, an online media platform. Participants from all 50 states and Puerto Rico completed activities remotely. Exposure: In utero exposure to COVID-19. Main Outcomes and Measures: Birth mothers completed the Ages & Stages Questionnaires, Third Edition, a validated screening tool for developmental delays, at 12, 18, and 24 months' post partum. A score below the cutoff in any domain (communication, gross motor, fine motor, problem-solving, and social skills) was considered an abnormal developmental screen (scores range from 0 to 60 in each domain, with higher scores indicating less risk for neurodevelopmental delay). Results: The cohort included 2003 pregnant individuals (mean [SD] age, 33.3 [4.2] years) enrolled before 10 weeks' gestation and who completed study activities; 1750 (87.4%) had earned a college degree. Neurodevelopmental outcomes were available for 1757 children at age 12 months, 1522 at age 18 months, and 1523 at age 24 months. The prevalence of abnormal screens for exposed vs unexposed offspring at age 12 months was 64 of 198 (32.3%) vs 458 of 1559 (29.4%); at age 18 months, 36 of 161 (22.4%) vs 279 of 1361 (20.5%); and at age 24 months, 29 of 151 (19.2%) vs 230 of 1372 (16.8%). In an adjusted mixed-effects logistics regression model, no difference in risk of abnormal neurodevelopmental screens was observed at age 12 months (adjusted risk ratio [ARR], 1.07 [95% CI, 0.85-1.34]), age 18 months (ARR, 1.15 [95% CI, 0.84-1.57]), or age 24 months (ARR, 1.01 [95% CI, 0.69-1.48]). Supplemental analyses did not identify differential risk based on trimester of infection, presence vs absence of fever, or breakthrough infection following vaccination vs primary infection. Conclusions and Relevance: In this cohort study of pregnant individuals and offspring, exposure to maternal COVID-19 was not associated with abnormal neurodevelopmental screening results through 24 months' post partum. Continued study of diverse groups of children is needed because, among other factors, evidence suggests sensitivity of the developing fetal brain to maternal immune activation.

In Utero Exposure to Maternal COVID-19 Vaccination and Offspring Neurodevelopment at 12 and 18 Months.

Importance: Uptake of COVID-19 vaccines among pregnant individuals was hampered by safety concerns around potential risks to unborn children. Data clarifying early neurodevelopmental outcomes of offspring exposed to COVID-19 vaccination in utero are lacking. Objective: To determine whether in utero exposure to maternal COVID-19 vaccination was associated with differences in scores on the Ages and Stages Questionnaire, third edition (ASQ-3), at 12 and 18 months of age. Design, Setting, and Participants: This prospective cohort study, Assessing the Safety of Pregnancy During the Coronavirus Pandemic (ASPIRE), enrolled pregnant participants from May 2020 to August 2021; follow-up of children from these pregnancies is ongoing. Participants, which included pregnant individuals and their offspring from all 50 states, self-enrolled online. Study activities were performed remotely. Exposure: In utero exposure of the fetus to maternal COVID-19 vaccination during pregnancy was compared with those unexposed. Main Outcomes and Measures: Neurodevelopmental scores on validated ASQ-3, completed by birth mothers at 12 and 18 months. A score below the established cutoff in any of 5 subdomains (communication, gross motor, fine motor, problem solving, social skills) constituted an abnormal screen for developmental delay. Results: A total of 2487 pregnant individuals (mean [SD] age, 33.3 [4.2] years) enrolled at less than 10 weeks' gestation and completed research activities, yielding a total of 2261 and 1940 infants aged 12 and 18 months, respectively, with neurodevelopmental assessments. In crude analyses, 471 of 1541 exposed infants (30.6%) screened abnormally for developmental delay at 12 months vs 203 of 720 unexposed infants (28.2%; χ2 = 1.32; P = .25); the corresponding prevalences at 18 months were 262 of 1301 (20.1%) vs 148 of 639 (23.2%), respectively (χ2 = 2.35; P = .13). In multivariable mixed-effects logistic regression models adjusting for maternal age, race, ethnicity, education, income, maternal depression, and anxiety, no difference in risk for abnormal ASQ-3 screens was observed at either time point (12 months: adjusted risk ratio [aRR], 1.14; 95% CI, 0.97-1.33; 18 months: aRR, 0.88; 95% CI, 0.72-1.07). Further adjustment for preterm birth and infant sex did not affect results (12 months: aRR, 1.16; 95% CI, 0.98-1.36; 18 months: aRR, 0.87; 95% CI, 0.71-1.07). Conclusions and Relevance: Results of this cohort study suggest that COVID-19 vaccination was safe during pregnancy from the perspective of infant neurodevelopment to 18 months of age. Additional longer-term research should be conducted to corroborate these findings and buttress clinical guidance with a strong evidence base.

Preconception Genetic Carrier Screening for Miscarriage Risk Assessment: A Bioinformatic Approach to Identifying Candidate Lethal Genes and Variants.

Purpose: Miscarriage, due to genetically heterogeneous etiology, is a common outcome of pregnancy. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. Here we assessed the theoretical impact of known and candidate genes on prenatal lethality and the PGCS among diverse populations. Methods: Human exome sequencing and mouse gene function databases were analyzed to define genes essential for human fetal survival (lethal genes), identify variants that are absent in a homozygous state in healthy human population, and to estimate carrier rates for known and candidate lethal genes. Results: Among 138 genes, potential lethal variants are present in the general population with a frequency of 0.5% or greater. Preconception screening for these 138 genes would identify from 4.6% (Finnish population) to 39.8% (East Asian population) of couples that are at-risk for miscarriage, explaining a cause for pregnancy loss for ∼1.1-10% of conceptions affected by biallelic lethal variants. Conclusion: This study identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The diversity of these genes amongst the various ethnic groups highlights the importance of designing a pan-ethnic PGCS panel comprising miscarriage-related genes.

Decision regret after failed autologous in vitro fertilization in women ≥42 years of age.

OBJECTIVE: To quantify the level of decision regret in women ≥42 years of age after autologous in vitro fertilization (IVF) and identify factors associated with moderate-to-severe regret. DESIGN: Cross-sectional survey. SETTING: Academic center. PATIENT(S): Ninety-four women ≥42 years of age who underwent autologous IVF between 2012 and 2018. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Decision regret score, with >25 as threshold for moderate-to-severe regret. RESULT(S): The overall response rate was 22%. Respondents had a median age of 43 years at the time of IVF. The median and mean decision regret scores were 10 and 17.1 (range, 0-75), respectively. Seventy-three percent (n = 69) had absent-to-mild regret (score, 0-25), and 27% (n = 25) had moderate-to-severe regret (score, >25) after IVF. Having no live births was associated with increased regret (odds ratio [OR], 22 [95% confidence interval {CI}, 2.82-171.82]). Among those who were unsuccessful, 40% (n = 24) had moderate-to-severe regret. Predictors for moderate-to-severe regret in this group included the lack of insurance coverage (OR, 0.33 [95% CI, 0.12-0.99]). Conversely, the perceived adequacy of information/counseling (OR, 0.44 [95% CI, 0.2-0.77]) and the perceived adequacy of emotional support (OR, 0.29 [95% CI, 0.15-0.55]) were protective factors inversely correlated with regret. CONCLUSION(S): Autologous IVF carries a low success rate and a considerable risk of decision regret in women ≥42 years of age. In those who were unsuccessful, the perceived adequacy of information and that of emotional support were protective factors against increased regret. Although concluding from a small, selected pool, our results strongly suggest that ample counseling and psychological support should be particularly emphasized within this patient population.

Endophenotypic correlates of cognitive function in reproductive-age individuals with polycystic ovary syndrome.

Objective: To characterize cognitive performance in relation to hormonal and metabolic factors in women with polycystic ovary syndrome (PCOS). Design: Cross-sectional study. Setting: Tertiary university center. Patients: A total of 48 individuals, aged 21-46 years, with PCOS according to the Rotterdam criteria. Interventions: Complete history and physical examinations, endovaginal ultrasounds, dermatologic assessments, neuropsychological assessments, and metabolic and hormonal serum tests. Main Outcome Measures: Sample-based z-scores on a comprehensive cognitive test battery. Results: Subjects were defined as having an androgenic (n = 31) or a nonandrogenic (n = 17) PCOS phenotype. Compared with their nonandrogenized counterparts, subjects with hyperandrogenism demonstrated lower relative performance on the tests of executive function (ß-coefficient for the executive function composite z-score, -0.44; 95% confidence interval, -0.79 to -0.09), despite similar performance on the tests of memory, verbal reasoning, and perceptual reasoning. These differences were independent of age, years of education, and obesity. In an exploratory analysis in which subjects were stratified by the presence of insulin resistance (IR), subjects with PCOS with both IR and hyperandrogenism showed the lowest performance on a composite score of executive function, followed by those with hyperandrogenism alone. Conclusions: In this small study, subjects with hyperandrogenic PCOS demonstrated lower performance on the tests of executive function than subjects with nonandrogenic PCOS. Additional research is needed to confirm these findings in larger cohorts and investigate the role of modifiable factors, including IR, on cognitive outcomes.

Association of obstructive sleep apnea risk with depression and anxiety symptoms in women with polycystic ovary syndrome.

STUDY OBJECTIVE: To determine whether obstructive sleep apnea (OSA) risk is associated with depression and anxiety symptoms in women with polycystic ovary syndrome (PCOS). METHODS: This is a cross-sectional study of women with PCOS, by the Rotterdam criteria, seen at a single academic center between June 2017 and June 2020. Depression symptoms, anxiety symptoms, and OSA risk were assessed with the self-administered Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Berlin questionnaires, respectively. Univariate and multivariate logistic regression analyses were used to determine the odds of moderate/severe symptoms of depression (PHQ-9 ≥ 10) and anxiety (GAD-7 ≥ 10) in the high-risk vs low-risk OSA groups. The primary multivariate model adjusted for age, body mass index, free testosterone, and insulin resistance. RESULTS: Of the 200 participants, the mean age was 28.0 years and 38% screened high risk for OSA. Women who screened high-risk OSA had > 3 times the odds of moderate/severe depression (odds ratio [OR]: 3.19; 95% confidence interval [CI]: 1.76-5.78; P < .001) and > 2 times the odds of having moderate/severe anxiety (OR: 2.49; 95% CI: 1.34-4.64; P = .004). These associations were only slightly attenuated in the adjusted models: the adjusted OR for moderate/severe depression was 3.06 (95% CI: 1.36-6.88; P = .01) and the aOR for moderate/severe anxiety was 2.39 (95% CI: 1.03-5.59; P = .04). CONCLUSIONS: Among women with PCOS, those at high risk of OSA experienced elevated depression and anxiety symptoms compared with those at low risk for OSA, independent of the effects of age, body mass index, hyperandrogenism, and insulin resistance. CITATION: Zhou X, Jaswa E, Pasch L, Shinkai K, Cedars MI, Huddleston HG. Association of obstructive sleep apnea risk with depression and anxiety symptoms in women with polycystic ovary syndrome. J Clin Sleep Med. 2021;17(10):XXX-XXX.

Diminished ovarian reserve is associated with reduced euploid rates via preimplantation genetic testing for aneuploidy independently from age: evidence for concomitant reduction in oocyte quality with quantity.

OBJECTIVE(S): To determine whether women with diminished ovarian reserve (DOR) (quantitatively) had lower rates of euploid blastocysts, as a proxy for oocyte quality. DESIGN: Retrospective cohort study. SETTING: University reproductive health clinic. PATIENT(S): A total of 1,152 women aged 19-42 years underwent 1,675 IVF cycles yielding 8,073 blastocysts for biopsy from 2010 to 2019. INTERVENTIONS(S): Preimplantation genetic testing for aneuploidy. MAIN OUTCOME MEASURE(S): Euploid rates, defined as the number of euploid blastocysts divided by the number of biopsied blastocysts per cycle. RESULT(S): A total of 225 women (20%) had DOR as infertility diagnosis per the Bologna criteria. Age was higher among the women with DOR (39.5 y vs. 37.0 y). Euploid rates were lower among women with vs. without DOR (29.0% vs. 44.9%). In generalized linear models controlling for age, women with DOR had 24% reduced odds of a biopsied blastocyst being euploid versus women without DOR. In a secondary analysis assigning DOR status to women producing the lowest quartile of age-adjusted mature oocyte yield, this relationship remained. No differences were identified in live birth rates between women with and without DOR after euploid single-embryo transfer independently from age (n = 944 transfers; 56.8% vs. 54.8%, respectively). CONCLUSION(S): Blastocysts from women with DOR are less likely to be euploid than those from women without DOR after adjustment for age. Given the concomitant reduction in euploid rates with quantity of oocytes observed in this study, quantitative ovarian reserve assessments (i.e., follicular machinery) may yield insight into relative ovarian aging.

Changing stimulation protocol on repeat conventional ovarian stimulation cycles does not lead to improved laboratory outcomes.

OBJECTIVE: To evaluate whether physicians' choice of ovarian stimulation protocol is associated with laboratory outcomes. DESIGN: Retrospective cohort study. SETTING: Single academic center. PATIENT(S): The subjects were 4,458 patients who completed more than one in vitro fertilization ovarian stimulation cycle within 1 year. On second stimulation, 49% repeated the same protocol and 51% underwent a different one. INTERVENTION(S): Estradiol priming antagonist, antagonist +/- oral contraceptive pill priming, long luteal protocol, Lupron (Lupron [AbbVie Inc, North Chicago, IL]) stop protocol, and flare were compared. Logistic or linear regression with cluster robust standard errors to account for covariates and paired data was used. MAIN OUTCOME MEASURE(S): Oocytes collected (OC), fertilization rate, blastocyst progression (BP), usable embryos (UE), and euploid rate (ER). RESULT(S): First stimulation outcomes were comparable across all protocols for FR, BP, UE, and ER but were different for OC, after adjustment for covariates. For OC, the effect of switching protocols differed according to the type of the second stimulation. There was improvement in OC if the same stimulation was repeated, except for flare. In addition, there were slight, significant improvements in fertilization rate (difference in values or coefficient of 0.02; 95% confidence interval [CI], 0.004, 0.4) and UE (coefficient 1.25; 95% CI, 0.79, 1.72) when the same stimulation was repeated. There were no changes in BP (coefficient 0.03; 95% CI, -0.01, 0.08) or ER (coefficient 0.01; 95% CI, -0.04, 0.06) when protocols were changed. In a low-BP subgroup, greater improvement was seen when the same protocol was repeated (coefficient 0.03; 95% CI 0.01, 0.04). CONCLUSION(S): There was a slight but significant improvement in laboratory outcomes when the same stimulation protocol was repeated, so careful consideration should be made before switching stimulation protocols for the purpose of improving laboratory outcomes.

Outcomes of screening mammography performed prior to fertility treatment in women ages 40-49.

OBJECTIVE: There are currently various conflicting recommendations for breast cancer screening with mammography in women between ages 40-49. There are no specific guidelines for breast cancer screening in women of this age group prior to assisted reproductive technology (ART) for the treatment of infertility. The purpose of our study was to evaluate outcomes of screening mammography, specifically ordered for the purpose of pre-fertility treatment clearance in women aged 40-49 years old. MATERIALS AND METHODS: This was an IRB approved retrospective study of women aged 40-49 presenting for screening mammography prior to ART between January 2010 and October 2018. Clinical history, imaging, and pathology results were gathered from the electronic medical record. Descriptive statistics were performed. RESULTS: Our study cohort consisted of 118 women with a mean age of 42 years (range 40-49). Sixteen of 118 (14%) women were recalled from screening for additional diagnostic work-up. Five of the 16 (31%) were recommended for biopsy (BI-RADS 4 or 5). One of 5 biopsies yielded a malignant result (PPV 20%). Overall cancer detection rate was 0.85% or 8.5 women per 1000 women screened. The single cancer in this cohort was an ER+ PR+ HER2- invasive ductal carcinoma. CONCLUSION: Screening mammography in women 40-49 performed prior to initiation of ART may identify asymptomatic breast malignancy. In accordance with ACR and SBI guidelines to screen women of this age group, women of this age group should undergo screening mammography prior to ART.

Pregnancy success rates for lesbian women undergoing intrauterine insemination.

OBJECTIVE: To compare the pregnancy outcomes of lesbian women undergoing donor sperm intrauterine insemination (IUI) with that of heterosexual women undergoing IUI using partner or donor sperm. DESIGN: Retrospective cohort analysis. SETTING: Two academic fertility practices. PATIENTS: All IUI cycles between 2007 and 2016. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Primary outcomes included clinical pregnancy (CP) rates and live birth/ongoing pregnancy (LB) rates. The baseline characteristics and cycle characteristics were compared between the two groups using absolute standardized differences (ASDs). To account for the correlation between cycles per patient, a generalized estimating equation method for multivariable logistic regression was used. RESULTS: A total of 11,870 IUI cycles were included, of which 393 were in lesbian women using donor sperm and 11,477 were in heterosexual women with infertility using either partner or donor sperm. The CP rates were similar between the lesbian and heterosexual groups (13.2% vs. 11.1%, respectively, ASD = 0.06). In addition, the LB rates were similar between the two groups (10.4% vs. 8.3%, respectively, ASD = 0.10). After implementing the generalized estimating equation in a multivariable logistic regression, the lesbian group had an overall higher odds of CP (adjusted odds ratio 1.40, 95% confidence interval: [1.04-1.88]) and LB (adjusted odds ratio 1.59, 95% confidence interval [1.15-2.20]) compared with the heterosexual group. The clinical miscarriage rate was higher in the heterosexual group compared with that in the lesbian group (23.8% vs. 15.4%, respectively, ASD = 0.21). CONCLUSION: Although the unadjusted rates were similar between the two groups, the adjusted CP and LB odds were significantly higher for lesbian women undergoing IUI for procreative management than those for heterosexual women undergoing IUI for infertility.

Highly elevated level of antimüllerian hormone associated with preterm delivery in polycystic ovary syndrome patients who underwent ovulation induction.

OBJECTIVE: To determine the relationship between high antimüllerian hormone (AMH) levels and increased preterm delivery risk in populations of women with polycystic ovary syndrome (PCOS) or unexplained infertility undergoing ovulation induction. DESIGN: Secondary analysis of data from two multicenter randomized clinical trials: Pregnancy in Polycystic Ovary Syndrome II (PPCOS II); and Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS). SETTING: Not applicable. PATIENTS: Live births at ≥24 weeks' gestation from both the PPCOS II (n = 172) and AMIGOS (n = 222) cohorts were evaluated, and those at risk for iatrogenic preterm delivery including placental conditions, fetal growth restriction, multiple gestations, hypertensive diseases of pregnancy, and pre-gestational diabetes were excluded. The final analysis included 118 women with PCOS from the PPCOS II cohort and 146 women with unexplained infertility from the AMIGOS cohort. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Spontaneous preterm delivery. RESULTS: In the PCOS population, median AMH overall was 5.5 ng/dL (interquartile range 2.9-9.3 ng/dL). In all, 62% of participants who delivered preterm had AMH levels above the 75th percentile. When comparing clinical covariates between the preterm and term deliveries, women with PCOS who delivered preterm had notably higher AMH than their term counterparts (11.1 vs. 5.4 ng/mL). In the univariate logistic regression analysis, each unit increase in AMH raised the odds of preterm delivery by 14% (odds ratio 1.14, 95% confidence interval 1.02-1.26). The effect was magnified only after adjusting for age, race, body mass index, smoking status, testosterone, homeostatic model assessment for insulin resistance, and treatment randomization group (adjusted odds ratio 1.25, 95% confidence interval 1.06-1.49). Unlike in the PCOS population, the unexplained infertility cohort had no significant difference in AMH levels between those with or without preterm delivery (2.3 vs. 2.6 ng/mL). CONCLUSIONS: Our findings suggest that women with PCOS and high AMH who conceived after ovulation induction represent a high-risk group for preterm delivery. These data indicate that closer monitoring in the third trimester of pregnancies in PCOS patients with early first trimester AMH levels above 9.3 ng/mL may be warranted. CLINICAL TRIAL REGISTRATION NUMBER: NCT01044862.

Comparison of metabolic syndrome elements in White and Asian women with polycystic ovary syndrome: results of a regional, American cross-sectional study.

OBJECTIVE: To examine differences in metabolic dysfunction between White, East Asian, and South Asian women with polycystic ovary syndrome (PCOS) living in the San Francisco Bay Area, California. DESIGN: Cross-sectional study. SETTING: Referral clinic at an academic center. PATIENTS: A total of 243 White, 25 South Asian, and 38 East Asian women with PCOS, according to the Rotterdam criteria, aged 14-57 years, were recruited from May 2006 to May 2017. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Fasting and 2-hour insulin and glucose, homeostasis model assessment of insulin resistance, and fasting lipids. Metabolic syndrome and its five individual components were defined according to the National Cholesterol Education Program Adult Treatment Panel guidelines. RESULTS: Median baseline body mass index (25.9 vs. 24.8 vs. 24.0 kg/m2) and age (28.3 vs. 25.2 vs. 29.4 years) did not differ between White, South Asian, and East Asian women. Two-hour insulin levels were elevated in East and South Asian women at >25-30 and >30 years, respectively, compared with White women in the same age groups. Two-hour glucose level was also elevated in East Asian women compared with White women at age >30 years. No other differences were detected in continuous metabolic markers or in the risk of metabolic syndrome and its components across the three race categories. CONCLUSIONS: White, South Asian, and East Asian women with PCOS living in the same geographic region have comparable metabolic profiles to one another, although Asian women have higher 2-hour insulin levels and East Asian women, in particular, have higher 2-hour glucose levels.

Increased Body Mass Index Is Associated With A Nondilutional Reduction in Antimüllerian Hormone.

CONTEXT: Controversy exists regarding if and how body mass index (BMI) impacts antimüllerian hormone (AMH) in women with and without polycystic ovary syndrome (PCOS). Understanding the BMI-AMH relationship has critical implications for clinical interpretation of laboratory values and could illuminate underlying ovarian physiology. OBJECTIVE: To test the hypotheses that (1) BMI is associated with reduced AMH in PCOS and ovulatory controls (OVAs) and (2) the reduction in AMH is not accounted for by dilutional effects. DESIGN/SETTING: Multicenter cohort. PARTICIPANTS: Women aged 25 to 40 years from 2 clinical populations: 640 with PCOS, 921 women as OVAs. MAIN OUTCOME MEASURES: Ovarian reserve indices: AMH, antral follicle count (AFC), and AMH to AFC ratio (AMH/AFC) as a marker of per-follicle AMH production. RESULTS: In both cohorts, increasing BMI and waist circumference were associated with reductions in AMH and AMH/AFC, after adjusting for age, race, smoking, and site in multivariate regression models. Increasing BMI was associated with reduced AFC in PCOS but not OVAs. Body surface area (BSA), which unlike BMI is strongly proportional to plasma volume, was added to investigate a potential dilutive effect of body size on AMH concentrations. After controlling for BSA, BMI retained independent associations with AMH in both cohorts; BSA no longer associated with AMH. CONCLUSIONS: In an adjusted analysis, BMI, but not BSA, was associated with reduced AMH; these data do not support a role for hemodilution in mediating the relationship between increased body size and reduced AMH. Decreased AMH production by the follicle unit may be responsible for reduced AMH with increasing BMI.