Racial and ethnic disparities in reproductive medicine in the United States: A narrative review of contemporary high-quality evidence.

There has been increasing debate around how or if race and ethnicity should be used in medical research-including the conceptualization of race as a biological entity, a social construct, or a proxy for racism. The objectives of this narrative review are to identify and synthesize reported racial and ethnic inequalities in obstetrics and gynecology (ob/gyn) and develop informed recommendations for racial and ethnic inequity research in ob/gyn. A reproducible search of the eight highest impact ob/gyn journals was conducted. Articles published between January 1, 2010, and June 30, 2023 containing keywords related to racial and ethnic disparities, bias, prejudice, inequalities, and inequities were included (n=318). Data were abstracted and summarized into four themes: 1) access to care, 2) adherence to national guidelines, 3) clinical outcomes, and 4) clinical trial diversity. Research related to each theme was organized topically under the headings i) obstetrics, ii) reproductive medicine, iii) gynecologic cancer, and iv) other. Additionally, interactive tables were developed. These include data on study timeline, population, location, and results for every article. The tables enable readers to filter by journal, publication year, race and ethnicity, and topic. Numerous studies identified adverse reproductive outcomes among racial and ethnic minorities as compared to white patients, that persist despite adjusting for differential access to care, socioeconomic or lifestyle factors, and clinical characteristics. These include higher maternal morbidity and mortality among Black and Hispanic/Latinx patients; reduced success during fertility treatments for Black, Hispanic/Latinx, and Asian patients; and lower survival rates and lower likelihood of receiving guideline concordant care for gynecological cancers for non-white patients. We conclude that many racial and ethnic inequities in ob/gyn cannot be fully attributed to patient characteristics or access to care. Research focused on explaining these disparities based on biological differences incorrectly reinforces the notion of race as a biological trait. More research that deconstructs race and assesses efficacy of interventions to reduce these disparities is needed.

State insurance mandates for in vitro fertilization are not associated with improving racial and ethnic disparities in utilization and treatment outcomes.

BACKGROUND: Racial and ethnic disparities in utilization and clinical outcomes following fertility care with in vitro fertilization in the United States are well-documented. Given the cost of fertility care, lack of insurance is a barrier to access across all races and ethnicities. OBJECTIVE: This study aimed to determine how state insurance mandates are associated with racial and ethnic disparities in in vitro fertilization utilization and clinical outcomes. STUDY DESIGN: This was a cohort study using data from the Society for Assisted Reproductive Technology Clinical Outcome Reporting System from 2014 to 2019 for autologous in vitro fertilization cycles. The primary outcomes were utilization-defined as the number of in vitro fertilization cycles per 10,000 reproductive-aged women-and cumulative live birth-defined as the delivery of at least 1 liveborn neonate resulting from a single stimulation cycle and its corresponding fresh or thawed transfers. RESULTS: Most (72.9%) of the 1,096,539 cycles from 487,191 women occurred in states without an insurance mandate. Although utilization was higher across all racial and ethnic groups in mandated states, the increase in utilization was greatest for non-Hispanic Asian and non-Hispanic White women. For instance, in the most recent study year (2019), the utilization rates for non-Hispanic White women compared with non-Hispanic Black/African American women were 23.5 cycles per 10,000 women higher in nonmandated states and 56.2 cycles per 10,000 women higher in mandated states. There was no significant interaction between race and ethnicity and insurance mandate status on any of the clinical outcomes (all P-values for interaction terms > .05). CONCLUSION: Racial and ethnic disparities in utilization of in vitro fertilization and clinical outcomes for autologous cycles persist regardless of state health insurance mandates.

Choice of statistical model in observational studies of ART.

Analyzing data on ART presents unique and sometimes complicated challenges related to choosing the unit(s) of analysis and the statistical model. In this commentary, we provide examples of how these challenges arise and guidance for overcoming them. We discuss the implications of different ways to count treatment cycles, considering the perspectives of research questions, data management and analysis and patient counseling. We present the advantages and disadvantages of different statistical models, and finally, we discuss the definition and calculation of the cumulative incidence of live birth, which is a key outcome of research on ART.

The importance of mediation in reproductive health studies.

A mediator is a factor that occurs after the exposure of interest, precedes the outcome of interest (i.e. between the exposure and the outcome) and is associated with both the exposure and the outcome of interest (i.e. is on the pathway between exposure and outcome). Mediation analyses can be valuable in many reproductive health contexts, as mediation analysis can help researchers to better identify, quantify and understand the underlying pathways of the association they are studying. The purpose of this commentary is to introduce the concept of mediation and provide examples that solidify understanding of mediation for valid discovery and interpretation in the field of reproductive medicine.

Seasonal variation, temperature, day length, and IVF outcomes from fresh cycles.

PURPOSE: It is known that delivery rates from spontaneous conception vary according to season which may be due to cultural or environmental factors; however, conflicting data exist regarding whether outcomes from IVF are also seasonally dependent. The present study was designed to test the hypothesis that the season at oocyte retrieval is associated with livebirth after fresh transfer. METHODS: Dates of oocyte retrieval for all autologous cycles in our IVF program between January 2012 and December 2017 were categorized by season. Dates were linked to local temperature (min, max, average) and day length obtained from meteorological records. Average maximum temperature and day length were categorized into tertiles. Multivariable logistic regression, adjusted for age and quadratic age, were used to model odds (aOR) of implantation, clinical pregnancy, spontaneous abortion, and livebirth. RESULTS: Patient characteristics were similar across seasons. As expected, temperature and day length varied by season. When compared with cycles started during winter, there was no difference in the age-adjusted odds of livebirth for the other three seasons (spring: aOR: 0.97, 95% CI: 0.82-1.13; summer: aOR: 1.05, 0.90-1.23; fall: aOR: 0.98, 0.84-1.15). There was a positive linear trend between temperature and odds of implantation, and clinical pregnancy (p value, test for linear trend (implantation, p = 0.02; clinical pregnancy, p = 0.01)) but no association with livebirth for temperature or day length. CONCLUSIONS: We found that season at oocyte retrieval was not associated with livebirth, contrary to patterns seen in naturally conceived populations. However, our data did suggest modestly higher odds of clinical pregnancy for retrievals in June and July, and that higher temperature at time of retrieval was associated with higher odds of clinical pregnancy but not livebirth.

Contributions of Disease Severity, Psychosocial Factors, and Cognition to Behavioral Functioning in US Youth Perinatally Exposed to HIV.

Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth, we evaluated the contributions of home environment, psychosocial, and demographic factors and, among PHIV only, HIV disease severity and antiretroviral treatment (ART), to cognitive functioning (CF) and behavioral functioning (BF). A structural equation modeling (SEM) approach was utilized. Exploratory factor analysis was used to reduce predictor variables to major latent factors. SEMs were developed to measure associations between the latent factors and CF and BF outcomes. Participants included 231 PHIV and 151 PHEU youth (mean age = 10.9 years) enrolled in the PHACS adolescent master protocol. Youth and caregivers completed assessments of CF, BF, psychosocial factors and HIV health. Medical data were also collected. Clusters of predictors were identified, establishing four parsimonious SEMs: child-assessed and caregiver-assessed BF in PHIV and PHEU youth. Among both groups, higher caregiver-child stress predicted worse BF. Caregiver resources and two disease severity variables, late presenter and better past HIV health, were significant predictors of CF in PHIV youth. Higher youth CF was associated with better caregiver-reported BF in both groups. Caregiver resources predicted caregiver-reported BF in PHEU youth, which was mediated via youth CF. Among PHIV youth, better past HIV health and caregiver resources mediated the effects of CF on caregiver-assessed BF. Using SEMs, we found a deleterious impact of caregiver and child stress on BF in both groups and of HIV disease factors on the CF of PHIV youth, reinforcing the importance of early comprehensive intervention to reduce risks for impairment.

Effect of body mass index on in vitro fertilization outcomes in women with polycystic ovary syndrome.

OBJECTIVE: The objective of the investigation was to study the effect of body mass index (BMI) on in vitro fertilization (IVF) outcomes within a polycystic ovary syndrome (PCOS) population. STUDY DESIGN: This was a retrospective cohort study including 101 cycles from 79 women younger than 40 years old with a clinically documented diagnosis of PCOS by Rotterdam criteria undergoing IVF at a university-based infertility clinic from 2001 through 2010. All participants were stratified by BMI calculated from height and weight recorded within 3 months of cycle start: lean (18.7-24.9 kg/m(2), n = 51), overweight (25-29.9 kg/m(2), n = 19), and obese (≥30 kg/m(2), n = 31). Linear, logistic, and Poisson regressions were used as appropriate to estimate the effect of a range of BMIs on IVF outcomes while adjusting for potential confounders. RESULTS: Obese PCOS women had 69% lower odds of clinical pregnancy per cycle start (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.11-0.86; P = .02) and 77% lower odds of clinical pregnancy per embryo transfer (OR, 0.23; 95% CI, -0.08 to 0.68; P = .008) compared with lean PCOS women. Among obese PCOS women, the odds of live birth were 71% lower per cycle start (OR, 0.29; 95% CI, 0.10-0.84; P = .02) and 77% lower per embryo transfer (OR, 0.23; 95% CI, 0.07-0.71; P = .01) compared with lean PCOS women. There was a trend toward decreased ovarian hyperstimulation syndrome incidence with increasing BMI among women with PCOS: 19.6% in lean, 10.5% in overweight, and 3.2% in obese. CONCLUSION: PCOS is a broad syndrome, with our results demonstrating 2 distinct populations, lean and obese, which have different IVF outcomes including ovarian hyperstimulation syndrome risk profiles. This information is important for clinicians because it informs treatment decisions.

Perceptions among infertile couples of lifestyle behaviors and in vitro fertilization (IVF) success.

PURPOSE: To assess how patients perceive various lifestyle behaviors impact IVF success. METHODS: Cross-sectional study of heterosexual, English-speaking couples (n = 138) who completed web-based surveys during IVF treatment cycle. Perceived impact of lifestyle choices assessed by multivariable logistic regression and p-value tests for linear trend (Pt). RESULT(S): During the IVF cycle, most patients consider it helpful for women to exercise (76 %), avoid stress (87 %) and limit activity after embryo transfer (92 %). The majority of patients (62 %) consider rigorous exercise (4+ h/week) helpful and nearly one-third (32 %) perceive benefit to complete bed rest after transfer. Overall, couples with a sex-specific infertility diagnosis are more likely to consider partner's lifestyle choices impactful: male-factor couples are more likely to consider it helpful for men to limit cellular phone use (OR:2.73,CI:1.06-7.04) and diminished ovarian reserve couples are more likely to consider it helpful for women to limit exposure to plastics (OR:2.38,CI:1.03-5.51). Patients at higher levels of education (Pt < 0.01) and income (P(t) < 0.01) are less likely to consider lifestyle impactful. CONCLUSION(S): Patient perceptions of the impact of lifestyle factors on IVF success vary by sex, infertility diagnosis and socioeconomic factors. Despite counseling to the contrary, many patients perceive benefit to rigorous exercise during the IVF cycle and complete bedrest following transfer. Results provide insight into patient beliefs and highlight opportunities to improve patient education, alleviate patient anxieties and potentially improve IVF outcomes.

Serum progesterone concentration on day of embryo transfer in donor oocyte cycles.

PURPOSE: To evaluate the association between serum progesterone (P) levels on the day of embryo transfer (ET) and pregnancy rates in fresh donor IVF/ICSI cycles. METHODS: Fresh donor cycles with day 3 ET from 10/2007 to 8/2012 were included (n = 229). Most cycles (93 %) were programmed with a gonadotropin releasing hormone (GnRH) agonist; oral, vaginal or transdermal estradiol was used for endometrial priming, and intramuscular P was used for luteal support (50-100 mg/day). Recipient P levels were measured at ET, and P dose was increased by 50-100 % if <20 ng/mL per clinic practice. The main outcome measure was rate of live birth (> = 24 weeks gestational age). Generalized estimating equations were used to account for multiple cycles from the same recipient, adjusted a priori for recipient and donor age. RESULTS: Mean recipient serum P at ET was 25.5 ± 10.1 ng/mL. Recipients with P < 20 ng/mL at ET, despite P dose increases after ET, were less likely to achieve clinical pregnancy (RR = 0.75, 95 % CI = 0.60-0.94, p = 0.01) and live birth (RR = 0.77, 95 % CI = 0.60-0.98, p = 0.04), as compared to those with P ≥ 20 ng/mL. P dose increases were more often required in overweight and obese recipients. CONCLUSIONS: Serum P levels on the day of ET in fresh donor IVF/ICSI cycles were positively correlated with clinical pregnancy and live birth rates. An increase in P dose after ET was insufficient to rescue pregnancy rates. Overweight and obese recipients may require higher initial doses of P supplementation. Future research is needed to define optimal serum P at ET and the interventions to achieve this target.

Distinct cytokine profiles in late pregnancy in Ugandan people with HIV.

During pregnancy, multiple immune regulatory mechanisms establish an immune-tolerant environment for the allogeneic fetus, including cellular signals called cytokines that modify immune responses. However, the impact of maternal HIV infection on these responses is incompletely characterized. We analyzed paired maternal and umbilical cord plasma collected during labor from 147 people with HIV taking antiretroviral therapy and 142 HIV-uninfected comparators. Though cytokine concentrations were overall similar between groups, using Partial Least Squares Discriminant Analysis we identified distinct cytokine profiles in each group, driven by higher IL-5 and lower IL-8 and MIP-1α levels in pregnant people with HIV and higher RANTES and E-selectin in HIV-unexposed umbilical cord plasma (P-value < 0.01). Furthermore, maternal RANTES, SDF-α, gro α -KC, IL-6, and IP-10 levels differed significantly by HIV serostatus (P < 0.01). Although global maternal and umbilical cord cytokine profiles differed significantly (P < 0.01), umbilical cord plasma profiles were similar by maternal HIV serostatus. We demonstrate that HIV infection is associated with a distinct maternal plasma cytokine profile which is not transferred across the placenta, indicating a placental role in coordinating local inflammatory response. Furthermore, maternal cytokine profiles in people with HIV suggest an incomplete shift from Th2 to Th1 immune phenotype at the end of pregnancy.

Plasma adipokines and endometriosis risk: a prospective nested case-control investigation from the Nurses' Health Study II.

STUDY QUESTION: Do higher leptin levels and lower adiponectin levels predict subsequent development of endometriosis? SUMMARY ANSWER: Plasma leptin and adiponectin levels were not associated with laparoscopically confirmed endometriosis when collected prior to disease diagnosis. WHAT IS KNOWN ALREADY: Case-control studies have identified altered levels of the inflammatory adipokines leptin and adiponectin in women with endometriosis, but it remains unclear whether inflammation results in endometriosis or whether the presence of endometriosis creates an inflammatory state. STUDY DESIGN, SIZE, DURATION: Nested, matched, case-control study within the prospective Nurses' Health Study II (NHS II) cohort. Blood samples were collected between 1996 and 1999 from 29 611 female nurses within the cohort. Women who reported endometriosis before blood collection were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS: Plasma leptin and adiponectin levels were assayed by ELISA. Three hundred and fifty cases of laparoscopically confirmed endometriosis were matched 1:2 with 694 controls of comparable race, age, infertility history, menopausal status and time of blood draw. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models adjusting for matching factors and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for BMI, there were no statistically significant associations between endometriosis and leptin [RR = 1.2; 95% CI = 0.7-2.0; P-value, test for linear trend (P(trend)) = 0.72], adiponectin (RR = 0.8; 95% CI = 0.5-1.2; P(trend) = 0.48) or the leptin to adiponectin ratio (RR = 0.8; 95% CI = 0.4-1.4; P(trend) = 0.14) when comparing the upper with the lower quartile. Results were unaltered when analyses were stratified by BMI or restricted to cases diagnosed ≥ 4 years after blood draw. To evaluate statistical significance and limit the role of chance to the gold standard of 5%, we present 95% CIs about the RRs, and for P-values calculated for linear tests of trend and tests of heterogeneity, we have set the α-level to be 0.05 (i.e. <0.05 is considered to be statistically significant). LIMITATIONS AND REASONS FOR CAUTION: A limitation of this study is the inability to differentiate the time of endometriosis 'diagnosis' from the time of disease 'onset' due to the impossibility in identifying a precise time point at which the disease process was first initiated at a molecular or cellular level. Additional limitations include lack of information regarding stage of endometriosis and the possibility of asymptomatic disease in the control population. WIDER IMPLICATIONS OF THE FINDINGS: The mean age at diagnosis of endometriosis in the study population is 41.7, ≈ 10 years older than the mean age of diagnosis in the general population. While this may limit the generalizability of the results, there is no reason to suspect that the association between adipokines and endometriosis risk should differ at a younger age of diagnosis in an adult population.

Body size and endometriosis: results from 20 years of follow-up within the Nurses' Health Study II prospective cohort.

STUDY QUESTION: Is there a relationship between body mass index (BMI), body shape and endometriosis? SUMMARY ANSWER: Endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. WHAT IS KNOWN ALREADY: The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, METHODS AND SETTING: Cases were restricted to laparoscopically confirmed endometriosis. Weight at age 18 and height were reported at baseline, and current weight was updated every 2 years. Waist and hip measurements were first taken in 1993 and updated in 2005. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models with time-varying covariates. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5504 incident cases of endometriosis were reported during 1 299 349 woman-years (incidence rate = 385 per 100 000 woman-years). BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P-value, test for linear trend <0.0001). Both associations were stronger among infertile women. Obese infertile women with current BMIs of 35-39.9 kg/m(2) and ≥ 40 kg/m(2) had a 55% (95% CI 0.30-0.67) and a 62% (95% CI 0.23-0.62) lower risk of endometriosis, respectively, compared with the low-normal BMI referent (18.5-22.4 kg/m(2)). Rates of endometriosis were nearly 3-fold higher in women with waist-to-hip ratios <0.60 (RR = 2.78, 95% CI 1.38-5.60) compared with those with waist-to-hip ratios between 0.70 and 0.79, although the sample size for this category was very small. LIMITATIONS AND REASONS FOR CAUTION: Although women with undiagnosed endometriosis certainly remain in the comparison population even in this prospective cohort study, the community prevalence of endometriosis in an asymptomatic population is very low. Moreover, the characteristics of this small proportion of undiagnosed cases are diluted among the >90 000 women accurately defined as being endometriosis-free and are, therefore, unlikely to impact on effect estimation. Although geographically diverse, the NHS II cohort is overwhelmingly Caucasian, which may limit generalizability to more ethnically diverse populations. WIDER IMPLICATIONS OF THE STUDY: The results of this study suggest that endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution.

Bisphenol-A and human oocyte maturation in vitro.

STUDY QUESTION: Does exposure to bisphenol-A (BPA) affect the maturation of human oocytes in vitro? SUMMARY ANSWER: There was a dose-response association of BPA exposure with altered human oocyte maturation in vitro. WHAT IS KNOWN ALREADY: There is widespread exposure of the general population to BPA. BPA has been detected in the human follicular fluid. Animal studies have shown that BPA exposure is associated with maturation arrest and spindle abnormalities in maturing oocytes. STUDY DESIGN, SIZE, DURATION: A randomized trial, using 352 clinically discarded oocytes from 121 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population was drawn from patients undergoing IVF/ICSI cycles in our program at Brigham and Women's Hospital from March 2011 to April 2012. Oocytes from only one cycle for each patient were included in the study. Cycles with at least two germinal vesicle stage oocytes were included with random allocation of one oocyte to culture for 30 h without BPA and remaining sibling oocytes to medium-containing BPA (20, 200 ng/ml or 20 µg/ml). Oocytes were fixed and labeled for tubulin, actin and chromatin and examined with immunofluorescence and confocal microscopy. Oocytes were assessed for meiotic stage (n = 292), and those at metaphase II (MII, n = 175) were further classified according to their spindle configurations and patterns of chromosome alignment. McNemar's test was used to compare dichotomized maturation status. Generalized estimating equations were used to account for the correlation between oocytes from the same woman and for the spindle analysis. MAIN RESULTS AND THE ROLE OF CHANCE: As the BPA dose increased, there was a decrease in the percentage of oocytes that progressed to MII (P = 0.002) and increases in the percentage of oocytes that were degenerated (P = 0.01) or that had undergone spontaneous activation (P = 0.007). Among MII oocytes, as the BPA dose increased, there was a significant trend (by test for trend) for a decreased incidence of bipolar spindles (P < 0.0001) and aligned chromosomes (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: Although we used sibling oocytes to overcome potential confounders, such as infertility diagnosis and maternal age, additional studies with a larger number of oocytes are required to confirm the present results. Having access only to clinically discarded oocytes, we were limited to evaluating only those oocytes that failed to mature in vivo despite having been exposed to gonadotrophin stimulation and the ovulatory trigger of HCG. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first study investigating the effect of BPA on oocyte meiotic maturation, spindle morphology and chromosome alignment in human oocytes. Together with prior animal studies, the data support the negative influences of BPA on cell cycle progression, spindle architecture and chromosome organization during oocyte maturation. Furthermore, the increased rates of abnormal maturation in oocytes exposed to BPA may be relevant to our understanding of the decrease in fertility reported in the last decades. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the NIEHS Center Grant Pilot Project (P30-ES000002). R.M. was sponsored by a fellowship from the Environmental Health Fund, Israel and by the Frederick L. Hisaw Endowment, Harvard School of Public Health. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: n/a.

Prenatal food allergen exposures and odds of childhood peanut, tree nut, or sesame seed sensitization.

BACKGROUND: The prevalence of peanut (PN) and tree nut (TN) allergy in children has tripled in the past decade. Prenatal exposures, including maternal diet and medications, may account for some of this increase. In the United States, progesterone for luteal support in assisted reproduction is commonly formulated in PN or sesame seed (SS) oil. OBJECTIVE: To determine whether prenatal exposure to PN or SS oil as progesterone in oil increases the child's odds of PN, TN, or SS allergy. METHODS: Parents of 1,272 children evaluated by allergists from May 2005 through October 2009 completed questionnaires on conception, prenatal exposures, dietary history, and allergic history, with review of the child's medical record and skin prick and specific IgE test results. Odds ratios and 95% confidence intervals were calculated using multivariable adjusted logistic regression models. RESULTS: Children of mothers with a history of infertility, in vitro fertilization, or use of progesterone in oil did not have increased odds of PN, TN, and/or SS sensitization. Maternal consumption of TNs during first 2 trimesters was associated with 60% higher odds of having a PN/TN/SS-sensitized child (95% confidence interval 1.01-2.51), with similarly increased odds with maternal SS ingestion. Odds of PN/TN/SS sensitization were doubled in children with asthma or environmental allergies. CONCLUSION: Neither maternal infertility nor exposure to PN or SS oils through progesterone support during assisted reproduction treatment was associated with increased odds of PN/TN/SS sensitization in the child. However, maternal ingestion of TNs and SS during pregnancy was associated with increased odds of PN/TN/SS sensitization in the child.

Predictors of twin live birth following cryopreserved double embryo transfer on day 3.

PURPOSE: To determine embryo and cycle-specific parameters associated with twin live birth in day 3 cryopreserved double embryo transfer (DET) cycles, and to propose a new prediction model for external validation. METHODS: All cycles with autologous or donor cryopreserved DET of day 3 embryos from 2002 to 2011 at a single academic institution with a singleton or twin live birth were included (n = 207). Patient characteristics, post-thaw embryo morphology and freeze-thaw parameters were compared between patients with a single and twin live birth. RESULTS: Demographic characteristics were similar, except that patients delivering twins were younger at age of cryopreserved embryo transfer (CET), fewer were parous and more were anovulatory. Duration of embryo storage, time in culture post-thaw, endometrial thickness and use of assisted hatching were comparable. Six predictors of twin delivery were identified: patient age <35 year at CET, intact survival of the lead embryo, resumption of mitosis, 7-8 viable cells in the non-lead embryo, transfer of a lead embryo with ≥7 cells and a sum of ≥14 viable cells in the two transferred embryos. Regression modeling predicted a step-wise increase in the probability of twins with addition of each predictor; with all six present, the risk of twins was predicted to be 53 % and with none present, the risk decreased to 6 %. CONCLUSIONS: The six identified variables associated with twin live birth following day 3 cryopreserved DET have been applied to derive a prediction model for estimating the risk of twin delivery. External validation of the model is required prior to clinical application.

Development of a Model to Estimate the Optimal Number of Oocytes to Attempt to Fertilize During Assisted Reproductive Technology Treatment.

Importance: Surplus cryopreserved embryos pose a challenge for in vitro fertilization patients and clinics; with Roe v. Wade overturned, some states may deem the discarding of surplus embryos illegal, radically changing in vitro fertilization practice. An evidence-based tool would help limit surplus embryo creation. Objective: To develop a prediction tool for determining how many oocytes should be exposed to sperm to create embryos to conserve the chance of live birth while minimizing surplus embryos. Design, Setting, and Participants: This diagnostic study used data from member clinics of the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System between 2014 to 2019. A total of 410 719 oocyte retrievals and 460 577 embryo transfer cycles from 311 237 patients aged 18 to 45 years old who initiated their first oocyte stimulation cycle between January 1, 2014, and December 31, 2019, were included. Data were analyzed from February to June 2022. Exposures: Female patient age, anti-mullerian hormone level, diminished ovarian reserve diagnosis, number of oocytes retrieved, and the state where the clinic is located were included in the final models. Main Outcomes and Measures: The algorithm was based on 3 models with outcomes: (1) day of transfer; (2) proportion of retrieved oocytes that become usable blastocysts; and (3) number of blastocysts needed for transfer for 1 live birth to occur. Results: The median (IQR) age at stimulation cycle start was 35 (29-32) years and the median (IQR) number of oocytes retrieved was 10 (6-17). The likelihood of recommending that all oocytes be exposed to sperm increased with age; less than 20.0% of retrievals among patients younger than 32 years and more than 99.0% of retrievals among patients older than 42 years received recommendations that all oocytes be exposed to sperm. Among cycles recommended to expose fewer than all oocytes, the median (IQR) numbers recommended for 1 live birth were 7 oocytes (7-8) for patients aged less than 32 years, 8 (7-8) for patients aged 32 to 34 years, and 9 (9-11) for patients aged 35 to 37 years. Conclusions and Relevance: In this diagnostic study of in vitro fertilization cycles, a prediction tool was developed to aid clinicians in determining the optimal number of oocytes to expose to sperm, reducing the number of unused embryos created and immediately addressing current patient and clinician concerns.

The association between severe obesity and characteristics of failed fertilized oocytes.

STUDY QUESTION: Is the cytoskeletal and chromosomal organization of failed fertilized oocytes from severely obese patients (BMI ≥ 35 kg/m²) altered compared with that in patients with normal BMI (BMI 18.5-24.9 kg/m²)? SUMMARY ANSWER: Compared with normal BMI patients, severe obesity was associated with a greater prevalence of spindle anomalies and non-aligned chromosomes in failed fertilized oocytes. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Obesity is associated with poor reproductive outcomes, but little is known regarding the underlying mechanisms. To address potential mechanisms, our study compared the cytoskeletal and chromosome organization in failed fertilized oocytes from severely obese and normal BMI patients. DESIGN: The study population was drawn from IVF patients treated in a hospital-based infertility clinic between February 2010 and July 2011. The prevalence of meiotic spindle and chromosome alignment anomalies in failed fertilized oocytes from patients with severe obesity (i.e. Class II and III; BMI 35.0-50.1 kg/m²) was compared with those from patients with normal BMI (BMI 18.5-24.9 kg/m²). Oocytes were fixed and then labeled for tubulin, actin and chromatin. Spindle number and integrity, as well as chromosome alignment, were assessed using immunofluorescence microscopy and, in some cases, confocal microscopy. Generalized estimating equations were applied, which account for the correlation among oocytes from the same patient to estimate odds ratio (OR), 95% confidence intervals (CIs) and two-sided Wald P-values. Models were adjusted for continuous age at cycle start, cycle type (IVF or ICSI) and polycystic ovarian syndrome (PCOS) a priori. PARTICIPANTS AND SETTING: University-affiliated infertility clinic. A total of 276 oocytes that failed to fertilize from 137 patients were evaluated: 105 oocytes from severely obese women (n = 47) and 171 oocytes from normal BMI patients (n = 90). MAIN RESULTS AND THE ROLE OF CHANCE: (i) Significantly more oocytes from the severely obese group exhibited two spindles compared with those from the normal BMI group (58.9 versus 35.1%; OR = 2.68, CI = 1.39-5.15, P-value = 0.003). (ii) Among oocytes with a single spindle, those from severely obese patients showed a significantly higher prevalence of disarranged spindles with non-aligned chromosomes compared with those from normal BMI patients (28.6 versus 8.6%; OR = 4.58, CI = 1.05-19.86, P-value = 0.04). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Inclusion of only failed fertilized oocytes, small sample size, unknown factors such as non-PCOS comorbidity. GENERALIZABILITY TO OTHER POPULATIONS: For this study, by design, it is unclear whether the findings are generalizable to successfully fertilized oocytes, and whether this oocyte-level influence of obesity is generalizable to infertile women who do not undergo stimulation or, more broadly, to spontaneous conceptions in fertile women. STUDY FUNDING/COMPETING INTEREST(S): none. TRIAL REGISTRATION NUMBER: n/a.

Day 3 embryo shape as a morphologic selection parameter in in vitro fertilization.

PURPOSE: To investigate whether embryo shape is a useful morphologic predictor of developmental competence in IVF cycles. METHODS: Two hundred eighteen day 3 single embryo transfer (SET) cycles and 225 day 3 double embryo transfer (DET) cycles in which only 8-cell non-fragmented embryos with symmetric blastomeres were transferred and in which the developmental fate of each embryo was known were analyzed for IVF outcomes with respect to embryo shape. Embryo shape was quantitatively calculated after digitizing embryo images using MATLAB, where a score of 1.0 represented a perfectly circular embryo. RESULTS: The SET data did not reveal a significant impact of embryo shape on embryo developmental fate. The DET data revealed a trend toward the best outcomes in cycles where both embryos exhibited "roundness" scores in the highest tertiles (T3) for embryo shape. However only one subgroup (T2/T1-one embryo in the middle shape tertile (T2) and one in the lowest shape tertile (T1)) was associated with significantly lower odds of live-birth as compared to the referent group (T3/T3). When SET and DET data were combined, embryo shape was not found to be a predictor of IVF outcome. CONCLUSIONS: Based on this retrospective analysis, the weak association of day 3 embryo shape with implantation potential suggests that this morphological characteristic is unlikely to be a useful additional marker for embryo selection after cell number, fragmentation, and blastomere symmetry. Further studies are planned to assess applicability of these conclusions to embryos of varying stages and grades.