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.

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.

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.

The association between season, day length, and temperature on clinical outcomes after cryopreserved embryo transfer.

OBJECTIVE: To investigate whether there is an association between season, temperature, and day length at oocyte retrieval and/or embryo transfer (ET) and clinical outcomes in frozen ET cycles. DESIGN: Retrospective cohort study. SETTING: Large academically affiliated research hospital. PATIENT(S): A total of 3,004 frozen ET cycles from 1,937 different women with oocyte retrieval and transfer between 2012 and 2017. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, spontaneous abortion, and live birth. RESULT(S): Frozen ETs with oocyte retrieval dates in summer had 45% greater odds of clinical pregnancy (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.15-1.82) and 42% greater odds of live birth (OR, 1.42; 95% CI, 1.13-1.79) compared with those with oocyte retrieval dates in winter. A 41% greater odds of clinical pregnancy (OR, 1.41; 95% CI, 1.16-1.71) and 34% greater odds of live birth (OR, 1.34; 95% CI, 1.10-1.62) were observed among transfers with an average temperature at oocyte retrieval in the highest tertile (17.2-33.3 °C) compared with those in the lowest tertile (-17.2-6.7 °C). There were no consistent associations between clinical outcomes and day length at oocyte retrieval or between season, day length, or temperature at transfer of thawed embryos. CONCLUSION(S): Warmer temperatures at oocyte retrieval are associated with higher odds of clinical pregnancy and live birth among frozen ET cycles. The consistent associations seen with oocyte retrieval dates and the lack of associations observed with ET dates suggest that any seasonality effects on in vitro fertilization success are related to ovarian function and not uterine receptivity.

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.

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.

Pharmacokinetics of human chorionic gonadotropin injection in obese and normal-weight women.

CONTEXT: Obese women have poorer in vitro fertilization outcomes, but underlying mechanisms remain unclear. OBJECTIVE: The objectives of the study were to compare the pharmacokinetics of human chorionic gonadotropin (hCG) and ovarian steroid hormone production, after subcutaneous (s.c.) and intramuscular (i.m.) injection of hCG in obese and normal-weight women. DESIGN AND SETTING: This was a randomized, experimental study. PATIENTS OR OTHER PARTICIPANTS: Twenty-two women aged 18-42 years with body mass index of 18.5-24.9 (normal) or 30-40 kg/m(2) (obese). INTERVENTIONS: Participants received im urinary hCG or s.c. recombinant hCG and returned for a second injection type after a 4-week washout. Intramuscular injections were performed under ultrasound guidance. Blood was taken 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 36 hours after injection. MAIN OUTCOME MEASURES: hCG was measured at each time point; estradiol, progesterone, 17-hydroxyprogesterone (17-OHP), testosterone (T), dehydroepiandrosterone, and SHBG were measured at 0 and 36 hours. RESULTS: Twenty-two women completed the study. In both normal-weight and obese women, peak serum concentration (Cmax), area under the curve (AUC), and average hCG concentration were higher after i.m. injection as compared with s.c. injection (all P < .003). Obese women had markedly lower Cmax, AUC, and average hCG concentration after s.c. injection as compared with normal-weight women (P = .02, P = .009, and P = .008, respectively). After i.m. injection, Cmax, AUC, and average concentration were similar for normal-weight and obese women (P = .31, P = .25, and P = .18, respectively). Thirty-six percent of obese women had muscular layers beyond the reach of a standard 1.5 inch needle. hCG caused a significant rise in 17-OHP in both obese and normal-weight women and an increase in T in obese but not normal-weight women (all P < .04). CONCLUSIONS: Subcutaneous injection yields lower hCG levels in obese women. Standard-length needles are insufficient to administer i.m. injections in many obese women.

Efficacy of intrauterine inseminations as a training modality for performing embryo transfer in reproductive endocrinology and infertility fellowship programs.

OBJECTIVE: To assess pregnancy rates before and after a training intervention in which reproductive endocrinology and infertility fellows were required to perform 100 IUIs before performing ETs. DESIGN: Retrospective cohort study. SETTING: Large, academic training program. PATIENT(S): Not applicable. INTERVENTION(S): Comparing pregnancy rates between two time periods: July 1998-June 2001 (before IUI intervention) and July 2001-June 2010 (after IUI intervention). MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR) for the first 100 ETs performed by fellows before and after the IUI training; median attending physician PR during each time period served as the referent. Multivariate generalized estimating equations were used to calculate odds of pregnancy per ET for fellows as compared with attending physicians. RESULT(S): Multivariate analyses revealed no significant difference in PR for the first 100 ETs performed by fellows as compared with attending physicians, before or after the IUI training requirement (odds ratio 0.99, 95% confidence interval 0.82-1.20 and odds ratio 0.91, 95% confidence interval 0.81-1.30, respectively). The median attending physician PR in the preintervention group was exceeded by fellows after the first 70 ETs; fellows in the postintervention group exceeded the median attending physician PR after 100 ETs. The PR in both groups improved as fellows progressed from the first 20 to 100 ETs. CONCLUSION(S): The PR for the first 100 ETs performed by fellows was unchanged after implementing an IUI training requirement. The substantial variation noted among individual fellows decreased as more ETs were completed.