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.

Repeat Pregnancies Among US Women Living With HIV in the SMARTT Study: Temporal Changes in HIV Disease Status and Predictors of Preterm Birth.

BACKGROUND: Birth rates among women living with HIV (WLHIV) have increased recently, with many experiencing multiple pregnancies. Yet, viral suppression is often not sustained between pregnancies. In addition, protease inhibitors (PIs) have been associated with preterm birth, but associations between integrase strand transfer inhibitors (INSTIs) and preterm birth are less well characterized. METHODS: We studied WLHIV with ≥2 live-born infants enrolled into the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring for Antiretroviral Treatment Toxicities (SMARTT) study between 2007 and 2018, comparing CD4 counts and viral loads (VLs) between 2 consecutive SMARTT pregnancies. We evaluated associations of covariates with CD4 and viral suppression and the association of PI/INSTI use during pregnancy with odds of preterm birth. RESULTS: There were 736 women who had ≥2 live-born children enrolled in SMARTT (1695 pregnancies). Median CD4 counts remained stable over repeat pregnancies. Although >80% of women achieved VL suppression during pregnancy, more than half had a detectable VL early in their subsequent pregnancy. In adjusted models including all singleton pregnancies, an increased odds of preterm birth was observed for women with first trimester PI initiation (adjusted odds ratio: 1.97; 95% confidence interval: 1.27 to 3.07) compared with those not receiving PIs during pregnancy and for first trimester INSTI initiation (adjusted odds ratio: 2.39; 95% confidence interval: 1.04 to 5.46) compared with those never using INSTIs during pregnancy. CONCLUSIONS: Most WLHIV achieved VL suppression by late pregnancy but many were viremic early in subsequent pregnancies. First trimester initiation of PIs or INSTIs was associated with a higher risk of preterm birth.

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.

Confounding and effect measure modification in reproductive medicine research.

The majority of research within reproductive and gynecologic health, or investigating ART, is observational in design. One of the most critical challenges for observational studies is confounding, while one of the most important for discovery and inference is effect modification. In this commentary, we explain what confounding and effect modification are and why they matter. We present examples illustrating how failing to adjust for a confounder leads to invalid conclusions, as well as examples where adjusting for a factor that is not a confounder also leads to invalid or imprecise conclusions. Careful consideration of which factors may act as confounders or modifiers of the association of interest is critical to conducting sound research, particularly with complex observational studies in reproductive medicine.

Association of maternal antiretroviral use with microcephaly in children who are HIV-exposed but uninfected (SMARTT): a prospective cohort study.

BACKGROUND: Perinatal HIV transmission has substantially decreased with combination antiretroviral regimens, but complications in children who are HIV-exposed but uninfected, such as microcephaly, warrant ongoing surveillance. We aimed to evaluate whether individual in utero antiretroviral exposures were associated with increased risk of microcephaly based on long-term follow-up of infants and children who are HIV-exposed but uninfected. METHODS: We evaluated children aged younger than 18 years who were HIV-exposed but uninfected with at least one head circumference measurement while enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the USA, including Puerto Rico. This prospective cohort study was done by the Pediatric HIV/AIDS Cohort Study network. Microcephaly was defined as having a head circumference Z score <-2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6-36 months old and according to Nellhaus standards (head circumference <2nd percentile) after 36 months (SMARTT criteria); an alternate definition for microcephaly was based on applying Nellhaus standards across all ages (Nellhaus criteria). Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero antiretroviral exposure and microcephaly status, adjusted for potential confounders. Neurodevelopmental functioning was compared in children who are HIV-exposed but uninfected with or without microcephaly. FINDINGS: Between March 21, 2007, and Aug 1, 2017, 3055 participants enrolled in SMARTT had at least one head circumference measurement. The cumulative incidence of microcephaly over a median of 5·1 years of follow-up (IQR 3·0-7·2) was 159 (5·2%, 95% CI 4·4-6·1) by Nellhaus criteria and 70 (2·3%, 1·8-2·9) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4·7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (adjusted RR 2·02, 95% CI 1·16-3·51) and SMARTT criteria (2·56, 1·22-5·37). These associations were more pronounced in children exposed to combination regimens of efavirenz that included zidovudine plus lamivudine than those including tenofovir plus emtricitabine. Protective associations were observed for darunavir exposure (adjusted RR 0·50, 95% CI 0·24-1·00). Children who are HIV-exposed but uninfected with microcephaly had lower mean scores on neurodevelopmental assessments at age 1 and 5 years and a higher prevalence of neurodevelopmental impairment than those without microcephaly. INTERPRETATION: These findings support consideration of alternatives to efavirenz as part of first-line antiretroviral therapy for pregnant women. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

A hierarchical modeling approach for assessing the safety of exposure to complex antiretroviral drug regimens during pregnancy.

Combination antiretroviral regimens have achieved tremendous success in reducing perinatal HIV transmission, and have become standard of care in pregnant women with HIV. However, the large variety of combination antiretroviral regimens utilized in practice raises the question of whether some of these highly potent drugs pose other risks to the pregnancy or infant. While HIV-infected pregnant women are almost always exposed to multiple antiretrovirals concurrently, standard safety screening strategies typically consider each individual antiretroviral separately, which fails to account for potential confounding due to simultaneous exposure to other antiretrovirals. In this paper, we evaluate a hierarchical modeling approach which groups antiretrovirals by drug class to screen for the safety of antiretrovirals taken during pregnancy, while still providing individual antiretroviral drug effect estimates. In simulation studies, we observed that the hierarchical approach may be advantageous as compared to considering each antiretroviral drug separately or simultaneously evaluating all antiretrovirals in a fixed effect model, particularly when there is prior evidence suggesting drugs from the same class behave similarly on the outcome. The characteristics of the hierarchical approach are illustrated in an application evaluating risk of preterm birth using a study including over 2000 pregnancies representing over 100 antiretroviral combinations, each involving up to three drug classes.

Cardiac status of perinatally HIV-infected children: assessing combination antiretroviral regimens in observational studies.

OBJECTIVE: To evaluate potential adverse associations of individual antiretroviral medications used in combination antiretroviral therapy regimens on cardiac structure and function in youth with perinatally-acquired HIV infection (PHIV). DESIGN: PHIV youth (N = 325) enrolled in a prospective multisite cohort study had a single echocardiogram at age 7-16 years to evaluate cardiac function and structure. METHODS: We applied several statistical approaches to evaluate associations between use of 18 individual antiretroviral medications with Z-scores for 11 measures of left ventricular function and structure. These included simultaneously evaluating all antiretroviral medications in adjusted linear regression models controlling for the false discovery rate (FDR), applying hierarchical models to estimate individual antiretroviral medication effects as deviations from drug class means, and evaluating latent measures of cardiac function and structure underlying multiple echocardiographic parameters. RESULTS: Youth taking combination regimens with a protease inhibitor (69%) had significantly better cardiac function than those on other regimens. After FDR control and adjustment for other antiretroviral medications, no individual antiretroviral medication was significantly associated with any measure of left ventricular function, but zidovudine was associated with higher adjusted mean Z-scores for one measure of left ventricular structure (end-systolic wall stress). Factor analysis identified three latent factors: heart function, heart size, and heart wall stress. Lopinavir was associated with better heart function scores, whereas zidovudine was associated with higher wall stress scores. Zidovudine and nevirapine were associated with higher heart size factor scores. CONCLUSIONS: Despite cardioprotective effects of combination regimens in PHIV youth, individual antiretroviral medications were associated with altered cardiac structure, which could progress to symptomatic cardiomyopathy in adulthood.

Estimating the Relative Excess Risk Due to Interaction in Clustered-Data Settings.

The risk difference scale is often of primary interest when evaluating public health impacts of interventions on binary outcomes. However, few investigators report findings in terms of additive interaction, probably because the models typically used for binary outcomes implicitly measure interaction on the multiplicative scale. One measure with which to assess additive interaction from multiplicative models is the relative excess risk due to interaction (RERI). The RERI measure has been applied in many contexts, but one limitation of previous approaches is that clustering in data has rarely been considered. We evaluated the RERI metric for the setting of clustered data using both population-averaged and cluster-conditional models. In simulation studies, we found that estimation and inference for the RERI using population-averaged models was straightforward. However, frequentist implementations of cluster-conditional models including random intercepts often failed to converge or produced degenerate variance estimates. We developed a Bayesian implementation of log binomial random-intercept models, which represents an attractive alternative for estimating the RERI in cluster-conditional models. We applied the methods to an observational study of adverse birth outcomes in mothers with human immunodeficiency virus, in which mothers were clustered within clinical research sites.

Gestational carrier in assisted reproductive technology.

OBJECTIVE: To compare clinical outcomes of in vitro fertilization (IVF) cycles with the use of gestational carriers (GCs) with non-GC IVF cycles. DESIGN: Retrospective cohort study of assisted reproductive technology (ART) cycles performed with (24,269) and without (1,313,452) the use of a GC. SETTING: ART centers. PATIENT(S): Infertile patients seeking IVF with or without use of a GC. INTERVENTIONS(S): Autologous and donor oocyte cycles, fresh and cryopreserved embryo transfer cycles. MAIN OUTCOME MEASURE(S): Live birth rate (LBR), twin and high-order multiple birth rates. RESULT(S): Approximately 2% of embryo transfers used a GC. Per embryo transfer, GCs had greater pregnancy rate and LBR across all IVF types compared with non-GC cycles in crude models and models adjusted a priori for potential confounders. For women with uterine-factor infertility, embryo transfer with the use of a GC resulted in a higher odds of live birth for autologous fresh embryos and for cryopreserved embryos compared with patients with non-uterine-factor infertility diagnoses. CONCLUSION(S): GC benefits LBRs for some patients seeking ART. The highest LBRs occurred when the indication for GC was uterine-factor infertility.

Evaluating effects of prenatal exposure to phthalate mixtures on birth weight: A comparison of three statistical approaches.

OBJECTIVES: We applied three statistical approaches for evaluating associations between prenatal urinary concentrations of a mixture of phthalate metabolites and birth weight. METHODS: We included 300 women who provided 732 urine samples during pregnancy and delivered a singleton infant. We measured urinary concentrations of metabolites of di(2-ethylhexyl)-phthalate, di-isobutyl-, di-n-butyl-, butylbenzyl-, and diethyl phthalates. We applied 1) linear regressions; 2) classification methods [principal component analysis (PCA) and structural equation models (SEM)]; and 3) Bayesian kernel machine regression (BKMR), to evaluate associations between phthalate metabolite mixtures and birth weight adjusting for potential confounders. Data were presented as mean differences (95% CI) in birth weight (grams) as each phthalate increased from the 10th to the 90th percentile. RESULTS: When analyzing individual phthalate metabolites using linear regressions, each metabolite demonstrated a modest inverse association with birth weight [from -93 (-206, 21) to -49 (-164, 65)]. When simultaneously including all metabolites in a multivariable model, inflation of the estimates and standard errors were noted. PCA identified two principal components, both inversely associated with birth weight [-23 (-68, 22), -27 (-71, 17), respectively]. These inverse associations were confirmed when applying SEM. BKMR further identified that monoethyl and mono(2-ethylhexyl) phthalate and phthalate concentrations were linearly related to lower birth weight [-51(-164, 63) and -122 (-311, 67), respectively], and suggested no evidence of interaction between metabolites. CONCLUSIONS: While none of the methods produced significant results, we demonstrated the potential issues arising using linear regression models in the context of correlated exposures. Among the other selected approaches, classification techniques identified common sources of exposures with implications for interventions, while BKMR further identified specific contributions of individual metabolites.

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.

Factors Associated with the Success of In Vitro Fertilization in Women with Inflammatory Bowel Disease.

BACKGROUND: It is unknown whether certain factors are associated with the success of in vitro fertilization (IVF) in women with inflammatory bowel disease (IBD). AIM: This study assessed whether certain characteristics are associated with greater success of live birth following IVF. METHODS: In a cohort study of 8684 women with IBD seen at two tertiary care centers, we identified 121 women with IBD who underwent IVF. We assessed the effect of numerous factors on likelihood of achieving live birth after IVF. RESULTS: Seventy-one patients with ulcerative colitis (UC) and 49 patients with Crohn's disease (CD) were analyzed. Patients with UC who achieved a live birth were younger (p = 0.03), had a shorter duration of disease (p = 0.01), and were more likely to be in remission (p = 0.03) versus those who did not achieve live birth. Patients with CD who achieved live birth were younger (p < 0.001), had lower body mass index (BMI) (p = 0.02), and had lower cycle day 3 follicle-stimulating hormone levels (p = 0.02). There was no difference in likelihood of achieving live birth among patients in remission and those with mild or unknown disease status (p = 0.69), though most CD patients (79.5 %) were in remission. Prior surgery was not associated with live birth in patients with UC (p = 0.31) or CD (p = 0.62). CONCLUSIONS: As in the general infertility population, younger patients and those with lower BMI were more likely to achieve live birth. History of surgery was not associated with live birth among IBD patients. This is important information for practitioners counseling IBD patients.