Methodological approaches to analyzing IVF data with multiple cycles.

Investigating the association between school substance programs and student substance use: accounting for informative cluster size.

Phthalates and other endocrine-disrupting chemicals: the 21st century's plague for reproductive health

Study question Does the incidence of DUC1 in IVF/ICSI cycles vary with the maternal profile and insemination method? Summary answer The incidence of DUC1 cycles is higher in patients with a more favourable prognosis. DUC1 embryos are more frequent in ICSI than in IVF cycles. What is known already The emergence of Time-Lapse Microscopy (TLM) has enabled a dynamic and thorough evaluation of in vitro embryo development, unveiling the occurrence of morphological phenomena unobserved with static observation, such as direct unequal cleavage (DUC), which is associated with a drastically reduced competence to implant. The incidence of DUC-1 (DUC immediately after syngamy) has been reported to vary from 8.3% to 26%, but the reasons underlying its occurrence and variability are unknown. There is evidence that the maternal profile and insemination method can impact embryo developmental competence, but whether they impact the incidence of DUC is also unknown. Study design, size, duration The study includes 2920 first IVF/ICSI cycles (2018 to 2022) providing 12492 embryos. Cycles presenting male infertility were excluded from the analysis. The percentages of DUC1 embryos in relation to total embryos and of cycles providing at least one DUC1 embryo in relation to total cycles were compared between AMA (advanced maternal age; ≥35) and pre-AMA (<35) cycles. Patient/cycle characteristics were compared between cycles with and without DUC1 occurrence in AMA and pre-AMA cycles, separately. Participants/materials, setting, methods Ovarian stimulation was induced with rFSH or with a combination of FSH and LH using classic antagonist or short agonist protocols. Oocytes were inseminated with either IVF or ICSI standard methodology. Embryo culture was performed in an integrated embryo culture Time-lapse System (EmbryoScope; Vitrolife). Differences between percentages were assessed by the Fisher’s exact test, while differences between continuous variables were assessed with the Wilcoxon sum rank test. Main results and the role of chance The percentage of DUC1 embryos in relation to total embryos did not vary between pre-AMA (5.4%) and AMA (5.2%; p > 0.05) cycles. Alternatively, the incidence of cycles providing at least one DUC1 embryo was higher in pre-AMA (21.7%) as compared with AMA patients (16.0%; p < 0.0001). In both pre-AMA and AMA cycles, DUC1 occurrence was associated with higher oocyte yield (13.5±7.7 vs. 10.6±6.7 and 11.0±6.3 vs. 7.5±5.5, respectively; p < 0.0001), higher AMH serum levels (4.4±4.7 vs. 3.4±3.2 and 3.0±3.6 vs. 2.1±2.1ng/mL, respectively; p < 0.004) and lower basal FSH serum levels (7.0±2.1 vs. 7.6±2.9 and 7.8±3.3 vs. 8.5±3.4mU/mL, respectively; p < 0.0001). Overall, the percentage of DUC1 embryos was higher in ICSI (5.6%) as compared to IVF (4.4%, p < 0.01) cycles. However, when the data was stratified by maternal age, DUC1 incidence was significantly higher in ICSI vs. IVF in AMA (5.6 vs 4.0%; p = 0.002) but not in pre-AMA (5.7 vs 5.0%; p = 0.19). All 21 DUC1 embryos transferred during the study failed to implant. Limitations, reasons for caution Our study is limited by its retrospective nature. The present conclusions must be confirmed in other patient populations with different race/genetics and habits. Wider implications of the findings The occurrence of cycles providing DUC1 embryos is paradoxically associated with a more favourable patient prognosis, and the percentage of DUC1 embryos is higher in ICSI as compared to IVF cycles in AMA patients. Our findings represent new valuable clues for the clarification of DUC1 underlying causes. Trial registration number NA

High Order Multiple (HOM) pregnancies and IVF cycle number: is there an association?

Associations Between Maternal Prenatal Phthalate Urinary Metabolite Concentrations and Child Mental and Motor Development at Age 3 Years

Recombinant or Urinary Human Chorionic Gonadotropin in Ovulation Induction?

Purpose: To describe and demonstrate methods for analyzing longitudinal correlated eye data with a continuous outcome measure. Methods: We described fixed effects, mixed effects and generalized estimating equations (GEE) models, applied them to data from the Complications of Age-Related Macular Degeneration Prevention Trial (CAPT) and the Age-Related Eye Disease Study (AREDS). In CAPT (N = 1052), we assessed the effect of eye-specific laser treatment on change in visual acuity (VA). In the AREDS study, we evaluated effects of systemic supplement treatment among 1463 participants with AMD category 3. Results: In CAPT, the inter-eye correlations (0.33 to 0.53) and longitudinal correlations (0.31 to 0.88) varied. There was a small treatment effect on VA change (approximately one letter) at 24 months for all three models (p = .009 to 0.02). Model fit was better with the mixed effects model than the fixed effects model (p < .001). In AREDS, there was no significant treatment effect in all models (p > .55). Current smokers had a significantly greater VA decline than non-current smokers in the fixed effects model (p = .04) and the mixed effects model with random intercept (p = .0003), but marginally significant in the mixed effects model with random intercept and slope (p = .08), and GEE models (p = .054 to 0.07). The model fit was better with the fixed effects model than the mixed effects model (p < .0001). Conclusion: Longitudinal models using the eye as the unit of analysis can be implemented using available statistical software to account for both inter-eye and longitudinal correlations. Goodness-of-fit statistics may guide the selection of the most appropriate model.

Background: Di(2-ethylhexyl) phthalate (DEHP) and its metabolites are known to affect lipid metabolism and adipogenesis, mainly by activation of peroxisome proliferator-activated receptors (PPARs). Exposure to DEHP has been linked with testicular impairment and male subfertility. However, the effects of DEHP on female reproductive health and metabolism have not been studied in detail.Objective: We examined the effects of dietary DEHP exposure on metabolism and fertility in female mice.Methods: In two independent approaches, female C3H/N mice were exposed to DEHP (0.05, 5, or 500 mg/kg of body weight per day) via their diet for 8 weeks, and we recorded food intake, weight gain, and litter size. After exposure, liver, visceral fat, and plasma from F0 females (study I) and F0 dams and their F1 offspring (study II) were analyzed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay.Results: In study I, DEHP-exposed F0 females (all dose groups) had a significant increase in body weight, food intake, and visceral adipose tissue compared with controls. In the 500-mg DEHP group, PPARα and PPARγ transcripts were significantly changed in liver tissue. In the same group, PPARγ mRNA was significantly reduced in liver but not in fat tissue. In addition, leptin and FABP4 (fatty acid binding protein 4) mRNA were increased in adipose tissue, whereas adiponectin was decreased. In study II, we detected a 100% abortion rate in F0 dams in the 500-mg group. F1 offspring exposed in utero and during lactation had an increase in visceral fat tissue and body weight.Conclusion: Fertility was impaired in mice exposed to high doses of DEHP, and body weight and visceral fat deposits were increased in mice exposed to environmentally relevant doses. Although F1 mice were exposed to DEHP only in utero and during lactation, we observed metabolic changes in the offspring of diet-exposed females.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer but shows diverse toxicity. To investigate the time- and maternal age-differences in metabolism process of DEHP in pregnant women, three urine samples were collected from each pregnant woman ( n = 847) at the first (T1, mean 13.04 gestational weeks), the second (T2, mean 23.63 gestational weeks) and the third time point (T3, mean 35.91 gestational weeks), respectively. Four metabolites of DEHP were analyzed in 2541 urine samples (847 × 3) by using ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry. The level of urinary mono(2-ethylhexyl) phthalate (MEHP) had a decreasing trend across the pregnancy periods. The geometric mean concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) were significantly decreased in T2 than T1, and recovered slightly in T3. The transformation rate of MEHP to MEHHP in T3 was significantly higher than those in other two time points. The transformation rate of MEHHP to MEOHP in T2 and T3 was significantly higher than that in T1, indicating the oxidation was more efficient in late pregnancy compared with early and middle pregnancy. The percentages of oxidation products MEHHP and MECPP were higher in the higher-age group compared with the lower-age group in the second trimester samples. It is therefore concluded that DEHP metabolism may be influenced by the pregnancy stage and maternal age. The findings may benefit the risk assessment and toxicity evaluation of DEHP.

Study question the impact of euploid blastocysts on reproductive performance by association between the number of previous failed IVF cycles and live birth rate per transfer Summary answer Our findings suggest a negative association between the number of previous failed IVF cycles per euploid transfers. implantation rates decreased following each consecutive FE-ET cycles What is known already In assisted reproductive technologies, implantation failure presents a challenging clinical dilemma since its underlying etiology is unknown. Implantation is a very complex process which involves a variety of factors related to the embryo, endometrium, and immune system (Fox et al. 2016). Therefore, implantation failure is also a complex pathological condition that involve both embryonic defects and/or endometrial dysfunctions (Das et al.2012). This situation poses a therapeutic dilemma. Hence implantation failure etiologies and treatments remain unresolved. which results in ongoing debate over whether embryonic chromosomal aneuploidy is a major contributor or within the endometrium itself. Study design, size, duration This observational cohort study included 387 patients undergoing euploid embryo transfer between January 2015 and until October 2022. Participants/materials, setting, methods Participants: Women with an anatomically normal uterus who underwent autologous vitrified-warmed euploid blastocyst transfer (Frozen Euploid Embryo Transfer: FE-ET) cycles were included in the study. Setting: Fertility center at a university-affiliated public hospital. Intervention(s): Trophectoderm biopsy and comprehensive preimplantation 24-chromosome analysis using Next Generation Sequencing (NGS). Main Outcome Measure(s): Cumulative outcomes from these cycles were analyzed. A logistic regression model was used to assess the differences in outcomes between the first, second, and third FE-ET. Main results and the role of chance The mean age of the patient population under investigation was 33.4 ± 5.3 years. Maternal age at oocyte retrieval was negatively associated with the mean euploidy rate per cohort of biopsied blastocysts from each patient (m-ER). The m-ER did not show any association with the number of previous failed IVF cycles (0/1-2/≥3) among different ranges of maternal age at oocyte retrieval (≤30/31-35/36-39/≥40). The transfer of the first single vitrified-warmed euploid blastocyst was associated with an implantation rate (IR) of 47%, a miscarriage rate of 17.9% and a live birth rate (LBR) of 33.9%. Miscarriage rate and LBR were sensitive to the number of previous failed IVF cycles, showing statistically significant differences between women with no previous and ≥3 failed IVF cycles (11.3% versus 27.8%, P = 0.04) and (40.7% versus 26.3%, P = 0.05) respectively. Sustained implantation rates of the first, second, and third FE-ET were 47%, 40.5%, and 30% per transfer, respectively. The sustained IR was sensitive to the number of consecutive euploid blastocyst transfers (P = 0.03). Limitations, reasons for caution The retrospective nature of the study. The data should also be verified using a multicenter approach, to increase the sample size. Wider implications of the findings After experiencing multiple unsuccessful IVF cycles, transferring euploid blastocysts leads to improved clinical outcomes, but these improvements eventually level off. Additional information beyond embryo euploidy is needed to further enhance clinical outcomes. Trial registration number not applicable

Study question Does including embryos from atypically pronucleated zygotes (APZs) in IVF cycles with preimplantation genetic testing for aneuploidy (PGT-A) offer a cost-effective advantage for infertility patients? Summary answer Including APZ-derived blastocysts in PGT-A cycles improves live-birth rates, reduces cost per live-birth, and remains cost-effective across various clinical settings based on willingness to pay. What is known already Cost-effectiveness (CE) analyses are an important tool to inform implementation of new technologies in healthcare. Until recently, all embryos derived from zygotes with atypical pronuclear patterns, such as 1PN and ≥3PN, were discarded due to concerns about ploidy abnormalities and viability. However, implementation of modern PGT technologies allowing ploidy assessment, or molecular fertilisation check by genotyping, have shown that all typologies of APZs can develop into viable diploid euploid blastocysts capable of implantation and live birth. While outcomes and clinical safety of utilising APZs have been explored, the financial impact of including them in PGT-A cycles remains undetermined. Study design, size, duration This cost-effectiveness study used a decision tree model to compare the costs and outcomes of including vs. excluding APZs in IVF pathways. The model accounted for up to two IVF cycles if the first failed, with egg donation as an option in 20% of second cycles. Data from 826 IVF cycles with PGT-A at a single private clinic (February2013–December2020) were analyzed. The primary outcome was the financial cost per live birth in both scenarios. Participants/materials, setting, methods Real-world IVF cycle data were integrated into a decision tree model to predict live birth probability after PGT-A and the likelihood of following specific treatment pathways. Live birth rates were determined by maternal age, euploid embryo count, and pronuclear status. APZ typologies were modelled using blastocyst development rates and PGT-based ploidy estimates. Cost-effectiveness was assessed via incremental cost per additional live birth, with ICER calculations and a willingness-to-pay threshold of €450 per incremental LBR point. Main results and the role of chance From the clinical dataset, 110 cycles (13.3%) included at least one APZ that developed to the blastocyst stage, marking the decision point for its inclusion in the PGT-A program. In the model, 60% of non-pregnant couples underwent another IVF cycle (with or without APZs), 30% chose egg donation, and 10% remained childless. The utilization of APZs predicted an increase in LBR from 39% to 44% per IVF cycle and from 59.9% to 66% following the decisional tree pathway, corresponding to 5 and 6 additional live births per 100 PGT-A cycles, respectively. The average financial costs for each couple in the two treatments pathways are €14,051.5 and €14,165 for 2PN and APZ, respectively, with a difference of €113.5 euro. The financial cost per live birth in the APZ-utilized pathway was €21,462, compared to €23,458 in the standard 2PN-only approach, reflecting a cost reduction of €1,996 per live birth. Incorporating APZs resulted in an ICER of €1,861.19, confirming it as a cost-effective strategy for improving IVF outcomes in this patient population when assessed against the willingness-to-pay (WTP) threshold. The cost-effectiveness remains valid up to an ICER of €2,700.00 per completed treatment journey, ensuring financial feasibility across varying clinical and economic scenarios. Limitations, reasons for caution This study analyzes retrospective cycle data and costs from a single center, which may vary based on assumptions and predefined IVF pathways. However, the buffer within the willingness-to-pay threshold supports the broader generalizability of findings and the financial feasibility across a wider infertile patient population. Wider implications of the findings This first-of-its-kind study highlights the economic, reproductive, and ethical advantages of incorporating APZ-derived blastocysts into PGT-A cycles. By maximizing embryo utilization, it supports more efficient resource allocation while reinforcing clinical viability and cost-effectiveness, advocating for its integration into routine IVF practice to improve success rates and accessibility. Trial registration number No

Men's meat intake and treatment outcomes among couples undergoing assisted reproduction

Science linking environmental contaminant exposures with fertility and reproductive health impacts in the adult male

Pharmacokinetic-Pharmacodynamic Modeling and Simulation

Analysis of categorical outcomes in a longitudinal study has been an important statistical issue. Continuous outcome in a similar study design is commonly handled by the mixed effects model. The longitudinal binary or Poisson-like outcome analysis is often handled by the generalized estimation equation (GEE) method. Neither method is appropriate for analyzing a multinomial outcome in a longitudinal study, although the cross-sectional multinomial outcome is often analyzed by generalized linear models. One reason that these methods are not used is that the correlation structure of two multinomial variables can not be easily specified. In addition, methods that rely upon GEE or mixed effects models are unsuitable in instances when the focus of a longitudinal study is on the rate of moving from one category to another. In this research, a longitudinal model that has three categories in the outcome variable will be examined. A continuous-time Markov chain model will be used to examine the transition from one category to another. This model permits an unbalanced number of measurements collected on individuals and an uneven duration between pairs of consecutive measurements. In this study, the explicit expression for the transition probability is derived that provides an algebraic form of the likelihood function and hence allows the implementation of the maximum likelihood method. Using this approach, the instantaneous transition rate that is assumed to be a function of the linear combination of independent variables can be estimated. For a comparison between two groups, the odds ratios of occurrence at a particular category and their confidence intervals can be calculated. Empirical studies will be performed to compare the goodness of fit of the proposed method with other available methods. An example will also be used to demonstrate the application of this method.