Analysis of <i>in vitro</i> fertilization data with multiple outcomes using discrete time‐to‐event analysis

Maity, Arnab; Williams, Paige L.; Ryan, Louise; Missmer, Stacey A.; Coull, Brent A.; Hauser, Russ

doi:10.1002/sim.6050

Cited by 13 publications

(13 citation statements)

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“…Each air pollutant was modeled continuously in interquartile range (IQR) increments (either on the original or transformed scale) so that the strength of the association for the different air pollution metrics could be compared. Multivariable Cox proportional hazards models for discrete survival time were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between the time-varying air pollutants and odds of failing IVF prior to live birth (Maity et al. 2014; Missmer et al.…”

Section: Methodsmentioning

confidence: 99%

Time-Varying Exposure to Air Pollution and Outcomes of in Vitro Fertilization among Couples from a Fertility Clinic

Gaskins

Fong

Awad

et al. 2019

Environ Health Perspect

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Background:A few studies suggest that air pollution may decrease fertility, but prospective studies and examinations of windows of susceptibility remain unclear.Objective:We aimed to examine the association between time-varying exposure to nitrogen dioxide (NO2), ozone (normalO3), fine particulate matter <2.5μm (PM2.5), and black carbon (BC) on in vitro fertilization (IVF) outcomes.Methods:We included 345 women (522 IVF cycles) for the NO2, normalO3, and PM2.5 analyses and 339 women (512 IVF cycles) for the BC analysis enrolled in a prospective cohort at a Boston fertility center (2004–2015). We used validated spatiotemporal models to estimate daily residential exposure to NO2, normalO3, PM2.5, and BC. Multivariable discrete time Cox proportional hazards models with four periods [ovarian stimulation (OS), oocyte retrieval to embryo transfer (ET), ET to implantation, implantation to live birth] estimated odds ratios (OR) and 95% confidence intervals (CI) of failing at IVF. Time-dependent interactions were used to identify vulnerable periods.Results:An interquartile range (IQR) increase in NO2, PM2.5, and BC throughout the IVF cycle was associated with an elevated odds of failing at IVF prior to live birth (OR=1.08, 95% CI: 0.95, 1.23 for NO2; OR=1.06, 95% CI: 0.88, 1.28 for PM2.5; and OR=1.16, 95% CI: 0.96, 1.41 for BC). This relationship significantly varied across the IVF cycle such that the association with higher exposure to air pollution during OS was strongest for early IVF failures. An IQR increase in NO2, PM2.5, and BC exposure during OS was associated with 1.42 (95% CI: 1.20, 1.69), 1.26 (95% CI: 0.96, 1.67), and 1.23 (95% CI: 0.96, 1.59) times the odds of failing prior to oocyte retrieval, and 1.32 (95% CI: 1.13, 1.54), 1.27 (95% CI: 0.98, 1.65), and 1.32 (95% CI: 1.10, 1.59) times the odds of failing prior to ET.Conclusion:Increased exposure to traffic-related pollutants was associated with higher odds of early IVF failure. https://doi.org/10.1289/EHP4601

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Section: Methodsmentioning

confidence: 99%

Time-Varying Exposure to Air Pollution and Outcomes of in Vitro Fertilization among Couples from a Fertility Clinic

Gaskins

Fong

Awad

et al. 2019

Environ Health Perspect

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“…Among studies that include multiple cycles per woman, discrete survival analysis has been employed to consider the association of an exposure with the number of cycles until live birth or with the cumulative rate of live birth (Malizia et al, 2009). Time-to-event methods have also been expanded to consider multiple points of failure within an individual (Maity et al, 2014). In addition to survival analysis, the embryo-uterus (EU) approach models the probability of live birth as a function of embryo viability and maternal characteristics (Speirs et al, 1983).…”

Section: Discussionmentioning

confidence: 99%

Methodological approaches to analyzing IVF data with multiple cycles

et al. 2018

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Which methodological approaches are most appropriate for analyzing IVF data with multiple cycles in the context of a binary outcome? SUMMARY ANSWER: Both mixed effect models and generalized estimating equation (GEE) modeling approaches can account for multiple IVF cycles and may reduce bias over first-cycle only approaches, but CIs were narrowest with cluster-weighted generalized estimating equation models (CWGEE). WHAT IS KNOWN ALREADY: There is a lack of consensus among investigators regarding how to best incorporate data from multiple cycles and whether to present odds or risks in the analysis of IVF data. Failure to account for correlated outcomes within individuals and informative cluster size may lead to invalid CIs and biased estimates. STUDY DESIGN, SIZE, DURATION: The Environment and Reproductive Health (EARTH) Study is an ongoing prospective cohort study of subfertile couples conducted at an academic medical center. This cohort was established in 2004 and follows couples seeking treatment for infertility throughout the course of their treatment and pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-46 years enrolled in the EARTH Study from 2004 to 2017 who initiated at least one IVF cycle were eligible. Cycle initiation was defined as beginning ovulation induction with the intent to progress through an IVF or ICSI cycle. This analysis included 442 women undergoing 642 cycles who met the study inclusion criteria. We compared the results and interpretations of log-binomial and logistic models restricting to the first cycle, as well as mixed effects models, unweighted GEE models, and CWGEE models including all cycles. This analysis was conducted for two distinct exposures: maternal age at cycle initiation, and maternal preconception urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites (previously reported to be associated with a decreased probability of live birth). MAIN RESULTS AND THE ROLE OF CHANCE: In general, the CIs were widest for mixed effects models and narrowest for CWGEE models. Further, in models evaluating the sum of urinary concentrations of DEHP metabolites (∑DEHP, available for 91% of women), the point estimates were surprisingly different between the first-cycle and multiple-cycle models. We observed significant associations between maternal age and live birth in all models. However, we observed no associations between ∑DEHP and live birth. LIMITATIONS, REASONS FOR CAUTION: This analysis was limited to an example dataset in which the true effect of any exposure is unknown. While this allows us to observe model performance in the context of real data, future analyses should be conducted within simulated datasets under various assumptions to further evaluate the appropriateness of each approach. In addition, we did not address differential loss to follow-up in our statistical approaches. WIDER IMPLICATIONS OF THE FINDINGS: The use of CWGEE models should be more widely considered in the analysis of IVF data with multiple cycles per woman. The CWGEE approach ...

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“…The main criticism of the intention to treat analysis, however, is that only cases at risk of the outcome should be included in the denominator when addressing questions of the biologic or mechanistic effects of an exposure [44]. Thus, moving forward, more sophisticated statistical techniques such as discrete survival models where the probability of failing at each ART stage is modeled conditional on succeeding in the previous stage should be more widely considered in ART studies [45]. …”

Section: Discussionmentioning

confidence: 99%

Epidemiologic Approaches for Studying Assisted Reproductive Technologies: Design, Methods, Analysis, and Interpretation

Messerlian

Gaskins

2017

Curr Epidemiol Rep

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Purpose While considerable progress has been made since the advent of assisted reproductive technology (ART), the field remains a complex and challenging one for clinicians and researchers alike. This review discusses some of the most salient issues pertaining to the study of ART and whenever possible suggestions on how to address them. Recent Findings More than 5 million babies have been born through ART to date, representing up to 4% of all births worldwide. While technologies continue to evolve and demand for treatment grows, it is more important than ever to conduct rigorous and timely research to help guide clinical practice that is safe and effective, and that minimizes potential short- and long-term adverse outcomes to mother and child. Summary ART research will require exceedingly more sophisticated research methods, designs, and analyses that are rooted in a reproductive epidemiological framework in order to improve future research and ultimately promote better outcomes for all subfertile couples and their children.

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Analysis of in vitro fertilization data with multiple outcomes using discrete time‐to‐event analysis

Cited by 13 publications

References 33 publications

Time-Varying Exposure to Air Pollution and Outcomes of in Vitro Fertilization among Couples from a Fertility Clinic

Time-Varying Exposure to Air Pollution and Outcomes of in Vitro Fertilization among Couples from a Fertility Clinic

Methodological approaches to analyzing IVF data with multiple cycles

Epidemiologic Approaches for Studying Assisted Reproductive Technologies: Design, Methods, Analysis, and Interpretation

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