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Spontaneous abortion (SAB), defined as a pregnancy loss before 20 weeks of gestation, affects up to 30% of conceptions, yet few modifiable risk factors have been identified. We estimated the effect of ambient air pollution exposure on SAB incidence in Pregnancy Study Online (PRESTO), a preconception cohort study of North American couples who were trying to conceive. Participants completed questionnaires at baseline, every 8 weeks during preconception follow-up, and in early and late pregnancy. We analyzed data on 4643 United States (U.S.) participants and 851 Canadian participants who enrolled during 2013-2019 and conceived during 12 months of follow-up. We used country-specific national spatiotemporal models to estimate concentrations of particulate matter <2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ) during the preconception and prenatal periods at each participant's residential address. On follow-up and pregnancy questionnaires, participants reported information on pregnancy status, including SAB incidence and timing. We fit Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of time-varying prenatal concentrations of PM 2.5 , NO 2 , and O 3 with rate of SAB, adjusting for individual- and neighborhood-level factors. Nineteen percent of pregnancies ended in SAB. Greater PM 2.5 concentrations were associated with a higher incidence of SAB in Canada, but not in the U.S. (HRs for a 5 μg/m 3 increase = 1.29, 95% CI: 0.99, 1.68 and 0.94, 95% CI: 0.83, 1.08, respectively). NO 2 and O 3 concentrations were not appreciably associated with SAB incidence. Results did not vary substantially by gestational weeks or season at risk. In summary, we found little evidence for an effect of residential ambient PM 2.5 , NO 2 , and O 3 concentrations on SAB incidence in the U.S., but a moderate positive association of PM 2.5 with SAB incidence in Canada., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Lauren A. Wise and Elizabeth E. Hatch reports financial support was provided by National Institute of Environmental Health Sciences. Lauren A. Wise reports a relationship with AbbVie Inc that includes: consulting or advisory. Dr. Lauren Wise serves as a consultant for AbbVie, Inc. and the Gates Foundation. She also receives in-kind donations for primary data collection in Pregnancy Study Online (PRESTO) from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility apps). All of these relationships are for work unrelated to this manuscript. The remaining authors report no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Animal and epidemiologic studies indicate that air pollution may adversely affect fertility. However, the level of evidence is limited and specific pollutants driving the association are inconsistent across studies., Methods: We used data from a web-based preconception cohort study of pregnancy planners enrolled during 2013-2019 (Pregnancy Study Online; PRESTO). Eligible participants self-identified as female, were aged 21-45 years, resided in the United States (U.S.) or Canada, and were trying to conceive without fertility treatments. Participants completed a baseline questionnaire and bi-monthly follow-up questionnaires until conception or 12 months. We analyzed data from 8,747 participants (U.S.: 7,304; Canada: 1,443) who had been trying to conceive for < 12 cycles at enrollment. We estimated residential ambient concentrations of particulate matter < 2.5 µm (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 ) using validated spatiotemporal models specific to each country. We fit country-specific proportional probabilities regression models to estimate the association between annual average, menstrual cycle-specific, and preconception average pollutant concentrations with fecundability, the per-cycle probability of conception. We calculated fecundability ratios (FRs) and 95% confidence intervals (CIs) and adjusted for individual- and neighborhood-level confounders., Results: In the U.S., the FRs for a 5-µg/m 3 increase in annual average, cycle-specific, and preconception average PM 2.5 concentrations were 0.94 (95% CI: 0.83, 1.08), 1.00 (95% CI: 0.93, 1.07), and 1.00 (95% CI: 0.93, 1.09), respectively. In Canada, the corresponding FRs were 0.92 (95% CI: 0.74, 1.16), 0.97 (95% CI: 0.87, 1.09), and 0.94 (95% CI: 0.80, 1.09), respectively. Likewise, NO 2 and O 3 concentrations were not strongly associated with fecundability in either country., Conclusions: Neither annual average, menstrual cycle-specific, nor preconception average exposure to ambient PM 2.5 , NO 2 , and O 3 were appreciably associated with reduced fecundability in this cohort of pregnancy planners., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Lauren A. Wise and Elizabeth E. Hatch reports financial support was provided by National Institutes of Health. Lauren A. Wise reports a relationship with AbbVie Inc that includes: consulting or advisory. Dr. Lauren Wise serves as a consultant for AbbVie, Inc. and the Gates Foundation, She also receives in-kind donations for primary data collection in Pregnancy Study Online (PRESTO) from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility apps). All of these relationships are for work unrelated to this manuscript.]., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Animal and epidemiologic studies indicate that air pollution may adversely affect fertility. Epidemiologic studies have been restricted largely to couples undergoing fertility treatment or have retrospectively ascertained time-to-pregnancy among pregnant women., Objectives: We examined the association between residential ambient air pollution and fecundability, the per-cycle probability of conception, in a large preconception cohort of Danish pregnancy planners., Methods: During 2007-2018, we used the Internet to recruit and follow women who were trying to conceive without the use of fertility treatment. Participants completed an online baseline questionnaire eliciting socio-demographic characteristics, lifestyle factors, and medical and reproductive histories and follow-up questionnaires every 8 weeks to ascertain pregnancy status. We determined concentrations of ambient nitrogen oxides (NO x ), nitrogen dioxide (NO 2 ), carbon monoxide (CO), ozone (O 3 ), particulate matter <2.5 µm (PM 2.5 ) and <10 µm (PM 10 ), and sulphur dioxide (SO 2 ) at each participant's residential address. We calculated average exposure during the year before baseline, during each menstrual cycle over follow-up and during the entire pregnancy attempt time. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders and co-pollutants. The analysis was restricted to the 10,183 participants who were trying to conceive for <12 cycles at study entry whose addresses could be geocoded., Results: During 12 months of follow-up, 73% of participants conceived. Higher concentrations of PM 2.5 and PM 10 were associated with small reductions in fecundability. For example, the FRs for a one interquartile range (IQR) increase in PM 2.5 (IQR = 3.2 µg/m 3 ) and PM 10 (IQR = 5.3 µg/m 3 ) during each menstrual cycle were 0.93 (95% CI: 0.87, 0.99) and 0.91 (95% CI: 0.84, 0.99), respectively. Other air pollutants were not appreciably associated with fecundability., Conclusions: In this preconception cohort study of Danish women, residential exposures to PM 2.5 and PM 10 were associated with reduced fecundability., (© 2021 John Wiley & Sons Ltd.)

Study Question: To what extent are ambient concentrations of particulate matter <2.5 microns (PM2.5), nitrogen dioxide (NO2) and ozone (O3) associated with risk of self-reported physician-diagnosed uterine leiomyomata (UL)?, Summary Answer: In this large prospective cohort study of Black women, ambient concentrations of O3, but not PM2.5 or NO2, were associated with increased risk of UL., What Is Known Already: UL are benign tumors of the myometrium that are the leading cause of gynecologic inpatient care among reproductive-aged women. Black women are clinically diagnosed at two to three times the rate of white women and tend to exhibit earlier onset and more severe disease. Two epidemiologic studies have found positive associations between air pollution exposure and UL risk, but neither included large numbers of Black women., Study Design, Size, Duration: We conducted a prospective cohort study of 21 998 premenopausal Black women residing in 56 US metropolitan areas from 1997 to 2011., Participants/material, Setting, Methods: Women reported incident UL diagnosis and method of confirmation (i.e. ultrasound, surgery) on biennial follow-up questionnaires. We modeled annual residential concentrations of PM2.5, NO2 and O3 throughout the study period. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for a one-interquartile range (IQR) increase in air pollutant concentrations, adjusting for confounders and co-pollutants., Main Results and the Role of Chance: During 196 685 person-years of follow-up, 6238 participants (28.4%) reported physician-diagnosed UL confirmed by ultrasound or surgery. Although concentrations of PM2.5 and NO2 were not appreciably associated with UL (HRs for a one-IQR increase: 1.01 (95% CI: 0.93, 1.10) and 1.05 (95% CI: 0.95, 1.16), respectively), O3 concentrations were associated with increased UL risk (HR for a one-IQR increase: 1.19, 95% CI: 1.07, 1.32). The association was stronger among women age <35 years (HR: 1.26, 95% CI: 0.98, 1.62) and parous women (HR: 1.28, 95% CI: 1.11, 1.48)., Limitations, Reasons for Caution: Our measurement of air pollution is subject to misclassification, as monitoring data are not equally spatially distributed and we did not account for time-activity patterns. Our outcome measure was based on self-report of a physician diagnosis, likely resulting in under-ascertainment of UL. Although we controlled for several individual- and neighborhood-level confounding variables, residual confounding remains a possibility., Wider Implications of the Findings: Inequitable burden of air pollution exposure has important implications for racial health disparities, and may be related to disparities in UL. Our results emphasize the need for additional research focused on environmental causes of UL., Study Funding/competing Interest(s): This research was funded by the National Cancer Institute (U01-CAA164974) and the National Institute of Environmental Health Sciences (R01-ES019573). L.A.W. is a fibroid consultant for AbbVie, Inc. and accepts in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, FertilityFriend.com and Kindara.com for primary data collection in Pregnancy Study Online (PRESTO). M.J. declares consultancy fees from the Health Effects Institute (as a member of the review committee). The remaining authors declare they have no actual or potential competing financial interests., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A growing literature indicates that changes in modifiable factors, including diet, can counteract the toxic developmental and reproductive health effects of chemical exposures. In this issue of the Journal, Gaskins et al. (Am J Epidemiol. 2019;000(000):000-000) present data supporting this hypothesis. Specifically, using data on a cohort of 304 women seeking fertility treatment in Boston, Massachusetts, they found that women with higher exposure to ambient air pollutants had lower fertility treatment success but only when they also consumed <800 μg/day of supplemental folate. No association was observed among women consuming ≥800 μg/day of supplemental folate. The public health importance of this interaction is high: Diet and dietary supplement intake are modifiable factors, whereas exposure to air pollution is less so. While this research question is grounded in a strong biological hypothesis related to epigenetic modifications, oxidative stress, and inflammation, this study raises several key questions. In this commentary, we discuss the inconsistency of the interaction across exposure metrics, the possibility of unmeasured confounding by folate intake, and the importance of examining this association in populations with lower folate intake and/or higher exposure to air pollution., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)