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Background: Water total trihalomethanes (TTHMs) are disinfectant byproducts found in municipal water supplies. TTHM exposure has been linked to cancer and may be associated with adverse reproductive outcomes. A non-optimal cervicovaginal microbiota and low cervicovaginal beta-defensin-2 levels are associated with increased risk of spontaneous preterm birth. Whether TTHM exposure increases the risk of spontaneous preterm birth or alters the cervicovaginal microbial or immune state is unknown., Objective: Investigate associations of water TTHM levels with spontaneous preterm birth, a non-optimal cervicovaginal microbiota, and beta-defensin-2 levels in a completed, diverse, urban pregnancy cohort. We hypothesized that higher TTHM levels would be associated with spontaneous preterm birth, a non-optimal cervicovaginal microbiota, and lower beta-defensin-2 levels., Design: Methods: This was a secondary analysis of participants (n = 474) in the Motherhood & Microbiome (M&M) study (n = 2000), who lived in Philadelphia and had cervicovaginal samples analyzed for cervicovaginal microbiota composition and beta-defensin-2 levels. The microbiota was classified into community state types (CSTs). CST IV (non-optimal microbiota) is characterized by a paucity of Lactobacillus species and wide array of anaerobes. Municipal water TTHM levels were obtained from 16 sites monthly across the city of Philadelphia to establish mean residential water supply levels for each participant for the first four months of pregnancy (prior to vaginal swab collection at 16-20 weeks' gestation). Associations of water TTHM levels with spontaneous preterm birth and a non-optimal cervicovaginal microbiota birth were analyzed using multivariable logistic regression. Multivariable linear regression was used to model associations of water TTHM levels with log-transformed cervicovaginal beta-defensin-2 levels. Since water TTHM levels vary by season and beta-defensin-2 levels have been shown to differ by race, stratified models by warm (April-September) and cold (October-March) seasons as well as by self-identified race were utilized., Results: Participants' water supply TTHM levels (mean μg/L [SD]) were higher in the warm (53.5 [9.4]) than cold (33.4 [7.5]) season (p < 0.0001). TTHM levels were non-significantly higher among Black participants than non-Black participants (44.8 [13.5] vs. 41.8 [11.8], p = 0.07). No associations were detected between TTHM with spontaneous preterm birth (per SD increment of TTHM, aOR 0.94, 95%CI: 0.66, 1.34) or with CST IV (aOR 0.94, 95%CI: 0.86, 1.16). Counter to our hypothesis, we observed positive associations of water TTHM with log-transformed cervicovaginal beta-defensin-2 levels in unadjusted models (β 0.20 [95%CI: 0.02, 0.39]) per SD increment of TTHM), but the association was null after adjustment for season. However, in models adjusted for covariates including season and stratified by race, TTHM was significantly associated with lower beta-defensin-2 levels among non-Black participants (β -0.75 [95%CI: -1.43, -0.08]) but not among Black participants (β 0.17 [95%CI: -0.15, 0.49]), interaction p = 0.013)., Conclusion: We did not detect associations of water TTHM levels with spontaneous preterm birth or the structure of the cervicovaginal microbiota. However, the finding of a significant interaction between TTHM and race on beta-defensin-2 levels suggest that environmental exposures may contribute to differences in reproductive tract innate immune function by race. Future studies to delineate environmental contributions to the cervicovaginal microbial-immune state, a potentially important biologic underpinning for preterm birth, are warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)