Periods of susceptibility for associations between phthalate exposure and preterm birth: Results from a pooled analysis of 16 US cohorts

Alexa Friedman¹, Barrett M Welch², Alexander P Keil³, Michael S Bloom⁴, Joseph M Braun⁵, Jessie P Buckley⁶, Dana Dabelea⁷, Pam Factor-Litvak⁸, John D Meeker⁹, Karin B Michels¹⁰, Vasantha Padmanabhan¹¹, Anne P Starling⁶, Clarice R Weinberg¹, Jenny Aalborg⁷, Akram N Alshawabkeh¹², Emily S Barrett¹³, Alexandra M Binder¹⁴, Asa Bradman¹⁵, Nicole R Bush¹⁶, Antonia M Calafat¹⁷, David E Cantonwine¹⁸, Kate E Christenbury¹⁹, José F Cordero²⁰, Stephanie M Engel⁶, Brenda Eskenazi²¹, Kim G Harley²¹, Russ Hauser²², Julie B Herbstman⁸, Nina Holland²¹, Tamarra James-Todd²², Anne Marie Z Jukic¹, Bruce P Lanphear²³, Thomas F McElrath¹⁸, Carmen Messerlian²², Roger B Newman²⁴, Ruby H N Nguyen²⁵, Katie M O'Brien¹, Virginia A Rauh⁸, J Bruce Redmon²⁶, David Q Rich²⁷, Emma M Rosen⁶, Sheela Sathyanarayana²⁸, Rebecca J Schmidt²⁹, Amy E Sparks³⁰, Shanna H Swan³¹, Christina Wang³², Deborah J Watkins⁹, Barry Weinberger³³, Abby G Wenzel²⁶, Allen J Wilcox¹, Kimberly Yolton³⁴, Yu Zhang²², Ami R Zota⁸, Kelly K Ferguson³⁵

Affiliations

¹ National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
² National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; University of Nevada, Reno, NV, USA.
³ National Cancer Institute, Bethesda, MD, USA.
⁴ George Mason University, Fairfax, VA, USA.
⁵ Brown University, Providence, Rhode Island, USA.
⁶ University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Columbia University, NY, USA.
⁹ University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹⁰ Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
¹¹ University of Michigan Medical School, Ann Arbor, MI, USA.
¹² Northeastern University, Boston, MA, USA.
¹³ Rutgers School of Public Health, Piscataway, NJ, USA.
¹⁴ University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁵ University of California, Merced, CA, USA.
¹⁶ University of California, San Francisco, San Francisco, CA, USA.
¹⁷ National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹⁸ Brigham and Women's Hospital, Boston, MA, USA.
¹⁹ DLH, LLC, Bethesda, MD, USA.
²⁰ University of Georgia, Athens, GA, USA.
²¹ University of California, Berkeley, CA, USA.
²² Harvard TH Chan School of Public Health, Boston, MA, USA.
²³ Simon Fraser University, Burnaby, British Columbia, Canada.
²⁴ Medical University of South Carolina, Charleston, SC, USA.
²⁵ University of Minnesota School of Public Health, Minneapolis, MN, USA.
²⁶ University of Minnesota Medical School, Minneapolis, MN, USA.
²⁷ University of Rochester Medical Center, Rochester, NY, USA.
²⁸ University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
²⁹ University of California, Davis, CA, USA.
³⁰ University of Iowa, Iowa City, IA, USA.
³¹ Icahn School of Medicine at Mount Sinai, NY, USA.
³² The Lundquist Institute at Harbor, UCLA Medical Center, West Carson, CA, USA.
³³ Cohen Children's Medical Center of New York, Northwell Health, Queens, NY, USA.
³⁴ Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
³⁵ National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Electronic address: kelly.ferguson2@nih.gov.

PMID: 40132438
PMCID: PMC12021553 (available on 2026-04-01)
DOI: 10.1016/j.envint.2025.109392

Periods of susceptibility for associations between phthalate exposure and preterm birth: Results from a pooled analysis of 16 US cohorts

Alexa Friedman et al. Environ Int. 2025 Apr.

. 2025 Apr:198:109392.

doi: 10.1016/j.envint.2025.109392. Epub 2025 Mar 20.

Authors

Affiliations

¹ National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
² National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA; University of Nevada, Reno, NV, USA.
³ National Cancer Institute, Bethesda, MD, USA.
⁴ George Mason University, Fairfax, VA, USA.
⁵ Brown University, Providence, Rhode Island, USA.
⁶ University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Columbia University, NY, USA.
⁹ University of Michigan School of Public Health, Ann Arbor, MI, USA.
¹⁰ Institute for Prevention and Cancer Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany.
¹¹ University of Michigan Medical School, Ann Arbor, MI, USA.
¹² Northeastern University, Boston, MA, USA.
¹³ Rutgers School of Public Health, Piscataway, NJ, USA.
¹⁴ University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁵ University of California, Merced, CA, USA.
¹⁶ University of California, San Francisco, San Francisco, CA, USA.
¹⁷ National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹⁸ Brigham and Women's Hospital, Boston, MA, USA.
¹⁹ DLH, LLC, Bethesda, MD, USA.
²⁰ University of Georgia, Athens, GA, USA.
²¹ University of California, Berkeley, CA, USA.
²² Harvard TH Chan School of Public Health, Boston, MA, USA.
²³ Simon Fraser University, Burnaby, British Columbia, Canada.
²⁴ Medical University of South Carolina, Charleston, SC, USA.
²⁵ University of Minnesota School of Public Health, Minneapolis, MN, USA.
²⁶ University of Minnesota Medical School, Minneapolis, MN, USA.
²⁷ University of Rochester Medical Center, Rochester, NY, USA.
²⁸ University of Washington and Seattle Children's Research Institute, Seattle, WA, USA.
²⁹ University of California, Davis, CA, USA.
³⁰ University of Iowa, Iowa City, IA, USA.
³¹ Icahn School of Medicine at Mount Sinai, NY, USA.
³² The Lundquist Institute at Harbor, UCLA Medical Center, West Carson, CA, USA.
³³ Cohen Children's Medical Center of New York, Northwell Health, Queens, NY, USA.
³⁴ Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
³⁵ National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Electronic address: kelly.ferguson2@nih.gov.

PMID: 40132438
PMCID: PMC12021553 (available on 2026-04-01)
DOI: 10.1016/j.envint.2025.109392

Abstract

Background: Phthalate exposure during pregnancy has been associated with preterm birth, but mechanisms of action may depend on the timing of exposure.

Objective: Investigate critical periods of susceptibility during pregnancy for associations between urinary phthalate metabolite concentrations and preterm birth.

Methods: Individual-level data were pooled from 16 US cohorts (N = 6045, n = 539 preterm births). We examined trimester-averaged urinary phthalate metabolite concentrations. Most phthalate metabolites had 2248, 3703, and 3172 observations in the first, second, and third trimesters, respectively. Our primary analysis used logistic regression models with generalized estimating equations (GEE) under a multiple informant approach to estimate trimester-specific odds ratios (ORs) of preterm birth and significant (p < 0.20) heterogeneity in effect estimates by trimester. Adjusted models included interactions between each covariate and trimester.

Results: Differences in trimester-specific associations between phthalate metabolites and preterm birth were most evident for di-2-ethylhexyl phthalate (DEHP) metabolites. For example, an interquartile range increase in mono (2-ethylhexyl) phthalate (MEHP) during the first and second trimesters was associated with ORs of 1.15 (95 % confidence interval [CI]: 0.99, 1.33) and 1.11 (95 % CI: 0.97, 1.28) for preterm birth, respectively, but this association was null in the third trimester (OR = 0.91 [95 % CI: 0.76, 1.09]) (p-heterogeneity = 0.03).

Conclusion: The association of preterm birth with gestational biomarkers of DEHP exposure, but not other phthalate metabolites, differed by the timing of exposure. First and second trimester exposures demonstrated the greatest associations. Our study also highlights methodological considerations for critical periods of susceptibility analyses in pooled studies.

Published by Elsevier Ltd.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. McElrath reported research support to their institution and equity from NxPrenatal Inc; serving on the scientific advisory board of and equity from Mirvie Inc; and serving on the scientific advisory board of and cash payment from Hoffmann-La Roche, Momenta Pharmaceuticals, Comanche Biopharma; and Tectonic Therapeutic. Dr. Schmidt has received funding to support the MARBLES Study through a grant from the Simons Foundation (SFARI #863967, RJS). RJS consulted for the Beasley Law Firm and Linus Technology, Inc. RJS has received travel support to present at the 35th Annual Meeting of the Organization of Teratology Information Specialists (OTIS) and to serve on the Observational Study Monitoring Board (OSMB) for HEALthy Brain and Child Development (HBCD) Study.

References

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Periods of susceptibility for associations between phthalate exposure and preterm birth: Results from a pooled analysis of 16 US cohorts

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Periods of susceptibility for associations between phthalate exposure and preterm birth: Results from a pooled analysis of 16 US cohorts

Authors

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Abstract

Conflict of interest statement

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