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  • Review Article
  • Published:

Prenatal metal(loid) exposure and preterm birth: a systematic review of the epidemiologic evidence

Journal of Exposure Science & Environmental Epidemiology volume 35, pages 696–708 (2025)Cite this article

Abstract

Background

Preterm birth (PTB) is a common pregnancy complication associated with significant neonatal morbidity. Prenatal exposure to environmental chemicals, including toxic and/or essential metal(loid)s, may contribute to PTB risk.

Objective

We aimed to summarize the epidemiologic evidence of the associations among levels of arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), manganese (Mn), lead (Pb), and zinc (Zn) assessed during the prenatal period and PTB or gestational age at delivery; to assess the quality of the literature and strength of evidence for an effect for each metal; and to provide recommendations for future research.

Methods

We adapted the Navigation Guide methodology and followed PRISMA guidelines. We searched the MEDLINE/PubMed database for epidemiologic studies from 1995 to 2023. We used a customized risk of bias protocol and evaluated the sufficiency of evidence for an effect of each metal(loid) on PTB risk.

Results

A total of 1206 studies were identified and screened. Of these, 139 were assessed for eligibility by reading the full-text, and 92 studies were ultimately included (arsenic: 40, cadmium: 30, chromium: 11, copper: 21, mercury: 27, manganese: 17, lead: 41, zinc: 18, metal(loid) mixtures: 12). We found sufficient evidence that lead increases the risk of PTB and, while the evidence was limited, suggestive evidence that cadmium and chromium increase the risk of PTB. The evidence was deemed inadequate to determine an effect for the other metal(loid)s.

Significance

Future research would benefit from more precise PTB clinical phenotyping, measuring exposure early and longitudinally throughout pregnancy, using an appropriate media for metal(loid)s under study, and evaluating metal mixtures. Given the strength of evidence linking lead exposure and PTB, active and comprehensive prenatal screening for lead exposure among pregnant individuals is warranted.

Impact

  • By summarizing 92 epidemiologic studies that investigated the associations between metal exposure and preterm birth using the rigorous Navigation Guide methodology, our review provides compelling evidence for a strong link between prenatal lead exposure and preterm birth.

  • Additionally, it suggests potential associations between cadmium and chromium exposure and preterm birth.

  • Given the robust nature of this evidence, there is an urgent need for prenatal screening for lead exposure during pregnancy, along with targeted interventions to reduce exposure. These actions are critical for advancing maternal and child health.

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Fig. 1: Forest plot summarizing data on studies that assessed the effect of cadmium exposure on preterm birth risk.
Fig. 2: Forest plot summarizing data on studies that assessed the effect of chromium exposure on preterm birth risk.
Fig. 3: Forest plot summarizing data on studies that assessed the effect of lead exposure on preterm birth risk.
Fig. 4: Summary of risk of bias rankings, summarized across all studies included for each metal.
Fig. 5: Graphical overview of key challenges in measuring and analyzing biomarkers in studies investigating the relationship between metals and preterm birth (PTB).

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Data availability

All data generated or analyzed in this review are included in this published article and its supplementary information files. The extracted data Excel sheet can be made available upon request.

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Acknowledgements

The authors wish to thank Alex P Keil, Julia E Rager, and Radhika Dhingra for their thoughtful edits on the earliest draft of this manuscript.

Funding

This research was supported, in part, by the National Institute of Environmental Health Sciences (Fry, P42ES031007, Fry, R01ES029531; Lodge, T32ES007018 and F30ES032302; Manuck K24ES031131), the National Institute for Minority Health and Health Disparities (Manuck/Fry, R01MD011609) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Lodge, T32HD007168).

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Authors and Affiliations

  1. Department of Environmental Sciences & Engineering, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Lauren A. Eaves, Kyle R. Roell & Rebecca C. Fry

  2. Institute for Environmental Health Solutions, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Lauren A. Eaves, Kyle R. Roell, Tracy A. Manuck & Rebecca C. Fry

  3. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Evans K. Lodge

  4. Department of Maternal and Child Health, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Wendy R. Rohin

  5. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Tracy A. Manuck

  6. Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Rebecca C. Fry

  7. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Rebecca C. Fry

Authors
  1. Lauren A. Eaves
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  2. Evans K. Lodge
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  3. Wendy R. Rohin
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  4. Kyle R. Roell
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  5. Tracy A. Manuck
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  6. Rebecca C. Fry
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Contributions

L.E: Conceptualization, Methodology, Formal Analysis, Data Curation, Writing- Original draft, Visualization, Project administration. E.L: Methodology, Formal Analysis, Writing—Review and editing. W.R: Data Curation, Writing- Review and editing. K.R: Software, Visualization. T.M: Writing—Review and editing, Resources, Funding acquisition. R.F: Writing-Review and editing, Resources, Funding acquisition.

Corresponding author

Correspondence to Rebecca C. Fry.

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Eaves, L.A., Lodge, E.K., Rohin, W.R. et al. Prenatal metal(loid) exposure and preterm birth: a systematic review of the epidemiologic evidence. J Expo Sci Environ Epidemiol 35, 696–708 (2025). https://doi.org/10.1038/s41370-025-00744-8

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