Abstract
Background
Exposure to tobacco smoke during pregnancy is an established risk factor for early birth including early term birth (ETB) and preterm birth (PTB). However, the underlying molecular mechanisms are minimally understood. In this study, we aimed to characterize the newborn metabolomic associations with early pregnancy maternal tobacco exposure biomarkers and early birth in 269 mother-child pairs in the Atlanta African American Maternal-Child Cohort (2016–2020).
Methods
Established tobacco exposure biomarkers, cotinine and trans-3′-hydroxycotinine (3HC), were measured in maternal urine samples collected between 8–14 weeks of gestation. Newborn dried blood spots were collected for high-resolution metabolomics profiling. Metabolome-wide association studies and pathway enrichment analyses were conducted to determine metabolomic signals and pathways associated with tobacco exposure biomarkers, ETB, and PTB.
Results
We show that biopterin metabolism is a significantly enriched pathway for all exposures and outcomes. Both tobacco exposure biomarkers are associated with riboflavin metabolism. The metabolites riboflavin and 5-hydroxytryptophan are associated with all exposures and outcomes.
Conclusions
Taken together, these findings demonstrate that the newborn metabolome is altered by prenatal tobacco exposure and that these alterations are associated with elevated risks of early birth. Furthermore, perturbation in biopterin metabolism is a potential mechanism linking maternal tobacco exposure to early birth.
Plain language summary
Maternal tobacco exposure during pregnancy increases the risk of babies being born too early, but the biological reasons for this are not well understood. In this study, we analyzed tiny chemical signals called metabolites in newborn blood samples and compared them with measures of tobacco exposure during early pregnancy and birth timing. We found that tobacco exposure is linked to specific changes in the newborn’s chemistry that are also associated with early birth. These changes point to a biological pathway that may help explain how tobacco affects pregnancy. Our findings improve understanding of how tobacco exposure influences early delivery and may help guide future prevention efforts for pregnant women with high exposure.
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Data availability
The raw and processed metabolomics data from this study have been archived in the Metabolomics Workbench (https://www.metabolomicsworkbench.org/, Study ID ST002692) through the UNC HHEAR Laboratory. Exposure and outcome data are not publicly available due to data privacy regulations. Source data for the main figures presented are found in the Supplementary Data file.
Code availability
Pathway enrichment analyses were performed using mummichog (version 2.7). All analysis scripts used in this study are available from the corresponding author upon reasonable request.
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Acknowledgements
P.C.N. is supported by the NIEHS T32 Training Program in Environmental Health and Toxicology (T32 ES012870). This study was also supported by National Institutes of Health (NIH) research grants [R01ES035738, R01NR014800, R01MD009064, R24ES029490, R01MD009746], NIH Center Grants [P50ES02607, P30ES019776, U2CES026560, U2CES026542, UH3OD023318], NIH Training Grant (K01ES035082), and Environmental Protection Agency (USEPA) center grant [83615301]. The untargeted metabolomics was supported by the Human Health Exposure Analysis Resource (HHEAR) program, NIEHS grant [1U2CES030857-01].
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P.C.N. completed the analysis, interpretation, data and code validations, manuscript visualizations, and writing of the manuscript. X.L. completed the initial analysis and initial writing of the manuscript. X.L., P.C.N., and D.L. were involved in the study’s conceptualization and methodology. A.L.D., E.J.C., D.B.B., P.B.R., D.P.J., and D.L. were involved in funding and resource acquisition, project administration, and manuscript review and editing. V.Y., P.P., B.R., S.L.M., and S.S. were involved in data collection, data curation, manuscript review, and editing. M.R., S.M.E., and Y.T. contributed to manuscript review and editing.
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Communications Medicine thanks Wenqian Lu, Stefan Röder, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Nesbeth, PD.C., Lyu, X., Dunlop, A.L. et al. Newborn metabolomic perturbations associated with prenatal tobacco smoke exposure and early birth. Commun Med (2026). https://doi.org/10.1038/s43856-026-01534-5
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DOI: https://doi.org/10.1038/s43856-026-01534-5
