Gestational exposure to metals and small vulnerable newborns: a systematic review and meta-analysis

Small vulnerable newborns (SVNs), defined as babies affected by preterm birth (PTB), small for gestational age (SGA), or low birth weight (LBW), face a substantially increased risk of chronic diseases over their lifespan and premature mortality. Gestational exposure to heavy metals may play a role in the aetiology of SVNs. Although previous limited systematic reviews have examined individual metal(loid)s and single SVN outcomes, their findings remain inconclusive. Given the recent surge in studies, the use of diverse biospecimens, and the narrow scope of prior search strategies, our study aims to addresses these gaps by comprehensively synthesizing evidence across multiple metal(loid)s, SVN outcomes, and biospecimen types, providing a more complete and up-to-date assessment.

We conducted a comprehensive search in three databases-PubMed, Web of Science, and Embase-for relevant articles published before 9th December 2025, investigating the associations between gestational exposure to metal(loid)s and outcomes of SVNs. Observational studies, including prospective and retrospective cohort studies, case-control studies, and cross-sectional studies, were included. Data were extracted from studies that assessed toxicologically relevant metal burdens using biomonitoring measurements. Meta-analysis was conducted and pooled odds ratios (ORs) and confidence intervals (CIs) were calculated using both fixed-effect and random-effects models, with further analyses stratified by biospecimen types. Two-stage dose-response analyses were performed. Publication bias and heterogeneity were assessed. The protocol was registered with PROSPERO, CRD42024571198.

Of the 43,695 publications identified and 102 studies with a total of 325,705 live births involving 20 heavy metals and either of SVNs outcomes met the inclusion criteria for final meta-analysis. Barium (Ba, n = 4541), Higher maternal Cadmium (Cd, n = 31,651), Mercury (Hg, n = 18,962), and lead (Pb, n = 92,082) exposure, defined based on study-specific exposure contrasts, were significantly related to increased risk of PTB, with pooled ORs (95% CIs) of 1.12 (1.01, 1.24) for Ba, 1.23 (1.10, 1.38) for Cd, 1.05 (1.01, 1.08) for Hg, and 1.27 (1.09, 1.48) for Pb. Additionally, higher Cd and Hg were significantly associated with an increased risk of LBW, with ORs of 1.12 (1.06, 1.18) and 1.09 (1.04, 1.14), respectively. Higher As, Cd and Pb were also significantly associated with increased risk of SGA, with corresponding ORs (95% CIs) of 1.04 (1.01, 1.07), 1.12 (1.07, 1.16), and 1.19 (1.12, 1.27), respectively. The significant associations between metal exposures and increased risk of SVNs persisted or became more pronounced with specific biospecimen types. Particularly, elevated blood Arsenic (As), Cd, Molybdenum (Mo), Pb and urinary Cd, Cobalt (Co), chromium (Cr), copper (Cu), Hg, and Nickel (Ni) were associated with increased odds of PTB: As (OR: 1.30, 95% CI: 1.001-1,70), Cd (OR: 1.26, 95% CI: 1.08-1.48), Mo (OR: 1.26, 95% CI: 1.01-1.58), Pb (OR: 1.27, 95% CI: 1.09-1.48), Cd (OR: 1.28, 95% CI: 1.06-1.54), Cr (OR: 1.65, 95% CI: 1.26-2.15), Cu (OR: 1.39, 95% CI: 1.24-1.56), and Hg (OR: 1.16, 95% CI: 1.03-1.30). Blood Cd and Hg were positively associated with LBW, with Cd (OR: 1.10, 95% CI: 1.02-1.18) and Hg (OR: 1.09, 95% CI: 1.04-1.14). Blood Cd and Pb showed positive associations with SGA. Significant dose-response associations were observed between different metals and SVN outcomes, including significant associations of Cd, Hg, Pb, and Thallium (Tl) with increased PTB risk, associations of Pb with increased risk of LBW and SGA, and significant associations between Selenium (Se) exposure and decreased risks of PTB and LBW.

A comprehensive synthesis of data among 325,705 live births demonstrated that gestational exposure to metal(loid)s, particularly As, Ba, Cd, Co, Cr, Cu, Hg, Mo, Ni, Pb, Sr and U, is significantly associated with increased risk of SVNs, which may have lifelong health implications for children and even their offspring. These findings underscore the critical need for monitoring and regulating environmental toxic metal exposures during pregnancy to mitigate adverse health outcomes at birth and later in life.