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

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.

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.

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.

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.

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.

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.