Preconception and Early Pregnancy Exposure to Ambient Air Pollution and Risk of Cleft Lip and/or Palate: A Case–Control Study Using Single‐Pollutant, Multi‐Pollutant, and Mixture‐Based Analyses

BACKGROUND: Cleft lip and/or palate (CLP) is among the most common congenital anomalies worldwide. Ambient air pollution has emerged as an important environmental exposure potentially contributing to its multifactorial etiology. This study investigated associations between ambient air pollutant exposures during the preconception period and first trimester of pregnancy and the risk of CLP. Associations between pollutant exposures and CLP risk were evaluated using adjusted single-pollutant, multi-pollutant, and weighted quantile sum (WQS) regression models. O₃ demonstrated the strongest and most consistent associations across exposure windows and analytical approaches, remaining the dominant contributor in WQS mixture analyses. In contrast, associations involving traffic-related pollutants were less consistent and were not retained across modeling approaches. Ambient air pollution, particularly ozone and particulate matter, was consistently associated with an increased risk of nonsyndromic CLP during the preconception period and early pregnancy. CONCLUSION: These findings support the potential importance of air quality within the multifactorial etiology of CLP and highlight the need for further studies using refined exposure assessment, larger populations, and phenotype-specific analyses to clarify causal pathways and inform prevention strategies.