Exposure to ambient air pollutants during early gestation and phenotypic variation in non-syndromic microtia

Prenatal exposure to ambient air pollution has been associated with congenital anomalies; however, its association with phenotypic variation among patients with microtia is poorly defined. In this single-center retrospective case-only study, we examined the associations of estimated ambient air-pollutant exposure during gestational weeks 5-9 and bilateral involvement and anatomical severity among patients with nonsyndromic microtia. Exposures to PM_2.5, PM₁₀, O₃, NO₂, SO₂, and CO were assessed using a spatiotemporal model linked to residential addresses recorded at initial clinical registration. Associations were examined using logistic regression and generalized estimating equations, with adjustment for sex, temperature, and relative humidity, as appropriate; false discovery rate correction was also applied. The analysis included 589 patients with 625 affected ears. O₃ showed a nominal positive association with bilateral involvement overall (P=0.033) and in men (P=0.014), whereas PM₁₀, SO₂, and CO showed nominal inverse associations overall. After FDR correction of the sex-stratified analyzes, only the inverse association between SO₂ and left-ear severity among males continued to be significant (q=0.019); however, no pollutant-by-sex interaction was found to be significant. In side-specific analyzes, SO₂ showed nominal positive and inverse associations with right-ear (P=0.014) and left-ear severity (P=0.049), respectively. A formal pollutant-by-ear-side interaction was observed for SO₂ (P for interaction=0.007; q=0.042). Prenatal air-pollutant exposure may be associated with phenotypic variation among patients with microtia, and severity associations may differ according to the ear side. These findings require confirmation in population-based studies that include unaffected controls.