Association of maternal heavy metal exposure during pregnancy with isolated cleft lip and palate in offspring: Japan Environment and Children’s Study (JECS) cohort study

BACKGROUND: Cleft lip and palate (cleft L/P) is one of the most common congenital anomalies and its etiology is assumed to be multifactorial. Recent epidemiological data involving a small number of participants suggested an association between perinatal exposure to heavy metals and cleft L/P in affected children. However, this association requires further investigation in a large cohort. METHODS: This nested case–control study used a dataset of The Japan Environment and Children’s Study, which is an ongoing research project to investigate the association between environmental factors and mother-child health. Participants were enrolled between 2011 and 2014. From the records of fetuses/children, we extracted data of isolated cleft L/P cases and matched children without cleft L/P at a ratio of 1:10. The exposures of interest were in utero exposure to four metals (mercury [Hg], lead [Pb], cadmium [Cd], and manganese [Mn]), which were sampled from mothers in the second/third trimester. Conditional logistic regression was used to assess the association between heavy metal exposure and isolated cleft L/P. Three sensitivity analyses were conducted to test the robustness of the findings, including the change in case definition and statistical methods. RESULTS: Of 104,062 fetal records involving both live-birth and stillbirth, we identified 192 children with isolated cleft L/P and 1,920 matched controls. Overall, the blood metal levels were low (for example, median Pb level was 5.85, 6.22, and 5.75 μg/L in the total cohort, cases, and controls, respectively). Univariate and multivariate analyses showed that levels of none of the four heavy metals in the mother’s blood during pregnancy were associated with the risk of cleft L/P in offspring; the adjusted odds ratios (per 1 μg/L increase) with 95% intervals were 0.96 (0.91–1.03), 1.01 (0.94–1.08), 1.00 (0.61–1.63) and 1.00 (0.97–1.03) for Hg, Pb, Cd and Mn, respectively. The results were consistent in all sensitivity analyses. CONCLUSIONS: Exposure to these four metals during pregnancy was not associated with isolated cleft L/P at the low exposure level in our cohort.