Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan.
Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa, Japan.
PLoS One. 2022 Mar 24;17(3):e0265648. doi: 10.1371/journal.pone.0265648. eCollection 2022.
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.
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.
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.
Exposure to these four metals during pregnancy was not associated with isolated cleft L/P at the low exposure level in our cohort.
唇腭裂（CL/P）是最常见的先天畸形之一，其病因被认为是多因素的。最近涉及少数参与者的流行病学数据表明，围产期暴露于重金属与受影响儿童的 CL/P 之间存在关联。然而，这一关联需要在大样本队列中进一步研究。
本巢式病例对照研究使用了日本环境与儿童研究（JECS）的数据集，这是一项正在进行的研究项目，旨在调查环境因素与母婴健康之间的关联。参与者于 2011 年至 2014 年期间入组。我们从胎儿/儿童的记录中提取了单纯 CL/P 病例的数据，并以 1:10 的比例匹配无 CL/P 的儿童。感兴趣的暴露是母亲在妊娠中期/晚期采集的四种金属（汞[Hg]、铅[Pb]、镉[Cd]和锰[Mn]）的宫内暴露。条件逻辑回归用于评估重金属暴露与单纯 CL/P 之间的关联。进行了三项敏感性分析，以检验结果的稳健性，包括病例定义和统计方法的改变。
在涉及活产儿和死产儿的 104062 份胎儿记录中，我们共确定了 192 名单纯 CL/P 患儿和 1920 名匹配对照。总体而言，血液中金属水平较低（例如，总队列、病例和对照组中母亲血铅水平中位数分别为 5.85、6.22 和 5.75μg/L）。单变量和多变量分析表明，妊娠期间母亲血液中四种重金属水平均与后代 CL/P 风险无关；调整后的比值比（每增加 1μg/L）的 95%区间分别为 0.96（0.91-1.03）、1.01（0.94-1.08）、1.00（0.61-1.63）和 1.00（0.97-1.03），Hg、Pb、Cd 和 Mn 分别。所有敏感性分析的结果均一致。
在本队列的低暴露水平下，妊娠期间接触这些四种金属与单纯 CL/P 无关。
