Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Oral and Maxillofacial Surgery, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
Hum Reprod. 2023 May 2;38(5):961-972. doi: 10.1093/humrep/dead006.
Is there an association between low-to-moderate levels of prenatal alcohol exposure (PAE) and children's facial shape?
PAE before and during pregnancy, even at low level (<12 g of alcohol per week), was found associated with the facial shape of children, and these associations were found attenuated as children grow older.
High levels of PAE during pregnancy can have significant adverse associations with a child's health development resulting in recognizably abnormal facial development.
STUDY DESIGN, SIZE, DURATION: This study was based on the Generation R Study, a prospective cohort from fetal life onwards with maternal and offspring data. We analyzed children 3-dimensional (3D) facial images taken at ages 9 (n = 3149) and 13 years (n = 2477) together with the data of maternal alcohol consumption.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined six levels of PAE based on the frequency and dose of alcohol consumption and defined three tiers based on the timing of alcohol exposure of the unborn child. For the image analysis, we used 3D graph convolutional networks for non-linear dimensionality reduction, which compressed the high-dimensional images into 200 traits representing facial morphology. These 200 traits were used for statistical analysis to search for associations with PAE. Finally, we generated heatmaps to display the facial phenotypes associated with PAE.
The results of the linear regression in the 9-year-old children survived correction for multiple testing with false discovery rate (FDR). In Tier 1 where we examined PAE only before pregnancy (exposed N = 278, unexposed N = 760), we found three traits survived FDR correction. The lowest FDR-P is 1.7e-05 (beta = 0.021, SE = 0.0040) in Trait #29; In Tier 2b where we examine any PAE during first trimester (exposed N = 756; unexposed N = 760), we found eight traits survived FDR correction. The lowest FDR-P is 9.0e-03 (beta = -0.013, SE = 0.0033) in Trait #139. Moreover, more statistically significant facial traits were found in higher levels of PAE. No FDR-significant results were found in the 13-year-old children. We map these significant traits back to the face, and found the most common detected facial phenotypes included turned-up nose tip, shortened nose, turned-out chin, and turned-in lower-eyelid-related regions.
LIMITATIONS, REASONS FOR CAUTION: We had no data for alcohol consumption more than three months prior to pregnancy and thus do not know if maternal drinking had chronic effects. The self-reported questionnaire might not reflect accurate alcohol measurements because mothers may have denied their alcohol consumption.
Our results imply that facial morphology, such as quantified by the approach we proposed here, can be used as a biomarker in further investigations. Furthermore, our study suggests that for women who are pregnant or want to become pregnant soon, should quit alcohol consumption several months before conception and completely during pregnancy to avoid adverse health outcomes in the offspring.
STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research. V.W.V.J. reports receipt of funding from the Netherlands Organization for Health Research (ZonMw 90700303). W.J.N. is a founder, a scientific lead, and a shareholder of Quantib BV.
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低至中度孕期酒精暴露（PAE）与儿童面部形状之间是否存在关联？
研究发现，妊娠前和妊娠期间的 PAE，即使水平较低（<12 克/周），也与儿童的面部形状有关，随着儿童年龄的增长，这些关联会减弱。
妊娠期间高水平的 PAE 会对儿童的健康发育产生重大不利影响，导致可识别的面部发育异常。
研究设计、大小和持续时间：本研究基于 Generation R 研究，这是一项从胎儿期开始的前瞻性队列研究，包含母婴和后代数据。我们分析了年龄为 9 岁（n=3149）和 13 岁（n=2477）的儿童的 3 维（3D）面部图像以及母亲饮酒数据。
参与者/材料、设置、方法：我们根据饮酒频率和剂量定义了六个 PAE 水平，并根据胎儿暴露于酒精的时间定义了三个等级。对于图像分析，我们使用了 3D 图卷积网络进行非线性降维，将高维图像压缩为代表面部形态的 200 个特征。这些 200 个特征用于统计分析，以寻找与 PAE 的关联。最后，我们生成了热图，以显示与 PAE 相关的面部表型。
在经过假发现率（FDR）校正的 9 岁儿童线性回归中，结果仍然存在。在仅在妊娠前检查 PAE 的第 1 层（暴露组 N=278，未暴露组 N=760）中，我们发现有三个特征通过了 FDR 校正。最低 FDR-P 为 1.7e-05（beta=0.021，SE=0.0040），在特征#29 中；在第 2b 层，我们检查了孕早期的任何 PAE（暴露组 N=756；未暴露组 N=760），有八个特征通过了 FDR 校正。最低 FDR-P 为 9.0e-03（beta=-0.013，SE=0.0033），在特征#139 中。此外，在更高水平的 PAE 中发现了更多具有统计学意义的面部特征。在 13 岁的儿童中没有发现 FDR 显著的结果。我们将这些显著的特征映射回面部，发现最常见的检测到的面部表型包括上翘的鼻尖、缩短的鼻子、外翘的下巴和内陷的下眼睑相关区域。
局限性、谨慎的原因：我们没有妊娠前三个月以上的酒精消费数据，因此不知道母亲的饮酒是否有慢性影响。自我报告的问卷可能无法反映准确的酒精测量值，因为母亲可能否认了她们的饮酒行为。
我们的研究结果表明，面部形态，如我们在这里提出的方法所量化的，可以作为进一步研究的生物标志物。此外，我们的研究表明，对于那些即将怀孕或希望尽快怀孕的女性，应在受孕前几个月停止饮酒，并在怀孕期间完全戒酒，以避免对后代的健康产生不良影响。
研究资金/利益冲突：这项工作得到了鹿特丹伊拉斯谟医疗中心、鹿特丹伊拉斯谟大学和荷兰健康研究组织的支持。V.W.V.J. 报告收到了荷兰健康研究组织（ZonMw 90700303）的资助。W.J.N. 是 Quantib BV 的创始人、科学领导人和股东。
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