Neonatal birth weight is a crucial indicator of intrauterine growth and development with important implications for child development and adult health. The birth weight of a newborn is closely linked to the nutrition and health of the mother during pregnancy as well as genetic factors. Therefore, assessing the metabolic status of the fetus in utero is greatly significant for understanding the mechanisms responsible for abnormal birth weight. While previous studies often analyzed the impact of maternal metabolism on fetal development using umbilical cord blood from pregnant women, such blood may not accurately reflect the actual intrauterine environment owing to the barrier function of the placenta; moreover, obtaining biological samples during the fetal period is challenging. Meconium, the first feces excreted by a newborn, provides ideal biological material for studying maternal and infant health. Metabolomics can reveal metabolic changes in living organisms by analyzing small molecules in biological samples; hence studying meconium samples using metabolomics technology is expected to reveal fetal metabolic changes during pregnancy, thereby providing new insights into fetal nutritional intake, growth, and development, as well as metabolic pathways related to birth weight. To gain a deeper understanding of the metabolic changes associated with birth weight, this study collected metabolomic data from the meconium of 484 newborns in the established Xiaogan birth cohort using an untargeted metabolomics technique based on liquid chromatography-high resolution mass spectrometry (LC-HRMS) and analyzed the association between meconium metabolites and birth weight. This cohort exhibited incidence rates of low birth weight (<2500 g) and macrosomia (>4000 g) of 3.3% and 7.2%, respectively, which were roughly equivalent to the national average. Orthogonal partial least squares discriminant analysis revealed significant differences between the meconium metabolomes of the low birth weight and macrosomic groups when compared to the normal weight group. We discovered significant distinctions between the differential metabolites of newborns of low birth weight and those of normal weight, as well as between macrosomic and normal weight newborns that point to disparate biological pathways. Newborns with low birth weight exhibited significantly lower levels of critical amino acids, such as glutamate and proline, compared to the normal weight group, which may be associated with placental dysfunction and maternal nutritional deficiencies. Conversely, the meconium of macrosomic newborns contained significantly elevated levels of hormone metabolites such as estrone that reflected the pathophysiological state associated with maternal metabolic diseases or excessive placental hormone levels. Our study suggests that the metabolomic profile of the meconium reflects the metabolic pathways and regulatory mechanisms at play during fetal growth and development, and offers potential metabolic biomarkers and directions for future in-depth research into diseases related to fetal development. However, this study was based solely on the Xiaogan birth cohort, which was limited to specific regions and populations. A multicenter, multiethnic, and multiregional study is expected to help validate the universality of our research findings.
新生儿出生体重是反映新生儿在宫内生长和发育情况的重要指标,其对儿童发育及成人健康状况评价具有重要的意义。胎便是新生儿在母体分娩后排出的最初粪便,被认为是研究母婴健康状况的理想生物样本。本研究依托孝感市妇幼保健院建立的出生队列,采用基于液相色谱-高分辨质谱的非靶向代谢组学技术,采集了484例新生儿胎便的代谢组数据,筛选出不同出生体重组间的差异代谢物,并探究了相关分子机理。在该出生队列中,低出生体重儿(<2500 g)和巨大儿(>4000 g)的发病率分别为3.3%和7.2%,与全国平均水平基本相当。正交偏最小二乘判别分析结果显示,与正常体重组相比,无论是低出生体重组还是巨大儿组,其胎便代谢组之间均存在显著差异(P<0.05)。实验还发现,低出生体重儿与正常体重儿之间以及巨大儿与正常体重儿之间的差异代谢物存在明显区别,分别指向不同的生物学途径。低出生体重儿胎便中的谷氨酸和脯氨酸等关键氨基酸的含量显著低于正常体重组(P<0.05),这可能与胎盘功能障碍和母体营养不足有关;与正常体重组相比,巨大儿胎便中的雌酮等激素代谢物水平显著升高(P<0.05),说明母体可能存在代谢性疾病或处于胎盘激素水平过高相关的生理状态。研究结果表明,胎便代谢物谱的差异可能是胎儿生长发育过程中不同代谢途径与调控机制的反映,该发现有望为胎儿发育相关疾病的深入研究提供潜在代谢标志物和研究方向。但是,本研究仅是基于孝感市出生队列开展,局限于特定的地区和人群,而建立多中心、多种族、多地区的研究方法将有助于验证研究结果的普适性。
Keywords: birth cohort; liquid chromatography-high resolution mass spectrometry (LC-HRMS); meconium; metabolomics; neonatal birth weight.