孕期补充微营养素对子代青少年多维度健康结局的长效作用

Long-term effects of maternal micronutrient supplementation during pregnancy on adolescent multidimensional health outcomes in offspring

摘要

目的 旨在探讨母亲孕期微营养素补充对子代青少年期多维度健康结局的长期影响,为明确母亲微营养素补充对子代健康结局的长效作用提供循证依据。方法 本研究基于一项西北农村地区母亲孕期微营养素干预整群随机对照试验的纵向随访数据,纳入的青少年健康结局指标包括体质指数、肺活量、血压、智力和行为问题等,通过熵权逼近理想解排序法(TOPSIS)方法构建出健康综合得分,并基于 K 均值聚类方法识别了本研究人群中存在的三类健康模式:健康问题低风险组、行为问题高风险组、代谢问题高风险组。最后采用广义估计方程模型(GEE)分析母亲孕期补充叶酸(对照)、铁/叶酸及多维营养素3种不同营养素干预方案对子代健康综合得分的影响,并用多元 Logistic 回归模型探讨不同营养素干预对健康模式之间的长效作用。在此基础上,进一步分析了孕期营养素干预的开始孕周时间与持续补充时间长度对干预效果的潜在修饰作用。结果 本研究最终纳入研究对象共1 767人,平均年龄12岁(标准差为0.78),其中男性1 050名(59%)；1 416(83%)名青少年性发育已经启动。GEE 模型结果显示在控制相关协变量后,与补充叶酸相比,孕期补充铁/叶酸和多维营养素均可以提高子代健康综合得分,但差异没有统计学意义[铁/叶酸组: β=0.31,95% CI:(-0.33,0.94)；多维营养素组:β=0.04,95% CI:(-0.61,0.68)]；多元 Logistic回归结果显示,相较于叶酸组,多维营养素干预可显著降低青少年代谢问题高风险的可能性[OR =0.70,95% CI:(0.54,0.92)],风险概率降低约30%。在分层分析中,虽然微营养素干预方案与营养素补充持续时间及起始时间的交互项没有统计学意义,但当补充起始时间早于孕12周时,铁/叶酸和多维营养素干预均显著降低代谢问题高风险的发生风险[铁/叶酸组:OR=0.65,95% CI:(0.43,0.98)；多维营养素组:OR=0.63,95% CI:(0.42,0.97)]。结论 母亲孕期补充多维营养素可降低子代在青少年期代谢问题的发生风险,提示保证母亲孕期足够的微营养素营养有利于促进子代生命周期的代谢健康,为孕期微营养素补充指南提供了基于生命历程健康结局的新的循证依据。

Abstract

Objective Maternal supplementation with multiple micronutrients during pregnancy can improve birth outcomes, but whether it has long-term effects on offspring health outcomes remains unclear. Therefore, this study aimed to examine the long-term impacts of maternal micronutrient supplementation during pregnancy on multidimensional health outcomes in adolescents so as to provide evidence on its sustained effects on offspring health. Methods This study utilized longitudinal follow-up data from a cluster-randomized controlled trial of antenatal micronutrient supplementation conducted in rural northwest China. Adolescent health outcomes included body mass index (BMI), vital capacity, blood pressure, intelligence, and behavioral issues. A comprehensive health score was constructed using the entropy-weighted Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method. K-means clustering was then used to identify three distinct health profiles among adolescents: low-risk group, behavior-problem high-risk group, and metabolic-problem high-risk group. Generalized Estimating Equation (GEE) models were applied to evaluate the effects of different antenatal supplementation regimens—folic acid (control), iron/folic acid, and multiple micronutrients—on the comprehensive health score of the offspring. Multivariate Logistic regression was used to explore the long-term effects of these regimens on the identified health patterns. Additionally, potential effect modifications by timing of supplementation initiation and duration were assessed. Results We recruited a total of 1 767 adolescents (mean age 12.0 years, SD=0.78; 59% male) in the final analysis, of whom 83% had entered puberty. After adjusting for relevant covariates, the GEE model showed that both iron-folic acid and multiple micronutrient supplementation slightly increased offspring health scores compared to folic acid alone, but the differences were not statistically significant [iron/folic acid: β=0.31, 95% CI: (-0.33, 0.94); multiple micronutrients: β=0.04, 95% CI: (-0.61, 0.68)]. However, multivariate Logistic regression indicated that multiple micronutrient supplementation significantly reduced the odds of being in the metabolic-problem high-risk group [OR =0.70, 95% CI: (0.54, 0.92)], suggesting a 30% risk reduction. Although interactions between supplementation regimen and timing/duration were not statistically significant, stratified analyses revealed that when supplementation began before 12 weeks of gestation, both iron/folic acid and multiple micronutrient interventions significantly reduced the risk of metabolic problems during adolescence [iron/folic acid: OR=0.65, 95% CI: (0.43, 0.98); multiple micronutrients: OR =0.63, 95% CI: (0.42, 0.97)]. Conclusion Maternal multiple micronutrient supplementation during pregnancy may reduce the risk of metabolic problems in offspring during adolescence. These findings underscore the importance of adequate antenatal micronutrient intake for promoting metabolic health across the life course and provide new evidence to support antenatal supplementation guidelines from a life-course perspective.

关键词

整群随机对照试验 / 孕期微营养素补充 / 纵向随访 / 多维度健康结局 / 长效作用

Key words

cluster-randomized controlled trial / antenatal micronutrient supplementation / longitudinal follow-up / multidimensional health outcome / long-term effect

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基金资助

国家自然科学基金资助项目(82103867)

中央高校基本科研业务费专项资金资助(xxj032025066)

陕西省重点研发计划项目(2024SF-YBXM-310)

陕西省创新能力支撑计划项目(2023-CX-PT-47)