母亲妊娠期间补充多种微量营养素使儿童更聪明
受孕后1000天内，大脑和认知（包括感觉、知觉、记忆、思维、想象、言语）发展受到多种先天性生物医学和后天性社会环境决定因素的影响，包括营养、健康、养育和刺激，故需深入了解这些因素的长期影响，以优先考虑公共卫生投资、优化人类发展。
2017年2月，英国《柳叶刀·全球卫生分册》正式发表印度尼西亚SUMMIT发展研究所、美国加利福尼亚大学戴维斯分校、澳大利亚迪肯大学、英国兰卡斯特大学、美国乔治城大学、印度尼西亚马塔兰大学、美国哈佛大学陈曾熙公共卫生学院的研究报告，发现母亲在妊娠期间补充多种微量营养素（MMN）与仅仅补充铁＋叶酸（IFA）相比，可以增强儿童的认知能力，儿童在9～12岁时的能力表现相当于比同龄人多上半年甚至一年的学。
注：世界卫生组织国际多种微量营养素胶囊（30mg铁＋400μg叶酸＋800μg视黄醇＋200IU维生素D＋10mg维生素E＋70mg维生素C＋1.4mg维生素B1＋1.4mg维生素B2＋18mg烟酸＋1.9mg维生素B6＋1.6μg维生素B12＋15mg锌＋2mg铜＋65μg硒＋150μg碘）
该研究为多种微量营养素干预试验（SUMMIT）双盲整群随机分组随访研究，由联合国儿童基金会（UNICEF）、美国国际发展署（USAID）等机构资助。该研究于2001～2004年在印度尼西亚入组31290位母亲，随机分入MMN组（15804位）或IFA组（15486位），确认出生后存活至3个月的婴儿27356位（MMN组13883位，IFA组13473位），2012～2014年重新入组未失访的9～12岁儿童19274位（70%，MMN组9828位，IFA组9446位），并从18230位在已知地点上学的学生中随机选择2879位儿童（MMN组1466位，IFA组1413位）。其中，母亲在SUMMIT入组时存在贫血或营养不良的儿童574位（MMN组279位，IFA组295位）。评估MMN和生物医学相关性（母亲和儿童的人体测量学、血红蛋白、早产与否）和社会环境决定因素（父母教育、社会经济地位、家庭环境、母亲抑郁与否）对一般智力、陈述性记忆、程序性记忆、执行能力、学业成就、精细动作灵活性、社会情感健康的影响。SUMMIT的国际标准随机对照试验编号（ISRCTN）为：34151616。
随访调查结果发现，母亲妊娠期间补充MMN，其后代的智力表现令人惊讶，比如有更好的程序性记忆能力，反映在学业成绩上，相当于比同龄儿童多上了半年至一年学的水平，尤其对于贫血母亲。母亲妊娠期间补充MMN的儿童程序性记忆平均评分比IFA组高0.11SD（95%置信区间：0.01～0.20，P=0.0319），相当于增加半年学时的评分。程序性记忆对儿童在学业和日常生活中的表现都非常重要，并与语言、打字、阅读、计算、驾驶等技能的学习相关。MMN组贫血母亲的儿童一般智力评分比IFA组高0.18SD（95%置信区间：0.06～0.31，P=0.0047），相当于增加一年学时。总体上，MMN组在21项测试中有18项评分比IFA组高0.00～0.18SD（P=0.0431）。
更令人吃惊的是，儿童认知能力与婴幼儿时期外界环境条件之间的相关性。母亲妊娠期间营养水平、出生时体重偏低、早产、婴儿时期体格发育不良等生物医学因素对儿童认知能力的影响，都不如外界环境因素影响大。这些因素包括家庭环境、母亲是否抑郁、父母教育程度、社会经济地位等。在多元回归模型中，社会环境决定因素系数为0.00～0.43SD，35项测试中的22项在95%置信区间水平有显著性，而生物医学系数为0.00～0.10SD，56项测试中的8项有显著性，表明社会环境因素的影响更大且更一致（P＜0.0001）。
因此，母亲补充MMN对9～12岁儿童认知发育具有长期益处，从而支持其对儿童早期发育的作用以及对MMN的政策调整。社会环境决定因素与认知改善之间的相关性更强，让儿童更聪明的重要社会环境决定因素包括：良好的早期养育环境、母亲的快乐情绪、父母的教育程度高，儿童从小的养育环境对其大脑发育和整体智力水平的影响甚至大于先天性生物医学决定因素，表明目前以先天性生物医学决定因素为重点的生殖、孕产妇、新生儿和儿童健康方案可能不足以增强儿童认知，解决社会环境决定因素的方案对于提高人口素质至关重要。
对此，英国伦敦大学卫生与热带医学院学者发表同期述评《产前营养、社会环境条件与儿童发育》。
Lancet Glob Health. 2017 Feb;5(2):e217-e228.
Maternal multiple micronutrient supplementation and other biomedical and socioenvironmental influences on children's cognition at age 9-12 years in Indonesia: follow-up of the SUMMIT randomised trial.
Prado EL, Sebayang SK, Apriatni M, Adawiyah SR, Hidayati N, Islamiyah A, Siddiq S, Harefa B, Lum J, Alcock KJ, Ullman MT, Muadz H, Shankar AH.
SUMMIT Institute of Development, Mataram, Nusa Tenggara Barat, Indonesia; University of California Davis, Davis, CA, USA; Deakin University, Melbourne, VIC, Australia; Lancaster University, Bailrigg, Lancaster, UK; Georgetown University, Washington, DC, USA; University of Mataram, Mataram, Nusa Tenggara Barat, Indonesia; Harvard TH Chan School of Public Health, Boston, MA, USA.
BACKGROUND: Brain and cognitive development during the first 1000 days from conception are affected by multiple biomedical and socioenvironmental determinants including nutrition, health, nurturing, and stimulation. An improved understanding of the long-term influence of these factors is needed to prioritise public health investments to optimise human development.
METHODS: We did a follow-up study of the Supplementation with Multiple Micronutrients Intervention Trial (SUMMIT), a double-blind, cluster-randomised trial of maternal supplementation with multiple micronutrients (MMN) or iron and folic acid (IFA) in Indonesia. Of 27,356 live infants from birth to 3 months of age in 2001-04, we re-enrolled 19,274 (70%) children at age 9-12 years, and randomly selected 2879 from the 18,230 who were attending school at a known location. Of these, 574 children were oversampled from mothers who were anaemic or malnourished at SUMMIT enrolment. We assessed the effects of MMN and associations of biomedical (ie, maternal and child anthropometry and haemoglobin and preterm birth) and socioenvironmental determinants (ie, parental education, socioeconomic status, home environment, and maternal depression) on general intellectual ability, declarative memory, procedural memory, executive function, academic achievement, fine motor dexterity, and socioemotional health. The SUMMIT trial was registered, number ISRCTN34151616.
FINDINGS: Children of mothers given MMN had a mean score of 0.11 SD (95% CI 0.01-0.20, p=0.0319) higher in procedural memory than those given IFA, equivalent to the increase in scores with half a year of schooling. Children of anaemic mothers in the MMN group scored 0.18 SD (0.06-0.31, p=0.0047) higher in general intellectual ability, similar to the increase with 1 year of schooling. Overall, 18 of 21 tests showed a positive coefficient of MMN versus IFA (p=0.0431) with effect sizes from 0.00-0.18 SD. In multiple regression models, socioenvironmental determinants had coefficients of 0.00-0.43 SD and 22 of 35 tests were significant at the 95% CI level, whereas biomedical coefficients were 0.00-0.10 SD and eight of 56 tests were significant, indicating larger and more consistent impact of socioenvironmental factors (p<0.0001).
INTERPRETATION: Maternal MMN had long-term benefits for child cognitive development at 9-12 years of age, thereby supporting its role in early childhood development, and policy change toward MMN. The stronger association of socioenvironmental determinants with improved cognition suggests present reproductive, maternal, neonatal, and child health programmes focused on biomedical determinants might not sufficiently enhance child cognition, and that programmes addressing socioenvironmental determinants are essential to achieve thriving populations.
FUNDING: Grand Challenges Canada Saving Brains Program.
PMID: 28104188
DOI: 10.1016/S2214-109X(16)30354-0
Lancet Glob Health. 2017 Feb;5(2):e127-e128.
Prenatal nutrition, socioenvironmental conditions, and child development.
Persson LA.
London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
PMID: 28104172
DOI: 10.1016/S2214-109X(16)30356-4