摘 要： 成年女性肥胖是全球性的公共卫生问题。母亲孕前肥胖可能会对子代的认知功能和智力发育产生不良影响, 并增加子代出现行为问题、注意力缺陷和多动障碍 (attention deficit hyperactivity disorder, ADHD) 以及孤独症谱系障碍 (autism spectrum disorders, ASD) 等的风险。孕前母亲肥胖对子代神经心理发育影响的具体机制尚未被完全理解, 可能与脑源性神经营养因子 (brain-derived neurotrophic factor, BDNF) 、子代大脑代谢改变及炎症等有关。本文对孕前母亲肥胖对子代神经心理发育影响及可能机制作以简要综述, 呼吁相关部门及医务人员积极预防母亲孕前肥胖发生, 以促进后代身心健康发展。
关键词： 孕前肥胖; 子代; 神经心理发育; 认知功能;
Abstract： Obesity in adult women is a global public health problem. Maternal pre-pregnancy obesity may have adverse effects on cognitive function and mental development of offspring and increase the risk of offspring's behavioral problems, attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) . The specific mechanism of maternal pre-pregnancy obesity on the neuropsychological development of offspring is not clear, brain-derived neurotrophic factor (BDNF) , the changes in offspring's brain metabolism and inflammation may be involved in it. This article briefly reviews the effect of maternal pre-pregnancy obesity on the neuropsychological development of offspring and the related mechanism, and calls on relevant departments and medical staff to actively prevent maternal pre-pregnancy obesity so as to promote the healthy development of offspring.
Keyword： maternal pre-pregnancy obesity; offspring; neuropsychological development; cognitive function;
成年女性肥胖是重要的世界性卫生问题。据WHO统计, 2016年全球约有40%的18岁及以上女性超重, 15%为肥胖[1]。肥胖不仅对成年女性自身健康造成危害[2], 若女性在怀孕前超重或肥胖还会增加子代神经心理发育不良的风险[3]。儿童神经心理发育是以神经系统的生长发育为基础, 主要表现在感知、运动、语言和心理活动等方面的发展[4], 若发育不良对婴儿期、儿童期甚至成人期的社会心理发展均会产生深远影响。本文就孕前母亲肥胖与子代神经心理发育不良的关系及相关机制作以简要综述。
1、 孕前母亲肥胖影响子代神经心理发育
1.1、 认知功能和智力发育
认知功能主要包括感知觉、记忆及思维等方面, 是个体重要的心理活动和人的意识的集中体现[5]。智力是使人能顺利地从事某种活动所必须的一般性认知能力, 也是一种综合的认识能力, 由注意力、观察力、想象力、记忆力和思维力等基本因素组成[5]。
多项研究证实, 与孕前体重正常的母亲相比, 肥胖母亲的子代认知功能和智力水平偏低[6-8]。Basatemur等[9]研究发现, 母亲孕前肥胖对子代5岁时的空间视觉能力有负面影响;对子代7岁时的语言能力、空间视觉和数字技能均有不良影响, 且孕前身体质量指数 (body mass index, BMI) 每增加10%, 其子代在7岁时的认知功能评分下降约1.5分。皮博迪个人成就测试常用于评估子代的认知能力, 研究者发现与孕前体重正常母亲的子代相比, 肥胖母亲子代的阅读识别和数字计算能力均下降[10]。另有研究通过记录完成威斯康星卡片分类测试中B部分的时间来评估子代执行功能, 结果表明孕前肥胖母亲的子代完成测试所需时间更长, 且其智商 (intelligence quotient, IQ) 评分比非肥胖母亲的子代低3.2[11]。值得注意的是, 在研究孕前母亲BMI与子代IQ之间关系时, 有学者发现二者呈倒U型关系, 即母亲孕前的BMI过低或过高都与子代智商较低有显着的相关性, 但BMI过高者其子代智商下降幅度高于BMI过低者的子代[12]。由此可见, 孕前母亲肥胖对子代的认知功能和智力发育均有不良影响。
1.2 、内化性与外化性行为问题
人们往往将儿童青少年行为问题划分为内化性和外化性两大类, 在评价过程中通常将退缩、躯体主诉、焦虑或抑郁等行为归入内化性行为, 将违纪、攻击性等表现归入外化性行为[13]。
孕前母亲肥胖与子代发生内化性行为和外化性行为风险之间的关系尚存争议。Van等[14]指出, 在控制混杂因素后, 相比孕前正常体重母亲的子代, 肥胖母亲的子代在2岁时仍有较高的外化性行为倾向, 而子代在1-2岁时的内化性行为表现并无明显变化, 与Brion等[15]的研究结果一致。澳大利亚妊娠队列研究结果显示, 子代外化性行为水平在儿童和青少年时期随着母亲孕前BMI的增加平稳升高, 内化性行为在8岁时显现, 并随着时间的推移逐渐加重[16]。英国一项双生子研究也表明, 相比孕前正常体重母亲的子代, 肥胖母亲的子代表现出外化性行为和攻击性倾向的比率更高[17]。还有学者发现, 孕前母亲肥胖的子代患焦虑和抑郁的风险上升, 提示孕前母亲肥胖对子代内化性行为也有负面影响[18-19]。以不同种族母亲和子代为观察对象的研究表明, 白人孕前肥胖母亲的子代内化和外化性行为风险升高, 但这种联系在黑人孕前肥胖母亲的子代中并不显着, 表明种族特征可能是孕前肥胖与子代内化和外化性行为关系的影响因素[20]。最近一项研究通过评价9～11岁儿童的行为问题, 结果发现在孕前肥胖母亲的子代中, 男孩外化性行为得分高于对照组, 而在女孩中并未发现显着差异, 提示孕前母亲肥胖对子代外化性行为的影响可能存在性别差异[21]。Jone等[22]在未校正的模型中发现孕前母亲肥胖与子代外化性行为有关, 但在控制家庭环境和母亲抑郁这两个因素后, 二者关联性消失, 他们推测家庭环境和母亲抑郁可能是造成两者相关的主要原因。
1.3、 注意力缺陷和多动障碍 (attention deficit hyperactivity disorder, ADHD)
ADHD又称多动症, 是以注意力不集中、活动过度、情绪冲动、学习困难为特征的综合征[23]。儿童发生ADHD往往与家族遗传、神经系统损害等多种因素有关, 是常见的儿童青少年心理卫生障碍[24]。
孕前母亲肥胖是子代患ADHD风险升高的重要危险因素。报道显示, 孕前母亲超重或肥胖可增加低龄儿童患ADHD的风险[6,25]。另有学者以10岁儿童为观察对象, 研究也发现与孕前母亲体重正常的子代相比, 肥胖母亲的孩子发生注意力不集中、冲动等ADHD相关症状的比率增高[26,27]。Andersen等[28]将丹麦国家出生队列数据库中的8万名独生子女和母亲进行一对一亲子配对, 统计结果显示子代确诊ADHD的年龄范围在10～16岁, 与体重正常组相比, 超重/肥胖母亲的孩子患ADHD的风险比高达1.28～1.95。在探索母亲孕前BMI与子代ADHD关系时, Chen[29]和Musser[30]先后将ADHD患儿与其同胞做了比较, 进行全人群分析时结果均显示孕前母亲肥胖增加子代患ADHD的风险, 孕前母亲BMI每增加一个单位, 子代患ADHD的风险升高4%, 在进一步进行同胞比较分析后发现, 孕前BMI与子代ADHD的关系不再有统计学意义, 学者将这种变化归因于家庭混杂因素的影响。
1.4、 孤独症谱系障碍 (autism spectrum disorders, ASD)
ASD也叫自闭症, 是一种以社交沟通障碍和重复刻板行为为主要特征的神经发育障碍性疾病[23], 严重影响儿童的身心健康和家长的健康状况及生存质量, 且增加患儿家庭的经济负担、养护负担和亲职压力[31]。 母亲孕前肥胖可增加子代患ASD的风险[32-34]。最近一项回顾性病例对照研究称, 孕前母亲体重水平和子代ASD之间呈J型关系, 即孕前母亲BMI越高, 子代患ASD的风险越大[35]。子代患ASD的风险增加不仅与孕前母亲肥胖有关, 且与母亲是否患有糖尿病有关, 若孕前母亲肥胖合并糖尿病, 则子代患ASD的风险高于二者单独作用, 表明孕前母亲肥胖和糖尿病具有协同作用[36]。我国学者将汉族705名ASD患儿和2 236名对照儿童作为研究对象, 调查母亲孕前BMI和妊娠期体重增长与子代发生ASD风险之间关系, 二元logistic回归分析结果显示母亲妊娠期体重增长过多的子代患ASD风险增高, 是对照儿童的1.3倍, 且孕前母亲超重/肥胖可使这种风险增高至2.5倍[37]。
2、 可能机制
目前, 人们对于孕前母亲肥胖对子代神经心理发育影响的具体机制仍不完全清楚, 现有研究观点主要集中在以下几个方面。
2.1、 脑源性神经营养因子 (brain-derived neurotrophic factor, BDNF)
孕前母亲肥胖可能是通过BDNF介导神经元突触可塑性改变, 对子代神经心理发育产生不良影响。BDNF是神经营养素家族的一员, 在神经元分化、突触可塑性及海马依赖性认知等方面起关键作用[38]。BDNF可调节长时程增强 (long-term potentiation, LTP) , LTP是兴奋性突触效能的持续增强, 也是学习和记忆的基础[39]。Tozuka等[40]用高脂饮食 (high fat diet, HFD) 诱导母鼠肥胖, 结果发现与孕前体重正常母鼠的子代相比, 肥胖母鼠的子代幼鼠海马中BDNF的表达减少, 新生神经元的树突受损, 空间认知功能下降。Park等[41]发现, 肥胖母亲的雄性子代海马区BDNF及其酪氨酸激酶B受体的表达被抑制, 神经元细胞增殖和分化减少, 空间学习能力下降, 这些变化能通过加强父亲运动得到改善。
2.2、 子代大脑代谢改变
孕前母亲肥胖可能通过改变子代大脑代谢对子代神经心理发育产生不良影响。研究发现, 与对照组相比, 孕前母亲高脂饮食的子代大脑内侧前额叶皮质和海马区氨基酸水平降低, 导致子代认知功能损伤, 其中对参考记忆和联想式学习的影响最为严重[42]。近期一项研究使用LepRdb/+小鼠模型来模拟孕前母亲肥胖, 子代在断奶后饲以HFD或低脂肪饮食, 采用Mirrors水迷宫测量子代认知功能, 气相色谱-质谱法分析子代的前额叶皮质和海马的脂肪酸代谢特征, 结果显示相比于对照组, 孕前母亲肥胖的雄性子代前额叶皮质中脂肪酸蓄积增多, 在子代继续进食HFD后, 雄性子代海马区的脂肪酸也可见大量蓄积, 并导致雄性子代空间认知能力下降[43]。
2.3、 炎症
炎症可能在孕前母亲肥胖致子代神经心理发育的不良影响中起重要作用。研究表明, 肥胖患者机体处于一种慢性低度炎症状态[44]。孕前肥胖的母亲体内促炎性细胞因子的水平高于体重正常者, 母亲BMI的增加与胎盘炎症通路的激活有关[45]。宫内炎症和胎盘炎症能改变胎儿细胞因子的表达, 造成胎儿神经元损伤[46]。研究人员从孕前4周开始, 用HFD饮食诱导母鼠肥胖, 结果发现与对照组相比, 肥胖母鼠的子代外周和海马区的促炎性细胞因子表达显着增加, 空间推理能力下降, 并有焦虑表现[47]。另一项研究也得出类似结论, 并且证实通过哺乳期母亲饮食干预, 子代社交能力能够得到改善[48]。铁调节和髓鞘形成紧密相关, 炎症可破坏这一过程, 从而对神经发育产生有害影响, 研究发现与孕前喂食对照饮食的母鼠相比, 喂食HFD母鼠的子代幼鼠血清和大脑中炎性细胞因子水平过高, 铁调节失衡, 雄性幼鼠的内侧皮质中髓鞘形成减少, 识别新物体行为发生变化[49]。
3、 小结与展望
综上所述, 孕前母亲肥胖可能会对子代的认知功能和智力发育造成诸多不良影响, 并可引起子代出现行为问题、患ADHD以及ASD等疾病的风险增高。尽管人们已认识到, BDNF表达减少介导的神经元受损和突触可塑性变化、子代大脑前额叶皮质/海马区的氨基酸水平降低和脂肪酸累积增多以及孕前肥胖母亲体内的慢性低度炎症引起孕母胎盘和子代大脑炎性细胞因子水平过高等多种因素可能是其原因, 但具体机制尚不清楚, 需要进一步进行探究。
人们发现孕前母亲肥胖还与子代癫痫[50]、哮喘[51]和脑瘫[52]等临床表现相关, 给孩子的身心健康造成严重危害。人们就孕前母亲肥胖导致子代神经心理发育等诸多不良结局的研究较多, 近期有学者从表观遗传学[53]和肠道菌群失调[54]等方面进行探索, 因为多种机制之间还互相联系, 具体如何作用尚需深入研究。相关医护人员及研究者未来应在这一领域投入更多的精力, 深入理解孕前母亲肥胖对子代的不良影响, 加强孕前及产前宣传教育, 鼓励育龄期女性适度锻炼、合理膳食、监测体重、重视围生期保健, 以利于下一代神经心理发育。
参考文献
[1] WHO.肥胖和超重[EB/OL]. (2017-10) [2018-11-21].http://www.who.int/mediacentre/factsheets/fs311/zh/.
[2] 徐继英, 严青华, 姚海宏.上海市成年人中心性肥胖者糖尿病的患病风险[J].实用预防医学, 2018, 25 (7) :810-813.
[3] Sanchez CE, Barry C, Sabhlok A, et al.Maternal pre-pregnancy obesity and child neurodevelopmental outcomes:a meta-analysis[J].Obes Rev, 2018, 19 (4) :464-484.
[4] 王卫平, 毛萌, 李廷玉.儿科学[M].北京:高等教育出版社, 2017:16-19.
[5] 姚本先, 桑青松, 桂守才.心理学[M].北京:高等教育出版社, 2018:83-164.
[6] Jo H, Schieve LA, Sharma AJ, et al.Maternal prepregnancy body mass index and child psychosocial development at 6 years of age[J].Pediatrics, 2015, 135 (5) :e1198-1209.
[7] Bliddal M, Olsen J, Stovring H, et al.Maternal pre-pregnancy BMI and intelligence quotient (IQ) in 5-year-old children:a cohort based study[J].PLoS One, 2014, 9 (4) :e94498.
[8] Alvarez-Bueno C, Cavero-Redondo I, Lucas-de la Cruz L, et al.Association between pre-pregnancy overweight and obesity and children's neurocognitive development:a systematic review and meta-analysis of observational studies[J].Int J Epidemiol, 2017, 46 (5) :1653-1666.
[9] Basatemur E, Gardiner J, Williams C, et al.Maternal prepregnancy BMI and child cognition:a longitudinal cohort study[J].Pediatrics, 2013, 131 (1) :56-63.
[10] Tanda R, Salsberry PJ, Reagan PB, et al.The impact of prepregnancy obesity on children's cognitive test scores[J].Matern Child Health J, 2013, 17 (2) :222-229.
[11] Pugh SJ, Richardson GA, Hutcheon JA, et al.Maternal obesity and excessive gestational weight gain are associated with components of child cognition[J].J Nutr, 2015, 145 (11) :2562-2569.
[12] Huang L, Yu X, Keim S, et al.Maternal prepregnancy obesity and child neurodevelopment in the Collaborative Perinatal Project[J].Int J Epidemiol, 2014, 43 (3) :783-792.
[13] 苏林雁, 李雪荣, 罗学荣, 等.Achenbach儿童行为量表的再标准化及效度检验[J].中国心理卫生杂志, 1998, (2) :4-6, 63.
[14] Van-Lieshout RJ, Schmidt LA, Robinson M, et al.Maternal pre-pregnancy body mass index and offspring temperament and behavior at 1 and 2 years of age[J].Child Psychiatry Hum Dev, 2013, 44 (3) :382-390.
[15] Brion MJ, Zeegers M, Jaddoe V, et al.Intrauterine effects of maternal prepregnancy overweight on child cognition and behavior in 2 cohorts[J].Pediatrics, 2011, 127 (1) :202-211.
[16] Van-Lieshout RJ, Robinson M, Boyle MH.Maternal pre-pregnancy body mass index and internalizing and externalizing problems in offspring[J].Can J Psychiatry, 2013, 58 (3) :151-159.
[17] Antoniou EE, Fowler T, Reed K, et al.Maternal pre-pregnancy weight and externalising behaviour problems in preschool children:a UK-based twin study[J].BMJ Open, 2014, 4 (10) :e005974.
[18] Mina TH, Lahti M, Drake AJ, et al.Prenatal exposure to very severe maternal obesity is associated with adverse neuropsychiatric outcomes in children[J].Psychol Med, 2017, 47 (2) :353-362.
[19] Robinson M, Zubrick SR, Pennell CE, et al.Pre-pregnancy maternal overweight and obesity increase the risk for affective disorders in offspring[J].J Dev Orig Health Dis, 2013, 4 (1) :42-48.
[20] Tanda R, Salsberry PJ.Racial differences in the association between maternal prepregnancy obesity and children's behavior problems[J].J Dev Behav Pediatr, 2014, 35 (2) :118-127.
[21] Deardorff J, Smith LH, Petito L, et al.Maternal prepregnancy weight and children's behavioral and emotional outcomes[J].Am J Prev Med, 2017, 53 (4) :432-440.
[22] Krzeczkowski JE, Boylan K, Arbuckle TE, et al.Neurodevelopment in 3-4 year old children exposed to maternal hyperglycemia or adiposity in utero[J].Early Hum Dev, 2018, 125:8-16.
[23] 美国精神医学学会.精神障碍诊断与统计手册[M].第5版.张道龙, 刘春宇, 译.北京:北京高等教育出版社, 2015:46-60.
[24] 陶芳标, 武丽杰, 马军.儿童少年卫生学[M].北京:人民卫生出版社, 2017:213-214.
[25] Daraki V, Roumeliotaki T, Koutra K, et al.Effect of parental obesity and gestational diabetes on child neuropsychological and behavioral development at 4 years of age:the Rhea mother-child cohort, Crete, Greece[J].Eur Child Adolesc Psychiatry, 2017, 26 (6) :703-714.
[26] Pugh SJ, Hutcheon JA, Richardson GA, et al.Gestational weight gain, prepregnancy body mass index and offspring attention-deficit hyperactivity disorder symptoms and behaviour at age 10[J].BJOG, 2016, 123 (13) :2094-2103.
[27] van der Burg JW, Jensen ET, van de Bor M, et al.Maternal obesity and attention-related symptoms in the preterm offspring[J].Early Hum Dev, 2017, 115:9-15.
[28] Andersen CH, Thomsen PH, Nohr EA, et al.Maternal body mass index before pregnancy as a risk factor for ADHD and autism in children[J].Eur Child Adolesc Psychiatry, 2018, 27 (2) :139-148.
[29] Musser ED, Willoughby MT, Wright S, et al.Maternal prepregnancy body mass index and offspring attention-deficit/hyperactivity disorder:a quasi-experimental sibling-comparison, population-based design[J].J Child Psychol Psychiatry, 2017, 58 (3) :240-247.
[30] Chen Q, Sjolander A, Langstrom N, et al.Maternal pre-pregnancy body mass index and offspring attention deficit hyperactivity disorder:a population-based cohort study using a sibling-comparison design[J].Int J Epidemiol, 2014, 43 (1) :83-90.
[31] 武丽杰.孤独症谱系障碍儿童家庭疾病负担的现状与思考[J].中国学校卫生, 2018, 39 (3) :321-324.
[32] Krakowiak P, Walker CK, Bremer AA, et al.Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders[J].Pediatrics, 2012, 129 (5) :e1121-1128.
[33] Dodds L, Fell DB, Shea S, et al.The role of prenatal, obstetric and neonatal factors in the development of autism[J].J Autism Dev Disord, 2011, 41 (7) :891-902.
[34] Connolly N, Anixt J, Manning P, et al.Maternal metabolic risk factors for autism spectrum disorder-an analysis of electronic medical records and linked birth data[J].Autism Res, 2016, 9 (8) :829-837.
[35] Getz KD, Anderka MT, Werler MM, et al.Maternal pre-pregnancy body mass index and autism spectrum disorder among offspring:a population-based case-control study[J].Paediatr Perinat Epidemiol, 2016, 30 (5) :479-487.
[36] Li M, Fallin MD, Riley A, et al.The association of maternal obesity and diabetes with autism and other developmental disabilities[J].Pediatrics, 2016, 137 (2) :e20152206.
[37] Shen Y, Dong H, Lu X, et al.Associations among maternal pre-pregnancy body mass index, gestational weight gain and risk of autism in the Han Chinese population[J].BMC Psychiatry, 2018, 18 (1) :11.
[38] Leal G, Afonso PM, Salazar IL, et al.Regulation of hippocampal synaptic plasticity by BDNF[J].Brain Res, 2015, 1621:82-101.
[39] Leal G, Bramham CR, Duarte CB.BDNF and hippocampal synaptic plasticity[J].Vitam Horm, 2017, 104:153-195.
[40] Tozuka Y, Kumon M, Wada E, et al.Maternal obesity impairs hippocampal BDNF production and spatial learning performance in young mouse offspring[J].Neurochem Int, 2010, 57 (3) :235-247.
[41] Park HS, Kim TW.Paternal physical exercise improves spatial learning ability by enhancing hippocampal neuroplasticity in male pups born from obese maternal rats[J].J Exerc Rehabil, 2017, 13 (3) :266-272.
[42] Wolfrum C, Peleg-Raibstein D.Maternal overnutrition leads to cognitive and neurochemical abnormalities in C57BL/6 mice[J].Nutr Neurosci, 2018:1-12.
[43] Zhu C, Han TL, Zhao Y, et al.A mouse model of pre-pregnancy maternal obesity combined with offspring exposure to a high-fat diet resulted in cognitive impairment in male offspring[J].Exp Cell Res, 2018, 368 (2) :159-166.
[44] Izaola O, de Luis D, Sajoux I, et al.Inflammation and obesity (lipoinflammation) [J].Nutr Hosp, 2015, 31 (6) :2352-2358.
[45] Aye IL, Lager S, Ramirez VI, et al.Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways[J].Biol Reprod, 2014, 90 (6) :129.
[46] Elovitz MA, Brown AG, Breen K, et al.Intrauterine inflammation, insufficient to induce parturition, still evokes fetal and neonatal brain injury[J].Int J Dev Neurosci, 2011, 29 (6) :663-671.
[47] Bilbo SD, Tsang V.Enduring consequences of maternal obesity for brain inflammation and behavior of offspring[J].FASEB J, 2010, 24 (6) :2104-2115.
[48] Kang SS, Kurti A, Fair DA, et al.Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring[J].J Neuroinflammation, 2014, 11:156.
[49] Graf AE, Lallier SW, Waidyaratne G, et al.Maternal high fat diet exposure is associated with increased hepcidin levels, decreased myelination, and neurobehavioral changes in male offspring[J].Brain Behav Immun, 2016, 58:369-378.
[50] Bell WL.Maternal obesity and epilepsy[J].JAMA Neurol, 2017, 74 (6) :637-639.
[51] Polinski KJ, Liu J, Boghossian NS, et al.Maternal obesity, gestational weight gain, and asthma in offspring[J].Prev Chronic Dis, 2017, 14:E109.
[52] Pan C, Deroche CB, Mann JR, et al.Is prepregnancy obesity associated with risk of cerebral palsy and epilepsy in children?[J].J Child Neurol, 2014, 29 (12) :Np196-201.
[53] Gali RT, Allen TJ, Davies A, et al.Maternal overnutrition programs epigenetic changes in the regulatory regions of hypothalamic Pomc in the offspring of rats[J].Int J Obes (Lond) , 2018, 42 (8) :1431-1444.
[54] Bruce-Keller AJ, Fernandez-Kim SO, Townsend RL, et al.Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice[J].PLoS One, 2017, 12 (4) :e0175577.
