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孕期环境暴露与儿童发育和健康
中华预防医学杂志, 2016,50(02): 192-197. DOI: 10.3760/cma.j.issn.0253-9624.2016.02.018
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孕期环境暴露对胎儿生长及儿童发育的负面效应已经得到证实,国内外研究均表明孕期环境暴露对胎儿生长发育、出生结局和儿童心理、行为及神经发育具有较大的影响。本文根据暴露的不同类型,重点从环境化学物、孕期不良生活方式及行为、孕期应激和其他因素等四个方面对环境暴露条件下胎儿或儿童的关键问题进行综述,探讨了环境因素对婴幼儿生长发育、儿童心理、行为、社会及认知方面的不良影响,如出生缺陷、孤独症谱系障碍、注意缺陷多动障碍、情绪问题、学习障碍及智力发育等,并提出未来应进一步加强环境暴露对儿童健康负面影响的发生机制研究。

引用本文: 陶舒曼, 陶芳标. 孕期环境暴露与儿童发育和健康 [J]. 中华预防医学杂志,2016,50( 2 ): 192-197. DOI: 10.3760/cma.j.issn.0253-9624.2016.02.018
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母体是胎儿生长发育的主要载体,母体环境时刻影响着胎儿的生长发育。随着母源性疾病、健康与疾病的发育起源(developmental origins of health and disease, DOHaD)理论的提出和发展,生命早期环境因素暴露对儿童健康的影响越来越受到各方关注。国内外的研究结果均认为孕期有毒有害的化学物质暴露、不良生活方式、心理社会应激可导致不良妊娠结局,甚至会诱发长期效应,增加儿童心血管系统、呼吸系统等生理功能紊乱以及心理行为问题及神经发育障碍的风险。本文主要综述了孕期不同的环境暴露对儿童生长发育的影响,为从生命早期预防疾病、促进儿童健康提供科学的依据。

一、孕期环境化学物暴露

生命早期多种环境化学物的暴露与儿童健康密切相关,包括不良出生结局、认知与运动发育和心理行为等。同时也关注到,人类往往同时暴露于多种环境化学混合物,在研究单独化学物的毒性时必须考虑其与其他化学物的交互作用。

(一)环境内分泌干扰物

近来年,孕母环境内分泌干扰物(environmental endocrine disruptors ,EEDs)暴露对胎儿的生长发育的不良影响受到学术界和公众的极大关注。EEDs是指一类外源性化学物质进入机体后,干扰体内正常分泌物质的合成、释放、转运、代谢、结合等过程,激活或抑制内分泌系统功能,从而破坏其维持机体稳定性和调控作用的物质[1],这些化合物被广泛应用于工业生产、建筑材料、农药杀虫剂及生活化妆品、染发剂、洗涤剂等,常见的如多氯联苯化合物(polychlorinated biphenyls,PCBs)、邻苯二甲酸酯类(phthalates ,PAEs)、双酚化合物(bisphenols ,BPs)、有机氯杀虫剂和除草剂及其他。这些化合物对胎儿的生长发育、出生缺陷、代谢紊乱等都具有明显的干扰效应。

1.双酚A (bisphenol A,BPA):

BPA是BPs中最具代表性的一种,广泛应用于工业制造,在固体废弃物、室内空气、食品及包装材料中均可发现。美国人群中95%的尿液样本中均含有BPA,孕妇的血清、羊水及胎儿出生时的脐带血中均存在BPA,表明产前时期是人类暴露于BPA的一个关键窗口期[2]。血清和尿液中BPA浓度与甲状腺功能减退、不孕症、心血管疾病和糖尿病风险增加有关[3]。BPA进入母体,尤其在母体中残留,并通过胎盘传递给胎儿,对胎儿的器官、功能、中枢神经系统发育、心理行为问题等产生影响。在全球众多出生队列研究中,均证明孕期母体BPA水平与儿童神经行为发育存在关联性。在美国的健康结局和环境测量(Health Outcomes and Measures of the Environment,HOME)队列研究中,Braun等[4]在2003—2006年招募249对母子,在孕16周、26周和出生时收集尿液样本,并在儿童2岁时进行内外化行为评定,结果发现孕16周和26周BPA浓度与女童的外化行为呈正相关。随后,在2004—2009年,Braun等[5]分别在儿童1、2和3岁时收集尿液样本,在3岁时评定儿童执行功能,结果显示母亲孕期BPA浓度与女童多动性、抑郁症状呈正相关,与情绪控制和抑制功能呈负相关;但与男童多动性呈负相关;此外,研究还表明儿童期BPA浓度与神经行为并不存在关联。近期,Braun等[6]收集孕妇血液和尿液样本,筛查了70种内分泌干扰物,分析其与4和5岁儿童的孤独症样行为之间的关联,结果发现,某些内分泌干扰物与儿童行为问题直接相关,但BPA与儿童问题行为并无关联。哥伦比亚儿童环境健康中心(Columbia Center for Children's Environmental Health,CCCEH)队列研究于1998—2003年招募198对母子作为研究对象,收集了孕24~40周母亲尿液样本和3~4岁儿童尿液样本,3~5岁时由母亲报告儿童心理行为发育,结果发现孕期BPA暴露水平与男童的反应性行为、攻击行为呈正比,但女童焦虑样或抑郁样行为、攻击性行为与母体BPA水平呈负相关,儿童期BPA暴露与心理行为并无关联[7]。随后,Roen等[8]对CCCEH队列中的250名7~9岁儿童进行再分析,发现孕期BPA浓度与男童内化和外化行为呈正相关,但与女童内化行为得分呈负相关;同时儿童期BPA浓度越高,女童内化和外化行为的症状越多,但男童的内化和外化症状越少。未来家庭研究Ⅱ (Study for Future Families Ⅱ,SF Ⅱ)于2002—2005年招募153对母子,收集母亲孕10~39周尿液样本(平均孕周为26.6周),由母亲报告儿童6~10.5岁时行为问题,结果表明宫内BPA暴露与男童外化行为、焦虑、攻击性行为、品行障碍及对立行为呈正相关,但在女孩中发现宫内BPA暴露水平越高行为问题越少的趋势[9]。孕期母体BPA暴露与儿童肥胖、2型糖尿病等代谢性疾病密切相关。在一项队列研究中,Harley等[10]分别分析了311名儿童5岁时和9岁时的超重或肥胖情况与孕期BPA暴露之间的关联性,发现孕期BPA暴露与9岁儿童肥胖呈正相关。Teppala等[11]分析2003—2008年美国健康和营养调查(National Health and Nutrition Examination Surveys, NHANES)调查数据发现尿液中BPA水平与糖尿病呈正相关。孕期母体BPA暴露与胎儿生长发育及出生结局存在联系,但也存在性别差异。有研究表明,宫内BPA暴露水平与男童出生体重和身长均存在关联,但在女童中这一联系并未发现[12]。然而,也有研究表明母亲孕期BPA暴露水平越高,胎儿低出生体重(low birth weight,LBW)的风险越大,这一关联在女童中更多见[13]。孕期BPA暴露与儿童哮喘、肺功能发育也存在关联[14]

2.PAEs:

PAEs是一类具有软化作用的化学品,被普遍用于儿童玩具、食品包装材料、个人护理用品(如指甲油、头发喷雾剂和洗发液)等产品中。PAEs对人体健康的影响是一个慢性的过程,并且可能通过胎盘和母乳喂养对胎儿产生影响,造成不良妊娠结局和婴幼儿神经发育障碍。有研究表明,孕前PAEs代谢物暴露与早期流产、新生儿低体重有关[15]。系统综述研究表明,产前PAEs及其代谢物暴露与0~12岁儿童认知及行为发育呈负相关,并且存在性别差异[16]。Téllez-Rojo等[17]报道孕27~40周尿液样本PAEs代谢物浓度与男童智力发育指数呈负相关,与女童精神运动发育指数呈负相关,但总体分析差异未达到统计学意义。另一项研究分析了孕33.1周尿液PAEs及其代谢物与儿童认知发育的关系,结果与Téllez-Rojo等[17]的报道一致,但其总体分析也得出了PAEs与智力发育指数之间呈负相关,且与退缩行为及内化行为呈正相关[18]。Kobrosly等[19]对SF Ⅱ队列中153对母子进行分析,发现孕期PAEs暴露与6~10岁儿童神经行为发育之间存在关联,结果显示各类PAEs代谢物能够增加男童注意力缺陷、违纪行为、攻击行为、品行问题、躯体问题和对立行为等的发生风险,但邻苯二甲酸单苄酯与女童焦虑症状得分降低有关。波兰亲子队列研究(Polish Mother and Child Cohort Study,REPR_OPL)收集孕晚期母亲尿液样本,检测11种PAEs代谢物,并评定儿童2岁精神运动发育状况,结果表明孕期PAEs代谢物暴露增加,儿童认知发育、运动能力、学习能力均有所下降[20]。这些研究结果均表明孕期暴露于PAEs及其代谢物对儿童神经行为发育的不良影响。

(二)重金属

重金属如铅(Pb)、镉(Cd)、砷(As)和汞(Hg)等具有生殖和发育毒性,还具有内分泌干扰作用,对孕期妇女的健康状况、胎儿出身结局及生长发育等具有较大的影响。英国Avon亲子纵向研究(Avon Longitudinal Study of Parents and Children,ALSPAC)是目前报道孕期妇女血液中Pb、Cd和Hg最大的队列研究,而且是英国第一个报道孕期血Pb水平和第二个报道孕期血Cd的研究[21]。美国一项队列研究表明孕期血中Cd较高暴露水平与根据孕周划分的出生体重百分位数呈负相关,且与小于胎龄儿(small for gestational age,SGA)风险增加有关[22]。新生儿脐带血中Cd暴露与顶踵长、阿普加5分钟评分、出生体重和SGA密切相关,血Cd暴露水平越高,顶踵长和胎盘厚度减少;胎盘中Cd暴露增加,脐带长度增加,胎盘厚度减少;母体血中Pb暴露水平影响胎盘厚度;脐带血和母体外周血中Hg暴露水平与胎盘厚度和胎盘重量极少相关,但胎盘中Hg暴露水平与新生儿头围、阿普加5分钟评分和脐带长度显著相关[23]。孕中期Pb暴露水平每增加0.001 mg/L,LBW和早产风险相对增加;与高水平血Pb暴露的不良效应类似,母体孕期血Pb含量低于0.01 mg/L时也会造成胎儿出生体重下降和孕周减少[24]。另外也有研究表明孕期Pb暴露与早产之间的相关性仅在男童中发现,女童中并未发现此种关联[25,26]。孕期Hg暴露与儿童神经发育障碍之间的关联性已经被证实。Boucher等[27]采用病例-对照的研究设计,选取出生于1987—2002年的162名病例和8 807名对照,分析围生期Hg暴露与儿童孤独症谱系障碍(autism spectrum disorders,ASDs)之间的关联性,结果表明,高剂量Hg暴露ASDs发生风险是低剂量Hg暴露的2倍。另外,也有队列研究表明围生期环境Hg暴露与儿童注意缺陷多动障碍(attention deficit hyperactivity disorder, ADHD)之间的关联性。一项队列研究在279名儿童脐带血中检测Hg暴露水平,暴露水平与ADHD的发生风险呈正相关,Hg暴露剂量为22.9~99.3 μg/L的儿童注意缺陷型和多动性型ADHD的发生风险分别是暴露剂量为1.0~11.2 μg/L的2.87和2.92倍[28]。此外,As对机体的危害是一个慢性蓄积过程,对母体妊娠结局及婴幼儿发育产生影响,有研究表明孕早期暴露于As与学龄儿童智力障碍呈正相关,其他研究也表明As暴露与儿童孤独症或行为问题显著相关[29,30]

二、孕期不良生活方式和行为

孕期不良生活方式包括孕期营养过剩或营养不良、吸烟、饮酒等,不健康的生活方式会增加孕妇、胎儿、儿童的发病风险,甚至影响终身健康。

1.营养过剩:

孕期营养过剩能够调节胎儿发育编程和改变胎儿生理,孕期饮食可以诱发胎儿基因组或表观基因组改变,从而导致成年期潜在的疾病风险[31]。实验研究表明,孕期高脂肪饮食模式可以增加小鼠子代胰岛素敏感性增加和体重增加[32]。近年来,孕期膳食结构不合理、盲目补充营养导致孕期肥胖和过度增重的现象也越来越受到学者关注,孕期增重与新生儿出生体重呈正相关,孕期过度增重与剖宫产增加、阿普加评分更低、大于胎龄儿和巨大儿等不良妊娠结局有关[33]。孕期增重不足9 kg的孕妇娩出低出生体重儿的风险是增重9~17 kg者的1.565倍[34]。在42 d及3、6、9、12个月时,孕期增重过多组婴儿年龄别体重的Z值均高于相应年龄的孕期增重适中组;孕期增重过多组婴儿在9、12个月时BMI高于适中组,差异均有统计学意义[35]。综述性研究也表明妇女孕前肥胖、孕期过度增重与儿童神经精神发育损伤有关,如智力障碍、ASDs、ADHD及海马发育损伤等[36]

2.营养不良:

营养不足在育龄期和孕期妇女中较为常见,孕期妇女为了满足妊娠过程中特殊的代谢需要,需要全面的、高品质的营养素来维持自身和胎儿的需求。胎儿出生体重与孕晚期维生素D摄入呈负相关,但与维生素B12呈正相关;新生儿身长与孕晚期镁摄入呈正相关;新生儿腹围与孕晚期维生素A摄入呈正相关,与孕晚期维生素E和硒摄入呈负相关;新生儿腰围身长比与孕晚期镁摄入呈负相关;肩胛下和肱三头肌皮褶厚度比与孕早期硒摄入呈负相关[37]。孕早期母体铁元素消耗与SGA风险增加相关,孕早期母体血红蛋白水平每增加10 g/L,SGA的风险降低30%,血红蛋白水平少于110 g/L,SGA风险增加3倍[38]。孕期维生素D、维生素E和锌摄入较低会增加儿童哮喘的风险[39]。维生素D缺乏,新生儿出生体重和身长分别减少107.6 g和0.3 cm[40]。另外综述性研究也表明孕期维生素D水平与子痫前期、妊娠期糖尿病、SGA和早产呈正相关[41]

3.吸烟:

从流行病学研究结果来看,大约有20%~30%孕妇主动吸烟,有50%不吸烟的孕妇被动吸烟[42]。有研究表明,与不吸烟的孕产妇相比,孕早期吸烟但后来终止吸烟和整个孕期持续吸烟会导致4~5岁儿童BMI标准差分(Z分)增加,孕中期平均每天吸烟的数量与儿童BMIZ分增加呈剂量反应关系[43]。孕期吸烟对儿童神经发育具有重要的作用。魁北克儿童发育纵向研究(Quebec Longitudinal Study of Children's Development)的数据也表明孕期吸烟与儿童智力和记忆能力下降存在关联[44]。REPR_OPL检测孕期烟草暴露标志物3次,并在儿童1岁和2岁时评价其神经行为发育,发现唾液可替宁水平与2岁儿童运动能力下降有关,但与认知及语言发育并无关联[45]。一些神经心理学试验也证明了孕期吸烟与儿童认知发育之间的关联性。Mezzacappa等[46]报道孕期暴露于烟草的儿童在神经心理学测试时平均反应时比未露于烟草的儿童慢40 ms。中国台湾地区的一项队列研究也表明孕期可替宁水平与2岁儿童认知、语言、精细运动等呈负相关[47]。此外,未吸烟孕妇孕期暴露于二手烟也会增加儿童发育迟滞的风险[48]

4.饮酒:

孕期酒精暴露对儿童心理、行为及神经均能够造成不良影响,包括ADHD、学习和记忆障碍及社会和情绪发育障碍等,最常见的不良影响是会导致胎儿酒精综合征(fetal alcohol syndrome, FAS)。ALSPAC研究表明孕早期每周摄入少于1杯酒与47个月女童的心理健康问题存在关联[49]。另外有研究表明,孕早期和孕中期酒精摄入与10岁非裔美国儿童认知发育有关[50]。丹麦研究者在单因素分析中发现孕早期和孕中期平均每周酒精摄入与智力、注意力和执行功能等呈负相关,多因素分析并未发现关联[51]

三、孕期心理应激

孕期心理应激会引起神经内分泌系统的改变,在应激状态下,下丘脑-垂体-肾上腺轴参与反应,使母体神经内分泌发生变化,对胎儿的身心健康产生影响。有研究表明孕期抑郁会导致儿童抑郁的风险增加4倍[52]。孕期或生命早期应激诱发的大脑发育可塑性可能会持续到成年期,对慢性疾病的发生发展和行为与认知-情绪系统具有终身影响[53]。流行病学研究表明孕期应激与新生儿出生体重具有较强的关联[54]。孕期抑郁能够诱导新生儿表观遗传改变[55];孕期相关焦虑能够导致脐带血中糖皮质激素受体基因NR3C1甲基化水平升高[56]。动物模型揭示了孕期抑郁能够导致断奶期和成年期小鼠杏仁核和海马中脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)表达减少和BDNF外显子Ⅳ甲基化水平升高[57]。孕期应激也能够诱导子代行为改变和海马和额叶皮质基因表达改变的性别差异[58]。在容易受到外界环境影响的发育时期,应激诱导的可塑性能够改变情绪、焦虑相关行为和认知功能,考虑到胎儿暴露于孕期应激的敏感性和孕期应激对表观遗传改变的影响,未来研究更多致力于如何来缓解孕期应激所带来的负面效应,甚至消除孕期应激。

四、其他因素

随着社会经济的加速发展,孕期职业性暴露、环境污染及气候变化等均能对胎儿的发育产生不良影响。有研究表明孕期职业暴露于有机溶剂与神经管畸形风险增加有关[59]。孕期暴露于极低频磁场的职业女性,儿童白血病的风险有所增加[60]。孕期PM2.5高水平暴露与永存动脉干、全肺静脉回流异常、主动脉狭窄、主动脉弓中断及先天性心脏病的风险增加有关[61],孕晚期PM2.5高水平暴露导致死产风险增加42%[62]。孕期暴露于热浪与儿科疾病如肾脏疾病、呼吸系统疾病、电解质失衡和发热等显著相关[63]。气候改变与子痫和子痫前期、白内障、LBW、早产、高血压及怀孕周期有关,寒潮天气LBW的风险更大,气温上升与早产的风险增加有关;子痫和子痫前期在寒冷潮湿的季节更普遍[64]

综上所述,任何能通过母体途径致胎儿发生的暴露都可以视作环境暴露,环境暴露对胎儿生理功能发育甚至可作用于儿童期或成年期,未来需要更多的流行病学研究和实验研究来揭示孕前和孕期环境暴露与胎儿生长发育、出生缺陷、心理行为问题等方面的病因关联,并致力于环境暴露对胎儿负面影响的发生机制,为预防出生缺陷、促进儿童健康成长提出适宜措施。

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关键词
主题词
环境暴露
内分泌干扰物
应激
妊娠结局