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甲状腺功能与妊娠结局关系的研究进展

作者:未知

   【关键词】 甲状腺功能亢进;甲状腺功能减退;甲状腺自身抗体;妊娠结局
   中图分类号:R714.256   文献标志码:A   DOI:10.3969/j.issn.1003-1383.2019.05.018
   甲状腺是人体最大的内分泌腺,主要受丘脑下部-脑垂体调节,亦可根据机体内甲状腺激素水平进行自身调节。甲状腺激素通过介导多种关键糖脂代谢通路对生长发育产生深远的影响,而妊娠期间,甲状腺功能异常可影响妊娠结局。现将妊娠期不同甲状腺功能状态与妊娠结局的关系做一综述,旨在指导临床妊娠孕妇甲状腺相关疾病的诊断与治疗,从而减少不良妊娠结局的发生。
  1 甲状腺功能减退与妊娠结局
   甲状腺功能减退包括临床甲减、亚临床甲减(Subclinical Hypothyroidism,SCH)及单纯低甲状腺素血症(低T4血症),后两者可简称轻度甲减。我国《妊娠和产后甲状腺疾病诊治指南》[1]提出“诊断妊娠期甲状腺功能异常,本单位或者本地区需要建立不同妊娠期特异血清甲状腺功能指标参考值”。例如甲减的诊断标准: 血清TSH >妊娠期特异参考值的上限(P97.5),血清FT4<妊娠期特异参考值的下限(P2.5)。
  1.1 临床甲减对妊娠的影响 目前公认临床甲减可导致不良妊娠结局,主要包括:贫血、妊娠期高血压、胎盘剥离、流产、产后出血、早产、低体重儿、先天性畸形、死胎等[2],亦可损害后代脑功能。Hou等[3]发现妊娠甲减母亲早产的发生率可增加2.5倍[4],低出生体重的发生率增加2.2倍[5]。妊娠期甲减时,可使血浆胶体渗透压降低、血脂紊乱、胰岛素抵抗等,进而促进妊娠期高血压的发生发展。近年来关于妊娠期甲减与后代精神行为障碍关系的研究得到重视,Roman等[6]研究发现,妊娠早期患有严重甲减母亲的小孩,6岁时具有较高的自闭症症状评分,Modesto等[7]发现即便是妊娠早期轻度的甲减,其小孩亦具有较多注意力缺陷多动障碍症状。Willoughby[8]等经磁共振扫描发现,妊娠期甲减孕妇的后代其左、右海马体积明显小于正常孕妇后代,记忆功能亦相应下降,且海马体积与母亲孕晚期甲状腺激素水平呈正相关。Shafiee 等[9]研究发现,孕期及产后初期甲减雌鼠,其子代大脑海马的神经营养因子水平降低且具有空间学习及运动障碍。妊娠甲减还可导致后代智力低下,Korevaar等[10]發现,FT4水平与智力呈剂量-反应关系,当FT4水平小于第10百分位数时其后代智力比正常儿童低2.4分,当FT4水平小于第5及第2.5百分位数时智力分别低3.4、4.2 分。但多数研究表明与后代学业成绩及受教育程度无明显关联[11]。Fitzpatrick建议对于妊娠期间发现的临床甲减应立即给予左旋甲状腺素(Levo thyroxine,L-T4)治疗,可降低妊娠不良结局尤其是改善子代智力水平[12]。
  1.2 亚临床甲减对妊娠的影响 SCH对妊娠结局的影响及治疗后母婴获益情况均存在争议,多数学者持肯定意见。我国最近一项研究[13]显示妊娠合并SCH比正常妊娠妇女较易发生胎儿生长受限、胎儿窘迫、妊娠期高血压、早产、产后出血、妊娠期糖尿病、流产等不良妊娠结局。有学者[14]发现,在日本孕中期SCH导致妊娠期糖尿病的发生率增高,但未发现与其他不良妊娠结局有关。Vissenberg等[15]通过测试3347名孕5周至37周的孕妇甲状腺功能,探讨其与足月臀位的关系,得出妊娠中期SCH可使足月臀位的风险增加,考虑与胎儿运动发育延迟或孕妇子宫收缩力减弱有关。有动物实验及临床研究[16]均表明妊娠期SCH可损害子代视觉发育,主要表现为视觉敏感度下降。妊娠期SCH亦可损害胎儿脑发育,使神经营养蛋白受体P75、促凋亡蛋白p53等的表达增加,促进脑皮质凋亡,损害子代的空间学习和记忆能力[17]。对于妊娠期SCH的治疗,存在一定的争议。美国甲状腺学会[18]建议实行L-T4替代治疗,尤其是合并有TPOAb阳性者。Maraka等[19]研究发现经L-T4替代治疗的妊娠期SCH妇女流产率较未治疗组显著降低,但早产、妊娠期糖尿病、子痫前期的发生率升高。Nazarpour等[20]研究发现,当TSH值为 2.5~4.0 mIU/L时,治疗组与未治疗组早产率差异不显著,当TSH值>4.0 mIU/L时,接受L-T4治疗的孕妇较未接受治疗的孕妇早产率显著降低,且早期实行L-T4替代治疗获益最大[21]。但也有学者提出质疑,Yamamoto等[22]通过荟萃分析近30年有关妊娠期SCH治疗的文献,未发现L-T4治疗可改善产科、新生儿和儿童智商。
  2 甲状腺功能亢进与妊娠结局
   妊娠期甲状腺功能亢进以HCG相关性甲亢最常见,HCG引起的妊娠期一过性甲状腺毒症(gestational transient tyrotoxicosis,GTT)是其主要原因;其次为毒性弥漫性甲状腺肿(Graves病);非自身免疫因素相对少见。妊娠期临床甲亢发病率稍低于亚临床甲亢,分别为0.4%和0.6%[1]。
  甲状腺激素可使交感神经兴奋及代谢亢进。妊娠合并甲亢可导致流产、妊娠期高血压、胎盘早剥、早产、胎儿生长受限、宫内窘迫、死胎等不良妊娠结局。Pillar等[23]通过对以色列185636名单胎妊娠妇女的回顾分析得出,妊娠合并甲亢组流产、妊娠期高血压、胎盘早剥发生率明显升高。杨媛嘉等[24]研究表明,妊娠合并甲亢组发生妊娠期高血压、流产、早产、胎膜早破、产后出血及新生儿的低体质量、窒息、甲亢、甲减均明显高于对照组(P<0.05或0.01)。妊娠不同时期的甲亢导致的结局有所区别,妊娠早期甲亢可使孕妇流产率增加,中、晚期则增加早产、胎儿生长受限、宫内窘迫、死胎等发生率。妊娠合并甲亢与甲减对子代大脑发育影响不同,Ahmed等[25]经研究发现妊娠甲亢通过调节子鼠大脑神经递质系统影响脑发育。由于甲状腺激素对心脏的兴奋作用和妊娠的超动力变化,有并发心力衰竭可能,据研究[26]约9%未经治疗的妊娠期Graves病可发生心力衰竭,且常见于妊娠晚期。甲亢危象的发生相对少见。约1%Graves病母亲分娩的新生儿会发生甲亢[27],其中免疫性先天性甲亢被认为是来自母体体内的甲状腺刺激抗体与胎儿的TSH受体结合,导致新生儿甲亢,多数可在出生后约20周逐渐缓解。非免疫性先天性甲亢与TSH受体基因激活突变有关。GTT于妊娠早期首次出现,被认为与妊娠早期HCG的类TSH作用异常增强相关。以甲状腺抗体阴性、缺乏Graves 病体征、在妊娠第一期末或第二期初自行缓解为特征,已证实与妊娠剧吐有关,可伴甲亢症状,与Graves病难以鉴别。妊娠期甲亢对妊娠结局的影响取决于激素水平是否得到很好的控制,研究表明,经治疗后可明显改善预后。Wang等[28]通过对10 427名妊娠妇女检测后,将其分为正常妊娠组、妊娠合并甲亢治疗组、妊娠合并甲亢未治疗组,发现治疗组较未治疗组不良妊娠结局(妊娠期高血压、甲亢性心脏病、甲亢危象、早产和其他产科并发症、新生儿低出生体重、新生儿窒息、新生儿甲状腺功能异常)发生率低,差异有明显统计学意义,而正常妊娠组与治疗组之间发生不良妊娠结局及新生儿不良结局并无差异。目前亚临床甲亢被认为是自限性疾病,不引起不良妊娠结局,亦无需治疗。   3 甲状腺自身抗体与妊娠结局
   甲状腺抗体主要包括:TPOAb、抗甲状腺球蛋白抗体(TGAb)、促甲状腺激素受体抗体 (TRAb)。经研究发现母亲甲状腺抗体阳性率随着妊娠进程呈下降趋势,分娩后升高[29],产后6个月TPOAb和TGAb浓度达到高峰。多数研究表明,甲状腺抗體阳性对妊娠妇女有不良影响,考虑与抗体导致的亚临床或临床甲减有关。1990年Stagnaro-Green 等[30]发现甲状腺抗体与自然流产密切相关,从此甲状腺抗体与妊娠结局关系得到了大家的广泛关注。国内吴晓雯等[31]通过检测352名妊娠前半期孕妇甲状腺功能发现, TPOAb阳性甲功正常组早产、流产、胎儿窘迫、低体质量儿的发生率均高于TPOAb阴性组,差异有显著性。妊娠早期TPOAb阳性妇女产后1年内甲状腺炎(postpartum thyroiditis,PPT)的发生率高达50%,明显高于TPOAb阴性组,且TPOAb滴度越高,更易发生PPT[32]。甚至有研究认为TPOAb可作为PPT的诊断指标,特异性高达95.5%[33]。Dama等[34]研究发现围产期TPOAb水平升高与产后抑郁症的风险增加有关,可作为产后抑郁症的预测因子。关于单纯甲状腺抗体与妊娠期糖尿病的关系研究结果不一,Yang等[35]Meta分析显示,两者间无明显相关性。Wilson等[36]发现单纯甲状腺抗体阳性的母亲生产的胎儿比阴性对照组母亲生产的胎儿头围小,脑重量减少及脑/身体比值减小。目前L-T4治疗单纯甲状腺抗体阳性孕妇对妊娠结局影响的证据有限,Nazarpour等[37]研究表明经L-T4治疗的65例单纯TPOAb阳性妊娠妇女早产发生率明显低于未治疗组,并与正常对照组的早产率比较差异无统计学意义。
  妊娠期甲状腺功能异常与妊娠结局的关系已在上述逐一进行阐述,目前轻度甲状腺功能异常对妊娠结局的影响及治疗后母婴获益情况还有很大争论,需要建立本国的大样本研究。建议妊娠妇女在孕早期常规筛查甲状腺功能,经过积极的治疗与干预可有效改善妊娠结局,减少母婴并发症的发生。
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