【作者】 蒋优君；

【导师】 梁黎；

【作者基本信息】 浙江大学 ， 儿科学， 2004， 硕士

【摘要】 研究背景 自身免疫性甲状腺疾病如Graves病或慢性淋巴细胞性甲状腺炎，好发于妊娠期妇女，发病率为0.2％。孕母患自身免疫性甲状腺疾病如处理不当除了引起围产期并发症增多外，还可使新生儿甲状腺功能异常的发病率增加。新生儿甲状腺功能异常如未能及时发现，重者引起死亡、轻者引起智能发育障碍和生长迟缓。 在过去的十年中，人们陆续发现自身免疫性甲状腺疾病孕母的新生儿发生原发性甲状腺功能低下、垂体性甲低、甲状腺功能亢进和高TSH血症，并在有些新生儿体内测到了高浓度的促甲状腺素受体(?)体(TRAb)，因此推测这些新生儿甲状腺功能异常可能与TRAb有关。但以往的研究只是考虑单个因素的作用，其实影响婴儿甲状腺功能的因素是多方面的。孕母妊娠期服药、孕母妊娠期甲状腺功能状态、孕母所患的甲状腺疾病种类、孕母选择的治疗方案等等对婴儿甲状腺功能有无影响?影响有多大?这些问题有待于进一步研究。 研究目的 孕母患自身免疫性甲状腺疾病对婴儿甲状腺功能有影响。但影响有多大，哪些因素与之有关目前仍不明确。本课题通过浙江省新生儿疾病筛查的网络系统，采用病例对照研究的方法，在国内首次在全省范围内开展对母亲患自身免疫性甲状腺疾病的婴儿甲状腺功能的跟踪调查，研究这些婴儿甲状腺功能情况以及甲状2004年浙江大学硕士学位论文腺功能异常的发病率，探讨孕母患自身免疫性甲状腺疾病对婴儿甲状腺功能的影响因素。研究对象 2001年7月1日至2003年6月30日在浙江省(除宁波市外)各县、市、省级医院产科分娩的孕母患自身免疫性甲状腺疾病(符合纳入标准)的婴儿，且无产时窒息史的足月儿作为研究对象。对照组:为同期在浙江省(除宁波市外)各县、市、省级医院产科分娩的无甲状腺疾病孕母的婴儿。 纳入标准:对妊娠前或妊娠期间曾在省、市级医院检查有甲状腺功能减退且伴有抗微粒体抗体或抗甲状腺过氧化物酶抗体、抗甲状腺球蛋白抗体增高者为慢性淋巴细胞性甲状腺炎孕母;有甲状腺功能亢进且甲状腺B超或甲状腺ECT扫描或甲状腺细针穿刺病理检查证实、并排除高功能腺瘤及多发性结节者为Graves病孕母。研究方法 对生后满3天的新生儿由各产科医院采足跟血，标本干燥后送浙江省新生儿疾病筛查中心，用滤纸血斑时间分辨荧光法检测促甲状腺素(TSH)。对TSH>9 mU/L者于结果报告后1一3天立即召回母亲及新生儿(健康孕母者只召回新生儿)，对TSH正常者于分娩后28一35天召回医院。记录孕母所患的甲状腺疾病种类、病程、妊娠期甲状腺功能状态、服药史、母亲妊娠年龄、胎龄及新生儿出生体重，复查婴儿及母亲的甲状腺功能，并留母亲及婴儿的血清测定抗过氧化物酶抗体(TPOAb)、抗甲状腺球蛋白抗体(TGAb)，促甲状腺激素受体抗体 (TRAb)、甲状腺素刺激抗体(TSAb)。用化学发光免疫法检测T3、几、TSH、FT3、FT4、Tp0Ab，采用美国nPC公司的Immulite化学发光仪检测，用放射免疫法测定TGAb(药合由北京原子能研究所提供)，采用EUSA法测定母亲及婴儿体内的促甲状腺激素受体抗体(TRAb)、甲状腺素刺激抗体(TSAb)。TRAb2004年浙江大学硕士学位论文药盒为德国汉堡nLn oesel一sehan仙Diagnosti恤und medi‘nisehe Gerate mbH生产，TSAb药盒为天津医科大学生物实验厂提供。对确诊先天性甲状腺功能低下(TsH增高伴T4下降)的新生儿进行优甲乐治疗，对高TSH血症者(滤纸片法TSH>9闪u/ml或血清TsH>4.4 mlu/L，而其它指标均正常)，每月一次复查甲状腺功能直至TSH恢复正常。所有数据由SSPSS10.0软件处理，以p<0.05为有显著差异。健康孕母的婴儿与自身免疫性甲状腺疾病孕母的婴儿，其甲状腺功能异常的发病率比较采用两百分率比较的u检验。母婴体内的抗甲状腺抗体分析采用双变量相关分析，两组之间的比较采用独立样本t检验，婴儿甲状腺功能异常的危险因素分析，采用非条件多元loglstic回归分析。结果 1.孕母患自身免疫性甲状腺疾病对婴儿甲状腺功能的影响78例自身免疫性甲状腺疾病孕母的婴儿，确诊先天性原发性甲低7例，占9.0%(7/78)高TSH血症33例，占42.3%(33/78)，甲状腺功能亢进1例，占1 .3%(1/78)，而同期浙江省新生儿疾病筛查中心(除宁波市外)共筛查新生儿424665例，确诊先天性原发性甲状腺功能低下305例，占0.7%。，暂时性TSH增高1 993例，占4.7%0，甲亢O例，二者比较有显著差异(U甲低=28.996，尸<0.01，UTsH增高=53.628，P<0 .01)o 2.母婴体内抗甲状腺自身抗体的关系对分娩后25~35天的母亲及婴儿测定体内抗甲状腺自身抗体:TPOAb、TGAb、TRAb、TSAb，经双变量相关分析，speannan相关系数分别为0.636、0.574、0.619、0.473，尸均(0.01。甲状腺功能异常的婴儿，其体内TRAb、TPOAb分别为5.53士1.20(IU/L)、41.65士2.89(Iu/L)明显高于甲状腺功能正常的婴儿夏4.12士1.41(Iu几)24.27士3.03 (Iu几)}，而ToAb、TSAb两组之间则无差异。 3.婴儿甲状腺功能异常的危险因素分析经单因素logistic回归分析，筛选2004年浙江大学硕士学位论文更多还原

【Abstract】 It was well documented that women in pregnancy were trend to suffer from autoimmune thyroid disease such as Graves or Hashimoto thyroiditis with a prevalence of 0.2% and has been shown to affect neonatal thyroid function as well as other outcomes such as spontaneous abortion, intrauterine growth retardation, still birth, premature labor and congenital malformation if they were not appropriately treated. Neonatal thyroid dysfunction without therapy will lead to mental and physical retardation, and some times even result in death.In the last decade, neonates born to mothers with autoimmune thyroid disease were in succession to be found to have primary hypothyroidism, pituitary hypothyroidism, hyperthyroidism or hyperthyrotropinemia, and some were found to have high anti-TSH receptor antibody (TRAb). Previous researches about neonatal thyroid dysfunction were concerned in single factor, very little data were available from early infancy . their mothers and environment based studies on the risk factors for early infantile thyroid dysfunction. While factors such as the state of maternal thyroid function during pregnancy, maternal medical treatment or therapy program during pregnancy and the type of maternal thyroid disease will affect neonatal thyroid function and how widely will they contribute to?ObjectiveIn order to minimize complications and to improve maternal and neonatal outcomes, a cohort of 78 infants born to mothers with autoimmune thyroid disease was investigated to evaluate the impact of maternal thyroid dysfunction during pregnancy and postpartum on infant thyroid function and to identify the possible maternal, neonatal and /or environmental risk factors for causing early infantile thyroid dysfunction by Provincial Neonatal Disease Screening Network which covers nearly thirty seven thousand neonates a year in south east part of China Patients:All the newborns delivered to mothers with autoimmune thyroid disease as defined by criteria from Zhejiang Province (except for Ningbo city) during July 1st of 2001 to June 30th of 2003 were investigated. Seventy eight term, non-asphyxiated neonates met the criteria were recruited into the study. Neonates born to healthy mothers at the same period were set as controls according to Provincial Neonatal Disease Screening Network.The criteria for the diagnosis of Graves’ disease or Hashimoto thyroiditis was as follows:Graves disease in the mothers had been diagnosed by clinical and laboratory evidence of hyperthyroidism, increased TPOAb and TPOAb level and a diffuse goiter, excluding other common causes of thyrotoxicosis such as toxic multinodular goiter or toxic adenoma by thyroid ultrasonography or ECT scan or fine-needle biopsy of thyroid tissue.Hashimoto thyroiditis was diagnosed by the presence of increased TPO-Ab and TGAb level, clinical and laboratory evidence of hypothyroidism at the time ofdiagnosis, and decreased echogenicity of the thyroid gland. Some cases with lymphocytic infiltration were confirmed by a fine-needle biopsy of thyroid tissue. Methods:Heel capillary blood was collected on 3-day newborn by obstetrician of local hospital. Samples of blood dried on filter paper were sent to Provincial Neonatal Disease Screening Center to be detected on TSH by Time difference fluorescent analysis (1420 type II, Wallac company, Finland). The neonate was called back immediately if his or her TSH was over 9 mU/L, and the others were called back at 28 to 35 days after birth. The data of mothers and newborns’ status were recorded in detail including the type of maternal thyroid disease (Graves disease or Hashimoto thyroiditis), the maternal thyroid function during the pregnancy (three groups were divided: Group A: hyperthyroidism, Group B: hypothyroidism, Group C: euthyroidism based on the level of FT3 FT4 and TSH during pregnancy), the history of medication, the maternal age of pregnancy, the gestational age of baby and neonatal birth weight . The serum concentrations of T3, T4, TSH, FT3, FT4, TPOAb were m更多还原