孕母患自身免疫性甲状腺疾病对婴儿智能发育影响的研究
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摘要
研究背景
自身免疫性甲状腺疾病如弥漫性甲状腺肿伴甲亢(Greaves病)或慢性淋巴细胞性甲状腺炎(桥本氏病)均好发于青春期以后的女性，两者发病率分别为0.02～0.2％和1／1600～1／2000。怀孕母亲患自身免疫性甲状腺疾病如处理不当除了可能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，如未能及时发现和干预，轻者引起智能发育障碍和生长迟缓、重者可能引起死亡。
新生儿(婴儿)的甲状腺功能与智能发育密切相关。在过去的十年中国内外陆续有报道认为，孕母如果患自身免疫性甲状腺疾病，其分娩的新生儿有可能发生甲状腺功能低下(包括原发性或垂体性)、甲状腺功能亢进和暂时性高TSH血症，并在部分新生儿体内测到了高浓度的促甲状腺素受体(TRAb)，由此推测这些新生儿甲状腺功能异常可能与某些自身抗体有关。但以往的研究只是局限于考虑单个因素的作用，而事实上影响新生儿(婴儿)甲状腺功能的因素是多方面的，包括孕母所患的甲状腺疾病种类、孕母妊娠期甲状腺功能状态、妊娠期服药史、及其它治疗方案等等，这些因素对婴儿甲状腺功能有无影响?母婴的甲状腺功能对婴儿的智能发育有无影响?哪些因素有影响?影响程度有多大?这些问题有待于进一步研究。
2004年浙江大学硕士学位论文
研究目的
孕母患自身免疫性甲状腺疾病对婴儿智能发育可能有影响。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智能发育的跟踪调查，研究这些婴儿智能发育情况以及与
母、婴甲状腺功能情况之间的关系，旨在探讨孕母患自身免疫性甲状腺疾病对婴
儿智能发育的影响因素。
研究对象
通过全省新生儿疾病筛查网络，将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
母所生的婴儿。
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(TMAb)或抗甲状腺过氧化物酶抗体(TPOAb)、抗甲状腺
球蛋白抗体(TGAb)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
2004年浙江大学硕士学位论文
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>gmU/L者于1~3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，并取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)。所有观察对象在1月龄、3月龄、6月龄、12月龄
采用Gesell发育量表进行跟踪调查，由专人进行评估，结果以发育商(DQ)表
达，采用病例对照研究的方法对可能影响婴儿应人能、应物能、粗动作能、细动
作能发育的因素进行非条件logistic回归分析，各能区的自身比较采用单因素方
差分析(两两比较用LSD法，方差不齐者用D~et，sC检验);母婴体内的抗甲
状腺抗体的相互关系用双变量相关分析;所有数据由SPSSIO.0软件处理。
结果
1、孕母患自身免疫性甲状腺疾病对婴儿智能发育的影响
孕母患自身免疫性甲状腺疾病的婴儿其应人能、应物能、粗动作能、细动作
能发育落后，与健康孕母的婴儿比较有显著差异(P<0.01)，慢性淋巴细胞性甲
状腺炎孕母的婴儿其细动作能、应物能的发育比Graves病孕母的婴儿差，二者
比较差异具显著性(p<0.05)。
2、母婴体内抗甲状腺自身抗体的关系
对分娩后25~35天的母亲及新生儿/婴儿测定其体内抗甲状腺自身抗体:
TPOAb、TGAb、TRAb、TsAb，经双变量相关分析，Spe~an相关系数分别
2004年浙江大学硕士学位论文
为0，636、0.574、0.6一9、0.473，夕均(0.02。
3、婴儿智能发育异常的危险因素分析
经多因素非条件logisti。回归分析筛选出婴儿体内的仰oAb、母体内的TRAb
与婴儿的应物能、应人能，粗动作能有关，而母体内n，OAb、孕期母亲甲状腺
功能则与细动作能有关(p<0.05)
结论
1、孕母患自身免疫性甲状腺疾病对婴儿智能发育有负影响。
2、与Graves病相比较，孕母患慢性淋巴细胞性甲状腺炎对婴儿智能发育的影响
更大。
3、母婴体内的TPOAb、TRAb及孕母妊娠其甲状腺功能状态与婴儿应人能、应
物能、粗动作能、细动作能发育落后有关。
4、合并自身免疫性甲状腺疾病的孕母一定要接受合理的治疗，以减少对婴儿的
影响。
Background
Autoimmune thyroid diseases, such as diffuse toxic goiter (Greaves disease) and lymphocytic thyroiditis (Hashimoto's thyroiditis), are more frequent in female after adolescence. The incidences of Greaves disease and Hashimoto's thyroiditis were about 0.02%~0.2% and 1/1600-1/2000 respectively. Maternal autoimmune thyroid disease may increase not only the incidence of complication in prenatal, but also the incidence of abnormal thyroid function in neonate. Moreover, without diagnosis and treatment early, it could cause the retardation of intellectual and physical development, and even deaths.
The thyroid function in neonate and infant is close associated with intellectual development. In the last ten years, several studies reported that those neonates whose mother suffered with autoimmune thyroid diseases might increase the incidence of hypothyroidism (including primary or pituitary), hyperthyroidism and transitory hypothyroidism, that higher levels of thyroid stimulating hormone (TSH) receptor antibody (TRAb) were estimated in some of these neonates. These implied that the thyroid function of neonate maybe associated with some anti-thyroid auto-antibody. However, these previous studies consider with just one certain factor. In fact, these are many factors which maybe associated with the neonatal thyroid function, such as the pattern of maternal thyroid disease, the maternal thyroid function in pregnancy, the
drug used in pregnancy, other treatment, and so on. If these factors have any effect on neonatal thyroid function? If the thyroid function of mother and infant have effect on the intellectual development in neonate and infant? Which factors affect the infantile intellectual development? How about the degree of the effect? All these are needed to study deeply.
Objective
In this study, we investigated continuous the intellectual development of these infant whose mother suffered with autoimmune thyroid diseases in our province, study the association between the infant intellectual development and the maternal thyroid statue, and find the maternal risk factors associated with thyroid disease effect on the infant intellectual development.
Subject
Through the Zhejiang provincial neonatal disease screening network system, all the term newborn who born from mother with autoimmune thyroid disease (selection criteria) without asphyxia in all county, city, and provincial hospital in Zhejiang province (except Ningbo City) from July 2001 to June 2003 were enrolled. The control group was defined as the neonates who were born from mother without thyroid disease in these hospitals in the same time.
Selection criteria: Hypothyroidism with the increased thyroid microsomal antibodies (TMAb), thyroid peroxides antibody (TPOAb), or thyroglobalin antibody (TGAb) which detected in city, and provincial hospital in gestation or before pregnancy were diagnosis as Hashimoto's thyroiditis. Hyperthyroidism supported with the thyroid ultrasonography or ECT scans or confirmed by fine-needle-aspirate biopsy of the thyroid, excluded the hyperfunctioning thyroid adenoma and multinodular goiter, were diagnosis as Graves disease.
Methods
Heel capillary blood samples were collected from neonate older than 3 days in local hospitals and sent to the center of Zhejiang provincial neonatal disease screening network system. TSH levels were measured by Time difference fluorescent analysis device (1420 II type, American EGG Company). If the levels of TSH were over 9mU/L, the neonates and their mother were call back to the center in 3 days. If the levels of TSH was normal, they were call back to hospitals at age of 28 ~35 days. The pattern of maternal thyroid disease, duration, thyroid function, the history of maternal ingestion of drug, maternal age, gestation age and weight of the neonate were recoded. Re-measured the neonatal and maternal serum thyroid function and measured the serum TPOAb, TGAb, TRAb and TSAb levels both in neonate and their mother as well. A 1-year follow-up study was done and all these sub
自身免疫性甲状腺疾病如弥漫性甲状腺肿伴甲亢(Greaves病)或慢性淋巴细胞性甲状腺炎(桥本氏病)均好发于青春期以后的女性，两者发病率分别为0.02～0.2％和1／1600～1／2000。怀孕母亲患自身免疫性甲状腺疾病如处理不当除了可能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，如未能及时发现和干预，轻者引起智能发育障碍和生长迟缓、重者可能引起死亡。
新生儿(婴儿)的甲状腺功能与智能发育密切相关。在过去的十年中国内外陆续有报道认为，孕母如果患自身免疫性甲状腺疾病，其分娩的新生儿有可能发生甲状腺功能低下(包括原发性或垂体性)、甲状腺功能亢进和暂时性高TSH血症，并在部分新生儿体内测到了高浓度的促甲状腺素受体(TRAb)，由此推测这些新生儿甲状腺功能异常可能与某些自身抗体有关。但以往的研究只是局限于考虑单个因素的作用，而事实上影响新生儿(婴儿)甲状腺功能的因素是多方面的，包括孕母所患的甲状腺疾病种类、孕母妊娠期甲状腺功能状态、妊娠期服药史、及其它治疗方案等等，这些因素对婴儿甲状腺功能有无影响?母婴的甲状腺功能对婴儿的智能发育有无影响?哪些因素有影响?影响程度有多大?这些问题有待于进一步研究。
2004年浙江大学硕士学位论文
研究目的
孕母患自身免疫性甲状腺疾病对婴儿智能发育可能有影响。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智能发育的跟踪调查，研究这些婴儿智能发育情况以及与
母、婴甲状腺功能情况之间的关系，旨在探讨孕母患自身免疫性甲状腺疾病对婴
儿智能发育的影响因素。
研究对象
通过全省新生儿疾病筛查网络，将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
母所生的婴儿。
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(TMAb)或抗甲状腺过氧化物酶抗体(TPOAb)、抗甲状腺
球蛋白抗体(TGAb)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
2004年浙江大学硕士学位论文
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>gmU/L者于1~3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，并取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)。所有观察对象在1月龄、3月龄、6月龄、12月龄
采用Gesell发育量表进行跟踪调查，由专人进行评估，结果以发育商(DQ)表
达，采用病例对照研究的方法对可能影响婴儿应人能、应物能、粗动作能、细动
作能发育的因素进行非条件logistic回归分析，各能区的自身比较采用单因素方
差分析(两两比较用LSD法，方差不齐者用D~et，sC检验);母婴体内的抗甲
状腺抗体的相互关系用双变量相关分析;所有数据由SPSSIO.0软件处理。
结果
1、孕母患自身免疫性甲状腺疾病对婴儿智能发育的影响
孕母患自身免疫性甲状腺疾病的婴儿其应人能、应物能、粗动作能、细动作
能发育落后，与健康孕母的婴儿比较有显著差异(P<0.01)，慢性淋巴细胞性甲
状腺炎孕母的婴儿其细动作能、应物能的发育比Graves病孕母的婴儿差，二者
比较差异具显著性(p<0.05)。
2、母婴体内抗甲状腺自身抗体的关系
对分娩后25~35天的母亲及新生儿/婴儿测定其体内抗甲状腺自身抗体:
TPOAb、TGAb、TRAb、TsAb，经双变量相关分析，Spe~an相关系数分别
2004年浙江大学硕士学位论文
为0，636、0.574、0.6一9、0.473，夕均(0.02。
3、婴儿智能发育异常的危险因素分析
经多因素非条件logisti。回归分析筛选出婴儿体内的仰oAb、母体内的TRAb
与婴儿的应物能、应人能，粗动作能有关，而母体内n，OAb、孕期母亲甲状腺
功能则与细动作能有关(p<0.05)
结论
1、孕母患自身免疫性甲状腺疾病对婴儿智能发育有负影响。
2、与Graves病相比较，孕母患慢性淋巴细胞性甲状腺炎对婴儿智能发育的影响
更大。
3、母婴体内的TPOAb、TRAb及孕母妊娠其甲状腺功能状态与婴儿应人能、应
物能、粗动作能、细动作能发育落后有关。
4、合并自身免疫性甲状腺疾病的孕母一定要接受合理的治疗，以减少对婴儿的
影响。
Background
Autoimmune thyroid diseases, such as diffuse toxic goiter (Greaves disease) and lymphocytic thyroiditis (Hashimoto's thyroiditis), are more frequent in female after adolescence. The incidences of Greaves disease and Hashimoto's thyroiditis were about 0.02%~0.2% and 1/1600-1/2000 respectively. Maternal autoimmune thyroid disease may increase not only the incidence of complication in prenatal, but also the incidence of abnormal thyroid function in neonate. Moreover, without diagnosis and treatment early, it could cause the retardation of intellectual and physical development, and even deaths.
The thyroid function in neonate and infant is close associated with intellectual development. In the last ten years, several studies reported that those neonates whose mother suffered with autoimmune thyroid diseases might increase the incidence of hypothyroidism (including primary or pituitary), hyperthyroidism and transitory hypothyroidism, that higher levels of thyroid stimulating hormone (TSH) receptor antibody (TRAb) were estimated in some of these neonates. These implied that the thyroid function of neonate maybe associated with some anti-thyroid auto-antibody. However, these previous studies consider with just one certain factor. In fact, these are many factors which maybe associated with the neonatal thyroid function, such as the pattern of maternal thyroid disease, the maternal thyroid function in pregnancy, the
drug used in pregnancy, other treatment, and so on. If these factors have any effect on neonatal thyroid function? If the thyroid function of mother and infant have effect on the intellectual development in neonate and infant? Which factors affect the infantile intellectual development? How about the degree of the effect? All these are needed to study deeply.
Objective
In this study, we investigated continuous the intellectual development of these infant whose mother suffered with autoimmune thyroid diseases in our province, study the association between the infant intellectual development and the maternal thyroid statue, and find the maternal risk factors associated with thyroid disease effect on the infant intellectual development.
Subject
Through the Zhejiang provincial neonatal disease screening network system, all the term newborn who born from mother with autoimmune thyroid disease (selection criteria) without asphyxia in all county, city, and provincial hospital in Zhejiang province (except Ningbo City) from July 2001 to June 2003 were enrolled. The control group was defined as the neonates who were born from mother without thyroid disease in these hospitals in the same time.
Selection criteria: Hypothyroidism with the increased thyroid microsomal antibodies (TMAb), thyroid peroxides antibody (TPOAb), or thyroglobalin antibody (TGAb) which detected in city, and provincial hospital in gestation or before pregnancy were diagnosis as Hashimoto's thyroiditis. Hyperthyroidism supported with the thyroid ultrasonography or ECT scans or confirmed by fine-needle-aspirate biopsy of the thyroid, excluded the hyperfunctioning thyroid adenoma and multinodular goiter, were diagnosis as Graves disease.
Methods
Heel capillary blood samples were collected from neonate older than 3 days in local hospitals and sent to the center of Zhejiang provincial neonatal disease screening network system. TSH levels were measured by Time difference fluorescent analysis device (1420 II type, American EGG Company). If the levels of TSH were over 9mU/L, the neonates and their mother were call back to the center in 3 days. If the levels of TSH was normal, they were call back to hospitals at age of 28 ~35 days. The pattern of maternal thyroid disease, duration, thyroid function, the history of maternal ingestion of drug, maternal age, gestation age and weight of the neonate were recoded. Re-measured the neonatal and maternal serum thyroid function and measured the serum TPOAb, TGAb, TRAb and TSAb levels both in neonate and their mother as well. A 1-year follow-up study was done and all these sub
引文
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10. Pop VJ, De Vries E, Van Baar AL, et al. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol
Metab, 1995,80(12):3561-3566.
11. Pop VJ, Kuiipens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrlinol (Oxf), 1999,50(2): 147-148.
12. Pop VJ, Brouwers EP, Vader HL, et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clinical Endocrinology, 2003,59,282-288.
13. Radetti G, Gentili L, Paganini C, et al. Psychomotor and audiological assessment of infants born to mothers with subclinical thyroid dysfunction in early pregnancy. Minerva Pediatrica, 2000, 52(12): 691-698.
14. Liu H, Momotani N, Noh JY, et al. Maternal hypothyroidism during early pregnancy and intellectual development of the progeny. Arch Intern Med, 1994, 154(7): 785-787.
15. Yasuda T, Ohnishi H, Wataki K, et al. Outcome of a baby born from a mother with acquired juvenile hypothyroidism having undetectable thyroid hormone concentrations. J Clin Endocrinol Metab, 1999, 84(8): 2630-2632.
16. Calvo RM, Jauniaux E, Gulbis B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phase of development. J Clin Endocrinol Metab, 2002, 87(4): 1768-1777.
17. Wada K, Kazukawa I, Someya T, et al. Maternal hypothyroidism in autoimmune thyroiditis and the prognosis of infants. Endocr J, 2000, 47 Suppl: S133-135.
18. Oppenheimer JH, Schwartz HL. Molecular basis of thyroid hormone-dependent
brain development. Endocr Rev, 1997,18(4):462-475.
19. Lavado-Autric R, Auso E, Garcia-Velasco JV, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest,2003, 111(7): 1073-1082.
20．谢超，罗敏，杨义生，等．甲状腺反应蛋白的基因——一个新的鼠脑甲状腺素反应蛋白的克隆、表达分布及其功能的预测．中华内分泌代谢杂志，2003，19(5)：341-344．
2. Phoojaroenchanachai M, Sriussadaporn S, Peerapatdit T, et al. Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clinical Endocrinology, 2001, 54(3): 365-370.
3．韩凤珍，刘俊涛，边旭明等．妊娠合并甲状腺机能亢进．中华妇产科杂志，2001，36(6)：383-384．
4. Montoro MN, Management of Hyperthyroidism during pregnancy. Clin Obstet Gynecol,1997,40(1):65-80.
5. Lieutaud H. Pregnancy and the thyroid gland. Ann Med Interne,1999, 150(5): 397-407.
6. Corssmit EP, Wiersinga WM, Boer K, et al. Pregnancy(conception) in hyper-hypothyroidism. Ned Tijdschr Geneeska,.2001,145(15):727-731.
7. Vohra S, Koren G. Hypothetical framework for a relationship between maternal thyroid function, nausea and vomiting of pregnancy, and congenital heart disease. Medical Hypotheses,2001,56(3):392-394.
8. Smit BJ, Kok JH, Vulsma T, et al. Neurologic development of the newborn and young child in relation to maternal thyroid function. Acta Paediatr, 2000,89(3): 291-295.
9．松浦信夫．医学，157(1)：110，1991．
10. Pop VJ, De Vries E, Van Baar AL, et al. Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? J Clin Endocrinol
Metab, 1995,80(12):3561-3566.
11. Pop VJ, Kuiipens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrlinol (Oxf), 1999,50(2): 147-148.
12. Pop VJ, Brouwers EP, Vader HL, et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clinical Endocrinology, 2003,59,282-288.
13. Radetti G, Gentili L, Paganini C, et al. Psychomotor and audiological assessment of infants born to mothers with subclinical thyroid dysfunction in early pregnancy. Minerva Pediatrica, 2000, 52(12): 691-698.
14. Liu H, Momotani N, Noh JY, et al. Maternal hypothyroidism during early pregnancy and intellectual development of the progeny. Arch Intern Med, 1994, 154(7): 785-787.
15. Yasuda T, Ohnishi H, Wataki K, et al. Outcome of a baby born from a mother with acquired juvenile hypothyroidism having undetectable thyroid hormone concentrations. J Clin Endocrinol Metab, 1999, 84(8): 2630-2632.
16. Calvo RM, Jauniaux E, Gulbis B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phase of development. J Clin Endocrinol Metab, 2002, 87(4): 1768-1777.
17. Wada K, Kazukawa I, Someya T, et al. Maternal hypothyroidism in autoimmune thyroiditis and the prognosis of infants. Endocr J, 2000, 47 Suppl: S133-135.
18. Oppenheimer JH, Schwartz HL. Molecular basis of thyroid hormone-dependent
brain development. Endocr Rev, 1997,18(4):462-475.
19. Lavado-Autric R, Auso E, Garcia-Velasco JV, et al. Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. J Clin Invest,2003, 111(7): 1073-1082.
20．谢超，罗敏，杨义生，等．甲状腺反应蛋白的基因——一个新的鼠脑甲状腺素反应蛋白的克隆、表达分布及其功能的预测．中华内分泌代谢杂志，2003，19(5)：341-344．
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