抗甲状腺抗体与反复自然流产关系的研究
摘要
[目的]反复自然流产(Recurrent Spontaneous Abortion，RSA)是发生2次或2次以上的自然流产，发生率为1-2％，是妊娠期常见的并发症。习惯性流产的病因十分复杂，涉及遗传、内分泌、解剖和感染和环境因素等多因素，其中约50-60％与免疫有关。免疫相关RSA分为同种免疫型和自身免疫型两种。自身免疫型RSA占免疫相关RSA的1／3，与自身抗体有关。对抗甲状腺抗体(Antithyroid Antibodies，ATA)与妊娠关系的研究开始得比较晚。本实验探讨ATA与反复流产的关系，为RSA的免疫因素诊断提供参考指标，进一步指导对RSA的临床治疗。
[材料与方法]本实验采用酶联免疫吸附法(Enzyme LinkedImmunosorbernt Assays，ELISA)对80例RSA患者进行ATA的检测，所有患者均无自身免疫病，并通过妇科常规检查、盆腔B超检查、子宫输卵管碘油造影或宫腔镜、性激素及甲状腺功能的检查，夫妻双方染色体核型分析及ABO系统血型检测，病毒及细菌感染的检测，血抗精子抗体的检查排除了因遗传、解剖、内分泌、感染等因素所致的复发性自然流产。其中两次流产者48例，三次以上流产者32例；早期流产(＜12周)者50例，晚期流产(≥12周)者30例。年龄23—39岁，平均28.3岁；流产次数2-5次，平均2.6次。并以40例健康育龄妇女为对照，年龄23－36岁，
吉林大学硕士学位论文
平均年龄28.8岁，妊娠次数1一4次，平均妊娠次数2.4次。无不孕、流
产、死胎、死产史，未患系统疾病，
与生殖障碍关系密切的抗甲状腺抗体主要有两种，抗甲状腺过氧化物
酶抗体(Antithyroid Peroxidase Antibodies，a一TPO)和抗甲状腺球蛋
白抗体(AntithyroglobulinAntibodies，a一TG)。本实验分别检测了此
两种抗体在RSA妇女和健康对照组妇女血清中的水平。
【结果】到目前的不同研究中，RsA的妇女中ATA阳性率波动在
22.5%39%之间。本实验结果为33.8%，明显高于正常妇女组10.0%，统计
学上有显著差异(P<0 .01)，提示ATA与RSA密切相关。
ATA与RSA妇女妊娠月份的关系为:早期流产组(孕周<12周)中
ATA的阳性率为38.0%，晚期流产组(孕周)12周)为26、7%，早期流产
组中的阳性率与正常对照组有明显的统计学上的差异，而晚期流产组的阳
性率高于正常对照组，但无统计学上的差异。说明ATA与早期流产关系密
本实验结果还显示流产次数与ATA的关系:2次流产患者中的ATA阳
性率为33.3%，略低于3次或以上者的阳性率34.4%。两组流产患者的阳
性率都显著高于正常对照组。两组流产患者ATA的阳性率无统计学上的差
异。表明流产次数的多少与ATA阳性率无关。
吉林大学硕士学位论文
关于ATA的两种亚型与RSA的关系:本研究中，流产组a一TPO阳性率
为25.0%，高于正常对照组，统计学上有差异。a一TG的阳性率在RSA妇女
中18.8%，高于正常对照组，有统计学意义。据本实验结果a一TG和a一TPO
与RSA有密切相关，实际工作中推荐两种亚型的联合测定。
【结论】a一TG和a一TPO均与反复自然流产有密切关系;抗甲状腺抗体
可作为RsA病因的检测指标;ATA与早期RSA(孕周<12周二相关;流产
次数与RSA病人中的ATA的阳性率无相关。
对于ATA与RSA的关系的研究国内进行的甚少，本实验在国内率先进
行了对于ATA与RSA的关系的研究，阐明了ATA与RSA密切相关。目前认
为ATA是自身免疫亢进的继发标志，而不是导致妊娠失败的直接因素，ATA
反映导致妊娠失败的异常免疫反应，而且有报道提示ATA阳性的RSA妇女
中抗磷脂抗体不一定阳性，ATA可作为监测RSA危险的独立指标。妊娠前
和妊娠中对ATA的检测提高RSA风险的诊断率，而且对于进行及时的治疗
也有意义。
The recurrent spontaneous abortion(RSA) refers to the occurrence of two or more consecutive spontaneous abortions. RSA is a common gestational complication with an incidence rate of 1-2%. The etiological factors involved in RSA include genetics, endocrine, anatomy, infection and other environmental factors.50-60% of RSA are related to immunological causes .which are divided into alloimmune and autoimmune factors. Autoimmune factors account for 1/3 of immune-related RSA, this type of RSA is typical with existence of autoantibodies. The studies on the relationship between the antithyroid antibodies(ATA) and RSA were carried out lately. The purpose of this study is to provide experimental evidences for clinical diagnosis and treatment of RSA.
In our study, serum levels of ATA were determined by ELISA in 80patients with the histories of unexplained RSA(study group) and 40 normal healthy women(control group) to investigate the relationship between RSA and ATA.
Among antithyroid antibodies, two subtypes , antithyroid peroxidase antibodies(a-TPO) and antithyroglobulin antibodies contribute much to RSA. Our research detected the serum levels of the two subtypes in the RSA patients and control group. So far, in relevant studies, the positive rates of ATA range from 22. 5% to 39% among RSA patients. In our study, the women with RSA show a higher incidence of ATA(33.8%) compared with normal controls(10.0%),
which is statistically significant (P<0. 01) . This result indicates that there is important correlation between ATA and RSA.
The relationship between ATA and durations of pregnancy: the incidence rate of ATA is 38.0% in the first trimester, while the incidence is 26.7% in late abortions. The positive rate of ATA in early abortions is statistically significant compared with normal controls, while the incidence of ATA is not significantly high in late abortions, and no difference between two groups. This result shows that ATA are associated with early abortions.
As far as the relationship between ATA and times of abortions is concerned, our results show positive rate of ATA in patients with 2 times abortions is 33.3%, lower than that(34. 4%) in 3 times or more abortions, both groups have significant higher rates than control group. But there is no difference between two groups. This outcome indicates ATA have no apparent relation with times of abortions.
Our study also shows relations of the subtypes of ATA and pregnancy loss: The incidence of a-TPO with the rate of 25.0% is higher in RSA groups than normal controls, having statistic significance. While the positive rate of a-TG is 18.8%, significantly higher in study group than in controls. These results indicate both a-TPO and a-TG have close relation with RSA occurrence.
The study on ATA and RSA is rare in our country. Our study is advanced in our country to illustrate the relation between ATA and
RSA. Nowadays ATA is considered to be a marker of abnormal immune condition, and some studies showed that women with RSA had ATA but did not have increased antiphospholipid antibodies. So ATA also can be an independent marker of the risk of pregnancy loss. It is of high significance to determine serum ATA level for diagnosis and timely treatment of RSA.
[材料与方法]本实验采用酶联免疫吸附法(Enzyme LinkedImmunosorbernt Assays，ELISA)对80例RSA患者进行ATA的检测，所有患者均无自身免疫病，并通过妇科常规检查、盆腔B超检查、子宫输卵管碘油造影或宫腔镜、性激素及甲状腺功能的检查，夫妻双方染色体核型分析及ABO系统血型检测，病毒及细菌感染的检测，血抗精子抗体的检查排除了因遗传、解剖、内分泌、感染等因素所致的复发性自然流产。其中两次流产者48例，三次以上流产者32例；早期流产(＜12周)者50例，晚期流产(≥12周)者30例。年龄23—39岁，平均28.3岁；流产次数2-5次，平均2.6次。并以40例健康育龄妇女为对照，年龄23－36岁，
吉林大学硕士学位论文
平均年龄28.8岁，妊娠次数1一4次，平均妊娠次数2.4次。无不孕、流
产、死胎、死产史，未患系统疾病，
与生殖障碍关系密切的抗甲状腺抗体主要有两种，抗甲状腺过氧化物
酶抗体(Antithyroid Peroxidase Antibodies，a一TPO)和抗甲状腺球蛋
白抗体(AntithyroglobulinAntibodies，a一TG)。本实验分别检测了此
两种抗体在RSA妇女和健康对照组妇女血清中的水平。
【结果】到目前的不同研究中，RsA的妇女中ATA阳性率波动在
22.5%39%之间。本实验结果为33.8%，明显高于正常妇女组10.0%，统计
学上有显著差异(P<0 .01)，提示ATA与RSA密切相关。
ATA与RSA妇女妊娠月份的关系为:早期流产组(孕周<12周)中
ATA的阳性率为38.0%，晚期流产组(孕周)12周)为26、7%，早期流产
组中的阳性率与正常对照组有明显的统计学上的差异，而晚期流产组的阳
性率高于正常对照组，但无统计学上的差异。说明ATA与早期流产关系密
本实验结果还显示流产次数与ATA的关系:2次流产患者中的ATA阳
性率为33.3%，略低于3次或以上者的阳性率34.4%。两组流产患者的阳
性率都显著高于正常对照组。两组流产患者ATA的阳性率无统计学上的差
异。表明流产次数的多少与ATA阳性率无关。
吉林大学硕士学位论文
关于ATA的两种亚型与RSA的关系:本研究中，流产组a一TPO阳性率
为25.0%，高于正常对照组，统计学上有差异。a一TG的阳性率在RSA妇女
中18.8%，高于正常对照组，有统计学意义。据本实验结果a一TG和a一TPO
与RSA有密切相关，实际工作中推荐两种亚型的联合测定。
【结论】a一TG和a一TPO均与反复自然流产有密切关系;抗甲状腺抗体
可作为RsA病因的检测指标;ATA与早期RSA(孕周<12周二相关;流产
次数与RSA病人中的ATA的阳性率无相关。
对于ATA与RSA的关系的研究国内进行的甚少，本实验在国内率先进
行了对于ATA与RSA的关系的研究，阐明了ATA与RSA密切相关。目前认
为ATA是自身免疫亢进的继发标志，而不是导致妊娠失败的直接因素，ATA
反映导致妊娠失败的异常免疫反应，而且有报道提示ATA阳性的RSA妇女
中抗磷脂抗体不一定阳性，ATA可作为监测RSA危险的独立指标。妊娠前
和妊娠中对ATA的检测提高RSA风险的诊断率，而且对于进行及时的治疗
也有意义。
The recurrent spontaneous abortion(RSA) refers to the occurrence of two or more consecutive spontaneous abortions. RSA is a common gestational complication with an incidence rate of 1-2%. The etiological factors involved in RSA include genetics, endocrine, anatomy, infection and other environmental factors.50-60% of RSA are related to immunological causes .which are divided into alloimmune and autoimmune factors. Autoimmune factors account for 1/3 of immune-related RSA, this type of RSA is typical with existence of autoantibodies. The studies on the relationship between the antithyroid antibodies(ATA) and RSA were carried out lately. The purpose of this study is to provide experimental evidences for clinical diagnosis and treatment of RSA.
In our study, serum levels of ATA were determined by ELISA in 80patients with the histories of unexplained RSA(study group) and 40 normal healthy women(control group) to investigate the relationship between RSA and ATA.
Among antithyroid antibodies, two subtypes , antithyroid peroxidase antibodies(a-TPO) and antithyroglobulin antibodies contribute much to RSA. Our research detected the serum levels of the two subtypes in the RSA patients and control group. So far, in relevant studies, the positive rates of ATA range from 22. 5% to 39% among RSA patients. In our study, the women with RSA show a higher incidence of ATA(33.8%) compared with normal controls(10.0%),
which is statistically significant (P<0. 01) . This result indicates that there is important correlation between ATA and RSA.
The relationship between ATA and durations of pregnancy: the incidence rate of ATA is 38.0% in the first trimester, while the incidence is 26.7% in late abortions. The positive rate of ATA in early abortions is statistically significant compared with normal controls, while the incidence of ATA is not significantly high in late abortions, and no difference between two groups. This result shows that ATA are associated with early abortions.
As far as the relationship between ATA and times of abortions is concerned, our results show positive rate of ATA in patients with 2 times abortions is 33.3%, lower than that(34. 4%) in 3 times or more abortions, both groups have significant higher rates than control group. But there is no difference between two groups. This outcome indicates ATA have no apparent relation with times of abortions.
Our study also shows relations of the subtypes of ATA and pregnancy loss: The incidence of a-TPO with the rate of 25.0% is higher in RSA groups than normal controls, having statistic significance. While the positive rate of a-TG is 18.8%, significantly higher in study group than in controls. These results indicate both a-TPO and a-TG have close relation with RSA occurrence.
The study on ATA and RSA is rare in our country. Our study is advanced in our country to illustrate the relation between ATA and
RSA. Nowadays ATA is considered to be a marker of abnormal immune condition, and some studies showed that women with RSA had ATA but did not have increased antiphospholipid antibodies. So ATA also can be an independent marker of the risk of pregnancy loss. It is of high significance to determine serum ATA level for diagnosis and timely treatment of RSA.
引文
1．林其德．免疫所致复发性流产和习惯性流产．中华妇产科杂志，2000，35(12)：760．
2．关铮．习惯性流产的免疫学．北京医学，1995，17(5)：281-283．
3．王越，牛秀珑，等．习惯性流产免疫学病因的研究进展．国外医学妇产科学分册，2001，28(6)：348-350．
4．林羿，洪彤，等．反复自然流产的几种免疫相关因素．生殖与避孕，1999，19(3)：182-188．
5．杨大森，吴锦芝．抗心磷脂抗体与习惯性流产或死胎的关系．生殖与避孕，1992，12(3)：3-6．
6．王丽君，李菏莲．不孕症与自身抗体的关系．吉林医学，2002，23(4)：199-200．
7．郝素珍．狼疮抗凝因素的研究进展．国外医学免疫学分册，1995．2：77-80．
8．李翘竹，李慧芳，等．原因不明习惯性流产患者自身抗体的研究．中华妇产科杂志，1998，33(1)：13-16．
9．杨大森，吴锦芝，等．习惯性流产患者抗心磷脂抗体和抗DNA抗体测定．中华妇产科杂志，1994，29(6)：371-372．
10．周从容，李荣荣，等．习惯性流产或死胎与自身免疫关系的探讨．贵州医药，1998，22(1)：41-42．
11．张师前，董建春，等．习惯性流产患者抗心磷脂抗体和抗DNA抗体测定．中国免疫学杂志，11(6)：369．
12．费克香，彭先高，等．抗磷脂综合征的研究进展．医学综述，1998，4(8)：423-424．
13．李传余，李静．抗磷脂综合征研究进展．国外医学免疫学分册，1997 20(5)：258-262．
14．陶静芬．血清TPOAb与TMA、TGA在桥本氏甲状腺炎诊断中的临床意义．放射免疫学杂志，2000，13(5)：299-300．
15．王金彪，等．碘对甲状腺自身免疫功能影响的研究．中国地方病学杂志，2002，21(4)：301-303．
16．余南，等．甲状腺球蛋白及其抗体在自身免疫性甲状腺病中的作用．上海免疫学杂志，1999，19(4)：254-256．
17．魏文青，等．甲状腺抗体与自身免疫性甲状腺疾病．国外医学临床生物化学与检验学分册，1997，18(6)：272-273．
18．张红烨，等．自身免疫与生殖．男科学报，1998，4(1)：44-48．
19．刘红燕．产后甲状腺炎研究近况．医学文选，2003，22(3)：
368-371．
20．兰玲，等．产后甲状腺炎研究进展．国外医学妇幼保健分册，2003，14(4)：235-237．
21. B. Lejeune, et al. Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension. Br J Obstet and Gynecol, 1993, 100: 669-6?2.
22. A. Singh, et al. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies. Fertil Steril, 1995,63(2): 364-369.
23. TAKASHI IIJIMA, et al. Effects ofautoantibodies on the course of pregnancy and fetal growth. Obst & Gynecol,1997,90(3): 277-281.
24. W. H. Kutteh, et, al. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction. Fertil Steril, 1999,71(5): 843-848.
25. F. Mecacci, et al. Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclmpsia. J Reprod Immunol, 2000,46(1):39-50.
26. J. H. Lazarus and A. Kokandi. Thyroid disease in relation to pregnancy: A decade of change. Clin Endocrinol, 2000, 53:265-278.
27. D. Pratt, et al. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss. Am J Obstet Gynecol, 1993, 168:837-841.
28. M. S. Esplin, et al. Thyroid autoantibodies are not associated with recurrent pregnancy loss. Am J Obstet Gynecol, 1998,179: 1583-1586.
29. R. M. Lee, et al. Anti-β_2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome. Am J Obstet Gynecol, 1999, 181(3): 642-648.
30. C. Stern, et al. Antibodies to β_2-glycoprotein I are associatied with in vitro fertilization implantation
failure as well as recurrent miscarriage:results of a prevalence study. Fertil Steril, 1998,70(8): 938-943.
31. R.M. Lee, et al. Immnoglobulin A anti-β_2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death. Am J Obstet Gynecol, 2001, 185(3): 738-753.
32. R.B. Stricker, et al. Sucessful treatment of immunologic abortion with low -dose intravenous immunoglobulin. Fertil Steril, 2000, 73(3): 536-540.
33. C.A. Omwandho, et al. Recurrent pregnancy losses and the role of immunotherapy. Arch Gynecol Obstet, 2000 264:3-12.
34. A.L. Clark, et al,.Pregnancy complicated by the Antiphospholipid Syndrome: Outcomes with intravenous immunoglobulin Therapy. Obstet & Gynecol, 1999, 93(3): 437-441.
35. Brauch D.W.,et al. Obstetric complications associated with the lupus anticoagulant. New Engl J Med,1985, 313:1322-1326.
36. Cowshock S. et al. Subclinical autoimmune disease and unexplained abortion. Am J Obstet Gynecol 1984, 150: 367-371.
37. Maier D. B.& Parke A. subclinical autoimmunity in recurrent aborters. Fertil Steril 1989,51:280-285.
38. Stagnaro-Green A, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid antibodies. JAMA, 1990, 264:1422-1425.
39. Oeva E ,et al. Autoimmunity and reproduction. Fertil Steril, 1997:67(4): 599
40. Bussem SS, Steck T. Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters). Eur J Obstet Gynecol Reprod Biol 1997, 74:139-43.
41．裘晟等，抗磷脂抗体综合征的研究进展医学综述1998年第4卷第10期：551-552。
2．关铮．习惯性流产的免疫学．北京医学，1995，17(5)：281-283．
3．王越，牛秀珑，等．习惯性流产免疫学病因的研究进展．国外医学妇产科学分册，2001，28(6)：348-350．
4．林羿，洪彤，等．反复自然流产的几种免疫相关因素．生殖与避孕，1999，19(3)：182-188．
5．杨大森，吴锦芝．抗心磷脂抗体与习惯性流产或死胎的关系．生殖与避孕，1992，12(3)：3-6．
6．王丽君，李菏莲．不孕症与自身抗体的关系．吉林医学，2002，23(4)：199-200．
7．郝素珍．狼疮抗凝因素的研究进展．国外医学免疫学分册，1995．2：77-80．
8．李翘竹，李慧芳，等．原因不明习惯性流产患者自身抗体的研究．中华妇产科杂志，1998，33(1)：13-16．
9．杨大森，吴锦芝，等．习惯性流产患者抗心磷脂抗体和抗DNA抗体测定．中华妇产科杂志，1994，29(6)：371-372．
10．周从容，李荣荣，等．习惯性流产或死胎与自身免疫关系的探讨．贵州医药，1998，22(1)：41-42．
11．张师前，董建春，等．习惯性流产患者抗心磷脂抗体和抗DNA抗体测定．中国免疫学杂志，11(6)：369．
12．费克香，彭先高，等．抗磷脂综合征的研究进展．医学综述，1998，4(8)：423-424．
13．李传余，李静．抗磷脂综合征研究进展．国外医学免疫学分册，1997 20(5)：258-262．
14．陶静芬．血清TPOAb与TMA、TGA在桥本氏甲状腺炎诊断中的临床意义．放射免疫学杂志，2000，13(5)：299-300．
15．王金彪，等．碘对甲状腺自身免疫功能影响的研究．中国地方病学杂志，2002，21(4)：301-303．
16．余南，等．甲状腺球蛋白及其抗体在自身免疫性甲状腺病中的作用．上海免疫学杂志，1999，19(4)：254-256．
17．魏文青，等．甲状腺抗体与自身免疫性甲状腺疾病．国外医学临床生物化学与检验学分册，1997，18(6)：272-273．
18．张红烨，等．自身免疫与生殖．男科学报，1998，4(1)：44-48．
19．刘红燕．产后甲状腺炎研究近况．医学文选，2003，22(3)：
368-371．
20．兰玲，等．产后甲状腺炎研究进展．国外医学妇幼保健分册，2003，14(4)：235-237．
21. B. Lejeune, et al. Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension. Br J Obstet and Gynecol, 1993, 100: 669-6?2.
22. A. Singh, et al. Presence of thyroid antibodies in early reproductive failure: biochemical versus clinical pregnancies. Fertil Steril, 1995,63(2): 364-369.
23. TAKASHI IIJIMA, et al. Effects ofautoantibodies on the course of pregnancy and fetal growth. Obst & Gynecol,1997,90(3): 277-281.
24. W. H. Kutteh, et, al. Increased prevalence of antithyroid antibodies identified in women with recurrent pregnancy loss but not in women undergoing assisted reproduction. Fertil Steril, 1999,71(5): 843-848.
25. F. Mecacci, et al. Thyroid autoimmunity and its association with non-organ-specific antibodies and subclinical alterations of thyroid function in women with a history of pregnancy loss or preeclmpsia. J Reprod Immunol, 2000,46(1):39-50.
26. J. H. Lazarus and A. Kokandi. Thyroid disease in relation to pregnancy: A decade of change. Clin Endocrinol, 2000, 53:265-278.
27. D. Pratt, et al. Antithyroid antibodies and the association with non-organ-specific antibodies in recurrent pregnancy loss. Am J Obstet Gynecol, 1993, 168:837-841.
28. M. S. Esplin, et al. Thyroid autoantibodies are not associated with recurrent pregnancy loss. Am J Obstet Gynecol, 1998,179: 1583-1586.
29. R. M. Lee, et al. Anti-β_2-glycoprotein I antibodies in women with recurrent spontaneous abortion, unexplained fetal death, and antiphospholipid syndrome. Am J Obstet Gynecol, 1999, 181(3): 642-648.
30. C. Stern, et al. Antibodies to β_2-glycoprotein I are associatied with in vitro fertilization implantation
failure as well as recurrent miscarriage:results of a prevalence study. Fertil Steril, 1998,70(8): 938-943.
31. R.M. Lee, et al. Immnoglobulin A anti-β_2-glycoprotein antibodies in women who experience unexplained recurrent spontaneous abortion and unexplained fetal death. Am J Obstet Gynecol, 2001, 185(3): 738-753.
32. R.B. Stricker, et al. Sucessful treatment of immunologic abortion with low -dose intravenous immunoglobulin. Fertil Steril, 2000, 73(3): 536-540.
33. C.A. Omwandho, et al. Recurrent pregnancy losses and the role of immunotherapy. Arch Gynecol Obstet, 2000 264:3-12.
34. A.L. Clark, et al,.Pregnancy complicated by the Antiphospholipid Syndrome: Outcomes with intravenous immunoglobulin Therapy. Obstet & Gynecol, 1999, 93(3): 437-441.
35. Brauch D.W.,et al. Obstetric complications associated with the lupus anticoagulant. New Engl J Med,1985, 313:1322-1326.
36. Cowshock S. et al. Subclinical autoimmune disease and unexplained abortion. Am J Obstet Gynecol 1984, 150: 367-371.
37. Maier D. B.& Parke A. subclinical autoimmunity in recurrent aborters. Fertil Steril 1989,51:280-285.
38. Stagnaro-Green A, et al. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid antibodies. JAMA, 1990, 264:1422-1425.
39. Oeva E ,et al. Autoimmunity and reproduction. Fertil Steril, 1997:67(4): 599
40. Bussem SS, Steck T. Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters). Eur J Obstet Gynecol Reprod Biol 1997, 74:139-43.
41．裘晟等，抗磷脂抗体综合征的研究进展医学综述1998年第4卷第10期：551-552。