甲状腺过氧化物酶抗体阳性对妊娠结局的影响

妊娠妇女中,甲状腺过氧化酶抗体(TPOAb)的阳性率为3%～10%.不孕妇女中TPOAb阳性率是否显著高于一般妇女目前还存在争议.甲状腺自身免疫异常(TAI)对妊娠结局可能产生负面影响,TAI人群流产率与早产率都高于对照组,这在未经选择的一般人群以及行人工辅助生殖(ARTs)的人群中均有研究支持.TAI的干预有静脉注入免疫球蛋白、甲状腺素替代治疗和硒治疗几种方式.每种干预方法的机制及疗效评价均需更多证据支持.     

甲状腺自身抗体对妊娠结局和后代的影响及干预

母体甲状腺功能正常、单纯甲状腺自身抗体阳性可以导致不良的妊娠结局,如流产、早产等,使妊娠妇女和新生儿的TSH常高于正常参考范围上限,并影响后代智力发育.甲状腺自身抗体对妊娠结局和后代影响的机制尚未阐明,干预主要为左旋甲状腺素与硒制剂.本文就当前甲状腺自身免疫对妊娠结局与后代的影响以及干预作一综述.     

甲状腺疾病对女性生殖功能的影响

甲状腺激素（TH）一方面直接作用于卵巢,另一方面通过影响性激素结合球蛋白（SHBG）的合成,调节泌乳素（PRL）、促性腺激素释放激素（GnRH）的分泌和凝血因子的功能而对月经周期进行调控。不孕女性的自身免疫性甲状腺疾病（AITD）患病率明显高于年龄匹配的经产妇,尤其是继发于子宫内膜异位或多囊卵巢综合征（PCOS）的不孕女性。伴或不伴AITD的妇女行辅助生殖技术（ART）的成功率并无显著差异。但患AITD的孕妇在妊娠前3个月发生流产的风险明显高于正常孕妇。此外,行ART之前的控制性超排卵（COH）过程对甲状腺功能有着不可忽略的影响,特别是对于合并AITD的妇女。故不孕妇女应于行ART之前筛查甲状腺功能,及时发现AITD,并在COH之后和妊娠期随访AITD妇女的甲状腺功能。妊娠早期阶段出现甲状腺功能异常的孕妇应接受L-Td治疗以避免妊娠并发症的发生。但关于是否应在孕前或孕期使用L—T。治疗甲状腺功能正常的AITD妇女仍缺乏足够的临床研究。     

甲状腺自身免疫与妊娠

自身免疫甲状腺病(AITD)是一种常见的内分泌疾病，女性显著高发。由于妊娠期母体免疫状态的改变，AITD在妊娠和产后表现了许多特殊的形式。以下重点介绍产后甲状腺炎、甲状腺自身免疫与自发性流产、甲状腺自身免疫对胎儿智力的影响。     

自身免疫性甲状腺炎对妊娠结局的影响

自身免疫性甲状腺炎(AIT)的发病受遗传、环境等多重因素影响,其在育龄期女性中的患病率颇高,可增加孕早期流产、早产、死胎、辅助生殖技术(ART)时流产等不良妊娠结局及低体重儿的患病率,其可能与免疫异常、甲状腺功能紊乱以及孕妇高龄等因素有关.其治疗措施主要包括免疫调节、甲状腺功能干预,二者效果如何仍待进一步研究.     

981名女性宫颈分泌物沙眼衣原体检测分析

沙眼衣原体,是引起女性生殖道感染的常见性传播疾病.常常与女性宫颈炎、急性输卵管炎、不孕有关,且可导致流产、早产、不良妊娠并发症的发生[1].由于沙眼衣原体感染无特殊临床表现且症状隐匿,人们常忽视对沙眼衣原体感染的治疗.     

甲状腺自身免疫与流产关联性的meta分析

目的 综合评价甲状腺自身免疫(TAI)与流产的关联性.方法 通过文献检索收集2009年3月以前发表的有关甲状腺自身免疫与流产相关性的病例对照研究以及队列研究,剔除不符合要求的文献,以漏斗图检验入选文献的发表偏倚,并根据各入选文献的同质性检验结果进行数据合并,分别计算合并OR值与RR值,应用meta分析软件包RevMan 4.3.1进行计算.结果 经检索得到23篇文献,剔除综述4篇,余19项临床研究均符合本次meta分析的纳入标准.纳入的19项研究中,7项为病例对照研究,12项为队列研究.7项病例对照研究得到的合并OR值为2.72(95% CI 1.27～5.80,P=0.01);12项队列研究得到的合并RR值为2.41(95% CI 1.96～2.96,P＜0.01).甲状腺自身抗体(TA)阳性妇女较TA阴性者平均年长1.29岁(95% CI 0.43～2.16,P=0.003),TA阳性妇女的TSH较TA阴性者平均高0.61 mIU/L(95% CI 0.51～0.71,P＜0.01).结论 TAI与流产显著关联.除了TA的直接效应以外,TA阳性孕妇轻度的增龄与甲状腺功能不足亦可能是导致流产风险增加的潜在原因.     

亚临床甲状腺功能减退症

亚临床甲状腺功能减退症(甲减)是一种业临床甲状腺疾病.诊断标准是血清促甲状腺激素(TSH)水平高于正常上限而游离T4水平尚在正常范围.目前全世界业临床甲减的平均患病率为4%～10%,主要发生在女性和老年人群.桥本甲状腺炎是最常见的病因.其卡要的临床危害包括引起血脂异常、导致动脉粥样硬化和,冠心病、影响认知功能,还可导致不孕和流产.治疗主要针对血清TSH10 mIU/L的患者,应用左旋-T4替代治疗.对于血清TSH 4～10 mIU/L,特别是甲状腺自身抗体阳性者需密切监测.此外,对妊娠期亚临床甲减患者的治疗要求控制TSH<2.5 mlU/L.     

妊娠早期母体甲状腺功能及其抗体异常对妊娠结局的影响

目的 评估妊娠早期甲状腺疾病与产科并发症关系.方法 2 517名来自沈阳市10家医院妊娠12周内的妇女,测定血清TSH、FT4、甲状腺过氧化物酶抗体(TPOAb)水平.收集妊娠结局资料,评价妊娠早期TPOAb(+)、TSH升高或降低以及抗甲状腺药物或左旋甲状腺素钠(L-T4)治疗对产科并发症的影响.结果 妊娠早期TSH升高妇女自发性流产发生率增加(8.69％对6.38％.P=0.048),并且亚临床甲状腺功能减退即可显著增加自发性流产发生率(9.50％对6.38％,P=0.009).TPOAb(+)组与TPOAb(-)组相比自发性流产发生率无差别(5.22％对7.41％,P=0.204).Logistic回归分析显示,血清TSH水平升高、妊娠期间被动吸烟、年龄≥30岁均是妊娠期间自发性流产的独立危险因素(分别为OR=1.572,95％ CI1.120-2.208;OR=1.432,95％CI1.012～2.025;OR=1.904,95％CI1.245 ～2.914).甲状腺功能亢进或甲状腺功能减退药物治疗维持妊娠期间正常甲状腺功能可降低自发性流产的发生.血清TSH水平升高或降低、TPOAb(+)与其他产科并发症无关.结论 妊娠早期血清TSH水平升高是妊娠期自发性流产的危险因素;甲状腺功能亢进或甲状腺功能减退经药物治疗维持妊娠期间TSH在正常范围可降低自发性流产发生率.     

甲状腺过氧化物酶抗体检测的临床意义

甲状腺过氧化物酶表达于甲状腺滤泡细胞表面,主要参与甲状腺激素的合成与释放,并与细胞介导的细胞毒效应有关.甲状腺过氧化物酶能诱导机体产生高亲和力的IgG抗体(TPOAb)与甲状腺过氧化物酶特异的T淋巴细胞,分别参与甲状腺的浸润与破坏.TPOAb定量检测最常用的方法为酶联免疫吸附法.与TPOAb相关的疾病包括恶性贫血、结缔组织病、糖尿病、炎症性肠病、情感障碍以及一些妇产科疾病如流产、不孕、体外受精失败、早产、产后甲状腺炎等.正确认识TPOAb检测的指征,如对甲状腺肿以及Graves病或桥本甲状腺炎等自身免疫性甲状腺疾病的诊断和鉴别诊断、预测亚临床甲状腺疾病发生甲状腺功能减退症的风险等具有十分重要的临床意义.     

Thyroid disorders in infertile women.

Thyroid hormones have profound effects on reproduction and pregnancy. There is a known association of hyper- and hypothyroidism with menstrual disturbances and decreased fecundity. Women with reproductive failure also have an increased prevalence of organ specific autoimmunity compared to fertile women. The present study aims to answer the following questions: 1) is there an increased prevalence of thyroid antibodies in infertile women? 2) are thyroid antibodies associated with a particular cause of infertility? and 3) do these antibodies influence outcome of the in vitro fertilization procedure? The answers to the two first questions were evaluated with a case-control study looking at the occurrence of thyroid autoimmunity and thyroid function tests among women of infertile couples (n=438), presenting for the first time at the department of reproductive medicine. For comparison, a control population of parous women (n=100), matched for age, was included. In 45% of the infertile couples a female cause of infertility was identified: endometriosis (11%), tubal disease (30%) and ovarian dysfunction (59%). Male infertility was diagnosed in 38% and idiopathic infertility in 17% of the couples. Mean serum TSH levels were significantly higher in patients with infertility compared with control patients: 1.6 +/- 2.6 versus 1.2 +/- 0.7 mIU/L. The proportion of positive TPO-Abs was higher in all women of infertile couples, compared with controls (14% versus 8%), but the difference was not significant. Considering only the female causes of infertility a significant higher proportion of women had positive TPO-Abs compared with controls (18% versus 8%), and in particular a high prevalence of thyroid autoimmunity was found in women suffering from endometriosis (29%). Both hypo- and hyperthyroidism were more frequent when TPO-Abs were positive, compared to women without thyroid autoimmunity. The results of the present study indicate that endometriosis, increases the relative risk for associated thyroid autoimmunity to 2.3, and therefore screening for thyroid auto-antibodies could be systematically proposed in these women.     

The role of thyroid autoimmunity in fertility and pregnancy

The thyroid gland and gonadal axes interact continuously before and during pregnancy. Hypothyroidism influences ovarian function by decreasing levels of sex-hormone-binding globulin and increasing the secretion of prolactin. In women of reproductive age, hypothyroidism can be reversed by thyroxine therapy to improve fertility and avoid the need for use of assisted reproduction technologies. For infertile women, preparation for medically assisted pregnancy comprises controlled ovarian hyperstimulation that substantially increase circulating estrogen concentrations, which in turn can severely impair thyroid function. In women without thyroid autoimmunity these changes are transient, but in those with thyroid autoimmunity estrogen stimulation might lead to abnormal thyroid function throughout the remaining pregnancy period. Prevalence of thyroid autoimmunity is significantly higher among infertile women than among fertile women, especially among those whose infertility is caused by endometriosis or ovarian dysfunction. Presence of thyroid autoimmunity does not interfere with normal embryo implantation, but the risk of early miscarriage is substantially raised. Subclinical and overt forms of hypothyroidism are associated with increased risk of pregnancy-related morbidity, for which thyroxine therapy can be beneficial. Systematic screening for thyroid disorders in pregnant women remains controversial but might be advantageous in women at high risk, particularly infertile women.     

Thyroid disease in pregnancy

Thyroid diseases are common in women of childbearing age and it is well known that untreated thyroid disturbances result in an increased rate of adverse events, particularly miscarriage, preterm birth and gestational hypertension. Furthermore, thyroid autoimmunity per se seems to be associated with complications such as miscarriage and preterm delivery. While strong evidence clearly demonstrates that overt dysfunctions (hyper- or hypothyroidism) have deleterious effects on pregnancy, subclinical disease, namely subclinical hypothyroidism, has still to be conclusively defined as a risk factor for adverse outcomes. Additionally, other conditions, such as isolated hypothyroxinemia and thyroid autoimmunity in euthyroidism, are still clouded with uncertainty regarding the need for substitutive treatment.     

Hepatitis C virus infection and thyroid diseases]

INTRODUCTION: The combination of hepatitis C virus (HCV) infection and thyroid diseases raises several issues that are the prevalence of thyroid autoimmunity in patients with chronic hepatitis C, the prevalence of HCV infection in patients with autoimmune thyroid diseases, and the effects of interferon alpha treatment on thyroid function in chronic HCV hepatitis. CURRENT KNOWLEDGE AND KEY POINTS: The prevalence of anti-thyroid auto-antibodies ranges from 4.6 to 15% in HCV infection, which is considered as significant by various authors. Results have to be interpreted according to the following: the type of auto-antibodies detected, the age, sex, ethnic origin of the population studied, and characteristics of the control population. Recent data are suggestive of a high prevalence of anti-thyroid auto-antibodies in females with HCV infection. An increased prevalence of HCV infection in patients with Hashimoto's thyroiditis is not confirmed. During treatment of chronic hepatitis C, interferon alpha induces thyroid dysfunctions (3 to 15% of the cases) with various clinical presentations. Hypothyroidism is more common (two out of three cases) than hyperthyroidism (one out of three cases). Hyperthyroidism followed by hypothyroidism has also been described. Clinical symptoms vary, ranging from subclinical to severe manifestations. Thyroid dysfunction may be delayed after discontinuation of the interferon treatment. Hypothyroidism is easily cured by L-thyroxine replacement therapy when necessary, and regression may be observed following discontinuation of interferon treatment. Each case of hyperthyroidism has to be precisely evaluated. Development of anti-thyroid antibodies or an increase in anti-thyroid antibodies titers is often observed during interferon alpha treatment, thus suggesting the existence of immunological mechanisms at the origin of thyroid dysfunction. Furthermore, interferon would directly act on iodine. FUTURE PROSPECTS AND PROJECTS: Clinical studies are still necessary to better clarify the links between HCV infection and thyroid autoimmunity, and to determine risk factors for the development of thyroid dysfunction during interferon alpha therapy. The effects of HCV and interferon alpha on thyroid autoimmunity and function have to be investigated in basic research.     

Thyroid pathology and female fertility: Myth or reality?

The relationship between thyroid state and female fertility is an area of particular interest for both clinicians and researchers worldwide. This is partially due to the increasing prevalence of infertility and to the understanding of its complex and multifactorial aetiology. Studies conducted in variable forms of female infertility (e.g., recurrent miscarriages or polycystic ovarian syndrome) together with the worldwide rising use of assisted reproduction technologies (ART) contributed the uncovering of the potential role of thyroid conditions in relation to ovarian function and fertility. However, as the title of this short review suggests, several aspects are yet to be elucidated and several questions are still awaiting an answer. This short review is mainly focusing on the distinct roles of thyroid dysfunction and thyroid autoimmunity in infertile women undergoing ART procedures.     

Thyroid dysfunction and autoimmunity in infertile women.

A prospective study was undertaken in 438 women (ages, 32 +/- 5 years) with various causes of infertility, and in 100 age-matched (33 +/- 5 years) healthy parous controls with the aim of assessing the prevalence of autoimmune thyroid disease (AITD) and hitherto undisclosed alterations of thyroid function. Female origin of the infertility was diagnosed in 45% of the couples, with specific causes including endometriosis (11%), tubal disease (30%), and ovarian dysfunction (59%). Male infertility represented 38% and idiopathic infertility 17% of the couples. Overall, median thyrotropin (TSH) was significantly higher in patients with infertility compared to controls: 1.3 (0.9) versus 1.1 (0.8) mIU/L. Serum TSH above normal (>4.2 mIU/L) or suppressed TSH (<0.27 mIU/L) levels were not more prevalent in the infertile women than in controls. The prevalence of positive thyroid peroxidase antibody (TPO-Ab) was higher in all investigated women of infertile couples, compared to controls (14% vs. 8%), but the difference was not significant. However, in infertility of female origin, a significant higher prevalence of positive TPO-Ab was present, compared to controls: 18% versus 8%. Furthermore, among the female causes, the highest prevalence of positive antibodies was observed in women with endometriosis (29%). When thyroid antibodies were positive, both hypothyroidism and hyperthyroidism were more frequent in all women of infertile couples and in the women with a female infertility cause, compared to women in the same groups but without positive TPO-Ab. The present study shows that in infertile women, thyroid autoimmunity features are significantly more frequent than in healthy fertile controls and this was especially the case for the endometriosis subgroup.     

Optimal management of hypothyroidism,hypothyroxinaemia and euthyroid TPO antibody positivity preconception and in pregnancy

Normal physiological changes of pregnancy warrant the need to employ gestation specific reference ranges for the interpretation of thyroid function tests. Thyroid hormones play crucial roles in foetal growth and neurodevelopment which are dependent on adequate supply of maternal thyroid hormones from early gestation onwards. The prevention of significant adverse obstetric and neurodevelopmental outcomes from hypothyroidism requires a strategy of empirical levothyroxine dose increases and predictive dose adjustments in pregnancy combined with regular thyroid function testing, starting before pregnancy and until the postpartum period. Subclinical hypothyroidism has been associated with an increased risk of pregnancy loss and neurocognitive deficits in children, especially when diagnosed before or during early pregnancy. Whilst trials of levothyroxine replacement for mild hypothyroidism in pregnancy have not indicated definite evidence of improvements in these outcomes, professional guidelines recommend treatment, especially if evidence of underlying thyroid autoimmunity is present. Studies of isolated hypothyroxinaemia in pregnancy have shown conflicting evidence with regards to adverse obstetric and neurodevelopmental outcomes and no causative relationships have been determined. Treatment of this condition in pregnancy may be considered in those with underlying thyroid autoimmunity. Whilst the evidence for a link between the presence of anti‐TPO antibodies and increased risks of pregnancy loss and infertility is compelling, the results of ongoing randomized trials of levothyroxine in euthyroid women with underlying autoimmunity are currently awaited. Further studies to define the selection of women who require levothyroxine replacement and to determine the benefits of a predictive dose adjustment strategy are required.     

Thyroid disease and female reproduction

The menstrual pattern is influenced by thyroid hormones directly through impact on the ovaries and indirectly through impact on SHBG, PRL and GnRH secretion and coagulation factors. Treating thyroid dysfunction can reverse menstrual abnormalities and thus improve fertility. In infertile women, the prevalence of autoimmune thyroid disease (AITD) is significantly higher compared to parous age-matched women. This is especially the case in women with endometriosis and polycystic ovarian syndrome (PCOS). AITD does not interfere with normal foetal implantation and comparable pregnancy rates have been observed after assisted reproductive technology (ART) in women with and without AITD. During the first trimester, however, pregnant women with AITD carry a significantly increased risk for miscarriage compared to women without AITD, even when euthyroidism was present before pregnancy. It has also been demonstrated that controlled ovarian hyperstimulation (COH) in preparation for ART has a significant impact on thyroid function, particularly in women with AITD. It is therefore advisable to measure thyroid function and detect AITD in infertile women before ART, and to follow-up these parameters after COH and during pregnancy when AITD was initially present. Women with thyroid dysfunction at early gestation stages should be treated with l-thyroxine to avoid pregnancy complications. Whether thyroid hormones should be given prior to or during pregnancy in euthyroid women with AITD remains controversial. To date, there is a lack of well-designed randomized clinical trials to elucidate this controversy.     

Female infertility and the thyroid

Difficulty to conceive or subfertility constitutes a major psychological burden. Assisted reproductive technology changed significantly the outcome of couples faced with subfertility. These techniques consequently increased tremendously our understanding of the mechanisms underlying reproductive failure and opened new perspectives for future interventions, not only to increase cumulative conception rates after ART, but also spontaneous pregnancy rates. Thyroid dysfunction adversely affects fertility. Many studies imply a role for immunology, including thyroid autoimmunity in conception failure. In this review we attempt to update the available information on the adverse effect of thyroid dysfunction and/or thyroid autoimmunity on subfertility and we propose a rationale for testing and potential treatment options.     

Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function

Thyroid dysfunction and the presence of thyroid antibodies increase the risk of infertility and miscarriage. The aim of the present study was to assess if patients with autoimmune thyroid disease undergoing assisted reproduction technologies (ART) are afflicted by poor pregnancy and/or delivery rate and if the outcome is conditioned by pre-ART thyroid status. The study was retrospective (from January 2000 to January 2005) and was carried out at the Division of Physiopathology of Human Reproduction. Women who underwent ART were tested for TSH, free T4 (FT4), thyroid peroxidase antibodies (TPOAb) before and during pregnancy. A total of 416 euthyroid women were selected; 42 (10.1%) were TPOAb (+). Women >35 yr were excluded. The endpoints were pregnancy and delivery rates. RESULTS: no differences in pregnancy and delivery rates were observed between women with and without antibodies. In TPOAb (+), women who failed to become pregnant or miscarried displayed higher TSH values before ART (2.8 mIU/l) compared to the ones who delivered (1.6 mIU/l; p=0.032) and compared to TPOAb (-) (1.1 mIU/l; p=0.018). CONCLUSIONS: in euthyroid women undergoing ART the pregnancy and delivery rates are not affected by the presence of TPOAb. In TPOAb (+) high-normal TSH values are associated with increased risk of unsuccessful pregnancy or subsequent miscarriage. Further studies are required to ascertain possible benefits of levo-T4 (L-T4) in such patients.