Infertility journal reading Relationship between Antithyroid Antibody and Pregnancy Outcome following in Vitro Fertilization and Embryo Transfer 孫怡虹/蔡永杰 Tuesday 5th June 2012 Infertility journal reading

Introduction

Antithyroid antibody (ATA) Directed against the thyroid gland  Inflammation of the thyroid gland  affect its function Ex.: Antithyroglobulin & antimicrosomal antibodies Antithyroglobulin antibodies:  Hashimoto thyroiditis (autoimmune thyroid disease),  Graves disease (overactivity of the thyroid), hypothyroidism (underactivity of the thyroid),  thyroid cancer, lupus, rheumatoid arthritis, autoimmune hemolytic anemia and Sjogren syndrome.

Antithyroid antibody (ATA) In general population: Frequently encountered Childbearing-age women  ~ 1/5  (+) Anti-thyroid peroxidase antibody (TPO-Ab) or Anti-thyroglobulin antibody (TG-Ab) Infertility women  10.5%  ATA (+) TPO-Ab level  Thyroid-stimulating hormone (TSH) level: TPO-Ab (+) ♀  Significantly ↑TSH  Some with normal TSH

Presence of ATA in euthyroid women May be related to some fertility problems ↑ Abortion rate & ↑ Incidence of infertility Assisted conception women, (+) ATA  Poor outcome of IVF (even euthyroid) The impact of ATA on the outcome of IVF-ET  No consensus Before & during IVF  Whether to give adjuvant therapy  regulate the thyroid autoimmunity  Controversial

Materials and methods

Patients selection In the center of Re-productive Medicine of the First Affiliated Hospital, Sun Yat-sen University August 2009 ~ August 2010 Patients receiving IVF/ICSI (2 groups) ATA+ (Positive for TG-Ab and/or TPO-Ab) 90 women (Total 156 cycles) Controls (negative for TG-Ab and/or TPO-Ab) 676 women (total 1062 cycles, 981 ET cycles & 81 embryo cryopreservation cycles)

Exclusion criteria Receive any adjuvant Treatment such as glucocorticoids, anti-coagulants Patients with other autoimmune diseases Positive for anti-cardiolipin antibody anti-nuclear antibody lupus anticoagulant rheumatoid factor

IVF-ET All: Long-term pituitary down-regulation Sequential regimen for ovarian hyperstimulation: Gonadotropin-releasing hormone agonist (GnRH-a) Gonadotropin (Gn) Human chorionic gonadotropin (HCG) Doses were adjusted according to: Age Number of antral follicles Sex hormone level at baseline

Selection of fertilization program (IVF or ICSI) Based on: semen condition on the day when the oocytes were collected At 3 days after oocyte collection: ≤ 3 embryos  transferred into the uterine From the day of oocyte collection: HCG or progesterone  for luteal support 14 days after embryo transfer: Measure urine and serum HCG  once (+)  ultrasonography 2 weeks later

Collection of clinical information Baseline data: Age Body mass index (BMI) Duration of infertility, Basal serum levels Follicle stimulating hormone (bFSH) Luteinizing hormone (bLH)

Collection of clinical information During the IVF treatment: Days of Gn treatment Total Gn dose E2 level on the day of HCG Number of oocytes retrived Fertilization rate Number of available embryos Number of embryo for transferring Pregnancy / Implantation / Abortion rate

Detection of serum ATA ARCHITECT Anti-TPO & Anti-Tg kit (Abbott La-boratories, Abbott Park, IL, USA) Chemiluminescent Microparticle Immunoassay (CMIA) In human serum and plasma Quantitative determination: the IgG class of Thyroid peroxidase autoantibodies & Thyroglobulin antoan-tibodies

Detection of serum ATA Anti-TPO Anti-Tg Positive predictive value ≥5.61 IU/ml ≥4.11 IU/ml Analytical sensitivity (limit of detection) ≤1.0 IU/ml Concordance 92.6% 92.7%

Statistical analysis SPSS version 13.0 statistic software package Comparisons of Quantitative data: t test or Wilcoxon rank sum test Comparisons of Qualitative data: chi square test Significance level (alpha): 0.05 P<0.05: statistically significant

Results

General Characteristics All without marked differences

Comparison of Controlled Ovarian Stimulation and IVF-ET Outcome between ATA+ and ATA- group

Discussion

Thyroid autoimmunity & IVF outcome In women receiving IVF-ET  Incidence of auto-antibodies is relatively high  may be attributed to the poor IVF outcome In the present study Compare IVF outcome: ATA (+)  ATA (-) Results: fertilization rate, number of available embryos, implantation rate, pregnancy rate  ATA (+) women < ATA (-) women

Thyroid autoimmunity & IVF outcome Kin et al. ATA (+) infertile ♀ : lower pregnancy rate (26.3 vs. 39.3%)  At least partly consistent with present study Revelli et al. No significant difference in the proportion of ATA (+) between infertile ♀  normal fertile ♀ ATA (+) infertile ♀ : a poorer IVF outcome

Thyroid autoimmunity & IVF outcome Other researchers ♀ Receiving ART  did not have an ↑ incidence of ATA positivity Pregnancy outcome: not closely  ATA Limitations(may lead to inaccurate results): Incomplete basic clinical information (lack of age, basal hormone levels…), small sample size

Thyroid autoimmunity & IVF outcome Kim et al. & Revelli et al.: Didn’t investigate the mechanism underlying the association between ATA level  IVF outcome (never extensively studied so far) Present study: ATA(+)  ↓ fertilization rate, implantation rate, pregnancy rate & ↑ abortion rate Marked ↓ fertilization rate, ↓ available embryos in patients with ATA  may be due to relatively larger sample size

This study did not resolve the problem also… How ATA could interfere with fertilization, embryo development, implantation potential? This study did not resolve the problem also… ATA bind to the surface of the egg and/or embryo  interfere with fertilization & subsequent embryo development The presence of ATA in endometrium  detrimental effect on embryo implantation  induce early pregnancy loss Further studies: immunologic mechanism

Thyroid autoimmunity & natural abortion Present study: ATA (+)♀ significant ↑ abortion rate Previous study: TPO-Ab (+)♀ Advanced age & high BMI & largely pluripara ♀ with Natural abortion  22.5%  ATA (+) ♀ received ART  19.2%  ATA (+) Healthy ♀  14.5%  ATA (+) TPO-Ab (+)  13.8%  ↑ TSH level TPO-Ab (-)  2.4%  ↑ TSH level

Thyroid autoimmunity & natural abortion After adjusting the age & TSH  ATA positivity  Independent risk factor of natural abortion Present study: No significant differences in the age, BMI, duration of infertility, bFSH and Blh  Exclude the influence of age, body weight & endocrine factors Could not collect TSH level for all patients  patients with abnormal TSH level may be included Consistent with those reported recently

Thyroid autoimmunity & natural abortion Euthyroid mice  actively immunized with thyroglobulin TG-Ab (+)  Significantly ↑ abortion rate Early stage of pregnancy: ATA (+)  ↑ abortion rate (can not be influenced by the thyroid hormone and anticardiolipin antibody) Mild thyroid dysfunction  ↑ abortion rate: Impaired regulation of thyroid function↑ abortion rate Abnormal thyroid autoimmunity  closely ↑ abortion Specific mechanism is still poorly understood

Thyroid autoimmunity & natural abortion Explanation between ATA  Pregnancy loss: ATA (+) ♀ have potential mild hypothyroidism Abnormal thyroid autoimmunity  delay the time of conception  ♀ with advanced age  correspondingly ↑ abortion rate ATA  a marker : activation of autoimmunity (may be as a result of heredity or early immune response)  rejection of embryos by mother's immune system ATA  a 2nd biomarker of autoimmune disease trend, but not a real cause of abortion

Thyroid autoimmunity and infertility The relationship was controversy ATA (+) Infertility due to ♀ factors Often involves autoimmunity (ATA: can be a marker of abnormal autoimmunity) ♀, implantation failure & infertility of unknown cause Proportion of ATA (+) & ATA level: markedly ↑

Thyroid autoimmunity and infertility TPO-Ab (+) In Euthyroid patients  Beneficial to identified patients: “having high risk for hypothyroidism” In ♀ prepare for pregnancy & have high risk for hypothyroidism following pregnancy Can be used to predict Hypothyroidism in the early stage of pregnancy Postpartum thyroid dysfunction Some have no obvious thyroid lesions Different antibodies(?) or these autoantibodies(?) together with other risk factors  still unclear

Thyroid autoimmunity and infertility Controlled ovarian stimulation (COS) Has influence on the thyroid function Especially in ♀ with abnormal thyroid autoimmunity Recommendation: Before assisted reproduction… Evaluate thyroid function & autoimmunity Especially for ♀ with : Recurrent failure of IVF-ET or abortion Autoimmune diseases or related diseases (ex. endometriosis)

After COS & during the pregnancy Thyroid autoimmunity and infertility Controlled ovarian stimulation (COS) Following COS △Thyroid function  can not be used to predict pregnancy outcome After COS & during the pregnancy Autoimmune thyroid disease (AITD) patients  should be closely monitored Thyroid function & treat if necessary

Thyroid autoimmunity and infertility Detection of thyroid function as a routine examination during the pregnancy  No strong evidence Hill et al.: Detection of ATA and evaluation of “reproductive immunology phenotype” not of clinical importance for women receiving IVF-ET Present study: ATA (+)  Significantly ↓ fertilization & pregnancy rate, ↑ abortion rate Further studies: Explore specific treatment for women with abnormal thyroid autoimmunity  improve their IVF and pregnancy outcome

Conclusion Patients with anti-thyroid antibody vs. those without anti-thyroid antibody: significantly ↓ Fertilization rate ↓ Implantation rate ↓ Pregnancy rate ↑ Risk for abortion following IVF-ET 4/28/2017

The presence of anti-thyroid antibody  Detrimental for the pregnancy outcome following IVF-ET Further studies: Appropriate treatment Regulate immune function of ATA(+) patients To improve IVF outcome

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