1. 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

2. Introduction

3. 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.

4. 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

5. 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

6. Materials and methods

7. 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)

8. 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

9. 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

10. 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

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

12. 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

13. 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

14. 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%

15. 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

16. Results

17. General Characteristics
All without marked differences

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

19. Discussion

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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 ↑

30. 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

31. 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)

32. 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

33. 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

34. 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

35. 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

36. Thank you for listening