The Effects And Mechanisms Of Autoimmune Thyroid Disease On Euthyroid Infertile Women's Pregnancy Outcomes After In Vitro Fertilization And Embryo Transfer(IVF-ET)

Introduction Autoimmunity thyroid disease(AITD)is the most prevalent autoimmune state that affects up to5%?20%women during the age of fertility who are positive for the anti-thyroid peroxidase antibody(TPO-Ab)or anti-thyroglobulin antibody(TG-Ab).Infertility patients present a greater prevalence of thyroid autoimmunity than normal fertile patients.There is a large body of evidence suggesting thyroid autoimmunity as a cause of infertility,miscarriage,recurrent spontaneous abortion,premature delivery,and late pregnancy complications.The presence of thyroid autoimmunity has also been related to recurrent embryo implantation failure,and many studies found thyroid autoantibodies were independent for the failure of assisted reproductive techniques.But Muller et al observed four hundred eighty-nine women in an IVF program,they found no association between the presence of TPO antibodies and miscarriage.The results of different study have come to a point of divergence.The machanisms responsible for the association between AITD and IVF-ET outcomes are still under debate.Human ovary is commoily the target of an autoimmune attack in cases of organ-or non-organ-specific autoimmune disorders.Whether it is thyroid function or thyroid autoimmunity that affects functional ovarian reserve reflected in anti-Mullerian hormone(AMH)has,however,remained under dispute.Several studies support a potential link between-5 TAI and the reduction in ovarian reserve.However,robust evidence regarding its prevalence in women with DOR is lacking.A study by Monteleone et al found that thyroid autoantibodies were measurable in follicular fluid in AITD women who had lower oocyte fertilization and the grade A embryos.Therefore it was speculated that thyroid autoantibodies might cause antibody mediated cytotoxicity in the growth and maturation of oocytes.Controlled ovarian hyperstimulation(COH)is an integral part of many assisted reproduction technology(ART)procedures.In IVF cycles there will be a rapid increases in circulating estrogen(E2)which may be capable of inducing hepatic production of thyroxine-binding globulin(TBG).Thyroxine(T4)circulates in the blood bound to TBG and only free,unbound T4 is available to tissues.Then the free fraction of T4 diminishes during this period,and may be inducing a short-term state of hypothyroidism in women,although they may have been biochemically euthyroid at the start of the cycle.Whether thyroid function or thyroid autoantibody was changed after COH?Although there is some evidence that COH can impair thyroid function,the relevant pathophysiology has not been fully elucidated.The results of different study have come to a point of divergence,maybe beacause they have diverse ART protocols,patient population and timing of measurements.And the role of TSH and TAI on the outcome of IVF cycles remains to be investigated.Objective The aim of this study was to evaluate the impacts of s thyroid autoantibodies on clinical results for euthyroid patients after in vitro fertilization and embryo transfer(OVF-ET).We aimed to evaluate the possible negative association between thyroid autoimnunity/TSH and ovarian reserve,by measuring serum AMH concentrations and thyroid autoantibodies in follicular fluid,and their role on the outcome of COH.Finally,we want to determine whether high E2 levels after COH affect thyroid function and thyroid autoantibodies.Materials and Methods A retrospective cohort study was performed in our center.We reviewed the medical records of 1129 women aged 38 years or less who underwent their first non-donor IVF retrieval cycle between March 2011 and October 2013.All patients underwent screening for TSH,free triiodothyronine(ff3),and free thyroxin(fT4),anti-thyroid antibodies,anti-thyroglobulin antibody,and anti-thyroperoxidase antibody.The criteria is as following:(?)Day 3 Follicle-stimulating hormone(FSH)<10IU/1,oestradiol<80pg/ml,and the normal range of prolactin was 6.0-29.9ng/ml before ovarian stimulation;(?)both ovaries present;(?)presence of a normal uterine cavity;(?)normal TSH concentration or euthyroid as determined by the investigator,and the normal range of our institution's laboratory was 0.27-4.2 mlU/L.(?)no past or current diseases affecting the thyroid.The women who had recurrent spontaneous abortion were excluded.(?)the etiology of infertility was in tubal factor.We compared the clinical characteristics and IVF outcomes in patients with AITD and without AITD.Then we investigated in 350 infertile women including 140 women with AITD and 210 women without AITD.They fulfilled the same criteria as above.Blood was collected before stimulation and follicular fluid was collected on the day of pickup.Samples were frozen at-80? and analyzed together for AMH and thyroid antoantibodies.We compared the clinical characteristics including stimulation length,total amount of Gn,retrived oocytes,fertilization rate,grade A embryos rate,clinical pregnancy rate,early miscarriage rate and premature delivery rat.Finally,there were 94 women with AITD and 110 women without AITD transfered embryo and collected blood at three time points:before stimulation,at HCG administration,at serum pregnancy test.Samples were frozen at-80? and analyzed together for TSH,free T4 and thyroid antoantibodies.Finally we observed the clinical characteristics and IVF outcomes in patients with AITD after freeze-all and frozen embryo transfer.Results ?The major finding of our retrospective study is that in women who undergoing the first IVF cycle,grade A embryos rates were significantly lower in cycles with a TSH>2.5mIU/L compared with TSH?2.5 mIU/L,We also found that the presence of thyroid autoantibodies in patients with TSH>2.5mIU/L caused higher miscarriage rate(P=0.03)which was not found in patients with TSH?2.5mIU/L.?No significant differences were observed in the levels of AMH between women with and without AITD.TSH>2.5mIU/L in euthyroid infertility patients was associated with significantly lower AMH than TSH?2.5mIU/U(p=0.004)?The thyroid-7 autoantibodies were measurable in follicular fluid,and the follicular fluid concentrationa of thyroid autoantibodies were approximately two third of those found in serum.And at the same time we found the total stimulation days,gonadotrophin dosage and preterm delivery rate were increased obviously in women with AITD(p<0.05).We also found grade A embryos rates were significantly lower in cycles with a TSH>2,5mIU/L compared with TSH?2.5 mIU/L(p<0.05).?As E2 levels rose during COH,serum concentrations of TSH had a statistically significant increase between basal levels and levels at time of serum pregnancy test.The TSH level rised significantly higher in patients with AITD than those without AITD(p<0.05).In AITD patients,the TSH level rised significantly higher in pregnant patients than those who were not,at time of serum pregnancy test.And the levels of free T4 and the thyroid autoantibodies decreased after COH,but they did not have statistical difference.?Freeze-all and frozen embryo transfer is generally superior to fresh embryo transfer to achieve pregnancy in women with AITD.Conclusion AITD has a negative effect on the early outcome of COH,especially with TSH>2.5mIU/L.We found a significant association of TSH levels with AMH,even within normal thyroid function levels.During COH women with AITD need more stimulation days and gonadotrophin dosage,although there was no association between thyroid autoimmunity and ovarian reserve.The thyroid autoantibodies were measurable in follicular fluid,and that might mediate cytotoxicity in the growth and maturation of oocytes.TSH increases clinically significant on the day of pregnancy test during ART.And this change was obvious in patients with AITD.The thyroid antibodies and free T4 levels did not changed obviously.So the mechanisms of autoimmune thyroid disease on euthyroid infertile women's pregnancy outcomes after IVF-ET are intricate.But we suggest that the screening for thyroid disorders and treatment with levothyroxine is necessary if a serum TSH>2.5mIU/L before IVF,especially in the patients with AITD.And thyroid function should be done at the time as the pregnancy test,especially in the pregnant patients with AITD,in order to identify those patients requiring replacement,or freeze-all and frozen embryo transfer should be done,so we can improve the pregnancy rate and decrease the miscarriage rate.