Analysis of the risk factors and treatment for repeated implantation failure: OPtimization of Thyroid function, IMmunity, and Uterine Milieu (OPTIMUM) treatment strategy

Abstract

Problem What are the pregnancy outcomes after the OPtimization of Thyroid function, Immunity, and Uterine Milieu (OPTIMUM) treatment strategy in patients with repeated implantation failure (RIF)? Method of study Infertile women with a history of RIF after more than three embryo transfer (ET) cycles underwent implantation testing, including a hysteroscopy, endometrial biopsy for CD138 immunostaining and bacterial culture, and serum 25‐hydroxyvitamin D3, interferon‐γ‐producing helper T (Th1) cell, IL‐4‐producing helper T (Th2) cell, thyroid‐stimulating hormone, thyroid peroxidase antibody, and thrombophilia screening between April 2017 and August 2018. We treated chronic endometritis with antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus intake, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low‐dose aspirin. Of the 116 RIF women, 88 women with 133 ET cycles were recruited from a questionnaire‐based survey regarding pregnancy outcomes. Fifty‐nine consecutive RIF patients without the OPTIMUM treatment strategy were also recruited as a control. Results The 116 women with RIF after the OPTIMUM treatment strategy were 38.3 ± 3.8 years old and had an implantation failure history over 5 (3‐19) ET cycles. Implantation testing identified impaired intrauterine circumstances in 75 women (64.7%), an aberrant elevated Th1/Th2 cell ratio in 56 women (48.3%), and thyroid abnormalities in 33 women (28.4%). Cumulative ongoing pregnancy rates including spontaneous pregnancy in the patients aged < 40 and ≥ 40 years were 72.7% and 45.5% within two ET cycles, respectively. The pregnancy outcomes in the OPTIMUM group were significantly higher than those in the control. Conclusions The OPTIMUM treatment strategy improved pregnancy outcomes in patients with RIF.

Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio

“…Between April 2017 and August 2018, 197 consecutive patients with a history of RIF and/or RPL underwent Th cell testing in Juntendo University Hospital or Sugiyama Clinic Shinjuku. RIF was defined as implantation failure after three or more ET cycles using morphologically good embryos as previous our report 21 . In Japan, preimplantation genetic testing for aneuploidy (PGTA) remains in clinical trials; therefore, RIF was defined without PGTA.…”

“…Vitamin D insufficiency is associated with an abnormally elevated Th1/Th2 cell ratio 24 ; thus, the storage type of vitamin D, 25‐hydroxyvitamin D 3 (25OHVD), was also examined in all patients. We excluded 42 women aged ≥44 years and 9 women who were receiving vitamin D supplementation during Th cell testing because vitamin D supplementation for lack of vitamin D suppresses high Th1/Th2 cell ratios 21,24 . Therefore, we recruited 146 women including 79 with RIF and 81 with RPL.…”

“…Successful pregnancy requires a balance of pro‐ and anti‐inflammation‐related cytokines, which are secreted by Th1 and Th2 cells, respectively, with the importance initially of pro‐inflammatory cytokines, subsequent regulation by T regulatory cells via HLA and soluble hCG and then a Th2 dominance 10,11 . There is insufficient evidence on the modulation of an imbalanced Th1/Th2 cell ratio for RIF and RPL 14 ; however, therapeutic effects of optimizing the Th1/Th2 cell imbalance via immunotherapy have been reported in patients with a history of RIF and RPL 12,15–21 …”

Novel approaches to the management of recurrent pregnancy loss: The OPTIMUM (OPtimization of Thyroid function, Thrombophilia, Immunity, and Uterine Milieu) treatment strategy

“…In some women with a history of RIF, the intake of tacrolimus was initiated from 1 day before the day of embryo transfer, as in our previous trial. 11 In women with aberrant elevated Th1 cell levels (≥28.8), the dosage of tacrolimus was increased by a further 1 mg. 42 F I G U R E 2 Recurrent pregnancy loss testing and treatment for risk factors of pregnancy loss. Recurrent pregnancy loss (RPL) testing included a hysteroscopy, endometrial biopsy for CD138 immunostaining and bacterial culture, and blood testing for 25-hydroxyvitamin D 3 , interferonγ-producing helper-T (Th1) cell, interleuking-4-producing helper-T (Th2) cell, thyroid function, and thrombophilia.…”

Effects of Periconceptional Multivitamin Supplementation on Folate and Homocysteine Levels Depending on Genetic Variants of Methyltetrahydrofolate Reductase in Infertile Japanese Women

“…Vitamin D insufficiency with storage-type vitamin D 25-hydroxyvitamin D3 (25 OHVD) levels of <30 ng/mL was also treated with vitamin D supplementation (Sugiyama Clinic Original Vitamin D supplement, Calinesse, Tokyo, Japan) containing vitamin D3 (cholecalciferol). Additional vitamin D supplementation was provided at a daily dose of 25 or 50 µg (32 or 57 µg in total) in infertile patients with 25 OHVD levels of ≥20 and <30 ng/mL or <20 ng/mL, respectively, according to our previous study [24,25]. Of 49 who reexamined serum folate and homocysteine levels, 47 women had additional vitamin D supplementation.…”