Tacrolimus Treatment Improved Pregnancy Rate with Euploid Blastocyst in Women with Repeated Implantation Failures and Elevated T Helper 1/2 Cell Ratios - European Medical Journal

Tacrolimus Treatment Improved Pregnancy Rate with Euploid Blastocyst in Women with Repeated Implantation Failures and Elevated T Helper 1/2 Cell Ratios

2 Mins
Reproductive Health
Authors:
*Koji Nakagawa,1 Joanne Kwak-Kim,2 Takashi Horikawa,1 Keiji Kuroda,3 Michi Hisano,4 Rikikazu Sugiyama,1 Koushi Yamaguchi4
  • 1. Sugiyama Clinic Shinjuku, Tokyo, Japan
  • 2. Reproductive Immunology, Obstetrics and Genecology, Clinical Science department, Chicago Medical School at Rosalind Franklin University of Medicine and Science, Vernon Hills, Illinois, USA
  • 3. Sugiyama Clinic Marunouchi, Tokyo, Japan
  • 4. Department of Maternal‐Fetal Biology, National Center for Child Health and Development, Tokyo, Japan
*Correspondence to [email protected]
Disclosure:

The authors declare no conflicts of interest.

Citation:
EMJ Repro Health. ;10[1]:34-36. https://doi.org/10.33590/emjreprohealth/UMQC7630.
Keywords:
Euploid blastocyst, repeated implantation failure, tacrolimus, T helper 1/2 cell ratios (Th1/Th2).

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

INTRODUCTION

In organ transplantation, the transplanted organ is usually attacked by various lymphocytes. In contrast, a transferred embryo might be attacked by various lymphocytes in treatment with antiretroviral therapy. An underlying mechanism of embryo rejection is considered to be similar to an allograft rejection. According to this speculation, embryonic rejection is one of the reasons for repeated implantation failure (RIF). Therefore, the authors used the immunosuppressive agent tacrolimus for women with RIF (≥4 times) and elevated T helper (Th) 1/Th2 cell ratios (≥10.3). This resulted in the pregnancy rate being significantly improved.1 However, this first study did not include the use of euploid blastocysts, so embryonic concerns could not be ruled out. In this study, the authors attempted to confirm the effectiveness of the tacrolimus treatment on women with RIF showing elevated Th1/Th2 cell ratios using euploid blastocyst.

MATERIALS AND METHODS

A prospective cohort study was performed, including 569 women who are infertile with RIF four or more times. The study participants received frozen-thawed blastocyst transfer with euploid blastocysts from September 2020–November 2021. All transferred blastocysts were confirmed as euploid or low-frequency mosaic by preimplantation genetic testing for aneuploidy, and the endometrial preparation for  embryo transfer (ET) was made by using either hormone replacement cycle or natural ovulatory cycle. All participants were measured for their peripheral blood Th1/Th2 (CD4+IFN-γ+/ CD4+IL-4+) cell ratios in the secretory phase before ET. Women who had elevated Th1/Th2 cell ratios (≥10.3) received tacrolimus (2–4 mg daily).2 Tacrolimus was started 2 days before ET until the day of pregnancy test.

RESULTS

Among the women, 174 (30.6%) showed a ratio of 10.3 or above were divided into two groups: 148 women received tacrolimus (Tac group) and the others (n=26) did not receive any drugs (no-Tac group). The remaining 395 showed a ratio of 10.3 or less and were considered as controls (control group).

The human chorionic gonadotropin-positive and gestational sac (GS) rates of the Tac group were 73.0% and 64.2%, respectively; similar to the no-Tac group (69.2% and 57.7%, respectively; P is non-significant). Meanwhile, the human chorionic gonadotropin-positive and GS rates of the control group were 70.6% and 60.0%, respectively (P is non-significant).

Recently, the authors reported an adjusted cut-off value of the Th1/Th2 cell ratios (≥11.8) for women with RIF based on the retrospective analysis.3 When the Th1/Th2 cell ratio cut-off value was set to ≥11.8, 123 women of the 569 participants (21.6%) had elevated Th1/Th2 cell ratios (≥11.8). Among them, 112 received tacrolimus (Tac2 group), and 11 did not receive tacrolimus (no-Tac2 group). The remaining 410 women were a control group (Control2 group). The GS rate of the Tac2 group was 67.0%, which was significantly higher than that of the no-Tac group (36.3%; p<0.05, Figure 1), while the GS rate of the Control2 group was 60.5% (P is non-significant).

Figure 1: Gestational sac rate after euploid blastocyst transfer between two groups.
GS: gestational sac; Tac: tacrolimus.

 

CONCLUSION

The authors concluded that tacrolimus was an effective treatment for women with RIF showing elevated Th1/Th2 cell ratios using euploid blastocyst, and that the elevated Th1/Th2 cell ratio cut-off value should be set to 11.8. Since then, they have set 11.8 as the new criteria value for tacrolimus treatment.

References
Nakagawa K et al. Immunosuppressive treatment with tacrolimus improves reproductive outcome for repeated implantation failures patients who have elevated in Th1/Th2 cell ratios. Am J Reprod Immunol. 2015;73(4)353-61. Nakagawa K et al. Immunosuppressive treatment using tacrolimus promotes pregnancye outcome in infertile women with repeated implantation failure. Am J Reprod Immunol. 2017;DOI:10.1111/aji.12682. Kuroda K et al. Increasing number of implantation failures and pregnancy losses associated with elevated Th1/Th2 cell ratio. Am J Reprod Immunol. 2019;86(3):e13429.

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