Obstetric and perinatal outcome of the women with repeated implantation failures or recurrent pregnancy losses who received pre‐ and post‐conception tacrolimus treatment

Abstract

ProblemPreviously, we reported the clinical efficacy of tacrolimus in women with repeated implantation failures (RIF) of immune etiologies. Safety of tacrolimus in pregnant women has been reported in women with organ transplantations. However, the safety of tacrolimus for women with RIF undergoing assisted reproductive technology cycles and their babies has not been reported prior.Method of studyThis study is a prospective observational study of 109 women with RIF or recurrent pregnancy losses (RPL) who showed elevated peripheral blood Th1/Th2 (CD4+IFN‐γ+/CD4+IL‐4+) cell ratios (≥10.3). All received tacrolimus before and during pregnancy (1‐4 mg/d) and delivered a live‐born infant(s). Blood concentrations of tacrolimus were measured. Neuromotor development of the babies was also evaluated.ResultsTotal 113 babies were born from 109 women, including four twin pregnancies. Nine pregnancies including four twins were delivered prematurely (8.3%). Two of 109 women showed obstetric complications, such as hypertensive disorder of pregnancy, and only one baby (0.9%) had a congenital abnormality. There were no differences in babies' birthweight, placental weight, and lymphocyte proportion (%) of the umbilical cord among the women with different tacrolimus dosing. Tacrolimus was detected in the maternal plasma, and its concentration did not significantly fluctuate during pregnancy while on daily administration regimen. Neuromotor development of the babies exposed to tacrolimus in utero was comparable with that of babies from the general population.ConclusionAccording to our data, tacrolimus treatment for women with RIF and RPL was not associated with obstetrical and perinatal complications. A large size study is needed to confirm this finding.

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

“…However, tacrolimus has side effects, such as nephron‐ and neurotoxicity, hypertension, and infection, when administered at a concentration ≥ 20 ng/mL 48 . In our study, only 1‐3 mg of tacrolimus was administered per day, which is equivalent to ≤ 6 ng/mL 24 . This concentration was safe without obstetrical and perinatal complications according to our previous study 24 .…”

“…In our study, only 1‐3 mg of tacrolimus was administered per day, which is equivalent to ≤ 6 ng/mL 24 . This concentration was safe without obstetrical and perinatal complications according to our previous study 24 . In the OPTIMUM treatment strategy, no side effects were reported from tacrolimus intake in all cases.…”

“…Thus, successful pregnancy requires a balance of Th1 and Th2 cells, which secrete pro‐ and anti‐inflammation‐related cytokines, respectively; therefore, imbalances in the Th1/Th2 cell ratio can cause reproductive failure, including implantation failure and pregnancy loss 19,20 . There is insufficient evidence on the modulation of the imbalanced Th1/Th2 cell ratio for RIF 22 ; however, we have reported the effects and safety of an immunosuppressive drug, tacrolimus, for RIF patients with an elevated Th1/Th2 cell ratio 21,23,24 . Vitamin D is also an important modulator of immune function; therefore, the lack of vitamin D is involved in an increased risk of infertility and pregnancy complications, such as pregnancy loss, pregnancy‐induced hypertension, and pre‐eclampsia 25 .…”

Therapeutic Potentials of Low-Dose Tacrolimus for Aberrant Endometrial Features in Polycystic Ovary Syndrome

“…The efficacy of tacrolimus to promote endometrial receptivity may reside in its intrinsic ability to regulate the endometrial progesterone receptor signaling while suppressing systemic immune aberrancies and associated endometrial immune irregularities in PCOS. Lastly, while the present data from experimental and human studies point to the relative perinatal safety for the use of low-dose tacrolimus in treating female infertility [90,164], further studies are needed to establish the best-fit tacrolimus-based monotherapeutic interventions in the management of PCOS-associated female infertility.…”

Bioinformatics of Potential Biomarkers in Patients with Repeated Implantation Failure

“…However, the multiple embryo transfers were performed frequently due to relatively low pregnancy rates in IVF-ET patients [1, 2] , and many patients suffer from repeated implantation failure (RIF) through the procedure. Though the term is not clearly defined, RIF is deemed when the patient fails to get a clinical pregnancy after three cycles of IVF-ET or after at least four good-quality embryo transfers [3,4,5] . Previous studies on RIF were mostly conducted in clinical trials, and the limited amount of biomarkers were detected in the peripheral blood; few studies investigated the local endometrial tissues and RIF gene expression.…”