The Efficacy and Safety of the Zhuyun Formula and Auricular Acupressure for the Infertile Women with Recurrent Implantation Failure: A Randomized Controlled Trial

Abstract

Background. Recurrent implantation failure (RIF), a clinical disorder characterized by failure to achieve pregnancy after repeated (≥3) embryo transfer, is a challenge for reproductive demands worldwide. In our preliminary work, the Zhuyun formula (ZYF) with auricular acupressure, a complementary and alternative medicine (CAM) with a small sample size for RIF, can improve the clinical pregnancy rate (41.2% vs. 26.7%, treatment group vs. control group, $p<0.05$ ). Based on the toxicological and pregnancy-related pharmacological analysis of ZYF for RIF, the T-cell receptor signaling pathway might be involved in the pharmacological activity. This study aimed at evaluating the efficacy and safety of the CAM therapy according to pregnancy outcomes and maternal and child health and investigating the changes of T-helper (Th) cells in the peripheral blood of unexplained RIF women. Materials and Methods. We conducted a prospective, two-arms, randomized, nonblinded study. All eligible women were randomly assigned to the treatment group (TG) and the control group (CG) according to a computer-generated randomization list in sealed opaque envelopes. Blood samples were collected from the two groups, and serum Th1, Th2, and Treg were detected by flow cytometry. The cytokines were detected by an enzyme-linked immunosorbent assay (ELISA). The TG was administrated with ZYF and auricular acupressure for three months before ovarian stimulation, while the control group was on a waiting list for the same period. The primary outcome was CPR. The second outcomes were the serum levels of immune parameters. For the safety evaluation, the perinatal outcomes of maternal and child were obtained by follow-up. Post-hoc sensitivity analyses were performed to assess the effect of missing data. Results. One hundred and twenty-three women were randomized into the TG (n = 62) and CG (n = 61). The CPR was increased significantly in the TG (45.2%) than CG (26.2%) (p = 0.029). Twenty blood samples were collected, and the Th2/Th1 and Treg expression level was significantly higher in the TG than in the CG. IL-2, IL-10, and Foxp3 were higher significantly in the TG than in the CG. The maternal and child perinatal outcomes were not significantly different between the two groups. Conclusions. The ZYF with auricular acupressure was effective and safe in improving the pregnancy outcomes of RIF. It might be related to balancing the level of cytokines related to the immune tolerance of the maternal-fetal interface to protect the embryo from the maternal immune system. Clinical Trial Registration: Clinical Trial Registry; date: 14/Dec/2013; no. NCT03078205.