Discussion
REGRESSION
The present study found no significant differences in ongoing pregnancy and live birth rates between additional hCG supplementation as luteal phase support before the embryo transfer compared with the routine protocol in women undergoing AC-FET.Traditionally, hCG plays an essential role in maintaining progesterone secretion by corpus luteum in the early stage of pregnancy and it is also used in natural or stimulated cycles in FET to induce ovulation by mimicking the LH surge. However, the transcription of hCG gene by embryo begins very early due the micro-amount of hCG has been detected from the stage of 2PN in embryo culture medium. With the identification of endometrial hCG receptors, it has been thus proposed that hCG may have direct effects on embryo-endometrial communication during implantation of human embryos (Intrauterine administration of hCG has been suggested to improve clinical outcome in IVF patients. Many studies have investigated the effect of intrauterine hCG infusion on clinical outcomes but the conclusions of these studies were inconsistent due to the heterogeneity of study design (The endometrial cells were exposed to exogenous hCG for only a short time when infusion of hCG. However, in experiments conducted by Sherwin et al. showed that prolonged exposure of hCG may be down regulate the pro-implantation factors and have deleterious effects on endometrial receptivity (There is no consensus on the optimal schedule, such as dose, time point and frequency of supplementation for the introduction of hCG. Some schemes have been reported, including 3000 IU every three days since the third day of starting progesterone for three doses (The main strength of the current study is the sufficient follow-up data to report ongoing pregnancy and live birth rate, which is the most important outcome for patients undergoing IVF. The complete follow-up for all women was another strength of the present study. Besides, we conducted logistic regression analysis and subgroup analysis to ensure the stability of the conclusion. On the other hand, our study only included the first FET cycle, which may minimize some potential bias from patients and clinicians (such as clinic variability or patients’ psychological factor). Furthermore, in order to reduce bias, the physician who conducted endometrial preparation protocol and staff who conducted the follow-up were blinded to the group assignment.This study had some limitations. First, some characteristics of FET cycles, such as type and number of embryos transferred, differed between the groups. However, multivariable logistic analysis and subgroup analysis were performed to minimize the potential impact. Second, as this was a clinical trial, it could not explain the mechanism of the ineffectiveness of IM-hCG on clinical outcome. It may be due to the insufficient concentration of hCG in the endometrium. However, at least, the schedule we used had no significant difference when compared with the control group in terms of clinical outcomes. Third, the COVID-19 pandemic resulted in lockdown from January 24, 2020, and all IVF treatments were halted at our hospital. More than 80% (245/294) of the calculated sample size was reached at that time. In addition, it is difficult to require women to visit the clinic or hospital for an HCG injection every day. We stopped our trial early even though the lockdown was lifted two months later. Nevertheless, all the follow-up data were complete. The current study provided the ongoing pregnancy rates of the two groups based on the admittance standards during the study period. Lastly, no significant difference was found in terms of ongoing pregnancy and live birth rate in women undergoing AC-FET with or without additional hCG administration as luteal phase support through the multivariate analysis and subgroup analysis. The data could be a reference for the multi-center with larger sample sizes analyses and molecular mechanism research. And the trial could also be useful to include in a meta-analysis with other available evidence in the future.In conclusion, clinicians should be cautious in recommending IM-hCG as an adjuvant therapy to improve clinical outcomes, and the addition of hCG may impose unnecessary financial burden on patients. More multi-center, larger sample sizes analyses are needed to validate the results of this study. In addition, further studies on the physiological level are also needed to analyze the molecular mechanisms of the effect of hCG on embryonic-maternal cross-talk.