Endometrial receptivity is widely considered as an important player in the success of pregnancy and so optimum treatment of the endometrium has been a key focus of interest for decades due to its potential clinical importance(21). In this study, we showed that in the overall population, the HRT group had higher rates of positive biochemical pregnancy, positive clinical pregnancy and live births than the GAC and OC groups (p < 0.001), with no significant differences compared to the NC group. The findings in this study confirm previous studies that also showed similar pregnancy outcomes between the natural cycle group and other endometrial preparation regimen groups. A retrospective cohort study analysed 214 NC cycles and 276 HRT cycles, with similar live birth rates (NC = 33.6% HRT = 29.3%, P = 0.47) and clinical pregnancy rates (NC = 40.2% HRT = 36.6%, P = 0.35) in the two groups(22). In addition, a prospective randomized controlled trial comparing clinical data from the NC group (n = 59) and the OC group (n = 60) showed no significant differences between the two groups in terms of positive biochemical pregnancy rate (NC = 34.0% OC = 23.1%, P = 0.22), clinical pregnancy rate (OC: 13/53 = 24.5%; NC: 12/52 = 23.1%; P = 0.86) and live birth rate (OC = 24.5% and NC = 23.1%, P = 0.86) (23). In this study also, there were no significant differences in ectopic pregnancy rates and miscarriage rates between the four groups in our study. These findings are also consistent with a prospective RCT trial which did not find any difference in pregnancy outcome between the NC and GAC groups(24). Another study also corroborated that the NC and OC groups had similar clinical outcomes in frozen embryo transfer which is consistent with the results of our study(25). Although, we did not compute pregnancy outcome with age, a study showed that reduced pregnancy outcome has been seen to increase with increasing age of women, with the most occurring in women beyond 40 years of age. This implies that women below the age of 40 years tend to benefit from frozen embryo transfer(26).
After adjusting for confounding factors, there were no statistically significant differences in pregnancy outcomes in any of the three endometrial preparation groups compared to the NC group, which is consistent with the results of previous studies(22, 27).Similarly, a retrospective cohort study primarily compared live birth rates between 923 GnRH agonist artificial cycles and 105 natural cycles. After adjusting for female age, body mass index, diagnosis, preimplantation genetic screening/diagnosis, year and number of embryo transfers in a logistic regression model, the results showed no difference in any pregnancy outcome, with live birth rates aOR1.0,95%CI0.6-1.5(28). Compared to the other three groups, the HRT group having the lowest endometrial thickness at one day before transplantation. Two retrospective cohort studies also showed that the endometrial thickness was less in the HRT group than in the NC group(29, 30).However, there was no statistical difference in the incidence of biochemical pregnancy, clinical pregnancy, miscarriage or live birth between the two groups(30), probably because endometrial thickness is not a decisive parameter for successful pregnancy (31). However, a study by Shaodi et al (2020) showed that to obtain optimal live birth rate, the endometrial thickness must remain within the range of 8.7-14.5mm as too thin or too thick endometrium would reduce the live birth live(32) .More studies are needed to address the effect of endometrial thickness on pregnancy outcome.
Patient specificity and acceptability need to be considered when deciding on the optimal endometrial preparation protocol for an individual. A study by Dancet and colleagues identified four treatment dimensions to be considered in the clinical advice given to patients during fertility treatment: burden, effectiveness, safety, and costs(33). Prato et al. also suggest that when two treatment options produce the same result, the less expensive option should be chosen(34). Natural cycles have a natural hormone-induced endometrial environment, avoid the use of exogenous hormones, avoid OHSS and are more conducive to embryo implantation, while being less costly and simple in terms of late luteal support, and are most acceptable to patients(35). Therefore, the natural cycle protocol could be the recommended option for endometrial preparation in the FET population. However, further research is needed in the future to determine the optimal endometrial preparation regimen in populations with different causes of infertility.
The strengths of this study include its relatively large sample size, limited exclusion criteria, and inclusion of women of all ages and infertility diagnoses. Furthermore, our study also took into consideration four endometrial preparation protocols commonly used in clinical practice and adjusted for other confounding factors using a multivariate logistic regression analysis model when exploring the effect of endometrial preparation protocols on pregnancy outcomes. However, the nature of the retrospective cohort study makes this study somewhat limited and more prospective cohort studies or RCT trial could be conducted in the future to explore pregnancy-related illnesses, fetal growth and development. Moreover, cost-effectiveness is an important factor to consider when developing a protocol for patients, and more research is needed in the future to investigate the optimal endometrial preparation protocol in the frozen-thawed embryo transfer population in relation to cost and different causes of infertility.