Clinicians frequently preferred the artificial endometrial preparation for its advantage of easier programming of embryo transfer . The increasing number of artificial cycles raises the question of the serum P levels required to optimize the pregnancy outcome. In this large-sample retrospective study, we investigated the contribution of strengthened LPS for the pregnancy outcome in patients with low serum P on the FET day in artificial cycles. The strengthened LPS for the section of patients produced 39.5% live birth in the groups of low serum P, a slightly lower (3.8%) than the groups with normal serum P levels and usage of routine LPS.
The principles for choosing LPS include of the minimum effective dose, good safety and tolerability . This is an open question with many alternative answers, and the heterogeneous applications of the dose and routes make it difficult to compare LPS in different studies [3, 13]. The pregnancy outcomes, especially live birth rate, become the endpoint of evaluating the effects of LPS in artificial FET cycles. Vaginal administration was the first choice of doctors, used alone or in combination with oral or intramuscular injection in a recent large survey . In our center, the most popular regimen of LPS was using oral dydrogesterone 20 mg twice daily and vaginal micronized P 200 mg twice daily in artificial cycles. In this context, serum P level was a surrogate marker reflecting the systematic absorption extent of vaginal P administration. It might be interfered by individual variability, such as BMI, mucus surface area, amount of cervical mucus and the difference of vaginal microbiome . Thus, a marked inter-individual difference of serum P concentrations on the luteal phase was present despite the same dose of vaginal P administration, the possibility of LPS insufficiency by vaginal route can not be excluded for the section of patients with low serum P concentration in artificial cycles. The previous report compared three arms in artificial cycles using a randomized control trial (vaginal 200 mg twice daily, im P 50 mg daily only, vaginal 200 mg twice daily + im P 50 mg every third day), vaginal P only group was found a significantly lower ongoing pregnancy rate compared the other two groups (31% vs 50% vs 47%), and the trial did not continue after inter analysis for the higher proportion of biochemical pregnancy loss and miscarriage . Unfortunately, no data on serum progesterone levels in the three groups were available from that study. The low serum P levels on the FET day in artificial cycles using vaginal route were previously reported to be associated with poorer reproductive outcomes, the cutoff value was varied in previous reports (5.0–12.0 ng/ml) [5–8]. In this study, the cutoff value was set as 10.0 ng/ml.
In this study, the strengthened P replacement was a protective approach, with attempting to mitigate the effects of low serum P4 that fell below this threshold. For the topic, the ideal control was using routine LPS for the patients with low serum P on the FET day, but our previous tendency of doctors was to add P to avoid the possible harm and maximize the patients’ benefits in a conservative view. Limited by the real-world data in our clinic, we converted to use the population of normal serum P and routine LPS as controls, the current data showed slight lower pregnant outcomes of strengthened LPS in the lower P group. Although our study can not distinguish the difference origin from the harm caused by lower serum P or the benefits of additional P, the current comparison data still provided some meaningful information. Firstly, the patients of low serum P and strengthened LPS showed a slightly lower clinical pregnancy and live birth rate compared with the normal control, it decreased the chance of clinical pregnancy by 19% after adjusting confounding factors. Similar results were reported in Alsbjerg et al , serum P levels below 11.0 ng/ml (35 nmol/l) decreased the chance of ongoing pregnancy with a risk reduction of 14% in hormone replacement therapy FET cycles. Using the logistic regression model in this study, the low serum P level, as categorical variable, was a risk factor for the chance of pregnancy in artificial endometrial preparation cycles, which indicated the suboptimal condition in this section of patients with low serum P.
Secondly, the pregnancy outcome of the groups of low P and strengthened LPS was an acceptable result, clinical pregnancy rate (48.4%) and live birth rate (39.5%) appeared reasonable, the similar proportion of biochemical pregnancy loss and miscarriage also approved the efficacy of strengthened LPS. As such, even though serum P has been inadequate on the FET day, this was potentially remedied by additional P administration, reinforcing intervention might still be possible beyond the day of transfer. The results were in coincide with the recent report of Volovsky et al, P replacement enhanced the pregnancy outcome if the P on the FET day was lower than 8.0 ng/ml . In a recent study of Polats et al., the intramuscular P supplementation every third day did not increase the ongoing pregnancy rate compared with vaginal P only in vitrified blastocyst transfer cycles (48.3% vs 51.8%). However, the patients with serum P less than 8.75 ng/ml in vaginal P only group had a numerically lower ongoing pregnancy rate (28.6% vs 46.6%), but did not reach the statistically significant difference .
The current study also had several strengths. The vaginal P administration achieved higher endometrial tissue concentrations and lower systemic exposures than observed after intramuscular injection, and the dose-effect relationship was not obvious in the same route of P administration , so the combination of two or three routes, rather than increasing dose of single route, is a reasonable choice to meet the requirement of endometrial transfection in artificial cycles. Multiple routes of P administration provided sufficient luteal support in artificial FET cycles. The secondary strength was the large cohort size, it had sufficient power to answer the question whether it was beneficial of strengthened LPS to overcome the possible negative influence in the cycles with low serum P on the FET day. All cycle data were derived from a single institution, where practice consistency can be assured.
Our study was limited by its retrospective design. In this context, we screened the database with strict inclusion criteria, analysis was restricted to first artificial cycles and normal ovarian reserve, and a number of potential confounders were well controlled in the current study. Additionally, the vast majority of patients in the present study were young and normal ovarian reserve, so the extrapolation to an unselected population needs to be validated.
In the previous report of Yovich et al., maternal age, embryo quality and mid-luteal serum progesterone levels were listed as three important factors governing the implantation rates for artificial FET cycles . In this study, serum P levels on the FET day, as a categorical variable, were found to be a significant independent prognosticator of clinical pregnancy, while it did not reach the statistically significance for live birth rate. The explanation of the results should be cautious. Strengthen LPS might be useful for the patients with low serum P levels on the FET day in artificial cycles, further study is need to perform randomized controlled trials to evaluate the individualization of P dosage.