Rescue P4 dosing with low P4 results in comparable pregnancy rate to patients with adequate progesterone
Over the last decade, frozen embryo transfer (FET) has been increasingly adopted in contemporary fertility clinics. Over the last few years, researchers have been particularly interested in evaluating the association between P4 levels around the day of embryo transfer and pregnancy outcomes.
The researchers concluded that in oocyte donation cycles, patients with progesterone levels < 9.2ng/ml had 20% lower ongoing pregnancy rates (OPR) than those with higher P4 levels. These results appeared later to apply both to patients treated with donated and autologous oocytes. Similarly, several studies have outlined that minimum P4 levels are required in the luteal phase to optimize pregnancy outcomes, albeit different P4 thresholds are reported. According to recent literature, one of the most accepted reference values is around 10 ng/ml.
The question at hand is whether treatment outcomes in patients with low P4 levels around the embryo transfer day can be improved with rescue P4 supplementation. Several observational studies have examined this hypothesis over the last years aiming to overcome the “one-size-fits-all” strategy and to establish a more individualized approach for patients with low P4 levels. The aim of this systematic review and meta-analysis was to analyze the impact on reproductive outcomes of P4 supplementation in patients with low P4 levels around the embryo transfer day compared to patients with adequate circulating P4 levels.
The study was conducted according to the PRISMA guidelines and prospectively registered under the PROSPERO database. Six databases (Embase, MEDLINE®, APA PsycInfo, Global Health, HMIC Health 70 Management Information Consortium and Google Scholar) and two additional sources were searched from inception to 29 August 2022.
Prospective and retrospective cohort studies, reporting the association between rescue progesterone and one or more pregnancy outcomes, were included. Quality of the included studies were assessed using the Newcastle-Ottawa Scale (NOS) whilst quality of evidence by the GRADE framework. Summative and subgroup data as well as heterogeneity were generated by the Cochrane platform RevMan (V. 5.4).
The study compared ongoing pregnancy rate (OPR) as primary outcome and clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR) as secondary outcomes between patients with low (<10 ng/ml) receiving rescue 81 progesterone vs. those with adequate levels of progesterone (≥ 10ng/ml). ><10 ng/ml) receiving rescue progesterone vs. those with adequate levels of progesterone (≥ 10ng/ml).
Overall, 7 observational studies were included in the analysis, with a total of 5927 patients of median age 34 [IQR 31.55, 37.13]. Overall, patient group comparison, namely those with low progesterone that received a rescue dose (R) and those with adequate progesterone (N) levels did not yield significant differences for either the primary or secondary outcomes. For ongoing clinical pregnancy R vs. N was OR 0.98, P= 0.86, I2 41%, while for miscarriage events, OR was 0.98, P= 0.80, I2 0%. Equally, for clinical pregnancy OR was 0.91, P= 0.24, I2 33% and for live birth OR 0.92, P= 0.33, I2 43%. Subgroup analysis on the basis or rescue administration route successfully explained summative heterogeneity.
In the present systematic review and meta-analysis, authors aimed to explore whether strengthened luteal support with additional P4 supplementation in women presenting with low P4 levels around the embryo transfer day, could rescue the cycle and achieve comparable outcomes to those with adequate P4. Study findings suggest that the clinical pregnancy, ongoing pregnancy, miscarriage, and live birth events between the two groups were comparable, proposing that if a rescue dose is administered in the low P4 group, similar pregnancy rates with those patients having adequate circulating P4 levels, may be achieved.
“Our meta-analysis did not yield significant differences in terms of pregnancy rates between patients with low P4 levels who received rescue dose and patients with adequate serum P4 concertation around the embryo transfer day. The measurement of P4 either on the embryo transfer or the previous day, may create an opportunity for P4 supplementation in those patients with low circulating levels which may facilitate treatment management in this population, avoiding adverse reproductive outcomes. Robust randomized controlled trials, comparing low P4 with or without rescue treatment against an adequate P4 patient control group are vital in view of definitively evaluating and improving reproductive outcomes for those women with low progesterone.”
Source:Stavridis K, Kastora SL, Triantafyllidou O, Mavrelos D, Vlahos N, Effectiveness of progesterone rescue in women presenting low circulating progesterone levels around the day of embryo transfer: a systematic review and meta-analysis., Fertility and Sterility (2023), doi: https://doi.org/10.1016/j.fertnstert.2023.02.007
