Effectiveness of progesterone rescue in women presenting low circulating progesterone levels around the day of embryo transfer: a systematic review and meta-analysis.

Importance: Over the last decade, frozen embryo transfer (FET) has been increasingly used in contemporary fertility units. Despite the rapid increase in FET, there is still insufficient evidence to recommend an optimized protocol for endometrial preparation especially in patients with lower progesterone (P4) levels. Previous studies have concluded that P4 levels <10 ng/mL are associated with poorer pregnancy outcomes than those reported with high levels of circulating P4.

Objective: To identify whether rescue P4 dosing in patients with low P4 can salvage adverse outcomes associated with low P4 levels, resulting in outcomes comparable to patients with adequate progesterone.

Data Sources: The study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-analyses guidelines and prospectively registered under the PROSPERO database (CRD42022357125). Six databases (Embase, MEDLINE, APA PsycInfo, Global Health, HMIC Health Management Information Consortium, and Google Scholar) and 2 additional sources were searched from inception to August 29, 2022.

Study Selection And Synthesis: Prospective and retrospective cohort studies, reporting the association between rescue progesterone and one or more pregnancy outcomes, were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS), while the quality of evidence by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Summative and subgroup data as well as heterogeneity were generated by the Cochrane platform RevMan (V. 5.4).

Main Outcome Measure(s): To compare ongoing pregnancy rate as primary outcome and clinical pregnancy rate, miscarriage rate, and live birth rate as secondary outcomes between patients with low (<10 ng/mL) receiving rescue progesterone vs. those with adequate levels of P4 (≥10 ng/mL).

Result(s): Overall, 7 observational studies were included in the analysis, with a total of 5927 patients of median age 34 (interquartile range [IQR]: 31.55, 37.13). Overall, patient group comparison, namely those with low P4 that received a rescue dose and those with adequate P4 levels, did not yield significant differences for either the primary or secondary outcomes. For ongoing clinical pregnancy, patients with low P4 receiving the rescue dose vs. those with adequate P4 levels was odds ratio (OR) 0.98 (95% CI: 0.78, 1.24; P = .86, I: 41%), whereas for miscarriage events, OR was 0.98 (95% CI: 0.81, 1.17; P = .80, I: 0). Equally, for clinical pregnancy, OR was 0.91 (95% CI: 0.78, 1.06; P = .24; I: 33%), and for live birth, OR was 0.92 (95% CI: 0.77, 1.09; P = .33; I: 43%). Subgroup analysis on the basis or rescue administration route successfully explained summative heterogeneity.

Conclusion(s): Rescue P4 dosing in patients with low P4 results in ongoing pregnancy rate, clinical pregnancy and live birth rates were comparable to those of patients with adequate P4 levels. However, robust randomized controlled trials assessing rescue treatment in women with low P4 are needed to confirm these findings. Rescue P4 in patients with low circulating P4 around embryo transfer day may result in reproductive outcomes comparable to those with adequate P4 levels.

Study Registration: CRD42022357125 (PROSPERO).