A network meta-analysis yields new insights on the efficacy of different progestogen regimens for luteal support in fresh embryo in vitro fertilization

Abstract Study question How do seven progestogen regimens rank in their efficacy for achieving clinical pregnancy when used as luteal support in women undergoing fresh embryo transfer? Summary answer Given as luteal support and based on clinical pregnancy rate, intramuscular progesterone was most effective, followed by oral dydrogesterone and then micronized vaginal progesterone gel. What is known already A large number of randomized controlled trials (RCTs) have compared fresh in vitro fertilisation cycle luteal support with progestogens. A number of systematic reviews and conventional meta-analyses have likewise been published. A network meta-analysis integrates direct and indirect comparisons between treatments in a single analysis, and allows the ranking of treatments and the estimation of heterogeneity in both the effect of any given treatment and the inconsistency (‘incoherence') in the evidence from different pairs of treatments. Network meta-analyses can thus increase the precision and robustness of inferences from the literature on treatment effect estimates. Study design, size, duration A literature search was performed using BIOSIS, Embase, and MEDLINE and supplemented with manual searches to identify RCTs reporting the efficacy of progestogen regimens in luteal support during fresh embryo transfer. A single network meta-analysis was used to compare progestogen regimens, combining both direct and indirect evidence across the selected studies using the R package ‘netmeta’ and fixed and random effects models. The analysis was repeated and confirmed using SAS. Participants/materials, setting, methods Peer-reviewed full publications that compared individual progestogens (either with placebo or another progestogen) were included. Studies were excluded if they included frozen embryo transfers, used human chorionic gonadotropin or formulations not currently available for the indication, or if they did not report at least clinical pregnancy rate. Two authors (EK, QW) individually reviewed papers to collect data. Where doses differed between studies for an individual progestogen the doses were noted and the results combined. Main results and the role of chance Among studies from 1987–2022, 35 RCTs met the inclusion criteria, comprising 17,955 observations of 7 treatments plus placebo and resulting in 43 pairwise comparisons for the network meta-analysis of clinical pregnancy rate (the primary outcome). Based on the random effects model, the top three regimens versus placebo were intramuscular (IM) progesterone, Duphaston® (oral dydrogesterone), and Crinone® (micronized progesterone vaginal gel) (see Figure). Compared with placebo, only the top 3 ranking compounds had confidence intervals that excluded zero, with a risk difference to placebo (95% confidence interval) of 0.08 (0.01-0.14) for IM progesterone and 0.07 (0.01-0.13) for both Duphaston® and Crinone®. The P-score (fixed, random) ranking for the compounds was: IM progesterone 0.77, 0.79; Duphaston® 0.78, 0.69; Crinone® 0.65, 0.65; Cyclogest® (vaginal micronized progesterone) 0.58, 0.60; Endometrin® (vaginal micronized progesterone) 0.52, 0.54; Prolutex® (subcutaneous progesterone) 0.31, 0.36; Utrogestan® (vaginal micronized progesterone) 0.34, 0.31; and placebo 0.05, 0.06. Ranking was confirmed by SUCRA score (surface under the cumulative ranking curve). Studies were thoroughly reviewed to ensure similarity assumption. Homogeneity and consistency of the network were investigated and fulfilled. Exclusion of placebo-controlled studies did not impact the overall results or rankings. Limitations, reasons for caution Treatment duration was assumed identical across arms in each study and therefore was not included in this analysis. Most studies were single-centre with a small sample size. Methodological rigor was heterogenous between trials. Direct comparisons with placebo were only available for the top three compounds. Wider implications of the findings Three progestogen regimens showed a positive effect on clinical pregnancy rate versus placebo. Frequently used vaginal preparations do not lead the efficacy league table when the available direct and indirect comparative evidence is collated. Relevant efficacy differences likely exist between the available progesterone regimens. Trial registration number n/a