Overweight and Obesity Affect The Efficacy of Vaginal vs. Intramuscular Progesterone for Luteal-Phase Support in Vitrified-Warmed Blastocyst Transfer

ABSTRACT The prevalence of obesity in reproductive age women continues to increase worldwide. Recent meta-analyses suggest that female obesity is negatively associated with live birth rate (LBR) after in vitro fertilization, as well as a higher risk of miscarriage after euploid embryo transfer. The interplay between adiposity and reproductive hormones such as progesterone may be partially responsible, and research shows that obese women may require higher progesterone supplementation in frozen-thawed embryo transfer (FET). Although the vaginal route of progesterone supplementation has predominated in most in vitro fertilization centers globally, the route of supplementation has been gaining interest. Studies comparing different routes have focused on the general infertility population, and it remains essential to investigate the interrelationship between the routes of progesterone supplementation, overweight/obesity, and treatment outcomes. This retrospective cohort study aimed to compare the difference in the LBR between vaginal progesterone and intramuscular progesterone in cryopreserved blastocyst transfer cycles and assess whether obesity may modify these associations. Patients who underwent a single, vitrified-warmed, blastocyst transfer between January 2018 and June 2021 and received exogenous hormone replacement for endometrial preparation were included. The route of progesterone supplementation was based on patient preference. The primary study outcome was live birth, and secondary outcomes included a positive b-hCG test result, clinical pregnancy, miscarriage, and total pregnancy loss. Normal weight was defined as 18.5–24.9 kg/m 2 , overweight was defined as a body mass index (BMI) of 25–29 kg/m 2 , and obese was defined as ≥30 kg/m 2 . Multivariate regression was used to assess the association between the route of progesterone supplementation and LBR while controlling for known potential covariates, and an interaction analysis was performed with overweight/obesity as the interaction term. A total of 6905 FET cycles from 6251 patients were included for this analysis, with 4616 cycles using vaginal progesterone and 2289 cycles using intramuscular progesterone. The proportions of overweight and obese women were comparable between the 2 groups. After adjusting for confounding variables, the LBR in the vaginal and intramuscular progesterone groups were 46.23% (2134/4616) and 48.62% (1113/2289), respectively (adjusted odds ratio [aOR], 0.89; 95% confidence interval [CI], 0.81–0.98). Although the rates of a positive serum hCG result and clinical pregnancy were similar between the 2 groups, miscarriage rate (15.34% vs 11.40%; aOR, 1.40; 95% CI, 1.20–1.63) and total pregnancy loss (22.22% vs 18.90%; aOR, 1.23; 95% CI, 1.08–1.40) per FET were significantly higher in the vaginal progesterone group than in the intramuscular progesterone group. Among normal-weight women, the LBR was lower in the vaginal progesterone group than the intramuscular progesterone group (aOR, 0.84; 95% CI, 0.75–0.95), and among women with overweight/obesity, the LBR was similar between the 2 groups. Analysis with BMI as a continuous variable on route of progesterone showed a nonlinear relationship between route and LBR after adjustment. Among overweight/obese women, BMI modified the association between route of progesterone and LBR ( P interaction = 0.047); however, among women with normal weight, this was not significant ( P interaction = 0.569). The result of this study demonstrates that the rate of pregnancy loss for vaginal progesterone was significantly increased and resulted in a lower LBR in patients receiving vitrified blastocysts, and suggested that overweight/obesity influenced the relationship between route of progesterone supplementation and LBR. Interestingly, an LBR advantage for the intramuscular route over the vaginal route was observed exclusively in women with normal weight.