Progesterone in Oil: A Retrospective Study of the Prevalence of Progesterone Hypersensitivity in Medicated Frozen Embryo Transfer Cycles and Its Impact on Reproductive Outcomes

Background: In medicated frozen embryo transfer (FET) cycles, exogenous progesterone is essential during the luteal phase to support implantation and early pregnancy due to the absence of the corpus luteum. Among the variable forms of exogenous progesterone, intramuscular (IM) progesterone in oil (P-in-oil) is generally considered the most effective. However, some patients experience hypersensitivity reactions, raising concerns about their potential impact on implantation success and early pregnancy development. Progesterone plays a central role in the dynamic immune balance necessary to establish and maintain a successful pregnancy. Progesterone hypersensitivity reaction could disrupt this delicate balance, potentially leading to adverse reproductive outcomes and affecting future fertility care. Although hypersensitivity reactions to P-in-oil are rare, they warrant attention due to their potential implications for clinical management and patient outcomes. Notably, data on reproductive outcomes in patients experiencing hypersensitivity to exogenous progesterone, particularly P-in-oil, remains limited. Objectives: This study aims to evaluate the prevalence of progesterone hypersensitivity in women undergoing medicated FET cycles utilizing P-in-oil and to investigate the clinical implications of such reactions on reproductive outcomes. Methods: A retrospective cohort study was conducted including 814 medicated FET cycles at a private assisted reproductive technology program between April 2022 to August 2023. All patients received exogenous IM P-in-oil for luteal phase support. We excluded cycles involving donor oocytes or embryos, as well as those using gestational carriers, to ensure a homogeneous study population. Cycles that involved alternative or combined progesterone regimens were also excluded to isolate the effects of IM P-in-oil. Statistical analysis included Chi-squared tests for categorical variables and T-tests for continuous variables. Relative risks (RR) and 95% confidence intervals (CI) were calculated using multivariate logistic regression to adjust for potential confounders. A p-value of < 0.05 was considered statistically significant throughout the analysis. This study was approved by the Institutional Review Board of Indiana University. Results: A total of 673 patients who underwent medicated FET cycles were analyzed within the cohort. Approximately 10.3% (n=69) of patients using P-in-oil supplementation reported experiencing a reaction during one of their treatment cycles, resulting in an overall reaction rate per cycle of 8.5%. Symptoms of progesterone hypersensitivity (PH) varied widely and included dermatitis, urticaria, edema, fever, nausea, and dyspnea. Dermatologic manifestations were the most frequently reported symptoms, occurring in 95.5% of patients who experienced adverse reactions. In contrast, systemic adverse reactions were uncommon, reported in less than 5% of cases. The live birth rate was significantly higher in patients who experienced a reaction (68.1%, n=47) compared to those without a reaction (47.7%, n=355) (p = 0.001; RR 2.19, CI 1.35-3.56). No significant difference was found in the miscarriage rate between patients with and without reported reactions (8.7%, n=6 vs. 8.7%, n=65, respectively) (p = 0.99; RR 1.00, CI 0.45 – 2.22). Conclusions: Hypersensitivity to P-in-oil presents a unique and underrecognized challenge in management of patients undergoing medicated FET cycles. This is the largest cohort analyzing progesterone hypersensitivity in patients using P-in-oil. Our data suggests that this rare occurrence has a minimal negative impact on reproductive outcomes. Notably, patients who experienced hypersensitivity reactions during P-in-oil use were more than twice as likely to achieve a live birth compared to those without reactions. Patients who experience hypersensitivity reactions while using P-in-oil can be reassured that their medication regimen is unlikely to negatively impact their success rates. However, given the complex immune-hormonal interactions involved in early pregnancy, larger prospective studies are warranted to validate these findings and better understand their clinical implications.