OBJECTIVE: To estimate the efficacy and safety of mifepristone antagonization with high-dose oral progesterone. METHODS: We planned to enroll 40 patients in a double-blind, placebo-controlled, randomized trial. We enrolled patients at 44–63 days of gestation with ultrasound-confirmed gestational cardiac activity who were planning surgical abortion. Participants ingested mifepristone 200 mg and initiated oral progesterone 400 mg or placebo 24 hours later twice daily for 3 days, then once daily until their planned surgical abortion 14–16 days after enrollment. Follow-up visits were scheduled 3±1, 7±1, and 15±1 days after mifepristone intake with ultrasonography and blood testing for human chorionic gonadotropin and progesterone. Participants exited from the study when they had their surgical abortion or earlier for gestational cardiac activity absence, gestational sac expulsion, or medically indicated suction aspiration. We assessed the primary outcome of continued gestational cardiac activity at approximately 2 weeks (15±1 day), side effects after drug ingestion, and safety outcomes including hemorrhage and emergent treatment. RESULTS: We enrolled participants from February to July 2019 and stopped enrollment after 12 patients for safety concerns. Mean gestational age was 52.5 days. Two (one per group) voluntarily discontinued 3 days after mifepristone ingestion for subjective symptoms (nausea and vomiting, bleeding). Among the remaining 10 patients (five per group), gestational cardiac activity continued for 2 weeks in four in the progesterone group and two in the placebo group. One patient in the placebo group had no gestational cardiac activity 3 days after mifepristone use. Severe hemorrhage requiring ambulance transport to hospital occurred in three patients; one received progesterone (complete expulsion, no aspiration) and two received placebo (aspiration for both, one required transfusion). We halted enrollment after the third hemorrhage. No other significant side effects were reported. CONCLUSION: We could not estimate the efficacy of progesterone for mifepristone antagonization due to safety concerns when mifepristone is administered without subsequent prostaglandin analogue treatment. Patients in early pregnancy who use only mifepristone may be at high risk of significant hemorrhage. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03774745.

Seasonal plasticity is accomplished via tightly regulated developmental cascades that translate environmental cues into trait changes. Little is known about how alternative splicing and other posttranscriptional molecular mechanisms contribute to plasticity or how these mechanisms impact how plasticity evolves. Here, we use transcriptomic and genomic data from the butterfly Bicyclus anynana, a model system for seasonal plasticity, to compare the extent of differential expression and splicing and test how these axes of transcriptional plasticity differ in their potential for evolutionary change. Between seasonal morphs, we find that differential splicing affects a smaller but functionally unique set of genes compared to differential expression. Further, we find strong support for the novel hypothesis that spliced genes are more susceptible than differentially expressed genes to erosion of genetic variation due to selection on seasonal plasticity. Our results suggest that splicing plasticity is especially likely to experience genetic constraints that could affect the potential of wild populations to respond to rapidly changing environments.