Active Treatment or No Treatment (ACT or NOT) for Persisting Pregnancy of Unknown Location;  A Randomized Clinical Trial

Abstract

Background: Women in early gestation without a pregnancy visualized on ultrasound and serial hCG values consistent with a nonviable gestation are at high risk for ectopic pregnancy. The goal of this trial was to determine if active management is superior to expectant management, and if two active management strategies are non-inferior. Methods: This multi-center study, 255 women with a persistent pregnancy of unknown location were randomized to expectant management or active management in a 1:2 ratio, and 1:1 within active management to a) uterine evacuation followed by methotrexate if needed or b) empiric methotrexate. The primary outcome was successful resolution of the pregnancy without change from initial strategy. Findings: Women treated with active management had a significantly higher percentage of successful resolution, Rate ratio 1·43 (1·04–1·96) intention to treat (ITT) and 1·64 (1·39–1·94) as treated (AT) and a lower rate of unscheduled surgery RR 0·43 (0·25-0·74) ITT and 0·24 (0·11-0·55) AT. Methotrexate was non-inferior to uterine evacuation (difference=6·6% (-8.4% to 21.6%) ITT. As treated, time to resolution was 8·1 days shorter after uterine evacuation compared to methotrexate. All strategies were safe and were rated with high acceptability and satisfaction. Women expressed a preference for expectant management with differential cross-over within this trial. Interpretation: A greater percentage of women achieved uneventful resolution with active management compared to expectant management with at least a 50% reduction in unscheduled interventions. Uterine evacuation resulted in a shorter time to resolution. Acceptability and safety of treatment were high for all strategies, but subjects expressed a preference for expectant management. Trial Registration: The trial was performed under IND #56407 and clinical trial registration number NCT02152696. Funding Statement: This work was supported by the National Institutes of Health (NIH)/ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Declaration of Interests: Dr. Barnhart reports consulting fees to Swiss Precision Diagnostics and Bayer. Dr. Hansen reports research grants from Roche Diagnostics and Ferring outside of the submitted work. Dr. Diamond reports institutional grants/contracts from Bayer, ObsEva, and AbbVie; serving as a member of the Board of Directors and a stockholder of Advanced Reproductive Care; and serving as a Consultant for Seikagaku, Actamax, AEGEA, Temple Therapeutics, and ARC Medical Devices. Dr. Steiner reports consulting fees from Seikagaku and Prima-Temp. Dr. Cedars reports research funding from Ferring Pharmaceuticals outside of the submitted work. Dr. Wild reports Ablacare PCOS, Amgen Repatha in Pg and Partners Mass General Menopause Reviews, outside of the submitted work. Dr Hoeger reports consultation to Bayer and Ablacare and research funding from Abbvie. Dr. Krawetz reports a research grant from Merck outside of the submitted work. Dr. Santoro reports consulting for Ansh Lab, and is a Scientific Advisor to Astellas and Menogenix, Inc. Ethics Approval Statement: The protocol was approved by a National Institutes of Health appointed advisory board and a data and safety monitoring board. The University of Pennsylvania served as single IRB (IRB # 815013).