Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial

Abstract

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities.

Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed.

Design, setting, and participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019).

Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82).

Main outcomes and measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%.

Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%).

Conclusions and relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results.

Trial registration: ClinicalTrials.gov Identifier: NCT02152696.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Barnhart reported receiving consulting fees from Swiss Precision Diagnostics and Bayer. Dr Hansen reported receiving research grants from Roche Diagnostics and Ferring International Pharmascience Center US, and personal fees from Ablacare for serving on a data and safety monitoring board. Dr Steiner reported receiving consulting fees from Seikagaku and Prima-Temp. Dr Cedars reported receiving research funding from Ferring Pharmaceuticals. Dr Hoeger reported serving as a consultant to Bayer and Ablacare and receiving research funding from AbbVie. Dr Krawetz reported receiving a research grant from Merck and personal fees from Taylor and Francis. Dr Diamond reported receiving institutional grants and contracts from Bayer, ObsEva, and AbbVie; serving as a member of the board of directors and being a stockholder of Advanced Reproductive Care and serving as a consultant for Seikagaku, Actamax, AEGEA, Temple Therapeutics, and ARC Medical Devices and has a patent for ectopic pregnancy. Dr Wild reported receiving grants from Oklahoma University Health Sciences Center, Ablacare, Amgen Repatha, and Partners Mass General Menopause Reviews. Dr Santoro reported serving as a consultant to Ansh Lab, and is a scientific advisor to Astellas and Menogenix, Inc. Dr Eisenberg reported that he is a government employee. No other disclosures were reported.

Figures

Figure.. Eligibility, Randomization, and Follow-up of Patients With a Pregnancy of Unknown Location Participant Flow Through the ACT or NOT Randomized Clinical Trial

aRandomization was stratified by site.