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Original Investigation
August 3, 2021

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

Author Affiliations
  • 1Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania
  • 2Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City
  • 3Department of Obstetrics and Gynecology, University of Illinois at Chicago
  • 4Department of Obstetrics and Gynecology, Atrium Health, Charlotte, North Carolina
  • 5Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill
  • 6Department of Obstetrics and Gynecology, University of California at San Francisco
  • 7Department of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois
  • 8Department of Obstetrics and Gynecology, University of Rochester, Rochester, New York
  • 9Department of Obstetrics and Gynecology and Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan
  • 10Department of Obstetrics & Gynecology, Prisma Health, University of South Carolina School of Medicine–Greenville
  • 11Department of Obstetrics and Gynecology, University of Colorado and Denver Health Medical Center, Denver
  • 12Department of Obstetrics and Gynecology, Augusta University, Augusta, Georgia
  • 13Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora
  • 14Department of Obstetrics and Gynecology, University of Colorado, Denver
  • 15Fertility and Infertility Branch, National Institute of Child Health and Human Development, Rockville, Maryland
  • 16Department of Biostatistics, Yale University, New Haven, Connecticut
JAMA. 2021;326(5):390-400. doi:10.1001/jama.2021.10767
Key Points

Question  When a woman has an early nonviable pregnancy and the location is unknown, does an active management strategy (with either methotrexate alone or uterine evacuation with methotrexate as needed) more frequently lead to successful resolution of the pregnancy compared with an expectant management strategy?

Findings  In this randomized clinical trial involving 255 women, a significantly greater percentage of patients randomized to receive active management than those randomized to receive expectant management experienced a successful resolution of the pregnancy without change from the initial management strategy (51.5% vs 36.0%, respectively).

Meaning  Among patients with a persisting pregnancy of unknown location, an initial active management strategy, compared with an expectant management strategy, more frequently resulted in successful pregnancy resolution without change from the initial strategy, although the large proportion of patients who declined the management strategy to which they were originally randomized should be considered when interpreting the trial results.

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

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