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Grand Rounds

RCT Results: Active or Expectant Management for Persisting Pregnancy of Unknown Location?

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BACKGROUND AND PURPOSE:

  • Persisting pregnancy of unknown location
    • Ultrasound cannot identify the location of a pregnancy and hCG concentrations suggest neither a viable gestation nor a spontaneously resolving pregnancy loss
    • Guidelines for management are limited
  • Barnhart et al. (JAMA, 2021) sought to determine
    • Whether active management is more effective than expectant management in achieving resolution of pregnancy without change from initial strategy

METHODS:

  • Multicenter randomized clinical trial
  • Participants
    • Hemodynamically stable women
    • Diagnosis of persisting pregnancy of unknown location
  • Interventions
    • Expectant: Close clinical surveillance and monitoring, with serial hCG values at least every 4 to 7 days
    • Evacuation: Active management with uterine evacuation followed by methotrexate if needed
    • Methotrexate: Active management with empirical methotrexate using a 2-dose protocol
  • Study design
    • Random assignment 1:1:1 to an intervention group
    • The primary hypothesis tested for superiority of the active groups combined vs expectant management | Sample size calculated for 90% power
    • The secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed, using a noninferiority margin of −12% | Sample size calculated for 80% power
    • Methotrexate given at 24 hours after uterine evacuation if there was not a decline in hCG of at least 15% a day after the procedure
  • Change in assigned strategy
    • Voluntary change (crossover): Participant who immediately declined the assigned strategy
    • Clinical change: Medical need for additional treatment based on clinical decisions or by patient request after the initial treatment strategy had started.
  • Primary outcome
    • Successful resolution of pregnancy without change from initial strategy
  • Secondary outcomes
    • Number and type of unscheduled interventions | Time until resolution | Number of clinic visits | Adverse events | Patient acceptability, satisfaction, and preference

RESULTS:

  • Expectant: 86 women | Evacuation: 87 women | Methotrexate: 82 women
    • Median age 31 years (IQR 27 to 36 years)
  • 39% declined randomization and crossed over to another group
    • Declined expectant management: 26.7%
    • Declined uterine evacuation: 48.3%
    • Declined empirical methotrexate: 41.5%
  • 44% receiving uterine evacuation did not require further treatment
  • Women randomized to active management vs randomized to expectant management were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy
    • Active management: 51.5% successful
    • Expectant management: 36.0% successful
    • Difference 15.4% (95% CI, 2.8% to 28.1%)
    • Rate ratio (RR) 1.43 (95% CI, 1.04 to 1.96)
  • Empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed
    • Methotrexate: 54.9%
    • Evacuation: 48.3%
    • Difference 6.6% (1-sided 97.5% CI, −8.4% to ∞)
  • The most common adverse event was vaginal bleeding for all 3 management groups (44.2%-52.9%)
  • Ectopic pregnancy: 5 women (all treated successfully with laparoscopy)
    • Randomized to expectant management: 2
    • Randomized to uterine evacuation: 3
    •  Actual treatment expectant management: 2
    • Actual uterine evacuation: 2
    • Methotrexate: 1 

Post Hoc Analysis for As-Treated Analysis

  • As-treated analysis also demonstrated greater likelihood of successful resolution with active management vs expectant management
    • RR, 1.99 (95% CI, 1.35-2.94)
  • Analysis restricted to patients with no voluntary change also demonstrated greater likelihood of success with active management
    • RR 1.89 (95% CI, 1.32-2.70)

CONCLUSION:

  • Women with persisting pregnancy of unknown location who were randomized to receive active management more frequently achieved pregnancy resolution without change from initial strategy vs expectant management
  • There was substantial crossover between the groups (preferentially to expectant management) which may introduce bias
  • The authors note that

This is the first randomized trial, to our knowledge, to compare uterine evacuation to empirical methotrexate

Active management with empirical administration of methotrexate was noninferior to a dilation and evacuation followed by methotrexate as needed

Learn More – Primary Sources:

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

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Related ObG Topics:

Pregnancy of Unknown Location – Next Steps
Ectopic Pregnancy: Expectant Management vs. Methotrexate?
Ectopic Pregnancy Methotrexate Protocol: Single-Dose or 2-Dose?
What Model is Best for Managing a Pregnancy of Unknown Location?

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