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

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?