Managing pregnancy of unknown location


“We have refined how to diagnose women with early pregnancy loss, but noted a gap in our understanding of the optimal way to care for these women,” Barnhart told Contemporary OB/GYN®.

A multicenter, randomized clinical trial of women with a persisting pregnancy of unknown location has found that those who received active management were significantly more likely to achieve successful pregnancy resolution without a change from their initial management strategy, compared to women who received expectant management.

Principal investigator Kurt Barnhart, MD, MSCE, a professor of ob-gyn and epidemiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, said the study in JAMA was an evolution from his previous investigation and clinical care of women with pregnancy loss.

“We have refined how to diagnose women with early pregnancy loss, but noted a gap in our understanding of the optimal way to care for these women,” Barnhart told Contemporary OB/GYNÒ.

The study recruited 255 hemodynamically stable women (median age 31 years) with a diagnosed persisting pregnancy of unknown location at 12 medical centers across the United States between July 2014 and June 2019.

“The transient state termed a pregnancy of unknown location is when ultrasound does not definitively identify the location of the pregnancy in the uterus or in the adnexa,” Barnhart said. “In our study, we defined a persisting pregnancy of unknown location as a pregnancy of unknown location and pattern in serial human chorionic gonadotropin (hCG) concentrations, suggesting neither an ongoing viable gestation nor a spontaneously resolving pregnancy loss.”

Patients were equally randomized to 1 of 3 groups: expectant management, consisting of close clinical surveillance and monitoring serial hCG values at least every 4 to 7 days (n = 86); active management with uterine evacuation followed by methotrexate, if needed (n = 87); and active management with empirical methotrexate via a 2-dose protocol (n = 82).

Overall, 51.5% of patients in the 2 groups of active management had successful pregnancy resolution versus only 36% in the expectant management group.

“Resolution of the pregnancy was a decline in serum hCG to undetectable levels, spontaneously or after treatment,” Barnhart said.

For active management, empirical methotrexate was comparable to uterine evacuation followed by methotrexate, if needed, to successful pregnancy resolution without change in management strategy: 54.9% vs 48.3%, respectively.

Themost common adverse event for all 3 management groups was vaginal bleeding, ranging from 44.2% to 52.9%.

“Two results of the study surprised me,” said Barnhart, director of the Women's Health Clinical Research Center at the medical school. “First, there was a strong desire for a specific treatment for women we approached to enter this trial, without objective data to suggest which method was optimal.”

The second unexpected outcome was that clinicians may be declaring a pregnancy nonviable too quickly. “The current thresholds that define viability are not foolproof, so we should take more time before we act,” Barnhart said.

The study provides objective evidence to inform the choice of management for women facing a persisting pregnancy of unknown location. “If the goal is to minimize unscheduled intervention, active management is best,” Barnhart said. “If the goal it to shorten time to resolution, uterine evacuation is best. If the goal is to avoid active management, we now have an objective estimate on how frequently that will succeed or fail.”

For active management, Barnhart recommends a 2-dose regiment of methotrexate instead of a single dose. “Also, uterine evacuation is the only intervention that will allow one to know if the failed gestation was a miscarriage or an ectopic pregnancy, while achieving the fastest resolution,” he said.

Women should be asked which treatment they prefer. “Is their goal to know where the pregnancy was located? To avoid intervention if possible? To resolve the situation as quickly as possible?” Barnhart said. “These desires and goals ought to impact the choice of therapy.”



Barnhart reports no relevant financial disclosures.


Barnhart KT, Hansen KR, Stephenson MD, et al. 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. JAMA. 2021 Aug 3;326(5):390-400. doi:10.1001/jama.2021.10767

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