Active management bests expectant to achieve successful resolution in pregnancy of unknown location: JAMA

Uterine evacuation can confirm an intrauterine pregnancy loss (miscarriage) by the presence of chorionic villi on pathology. If the serum hCG concentration does not decline after uterine evacuation, the pregnancy is presumed to be extrauterine and can be treated medically with methotrexate (a competitive inhibitor of dihydrofolate reductase). Medical management of ectopic pregnancy with methotrexate is common and it has also been advocated to use methotrexate empirically to treat a woman with a persisting pregnancy of unknown location.

A study was conducted by Kurt T. Barnhart and team published in JAMA network. The goals of the pragmatic randomized clinical trial were to determine (1) if active management of women with a persisting pregnancy of unknown location is more effective than expectant management, and (2) if empirical treatment with methotrexate is noninferior to uterine evacuation followed by use of methotrexate (if needed) with regard to achieving successful pregnancy resolution.

This was a multicenter randomized clinical trial that 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).

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).

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%.

• Among 255 patients who were randomized (median age, 31 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%).

In this randomized clinical trial, active management was more effective than expectant management in achieving resolution of a persistent pregnancy of unknown location without a change in initiated management strategy.

It is possible the use of the 2-dose protocol and the use of uterine evacuation contributed to higher success of active management in this trial. In this study a total of 56% of women achieved uneventful successful resolution with expectant management.

Active management with empirical administration of methotrexate was noninferior to a dilation and evacuation followed by methotrexate as needed. A large decrease in hCG levels after uterine evacuation is more consistent with failed intrauterine pregnancy than ectopic pregnancy. A threshold that demarcates elimination of surveillance of hCG to distinguish the 2 has not been defined.

In this study, methotrexate was administered 24 hours after uterine evacuation only if hCG concentration failed to decline less than 15% to maximize resolution without further treatment. This strategy resulted in shorter time to resolution than empirical methotrexate, likely because 44% (27 of 62) of women who received uterine evacuation needed no further treatment. Removal of trophoblast cells from a nonviable intrauterine pregnancy will result in a more rapid clearance of hCG because any residual production has been eliminated.

In this study, a majority of women found the treatment they received satisfactory and acceptable. Distribution of serious events was not unexpectedly different across groups.

The authors concluded, "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."

Source: JAMA. 2021;326(5):390-400. doi:10.1001/jama.2021.10767