Infant Outcomes, Risk Factors, and Diagnostic Yield After a Brief Resolved Unexplained Event: A Systematic Review and...

Since the introduction of the brief resolved unexplained event (BRUE) terminology, underpowered and conflicting research has led to persistent clinical uncertainty regarding the frequency of adverse outcomes, prognostic risk factors, and the diagnostic testing utility, contributing to wide practice variations.

To (1) establish the frequency of serious underlying diagnoses and 3-month mortality after a BRUE in infants; (2) identify prognostic risk factors; and (3) quantify the diagnostic yield of common investigations.

PubMed, Embase, Cochrane, and gray literature sources from January 2016 through July 2025.

Cohort studies, case-control studies, and clinical trials of infants meeting 2016 American Academy of Pediatrics diagnostic criteria for BRUE.

Data were extracted by 1 reviewer and verified by a second. Random-effects meta-analyses were used to pool data. Grading of Recommendations Assessment, Development, and Evaluation was used to assess certainty in evidence.

The primary outcomes were pooled prevalence of serious underlying diagnosis and 3-month cumulative mortality. Secondary outcomes included prognostic risk factors and diagnostic yield of specific tests.

From 664 citations, 24 studies (6603 infants) were included. The pooled prevalence of a serious underlying diagnosis was 6.0% (95% CI, 4.6%-7.9%; high certainty), and cumulative 3-month mortality was 1 death per 1851 infants (95% CI, 1 death per 597-5739 infants; moderate certainty). A history of multiple events (risk difference [RD], 3.7%; 95% CI, 1.7%-6.2%; high certainty) and prematurity (RD, 2.6%; 95% CI, 0.6%-5.2%; high certainty) were associated with increased risk of serious underlying diagnosis, while being aged 60 days or younger was not (RD, -0.5%; 95% CI, -2.7% to 3.0%; high certainty). Routine investigations were exceedingly low yield: metabolic panels had 0% yield (95% CI, 0%-0.5%; number needed to test [NNT] = 852; moderate certainty), electrocardiograms, 0.2% yield (95% CI, 0.0%-0.9%; NNT = 623; high certainty); and chest radiographs, 0.4% yield (95% CI, 0.2%-1.0%; NNT = 256; high certainty).

This systematic review and meta-analysis found that infant mortality after a BRUE was exceedingly rare, and a serious underlying diagnosis was present in a small but important group of infants; most routine diagnostic tests added little value and not infrequently had false-positive results. Clinical focus should therefore shift from blanket investigations to a targeted, risk-informed approach grounded in a few reliable higher-risk features. These findings provide a robust evidence basis for guideline revision.