Written by Joshua Belfer
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A systematic review and meta-analysis found that serious diagnoses after a brief resolved unexplained event (BRUE) are uncommon, with most diagnostic testing yielding little value.
A scary event, but usually not a serious diagnosis
BRUE are anxiety-provoking for families and clinicians alike, but the true risk of underlying disease and the value of extensive testing remain uncertain. This systematic review and meta-analysis evaluated infant outcomes, risk factors, and diagnostic yield after a BRUE to better define which patients may benefit from further evaluation.
Investigators analyzed 24 studies including 6603 infants with BRUE. The pooled prevalence of a serious underlying diagnosis was 6.0% (95%CI 4.6–7.9%), while 3-month mortality was extremely rare at 1 death per 1851 infants. The diagnostic yield of commonly performed tests was generally low; for example, a CBC had a pooled diagnostic yield of 1.6%, and electrolyte analyses had a yield of 0.4%. Panels targeting inborn errors of metabolism (n = 729), liver enzymes (n = 518), and blood gas (n = 737) did not identify any relevant underlying metabolic conditions. An electrocardiogram had a yield of 0.2%, and a chest radiograph had a yield of 0.4%.
Despite these reassuring findings, certain features were associated with higher risk, including a history of multiple events and prematurity, while being ≤60 days was not. As with many systematic reviews, heterogeneity among included studies and variability in how BRUE and related events were defined limit generalizability.
How will this change my practice?
Perhaps reflecting both parental anxiety and the diagnostic uncertainty clinicians face, there has been a surge of publications examining BRUE. The results of this meta-analysis add to this recent study and review, emphasizing that while scary, there is typically a low risk of underlying serious disease. When considering the evidence, it is helpful to know that the individual tests examined have such low diagnostic yield. The reality, though, is that parents will almost always be fearful when their child experiences a BRUE. That fear is what continues to make these presentations challenging for clinicians, although the growing evidence base can help guide discussions with families about the need—or lack thereof—for extensive testing.
Source
Infant Outcomes, Risk Factors, and Diagnostic Yield After a Brief Resolved Unexplained Event: A Systematic Review and Meta-Analysis. JAMA Pediatr. 2026 Mar 1;180(3):250-262. doi: 10.1001/jamapediatrics.2025.5858. PMID: 41587068; PMCID: PMC12836278.
View JournalFeed Critical Appraisal
Critical Appraisal
Study Identification
Background
Study Question
Study Design & Conduct
Prospective / Retrospective: Prospective
Multicenter: Not applicable
Unit of Allocation: Not applicable
Unit of Analysis: Infants
Randomization Method: Not applicable
Allocation Concealment: Not applicable
Blinding: Not applicable
Follow-up Duration: 3 months (for mortality and recurrence), 1 year (for serious underlying diagnosis)
Population
- Cohort studies, case-control studies, and clinical trials
- Infants younger than 12 months
- Meeting 2016 American Academy of Pediatrics diagnostic criteria for BRUE
- Addressed at least 1 of the review's 3 aims
- Studies not distinguishing BRUE from other events
- Studies relying solely on International Classification of Diseases codes without clinical verification
Number Enrolled: 6603
Number Analyzed: 6603
Key Baseline Characteristics
Sex: 51.8% female (3385 of 6529 infants)
Disease Severity: Not reported
Care Setting Distribution: Not applicable (systematic review of studies from various settings)
Exposures / Interventions
Description: Occurrence of a Brief Resolved Unexplained Event (BRUE) in infants and specific prognostic risk factors.
Definition / Dose: Meeting 2016 American Academy of Pediatrics diagnostic criteria for BRUE.
Timing: Not applicable
Classification Method: Based on AAP diagnostic criteria and clinical/demographic features.
Protocolized / Discretionary: Not applicable
Description: Absence of specific risk factors or different diagnostic tests.
Definition: Not applicable
Outcomes & Results
Primary Outcomes
Definition: Diagnoses potentially explaining the BRUE, likely to increase morbidity or mortality if diagnosis or treatment were delayed (e.g., seizures, child abuse), and identified within 1 year.
Time Point: Within 1 year of BRUE
Measurement Method: Pooled data from included studies using random-effects meta-analysis.
Results: 6.0% (95% CI, 4.6%-7.9%; high certainty)
Definition: Deaths during hospitalization or within 3 months.
Time Point: Within 3 months of BRUE
Measurement Method: Pooled data from included studies using Poisson-normal random-effects model.
Results: 1 death per 1851 infants (95% CI, 1 death per 597-5739 infants; moderate certainty)
Secondary Outcomes
Definition: Any repeated BRUE within 3 months, including during the same hospital visit or admission or leading to repeated presentation.
Time Point: Within 3 months
Measurement Method: Pooled data from included studies using random-effects meta-analysis.
Results: 13.6% (95% CI, 11.1%-16.7%; low certainty)
Definition: Association between specific clinical and demographic features and serious underlying diagnosis.
Time Point: Not applicable
Measurement Method: Pooled odds ratios converted to absolute risk differences (RDs) using random-effects model.
Results: Multiple events (RD, 3.7%; 95% CI, 1.7%-6.2%; high certainty); Prematurity (RD, 2.6%; 95% CI, 0.6%-5.2%; high certainty); Abnormal medical history (RD, 3.1%; 95% CI, 1.3%-5.5%; high certainty); Concerning family history (RD, 2.7%; 95% CI, 0.4%-5.9%; moderate certainty); Color change during event (RD, 1.7%; 95% CI, 0.3%-3.6%; high certainty); Age ≤60 days not associated (RD, -0.5%; 95% CI, -2.7% to 3.0%; high certainty).
Definition: Association between specific clinical and demographic features and event recurrence.
Time Point: Not applicable
Measurement Method: Pooled odds ratios converted to absolute risk differences (RDs) using random-effects model.
Results: Multiple events (RD, 11.1%; 95% CI, 4.2%-20.3%; high certainty); Age ≤60 days (RD, 4.7%; 95% CI, 2.4%-7.4%; high certainty); Prematurity (RD, 6.0%; 95% CI, 0.5%-12.9%; low certainty); Abnormal medical history (RD, 6.7%; 95% CI, 4.1%-9.5%; moderate certainty); Concerning family history (RD, 8.5%; 95% CI, 2.3%-16.1%; low certainty); Event duration >1 minute associated with decreased risk (RD, -3.4%; 95% CI, -5.3% to -1.2%; high certainty).
Definition: Proportion of tested patients who received a confirmed serious underlying diagnosis directly attributable to a specific test.
Time Point: Not applicable
Measurement Method: Pooled data from included studies using random-effects meta-analysis on natural-log scale, reported as yield and Number Needed to Test (NNT).
Results: Metabolic panels: 0% yield (NNT=852); ECG: 0.2% yield (NNT=623); Chest radiographs: 0.4% yield (NNT=256); CBC: 1.6% yield (NNT=62); Electrolytes: 0.4% yield (NNT=264); Kidney function tests: 0.2% yield (NNT=423); Liver enzymes: 0.3% yield (NNT=326); Blood gas: 1.2% yield (NNT=82); Respiratory pathogen panels: 3.0% yield (NNT=34); Pertussis testing: 4.3% yield (NNT=23); Echocardiogram: 0.7% yield (NNT=143); EEG: 5.5% yield (NNT=18).
Risk of Bias
Risk of Bias - AMSTAR 2
- Was an a priori design provided? (Low): The systematic review was prospectively registered with PROSPERO (CRD42024567336), and a detailed protocol was provided in the eMethods in Supplement 1.
- Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report of the review provide accessible documentation of the protocol? (Low): The PROSPERO registration number is provided, indicating that the methods were established prior to the review's conduct and documented.
- Did the review authors explain their selection of the study designs for inclusion in the review? (Low): The authors explicitly stated inclusion of 'Cohort studies, case-control studies, and clinical trials' that met specific criteria.
- Was a comprehensive literature search strategy used? (Low): The search strategy included PubMed, Embase, Cochrane, and gray literature sources from January 2016 through July 2025, indicating a comprehensive approach.
- Was study selection performed in duplicate? (Low): Two independent reviewers screened abstracts and full-text articles for eligibility.
- Was data extraction performed in duplicate? (Low): Data were extracted by 1 reviewer and verified by a second, with discrepancies resolved by consensus or a third reviewer.
- Did the review provide a list of excluded studies and justify the exclusions? (High): The review does not explicitly provide a list of excluded studies or detailed justifications for their exclusion in the main text or supplementary materials, which is a critical flaw for AMSTAR 2.
- Was the risk of bias of individual studies assessed? (Low): Two reviewers independently assessed the risk of bias using the Joanna Briggs Institute checklist for prevalence and prognostic studies and the Quality Assessment of Diagnostic Accuracy Studies 2 tool.
- Was the risk of bias of individual studies used in interpreting the results of the review? (Low): Sensitivity analyses were conducted, restricted to studies rated at low risk of bias, indicating that risk of bias was considered in the interpretation of results.
- Was the appropriateness of the meta-analytic methods used evaluated? (Low): Random-effects meta-analyses were used to pool data, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess certainty in evidence.
- Was the potential impact of publication bias on the results discussed? (Low): Publication bias was evaluated using funnel plots and Egger regression tests.
- Was the extent and sources of heterogeneity reported and discussed? (Low): Heterogeneity was assessed visually with forest plots, and the discussion section addresses the implications of heterogeneity.
- Did the review authors report on the sources of funding for the studies included in the review? (High): The review reports funding for the systematic review itself but does not report on the sources of funding for the individual studies included in the review, which is a critical flaw for AMSTAR 2.
- Did the review authors provide a satisfactory explanation for any unexplained heterogeneity? (Low): The discussion section acknowledges and attempts to explain sources of heterogeneity, such as the varied nature of underlying diagnoses and diagnostic test uptake across studies.
- Did the review authors report any conflicts of interest? (Low): A conflict of interest disclosure statement is present, noting one author reported grants outside the submitted work and no other disclosures.
Transparency
COI Statement Present: TRUE
