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Atypical metabolic markers from routine newborn screening were associated with sudden infant death syndrome (SIDS), a case-control study suggested.

Fourteen metabolic markers significantly correlated with the 354 cases of SIDS among more than 2.2 million eligible infants, as researchers led by Scott Oltman, MS, of the University of California San Francisco, reported in .

A final multivariable model with the best performance in identifying infants with SIDS incorporated eight metabolic markers and known risk factors with an area under the curve (AUC) of 0.75 (95% CI 0.72-0.79) in a training set and 0.70 (95% CI 0.65-0.76) in a test set.

Furthermore, among 32 infants in the test set with model-predicted probability greater than 0.5, 62.5% had SIDS, they added. These infants had 14.4 times the odds (95% CI 6.0-34.5) of SIDS compared with those with a model-predicted probability less than 0.1.

"Although there are numerous established risk factors for SIDS, including smoking and alcohol use during pregnancy, structural racism, low socioeconomic status, prematurity, male infant sex, gestational hypertension, inadequate prenatal care, prone sleeping position, and air pollution, and pathophysiological factors, including genetics, serotonin, and epilepsy, complete identification of etiologic pathways remains elusive," Oltman and colleagues wrote.

The study findings "suggest that metabolic profiles at birth may have utility for individualized, targeted counseling aimed at identifying infants with an increased vulnerability to SIDS," they wrote. "Further, these patterns point to novel inroads for scientists and clinicians to further investigate mechanisms of aberrant metabolites in SIDS in order to develop targeted therapeutics."

The 14 metabolic markers found to be associated with SIDS in a univariate analysis included one hormone (17-hydroxyprogesterone), five amino acids (alanine, proline, tyrosine, methionine, and valine), and eight acylcarnitines (free carnitine, acetyl-L-carnitine, malonyl carnitine [C-3DC], glutarylcarnitine [C-5DC], lauroyl-L-carnitine, dodecenoylcarnitine [C-12:1], 3-hydroxytetradecanoylcarnitine [C-14OH], and linoleoylcarnitine [C-18:2]).

The final multivariable model consisted of total parenteral nutrition administration, age at blood spot collection, infant sex, adequacy of prenatal care, race and ethnicity, and maternal age, as well as the metabolic markers 17-hydroxyprogesterone, alanine, glycine, free carnitine, propionyl-L-carnitine (C-3), C-5DC, C-12:1, and C-14OH.

Oltman and colleagues reported that the link with acylcarnitines was the "most noteworthy metabolic pattern" in their study, with elevated levels of free carnitine and C-14OH generally linked to a higher risk of SIDS, but increased levels of C-3, C-5DC, and C-12:1 consistently associated with lower risk.

They noted that "aberrant levels of acylcarnitines may indicate systemic dysfunction of fatty acid oxidation," which corroborates with previous studies finding associations between enzymes of fatty acid oxidation and SIDS.

Oltman and colleagues used data from the California Office of Statewide Health Planning and Development and the state Department of Public Health to complete their study. The study population consisted of infants born between 2005 and 2011 who had full metabolic data collected as part of routine newborn screening.

SIDS cases were matched to controls at a one-to-four ratio by gestational age and birth weight z-score. And the matched sample was randomly divided into two-thirds for training and one-third for testing.

The infants with SIDS designated as cause of death had a mean gestational age of 38.3 weeks, and slightly more than 62% of them were male. The largest proportion were Hispanic (41.2%), followed by non-Hispanic white (29.7%), while another 9.6% were Black, 9.3% were Asian, and 10.2% had other race or ethnicity.

Limitations included the retrospective nature of the data as well as inconsistency in SIDS criteria, potentially leading to some deaths being misclassified, Oltman and colleagues noted.

Validation of the model in other clinical and population-based samples is crucial, they added, "preferably in a prospective setting, to confirm whether these metabolic patterns are reliable indicators of SIDS risk."

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