Neonatal bilirubin trajectory phenotypes and composite adverse outcomes: a two-database latent-class analysis (MIMIC-III and PIC)
Abstract
Total serum bilirubin (TSB) is measured routinely in neonates, but whether its trajectory over the first postnatal week adds prognostic value beyond a single measurement is unclear. In this preregistered two-database retrospective cohort study, we fitted latent-class trajectory models separately within each database (primary analysis) and on the pooled population (secondary analysis), including neonates admitted at < 28 days of age with at least three TSB measurements on postnatal days 0–7 (MIMIC-III, n = 2,951; PIC, n = 1,817). Site-specific models identified four classes in MIMIC-III and two in PIC; agreement with pooled classes was low (adjusted Rand index 0.23 and 0.25). High-risk classes were associated with the composite outcome of in-hospital death, necrotizing enterocolitis, or late-onset sepsis in both databases (MIMIC-III: OR 5.66 [95% CI 3.72–8.61] and 3.16 [2.10–4.77]; PIC: OR 2.13 [1.40–3.24]). Outcome drivers differed: MIMIC-III associations reflected necrotizing enterocolitis and late-onset sepsis, whereas the PIC association reflected death. In MIMIC-III, birth-weight adjustment substantially attenuated the associations (Class 4 3.05→1.16; Class 1 5.47→1.85), whereas in PIC, where birth weight was unavailable, admission-weight adjustment strengthened the Class 1 association (OR 2.45→3.81). The trajectory model did not exceed the peak TSB value in MIMIC-III (AUC 0.825 vs. 0.827) and performed poorly in PIC (AUC 0.582; corrected calibration slope 0.719), indicating failed external validation. The hour-specific Bhutani nomogram comparison was applied outside its validated ≥ 35-week population. Bilirubin trajectories largely mark underlying immaturity and illness severity rather than a bilirubin-specific effect; these hypothesis-generating findings require prospective validation, particularly in infants born at ≥ 35 weeks.
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BibTeX
@article{lu2026neonatal,
title = {{Neonatal bilirubin trajectory phenotypes and composite adverse outcomes: a two-database latent-class analysis (MIMIC-III and PIC)}},
author = {Jingchuan Lu and Meiding Wang and Haiyi Xu and Shuangyan Zhu},
journal = {Scientific Reports},
year = {2026},
month = oct,
doi = {10.1038/s41598-026-76725-0},
url = {https://www.nature.com/articles/s41598-026-76725-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Neonatal bilirubin trajectory phenotypes and composite adverse outcomes: a two-database latent-class analysis (MIMIC-III and PIC)
AU - Jingchuan Lu
AU - Meiding Wang
AU - Haiyi Xu
AU - Shuangyan Zhu
PY - 2026
DA - 2026/10/25
JO - Scientific Reports
DO - 10.1038/s41598-026-76725-0
UR - https://www.nature.com/articles/s41598-026-76725-0
AB - Total serum bilirubin (TSB) is measured routinely in neonates, but whether its trajectory over the first postnatal week adds prognostic value beyond a single measurement is unclear. In this preregistered two-database retrospective cohort study, we fitted latent-class trajectory models separately within each database (primary analysis) and on the pooled population (secondary analysis), including neonates admitted at < 28 days of age with at least three TSB measurements on postnatal days 0–7 (MIMIC-III, n = 2,951; PIC, n = 1,817). Site-specific models identified four classes in MIMIC-III and two in PIC; agreement with pooled classes was low (adjusted Rand index 0.23 and 0.25). High-risk classes were associated with the composite outcome of in-hospital death, necrotizing enterocolitis, or late-onset sepsis in both databases (MIMIC-III: OR 5.66 [95% CI 3.72–8.61] and 3.16 [2.10–4.77]; PIC: OR 2.13 [1.40–3.24]). Outcome drivers differed: MIMIC-III associations reflected necrotizing enterocolitis and late-onset sepsis, whereas the PIC association reflected death. In MIMIC-III, birth-weight adjustment substantially attenuated the associations (Class 4 3.05→1.16; Class 1 5.47→1.85), whereas in PIC, where birth weight was unavailable, admission-weight adjustment strengthened the Class 1 association (OR 2.45→3.81). The trajectory model did not exceed the peak TSB value in MIMIC-III (AUC 0.825 vs. 0.827) and performed poorly in PIC (AUC 0.582; corrected calibration slope 0.719), indicating failed external validation. The hour-specific Bhutani nomogram comparison was applied outside its validated ≥ 35-week population. Bilirubin trajectories largely mark underlying immaturity and illness severity rather than a bilirubin-specific effect; these hypothesis-generating findings require prospective validation, particularly in infants born at ≥ 35 weeks.
SN - 2045-2322
ER -