Physiology and diagnostic potential of beta-hydroxybutyrate in neonatal glycemia—a prospective cohort study

CONTEXT: Neonatal hypoglycemia is the most common metabolic disorder in newborns and may lead to adverse neurodevelopment. The role of alternative substrates such as beta-hydroxybutyrate (BOHB) during neonatal hypoglycemia is poorly understood. OBJECTIVE: To examine BOHB in neonates with and without hypoglycemia risk factors across different feeding regimens, and to estimate the potential to guide discontinuation of blood glucose (BG) screening. DESIGN: Prospective cohort study (05/2020-09/2022). Standardized BG and BOHB measurements. SETTING: Single-center tertiary hospital. PARTICIPANTS: 895 neonates with (n = 752) and without (n = 143, controls) hypoglycemia risk factors. INTERVENTION: None. MAIN OUTCOMES MEASURES: Comparison of BG and combined BG + BOHB values and percentiles across different risk factors and feeding regimens. Ketonemia was defined as BOHB >0.5 mmol/L. RESULTS: Of 516 neonates with BOHB measurements at ≥24 hours of age, 107 (20.7%) had ketonemia. Ketonemia was more frequent in controls than in at-risk neonates (28.2% (33/117) vs. 18.6% (74/399), P = .023), and in neonates receiving exclusively breastmilk than in exclusively formula-fed neonates (34% (16/47) vs. 3% (1/39), P < .001). BG and BG + BOHB percentile trajectories diverged more over time in controls, large-for-gestational-age neonates, and infants of diabetic mothers than in small-for-gestational and/or fetal-growth-restricted, preterm, or perinatally stressed neonates. CONCLUSIONS: Neonates with hypoglycemia risk factors and those receiving formula developed less ketonemia. The low overall incidence of ketonemia and its dependence on feeding regimen - particularly among at-risk neonates - limit the utility of BOHB, alone or in combination with BG, as a broadly applicable marker for determining when hypoglycemia screening can be safely discontinued.