Objective To compare management recommendations of the National Institute for Health and Care Excellence (NICE) guidelines with the Kaiser Permanente sepsis risk calculator (SRC) for risk of early onset neonatal sepsis (EONS).

Design Multicentre prospective observational projection study.

Setting Eight maternity hospitals in Wales, UK.

Patients All live births ≥34 weeks gestation over a 3-month period (February–April 2018).

Methods Demographics, maternal and infant risk factors, infant’s clinical status, antibiotic usage and blood culture results from first 72 hours of birth were collected. Infants were managed using NICE recommendations and decisions compared with that projected by SRC.

Main outcome measure Proportion of infants recommended for antibiotics on either tool.

Results Of 4992 eligible infants, complete data were available for 3593 (71.9%). Of these, 576 (16%) were started on antibiotics as per NICE recommendations compared with 156 (4.3%) projected by the SRC, a relative reduction of 74%. Of the 426 infants avoiding antibiotics, SRC assigned 314 (54.6%) to normal care only. There were seven positive blood cultures—three infants were recommended antibiotics by both, three were not identified in the asymptomatic stage by either; one was a contaminant. No EONS-related readmission was reported.

Conclusion The judicious adoption of SRC in UK clinical practice for screening and management of EONS could potentially reduce interventions and antibiotic usage in three out of four term or near-term infants and promote earlier discharge from hospital in >50%. We did not identify any EONS case missed by SRC when compared with NICE. These results have significant implications for healthcare resources.