This is the first calculator and scoring system to guide early diagnosis of EONS in asymptomatic term infants by using a combination of maternal factors and umbilical cord blood analysis. Besides the being the highest proportion of infants in the clinical settings, the term infant population was chosen in order to avoid the confounding effect of immature adaptive immunity in preterm infants.13 The incidence of proven EONS in this study was 18.5% of infants born to mother with PROM, while the global EONS incidence is 2.2 – 9.8 per 1,000 live birth.14
There have been few studies of EONS in asymptomatic infants born after PROM. According to CDC 2002 guidelines12, asymptomatic term infants born after PROM should be observed in the first 48 hours to detect any clinical sign of EONS. The decision to start antibiotics should then be supported by septic screening results.12 Yet, no consensus was agreed for infants born to mothers with unknown GBS status. In addition, the most common etiology of EONS cases which occur in developing countries are Gram negatives such as E. coli or Klebsiella sp. rather than GBS which would be evident on both the sub-cultured blood and MacConkey agar plates..3, 15 The establishment of this calculator and scoring system would give additional valuable evidence for clinicians to consider when to start antibiotics in well-appearing newborns.
Vaginal birth and foul-smelling amniotic fluid are well known independent risk factors for EONS.15 Consistent with previous studies, elevated maternal and cord blood WBC is also an accurate laboratory parameter of EONS in this study.16 However, in contradiction, our study found that cord neutrophil count was not a predictor of EONS. This may be because the neutrophil count can fall significantly in severe sepsis so it is hard to interpret and therefore has low diagnostic prediction.17 We do not consider the history of intrapartum antibiotic administration as a protective factor since it is done routinely in less than 25% of low and middle income countries as there is no GBS screening performed.18
Recent studies showed that the use of umbilical cord blood examination is a promising diagnostic tools in EONS diagnosis. Cord blood culture has comparable organism detection to peripheral venous blood culture.19 The sensitivity of cord blood culture is 80-100% and specificity is 91-94%, while the positive and negative predictive value are 33-72% and 94-100%, respectively.19, 20 It is less invasive and painful, easier to preform, and a larger volume of blood is available compared with peripheal blood cultures. A good technique will reduce the risk of contamination.21
We found that umbilical cord blood infection markers played an important role in predicitng EONS. The median of hs-CRP in this study was lower than previous studies.22 but still is a significant predictor as it accurately reflects an inflammatory process in the placenta.23 This study also investigated IL-6 as a specific independent cytokine that arises in the early choriovasculitis and funisitis stages of chorioamnionitis. We found that IL-6 was a strong predictor of EONS which is consistent with the result of a previous systematic review.24 It identified 12 out of the 31 patients in the IndEONS 1 model. Since measuring IL-6 requires an advanced laboratory we excluded IL-6 in our second model (IndEONS 2) so that clinicians in resource limitted neonatal care settings could still use this scoring system, albeit the simplified one.
We provide two models for clinicians with different resource settings. Both models have good discrimination and calibration performance and have been validated internally and externally. In advanced neonatal care, IndEONS 1 is a good prediction tools to estimate the possibility of EONS in asymptomatic term infants with PROM. This would optimize the role of umbilical cord blood examination, mainly hs-CRP and IL-6, in clinical practice. Umbilical cord blood examination has now become a routine practice in developing countries. IndEONS 2 score, with a quite simillar performance, is provided to help clinicians in resource limitted settings. With two cut-off values, we expect no potentially fatal cases would be missed. The performance between calculator and scoring system is comparable. While the IndEONS score is practically easier to use, the IndEONS calculator provides more precision.
Strict criteria were made in our model in order to enforce antibiotic stewardship. The first cut-off (optimal cut-off), with the highest diagnostic performance based on AUC, would only exclude samples with the lowest possibility of prediciting EONS. Infants with this criteria could immediately be discharged from the newborn nursery to have rooming-in with their mothers. On the other hand, a second cut-off (ideal cut-off), would include those infants most likely to have EONS to receive antibiotics and have rigorous vital sign monitoring. These tight criteria are not expected to overestimate a diagnosis of EONS which has then been proven in internal and external validity analysis.
The utilization of these scoring systems among infants born without prior cord blood collection is the main limitation. Another possible limitation is the routine practice of cord blood examination. Physicians should be encouraged to routinely do this examination since it has proven to be a more reliable predictor of EONS than peripheral venous blood examination.
We recommend the IndEONS calculator as it would present the probability of EONS and risk stratification after the physician had input all the data. Meanwhile, physicians could directly interpret the final score if using the IndEONS score. We recommend that low risk infants should have essential newborn care and rooming-in with the mother so that they do not experience a delay of early breastfeeding. Medium risk infants should have close observation in a neonatal nursery without antibiotic administration, but we suggest a blood culture. Antibiotics could be started if any clinical deterioration occurs or if the blood culture becomes positive. High risk infants should have immediate empirical antibiotic administration. We recommend a complete septic workup before antibiotic administration and rigorous monitoring of vital signs. Transfer to a higher care and consultation with a neonatologist should also be considered. We suggest another research group conduct a prospective multicenter study in order to test and external validity of our models. A comparison study to CDC guidelines or the Kaiser calculator should also be done in the future.