In this large prospective cohort of extremely preterm infants, infants who developed medical NEC were not at statistically significantly increased risk of any of the developmental disorders we assessed or of microcephaly. On the other hand, children who had surgical NEC without accompanying late bacteremia were at an increased risk of a PDI <70. Children who developed surgical NEC and had culture-proven late bacteremia were at prominently increased risk of diparetic cerebral palsy and microcephaly. Children who had late bacteremia unaccompanied by surgical NEC were at increased risk of an MDI <70.
Despite the large size of our sample, only 59 children had medical NEC and 42 had surgical NEC. Consequently, the confidence intervals for the odds ratios are wide. In addition, the precise timing of the NEC diagnosis relative to the late bacteremia diagnosis is unknown. Strengths of our study include the large multi-center cohort, prospective collection of data about NEC and bacteremia, and outcome assessments by examiners who were unaware of neonatal exposures.
Our findings lead to several inferences. In one set, NEC pathophysiology is not in the causal chain. Rather, NEC conveys information about other risk factors. For example, NEC (as an indicator of bowel immaturity) might provide information about brain immaturity/vulnerability beyond that identified by gestational age, or it might be a marker for overall severity of illness during the NICU stay, or it might convey information about exposure to associated risk factors such as anesthesia during abdominal surgery.19
Conversely, NEC might be associated with the absence of factors that are associated with improved neurodevelopmental outcome, such as human milk.20, 21
In a second set of inferences, NEC pathophysiology is in the causal chain. This set is especially plausible because our findings support the view that NEC can be classified by severity with no NEC as the referent, and increasing with medical NEC, surgical NEC without accompanying late bacteremia, and culminating with surgical NEC accompanied by late bacteremia.
The more severe the NEC, the greater the likelihood of intestinal wall inflammation22
and the greater the likelihood of intestinal barrier dysfunction.23, 24
Intestinal barrier dysfunction manifests as the translocation of inflammatory mediators into the systemic circulation. For example, platelet activating factor plasma levels are significantly higher in NEC patients than in controls and correlate with NEC severity.25
Likewise, plasma levels of interleukin-6, a monocyte-derived cytokine, correlated with disease severity in infants with NEC26
; and, in another study, were highest among infants with severe NEC and in infants who had both sepsis and NEC, and less elevated among infants with either sepsis or NEC alone.27
As one of the largest defense barriers of the infant, the neonatal gut regulates immune function and the inflammatory response. Disruption or injury to this barrier, as can occur in severe NEC, leads to an increased risk for bacterial translocation, leading to bacteremia, and increased production of pro-inflammatory mediators, which can initiate as well as propagate a systemic inflammatory response.28
Unmitigated systemic inflammation contributes to neuronal injury and to the pathogenesis of other co-morbidities such as retinopathy of prematurity29
and chronic lung disease.30
The observation of adverse neurodevelopment with increased severity of disease (surgical versus medical NEC) or with the prolonged presence of diseased bowel (management with a penrose drain)31
supports the hypothesis that the injured gut contributes to a systemic inflammatory response, which, in turn, can affect the developing brain.
In previously published studies of premature infants, NEC predicted poor neurodevelopmental outcomes1, 3, 5-9, 11, 32
as well as cystic periventricular leukomalacia on head ultrasound1
and white matter injury on magnetic resonance imaging.33
Our findings may support some of these earlier studies. Furthermore, the relationship between NEC and poor neurodevelopmental outcomes is strongest among the more ill infants, as demonstrated by an advanced stage of NEC or need for surgical intervention.1, 7, 9, 32
Our findings are also consistent with these previous reports that children with NEC who required surgery were at greater risk for adverse neurodevelopment than infants with NEC who did not require surgery.
In a large study of extremely low birth weight infants, those who were infected were more likely to have cerebral palsy, low MDI and PDI scores, and microcephaly than children who did not have a neonatal infection.10
In our large sample of ELGANs, we found that in the absence of NEC, late bacteremia was associated with an increased risk of low MDI scores. Potential explanations for the outcome differences between these two studies are that the former study was a birth weight defined cohort of < 1000 grams, and our study was defined by a gestational age of < 28 weeks’ gestation; and, the former study included the diagnoses of early-onset sepsis, suspected sepsis (culture negative) and NEC in their infected groups.
A unique contribution of our study to the NEC-sepsis literature is our distinction between early and late-onset sepsis, proven and clinically suspected sepsis, and NEC with or without late onset bacteremia. Each of these designations helped us evaluate the influence of NEC alone and NEC plus late bacteremia on later neurodevelopment.