Our first main finding is that that the major antecedents of early bacteremia are maternal and pregnancy characteristics, while neonatal characteristics are closely associated with late bacteremia. A second important finding is that multiple risk factors appear to be present in both presumed and definite bacteremia. Third, probably the most important postnatal correlates of late bacteremia are necrotizing enterocolitis and isolated intestinal perforation.
The major advantages of our analysis are the wealth of antenatal, perinatal, and postnatal information we had available, the large size of our data set, and the associated benefit of multivariable adjustment for confounders. With regard to bacteremia, however, one major limitation is that no detailed information was available about the species of bacteria isolated from cultures. Another drawback is that clinicians, as well as investigators, are sometimes unable to distinguish between pathogens and contaminants.
In a previous report based on our ELGAN sample, women with cervical insufficiency as the proximate cause of delivery were the most likely to have had vaginitis during pregnancy (11
). Maternal vaginitis was a risk factor for early bacteremia, presumed and definite, while cervical insufficiency was a risk factor for early definite bacteremia.
Fetal indication was also an antecedent of early definite bacteremia. In this sample, ELGANs delivered for fetal indications tended to have the lowest birthweights, but not necessarily the lowest gestational age. Thus, it seems as if, among ELGANs, fetal indications define a group of preterm newborns who are growth restricted and at high risk of neonatal bacteremia. ELGANs born to women with preeclampsia, the only maternal indication for preterm delivery in this sample, also tended to be growth restricted. Yet, neither preeclampsia, nor an increased number of syncytial knots, one of the main histologic characteristics of preeclampsia, was associated with bacteremia. On the other hand, infarcts, another histologic characteristic of preeclampsia were associated with increased risk of presumed late bacteremia, but not documented late bacteremia. Since many of our findings for presumed late bacteremia are concordant with our findings for definite late bacteremia, we place a good deal of credence on the concordance between presumed and definite late bacteremia. Therefore, our failure to find such concordance with regard to placenta histology prompts us to be cautious about inferences that can be drawn from the histologic findings.
Pure (single species) cultures of the placenta, but not multi-species cultures, identified children at increased risk for bacteremia. The polymicrobial cultures were more likely than pure cultures to contain lower virulence organisms. Thus, the virulence of placenta organisms, rather than their diversity, might be more important in identifying a heightened risk of early bacteremia.
Umbilical cord vasculitis was associated with a significantly increased risk for early definite bacteremia. A prominent histologic expression of the fetal inflammatory response (20
), umbilical vasculitis is often accompanied by microorganisms in the placenta (11
). Umbilical vasculitis is also slightly more common among growth restricted infants (70%) than among infants with a birthweight Z-score >-1 (58%) (20
). In light of these findings, umbilical vasculitis, recovery of organisms from the placenta, and growth restriction share information about the increased risk of early bacteremia.
By and large, the antecedents of late onset bacteremia are neonatal morbidities encountered in the NICU, such as extended duration of intubation, tracheal colonization, CSF infection, patent ductus arterious, pulmonary hemorrhage, and chronic lung disease.
NEC, an inflammatory bowel disease largely confined to the preterm population, was also prominently associated with documented late bacteremia. Others have also found that newborns with NEC are more likely than their peers to have bacteremia (2
). At least part of the association we observed between presumed bacteremia and NEC might be due to the fact that prescription of antibiotic is standard treatment for NEC and also part of our definition of presumed bacteremia. In addition, the increased risk of late definite bacteremia among infants with a patent ductus arteriosus might reflect the increased risk of NEC that has been associated with PDA (21
Characterized by a disruption of intestinal mucosal integrity, NEC is often accompanied by bacteria and other pro-inflammatory stimuli in the blood, including endotoxin, cytokines, chemokines and nitric acid (22
). This suggests that late bacteremia might be a consequence of NEC and related phenomena.
Compared to their peers, children who developed an isolated perforation were at twice the risk for early and late definite bacteremia. Unfortunately, we do not know which came first.
In light of the many parallels and links between late bacteremia and NEC, as well as between late bacteremia and isolated intestinal perforation, we suggest that these bowel disorders be considered in studies of late bacteremia. This is especially important until the contribution of each to the occurrence of the other is clarified.