A signature of fetal systemic inflammatory response in the pattern of heart rate variability measures matrix: A prospective study in fetal sheep model of lipopolysaccharide (LPS)‐induced sepsis

Fetal cholinergic anti‐inflammatory pathway (CAP) provides negative feedback on systemic inflammation. This is reflected in subtle alterations of fetal heart rate (FHR) variability (fHRV). We hypothesized that distinct patterns of fHRV correlation to pro‐inflammatory cytokines will reflect CAP's spontaneous versus inflammatory response states. We induced variable degrees of inflammatory response with LPS in chronically instrumented near‐term fetal sheep (n=8). CAP activity was quantified by 99 fHRV measures using CIMVA (continuous individualized multivariate variability analysis). We correlated the time‐matched fHRV and TNF‐α, IL‐1β and IL‐6. IL‐6, but not TNF‐α and IL‐1β, peaked at 3 hours. At baseline, a distinct set of seven fHRV measures from invariant, geometric and statistical domains correlated to cytokines. During fetal inflammatory response state, another subset of thirteen fHRV measures from invariant, geometric, statistical and energetic domains correlated to these cytokines. Distinctive subsets of fHRV measures can be identified that correlate with levels of inflammation. This opens a new way to study fetal inflammatory response as a function of neuroimmunological behaviour reflected in patterns of fHRV.