Maternal fever during labor and the risk of neonatal encephalopathy: duration and magnitude of hyperthermia

Maternal fever occurs in up to 10% of laboring individuals. It is associated with adverse maternal and neonatal outcomes such as low Apgar scores, respiratory distress, sepsis, meconium aspiration syndrome, and death. Few studies have investigated the dose-response relationship between the duration and magnitude of maternal hyperthermia and hypoxic-ischemic encephalopathy (HIE). To examine if the height of maximal maternal temperature and the duration from fever onset to delivery modify the risk of HIE. Population-based cohort study of non-anomalous singleton neonates born ≥ 35 weeks at 15 Kaiser Permanente Northern California hospitals (2012 - 2019). Births by elective cesarean section were excluded. Maternal fever was defined as at least one temperature ≥38°C before delivery. Maximal maternal temperature and timing of the first maternal fever were extracted from electronic medical records. Maximal maternal temperature was further classified as a five-level ordinal exposure: <37.5°C, 37.5-37.9°C, 38-38.4°C, 38.5-38.9°C, and ≥39°C. Duration of fever was defined as the duration from fever onset to delivery. HIE was defined as the presence of neonatal encephalopathy and perinatal acidosis (cord pH<7 or base deficit ≥10 within 2 hours after birth). Secondary outcomes included therapeutic hypothermia, neonatal seizures, acidosis, 5-min Apgar score<7, early onset sepsis, and neonatal intensive care unit admission. We used regression modeling, clustered by hospital sites, to evaluate the associations between maximal maternal temperature and duration of fever and neonatal outcomes, adjusting for duration between hospital admission and delivery, and duration of membrane rupture as proxies for labor duration. Among 248,594 laboring mothers, 25,760 (10.4%) had a fever during labor, and 487 (0.2%) delivered an infant with HIE. The presence of maternal fever was associated with a nearly fourfold increased risk of HIE compared to no fever (RR 3.92 [95% CI 3.24-4.75]). Even mild temperature elevations were associated with an increased risk of HIE; compared to mothers with a maximal temperature <37.5°C, the risk of HIE was higher among mothers with a temperature of 37.5°C to <38°C (RR 1.70 [95% CI 1.31-2.19]), 38°C to <38.5°C (RR 3.43 [95% CI 2.66-4.43]), 38.5°C to <39°C (RR 4.71 [95% CI 3.47-4.67] and ≥39°C (RR 8.47 [95% CI 5.92-12.1]). After adjusting for the duration of labor, the association between increasing maternal temperature and the risk of HIE remained significant. Similarly, the incidence of HIE increased with increasing duration from fever onset to delivery, even after adjusting for duration of labor. The higher the maternal temperature and the longer the duration from fever onset to delivery, the greater the risk of developing HIE, even when adjusting for the duration of labor. Novel strategies to predict and prevent HIE during labor and delivery should incorporate information regarding the height and duration of maternal fever during labor.