OBJECTIVESpontaneous labor at term involves the activation of placental corticotropin-releasing hormone and the fetal adrenal axis, but the basis for extreme preterm labor is unknown. Our objective was to determine whether placental corticotropin-releasing hormone is activated in extreme preterm labor.STUDY DESIGNOne thousand five hundred six mothers delivering at less than 28 weeks' gestation were enrolled. Each mother/infant pair was assigned to the category that described the primary reason for hospitalization. Observers who had no knowledge of patient categorization assessed placenta microbiology, histology, and corticotropin-releasing hormone expression. These were correlated with the primary reason for hospitalization.RESULTSAmong infants delivered at less than 28 weeks' gestation, spontaneous (vs induced) delivery was associated with less placental corticotropin-releasing hormone expression and more frequent signs of placental inflammation and infection.CONCLUSIONInflammation and infection, rather than premature activation of the fetal adrenal axis, should be the major focus of research to prevent extremely preterm human birth.