Gender and Neonatal Inflammation in Preterm Outcome

Abstract

Introduction: Preterm neonates are at high risk of sepsis and sepsis-related complications. Despite the prominence of sepsis in neonatal practice, there is no consensus definition and the role of organ dysfunction in screening for neonatal sepsis remains unknown. Male preterm neonates are at especially high risk of sepsis compared to females. A combination of genetic, hormonal and immunological factors are thought to underlie this male disadvantage. There is ample evidence suggesting clinically important differences in innate immune response between the sexes in older children and adults though similar studies in preterm neonates are lacking. Methods: Preterm neonates <1500 grams and healthy term controls were enrolled, and immune studies were compared between the sexes. TLR2 and CD11b expression were quantified on peripheral blood neutrophils and monocytes using flow cytometry, ELISA was used to quantify pro- and anti-inflammatory cytokines and the effect of female sex hormones on these aspects of immune response was examined. miRNA profiles were examined and expression of X-linked genes with immune function along with genes involved in the inflammasome were quantified with PCR. A literature review was undertaken to examine the current approaches to defining neonatal sepsis and clinical measurements on patients enrolled in this study were used to examine the value of organ dysfunction in preterm neonates both during and outside of sepsis. Results: Term and preterm female neonates displayed more robust cytokine, CD11b and TLR2 responses following immune stimulation compared to males. Estrogen and progesterone showed promise as immunomodulators with significant effects on the expression of many cytokines. Males had higher levels of organ dysfunction and had poorer clinical outcomes compared to females. Literature review highlighted the weakness of current approaches to defining neonatal sepsis and our complementary clinical study showed that organ dysfunction has prognostic value in screening for neonatal sepsis. Conclusion: Male neonates have impaired immune responses and have greater levels of organ dysfunction compared to females of equivalent gestation. Female sex hormones have potentially important effects on innate immune response and suggest that antenatal steroid and antenatal progesterone may provide opportunities for immunomodulation.