The Need to Address Sex as a Biological Variable in Neonatal Clinical Studies

Abstract

Male sex has been identified as a risk factor associated with mortality in preterm neonates [ 1 Brothwood M. Wolke D. Gamsu H. Benson J. Cooper D. Prognosis of the very low birthweight baby in relation to gender. Arch Dis Child. 1986; 61: 559-564 Crossref PubMed Scopus (117) Google Scholar , 2 Stevenson D.K. Verter J. Fanaroff A.A. Oh W. Ehrenkranz R.A. Shankaran S. et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage. Arch Dis Child Fetal Neonatal. 2000; 83: F182-F185 Crossref PubMed Google Scholar , 3 Ito M. Tamura M. Namba F. Japan NRN ofRole of sex in morbidity and mortality of very premature neonates. Pediatr Int. 2017; 59: 898-905 Crossref PubMed Scopus (35) Google Scholar , 4 O’Driscoll D.N. McGovern M. Greene C.M. Molloy E.J. Gender disparities in preterm neonatal outcomes. Acta Paediatr. 2018; 107: 1494-1499 Crossref Scopus (58) Google Scholar ]. Even though male preterm neonates have shown faster declines in mortality, respiratory distress syndrome (RDS), and bronchopulmonary dysplasia (BPD), they still have a significantly higher risk of mortality before hospital discharge, RDS, necrotizing enterocolitis (NEC), late-onset sepsis, severe intra-ventricular hemorrhage (IVH), severe retinopathy of prematurity (ROP), and BPD [ [5] Boghossian N.S. Geraci M. Edwards E.M. Horbar J.D. Sex Differences in Mortality and Morbidity of Infants Born at Less Than 30 Weeks’ Gestation. Pediatrics. 2018; 142https://doi.org/10.1542/PEDS.2018-2352 Crossref PubMed Google Scholar ]. Similar results of increased mortality in premature male neonates have been reported from neonatal cohorts from Korea, Canada, Japan, Austria, and Switzerland [ [3] Ito M. Tamura M. Namba F. Japan NRN ofRole of sex in morbidity and mortality of very premature neonates. Pediatr Int. 2017; 59: 898-905 Crossref PubMed Scopus (35) Google Scholar , 6 Hwang J.H. Jung E. Lee B.S. Kim E.A.R. Kim K.S. Survival and Morbidities in Infants with Birth Weight Less than 500 g: a Nationwide Cohort Study. J Korean Med Sci. 2021; 36: 1-9 Crossref Google Scholar , 7 Garfinkle J. Yoon E.W. Alvaro R. Nwaesei C. Claveau M. Lee S.K. et al. Trends in sex-specific differences in outcomes in extreme preterms: progress or natural barriers?. Arch Dis Child Fetal Neonatal Ed. 2020; 105: F158-F163 Crossref PubMed Scopus (22) Google Scholar , 8 Steurer M.A. Adams M. Bacchetti P. Schulzke S.M. Roth-Kleiner M. Berger T.M. Swiss medical centres vary significantly when it comes to outcomes of neonates with a very low gestational age. Acta Paediatr. 2015; 104: 872-879 Crossref PubMed Scopus (20) Google Scholar , 9 Kiechl-Kohlendorfer U. Simma B. Urlesberger B. Maurer-Fellbaum U. Wald M. Wald M. et al. Low mortality and short-term morbidity in very preterm infants in Austria 2011-2016. Acta Paediatr. 2019; 108: 1419-1426 Crossref PubMed Scopus (0) Google Scholar ]. In one meta-analysis, 26 of the 32 studies showed increased mortality in premature males, while 6 reported no sex difference [ [10] Vu H.D. Dickinson C. Kandasamy Y. Sex Difference in Mortality for Premature and Low Birth Weight Neonates: A Systematic Review. Am J Perinatol. 2018; 35: 707-715 Crossref PubMed Scopus (32) Google Scholar ].