In this secondary analysis of data from two randomized controlled trials, we found sex-specific differences in nutritional outcomes over the first 6 weeks following birth among preterm VLBW infants. While previous research has examined sex-related growth differences, to our knowledge this is the first to examine nutritional outcomes in addition to growth. Because early nutrition correlates with risk of chronic disease in adulthood and improved neurodevelopmental outcomes, strategies to optimize the nutritional support of infants born preterm are essential and nutritional interventions may need personalization based upon infant sex.2,3,14
Males reached full feedings two days later, required PN almost 4 days and a central line more than 3 days longer than females which may be clinically significant. Although the incidence of direct hyperbilirubinemia was similar, male infants had statistically significantly higher direct bilirubin levels. Because the most common cause of increased bilirubin is PN cholestasis, it is possible that the longer PN requirement in males led to higher bilirubin levels.15
Male infants experienced significantly more episodes of emesis than females, although there were no differences in abdominal distension between sexes. It is possible that concern for emesis led clinicians to prescribe a slower advancement of feedings which delayed time to full feeds. Due to prematurity-related intestinal dysfunction, feeding intolerance is common in infants born preterm and VLBW and it is possible that intestinal immaturity is more significant in males.16
Consistent with previous research, we found a higher incidence of late-onset sepsis in male infants.17 Because a longer duration of central line access is known to increase the risk of late-onset sepsis, it is possible that the longer time male infants required a central line may have increased their risk of LOS.18 Moreover, sex-related differences in systemic immunity may increase the susceptibility of male infants to infection. Full term male infants have been found to exhibit weaker innate and adaptive immunity, reduced vaccine response and poorer pathogen clearance than females, and these sex related differences may begin in-utero as evidenced by greater pro-inflammatory response found in cord blood.19-21
Although male infants were heavier at birth, weight at 6-weeks was similar between groups. In addition, while the slope of weight increase from birth to 6-weeks was higher in males, female infants tended to have a higher growth velocity, consistent with previous research suggesting that female infants have more adequate growth during their NICU hospitalization.7,22 In addition, while fat mass is known to be higher in female infants born term, this is not true among preterm infants suggesting inadequacies in the nutrition provided to male infants in the NICU.23,24
While male infants were heavier at birth, there were no differences between sexes regarding length or head circumference at either time point or in weight at 6-weeks. The slope of weight increase from birth to 6 weeks was higher in males (p=0.02) but not length (p=0.66) or head circumference (p=0.82). This was an unexpected finding since head circumference and length at birth are greater in male infants born at term.25 Because appropriate head growth is necessary for optimal neurodevelopmental outcomes and provision of enhanced nutrition has been shown to improve head growth at 18 months, particularly in male infants, this may be especially important.26,27 The higher risk of poor neurodevelopmental outcomes in males and findings that enhanced nutrition may be more important in the neurodevelopment of males emphasizes the need to optimize nutrition in preterm male infants.4,6,17
While the exact cause for the higher risk of poor growth in male infants is unknown, it may be related to hormonal differences both in-utero and after birth. Males have higher testosterone levels beginning in-utero, increasing over the first few weeks of life and enhancing lean body mass.28,29 Furthermore, protein and lipid levels are higher in the milk from mothers of male infants which may partially explain the increased growth rates in male infants.30
Limitations of this research included a lack of control for clinical acuity and the possibility that collecting data from two separate studies could have affected outcomes. In addition, we defined as attainment of full feeds as reaching feeds of 120 mL/kg/d but did not consider whether infants were sustained on this feeding volume.
Preterm VLBW infants are hospitalized in the NICU during a critical period of growth and development, during which provision of insufficient nutrition may adversely affect long-term growth and development. While sex-based growth differences are known to occur in term infants and human milk composition differs based on infant sex, sex-based differences in nutritional requirements are not considered in the NICU, which may be an essential nutritional strategy. Understanding potential sex-related differences in nutritional outcomes in preterm infants may lead to more targeted therapies and interventions to lessen potential sex disparities for male infants in the NICU.