By Yeji Hong
Early nutrient intake and postnatal growth patterns closely relate to neurodevelopment outcomes and metabolic risk. There is increasing recognition that in addition to the quantity, quality of growth is important during the critical period for developmental programming. All infants are vulnerable to nutrition deficits, but infants of different sexes may have different nutritional needs, highlighting the potential that universal nutrition intervention may have different effects on boys and girls born preterm (Tottman et al., 2020). This discovery is especially important, considering that for the past 50 years, boys born preterm have been recognised to be more vulnerable to adverse outcomes than girls born preterm (Naeye et al., 1971). Despite advances being made in neonatal intensive care and overall improvements in neonatal morbidity and mortality, preterm boys continue to show worse short-term and long-term outcomes than girls, remaining at a higher risk of neurodevelopment impairment and metabolic syndromes.
The biological factors that cause males to be more highly vulnerable have yet to be fully elucidated, but it is important to recognise that foetal sex mediates differences from the first trimester of pregnancy. There are sex differences in metabolism from the blastocyst stage of embryonic development, and studies suggest that males may be more responsive to growth-promoting factors and hence more susceptible to inadequate nutrient supply (Bermejo-Alvarez, et al., 2008). Furthermore, is has been shown that pregnancies with a male foetus are more likely to be affected by metabolic and cardiovascular complications, leading to shorter gestation. Animal studies have also shown that, during pregnancy, maternal nutritional stressors show evidence of insult selectively in the male offspring (Tchoukalova et al., 2014).
Body composition, and in particular, adipose tissue is of interest when considering long-term metabolic risk, since differences in fat deposition are thought to contribute to the differences in metabolic risk between sexes (O’Sullivan, 2009). Body composition diverges between sexes in neonates, and a recent study showed that whilst fat mass was similar between preterm boys and girls, boys had a significantly more lean mass. Animal models have also been used to explore the interactions between sex, foetal growth and postnatal diet and how they may alter long-term metabolic risk profiles. Studies suggest that even slight nutritional manipulations during critical development windows have a possibility to alter life-long metabolic risk by inducing sex-specific genetic changes. Male lambs who received nutritional supplement for 2 weeks after birth showed altered gene expression in pancreatic cells and poorer glucose tolerance compared to same-sex controls at 4 months of age. Meanwhile, supplemented female lambs had better glucose tolerance than their same sex unsupplemented control groups (Jacquiery et al., 2016). Furthermore, in very preterm infants being managed for hyperglycaemia, it was found that girls secrete nearly double of endogenous insulin than boys (Dickson et al., 2015). Overall, these results suggested that girls may have greater metabolic flexibility and thus are able to adapt more rapidly to their postnatal nutritional environment than boys born preterm.
Previous preterm studies have reported growth and neurodevelopment outcomes by sex, with most suggesting that boys need higher nutrition. One study involved 125 infants being fed either term or preterm infant formula after hospital discharge until 6 months of age to compare body compositions (Cooke et al., 1999). A systematic review of this data revealed that supplemented boys had greater length/height than unsupplemented boys but no significant differences were found in girls. Another study assessed structural brain changes in teenagers that were born preterm (Isaacs et al., 2008). Males that were provided a 4-week nutritional intervention to increase enteral protein and energy content shortly after birth were associated with increased volumes of caudate nuclei; however, this effect was not seen in females. These studies indicate that boys may require higher nutritional intake than girls to support optimal linear growth and body composition.
Another critical factor to take into account are the nutrients that infants receive from breastmilk. Maternal breastfeeding is closely associated with beneficial neurodevelopment and metabolic outcomes in both term and preterm populations. There is evidence that composition of breastmilk may differ by offspring sex, but this requires further investigation. Apart from differences in macronutrient composition (e.g. lipid, energy), components of breastmilk that show sex-specific differences include immunoglobulin content, glucocorticoid concentration, hormone content and milk microbiomes (Moossavi et al., 2019). If hormones such as insulin-like growth factor 1 and glucocorticoids differ by offspring sex, it is possible to affect growth. The possibility of offspring sex-specific breastmilk composition may offer an explanation to some observations, such as the absence of a difference in growth between sexes in studies where enteral nutrition was predominantly breastmilk, and to the differences in growth between sexes where boys and girls received interventions of identical composition.
Currently, protocols of nutritional delivery in preterm neonates do not take into account infant sex. This all-inclusive approach to early nutrition involves delivering nutrient contents to fulfil the recommended daily intakes, but boys remain at higher risk of postnatal. This indicates that a universal method for all infants is not sufficiently optimised for boys and girls with different nutritional needs. There is a need to implement sex-specific intravenous nutrition solutions to optimise growth and development, and it is critical that future studies relating to neonatal nutritional interventions take infant sex into consideration.
Tottman, A.C., Oliver C.J., Alsweiler, J.M., Cormack, B.E. (2020) Do preterm girls need different nutrition to preterm boys? Sex-specific nutrition for the preterm infant. Paediatr Res. Available from: https://doi.org/10.1038/s41390-020-01252-1 [Accessed 20th November 2020]
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