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Roggero, P. Sex-Specific Effects of Nutritional Supplements for Infants. Encyclopedia. Available online: https://encyclopedia.pub/entry/19826 (accessed on 16 November 2024).
Roggero P. Sex-Specific Effects of Nutritional Supplements for Infants. Encyclopedia. Available at: https://encyclopedia.pub/entry/19826. Accessed November 16, 2024.
Roggero, Paola. "Sex-Specific Effects of Nutritional Supplements for Infants" Encyclopedia, https://encyclopedia.pub/entry/19826 (accessed November 16, 2024).
Roggero, P. (2022, February 23). Sex-Specific Effects of Nutritional Supplements for Infants. In Encyclopedia. https://encyclopedia.pub/entry/19826
Roggero, Paola. "Sex-Specific Effects of Nutritional Supplements for Infants." Encyclopedia. Web. 23 February, 2022.
Sex-Specific Effects of Nutritional Supplements for Infants
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This entry is adapted from the peer-reviewed paper 10.3390/nu14020392

Neonatal nutritional supplements may improve early growth for infants born small, but effects on long-term growth are unclear and may differ by sex. Macronutrient supplementation for infants born small may not alter BMI in childhood. Supplementation increased growth in infancy, but these effects did not persist in later life. The effects did not differ between boys and girls. 

macronutrient supplementation preterm infants small-for-gestational-age infants growth

1. Introduction

The risk of poor growth, slow development and disability are increased in preterm and small-for-gestational-age (SGA) infants [1][2][3][4]. Providing preterm and SGA infants with more protein and energy during the first few weeks after birth may improve short-term growth and result in better developmental outcomes from infancy to adolescence [5][6][7][8][9][10]. However, in observational studies, rapid Body Mass Index (BMI) gain and linear growth in infancy are associated with better cognitive development, but at the expense of increased risk for adiposity, metabolic and cardiovascular disease in adulthood [11]. Further, bone mineral content is often lower in preterm than term infants and the rate of metabolic bone disease is inversely proportional to birthweight and gestational age [12][13][14]. In turn, metabolic bone disease during infancy may result in neonatal rickets, childhood fractures, and impaired growth [14].
Nutritional supplementation is widespread as standard practice for infants born preterm or SGA [8], but there has been limited evidence regarding potential long-term consequences. Further, different prenatal growth patterns between girls and boys may potentially result in sex-specific responses to nutritional supplements [15]. Previous randomised trials have found sex-specific effects of early macronutrient supplements [6][16], and a recent systematic review found enhanced nutrition may improve length in toddler boys but not girls [17]. However, although thousands of infants have participated in randomised trials of enhanced nutrition, few trials have analysed girls and boys separately, and the long-term and the sex-specific effects of supplementation remain unclear.

2. Sex-Specific Effects of Nutritional Supplements for Infants 

Early macronutrient supplementation did slightly increase growth in infancy, but none of these effects persisted into later life, and there were no significant sex differences.

Early supplements did not alter BMI or fat mass from infancy through to adolescence. Early macronutrient supplements are very unlikely to increase later adiposity or risk of obesity.

Supplementation slightly increased length in infancy despite significant heterogeneity but had no effect on weight, head circumference, or lean mass in infancy.  Supplementation does increase growth in infancy, but effects are small and do not persist after the first year. 

Different growth patterns between girls and boys before birth may potentially determine sex-specific responses to early environmental perturbations, including nutrition [15]. As is well known, preterm boys are at greater risk of adverse health outcomes than preterm girls [18]. Sex-specific effects have also been reported in animal studies. For example, in sheep, prenatal testosterone treatment reduced the body weight and height of newborn sheep from both sexes, but only females exhibited catch-up growth during 2–4 months of postnatal life [19]. Therefore, the effect of early macronutrient supplements might differ between girls and boys. However, there is no sex-specific effects of supplements on BMI in childhood. Supplementation did increase height z-scores in toddler boys but not girls, but the interaction terms were not statistically significant. Thus there is no evidence of widespread sex-specific effects of nutritional supplements in preterm and SGA infants, and therefore no evidence that neonatal nutritional supplements should differ for girls and boys.

Supplementation increased height z-scores for toddlers born >1 kg and decreased height in childhood and height z-scores at >3 years for children born ≤1 kg, although the interaction terms were not significant. Infants born preterm usually have low birthweight, and optimal nutrition plays a crucial role in supporting their growth to reduce morbidity in later life [8]. Furthermore, children with birth weight ≤1 kg usually have poorer growth than children with birth weight >1 kg [20][21].

Supplemented children born very preterm had lower BMI and BMI z-scores during toddlerhood and childhood and lower weight-for-length scores in toddlers than unsupplemented children, but these effects were not seen in children born extremely or moderate to late preterm, although the numbers of included children and trials are smallest in the moderate to late preterm group. The reasons for differences between gestational age at birth groups are not clear but might include greater neonatal illness in the smallest infants, thereby restricting growth in this group, and that weight gain in preterm infants is disproportionately fat [22].

Children who had received supplements post-discharge, but not those who received supplements in hospital, had greater weight, length in infancy, and height z-scores in toddlers. Children who had received supplements in hospital with additional protein also had lower BMI and measures of adiposity into adolescence.

Supplements increased height in toddlers only if the primary feed was formula, but not if the primary feed was breastmilk or if supplements were provided as both parenteral and enteral feeds. Supplemented infants whose primary feed was formula also had greater length and BMC in infancy but lower head circumference and head circumference z-scores in toddlers, although none of these interaction terms were significant. It had hypothesised that infants whose primary feed was breastmilk would receive less baseline (unsupplemented) nutritional intake and may therefore show greater effects of supplementation. Consistent with this, estimated protein intake was lower if breastmilk was the primary feed, and supplements provided a much greater increase in protein, carbohydrate, and energy intakes than for infants who received formula as primary feed. Therefore, comparison of nutrition intakes cannot explain the effect of supplements in the formula group. Another possible explanation may be the effect of growth-regulating hormones and growth factors in breastmilk. One study found a positive correlation between insulin-like growth factor (IGF)-I and weight z-scores in healthy infants [23]; infants fed formula milk had higher IGF-I levels than those fed breastmilk [24]. Leptin, adiponectin, and cortisol in breast milk could also play roles in the short-term control of food intake and have long-term effects on energy balance and body weight regulation [25][26].

References

  1. Blencowe, H.; Cousens, S.; Chou, D.; Oestergaard, M.; Say, L.; Moller, A.-B.; Kinney, M.; Lawn, J.; The Born Too Soon Preterm Birth Action Group. Born Too Soon: The global epidemiology of 15 million preterm births. Reprod. Health 2013, 10 (Suppl. 1), S2.
  2. Scharf, R.; Stroustrup, A.; Conaway, M.R.; DeBoer, M. Growth and development in children born very low birthweight. Arch. Dis. Child. Fetal Neonatal Ed. 2016, 101, F433–F438.
  3. Katz, J.; Lee, A.C.; Kozuki, N.; Lawn, J.E.; Cousens, S.; Blencowe, H.; Ezzati, M.; Bhutta, Z.A.; Marchant, T.; Willey, B.A.; et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: A pooled country analysis. Lancet 2013, 382, 417–425.
  4. Christian, P.; Lee, S.E.; Angel, M.D.; Adair, L.S.; Arifeen, S.; Ashorn, P.; Barros, F.C.; Fall, C.; Fawzi, W.W.; Hao, W.; et al. Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries. Int. J. Epidemiol. 2013, 42, 1340–1355.
  5. Lucas, A.; Fewtrell, M.S.; Morley, R.; Lucas, P.J.; Baker, B.A.; Lister, G.; Bishop, N.J. Randomized outcome trial of human milk fortification and developmental outcome in preterm infants. Am. J. Clin. Nutr. 1996, 64, 142–151.
  6. Lucas, A.; Morley, R.; Cole, T.J. Randomised trial of early diet in preterm babies and later intelligence quotient. BMJ 1998, 317, 1481–1487.
  7. Lucas, A.; Morley, R.; Cole, T.J.; Gore, S.M. A randomised multicentre study of human milk versus formula and later development in preterm infants. Arch. Dis. Child. Fetal Neonatal Ed. 1994, 70, F141–F146.
  8. Kumar, R.K.; Singhal, A.; Vaidya, U.; Banerjee, S.; Anwar, F.; Rao, S. Optimizing Nutrition in Preterm Low Birth Weight Infants—Consensus Summary. Front. Nutr. 2017, 4, 20.
  9. Belfort, M.B.; Rifas-Shiman, S.L.; Sullivan, T.; Collins, C.T.; McPhee, A.J.; Ryan, P.; Kleinman, K.P.; Gillman, M.W.; Gibson, R.A.; Makrides, M. Infant Growth Before and After Term: Effects on Neurodevelopment in Preterm Infants. Pediatrics 2011, 128, e899–e906.
  10. Brown, J.V.E.; Embleton, N.; Harding, J.E.; McGuire, W. Multi-nutrient fortification of human milk for preterm infants. Cochrane Database Syst. Rev. 2016, 2016, CD000343.
  11. Peacock, J.L.; Marston, L.; Marlow, N.; Calvert, S.A.; Greenough, A. Neonatal and infant outcome in boys and girls born very prematurely. Pediatr. Res. 2012, 71, 305–310.
  12. Rustico, S.E.; Calabria, A.C.; Garber, S.J. Metabolic bone disease of prematurity. J. Clin. Transl. Endocrinol. 2014, 1, 85–91.
  13. Embleton, N.; Wood, C.L. Growth, bone health, and later outcomes in infants born preterm. J. Pediatr. 2014, 90, 529–532.
  14. Rehman, M.U.; Narchi, H. Metabolic bone disease in the preterm infant: Current state and future directions. World J. Methodol. 2015, 5, 115–121.
  15. Aiken, C.E.; Ozanne, S.E. Sex differences in developmental programming models. Reproduction 2013, 145, R1–R13.
  16. Cooke, R.J.; Embleton, N.D.; Griffin, I.J.; Wells, J.C.; McCormick, K.P. Feeding Preterm Infants after Hospital Discharge: Growth and Development at 18 Months of Age. Pediatr. Res. 2001, 49, 719–722.
  17. Lin, L.; Amissah, E.; Gamble, G.D.; Crowther, C.A.; Harding, J.E. Impact of macronutrient supplements on later growth of children born preterm or small for gestational age: A systematic review and meta-analysis of randomised and quasirandomised controlled trials. PLoS Med. 2020, 17, e1003122.
  18. Glass, H.C.; Costarino, A.T.; Stayer, S.A.; Brett, C.M.; Cladis, F.; Davis, P.J. Outcomes for Extremely Premature Infants. Anesth. Analg. 2015, 120, 1337–1351.
  19. Manikkam, M.; Crespi, E.J.; Doop, D.D.; Herkimer, C.; Lee, J.S.; Yu, S.; Brown, M.B.; Foster, D.L.; Padmanabhan, V. Fetal Programming: Prenatal Testosterone Excess Leads to Fetal Growth Retardation and Postnatal Catch-Up Growth in Sheep. Endocrinology 2004, 145, 790–798.
  20. Stoll, B.J.; Hansen, N.I.; Adams-Chapman, I.; Fanaroff, A.A.; Hintz, S.R.; Vohr, B.; Higgins, R.D. Neurodevelopmental and Growth Impairment Among Extremely Low-Birth-Weight Infants with Neonatal Infection. JAMA 2004, 292, 2357–2365.
  21. Saigal, S.; Stoskopf, B.L.; Streiner, D.L.; Burrows, E. Physical growth and current health status of infants who were of extremely low birth weight and controls at adolescence. Pediatrics 2001, 108, 407–415.
  22. Ramel, S.E.; Zhang, L.; Misra, S.; Anderson, C.G.; Demerath, E.W. Do anthropometric measures accurately reflect body composition in preterm infants? Pediatr. Obes. 2017, 12, 72–77.
  23. Savino, F.; Nanni, G.; Maccario, S.; Oggero, R.; Mussa, G. Relationships between IGF-I and Weight Z Score, BMI, Tricipital Skin-Fold Thickness, Type of Feeding in Healthy Infants in the First 5 Months of Life. Ann. Nutr. Metab. 2005, 49, 83–87.
  24. Savino, F.; Fissore, M.F.; Grassino, E.C.; Nanni, G.E.; Oggero, R.; Silvestro, L. Ghrelin, leptin and IGF-I levels in breast-fed and formu-la-fed infants in the first years of life. Acta Paediatr. 2005, 94, 531–537.
  25. Stocker, C.J.; Cawthorne, M.A. The influence of leptin on early life programming of obesity. Trends Biotechnol. 2008, 26, 545–551.
  26. Palou, A.; Pico, C. Leptin intake during lactation prevents obesity and affects food intake and food preferences in later life. Appetite 2009, 52, 249–252.
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Subjects: Pediatrics
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Paola Roggero
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