Abstract
Early macronutrient supplementation in preterm and/or small-for-gestational-age (SGA) infants may improve growth but have detrimental effects on later cardio-metabolic health which may be sex-specific. We systematically reviewed the long-term effects of early macronutrient supplementation in preterm and SGA animals and whether these differ by sex. Using Cochrane Neonatal and SYRCLE methodologies we included random or quasi-random studies that allocated non-human mammals to macronutrient supplements or no supplements between birth and weaning and assessed post-weaning outcomes. We used random-effects models to calculate standardized mean differences (SMD) with 95% confidence intervals (CIs). Six studies provided low to very-low-quality evidence that macronutrient supplementation increased weight in juvenile rats (SMD; 95% CI: 2.13; 1.00, 3.25; 1 study, n = 24), increased leptin concentrations in older adults (1.31; 0.12, 2.51; 1 study, n = 14 male rats), but decreased leptin concentrations in young adults (−1.13; −2.21, −0.05; 1 study, n = 16 female rats) and improved spatial learning and memory (qualitative data; 1 study). There was no evidence of sex-specific effects and no overall effect on length, serum lipids, body composition, HOMA-IR, or blood pressure. Macronutrient supplements may affect later growth, metabolism, and neurodevelopment of preterm and SGA animals, but evidence is limited and low quality.
Highlights
Animal studies have supported an association between early life nutrition and long-term risk of metabolic dysfunction[7,8,9,10]
There were no differences between groups for HOMA-IR (SMD −0.17, 95% confidence intervals (CIs) −0.94 to 0.60; 1 study, n = 26 pigs, low-quality evidence), insulin sensitivity (SMD −0.26, 95% CI −0.64 to 0.12; 1 study, n = 38 sheep), fasting insulin concentrations (SMD 0.24, 95% CI −0.66 to 1.15; 2 studies, n = 63 sheep, I2 = 68%), or fasting plasma glucose concentrations (SMD 0.43, 95% CI −0.34 to 1.20; 2 studies, n = 63 sheep, I2 = 56%) (Fig. 6)
This study found using the Morris water maze test that pubertal pups born preterm and supplemented with sufficient and www.nature.com/scientificreports enriched docosahexaenoic fatty acid (DHA) had improved spatial learning and memory while those supplemented with excess or no DHA had delayed spatial learning and memory
Summary
Animal studies have supported an association between early life nutrition and long-term risk of metabolic dysfunction[7,8,9,10]. Some have reported sex-specific differences in the impact of early nutritional interventions on later outcomes. Another study which fed methyl-deficient diets to female rats 3 weeks prior to conception and during the first 5 days of gestation noted sex-specific changes in insulin action in the offspring[13], while in neonatal lambs, nutritional supplementation with a milk fortifier showed sex-specific effects on later pancreatic function[14]. There is a paucity of data from clinical studies regarding sex differences in the short- and long-term effects of early life nutritional interventions. We aimed to systematically evaluate the available evidence from randomized or quasi-randomized studies on the long-term effects of early macronutrient supplementation in preterm and/or growth restricted or SGA animals, and whether these differ between sexes. The results of this review were intended to inform the design of new clinical trials to improve long-term health outcomes of preterm and SGA infants by providing appropriate sex-specific macronutrient supplements
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