Impact of macronutrient supplements for children born preterm or small for gestational age on developmental and metabolic outcomes: A systematic review and meta-analysis

BACKGROUND: Nutritional supplements may improve development of infants born small (preterm or small for gestational age [SGA]) but may increase the risk of later metabolic disease. We conducted a systematic review and meta-analysis to assess the effects of macronutrient supplements for infants born small on later development and metabolism. METHODS AND FINDINGS: We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to April 1, 2019, and controlled-trials.com, clinicaltrials.gov, and anzctr.org.au. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and assessed post-discharge outcomes. Co-primary outcomes were cognitive impairment and metabolic risk, evaluated in toddlers (<3 years), childhood (3 to 8 years), and adolescence (9 to 18 years). Two reviewers independently extracted data. Quality was assessed using the Cochrane Risk of Bias tool, and data were pooled using random-effect models. Twenty-one randomised and one quasirandomised trial of variable methodological quality involving 3,680 infants were included. In toddlers born small, supplementation did not alter cognitive impairment (relative risk [RR] 1.00; 95% confidence interval [CI] 0.67 to 1.49; P = 0.99), and there were no differences in cognitive scores (mean difference [MD] 0.57; 95% CI −0.71 to 1.84; P = 0.38) or motor scores (MD 1.16; 95% CI −0.32 to 2.65; P = 0.12) between supplemented and unsupplemented groups. However, fewer supplemented children had motor impairment (RR 0.76; 95% CI 0.62 to 0.94; P = 0.01). In subgroup analyses, supplementation improved cognitive scores in boys (MD 5.60; 95% CI 1.07 to 10.14; P = 0.02), but not girls born small (MD −2.04; 95% CI −7.04 to 2.95; P = 0.42), and did not alter cognitive or motor scores in the subgroup of children born SGA. In childhood, there was no difference in cognitive impairment (RR 0.81; 95% CI 0.26 to 2.57; P = 0.72) or cognitive scores (MD 1.02; 95% CI −1.91 to 3.95; P = 0.50) between supplemented and unsupplemented groups. There were also no differences in blood pressure, triglyceride, and low-density lipoprotein (LDL) concentrations (all P > 0.05). However, supplemented children had lower fasting glucose (mmol/L: MD −0.20; 95% CI −0.34 to −0.06; P = 0.005) and higher high-density lipoprotein (HDL) concentrations (mmol/L: MD 0.11; 95% CI 0.02 to 0.19; P = 0.02). In subgroup analyses, there was no evidence of differences in blood pressure between supplemented and unsupplemented groups in boys or girls born small, or in SGA children. In adolescence, there was no difference between supplemented and unsupplemented groups in blood pressure, triglycerides, LDL and HDL concentrations, fasting blood glucose, insulin resistance, and fasting insulin concentrations (all P > 0.05). Limitations include considerable unexplained heterogeneity, low to very low quality of the evidence, and limited data beyond early childhood. CONCLUSIONS: In this systematic review and meta-analysis of randomised trials, we found no evidence that early macronutrient supplementation for infants born small altered later cognitive function, although there was some evidence that supplementation may decrease motor impairment in toddlers. Contrary to the findings from observational studies, evidence from randomised trials suggests that early macronutrient supplementation for infants born small improves some metabolic outcomes in childhood. PROSPERO REGISTRATION: CRD42019127858.