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

Background Nutritional supplements may improve short-term growth of infants born small (preterm or small for gestational age), but there are few data on long-term effects and concerns that body composition may be adversely affected. Effects also may differ between girls and boys. Our systematic review and meta-analysis assessed the effects of macronutrient supplements for infants born small on later growth. Methods and findings We searched OvidMedline, Embase, Cochrane CENTRAL, and Cochrane Database of Systematic Reviews from inception to January 30, 2020, and controlled-trials.com, clinicaltrials.gov, and anzctr.org. au on January 30, 2020. Randomised or quasirandomised trials were included if the intention was to increase macronutrient intake to improve growth or development of infants born small and growth was assessed after discharge. Primary outcome was body mass index (BMI) in childhood. Data were pooled using random-effect models. Outcomes were evaluated in toddlers (< 3 years), childhood (3 to 8 years), adolescence (9 to 18 years), and adulthood (>18 years). Forty randomised and 2 quasirandomised trials of variable methodological quality with 4,352 infants were included. Supplementation did not alter BMI in childhood (7 trials, 1,136 children; mean difference [MD] −0.10 kg/m2, [95% confidence interval (CI) −0.37 to 0.16], p = 0.45). In toddlers, supplementation increased weight (31 trials, 2,924 toddlers; MD 0.16 kg, [0.01 to 0.30], p = 0.03) and length/height (30 trials, 2,889 toddlers; MD 0.44 cm, [0.10 to 0.77], p = 0.01), but not head circumference (29 trials, 2,797 toddlers; MD 0.15 cm, [−0.03 to 0.33], p = 0.10). In childhood, there were no significant differences between groups in height (7 trials, 1,136 children; MD 0.22 cm, [−0.48 to 0.92], p = 0.54) or lean mass (3 trials, 354 children; MD −0.07 kg, [−0.98 to 0.85], p = 0.88), although supplemented children appeared to have higher fat mass (2 trials, 201 children; MD 0.79 kg, [0.19 to 1.38], p = 0.01). In adolescence, there were no significant differences between groups in BMI (2 trials, 216 adolescents; MD −0.48 kg/m2, [−2.05 to 1.08], p = 0.60), height (2 trials, 216 adolescents; MD −0.55 cm, [−2.95 to 1.86], p = 0.65), or fat mass (2 trials, 216 adolescents; MD −1.3 5 kg, [−5.76 to 3.06], p = 0.55). In adulthood, there also were no significant differences between groups in weight z-score (2 trials, 199 adults; MD −0.11, [−0.72 to 0.50], p = 0.73) and height z-score (2 trials, 199 adults; MD −0.07, [−0.36 to 0.22], p = 0.62). In subgroup analysis, supplementation was associated with increased length/height in toddler boys (2 trials, 173 boys; MD 1.66 cm, [0.75 to 2.58], p = 0.0003), but not girls (2 trials, 159 girls; MD 0.15 cm, [−0.71 to 1.01], p = 0.74). Limitations include considerable unexplained heterogeneity, low to very low quality of evidence, and possible bias due to low or unbalanced followup. Conclusions In this systematic review and meta-analysis, we found no evidence that early macronutrient supplementation for infants born small altered BMI in childhood. Although supplements appeared to increase weight and length in toddlers, effects were inconsistent and unlikely to be clinically significant. Limited data suggested that supplementation increased fat mass in childhood, but these effects did not persist in later life. PROSPERO registration: CRD42019126918.