Effect of nutritionally modified infant formula on academic performance: linkage of seven dormant randomised controlled trials to national education data

OBJECTIVE: To compare differences in academic performance between adolescents who were randomised in infancy to modified or standard infant formula. DESIGN: Linkage of seven dormant randomised controlled trials to national education data. SETTING: Five hospitals in England, 11 August 1993 to 29 October 2001, and schools in England, September 2002 to August 2016. PARTICIPANTS: 1763 adolescents (425 born preterm, 299 born at term and small for gestational age, 1039 born at term) who took part in one of seven randomised controlled trials of infant formula in infancy. INTERVENTIONS: Nutrient enriched versus standard term formula (two trials), long chain polyunsaturated fatty acid (LCPUFA) supplemented versus unsupplemented formula (two trials), high versus low iron follow-on formula (one trial), high versus low sn-2 palmitate formula (one trial), and nucleotide supplemented versus unsupplemented formula (one trial). MAIN OUTCOME MEASURES: The primary outcome, determined by linkage of trial data to school data, was the mean difference in standard deviation scores for mandated examinations in mathematics at age 16 years. Secondary outcomes included differences in standard deviation scores in English (16 and 11 years) and mathematics (11 years). Analysis was by intention to treat with multiple imputation for participants missing the primary outcome. RESULTS: 1607 (91.2%) participants were linked to school records. No benefit was found for performance in mathematics examinations at age 16 years for any modified formula: nutrient enriched in preterm infants after discharge from hospital, standard deviation score 0.02 (95% confidence interval −0.22 to 0.27), and nutrient enriched in small for gestational age term infants −0.11 (−0.33 to 0.12); LCPUFA supplemented in preterm infants −0.19 (−0.46 to 0.08) and in term infants −0.14 (−0.36 to 0.08); iron follow-on formula in term infants −0.12 (−0.31 to 0.07); and sn-2 palmitate supplemented formula in term infants −0.09 (−0.37 to 0.19). Participants from the nucleotide trial were too young to have sat their General Certificate of Secondary Education (GCSE) examinations at the time of linkage to school data. Secondary outcomes did not differ for nutrient enriched, high iron, sn-2 palmitate, or nucleotide supplemented formulas, but at 11 years, preterm and term participants randomised to LCPUFA supplemented formula scored lower in English and mathematics. CONCLUSIONS: Evidence from these randomised controlled trials indicated that the infant formula modifications did not promote long term cognitive benefit compared with standard infant formulas.