title: Infant formula and neurocognitive outcomes: impact of study end-point selection.
abstract: OBJECTIVE
  Assessing validity and reliability of end points used in docosahexanoic and arachidonic acids (DHA and ARA) infant formula supplementation trials as an example for addressing the impact of end-point selection and critical need for well-defined, reliable and validated clinical outcome assessments for neurocognitive assessment in neonates and infants.
  
  
  METHODS
  We searched eight electronic databases and reviewed all randomized, controlled human trials using DHA/ARA supplements with neurodevelopment clinical outcomes. We systematically evaluated the validity and reliability of end-point measures based on the criteria for studying nutritional additives recommended by the Institute of Medicine, criteria described in the Food and Drug Administration guidance for clinical outcome assessment, development and literature review.
  
  
  RESULTS
  We identified 29 articles that met the selection criteria. The end points that were used for neurodevelopment measures in 23 out of 29 original short-term studies included the Bayley Scale of Infant Development (BSID)-I and -II (n=12), Brunet-Lezine test (n=2), videotape infant's movements (n=1), record time to milestones including sitting, crawling, standing and walking (n=1), problem-solving test (n=2), brainstem auditory-evoked potential (n=1), Touwen examination (n=1), Fagan test of infant intelligence (n=2) and visual habituation protocol (n=1). None of these end points have a long-term predictive property for neurocognitive assessment. Compared with standard infant formula, the beneficial effects of DHA/ARA supplementation on neurodevelopment were reported in 2 out of 12 studies using BSID vs 8 out of 11 studies using other end-point measures. In addition, 6 out of 29 long-term follow-up studies used the end points including Stanford-Binet IQ test (n=1), Wechsler Preschool and Primary Scale of Intelligence (n=4) and Bracken Basic Concept Scale (n=1), which are generally scales of intellectual ability and typically do not change substantively in the short term. None of these long-term follow-up studies demonstrated beneficial effects of DHA/ARA supplementation on neurodevelopment.
  
  
  CONCLUSIONS
  The choice of end-point measures affects the outcomes of DHA/ARA-supplemented infant formula trials. Available data are currently inadequate to conclude that DHA/ARA supplementation has a clinically meaningful beneficial effect upon neurological development. Although BSID is validated to assess early developmental delays, it is not designed to predict long-term neurocognitive outcome. A well-defined, valid and reliable clinical outcome assessment that measures neurocognitive function in neonates and infants is essential to provide the scientific evidence required for future clinical trials.
authors.affiliation: Office of Pediatric Therapeutics/Office of Commissioner, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.affiliation: Office of Pediatric Therapeutics/Office of Commissioner, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Como
authors.affiliation: Division of Neonatology, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Downey
authors.affiliation: Office of Pediatric Therapeutics/Office of Commissioner, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Murphy
authors.affiliation: Office of Pediatric Therapeutics/Office of Commissioner, Food and Drug Administration, Silver Spring, MD, USA.|Division of Neonatology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Ariagno
authors.affiliation: Office of Pediatric Therapeutics/Office of Commissioner, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: W
authors.initials: W
authors.lastname: Rodriguez
mesh_terms: D001095:Arachidonic Acids / Q000008:administration & dosage*; D019587:Dietary Supplements / Q000592:standards*; D004281:Docosahexaenoic Acids / Q000008:administration & dosage*; D006801:Humans; D007223:Infant; D041943:Infant Formula / Q000592:standards*; D007227:Infant Nutritional Physiological Phenomena; D007231:Infant, Newborn; D007361:Intelligence Tests / Q000592:standards*; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results
chemical_list: D001095:Arachidonic Acids; D004281:Docosahexaenoic Acids