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.
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.
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.
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.
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We acknowledge Drs Peter Lurie at the FDA and Brian Smith from the Duke University Medical Center for the scientific discussions and valuable inputs. We acknowledge Ms Margaret Renner and Ann Myers for critically reviewing and editing the manuscript. We also acknowledge Ms Lee S Bernstein, an FDA librarian, for the literature search.
The authors declare no conflict of interest.
Views expressed in this manuscript are those of the authors and do not necessarily reflect official positions or policies of the FDA.
Supplementary Information accompanies the paper on the Journal of Perinatology website
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