Table 6.
Supplementation During Childhood and Adolescence: Instrumentation and Results.
| Outcome measure | Results | Conclusion | Confounding variables/limitations | Funding source | ||
|---|---|---|---|---|---|---|
| Primary/cognitive | Secondary/other | |||||
| Åberg et al. (2009) | Intelligence tests conducted as part of the Swedish military conscription examination | Compared to those who consumed fish meals less than once per week, those who consumed more than one fish meal per week had higher scores of combined intelligence 3 years later, as well as higher scores in verbal and visuospatial performance, even after accounting for education level | Fish intake has a significant effect on composite, visual, and visuospatial intelligence, measured 3 years later | Physical activity may have been a confounding variable; lack of information on diet other than fish | Swedish Society of Medicine; Department of Public Health at the Västra Götaland Region; Swedish Science Council | |
| Baumgartner et al. (2012) | Hopkins Verbal Learning Test (HVLT) and subscales of the Kaufman Assessment Battery for Children | DHA/EPA did not produce a benefit on any of the cognitive tests, and appeared to have a negative impact on working memory | n-3 supplementation does not appear to have cognitive benefits for children with iron deficiency | Study period/dosage, and previous level of FAs in the population may have affected the results | Unilever Research and Development; Medicor Foundation, Vaduz; Principality of Liechtenstein; North-West University | |
| Bos et al. (2015) | fMRI study with a traditional Go-NoGo paradigm | Parent-rated Child Behavior Checklist (CBCL) and Strengths and Weaknesses of ADHD symptoms and Normal behavior scale (SWAN); Essential Fatty Acids Questionnaire (EFAQ) | Supplementation improved parent-rated ADHD symptoms, but did not affect cognitive control or fMRI results | Omega-3 supplementation can complement other ADHD treatments | Some participants had changes to ADHD medication during the intervention period | Two authors are employees of Unilever |
| Brew et al. (2015) | National Assessment Program—Literacy and Numeracy (NAPLAN) scores | Supplementation did not improve long-term academic performance as measured by the NAPLAN; however, n-3 LC PUFA levels at 8 years of age did correlate with academic performance from between 8 and 14 years of age | Other variables (like maternal education and SES) may explain the correlation between LC PUFA levels at age 8 and test scores, in part because children’s n-3 levels by that time were food- rather than supplement-derived | High attrition rates for follow-up; potential consequent introduction of selection bias | Not industry funded (individual authors supported by various NHMRC/Swedish Research Council Grants); one author declared an advisory board role with Novartis | |
| Cornu et al. (20 180 | Attention-Deficit Hyperactivity Disorder Rating Scale version 4 | Alouette test; Test of Attentional Performance for Children; 48-item Conners Parent Rating Scale-Revised; Children’s Depression Inventory—CDI | ADHD rating scale score reduction was more significant in the placebo than intervention group | Supplementation does not appear to produce a positive effect on ADHD symptoms | Did not measure blood levels | URGO laboratories |
| Crippa et al. (2019) | ADHD rating scale IV Parent Version–Investigator | Conners’ Parent Rating Scale–R; Strengths and Difficulties Questionnaire (SDQ); Child Health Questionnaire; Clinical Global Impression—severity Scale; Amsterdam Neuropsychological Tasks | No differences between treatment groups identified for the primary outcome measure; DHA supplementation also produced a significant (though small) improvement in measures of focused attention | Small improvements in the CHQ Psychosocial summary and improved in parental ratings of emotional problems on SDQ indicate a limited potential benefit of n-3 supplementation among this population | Small sample size; underpowered to detect the effect of n-3 supplementation | Dietetic Metabolic Food srl. (prescription drug industry) |
| Dalton et al. (2009) | Hopkins Verbal Learning Test; Reading test; Spelling test | Biochemical analysis; blood samples | EPA and DHA significantly increased in the intervention group; as did scores on the Hopkins Verbal Learning Test Recognition, Discrimination Index, and Spelling test | Dietary omega-3 supplementation improves children’s memory and verbal learning | Mental performance may have been affected by other nutritional factors; another component of the fish flour than DHA may have produced the improvements | Department of Science and Technology Innovation Fund |
| Darcey et al. (2019) | Behavior Rating Inventory of Executive Function; Go/No-Go Task | Kauffman Brief Intelligence Questionnaire; Pubertal Development Scale; family socioeconomic status | Higher omega-3 intake levels associated with caregiver-assessed inhibitory control, as well as task-based impulse control | Results also indicate poorer cortical development (based on activation in the dorsal anterior cingulate), indicating the importance of omega-3s in adolescent development | Food-frequency questionnaire relies on diet recall | NIH/NIAAA |
| de Groot et al. (2012) | End term grades; Amsterdam Vocabulary Test; Youth Self-Report | More fish intake (up to the recommended amount) correlated with higher end-term grades and better vocabulary | Adolescents should be advised to eat fish twice a week | Non-intervention; portion size not accounted for | n/s | |
| Demmelmair et al. (2018) | Raven’s Progressive Matrices (RPM) | Latencies of visually evoked potentials; Lincoln-Oseretzky Motor Development Scale was used to test fine and gross motor skills; glycerophospholipid (GPL) fatty acids measured | While amount of DHA in GPL increased proportionally to treatment group, there were no differences in cognitive and neurological functions | The researchers also evaluated fatty acid desaturase genotypes, and found that they were associated with AA levels and with DHA levels when accounting for previous ALA levels as a precursor to DHA | Smaller than expected sample size; inconsistencies measuring the Phe level; differences in test procedures across included centers | Commission of the European Communities, the Sixth Framework Programme NUTRIMENTHE; Nutricia (medical nutrition industry) |
| Devlin et al. (2017) | Bayley Scales of Infant and Toddler Development 3rd Edition (Bayley-III) | Beery–Buktenica Developmental Test of Visual–Motor Integration; measures of attention during play | No significant effects of supplementation identified on the primary cognitive function and language development measures; boys in the supplement group exhibited fewer inattention episodes than those in the control group; positive association between ARA levels in red blood cell phosphatidylethanolamine and cognition, only among boys; both boys’ and girls’ ARA levels correlated with their language scores | Future research should further investigate the ideal DHA and ARA levels for this age group using more sensitive measures of cognition | Outcome measures may have been insufficiently sensitive | DSM Nutritional Products (supplement manufacturer) |
| Handeland et al. (2017) | Attention performance measured by the d2 test of attention | Performance in a Norwegian reading and spelling test named “Kartleggeren” was assessed but not reported, due to considerable ceiling effects in nearly all outcomes at pre and post intervention. Mental health status was measured with the Strengths and Difficulties Questionnaire (SDQ) | The results of the d2 test of attention indicate that, for total performance and processing speed, the fish meal group scores were significantly higher than the supplement and meat groups. While omission errors decreased in the meat group, this finding was not significant after controlling for dietary compliance | The benefit of omega-3s on speed of cognition was identified even in individuals with low levels of dietary compliance, which should prompt careful interpretation of the results | No pure placebo group; low dietary compliance; only one cognitive outcome | The Norwegian Seafood Research Fund |
| Kean et al. (2017) | Conners Parent Rating Scales (CPRS) | Test of Variables of Attention and Computerised Mental Performance Assessment System as the secondary outcome variables to assess cognition and hyperactivity/attention symptoms | The results did not indicate any correlation between treatment group and CPRS measures; however, subgroup analysis showed that participants with non-combined type participants with less severe symptoms showed improved CPRS hyperactivity scores, as well as those on behavior at home and learning abilities | Participants in the intervention groups demonstrated improved memory in cognitive tasks, indicating the potential benefit of n-3 supplementation on delayed working memory in particular | Variety in participant demographics | Pharmalink Pty Ltd. (industry) |
| Keim et al. (2018) | Bayley-III composite score | The Bayley-III language and motor composite scores and the IBQ-R and Early Childhood Behavior Questionnaire effortful control and activity level scores | The results did not indicate improvement on the basis of daily DHA and AA supplementation for this population | In all but the poorest groups and those with the lowest birth weight, some negative effects in early language ability were identified, suggesting that those children may not have been previously deficient in DHA/AA and the supplementation therefore upset their previous fatty acid balance in the brain | Smaller than planned sample size; underpowered to detect subgroup differences | US Health Resources and Services Administration Maternal and Child Health Field–initiated Innovative Research Studies Program; the March of Dimes, the Allen Foundation; Cures Within Reach; National Center for Advancing Translational Sciences/National Institutes of Health; Research Institute at Nationwide Children’s Hospital |
| Kim et al. (2010) | Academic grades | Participants who reported fish consumption more than once per week reported higher grades than those with lower levels of fish consumption | Fish consumption may correlate with higher academic achievement | Lack of more detailed dietary information | Swedish Society of Medicine, the Department of Public Health at the Västra Götaland Region | |
| Kennedy et al. (2009) | Internet Battery; Cognitive Drug Research (CDR) Battery | Those in the 400 mg DHA group performed better on the word recognition task, while those in the higher dosage group performed more slowly | The authors suggested that this findings was likely due to chance | Sample size; slight lack of power | Martek Biosciences | |
| Kirby et al. (2010) | Kaufman Brief Intelligence Test, Wechsler Individual Achievement Test Working Memory Test Battery for Children, Creature Counting for attention, the Matching Familiar Figures Task (MFFT), the Computerised Penmanship Evaluation Tool, the SNAP-IV ADHD rating scale, and the SDQ | On the MFFT (which measures impulsivity and visual perception), the supplemented group had a significantly higher number of first correct responses than the control group. The placebo group also demonstrated lower levels of parent-reported prosocial behavior | Supplementation could have had a protective effect against decline in prosocial functioning | Longer supplementation period may have been necessary; while statistically significant, correlations identified were weak | Seven Seas Ltd (supplement production) | |
| Mazahery et al. (2019) | Social responsiveness scale (SRS) and sensory processing measure (SPM) | Biochemical analysis | Of the four social functioning domains assessed in the SRS, improved social awareness was found to be significantly correlated with both the n-3 and n-3 + vitamin D interventions. The SPM results indicate possible correlations between the taste and smell domain with n-3 + vitamin D supplementation and between the balance and motion domain with n-3 supplementation | Noting that other studies have speculated on the benefit of n-3 and vitamin D supplementation in combination, given that they have shared/complementary nutrient functions, the authors noted this type of combined treatment to have a nonsignificant positive effect on social interaction and communication | Smaller than anticipated sample size | Massey University Strategic Innovation Fund, Massey University, New Zealand |
| Milte et al. (2012) | Wechsler Individual Achievement Test III (literacy); Conners Rating Scales (behavior) | Test of Everyday Attention for Children; computerized go/no-go task | DHA proportion was associated with improved scores on word reading measures and lower parent-rated oppositional behavior; DHA level associated with improved reading, spelling, ability to divide attention, parent-ratted oppositional behavior, hyperactivity, restlessness, and ADHD symptoms | Among children with ADHD, LC PUFA supplementation can improve literacy and behavior outcome measures | Smaller than intended sample size; not all children had a clinical ADHD diagnosis | South Australian Health Department; Australian Research Council Linkage Project; Novasel Australia |
| Milte et al. (2015) | Wechsler Individual Achievement Test–III and the Wechsler Scale of Children’s Intelligence–III for the primary outcome measures of literacy and behavior | A test battery from the TEA-ch was used to assess for attention and inhibition behaviors as a secondary outcome measure compared with erythrocyte PUFA status | Increased erythrocyte levels of EPA, DHA, and n-3 FAs overall (resulting in lower n-6 to n-3 ratios) correlated with improved overall literacy, attention, and parent-rated behavior measures | Contrary to previous findings on the importance of EPA over DH, results indicate DHA as an important factor in the positive results observed in this study | Small sample size | Australian Research Council Linkage Grant; Novasel Australia (industry) |
| Montgomery et al. (2013) | British Ability Scales (II); Connors’ rating scales | Lower levels of DHA were found to correspond to lower reading levels and inferior working memory performance; higher levels of oppositional behavior and emotional liability | The authors suggested that DHA supplementation may be particularly useful for children with learning differences | Other nutritional ingredients/components of fish may have produced the positive results; further study is required | Martek Biosciences | |
| Øyen et al. (2018) | Wechsler Pre-school and Primary Scale of Intelligence, 3rd edition (WPPSI-III) and the 9-Hole Peg Test (9-HPT) | Biological samples and caregiver questionnaires | Overall, there were no differences between the groups on the WPPSI-III, and a slightly better improvement, with the non-dominant hand, on the 9-HPT for the fish group. However, when researchers adjusted for dietary compliance, the WPPSI-III total raw score improved more in the fish than the control group: more specifically, fatty fish intake correlated with the Vocabulary, Block Design, and Symbol Search subtests of the outcome measure | Red blood cell DHA concentration was found to be a mediating factor for the WPPSI-III total raw score | Smaller than expected sample size; a longer intervention period may have yielded different results | The Norwegian Seafood Research Fund |
| Parletta et al. (2013) | (Draw-A-Person) non-verbal cognitive development; reading; and spelling | Conners Behaviour Rating Scales (completed by teachers) | Improvements in Draw-A-Person scores in treatment group, and in placebo group after switching to treatment | The intervention appeared to produce improvements in cognitive development, but not literacy | Low dosage; longer intervention may have produced more effects | Australian Research Council; Vifor Pharma |
| Portillo-Reyes et al. (2014) | Neuropsychological test battery | Anthropometric and academic measures; parent-completed food frequency questionnaire | Among more than 70% of malnourished children in the treatment group, improvements were seen in processing speed; perceptual integration; visual-motor coordination; attention; executive function | Clinically significant cognitive improvements of 3 months of supplementation among malnourished children | Homogenous group in terms of SES; serum and n-3 to n-6 ratios not assessed | n/s |
| Raz et al. (2009) | Conners’ Abbreviated Parent-Teacher questionnaire; DSM-IV questionnaire for ADHD; Continuous Performance Test | Blood tests; EFA deficiency questionnaire | Both the EFA and the 1000 mg vitamin C placebo appeared to improve ADHD symptoms | EFA supplementation does not appear to work beyond a placebo effect on improving ADHD symptoms | EFA amount or composition may have been less than optimal | No disclosures reported |
| Richardson and Montgomery (2005) | Movement Assessment Battery for Children; Wechsler Objective Reading Dimensions; Conners’ Teacher Rating Scales, Long Version | No effect on motor skills; significant improvements to reading, spelling, and behavior scores | FA supplementation may function as a treatment option for DCD | Optimal dosage information unknown; more studies required | Dyslexia Research Trust; Durham Local Education Authority | |
| Richardson et al. (2012) | Reading; working memory; parent- and teacher-rated behavior | No effect of supplementation on reading for the group overall; a subgroup of more significantly underperforming students showed significant reading improvements; parent-rated behavior improved | DHA supplementation offers potential for improvements to reading, particularly among severely underperforming children | Missing data from parent ratings may have caused positive bias | Martek Biosciences | |
| Ryan and Nelson (2008) | Leiter-R Test of Sustained Attention, Peabody Picture Vocabulary Test (PPVT), Day-Night Stroop Test, and Conners’ Kiddie Continuous Performance Test | Interaction between blood DHA levels and efficacy end points | While the results did not indicate significant treatment effects on the primary outcome measures, regression analysis did indicate a significant positive correlation between DHA level and higher PPVT scores | Since the PPVT tests for comprehension in English, and is associated with memory and cognitive function, these results suggest potential implications in those domains in particular | Ceiling effect reduced the sample size | n/s |
| Sheppard and Cheatham (2013) | Cambridge Neuropsychological Test Assessment Battery (specifically focused on executive function and working memory) | Spatial Working Memory (SWM); Spatial Span (SSP); Stockings of Cambridge (SOC); Intra-Extra Dimensional Set Shift | Participants with balanced n-6 to n-3 ratios demonstrated shorter initial processing times on the spatial working memory task, shorter mean planning times on the planning task, and better executive function scores overall | Balanced intake of n-3 and n-6 fatty acids is important, as when n-3 and n-6 intake were both low (low ratio) and when n-3 intake was high and n-6 intake was very high (high ratio), results were good | Small but sufficiently powered sample size; results require replication; only spatial memory tests included in this study | North Carolina Translational and Clinical Science Institute |
| Sinn et al. (2008) | ADHD-related symptoms on Conners’ Parent Rating Scales (CPRS)—Revised; cognitive test battery | Significant improvements in ability to shift and control attention among the supplementation group | Supplementation may yield minor improvements for this population | Not possible to detect meaningful cognitive outcomes on all tests; lack of intention-to-treat analysis | University of South Australia; Commonwealth Scientific and Industrial Research Organisation | |
| Sørensen et al. (2015) | d2-test of attention and Danish standard tests in reading and maths | Physical activity; dietary intake; biomarkers of PUFA status | Overall school performance, reading comprehension and blood EPA + DHA levels improved as a result of the intervention | Dietarily derived n-3 LC PUFAs have positive cognitive effects on school-aged children | No participant blinding; short study period | Nordea Foundation |
| Widenhorn-Müller et al. (2014) | Cognitive assessment: Hamburg Wechsler Intelligence Scales for Children–IV (particularly working memory and processing speed domains); “Test-batterie zur Aufmerksamkeitsprüfung für Kinder” (KITAP 6–10 y) and the “Testbatterie zur Aufmerksamkeitsprüfung” (TAP 10-18y) for attentional performance | Behavior assessment: FBB ADHS parent-rated and teacher-rated questionnaires; Child Behavior Checklist 4–18 y; Teacher's Report Form 5-18 y | While scores for parent-rated (DISYPS-II, CBCL) and teacher-rated (DISYPS-II, TRF) behavior did not change significantly, there was a significant improvement in working memory among the intervention group; there was a significant decrease of parent-rated thought problems in the placebo group, which may have been caused by the oleic acid in the placebo capsules | The authors suggested that the working memory improvement may be specific to a population with ADHD, but that future research is required to determine this | Small sample size; inability to determine whether the working memory finding was specific to children with ADHD | German Federal Ministry of Education and Research |
| van der Wurff et al. (2016) | Letter Digit Substitution Test (LDST), D2 test of attention, Digit Span Forward and Backward, Concept Shifting Test, and Stroop test | Questionnaires to assess covariates and fish consumption | On the LDST, results indicate that a higher omega-3 index was associated with better information processing speeds: each 1% higher the omega-3 index, the LDST score improved by 1.23 digits. On the D2 test of attention, participants with higher omega-3 levels had fewer errors of omission, which indicates less impulsivity | Overall, the results indicate a positive effect of omega-3 supplementation on select cognitive measures | Observational study; cannot prove causality | Food, Cognition and Behaviour from the Dutch Scientific Organisation |
| van der Wurff et al. (2019) | Letter digit substitution task (LDST), the D2 test of attention (D2), and the Digit Span backward and forward. After these group tests were administered, the Stroop Interference Test and the Concept Shifting Task were administered individually | Pubertal Development Scale; demographic questionnaires | The results did not indicate an effect of one year of krill oil supplementation on participants, or between O3I and neurocognitive test scores | However the authors noted a high level of non-compliance, and suggested that adherence difficulties may have contributed to the lack of demonstrated correlation between krill oil supplementation and neurocognitive benefits | High drop-out rate; low adherence | The Netherlands Organization for Scientific Research; AkerBiomarine (fishing and biotech with krill interests) |
| Vesco et al. (2018) | Behavior Rating Inventory of Executive Functioning (BRIEF) | Mood disorders and mood symptom severity assessed using K-SADS Depression (KDRS) and Mania Rating Scales (KMRS) (Geller et al., 2001), the Children’s Depression Rating Scale-Revised (CDRS-R), and Young Mania Rating Scale (YMRS) | Both intervention groups receiving n-3 supplementation (with and without PEP), showed a significant improvement in executive functioning, particularly in the areas of inhibition control, adaptability to emotions, and cognitive flexibility | The authors noted that, while this study indicates a potentially positive effect of n-3 supplementation on executive functioning treatment for mood disorders, further research should be conducted to assess for ideal supplementation amounts and to identify moderating effects | Potential parental bias on symptom ratings; short-term nature of follow-up; uncertainty as to whether results generalize to populations without mood disorders | National Institute of Mental Health; National Center for Research Resources |
| Voigt et al. (2001) | Test of Variables of Attention and Children’s Color Trails test (inattention measures); Child Behavior Checklist, Conners’ Rating Scale (parent-rated behavior scales | Plasma phospholipid DHA content | No statistically significant effect of supplementation on ADHD among this population | The treatment intervention did not appear to be efficacious in improving inattention or parent-rated behavior related to ADHD | Plasma phospholipid DHA content may not indicate DHA presence in brain or synapses | US Department of Agriculture; Martek Biosciences Corporation |