Table 4.
Supplementation during Infancy: Instrumentation and Results.
| Outcome measures | Results | Conclusion | Confounding variables/limitations | Funding source | ||
|---|---|---|---|---|---|---|
| Primary/cognitive | Secondary/other | |||||
| Almaas et al. (2016) | Behavioral outcomes measured with the Strengths and Difficulties Questionnaire [SDQ)] parent report version | Cerebral white matter microstructure (measured by diffusion tensor imaging [DTI]) | No significant differences between the treatment and placebo groups on behavioral outcomes or cerebral white matter microstructure; the intervention group did exhibit higher fractional anisotropy in the corpus callosum | While the fractional anisotropy finding was non-significant, it may warrant additional research on this subject | Supplementation level may have been insufficient to produce long-term effects; confounding variables may have been present by age 8; exclusion of neurologically vulnerable groups | The Research Council of Norway, the South-Eastern Norway Regional Health Authority and the University of Oslo, Norway |
| Auestad et al. (2003) | Stanford-Binet Intelligence Scale Form L-M; the Peabody Picture Vocabulary Test-Revised (PPVT-R); and the Beery Visual-Motor Index test | Visual-motor function, red blood cell fatty acid levels, and the frequency of illnesses and hospitalizations since birth | At 39 months, the cognitive outcome measures did not differ among the intervention groups | Given that their previous results indicated lower vocabulary scores at 14 months among supplemented groups, the authors concluded that this follow-up confirmed that these results were either transient or anomalous, and that DHA + ARA supplementation in formula does support visual and cognitive development | Sample size | Ross Products Division, Abbott Laboratories, Columbus, Ohio |
| Birch et al. (2000) | BSID-II at 18 months | Blood fatty-acid composition, sweep visual evoked potential acuity, and forced-choice preferential looking acuity at 4 and 12 months | Mean increase of 7 points on the mental development index scale of the Bayley test for the DHA + AA group, and a trend toward more accelerated performance on the same subscale amount this group | The authors concluded that early dietary DHA supply correlated with improved performance on the MDI. | Forced-choice preferential looking acuity was not found to correlate with 18-month MDI scores, and may not have been an effective measure of cognitive development; BSID scores’ ability to predict school-age performance may have been limited as the sample did not include a range of developmental speeds (most were within normal range) | NIH and Mead Johnson Nutrition (infant formula manufacturer) |
| Birch et al. (2007) | Wechsler preschool and primary scale of intelligence | HOTV visual acuity | In visual acuity and IQ maturation, the supplemented groups had similar scores to the breast-fed group | DHA + ARA supplemented formula is a comparable alternative to breast feeding in terms of cognitive outcomes | Maternal variables associated with decision to breastfeed | NIH |
| Cheatham et al. (2011) | Infant Planning Test (means end problem solving); Woodcock Johnson Tests of Cognitive Abilities III (speed of cognitive processing); Stroop task (higher-order cognitive functioning) | Socio-emotional functioning (Strength and Difficulties Questionnaire) | No differences between groups for the processing speed measure; the prosocial score on the SDQ tended to be higher in the control group, which was significant when only boys’ results were included. Maternal LC PUFA intake level and maternal education level were significant predictors for speed of processing | The authors noted that lower language comprehension scores among boys in the fish oil group may have contributed to their lower prosocial scores, but did not discern why fish oil supplementation would have produced a negative effect on these measures | Sample size may have been too small to detect small effect size; results may not be generalizable given the typically high fish intake among Danish people; not powered to detect a potential inverted-U effect of FO supplementation | Food Technology Research and Development Programme, Denmark (FØTEK) |
| Collins et al. (2015) | Full Scale IQ of the Wechsler Abbreviated Scale of Intelligence | Subtests of: of Everyday Attention for Children; Rey Auditory Verbal Learning Test; Test of Visual Perceptual Skill; Wide Range Achievement Test. Conners 3rd Edition ADHD Index; Strengths and Difficulties Questionnaire | No effect of supplementation on IQ, attention, executive function, behavior, visual-spatial perceptual skills, educational progress, or quality of life at 7 years of age | No long-term benefit of this type of supplementation | Variations in maternal compliance/DHA concentrations in human milk; no teacher assessment of children’s cognitive function | National Health and Medical Research Council, Australia; Mead Johnson Nutrition |
| Dalmeijer et al. (2016) | Cito standardized school achievement test and teachers’ assessment of secondary school potential | n/a | No association between Cito score and LC PUFAs among boys; girls who received human milk with high amounts of n-3 LC PUFAs scored higher on the Cito test | While some of this effect can be explained by sociodemographic factors, high levels of PUFA content, particularly DHA, in human milk can produce cognitive benefits among girls at the age of 12 | Only one sample of human milk obtained; not known whether LC PUFA levels remained consistent throughout lactation; sample size sufficient to evaluate results based on sex, but not to have more than two groups | Netherlands Organization for Health Research and Development; Netherlands Organization for Scientific Research; Netherlands Asthma Fund; Netherlands Ministry of Spatial Planning, Housing, and the Environment; Netherlands Ministry of Health, Welfare, and Sport |
| de Jong et al. (2010) | Neurological examination according to Touwen | Obstetrical Optimality Score; maternal intelligence; social condition | Cognitive outcome measures (Neurological Optimality Score) did not differ between the two formula groups | Postnatal n-3 supplementation does not have an effect at 9 years of age | Attrition rates | Food Quality and Safety Priority of the Sixth Framework Programme for Research and Technical Development of the European Community |
| de Jong et al. (2015) | Minor neurological dysfunction | IQ; behavioral development | Among boys, those with minor neurological dysfunction were more likely to have had lower umbilical vein DHA levels | Higher levels of DHA at birth correlate with lower levels of neurological dysfunction at 9 years of age, only among boys | Attrition rates | Food Quality and Safety Priority of the Sixth Framework Programme for Research and Technical Development of the European Community |
| Drover et al. (2011) | Bayley Scales of Infant Development, 2nd edition (BSID II) | Fatty acid analysis | No significant between-group cognitive difference. When all intervention groups together were compared to the control group, supplemented children had better Mental Development Index scores | The results indicate a threshold effect at .32% concentration of DHA in formula, which is beneficial for cognitive development up to 18 months | There are several alternative explanations (other than increased DHA status) for these findings; further research is required | Mead Johnson Nutrition |
| Fewtrell et al. (2004) | Bayley Mental and Psychomotor Indexes | Growth; safety and tolerance outcomes | No overall difference between groups in neurodevelopment outcomes; only among boys, those in the LC PUFA group had significantly higher mental development index scores than those in the control group | The supplementation proved to be safe and to have mental development index improvement implications for boys, and growth implications for all children | Global outcome measure tests may not have been sufficiently subtle | H. J. Heinz Company Ltd |
| Gale et al. (2010) | Wechsler Pre-School and Primary Scale of Intelligence; Test of Visual-Perceptual Skills (Non-Motor); Developmental Neuropsychological Assessment | Dietary assessment; maternal and child characteristics | Higher total and verbal IQ scores for children who were breast fed or fed with DHA-fortified formula than those fed unfortified formula | These results may be explained by maternal or family characteristics | Women who took part in the survey tended to be better education with a higher SES | Medical Research Council and the Dunhill Medical Trust |
| Henriksen et al. (2008) | Ages and Stages Questionnaire (ASQ) | Event related potentials—recognition memory | Plasma DHA levels increased by 12% in the treatment group and decreased by 9% in the control group during the intervention; the intervention group scored higher on the problem solving subtest of the ASQ. The results of the event-related potentials testing showed a significant benefit on working memory in the intervention group | DHA and/or AA have cognitive benefits in terms of problem solving and working memory at 6 months of age | Low power for detecting ASQ differences; possibility of type 2 errors | Norwegian Foundation for Health and Rehabilitation; Johan Throne Holst Foundation for Nutrition Research; Freia Medical Research Foundation; Research Council of Norway; Thematic Program on Perinatal Nutrition, Faculty of Medicine, University of Oslo |
| Henriksen et al. (2016) | Wechsler Abbreviated Scale of Intelligence | Growth measures and blood biomarkers | While supplementation with DHA and AA produced lower levels of insulin-like growth factor-1 (IGF-1) at follow-up, it did not affect weight, length, or IQ; however, blood DHA levels at follow-up did correlated with higher IQ after correcting for birth weight and maternal education | The results are in alignment with those of previous studies, which did not find significant long-term effects of LC-PUFA supplementation, but do indicate that DHA should be supplied specifically throughout life | Number of participants inhibits subgroup analyses and many have increased the risk of type 2 errors | Research Council of Norway, the South-Eastern Norway Regional Health Authority, and the University of Oslo |
| Isaacs et al. (2011) | Wechsler Abbreviated Scale of Intelligence, the Neuropsychological Test for Children, the word pairs test from the Children’s Memory Scale (to assess association learning ,which is related to the hippocampus), the Weschler Individual Achievement Test, the Test of Everyday Attention for Children, and the Behavioural Assessment of the Dysexecutive Syndrome for Children | n/a | 10-year-old girls in the supplemented group demonstrated improved performance in reading and spelling measures of the Weschler Individual Achievement test | The results also indicate that both groups that received human milk scored higher on subscales of the Weschler Individual Achievement Test, again prompting the question of whether breastfeeding or PUFAs was the cause of the positive effect | Relatively small group numbers (low follow-up participation rate) | European Union Early Nutrition Programming Project, as part of the Sixth Framework Program; Heinz UK; two researchers received funding from infant feeding manufacturers |
| Jacobson et al. (2008) | Teller Visual Acuity Card Test; Fagan Test of Infant Intelligence (6 months); and the same as well as the Bayley Scales of Infant Development, 2nd edition at 11 months | Demographic control variables | Higher cord DHA correlated with longer gestation, better visual acuity and novelty preference scores, and better Bayley Scale scores, but higher maternal milk DHA did not have any significant effect | The results confirm the third trimester as the crucial period for DHA accretion | Less precise measurement techniques available for breastfeeding than for prenatal intake, which may have affected the results | National Institute of Environmental Health Sciences; Indian and Northern Affairs, Canada; Health Canada; Hydro-Quebec; Joseph Young, Sr, Fund of the State of Michigan |
| Jensen et al. (2005) | Bayley Scales of Infant Development | Gesell Developmental Inventory; Clinical Linguistic and Auditory Milestone Scale; Clinical Adaptive Test | Bayley Psychomotor Development Index scores were higher in the supplemented group at 30 months of age | No other advantages, and none identified at testing before 30 months | Inadequate sensitivity of motor function tests early in life may have affected the results | US Department of Agriculture/National Research Initiative; Martek Biosciences Corp; Mead-Johnson Nutritionals |
| Jensen et al. (2010) | Bailey-Lovie acuity chart, transient visual evoked potential, sweep visual evoked potential testing | No differences between DHA and control groups at 5 years of age, except on the on the Sustained Attention Subscale of the Leiter International Performance Scale (in which supplemented children performed significantly better | DHA supplementation during infancy can have long-term effects on sustained attention | Attrition | Martek Biosciences Corp; U.S. Department of Agriculture/ National Research Initiative | |
| Kalhoff et al. (2020) | Flash visual evoked potential (FVEP); Bayley Scales of Infant Development | No significant differences between intervention and control groups | This dietary intervention did not appear to influence either cognitive or visual development of infants at 10 months of age | Explorative evaluation of functional outcomes; sample size | Federal Ministry of Education and Research | |
| Lauritzen et al. (2005) | Willatts Infant Planning Test; MacArthur Communicative Development Inventory | No effect on problem solving ability; word comprehension inversely associated with DHA level at 4 months | There may be a small adverse effect of supplementation on early language development, which may be transient | Lower than suspected power for outcome measures; not all participants were breastfed for the entire study period | Danish Research and Development Program for Food and Technology; BASF Aktiengesellschaft | |
| Lepping et al. (2018) | Functional (fMRI, Flanker task), resting state (rsMRI), anatomic, and proton magnetic resonance spectroscopy (1H MRS) | Supplemented children showed more activity in anterior cingulate cortex (ACC) and parietal regions; greater connectivity between prefrontal and parietal regions in the .64% DHA group; greater white matter volume in ACC and parietal region for .32 and .64% groups | LCPUFA supplementation during infancy appears to have long-term effects on brain structure | Small sample size; some problems with children participating in the imaging studies | Mead Johnson Nutrition | |
| Liao et al. (2018) | Group differences in behavior and event-related potentials (ERPs) while performing a task requiring response inhibition (Go/No-Go) | n/a | No significant difference in either accuracy or reaction time between the dose levels; while the intervention groups collectively tended to have better reaction times than the control group, these results were not significant; participants in the intervention groups exhibited activation of a larger, synchronized neuronal network than the control group | Early LC PUFA supplementation can have an important programming effect on the brain during development | Smaller sample size/participants lost to follow-up | Mead Johnson Nutrition |
| Meldrum et al. (2012) | Bayley Scales of Infant and Toddler Development and the Child Behavior Checklist; Macarthur–Bates Communicative Development Inventory (language development) | Allergy outcomes | No effect on neurodevelopmental skills on Bayley Scales; more observed anxious/depressed behaviors among FO group; FO group performed better in language assessments, with a higher number of gestures | While the results do not fully support the hypothesis, further studies with larger sample sizes are warranted | The majority of participants correctly guessed group allocation—potential for bias; discrepant sample sizes for different assessment measures | National Health and Medical Research Council (NHMRC) of Australia |
| Westerberg et al. (2011) | Bayley MDI and Ages and Stages questionnaire | Free-play session to assess attention | No significant between-group differences on the Bayley scale or the ASQ; in the free-play sessions, the intervention group demonstrated more time sequences with a high level of attention and higher levels of sustained attention than the control group | The results do not fully support the hypothesis, and small sample size means that their significance is limited; further study is required to discern the impact of supplementation on attention | High level of follow-up attrition; lack of statistical power to detect small between-group differences | Norwegian Foundation for Health and Rehabilitation; Johan Throne Holst Foundation for Nutrition Research; Faculty of Medicine at the University of Oslo; Freia Medical Research Foundation; Research Council of Norway |
| Willatts et al. (2013) | IQ attention control (Day-Night Test), and speed of processing on the Matching Familiar Figures Test (MFFT) | The results did not indicate any difference between the two groups in terms of IQ scores. On the impulsivity/information processing efficiency test (the MFFT), response latencies of children in the intervention group were shorter | Supplementation with LC PUFAs does not appear to improve problem solving ability, but does improve its efficiency. The LC PUFAs in this study were derived from egg yolks (and therefore in phospholipid rather than triglyceride form), and DHA was at the lower end of the recommended amounts scale, which may have affected the result | Potential selection bias (children in follow-up had higher birth weight/several other advantageous demographic factors, making them less susceptible to developmental delays) | Numico Research, Friedrichsdorf, Germany | |
| van der Merwe et al. (2013) | Willatts’ 2-step Infant Planning Test, and a single-object task attention test | Anthropometric measures; gut integrity | There were no significant differences on either of these cognitive outcome measures, but the intervention did result in a significant increase in mid-upper arm circumference | Maternal human milk LC PUFA levels in The Gambia appeared, unexpectedly, to be sufficiently high, which may have affected the study results; further studies should address low-income settings | Sufficient maternal n-3 PUFA levels; intervention may have been more effective if infants who were not breastfed had been targeted | UK Medical Research Council, the Overseas Research Students Awards Scheme, and the Ernest Oppenheimer Memorial Trust |