Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: The influence of LCPUFA on neural development, aging, and neurodegeneration

Background
The long chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and arachidonic acid (AA) are considered essential for maturation of the developing brain, retina and other organs in newborn infants. Standard infant milk formulae are not supplemented with LCPUFA; they contain only alpha-linolenic acid and linoleic acid, from which formula-fed infants must synthesise their own DHA and AA, respectively. Over the past few years, some manufacturers have added LCPUFA to formula milk and have marketed these products as providing an advantage for the overall development of full-term infants.

Objectives
To assess whether supplementation of formula milk with LCPUFA is both safe and beneficial for full-term infants, while focusing on effects on visual function, neurodevelopment and physical growth.

Search methods
Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL; December 2016), MEDLINE (Ovid, 1966 to December 2016), Embase (Ovid, 1980 to December 2016), the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1980 to December 2016) and abstracts of the Pediatric Academic Societies (2000 to 2016). We applied no language restrictions.

Selection criteria
We reviewed all randomised controlled trials (RCTs) evaluating effects of LCPUFA supplemented versus non-supplemented formula milk on visual function, neurodevelopment and physical growth. We did not include trials reporting only biochemical outcomes.

Data collection and analysis
Two review authors extracted data independently. We assessed risk of bias of included studies using the guidelines of the Cochrane Neonatal Review Group. When appropriate, we conducted meta-analysis to determine a pooled estimate of effect.

Main results
We identified 31 RCTs and included 15 of these in the review (N = 1889).

Nine studies assessed visual acuity, six of which used visual evoked potentials (VEP), two Teller cards and one both. Four studies reported beneficial effects, and the remaining five did not. Meta-analysis of three RCTs showed significant benefit for sweep VEP acuity at 12 months (log of the minimum angle of resolution (logMAR)) (mean difference (MD) -0.15, 95% confidence interval (CI) -0.17 to -0.13; I2 = 0; three trials; N = 244), but meta-analysis of three other RCTs showed no benefit for visual acuity measured with Teller cards at 12 months (cycles/degree) (MD -0.01, 95% CI -0.12 to 0.11; I2 = 0; three trials; N = 256). GRADE analysis for the outcome of visual acuity indicated that the overall quality of evidence was low.

Eleven studies measured neurodevelopmental outcomes at or before two years. Nine studies used Bayley Scales of Infant Development, version II (BSID-II), and only two of these studies reported beneficial effects. Meta-analysis revealed no significant differences between LCPUFA and placebo groups in BSID Mental Developmental Index (MDI) scores at 18 months (MD 0.06, 95% CI -2.01 to 2.14; I2 = 75%; four trials; N = 661) and no significant differences in BSID Psychomotor Development Index (PDI) scores at 18 months (MD 0.69, 95% CI -0.78 to 2.16; I2 = 61%; four trials; N = 661). Results showed no significant differences between the two groups in BSID-II scores at one year and two years of age. One study reported better novelty preference measured by the Fagan Infant Test at nine months. Another study reported better problem solving at 10 months. One study used the Brunet and Lezine test to assess the developmental quotient and found no beneficial effects. Follow-up of some infants in different studies at three, six and nine years of age revealed no beneficial effects of supplementation. GRADE analysis of these outcomes indicated that the overall quality of evidence was low.

Thirteen studies measured physical growth; none found beneficial or harmful effects of supplementation. Meta-analysis of five RCTs showed that the supplemented group had lower weight (z scores) at one year of age (MD -0.23, 95% CI -0.40 to -0.06; I2 = 83%; N = 521) and that the two groups showed no significant differences with respect to length and head circumference (z scores). Meta-analysis at 18 months and at two years revealed no significant differences between the two groups with respect to weight (kg), length (cm) and head circumference (cm). GRADE analysis of these outcomes indicated that the overall quality of evidence was low.

Authors' conclusions
Most of the included RCTs reported no beneficial effects or harms of LCPUFA supplementation on neurodevelopmental outcomes of formula-fed full-term infants and no consistent beneficial effects on visual acuity. Routine supplementation of full-term infant milk formula with LCPUFA cannot be recommended at this time.

Long chain polyunsaturated fatty acid supplementation in infants born at term

Impact of maternal diet on human milk composition and neurological development of infants

Docosahexaenoic acid (DHA) is the predominant omega-3 (n-3) polyunsaturated fatty acid (PUFA) found in the brain and can affect neurological function by modulating signal transduction pathways, neurotransmission, neurogenesis, myelination, membrane receptor function, synaptic plasticity, neuroinflammation, membrane integrity and membrane organization. DHA is rapidly accumulated in the brain during gestation and early infancy, and the availability of DHA via transfer from maternal stores impacts the degree of DHA incorporation into neural tissues. The consumption of DHA leads to many positive physiological and behavioral effects, including those on cognition. Advanced cognitive function is uniquely human, and the optimal development and aging of cognitive abilities has profound impacts on quality of life, productivity, and advancement of society in general. However, the modern diet typically lacks appreciable amounts of DHA. Therefore, in modern populations, maintaining optimal levels of DHA in the brain throughout the lifespan likely requires obtaining preformed DHA via dietary or supplemental sources. In this review, we examine the role of DHA in optimal cognition during development, adulthood, and aging with a focus on human evidence and putative mechanisms of action.

https://www.mdpi.com/2072-6643/8/2/99/pdf

Docosahexaenoic Acid and Cognition throughout the Lifespan.

The question of whether a dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (ARA) imparts advantages to visual or cognitive development in term infants has been debated for many years. DHA and ARA are present in human milk, and nursing infants consume these fatty acids needed for rapid synthesis of cell membranes, particularly neural cells. The reported mean DHA and ARA levels of human milk worldwide are 0.32% and 0.47% of total fatty acids, respectively. Prior to 2002 in the US, formula-fed infants did not receive these fatty acids and relied solely on endogenous conversion of the dietary essential omega-3 (n-3) and omega-6 (n-6) fatty acids, α-linolenic and linoleic acids, to DHA and ARA, respectively. Formula-fed infants were found to have significantly less accretion of DHA in brain cortex after death than breastfed infants. Numerous studies have found positive correlations between blood DHA levels and improvements in cognitive or visual function outcomes of breastfed and formula-fed infants. Results of randomized controlled clinical trials of term formula-fed infants evaluating functional benefits of dietary DHA and ARA have been mixed, likely due to study design heterogeneity. A comparison of visual and cognitive outcomes in these trials suggests that dietary DHA level is particularly relevant. Trials with formulas providing close to the worldwide human milk mean of 0.32% DHA were more likely to yield functional benefits attributable to DHA. We agree with several expert groups in recommending that infants receive at least 0.3% DHA, with at least 0.3% ARA, in infant feedings; in addition, some clinical evidence suggests that an ARA:DHA ratio greater than 1:1 is associated with improved cognitive outcomes.

Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: A review of randomized controlled trials

http://www.omega-3centre.com/images/stories/articles/Research/diamond%20study%20ajcn.pdf

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid

Studies of docosahexaenoic acid (DHA) intake and status in US toddlers are lacking. One national survey found low DHA intakes. The objectives of this double-blind, randomized study were to (a) determine usual DHA intakes, (b) measure the effect of consuming formulas with DHA on red blood cell (RBC) and plasma DHA and (c) record adverse events in US children between 18 and 36 months of age. Children aged 18–36 months were provided 237-ml formula with 0, 43, or 130mg DHA per day for 60 days. Blood was obtained at 0 and 60 days and 24-hour dietary recalls at 0, 30 and 60 days. Usual median daily DHA intake was 13.3mg. RBC DHA increased in a dose-dependent manner with increasing DHA intake ( p p =0.007) and a lower incidence of respiratory illness ( p =0.024), compared to the formula without DHA. US toddlers have low DHA intake and status. Modest increases in DHA intake in toddlers might improve development, including respiratory health.

Toddler formula supplemented with docosahexaenoic acid (DHA) improves DHA status and respiratory health in a randomized, double-blind, controlled trial of US children less than 3 years of age

Abstract Pre-eclampsia is associated with postnatal cardiac dysfunction; however, the nature of this relationship remains uncertain. This multicentre retrospective cohort study aimed to determine the prevalence of pre-eclampsia in women with pre-existing cardiac dysfunction (left ventricular ejection fraction &lt; 55%) and explore the relationship between pregnancy outcome and pre-pregnancy cardiac phenotype. In this cohort of 282 pregnancies, pre-eclampsia prevalence was not significantly increased (4.6% [95% C.I 2.2–7.0%] vs. population prevalence of 4.6% [95% C.I. 2.7–8.2], p = 0.99); 12/13 women had concurrent obstetric/medical risk factors for pre-eclampsia. The prevalence of preterm pre-eclampsia (&lt; 37 weeks) and fetal growth restriction (FGR) was increased (1.8% vs. 0.7%, p = 0.03; 15.2% vs. 5.5%, p &lt; 0.001, respectively). Neither systolic nor diastolic function correlated with pregnancy outcome. Antenatal ß blockers (n = 116) were associated with lower birthweight Z score (adjusted difference − 0.31 [95% C.I. − 0.61 to − 0.01], p = 0.04). To conclude, this study demonstrated a modest increase in preterm pre-eclampsia and significant increase in FGR in women with pre-existing cardiac dysfunction. Our results do not necessarily support a causal relationship between cardiac dysfunction and pre-eclampsia, especially given the population’s background risk status. The mechanism underpinning the relationship between cardiac dysfunction and FGR merits further research but could be influenced by concomitant ß blocker use. 

/pdf/prevalence-of-pre-eclampsia-and-adverse-pregnancy-outcomes-detegauk.pdf

Laura M. Minns

Papers

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid

Toddler formula supplemented with docosahexaenoic acid (DHA) improves DHA status and respiratory health in a randomized, double-blind, controlled trial of US children less than 3 years of age

Prevalence of pre-eclampsia and adverse pregnancy outcomes in women with pre-existing cardiomyopathy: a multi-centre retrospective cohort study