• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Nutrición y desarrollo cerebral
 

Nutrición y desarrollo cerebral

on

  • 3,720 views

 

Statistics

Views

Total Views
3,720
Views on SlideShare
3,320
Embed Views
400

Actions

Likes
2
Downloads
0
Comments
0

7 Embeds 400

http://ejerciciodeunarte.blogspot.com 312
http://feeds.feedburner.com 51
http://ejerciciodeunarte.blogspot.mx 26
http://www.ejerciciodeunarte.blogspot.com 4
http://ejerciciodeunarte.blogspot.com.es 4
http://ejerciciodeunarte.blogspot.pt 2
http://ejerciciodeunarte.blogspot.com.ar 1
More...

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • Like all life processes, brain growth and development and subsequently its functions are subject to the influence of biological and nutritional factors and their interplay.During embryonic, fetal and early postnatal life, genes determine the fate of neuronal progenitors, their migration to brain regions and modulate synaptic signal transmission. At the same time, environmental determinants play an equally critical role in shaping the neural configuration. Some of these environmental determinants act by modifying gene expression through epigenetic changes. References: Hsu YC, et al. Neural stem cells, neural progenitors, and neurotrophic factors. CellTransplant 2007;16:133–50.
  • What is the role of nutrition in this complex process?Brain functions are very demanding in terms of energy and special nutrients supply such as choline, folic acid, iron, zinc and special fats (e.g. gangliosides, sphingolipids and docosahexaenoic acid (DHA)). Some of these nutrients are structural components (lipids), as DHA.Other nutrients are mediators of metabolic processes (iron, iodine, zinc) acting as cofactors of enzymatic processes. Nutrition and nutrients have also epigenetic effects modifying the influence of biological factors, such as gene expression, for example the effects exerted by altering histone acetylation (folic acid, choline as methyl donors). The importance of adequate provision of protein and calories in order to sustain the processes of neuronal and glial cells proliferaion and differentatiation , synapse formation and myelinisation are illustrated by the effects of malnutrition on the developing brain. References: Levi RS, Sanderson IR. Dietary regulation of gene expression. Curr Opin Gastroenterol 2004;20:139–42.
  • Nutrients’ essentiality depends on the timing of their delivery in relation to critical periods during brain development.A critical period is referred as a relatively narrow time-frame during which a particular brain region develops or in which a specific experience must occur. Prenatal development has well defined milestones or critical periods, like formation of the neural tube from which eventually evolves the central nervous system, during which period folic acid is essential for neural tube closure for a short period around 22 days human gestation (1). Post-natal brain development milestones and timeframes are generally less well defined in onset; they are also broader and protracted in time. Thompson and Nelson (2) have characterized these periods of brain development during postnatal life as sensitive periods because they are flexible and the time period in which they function is broader. For example, in the case of the visual and auditory cortex, the formation of experience-dependent synapses peaks about the fourth postnatal month (2).REFERENCES1. Czeizel A, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992;327:1832–35. 2. Thompson RA, Nelson CA. Developmental science and the media. Early brain development. Am Psychol 2001;56(1):5–15.
  • All nutrients are necessary for prenatal and post-natal brain development and function; however, there are some nutrients that have specific critical roles in brain nutrition (e.g., vitamin A, DHA, iodine, iron, zinc, choline); The brain effects of these particular nutrients are intrinsically related to their physicochemical characteristics (e.g., metals like iron, zinc and iodine are enzyme components, fatty acids like DHA are a membrane component) and thus, nutritional effects can be quite specific. The essential roles of nutrients are time and dose dependent (e.g.,periconceptional supplementation with vitamin A is teratogenic, whereas immediately postnatal, it is beneficial);
  • The PUFAs linoleic acid (omega-6, LA; 18:2,n-6) and a-linolenic acid (omega-3,ALA; 18:3,n-3) are essential fatty acids in many mammals, including humans, because humans, like all mammals, cannot make them and must obtain them in their diet. Their biological importance derives in part from their role as constituents of structural lipids in cellular membranes, which influence the activities of membrane-linked functional molecules (receptors, enzymes, and transporters) and as precursors of important second messengers (prostaglandins, prostacyclins, and leukotrienes).The long chain omega-3 fatty acid docosahexaenoic acid (DHA, 22:6 n-3) is specifically enriched in brain gray matter and the rod and cone outer segment membranes of the retina. Typically, DHA represents about 10% of total fatty acids in brain grey matter, with lower amounts in white matter. The rod and cone outer segments, on the other hand, are a highly specialized series of membrane disks in which DHA represents about 35% of the total fatty acids. REFERENCELanting CI,et al. Lipids in infant nutrition and their impact on later development. Curr Opin Lipidol. 1996;7:43-7.
  • Mammals are not able to synthesize the parent compounds of both EFA families, the ω-6 fatty acid LA and the corresponding ω-3 fatty acid ALA.Therefore, they must be obtained through the consumption of food. In contrast, humans and most animals (except cats, that are obligatory carnivores) are capable of synthesizing the long-chain derivatives of these fatty acids, in particular AA, EPA and DHA, from LA and ALA in a multistage conversion process, which primarily takes place in the ER of liver cells The competitive desaturation of the (n-3), (n-6) and (n-9) series by delta-5 and -6 desaturase is of major significance because this is the controlling step of the pathway. Metabolic transformation of essential fatty acids (EFA) to form long-chain PUFA (LCPUFA) is shown. Parent EFA are derived from dietary sources for both (n-3) (18:3, α-linolenic acid) and (n-6) series (18:2, linoleic acid). The pathway generally accepted for further metabolism of EPA to DHA involves 2 sequential elongations of EPA to 24:6(n-3), followed by transport to the peroxisomes, and then a single cycle of b-oxidation to yield DHA, which is then transported back to the microsomes for incorporation into glycerolipids.REFERENCESInnis SM.The role of dietary n-6 and n-3 fatty acids in the developing brain. Dev Neurosci. 2000 Sep-Dec;22(5-6):474-80
  • ALA conversion to DHA is low in humans, with ,1% dietary ALA converted to DHA. Increased dietary intakes of ALA do not increase DHA in blood. Dietary DHA, however, is well absorbed and readily incorporated into plasma and blood cell lipids in humans and animal studies have also shown that dietary DHA is readily incorporated into lipids of the developing brain, both before and after birth.The conversion process is regulated by various endogenous and exogenous factors: 1. FADS 1 and FADS 2 genes code for the enzymes delta-5 desaturase and delta-6 desaturase, which play a major role in the conversion of LA and ALA into the long-chain derivatives. SNPs (single-nucleotide polymorphisms) have been identified in the FADS 1 and FADS 2 (fatty acid desaturase) gene clusters. The potential functional effects of these SNPs are still unclear. 2. Conversion efficiency also appears to be gender-specific dependent on sex hormones. In vivo studies have shown that the conversion of ALA into EPA and DHA is much more efficient in women. Experiments on rodents suggest that male animals are particularly at risk for PUFA deficiencies or imbalances, as testosterone inhibits the synthesis of LC-PUFAs, whereas estrogens protect them from breaking down.3. The status of mineral cofactors also appears to have an influence on the conversion and status of ω-3 fatty acids. Minerals such as magnesium and zinc are crucial desaturases enzyme’ cofactors. A lack of these micronutrients results in an inhibition of enzyme activity. 4. Furthermore, the conversion of ALA into EPA and DHA is competitively lowered by a high supply of LA. Excess dietary LA associated with some vegetable oils, particularly safflower, sunflower and corn oils, may decrease the formation of DHA from ALA because the delta-6 desaturase is inhibited by excess substrate.5. Oxidative stress is a potential influencing factor for an elevated metabolism rate of LC-PUFA, and in particular ω-3 fatty acids REFERENCEHussein N, et al. Long-chain conversion of [13C]linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. J Lipid Res. 2005;46:269-80
  • Omega-6 and omega-3 polyunsaturated fatty acids (PUFAs) play a central role in the normal development and functioning of the brain and central nervous system. Long-chain PUFAs (LC-PUFAs) such as eicosapentaenoic acid (EPA, C20:5, n-3), docosahexaenoic acid (DHA, C22:6,n-3) and arachidonic acid (AA, C20:4,n-6), in particular, are involved in numerous neuronal processes, ranging from effects on membrane fluidity to gene expression regulation. Because brain DHA accretion is greatest during fetal development and early infancy, it is generally considered that this reflects a critical time during which deficiency of DHA may have long-term consequences for later brain function. Lipid-bound DHA in the membrane bilayer It is suggested that increasing proportion of ω-3 fatty acids modifies the physical properties of the neuronal cell membranes, which influences the proteins (receptors, transporters, channels) enclosed in the membrane.As a result of changes in the properties of the lipid phase, DHA plays a significant role in maintaining optimal membrane integrity and fluidity , which is necessary for signal processes within the cell. An altered fluidity of the neuronal membrane phospholipids affects the structure of the membrane channels and membrane-bound receptors, which, in turn, has an effect on their function and activity. Owing to this biophysical model of action, LC-PUFAs are able to influence cellular signal processes and transmissions, for example by changing the binding or release of neurotransmitters. Consequently, optimal physiological membrane function—being a precondition for corresponding intercellular communication—is dependent on optimal ratio of ω-6 and ω-3 fatty acids.REFERENCEBelkind-Gerson J, et al.Fatty acids and neurodevelopment. J Pediatr Gastroenterol Nutr. 2008 Aug;47 Suppl 1:S7-9.
  • Unesterified DHA, on the other hand, appears to have roles in regulating gene expression, neurotransmitters’ metabolism and neuronal protectionThese effects are mediated by fatty acid-binding proteins (FABP), a multi-gene family of small cytosolic proteins that function as cytoplasmic fatty acidtransporters, playing key roles in fatty acid transfer to membranes, and mediating the effects of fatty acids on gene expression, and as precursors for synthesis of other metabolites. 1. The (n-3) and (n-6) fatty acids are ligands for PPAR, a group of nuclear transcription factors that heterodimerize with the retinoid X receptor (RXR) and bind to specific regions of DNA to regulate transcription of target genes. Together with its retinoic acid receptor (RAR), RXR play key roles in many aspects of development, including neurogenesis during embryogenesis, morphological differentiation of catecholaminergic neurons, and activity-dependent plasticity.2. DHA affects monoaminergic and cholinergic systems at multiple levels, including synthesis, storage, release, and receptor-mediated uptake, with effects that also differ among different regions of the cortex.3. There is evidence that DHA may influence brain development through protection against apoptotic cell death. 4. Recent studies also point to important roles for DHA in inhibition of oxidative stress. DHA has shown important free radical scavenging properties and protects against peroxidative damage of lipids and proteins in developing and adult brains, with attenuation of neuron loss and cognitive and locomotor deficits in animal models of ischemia-reperfusion brain injury.5. The nutritionally relevant role of long-chain ω-6 and ω-3 fatty acids as eicosanoid precursors is also significant with regard to their effect on brain function. REFERENCEInnis SM.Dietary omega 3 fatty acids and the developing brain. Brain Res. 2008 Oct 27;1237:35-43.
  • Term infants need an exogenous supply of AA and DHA to achieve similar accretion of FA in plasma and RBC comparable to breast-fed infants. Beginning in the 1980s, several studies reported lower plasma and erythrocyte levels of DHA in infants fed formula containing LA and ALA as the onlypolyunsaturated fatty acids, when compared to breast-fed infants. Including a source of DHA in formula, however, increases blood lipid levels of DHA in formula-fed infants to the same levels as that in infants receiving a similar amount of DHA from human milk. 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. Several studies, not all 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. The addition of LCPUFA in infant formulas for term infants, with appropriate regard for quantitative and qualitative qualities, is safe and will enable the formula-fed infant to achieve the same blood LCPUFA status as that of the breast-fed infant.Rationale for addition of LC-PUFA to IFHuman milk contains n-3 and n-6 LCPUFA (long chain polyunsaturated fatty acids), which are absent from many infant formulas. During neonatal life, there is a rapid accretion of AA (arachidonic acid) and DHA (docosahexaenoic acid) in infant brain, DHA in retina and of AA in the whole body. The DHA status of breast-fed infants is higher than that of formula-fed infants when formulas do not contain LCPUFA. Plasma and RBC FA status of infants fed formulas supplemented with both n-3 and n-6 LCPUFA was closer to the status of breast-fed infants than to that of infants fed formulas containing no LCPUFA. Studies report that visual acuity of breast-fed infants is better than that of formula-fed infants, but other studies do not find a difference. Cognitive development of breast-fed infants is generally better, but many sociocultural confounding factors may also contribute to these differences. Functional, long term benefits in particular visual or neural development from IF containing LCPUFA remains controversial. Potential for excessive and/or imbalanced intake of n-6 and n-3 fatty acids exists with increasing fortification of LCPUFA to infant foods other than IF.
  • There are several possible reasons for the inconsistent findings in these studies: differences in the amounts of α-linolenic acid (1.1%–2.6% of fatty acids), DHA (0.12%–0.36% of fatty acids), and/or ARA (0.30%–0.72%) in the formulas studied; other differences among the formulas (eg, sources of fats); differences in the test instruments used, testing procedures, or outcomes studied; sample size limitations; 5) whether the infants were term or preterm.
  • Infant formula supplementation with long-chain polyunsaturated fatty acids has no effect on Bayley developmental scores at 18 months of age--IPD meta-analysis of 4 large clinical trials. Beyerlein A, et al. J Pediatr G,N. 2010;50:79-84.OBJECTIVES: Whether supplementation of formula milk by long-chain polyunsaturated fatty acids (LCPUFA) affects neurodevelopment at 18 months of age in term or preterm infants by an individual patient data (IPD) meta-analysis.MATERIALS AND METHODS: Data of 870 children from 4 large randomised clinical trials for formula milk with and without LCPUFAs allowed for assessing the effect of LCPUFA with adjustment for potential confounders and extensive subgroup analysis on prematurity, LCPUFA source, and dosage. The sample size was sufficient to detect clinically relevant differences in Bayley Scales even in subgroups.RESULTS: There were no significant differences in mental or psychomotor developmental indexes between LCPUFA-supplemented and control groups for all children or in subgroups. This was confirmed with adjustment for the possible confounders: sex, gestational age, birth weight, maternal age, and maternal smoking. The adjusted mean differences in mental developmental index and psychomotor developmental index for all of the children were -0.8 (95% confidence interval -2.8 to 1.2) and -1.0 (-2.7 to 0.7), respectively.CONCLUSIONS: These data based on considerable sample size provide substantial evidence that LCPUFA supplementation of infant formula does not have a clinically meaningful effect on the neurodevelopment as assessed by Bayley scores at 18 months. Inclusion of all relevant data should not have led to differing conclusions except, possibly, for very-low-birth-weight infants.IPD meta-analysis shows no effect of LC-PUFA supplementation on infant growth at 18 months. Rosenfeld E, et al. Acta Paediatr. 2009;98:91-7 AIM: Clinical trials on the effects of long-chain polyunsaturated fatty acids (LC-PUFA) supplementation of formula milk on growth of term and preterm children have shown conflicting results. We examined the effects of LC-PUFAs-- especially docosahexaenoic acid (DHA) and arachidonic acid (AA)--on growth at 18 months.METHODS: We performed a meta-analysis based on individual patient data (IPD) of 901 children from four large, randomised clinical trials of formula milk with and without LC-PUFAs. Anthropometrics were assessed by z-scores based on weight for age, length for age, head circumference for age and body mass index (BMI) for age at 18 months. The studies differed in LC-PUFA composition and infant characteristics (two studies on preterm children, two on term children).RESULTS: Multivariate regression analyses including the possible confounders, sex, gestational age, birth weight, smoking in the last trimester and maternal age, as well as interaction terms showed no significant effects of LC-PUFA supplementation on any z-score. Subgroup analyses on trials with high amounts of DHA and on studies with duration of supplementation of at least 6 months yielded the same result. These findings cannot be explained by the lack of power.CONCLUSION: Our IPD meta-analysis shows no evidence that LC-PUFA supplementation affects children's growth at 18 months of age.Docosahexaenoic acid supplementation and time at achievement of gross motor milestones in healthy infants: a randomized, prospective, double-blind, placebo-controlled trial. Agostoni C, et al.Am J Clin Nutr. 2009;89:64-70. OBJECTIVE: Assess the effects of DHA supplementation throughout the first year of life on the achievement of four gross motor milestones in healthy infants.DESIGN: In this multicenter prospective, randomized, double-blind, placebo-controlled trial, 1160 healthy neonates were assigned to receive supplementation with either 20 mg liquid DHA (n = 580) or placebo (n = 580) orally once daily throughout the first year of life. The primary endpoint was the time at achievement of 4 gross motor milestones (sitting without support, hands-and-knees crawling, standing alone, and walking alone). All analyses were performed on an intention-to-treat basis.RESULTS: The time to achievement of sitting without support was shorter (P < 0.001) in infants who received DHA than in placebo. No significant difference between infants who received DHA or placebo was found for hands-and-knees crawling, standing alone and walking aloneCONCLUSIONS: Despite the 1-wk advance in sitting without support associated with DHA supplementation, no demonstrable persistent effects of DHA supplementation on later motor development milestones were found. Thus, the long-term clinical significance of the 1-wk change in sitting without support, if any, remains unknownVisual acuity and cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant formula. Birch EE, et al.Early Hum Dev. 2007;83:279-84. BACKGROUND: While there is a large body of data on the effects of long-chain polyunsaturated fatty acid supplementation of infant formula on visual and cognitive maturation during infancy, long term visual and cognitive outcome data from randomized trials are scarce.AIM: To evaluate docosahexaenoic acid (DHA) and arachidonic acid (ARA)-supplementation of infant formula on visual and cognitive outcomes at 4 years of age.METHODS: Fifty-two of 79 healthy term infants who were enrolled in a single-center, double-blind, randomized clinical trial of DHA and ARA supplementation of infant formula were available for follow-up at 4 years of age. In addition, 32 breast-fed infants served as a "gold standard". Outcome measures were visual acuity and the Wechsler Preschool and Primary Scale of Intelligence--Revised.RESULTS: At 4 years, the control formula group had poorer visual acuity than the breast-fed group; the DHA- and DHA+ARA-supplemented groups did not differ significantly from the breast-fed group. The control formula and DHA-supplemented groups had Verbal IQ scores poorer than the breast-fed group.CONCLUSION: DHA and ARA-supplementation of infant formula supports visual acuity and IQ maturation similar to that of breast-fed infants.The effect of alpha-linolenic acid and linoleic acid on the growth and development of formula-fed infants: a systematic review and meta-analysis of randomized controlled trials. Udell T, et al. PUFA Study Group.Lipids. 2005;40:1-11. This systematic review and meta-analysis aimed to evaluate the effect of modifying 18-carbon PUFA [18-C PUFA: alpha-linolenic acid (ALA, 18:3n-3) and linoleic acid (LA, 18:2n-6)] in the diets of term and preterm infants on DHA (22:6n-3) status, growth, and developmental outcomes. Only randomized controlled trials (RCT) involving formula-fed term and preterm infants, in which the 18-C PUFA composition of the formula was changed and growth or developmental outcomes were measured, were included. Differences were presented as control (standard formula) and treatment (18-C PUFA-supplemented formula). Primary analyses for term infants were 4 and 12 month and for preterm infants 37-42 and 57 wk postmenstrual age. Five RCT involving term infants and three RCT involving preterm infants were included in the systematic review. Infants fed ALA-supplemented formula had significantly higher plasma and erythrocyte phospholipid DHA levels than control infants. There was no effect of ALA supplementation on the growth of preterm infants. In term infants, ALA supplementation was associated with increased weight and length at 12 months, which was at least 4 months after the end of dietary intervention. Developmental indices of term infants did not differ between groups. There was a transient improvement in the retinal function of preterm infants fed ALA-supplemented diets compared with controls. The findings suggest that ALA-supplemented diets improve the DHA status of infants. Further studies are needed to provide convincing evidence regarding the effects of ALA supplementation of formula on infant growth and development.Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age. Auestad N, et al.Pediatrics. 2003112:e177-83.The present follow-up study evaluated IQ, receptive and expressive vocabulary, visual-motor function, and visual acuity of children from the original trial when they reached 39 months of age.CONCLUSIONS: When the infants were reassessed at 39 months using age-appropriate tests of receptive and expressive language as well as IQ, visual-motor function and visual acuity, no differences among the formula groups or between the formula and breastfed groups were found. The 14-month observation thus may have been a transient effect of DHA (without ARA) supplementation on early vocabulary development or may have occurred by chance. The absence of differences in growth achievement adds to the evidence that DHA with or without ARA supports normal growth in full-term infants. In conclusion, adding both DHA and ARA when supplementing infant formulas with long-chain polyunsaturated fatty acids supports visual and cognitive development through 39 months.Growth and development in term infants fed long-chain polyunsaturated fatty acids: a double-masked, randomized, parallel, prospective, multivariate study. Auestad N, et al.Pediatrics. 2001 Aug;108(2):372-81.OBJECTIVE: To evaluate the effects of dietary intake of the long-chain polyunsaturated fatty acids, arachidonic acid (AA), and docosahexaenoic acid (DHA) on multiple indices of infant growth and development.DESIGN: A double-masked, randomized, parallel trial was conducted with term infants fed formulas with or without AA+DHA for 1 year (N = 239). Reference groups of breastfed infants (N = 165) weaned to formulas with and without AA+DHA were also studied. Infants in the formula groups were randomized at < 7 d old were randomized to be fed formulas containing linoleic acid (approximately 10% kcal) and alpha-linolenic acid (approximately 1% kcal) plus (1) no added LCP fatty acids (control formula), (2) DHA (0.12 wt% fatty acids) and AA (0.43 wt%) from egg yolk phospholipid (AA + DHA formula), or (3) DHA (0.2 wt%) from fish oil (DHA formula). A breast-fed group was studied concurrently and permitted formula supplementation after 3 mo. Infants fed the AA + DHA formula had levels of both LCP within approximately 10% of the values for infants in the breast-fed group. There were no differences in growth or in visual function during this 12-mo feeding study.
  • Infant formula supplementation with long-chain polyunsaturated fatty acids has no effect on Bayley developmental scores at 18 months of age--IPD meta-analysis of 4 large clinical trials. Beyerlein A, et al. J Pediatr G,N. 2010;50:79-84.OBJECTIVES: Whether supplementation of formula milk by long-chain polyunsaturated fatty acids (LCPUFA) affects neurodevelopment at 18 months of age in term or preterm infants by an individual patient data (IPD) meta-analysis.MATERIALS AND METHODS: Data of 870 children from 4 large randomised clinical trials for formula milk with and without LCPUFAs allowed for assessing the effect of LCPUFA with adjustment for potential confounders and extensive subgroup analysis on prematurity, LCPUFA source, and dosage. The sample size was sufficient to detect clinically relevant differences in Bayley Scales even in subgroups.RESULTS: There were no significant differences in mental or psychomotor developmental indexes between LCPUFA-supplemented and control groups for all children or in subgroups. This was confirmed with adjustment for the possible confounders: sex, gestational age, birth weight, maternal age, and maternal smoking. The adjusted mean differences in mental developmental index and psychomotor developmental index for all of the children were -0.8 (95% confidence interval -2.8 to 1.2) and -1.0 (-2.7 to 0.7), respectively.CONCLUSIONS: These data based on considerable sample size provide substantial evidence that LCPUFA supplementation of infant formula does not have a clinically meaningful effect on the neurodevelopment as assessed by Bayley scores at 18 months. Inclusion of all relevant data should not have led to differing conclusions except, possibly, for very-low-birth-weight infants.IPD meta-analysis shows no effect of LC-PUFA supplementation on infant growth at 18 months. Rosenfeld E, et al. Acta Paediatr. 2009;98:91-7 AIM: Clinical trials on the effects of long-chain polyunsaturated fatty acids (LC-PUFA) supplementation of formula milk on growth of term and preterm children have shown conflicting results. We examined the effects of LC-PUFAs-- especially docosahexaenoic acid (DHA) and arachidonic acid (AA)--on growth at 18 months.METHODS: We performed a meta-analysis based on individual patient data (IPD) of 901 children from four large, randomised clinical trials of formula milk with and without LC-PUFAs. Anthropometrics were assessed by z-scores based on weight for age, length for age, head circumference for age and body mass index (BMI) for age at 18 months. The studies differed in LC-PUFA composition and infant characteristics (two studies on preterm children, two on term children).RESULTS: Multivariate regression analyses including the possible confounders, sex, gestational age, birth weight, smoking in the last trimester and maternal age, as well as interaction terms showed no significant effects of LC-PUFA supplementation on any z-score. Subgroup analyses on trials with high amounts of DHA and on studies with duration of supplementation of at least 6 months yielded the same result. These findings cannot be explained by the lack of power.CONCLUSION: Our IPD meta-analysis shows no evidence that LC-PUFA supplementation affects children's growth at 18 months of age.Docosahexaenoic acid supplementation and time at achievement of gross motor milestones in healthy infants: a randomized, prospective, double-blind, placebo-controlled trial. Agostoni C, et al.Am J Clin Nutr. 2009;89:64-70. OBJECTIVE: Assess the effects of DHA supplementation throughout the first year of life on the achievement of four gross motor milestones in healthy infants.DESIGN: In this multicenter prospective, randomized, double-blind, placebo-controlled trial, 1160 healthy neonates were assigned to receive supplementation with either 20 mg liquid DHA (n = 580) or placebo (n = 580) orally once daily throughout the first year of life. The primary endpoint was the time at achievement of 4 gross motor milestones (sitting without support, hands-and-knees crawling, standing alone, and walking alone). All analyses were performed on an intention-to-treat basis.RESULTS: The time to achievement of sitting without support was shorter (P < 0.001) in infants who received DHA than in placebo. No significant difference between infants who received DHA or placebo was found for hands-and-knees crawling, standing alone and walking aloneCONCLUSIONS: Despite the 1-wk advance in sitting without support associated with DHA supplementation, no demonstrable persistent effects of DHA supplementation on later motor development milestones were found. Thus, the long-term clinical significance of the 1-wk change in sitting without support, if any, remains unknownVisual acuity and cognitive outcomes at 4 years of age in a double-blind, randomized trial of long-chain polyunsaturated fatty acid-supplemented infant formula. Birch EE, et al.Early Hum Dev. 2007;83:279-84. BACKGROUND: While there is a large body of data on the effects of long-chain polyunsaturated fatty acid supplementation of infant formula on visual and cognitive maturation during infancy, long term visual and cognitive outcome data from randomized trials are scarce.AIM: To evaluate docosahexaenoic acid (DHA) and arachidonic acid (ARA)-supplementation of infant formula on visual and cognitive outcomes at 4 years of age.METHODS: Fifty-two of 79 healthy term infants who were enrolled in a single-center, double-blind, randomized clinical trial of DHA and ARA supplementation of infant formula were available for follow-up at 4 years of age. In addition, 32 breast-fed infants served as a "gold standard". Outcome measures were visual acuity and the Wechsler Preschool and Primary Scale of Intelligence--Revised.RESULTS: At 4 years, the control formula group had poorer visual acuity than the breast-fed group; the DHA- and DHA+ARA-supplemented groups did not differ significantly from the breast-fed group. The control formula and DHA-supplemented groups had Verbal IQ scores poorer than the breast-fed group.CONCLUSION: DHA and ARA-supplementation of infant formula supports visual acuity and IQ maturation similar to that of breast-fed infants.The effect of alpha-linolenic acid and linoleic acid on the growth and development of formula-fed infants: a systematic review and meta-analysis of randomized controlled trials. Udell T, et al. PUFA Study Group.Lipids. 2005;40:1-11. This systematic review and meta-analysis aimed to evaluate the effect of modifying 18-carbon PUFA [18-C PUFA: alpha-linolenic acid (ALA, 18:3n-3) and linoleic acid (LA, 18:2n-6)] in the diets of term and preterm infants on DHA (22:6n-3) status, growth, and developmental outcomes. Only randomized controlled trials (RCT) involving formula-fed term and preterm infants, in which the 18-C PUFA composition of the formula was changed and growth or developmental outcomes were measured, were included. Differences were presented as control (standard formula) and treatment (18-C PUFA-supplemented formula). Primary analyses for term infants were 4 and 12 month and for preterm infants 37-42 and 57 wk postmenstrual age. Five RCT involving term infants and three RCT involving preterm infants were included in the systematic review. Infants fed ALA-supplemented formula had significantly higher plasma and erythrocyte phospholipid DHA levels than control infants. There was no effect of ALA supplementation on the growth of preterm infants. In term infants, ALA supplementation was associated with increased weight and length at 12 months, which was at least 4 months after the end of dietary intervention. Developmental indices of term infants did not differ between groups. There was a transient improvement in the retinal function of preterm infants fed ALA-supplemented diets compared with controls. The findings suggest that ALA-supplemented diets improve the DHA status of infants. Further studies are needed to provide convincing evidence regarding the effects of ALA supplementation of formula on infant growth and development.Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age. Auestad N, et al.Pediatrics. 2003112:e177-83.The present follow-up study evaluated IQ, receptive and expressive vocabulary, visual-motor function, and visual acuity of children from the original trial when they reached 39 months of age.CONCLUSIONS: When the infants were reassessed at 39 months using age-appropriate tests of receptive and expressive language as well as IQ, visual-motor function and visual acuity, no differences among the formula groups or between the formula and breastfed groups were found. The 14-month observation thus may have been a transient effect of DHA (without ARA) supplementation on early vocabulary development or may have occurred by chance. The absence of differences in growth achievement adds to the evidence that DHA with or without ARA supports normal growth in full-term infants. In conclusion, adding both DHA and ARA when supplementing infant formulas with long-chain polyunsaturated fatty acids supports visual and cognitive development through 39 months.Growth and development in term infants fed long-chain polyunsaturated fatty acids: a double-masked, randomized, parallel, prospective, multivariate study. Auestad N, et al.Pediatrics. 2001 Aug;108(2):372-81.OBJECTIVE: To evaluate the effects of dietary intake of the long-chain polyunsaturated fatty acids, arachidonic acid (AA), and docosahexaenoic acid (DHA) on multiple indices of infant growth and development.DESIGN: A double-masked, randomized, parallel trial was conducted with term infants fed formulas with or without AA+DHA for 1 year (N = 239). Reference groups of breastfed infants (N = 165) weaned to formulas with and without AA+DHA were also studied. Infants in the formula groups were randomized at < 7 d old were randomized to be fed formulas containing linoleic acid (approximately 10% kcal) and alpha-linolenic acid (approximately 1% kcal) plus (1) no added LCP fatty acids (control formula), (2) DHA (0.12 wt% fatty acids) and AA (0.43 wt%) from egg yolk phospholipid (AA + DHA formula), or (3) DHA (0.2 wt%) from fish oil (DHA formula). A breast-fed group was studied concurrently and permitted formula supplementation after 3 mo. Infants fed the AA + DHA formula had levels of both LCP within approximately 10% of the values for infants in the breast-fed group. There were no differences in growth or in visual function during this 12-mo feeding study.
  • MAIN RESULTS: Twenty randomised studies were identified. Fourteen were included (n = 1719) and six excluded. Eleven included studies were of good quality. The main outcomes assessed were visual acuity, neurodevelopmental and physical growth. Visual acuity was measured at various stages throughout the first three years of life by nine studies. Visual evoked potential was used to assess visual acuity in five studies. The remaining four used Teller visual acuity cards. The results were inconsistent. Three studies reported beneficial effect of LCPUFA supplementation on visual acuity while the remaining six did not. Neurodevelopmental outcome was measured at different ages throughout the first two years by eleven studies. Bayley scales of infant development (BSID) was used in eight studies. Only one showed beneficial effect of LCPUFA supplementation on BSID scales. Pooled meta-analysis of the data also did not show any statistically significant benefit of LCPUFA supplementation on either mental or psychomotor developmental index of BSID. One study reported better novelty preference measured by Fagan Infant test at nine months in supplemented infants compared with controls. Another study reported better problem solving at 10 months with supplementation. One study used Brunet and Lezine developmental test to assess the developmental quotient and did not find beneficial effects of LCPUFA supplementation. Physical growth was measured at various ages throughout first three years of life by twelve studies. Some studies reported the actual measurements while some reported the rate of growth over a time period. Some studies z scores. Irrespective of the type of LCPUFA supplementation, duration of supplementation and method of assessment, none of the individual studies found beneficial or harmful effects of LCPUFA supplementation. Meta-analysis of relevant studies also did not show any effect of LCPUFA supplementation on growth of term infants.AUTHORS' CONCLUSIONS: The results of most of the well conducted RCTS have not shown beneficial effects of LCPUFA supplementation of formula milk on the physical, visual and neurodevelopmental outcomes of infants born at term. Only one group of researchers have shown some beneficial effects on VEP acuity. Two groups of researchers have shown some beneficial effect on mental development. Routine supplementation of milk formula with LCPUFA to improve the physical, neurodevelopmental or visual outcomes of infants born at term can not be recommended based on the current evidence. Further research is needed to see if the beneficial effects demonstrated by Dallas 2005 trial of Birch et al can be replicated in different settings.Simmer K, Patole SK, Rao SC.Longchain polyunsaturated fatty acid supplementation in infants born at term. Cochrane Database Syst Rev. 2008;(1):CD000376.
  • Whether infant formulas should be supplemented with long-chain polyunsaturated fatty acids has been hotly debated during the past decade. Some studies have reported improved visual acuity and/or cognitive development with supplementation, whereas others found no benefitsTrials 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. There have been very few reports of adverse events ininfants fed LCPUFA containing IF . Most of the adverse events seem to be associatedwith the use of IF containing DHA only. Preterm infants fedIF with DHA but without ARA have lower absolute or Z scoresin weight, length or head circumference,and a decreased fat free mass (1).For infants fed DHA and ARA containing IF there has been nodocumented adverse growth except for one report in preterm infants (2). It showed preterm infants fed IF with DHA and ARA duringtheir hospital stay had lower weight and length upon followup at 18 month corrected age compared to those fed IF containingonly the essential fatty acid precursors.DHA supplemented IF raises DHA level in red cell and plasma,but there was an associated decreased in the level of ARA interm and preterm infants. This presumablyreflects the imbalanced intake of n-6 and n-3 fatty acidsalthough the functional significance of this alteration is notknown (3).Increasing fortification of DHA of commercial baby food becomesan added safety concern both from the excessive intake and/orimbalanced ratio of n-6 and n-3 fatty acids.REFERENCESCarlson SE, Werkman SH, Tolley EA: Effect of long-chain n-3 fatty acid supplementation on visual acuity and growth of preterm infants with and without bronchopulmonary dysplasia.Am J Clin Nutr63 :687 –697,1996 Fewtrell MS, Morley R, Abbott RA, Singhal A, Isaacs EB, Stephenson T, MacFadyen U, Lucas A: Double-blind, randomized trial of long-chain polyunsaturated fatty acid supplementation in formula fed to preterm infants.Pediatrics110 :73 –82,2002 Sauerwald TU, Hachey DL, Jensen CL, Chen H, Anderson RE, Heird WC: Effect of dietary alpha-linolenic acid intake on incorporation of docosahexaenoic and arachidonic acids into plasma phospholipids of term infants.Lipids 31(Suppl) :S131 –S135,1996 .
  • The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendationsConsensus recommendations and practice guidelines for health-care providers supported by the World Association of Perinatal Medicine, the Early Nutrition Academy, and the Child Health Foundation are provided. For healthy term infants, we recommend and fully endorse breastfeeding, which supplies preformed LC-PUFA, as the preferred method of feeding. When breastfeeding is not possible, we recommend use of an infant formula providing DHA at levels between 0.2 and 0.5 weight percent of total fat, and with the minimum amount of AA equivalent to the contents of DHA. Dietary LC-PUFA supply should continue after the first six months of life, but currently there is not sufficient information for quantitative recommendations. Koletzko B, et al. World Association of Perinatal Medicine Dietary Guidelines Working Group. J Perinat Med. 2008;36(1):5-14.Emphasize:Clinical trials of the effects of AA and DHA on cognitive, social, and motor development have been inconsistent. Although no harm has been demonstrated, most well-conducted randomized trials show no benefit. Thus, recent Cochrane reviews conclude that supplementation of formula with DHA and AA cannot be recommended based on current evidence. Additionally, cost of these formula is also to be considered
  • Iron deficiency (ID) and iron deficiency anemia (IDA) are among the most prevalent nutritional problems in the world today, that affect an estimated 20% to 25% of infants worldwide.The prevalence of ID and IDA among toddlers (1–3 years of age) in the United States, derived from National Health and Nutrition Examination Survey data collected between 1999 and 2002 is: ID in 6.6% to 15.2% of toddlers, depending on ethnicity and socioeconomic status. The prevalence of IDA is 0.9% to 4.4%, again depending on race/ethnicity and socioeconomic status.Infants are at particular risk due to their rapid growth and limited dietary sources of iron. Iron is involved in many central nervous system processes that could affect infant behavior and development.Cusick SE, et al. Unexplained decline in the prevalence of anemia among US children and women between1988 –1994 and 1999 –2002. Am J Clin Nutr.88:1611: 20081617Infants are at particular risk due to their rapid growth and limited dietary sources of iron.Iron plays an essential role in many important biochemical processes. The requirement for iron is greater during periods of rapid growth and differentiation such as in the late fetal and neonatal period. Consequently, poor iron homeostasis during this period can result in disordered development.The nervous system, which develops rapidly during the late fetal and early neonatal period, seems to be particularly susceptible to iron deficiency and excess. Consequently, anemia, iron deficiency can have severe effects on neurodevelopment that, in the case of iron deficiency, may not be reversed by iron supplementation.
  • The mechanism by which iron deficiency affects brain development is incompletely understood, but it may involve general metabolic deficiencies, disordered myelination, disordered synaptogenesis and changes in specific neurotransmitter function1. Iron deficiency either in utero or in early postnatal life because iron is essential for proper neurogenesis and differentiation of certain brain cells and brain regions. Iron is essential for proper neurogenesis and differentiation of certain brain cells and regions. The recent studies in rodents clearly identify the hippocampus and striatum as 2 areas in which morphology is altered. There is a decreased arborization of dendrites that decreases the number and complexity of interneuronal connections. A second morphological alteration is the location and functioning of oligodendrocytes, the cells responsible for making myelin. Iron deficiency in early life is associated with hypomyelination of nerve cells. These cells are particularly sensitive to iron deprivation, and their deficiency results in altered composition and amount of myelin in white matter. These alterations appear to be persistent and do not return to normal levels later in life. 2. The second biological dimension suspected of being altered by iron deficiency is neurochemistry and specifically the monoaminergic pathways, with dopamine and norepinephrine metabolism are altered by iron deficiency. Iron deficiency appears to alter the synthesis and catabolism of the monoamines, and early repletion of iron status after gestational iron deficiency only overcomes the lasting effects. Dopamine and norepinephrine alterations are potential biological explanations for human dysfunctions in motor control, sleep cycles and activity, and learning and memory. 3. The third biological dimension being actively investigated is the effect of iron deficiency on bioenergetics. Using MRI technology and evaluation of ATP production has been shown that fuel utilization in the iron-deficient brain is deficient compared to control brains.
  • Almost all case-control studies comparing otherwise healthy full-term infants with iron-deficiency anemia to infants with better iron status, showed that mental development test scores averaged 6 to 15 points lower. Infants not supplemented with iron had longer looking times on a visual recognition memory task, suggesting poorer high-speed information processing on a measure that predicts later IQ.Among case-control studies that included an assessment of motor development, most found that infants with iron-deficiency anemia received lower motor test scores, averaging 6 to 17 points lower. A population study in the UK found that hemoglobin (Hb) levels under 95 g/L at 8 months predicted poorer locomotor development at 18 months. Virtually every case-controlled study that examined social-emotional behavior found differences in iron-deficient anemic infants (e.g., more wary, hesitant, solemn, unhappy, kept closer to their mothers). Infants who did not receive prophylactic iron received poorer scores in the personal/social domain, showed no social interaction, no positive affect, no social referencing, inability to be soothed by words or objects, and a lack of protest when toys were taken away.Studies including neurophysiologic assessment also showed differences in the speed of neural transmission in the auditory system, rapid eye movement density in active sleep, recognition memory with event-related potentials (ERP), and EEC frontal asymmetry.Many of the case-controlled studies have included assessments before and immediately after iron therapy. Most studies report that differences in behavior and development persist in the majority of iron-deficient anemic infants even after a full course of iron treatment (2–6 months, depending on the study).However, few studies reported improvements, sometimes dramatic, in mental and/or motor test scores after iron therapy.Perinatal (late fetal and early neonatal) iron deficiency has received less attention. However, 2 studies related perinatal iron deficiency to newborn behavior. One reported higher levels of irritability in infants whose mothers were iron deficient. In the other, lower levels of neonatal Hb and serum iron were correlated with lower levels of alertness and soothability. A small randomized, controlled trial involving breast-fed infantsin Canada showed a benefit of early (between 1 and 6 months of age) iron supplementation on motor development and visual acuity at 12 months.
  • There are several studies, of the long-term effects of early postnatal iron deficiency. These studies, most of which have been conducted at late preschool or early school age, followed children who had anemia, presumly iron-deficiency anemia, or other indications of chronic severe iron deficiency in infancy. Control for background factors is an important consideration in interpreting follow-up results and will be specified in reviewing each study.Late preschool-age follow up: Palti H, et al. Hum Biol 1983, included a relatively large group of Israeli children who had Hb determinations at 9 months and assessed their development at 2, 3, and 5 years (N = 873, 388, and 239, respectively). After statistical control for the influence of basic background characteristics, Hb at 9 months correlated with IQ at 5 years (trends at 2 and 3 years were suggestive). Dommergues JP, Arch Fr Pediatr 1989. MCV concentration at 2 years, controlling for a limited set of background factors, was positively associated with overall developmental, motor, and social quotients at 2 years and with overall developmental quotient at 4 years. After controlling for background variables including maternal IQ, HOME, and infant lead level, all studies showed that the group with moderate iron-deficiency anemia had lower test scores on performance IQ; quantitative, preschool cluster, perceptual speed, and visual matching subtests of the Woodcock Johnson; visual motor integration; and gross and fine motor performance, displayed lower levels of physical activity, positive affect, verbalization, and reciprocalinteraction. Lozoff B, et al. Long-term developmental outcome of infants with iron deficiency. N Engl J Med 1991;325:687–694.
  • Recommended dietary allowance (RDA) for iron: The average daily dietary intake that is sufficient to meet therequirements of nearly all individuals (97%–98%) of a given age and gender.Adequate intake (AI) for iron: This term is used when there is not enough information to establish a recommended dietary allowance for a population (eg, term infants, 0–6 months of age), based on the estimated average nutrient intake by a group (or groups) of healthy individuals.according to the IOM, the RDA for this age is 11 mg/dayInstitute of Medicine. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron,Chromium, Copper, Iodine, Iron, Manganese,Molybdenum, Nickel, Silicon,Vanadium, and Zinc. Washington, DC: National Academies Press; 2003
  • Zinc is known to be essential for the normal growth and development of the fetus. Zinc deficiency affects more than 20% of world population and is highest in the developing countriesThe postulated mechanisms underlying Zinc actions are modulation of neurogenesis and neuronal apoptosis.Zinc deficiency also induces apoptotic neuronal death through the intrinsic (mitochondrial) pathway, which can be triggered by the activation of the zinc-regulated enzyme caspase-3. Alterations in the finely tuned processes of neurogenesis, neuronal migration, differentiation, and apoptosis, which involve the developmental shaping of the nervous system, could have a long-term impact on brain health. Zinc deficiency during gestation, even at the marginal levels observed in human populations, could increase the risk for behavioral/neurological disorders in infancy, adolescence, and adulthood.A deficiency of this nutrient in pregnant animals has been shown to result in malformations and abnormal development and functioning of the central nervous system of the offspring. Many studies have evaluated the association between fetal zinc status and brain development in early life and established a negative effect of prenatal zinc deficiency on the brain function of experimental animals. Adverse consequences include reduced activity and responsiveness; impaired learning ability, attention, and memory; and increased aggressiveness. Adamo AM, Oteiza PI.Zinc deficiency and neurodevelopment: the case of neurons. Biofactors. 2010;36:117-24
  • Evidence from the human literature is less clear. The most striking evidence has emerged from the studies conducted during infancy. Low maternal zinc status has been associated with worse motor functioning at 6 mo of age, whereas zinc supplementation has been associated with better motor development in very-low-birth-weight infants, more vigorous activity in Indian infants and toddlers, and more functional activity in Guatemalan infants and toddlers. Zinc supplementation was associated with better neuropsychologic functioning in first-grade students in China. However, there were no relations between zinc supplementation and measures of attention through standardized test performance in school-age, stunted children in a cross-sectional study in Guatemala or a supplementation trial in Canada.Recent evidence that mild zinc deficiency may be widespread, even in populations that are adequately nourished, raises questions about the effect of zinc deprivation without the complicating factors of overall nutritional deprivation or poverty. Research that examines response to zinc supplementation (or fortification) in populations that are zinc deficient in the absence of poverty would help to clarify the relation between zinc deficiency and cognitive development. Thus, zinc deficiency may be a serious public health problem that compromises the development of millions of children in both developing and industrialized countries.Maureen M Black. Zinc deficiency and child development. Am J ClinNutr 1998;68(suppl):464S–9S
  • Based on extensive epidemiological observation, fruits and vegetables that are a rich source of carotenoids are thought to provide health benefits by decreasing the risk of various diseases, particularly certain cancers and eye diseases. The carotenoids that have been most studied in this regard are beta-carotene, lycopene, lutein and zeaxanthin. In part, the beneficial effects of carotenoids are thought to be due to their role as antioxidants. β-Carotene may have added benefits due its ability to be converted to vitamin A. Additionally, lutein and zeaxanthin may be protective in eye disease because they absorb damaging blue light that enters the eye. Food sources of these compounds include a variety of fruits and vegetables, although the primary sources of lycopene are tomato and tomato products. Additionally, egg yolk is a highly bioavailable source of lutein and zeaxanthin.Lutein was found to be concentrated in the macula lutea, a small area of the retina responsible for central vision. The hypothesis for the natural concentration is that lutein helps keep the eyes safe from oxidative damage and the high-energy photons of blue light. Lutein is a natural part of human diet when fruits and vegetables are consumed. For individuals lacking sufficient lutein intake, lutein-fortified foods are available. RDA have not been published for lutein, as for other nutrients. Positive effects have been claimed at dietary intake levels of 6–10 mg/day. The side effect of excess lutein consumption is carotenodermia.There is epidemiological evidence of a relationship between low plasma concentrations of lutein and zeaxanthin, and an increased risk of developing age-related macula degeneration (AMD). A 6-year study, John Paul SanGiovanni have found that lutein and zeaxanthin protect against blindness (macular degeneration).
  • As a main constituent of cellular membranes, the phospholipid phosphatidylcholine (PtdCho) is required for cell division and growth with subsequent effects on brain structure and function. Sphingomyelin, a PtdCho derived phospholipid, is abundant in nervous tissue and is required for myelination of nerve fibers (axons) in both the central and peripheral nervous system.
  • Choline, importance: 1. Structural function2. Besides the structural role, choline is needed for the synthesis of several important metabolites that play key roles in fetal development, particularly the brain. Acetylcholine also has trophic properties and influences the structure and organization of brain regions, neurogenesis, myelination, and synapse formation.3. Furthermore, as a methyl donor in liver, kidney, embryonic stem cells, and lens of eye, the choline derivative betaine can be used for remethylation of homocysteine to methionine. By influencing the activation of methionine to S-adenosylmethionine production, choline/betaine availability has putative effects on methyl group availability in brain (and other tissues), genome expression, and fetal programming. The development of the central nervous system is particularly sensitive to choline availability with evidence of effects on neural tube closure, hypocampal development and cognition/ memory.The importance of choline in human development is supported by observations that a human fetus receives a large supply of choline during gestation; pregnancy causes depletion of hepatic choline pools in rats consuming a normal diet. Furthermore, human neonates are born with blood levels that are three times higher than maternal blood concentrations; and large amounts of choline are present in human milk. Fat provide 45-55% of energy of human milk. Triglycerides account for 97-98% of fat in human milk, phospholipds and shingolipids 0.7% and cholesterol 0.5%. Human milk triglycerides are partially plasma derived (long-chain FA) and partially synthesized within the mammary epithelial cells. Secreted milk fat is packed with the other lipid components into fat globules, surrounded by a bipolar milk fat membrane derived from the mammary apical plasma and Golgi vesicles membrane. Phospholipids are the components of the milk fat membrane. Free choline is actively taken up by the mammary gland against a steep concentration gradient by a sodium dependent transporter. In this regard, the free choline content of human milk is approximately 10 to 15 times higher than the amount present in circulation. The phospholipids are synthesized within the mammary gland. Choline in human milk is present as phosphocholine (45%), glycerophosphocholine (29%), sphingomyelin (10%), free choline (9%), and PtdCho (7%)Although human beings’ requirement for choline is unknown, an Adequate Intake level of 425 mg/day was established for women with upward adjustments to 450 and 550 mg/day during pregnancy and lactation, respectively.Although infant formulas contain choline, the concentration may not be sufficient to meet the increased demands of infant during this period. Choline and its metabolites are found in both animal and plant foods, animal products generally contain more choline per unit weight than plants. Nonetheless, with the exception of fruits and most grain products, choline-rich foods are present in each food group.Further studies are needed to identify the dietary choline intake level required to optimize maternal and fetal choline related endpoints (ie,lipid and one-carbon metabolism, membrane integrity,genome stability and expression, and developmental outcomes).REFERENCECaudill MA. Pre- and Postnatal Health: Evidence of Increased Choline Needs.J Am Diet Assoc. 2010;110:1198-1206

Nutrición y desarrollo cerebral Nutrición y desarrollo cerebral Presentation Transcript

  • Nutrición y Desarrollo Cerebral Dr. Marco Rivera Meza Médico Pediatra
  • Tópicos a discutir Leche materna, el standard de oro Avances en la investigación nutricional infantil: Composición versus desempeño  Qué hacer para reducir las distancias entre el desempeño de la Lactancia Materna y la Fórmula Infantil Neuro-nutrientes Estudios clínicos
  • Evolución de la Investigación de Fórmulas InfantilesANTES Imitación Composición de la Leche Materna  Crecimiento antropométrico  Prevención de deficienciasAHORA Desempeño similar al del lactante alimentado con LM  Identificación de variables de tipo fisiológico/desarrollo  Variables/resultados clínicos
  • Similitud con la Leche Materna Retos • La LM no puede ser reproducida exactamente • Lo que se puede reproducir es el desempeño que se obtiene por lactantes alimentados con LMEstrategia de las investigaciones• Identificar las diferencias entre los lactantes alimentados con leche materna versus los que son alimentados con fórmulas• Desarrollar estrategias que reducan las diferencias
  • “Teoría de la Programación Nutricional”“Una nutrición subóptima durante las etapas deldesarrollo cognitivo a temprana edad, puede tenerefectos a largo plazo en la función cognitiva” A. Lucas, BMJ. 1998
  • Desarrollo Cerebral y Función Período Genético “Embrionico”Desarrollo Cerebral Período Fetaly Función Medio Postnatal ambiente
  • Función de la Nutrición Componentes • Lipidos Estructurales • DHA Procesos • Hierro • Zinc Metabolicos • iodine Factores • Acido Fólico Epigeneticos • Vitaminas Suplementos de proteinas y energía
  • Períodos Críticos y Sensitivos Periodo Periodo Critico Sensitivo Formacion Desarrollo Visual Acido DHA Folico
  • Nutrientes Importantes Durante el Desarrollo Fetal y PostnatalNutriente Función en desarrollo cerebral Región cerebral afectadaProteína- Proliferación celular y diferenciación Corteza globalenergía SinaptogénesisLC-PUFA Sinaptogénesis Corteza, visión Formación de MielinaHierro Síntesis de Monoamina Sustancias blanca/gris Energía metabólica neuronal y glial Corteza frontal, hipocampoIodo Neurogénesis, migración neuronal, Corteza global mielinización, sinaptogénesis
  • Nutrientes Importantes Durante el Desarrollo Fetal y PostnatalNutriente Función en el Región cerebral afectada desarrollo cerebralZinc Síntesis de ADN Liberación SN autónomo de Neurotransmisores Hipocamo, cerebeloColina Síntesis de Sustancias blanca/gris Neurotransmisores Corteza frontal, hipocampo Metilación del ADNSelenio Component e de las Corteza global selenoproteínas: glutatión peroxidasa e yodotironina deiodinasaCobre Síntesis de Cerebelo Neurotransmisores Actividad antioxidante
  • Ácidos Grasos Esenciales (AGE) Ácidos Grasos Esenciales:  ώ-6 (LA), ácido linolénico, 18:2,n-6  ώ-3 (ALA), ácido α linolénico, 18:3,n-3 ώ-6 (LA) y ώ-3 (ALA):  Lípidos estructurales del cerebro y membranas celulares  DHA representa 10-15% del total de AG en la materia gris  DHA representa 10-15% del total de AG en bastones y conos de los segmentos externos  Precursores de los eicosanoides
  • Síntesis de los LC-PUFA de los AGE 18:2ώ-6 18:3ώ-3 Liver ER α Linolenic acid Linoleic acid Δ5 Desaturase Δ6 Desaturase 20:4ώ-6 20:5ώ-3 Eicosapentanoic Arachidonic acid acid Δ5 Desaturase Β Oxidation 22:5ώ-6 Docosapentanoic 22:6ώ-3 acid Docosahexanoic acid
  • Regulación de la Síntesis de LC-PUFA Síntesis de LC-PUFA – baja producción Factores que regulan:  Factores genéticos  Polimorfismos FADS1 y FADS2  Relacionado con el Género  Varias vitaminas y cofactores minerales  Ingesta de otros ácidos grasos  Niveles de hormonas de estrés  Presencia de estrés oxidativo
  • La Función del DHA• Propiedades físicas de las membranas celulares neuronales• Formación de balsas lipídicas y biogénesis de la membrana  Sistemas de neurotransmisores/ transducción de señales  Altera la fluidez de la membrana  Regulación de los canales iónicos  Modulación de endocitosis y exocitosis  Modulación de las actividades de receptores de membrana (hormonal, efectos inmunológicos, expresión genética)
  • La Función del DHA DHA desesterificado:  Regulación de la expresión genética  Metabolismo del neurotransmisor  Neurogénesis y migración de neuronas  Protección contra el daño peroxidativo de lípidos y proteínas  Precursores de eicosanoides
  • LC-PUFA en la Fórmula para Lactantes Nacidos a Término Razón fundamental para la adición de LC-PUFA a la fórmula infantil (FI):  Los LC-PUFA se encuentran en grandes cantidades en la leche materna, el cerebro y la retina de los lactantes  No hay aumento de LC-PUFA después de añadir precursores de LC-PUFA a la fórmula infantil  Los lactantes alimentados con una fórmula infantil que contiene LC-PUFA y los lactantes alimentados con leche materna tienen niveles comparables de ARA y DHA en los glóbulos rojos y el plasma Sin embargo, los beneficios funcionales en el desarrollo particular visual o neuronal de la fórmula infantil que contiene LCPUFA , especialmente en lactantes nacidos a término, sigue siendo controversial
  • LC-PUFA en la Fórmula Infantil Causas de inconsistencias:  Diferencias en el contenido de LC-PUFA entre distintas Fórmulas Infantiles  Diferencias en otros componentes de la FI  Diferencias en los diseños del estudio  Diferencias en los procedimientos de análisis, resultados  Diferencias en la duración del suministro de LC-PUFA  Diferencias en el tamaño de la muestra y la edad en los análisis y en los grupos de control  Reproducibilidad de las medidas de resultados
  • Suplementación de la Fórmula Infantil para lactantes nacidos a término con LC-PUFA: Efecto en el NeurodesarrolloEstudio Tipo y Intervención/ Resultados e intervención de número Control Resultados versus PlaceboMakrides M, et al.Pediatrics. DBPC AA versus DHA versus IDM de Bayley y PEV no muestran diferencias2000 Jan;105(1 Pt 1):32-8. 114 nacidos a control versus término amamantados de 1 semana a 1 añoAuestad N, et al.Pediatrics. 2001 DBPC AA versus DHA versus Los lenguajes receptivos y expresivos así como elAug;108(2):372-81. 404 nacidos a control versus CI, función motora y visual y la agudeza visual noFollow up at 12 and 39 months término amamantados de 1 muestran diferencias comparadas con los lactantes semana a 1 año amamantadosBirch EE, et al.Early Hum Dev. 52 Lactantes sanos DHA versus control El grupo con la fórmula de control tuvo una agudeza2007;83:279-84. nacidos a término versus amamantados visual más pobre que los lactantes amamantados 4 años de El DHA fue simila al de los lactantes amamantados con seguimiento respecto a la agudeza visual El grupo Control y con DHA tuvo una puntuación de CI verbal más pobre versus los lactantes amamantadosAgostoni C, et al.Am J Clin Nutr. 1160 recién nacidos 20 mg DHA líquido No hay efectos persistentes demostrables de la2009;89:64-70. sanos versus placebo suplementación con DHA en los hitos del desarrollo motor posteriorBeyerlein A, et al. J Pediatr G,N. Metanálisis de DPI 4 Suplementados con LCPUFA supplementation of infant formula does2010;50:79-84. ensayos clínicos DHA versus control not have a clinically meaningful effect on the 870 niños neurodevelopment assessed by Bayley scores at 18 m, except, possibly, for very-low-birth-weight
  • Suplementación con LC_PUFA de la Fómula Infantil para lactantes nacidos a término Efecto en el CrecimientoEstudio Type and Intervención Resultado e Intervención de number / Control Resultados versus PlaceboUdell T, et al. PUFA Study 5 RCT term DHA versus fórmula Mejor crecimiento solamente en lactantes aGroup.Lipids. 2005;40:1-11. infants 3 RCT infantil de control término preterm infants Los índices de desarrollo de los lactantes a término no mostraron diferencias Mejoría transitoria en la función de la retina de lactantes prematurosRosenfeld E, et al. Acta Metanálisis de Suplementación con No hay evidencia de que la suplementación conPaediatr. 2009;98:91-7 Datos de DHA versus control LC-PUFA altere el crecimiento de los niños a pacientes los 18 meses de edad individuales DPI
  • Suplementación con LC-PUFA de la Fórmula Infantil para Lactantes Nacidos a TérminoSimmer K, et al. Revisión 2008 de la Base de DatosCochrane Incluidos 14 RCT trials, 1719 lactantes 9 estudios evaluaron la agudeza visual (distintos métodos, distintas edades)  3 mejorías/ 5 sin efecto 11 estudios evaluaron el resultado del desarrollo neurológico  El conjunto de datos no mostró diferencias en el índice de desarrollo mental ni psicomotor de la escala de Bayley 12 estudios evaluaron el crecimiento físico – no hubo efectos en los lactantes nacidos a término
  • LC-PUFA en la Fórmula Infantil Aspectos Problemáticos:  Dificultad de imitar leche materna por contenido variable de LC-PUFA  Falta de datos sobre la cantidad óptima y proporción de n-6 a n-3  No hay consenso sobre las pruebas adecuadas para evaluar el neurodesarrollo o el beneficio funcional  La comparación entre los niños alimentados con leche materna y con fórmula es inadecuada y se confunde por distintos factores adicionales  No existe datos sobre la seguridad
  • LC-PUFA en la Fórmula Infantil de Lactantes Nacidos a Término Conclusiones y Recomendaciones La alimentación con leche materna es el método de alimentación de preferencia en lactantes sanos nacidos a término Se recomienda una fórmula infantil para lactantes nacidos a término, que provea el DHA en niveles entre 0.2 y 0.5 del porcentaje en peso del total de grasas, con el fin de proveer LC-PUFA similares a los de la leche materna, en caso de que ésta no esté disponible.Asociación Muncial de Meidina Perinatal, Academia de Nutrición Temprana y Fundación de la Salud Infantil
  • Recomendaciones de los Expertos de AA y DHA en la Fórmula para Lactantes Nacidos a Término % del Total de Ácidos GrasosOrganización Año AA DHAESPGHAN 1991/2005 † †Fundación Británica de Nutrición 1992 0.4 0.4Organización Mundial de la Salud 1994 0.65 0.33Las recomendaciones de la OMS se basan enmg/kg al díaOficina de Investigación de Ciencias de la Vida 1998 † †Child Health Foundation (Fundación de Salud Infantil) 2001 0.35 0.20Academia Americana de Pediatría/Comité de Nutrición 2002 † †Comisión de Dirección de EE.UU 2006 > 0.20 0.20Revisión de Cochrane 2008 † † † Evidencia insuficiente para garantizar la recomendación de AA & DHA
  • El Hierro y el Desarrollo Cerebral La deficiencia de hierro (DH) es una de las deficiencias nutricionales mundiales más comunes  La DH ocurre en un 6.6% a 15.2% de niños pequeños en EE.UU  La prevalencia de la Anemia por Deficit de Hierro (IDA) es de 0.9% a 4.4% en EE.UU. Los niños se encuentran en un riesgo particular El hierro está involucrado de muchas maneras en el desarrollo y función del cerebro
  • El Hierro y el Desarrollo Cerebral El hierro es esencial para la función del cerebro:  Neurogénesis Normal:  Hipocampo y striatum  Ubicación y función de los oligodendrocitos  Metabolismo del Neurotransmisor  Falla en la utilización del ATP.
  • Estudios en Humanos sobre los Efectos en el Desarrollo por la Deficiencia de Hierro Se ha demostrado que casi todos los aspectos del desarrollo humano infantil se ven alterados por la deficiencia de hierro durante la infancia:  Desarrollo mental  Desarrollo motor  Conducta social y emocional  Parámetros neuropsicológicos La deficiencia de hierro perinatal puede tener efectos similares en el desarrollo infantil
  • Efectos a Largo Plazo de la Deficiencia de HierroSeguimiento a finales de la edad pre-escolar (seis estudios) Conclusiones:  Incluso después de controlar la madurez neurológica y factores de antecedentes, las diferencias en las habilidades psico-educativas, de lenguaje y motoras finas aún fueron estadísticamente significativas Lozoff B, et al. N Engl J Med 1991;325:687–694
  • Requerimientos de Hierro/ Fuentes por Edad Embarazo:  El 80% del hierro presente en un recién nacido a término se va acumulando durante el tercer trimestre del embarazo Niños de 0-6 meses de edad:  El porcentaje del contenido de hierro de la leche materna es de aproximadamente 0.35mg/L  Esto proporciona una ingesta de 0.27 mg/día (considerada adecuada para recién nacidos a término de 0-6 meses de edad) Niños de 6-12 meses de edad:  Según la OIM, el DRI para esta edad es de 11 mg/día Niños pre-escolares de 1-3 años de edad  El OIM determinó que el DRI de hierro de 1 a 3 años de edad es de 7 mg/día The Institute of Medicine (IOM)
  • El Zinc y el Desarrollo Cerebral La deficiencia de Zinc afecta a más del 20% de la población mundial El Zinc es esencial para el crecimiento y desarrollo normal del feto La deficiencia de Zinc altera la neurogénesis, la migración neuronal, la diferenciación y la apoptosis Se ha demostrado que la deficiencia de Zinc en animales preñados resulta en malformaciones y un desarrollo y funcionamiento anormal del SNC
  • El Zinc y el Desarrollo Cerebral La evidencia de la literatura humana es menos clara La deficiencia de Zinc ha sido vinculada con  Pobre desarrollo cognitivo  Disminución en la actividad, atención y desarrollo motor Los estudios de intervención muestran relaciones conflictivas entre la suplementación con zinc y diferentes pruebas neuropsicológicas en distintas poblaciones
  • Luteína Pigmento amarillo, miembro del grupo de los carotenoides Frutas, legumbres de hojas verdes y la yema del huevo son ricas fuentes de luteína En los humanos la luteína se concentra en la mácula lútea de la retina Función: protección de fotorreceptores contra la iniciación del daño oxidativo leve La Luteína puede proteger contra la ceguera (degeneración macular) y la degeneración macular relacionada con la edad (estudios epidemiológicos) El Calostro y la leche materna son ricos en retinoides y carotenoides, pero las concentraciones varían Para individuos que carecen de una ingesta suficiente de luteína, están disponibles los alimentos fortificados con luteína
  • Fosfolípidos Los fosfolípidos (FL) son lípidos dipolares Los fosfolípidos son los principales consituyentes de la membrana celular bicapa lipídica Estructura básica de los fosfolípidos:  Diglicerol/ esfingosina  Grupo de fosfatos  Molécula adicional: colina/ serina/ inositol/ etanolamina Las principales clases de fosfolípidos son:  Sphingomyelin  Fosfatidilcolina (lecitina)  Fosfatidiletanolamina  Fosfatidilserina  Fosfatidilinositol
  • Funciones de los Fosfolípidos Principales constituyentes de la membranas celulares (fosfatidilcolina) Constituyentes de la mielina (shingomyelin) con galactocerebrósidos Precursores de moléculas de señalización (acetilcolina)
  • La Colina y el Desarrollo Cerebral Colina – el componente de la fosfatidilcolina y shingomyelin  La colina y sus metabolitos tienen tres papeles principales:  Integridad estructural y funciones de señalización en la membrana celular  Neurotransmisión (síntesis de la acetilcolina)  Principal fuente para los grupos metilos a través de sus metabolitos, betaína El desarrollo del SNC es particularmente sensible a la disponibilidad de colina Los requerimientos de colina son altos durante el embarazo y el período postnatal La colina se presenta en grandes cantidades en la leche materna y es suplementada en las fórmulas infantiles
  • Estudios Cerebrales & Visuales en Recién Nacidos a TérminoEstudio prospectivo, aleatorio, doble ciego de recién nacidos sanos a término en los EE.UU.  1a evaluación a los 12 meses de edad  2a evaluación a los 14 meses de edad  3a evaluación a los 39 meses de edad  Ensayo de confirmación (Auestad et al., 2001, Pediatrics)
  • Primera Evaluación: Diseño del Estudio Grupos de Estudio  Fórmula control: sin AA/DHA (n=65)  Fórmula que contiene 0.23% de DHA (n=65)  Fórmula que contiene tanto AA (0.43%) como DHA (0.12% ) (n=66) Grupo de referencia (n=80), exclusivamente amamantados por 3 meses y luego aleatorizados a una fórmula Resultados: Agudeza Visual y niveles de glóbulos rojos Auestad et al., 1997, Pediatric Research
  • DHA en los Glóbulos Rojos a los 4 y 12 Meses de Edad 4 Months 12 Months DHA in RBC-PE DHA in RBC-PE g/100 g total fatty acids g/100 g total fatty acids 8 8 6 6 4 4 2 2 0 0 DHA 0.15 0 0.12 0.23 DHA 0.15 0 0.12 0.23 (% FA) HM SWI Sim DHA (% FA) HM SWI Sim DHA Advance (0-AA) Advance (0-AA) DHA in RBC-PC DHA in RBC-PC g/100 g total fatty acids g/100 g total fatty acids 3 3 2 2 1 1 0 0 DHA 0.15 0 0.12 0.23 DHA 0.15 0 0.12 0.23 (% FA) HM SWI Sim DHA (% FA) HM SWI Sim DHA Advance (0-AA) Advance (0-AA) PE – phosphatidylethanolamine PC - phosphatidylcholine
  • Tarjetas de Agudeza de Teller y Potencial Evocado Visual 16 20/40 AA+DHA Equivalent Snellen Values Fórmula:Visual Acuity, cy/deg 8 20/75 Agudeza Visual durante los 12 4 20/150 meses como los recién nacidos 2 Human Milk 20/300 amamantados Control AA-DHA 1 DHA 20/600 2 4 6 8 10 12 Age, months
  • Segunda Evaluación – Resultados Medidos Las Escalas de Bayley de Desarrollo Infantil a los 12 meses de edad  IDM  PDI Innventarios de Desarrollo de la Comunicación de MacArthur a los 14 meses de edad  Comprensión  Producción Scott et al., 1998, Pediatrics
  • Segunda Evaluación – IDM e IEP a los 12 Meses de Edad 125 100Standard Score 75 50 25 0 Mental Index Psychomotor Index Human Milk Control AA-DHA DHA X SD
  • Segunda Evaluación – Índice de Comunicación de MacArthur Vocabulario a los 14 meses Comprensión ProducciónLeche materna 101* 97Control 100 101*DHA/AA 98 98DHA 92* 92* *p < 0.05 Scott et al., 1998, Pediatrics
  • Tercera Evaluación: Medición de Resultados Cognición Prueba de Fagan IDM Prueba de Stanford Binet Comportamiento Evaluación de Comunicación Crecimiento Visual Auestad et al 2003, Pediatrics
  • Resultados del Desarrollo de la Comunicación Vocabulario Vocabulario Receptivo Expresivo100 80 60 BM 40 Exp. Formula 20 0 14 mo 39 mo. 14 mo. 39 mo. p=NS Auestad et al 2003, Pediatrics
  • Resultados: Desarrollo Cognitivo100 BM 50 Exp. Formula 0 Fagan (6m) MDI (12m) St. Binet (39m)p=NS Auestad et al 2003, Pediatrics
  • Resultados de Desempeño del Comportamiento64 BM2 Exp. Formula0 AL DNS DL S&Lp=NS AL: Activity level DNS: Distress to novel stimuli DL: Distress to limitations S&L: Smiling and laughter
  • Ensayo de Confirmación Diseño del estudio 239 recién nacidos a término aleatorizados • Control (sin AA/DHA); n=77 • AA/DHA (huevo-DTG); n=80 • AA/DHA (pescado/hongos); n=82 Alimentación con las fórmulas del estudio por 12 meses 2 grupos de referencia de 165 recién nacidos alimentados exclusivamente con leche materna por 3 meses y luego aleatoriados a una fórmula. Auestad et al., 2001, Pediatrics
  • Ensayo de Confirmación Resultados Medidos Ácidos grasos en los glóbulos rojos Crecimiento Agudeza Visual Desarrollo Mental  Procesamiento de la Información- Prueba Fagan de la Inteligencia Infantil  Bayley: IDM/IEP  Lenguaje – Comunicación de MacArthur  Temperamento – Cuestionario de Comportamiento Infantil Auestad et al., 2001, Pediatrics
  • Ensayo de Confirmación ResultadosLos recién nacidos alimentados con leche materna ycon fórmula no mostraron diferencias en… • Agudeza Visual – Método de Tarjetas de Agudeza de Teller • Bayley: IDM, IEP • Prueba de Fagan de Inteligencia Infantil – Procesamiento de Información • Vocabulario
  • RESULTADOS GENERALESLos Resultados del grupo Experimental No difieren del Grupode Referencia Alimentado con Leche Materna Temperamento Infantil 8 pruebas visuales & Procesamiento Agudeza de Información cognitivas Visual medidas!! Vocabulario de imágenes CI Peabody Stanford-Binet Índice de Escalas de Escalas de Comunicación Bayley para la Bayley para el de MacArthur IEP IDM
  • Conclusiones■ La adecuada nutrición durante la niñez y la primera infancia es esencial para un óptimo desarrollo cognitivo■ El rápido desarrollo del cerebro es más vulnerable a la insuficiencia nutricional en la edad temprana■ Evidencia científica significativa ha demostrado que ciertos neuro-nutrientes juegan un papel muy importante en el desarrollo cerebral y visual■ Los ensayos clínicos son obligatorios para la evaluación del verdadero desempeño de cualquier desarrollo de fórmula. Siempre utilizando el estándar de oro “niños alimentados con leche materna” como término de comparación