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1. A randomized controlled trial of early dietary supply of LC-PUFA and mental development in

term infantsThe effects of dietary docosahexaenoic acid (DHA) supply during infancy on later cognitive

development of healthy term infants were evaluated in a randomized clinical trial of infant formula milk

supplemented with 0!"# DHA or with 0!$# DHA and 0% arachidonic acid (AA)' or control formula

which provided no DHA or AA iftysix *+monthold children (&$ male' !0 female) who were enrolled in

the trial within the first " days of life and fed the assigned diet to *% weeks of age were tested using the

,ayley -cales of .nfant Development' &nd edition (,-.D..) (,ayley *//!) at the etina oundation of the

-outhwest' Dallas' T1 These children had also 2een assessed at 3 months and *& months of age for 2lood

fattyacid composition' sweep visual evoked potential (456) acuity' and forcedchoice preferential looking

(67) acuity (,irch et al *//+) -upplementation of infant formula with DHA8AA was associated with a

mean increase of % points on the 9ental Development .ndex (9D.) of the ,-.D.. ,oth the cognitive and

motor su2scales of the 9D. showed a significant developmental age advantage for DHA and DHA8AA

supplemented groups over the control group :hile a similar trend was found for the language su2scale' it

did not reach statistical significance ;either the 6sychomotor Development .ndex nor the ,ehavior ating

-cale of the ,-.D.. showed significant differences among diet groups' consistent with a specific advantage

of DHA supplementation on mental development -ignificant correlations 2etween plasma and , however' it is difficult in most studies to

discern whether the advantage of 2reastfeeding resides in the nutrient composition of human milk or is due

to maternal varia2les associated with the decision to 2reastfeed (eg .?' education level' socioeconomic

status' maternal@infant interaction) and the act of 2reastfeeding itself ecently' in randomized clinical trials

of infant formula composition' there has 2een evidence that a specific nutritional component of human milk'

docosahexaenoic acid (DHA)' may confer an advantage in cognitive development DHA in the diet of

preterm or term infants has 2een associated with higher mental development scores (measured on the 9ental

Development .ndex 9D.B of the ,-.D' higher psychomotor development scores' shorterlook durations to

novel stimuli on the agan test' and 2etter pro2lem solving skills (.nfant 6lanning Test Cn the other hand'

DHA in the infant diet has also 2een reported to 2e associated with poorer psychomotor development scores(,ayley -cales 6D.B) and poorer voca2ulary comprehension and production 9ore commonly' randomized

clinical trials of DHA supplementation of preterm or term infant formula milks have employed measures of

visual acuity as indices of the functional status of the 2rain The focus on visualacuity outcomes makes

sense from the point of view that uantitative' relia2le' valid techniues are availa2le for the infant age

range' including visual evoked potential acuity and preferential looking acuity .t is important to keep in

mind that the motive for visualacuity assessment in studies of DHA supplementation has not 2een detection

of visual deficits reuiring ophthalmological care or early educational intervention 2ut' rather' the

uantification of su2tle differences in visual acuity as indirect measures of differences in the maturation of

2rain function However' in the context of clinical trials of infant nutrition' it is unknown whether early

measurement of infant visual acuity is predictive of later cognitive function The primary aim of our study

was to evaluate the effects of dietary DHA supply during early infancy on later cognitive development of

healthy term infants in the context of a randomized dou2le2lind clinical trial A second aim was todetermine whether early measures of infant visual acuity are predictive of later cognitive development

Discussion

-upplementation of term infant formula milk with 0!$# DHA and 0% AA during the first 3 months of

life was associated with a mean increase of % points on the 9ental Development .ndex of the ,ayley -cales

at *+ months of age over the control formula group 6ower calculations for this trial were initially 2ased on

the sample size necessary to detect a *"point difference (*-D) in the 9D. and 6D. scores 2etween groups

However' our sample sizes at *+ months exceeded *"perdiet group and the standard deviations of

measurement were smaller than anticipated (9D. -D ranged from + to ** and 6D. interuartile intervals

ranged from % to *0) The smaller than expected standard deviations may have resulted from the more

restrictive inclusion and exclusion criteria for EnormalF term infants used in the present study versus the,ayley normative sample' the segregation of infants 2y early diet (unlike the ,ayley norms)' the use of a

single examiner for all ,ayley tests (unlike the ,ayley norms)' or other unknown factors Due to the smaller

than expected standard deviations' we were a2le to detect smaller differences 2etween groups than


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anticipated .t should 2e noted that' while a %point increase in the 9D. is a small shift for an individual

child relative to the standard deviation of the normative sample' % points represents a significan shift in the

mean performance of a cohort of children .n addition to a higher 9D. score in the DHA8AAsupplemented

group' there was a trend toward higher prevalence of accelerated performance on the 9D. in the DHA8AA

supplemented group -upplementation of milk2ased term infant formula with 0!$# DHA alone was

associated with a mean increase of 3 points on the 9D. ,oth the cognitive and motor su2scales of the 9D.

showed a significant developmental age advantage for DHA and DHA8AAsupplemented groups over the

control group :hile a similar trend was found for the language su2scale' it did not reach statistical

significance These data support a longterm cognitive advantage of infant dietary DHA supply during the

first 3 months of life The significant correlations 2etween plasma and ,


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Thus' the fetus and new2orn is completely dependent on maternal supply of 5As -everal factors can

interfere with the conversion of 5As into their specific compounds These factors includeG intake of

saturated fatty acids and hydrogenated lipids> deficiency of vitamins and minerals that act as cofactors

(mainly zinc deficiency) and> excessive alcohol consumption and stressrelated hormones These conditions

indicate that even with an adeuate dietary intake of 5As' deficiency of AA and DHA may still occur

Therefore' differences in the meta2olism of constitutional 5As have 2een recognized among possi2le risk

factors of neurodevelopmental disorders

#OL$ OF O%$&A-3 O' D$V$LO"%$'( OF $'(#AL VI)*AL O''$(IO')

DHA has 2een shown to exert several roles in the visual system from photoreceptor differentiation to

synaptic plasticity in a series of events leading to a direct influence on visual acuity .n order to address a

more specific role for omega! in the developing visual system' we used a nutritional approach in which

female rats were given an isocaloric diet containing coconut oil as a lipid source This diet protocol started "

weeks 2efore mating in order to deplete omega! fatty acids emales were then kept under this nutritional

restriction during mating' pregnancy' and after delivery until the litters reached postnatal day (6;D) 7ipid

levels were measured in samples from the collicular visual layers of rats at 6;D Those samples revealed a

"!# reduction in the levels of DHA without any changes in AA content .n conclusion' omega! nutritional

restriction directly impacts DHA availa2ility within visual nuclei and dramatically alters the time course of

topographical refinement and critical period windows The conseuences of those influences on such a precisely regulated timecourse may explain the dysfunctions o2served in DHA deficient children' who

display reduced visual acuity and impaired cognitive performance Thus' an improved understanding of the

role of essential fatty acids in visual system development is' thus' mandatory for the esta2lishment of

adeuate dietary reuirements for these essential lipids during early postnatal life

3. Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant

development in the eychelles Child !evelopment "utrition tudyish consumption during gestation can provide the fetus with 7


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The 4$K4! 7


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phenomenon linked to consumption of shore2ased foods 9ost current evidence suggests that the DHArich

human 2rain reuired an ample and sustained source of dietary DHA to reach its full potential

D+A inta,e du!ing infancy

:hile it is well accepted that DHA accumulation in the 2rain is important for optimal 2rain

development' there is still not a consensus that term infants as a group 2enefit from preformed DHA

intake The outcomes chosen for measurement in most studies have generally not 2een chosen with input

from developmental scientists As already mentioned in the section a2ove' the ,-.D 9D. is a freuent

choice as an early developmental measure and thus lends itself to systematic reviews even though there is

little evidence it is influenced 2y DHA status 9eanwhile' 2ehavioral outcomes that are associated with

reduced 2rain DHA are less freuently measured and these studies are often omitted in these reviews Cne

pro2lem is that the authors of metaanalyses and systematic reviews typically do not have the expertise in

child development to take into account the uality of design and the validity of the outcomes measured

decrease platelet aggregation' 2lood viscosity' and fi2nnogenG

and increase erythrocyte deforma2ility' thus decreasing the tendency to throm2us formation .n no clinical

trial' including coronary artery graft surgery' has there 2een any evidence of increased 2lood loss due to

ingestion of w! fatty acids 9any studies show that the effects of w! fatty acids on serum lipids depend onthe type of patient and whether the amount of saturated fatty acids in the diet is held constant .n patients

with hyperlipidemia' w! fatty acids decrease lowdensitylipoprotein (7D7) cholesterol if the saturated fatty

acid content is decreased' otherwise there is a slight increase' 2ut at high doses (!& g) they lower 7D7

cholesterolG furthermore' they consistently lower serum triglycerides in normal su2=ects and in patients with

hypertriglyceridemia whereas the effect on highdensity lipoprotein (HD7) varies from no effect to slight

increases The discrepancies 2etween animal and human studies most likely are due to differences 2etween

animal and human meta2olism .n clinical trials eicosapentaenoic acid (56A) and docosahexaenoic acid

D+A in the form of fish oils along with antirheumatic drugs improve =oint pain in patients with

rheumatoid arthritisG have a 2eneficial effect in patients with ulcerative colitisG and in com2ination with

drugs' improve the skin lesions' lower the hyperlipidemia from etretinates' and decrease the toxicity of

cyclosporin in patients with psoriasis .n various animal models w! fatty acids decrease the num2er and size

of tumors and increase the time elapsed 2efore appearance oftumors -tudies with nonhuman primates


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and human new2orns indicate that D;A is essential for the normal functional development of the retina and

2rain' particularly in premature infants ,ecause w! fatty acids are essential in growth and development

throughout the life cycle' they should 2e included in the diets of all humans Cmega! and w$ fatty

acids are not interconverti2le in the human 2ody and are important components ofpractically all cell

mem2ranes :hereas cellular proteins are genetically determined' the polyunsaturated fatty acid (6IA)

composition ofcell mem2ranes is to a great extent dependent on the dietary intake Therefore appropriate

amounts ofdietary w$ and w! fatty acids need to 2e considered in making dietary recommendations' and

these two classes of 6IAs should 2e distinguished 2ecause they are meta2olically and functionally distinct

and have opposing physiological functions Their 2alance is important for homeostasis and normal

development


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noted in normal fetal development 9artinezFs findings in the retinas of two postnatally malnourished

infants were similar to those descri2ed in the liver of children receiving high intravenous doses of *+G&w$

Cne of the malnourished children had mucoviscidosis ,oth children had unusually high concentrations of

&&G"w$ in retin and phosphatidylcholine as a sign of DHA deficiency Cne premature infant (&" wk

gestation) had received commercial milk formulas with w$Gw! varying 2etween . +G * and $$G * during the

first 3 mo oflife The retina of this infant was very deficient in &&G$w! .t can 2e concluded that diets with a

high w$Gw! can 2e considered un2alanced relative to human 2reast milk and that these diets are damaging to

the 6IA composition ofthe developing central nervous system in humans 9artinez stated that Pwhen high

doses of l+G&w$ are given intravenously' the inhi2iting effect on the O series is very strong even with a

theoretically correct omega$Gomega! ratio' pro2a2ly 2ecause su2strate inhi2ition adds to competition

2etween families of fatty acids for the desaturase systems This should serve as a warning against

manufacturing such unphysio2ogical fatty acid mixtures for use in pediatric nutritionQ

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