Essential Fatty Acids | Linus Pauling Institute

Omega-6 and omega-3 fatty acids are polyunsaturated fatty acids (PUFA), meaning they contain more than one cis double bond (1). In all omega-6 (ω6 or n-6) ... 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Supplements Infantformula Safety Adverseeffects Druginteractions Nutrientinteractions IntakeRecommendations USInstituteofMedicine 2015-2020DietaryGuidelinesforAmericans AHArecommendation Internationalrecommendations LPIRecommendation AuthorsandReviewers References 日本語 Summary Linoleicacid(LA),anomega-6fattyacid,andα-linolenicacid(ALA),anomega-3fattyacid,areconsideredessentialfattyacidsbecausetheycannotbesynthesizedbyhumans.(Moreinformation) Thelong-chainomega-3fattyacids,eicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA),canbesynthesizedfromALA,butduetolowconversionefficiency,itisrecommendedtoconsumefoodsrichinEPAandDHA.(Moreinformation) Bothomega-6andomega-3fattyacidsareimportantstructuralcomponentsofcellmembranes,serveasprecursorstobioactivelipidmediators,andprovideasourceofenergy.Long-chainomega-3polyunsaturatedfattyacids(PUFAinparticularexertanti-inflammatoryeffects;itisrecommendedtoincreasetheirpresenceinthediet.(Moreinformation) Bothdietaryintakeandendogenousmetabolisminfluencewholebodystatusofessentialfattyacids.Geneticpolymorphismsinfattyacidsynthesizingenzymescanhaveasignificantimpactonfattyacidconcentrationsinthebody.(Moreinformation) DHAsupplementationduringpregnancymayreducetherisksofearlyprematurebirth(birthbefore34weeks'gestation)andverylowbirthweight(<1.5kg[<3pounds5ounces]).(Moreinformation) DHAisimportantforvisualandneurologicaldevelopment.However,supplementationwithlong-chainduringpregnancyorearlyinfancyappearstohavenosignificanteffectonchildren'svisualacuity,neurodevelopment,andphysicalgrowth.(Moreinformation) Replacingsaturatedfatinthedietwithomega-6lowerstotalbloodcholesterol;yet,randomizedcontrolledtrialshavefailedtodemonstratecardiovascularbenefitsinhealthypeopleandpeopleatriskfororwithtype2diabetesmellitus.Long-chainomega-3PUFAsupplementationmaybeusefultoreducemortalityinpatientswithprevalentcoronaryheartdisease(CHD)andinthosewithheartfailurewithoutpreservedventricularfunction.(Moreinformation) IncreasingEPAandDHAintakemaybenefitindividualswithtype2diabetesmellitus,especiallythosewithelevatedserumtriglycerides.However,evidencefromlarge-scalerandomizedtrialsisinsufficienttosupporttheuseofomega-3PUFAsupplementsforcardiovasculardiseasepreventioninthosewithtype2diabetes.(Moreinformation) ObservationalstudieshavefoundfishintaketobeassociatedwithlowerrisksofcognitivedeteriorationandAlzheimer’sdisease,butitisnotyetclearwhethersupplementationwithmarine-derivedomega-3PUFAcanhelppreventcognitivedecline.(Moreinformation) Severalomega-3formulationshavebeenapprovedbytheUSFoodandDrugAdministrationfortheindicationoftreatingseverehypertriglyceridemia.(Moreinformation) Althoughomega-3PUFAdeficiencymaynotbeuncommoninneurodevelopmentalandneuropsychiatricdisorders,thereislittleevidencetosuggestthatsupplementationmaybeabeneficialadjunctinthemanagementofaffectedindividuals.(Moreinformation) TheFoodandNutritionBoardoftheUSInstituteofMedicine(nowtheNationalAcademyofMedicine)establishedadequateintakes(AI)foromega-6andomega-3fattyacids.(Moreinformation) Introduction Omega-6andomega-3fattyacidsarepolyunsaturatedfattyacids(PUFA),meaningtheycontainmorethanonecisdoublebond(1).Inallomega-6(ω6orn-6)fattyacids,thefirstdoublebondislocatedbetweenthesixthandseventhcarbonatomfromthemethylendofthefattyacid.Likewise,allomega-3fattyacids(ω3orn-3)haveatleastonedoublebondbetweenthethirdandfourthcarbonatomcountingfromthemethylendofthefattyacid.Scientificabbreviationsforfattyacidstellthereadersomethingabouttheirchemicalstructure.Forexample,thescientificabbreviationforα-linolenicacid(ALA)is18:3n-3.Thefirstpart(18:3)tellsthereaderthatALAisan18-carbonfattyacidwiththreedoublebonds,whilethesecondpart(n-3)tellsthereaderthatthefirstdoublebondisinthen-3position,whichdefinesthisfattyacidasanomega-3(Figures1a&b).Doublebondsintroducekinksinthehydrocarbonchainthatinfluencethestructureandphysicalpropertiesofthefattyacidmolecule(Figure1c). Althoughhumansandothermammalscansynthesizesaturatedfattyacidsandsomemonounsaturatedfattyacidsfromcarbongroupsincarbohydratesandproteins,theylackthedelta(Δ)12andΔ15desaturaseenzymesnecessarytoinsertacisdoublebondatthen-6orthen-3positionofafattyacid(1).Consequently,omega-6andomega-3fattyacidsareessentialnutrients.Theparentfattyacidoftheomega-6seriesislinoleicacid(LA;18:2n-6),andtheparentfattyacidoftheomega-3seriesisALA(Figure2andTable1).Humanscansynthesizelong-chain(20carbonsormore)omega-6fattyacids,suchasdihomo-γ-linolenicacid(DGLA;20:3n-6)andarachidonicacid(AA;20:4n-6),fromLAandlong-chainomega-3fattyacids,suchaseicosapentaenoicacid(EPA;20:5n-3)anddocosahexaenoicacid(DHA;22:6n-3),fromALA(seeMetabolismandBioavailability). [Figure1aand1b-ClicktoEnlarge][Figure1c-ClicktoEnlarge] [Figure2-ClicktoEnlarge]   Table1.NamesandAbbreviationsoftheOmega-6andOmega-3FattyAcids Omega-6FattyAcids Omega-3FattyAcids Linoleicacid LA 18:2n-6 α-Linolenicacid ALA 18:3n-3 γ-Linolenicacid GLA 18:3n-6 Stearidonicacid SDA 18:4n-3 Dihomo-γ-linolenicacid DGLA 20:3n-6 Eicosatetraenoicacid ETA 20:4n-3 Arachidonicacid AA 20:4n-6 Eicosapentaenoicacid EPA 20:5n-3 Adrenicacid   22:4n-6 Docosapentaenoicacid DPA(n-3) 22:5n-3 Tetracosatetraenoicacid   24:4n-6 Tetracosapentaenoicacid   24:5n-3 Tetracosapentaenoicacid   24:5n-6 Tetracosahexaenoicacid   24:6n-3 Docosapentaenoicacid DPA(n-6) 22:5n-6 Docosahexaenoicacid DHA 22:6n-3 MetabolismandBioavailability Priortoabsorptioninthesmallintestine,fattyacidsmustbehydrolyzedfromdietaryfats(triglyceridesandphospholipids)bypancreaticenzymes(2).Bilesaltsmustalsobepresentinthesmallintestinetoallowfortheincorporationoffattyacidsandotherfatdigestionproductsintomixedmicelles.Fatabsorptionfrommixedmicellesoccursthroughoutthesmallintestineandis85%-95%efficientundernormalconditions. Concentrationsoffattyacidsinblood(i.e.,wholeblood,plasma,serum,andredbloodcells)reflectbothdietaryintakeandbiologicalprocesses(3).Humanscansynthesizelongeromega-6andomega-3fattyacidsfromtheessentialfattyacidslinoleicacid(LA)andα-linolenicacid(ALA),respectively,throughaseriesofdesaturation(additionofadoublebondbetweentwocarbonatoms)andelongation(additionoftwocarbonatoms)reactions(Figure3)(4,5).LAandALAcompeteforthesameelongaseanddesaturaseenzymesinthesynthesisoflongerpolyunsaturatedfattyacids(PUFA),suchasarachidonicacid(AA),eicosapentaenoicacid(EPA),anddocosahexaenoicacid(DHA). StudiesofALAmetabolisminhealthyyoungmenindicatedthatapproximately8%ofdietaryALAwasconvertedtoEPAand0%-4%wasconvertedtodocosahexaenoicacid(DHA)(6).Inhealthyyoungwomen,approximately21%ofdietaryALAwasconvertedtoEPAand9%wasconvertedtoDHA(7).Thebettercapacitytogeneratelong-chainPUFAfromALAinyoungwomencomparedtomenisrelatedtotheeffectsofestrogen(8,9).AlthoughonlytheessentialityofALAisrecognizedbecauseitcannotbesynthesizeddenovobyhumans,therelativelylowrateofALAconversionintoEPAandDHAsuggeststhattheselong-chainomega-3PUFAmaybeconsideredconditionallyessentialnutrients. Inadditiontogenderdifferences,geneticvariabilityinenzymesinvolvedinfattyacidmetabolisminfluencesone’sabilitytogeneratelong-chainPUFA.Twokeyenzymesinfattyacidmetabolismaredelta6desaturase(FADS2)anddelta5desaturase(FADS1)(Figure3)(10).Twocommonhaplotypes(aclusterofpolymorphisms)intheFADSgenesdifferdramaticallyintheirabilitytogeneratelong-chainPUFA:haplotypeDisassociatedwithincreasedFADSactivity(bothFADS1andFADS2)andhigherconversionrateoffattyacidprecursors(LAandALA)tolong-chainPUFA(EPA,GLA,DHA,andAA)(11).TheseFADSpolymorphismsarerelativelycommoninthepopulationandmayexplainupto30%ofthevariabilityinbloodconcentrationsofomega-3andomega-6fattyacidsamongindividuals(3). Finally,DHAcanberetro-convertedtoEPAandDPAatalowbasalrateandfollowingsupplementation(Figure3)(12).Aftersupplementingomnivores(n=8)andvegetarians(n=12)forsixweekswithanEPA-freepreparationofDHA(1.62g/day),EPA,DPA,andDHAconcentrationsincreasedinserumandplateletphospholipids(13).Basedonthemeasuredchanges,theestimatedpercentretroconversionofDHAtoEPAwas7.4%-11.4%(basedonserumphospholipiddata)and12.3%-13.8%(basedonplateletphospholipiddata),withnosignificantdifferencebetweenomnivoresandvegetarians.Duetothisnontrivialretroconversionefficiency,DHAsupplementationmayrepresentanalternativetofishoiltoincreasebloodandtissueconcentrationsofEPA,DPA,andDHA(seeSupplements)(5). [Figure3-ClicktoEnlarge] BiologicalActivities Membranestructureandfunction Omega-6andomega-3PUFAareimportantstructuralcomponentsofcellmembranes.Whenincorporatedintophospholipids,theyaffectcellmembraneproperties,suchasfluidity,flexibility,permeability,andtheactivityofmembrane-boundenzymesandcell-signalingpathways(14,15).Inadditiontoendogenousmetabolism,dietaryconsumptionoffattyacidscanmodifythecompositionandmolecularstructureofcellularmembranes.Thus,increasingomega-3fattyacidintakeincreasestheomega-3contentofredbloodcells,immunecells(16),atheroscleroticplaques(17),cardiactissue(18),andothercelltypesthroughoutthebody. DHAisselectivelyincorporatedintoretinalcellmembranesandpostsynapticneuronalcellmembranes,suggestingitplaysimportantrolesinvisionandnervoussystemfunction.Infact,DHArepresentsthepredominantPUFAintheretinaandneuronalcells(19). Vision DHAisfoundatveryhighconcentrationsinthecellmembranesoftheretina;theretinaconservesandrecyclesDHAevenwhenomega-3fattyacidintakeislow(20).AnimalstudiesindicatethatDHAisrequiredforthenormaldevelopmentandfunctionoftheretina.Moreover,thesestudiessuggestthatthereisacriticalperiodduringretinaldevelopmentwheninadequateDHAwillresultinpermanentabnormalitiesinretinalfunction.ResearchindicatesthatDHAplaysanimportantroleintheregenerationofthevisualpigmentrhodopsin,whichplaysacriticalroleinthevisualtransductionsystemthatconvertslighthittingtheretinatovisualimagesinthebrain(21). Nervoussystem Thephospholipidsofthebrain'sgraymattercontainhighproportionsoflong-chainPUFA,suggestingtheyareimportanttocentralnervoussystemfunction(22).AAstimulatesglucoseuptakebycorticalastrocytes,meaningthatitisimportantforenergymetabolism(23).AAandDHAalsoincreasethereleaseofacetylcholine,whichenhancessynapticplasticityandmemory,therebyimprovinglearningabilities(24).AlthoughtrialsofPUFAsupplementationduringpregnancyand/orearlyinfancyfailedtoshowcognitiveimprovementsinoffspring(seeDiseasePrevention),theavailabilityofomega-3andomega-6fattyacidstothefetusandinfantsisessentialforthegrowthoftheirbrainanddevelopmentofbrainfunctions.ThereiscompellingevidencetosuggestthatPUFAareessentialtoneuronalgrowthandsynapseformation,andforappropriateneurotransmission(reviewedin25). Synthesisoflipidmediators Oxylipins OxylipinsarepotentchemicalmessengersderivedfromPUFA.Theyplaycriticalrolesinimmuneandinflammatoryresponses.Themostcommonoxylipinsareeicosanoidsthatencompassnumerousbioactivelipidmediatorsderivedfrom20-carbon("eicosa-")AA.Followingstimulationbyhormones,cytokines,andotherstimuli,PUFAboundtomembranephospholipidsarereleasedfromcellmembranesandbecomesubstratesfordodecanoid,eicosanoid,anddocosanoidproduction.Oxylipinsynthesisreliesprimarilyonthreefamiliesofenzymes:cyclooxygenases(COX),lipoxygenases(LOX),andcytochromep450mono-oxygenases(P450s)(26).FromC18-C22 precursors,COXenzymesproduceprostaglandins,prostacyclins,andthromboxanes(collectivelyknownasprostanoids);LOXproducesleukotrienesandhydroxyfattyacids;andP450sproducehydroxyeicosatetraenoicacids("HETEs")andepoxides(Figure4). PhysiologicalresponsestoAA-derivedeicosanoidsdifferfromresponsestoEPA-derivedeicosanoids.Ingeneral,EPAisapoorsubstrateforeicosanoidproductionandEPA-deriveseicosanoidsarelesspotentinducersofinflammation,bloodvesselconstriction,andcoagulationthaneicosanoidsderivedfromAA(19,27). Nonetheless,itisanoversimplificationtolabelallAA-derivedeicosanoidsaspro-inflammatory.AA-derivedprostaglandinsinduceinflammationbutalsoinhibitpro-inflammatoryleukotrienesandcytokinesandinduceanti-inflammatorylipoxins,therebymodulatingtheintensityanddurationoftheinflammatoryresponsevianegativefeedback(Figure4)(17). [Figure4-ClicktoEnlarge] Pro-resolvingmediators AseparateclassofPUFA-derivedbioactivelipids,specializedpro-resolvingmediators(SPMs),hasbeenmorerecentlyidentified(reviewedin28).Thesemoleculesfunctionaslocalmediatorsoftheresolutionphaseofinflammation,activelyturningofftheinflammatoryresponse.SPMsarederivedfrombothomega-6andomega-3PUFA(Figure4)(29).TheS-seriesofSPMsresultsfromtheLOX-mediatedoxygenationofEPAandDHA,givingrisetoS-resolvins,S-protectins,andS-maresins.AsecondclassofSPMs,theR-series,isgeneratedfromtheaspirin-dependentacetylationofCOX-2andsubsequentgenerationofaspirin-triggeredSPMsfromAA,EPA,andDHA.Itappearsthatthesemediatorsmayexplainmanyoftheanti-inflammatoryactionsofomega-3fattyacidsthathavebeendescribed(16,30). Isoprostanes Isoprostanesareprostaglandin-likecompoundsthatareformedbynon-enzymatic,freeradical-inducedoxidationofanyPUFAwiththreeormoredoublebonds(Figure4)(26).Becausetheyareproduceduponexposuretofreeradicals,isoprostanesareoftenusedasmarkersforoxidativestress.Incontrasttoprostanoids,isoprostanesaresynthesizedfromesterifiedPUFAprecursorsandremainboundtothemembranephospholipiduntilcleavedbyPLA2andreleasedintocirculation.Inadditiontobeingusedasmarkersofoxidativestress,isoprostanesmayalsofunctionasinflammatorymediators,exertingbothpro-andanti-inflammatoryeffects(26). Regulationofgeneexpression PUFAarepleiotropicregulatorsofcellfunction.Theycanregulategeneexpressiondirectlybyinteractingwithtranscriptionfactorsorindirectlybyinfluencingmembranelipidcompositionandcellsignalingpathways. Theresultsofcellcultureandanimalstudiesindicatethatomega-6andomega-3fattyacidscanmodulatetheexpressionofanumberofgenes,includingthoseinvolvedwithfattyacidmetabolismandinflammation(31,32).Omega-6andomega-3fattyacidsregulategeneexpressionbyinteractingwithspecifictranscriptionfactors,suchasperoxisomeproliferator-activatedreceptors(PPARs)(33).Inmanycases,PUFAactlikehydrophobichormones(e.g.,steroidhormones)tocontrolgeneexpressionandbinddirectlytoreceptorslikePPARs.Theseligand-activatedreceptorsthenbindtothepromotersofgenesandfunctiontoincrease/decreasetranscription. Inothercases,PUFAregulatetheabundanceoftranscriptionfactorsinsidethecell'snucleus(14).TwoexamplesincludeNFκBandSREBP-1.NFκBisatranscriptionfactorinvolvedinregulatingtheexpressionofmultiplegenesinvolvedininflammation.Omega-3PUFAsuppressNFκBnuclearcontent,thusinhibitingtheproductionofinflammatoryeicosanoidsandcytokines.SREBP-1isamajortranscriptionfactorcontrollingfattyacidsynthesis,bothdenovolipogenesisandPUFAsynthesis.DietaryPUFAcansuppressSREBP-1,whichdecreasestheexpressionofenzymesinvolvedinfattyacidsynthesisandPUFAsynthesis.Inthisway,dietaryPUFAfunctionasfeedbackinhibitorsofallfattyacidsynthesis. Byalteringcellmembranefluidity,fattyacidscaninterferewiththeactivityofmembranereceptorsystemsandthusindirectlyinfluencesignalingpathwaysandgeneexpression(34). Deficiency Essentialfattyaciddeficiency Clinicalsignsofessentialfattyaciddeficiencyincludeadryscalyrash,decreasedgrowthininfantsandchildren,increasedsusceptibilitytoinfection,andpoorwoundhealing(35).Omega-3,omega-6,andomega-9fattyacidscompeteforthesamedesaturaseenzymes.Thedesaturaseenzymesshowpreferenceforthedifferentseriesoffattyacidsinthefollowingorder:omega-3>omega-6>omega-9.Consequently,synthesisoftheomega-9fattyacideicosatrienoicacid(20:3n-9,meadacid,or5,8,11-eicosatrienoicacid)increasesonlywhendietaryintakesofomega-3andomega-6fattyacidsareverylow;therefore,meadacidisonemarkerofessentialfattyaciddeficiency(36).Aplasmaeicosatrienoicacid:arachidonicacid(triene:tetraene)ratiogreaterthan0.2isgenerallyconsideredindicativeofessentialfattyaciddeficiency(35,37).Inpatientswhoweregiventotalparenteralnutritioncontainingfat-free,glucose-aminoacidmixtures,biochemicalsignsofessentialfattyaciddeficiencydevelopedinaslittleas7to10days(38).Inthesecases,thecontinuousglucoseinfusionresultedinhighcirculatinginsulinconcentrations,whichinhibitedthereleaseofessentialfattyacidsstoredinadiposetissue.Whenglucose-freeaminoacidsolutionswereused,parenteralnutritionupto14daysdidnotresultinbiochemicalsignsofessentialfattyaciddeficiency.Essentialfattyaciddeficiencyhasalsobeenfoundtooccurinpatientswithchronicfatmalabsorption(39)andinpatientswithcysticfibrosis(40).Ithasbeenproposedthatessentialfattyaciddeficiencymayplayaroleinthepathologyofprotein-energymalnutrition(36). Omega-3fattyaciddeficiency Atleastonecaseofisolatedomega-3fattyaciddeficiencyhasbeenreported.AyounggirlwhoreceivedintravenouslipidemulsionswithverylittleALAdevelopedvisualproblemsandsensoryneuropathy;theseconditionswereresolvedwhenshewasadministeredanemulsioncontainingmoreALA(41).Isolatedomega-3fattyaciddeficiencydoesnotresultinincreasedplasmatriene:tetraeneratios,andskinatrophyanddermatitisareabsent(1).PlasmaDHAconcentrationsdecreasewhenomega-3fattyacidintakeisinsufficient,butnoacceptedplasmaomega-3fattyacidoreicosanoidconcentrationsindicativeofimpairedhealthstatushavebeendefined(1).Studiesinrodentshaverevealedsignificantimpairmentofn-3PUFAdeficiencyonlearningandmemory(42,43),promptingresearchinhumanstoassesstheimpactofomega-3PUFAoncognitivedevelopmentandcognitivedecline(seeCognitiveandvisualdevelopmentandAlzheimer'sdisease). Omega-3index Theomega-3indexisdefinedastheamountofEPAplusDHAinredbloodcellmembranesexpressedasthepercentoftotalredbloodcellmembranefattyacids(44).TheEPA+DHAcontentofredbloodcellmembranescorrelateswiththatofcardiacmusclecells(45,46),andseveralobservationalstudiesindicatethataloweromega-3indexisassociatedwithanincreasedriskofcoronaryheartdiseasemortality(47).Itisthereforeproposedthattheomega-3indexbeusedasabiomarkerforcardiovasculardiseaserisk,withsuggestedcutoffsasfollows:highrisk,<4%;intermediaterisk,4%-8%;andlowrisk,>8%(48). SupplementationwithEPA+DHAfromfishoilcapsulesforapproximatelyfivemonthsdose-dependentlyincreasedtheomega-3indexin115healthy,youngadults(ages,20-45years),validatingtheuseoftheomega-3indexasabiomarkerofEPA+DHAintake(49).Beforetheomega-3indexcanbeusedinroutineclinicalevaluation,however,clinicalreferencevaluesinthepopulationmustbeestablished(50).Additionally,fattyacidmetabolismmaybealteredincertaindiseasestates,potentiallymakingtheomega-3indexlessrelevantforsomecardiovascularconditions(5). DiseasePrevention Pregnancyandearlychildhooddevelopmentaloutcomes Supplementationduringpregnancy Effectonpregnancy-associatedconditionsandneonataloutcomes:Theresultsofrandomizedcontrolledtrialsduringpregnancysuggestthatomega-3polyunsaturatedfattyacid(PUFA)supplementationdoesnotdecreasetheincidenceofgestationaldiabetesandpreeclampsia(51-54)butmayresultinmodestincreasesinlengthofgestation,especiallyinwomenwithlowomega-3fattyacidconsumption.A2006meta-analysisofsixrandomizedcontrolledtrialsinwomenwithlow-riskpregnanciesfoundthatomega-3PUFAsupplementationduringpregnancyresultedinanincreasedlengthofpregnancyby1.6days(55).A2007meta-analysisofrandomizedcontrolledtrialsinwomenwithhigh-riskpregnanciesfoundthatsupplementationwithlong-chainPUFAdidnotaffectpregnancydurationortheoverallincidenceofprematurebirths(birthbefore37weeks'gestation)butdecreasedtheincidenceofearlyprematurebirths(birthbefore34weeks'gestation;2trials,291participants)(56).Analysesofthesecondaryoutcomesofthe2010DHAtoOptimizeMother-InfantOutcome(DOMInO)trialin2,399participantsshowedthatsupplementationwithDHA-enrichedfishoilcapsules(800mg/dayofDHAand100mg/dayofEPA)duringpregnancy(from<21gestationalweeksuntilbirth)reducedtheriskofearlyprematurebirthbutincreasedtheriskofobstetricalinterventionsliketheneedforinductionorcesareansection,whencomparedtosupplementationwithDHA-freevegetableoilcapsules(57).A2016meta-analysisoftrialsfoundevidencetosuggestthatomega-3PUFAsupplementationduringpregnancyreducedtheoverallriskofprematurityandtheriskofearlyprematurebirths,increasedgestationalageatdeliveryandbirthweight,andhadnoeffectontherisksofperinataldeathandlowApgarscoresat1minutepostbirth(58).Adose-responseanalysisfoundacontinuousreductionoftherisksofearlyprematurebirth(birthbefore34weeks'gestation)andverylowbirthweight(birthweight<1,500g)withdailydosesofDHAsupplementuptoatleast600mgduringpregnancy(59).Thereiscurrentlylimitedevidencetosupportaroleforomega-3supplementationinthepreventionofrecurrentintrauterinegrowthrestriction(IUGR)(60)orrecurrentpretermbirth(61). Effectonchildren'scognitiveandvisualdevelopment:Theeffectofmaternalomega-3long-chainPUFAsupplementationonearlychildhoodcognitiveandvisualdevelopmentwassummarizedina2013systematicreviewandmeta-analysis(62).Includedinthisassessmentwere11randomizedcontrolledtrials(atotalof5,272participants)thatsupplementedmaternaldietwithomega-3long-chainPUFAduringpregnancyorbothpregnancyandlactation.Resultsregardingvisualoutcomes(eighttrials)couldnotbepooledtogetherduetovariabilityinassessments;overall,fourofsixtrialshadnullfindingsandtheremainingtwotrialshadveryhighratesofattrition.Cognitiveoutcomes(ninetrials)includedtheDevelopmentalStandardScore(DSS;ininfants,toddlers,andpreschoolers)orIntelligenceQuotient(IQ;inchildren)andotheraspectsofneurodevelopment,suchaslanguage,behavior,andmotorfunction.NodifferenceswerefoundbetweenDHAandcontrolgroupsforcognitionmeasuredwithstandardizedpsychometricscalesininfants(<12months),toddlers(12-24months),andschool-agedchildren(5-12years);preschoolchildren(2-5years)intheDHAtreatmentgrouphadasubstantiallyhigherDSSscorecomparedtocontrols.Theauthorsnotedthatmanyofthetrialsoflong-chainPUFAsupplementationinpregnancyhadmethodologicalweaknesses(e.g.,highratesofattrition,smallsamplesizes,highriskofbias,multiplecomparisons),limitingtheconfidenceandinterpretationofthepooledresults.Ofnote,aseven-yearfollow-upoftheDOMInOtrialiscurrentlyunderwaytoassesstheeffectofDHAsupplementationduringpregnancyonchildIQandvariousmeasuresofcognitivedevelopment(e.g.,executivefunctioning,memory,language)(63). Effectonchildren’sbodycomposition:Thefollow-upof1,531childrenwhosemotherswererandomizedtosupplementalDHA(800mg/day)oracontrolduringthesecondhalfofpregnancyintheDOMInOtrialshowednoeffectofmaternalDHAsupplementationonthebodymassindex(BMI)-for-agezscoreandpercentageofbodyfatoftheirchildrenatthreeandfiveyearsofage(64).Measuresofinsulinresistancein5-year-oldchildrenwereunexpectedlyhigherinchildrenwhosemotherswereintheDHAgroupthaninthosewhosemotherswereinthecontrolgroup(64).Furtheranalysesconductedinasubsetofchildren(252)atagesevenyearsagainshowednoeffectofDHAsupplementationonBMIzscore,percentageofbodyfat,height,weight,andwaist/hipcircumference(65).Currentevidencefrom10randomizedcontrolledtrialsprimarilyconductedinhigh-incomecountries(allbutone)suggestsnoinfluenceofmaternalsupplementationwithlong-chainPUFAonthebodycompositionandanthropometryoftheoffspring(66). Effectonchildren'sriskofallergiesandasthma:A2018meta-analysisofrandomizedcontrolledtrialsin2,047childrenfollowedforsixmonthsto16yearsfounda19%lowerriskofwheezingand/orasthmawithmaternalsupplementationofomega-3PUFA(primarilyEPAandDHA)fromasearlyasthe20thweekofgestationuntildelivery(67).However,therewasnoeffectofprenatalsupplementationwhentheanalysiswasrestrictedtothethreetrialsthatreportedontheincidenceofchildhoodasthmaonly(67).Anothermeta-analysisofninetrialsin3,637children,includingthreetrialsinwhichmaternalsupplementationwithomega-3PUFAcontinuedafterbirth,foundnoeffectofprenatalsupplementsontheriskofanyallergy(threetrials),theriskofwheezeand/orasthma(seventrials),theriskofeczema(sixtrials),thedevelopmentofallergicrhinitis(twotrials),andtheriskoffoodallergy(threetrials)inchildren(68).Therewas,however,someevidencetosuggestthatprenatalsupplementationcouldlowertheincidenceofsensitizationtospecificallergens,namelyegg(threetrials;-46%)andpeanut(twotrials;-38%)(68). Supplementationtobreast-feedingmothers A2015systematicreviewandmeta-analysissummarizedtheresultsofeightrandomizedcontrolledtrialsthatexaminedtheeffectofmaternalsupplementationwithlong-chainPUFAduringeitherpregnancyandlactationorlactationonlyonthedevelopmentandgrowthoftheirinfantsoverthefirsttwoyearsoflifeandbeyond(69).Allstudieswereconductedinhigh-incomecountries.Nodifferencesbetweenlong-chainPUFAsupplementationandcontrolwereobservedintermsoflanguagedevelopment,intelligenceorproblem-solvingability,psychomotordevelopment,andanthropometricmeasurements(weight,length/height,headcircumference,BMI,fatmassdistribution)(69). Supplementationininfants ThelasttrimesterofpregnancyandfirstsixmonthsofpostnatallifearecriticalperiodsfortheaccumulationofDHAinthebrainandretina(70).Humanmilkcontainsamixtureofsaturatedfattyacids(~46%),monounsaturatedfattyacids(~41%),omega-6PUFA(~12%),andomega-3PUFA(~1.3%)(71).AlthoughhumanmilkcontainsDHAinadditiontoALAandEPA,ALAwastheonlyomega-3fattyacidpresentinconventionalinfantformulasuntiltheyear2001.AlthoughinfantscansynthesizeDHAfromALA,theygenerallycannotsynthesizeenoughtopreventdeclinesinplasmaandcellularDHAconcentrationswithoutadditionaldietaryintake.Therefore,itwasproposedthatinfantformulasbesupplementedwithenoughDHAtobringplasmaandcellularDHAconcentrationsofformula-fedinfantsuptothoseofbreast-fedinfants(72). Allinfants:AlthoughformulasenrichedwithDHAraiseplasmaandredbloodcellDHAconcentrationsinpretermandterminfants,theresultsofrandomizedcontrolledtrialsexaminingmeasuresofvisualacuityandneurologicaldevelopmentininfantsfedformulawithorwithoutaddedDHAhavebeenmixed.Forinstance,a2012meta-analysisofrandomizedcontrolledtrials(12trials,1,902infants)comparinglong-chainPUFA-supplementedandunsupplementedformula,startedwithinonemonthofbirth,foundnoeffectoflong-chainPUFAsupplementationoninfantcognitionassessedatapproximatelyoneyearofage(73).Alackofeffectwasobservedregardlessofthedoseoflong-chainPUFAortheprematuritystatusoftheinfant.Withrespecttovisualacuity,a2013meta-analysisofrandomizedcontrolledtrials(19trials,1,949infants)foundabeneficialeffectoflong-chainPUFA-supplementedformula,startedwithinonemonthofbirth,oninfantvisualacuityupto12monthsofage(74).Notably,twodifferenttypesofvisualacuityassessmentwereevaluatedinthemeta-analysis.VisualacuityassessedbyusingtheVisuallyEvokedPotential(10trials,852infants)showedasignificantpositiveeffectoflong-chainPUFA-supplementedformulaat2,4,and12monthsofage.WhenassessedbytheBehavioralMethod(12trials,1,095infants),asignificantbenefitoflong-chainPUFA-supplementedformulaonvisualacuitywasfoundonlyattheageoftwomonths.Nomoderatingeffectsofdoseorprematuritystatuswereobserved. Preterminfants:Afewtrialshavebeenspecificallyconductedinpreterminfants.ThisisthecaseoftheDHAfortheImprovementofNeurodevelopmentalOutcome(DINO)trialthatinitiallyenrolled657verypreterminfants(born<33gestationalweeks)infiveAustralianhospitals(75).TheaimofthetrialwastoexaminetheeffectofenteralfeedswitheitherhighDHA(1%oftotalfattyacids)orstandardDHAlevel(0.3%oftotalfattyacids)topreterminfantsfromage2to4daysoflifeuntilterm'scorrectedage(meanduration,9.4weeks)ontheirmentalandpsychomotordevelopment,assessedat18months'and7years'correctedages.Atthe18-monthfollow-up,therewasnodifferenceinmeanMentalDevelopmentIndex(MDI)andPsychomotorDevelopmentIndex(PDI)testscoresbetweenhigh-DHAandstandard-DHAgroups;yet,betterMDIscoresingirlsfedhigh-DHAversusthosefedstandard-DHAfeedswerereportedinsubgroupanalyses(75).Post-hocanalysesalsosuggestedfewercaseswithdelayedmentaldevelopmentamonggirlsandinfantsweighing<1,250kgatbirthinthehigh-versusstandard-DHAgroup(75).Follow-upat7years’correctedageshowednodifferencebetweengroupsinmeasuresofIQandcognitivedevelopment,includingattention,short-termverbalmemoryandlearningability,executivefunctioning,visualperception,andacademicachievement(76).A2016systematicreviewof17trialsfoundlittleevidencetosuggestthatsupplementingpreterminfantswithlong-chainPUFA(primarilyAAandDHA)improvedmeasuresofvisualacuity,neurodevelopment,andphysicalgrowthduringinfancy(77). Cardiovasculardisease Omega-6fattyacids Linoleicacid(LA)isthemostabundantdietaryPUFAandaccountsforapproximately90%ofdietaryomega-6PUFAintake(78). Observationalstudies:Apooledanalysisof13prospectivecohortstudies,encompassing310,602individualsand12,479coronaryheartdisease(CHD)events(ofwhichresultedin5,882CHDdeaths)overfollow-upperiodsof5.3to30years,foundhigherLAintakestobeassociatedwitha15%lowerriskofCHDeventsanda21%lowerriskofCHDmortality(79).Adose-responseanalysisfoundthatreplacing5%ofenergyfromsaturatedfattyacidswithLAwasassociatedwitha9%lowerriskofcoronaryeventsanda13%lowerriskofcoronarydeaths(79).A2019meta-analysisof30prospectivecohortstudiesin68,659participantsfoundthatindividualsinthehighestversuslowestquintileofLAconcentrationsintissues(primarilybloodcompartments)hada23%lowerriskofcardiovascularmortality(80).NoassociationswerefoundbetweenLAconcentrationsintissuesandtherisksofCHD,ischemicstroke,ortotalcardiovasculardisease(80). Randomizedcontrolledtrials:Takingintoconsiderationtheresultsfromfourrandomizedcontrolledtrials(81-85)thatcomparedtheeffectsofdietseitherhighinsaturatedfattyacidsorPUFAoveratleasttwoyears,a2016systematicreviewandpresidentialadvisoryfromtheAmericanHeartAssociationconcludedthatloweringsaturatedfatintakeandreplacingitwithvegetableoilrichinPUFA(primarilysoybeanoil)couldreducetheriskofCHDby29%(86).Ofnote,thesetrialswereconductedinthe1960sand1970s,whentheuseofcholesterol-loweringdrugstatinwasnotwidespreadandthesaturatedfatcontentindietswashigher;allbutonetrial(84,85)wereinmenwithdiagnosedcardiovasculardisease(CVD).Amongthesefourtrials,theOsloDiet-HeartStudy(83)increasedbothomega-3andomega-6PUFAintake,andtheFinnishMentalHospitalStudy(84,85)usedacross-overdesign — bothtrialswereexcludedfromaCochranesystematicreviewof19randomizedcontrolledtrialsthatexaminedtheeffectofincreasingomega-6PUFAintakeonCVDoutcomes(87).Ofthese19trials,sevenassessedtheeffectofsupplementalγ-linolenicacid(GLA)and12assessedtheeffectofsubstitutingdietaryLAforsaturatedormonounsaturatedfattyacids.Thepooledanalysisofstudiesshowednoeffectofincreasingomega-6intakeontherisksofCHDorCVDevents,majoradversecardiacandcerebrovascularevents,myocardialinfarction(MI),stroke,CVDmortality,orall-causemortality(low-qualityevidence)(87).Moreover,manytrialsthatexaminedtheeffectofreplacingsaturatedfattyacidswithmostlyomega-6PUFAmaynothavebeenadequatelycontrolled.Forexample,insometrials,onlytheexperimentalgroup(thehighomega-6PUFAgroup)receiveddietaryadviceregardingmorethanjustreplacingsaturatedfattyacidsbyomega-3PUFA,e.g.,toavoiddietarysourcesoftransfattyacidsandprocessedfoods,toconsumemorewhole-plantfoods,tolowersugarconsumption,toincreaseconsumptionoffishandshellfish,whichcouldhavebiasedtheresults(88).Additionally,arecentmeta-analysisoftrialswithlowriskofbias(i.e.,freeofdifferencesbetweeninterventionandcontrolgroupsotherthanthoseunderexamination)showednoevidenceofaneffectofsubstitutingomega-6PUFAforsaturatedfattyacidsontherisksofmajorCHDevents(MIandsuddendeath),totalCHDevents,CHDmortality,andall-causemortality(88). Yet,replacingdietarysaturatedfattyacidswithomega-6PUFAwasconsistentlyfoundtolowertotalbloodcholesterolconcentrations(87,89).Infact,LAhasbeenshowntobethemostpotentfattyacidforloweringtotalcholesterolwhensubstitutedfordietarysaturatedfattyacids(90).ThepotentialmechanismsbywhichLAreducesbloodcholesterolinclude(1)theupregulationofLDLreceptorandredistributionofLDL-cholesterolfromplasmatotissue,(2)theincreaseinbileacidproductionandcholesterolcatabolism,and(3)thedecreasedVLDL-to-LDLconversion(91).However,ifsubstitutingomega-6PUFAforsaturatedfattyacidscanreducebloodcholesterol,themostrecentsystematicreviewsandmeta-analyseshavefailedtofindevidenceofclinicalcardiovascularbenefits(seeabove)(87,88,92). Omega-3fattyacids Observationalstudies:Ameta-analysisof17prospectiveandtworetrospectivecohortstudiesin45,637generallyhealthyparticipantsfoundthatcirculatingconcentrationsofα-linolenicacid(ALA)andlongerchainomega-3PUFA(i.e.,eicosapentaenoicacid[EPA],docosapentaenoicacid[DPA],docosahexaenoicacid[DHA])wereinverselyassociatedwiththeriskoffatalcoronaryheartdisease(CHD)(93). SeveralobservationalstudiesalsoexaminedtherelationshipbetweendietaryALAintakeandtheriskofCHD.A2018meta-analysisof14prospectivecohortstudiesinatotalof345,202participantsfreeofcardiovasculardisease(CVD)evaluatedtheriskofcompositeCHDoutcomes(combiningdifferentCHDevents)andfatalCHDinrelationtodietaryconsumptionofALA(94).Overall,thepooledanalysisfounda9%lowerriskofcompositeCHDoutcomesanda15%lowerriskoffatalCHDwithhigherALAexposure(94).Further,anumberofprospectivecohortstudieshaveexaminedtheconsumptionoffish,richinlong-chainomega-3PUFA(mainlyEPAandDHA),inrelationtovariouscardiovasculareventsandmortality.A2018reviewoftheevidenceandadvisoryfromtheAmericanHeartAssociationconcludedthatseafoodintakewasassociatedwithmodestlylowerrisksofCHD,ischemicstroke,andsuddencardiacdeath,andnotedagreaterbenefitwhenintakewentfromzerotooneortwoseafoodmealsperweekandwhenseafoodwassubstitutedforlesshealthyoptionslikeprocessedmeat(95).Incontrast,recentlypublishedmeta-analysesofprospectivecohortstudiesfoundlittleevidenceofinverseassociationsbetweenfishconsumptionandeitherCHDorstroke(96,97).Higherfishconsumptionwasfoundtobeassociatedwithlowerrisksofmyocardialinfarction(MI)(98)andcongestiveheartfailure(96).Inaddition,onemeta-analysisof12prospectivecohortstudiesfounda6%lowerriskofall-causemortalitywiththehighestversuslowestleveloffishconsumption(99).Yet,anothermeta-analysisfoundnoassociationbetweenfishintakeandall-causemortalitybuta4%lowerriskofCVDmortalityforeach20-g/dayincrementinfishintake(100). Thepotentialcardiovascularbenefitofseafoodconsumptionappearstobetightlylinkedtothetypeofseafood(e.g.,fattyorleanfish),thewayitisprepared(e.g.,baked,broiled,orfried),thepresenceoftoxicmetalsandenvironmentalcontaminants,andthehabituallevelofconsumption(highversuslow) — thesefactorsmaybeconfoundingtheresultsreportedinobservationalstudiesandpooledanalyses(95).Althoughseafoodisagoodsourceoflong-chainomega-3PUFA,healthbenefitsassociatedwithfishconsumptioncouldbeattributedtothepresenceofothernutritionalfactors(e.g.,micronutrientsandhigh-qualityprotein)andthatseafoodconsumptionisusuallyamarkerofhighersocioeconomicstatus,aswellashealthylifestyles(101,102). Randomizedcontrolledtrials:A2018CochranesystematicreviewassessedtheevidenceforacardioprotectiveeffectofALAandlong-chainomega-3PUFAinindividualseitheratloworhighriskofCVD(103).Moderate-to-highqualityevidencefromrandomizedcontrolledtrials(ofatleast12months)suggestednoeffectofomega-3PUFA(eithersupplemented,enrichedinmeals,oradvisedtobeconsumed)ontheriskofCHDevents,CVDevents,arrhythmia,stroke,CHDmortality,CVDmortality,orall-causemortality.Therewasalsonoevidenceofaneffectonsecondaryoutcomes,includingmajoradversecerebrovascularorcardiovascularevents,MI,suddencardiacdeath,anginapectoris,heartfailure,revascularization,peripheralarterialdisease,andacutecoronarysyndrome(103).A2017reviewandadvisoryfromtheAmericanHeartAssociationfoundnoevidencetosuggestabenefitoflong-chainomega-3PUFAsupplementationforthepreventionofcardiovascularmortalityinpatientswithoratriskoftype2diabetesmellitus,thepreventionofCHDinpatientswithatheroscleroticdisease(e.g.,withpriorstroke,peripheralvasculardisease,diabetes,hypercholesterolemia),thepreventionofstrokeinpatientswithorwithoutahistoryofstroke,andthepreventionofatrialfibrillationinpatientswithprioratrialfibrillationorinthoseundergoingcardiacsurgery(104).Therewassomeevidencetosuggestthatsupplementationwithlong-chainomega-3PUFAinpatientswithpriorclinicalCHDmightreducetheriskofCHDdeath,possiblybecauseofareductionintheriskofischemia-inducedsuddencardiacdeath(104). Hypertriglyceridemia(borderlinehigh:serumtriglycerides150-199mg/dL;high:serumtriglycerides>200mg/dL)isanindependentriskfactorforcardiovasculardisease(105).NumerouscontrolledclinicaltrialshavedemonstratedthatincreasingintakesofEPAandDHAsignificantlylowerserumtriglycerideconcentrations(103).Thetriglyceride-loweringeffectsofEPAandDHAincreasewithdose(106),butclinicallymeaningfulreductionsinserumtriglycerideconcentrationshavebeendemonstratedatdosesof2g/dayofEPA+DHA(107).Althoughlong-chainomega-3PUFAcanreducetriglycerideconcentrations,theyhavenoeffectontotalcholesterol,LDL-cholesterol,orHDL-cholesterolinblood(103).Ofnote,themechanismsbywhichlong-chainomega-3PUFAsupplementsmayreduceCHDdeathareunlikelytoinvolvealoweringoftriglyceridesasdosesusedinthestudies(~1g/day)weregenerallytoolow(104).Somestudiesincellcultureindicatedthatlong-chainomega-3PUFAmaydecreasetheexcitabilityofcardiacmusclecells(myocytes)bymodulatingionchannelconductance,whichwouldbeconsistentwithanti-arrhythmiceffectsobservedinanimalmodels(seealsoHypertriglyceridemia)(108,109). Summary Replacingdietarysaturatedfattyacidswithomega-6PUFAlowerstotalbloodcholesterol,yetthereisnoconvincingevidenceofaneffectofomega-6PUFAontheriskofmajorCVDevents.Althoughevidencesupportstheadoptionofaheart-healthydietarypatternthatincludestwoservingsofseafoodperweek(95),supplementationwithlong-chainomega-3fattyacidsisunlikelytoresultincardiovascularbenefitsingenerallyhealthypeoplewithalowCVDriskorinindividualsatriskoforwithtype2diabetesmellitus(104).Initsrecommendationsregardingomega-3fattyacidsandcardiovasculardisease(seeIntakeRecommendations),theAmericanHeartAssociationindicatesthatlong-chainomega-3PUFAsupplementationmaybeusefultoreducemortalityinpatientswithprevalentCHD(e.g.,whosufferedarecentMI)andinthosewithheartfailurewithoutpreservedventricularfunction(104). Cardiometabolicriskfactorsinindividualswithdiabetesmellitus Type2diabetesmellitus:Cardiovasculardiseaseistheleadingcauseofdeathinindividualswithdiabetesmellitus.Thedyslipidemiatypicallyassociatedwithdiabetesischaracterizedbyacombinationofhypertriglyceridemia(serumtriglycerides>200mg/dL),lowHDL-cholesterol,andabnormalLDL-cholesterol(110).Lipid-loweringtherapytonormalizediabeticdyslipidemiaandreducecardiovascularriskincludeslifestylemodificationandmedications — particularlytheuseofcholesterol-loweringstatins(111,112).Additionally,achievingglucosecontrolinpeoplewithtype2diabeteshasbeenshowntodecreasetheoccurrenceofmajormicrovascularandmacrovascularevents(113). A2014meta-analysisof19randomizedcontrolledtrials,including24,788individualswitheitherimpairedglucosemetabolismortype2diabetesmellitus,foundthatlong-chainomega-3PUFAsupplementation(doses,360-10,000mg/day;for6weeksto6years)loweredserumtriglycerideconcentrationsby0.25mmol/Lbuthadnosubstantialeffectontotalcholesterol,LDL-cholesterol,orHDL-cholesterol(114).TherewasalsonosignificanteffectonHbA1c,fastingglucose,bloodpressure,heartrate,orameasureofendothelialfunction.Fourtrialsthatlastedoverayearreportedoncardiovascularoutcomes,includingmortality.Thepooledanalysisofthesetrialsfoundnoeffectofsupplementationwithomega-3PUFAontheriskofmajorcardiovascularevents,cardiovascularmortality,all-causemortality,oracompositeendpointofall-causemortalityandhospitalizationforacardiovascularcause.Itisworthnotingthattwoofthesetrials — theAlphaOmegaTrial(115)andtheORIGINtrial(116)— includedahighproportionofparticipantswhotookcardiovascularmedications(i.e.,cholesterol-loweringstatins)(114).Anothermeta-analysisof45randomizedcontrolledtrialsin2,674participantswithtype2diabetesfoundthatsupplementationwithomega-3(400-1,800mg/dayfor2weeksto2years)ledtosmalldecreasesinbloodconcentrationsoftriglycerides,VLDL-triglycerides,LDL-cholesterol,andvLDL-cholesterol(117).Therewasnoevidenceofaneffectontotalcholesterol,HDL-cholesterol,non-esterifiedfattyacids,apolipoprotein-A1,andapolipoprotein-B.Therewasareductionincirculatingconcentrationsofpro-inflammatorycytokines,TNF-αandIL-6,inresponsetoomega-3supplementation,yetnotofC-reactiveprotein(CRP) — amarkeroflow-gradeinflammation.Omega-3PUFAsupplementationhadnoeffectonsystolicordiastolicbloodpressure.Finally,asmalldecreaseinHbA1cwasreportedinresponsetosupplementalomega-3fattyacids,yettherewasnoeffectonotherindicatorsofglycemiccontrol,especiallyfastingglucose,fastinginsulin,connecting(C-)peptide,andameasureofinsulinresistance(117). Lifestylechangesinvolvingdietarymodifications,suchasthesubstitutionofhealthyfats(mono-andpoly-unsaturatedfattyacids)forsaturatedandtransfats,arerecommendedtoreducetheriskofcardiovasculardiseaseinpeoplewithtype2diabetesmellitus(118).Intheirmostrecentupdatedrecommendationsonthepreventionofcardiovasculardiseaseinadultswithtype2diabetes,theAmericanDiabetesAssociationandAmericanHeartAssociationfoundinsufficientevidencefromlarge-scalerandomizedtrialsinindividualswithtype2diabetestosupporttheuseofomega-3fattyacidsupplements(combinedwithaheart-healthydiet)inthepreventionofcardiovascularevents(118). Gestationaldiabetes:Poorglycemiccontrolduringpregnancy,whetherduetotype1diabetes,type2diabetes,orgestationaldiabetes,increasestheriskoffetalanomalies,preeclampsia,spontaneousabortion,stillbirth,macrosomia,neonatalhypoglycemia,andneonatalhyperbilirubinemia(119).Diabetesduringpregnancyisalsoassociatedwithahigherriskofmetabolicdisordersinoffspringlaterinlife(119).AteamofinvestigatorsinIranexaminedtheeffectofomega-3PUFAsupplementationduringpregnancy,beginningat24to28weeks'gestationforsixweeks,inwomenwithgestationaldiabetes.Overall,therewasevidenceofbeneficialeffectsof1,000mg/dayofomega-3alone(120)ortogetherwithvitaminE(121)orvitaminD(122)onmarkersofglucosehomeostasisand,toalesserextent,onmarkersofoxidativestressandinflammationandbloodlipidprofile.Inonerandomized,placebo-controlledtrialin60womenwithgestationaldiabetes,supplementationwithomega-3fattyacidsandvitaminEreducedtheriskofneonatalhyperbilirubinemiayethadnoeffectontherateofcesareansection,needforinsulintherapy,maternalhospitalization,newborns'hospitalization,gestationalage,birthsize,andApgarscore(122). CurrentrecommendationsbytheAmericanDiabetesAssociationforthemanagementofgestationaldiabetesencouragethedevelopmentofanindividualizednutritionplanbetweenawomanandaregistereddietitian,highlightingtheimportanceoftheamountandtypeofcarbohydratesinthediet(119).Theuseofomega-3supplementsinthemanagementofgestationaldiabetesisnotcurrentlyunderconsideration. Type2diabetesmellitus Ameta-analysisof13randomized,controlledfeedingtrialsthatsubstitutedplant-derivedPUFA(primarilylinoleicacid[LA])forsaturatedfattyacidsorcarbohydratesfor3to16weeksingenerallyhealthyadultsshowedadecreaseinfastinginsulinconcentrationandinsulinresistancebutnoeffectonfastingglucoseconcentration(123).Moststudiesusedamixtureofomega-3andomega-6PUFAintheformofplant-derivedoilssuchthatpotentialdifferencesineffectbetweenthemcouldnotbeexamined. Ameta-analysisof20prospectivecohortstudiesconductedin10countries,inatotalof39,740participantsfreefromdiabetesatbaseline,examinedbiomarkersofomega-6intakeinrelationtotheriskofdevelopingtype2diabetesmellitus(124).LArangedfrom8.3%oftotalfattyacidsinerythrocytephospholipidsto54.5%inplasmacholesterolesters.Thelowestpercentageofarachidonicacid(AA)wasfoundinadiposetissue(0.3%)andthehighestinerythrocytephospholipids(17.0%).ThehighestversuslowestconcentrationofLAmarkersineachcompartment(phospholipids,plasmaorserum,cholesterolesters)exceptadiposetissuewasassociatedwitha35%lowerriskoftype2diabetes.Incontrast,onlyAAinplasmaorserumwasinverselyassociatedwiththeriskoftype2diabetes(124).IfLAconcentrationinbloodandadiposetissuecanprovideanobjectiveassessmentofdietaryLAintake(125),theseresultssuggestthatdietaryLAmaybeimportantforglycemiccontrolanddiabetesprevention. Metabolicsyndrome A2019meta-analysisof13observational(9cross-sectional,2case-control,1nestedcase-control,and1prospectivecohort;36,542participants)studiesshowedhigherconcentrationsofomega-3inbloodandadiposetissueandhigherlevelofomega-3intaketobeassociatedwithalowerriskofmetabolicsyndrome(126).Noassociationwasfoundbetweentissueomega-6concentrationordietaryomega-6intakelevelandtheriskofmetabolicsyndrome(126). CognitivedeclineandAlzheimer'sdisease Alzheimer’sdiseaseisthemostcommoncauseofdementiainolderadults(127).Alzheimer'sdiseaseischaracterizedbytheformationofamyloidplaqueinthebrainandnervecelldegeneration.Diseasesymptoms,includingmemorylossandconfusion,worsenovertime(128). Observationalstudies:SeveralobservationalstudieshaveexamineddietaryfishandPUFAconsumptioninrelationtorisksofcognitivedecline,dementia,andAlzheimer'sdisease.Thepooledanalysisoffivelargeprospectivecohortstudies(Three-CityStudy,Nurses'HealthStudy,Women'sHealthStudy,ChicagoHealthandAgingProject,andRushMemoryandAgingProject)thatfollowedatotalof23,688older(ages,≥65years)participants(88%women)for3.9to9.1yearsfoundslowerratesofdeclineinepisodicmemoryandglobalcognitionwithincreasingfishintakes(129).PreviousstudieshavesuggestedthattheeffectoffishorPUFAconsumptiononcognitionmaybedependentonapolipoproteinE(APOE)genotype(130,131).OfthreecommonAPOEalleles(epsilon2[ε2],ε3,andε4),thepresenceoftheAPOEε4(E4)allelehasbeenassociatedwithincreasedriskandearlieronsetofAlzheimer'sdisease(132).Itwasfoundthatlong-chainomega-3PUFAsupplementationdidnotincreaseplasmaomega-3concentrationstothesameextentinE4carriersthaninnon-carriers(133)andthatDHAmetabolismdiffersinE4carrierscomparedtonon-carriers,withgreateroxidationandlowerplasmaconcentrationsinE4carriers(134).However,neitherAPOEgenotypenorpolymorphismsin11othergenesassociatedwithAlzheimer'sdiseasewerefoundtomodifytheinverserelationshipbetweenfishintakeandriskofcognitivedeclineinthepooledanalysisofthefivecohorts(129). Inarecentmeta-analysisofobservationalstudies,eachone-servingincreaseoffishintakeperweekwasfoundtobeassociatedwitha5%lowerriskofdementiaanda7%lowerriskofAlzheimer'sdisease(135).Dietaryintakelevelofmarine-derivedDHA — butnotbloodDHAconcentration — wasalsoinverselyassociatedwiththerisksofdementiaandAlzheimer'sdisease;forinstance,a100mg/dayincrementindietaryDHAintakewasassociatedwithlowerrisksofdementia(-14%)andAlzheimer'sdisease(-37%)(135).Resultsfromtwolargecohortstudiespublishedafterthisdose-responsemeta-analysisshowedbloodDHAconcentrationtobepositivelyassociatedwithcognitiveperformanceinadults(136,137).Findingsfrompreclinicalstudiessuggestthatlong-chainomega-3fattyacidsmayhaveneuroprotectiveeffects,potentiallythroughmitigatingneuroinflammation,improvingcerebralbloodflow,and/orreducingamyloidaggregation(138). Randomizedcontrolledtrials:A2012systematicreviewidentifiedthreerandomizedcontrolledtrialsthatexaminedtheeffectofomega-3supplementationontheriskofcognitivedeclineincognitivelyhealthyolderorelderlyadults(139).Therewasnoevidenceshowinganeffectofomega-3onmeasuresofcognitivefunctionsintheseclinicaltrials.Inamorerecentsystematicreviewthatidentifiedseventrialsconductedincognitivelyhealthyparticipants,theauthorsreportedpositiveeffectsoflong-chainomega-3supplementationonmeasuresofcognitiveoutcomesinallstudiesbutthesecondlongestandthetwolargesttrials(140).Anotherseventrialsexaminedtheeffectoflong-chainomega-3supplementationinindividualswithmildcognitiveimpairment;allbutthreetrialsshowedasignificantbenefitonmeasuresofcognitivefunctionorspecificmemorytasks(140).Yet,twotrialsthatfoundnoimprovementincognitiveperformanceincludedomega-3supplementsinbothinterventionandcontrolarms(141,142). Overall,thedatafavorarolefordietsrichinlong-chainomega-3fattyacidsinslowingcognitivedecline,butlargertrialswithlongerinterventionperiodsmaybenecessarytoseeaconsistentbeneficialeffectofomega-3supplementationinolderindividualswithnormalordecliningcognitivefunctions. DiseaseTreatment Hypertriglyceridemia Aboutone-thirdofUSadultshaveserumtriglycerides>150mg/dL,and16%ofUSadultshaveserumtriglycerides>200mg/dL(143).The2011AmericanHeartAssociationguidelinesontriglyceridemanagementrecommendedtheuseofmarine-derivedomega-3fattyacidsupplements(2-4g/dayofEPAplusDHA)undermedicalsupervisiontoreducetriglycerideconcentrationsbelow100mg/dL(143).Hypertriglyceridemiacanhavevariouscauses,suchasinheritedandacquireddisordersoftriglyceridemetabolism,poordiet,and/oruseofcertainmedications(143). Severalomega-3fattyacidpreparationshavebeenapprovedbytheUSFoodandDrugAdministrationforthetreatmentofhypertriglyceridemia(104).Outofthefivecurrentlyavailablepreparations,fourcontainethylestersofEPAand/orDHAandonecontainslong-chainomega-3PUFAasfreefattyacids(104).TheEpanovaforloweringveryhightriglycerides(EVOLVE)randomizedcontrolledtrialdemonstratedthattheomega-3freefattyacidformulation(2-4g/dayfor12weeks)effectivelyreducedtriglyceridesandotheratherogenicfactors,includingvLDL-cholesterolandremnant-likecholesterolparticles,whencomparedtooliveoil(4g/day)inpatientswithseverehypertriglyceridemia(serumtriglycerides>500mg/dL)(reviewedin144).Omega-3supplementationalsodecreasedinflammation(asshownbyareductioninlipoprotein-associatedphospholipaseA2)andplateletactivation(asshownbyareductionincirculatingconcentrationsofarachidonicacid)(144,145).Thisomega-3formulationalsoprovedtobeeffectiveinreducingpersistenthypertriglyceridemia(serumtriglycerides,200-499mg/dL)inpatientstreatedwithstatins(cholesterol-loweringdrugs)(146).Statinusehasbeenfoundtoeffectivelyreducetriglycerideconcentrationsbyabout5%-20%(147).However,aresidualelevationintriglyceridesandtriglyceride-richlipoproteincholesterolmayremaininasubstantialfractionofpatientstreatedwithstatins.Comparedto4g/dayofoliveoil,omega-3supplementationwith2or4g/dayforsixweeksreducedtriglyceridesby14.6%and20.6%andnon-HDL-cholesterolby3.9%and6.9%,respectively(146).Themagnitudeofthesereductionsintriglycerideandnon-HDL-cholesterolconcentrationswassimilartowhathasbeenobservedinothertrialsthatexaminedtheuseofethylesteromega-3supplementsasadd-onstostatintherapy(146,148-150).Astudyisunderwaytoassessthebenefitofcombiningomega-3fattyacidsandstatinsontheriskofmajorcardiovasculareventsoverathree-tofive-yearperiodinpatientswithhypertriglyceridemia(144,151). Nonalcoholicfattyliverdisease Oftenassociatedwithmetabolicdisorders,nonalcoholicfattyliverdisease(NAFLD)isaconditioncharacterizedbyanexcessivelipidaccumulationintheliver(i.e.,hepatosteatosis).NAFLDcanprogresstononalcoholicsteatohepatitis(NASH)inaboutone-thirdofthepatientswithNAFLD,therebyincreasingtheriskofcirrhosisandhepatocellularcarcinoma(152,153).AnemergingfeatureofNAFLDisthedeclineinhepaticomega-3andomega-6PUFAwithdiseaseprogression(154).ConsideringthatC20-22omega-3PUFAcanreducefattyacidsynthesisandinflammation,apossibletherapeuticstrategywouldbetoincreasedietaryintakeoflong-chainomega-3PUFA.A2018meta-analysisof18randomizedcontrolledtrialsin1,424participantswithNAFLDfoundthatomega-3supplementationshowedbeneficialeffectsonliverfat,specificliverenzymaticactivities,serumtriglycerides,fastingglucose,andinsulinresistance(155).However,therewasnoevidenceofaneffectontotalcholesterol,LDL-cholesterol,HDL-cholesterol,fastinginsulin,bloodpressure,BMI,andwaistcircumference(155).Otherrecentmeta-analyseshavealsoreportedthatsupplementationwithlong-chainomega-3fattyacidsfromfish/sealoil(0.25-6.8g/dayfor3-25months)improvedhepatosteatosisandothermetabolicdisordersinbothchildrenandadultswithNAFLD(reviewedin153).AdditionalstudiesareneededtoexaminetheirefficacyinmoreseverecasesofNASH. Inflammatorydiseases Rheumatoidarthritis A2017meta-analysisof20randomizedcontrolledtrialsin1,252participantswithrheumatoidarthritisassessedtheefficacyoflong-chainomega-3PUFAsupplementationonaseriesofclinicaloutcomes(156).Omega-3supplementation(0.3-9.6g/day)for3to18monthsreducedthenumberoftenderjoints(14trials),aswellasearlymorningstiffness(15trials)andpainlevel(16trials)comparedtoplacebo.Bloodconcentrationsoftriglycerides(3trials)andpro-inflammatoryleukotrieneB4(5trials)werealsodecreasedwithsupplementalomega-3PUFA(156).Another2017meta-analysisof42randomizedcontrolledtrialsexaminedtheeffectofomega-3supplementation(mainlyasfishoil)onarthriticpaininpatientsdiagnosedwithdifferenttypesofarthritis(157).Dailyadministrationofmarine-derivedEPA(0.01-4.1g)andDHA(0.01-2.7g)forupto18monthsresultedinareductioninpatients’reportedpain(usingavisualanalogscale[VAS]forpain)inthosesufferingfromrheumatoidarthritis(22trials)andthosewithothertypesofarthritis(i.e.,juvenilearthritis,psoriaticarthritis)ormixeddiagnoses(3trials),yetnotinthosewithosteoarthritis(5trials).Theevidenceofaneffectofomega-3supplementsinpatientswithrheumatoidarthritiswasdeemedofmoderatequality(157).Ina2017systematicreviewof18trials,including1,143subjectswithrheumatoidarthritis,only4of18placebo-controlledtrialsshowedabenefitofomega-3PUFAsupplementation(2.2-3.6g/dayfor12-36weeks)onpainlevel — reportedbypatientsand/orassessedbyphysicians(158).Inmosttrials,theuseofmedications(nonsteroidalanti-inflammatorydrugs[NSAIDs]and/ordisease-modifyinganti-rheumaticdrugs[DMARDs])wascontinuedthroughouttheinterventionperiod.Resultsofafewtrialssuggestedthatomega-3PUFAcouldsparetheneedforanti-inflammatorymedicationsinsomepatientsyetfailedtoshowsuperiorityofPUFAinpainmanagement(159,160). Thelimitedbodyofevidencethatsuggestspotentialbenefitsofomega-3supplementationinrheumatoidarthritistreatmentneedsstrengtheningwithdatafromlargerstudiesconductedforlongerinterventionperiods(157,158). Inflammatoryboweldisease Crohn'sdisease:A2013systematicreviewevaluatedtheefficacyofomega-3supplementationinpatientswithCrohn'sdisease,consideringtheevidencebasefrombothshort-term(9to24weeks)andlong-term(1year)trials(161).Amongfivetrialsthatevaluatedtheefficacyofomega-3supplementationonrelapserates,conflictingoutcomeswerereported.Mosttrialswerelimitedbysmallsamplesizesandshortduration — uptothreeyearsmaybenecessarytoseeaneffectonrelapseratesgiventhenaturalrelapsing-remittingcourseofthedisease.Thetwolargestandmostrecenttrials(EPIC-1andEPIC-2)showednosignificanteffectofomega-3supplementationonindicatorsofCrohn'sdiseaseremissioncomparedtoplacebo(162).Othersystematicreviewsoftheliteraturereachedsimilarconclusions(163-165).Threeshort-termtrialsshowedpositiveeffectsofomega-3supplementationonplasmabiochemicalparameters(e.g.,reducedinflammatorycytokineexpression,increasedplasmaEPAandDHAconcentrations)comparedtocontrols(161).Inspiteofitsimpactonbiochemicalchangesintheshort-term,however,theabilityofomega-3supplementationtomaintainremissionoreffectclinicallymeaningfulchangesinCrohn'sdiseaseisnotsupportedbythecurrentevidence(164). Ulcerativecolitis:Sevenrandomizedcontrolledtrialsoffishoilsupplementationinpatientswithactiveulcerativecolitisreportedsignificantimprovementinatleastoneoutcomemeasure,suchasdecreasedcorticosteroiduse,improveddiseaseactivityscores,orimprovedhistologyscores(163).Inpatientswithinactiveulcerativecolitis,omega-3supplementationhadnoeffectonrelapseratescomparedtoplaceboinfourseparatetrials(163,165). Whilenoserioussideeffectswerereportedinanytrialsoffishoilsupplementationforthemaintenanceorremissionofinflammatoryboweldisease,diarrheaanduppergastrointestinalsymptomsoccurredmorefrequentlywithomega-3treatment(163-165). Asthma Inflammatoryeicosanoids(leukotrienes)derivedfromarachidonicacid(AA;20:4n-6)arethoughttoplayanimportantroleinthepathologyofasthma(32).Becauseincreasingomega-3fattyacidintakehasbeenfoundtodecreasetheformationofAA-derivedleukotrienes,anumberofclinicaltrialshaveexaminedtheeffectsoflong-chainomega-3fattyacidsupplementationonasthma.Althoughthereissomeevidencethatomega-3fattyacidsupplementationcandecreasetheproductionofinflammatorymediatorsinasthmaticpatients(166,167),evidencethatomega-3fattyacidsupplementationdecreasestheclinicalseverityofasthmaincontrolledtrialshasbeeninconsistent(168).Threesystematicreviewsofrandomizedcontrolledtrialsoflong-chainomega-3fattyacidsupplementationinasthmaticadultsandchildrenfoundnoconsistenteffectsonclinicaloutcomemeasures,includingpulmonaryfunctiontests,asthmaticsymptoms,medicationuse,orbronchialhyperreactivity(169-171). ImmunoglobulinAnephropathy ImmunoglobulinA(IgA)nephropathyisakidneydisorderthatresultsfromthedepositionofIgAintheglomeruliofthekidneys.ThecauseofIgAnephropathyisnotclear,butprogressiverenalfailuremayeventuallydevelopin15%-40%ofpatients(172).SinceglomerularIgAdepositionresultsinincreasedproductionofinflammatorymediators,omega-3fattyacidsupplementationcouldpotentiallymodulatetheinflammatoryresponseandpreserverenalfunction. A2012meta-analysisassessedtheefficacyofomega-3fattyacidsupplementationonadultIgAnephropathy(173).Fiverandomizedcontrolledtrialswereincludedinananalysisinvolving239patients(meanage,37-41years)whoreceivedplaceboorsupplementalEPA+DHAatdosesof1.4to5.1g/dayfor6to24months.Comparedwithcontrolgroups,omega-3supplementationhadnosignificanteffectonurineproteinexcretionorglomerularfiltrationrate.Onlytwotrialsmeasuredchangesinserumcreatinine(amarkerofrenalfunction)andend-stagerenaldisease — omega-3treatmenthadabeneficialeffectonthesetwoparametersinbothtrials.Noadverseeventsassociatedwithomega-3supplementationwerereportedinanyofthetrials.Amorerecentreviewoftheliteratureidentifiedsixtrialsshowingevidenceofomega-3supplementationslowingIgAnephropathydiseaseprogressionandthreetrialsreportingnoeffect(174).Additionally,preliminarydatasuggestedthatthepotentialsynergisticactionsofaspirinandlong-chainomega-3PUFAsmightconstituteapromisingtreatmentoption(168). Neuropsychiatricdisorders Autismspectrumdisorders Autismspectrumdisorders(ASD)refertothreeneurodevelopmentaldisordersofvariableseverity,namelyautism,Aspergersyndrome,andpervasivedevelopmentdisorder.ASDarecharacterizedbyabnormalinformationprocessinginthebrainduetoalterationsinthewaynervecellsandtheirsynapsesconnectandorganize.ASDarethoughttohaveastronggeneticbasis,yetenvironmentalfactorsincludingdietmayplayanimportantrole.Giventhatomega-3andomega-6PUFAarenecessaryforneuronalgrowthandsynapseformation(seeBiologicalActivities),theymaybeofsignificantbenefitinthepreventionand/ormanagementofASD.ThisissupportedbyobservationsofPUFAabnormalitiesinbloodofchildrenwithASD,whencomparedtotheirpeerswithnoneurodevelopmentaldisorders(175).Ameta-analysisofcase-controlstudiesreportedlowerbloodconcentrationsofDHAandEPAinchildrenwithASDcomparedtotypicallydevelopingchildren;yet,theratiooftotalomega-6toomega-3fattyacidswassimilarbetweenchildrenwithandwithoutASDsymptoms(176).Asystematicreviewbythesameauthorsidentifiedsixrandomizedcontrolledtrialsthatexaminedtheeffectofprimarilylong-chainomega-3PUFAonASDsymptoms(176).Allthestudiesincludedchildren;onestudyalsoincludedadults≤28years(177).FourtrialsusedEPA(0.70-0.84g/day)plusDHA(0.46-0.70g/day)(178-181),onetrialusedDHA(0.24g/day)plusAA(0.24g/day)(177),andonetrialonlyusedonlyDHA(0.20g/day)(182).Apooledanalysisoffour(177-180)ofthesetrials,includingatotalof107participants,showedasmallimprovementinmeasuresofsocialinteractionandrepetitiveandrestrictiveinterestsandbehaviorswithlong-chainPUFAsupplementationfor6to16weeks;however,therewasnoeffectonmeasuresofcommunicationandASDco-existingconditions,suchashyperactivity,irritability,sensoryissues,andgastrointestinalsymptoms(176).Twoadditionalsystematicreviewsandmeta-analyses,alsopublishedin2017,identifiedthesamesetoftrials.Onemeta-analysissuggestedabenefitoflong-chainPUFAonmeasuresoflethargyandstereotypybutfoundnooverallclinicalimprovementcomparedtoplacebo(183).Theothermeta-analysissuggestedanimprovementregardinglethargyyetaworseningofexternalizingbehaviorandsocialskillsinchildrensupplementedwithomega-3PUFA(184). Theavailableevidenceisbasedonfewtrialsofsmallsamplesizesandisthustoolimitedtodrawfirmconclusionsregardingthepotentialbenefitoflong-chainPUFAsupplementationinASDmanagement. Majordepressionandbipolardisorder Datafromecologicstudiesacrossdifferentcountriessuggestedaninverseassociationbetweenseafoodconsumptionandnationalratesofmajordepression(185)andbipolardisorder(186). Severalsmallstudieshavefoundomega-3fattyacidconcentrationstobelowerinplasma(187-189)andadiposetissue(190)ofindividualssufferingfromdepressioncomparedtocontrols.Althoughitisnotknownhowomega-3fattyacidintakeaffectstheincidenceofdepression,modulationofneuronalsignalingpathwaysandeicosanoidproductionhavebeenproposedaspossiblemechanisms(191).Theremaybesomebenefitofomega-3PUFAsupplementationondepressivedisorders,butitisdifficulttocomparestudiesanddrawconclusionsduetogreatheterogeneityamongthetrials(192,193).Smallsamplesizes,lackofstandardizationoftherapeuticdoses,typeofomega-3PUFAadministered,co-treatmentwithpharmacologicalagents,anddiagnosticcriteriavaryamongthetrials.A2012systematicreviewofallpublishedrandomizedcontrolledtrialsinvestigatedtheeffectofomega-3PUFAsupplementationonthepreventionandtreatmentofseveraltypesofdepressionandotherneuropsychiatricdisorders(192).Withrespecttomajordepression,moststudiesreportedapositiveeffectofomega-3supplementsondepressivesymptoms,thoughefficacyisstillconsideredinconclusivegiventhegreatvariabilityamongtrials.Afewthemesemergedfromthisreview:moretrialsreportedpositiveeffectforomega-3PUFAsupplementsasanadjuncttopharmacologicaltreatment;inmonotherapytrials,EPAalonewasmoreeffectivethanDHAalone;andincombinationtrials,positiveeffectsweremorelikelyifanEPA:DHAratioof>1.5–2.0wasadministered. A2014meta-analysisgroupedtrialsbytypeofdiagnosisofdepression(194).Apositiveeffectofomega-3supplementationwasfoundin11trialsinparticipantswithadiagnosisofmajordepressivedisorder(accordingtotheDiagnosticandStatisticalManualofMentalDisorders[DSM]criteria).Omega-3supplementationalsoappearedtobeeffectiveinthepooledanalysisofeighttrialsinparticipantsnotformallydiagnosedwithmajordepressivedisorder,i.e.,adultswithdepressivesymptomsdespiteongoingtreatment,untreatedpatientswithmild-to-severedepressedmood,patientswithahistoryofatleastonemajordepressiveepisode,womenwithborderlinepersonalitydisorder,patientswithrecurrentself-harm,andpostmenopausalwomenwithpsychologicaldistressanddepressivesymptoms.Therewasnomoodimprovementwithomega-3supplementsingenerallyhealthyadultsexperiencingdepressivesymptoms,assuggestedbythepooledanalysisofsixtrials(194). Finally,a2017Cochranesystematicreviewandmeta-analysisof20randomizedcontrolledtrialsreportedasmallbenefitofomega-3supplementationondepressivesymptomswhencomparedtoplacebo,yettheevidencewasdeemedofverylowqualityandthepositiveeffectwasjudgedlikelytobebiasedandnotclinicallysignificant(195). Unipolardepressionandbipolardisorderareconsidereddistinctpsychiatricconditions,althoughmajordepressionoccursinboth.A2016meta-analysisofeightcase-controlstudiesthatcomparedthePUFAcompositionofredbloodcellmembranesbetweenpatientswithbipolardisorderandhealthysubjectsshowedabnormallylowredbloodcellDHAconcentrationswithbipolardisorder(196).Aswithmajordepression,reviewsoftrialsindicatedthatomega-3supplementationmayhaveapositiveeffectasanadjuncttotherapyinpatientswithbipolardisorder(192,194).Additionally,a2016randomized,placebo-controlledtrialin100participantswithbipolardisorderreportedareductionintheseverityofmanicepisodeswithdailysupplementationof1,000mgomega-3PUFAforthreemonths(197). Whilethereissomepromisingevidencefortheuseofomega-3fattyacidsformajordepressionandbipolardisorder,additionaltrialsthataccountfordietaryomega-3intake,changesinredbloodcellPUFAconcentrations,theratioofEPA:DHAprovided,andco-treatmentwithmedicationsarenecessary. Schizophrenia A2013meta-analysisof18studiescomparedthePUFAcompositionofredbloodcellmembranesinpatientswithschizophreniatoindividualswithoutthedisorder(198).Themajorityofstudiesinvestigatedmedicatedpatients,thoughtheauthorsseparatedtheanalysisintothreegroupsofpatientsattimeofmeasurementinordertoaccountforpossibleconfoundingfrompharmacologicagents:antipsychotic-medicated,antipsychotic-naïve,andantipsychotic-free.Overall,decreasedconcentrationsofDPA,DHA,andAAinredbloodcellmembraneswereassociatedwiththeschizophrenicstate.SeveralmechanismsmayaccountforPUFAabnormalitiesinschizophrenia,suchasalteredlipidmetabolism,increasedoxidativestress,orchangesindietconsequenttodisease-relatedbehavior.  Theuseoflong-chainomega-3fattyacidsupplementstoalleviatesymptomsofschizophreniaortomitigateadverseeffectsofantipsychoticmedicationshasbeeninvestigatedinanumberofclinicaltrials(194,199).Inarecentrandomized,placebo-controlledtrialin50subjectswithrecentonsetofschizophreniawhoweremedicated,dailysupplementationwithEPA(740mg)andDHA(400mg)reducedpsychoticsymptoms(assessedwiththeBriefPsychiatricRatingScale)onlyinthosewhowerenottakingtheanxiolytic,lorazepam(Ativan)(200).Overall,however,therewasnoeffectoflong-chainPUFAsupplementsonschizophreniasymptoms.Yet,giventhehighsafetyprofileoffishoilsupplementsandsomeevidenceofapositiveeffectofEPAsupplementationinasubsetoftrials,somecliniciansmayconsiderEPAausefuladjuncttoantipsychotictherapyinpatientswithschizophrenia. Alzheimer'sdiseaseanddementia Severalmechanismssuggestthatomega-3PUFAsupplementationmayimprovethecognitiveperformanceofindividualswithAlzheimer'sdiseaseandothertypesofdementia.Inparticular,theantioxidativeandanti-inflammatorypropertiesofthesePUFAmayhelpprotectneurons,promotesynapticplasticity,andlimitcellulardeath.ThePUFAcompositionofthedietappearstoinfluencebloodcholesterol,whichmayplayaroleinthepathologyofAlzheimer'sdisease.However,thecurrentevidencefromclinicaltrialsisnotsupportiveofomega-3supplementationinthetreatmentofAlzheimer’sdiseaseinhumans.A2016Cochranereviewidentifiedthreerandomized,placebo-controlledtrialsinpatientswithAlzheimer'sdiseaseofmild-to-moderateseverity(201).ThesetrialscompareddailysupplementationwithDHA(between675mgand1,700mg)andEPA(between600mgand975mg)toaplacebofor12months(202,203)or18months(204).Ofnote,thestudybyQuinnetal.(204)alsoincluded4mg/dayofvitaminE(usedaspreservative — seealsoNutrientinteractions)intheinterventionarm,andthestudybyFreund-Levietal.(202)includedDHA(900-1,100mg/day)butnoEPA.Thepooledanalysisofthesetrialsshowednobeneficialeffectofomega-3supplementationonmeasuresofglobalandspecificcognitivefunctions,measuresoffunctionaloutcomes,andmeasuresofdementiaseverity(201).Therewasnodifferencebetweeninterventionandplaceboarmsregardingtheoccurrenceofadverseeffects(201). Sources Foodsources Humanscansynthesizearachidonicacid(AA)fromlinoleicacid(LA)andeicosapentaenoicacid(EPA)anddocosapentaenoicacid(DHA)fromα-linolenicacid(ALA)throughaseriesofdesaturationandelongationreactions.EPAanddocosapentaenoicacid(DPA)arealsoobtainedfromtheretroconversionofDHA(seeMetabolismandBioavailability).Duetolowconversionefficiency,itisadvisedtoobtainEPAandDHAfromadditionalsources. Omega-6fattyacids Linoleicacid(LA):FoodsourcesofLAincludevegetableoils,suchassoybean,safflower,andcornoil;nuts;seeds;andsomevegetables.DietarysurveysintheUSindicatethattheaverageadultintakeofLArangesfrom17to20g/dayformenand12to13g/dayforwomen(78).SomefoodsthatarerichinLAarelistedinTable2. Table2.FoodSourcesofLinoleicAcid(18:2n-6)(205) Food Serving LinoleicAcid(g) Saffloweroil 1tablespoon 10.1 Sunflowerseeds,oilroasted 1ounce 9.7 Pinenuts 1ounce 9.4 Sunfloweroil 1tablespoon 8.9 Cornoil 1tablespoon 7.3 Soybeanoil 1tablespoon 6.9 Pecans,oilroasted 1ounce 6.4 Brazilnuts 1ounce 5.8 Sesameoil 1tablespoon 5.6 Arachidonicacid:Animals,butnotplants,canconvertLAtoAA.Therefore,AAisabsentinvegetableoilsandfatsandpresentinsmallamountsinmeat,poultry,andeggs. Omega-3fattyacids α-Linolenicacid(ALA):Flaxseeds,walnuts,andtheiroilsareamongtherichestdietarysourcesofALA.CanolaoilisalsoanexcellentsourceofALA.DietarysurveysintheUSindicatethataverageadultintakesforALArangefrom1.8to2.0g/dayformenandfrom1.4to1.5g/dayforwomen(78).SomefoodsthatarerichinALAarelistedinTable3. Table3.FoodSourcesofα-LinolenicAcid(18:3n-3)(205) Food Serving α-Linolenicacid(g) Flaxseedoil 1tablespoon 7.3 Chiaseeds,dried 1ounce 5.1 Walnuts,English 1ounce 2.6 Flaxseeds,ground 1tablespoon 1.6 Walnutoil 1tablespoon 1.4 Canolaoil 1tablespoon 1.3 Soybeanoil 1tablespoon 0.9 Mustardoil 1tablespoon 0.8 Walnuts,black 1ounce 0.6 Tofu,firm ½cup 0.2 Eicosapentaenoicacid(EPA)anddocosahexaenoicacid(DHA):DietarysurveysintheUSindicatethataverageadultintakesofEPArangefrom0.03to0.06g/day,andaverageadultintakesofDHArangefrom0.05to0.10g/day(78).OilyfisharethemajordietarysourceofEPAandDHA;omega-3fattyacid-enrichedeggsarealsoavailableintheUS.SomefoodsthatarerichinEPAandDHAarelistedinTable4. Table4.FoodSourcesofEPA(20:5n-3)andDHA(22:6n-3)(107) Food Serving EPA(g) DHA(g) AmountProviding 1gofEPA+DHA Herring,Pacific 3ounces* 1.06 0.75 1.5ounces Salmon,chinook 3ounces 0.86 0.62 2ounces Sardines,Pacific 3ounces 0.45 0.74 2.5ounces Salmon,Atlantic 3ounces 0.28 0.95 2.5ounces Oysters,Pacific 3ounces 0.75 0.43 2.5ounces Salmon,sockeye 3ounces 0.45 0.60 3ounces Trout,rainbow 3ounces 0.40 0.44 3.5ounces Tuna,canned,white 3ounces 0.20 0.54 4ounces Crab,Dungeness 3ounces 0.24 0.10 9ounces Tuna,canned,light 3ounces 0.04 0.19 12ounces *Athree-ounceservingoffishisaboutthesizeofadeckofcards. Supplements Omega-6fattyacids Borageseedoil,eveningprimroseoil,andblackcurrantseedoilarerichinγ-linolenicacid(GLA;18:3n-6)andareoftenmarketedasGLAoressentialfattyacid(EFA)supplements(206). Omega-3fattyacids Flaxseedoil(alsoknownasflaxoilorlinseedoil)isavailableasanALAsupplement.Anumberoffishoilsaremarketedasomega-3fattyacidsupplements.Theomega-3fattyacidsfromnaturalfishoilareinthetriglycerideform,oftenwithonlyoneofthreeattachedfattyacidsanomega-3;thus,upto70%offattyacidsprovidedmaybeothertypes(3).EthylestersofEPAandDHA(ethyl-EPAandethyl-DHA)areconcentratedsourcesoflong-chainomega-3fattyacidsthatprovidemoreEPAandDHApergramofoil.KrilloilcontainsbothEPAandDHAandisconsideredcomparabletofishoilasasourceoftheselong-chainPUFA(207).CodliveroilisalsoarichsourceofEPAandDHA,butsomecodliveroilpreparationsmaycontainexcessiveamountsofpreformedvitaminA(retinol)andvitaminD(206).DHAsupplementsderivedfromalgalandfungalsourcesarealsoavailable.BecausedietaryDHAcanberetroconvertedtoEPAandDPAinhumans,DHAsupplementationrepresentsyetanotheralternativetofishoilsupplements(seeMetabolismandBioavailability). ThecontentofEPAandDHAvariesineachofthesepreparations,makingitnecessarytoreadproductlabelsinordertodeterminetheEPAandDHAlevelsprovidedbyaparticularsupplement.Allomega-3fattyacidsupplementsareabsorbedmoreefficientlywithmeals.Dividingone'sdailydoseintotwoorthreesmallerdosesthroughoutthedaywilldecreasetheriskofgastrointestinalsideeffects(seeSafety). Infantformula In2001,theFDAbeganpermittingtheadditionofDHAandAAtoinfantformulaintheUnitedStates(208).Presently,manufacturersarenotrequiredtolisttheamountsofDHAandAAaddedtoinfantformulaonthelabel.However,mostinfantformulamanufacturersprovidethisinformation.TheamountsaddedtoformulasintheUSrangefrom8to17mgDHA/100calories(5floz)andfrom16to34mgAA/100calories.Forexample,aninfantdrinking20flozofDHA-enrichedformuladailywouldreceive32to68mg/dayofDHAand64to136mg/dayofAA. Safety Adverseeffects γ-Linolenicacid(18:3n-6) Supplementalγ-linolenicacidisgenerallywelltolerated,andseriousadversesideeffectshavenotbeenobservedatdosesupto2.8g/dayfor12months(209).Highdosesofborageseedoil,eveningprimroseoil,orblackcurrantseedoilmaycausegastrointestinalupset,loosestools,ordiarrhea(206).Becauseofcasereportsthatsupplementationwitheveningprimroseoilinducedseizureactivityinpeoplewithundiagnosedtemporallobeepilepsy(210),peoplewithahistoryofseizuresoraseizuredisorderaregenerallyadvisedtoavoideveningprimroseoilandotherγ-linolenicacid-richoils(206). α-Linolenicacid(18:3n-3) Althoughflaxseedoilisgenerallywelltolerated,highdosesmaycauseloosestoolsordiarrhea(211).Allergicandanaphylacticreactionshavebeenreportedwithflaxseedandflaxseedoilingestion(212). Eicosapentaenoicacid(20:5n-3)anddocosahexaenoicacid(22:6n-3) SeriousadversereactionshavenotbeenreportedinthoseusingfishoilorotherEPAandDHAsupplements.ThemostcommonadverseeffectoffishoilorEPAandDHAsupplementsisafishyaftertaste.Belchingandheartburnhavealsobeenreported.Additionally,highdosesmaycausenauseaandloosestools. Potentialforexcessivebleeding:Thepotentialforhighomega-3fattyacidintakes,especiallyEPAandDHA,toprolongbleedingtimeshasbeenwellstudiedandmayplayaroleinthecardioprotectiveeffectsofomega-3fattyacids.AlthoughexcessivelylongbleedingtimesandincreasedincidenceofhemorrhagicstrokehavebeenobservedinGreenlandEskimoswithveryhighintakesofEPA+DHA(6.5g/day),itisnotknownwhetherhighintakesofEPAandDHAaretheonlyfactorresponsiblefortheseobservations(1).TheUSFDAhasruledthatintakesupto3g/dayoflong-chainomega-3fattyacids(EPAandDHA)areGenerallyRecognizedAsSafe(GRAS)forinclusioninthediet,andavailableevidencesuggeststhatintakeslessthan3g/dayareunlikelytoresultinclinicallysignificantbleeding(107).AlthoughtheUSInstituteofMedicinedidnotestablishatolerableupperintakelevel(UL)foromega-3fattyacids,cautionwasadvisedwiththeuseofsupplementalEPAandDHA,especiallyinthosewhoareatincreasedriskofexcessivebleeding(seeDruginteractionsandNutrientinteractions)(1,206). Potentialforimmunesystemsuppression:Althoughthesuppressionofinflammatoryresponsesresultingfromincreasedomega-3fattyacidintakesmaybenefitindividualswithinflammatoryorautoimmunediseases,anti-inflammatorydosesofomega-3fattyacidscoulddecreasethepotentialoftheimmunesystemtodestroypathogens(213).Studiescomparingmeasuresofimmunecellfunctionoutsidethebody(exvivo)atbaselineandaftersupplementingpeoplewithomega-3fattyacids,mainlyEPAandDHA,havedemonstratedimmunosuppressiveeffectsatdosesaslowas0.9g/dayforEPAand0.6g/dayforDHA(1).Althoughitisnotclearifthesefindingstranslatetoimpairedimmuneresponsesinvivo,cautionshouldbeobservedwhenconsideringomega-3fattyacidsupplementationinindividualswithcompromisedimmunesystems. Potentialothereffects:Althoughfishoilsupplementsareunlikelytoaffectglucosehomeostasis,peoplewithdiabetesmellituswhoareconsideringfishoilsupplementsshouldinformtheirphysicianandbemonitorediftheychoosetotakethem(206). Infantformula InearlystudiesofDHA-enrichedinfantformula,EPA-andDHA-richfishoilwasusedasasourceofDHA.However,somepreterminfantsreceivingfishoil-enrichedformulahaddecreasedplasmaAAconcentrations,whichwereassociatedwithdecreasedweight(butnotlengthandheadcircumference)(214,215).ThiseffectwasattributedtothepotentialforhighconcentrationsofEPAtointerferewiththesynthesisofAA,whichisessentialfornormalgrowth.Consequently,EPAwasremovedandAAwasaddedtoDHA-enrichedformula.CurrentlyavailableinfantformulasintheUScontainonlyAAandDHAderivedfromalgalorfungalsources,ratherthanfishoil.RandomizedcontrolledtrialshavenotfoundanyadverseeffectsongrowthininfantsfedformulasenrichedwithAAandDHAforuptooneyear(216). Pregnancyandlactation Thesafetyofsupplementalomega-3andomega-6fattyacids,includingborageseedoil,eveningprimroseoil,blackcurrantseedoil,andflaxseedoil,hasnotbeenestablishedinpregnantorlactating(breast-feeding)women(217).Studiesoffishoilsupplementationduringpregnancyandlactationhavenotreportedanyseriousadverseeffects,butuseofomega-6/omega-3PUFA-containingsupplementsandfishoilsupplementsinpregnantornursingwomenshouldbemonitoredbyaphysician(seeContaminantsinfishandContaminantsinsupplements)(206). Contaminantsinfish Somespeciesoffishmaycontainsignificantlevelsofmethylmercury,polychlorinatedbiphenyls(PCBs),orotherenvironmentalcontaminants(218).Ingeneral,largerpredatoryfish,suchasswordfish,tendtocontainthehighestlevelsofthesecontaminants.Removingtheskin,fat,andinternalorgansofthefishpriortocookingandallowingthefattodrainfromthefishwhileitcookswilldecreaseexposuretoanumberoffat-solublepollutants,suchasPCBs(219).However,methylmercuryisfoundthroughoutthemuscleoffish,sothesecookingprecautionswillnotreduceexposuretomethylmercury.Organicmercurycompoundsaretoxicandexcessiveexposurecancausebrainandkidneydamage.Thedevelopingfetus,infants,andyoungchildrenareespeciallyvulnerabletothetoxiceffectsofmercuryonthebrain.Inordertolimittheirexposuretomethylmercury,theUSFoodandDrugAdministration(FDA)andEnvironmentalProtectionAgencyhaveformulatedjointrecommendationsforwomenwhomaybecomepregnant,pregnantwomen,breast-feedingwomen,andparents.TheserecommendationsarepresentedinTable5. FormoreinformationabouttheFDA/EnvironmentalProtectionAgencyadvisoryforpregnantwomenandparentsofyoungchildrenoneatingfish,seetheironlinebrochure.MoreinformationaboutmercurylevelsincommercialfishandshellfishisavailablefromtheFDA. Ofnote,the2015-2020DietaryGuidelinesforAmericansrecommendtheconsumptionofsalmon,anchovies,herring, shad,sardines,Pacificoysters,trout,andAtlanticandPacificmackerel(notkingmackerel),whicharehigherinEPAandDHAandlowerinmethylmercury(220). Contaminantsinsupplements Althoughconcernshavebeenraisedregardingthepotentialforomega-3fattyacidsupplementsderivedfromfishoiltocontainmethylmercury,PCBs,anddioxins,severalindependentlaboratoryanalysesintheUShavefoundcommerciallyavailableomega-3fattyacidsupplementstobefreeofmethylmercury,PCBs,anddioxins(221).Theabsenceofmethylmercuryinomega-3fattyacidsupplementscanbeexplainedbythefactthatmercuryaccumulatesinthemuscle,ratherthanthefatoffish(107).Ingeneral,fishbodyoilscontainlowerconcentrationsofPCBsandotherfat-solublecontaminantsthanfishliveroils.Additionally,fishoilsthathavebeenmorehighlyrefinedanddeodorizedcontainlowerconcentrationsofPCBs(222).Pyrrolizidinealkaloids,potentiallyhepatotoxicandcarcinogeniccompounds,arefoundinvariouspartsoftheborageplant.Peoplewhotakeborageoilsupplementsshoulduseproductsthatarecertifiedfreeofunsaturatedpyrrolizidinealkaloids(206). Table5.RecommendationstoLimitExposuretoSeafoodMethylmercury(219) 1.Eat8-12ouncesofavarietyoffishaweek That’s2or3servingsoffishaweek Foryoungchildren,givethem2or3servingsoffishaweekwiththeportionrightforthechild’sageandcalorieneeds. 2.Choosefishlowerinmercury. Manyofthemostcommonlyeatenfisharelowerinmercury. Examplesincludesalmon,shrimp,pollock,tuna(lightcanned),tilapia,catfish,andcod. 3.Avoid4typesoffish:tilefishfromtheGulfofMexico,shark,swordfish,andkingmackerel. These4typesoffisharehighestinmercury. Limitwhite(albacore)tunato6ouncesaweek. 4.Wheneatingfishyouorothershavecaughtfromstreams,rivers,andlakes,payattentiontofishadvisoriesonthosewaterbodies. Ifadviceisn’tavailable,adultsshouldlimitsuchfishto6ouncesaweekandyoungchildrento1to3ouncesaweekandnoteatotherfishthatweek. 5.Whenaddingmorefishtoyourdiet,besuretostaywithinyourcalorieneeds.   Druginteractions γ-Linolenicacidsupplements,suchaseveningprimroseoilorborageseedoil,mayincreasetheriskofseizuresinpeopleonphenothiazines(neurolepticagents),suchaschlorpromazine(210).Highdosesofblackcurrantseedoil,borageseedoil,eveningprimroseoil,flaxseedoil,andfishoilmayinhibitplateletaggregation;therefore,thesesupplementsshouldbeusedwithcautioninpeopleonanticoagulantmedications(206).Inparticular,peopletakingfishoilorlong-chainomega-3fattyacid(EPAandDHA)supplementsincombinationwithanticoagulantdrugs,includingaspirin,clopidogrel(Plavix),dalteparin(Fragmin),dipyridamole(Persantine),enoxaparin(Lovenox),heparin,ticlopidine(Ticlid),andwarfarin(Coumadin),shouldhavetheircoagulationstatusmonitoredusingastandardizedprothrombintimeassay(internationalnormalizedratio[INR]).Onesmallstudyfoundthat3g/dayor6g/dayoffishoildidnotaffectINRvaluesin10patientsonwarfarinoverafour-weekperiod(223).However,acasereportdescribedanindividualwhorequiredareductionofherwarfarindosewhenshedoubledherfishoildosefrom1g/dayto2g/day(224). Nutrientinteractions VitaminE Outsidethebody,PUFAbecomerancid(oxidized)moreeasilythansaturatedfattyacids.Fat-solubleantioxidants,suchasvitaminE(α-tocopherol),playanimportantroleinpreventingtheoxidationofPUFA.Insidethebody,resultsofanimalstudiesandlimiteddatainhumanssuggestthattheamountofvitaminErequiredtopreventlipidperoxidationincreaseswiththeamountofPUFAconsumed(225).OnewidelyusedrecommendationforvitaminEintakeis0.6mgofα-tocopherolpergramofdietaryPUFA.Thisrecommendationwasbasedonasmallstudyinmenandtheratioofα-tocopheroltoLAintheUSdietandhasnotbeenverifiedinmorecomprehensivestudies.AlthoughEPAandDHAareeasilyoxidizedoutsidethebody,itispresentlyunclearwhethertheyaremoresusceptibletooxidativedamagewithinthebody(226).HighvitaminEintakeshavenotbeenfoundtodecreasebiomarkersofoxidativedamagewhenEPAandDHAintakesareincreased(227,228),butsomeexpertsbelievethatanincreaseinPUFAintake,particularlyomega-3PUFAintake,shouldbeaccompaniedbyanincreaseinvitaminEintake(1). IntakeRecommendations USInstituteofMedicine TheFoodandNutritionBoardoftheUSInstituteofMedicine(nowtheNationalAcademyofMedicine)hasestablishedadequateintake(AI)foromega-6andomega-3fattyacids(Tables6and7)(1). Table6.AdequateIntake(AI)forOmega-6FattyAcids(1) LifeStage Age Source Males(g/day) Females(g/day) Infants 0-6months Omega-6PUFA* 4.4 4.4 Infants 7-12months Omega-6PUFA* 4.6 4.6 Children 1-3years LA# 7 7 Children 4-8years LA 10 10 Children 9-13years LA 12 10 Adolescents 14-18years LA 16 11 Adults 19-50years LA 17 12 Adults 51yearsandolder LA 14 11 Pregnancy allages LA - 13 Breast-feeding allages LA - 13 *Thevariousomega-6polyunsaturatedfattyacids(PUFA)presentinhumanmilkcancontributetotheAIforinfants.#LA,linoleicacid Table7.AdequateIntake(AI)forOmega-3FattyAcids(1) LifeStage Age Source Males(g/day) Females(g/day) Infants 0-6months ALA,EPA,DHA* 0.5 0.5 Infants 7-12months ALA,EPA,DHA 0.5 0.5 Children 1-3years ALA 0.7 0.7 Children 4-8years ALA 0.9 0.9 Children 9-13years ALA 1.2 1.0 Adolescents 14-18years ALA 1.6 1.1 Adults 19yearsandolder ALA 1.6 1.1 Pregnancy allages ALA - 1.4 Breast-feeding allages ALA - 1.3 *Allomega-3polyunsaturatedfattyacidspresentinhumanmilkcancontributetotheAIforinfants.ALA,α-linolenicacid;EPA,eicosapentaenoicacid;DHA,docosahexaenoicacid. Giventheestablishedhealthbenefitsofconsumingatleasttwoservingsofoilyfishperweek,providingapproximately400to500mgEPA+DHA,someresearchershaveproposedthattheUSInstituteofMedicine(nowtheNationalAcademyofMedicine)establishdietaryreferenceintakes(DRIs)forEPA+DHA(27).Fornow,therearenoDRIsforEPAandDHAspecifically. Becausematernaldietaryintakeoflong-chainPUFAdeterminestheDHAstatusofthenewborn,severalexpertpanelsintheUSrecommendthatpregnantandlactatingwomenconsumeatleast200mgDHAperday,closetotheamountrecommendedforadultsingeneral(250mg/day)(70,229).Thepotentialbenefitsassociatedwithobtaininglong-chainomega-3fattyacidsthroughmoderateconsumptionoffish(e.g.,1-2servingsweekly)duringpregnancyandlactationoutweighanyrisksofcontaminantexposure,thoughfishwithhighconcentrationsofmethylmercuryshouldbeavoided(218).Forinformationaboutcontaminantsinfishandguidelinesforfishconsumptionbywomenofchildbearingage,seeContaminantsinfish. 2015-2020DietaryGuidelinesforAmericans The2015-2020DietaryGuidelinesproviderecommendationsfornutritionalgoalsforlinoleicacidandα-linolenicacidbasedontheDRIs(seeTables6and7).Seafood,nuts,seeds,andoils,whichareallpartofhealthydietarypatterns,provideessentialfattyacids.The2015-2020DietaryGuidelinesprovidedietaryrecommendationsregardingtheamountsofthesefoodsforthosewhochoosetofollowahealthyUS-styleeatingpattern,ahealthyMediterranean-styleeatingpattern,orahealthyvegetarianeatingpattern(Table8). Table8.2015-2020DietaryGuidelinesforAmericans’RecommendationsforSourcesofOmega-3andOmega-6PolyunsaturatedFattyAcids*(220) Food HealthyEatingPatterns US-style Mediterranean-style Vegetarian Seafood(oz-eq/week) 8 15 – Nuts,seeds,soyproducts(oz-eq/week) 5 5 7 Oils(g/week) 27 27 27 *Recommendationsfortotaldailyenergyneedsof2,000caloriesperday.Estimatesofdailycalorieneedsaccordingtoage,gender,andphysicalactivitycanbefoundintheAppendix2ofthe‘2015-2020DietaryGuidelinesforAmericans’report(220). Oz-eq,ounce-equivalent AmericanHeartAssociationrecommendation TheAmericanHeartAssociationrecommendsthatpeoplewithoutdocumentedcoronaryheartdisease(CHD)eatavarietyoffish(preferablyoily)atleasttwiceweekly(230).Twoservingsofoilyfishprovideapproximately500mgofEPAplusDHA.Pregnantwomenandchildrenshouldavoidfishthattypicallyhavehigherlevelsofmethylmercury(seeContaminantsinfish).PeoplewithdocumentedCHDandthosewithheartfailurewithoutpreservedleftventricularfunctionareadvisedtoconsumeapproximately1g/dayofEPA+DHApreferablyfromoilyfish,ortoconsiderEPA+DHAsupplementsinconsultationwithaphysician(104,107).Patientswhoneedtolowerserumtriglyceridesmaytake2to4g/dayofEPA+DHAsupplementsunderaphysician'scare(seeHypertriglyceridemia). Internationalrecommendations UponrequestoftheEuropeanCommission,theEuropeanFoodSafetyAuthority(EFSA)proposedadequateintakes(AI)fortheessentialfattyacidsLAandALA,aswellasthelong-chainomega-3fattyacidsEPAandDHA(231).EFSArecommendsanLAintakeof4%oftotalenergyandanALAintakeof0.5%oftotalenergy;anAIof250mg/dayisrecommendedforEPAplusDHA(232).TheEuropeanFoodandSafetyAuthority(EFSA)recommendsthatpregnantandlactatingwomenconsumeanadditional100to200mgofpreformedDHAontopofthe250mg/dayEPAplusDHArecommendedforhealthyadults(231). Foradults,theWorldHealthOrganizationrecommendsanacceptablemacronutrientdistributionrange(AMDR)foromega-6fattyacidintakeof2.5%-9%ofenergyandforomega-3fattyacidintakeof0.5%-2%ofenergy(233).TheirAMDRforEPAplusDHAis0.25to2g/day(theupperlevelapplyingtosecondarypreventionofcoronaryheartdisease). TheInternationalSocietyfortheStudyofFattyAcidsandLipids(ISSFAL)recommendshealthyadultshaveanLAintakeof2%energy,anALAintakeof0.7%energy,andaminimumof500mg/dayofEPAplusDHAforcardiovascularhealth(234). LinusPaulingInstituterecommendation TheLinusPaulingInstitutesupportstheAIfortheessentialfattyacids(seeTables6and7) and recommendsthatgenerallyhealthyadultsincrease theirintakeoflong-chainomega-3fattyacidsbyeatingfishtwiceweeklyandconsumingfoodsrichinALA,suchaswalnuts,flaxseeds,andflaxseedorcanolaoil. Ifyoudon'tregularlyconsumefish,considertakingatwo-gramfishoilsupplementseveraltimesaweek.Ifyouarepronetobleedingortakeanticoagulantdrugs,consultyourphysician. AuthorsandReviewers Originallywrittenin2003by: JaneHigdon,Ph.D. LinusPaulingInstitute OregonStateUniversity UpdatedinDecember2005by: JaneHigdon,Ph.D. LinusPaulingInstitute OregonStateUniversity UpdatedinApril2009by: VictoriaJ.Drake,Ph.D. LinusPaulingInstitute OregonStateUniversity UpdatedinApril2014by: GianaAngelo,Ph.D. LinusPaulingInstitute OregonStateUniversity UpdatedinMay2019by: BarbaraDelage,Ph.D. LinusPaulingInstitute OregonStateUniversity ReviewedinJune2019by: DonaldB.Jump,Ph.D. Professor,SchoolofBiologicalandPopulationHealthSciences PrincipalInvestigator,LinusPaulingInstitute OregonStateUniversity Copyright2003-2022 LinusPaulingInstitute References 1. FoodandNutritionBoard,InstituteofMedicine.DietaryFats:TotalFatandFattyAcids.DietaryReferenceIntakesforEnergy,Carbohydrate,Fiber,Fat,FattyAcids,Cholesterol,Protein,andAminoAcids.Washington,D.C.:NationalAcademiesPress;2002:422-541. (TheNationalAcademiesPress) 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