the use of nonnutritive sweeteners in children...2019/10/25 · remain.3 most nnss, including...

POLICY STATEMENT Organizational Principles to Guide and Define the Child HealthCare System and/or Improve the Health of all Children

The Use of Nonnutritive Sweetenersin ChildrenCarissa M. Baker-Smith, MD, MPH, FAAP,a Sarah D. de Ferranti, MD, MPH, FAAP,b William J. Cochran, MD, FAAP,c

COMMITTEE ON NUTRITION, SECTION ON GASTROENTEROLOGY, HEPATOLOGY, AND NUTRITION

abstractThe prevalence of nonnutritive sweeteners (NNSs) in the food supply hasincreased over time. Not only are more children and adolescents consumingNNSs, but they are also consuming a larger quantity of NNSs in the absence ofstrong scientific evidence to refute or support the safety of these agents. Thispolicy statement from the American Academy of Pediatrics is intended toprovide the pediatric provider with a review of (1) previous steps taken forapproved use of NNSs, (2) existing data regarding the safety of NNS use in thegeneral pediatric population, (3) what is known regarding the potentialbenefits and/or adverse effects of NNS use in children and adolescents, (4)identified gaps in existing knowledge and potential areas of future research,and (5) suggested talking points that pediatricians may use when discussingNNS use with families

INTRODUCTION

Nonnutritive sweeteners (NNSs), also known as noncaloric artificialsweeteners or high-intensity sweeteners, were first introduced into thefood supply in the late 1800s (eg, saccharin) and were first approved foruse as a food additive under the Food Additives Amendment of the FederalFood, Drug, and Cosmetic Act of 1958.1,2 NNSs increase the palatability offood and beverages without increasing caloric content. It has beenproposed that the lack of caloric content of the sweeteners may contributeto weight loss. To date, however, there has been no consistent orconclusive evidence that NNS use lends to a reduction in total caloricintake and thereby to weight loss in humans3–8 or in animal physiologymodels.9 Questions regarding the long-term safety of these agents alsoremain.3 Most NNSs, including saccharin, aspartame, acesulfamepotassium, sucralose, and neotame, have been approved by the US Foodand Drug Administration (FDA) for use as food additives and, as such,have undergone premarket review and approval (https://www.fda.gov/food/food-ingredients-packaging/overview-food-ingredients-additives-colors). Other agents such as stevia and luo han guo have been approved

aSchool of Medicine, University of Maryland, Baltimore, Maryland;bBoston Children’s Hospital, Boston, Massachusetts; and cGeisingerMedical Center, Danville, Pennsylvania

Dr Baker-Smith is the primary author and drafted this policystatement, conducted the literature search and literature review,created the evidence table used to support the content of this policystatement, and assisted with final revisions and review of thedocument; Dr de Ferranti reviewed the literature, assisted with thedrafting and editing of the policy statement, and conducted finalrevisions and review; Dr Cochran assisted with literature review,contributed to the creation of the evidence table used to support thecontent of this policy statement, and assisted with the final review ofthe document; and all authors approved the final version of themanuscript as submitted.

Policy statements from the American Academy of Pediatrics benefitfrom expertise and resources of liaisons and internal (AAP) andexternal reviewers. However, policy statements from the AmericanAcademy of Pediatrics may not reflect the views of the liaisons or theorganizations or government agencies that they represent.

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authors have filedconflict of interest statements with the American Academy ofPediatrics. Any conflicts have been resolved through a processapproved by the Board of Directors. The American Academy ofPediatrics has neither solicited nor accepted any commercialinvolvement in the development of the content of this publication.

The guidance in this statement does not indicate an exclusive courseof treatment or serve as a standard of medical care. Variations, takinginto account individual circumstances, may be appropriate.

All policy statements from the American Academy of Pediatricsautomatically expire 5 years after publication unless reaffirmed,revised, or retired at or before that time.

DOI: https://doi.org/10.1542/peds.2019-2765

To cite: Baker-Smith CM, de Ferranti SD, Cochran WJ, AAPCOMMITTEE ON NUTRITION, SECTION ON GASTROENTEROLOGY,HEPATOLOGY, AND NUTRITION. The Use of NonnutritiveSweeteners in Children. Pediatrics. 2019;144(5):e20192765

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https://doi.org/10.1542/peds.2019-2765

by the FDA under the “generallyrecognized as safe” (GRAS)distinction, a distinction that has beendetermined to be insufficient forensuring the safety of food additiveswithout specific protections againstconflict of interest and withoutmechanisms to ensure ongoingacquisition of safety data.10,11

Concerns regarding the safety ofNNSs were initially related to theirpotential carcinogenic effects.Cyclamate, first approved for use in1958, was later removed from the listof approved food additives in 1969because of concerns regarding anassociation between cyclamate useand the development of bladdercancer.1,2,10,12 The relationshipbetween cyclamate and cancer waslater refuted on the basis ofadditional scientific data in rats, mice,dogs, hamsters, and monkeys.

Cyclamate was not the only NNSinitially suspected of an associatedcancer risk. Beginning in the 1970sand 1980s, animal studies suggestedan association between saccharinintake and the development ofbladder cancer in rodents.3,13,14 Thisassociation was later refuted becauseit was determined that the “cancer-causing mechanisms in rodents arenot applicable to humans.”3,14

Furthermore, human studiesevaluating the relationship betweensaccharin intake and stomach,pancreatic, and endometrial cancerhave not identified a relationshipbetween the consumption ofsaccharin and cancer.2,3,15,16 Overall,it appears that science does notsupport a potential carcinogeniceffect of cyclamate, saccharin, orsucralose in humans.3,17–19 Therelationship between aspartame andthe development of attention-deficitdisorders, birth defects, diabetes, andlupus has also been refuted.3

A number of health organizationshave supported the use of NNSs butwithin an acceptable dietary intake(ADI) level.20–25 Despite this, studies

conclusively demonstrating the long-term safety and efficacy of NNSagents are lacking.3,26 Also lacking ispublished evidence of parentalconfidence in the safety of NNSs.Despite FDA assurances, publisheddata reveal that parents continue tohave questions about the safety ofNNSs. For instance, in a single-sitestudy, only 16% of parents respondedin the affirmative to the statement,“Nonnutritive sweeteners (ie,Splenda, Sweet‘N Low, and Equal) aresafe for my child to use.”27 Knowledgeof how to identify productscontaining NNSs remains poorbecause only 23% of parents wereable to correctly identify foodproducts that contain NNSs. In fact,53% of parents stated they seekitems labeled “reduced sugar,” butmost did not recognize that the sweettaste was instead being provided byan NNS,27 and only one-quarter ofyouth were able to distinguish thetaste of NNS from sucrose.28

Estimating total content of NNS inmanufactured products has beenchallenging. Manufactured productscontaining NNSs are not required tospecify the content of NNS ina product. However, the consumptionof NNSs among children hasincreased.29,30 The long-term safetyor potential benefit of the growingprevalence of NNS use in children hasnot been systematically reviewed.31

One barrier to better understandingthe health effects of NNS is thedifficulty inherent in measuring theamount of NNS consumed at theindividual and population levels. TheFDA designation of a food item as anadditive or GRAS means that althoughmanufacturers must report thata particular product containsa sweetener, there is no obligation tostate the amount of sweetenera product contains,1 making itdifficult to estimate how much NNSthe average American consumes perday. This is compounded by the factthat NNS can also be found in ourdrinking water.32 Thus, even those

who do not believe that they havebeen exposed to NNSs havedetectable levels of NNS in theirurine.32,33

Estimates of consumption are largelybased on dietary recall12,29,30,34,35;however, such studies are fraughtwith inaccuracies and thus may resultin underestimates of true intake.29

Ideally, intake of NNS remains withinthe ADI level. Studies from the late1990s and early 2000s, includingstudies in children, had suggestedthat intake of intense sweeteners wassubstantially below the ADI.34–36

Contemporary data addressing totaldaily intake of NNS in adults andchildren are limited. According toselect studies, intake of particularNNSs (eg, acesulfame potassium orcyclamate) may exceed the ADI.37

Historically, carbonated beverageshave contributed the greatestmilligram dosage to total daily intakeof NNS (eg, saccharin).12,38 However,there is a growing and wideningvariety of food, drink, and consumerproducts that contain NNSs (eg,chewing gum, oral rehydrationsolutions, mouthwash, etc; Table 1).10

Therefore, estimates of intake wouldbe difficult to capture given currentmethods of reporting.

Ongoing questions also existregarding the benefits of NNSs. Addedsugars are known to have detrimentaleffects,39,40 including an associationbetween sugar intake and increasedbody mass, dyslipidemia, and bloodpressure.40 Recommendations topromote cardiovascular health inchildren include limiting the totalintake of sugar-sweetened beverages(SSBs) to 4 to 6 oz per day in children1 to 6 years of age and limiting thetotal intake of SSBs to 8 to 12 oz perday in children 7 to 18 years of age.41

NNSs have been considered for useamong those aiming to reduce theirtotal SSB intake while still preservingthe sweet taste. In particular, NNS usehas been proposed among individualswith diabetes and among thoseaiming to lose or maintain weight.

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However, concerns have arisen thatNNS use in animals may alter gutmicrobiota in such a way that there isan enhanced risk for glucoseintolerance, insulin resistance,diabetes, and increased weight.42,43

This report summarizes the availableliterature regarding NNS use inchildren and adolescents, includingthe penetrance of these agents intothe pediatric food chain and effectson taste preferences in children. Thisstatement also addresses proposedpotential benefits of NNSs in specificpediatric populations (ie, those withobesity, diabetes, etc). Considerationof the strength of the data was alsoincluded. Our purpose with thisstatement is not to provide specificclinical guidance regarding the use ofNNSs in children but rather toprovide a summary of the existingdata. Finally, recommendations aremade for future directions in researchand policy.

METHODS

A systematic review was beyond thescope of this publication; however,the authors used a common searchstrategy to identify relevantpublications. A literature review wasconducted regarding the use andsafety of NNSs in the pediatricpopulation (ie, 0–18 years of age) in2011. The search was updated onOctober 15, 2014, and then again on

May 25, 2018, because of delays inpublication related to a lengthyreview process. A final selection ofreferences was performed by August20, 2018, resulting in 40 additionalreferences.

The following search terms were usedin PubMed (www.pubmed.gov):“nonnutritive sweetener” or the nameof each individual FDA-approvednonnutritive sweetener (ie,“aspartame,” “neotame,” “saccharin,”“sucralose,” “advantame,” or“acesulfame”). “Stevia” also wasincluded in the search because thisagent received the designation ofGRAS. The search was limited tostudies published within the previous10 years (before the initial search) inhuman subjects and written in theEnglish language. Eighty-three studieswere identified. Studies that did notpertain to the use, safety, potentialbenefits, or associated risks of NNSuse in children were excluded (n =31). Studies addressing the use ofNNSs in pain control were excluded.The reference lists of selected articleswere reviewed, and relevant citedreferences were also included.Additional searches were performedto fill in identified knowledge gaps(n = 30). Finally, policy statements ofother organizations on NNS use,including the Academy of Nutritionand Dietetics (AND),21–23 AmericanDiabetes Association (ADA),44 and

American Heart Association (AHA),12

were reviewed (n = 4). It should bestated that the highest-qualityevidence is derived from randomizedcontrolled trials (RCTs) within thepopulation of interest. To date,however, few such studies exist (n =6).4,45–49

SWEETENERS AND NNSS

Sweeteners can be classified assugars (ie, brown sugar, cane sugar,fructose, and high-fructose cornsyrup), alcohol sugars (ie, isomalt,maltitol, mannitol, sorbitol, andxylitol), and NNSs (ie, saccharin,aspartame, acesulfame potassium,sucralose, stevia, neotame, andadvantame). NNSs are high-intensitysweeteners that provide a sweet tastewith little to no glycemic responseand few to no calories.1

Eight NNSs are currently approved bythe FDA,1 and their levels ofsweetness range from 180 to20 000 times sweeter than sucrose(ie, table sugar). Each NNS possessesvarying properties; some are stablewhen heated. Some arecontraindicated for use in particularpatient populations, such asaspartame use in people withphenylketonuria (Table 2). Most havebeen approved for use as a foodadditive and, as such, have undergonea premarket approval process inaccordance with stipulations made by

TABLE 1 Commercial Products Reported to Contain NNS

NNS No.Products

Product Examples

Saccharin 100 Smucker’s Low Sugar Reduced Sugar Sweet Orange Marmalade, Bubble Yum Sugarless chewing gum, diet sodas (Tab), yogurtAspartame 2307 Jell-O, diet sodas (Diet Coke, Coke Zero, Diet Dr Pepper, Fresca, Tab), Country Time Sugar Free lemonadeAcesulfamepotassium

3882 SlimFast, Werther’s Original Sugar Free hard candies, Del Monte Mandarin Oranges No Sugar Added, Pedialyte, diet sodas(Pepsi One, Sprite Zero, Fresca)

Sucralose 5148 Lean Pockets, diet sodas (Diet Mountain Dew)Neotame 114 Sunny D, protein shakes, chewing gumStevia 642 Some Muscle Milk productsAdvantame 0 N/ALuo han guo 98 Some Celestial Seasonings products

Adapted from FoodFacts.com (accessed July 12, 2015); Franz M. Amounts of sweeteners in popular sodas. Available at: https://static.diabetesselfmanagement.com/pdfs/DSM0310_012.pdf.Accessed April 28, 2019; and Food Standards New Zealand Australia. Sweeteners. 2018. Available at: www.foodstandards.gov.au/consumer/additives/Pages/Sweeteners.aspx. AccessedApril 28, 2019. N/A, not applicable.

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http://www.foodstandards.gov.au/consumer/additives/Pages/Sweeteners.aspx

the 1958 Food Additives Amendmentto the Federal Food, Drug, andCosmetic Act.

Under the 1958 Food AdditiveAmendment to the Federal Food,Drug, and Cosmetic Act, onlysubstances with GRAS designation donot require premarket approval.Although the market studies foraspartame, acesulfame potassium,sucralose, advantame (anN-substituted analog of aspartame),saccharin, and neotame are notwidely available, these NNSs have

been studied for safety.1 Studiesnumber more than 100 foraspartame, nearly 100 for acesulfamepotassium, approximately 110 forneotame (in animals and humans),and 37 for advantame (in animals andhumans), the NNS food additive mostrecently approved by the FDA.1,52,53

Only 2 approved NNSs, Steviarebaudiana and luo han guo (or monkfruit), have been approved under theGRAS notification process. After thepassage of the 1958 Food AdditivesAmendment, President Nixon orderedan evaluation of GRAS substances,

largely in response to concerns raisedabout some of the substances withGRAS designation, includingcyclamate. After this order in the1970s, the FDA hired the LifeSciences Research Office, which thenselected qualified scientists (ie, theSelect Committee on GRASSubstances) as consultants to reviewand evaluate the availableinformation on each of the GRASsubstances. The select committee’sevaluations were madeindependently of the FDA or anyother governmental or

TABLE 2 FDA-Approved NNSs

Type (Approval Distinction) Commercial Name Kcal/g SweetnessCompared With

Sucrose

Introduction and/or FDAApproval

HeatingReducesSweetness

Contraindication and/orSafety Issues

Saccharin (1,2- benzisothiazolin-3-1, 1,1-dioxide) (food additive)

Sweet’N Low,Sugar Twin,Necta Sweet

0 200–700 Introduced in 1879; FDAapproved for use

No None

Aspartame (N-[l-a- Aspartyl]-L-phe,1-methyl ester) (food additive)

NutraSweet,Equal, SugarTwin

4a 180 Approved for limited use (ie,tabletop sweetener) bythe FDA in 1981 andapproved for general usein 1996

Yes Phenylketonuria; reportedcases of thrombocytopenia

(78)50

Acesulfame potassium and/oracelsulfame potassium(potassium 6–methyl-2,2-dioxo-oxathiazin-4-folate) (foodadditive)

Sunett, Sweet One 0 300 Discovered 1967; FDAapproved limited use 1988and general use(exceptions: meat andpoultry) in 2003

No Associated with cancer inanimals at high dose; noknown association in

humans

Sucralose (1,6- Dichloro-1, 6-dideoxy-b-D- fructofuranosyl-4-chloro-4-deoxy-a-D-galactopyranoside) (foodadditive)

Splenda 0 600 Discovered in 1976; FDAapproved for limited usein 1998 and for generaluse in 1999

No None

Neotame (N-[N-{3,3-dimethylbutyl}-L-a-aspartyl-L-phe 1-methylester]) (food additive)

Newtame 0 7000–13 000 FDA approved for generaluse 2002 (exceptions:meat and poultry)

No Contains phe and asp and istherefore contraindicated inthose with phenylketonuria

Stevia (1,1-dioxo-1,2-benzothiazol-3-1), GRAS

Truvia, Pure Via,Enliten

0 200–400 Accepted as GRAS April 20,2015

Yes None

Advantame ([N-{3-(3-hydroxy-4-methoxyphenyl)}-propyl-a-aspartyl]-L-phe 1-methylester)

None 3.85 20 000 FDA approved for generaluse 2014 (exceptions:meat and poultry)

No Determined to be safe foruse in children

Luo han guo fruit extract (GRAS) Monk Fruit in theRaw, PureLo LoHan Sweetener

Unknown 600 GRAS January 15, 2010;intended for use asa tabletop sweetener,food ingredient, andadditional sweeteningagent

Unknown None

Adapted from AND. Scientific opinion on the safety of advantame for the proposed uses as a food additive. EFSA J. 2013;11(7):3301; Fitch C, Keim KS; Academy of Nutrition and Dietetics.Position of the Academy of Nutrition and Dietetics: use of nutritive and nonnutritive sweeteners. J Acad Nutr Diet. 2012;112(5):739–758; Renwick AG. Postscript on advantame–a novel high-potency low-calorie sweetener. Food Chem Toxicol. 2011;49(suppl 1):S1; Kroger M, Meister K, Kava R. Low-calorie sweeteners and other sugar substitutes: a review of the safety issues.Compr Rev Food Sci Food Saf. 2006;5:35–47; and Magnuson BA, Roberts A, Nestmann ER. Critical review of the current literature on the safety of sucralose. Food Chem Toxicol. 2017;106(ptA):324–355.a Although aspartame contains 4 kcal/g, little is used, and therefore, it essentially provides no extra calories.51


nongovernmental group. In 1972,a GRAS affirmation process began.The FDA established procedures (21Code of Federal Regulations 170.35)that it would then use to affirm theGRAS status of substances. The GRASnotification process began in 1997.By the end of 2006, 193 GRAS noticeswere filed, and the glycoside isolatedfrom the plant S rebaudiana Bertoniand luo han guo were accepted asGRAS for use in baked foods and softdrinks.1,3 Additional informationregarding NNSs can be found inpreviously published reviewarticles.10,21,22,38,43,51–61

PENETRANCE OF NNSS INTO THE NORTHAMERICAN DIET: HOW MUCH NNS DOCHILDREN ACTUALLY CONSUME?

Information about NNS consumptionby children and adolescents is mostlyderived from dietary recall12,62–69

and cross-sectional analysis,29,30

which limits the ability to estimatethe quantity of NNS consumedbecause the quantity of NNS perserving of any given food is notpublicly available and because dietaryrecall is prone to error. Early studiesfound that approximately 15% of thepopulation older than 2 years oldconsumes some type of NNS per year(eg, 2003–2004).70 Older reviewarticles concluded that pediatric NNSintake was within the ADIlevel.34,62,63 Still others have found,on the basis of estimated intake from24-hour dietary recall, that intake ofcyclamate and saccharin may exceedthe ADI for some youth.69 Regardless,intake of NNS among children tendsto exceed NNS intake for adults whenassessed as milligrams per kilogramof body weight.12

The prevalence of NNS use isincreasing, and inclusion of NNSs indaily food products is morepervasive.10,70,71 A single prospectivestudy of youth with diabetes mellitus(n = 227) estimated, on the basis ofa 5-day food diary, that the theoreticalmaximum daily intake of saccharin,acesulfame potassium, and aspartame

did not exceed ADI but variedbetween 5% and 94% of the ADI.36

According to Web sites such asFoodFacts.com, the number of foodsand consumer products that includeat least 1 NNS as an ingredient hastripled within the last 4 to 5 years. In2010, Yang72 found that according toFoodFacts.com, 3648 productscontained at least 1 NNS.10 As of July12, 2015, approximately 12 291products contained at least 1 NNS.10

People are not always aware of theirintake of NNS. Some artificialsweeteners can be found ingroundwater and drinking water,although at magnitudes below theADI level.32 Furthermore, peopleinadvertently consume NNS,according to a recent study of 18reported “nonconsumers,” 44% ofwhom had sucralose in their urinethat was unexplained by the trivialamounts of sucralose that aresometimes reported in the watersupply.32,33

The majority of NNS intake is derivedfrom intake of NNS-containingbeverages (∼11%), followed by food(∼4%) and individual NNS packets(∼1%).38 Data from the NHANES1999–2000 to 2007–2008 show thatthe percentage of children consumingNNS-containing beverages increasedfrom ,1% to .7%.29 More recentNHANES cross-sectional data analysis(2009–2012) revealed that 25.1% ofchildren, compared with 44% ofadults, reported consumption ofNNSs.30 Most reported daily use(80% of children and 56% of adults).Analysis of the 2009–2012 NHANESdata suggests that NNS intake ishigher in women and girls,individuals with obesity (versus thosewith overweight or normal weight),non-Hispanic white individuals(versus non-Hispanic AfricanAmerican or Hispanic individuals),and individuals in the highest tertileof income.30 Between 4% and 18% ofcarbonated beverages consumed bychildren contain NNSs.71 Householdpurchase of NNS-containing

beverages has also increased at thesame time that the purchase of SSBshas decreased: between 2003 and2010.73

International recommendations haveestablished an ADI (per kilogram) forNNSs. The ADI is typically 100 timeslower than the dose of the sweetenerknown to cause toxicity in animals.71

The concept of the ADI wasestablished by an internationalscientific committee and the JointFood and Agriculture Organization ofthe United Nations–World HealthOrganization Expert Committee onFood Additives. Other organizationshave reported ADI levels for variousNNSs, including the European FoodSafety Authority and the DanishVeterinary and Food Administration(Table 3).70 US federal regulations(FDA Code 21 Code of FederalRegulations 170) do not require thatthe amount of NNS in a food item belisted on the product label if it hasbeen determined to be safe for use ina particular food.1 However, withoutproper knowledge of true content, itis difficult to know whether intake ofa particular sweetener is within theADI level.

It is also difficult to knowwhether intake of a particularNNS by a child is within the ADIlevel, but it is worth noting that therehave been few cases of reportedadverse events related to NNSintake.50 Proponents of NNS useargue that safety information can beassumed on the basis of more than30 years of use of these agents withrelatively few reported adverseeffects. However, it is also true thatthere has been no systematic orformal method for capturing andrecording adverse effects related tothe use of these agents.

Given the proliferation of productscontaining NNSs in the food supply,which may lead to both increasedconsumption and combined use ofNNSs, there is a need forcontemporary peer-reviewed studies




to estimate the current prevalence ofNNS use, amounts consumed bychildren, and any potential adverseeffects.

IMPACT OF NNSS ON APPETITE ANDTASTE PREFERENCE

Studies regarding the potentialimpact of NNS intake on appetite andtaste preference can be divided intoanimal studies and human studies.Animal models have shown thatnutritive sweeteners activate thesweet-taste receptors (ie, T1R familyand a-gustducin receptors).74,75

According to animal studies,saccharin intake weakens the abilityof Sprague Dawley rats to signal thecaloric “postingestive consequencesof eating” so that if saccharin isadministered, rats did not regulatetheir intake of sugar-sweetened foodand/or beverages after saccharin-sweetened solution intake.76 Thisstudy suggests that NNS intake mayaffect normal responses to caloricintake such that overeating may bemore likely if the diet after NNSadministration is a sweeter diet.76

In children, the taste receptors arelocated in the lingual taste buds andalong the intestinal mucosa.77

Activation of the sweet-tastereceptors results in stimulus to thepleasure-generating loci of thebrain,77 triggering glucose uptake and

appetite regulation. Individuals varyin their ability to perceive taste, andthus, individuals differ in theirpotential “gain” achieved fromvarious sweet stimuli.78,79 It was oncebelieved that only nutritivesweeteners activate the sweet-tastereceptors; however, it is now knownthat NNSs, which are several hundredtimes sweeter than table sugar, alsoactivate these receptors.70 The effectof NNS activation on taste preference,food intake, the activation ofmetabolic pathways, and appetite isnot well understood.80,81

Human studies have beeninconsistent in their reporting of thepotential impact of NNS use onappetite and taste preferences.Furthermore, genetic differences intaste perception may also exist andinfluence study results.82 A smallstudy of 10 healthy adults given 1 of 4drinks that contained either glucosealone or glucose plus 1 of 3sweeteners (eg, 45 g glucose and150 mg aspartame, 45 g glucose and20 mg saccharin, or 45 g glucose and85 mg acesulfame potassium in250 mL of water) did not reportdifferences in hunger or fullnesswithin 60 minutes of ingestion.83 Incontrast, a single study of 115 collegestudents 18 to 22 years of age giveneither Sprite Zero (NNS-containingbeverage), mineral water, or regular

Sprite reported that those whoconsumed NNS (ie, Sprite Zero) weremore likely to subsequently choosea bag of chocolate M&M’s (43%),whereas those who consumeda nutritive sweetener (eg, regularSprite) or water were more likely toselect a less-sweet snack, such aswater or chewing gum (41% and33%, respectively).84 The authorsconcluded that participants whoconsumed NNSs felt less satisfiedwith what they had drunk comparedwith those who consumed a sugar-sweetened or an unsweetenedbeverage (P = .004).84 As forassessing how intake of NNSinfluenced preference for sweet food,researchers found in this study of 115college students that participantswho consumed NNS were more likelyto provide the names of high-caloriefood items compared with those whoconsumed a sugar-sweetened or anunsweetened drink (P = .001)84 afterconsumption of the NNS-containingbeverage.

NNS use in children may beassociated with a greater preferencefor sweet foods77; however, the effectof NNSs on taste preference is notwell understood. Humans have aninnate preference for sweet foods,and children in particular prefer highlevels of sweetness.77 Children whoconsume large amounts of SSBs may

TABLE 3 ADI Level

Sweetener JECFA ADI, mg/kg EFSA ADI,mg/kg

DVFA ADI,mg/kg

FDA ADI,mg/kg

Number of Packets Equivalent to ADI (Based on a68-kg Person)

Saccharin (Sweet’N Low) 5 5 5 15 250Aspartame (NutraSweet and Equal) 40 40 15 50 165Acesulfame potassium (Sweet One) 15 9 40 15 165Sucralose (Splenda) 15 15 15 5 165Neotame 0–2 1 Unknown 0.3 200Stevia 4 4 Unknown 12 30Advantame 0–5 5 4000 33 4000

Adapted from US Food and Drug Administration. Food additives and ingredients. Available at: www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients. Accessed March26, 2019; Gardner C, Wylie-Rosett J, Gidding SS, et al; American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism, Council onArteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Disease in the Young, and the American Diabetes Association. Nonnutritive sweeteners: current use andhealth perspectives: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2012;126(4):509–519; and Mattes RD, Popkin BM.Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. Am J Clin Nutr. 2009;89(1):1–14. DVFA, Danish Veterinary and FoodAdministration; EFSA, European Food and Safety Agency; JECFA, Joint Food and Agriculture Organization of the United Nations–World Health Organization Expert Committee on FoodAdditives.


http://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients

tend to prefer foods that are richer inboth sugar and calories. TheAmerican Academy of Pediatrics(AAP) recognizes the detrimentaleffect of high sugar content on thehealth of children and the propensitythat high sugar content has forpromoting obesity inchildhood.6,39,85–87 The AAPrecommends against routineconsumption of sports and energydrinks because of their high sugarcontent.39 A single, small populationstudy found that adults whoconsumed NNSs tend to prefera sweet versus salty and/or savorysnack after this ingestion. Theauthors suggest that NNS intake canincrease the motivation for one toaccess sweet relative to savorysnacks88 and thereby alter energybalance in such a way that childrenwho consume these agents are morelikely to consume sugary food anddrinks.84 The temporal correlationbetween the increase in childhoodoverweight and obesity and theincrease in intake of NNS-containingbeverages is suggestive ofa relationship.38 However, therelationship may be one of reversecausality, whereby children who haveobesity (or their parents) may besubstituting food or beveragessweetened with NNSs for thosecontaining sugar in an attempt tolimit caloric intake.

In summary, increasing trends in NNSuse are coincident with an increase inthe prevalence of childhood obesity.Data suggest but do not conclusivelydemonstrate that NNS use maypromote the intake of sugary foodand drink by affecting tastepreferences. It has beendemonstrated that excessive intake ofSSBs (and increased calories) hasbeen associated with childhoodobesity. Additional informationregarding the effects of NNS use ontaste preferences and caloric intakeand comparison of the long-termeffect of NNS-containing versus SSBsis needed.

SAFETY AND NNS USE

Most NNSs have been approved bythe FDA for use as a food additive; 2NNSs were approved under the GRASdistinction for a particular intendeduse.1 Reviews and investigativestudies discussing and evaluating thesafety of NNSs, including sucralose,19

have been published. Studiesinvestigating the potential toxiceffects of NNSs have been performedin animals55–58 and humans.51,59

Results from these more recentstudies have concluded that there areno potential teratogenic effects ornegative effects of NNS use on weightor development in animals. However,cases of aspartame-inducedthrombocytopenia have beenreported.50 Furthermore, aspartameis uniformly contraindicated inpeople with phenylketonuria.

NNS USE AND CANCER RISK

Concerns regarding a potentialrelationship between NNSs andcancer were raised shortly after theintroduction of NNS into the foodsupply.1,10 Cyclamate was firstapproved for use in humans in the1950s89; however, concerns aroseregarding a potential increased riskfor bladder cancer after use ofcyclamate in rats.89 It was alsoproposed that the metabolism ofcyclamate to cyclohexylamine, whichis toxic to rats and dogs, causedtesticular atrophy and impairedspermatogenesis.89 Whenadministered to nonhuman primates,3 of 14 monkeys given cyclamatedeveloped neoplasms versus 0 of 16controls. The 3 tumors, developedafter receipt of “the equivalent of∼30 calorie-reduced drinks”(containing cyclamate), werea metastatic adenocarcinoma of thecolon, a metastatic hepatocellularcarcinoma, and a papillaryadenocarcinoma of the prostate. Theauthors concluded that there was “noevidence for carcinogenicity ofsodium cyclamate because the

tumors in the treatment group wereof different histologies and thetumors occurred at a rate frequentlyobserved in monkeys.”89 To date,there have been no case controlstudies of cyclamate, particularlyrelated to tumor formation inhumans.89 The relationship betweencyclamate and cancer was laterrefuted, and permissions for use ofcyclamate were thus reinstated in1992.2

A study of Sprague Dawley rats feddiets supplemented with 0%, 5%, and7.5% (of the total diet) saccharinexperienced differences in theproliferation of the epithelial cells(used as a marker of cancer risk) bydiet and concentration of saccharin.14

However, this study was not deemedto be relevant to humans because theform of saccharin used, sodium-saccharin, is considered“representative of a large group ofsodium salts known to act as tumorpromoters in the male rat urinarybladder when high doses (ofsaccharin) are administered.”14 TheFDA reports that a total of 30 humanstudies have been conducted to dateand have not found an associationbetween saccharin use and cancer ofany type.1 A large case control studyof people with bladder cancer (n =3010) and controls (n = 5783) foundno association between self-reportedpast NNS use and bladder cancer.66

However, not all studies have agreedwith this conclusion.16 A number ofobservational studies laterdetermined that the relationshipbetween saccharin and bladdercancer was specific to rodents.17

Saccharin was removed from the listof potential carcinogens in 2001 bythe National Toxicology Program ofthe National Institutes of Health.10

A case control study of adults withincident neoplasia (eg, stomach,pancreas, and endometrium) versusunaffected controls did not findgreater odds of cancer among thoseexposed to NNSs.90 However, 1 of thelimitations of this case control study


was low NNS use among participantsand potentially insufficient samplesize to detect even weak associationsbetween NNS use and cancer.90

A systematic review of the safety andpotential carcinogenic effect ofaspartame in mice found noassociation between aspartameadministration and risk of cancer.91 Ameta-analysis of studies of aspartamein rats showed no associationbetween aspartame and cancer.92 Areview of human (adult) cohort andcase control studies showed norelationship between most types ofcancer and aspartame use.18,51,92,93

Newer data have failed todemonstrate an association betweenNNS use and cancer.90 The longlatency period, the penetrance ofNNSs into the food supply (making itdifficult to isolate an adequateunexposed control group), and thediversity of potential mechanismshave made it difficult to definitivelyexclude potential carcinogenicproperties of NNSs but also make itdifficult to conclude that there is anysuch association. The type of researchthat would more definitively addressthe effects of NNS intake over thelong-term and across the life span(for example, long-term randomizedclinical trials or prospective cohortswith well-defined measures ofexposure over multiple time points)is not likely to occur.

In summary, observational data inadult-human studies show noassociation between NNS use andcancer. There are no long-termstudies in children. Studies have beenlimited to animal and adult-humanstudies, and the long-term risk ofcancer and other conditions amongchildren who use NNSs is not knownand is likely to be difficult to obtain.

NNS USE IN SELECT PEDIATRICPOPULATIONS

It can be reasonably argued thatcertain subpopulations of childrenmight benefit from the use of NNSs.

For example, children andadolescents who have obesity mightbenefit from lower total caloricintake. Children who have type 1 or 2diabetes mellitus might also benefitfrom the lack of a glycemic responsewhile enjoying the sweet taste ofNNSs. Similarly, those with multiplemetabolic or cardiovascular diseaserisk factors also might experiencea benefit because excesscarbohydrate intake is likely a factorcontributing to their health risk.94–96

NNS USE AND CHILDREN WITH OBESITY

NNSs pass through the humangastrointestinal tract without beingdigested, providing sweet tastewithout added calories, a propertythat is potentially advantageous forpreventing and controlling obesitygiven the association between sugarybeverage consumption andobesity.6,64,87,97 However, the data areconflicting as to whether consumingNNSs leads to weight loss or weightgain.6,87

Swithers et al98 also provided animalstudies reporting that use of artificialsweeteners may increase weight gain.Observational studies in adults showthat NNS intake is associated withincreased BMI. Analysis of the SanAntonio Heart Study, an adultprospective cohort study, showeda dose-response adverse effect of NNSintake on overweight and obesitystatus over 7 to 8 years of follow-up.99 However, these data arevulnerable to reverse causalitybecause it has been demonstratedthat individuals who are attemptingto lose weight are more likely to useNNSs.26 Additionally, the San Antonioanalysis is subject to the samevulnerabilities regarding the accuracyof estimated NNS intake, particularlybecause the baseline data werecollected decades before the currentera and estimates were reliant ondietary recall.

Several cross-sectional studies inchildren and adolescents have also

reported positive associationsbetween NNS intake and BMI (ie, highNNS intake is associated with higherBMI).64,100 However, results fromlongitudinal follow-up are conflicting,with a few studies supporting thesefindings6,86,87 and others suggestingeither no relationship101 or a smallbeneficial effect of NNS intake onBMI.97

A double-blind RCT from theNetherlands found that replacementof SSB intake with NNS intake inschool-aged children was associatedwith reduced weight gain (not weightloss) during an 18-month period.4 Astudy of aspartame use in adults withoverweight (eg, mean age 19 years)was associated with greater weightreduction than among the controlpopulation.102 Similarly, a study fromSouth Africa found that intake of25 mg of sucralose per day by youth 6to 11 years of age was associatedwith a lower BMI-for-age z score(control and nutritive sweetener of7.1 and micronutrient and NNS of 6versus control and sucrose of 10.8and micronutrient and NNS of 10.9)compared with sugar intake. Incontrast, a higher weight-for-age zscore change was associated withNNS use in a separate study.5

Prospective studies have revealedmixed results: Newby et al103 did notidentify an association between NNSintake and weight change ina prospective cohort study of 2- to 5-year-olds (n = 1345) but reportedthat intake of diet soda was low (,5oz per day), with poor correlationseen between estimated beverageintake at the time of the first visitcompared with at the second visit. Aprospective study investigating theeffect of intake of SSBs and NNSs onweight among school-aged youth (n =164) found that for each 12 oz of dietsoda consumed per day, there wasa 2-year BMI z score that was 0.156higher than predicted on the basis ofbaseline-BMI z score.6 A prospectivecohort study of 4746 youth foundthat consumption of low-calorie soft


drinks (positive association; P = .002)was associated with weight gain,whereas consumption of white milk(inverse association; P = .03) wasassociated with weight loss.104

Analysis of the relationship betweenNNS use and weight gain, however,did not control for parental weightand other important confounders.104

Limitations of prospective cohortstudies include failure to control forother dietary and lifestyle factors105

and shorter long-term follow-up.Interpretations of the relationshipbetween NNS use and BMI are limitedby the inability to determine causalitybecause of cross-sectional studydesign as well as reverse causalityand inaccurate dietary recording inprospective cohort study design.105

Youth who consume NNSs may havedifferent food consumption patternsand a variety and parental andenvironmental factors not adjustedfor in the prospective studies thatmay affect the relationship betweenNNS use and BMI.

Meta-analysis of 15 RCTs examiningthe relationship between NNS useand BMI in adults and youth (ages10–65 years) reported that intake ofNNS is associated with modestlyreduced body weight, BMI, fat mass,and waist circumference (WC) witha mean reduction in weight of 0.8kg.105 However, RCTs suggest thatsubstituting NNSs for SSBs isassociated with a modest reduction inbody weight for youth with thehighest baseline BMI but not for allyouth. Ebbeling et al reported resultsfrom a pilot study for an RCTevaluating the potential impact ofreplacement of SSBs with NNSs onbody weight in youth and found thatchange in BMI, adjusted for sex andage, was 0.076 0.14 (mean 6 SE) forthe intervention group and 0.21 60.15 for the control group with a netdifference of –0.14 6 0.21, which wasnot significant. Baseline BMI wasa significant effect modifier such thatyouth in the upper baseline-BMItertile experienced a significant

reduction in BMI between theintervention (–0.63 6 0.23) andcontrol (10.12 6 0.26) groups.47 Asystematic review and meta-analysisof NNS use and cardiometabolichealth evaluating change in BMIamong NNS consumers 12 years andolder from 7 RCTs and 30observational studies reported mixedresults. Analysis of data from 2 of the7 selected RCTs found that use ofNNS was not associated witha significant effect on BMI over a 6- to24-month period (–0.37; 95%confidence interval [CI]: 21.10 to0.36; I2: 9%).8 Two cohort studiesshowed a possible correlationbetween NNS use and BMI over a 3-to 13-year period, and a third cohortstudy found that participants whoconsumed NNSs daily had a greaterincrease in BMI during an 8-yearfollow-up period.8 As highlighted inthe systematic review, overall, datasuggest an increase in BMI with NNSuse over the long-term withoutconfirmation of these findings viaRCTs.8

Controlled experimental studies havetried to better address the question ofthe effect of NNS on weight by givingcontrolled meals and measuringcaloric intake after the controlledmeals. Some studies show lowercalorie consumption after foodscontaining NNSs compared withcalorically sweetened foods,106 butother studies support thephenomenon of “make-up” calorieconsumption, showing higherintake107–110 immediately after NNSintake. The make-up theory has notbeen proven conclusively81 andrepresents only the immediatepostprandial effects of NNS intake.

Most short-term studies supporta beneficial role of NNS in weightloss.111 A patient-blinded prospectivecohort study in adults comparingsatiety, energy intake, and bodyweight during a 10-weeksupplementation with either sucroseor artificial sweetener founda significant but modest reduction in

fat mass and body weight withartificial sweetener use.112 Arandomized 25-week interventionstudy of 103 adolescents 13 to18 years of age that included homedelivery of noncaloric beverages (4servings per day for the adolescentand 2 servings per day for eachadditional household member)revealed an additional BMI decreaseof 0.08 for every 1 at baseline. Thisstudy found that the effect of NNS useon BMI in adolescents was mostsignificant for adolescents witha baseline BMI .30.10,47 A differentRCT in children that combined NNSuse with total caloric restriction didnot find an association between NNSuse and weight loss.102 Given themultitude of factors affecting weight,including high-fat- and low-water-intake diets and the complexbehavioral interactions related toresponse to use of NNS, some haveargued that NNS use alone may not bean effective remedy for weightloss.113

The long-term effect of NNS use onweight remains poorly defined, andthus far, data suggest the benefits arelimited.69,114 A prospective double-blind study showed that children 4 to11 years of age with normal weightwho consume a beverage containingNNS per day experience less weightgain over an 18-month periodcompared with those who consumesugar-containing beverages4; thechange in weight between the 2cohorts differed by 2.2 lb (1 kg). TheAmerica On the Move study foundthat, combined with additionalchanges in lifestyle, use of NNSs maycontribute to slowed weight gain inoverweight and at-risk children46

over a 6-month study period. A studyin children with obesity showed thatuse of NNSs contributed to slowedweight gain over the first year, but thedifference in weight was notmaintained during the subsequentyear even when controlling forconfounders such as screen time,parental BMI, energy intake, physical


activity, and fat consumption.45

In that study, Ebbeling et al found

that NNS use did not result in

a significant change in BMI after

2 years of replacement of SSBs with

NNSs. Systematic reviews of the

existing data concluded that in

children, NNS use may prevent

excess weight gain over a period of

6 to 18 months but that, in general,studies evaluating the relationshipbetween NNS intake and obesity arelacking rigor.26 According to 1published systematic review, use ofNNSs in place of sugar, in childrenand adults, leads to reduced energyintake and a small reduction in bodyweight (on average, 1.3 kg).115 Finally,a Cochrane Review reported that NNSuse was associated witha significantly reduced body weight(21.07 kg [95% CI: 0.41 to 1.72]),and among people younger than18years, the NNS group demonstrateda significant reduction in body weight(1.18 kg [95% CI: 0.34 to 1.04]), anassociation that was notdemonstrated for adults.116

In summary, the preponderance ofdata suggests that the use of NNSscan lead to weight stabilization ora small degree of weight loss byhelping lower total caloric intake,especially among children andadolescents with obesity. Studiessuggest that NNSs may be consideredpart of a comprehensive program anda substitute for foods and beveragescontaining caloric sweeteners forweight loss or weight maintenance.The current data would suggest thatdepending on baseline BMI andwithout easily taking into accountwhat else is being consumed orsubstituted for, NNS use isassociated with a modestimprovement in weight. However, thelong-term effects of NNS use inchildren and adolescents, includinguse pertaining to weight loss orweight management, arecurrently unknown.31,106

NNS USE AND EFFECTS ON METABOLICSYNDROME AND DIABETES

Observational and experimental datain adults suggest that the use of NNSsmay alter glucose metabolism in thepresence of obesity, although thesestudies are subject to the samevulnerabilities as described abovewith regard to obesity.8 Cross-sectional analysis of 2856 adultsparticipating in the NHANESdemonstrated that aspartame intakeaffects the association between BMIand glucose tolerance (interaction:P = .004), showing worse glucosetolerance with increasing BMI inthose reporting consumption ofaspartame.117 Similarly, cross-sectional analysis of the FraminghamOffspring Cohort showed anassociation between diet sodaconsumption, as assessed by a foodfrequency questionnaire, andmetabolic syndrome.7

Prospective cohort data from theCoronary Artery Risk Development inYoung Adults (CARDIA) study of theevolution of cardiovascular diseaserisk showed that among young adultNNS consumers 18 to 45 years of age,consumers of NNS were more likelyto have metabolic syndrome anda higher WC. In comparing those whoconsumed a Western diet and NNSsversus individuals who consumeda Western diet but not NNSs, therewas no significant difference in WC,the presence of high fasting glucose,low low-density lipoproteinconcentration, high triglycerides, highblood pressure, or overall metabolicsyndrome. However, young adultswho consumed a prudent diet andNNSs (prudent consumers) were lesslikely to have a high fasting glucose(hazard ratio [HR]: 0.75; 95% CI: 0.57to 0.99) and a low high-densitylipoprotein concentration (HR: 0.69;95% CI: 0.54 to 0.87). There was nosignificant difference in the presenceof metabolic syndrome amongconsumers of the Western diet andprudent diet consumers of NNSs.However, prudent diet nonconsumers

of NNSs were less likely to havemetabolic syndrome (HR: 0.64; 95%CI: 0.5 to 82) compared withconsumers of a Western diet. Resultsfrom this study suggest thata prudent dietary pattern isconsistently associated with lowerrisk for metabolic syndrome, butbeing a nonconsumer of NNSs isnot.118 Use of NNSs can be associatedwith a lower likelihood of high fastingglucose and of low high-densitylipoprotein but did not significantlyaffect WC (prudent nonconsumerswere actually less likely to havea high WC [HR: 0.78; 95% CI: 0.62 to0.97]), the likelihood of hightriglycerides, or metabolicsyndrome.7,118 Findings from theCARDIA study were also observed inother prospective cohorts. Aprospective analysis of theassociation between beverageconsumption (SSBs and NNS sodaintake) found that intake of greaterthan or equal to 1 soft drink per day(regular or diet) was associated witha higher prevalence of metabolicsyndrome.7 Again, given the cross-sectional and observational design ofthese studies, causality cannot bedetermined; nonetheless, datasuggest that there is a correlationbetween NNS use and metabolicsyndrome.

The Multi-Ethnic Study ofAtherosclerosis cohort study showedthat daily consumption of diet sodawas associated with a 36% higherrelative risk of metabolic syndromeand a 67% higher relative risk of type2 diabetes mellitus.68 However, onceadjustments were made to accountfor baseline measures of adiposity,the association between diet sodaconsumption and metabolicsyndrome was no longer significant,but the association between diet sodaconsumption and diabetesremained.119 Findings suggest thatadditional factors among those whoconsume diet sodas may beassociated with a greater risk fordiabetes mellitus and metabolic


syndrome. Analysis of theFramingham study stopped short ofreporting an association betweenNNSs and WC but did find thatprudent nonconsumers of NNSs wereless likely to have a higher WC.

In the Atherosclerosis Risk inCommunities Study, diet sodaconsumption was associated withincident metabolic syndrome (P ,.001 for trend).120 Again, causalitycannot be determined inobservational study designs, andthere are likely significantconfounding factors, but longitudinalcohort studies show that there is anassociation between NNS use andabnormal glucose metabolism inadults.7,118–120

Few data exist regarding the role ofNNSs in children and youth withdiabetes, insulin resistance, ormetabolic syndrome. One small studyof youth and young adults 12 to25 years of age with type 1 (n = 9)and type 2 (n = 10) diabetes mellituscompared the effect of drinkingcarbonated water versus carbonatedbeverages with NNSs on glucosetolerance (with a 75 g oral glucosetolerance test) using a crossoverdesign.121 According to this study,there were no differences in glucoseor C-peptide secretion in people witheither type 1 or type 2 diabetesmellitus after NNS consumption.Youth with type 1 diabetes mellitusreleased more glucagonlike peptide 1after they consumed NNS-containingcarbonated beverages versuscarbonated water; no differenceswere seen in youth with type 2diabetes mellitus.

A systematic review of the evidencefrom prospective studies evaluatingthe association between early lifeNNS exposure on long-term metabolichealth identified conflicting resultsfrom 2 RCTs and 6 prospective cohortstudies.122 Studies selected includeda total of more than 15 000 childrenexposed to NNS for .6 months.122

The Growing Up Today Study,

a prospective cohort study that reliedon questionnaires administeredbetween 1996 and 1998 to examinethe relationship between beverageintake and change in BMI among.10 000 boys and girls ages 9 to17 years, demonstrated a relationshipbetween diet soda consumption andincreased BMI over 2 years’ follow-upin boys (P = .016) but not girls (P =.152).87,122 Data from theFramingham Children’s Study46,122

among 3- to 15-year-olds revealedthat although there was no consistenttrend in body fat associated withintake of SSBs or NNS-containingbeverages, the highest NNS intakewas associated with increased bodyfat, as measured by skinfolds.111

The mechanism by which NNSs mightadversely affect body weight, insulinresistance, and long-term metabolicrisk is unknown, but 1 hypothesis isthat it results in adverse effects onthe gut microbiome. Alterations inmicrobiota structure and functionhave been associated with a greaterpropensity for developing metabolicsyndrome.123 Suez et al42 publisheda small but frequently cited study inrodents with some human datacomparing the effects of NNSs (eg,saccharin, sucralose, and aspartame)on glucose tolerance in mice andchanges in the intestinal microbiota.43

The animal data showed that NNSintake, particularly saccharin, leads toa change in the structure and functionof the microbiota. A small study inhuman volunteers (who did notpreviously consume NNSs) showedthat receipt of saccharin within ADIlevels for 5 days was associated withthe development of glucoseintolerance.42 The findings from theseanimal data and the small, single,human (adult) study suggesta detrimental effect of NNS use on gutmetabolism, whereas a systematicreview suggests that NNS use doesnot alter blood glucose levels overtime.124 In adults, observational datafrom the CARDIA study show thatadults who consume diet soda

beverages at baseline, regardless ofwhether they followed a “prudent”(eg, fruit, fish, and whole grains) orWestern dietary pattern (eg, fastfoods, refined grains, and sugar-sweetened soda), had higher rates ofmetabolic syndrome compared withthose who did not consume diet sodabeverages.94,118

Better understanding is neededconcerning the effects of NNSs onmetabolism and risk of diabetes,125

including whether NNS intake ismerely correlated with a higher riskof metabolic syndrome and diabetesor there is a causal and harmfulrelationship mediated through the gutmicrobiome or other as-yet-unidentified pathways.

NNS USE AND CARDIOVASCULARDISEASE RISK FACTORS

Greater sweetened beverage use hasbeen associated with increase obesity,increased central obesity, andabnormal perturbations in the lipidprofile, all of which are risk factorsfor premature cardiovasculardisease.40 Although consumption ofadded sugars is known to causedetrimental effects on lipidconcentrations,94,96 no clinical trialshave addressed the effects of NNSs onlipid concentrations in childhood.

Current data regarding the potentialbenefit of NNSs in modifyingcardiovascular disease risk factorsare limited but suggest an associationbetween NNS consumption andmetabolic syndrome, an associationthat may be limited by reversecausation. There are no conclusivedata regarding the risk ofcardiovascular disease events andNNS intake.

NNS USE AND ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ANDAUTISM

The lay press has raised the concernthat NNS use is associated withbehavior, cognition, hyperactivity, andattention issues. Two RCTs show no


relationship between NNS use andbehavior and cognition among school-aged children.48,126 Several reviewarticles regarding the potentialimpact of NNS use on behavior havebeen published.114,127,128 Some datain adults also suggest an associationbetween short-term aspartameconsumption and more irritablemood, depression, and poorerperformance in spatial orientation.129

To date, however, there have been nostudies to conclude that there is anassociation between attention-deficit/hyperactivity disorder(ADHD) and NNS use.128 No literaturewas found to support a relationshipbetween NNS use and autism.130

At the present time, there are no datato support an association betweenNNS use and the development ofADHD or autism in children orworsening of ADHD symptoms.48

OTHER POTENTIAL HEALTH EFFECTS

With the exception of the use ofaspartame and neotame in childrenwith phenylketonuria, there are noabsolute contraindications to NNS usein children. NNSs may help to reducethe incidence of dental caries inchildren.131

PUBLISHED GUIDANCE ANDRECOMMENDATIONS

Several organizations have publishedsummary statements regarding theuse of NNSs, including the AND, ADA,and AHA.21–23,41 The AND states that“consumers can safely enjoy a rangeof nutritive and nonnutritivesweeteners when consumed in a dietthat is guided by current federalnutrition recommendations, such asthe Dietary Guidelines for Americansand the Dietary ReferencesIntakes.”21,22 With regard to thepotential benefit of NNSs on weightloss, the AND states that there isa good level of evidence to concludethat NNS use, as part ofa comprehensive weight loss ormaintenance program, may be

associated with weight loss and leadto improved weight managementover time in adults; the statementsfor children were less definitivebecause of a lack of data. Informationregarding use, safety, effect on tastepreferences, and potential benefits inspecial populations was either limitedor not available for other NNSs.

The ADA and AHA published a jointsummary statement on NNSs in 2012supporting the position that NNSs aresafe when consumed within the ADIlevels established by the FDA.Furthermore, the ADA and AHA haveargued that NNSs may be helpful inreducing weight gain by limitingcaloric intake if used in such a waythat total diet caloric intake isreduced. The statement specificallydid not address NNS use inchildren.38

RESEARCH GAPS

Gaps remain regarding ourknowledge of the impact on NNS useon energy sensing and effects onglycemic control, appetite, anddietary intake for .6 months, andeven fewer data exist specificallyaddressing the pediatricpopulation.132 Future research shouldexplore novel approaches to assessingthe long-term effects of NNS use inchildren (both type and amount), theeffect of age of exposure to NNSs andthe development of taste preferences,and the effects of age of exposure toNNSs on the development of diabetesmellitus, obesity, early cardiovasculardisease, and the developing brain.Research should explore these topicsacross the age continuum: toddlers,children, and adolescents.Comparisons should be made withnutritive sweeteners and otherbeverages (eg, water and milk).Additional research is neededregarding genetic differences thatmay affect a child’s response toa particular NNS and to determine ifvarious NNSs differ in their benefitsor risks. Approaches should take into

consideration the need for long-termfollow-up, adjust for multipleexposures, and account for impreciseexposure measures.

SUMMARY AND RECOMMENDATIONS

NNSs were introduced into the foodsupply to provide a noncaloric, sweet-tasting alternative to caloricsweeteners, which is useful for thosewith diabetes mellitus or who areavoiding sweet calories for otherreasons, including obesity preventionand reduction. Concerns were initiallyraised about an association withcancer, but research in animal modelsand adult-human populations hasshown no association between NNSuse and cancer.133 Someobservational data in cross-sectionaland prospective cohort studies inadults suggest that NNSs maypromote obesity and metabolicsyndrome but are subject toconfounding and reverse causation.26

Food challenge studies and short- andmedium-term interventional datasupport a small benefit in weightmaintenance or reduction in adultsand children when NNSs are used asa substitute for caloric sweeteners.However, work remains to betterunderstand the use of NNSs intoddlers, children, and adolescents inthe general population and in at-riskpopulations (eg, diabetes, obesity,etc). Because of the ubiquitouspresence of NNSs in everydayproducts and foods, it is unknownhow much NNSs youth areconsuming. Contemporary intake ofNNSs (type and amount) and howthey relate to ADI levels, specificallywith regard to younger children,requires better and more detaileddata. More information about the typeand quantity of NNSs contained invarious foods, beverages, and otherproducts is recommended to betterunderstand pediatric exposures. Inparticular, not only should theparticular NNS contained in a productbe noted as an ingredient, but theexact amount of any NNS within


a particular food item should also beincluded in the nutrition facts label.

KEY FINDINGS ANDRECOMMENDATIONS

Findings and recommendations are asfollows.

1. Current FDA-approved NNSsinclude saccharin, aspartame,acesulfame potassium, sucralose,neotame, stevia, and advantame.These agents are 180 to20 000 times sweeter than sugar,potentially affecting preferencesfor sweet taste.

2. NNSs are designated either asfood additives or as GRAS; thelong-term safety of NNSs inchildhood has not been assessedin humans.

3. No advice can be provided on theuse of NNS in children youngerthan 2 years old given theabsence of data on this age group.

4. The number of consumerproducts containing NNSs hasquadrupled over the past severalyears; manufacturers must listNNSs in the ingredient list butare not required to indicate theamount per serving.

5. When substituted for caloric-sweetened foods or beverages,NNSs can reduce weight gain orpromote small amounts of weightloss (∼1 kg) in children (andadults); however, data arelimited, and use of NNSs inisolation is unlikely to lead tosubstantial weight loss.

6. Individuals affected by certainconditions (eg, obesity and type 1or 2 diabetes mellitus) maybenefit from the use of NNSs ifsubstituted for caloricsweeteners. However, health careproviders should be aware thatNNS use in isolation is unlikely toresult in important weight loss,that observational studies showthat NNS intake is associatedwith higher rates of metabolic

syndrome and diabetes, and thata better understanding is neededabout whether NNS use hasa causal and harmful effect onmetabolism and the risk ofdiabetes mediated through thegut microbiome or other as-yet-unidentified pathways.

7. To better inform the public aboutconsumption of NNSs, the FDAshould require productsmarketed in the United States toinclude labels that list the typeand quantity of any NNScontained per serving ofa product.

8. Funding should be allocated toencourage researchers to conducthigh-quality research on the useof NNSs in childhood, focusing onage of exposure and tastepreferences, neurodevelopment,and effect on the microbiome andits relevance to obesity, metabolicsyndrome, and diabetes.

9. Health care providers areencouraged to remain alert tonew information and sensitive topatient and family preferences.

10. With the exception of aspartameand neotame in children withphenylketonuria, there are noabsolute contraindications to useof NNSs by children.

11. Use of NNSs has been associatedwith a reduced presence ofdental caries.

GUIDANCE FOR PEDIATRICIANS

Primary health care providersshould discuss with parents andpatients (as appropriate) theavailable evidence regarding thebenefits and harms of NNS use inchildren and adolescents. The AAPrecommends that pediatriciansdiscuss the following points withfamilies.

1. NNSs are FDA approved for use inhumans or are GRAS and, thereby,approved for use under the GRASdesignation.

2. The GRAS designation isbased on consumption of NNSswithin an ADI level; it is notpossible to measure anindividual’s daily intake of NNSsat this time.

3. Higher-quality data suggestthat NNS use is associated withweight stabilization and/or weightloss in the short-term. Currently,there is a paucity of long-term data.

4. High-quality evidence, includingmeta-analysis and data from RCTs,suggests that there is noassociation between hyperactivityand NNS use in children.

5. There are limited data regardingthe effect of NNS use on appetitechange and taste preference.

AUTHORS

Carissa M. Baker-Smith, MD, MPH,FAAP, General Pediatrics andPediatric Cardiology

Sarah D. de Ferranti, MD, MPH, FAAP,General and Preventive PediatricCardiology

William J. Cochran, MD, FAAP,Pediatric Gastroenterology

COMMITTEE ON NUTRITION, 2018–2019

Steven A. Abrams, MD, FAAP, Chair

George J. Fuchs III, MD, FAAP

Jae Hong Kim, MD, PhD, FAAP

C. Wesley Lindsey, MD, FAAP

Sheela N. Magge, MD, FAAP

Ellen S. Rome, MD, MPH, FAAP

Sarah Jane Schwarzenberg, MD, FAAP

PAST COMMITTEE MEMBERS

Jatinder J.S. Bhatia, MD, FAAP, PastChair

Mark R. Corkins, MD, FAAP

Stephen R. Daniels, MD, PhD, FAAP,Immediate Past Chair

Sarah D. de Ferranti, MD, MPH, FAAP


Neville H. Golden, MD, FAAP

LIAISONS

Jeff Critch, MD – Canadian PediatricSociety

Cria G. Perrine, PhD – Centers forDisease Control and Prevention

Janet M. de Jesus, MS, RD – NationalInstitutes of Health

Andrea Lotze, MD, FAAP – US Foodand Drug Administration

Valery Soto, MS, RD, LD – USDepartment of Agriculture

SECTION ON GASTROENTEROLOGY,HEPATOLOGY, AND NUTRITIONEXECUTIVE COMMITTEE, 2018–2019

Jenifer R. Lightdale, MD, MPH, FAAP,Chair

David Brumbaugh, MD, FAAP

Mitchell B. Cohen, MD, FAAP

Jennifer L. Dotson, MD, MPH, FAAP

Sanjiv Harpavat, MD, PhD, FAAP

Maria M. Oliva-Hemker, MD, FAAP

Leo A. Heitlinger, MD, FAAP,Immediate Past Chair

PAST COMMITTEE MEMBERS

Michael deCastro Cabana, MD,MPH, FAAP

Mark A. Gilger, MD, FAAP

Roberto Gugig, MD, FAAP

Melvin B. Heyman, MD, FAAP, PastChair

Ivor D. Hill, MD, FAAP

STAFF

Debra L. Burrowes, MHA

ABBREVIATIONS

AAP: American Academy ofPediatrics

ADA: American DiabetesAssociation

ADHD: attention-deficit/hyperactivity disorder

ADI: acceptable dietary intakeAHA: American Heart AssociationAND: Academy of Nutrition and

DieteticsCARDIA: Coronary Artery Risk

Development in YoungAdults

CI: confidence intervalFDA: US Food and Drug

AdministrationGRAS: generally recognized assafeHR: hazardratioNNS: nonnutritive sweetenerRCT: randomized controlledtrialSSB: sugar-sweetened beverageWC: waist circumference

Address correspondence to: Carissa Baker-Smith, MD, MPH, FAAP. Email: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2019 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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originally published online October 28, 2019; Pediatrics NUTRITION

ON NUTRITION, SECTION ON GASTROENTEROLOGY, HEPATOLOGY, AND Carissa M. Baker-Smith, Sarah D. de Ferranti, William J. Cochran and COMMITTEE

The Use of Nonnutritive Sweeteners in Children

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by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397. the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

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the use of nonnutritive sweeteners in children...2019/10/25 · remain.3 most nnss, including...

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