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

The Use of Nonnutritive Sweeteners in Children Carissa 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

The prevalence of nonnutritive sweeteners (NNSs) in the food supply has abstract increased over time. Not only are more children and adolescents consuming NNSs, but they are also consuming a larger quantity of NNSs in the absence of strong scientific evidence to refute or support the safety of these agents. This aSchool of Medicine, University of Maryland, Baltimore, Maryland; bBoston Children’s Hospital, Boston, Massachusetts; and cGeisinger policy statement from the American Academy of Pediatrics is intended to Medical Center, Danville, Pennsylvania provide the pediatric provider with a review of (1) previous steps taken for Dr Baker-Smith is the primary author and drafted this policy approved use of NNSs, (2) existing data regarding the safety of NNS use in the statement, conducted the literature search and literature review, general pediatric population, (3) what is known regarding the potential created the evidence table used to support the content of this policy statement, and assisted with final revisions and review of the benefits and/or adverse effects of NNS use in children and adolescents, (4) document; Dr de Ferranti reviewed the literature, assisted with the identified gaps in existing knowledge and potential areas of future research, drafting and editing of the policy statement, and conducted final revisions and review; Dr Cochran assisted with literature review, and (5) suggested talking points that pediatricians may use when discussing contributed to the creation of the evidence table used to support the content of this policy statement, and assisted with the final review of NNS use with families the document; and all authors approved the final version of the manuscript as submitted.

Policy statements from the American Academy of Pediatrics benefit from expertise and resources of liaisons and internal (AAP) and INTRODUCTION external reviewers. However, policy statements from the American Academy of Pediatrics may not reflect the views of the liaisons or the Nonnutritive sweeteners (NNSs), also known as noncaloric artificial organizations or government agencies that they represent. sweeteners or high-intensity sweeteners, were first introduced into the This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed food supply in the late 1800s (eg, saccharin) and were first approved for conflict of interest statements with the American Academy of use as a food additive under the Food Additives Amendment of the Federal Pediatrics. Any conflicts have been resolved through a process 1,2 approved by the Board of Directors. The American Academy of Food, Drug, and Cosmetic Act of 1958. NNSs increase the palatability of Pediatrics has neither solicited nor accepted any commercial food and beverages without increasing caloric content. It has been involvement in the development of the content of this publication. proposed that the lack of caloric content of the sweeteners may contribute The guidance in this statement does not indicate an exclusive course to weight loss. To date, however, there has been no consistent or of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. conclusive evidence that NNS use lends to a reduction in total caloric 3–8 All policy statements from the American Academy of Pediatrics intake and thereby to weight loss in humans or in animal physiology automatically expire 5 years after publication unless reaffirmed, 9 models. Questions regarding the long-term safety of these agents also revised, or retired at or before that time. 3 remain. Most NNSs, including saccharin, aspartame, acesulfame DOI: https://doi.org/10.1542/peds.2019-2765 potassium, sucralose, and neotame, have been approved by the US Food and Drug Administration (FDA) for use as food additives and, as such, To cite: Baker-Smith CM, de Ferranti SD, Cochran WJ, AAP have undergone premarket review and approval (https://www.fda.gov/ COMMITTEE ON NUTRITION, SECTION ON GASTROENTEROLOGY, food/food-ingredients-packaging/overview-food-ingredients-additives- HEPATOLOGY, AND NUTRITION. The Use of Nonnutritive colors). Other agents such as stevia and luo han guo have been approved Sweeteners in Children. Pediatrics. 2019;144(5):e20192765

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019:e20192765 FROM THE AMERICAN ACADEMY OF PEDIATRICS by the FDA under the “generally conclusively demonstrating the long- who do not believe that they have recognized as safe” (GRAS) term safety and efficacy of NNS been exposed to NNSs have distinction, a distinction that has been agents are lacking.3,26 Also lacking is detectable levels of NNS in their determined to be insufficient for published evidence of parental urine.32,33 ensuring the safety of food additives confidence in the safety of NNSs. Estimates of consumption are largely without specific protections against Despite FDA assurances, published based on dietary recall12,29,30,34,35; conflict of interest and without data reveal that parents continue to however, such studies are fraught mechanisms to ensure ongoing have questions about the safety of with inaccuracies and thus may result acquisition of safety data.10,11 NNSs. For instance, in a single-site in underestimates of true intake.29 study, only 16% of parents responded Ideally, intake of NNS remains within Concerns regarding the safety of in the affirmative to the statement, the ADI level. Studies from the late NNSs were initially related to their “Nonnutritive sweeteners (ie, 1990s and early 2000s, including potential carcinogenic effects. Splenda, Sweet‘N Low, and Equal) are fi studies in children, had suggested Cyclamate, rst approved for use in safe for my child to use.”27 Knowledge 1958, was later removed from the list that intake of intense sweeteners was of how to identify products – substantially below the ADI.34 36 of approved food additives in 1969 containing NNSs remains poor Contemporary data addressing total because of concerns regarding an because only 23% of parents were daily intake of NNS in adults and association between cyclamate use able to correctly identify food children are limited. According to and the development of bladder products that contain NNSs. In fact, 1,2,10,12 select studies, intake of particular cancer. The relationship 53% of parents stated they seek NNSs (eg, acesulfame potassium or between cyclamate and cancer was items labeled “reduced sugar,” but cyclamate) may exceed the ADI.37 later refuted on the basis of most did not recognize that the sweet fi Historically, carbonated beverages additional scienti c data in rats, mice, taste was instead being provided by have contributed the greatest dogs, hamsters, and monkeys. an NNS,27 and only one-quarter of milligram dosage to total daily intake youth were able to distinguish the Cyclamate was not the only NNS of NNS (eg, saccharin).12,38 However, taste of NNS from sucrose.28 initially suspected of an associated there is a growing and widening cancer risk. Beginning in the 1970s Estimating total content of NNS in variety of food, drink, and consumer and 1980s, animal studies suggested manufactured products has been products that contain NNSs (eg, an association between saccharin challenging. Manufactured products chewing gum, oral rehydration intake and the development of 10 containing NNSs are not required to solutions, mouthwash, etc; Table 1). bladder cancer in rodents.3,13,14 This specify the content of NNS in Therefore, estimates of intake would association was later refuted because fi a product. However, the consumption be dif cult to capture given current it was determined that the “cancer- methods of reporting. of NNSs among children has causing mechanisms in rodents are increased.29,30 The long-term safety not applicable to humans.”3,14 Ongoing questions also exist or potential benefit of the growing fi Furthermore, human studies regarding the bene ts of NNSs. Added prevalence of NNS use in children has evaluating the relationship between sugars are known to have detrimental not been systematically reviewed.31 39,40 saccharin intake and stomach, effects, including an association One barrier to better understanding pancreatic, and endometrial cancer between sugar intake and increased the health effects of NNS is the have not identified a relationship body mass, dyslipidemia, and blood difficulty inherent in measuring the 40 between the consumption of pressure. Recommendations to saccharin and cancer.2,3,15,16 Overall, amount of NNS consumed at the promote cardiovascular health in it appears that science does not individual and population levels. The children include limiting the total support a potential carcinogenic FDA designation of a food item as an intake of sugar-sweetened beverages effect of cyclamate, saccharin, or additive or GRAS means that although (SSBs) to 4 to 6 oz per day in children sucralose in humans.3,17–19 The manufacturers must report that 1 to 6 years of age and limiting the a particular product contains total intake of SSBs to 8 to 12 oz per relationship between aspartame and 41 the development of attention-deficit a sweetener, there is no obligation to day in children 7 to 18 years of age. state the amount of sweetener NNSs have been considered for use disorders, birth defects, diabetes, and 1 lupus has also been refuted.3 a product contains, making it among those aiming to reduce their difficult to estimate how much NNS total SSB intake while still preserving A number of health organizations the average American consumes per the sweet taste. In particular, NNS use have supported the use of NNSs but day. This is compounded by the fact has been proposed among individuals within an acceptable dietary intake that NNS can also be found in our with diabetes and among those (ADI) level.20–25 Despite this, studies drinking water.32 Thus, even those aiming to lose or maintain weight.

Downloaded from www.aappublications.org/news by guest on September 26, 2021 2 FROM THE AMERICAN ACADEMY OF PEDIATRICS TABLE 1 Commercial Products Reported to Contain NNS NNS No. Product Examples Products Saccharin 100 Smucker’s Low Sugar Reduced Sugar Sweet Orange Marmalade, Bubble Yum Sugarless chewing gum, diet sodas (Tab), yogurt Aspartame 2307 Jell-O, diet sodas (Diet Coke, Coke Zero, Diet Dr Pepper, Fresca, Tab), Country Time Sugar Free lemonade Acesulfame 3882 SlimFast, Werther’s Original Sugar Free hard candies, Del Monte Mandarin Oranges No Sugar Added, Pedialyte, diet sodas potassium (Pepsi One, Sprite Zero, Fresca) Sucralose 5148 Lean Pockets, diet sodas (Diet Mountain Dew) Neotame 114 Sunny D, protein shakes, chewing gum Stevia 642 Some Muscle Milk products Advantame 0 N/A Luo 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. Accessed April 28, 2019. N/A, not applicable.

However, concerns have arisen that May 25, 2018, because of delays in American Heart Association (AHA),12 NNS use in animals may alter gut publication related to a lengthy were reviewed (n = 4). It should be microbiota in such a way that there is review process. A final selection of stated that the highest-quality an enhanced risk for glucose references was performed by August evidence is derived from randomized intolerance, insulin resistance, 20, 2018, resulting in 40 additional controlled trials (RCTs) within the diabetes, and increased weight.42,43 references. population of interest. To date, however, few such studies exist (n = This report summarizes the available The following search terms were used 6).4,45–49 literature regarding NNS use in in PubMed (www.pubmed.gov): children and adolescents, including “nonnutritive sweetener” or the name the penetrance of these agents into SWEETENERS AND NNSS of each individual FDA-approved the pediatric food chain and effects nonnutritive sweetener (ie, Sweeteners can be classified as on taste preferences in children. This “aspartame,”“neotame,”“saccharin,” sugars (ie, brown sugar, cane sugar, statement also addresses proposed “sucralose,”“advantame,” or fructose, and high-fructose corn potential benefits of NNSs in specific “acesulfame”). “Stevia” also was syrup), alcohol sugars (ie, isomalt, pediatric populations (ie, those with included in the search because this maltitol, mannitol, sorbitol, and obesity, diabetes, etc). Consideration agent received the designation of xylitol), and NNSs (ie, saccharin, of the strength of the data was also GRAS. The search was limited to aspartame, acesulfame potassium, included. Our purpose with this studies published within the previous sucralose, stevia, neotame, and statement is not to provide specific 10 years (before the initial search) in advantame). NNSs are high-intensity clinical guidance regarding the use of human subjects and written in the sweeteners that provide a sweet taste NNSs in children but rather to English language. Eighty-three studies with little to no glycemic response provide a summary of the existing 1 were identified. Studies that did not and few to no calories. data. Finally, recommendations are made for future directions in research pertain to the use, safety, potential Eight NNSs are currently approved by fi 1 and policy. bene ts, or associated risks of NNS the FDA, and their levels of use in children were excluded (n = sweetness range from 180 to 31). Studies addressing the use of 20 000 times sweeter than sucrose METHODS NNSs in pain control were excluded. (ie, table sugar). Each NNS possesses A systematic review was beyond the The reference lists of selected articles varying properties; some are stable scope of this publication; however, were reviewed, and relevant cited when heated. Some are the authors used a common search references were also included. contraindicated for use in particular strategy to identify relevant Additional searches were performed patient populations, such as publications. A literature review was to fill in identified knowledge gaps aspartame use in people with conducted regarding the use and (n = 30). Finally, policy statements of phenylketonuria (Table 2). Most have safety of NNSs in the pediatric other organizations on NNS use, been approved for use as a food population (ie, 0–18 years of age) in including the Academy of Nutrition additive and, as such, have undergone – 2011. The search was updated on and Dietetics (AND),21 23 American a premarket approval process in October 15, 2014, and then again on Diabetes Association (ADA),44 and accordance with stipulations made by

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019 3 TABLE 2 FDA-Approved NNSs Type (Approval Distinction) Commercial Name Kcal/g Sweetness Introduction and/or FDA Heating Contraindication and/or Compared With Approval Reduces Safety Issues Sucrose Sweetness Saccharin (1,2- benzisothiazolin-3- Sweet’N Low, 0 200–700 Introduced in 1879; FDA No None 1, 1,1-dioxide) (food additive) Sugar Twin, approved for use Necta Sweet Aspartame (N-[l-a- Aspartyl]-L-phe, NutraSweet, 4a 180 Approved for limited use (ie, Yes Phenylketonuria; reported 1-methyl ester) (food additive) Equal, Sugar tabletop sweetener) by cases of thrombocytopenia Twin the FDA in 1981 and (78)50 approved for general use in 1996 Acesulfame potassium and/or Sunett, Sweet One 0 300 Discovered 1967; FDA No Associated with cancer in acelsulfame potassium approved limited use 1988 animals at high dose; no (potassium 6–methyl-2,2-dioxo- and general use known association in oxathiazin-4-folate) (food (exceptions: meat and humans additive) poultry) in 2003 Sucralose (1,6- Dichloro-1, 6- Splenda 0 600 Discovered in 1976; FDA No None dideoxy-b-D- fructofuranosyl-4- approved for limited use chloro-4-deoxy-a-D- in 1998 and for general galactopyranoside) (food use in 1999 additive) Neotame (N-[N-{3,3-dimethylbutyl}- Newtame 0 7000–13 000 FDA approved for general No Contains phe and asp and is L-a-aspartyl-L-phe 1-methyl use 2002 (exceptions: therefore contraindicated in ester]) (food additive) meat and poultry) those with phenylketonuria Stevia (1,1-dioxo-1,2-benzothiazol-3- Truvia, Pure Via, 0 200–400 Accepted as GRAS April 20, Yes None 1), GRAS Enliten 2015 Advantame ([N-{3-(3-hydroxy-4- None 3.85 20 000 FDA approved for general No Determined to be safe for methoxyphenyl)}-propyl- use 2014 (exceptions: use in children a-aspartyl]-L-phe 1-methyl meat and poultry) ester) Luo han guo fruit extract (GRAS) Monk Fruit in the Unknown 600 GRAS January 15, 2010; Unknown None Raw, PureLo Lo intended for use as Han Sweetener a tabletop sweetener, food ingredient, and additional sweetening agent 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(pt A):324–355. a Although aspartame contains 4 kcal/g, little is used, and therefore, it essentially provides no extra calories.51

the 1958 Food Additives Amendment been studied for safety.1 Studies largely in response to concerns raised to the Federal Food, Drug, and number more than 100 for about some of the substances with Cosmetic Act. aspartame, nearly 100 for acesulfame GRAS designation, including potassium, approximately 110 for cyclamate. After this order in the Under the 1958 Food Additive neotame (in animals and humans), 1970s, the FDA hired the Life Amendment to the Federal Food, and 37 for advantame (in animals and Sciences Research Office, which then Drug, and Cosmetic Act, only humans), the NNS food additive most selected qualified scientists (ie, the substances with GRAS designation do recently approved by the FDA.1,52,53 Select Committee on GRAS not require premarket approval. Only 2 approved NNSs, Stevia Substances) as consultants to review Although the market studies for rebaudiana and luo han guo (or monk and evaluate the available aspartame, acesulfame potassium, fruit), have been approved under the information on each of the GRAS sucralose, advantame (an GRAS notification process. After the substances. The select committee’s N-substituted analog of aspartame), passage of the 1958 Food Additives evaluations were made saccharin, and neotame are not Amendment, President Nixon ordered independently of the FDA or any widely available, these NNSs have an evaluation of GRAS substances, other governmental or

Downloaded from www.aappublications.org/news by guest on September 26, 2021 4 FROM THE AMERICAN ACADEMY OF PEDIATRICS nongovernmental group. In 1972, did not exceed ADI but varied beverages has also increased at the a GRAS affirmation process began. between 5% and 94% of the ADI.36 same time that the purchase of SSBs The FDA established procedures (21 According to Web sites such as has decreased: between 2003 and Code of Federal Regulations 170.35) FoodFacts.com, the number of foods 2010.73 that it would then use to affirm the and consumer products that include GRAS status of substances. The GRAS at least 1 NNS as an ingredient has International recommendations have notification process began in 1997. tripled within the last 4 to 5 years. In established an ADI (per kilogram) for By the end of 2006, 193 GRAS notices 2010, Yang72 found that according to NNSs. The ADI is typically 100 times fi lower than the dose of the sweetener were led, and the glycoside isolated FoodFacts.com, 3648 products 71 from the plant S rebaudiana Bertoni contained at least 1 NNS.10 As of July known to cause toxicity in animals. and luo han guo were accepted as 12, 2015, approximately 12 291 The concept of the ADI was GRAS for use in baked foods and soft products contained at least 1 NNS.10 established by an international fi drinks.1,3 Additional information scienti c committee and the Joint People are not always aware of their regarding NNSs can be found in Food and Agriculture Organization of intake of NNS. Some artificial – previously published review the United Nations World Health – sweeteners can be found in articles.10,21,22,38,43,51 61 Organization Expert Committee on groundwater and drinking water, Food Additives. Other organizations although at magnitudes below the have reported ADI levels for various PENETRANCE OF NNSS INTO THE NORTH 32 ADI level. Furthermore, people NNSs, including the European Food AMERICAN DIET: HOW MUCH NNS DO inadvertently consume NNS, CHILDREN ACTUALLY CONSUME? Safety Authority and the Danish according to a recent study of 18 Veterinary and Food Administration Information about NNS consumption reported “nonconsumers,” 44% of (Table 3).70 US federal regulations by children and adolescents is mostly whom had sucralose in their urine (FDA Code 21 Code of Federal – derived from dietary recall12,62 69 that was unexplained by the trivial Regulations 170) do not require that and cross-sectional analysis,29,30 amounts of sucralose that are the amount of NNS in a food item be which limits the ability to estimate sometimes reported in the water listed on the product label if it has 32,33 the quantity of NNS consumed supply. been determined to be safe for use in because the quantity of NNS per 1 The majority of NNS intake is derived a particular food. However, without serving of any given food is not from intake of NNS-containing proper knowledge of true content, it publicly available and because dietary fi beverages (∼11%), followed by food is dif cult to know whether intake of recall is prone to error. Early studies (∼4%) and individual NNS packets a particular sweetener is within the found that approximately 15% of the (∼1%).38 Data from the NHANES ADI level. population older than 2 years old 1999–2000 to 2007–2008 show that fi consumes some type of NNS per year It is also dif cult to know the percentage of children consuming (eg, 2003–2004).70 Older review whether intake of a particular NNS-containing beverages increased articles concluded that pediatric NNS NNS by a child is within the ADI from ,1% to .7%.29 More recent intake was within the ADI level, but it is worth noting that there NHANES cross-sectional data analysis level.34,62,63 Still others have found, have been few cases of reported (2009–2012) revealed that 25.1% of on the basis of estimated intake from adverse events related to NNS children, compared with 44% of 50 24-hour dietary recall, that intake of intake. Proponents of NNS use adults, reported consumption of cyclamate and saccharin may exceed argue that safety information can be NNSs.30 Most reported daily use the ADI for some youth.69 Regardless, assumed on the basis of more than (80% of children and 56% of adults). intake of NNS among children tends 30 years of use of these agents with Analysis of the 2009–2012 NHANES to exceed NNS intake for adults when relatively few reported adverse data suggests that NNS intake is assessed as milligrams per kilogram effects. However, it is also true that higher in women and girls, of body weight.12 there has been no systematic or individuals with obesity (versus those formal method for capturing and The prevalence of NNS use is with overweight or normal weight), recording adverse effects related to increasing, and inclusion of NNSs in non-Hispanic white individuals the use of these agents. daily food products is more (versus non-Hispanic African pervasive.10,70,71 A single prospective American or Hispanic individuals), Given the proliferation of products study of youth with diabetes mellitus and individuals in the highest tertile containing NNSs in the food supply, (n = 227) estimated, on the basis of of income.30 Between 4% and 18% of which may lead to both increased a 5-day food diary, that the theoretical carbonated beverages consumed by consumption and combined use of maximum daily intake of saccharin, children contain NNSs.71 Household NNSs, there is a need for acesulfame potassium, and aspartame purchase of NNS-containing contemporary peer-reviewed studies

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019 5 TABLE 3 ADI Level Sweetener JECFA ADI, mg/kg EFSA ADI, DVFA ADI, FDA ADI, Number of Packets Equivalent to ADI (Based on a mg/kg mg/kg mg/kg 68-kg Person) Saccharin (Sweet’N Low) 5 5 5 15 250 Aspartame (NutraSweet and Equal) 40 40 15 50 165 Acesulfame potassium (Sweet One) 15 9 40 15 165 Sucralose (Splenda) 15 15 15 5 165 Neotame 0–2 1 Unknown 0.3 200 Stevia 4 4 Unknown 12 30 Advantame 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 March 26, 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 on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Disease in the Young, and the American Diabetes Association. Nonnutritive sweeteners: current use and health 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 Food Administration; EFSA, European Food and Safety Agency; JECFA, Joint Food and Agriculture Organization of the United Nations–World Health Organization Expert Committee on Food Additives.

to estimate the current prevalence of appetite regulation. Individuals vary Sprite reported that those who NNS use, amounts consumed by in their ability to perceive taste, and consumed NNS (ie, Sprite Zero) were children, and any potential adverse thus, individuals differ in their more likely to subsequently choose effects. potential “gain” achieved from a bag of chocolate M&M’s (43%), 78,79 various sweet stimuli. It was once whereas those who consumed IMPACT OF NNSS ON APPETITE AND believed that only nutritive a nutritive sweetener (eg, regular TASTE PREFERENCE sweeteners activate the sweet-taste Sprite) or water were more likely to receptors; however, it is now known select a less-sweet snack, such as Studies regarding the potential that NNSs, which are several hundred water or chewing gum (41% and impact of NNS intake on appetite and times sweeter than table sugar, also 33%, respectively).84 The authors taste preference can be divided into 70 activate these receptors. The effect concluded that participants who animal studies and human studies. of NNS activation on taste preference, consumed NNSs felt less satisfied Animal models have shown that food intake, the activation of with what they had drunk compared nutritive sweeteners activate the metabolic pathways, and appetite is with those who consumed a sugar- sweet-taste receptors (ie, T1R family 80,81 not well understood. sweetened or an unsweetened and a-gustducin receptors).74,75 beverage (P = .004).84 As for According to animal studies, Human studies have been assessing how intake of NNS saccharin intake weakens the ability inconsistent in their reporting of the influenced preference for sweet food, of Sprague Dawley rats to signal the potential impact of NNS use on researchers found in this study of 115 caloric “postingestive consequences appetite and taste preferences. college students that participants of eating” so that if saccharin is Furthermore, genetic differences in who consumed NNS were more likely administered, rats did not regulate taste perception may also exist and to provide the names of high-calorie their intake of sugar-sweetened food fl 82 in uence study results. A small food items compared with those who and/or beverages after saccharin- study of 10 healthy adults given 1 of 4 consumed a sugar-sweetened or an sweetened solution intake.76 This drinks that contained either glucose unsweetened drink (P = .001)84 after study suggests that NNS intake may alone or glucose plus 1 of 3 consumption of the NNS-containing affect normal responses to caloric sweeteners (eg, 45 g glucose and beverage. intake such that overeating may be 150 mg aspartame, 45 g glucose and more likely if the diet after NNS 20 mg saccharin, or 45 g glucose and NNS use in children may be 76 administration is a sweeter diet. 85 mg acesulfame potassium in associated with a greater preference 77 In children, the taste receptors are 250 mL of water) did not report for sweet foods ; however, the effect located in the lingual taste buds and differences in hunger or fullness of NNSs on taste preference is not along the intestinal mucosa.77 within 60 minutes of ingestion.83 In well understood. Humans have an Activation of the sweet-taste contrast, a single study of 115 college innate preference for sweet foods, receptors results in stimulus to the students 18 to 22 years of age given and children in particular prefer high pleasure-generating loci of the either Sprite Zero (NNS-containing levels of sweetness.77 Children who brain,77 triggering glucose uptake and beverage), mineral water, or regular consume large amounts of SSBs may

Downloaded from www.aappublications.org/news by guest on September 26, 2021 6 FROM THE AMERICAN ACADEMY OF PEDIATRICS tend to prefer foods that are richer in SAFETY AND NNS USE tumors in the treatment group were both sugar and calories. The Most NNSs have been approved by of different histologies and the American Academy of Pediatrics the FDA for use as a food additive; 2 tumors occurred at a rate frequently ”89 (AAP) recognizes the detrimental NNSs were approved under the GRAS observed in monkeys. To date, effect of high sugar content on the distinction for a particular intended there have been no case control health of children and the propensity use.1 Reviews and investigative studies of cyclamate, particularly that high sugar content has for related to tumor formation in studies discussing and evaluating the 89 promoting obesity in safety of NNSs, including sucralose,19 humans. The relationship between 6,39,85–87 childhood. The AAP have been published. Studies cyclamate and cancer was later recommends against routine investigating the potential toxic refuted, and permissions for use of consumption of sports and energy cyclamate were thus reinstated in effects of NNSs have been performed 2 drinks because of their high sugar in animals55–58 and humans.51,59 1992. 39 content. A single, small population Results from these more recent A study of Sprague Dawley rats fed study found that adults who studies have concluded that there are diets supplemented with 0%, 5%, and consumed NNSs tend to prefer no potential teratogenic effects or 7.5% (of the total diet) saccharin a sweet versus salty and/or savory negative effects of NNS use on weight experienced differences in the snack after this ingestion. The or development in animals. However, proliferation of the epithelial cells authors suggest that NNS intake can cases of aspartame-induced (used as a marker of cancer risk) by increase the motivation for one to thrombocytopenia have been diet and concentration of saccharin.14 access sweet relative to savory reported.50 Furthermore, aspartame 88 However, this study was not deemed snacks and thereby alter energy is uniformly contraindicated in to be relevant to humans because the balance in such a way that children people with phenylketonuria. form of saccharin used, sodium- who consume these agents are more saccharin, is considered likely to consume sugary food and “ 84 representative of a large group of drinks. The temporal correlation NNS USE AND CANCER RISK sodium salts known to act as tumor between the increase in childhood promoters in the male rat urinary Concerns regarding a potential overweight and obesity and the bladder when high doses (of relationship between NNSs and increase in intake of NNS-containing saccharin) are administered.”14 The cancer were raised shortly after the beverages is suggestive of FDA reports that a total of 30 human 38 introduction of NNS into the food a relationship. However, the studies have been conducted to date supply.1,10 Cyclamate was first relationship may be one of reverse and have not found an association approved for use in humans in the causality, whereby children who have between saccharin use and cancer of 1950s89; however, concerns arose obesity (or their parents) may be any type.1 A large case control study regarding a potential increased risk substituting food or beverages of people with bladder cancer (n = for bladder cancer after use of sweetened with NNSs for those 3010) and controls (n = 5783) found cyclamate in rats.89 It was also containing sugar in an attempt to no association between self-reported proposed that the metabolism of limit caloric intake. past NNS use and bladder cancer.66 cyclamate to cyclohexylamine, which However, not all studies have agreed In summary, increasing trends in NNS is toxic to rats and dogs, caused with this conclusion.16 A number of use are coincident with an increase in testicular atrophy and impaired observational studies later the prevalence of childhood obesity. spermatogenesis.89 When determined that the relationship Data suggest but do not conclusively administered to nonhuman primates, between saccharin and bladder demonstrate that NNS use may 3 of 14 monkeys given cyclamate cancer was specific to rodents.17 promote the intake of sugary food developed neoplasms versus 0 of 16 Saccharin was removed from the list and drink by affecting taste controls. The 3 tumors, developed of potential carcinogens in 2001 by preferences. It has been after receipt of “the equivalent of the National Toxicology Program of demonstrated that excessive intake of ∼30 calorie-reduced drinks” the National Institutes of Health.10 SSBs (and increased calories) has (containing cyclamate), were been associated with childhood a metastatic adenocarcinoma of the A case control study of adults with obesity. Additional information colon, a metastatic hepatocellular incident neoplasia (eg, stomach, regarding the effects of NNS use on carcinoma, and a papillary pancreas, and endometrium) versus taste preferences and caloric intake adenocarcinoma of the prostate. The unaffected controls did not find and comparison of the long-term authors concluded that there was “no greater odds of cancer among those effect of NNS-containing versus SSBs evidence for carcinogenicity of exposed to NNSs.90 However, 1 of the is needed. sodium cyclamate because the limitations of this case control study

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019 7 was low NNS use among participants For example, children and reported positive associations and potentially insufficient sample adolescents who have obesity might between NNS intake and BMI (ie, high size to detect even weak associations benefit from lower total caloric NNS intake is associated with higher between NNS use and cancer.90 intake. Children who have type 1 or 2 BMI).64,100 However, results from diabetes mellitus might also benefit longitudinal follow-up are conflicting, A systematic review of the safety and from the lack of a glycemic response with a few studies supporting these potential carcinogenic effect of while enjoying the sweet taste of findings6,86,87 and others suggesting aspartame in mice found no NNSs. Similarly, those with multiple either no relationship101 or a small association between aspartame metabolic or cardiovascular disease beneficial effect of NNS intake on administration and risk of cancer.91 A risk factors also might experience BMI.97 meta-analysis of studies of aspartame a benefit because excess in rats showed no association 92 carbohydrate intake is likely a factor A double-blind RCT from the between aspartame and cancer. A – contributing to their health risk.94 96 Netherlands found that replacement review of human (adult) cohort and of SSB intake with NNS intake in case control studies showed no school-aged children was associated relationship between most types of NNS USE AND CHILDREN WITH OBESITY with reduced weight gain (not weight cancer and aspartame use.18,51,92,93 NNSs pass through the human loss) during an 18-month period.4 A Newer data have failed to gastrointestinal tract without being study of aspartame use in adults with demonstrate an association between digested, providing sweet taste overweight (eg, mean age 19 years) NNS use and cancer.90 The long without added calories, a property was associated with greater weight latency period, the penetrance of that is potentially advantageous for reduction than among the control NNSs into the food supply (making it preventing and controlling obesity population.102 Similarly, a study from difficult to isolate an adequate given the association between sugary South Africa found that intake of unexposed control group), and the beverage consumption and 25 mg of sucralose per day by youth 6 diversity of potential mechanisms obesity.6,64,87,97 However, the data are to 11 years of age was associated have made it difficult to definitively conflicting as to whether consuming with a lower BMI-for-age z score exclude potential carcinogenic NNSs leads to weight loss or weight (control and nutritive sweetener of properties of NNSs but also make it gain.6,87 7.1 and micronutrient and NNS of 6 difficult to conclude that there is any versus control and sucrose of 10.8 Swithers et al98 also provided animal such association. The type of research and micronutrient and NNS of 10.9) studies reporting that use of artificial that would more definitively address compared with sugar intake. In sweeteners may increase weight gain. the effects of NNS intake over the contrast, a higher weight-for-age z Observational studies in adults show long-term and across the life span score change was associated with that NNS intake is associated with (for example, long-term randomized NNS use in a separate study.5 increased BMI. Analysis of the San clinical trials or prospective cohorts Prospective studies have revealed Antonio Heart Study, an adult with well-defined measures of mixed results: Newby et al103 did not prospective cohort study, showed exposure over multiple time points) identify an association between NNS a dose-response adverse effect of NNS is not likely to occur. intake and weight change in intake on overweight and obesity a prospective cohort study of 2- to 5- In summary, observational data in status over 7 to 8 years of follow- year-olds (n = 1345) but reported adult-human studies show no up.99 However, these data are that intake of diet soda was low (,5 association between NNS use and vulnerable to reverse causality oz per day), with poor correlation cancer. There are no long-term because it has been demonstrated seen between estimated beverage studies in children. Studies have been that individuals who are attempting intake at the time of the first visit limited to animal and adult-human to lose weight are more likely to use compared with at the second visit. A studies, and the long-term risk of NNSs.26 Additionally, the San Antonio prospective study investigating the cancer and other conditions among analysis is subject to the same effect of intake of SSBs and NNSs on children who use NNSs is not known vulnerabilities regarding the accuracy weight among school-aged youth (n = and is likely to be difficult to obtain. of estimated NNS intake, particularly 164) found that for each 12 oz of diet because the baseline data were soda consumed per day, there was NNS USE IN SELECT PEDIATRIC collected decades before the current a 2-year BMI z score that was 0.156 POPULATIONS era and estimates were reliant on higher than predicted on the basis of dietary recall. It can be reasonably argued that baseline-BMI z score.6 A prospective certain subpopulations of children Several cross-sectional studies in cohort study of 4746 youth found might benefit from the use of NNSs. children and adolescents have also that consumption of low-calorie soft

Downloaded from www.aappublications.org/news by guest on September 26, 2021 8 FROM THE AMERICAN ACADEMY OF PEDIATRICS drinks (positive association; P = .002) reduction in BMI between the fat mass and body weight with was associated with weight gain, intervention (–0.63 6 0.23) and artificial sweetener use.112 A whereas consumption of white milk control (10.12 6 0.26) groups.47 A randomized 25-week intervention (inverse association; P = .03) was systematic review and meta-analysis study of 103 adolescents 13 to associated with weight loss.104 of NNS use and cardiometabolic 18 years of age that included home Analysis of the relationship between health evaluating change in BMI delivery of noncaloric beverages (4 NNS use and weight gain, however, among NNS consumers 12 years and servings per day for the adolescent did not control for parental weight older from 7 RCTs and 30 and 2 servings per day for each and other important confounders.104 observational studies reported mixed additional household member) Limitations of prospective cohort results. Analysis of data from 2 of the revealed an additional BMI decrease studies include failure to control for 7 selected RCTs found that use of of 0.08 for every 1 at baseline. This other dietary and lifestyle factors105 NNS was not associated with study found that the effect of NNS use and shorter long-term follow-up. a significant effect on BMI over a 6- to on BMI in adolescents was most Interpretations of the relationship 24-month period (–0.37; 95% significant for adolescents with between NNS use and BMI are limited confidence interval [CI]: 21.10 to a baseline BMI .30.10,47 A different by the inability to determine causality 0.36; I2: 9%).8 Two cohort studies RCT in children that combined NNS because of cross-sectional study showed a possible correlation use with total caloric restriction did design as well as reverse causality between NNS use and BMI over a 3- not find an association between NNS and inaccurate dietary recording in to 13-year period, and a third cohort use and weight loss.102 Given the prospective cohort study design.105 study found that participants who multitude of factors affecting weight, Youth who consume NNSs may have consumed NNSs daily had a greater including high-fat- and low-water- different food consumption patterns increase in BMI during an 8-year intake diets and the complex and a variety and parental and follow-up period.8 As highlighted in behavioral interactions related to environmental factors not adjusted the systematic review, overall, data response to use of NNS, some have for in the prospective studies that suggest an increase in BMI with NNS argued that NNS use alone may not be may affect the relationship between use over the long-term without an effective remedy for weight NNS use and BMI. confirmation of these findings via loss.113 RCTs.8 Meta-analysis of 15 RCTs examining The long-term effect of NNS use on Controlled experimental studies have the relationship between NNS use weight remains poorly defined, and tried to better address the question of and BMI in adults and youth (ages thus far, data suggest the benefits are the effect of NNS on weight by giving 69,114 10–65 years) reported that intake of limited. A prospective double- controlled meals and measuring NNS is associated with modestly blind study showed that children 4 to caloric intake after the controlled reduced body weight, BMI, fat mass, 11 years of age with normal weight meals. Some studies show lower and waist circumference (WC) with who consume a beverage containing calorie consumption after foods a mean reduction in weight of 0.8 NNS per day experience less weight containing NNSs compared with kg.105 However, RCTs suggest that gain over an 18-month period calorically sweetened foods,106 but substituting NNSs for SSBs is compared with those who consume other studies support the associated with a modest reduction in sugar-containing beverages4; the phenomenon of “make-up” calorie body weight for youth with the change in weight between the 2 consumption, showing higher highest baseline BMI but not for all cohorts differed by 2.2 lb (1 kg). The intake107–110 immediately after NNS youth. Ebbeling et al reported results America On the Move study found intake. The make-up theory has not from a pilot study for an RCT that, combined with additional been proven conclusively81 and evaluating the potential impact of changes in lifestyle, use of NNSs may represents only the immediate replacement of SSBs with NNSs on contribute to slowed weight gain in postprandial effects of NNS intake. body weight in youth and found that overweight and at-risk children46 change in BMI, adjusted for sex and Most short-term studies support over a 6-month study period. A study age, was 0.07 6 0.14 (mean 6 SE) for a beneficial role of NNS in weight in children with obesity showed that the intervention group and 0.21 6 loss.111 A patient-blinded prospective use of NNSs contributed to slowed 0.15 for the control group with a net cohort study in adults comparing weight gain over the first year, but the difference of –0.14 6 0.21, which was satiety, energy intake, and body difference in weight was not not significant. Baseline BMI was weight during a 10-week maintained during the subsequent a significant effect modifier such that supplementation with either sucrose year even when controlling for youth in the upper baseline-BMI or artificial sweetener found confounders such as screen time, tertile experienced a significant a significant but modest reduction in parental BMI, energy intake, physical

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019 9 activity, and fat consumption.45 NNS USE AND EFFECTS ON METABOLIC of NNSs were less likely to have SYNDROME AND DIABETES In that study, Ebbeling et al found metabolic syndrome (HR: 0.64; 95% CI: 0.5 to 82) compared with that NNS use did not result in Observational and experimental data in adults suggest that the use of NNSs consumers of a Western diet. Results a significant change in BMI after may alter glucose metabolism in the from this study suggest that 2 years of replacement of SSBs with presence of obesity, although these a prudent dietary pattern is NNSs. Systematic reviews of the studies are subject to the same consistently associated with lower existing data concluded that in vulnerabilities as described above risk for metabolic syndrome, but with regard to obesity.8 Cross- being a nonconsumer of NNSs is children, NNS use may prevent 118 sectional analysis of 2856 adults not. Use of NNSs can be associated excess weight gain over a period of participating in the NHANES with a lower likelihood of high fasting 6 to 18 months but that, in general, demonstrated that aspartame intake glucose and of low high-density studies evaluating the relationship affects the association between BMI lipoprotein but did not significantly between NNS intake and obesity are and glucose tolerance (interaction: affect WC (prudent nonconsumers 26 lacking rigor. According to 1 P = .004), showing worse glucose were actually less likely to have published systematic review, use of tolerance with increasing BMI in a high WC [HR: 0.78; 95% CI: 0.62 to NNSs in place of sugar, in children those reporting consumption of 0.97]), the likelihood of high and adults, leads to reduced energy aspartame.117 Similarly, cross- triglycerides, or metabolic 7,118 intake and a small reduction in body sectional analysis of the Framingham syndrome. Findings from the 115 weight (on average, 1.3 kg). Finally, Offspring Cohort showed an CARDIA study were also observed in a Cochrane Review reported that NNS association between diet soda other prospective cohorts. A use was associated with consumption, as assessed by a food prospective analysis of the a significantly reduced body weight frequency questionnaire, and association between beverage (21.07 kg [95% CI: 0.41 to 1.72]), metabolic syndrome.7 consumption (SSBs and NNS soda and among people younger than18 intake) found that intake of greater years, the NNS group demonstrated Prospective cohort data from the than or equal to 1 soft drink per day a significant reduction in body weight Coronary Artery Risk Development in (regular or diet) was associated with (1.18 kg [95% CI: 0.34 to 1.04]), an Young Adults (CARDIA) study of the a higher prevalence of metabolic association that was not evolution of cardiovascular disease syndrome.7 Again, given the cross- demonstrated for adults.116 risk showed that among young adult sectional and observational design of NNS consumers 18 to 45 years of age, these studies, causality cannot be In summary, the preponderance of consumers of NNS were more likely determined; nonetheless, data data suggests that the use of NNSs to have metabolic syndrome and suggest that there is a correlation can lead to weight stabilization or a higher WC. In comparing those who between NNS use and metabolic a small degree of weight loss by consumed a Western diet and NNSs syndrome. helping lower total caloric intake, versus individuals who consumed especially among children and a Western diet but not NNSs, there The Multi-Ethnic Study of adolescents with obesity. Studies was no significant difference in WC, Atherosclerosis cohort study showed suggest that NNSs may be considered the presence of high fasting glucose, that daily consumption of diet soda part of a comprehensive program and low low-density lipoprotein was associated with a 36% higher a substitute for foods and beverages concentration, high triglycerides, high relative risk of metabolic syndrome containing caloric sweeteners for blood pressure, or overall metabolic and a 67% higher relative risk of type weight loss or weight maintenance. syndrome. However, young adults 2 diabetes mellitus.68 However, once The current data would suggest that who consumed a prudent diet and adjustments were made to account depending on baseline BMI and NNSs (prudent consumers) were less for baseline measures of adiposity, without easily taking into account likely to have a high fasting glucose the association between diet soda what else is being consumed or (hazard ratio [HR]: 0.75; 95% CI: 0.57 consumption and metabolic substituted for, NNS use is to 0.99) and a low high-density syndrome was no longer significant, associated with a modest lipoprotein concentration (HR: 0.69; but the association between diet soda improvement in weight. However, the 95% CI: 0.54 to 0.87). There was no consumption and diabetes long-term effects of NNS use in significant difference in the presence remained.119 Findings suggest that children and adolescents, including of metabolic syndrome among additional factors among those who use pertaining to weight loss or consumers of the Western diet and consume diet sodas may be weight management, are prudent diet consumers of NNSs. associated with a greater risk for currently unknown.31,106 However, prudent diet nonconsumers diabetes mellitus and metabolic

Downloaded from www.aappublications.org/news by guest on September 26, 2021 10 FROM THE AMERICAN ACADEMY OF PEDIATRICS syndrome. Analysis of the a prospective cohort study that relied beverages at baseline, regardless of Framingham study stopped short of on questionnaires administered whether they followed a “prudent” reporting an association between between 1996 and 1998 to examine (eg, fruit, fish, and whole grains) or NNSs and WC but did find that the relationship between beverage Western dietary pattern (eg, fast prudent nonconsumers of NNSs were intake and change in BMI among foods, refined grains, and sugar- less likely to have a higher WC. .10 000 boys and girls ages 9 to sweetened soda), had higher rates of 17 years, demonstrated a relationship metabolic syndrome compared with In the Atherosclerosis Risk in between diet soda consumption and those who did not consume diet soda Communities Study, diet soda increased BMI over 2 years’ follow-up beverages.94,118 consumption was associated with in boys (P = .016) but not girls (P = incident metabolic syndrome (P , 87,122 Better understanding is needed 120 .152). Data from the .001 for trend). Again, causality 46,122 concerning the effects of NNSs on Framingham Children’s Study 125 metabolism and risk of diabetes, cannot be determined in among 3- to 15-year-olds revealed including whether NNS intake is observational study designs, and that although there was no consistent fi merely correlated with a higher risk there are likely signi cant trend in body fat associated with of metabolic syndrome and diabetes confounding factors, but longitudinal intake of SSBs or NNS-containing or there is a causal and harmful cohort studies show that there is an beverages, the highest NNS intake relationship mediated through the gut association between NNS use and was associated with increased body abnormal glucose metabolism in 111 microbiome or other as-yet- – fat, as measured by skinfolds. fi adults.7,118 120 unidenti ed pathways. The mechanism by which NNSs might Few data exist regarding the role of adversely affect body weight, insulin NNS USE AND CARDIOVASCULAR NNSs in children and youth with resistance, and long-term metabolic DISEASE RISK FACTORS diabetes, insulin resistance, or risk is unknown, but 1 hypothesis is metabolic syndrome. One small study Greater sweetened beverage use has that it results in adverse effects on of youth and young adults 12 to been associated with increase obesity, the gut microbiome. Alterations in 25 years of age with type 1 (n =9) increased central obesity, and microbiota structure and function and type 2 (n = 10) diabetes mellitus abnormal perturbations in the lipid have been associated with a greater fi compared the effect of drinking pro le, all of which are risk factors propensity for developing metabolic carbonated water versus carbonated for premature cardiovascular syndrome.123 Suez et al42 published 40 beverages with NNSs on glucose disease. Although consumption of a small but frequently cited study in tolerance (with a 75 g oral glucose added sugars is known to cause rodents with some human data tolerance test) using a crossover detrimental effects on lipid comparing the effects of NNSs (eg, 94,96 design.121 According to this study, concentrations, no clinical trials saccharin, sucralose, and aspartame) there were no differences in glucose have addressed the effects of NNSs on on glucose tolerance in mice and or C-peptide secretion in people with lipid concentrations in childhood. changes in the intestinal microbiota.43 either type 1 or type 2 diabetes Current data regarding the potential The animal data showed that NNS mellitus after NNS consumption. benefit of NNSs in modifying intake, particularly saccharin, leads to Youth with type 1 diabetes mellitus cardiovascular disease risk factors a change in the structure and function released more glucagonlike peptide 1 are limited but suggest an association of the microbiota. A small study in after they consumed NNS-containing between NNS consumption and human volunteers (who did not carbonated beverages versus metabolic syndrome, an association previously consume NNSs) showed carbonated water; no differences that may be limited by reverse that receipt of saccharin within ADI were seen in youth with type 2 causation. There are no conclusive levels for 5 days was associated with diabetes mellitus. data regarding the risk of the development of glucose cardiovascular disease events and A systematic review of the evidence intolerance.42 The findings from these NNS intake. from prospective studies evaluating animal data and the small, single, the association between early life human (adult) study suggest NNS exposure on long-term metabolic a detrimental effect of NNS use on gut NNS USE AND ATTENTION-DEFICIT/ HYPERACTIVITY DISORDER AND health identified conflicting results metabolism, whereas a systematic AUTISM from 2 RCTs and 6 prospective cohort review suggests that NNS use does studies.122 Studies selected included not alter blood glucose levels over The lay press has raised the concern a total of more than 15 000 children time.124 In adults, observational data that NNS use is associated with exposed to NNS for .6 months.122 from the CARDIA study show that behavior, cognition, hyperactivity, and The Growing Up Today Study, adults who consume diet soda attention issues. Two RCTs show no

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019 11 relationship between NNS use and associated with weight loss and lead consideration the need for long-term behavior and cognition among school- to improved weight management follow-up, adjust for multiple aged children.48,126 Several review over time in adults; the statements exposures, and account for imprecise articles regarding the potential for children were less definitive exposure measures. impact of NNS use on behavior have because of a lack of data. Information been published.114,127,128 Some data regarding use, safety, effect on taste SUMMARY AND RECOMMENDATIONS in adults also suggest an association preferences, and potential benefits in between short-term aspartame special populations was either limited NNSs were introduced into the food consumption and more irritable or not available for other NNSs. supply to provide a noncaloric, sweet- mood, depression, and poorer tasting alternative to caloric performance in spatial orientation.129 The ADA and AHA published a joint sweeteners, which is useful for those To date, however, there have been no summary statement on NNSs in 2012 with diabetes mellitus or who are studies to conclude that there is an supporting the position that NNSs are avoiding sweet calories for other association between attention- safe when consumed within the ADI reasons, including obesity prevention deficit/hyperactivity disorder levels established by the FDA. and reduction. Concerns were initially (ADHD) and NNS use.128 No literature Furthermore, the ADA and AHA have raised about an association with was found to support a relationship argued that NNSs may be helpful in cancer, but research in animal models between NNS use and autism.130 reducing weight gain by limiting and adult-human populations has caloric intake if used in such a way shown no association between NNS At the present time, there are no data that total diet caloric intake is use and cancer.133 Some to support an association between fi reduced. The statement speci cally observational data in cross-sectional NNS use and the development of did not address NNS use in and prospective cohort studies in ADHD or autism in children or 38 children. adults suggest that NNSs may worsening of ADHD symptoms.48 promote obesity and metabolic syndrome but are subject to RESEARCH GAPS OTHER POTENTIAL HEALTH EFFECTS confounding and reverse causation.26 With the exception of the use of Gaps remain regarding our Food challenge studies and short- and aspartame and neotame in children knowledge of the impact on NNS use medium-term interventional data fi with phenylketonuria, there are no on energy sensing and effects on support a small bene t in weight absolute contraindications to NNS use glycemic control, appetite, and maintenance or reduction in adults . in children. NNSs may help to reduce dietary intake for 6 months, and and children when NNSs are used as fi the incidence of dental caries in even fewer data exist speci cally a substitute for caloric sweeteners. children.131 addressing the pediatric However, work remains to better population.132 Future research should understand the use of NNSs in explore novel approaches to assessing toddlers, children, and adolescents in PUBLISHED GUIDANCE AND the long-term effects of NNS use in the general population and in at-risk RECOMMENDATIONS children (both type and amount), the populations (eg, diabetes, obesity, Several organizations have published effect of age of exposure to NNSs and etc). Because of the ubiquitous summary statements regarding the the development of taste preferences, presence of NNSs in everyday use of NNSs, including the AND, ADA, and the effects of age of exposure to products and foods, it is unknown and AHA.21–23,41 The AND states that NNSs on the development of diabetes how much NNSs youth are “consumers can safely enjoy a range mellitus, obesity, early cardiovascular consuming. Contemporary intake of of nutritive and nonnutritive disease, and the developing brain. NNSs (type and amount) and how sweeteners when consumed in a diet Research should explore these topics they relate to ADI levels, specifically that is guided by current federal across the age continuum: toddlers, with regard to younger children, nutrition recommendations, such as children, and adolescents. requires better and more detailed the Dietary Guidelines for Americans Comparisons should be made with data. More information about the type and the Dietary References nutritive sweeteners and other and quantity of NNSs contained in Intakes.”21,22 With regard to the beverages (eg, water and milk). various foods, beverages, and other potential benefit of NNSs on weight Additional research is needed products is recommended to better loss, the AND states that there is regarding genetic differences that understand pediatric exposures. In a good level of evidence to conclude may affect a child’s response to particular, not only should the that NNS use, as part of a particular NNS and to determine if particular NNS contained in a product a comprehensive weight loss or various NNSs differ in their benefits be noted as an ingredient, but the maintenance program, may be or risks. Approaches should take into exact amount of any NNS within

Downloaded from www.aappublications.org/news by guest on September 26, 2021 12 FROM THE AMERICAN ACADEMY OF PEDIATRICS a particular food item should also be syndrome and diabetes, and that 2. The GRAS designation is included in the nutrition facts label. a better understanding is needed based on consumption of NNSs about whether NNS use has within an ADI level; it is not a causal and harmful effect on possible to measure an KEY FINDINGS AND metabolism and the risk of individual’s daily intake of NNSs RECOMMENDATIONS diabetes mediated through the at this time. gut microbiome or other as-yet- Findings and recommendations are as 3. Higher-quality data suggest unidentified pathways. follows. that NNS use is associated with 7. To better inform the public about weight stabilization and/or weight 1. Current FDA-approved NNSs consumption of NNSs, the FDA loss in the short-term. Currently, include saccharin, aspartame, should require products there is a paucity of long- acesulfame potassium, sucralose, marketed in the United States to term data. neotame, stevia, and advantame. include labels that list the type These agents are 180 to 4. High-quality evidence, including and quantity of any NNS 20 000 times sweeter than sugar, meta-analysis and data from RCTs, contained per serving of potentially affecting preferences suggests that there is no a product. for sweet taste. association between hyperactivity 8. Funding should be allocated to and NNS use in children. 2. NNSs are designated either as encourage researchers to conduct food additives or as GRAS; the 5. There are limited data regarding high-quality research on the use long-term safety of NNSs in the effect of NNS use on appetite of NNSs in childhood, focusing on childhood has not been assessed change and taste preference. age of exposure and taste in humans. preferences, neurodevelopment, AUTHORS 3. No advice can be provided on the and effect on the microbiome and use of NNS in children younger its relevance to obesity, metabolic Carissa M. Baker-Smith, MD, MPH, than 2 years old given the syndrome, and diabetes. FAAP, General Pediatrics and absence of data on this age group. 9. Health care providers are Pediatric Cardiology 4. The number of consumer encouraged to remain alert to Sarah D. de Ferranti, MD, MPH, FAAP, products containing NNSs has new information and sensitive to General and Preventive Pediatric quadrupled over the past several patient and family preferences. Cardiology years; manufacturers must list 10. With the exception of aspartame NNSs in the ingredient list but William J. Cochran, MD, FAAP, and neotame in children with are not required to indicate the Pediatric Gastroenterology phenylketonuria, there are no amount per serving. absolute contraindications to use 5. When substituted for caloric- of NNSs by children. COMMITTEE ON NUTRITION, 2018–2019 sweetened foods or beverages, 11. Use of NNSs has been associated Steven A. Abrams, MD, FAAP, Chair NNSs can reduce weight gain or with a reduced presence of promote small amounts of weight George J. Fuchs III, MD, FAAP ∼ dental caries. loss ( 1 kg) in children (and Jae Hong Kim, MD, PhD, FAAP adults); however, data are C. Wesley Lindsey, MD, FAAP limited, and use of NNSs in GUIDANCE FOR PEDIATRICIANS isolation is unlikely to lead to Sheela N. Magge, MD, FAAP substantial weight loss. Primary health care providers Ellen S. Rome, MD, MPH, FAAP 6. Individuals affected by certain should discuss with parents and conditions (eg, obesity and type 1 patients (as appropriate) the Sarah Jane Schwarzenberg, MD, FAAP or 2 diabetes mellitus) may available evidence regarding the benefits and harms of NNS use in benefit from the use of NNSs if PAST COMMITTEE MEMBERS substituted for caloric children and adolescents. The AAP sweeteners. However, health care recommends that pediatricians Jatinder J.S. Bhatia, MD, FAAP, Past providers should be aware that discuss the following points with Chair families. NNS use in isolation is unlikely to Mark R. Corkins, MD, FAAP result in important weight loss, 1. NNSs are FDA approved for use in Stephen R. Daniels, MD, PhD, FAAP, that observational studies show humans or are GRAS and, thereby, Immediate Past Chair that NNS intake is associated approved for use under the GRAS with higher rates of metabolic designation. Sarah D. de Ferranti, MD, MPH, FAAP

Downloaded from www.aappublications.org/news by guest on September 26, 2021 PEDIATRICS Volume 144, number 5, November 2019 13 Neville H. Golden, MD, FAAP Jennifer L. Dotson, MD, MPH, FAAP ABBREVIATIONS Sanjiv Harpavat, MD, PhD, FAAP LIAISONS AAP: American Academy of Pediatrics Maria M. Oliva-Hemker, MD, FAAP Jeff Critch, MD – Canadian Pediatric ADA: American Diabetes Society Leo A. Heitlinger, MD, FAAP, Association fi Cria G. Perrine, PhD – Centers for Immediate Past Chair ADHD: attention-de cit/ Disease Control and Prevention hyperactivity disorder ADI: acceptable dietary intake Janet M. de Jesus, MS, RD – National PAST COMMITTEE MEMBERS AHA: American Heart Association Institutes of Health AND: Academy of Nutrition and Michael deCastro Cabana, MD, Andrea Lotze, MD, FAAP – US Food Dietetics MPH, FAAP and Drug Administration CARDIA: Coronary Artery Risk Development in Young Valery Soto, MS, RD, LD – US Mark A. Gilger, MD, FAAP Adults Department of Agriculture Roberto Gugig, MD, FAAP CI: confidence interval FDA: US Food and Drug SECTION ON GASTROENTEROLOGY, Melvin B. Heyman, MD, FAAP, Past Administration HEPATOLOGY, AND NUTRITION Chair GRAS: generally recognized assafe EXECUTIVE COMMITTEE, 2018–2019 HR: hazardratio Ivor D. Hill, MD, FAAP Jenifer R. Lightdale, MD, MPH, FAAP, NNS: nonnutritive sweetener Chair RCT: randomized controlledtrial SSB: sugar-sweetened beverage David Brumbaugh, MD, FAAP STAFF WC: waist circumference Mitchell B. Cohen, MD, FAAP Debra L. Burrowes, MHA

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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