Escalating rates of overweight and obesity are a threat to the health of billions of people across the globe.
In 2016, more than 1.9 billion adults aged 18 years and older were overweight (1). Of these, more than 600 million were obese. In 2020, more than 38 million children under 5 years of age were overweight -an increase of nearly 6 million during the past 20 years (2). High body mass index (BMI) was responsible for an estimated 4 million deaths in 2017 (3), with greater increases in BMI in the overweight and obesity range leading to a greater risk of mortality (4). Obesity is also a risk factor for many noncommunicable diseases (NCDs), including cardiovascular diseases (CVDs), type 2 diabetes and certain types of cancer. NCDs are the leading causes of death globally and were responsible for an estimated 41 million (71%) of the 55 million deaths in 2019 (5). Obesity and certain NCDs also increase the likelihood of becoming severely ill from COVID-19 infection (6)(7)(8)(9)(10).
A high level of free sugars intake is associated with poor dietary quality (11), obesity (12) and risk of NCDs (13), and the World Health Organization (WHO) has issued guidance on limiting free sugars intake to reduce the risk of unhealthy weight gain and dental caries (14). Since the release of the WHO guideline on free sugars intake, interest in the potential utility of non-sugar sweeteners (NSS) 1 to reduce sugars intake at the population level has increased.
Referred to by a variety of names, including high-intensity sweeteners, low-or no-calorie sweeteners, non-nutritive sweeteners, non-caloric sweeteners and sugar-substitutes, NSS have been developed as an alternative to free sugars. They are widely used as an additive in pre-packaged foods, beverages and personal care products (e.g. toothpaste, mouthwash), as well as added to foods and beverages directly by the consumer. Because of their ability to impart sweet taste without calories, NSS are generally marketed as aiding weight loss or maintenance of healthy weight. They are incorporated into prepared and packaged foods and beverages in a number of ways, including individually, in combinations of different NSS or in combination with free sugars (15). NSS are also frequently recommended as a means of controlling blood glucose levels in individuals with diabetes. NSS include a wide variety of synthetically derived chemicals and natural extracts that may or may not be chemically modified, and are generally many times sweeter than sugars, which allows them to be added to foods and beverages in very small quantities. Common NSS include acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, sucralose, stevia and stevia derivatives; certain D-amino acids, and several plant proteins and other extracts also impart a sweet taste.
NSS elicit sweet taste through binding and activation of sweet-taste receptors located in the oral cavity, with subsequent signalling to the brain (16). Sweet-taste receptors have more recently been found at sites outside the oral cavity, including the gastrointestinal tract, pancreas, brain and adipose tissue (17), and may be involved in various metabolic effects of NSS observed in a large body of in vitro, animal and human studies (18)(19)(20)(21)(22).
Individual NSS undergo toxicological assessment by various authoritative bodies, such as the Joint Food and Agriculture Organization of the United Nations (FAO)/WHO Expert Committee on Food Additives (JECFA), to establish safe levels of intake (i.e. acceptable daily intake, or ADI). Although results of randomized controlled trials (RCTs) have generally suggested that NSS may have limited impact on glucose metabolism and result in lower body weight (when coupled with energy restriction) in the short term, there is no clear consensus on whether NSS are effective for long-term weight loss or maintenance, or if they are linked to other longterm health effects at intakes within the ADI. In addition, although individual NSS interact with the same sweet-taste receptor to elicit sweet taste and likely result in the same physiological effects to some extent, they are not a homogeneous class of compounds: each has a unique chemical structure, which is reflected in different sweetness intensities, organoleptic properties and routes of processing by the body (15). As a result of these differences, individual NSS may have different physiological effects in humans (19).
Global trends in NSS use are unclear because NSS have yet to appreciably enter some markets, and robust longitudinal intake data are not readily available for many low-and middle-income countries (LMICs) (23,24). Nevertheless, available data indicate that the number of foods and beverages containing NSS and NSS use are significant in diverse settings worldwide (23)(24)(25)(26)(27)(28). Although intake rarely appears to exceed the ADI (29), NSS availability and use (predominantly in the form of consumption of beverages containing NSS) appear to be increasing in many locations -for example, in New Zealand, Norway, Slovenia and the United States of America (the United States) (30)(31)(32)(33)(34). This corresponds with a decline in consumption of sugar-sweetened beverages -for example, in the United States and Norway (31,33). Evidence suggests that the shift from free sugars to NSS occurring in the United States and elsewhere may also be occurring in other countries as global efforts to reduce the intake of free sugars intensify, particularly in settings that are implementing multiple policy actions to reduce free sugars intake (23).
Following  (14). The recommendation in this guideline is intended for the general population of children and adults, including pregnant women. The guidance in this guideline is based on evidence of health effects of NSS use at levels already considered safe by JECFA) 1 and is not intended to update or replace existing guidance on safe or maximal levels of intake. Safe levels of intake are based on toxicological assessments of individual NSS, which are undertaken by authoritative bodies before individual NSS are approved for commercial use. 2 Because the work of the Nutrition Guidance Expert Advisory Group (NUGAG) Subgroup on Diet and Health is focused on providing guidance on the prevention of unhealthy weight gain and diet-related NCDs, providing guidance on the management of diabetes in individuals with pre-existing diabetes is beyond the scope of this guideline.
The objective of this guideline is to provide evidence-informed guidance on the use of NSS. The recommendation in this guideline can be used by policy-makers and programme managers to address NSS use in their populations through a range of policy actions and public health interventions.
The WHO recommendation on NSS use is an important element of WHO's efforts in implementing the NCD agenda and achieving the "triple billion" targets set by the 13th General Programme of Work (2019-2023), including 1 billion more people enjoying better health and well-being. In addition, the recommendation and other elements of this guideline will support:

# Target audience
This guideline is intended for a wide audience involved in the development, design and implementation of policies and programmes in nutrition and public health. The end users for this guideline are thus:
 policy-makers at the national, local and other levels;
 managers and implementers of programmes relating to nutrition and NCD prevention;
 nongovernmental and other organizations, including professional societies, involved in managing and implementing programmes relating to nutrition and NCD prevention;

# Guideline development group

# External peer review group
External experts with diverse perspectives and backgrounds relevant to the topic of this guideline were invited to review the draft guideline to identify any factual errors, and comment on the clarity of the language, contextual issues and implications for implementation (Annex 3).

# Systematic review teams
Systematic review teams with expertise in both systematic review methodologies and the subject matter were identified. Teams consulted frequently with the WHO Secretariat to ensure that the reviews met the needs of the WHO guideline development process.

# Stakeholder feedback via public consultation
Two public consultations were held during the development of this guideline: one at the scoping phase of the process in 2016 (feedback was received from a total of 13 individuals and organizational stakeholders) and one on the draft guideline in July 2022 (feedback was received from a total of 45 individuals and organizational stakeholders). Stakeholders and others with an interest in the guideline were invited to provide feedback on overall clarity, any potentially missing information, setting-specific or contextual issues, considerations and implications for adaptation and implementation of the guideline, and additional gaps in the evidence to be addressed by future research. The consultation was open to everyone. Declaration of interest forms were collected from all those submitting comments, which were assessed by the WHO Secretariat, following the procedures for management of interests described in the next section. Comments were summarized, and together with WHO responses to the summary comments, posted on the WHO website. 1 Comments that helped to focus the scope of the guideline or improve clarity and usability of the draft guideline were considered in finalizing the scope and the guideline document.

# Management of conflicts of interest
Financial and intellectual interests of the members of the NUGAG Subgroup on Diet and Health, those serving as external peer reviewers, and individuals who prepared systematic reviews or contributed other analyses were reviewed by members of the WHO Secretariat, in consultation with the WHO Department of Compliance and Risk Management and Ethics, where necessary. Declared interests of members of the NUGAG Subgroup on Diet and Health and of the systematic review teams were reviewed before their original engagement in the guideline development process and before every meeting. In addition, each member of the NUGAG Subgroup on Diet and Health (and members of the systematic review teams, if present) verbally declared their interests, if required, at the start of each meeting of the group. Declared interests of external reviewers were assessed before they were invited to review the draft guideline. In addition to reviewing interests declared by the individuals themselves, an internet search was conducted for each contributor to independently assess financial and intellectual interests for the 4 years before their engagement in the development of the guideline, which was repeated as necessary. The overall procedures for management of interests outlined in the WHO handbook for guideline development (37) were followed.
Interests declared by members of the NUGAG Subgroup on Diet and Health, external reviewers and members of the systematic review teams, and the process for managing any identified conflicts of interest are summarized in Annex 4.

# Guideline development process

# Scoping of the guideline
The scientific literature was reviewed to identify important populations, outcomes and other topics relevant to the health effects of NSS use. Existing systematic reviews on the topic were identified. The information gathered was compiled and used to generate the key questions and outcomes that would guide the selection of existing systematic reviews or the undertaking of new systematic reviews.
Use of non-sugar sweeteners: WHO guideline

# Defining key questions and prioritizing outcomes
The questions were based on the needs of Member States and international partners for policy and programme guidance. The population, intervention, comparison and outcome (PICO) format was used in generating the questions (Annex 5). The PICO questions were first discussed and reviewed by the WHO Secretariat and the NUGAG Subgroup on Diet and Health, and were then made available for public comment in 2016.
The key questions that guided the systematic reviews undertaken are as follows.
 What is the effect on prioritized health outcomes in adults, children and pregnant women of higher intake of NSS compared with lower intake?
 What is the effect on prioritized health outcomes in adults, children and pregnant women of replacing free sugars with NSS?
Priority health outcomes considered for adults were overweight and obesity, dental caries, type 2 diabetes, CVDs, cancer, chronic kidney disease, eating behaviour (including sweet preference) and several cognitive parameters. Priority health outcomes for children were identical to those for adults, but also included asthma and allergies. Biomarkers of type 2 diabetes and CVDs (e.g. fasting glucose, fasting insulin, blood lipids) were implicitly included in the outcomes. Pregnant women were not treated as a separate population in the original scope of the guideline, but rather included in the context of adults. Subsequently, outcomes relevant to pregnancy and childbirth were added to those for adults, including gestational diabetes, birth outcomes, and health outcomes of offspring early in life. Additionally, all-cause mortality was not originally prioritized but was subsequently added based on screening of relevant studies.

# Evidence gathering and review
Two systematic reviews were conducted to assess the relationship between NSS use and health outcomes of interest in adults and children.
 A review of RCTs and observational studies that assessed the effects of NSS use in adults and children. This review, completed in 2019, did not include or assess studies in which NSS were not specified by name or type (38).
 An update of the 2019 review of RCTs and observational studies that assessed the effects of NSS use in adults and children, and included studies in which NSS were not specified by name or type, as well as studies conducted exclusively in pregnant women (39). This review was published in 2022.
Because the 2022 review is the most up to date and comprehensive, it was used in the development of this guideline.

# Assessment of certainty in the evidence
The GRADE 1 methodology was used to assess the certainty (i.e. confidence) in the evidence identified in the systematic reviews. GRADE assessments assigned by the systematic review teams were discussed by the NUGAG Subgroup on Diet and Health and the systematic review teams, and refined as necessary under the guidance of an expert with extensive expertise in GRADE methodology. GRADE assessments are summarized in Annex 6.

# Formulation of the recommendation
In formulating the recommendation and determining its strength, the NUGAG Subgroup on Diet and Health assessed the evidence in the context of the certainty in the evidence, desirable and undesirable effects of the recommended intervention, the priority of the problem that the intervention would address, values and preferences related to the effects of the intervention in different settings, the cost of the options available to public health officials and programme managers in different settings, the feasibility and acceptability of implementing the intervention in different settings, and the potential impact on equity and human rights (Annex 7). Based on the evidence and additional factors, the NUGAG Subgroup on Diet and Health developed the recommendation and associated remarks by consensus.
Summary of evidence

# Systematic review characteristics
A systematic review of RCTs and observational studies that assessed the health effects of NSS use in adults, children and pregnant women identified 283 unique studies, including 50 RCTs, 97 prospective cohort studies and 47 case-control studies (39). 1 Only studies in which NSS were consumed in amounts within the ADI, 2 either because this was explicitly stated in the study or it was reasonably inferred that the ADI was not being exceeded, were included in the systematic review. 3 Because assessing the effects of NSS use in individuals with diabetes was beyond the scope of this guideline, 4 studies specifically assessing the effects on individuals with pre-existing diabetes or including only such individuals were not included in the review. 5
The systematic review included 45 RCTs conducted in adults, four in children, and one including both adults and children. No RCTs in pregnant women were identified.
Trial duration in adults (including follow-up post-intervention) ranged from 7 days to more than 3 years. Trials in adults were conducted in lean (n = 10), mixed weight (n = 20) or exclusively overweight (n = 15) populations.
Thirteen of the trials used an unspecified NSS in their intervention, 12 used aspartame, six used sucralose, three used stevia, one used saccharin, five used a mix of more than one NSS, one used advantame, and four tested multiple NSS separately (saccharin, aspartame, rebaudioside A/stevia, sucralose; sucralose, stevia; aspartame, acesulfame K). Most trials assessed the effects of NSS via consumption of NSS-containing beverages. Trials in adults were conducted in Australia (n = 2), Denmark (n = 2), France (n = 2), Greece (n = 1), the Republic of Korea (n = 4), Iran (Islamic Republic of) (n = 1), Latvia (n = 1), Mexico (n = 6), New Zealand (n = 2), Switzerland (n = 1), Thailand (n = 1), the United Kingdom of Great Britain and Northern Ireland (the United Kingdom) (n = 7), the United States (n = 14) and multiple countries (n = 1).
RCTs in children lasted from 6 weeks to 18 months. Two trials used stevia in the intervention arm, one used a mix of sucralose and acesulfame K, and one used sucralose. One trial in children was conducted in each of the following countries: India, Italy, Netherlands (Kingdom of the) and South Africa.
The single trial conducted in adults and children included a mixed-sex population, with aspartame in the intervention arm, and was conducted in the United States.
Interventions in the trials included:
 dietary advice (with or without the provision of food) to effect behaviour change (e.g. replacing sugar-sweetened foods and/or beverages with foods and/or beverages containing NSS or that were unsweetened);
Use of non-sugar sweeteners: WHO guideline  supplemental foods and beverages containing sugars or NSS (in addition to existing diet);  asking habitual users of NSS to discontinue use; and  providing NSS in capsule form compared with a placebo.
The focus of the trials was not always on assessing the effects of NSS; many had the primary goal of testing the effects of sugars intake and used NSS as a control.

# Prospective cohort studies
The systematic review included 64 prospective cohort studies conducted in adults (representing 35 unique cohorts), 15 cohort studies in children (representing 13 unique cohorts), one cohort study in children and adults (representing one unique cohort) and 17 cohort studies in pregnant women (representing 12 unique cohorts). Of the studies in adults, 47 were of mixed sex, 15 were exclusively female, and 2 were exclusively male. All studies of children were of mixed sex, except one that was exclusively girls. Follow-up in cohort studies in adults ranged from 2 years to more than 30 years, in children from 8 months to 10 years, and in pregnant women from 8 months to 16 years. All but 11 of the cohort studies conducted in adults, one cohort study in pregnant women and all cohort studies in children exclusively assessed associations between NSScontaining beverages and health outcomes. The remaining cohort studies mostly assessed associations between NSS-containing beverages and foods together. Cohort studies in adults were conducted in Australia (n = 3), France (n = 4), Japan (n = 1), Mexico (n = 1), the Russian Federation (n = 1), Spain (n = 4), the United Kingdom (n = 1), the United States (n = 44) and multiple countries (n = 5). Cohort studies in children were conducted in Australia (n = 1), Denmark (n = 1), the United Kingdom (n = 1) and the United States (n = 12). The cohort study in children and adults was conducted in Australia. Cohort studies in pregnant women were conducted in Canada (n = 1), Denmark (n = 6), Germany (n = 1), Iceland (n = 1), Netherlands (Kingdom of the) (n = 1), Norway (n = 2), Slovenia (n = 1), the United Kingdom (n = 1) and the United States (n = 3).

# Case-control studies
The systematic review included 41 case-control studies (42 datasets) assessing cancer outcomes in adults. All case-control studies were conducted in populations of mixed weight. Two were conducted exclusively in males, three exclusively in females and the rest in mixed-sex populations. Twenty-two studies assessed unspecified sweeteners, 11 multiple sweeteners, seven saccharin and two aspartame. Studies were conducted in Argentina (n = 2), Canada (n = 4), Denmark (n = 3), Egypt (n = 1), France (n = 2), Italy (n = 2), Japan (n = 2), Lebanon (n = 1), China (n = 2), Serbia (n = 1), Spain (n = 1), Sweden (n = 2), the United Kingdom (n = 2), the United States (n = 15) and multiple countries (n = 1). Two studies conducted in the United States assessing cancer in children were also included. 1

# Results of systematic review
Results for adults are summarized in Table 1.

# Body fatness
Systematic review and meta-analyses of RCTs found that, at the end of the trials, those consuming more NSS had lower body weight than those consuming less or no NSS (-0.71 kg) and lower BMI (-0.14 kg/m 2, although the latter was not statistically significant. In contrast, higher intakes of NSS 2 were associated with a higher BMI (0.14 kg/m 2 and a 76% increase in risk of incident obesity, as assessed by meta-analyses of prospective cohort studies. Results of subgroup analyses of RCTs suggest that the effect of NSS on body weight and BMI may differ by comparator. Adding NSS to the diet compared with nothing (or placebo) and adding NSS to the diet compared with sugars (either NSS replacing sugars or both NSS and sugars being added to the diet in separate arms of a trial) both resulted in decreases in body weight and BMI, with the largest effects when NSS were compared with sugars. However, NSS compared with water showed no effect on body weight and a non-significant increase in BMI. When RCTs were limited to those that gave explicit instructions to habitual consumers of sugar-sweetened beverages or sugar-containing foods to replace these foods and beverages with alternatives sweetened with NSS, the effect on body weight remained but was slightly attenuated and became statistically non-significant (mean difference  -0.61 kg; 95% confidence interval : -1.28 to 0.06), and an effect on BMI was no longer observed (MD -0.01 kg/m 2 ; 95% CI: -0.38 to 0.35). The results of subgroup analyses also suggest that the effects observed on body weight may be greater in overweight or obese individuals and in those actively trying to lose weight -that is, trials in which weight loss was a primary aim and participants were instructed to both use NSS and reduce energy intake. However, results were not statistically significant, and the differences were small in the comparison by body weight status and highly heterogeneous in the comparison by weight loss status.
Results from a small number of RCTs and observational studies that could not be meta-analysed were largely consistent with results obtained from the meta-analyses described above.

# NCDs and mortality
Meta-analyses of prospective cohort studies showed that higher intakes of NSS were associated with a 23% increase in risk of type 2 diabetes when consumed in NSS-sweetened beverages and a 34% increase in risk when consumed as a tabletop item (i.e. added to foods and beverages by the consumer), as well as a 21% increase in risk of elevated fasting glucose. Results from meta-analyses of RCTs suggested no significant effect of NSS on biomarkers used in the assessment and diagnosis of diabetes and insulin resistance, including fasting glucose, fasting insulin and haemoglobin A1c (HbA1c). The majority of several RCTs that could not be included in the meta-analyses also reported no significant effect of NSS on biomarkers relevant to diabetes.
Higher intakes of NSS were also associated with a 32% increased risk of CVDs, including stroke (19% increase) and its precursor hypertension (13% increase), but not with coronary heart disease, cancer diagnoses or chronic kidney disease, as assessed by meta-analyses of prospective cohort studies. Results from RCTs suggested no significant effect of NSS on biomarkers used in the assessment and diagnosis of CVDs, including blood pressure, low-density lipoprotein (LDL) cholesterol and other blood lipids. Higher intakes of NSS (primarily saccharin) were associated with increased risk of bladder cancer as assessed in case-control studies, but were not associated with overall risk of cancer as assessed by meta-analysis of prospective cohort studies. Higher intakes of NSS were associated with a 10% increase in risk of death from any cause (i.e. all-cause mortality) and a 19% increase in risk of death from CVDs, but were not associated with death from cancer.

# Eating behaviour
Results from meta-analyses of RCTs found that, at the end of the trials, those consuming NSS had significantly reduced daily energy intake (-569 kJ) and daily sugars intake (-38.4 g). In subgroup analyses, a reduction in energy intake was only observed when NSS were compared with sugars; energy intake was not reduced when NSS were compared with placebo or water.
The overall certainty in the available evidence for an effect of NSS intake on outcomes in adults was assessed as low. 1 GRADE assessments for each outcome can be found in Annex 6, GRADE evidence profiles 1 and 2.
Evidence for health effects of NSS use in children was much more limited than that identified for adults.
One well-conducted RCT reported small but significant reductions in several measures of body fatness. However, results of meta-analyses of RCTs and prospective cohort studies found no significant relationships between NSS use and measures of body fatness, including risk of being overweight (Table 2).
Additionally, although two RCTs found that use of stevia reduced indicators of dental caries, the interventions varied greatly: one trial assessed effects of stevia-containing snacks, the other the effects of a stevia mouth 1 Based on the grades of evidence set by the GRADE Working Group. High certainty means that we are very confident that the true effect lies close to that of the estimate of the effect; moderate certainty means that we are moderately confident in the effect estimate -the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; low certainty means that our confidence in the effect estimate is limited -the true effect may be substantially different from the estimate of the effect; and very low certainty means that we have very little confidence in the effect estimate -the true effect is likely to be substantially different from the estimate of the effect (37). rinse. No significant relationships were found for other outcomes of interest, including biomarkers used in the assessment and diagnosis of type 2 diabetes, CVDs, cancer, neurocognition, or energy and sugars intake, although the number of studies contributing to the evidence base for these outcomes was limited.

# Summary of evidence
The overall certainty in the available evidence for an effect of NSS intake on outcomes assessed directly in children was assessed as moderate. GRADE assessments for each outcome can be found in Annex 6, GRADE evidence profile 3. In formulating the recommendation, because both adult data and child data were considered for children, the overall certainty in the available evidence across both groups was assessed as low.

# Pregnant women
Evidence for health effects of NSS use in pregnant women was also limited. Higher intakes of NSS were associated with a 25% increase in risk of preterm birth, as assessed by meta-analyses of three prospective cohort studies (odds ratio  1.25; 95% CI: 1.07 to 1.46; 129 009 pregnant women). A dose-response relationship was observed in the two studies that reported a significant association. Additional analyses suggested that the association was primarily for late preterm delivery (34-37 weeks), not early preterm delivery (<32 weeks), and that the observed risk was similar for lean and overweight women.
Results from prospective cohort studies on potential impact of NSS use during pregnancy on birth weight and body weight of offspring later in life were not amenable to meta-analyses and were inconsistent. Results from two prospective cohort studies suggested no association between NSS use during pregnancy and birth weight, whereas results from a third suggested an increase in birth weight. In addition, results from two separate prospective cohort studies suggested an association between NSS use during pregnancy and increased body fatness in offspring in early or mid-childhood, whereas results from a third suggested no association.
Results for other outcomes were generally limited to single studies. Results from one prospective cohort study suggested an association between NSS use during pregnancy and increased risk of asthma and allergies in offspring in early and mid-childhood, and results from another suggested an association between NSS use during pregnancy and early and mid-childhood cognition scores. No associations were observed between NSS use and risk of gestational diabetes.
The certainty in the available evidence for an effect of NSS intake on outcomes in pregnant women was assessed as very low overall. GRADE assessments for each outcome can be found in Annex 6, GRADE evidence profile 4. In formulating the recommendation, because both adult data and data from pregnant women were considered for pregnant women, the certainty in the available evidence across both groups was assessed as low.

# Interpreting the evidence
Several observations were made in interpreting the results of the systematic review, some based directly on data from the review, and others supported by background questions and information that helps to establish the context for the recommendation (37). They are summarized below.

# Varied interventions in RCTs.
The design of the interventions in RCTs included in the systematic review varied considerably, which reduced confidence that the overall results observed were highly relevant for the primary, intended purpose of NSS, which is to replace free sugars in the diet, particularly in the diet of individuals habituated to high levels of sweetness. Most trials provided NSS or free sugars (in beverage form) as an addition to the regular diet, often to assess whether individuals compensated energy intake when provided with additional free sugars, with NSS serving as a control. Although such studies can assess whether adding NSS to the diet affects energy intake or other relevant outcomes compared with adding free sugars, they do not assess the behavioural component of switching from free sugars to NSS, and thus are an indirect measure of the effects of replacing free sugars with NSS. Only four trials specifically assessed the effects on habitual consumers of sugar-sweetened beverages of replacing these beverages with NSSsweetened alternatives, and while effects on body weight remained, an effect on BMI was no longer observed. In the three studies that also assessed water as a replacement in a separate arm, water was found to be as effective as, or more effective than, NSS-sweetened beverages with respect to lowering body weight. In addition to these trials, a small number of trials provided NSS with water or nothing (placebo)
as the comparator (with or without accompanying instructions to restrict energy intake), provided NSS in capsule form, or assessed the effects of asking habitual consumers of NSS-sweetened beverages to switch to water. Therefore, although it was possible to compare how individuals responded to NSS compared with free sugars across a fairly large number of trials, the evidence for effects of specifically replacing free sugars with NSS is somewhat limited.

# Potential mechanisms of NSS action on body weight. The wide variety of interventions in the included
RCTs did allow assessment of the effects of NSS regardless of potential mechanism of action -that is, whether the effects observed for NSS use were a result of inherent pharmacological properties of NSS or changes in behaviour, such as modifying energy intake. Additional subgroup analyses allowed further assessment of effects of NSS by delivery mode, comparator, type of NSS and other parameters. Results of these analyses showed that a significant difference in body weight and BMI was only observed in trials that reported a reduction in energy intake, and energy intake was only significantly different in the arms of trials that compared NSS with free sugars. This suggests that the lower body weight and BMI observed in the RCTs is mediated at least in part by lower energy intake as a result of decreased free sugars intake, rather than primarily by an inherent property of NSS that can modulate body weight (independently of energy intake).

# Duration of RCTs.
Because weight loss or maintenance of a healthy weight must be sustained over the long term 1 in order to realize associated health benefits, any intervention being investigated for effects on body weight should provide evidence of sustained weight loss or maintenance. The majority of RCTs assessing NSS lasted 3 months or less, and the small number that lasted more than 3 months gave inconsistent results.
Of these, only one trial lasted longer than 18 months (40). However, this trial mainly assessed the outcome of asking habitual users of NSS to stop using NSS, and therefore did not directly assess the effects of replacing free sugars with NSS. In addition, both individuals who were instructed to continue using NSS and those who were instructed not to use NSS lost an equivalent amount of weight during the active weight loss phase of the trial (first 16 weeks). Only during the subsequent weight maintenance and follow-up phases did those not using NSS regain more weight, although, at 1 year after the weight loss phase, energy intakes were equivalent between the two groups and, at 3 years, the difference in aspartame intakes between the two groups narrowed considerably (although less than 50% of the original participants provided data).
Because results from the longer-term trials were inconsistent and difficult to interpret, and evidence from long-term observational studies suggested increased BMI and risk of obesity with NSS use, the NUGAG Subgroup on Diet and Health did not consider the observed weight loss in RCTs -driven primarily by trials lasting 3 months or less -to be indicative of health benefit.

# Possible differences in manner of NSS use between RCTs and prospective cohort studies.
The manner in which individuals consumed NSS and free sugars in the RCTs was carefully planned and controlled. In many trials, participants were provided with foods and beverages to be consumed according to a schedule, and otherwise were given explicit instructions on what to do. In some trials, participants also received additional or follow-up support from those conducting the trials (e.g. nutrition guidance, further instruction). Participants understood that they were taking part in a scientific study and generally, but not always, knew which intervention they were receiving (i.e. whether they were consuming NSS, free sugars, water, something else or nothing), although the actual aims of many of the trials were purposefully obscured so as to not influence the participants. The manner in which individuals consume NSS in the "real world" likely differs significantly from how they were consumed in the trials and is more accurately reflected in the prospective cohort studies. In free-living populations, NSS are likely consumed in complex ways (41)(42)(43)(44), often not as a conscious replacement for free sugars, but together with foods and beverages containing free sugars, or in a compensatory manner in which a food or beverage containing NSS is consumed so that another, often energy-dense, food can be consumed. Some may add foods and beverages containing NSS to existing diets with the general belief that NSS-containing foods are simply "healthier" (45). Rather than consuming fewer calories, as observed in many of the RCTs included in the systematic review, some evidence suggests that those using NSS in free-living populations may consume more calories than those who do not use NSS (43). There is also limited evidence to suggest that health effects may differ when certain NSS are consumed together with sugars compared with when they are consumed alone (46,47), though more research is needed to understand whether this is broadly applicable and what the implications may be.
Therefore, although NSS use has been shown to lower body weight in RCTs when a reduction in energy intake is achieved, the applicability of these results to free-living populations in which NSS are likely consumed in a number of different ways is uncertain.

# Potential role of reverse causation in the results from prospective cohort studies.
Reverse causation was noted as a possible explanatory factor for the associations observed between NSS and health outcomes in the observational studies included in the systematic review. Reverse causation suggests that those already at elevated risk of disease initiated or increased use of NSS because of their risk status, rather than NSS leading to increased risk in otherwise healthy or low-risk individuals. In some studies, those using NSS had a higher prevalence of relevant risk factors. Pre-existing overweight and obesity -risk factors for many of the outcomes for which associations were observed -was also noted as an important potential confounder and in several studies included in the systematic review, those with higher intakes of NSS had higher average BMI at baseline.
Most authors of the included studies appreciated the potential role of reverse causation and/or confounding by body weight, and made efforts to minimize the contribution these factors may have made to the results of their studies, including:
 controlling for relevant confounders (including BMI);
 stratifying results by body weight; and  conducting various sensitivity analyses, such as limiting analyses to individuals of normal body weight, removing from analyses those at risk for disease at baseline or who had intentionally lost weight prior to baseline, and excluding results from the first several years of follow-up to minimize the contribution to relevant health outcomes by individuals at high risk of disease at baseline who were subsequently diagnosed with the disease or experienced a relevant event shortly thereafter.
The impact of the various sensitivity analyses on results varied: some results were attenuated, some were strengthened, some were only observed at highest intakes, some remained when analyses were restricted to individuals of healthy weight, and some were more or less pronounced in overweight or obese individuals. However, in the majority of studies, particularly for type 2 diabetes, associations persisted in some way in fully adjusted models after sensitivity and other exploratory analyses. Since associations largely persist when body weight is controlled for, and there is limited evidence for an effect of NSS on incident obesity (48,49), it is possible that increased body weight (resulting from chronic NSS use) may be an intermediary step in the development of disease rather than a confounding factor.
Overall dietary quality has also been cited as a potential confounder. However, there was no consistent difference between levels of NSS use and diet quality at baseline in the studies included in the systematic review (i.e. diet quality was not consistently lower, higher or equivalent in individuals using more NSS compared with those using less), and many studies controlled for dietary quality without a significant impact on the observed associations.
It was concluded that, although reverse causation and residual confounding may be contributing factors, the available evidence suggests that the associations observed between NSS use and health outcomes in observational studies cannot be dismissed as being solely a result of reverse causation or residual confounding.

# Sources of NSS exposure in studies.
Most RTCs included in the systematic review assessed the effects of NSS-containing beverages. Associations observed between NSS use and priority health outcomes in prospective cohort studies of adults, children and pregnant women were also almost exclusively based on consumption of NSS-containing beverages. A small number of studies assessed the effects of tabletop NSS use (i.e. NSS added to foods or beverages by the consumer), consumption of NSS-containing foods, or some combination of beverage, food and tabletop sources. As described elsewhere in this section, the underlying mechanisms for the observed associations -particularly in observational studies -are unclear, are likely complex, and may or may not be modulated by whether NSS are primarily consumed in foods or beverages. Therefore, although most of the evidence is based on consumption of NSS-containing beverages, it was considered appropriate to evaluate the evidence with a focus on the exposure to NSS regardless of how it was consumed, and formulate recommendations accordingly.

# Potential mechanisms for associations with cardiometabolic health in prospective cohort studies.
Putative mechanisms have been proposed that may help to explain the associations observed between NSS use and increased risk of poor cardiometabolic health, some of which may be attributed to the expression of sweet taste receptors outside the oral cavity, including in glucose-sensing cells of tissues such as the gastrointestinal tract and pancreas (17). A detailed discussion of the proposed mechanisms (and the data compiled in exploring these mechanisms) is beyond the scope of this guideline, and this topic has been reviewed extensively elsewhere (18)(19)(20)(21)(22). In brief, potential mechanisms include effects on taste perception (e.g. sweet taste preference, thresholds of sweet-taste sensitivity), eating behaviour (e.g. hunger, appetite) and other neural responses (e.g. hedonic response to sweet taste, memory and reward pathways in the brain); pathways that link the sensing of sweet taste in the oral cavity with the expectation of subsequent energy delivery to the digestive tract; release of metabolic hormones and other biological molecules; and alterations to the bacteria colonizing the small and large intestines (i.e. gut microbiota). Proposed mechanisms are not mutually exclusive and may ultimately differ between individual NSS.
Much of the research into biological mechanisms has been carried out in in vitro and rodent models, and further research is needed to determine whether observations in non-human models translate to humans. Although there are as yet no conclusive mechanistic links between NSS use and many of the associations observed in prospective cohort studies, that plausible mechanisms have been identified, tested and in some cases validated (albeit mostly in non-human models) reinforces the seriousness with which the associations observed in prospective cohort studies should be considered and highlights the need for further exploration of possible mechanisms with additional research.

# Individual versus "class" effects of NSS.
Although different NSS interact with the same sweet-taste receptor to elicit sweet taste and likely result in shared physiological effects to some extent, they are not a homogeneous class of compounds: each has a unique chemical structure, which is reflected in different sweetness intensities, organoleptic properties and routes of processing by the body (15). As a result of these differences, individual NSS may have different physiological effects in humans (19). However, further research is necessary to allow for definitive conclusions.

# Sources of potential differences in effects of NSS use.
Evidence from studies included in the systematic review and elsewhere suggests that there may be important differences in the response to NSS based on sex, ethnicity and body weight status. Although evidence is currently insufficient to reach any firm conclusions regarding such differences, they may be an important consideration when assessing future evidence and should be explored further with appropriately designed studies. In addition, some outcomes (e.g. those assessing glucose metabolism) commonly assessed in RCTs of NSS use may be influenced by history of NSS use of participants at enrolment -that is, regular users of NSS may already be affected by, or desensitized to, the effects of NSS compared with non-users or infrequent users; this may explain some of the differences observed in such studies. Similarly, patterns of NSS use prior to baseline exposure assessment in prospective cohort studies may affect results. Therefore, additional research is needed to further explore the potential moderating effect of prior NSS consumption patterns on empirically obtained data.

# Evidence to recommendations
In translating the evidence into recommendations, the NUGAG Subgroup on Diet and Health assessed the evidence in the context of the certainty in the evidence, desirable and undesirable effects of the intervention, priority of the problem that the intervention would address, values and preferences related to the effects of the intervention in different settings, the feasibility and acceptability of implementing the intervention in different settings, the potential impact on equity and human rights, and the cost of the options available to public health officials and programme managers in different settings.
Because the recommended "intervention" in this guideline is a suggestion to not include NSS in the diet, it can be viewed as a dietary goal, rather than a specific intervention, and can therefore be translated into policies and actions in a number of ways. These include various behaviour change interventions, fiscal policies, regulation of the marketing of foods and beverages, product labelling schemes, and reformulation of manufactured products, among others. Because each of these interventions has its own evidence base (which was not reviewed by the NUGAG Subgroup on Diet and Health) and requires individual consideration of the additional evidence to recommendation factors, a detailed discussion of these factors for each of the possible means of achieving the recommendation is beyond the scope of this guideline. However, forthcoming WHO guidelines will provide specific guidance on nutrition labelling policies, policies to restrict the marketing of food and non-alcoholic beverages to children, fiscal policies, and school food and nutrition policies, which will enable policy-makers to translate dietary goals into evidence-informed policy actions. 1 Therefore, in assessing the factors relevant to translating the evidence into recommendations for this guideline, the NUGAG Subgroup on Diet and Health primarily considered each in the context of achieving the recommended dietary goal.
Evidence for this process was gathered via comprehensive searches of relevant scientific databases and identification of high-quality studies, including recent systematic reviews, where available. An evidence to recommendations table can be found in Annex 7.

# Overall certainty in the evidence
The overall certainty in the evidence was as assessed as low and is based on undesirable effects of NSS use on prioritized health outcomes observed in prospective cohort studies, which were individually assessed as having very low to low certainty of evidence.

# Balance of desirable and undesirable effects
Although short-term benefit of NSS use on measures of body fatness was observed in controlled experimental settings, the NUGAG Subgroup on Diet and Health concluded that the lack of evidence to suggest that NSS use is beneficial for body weight and other measures of body fatness over the long term together with possible long-term adverse effects in the form of increased risk of death and disease, offset any potential short-term health benefit resulting from the relatively small reduction in body weight and BMI observed in randomized controlled trials. In addition, limited evidence for beneficial effects of NSS use on dental caries was observed in studies of children. However, this was generally only observed in studies where intake of NSS was compared with intake of free sugars, suggesting that NSS do not have any inherent properties that impact risk of dental caries; rather, the effect is a result of displacing free sugars.
In the case of NSS, the potential undesirable effects carry a greater weight when assessing desirable vs undesirable effects because a reduction in free sugars intake can be achieved and corresponding desirable health benefits realized without the use of NSS. In addition, unlike the potential effects observed from longterm exposure in adults, the evidence from prospective studies of pregnant women suggests that potential adverse effects from NSS use occur over the relatively short period of gestation.
Evidence from RCTs suggests that the effects of NSS in these studies primarily occur via a reduction in energy intake. Therefore, any potential benefit of NSS use would largely be for those who are trying to lose or maintain body weight via restriction of energy intake (resulting from replacing free sugars with NSS). NSS use may not produce desirable effects for those who are not regular consumers of free sugars or who are otherwise not at risk of excess energy intake resulting from free sugars intake. This segment of the general population would therefore likely only be subjected to the potential undesirable effects of NSS use.
NSS are not essential dietary components and provide no nutritional value themselves, and are frequently a component of highly processed foods. Therefore, a possible undesirable effect of NSS use in the context of reducing free sugars intake is the inclusion of a greater number of highly processed foods and beverages in the diet than would be included if free sugars were reduced without NSS use (50).
The recommendation to not use NSS could result in potential undesirable effects, not inherent to NSS, if some individuals currently using NSS discontinue use and increase free sugars intake in order to maintain the level of sweetness in their diet. However, the undesirable effects of free sugars intake are well documented, and awareness of these effects among the general public is fairly high. Together with the fact that the recommendation in this guideline should be considered in the context of the WHO recommendations to reduce free sugars intake ( 14), this suggests that individuals switching from NSS to free sugars would not be a widespread occurrence.
Overall, the NUGAG Subgroup on Diet and Health concluded that the desirable effects of not using NSS outweighed the undesirable effects.

# Priority of the problem, and values and preferences
Although NSS as a replacement for free sugars is generally discussed in the context of their potential impact on overweight and obesity, the evidence reviewed for the development of this guideline suggests that NSS use may also be relevant to other important health outcomes, including type 2 diabetes, CVDs and mortality, impacts on which may partly be mediated by changes in body weight.
Escalating rates of obesity threaten the health and lives of hundreds of millions individuals worldwide (3,4), and NCDs are the leading causes of death globally (5). Therefore, interventions and programmes targeting reduction in risk of these outcomes are valuable in all contexts and a high priority for many countries. Despite the global burden of these outcomes, the priority placed on this problem by authorities at different levels may vary depending on the real or perceived magnitude of the problem within a particular country or region. The spotlight on prevention and management of obesity has intensified recently as a result of the COVID-19 pandemic, as there is increasing recognition that individuals with certain NCDs or obesity may be at increased risk of adverse outcomes associated with COVID-19 (6)(7)(8)(9)(10).
The recommendation in this guideline places a high value on reducing the risk of mortality, overweight, obesity and NCDs. Although individuals almost universally value the prevention of premature mortality, those that may be impacted by the recommendation may place different values on the benefit of reducing the risk of obesity and associated disease, based on personal preferences, beliefs and customs. For example, because CVDs are a high-profile public health topic, including in many LMICs where they represent a growing threat (51), it is expected that most individuals would value efforts to reduce risk. However, in real-world settings, perception of the risk varies considerably (52)(53)(54)(55)(56), and outreach and communication efforts may therefore be needed to improve understanding. Similarly, although many people in LMICs are increasingly aware of negative health effects associated with being overweight or obese, some cultures still consider overweight to be a desirable or positive attribute (57)(58)(59). Others believe body weight to be hereditary and therefore not amenable to management via lifestyle changes (56,60). And many, regardless of personal beliefs, incorrectly perceive their own body weight in the context of overweight and obesity -that is, they believe that they are at a healthy body weight when in fact they are overweight or obese according to accepted standards for assessing body weight outcomes (56,60,61).
Evidence to recommendations
Use of non-sugar sweeteners: WHO guideline
The recommendation in this guideline can be implemented in numerous ways, including through behaviour change interventions, fiscal policies, regulation of marketing of foods and beverages, product labelling schemes, and reformulation of manufactured products. Feasibility of these interventions will depend on the country context. Regardless of specific modes of implementation, the recommendation can be incorporated into existing measures designed to promote healthy diets and would naturally complement existing efforts to reduce intake of free sugars. For example, appropriate messaging on NSS use can readily be added to existing food-based dietary guidelines and the increasing number of actions being taken to address free sugars intake, such as behaviour change and education campaigns, fiscal policies, marketing and labelling policies, and reformulation. A number of countries and municipalities already include beverages sweetened with NSS in existing food and beverage tax legislation (62), and several national food-based dietary guidelines already provide guidance on NSS use (63). This suggests that implementing the recommendation to not use NSS is feasible, particularly in settings that already have robust dietary guidelines and established health messaging infrastructure. However, existing efforts to reduce free sugars intake also have the potential to make implementation of the NSS recommendation more challenging: recent evidence suggests that sales of NSS-containing beverages (but not NSS-containing foods) are increasing in regions that have implemented multiple policy actions targeting free sugars intake, relative to regions that have implemented fewer or no actions (23). Because NSS, and foods and beverages containing NSS are already widely available and used by large segments of the global population, implementing the recommendation will have its challenges, particularly in settings without robust infrastructure for implementing public health measures, including behaviour change communications and messaging, or where "piggy backing" on efforts to address free sugars intake is not possible.
Regardless of which interventions and policy actions are used to implement the recommendation, some amount of behaviour change at the individual level will likely be required; the extent to which this can be achieved will depend on the willingness of individuals who have become habituated to a certain level of sweetness in foods and beverages to reduce the overall sweetness in their diets. For those not habituated to high levels of sweetness in the diet (including infants and young children), avoiding NSS (and excess free sugars) -particularly in beverage form -should be very feasible. However, as noted below, because of the way in which NSS-containing foods and beverages are labelled, avoiding NSS may require vigilance on the part of consumers.
The level to which NSS use can be reduced will depend not only on the success of public health efforts and individual choice, but the extent to which consumers are aware of the NSS content in products they purchase. Evidence suggests that some consumers may not be aware that many of the food and beverages they are purchasing contain NSS (45,64), and generally may have difficulties interpreting nutrient declaration labels, health claims and other relevant labelling (65)(66)(67)(68)(69).
Although the recommendation in this guideline is already in line with existing national guidance in a number of countries, acceptability may vary across different countries, and socioeconomic and cultural contexts.
Acceptability may be influenced by:
 how the recommendation is translated into policies and actions -some means of implementation may be more acceptable than others;
 the level of awareness of the potential health problems associated with NSS use -interventions may be less acceptable in settings where awareness is low;
 the potential impact on national economies; and  compatibility with existing policies.
At an individual level, because adhering to the recommendation to not use NSS together with WHO recommendations to reduce free sugars might require a reduction in the overall sweetness of the diet, acceptability of the recommendation may be low, particularly for those accustomed to sweetness in certain types of food and beverages. Popular perceptions about NSS may also feed into acceptability to consumers. These encompass both positive and negative feelings about sweeteners, which might be affected by whether sweeteners are categorized and marketed as "artificial" or "natural". However, for those who acknowledge the potential health risks of consuming NSS over the long term and value reducing this risk, acceptability should be high, because obesity, CVDs and type 2 diabetes are significant, recognized global health problems.
Acceptability of this recommendation can be improved through appropriate public health measures, including behaviour change communication and messaging. This should encompass not only NSS use and free sugars intake, but more broadly an overall healthy diet, including the message that whole fruits can provide a healthy source of sweetness in the diet, along with beneficial nutrients.

# Equity and human rights
The impact of the recommendation on equity and human rights is not conclusively known, given the uncertainty around long-term health effects of NSS use. Assuming that the long-term associations between NSS use and increased risk of unhealthy weight gain and NCDs are valid, the recommendation in this guideline has the potential to reduce health inequity by improving the long-term health of people of lower socioeconomic status, as they are generally disproportionately affected by overweight, obesity and NCDs (70)(71)(72)(73). However, in some LMIC settings, people of higher socioeconomic status may be more at risk than those of lower socioeconomic status and may benefit more from relevant interventions (74,75). Regardless, the effect on equity and human rights would likely be affected by how the recommendation is translated into policies and actions. For example, a small number of studies suggest that fiscal policies targeting foods and beverages, front-of-pack labelling and restrictions on marketing unhealthy foods may increase health equity (76). However, if such measures affect all individuals in a population equally, relevant inequalities may not be addressed (77). Overall, evidence is extremely limited and inconclusive.

# Resource implications
Absolute costs of translating the recommendation in this guideline into policy actions and interventions will vary widely depending on which approaches are taken. Costs may be minimized by coupling measures taken with existing efforts to reduce free sugars intake and promote healthy diets. For example, as noted under Feasibility above, it may be possible to incorporate the recommendation into existing policy actions and interventions, such as food-based dietary guidelines and fiscal policies targeting sugar-sweetened beverages, which might limit the resources required to implement the recommendation. Implementation of the recommendation will likely require consumer education and public health communications. These can also be incorporated into existing public health nutrition education campaigns and other existing nutrition programmes at the global, regional, national and subnational levels.
Whether or not implementing the recommendation is cost-effective (i.e. the savings in health-care costs offset or exceed the cost of implementation) is not conclusively known, given the uncertainty of longterm health effects of NSS use. However, assuming that the long-term associations between NSS use and increased risk of unhealthy weight gain and NCDs are valid, implementing the recommendation may be associated with long-term savings in costs of health care, though the extent of the savings depends on strategies chosen for implementation and the timescale for evaluation. For example, although very few (if any) cost-effectiveness analyses have been conducted for NSS use, a number of cost-effectiveness studies on taxation of sugar-sweetened beverages have been published, with most finding that taxes have the potential to result in substantial cost savings and health impact with respect to obesity and diet-related NCDs (78)(79)(80)(81)(82). Similarly, limited evidence suggests that other policies and interventions that would be relevant to NSS, such as restrictions on marketing of unhealthy foods and beverages to children, may be cost-effective (76).
In general, not using NSS should lead to a decrease in both the purchase of NSS themselves (for use by the consumer) and the purchase of foods and beverages containing NSS. In the case of NSS and certain foods and beverages with no caloric value, further adjustments to the diet would not be needed, and money could be saved by simply forgoing these purchases. Adhering to the recommendation could therefore have a positive or negative impact on disposable income, which might be amplified in people of lower socioeconomic status -particularly in LMICs -as they tend to spend a higher proportion of their income on foods and beverages (83-85).

# Recommendation and supporting information
This recommendation should be considered in the context of WHO recommendations to reduce free sugars intake (14) and other guidance promoting healthy diets, including WHO guidelines on carbohydrates (86), total fat (87), saturated and trans-fatty acids (88), polyunsaturated fatty acids (36), 1 sodium (89) and potassium ( 90). An explanation of the strength of WHO recommendations can be found in Box 1.

# WHO recommendation
WHO suggests that non-sugar sweeteners not be used as a means of achieving weight control or reducing the risk of noncommunicable diseases (conditional recommendation).

# Rationale and remarks
The following provides the reasoning (rationale) behind the formulation of the recommendation, as well as remarks designed to provide context for the recommendation and facilitate its interpretation and implementation.
 The recommendation is based on evidence of low certainty overall, from a systematic review that assessed the health effects of higher compared with lower intake of NSS (39). 2 The systematic review found no evidence of long-term benefit on measures of body fatness in adults or children, and potential undesirable effects from long-term use in the form of increased risk of type 2 diabetes, CVDs and mortality in adults. Limited evidence suggests potential undesirable effects in the form of increased risk of preterm birth with NSS use during pregnancy.
 Specific findings from the systematic review supporting this recommendation are as follows.
Evidence from randomized controlled trials (RCTs) was as follows.
NSS use in any manner 3 resulted in reduced sugars and energy intake, lower body weight and lower BMI in short-term RCTs (all low certainty evidence), the majority of which lasted 3 months or less. NSS use did not significantly affect other measures of body fatness or intermediate markers of cardiometabolic health, including glucose, insulin or blood lipids (very low to moderate certainty evidence). Evidence from a small number of longer-term trials lasting 6-18 months did not suggest an effect on body weight but was difficult to interpret because of many differences in how these trials were conducted and results reported.
When intake of NSS was directly compared with intake of free sugars (i.e. one group in a trial received NSS, and another group received free sugars), those receiving NSS had lower body weight and BMI, similar in magnitude to the results when NSS was used in any manner. However, most of these trials provided foods and beverages containing NSS or free sugars in addition to existing diets and therefore did not directly measure the effects of replacing free sugars with NSS. When NSS were compared with nothing/placebo or water (i.e. one group in a trial received NSS, and another group received nothing/placebo or water), no effects on body weight or BMI were observed.
When NSS were assessed specifically as replacements for free sugars in a small number of RCTs (i.e. habitual consumers of foods or beverages containing free sugars were asked to switch to versions containing NSS in place of free sugars), the effect on body weight was significantly weakened relative to that observed for NSS used in any manner, and an effect on BMI was no longer observed.
Evidence from prospective observational studies, with up to 10 years of follow-up, was as follows.
Higher intakes of NSS were associated with higher BMI and increased risk of incident obesity, but not other measures of body fatness (very low to low certainty evidence).
Higher intakes of NSS were associated with increased risk of type 2 diabetes, CVDs and CVD mortality, and all-cause mortality in long-term prospective observational studies with average follow-up of 13 years (very low to low certainty evidence), but were not associated with differences in overall cancer incidence or mortality (very low certainty evidence).
Use of NSS (predominantly saccharin) was associated with increased risk of bladder cancer as assessed in case-control studies (very low certainty evidence).
One RCT conducted in children reported a reduction in several measures of body fatness when sugarsweetened beverages were replaced with those containing NSS (91) (moderate certainty evidence). However, when results for BMI z-score 1 were combined with those from a second trial (92), no effect was observed (moderate certainty evidence), and results from prospective observational studies did not suggest any significant associations between NSS use and measures of body fatness (very low certainty evidence). All other identified studies reported no significant associations between NSS use and prioritized health outcomes in children.
1 BMI z-scores are adjusted for sex and age relative to standardized reference values.
Recommendation and supporting information

# Box 1. Strength of WHO recommendations
WHO recommendations can either be strong or conditional, based on a number of factors including overall certainty in the supporting scientific evidence, balance of desirable and undesirable consequences, and others as described in the Evidence to recommendations section of the guideline.
Strong recommendations are those recommendations for which the WHO guideline development group is confident that the desirable consequences of implementing the recommendation outweigh the undesirable consequences. Strong recommendations can be adopted as policy in most situations.
Conditional recommendations are those recommendations for which the WHO guideline development group is less certain that the desirable consequences of implementing the recommendation outweigh the undesirable consequences or when the anticipated net benefits are very small. Therefore, substantive discussion amongst policy-makers may be required before a conditional recommendation can be adopted as policy.
The reasoning behind the strength of the recommendation in this guideline is provided in the rationale for the recommendation. Additional information on assessing the strength of WHO recommendations can be found in the WHO handbook for guideline development (54).

# Pregnant women
Meta-analysis of three prospective observational studies found an increased risk of preterm birth with higher NSS use during pregnancy (low certainty evidence), but associations between birth weight or weight of offspring later in life and NSS use during pregnancy were inconsistent (very low certainty evidence). Other individual prospective observational studies reported associations between NSS use during pregnancy and outcomes in offspring, including increased risk of asthma and allergies, and poorer cognitive function (very low certainty evidence). No associations were observed between NSS use and risk of gestational diabetes.
 The lack of evidence for long-term benefit of NSS use on measures of body fatness assessed in RCTs and potential long-term effects of NSS use observed for adults in prospective observational studies were considered to be relevant for women during pregnancy, and were reasonably expected to be relevant for children and adolescents as well. Therefore, in addition to the limited direct evidence for children and pregnant women, the evidence from RCTs and observational studies in adults was extrapolated to children, adolescents and pregnant women without downgrading for indirectness.
 In reviewing the evidence and formulating the recommendation, the NUGAG Subgroup on Diet and Health noted the following.
Because the primary role of NSS use is presumably to reduce free sugars intake (and consequently risk of unhealthy weight gain and disease associated with excess free sugars intake), the currently available evidence on which to base a recommendation on NSS is largely indirect -that is, most RCTs comparing intake of NSS with intake of free sugars did not explicitly assess the replacement of free sugars with NSS.
Because weight loss and maintenance of a healthy weight must be sustained over the long term 1 to have a meaningful impact on health, evidence of minor weight loss or reduced BMI over several months or less, as observed in the RCTs, without additional evidence of long-term impact, does not represent a health benefit.
The discordant results between the RCTs and prospective cohort studies suggest that the small amount of weight loss resulting from NSS use in short-term experimental settings may not be relevant to the effects of long-term NSS use in the general population.
In addition, the NUGAG Subgroup on Diet and Health noted that:
there were no identified undesirable effects or other mitigating factors 2 that would argue against not using NSS;
NSS are not essential dietary factors and have no nutritional value; and use of NSS is not the only way to achieve a reduction in free sugars intake; viable alternatives exist that are compatible with features of a healthy diet including consumption of foods with naturally occurring sugars, such as fruit, and unsweetened foods and beverages.
Based on the evidence and other considerations noted above, the NUGAG Subgroup on Diet and Health concluded that the lack of evidence to suggest that NSS use is beneficial for body weight or other measures of body fatness over the long term, together with possible long-term undesirable effects in the form of increased risk of NCDs and death, outweighed any potential short-term health effects resulting from the small reductions in body weight and BMI observed in RCTs.
 Because of lack of certainty about the overall balance of desirable and undesirable effects associated with long-term NSS use for reducing NCD risk, including the possibility that reverse causation 3 may have contributed to one or more of the associations observed between long-term NSS use and risk of disease in prospective observational studies, a conservative approach was taken, leading to a conditional recommendation.
 With the exception of individuals with diabetes (as noted below), this recommendation is relevant for everyone: children and adults of any age, including pregnant and lactating women.
 The objective of this guideline is to provide guidance on the use of NSS in efforts to prevent unhealthy weight gain and diet-related NCDs, in the context of reducing free sugars intake. Assessing the health effects of NSS on individuals with pre-existing diabetes with the aim of providing guidance on disease management was beyond the scope of the guideline. Consequently, in the evidence reviewed, studies conducted exclusively in individuals with pre-existing diabetes were excluded, and in studies with mixed populations, diabetes was often controlled for as a potential confounding characteristic. Therefore, although individuals with diabetes can also reduce free sugars intake without the need for NSS, the recommendation does not apply to individuals with existing diabetes.
 The recommendation is relevant for all NSS, which are defined in this guideline as all synthetic and naturally occurring or modified non-nutritive sweeteners that are not classified as sugars. Common NSS include acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, sucralose, stevia and stevia derivatives. Because low-calorie sugars and sugar alcohols (polyols) are sugars or sugar derivatives containing calories, they are not considered NSS, and therefore the recommendation does not apply to these sweeteners.
 In this recommendation, "use" of NSS means consumption of foods or beverages that contain NSS, or the addition of NSS to food or beverages by the consumer.
 Many medications, and personal care and hygiene products contain NSS in small amounts to make them more palatable. The recommendation in this guideline does not apply to such products.
 "Weight control" in this recommendation refers to weight loss in cases of existing overweight or obesity, and preventing unhealthy weight gain by maintaining a healthy weight.
 The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has set acceptable daily intakes (ADIs) for most commercially used NSS. Evidence supporting this WHO recommendation comes from a systematic review of studies in which NSS were consumed in amounts within the ADI set by JECFA, either because this was explicitly stated in the study or it was reasonably inferred that the ADI was not being exceeded. 1  The recommendation in this guideline was made based on evidence that suggests that there may be health effects associated with NSS use irrespective of which NSS is being used -that is, NSS as a class of compounds, despite individual NSS having different chemical structures, may have an impact on health. It is recognized that NSS are not a homogeneous class of compounds: each has a unique chemical structure. As a result, individual NSS have different sweetness intensities and organoleptic properties, and are processed differently by the body. Although limited evidence suggests that individual NSS may also differ in some of their physiological effects in humans, the evidence is currently insufficient to make recommendations for individual NSS.
 Efforts to reduce free sugars intake should be implemented in the context of achieving and maintaining a healthy diet. Because free sugars are often found in highly processed foods and beverages with undesirable nutritional profiles, simply replacing free sugars with NSS results means that the overall quality of the diet is largely unaffected. Replacing free sugars in the diet with sources of naturally occurring sweetness, such as fruits, as well as minimally processed unsweetened foods and beverages, will help to improve dietary quality, and should be the preferred alternatives to foods and beverages containing free sugars.

# Uptake of the guideline and future work
The guideline will be disseminated through:
 the WHO e-Library of Evidence for Nutrition Actions (eLENA), 1 which is an online library of evidenceinformed guidance for nutrition interventions that provides policy-makers, programme managers, health workers, partners, stakeholders and other interested actors with access to the latest nutrition guidelines and recommendations, as well as complementary documents, such as systematic reviews, and biological, behavioural and contextual rationales for the effectiveness of nutrition actions;
 relevant nutrition webpages on the WHO website, including a summary of the guideline in all six official WHO languages;
 the electronic mailing lists of the WHO Department of Nutrition and Food Safety, and the UN Standing Committee on Nutrition;
 the network of the six WHO regional offices and country offices; and  the WHO collaborating centres.
The guideline will also be disseminated at various relevant WHO meetings, as well as at global and regional scientific meetings.

# Translation and implementation
The recommendation in this guideline should be considered in conjunction with other WHO guidance on healthy diets -in particular, guidelines relating to free sugars (14), as well as carbohydrates (86), total fat (87), saturated and trans-fatty acids (88), polyunsaturated fatty acids (36), 2 sodium (89) and potassium (90), to guide effective policy actions and intervention programmes to promote healthy diets and nutrition, and prevent unhealthy weight gain and diet-related NCDs.
A detailed discussion of how the recommendation on NSS use might be implemented is beyond the scope of this guideline, however they can be considered by policy-makers and programme managers when discussing possible measures, including:
 monitoring of NSS intake and its use in food and beverage production;
 regulation of marketing of foods and beverages;
 restrictions on the promotion and sales of food and beverages containing NSS in public institutions, including schools;
 fiscal policies targeting foods and beverages that contain NSS;  nutrition labelling;  consumer education; and  translation of the recommendation at the country level into culturally and contextually specific foodbased dietary guidelines that take into account locally available food and dietary customs.
Efforts should be targeted to the general population, with a particular focus on infants and young children who have not yet been directly exposed to foods and beverages containing free sugars and/or NSS, as well as their caregivers, as evidence suggests that early taste exposures shape taste preferences and eating behaviour later in life (93)(94)(95).
Because a significant percentage of NSS consumed globally comes in the form of NSS-sweetened beverages and much of the global effort to reduce the intake of free sugars is focused on sugar-sweetened beverages, messaging about potable water as a preferred replacement for sugar-sweetened beverages and as a mode of hydration generally can be incorporated into public health communications and food-based dietary guidelines. Similar messaging regarding tabletop addition of NSS to beverages can be developed, with a focus on unsweetened beverages.

# Monitoring and evaluation
The impact of this guideline can be evaluated by assessing its adoption and adaptation across countries.
Evaluation at the global level will be through the WHO Global database on the Implementation of Nutrition Action (GINA) 1 -a centralized platform developed by the WHO Department of Nutrition and Food Safety for sharing information on nutrition actions in public health practice implemented around the world. GINA currently contains information on thousands of policies (including laws and legislation), nutrition actions and programmes in more than 190 countries. GINA includes data and information from many sources, including the first and second WHO global nutrition policy reviews conducted in 2010-2011 and 2016-2017, respectively (96,97). By providing programmatic implementation details, specific country adaptations and lessons learned, GINA serves as a platform for monitoring and evaluating how guidelines are being translated into policy actions and intervention programmes to address the issues related to fat intake in various countries.

# Research gaps and future initiatives
Based on the results of the systematic reviews and discussions with the NUGAG Subgroup on Diet and Health, a number of questions and gaps in the current evidence that should be addressed by future research were identified. Further research is needed to achieve a better understanding of:

# Updating the guideline
WHO regularly updates its guidelines and recommendations to reflect the latest scientific and medical knowledge. This guideline will therefore be updated as part of the ongoing efforts of WHO to update existing dietary goals and nutrition guidance for promoting healthy diets, nutrition and the prevention of NCDs.
Because the evidence base for NSS use is rapidly evolving, the literature will be monitored on a regular basis. It is planned that the recommendation in this guideline will be reviewed when new data and information become available that might alter the overall body of evidence such that it would need to be re-evaluated.
The WHO Department of Nutrition and Food Safety, together with partners in other departments within the WHO Secretariat, will be responsible for coordinating the updating of this guideline, following the formal procedure described in the WHO handbook for guideline development (37). At the time the guideline is due for review, WHO will welcome suggestions for additional questions that could be addressed in a potential update of the guideline. Unless otherwise noted, observational studies are prospective cohort studies that assessed outcomes by comparing the highest quantile of intake with the lowest. Some cohort studies assessed outcomes continuously, as noted in the evidence profile.
All studies were conducted in the population of interest (i.e. general adult population). Although most studies were conducted in North America and Europe, and very few were conducted in LMICs, physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweet-tasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless NSS are introduced to these populations. With the exception of LDL cholesterol, blood lipids, glycaemic markers and blood pressure are largely unvalidated intermediate markers of disease and, although informative, are not a surrogate for disease. However, the WHO NUGAG Subgroup on Diet and Health prioritized intermediate markers in the outcomes of interest and, therefore, none of these outcomes were downgraded for indirectness.
3 Funnel plot analyses conducted for outcomes with 10 studies or more. Unless otherwise noted, funnel plot analysis did not suggest significant risk of publication bias.
Based on the event rate in the studies -that is, the number of people with events divided by the total number of people. The absolute effect (per 1000 people) is calculated using the following equation: absolute effect = 1000 . The magnitude of absolute effect in "real world" settings depends on baseline risk, which can vary across different populations.
Critical outcomes in this evidence profile are shown in blue and important outcomes in black, as prioritized by the WHO NUGAG Subgroup on Diet and Health. Outcomes can be assessed as either not important, important or critical for decision-making in the WHO guideline development process (2).
Most RCTs included in the meta-analyses for measures of body fatness were assessed as having unclear risk of bias overall as a result of lack of necessary detail in reporting the methods that were used. Less than half the trials for body weight and slightly more than half for BMI appeared to use appropriate methods of random sequence generation (one or two employed inadequate randomization methods). Less than a quarter of the trials reported adequate allocation concealment for body weight and a third for BMI (except for one trial with inadequate allocation concealment for body weight; details in remaining trials were not reported and thus assessed as unclear). Blinding of participants was only possible in one or two studies; it was not possible in half the remaining trials (studies comparing NSS with water or nothing) and unclear in the other half (NSS compared with sugars, because it is unknown to what extent the participants could taste the difference between foods and beverages sweetened with NSS and those sweetened with sugars). Only a very small number of trials provided sufficient information to enable an assessment regarding blinding of outcome assessment. A little fewer than half the trials did not report significant participant dropout or imbalance in dropout rates across arms, and about half the remaining trials reported significant dropout rates (>15%), which represent a serious concern. However, most trials did not provide sufficient detail regarding reasons for participant dropout, so it is difficult to determine whether attrition might have affected results. Selective reporting of outcomes was clearly evident in only a very small number of trials; of the remaining trials, about half were assessed as having low risk of bias and half unclear risk of bias. No other significant sources of bias were identified. Although most trials appeared to be well conducted, the widespread lack of detail in the reporting of methods creates significant uncertainty regarding risk of bias. Downgraded once as a conservative measure.
8 I 2  50%, indicating a significant level of heterogeneity. Where the number of studies was sufficient to explore heterogeneity via subgroup and sensitivity analyses, results of the analysis did not significantly explain the observed heterogeneity. Downgraded once.
Mean Newcastle-Ottawa Score of >5 with very conservative application of ratings. Not downgraded.
A small mean effect, likely of little to no clinical significance, and neither bound of the 95% CI includes a potentially important benefit or harm. Therefore, considered a sufficiently precise estimate of no effect. Not downgraded.
Mean Newcastle-Ottawa Score of 5 with very conservative application of ratings. Downgraded once.
12 One bound of the 95% CI includes potentially important benefit or harm, and the other bound crosses the null in the opposite direction, but only very slightly and as a result of the outlying effect in one study (3).
In sensitivity analysis in which the study is removed, the upper bound no longer crosses the null. Not downgraded.
The sample size is relatively small for prospective cohort studies, but sufficiently large and with a high event rate. Not downgraded.
One bound of the 95% CI includes potentially important benefit or harm, and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.
Only one trial was assessed as having adequately randomized and maintained allocation concealment (others unclear). One trial was an abstract only, with overall high risk of bias. Remaining domains for the other two trials were assessed as half with low risk of bias and half with unclear risk. Downgraded once.
A small mean effect, likely of little to no clinical significance, and neither bound of the 95% CI includes a potentially important benefit or harm. However, the sample size is small. Downgraded once.
All but one trial had adequate randomization, and nearly half had adequate allocation concealment (the remainder were unclear). One trial had incomplete data, and another concerns about selective reporting. Six trials could not blind participants, and it was unclear whether participants were blinded in the other two. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
The majority of trials had adequate randomization, but only one or two had adequate allocation concealment (the remainder were unclear). Two trials had incomplete data. Two trials could not blind participants, and it was unclear whether participants were blinded in the remaining trials. For fat mass (%), there were concerns in one trial about selective reporting. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
Six of the 10 comparisons that reported a P trend reported a P trend of <0.05, suggesting a dose-response relationship within these individual studies. However, as a conservative measure, it was not upgraded.
Funnel plot analysis suggested a slight possibility of publication bias, but not of significant concern. Not downgraded.
Slightly more than half the trials had adequate randomization, and one had inadequate randomization. Only four of the trials had adequate allocation concealment (the remainder were unclear). More than half the trials could not blind participants to treatment. Two trials had incomplete data, and there were concerns about selective reporting in two trials (one trial had both). One trial was an abstract only with overall high risk of bias. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
In these trials, the majority had adequate randomization, and one had inadequate randomization. Half had adequate allocation concealment (the remainder were unclear). Slightly more than half the trials could not blind participants to treatment. One trial had incomplete data. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
In these trials, the majority had adequate randomization, and half had adequate allocation concealment (the remainder were unclear). Half the trials could not blind participants to treatment. One trial had incomplete data, and one had concerns about selective reporting. One trial was an abstract only with overall high risk of bias. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
Fewer than half the trials had adequate randomization, and one had inadequate randomization. Only four of the trials had adequate allocation concealment (the remainder were unclear). More than half the trials could not blind participants to treatment. Two trials had incomplete data. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
This single study had adequate randomization but insufficient information to assess allocation concealment, blinding of outcome assessment or selective reporting. It was at high risk of bias for blinding of participants and incomplete data. Downgraded once.
Unable to assess inconsistency in a single study. Downgraded once.
Extremely small sample size. Downgraded twice.
The data for dental caries were reported in the original publication of this trial (Maersk et al. 2012) (4).
The majority of trials had adequate randomization, but fewer than half had adequate allocation concealment (the remainder were unclear). A significant number of trials could not blind participants, and it was unclear whether participants were blinded in the remaining trials. One or two trials trial had incomplete data, and there were concerns in 1-3 trials about selective reporting. One or two of the trials for most outcomes were abstracts only and of high risk of bias overall. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
The majority of trials had adequate randomization, but only one had adequate allocation concealment (the remainder were unclear). Only one trial could not blind participants. The remaining domains were approximately half with low risk of bias and half unclear. Not downgraded.
One trial was fairly well reported, and the other was mostly unclear, with concerns about selective reporting of outcomes. Downgraded once.
The 95% CI crosses the null and includes both significant benefit and harm. Downgraded twice.
A little fewer than half the trials had adequate randomization, and about a quarter had adequate allocation concealment (the remainder were unclear). One trial was at high risk of bias for both inadequate randomization and allocation concealment. Half the trials could not blind participants, and it was unclear whether participants were blinded in all but two of the remaining trials. Eight trials had incomplete data, and there were concerns in one trial about selective reporting. The remaining domains were approximately half with low risk of bias and half unclear. Downgraded once.
A third of the trials had adequate randomization, and one had adequate allocation concealment (the remainder were unclear). One trial was at high risk of bias for both inadequate randomization and allocation concealment. More than half the trials could not blind participants, and it was unclear whether participants were blinded in all but one of the remaining trials. Three trials trial had incomplete data. The remaining domains were more low risk of bias than unclear, but not by a significant margin. Downgraded once.  (6).
In another trial, mouth rinse containing stevia or placebo was used daily by children for 6 months. At the end of the trial, there was a significant improvement in the stevia arm compared with the placebo group in plaque scores (P = 0.03) and gingival scores (P = 0.01). There were no changes in the number of cavitated lesions in the stevia arm, but there was an increase in cavitated lesions in the placebo arm (from 5.6% to 5.8%) (7).

# Unable to meta-analyse
In one cohort study, energy intake in initiators of NSS-sweetened beverages was 432 kJ/day higher and in chronic/existing consumers of NSS-sweetened beverages was 2462 kJ/day higher than in those who did not consume NSS-sweetened beverages after 1 year of follow-up (5).
In the second cohort study, energy intake was 122 kJ/day higher per 100 g/day increase in consumption of NSS-sweetened beverages (10).

# Unable to meta-analyse
In one cohort study, chronic users of NSSsweetened beverages had a 40.2 g/day (SE 11.6) higher sugars intake than never users, whereas initiators of NSS-sweetened beverages had a -23.9 g/day (SE 17.9) lower sugars intake than never users (5).
In a second cohort study, sugars intake was not associated with consumption of NSSsweetened beverages (10). Unless otherwise noted, observational studies are prospective cohort studies that assessed outcomes by comparing the highest quantile of intake with the lowest. Some cohort studies assessed outcomes continuously, as noted in the evidence profile.
2 Unless otherwise noted, all studies were conducted in the population of interest (i.e. general child population). Although most studies were conducted in North America and Europe, and very few were conducted in LMICs, physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweettasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless NSS are introduced to these populations.  This single RCT was well conducted, with adequate randomization and allocation concealment. There was a high attrition rate, with more than 20% of participants dropping out; however, imputation of missing values suggested no imbalance in arms with or without missing participants. Not downgraded.
Unable to assess inconsistency as there is only a single study. Downgraded once.
Mean Newcastle-Ottawa Score of >5 with very conservative application of ratings. Not downgraded.
A small mean effect, likely of little to no clinical significance, and neither bound of the 95% CI includes a potentially important benefit or harm. Therefore, considered a sufficiently precise estimate of no effect. Not downgraded.
I 2  50%, indicating a significant level of heterogeneity. Downgraded once.
One bound of the 95% CI includes potentially important benefit or harm, and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.
These RCTs were well conducted, although for one it was unclear whether it was adequately randomized. Both had adequate allocation concealment. There was a high attrition rate, with more than 20% of participants dropping out of one trial; however, imputation of missing values suggested no imbalance in arms with or without missing participants. No other sources of significant bias were noted. Not downgraded.
12 Mean Newcastle-Ottawa Score of 5 with very conservative application of ratings. Downgraded once.
This single, very small cohort was conducted exclusively in overweight Hispanic adolescents. As evidence from this review suggested that people with overweight and/or obesity may respond differently to the use of NSS from people of normal weight, this cohort may not be an adequate representation of the general child population. Downgraded once, together with inconsistency.
The 95% CI crosses the null and includes both significant benefit and harm. Downgraded twice.
Neither trial included sufficient information to assess whether randomization was adequate, but both had adequate allocation concealment, and other domains were mostly assessed as having low risk of bias. Not downgraded.
Unable to assess inconsistency as there are only two studies, which could not be meta-analysed, although both report lower risk of caries with NSS. Downgraded once as a conservative measure.
Unable to assess. Downgraded once.
It was unclear whether this single, well-conducted trial was adequately randomized, but other domains -save for blinding of participants (unclear) -were assessed as having low risk of bias. Not downgraded.

# GRADE evidence profile 4
Question: What is the effect of higher compared with lower NSS intake in pregnant women? Population: Pregnant women All studies were conducted in the population of interest (i.e. general population of pregnant women). Although most studies were conducted in North America and Europe, and very few were conducted in LMICs, physiological responses to NSS are not expected to differ significantly across different populations. Behavioural responses may differ between those who are habituated to sweet-tasting foods and beverages and those whose diets contain little to no sweet foods or beverages. However, in populations with limited exposure to NSS (which may be found more widely in LMICs), the effects observed on the consumption of NSS in this review may be largely irrelevant unless NSS are introduced to these populations. Too few studies to conduct funnel plot analyses.
Outcomes specific to pregnancy were not prioritized by the WHO NUGAG Subgroup on Diet and Health, and therefore there is no designation as critical or important.
Mean Newcastle-Ottawa Score of >5 with very conservative application of ratings. Not downgraded.
Unable to assess inconsistency as there is only a single study, or a small number of studies that could not be meta-analysed. Downgraded once.
One bound of the 95% CI includes potentially important benefit or harm, and the other bound crosses the null in the opposite direction, and/or the sample size is small. Downgraded once.
Mean Newcastle-Ottawa Score of 5 with very conservative application of ratings. Downgraded once.
Unable to assess. Downgraded once.
Based on the reporting of other beverage types in this study, it was determined that "low-calorie beverages" consisted primarily, if not entirely, of NSS-sweetened beverages.

# Annex 7
Evidence to recommendations table In 2016, more than 1.9 billion adults aged 18 years and older were overweight (1). Of these, more than 600 million were obese. In 2020, more than 38 million children under 5 years of age were overweight -an increase of about 6 million over the past 20 years (2). High BMI was responsible for an estimated 4 million deaths in 2017 (3), and increases in BMI in the overweight and obesity range led to a greater risk of mortality (4). Overweight and obesity are also risk factors for many NCDs, including CVDs, type 2 diabetes and certain types of cancer. NCDs are the leading causes of death globally and were responsible for an estimated 41 million (71%) of the 55 million deaths in 2019 (5).

# Rates of obesity and diet-related
NCDs are growing rapidly in LMICs.

# Desirable effects
How substantial are the desirable anticipated effects?
 Trivial  Small  Moderate  Large  Varies   Don't know
The NUGAG Subgroup on Diet and Health did not consider the short-term weight loss observed in RCTs of varied design to be a health benefit (desirable effect). Because the evidence for reduced energy and sugars intake also came from the same short-term trials (and is only relevant to the extent that it contributes to weight loss or healthy weight maintenance), these were also not considered desirable effects. Therefore, the NUGAG Subgroup on Diet and Health does not know whether there are desirable effects on body weight with NSS use. The effects observed are summarized below; they were considered to be small (body weight, BMI) to moderate (energy intake, sugars intake).

# Higher compared with lower NSS intake
Body weight: MD -0.71 kg (95% CI: -1.13 to -0.28) BMI: MD -0.14 kg/m 2 (95% CI: -0.30 to 0.02) Energy intake: -569 kJ/day (95% CI: -859 to -278) Sugars intake: -38.4 g/day (95% CI: -57.8 to -19.1)

# Replacement of sugars with NSS
The overall certainty in the evidence for effects in adults of higher intakes of NSS compared with lower (or no) intake is low, and for NSS as a replacement for sugars is moderate. Because the associations with possible increased risk of death and disease observed in prospective cohort studies would be sufficient on their own to make recommendations, and are very low to low certainty, the overall certainty in the evidence for adults is low. Certainty in the evidence for key outcomes is listed below.
The associations with possible increased risk of death and disease observed in prospective cohort studies for adults would be sufficient on their own to make recommendations and have been extrapolated to children. Therefore, the overall certainty in the evidence for children is low. Certainty in the evidence for key outcomes assessed directly in children is listed below. Because the NUGAG Subgroup on Diet and Health concluded that the potential long-term undesirable effects outweighed any effects of short-term weight loss, the overall certainty in the evidence was based on that assigned to adults.

# Pregnant women
The associations with possible increased risk of death and disease observed in prospective cohort studies for adults would be sufficient on their own to make recommendations and are relevant for pregnant women. Therefore, the overall certainty in the evidence for pregnant women is low. Certainty in the evidence for key outcomes assessed directly in pregnant women is listed below. The recommendation in this guideline places a high value on reducing the risk of mortality, overweight, obesity and NCDs.
Although individuals almost universally value the prevention of premature mortality, those that may be impacted by the recommendation may place different values on the benefit of reducing the risk of obesity and associated disease, based on personal preferences, beliefs and customs. For example, because CVDs are a high-profile public health topic, including in many LMICs where they represent a growing threat (6), it is expected that most individuals would value efforts to reduce risk. However, in real-world settings, perception of the risk varies considerably (7)(8)(9)(10)(11), and outreach and communication efforts may therefore be needed to improve understanding. Similarly, although many people in LMICs are increasingly aware of negative health effects associated with being overweight or obese, some cultures still consider overweight to be a desirable or positive attribute (12)(13)(14). Others believe body weight to be hereditary and therefore not amenable to management via lifestyle changes (11,15). And many, regardless of personal beliefs, incorrectly perceive their own body weight in the context of overweight and obesity -that is, they believe that they are at a healthy body weight when in fact they are overweight or obese according to accepted standards for assessing body weight outcomes (11,15,16). Although short-term benefit of NSS use on measures of body fatness was observed in controlled experimental settings, the NUGAG Subgroup on Diet and Health concluded that the lack of evidence to suggest that NSS use is beneficial for body weight and other measures of body fatness over the long term together with possible long-term adverse effects in the form of increased risk of death and disease, offset any potential short-term health benefit resulting from the relatively small reduction in body weight and BMI observed in randomized controlled trials. In addition, limited evidence for beneficial effects of NSS use on dental caries was observed in studies of children. However, this was generally only observed in studies where intake of NSS was compared with intake of free sugars, suggesting that NSS do not have any inherent properties that impact risk of dental caries; rather, the effect is a result of displacing free sugars.

# Balance of effects
In the case of NSS, the potential undesirable effects carry a greater weight when assessing desirable vs undesirable effects because a reduction in free sugars intake can be achieved and corresponding desirable health benefits realized without the use of NSS. In addition, unlike the potential effects observed from long-term exposure in adults, the evidence from prospective studies of pregnant women suggests that potential adverse effects from NSS use occur over the relatively short period of gestation.
Evidence from RCTs suggests that the effects of NSS in these studies primarily occur via a reduction in energy intake. Therefore, any potential benefit of NSS use would largely be for those who are trying to lose or maintain body weight via restriction of energy intake (resulting from replacing free sugars with NSS). NSS use may not produce desirable effects for those who are not regular consumers of free sugars or who are otherwise not at risk of excess energy intake resulting from free sugars intake. This segment of the general population would therefore likely only be subjected to the potential undesirable effects of NSS use.
The assessment that the balance between desirable and undesirable effects probably favours not using NSS was made taking into account the uncertainty in the results of the prospective observational studies. If there were greater certainty in these results, an assessment of "Favours not using NSS" would likely have been made.
Research evidence Additional considerations

# Balance of effects
NSS are not essential dietary components and provide no nutritional value themselves, and are frequently a component of highly processed foods. Therefore, a possible undesirable effect of NSS use in the context of reducing free sugars intake is the inclusion of a greater number of highly processed foods and beverages in the diet than would be included if free sugars were reduced without NSS use (17).
The recommendation to not use NSS could result in potential undesirable effects, not inherent to NSS, if some individuals currently using NSS discontinue use and increase free sugars intake in order to maintain the level of sweetness in their diet. However, the undesirable effects of free sugars intake are well documented, and awareness of these effects among the general public is fairly high. Together with the fact that the recommendation in this guideline should be considered in the context of the WHO recommendations to reduce free sugars intake (18), this suggests that individuals switching from NSS to free sugars would not be a widespread occurrence.
Overall, the NUGAG Subgroup on Diet and Health concluded that the desirable effects of not using NSS outweighed the undesirable effects. Absolute costs of translating the recommendation in this guideline into policy actions and interventions will vary widely depending on which approaches are taken. Costs may be minimized by coupling measures taken with existing efforts to reduce free sugars intake and promote healthy diets. For example, as noted under "Feasibility" above, it may be possible to incorporate the recommendation into existing policy actions and interventions, such as food-based dietary guidelines and fiscal policies targeting sugar-sweetened beverages, which might limit the resources required to implement the recommendation. Implementation of the recommendation will likely require consumer education and public health communications. These can also be incorporated into existing public health nutrition education campaigns and other existing nutrition programmes at the global, regional, national and subnational levels.
In general, not using NSS should lead to a decrease in both the purchase of NSS themselves (for use by the consumer) and the purchase of foods and beverages containing NSS. In the case of NSS and certain foods and beverages with no caloric value, further adjustments to the diet would not be needed, and money could be saved by simply forgoing these purchases. Adhering to the recommendation could therefore have a positive or negative impact on disposable income, which might be amplified in people of lower socioeconomic status -particularly in LMICs -as they tend to spend a higher proportion of their income on foods and beverages (19)(20)(21)). Whether or not implementing the recommendation is cost-effective (i.e. the savings in health-care costs offset or exceed the cost of implementation) is not conclusively known, given the uncertainty of long-term health effects of NSS use. However, assuming that the long-term associations between NSS use and increased risk of unhealthy weight gain and NCDs are valid, implementing the recommendation may be associated with long-term savings in costs of health care, though the extent of the savings depends on strategies chosen for implementation and the timescale for evaluation. For example, although very few (if any) cost-effectiveness analyses have been conducted for NSS use, a number of cost-effectiveness studies on taxation of sugar-sweetened beverages have been published, with most finding that taxes have the potential to result in substantial cost savings and health impact with respect to obesity and diet-related NCDs (22)(23)(24)(25)(26). Similarly, limited evidence suggests that other policies and interventions that would be relevant to NSS, such as restrictions on marketing of unhealthy foods and beverages to children, may be cost-effective (27).
Overall, the cost-effectiveness of different approaches will likely vary and cannot be determined with certainty. The impact of the recommendation on equity and human rights is not conclusively known, given the uncertainty around long-term health effects of NSS use. Assuming that the long-term associations between NSS use and increased risk of unhealthy weight gain and NCDs are valid, the recommendation in this guideline has the potential to reduce health inequity by improving the long-term health of people of lower socioeconomic status, as they are generally disproportionately affected by overweight, obesity and NCDs (28)(29)(30)(31). However, in some LMIC settings, people of higher socioeconomic status may be more at risk than those of lower socioeconomic status and may benefit more from relevant interventions (32,33). Regardless, the effect on equity and human rights would likely be affected by how the recommendation is translated into policies and actions. For example, a small number of studies suggest that fiscal policies targeting foods and beverages, front-of-pack labelling and restrictions on marketing unhealthy foods may increase health equity (34). However, if such measures affect all individuals in a population equally, relevant inequalities may not be addressed (35).
Overall, evidence is extremely limited and inconclusive. Although there is a suggestion that implementing the recommendation might reduce health inequity, it is ultimately unknown.

# Research evidence Additional considerations
Feasibility sugars intake also have the potential to make implementation of the NSS recommendation more challenging: recent evidence suggests that sales of NSScontaining beverages (but not NSS-containing foods) are increasing in regions that have implemented multiple policy actions targeting free sugars intake, relative to regions that have implemented fewer or no actions (38). Because NSS, and foods and beverages containing NSS are already widely available and used by large segments of the global population, implementing the recommendation will have its challenges, particularly in settings without robust infrastructure for implementing public health measures, including behaviour change communications and messaging, or where "piggy backing" on efforts to address free sugars intake is not possible.
Regardless of which interventions and policy actions are used to implement the recommendation, some amount of behaviour change at the individual level will likely be required; the extent to which this can be achieved will depend on the willingness of individuals who have become habituated to a certain level of sweetness in foods and beverages to reduce the overall sweetness in their diets.
For those not habituated to high levels of sweetness in the diet (including infants and young children), avoiding NSS (and excess free sugars) -particularly in beverage formshould be very feasible. However, as noted below, because of the way in which NSS-containing foods and beverages are labelled, avoiding NSS may require vigilance on the part of consumers.
The level to which NSS use can be reduced will depend not only on the success of public health efforts and individual choice, but the extent to which consumers are aware of the NSS content in products they purchase. Evidence suggests that some consumers may not be aware that many of the food and beverages they are purchasing contain NSS (39,40), and generally may have difficulties interpreting nutrient declaration labels, health claims and other relevant labelling (41)(42)(43)(44)(45).