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Understanding Flavored Waters with Artificial Sweeteners and Diabetes Management
Flavored waters with artificial sweeteners have become increasingly popular among health-conscious consumers, particularly those managing diabetes. The market for artificial sweeteners has been projected to increase by almost 75% from 2025 through 2033, or from $3.11 billion to $5.44 billion, reflecting a growing demand for low-calorie beverage alternatives. For people with diabetes, these products offer the promise of enjoying flavorful drinks without the blood sugar spikes associated with traditional sugary beverages. However, understanding the safety, efficacy, and potential concerns surrounding these products is essential for making informed dietary choices.
This comprehensive guide explores the science behind artificial sweeteners, their impact on blood glucose management, potential health considerations, and practical recommendations for people with diabetes who are considering flavored waters as part of their dietary regimen.
What Are Artificial Sweeteners and How Do They Work?
Artificial sweeteners, also known as non-nutritive sweeteners (NNS) or high-intensity sweeteners, are substances used to add sweetness to food and drinks without the addition of extra calories from sugar or high fructose corn syrup, providing little to no calories or nutritional value. These sweeteners are significantly sweeter than traditional sugar, often hundreds to thousands of times sweeter in comparison.
FDA-Approved Artificial Sweeteners
Currently, six artificial sweeteners are approved by the FDA, namely advantame, aspartame, saccharin, ace-K, neotame, and sucralose, together with two natural high-intensity sweeteners, steviol glycosides produced from the stevia plant and monk fruit extracts, currently classified as “Generally Regarded as Safe” (GRAS). Each of these sweeteners has undergone rigorous testing and evaluation before receiving approval for consumer use.
The most commonly encountered artificial sweeteners in flavored waters include:
- Aspartame: Found in many diet beverages and marketed under brand names like NutraSweet and Equal
- Sucralose: A popular sweetener used in numerous sugar-free products, known by the brand name Splenda
- Acesulfame Potassium (Ace-K): Often used in combination with other sweeteners to enhance flavor profiles
- Saccharin: One of the oldest artificial sweeteners, commonly found in Sweet’N Low
- Stevia: A natural high-intensity sweetener derived from the stevia plant
How Artificial Sweeteners Differ from Sugar
Artificial sweeteners, also called sugar substitutes, offer the sweetness of sugar without the calories. Unlike regular sugar, which contains approximately 4 calories per gram and directly impacts blood glucose levels, artificial sweeteners provide intense sweetness with minimal to no caloric content. This fundamental difference makes them attractive options for individuals managing diabetes or trying to reduce their overall caloric intake.
The increased usage of artificial sweeteners is often influenced by their potential for assisting in weight management and controlling blood glucose levels, and they are extensively utilized in a wide range of beverages and food products, including diet soft drinks, yogurts, desserts, and chewing gum.
The Science Behind Artificial Sweeteners and Blood Sugar Control
One of the primary concerns for people with diabetes is how different foods and beverages affect blood glucose levels. Understanding the relationship between artificial sweeteners and blood sugar management is crucial for making informed dietary decisions.
Immediate Impact on Blood Glucose Levels
Artificial sweeteners, due to their low caloric content and minimal impact on blood glucose levels, offer promising potential as sugar substitutes for individuals aiming to manage glycemic control. Artificial sweeteners have been shown to aid in weight management, a key factor in reducing diabetes risk, and do not impact immediate blood glucose levels, offering improved glucose control for individuals with diabetes.
Multiple research studies have confirmed this finding. Following artificially sweetened beverage or soda water consumption, oral glucose tolerance test results did not differ significantly in terms of blood glucose and C-peptide areas under the curve from 10 min before to 180 min after glucose loading among healthy individuals and type 1 diabetes mellitus and type 2 diabetes mellitus cohorts. This suggests that for most people with diabetes, consuming flavored waters with artificial sweeteners does not cause immediate blood sugar spikes.
Insulin Response and Sensitivity
While artificial sweeteners generally do not raise blood glucose levels directly, questions remain about their potential effects on insulin response and sensitivity. Compounds such as aspartame, sucralose, and stevia mimic the sweetness of sugar without causing hyperglycemia, making them suitable for diabetic patients.
However, the research on insulin sensitivity presents a more complex picture. The levels of insulin and HbA1c increased compared to healthy participants in studies, and these findings may be generalizable to adult patients with type 2 diabetes, suggesting that healthcare professionals should consider monitoring insulin levels more closely when recommending artificial sweeteners as sugar substitutes.
It’s important to note that individual responses can vary. When eaten in moderation, artificial sweeteners can be safe for people with diabetes, though research is ongoing regarding some potential risks.
Safety Profile of Artificial Sweeteners for Diabetics
The safety of artificial sweeteners has been extensively studied and debated within the scientific and medical communities. Understanding both the regulatory approval process and ongoing research is essential for people with diabetes considering these products.
Regulatory Approval and Safety Standards
Artificial sweeteners undergo rigorous testing to confirm they are safe for consumption, and being classified as GRAS means that, given the science we have, these products haven’t been proven to be harmful when used as intended. The FDA establishes acceptable daily intake (ADI) levels for each approved sweetener, representing the amount that can be safely consumed daily over a lifetime without adverse effects.
The FDA and food safety agencies in other countries suggest how much of a sugar substitute you can safely have each day, called the acceptable daily intake, and in general, artificial sweeteners are safe in limited amounts for healthy people, including pregnant people.
Special Considerations and Precautions
While artificial sweeteners are generally considered safe for most people with diabetes, certain individuals should exercise caution or avoid specific sweeteners:
People should limit or cut out sugar substitutes if living with a rare genetic disease called phenylketonuria, as foods and drinks with aspartame can lead to serious health problems, or if they have a bowel disease, as using sugar substitutes might make symptoms flare up.
Aspartame is a source of phenylalanine, which is an ingredient people with phenylketonuria (PKU) should avoid, and packages of aspartame include that warning. This is particularly important for individuals with this rare genetic condition to be aware of when selecting flavored waters.
Recent Research and Ongoing Debates
The scientific community continues to investigate the long-term effects of artificial sweetener consumption. Despite their growing use, the long-term safety of artificial sweeteners remains a subject of ongoing debate and contradictory study findings, raising questions about potential health consequences, with scientific opinion remaining divided and many studies reaching contradictory conclusions.
One area of particular interest involves the World Health Organization’s assessment of aspartame. In 2023, a study of more than 100,000 people followed over eight years led the World Health Organization to declare aspartame a possible cause of cancer, listed as a Group 2B carcinogen alongside things like lead and car exhaust, a designation that means there’s evidence to support the idea that aspartame may be cancer-causing in certain situations, but there’s not yet enough evidence to know for sure.
It’s crucial to understand that this classification indicates possible risk rather than confirmed danger, and the amounts consumed in typical dietary patterns are generally well below levels of concern. More research is needed to fully understand any potential long-term health implications.
Potential Health Concerns and Emerging Research
While artificial sweeteners offer benefits for blood sugar management, emerging research has identified several areas of potential concern that people with diabetes should be aware of when consuming flavored waters and other products containing these sweeteners.
Impact on Gut Microbiome
One of the most significant areas of recent research involves the effects of artificial sweeteners on gut bacteria. Recent articles published in nature reported that non-nutritive sweetener ingestion in mice for 11 weeks led to the development of glucose intolerance by altering the gut microbiome, with saccharin fed mice developing marked glucose intolerance as compared to the control group, raising alarms whether NNS use in humans can exacerbate metabolic disorders due to dysbiosis and raise the risk for progression to diabetes and obesity.
The gut microbiome plays a crucial role in overall health, including metabolic function, immune response, and even mental health. Disruptions to the delicate balance of gut bacteria could potentially have far-reaching health implications. Artificial sweeteners could modify the gut microbiota, increase glucose absorption, and trigger insulin production, with AS-associated dysbiosis increasing SCFAs and LPS, which leads to insulin secretion and insulin insensitivity respectively.
However, it’s important to note that much of this research has been conducted in animal models, and more human studies are needed to fully understand the implications for people with diabetes consuming flavored waters with artificial sweeteners.
Effects on Appetite and Weight Management
Another area of ongoing investigation involves the potential effects of artificial sweeteners on appetite regulation and weight management. Some studies have found that artificial sweeteners can contribute to weight gain by increasing sugar cravings and dependence.
The theory behind this concern is that consuming sweet-tasting substances without the accompanying calories might disrupt the body’s natural ability to regulate calorie intake based on sweetness. This could potentially lead to increased consumption of other foods or beverages, ultimately affecting weight management efforts that are crucial for diabetes control.
However, the evidence remains mixed. Research shows that sugar substitutes may be beneficial for weight management in adults and children with overweight or obesity, as well as among people with type 2 diabetes, since artificial sweeteners are indigestible and do not elicit an insulin response.
Cardiovascular and Metabolic Considerations
Recent research has also explored potential connections between artificial sweetener consumption and cardiovascular health. Some research on long-term, daily use of artificial sweeteners suggests a link to a higher risk of stroke, heart disease and death overall, but other things people do, or healthy habits that people don’t do, may be the cause of the higher risk.
A study found that chronic consumption of artificial sweeteners at safe intake levels caused vascular endothelial dysfunction and increased adipose tissue storage in healthy rats, potentially impairing insulin sensitivity and glycemic control, suggesting a link to the elevated cardiometabolic risk seen in epidemiological studies.
These findings underscore the importance of considering artificial sweeteners as part of an overall dietary pattern rather than viewing them as a simple solution to sugar reduction. People with diabetes, who already face elevated cardiovascular risk, should discuss these considerations with their healthcare providers.
Digestive Side Effects
Some individuals may experience digestive discomfort when consuming products with artificial sweeteners. Sugar alcohols, stevia and luo han guo can cause bloating, gas and diarrhea, with the amount of sugar alcohol that causes these symptoms varying from person to person.
While these side effects are generally mild and temporary, they can be uncomfortable and may affect quality of life. People with diabetes who experience digestive issues after consuming flavored waters with artificial sweeteners should consider trying different products or limiting their intake.
Comparing Different Types of Flavored Waters
Not all flavored waters are created equal. Understanding the differences between various products can help people with diabetes make informed choices that align with their health goals and preferences.
Commercial Flavored Waters with Artificial Sweeteners
Many commercially available flavored waters contain artificial sweeteners to provide taste without calories or sugar. These products typically feature combinations of sweeteners to achieve optimal flavor profiles. Each MiO product is available in a variety of flavors and sweetened with the artificial sweeteners sucralose and acesulfame potassium, which is representative of many water enhancer products on the market.
When selecting commercial flavored waters, people with diabetes should:
- Read ingredient labels carefully to identify which artificial sweeteners are used
- Check for additional ingredients like artificial colors, preservatives, or added vitamins
- Consider products that use a single sweetener if they have known sensitivities
- Be aware of serving sizes and recommended daily limits
- Monitor their individual blood glucose response after consumption
Naturally Flavored Waters
Flavored water with natural fruits, herbs and low-calorie, low-sugar ingredients can keep you hydrated and healthy if you avoid artificial sweeteners. Creating naturally flavored water at home offers an alternative for those who prefer to avoid artificial sweeteners entirely.
Options for natural flavoring include:
- Fresh citrus slices (lemon, lime, orange, grapefruit)
- Fresh berries (strawberries, blueberries, raspberries)
- Cucumber slices
- Fresh herbs (mint, basil, rosemary)
- Ginger root
- Watermelon chunks
If you’re looking for an alternative to the off-the-shelf water enhancers, try adding some slices of citrus fruits like lemons, oranges or limes, or infusing your water with fresh berries for a less artificial taste. These natural options provide subtle flavor without artificial sweeteners, though they may contain small amounts of natural sugars from the fruit.
Sparkling Waters and Carbonated Options
Sparkling or carbonated waters offer another alternative for people with diabetes seeking variety in their beverage choices. Many sparkling waters are available both unsweetened and with artificial sweeteners. Unsweetened sparkling waters provide carbonation and sometimes natural flavoring without any sweeteners, making them a neutral option for blood sugar management.
When choosing sparkling waters, people with diabetes should verify that products labeled as “flavored” don’t contain added sugars or excessive amounts of artificial sweeteners. Some brands use natural essences or oils to provide flavor without sweeteners of any kind.
Practical Guidelines for Diabetics Consuming Flavored Waters
For people with diabetes considering flavored waters with artificial sweeteners, following evidence-based guidelines can help maximize benefits while minimizing potential risks.
Moderation and Monitoring
Artificial sweeteners can help some people enjoy sweetness without excess calories, and if used in moderation, artificial sweeteners can be part of a healthy diet. The key word here is moderation. Rather than consuming unlimited quantities of artificially sweetened beverages, people with diabetes should aim for balanced consumption as part of an overall healthy dietary pattern.
Practical monitoring strategies include:
- Testing blood glucose levels before and after consuming flavored waters to assess individual response
- Keeping a food and beverage diary to track consumption patterns
- Noting any digestive symptoms or other side effects
- Discussing consumption patterns with healthcare providers during regular check-ups
- Staying within recommended acceptable daily intake levels for specific sweeteners
Reading and Understanding Labels
Becoming proficient at reading product labels is essential for people with diabetes. The general omission of information about the concentration of artificial sweeteners on market product labels makes it challenging to determine the amounts of artificial sweeteners consumed by people.
When examining labels, look for:
- The specific types of artificial sweeteners used
- Total carbohydrate content (should be zero or minimal for sugar-free products)
- Serving size information
- Any added vitamins, minerals, or other ingredients
- Warnings for specific populations (such as phenylketonuria warnings for aspartame)
- Calorie content per serving
Balancing with Overall Dietary Goals
Sugar substitutes are an option to provide desired sweetness to food without spiking blood sugars, but balance is key, and they should be consumed in moderation. Flavored waters with artificial sweeteners should be viewed as one component of a comprehensive diabetes management plan that includes:
- A balanced diet rich in whole foods, vegetables, lean proteins, and healthy fats
- Regular physical activity
- Appropriate medication management as prescribed
- Regular blood glucose monitoring
- Adequate hydration from various sources
- Stress management and adequate sleep
Products made with sugar substitutes may give you the wrong message about processed foods, as a snack labeled low sugar or no sugar may not be the most nutritious choice, while whole foods, such as fruits and vegetables, usually have the best mix of nutrients for the body.
Hydration Strategies
While flavored waters can contribute to daily fluid intake, plain water remains the gold standard for hydration. If a flavoring additive makes someone more likely to drink the water they need, then that’s fine, and some people simply just don’t like plain water, in which case drinking any kind of water is a win, as adequate water is important and sustains life.
A balanced hydration approach might include:
- Starting the day with plain water
- Using flavored waters as occasional alternatives rather than primary hydration sources
- Alternating between plain and flavored waters throughout the day
- Ensuring total daily fluid intake meets individual needs (typically 8-10 cups for most adults)
- Adjusting fluid intake based on activity level, climate, and individual health needs
Special Considerations for Different Types of Diabetes
While artificial sweeteners are generally considered safe for people with diabetes, there are some specific considerations depending on the type of diabetes and individual circumstances.
Type 1 Diabetes
People with Type 1 diabetes who use insulin therapy need to carefully manage their carbohydrate intake and insulin dosing. Flavored waters with artificial sweeteners offer a way to enjoy variety in beverages without requiring insulin adjustments, as they contain minimal to no carbohydrates.
Findings may be generalizable to adult patients with type 2 diabetes, as most included studies investigated this population, however, they might not directly apply to patients with type 1 diabetes or gestational diabetes, where insulin regulation differs. This highlights the importance of individualized approaches and monitoring.
Type 2 Diabetes
For people with Type 2 diabetes, weight management often plays a crucial role in disease management. Artificial sweeteners in flavored waters can help reduce overall calorie intake when used as replacements for sugar-sweetened beverages. Type 2 diabetes is a disease characterized by glucose imbalance due to the diminished response of insulin, commonly known as insulin resistance.
However, it’s important to remember that simply switching to artificially sweetened beverages is not a complete solution. Comprehensive lifestyle modifications including diet, exercise, and medication management remain essential for optimal Type 2 diabetes control.
Gestational Diabetes
Pregnant women with gestational diabetes face unique considerations when it comes to artificial sweetener consumption. In general, artificial sweeteners are safe in limited amounts for healthy people, including pregnant people. However, pregnant women should always consult with their healthcare providers before making significant dietary changes, including increased consumption of artificially sweetened products.
Some research has explored potential connections between artificial sweetener consumption during pregnancy and various outcomes, though more research is needed to draw definitive conclusions. Pregnant women with gestational diabetes should work closely with their healthcare team to develop an appropriate dietary plan.
Prediabetes
For individuals with prediabetes, preventing progression to Type 2 diabetes is a primary goal. Reducing sugar intake and managing weight are key strategies. Flavored waters with artificial sweeteners can support these goals by providing satisfying alternatives to sugar-sweetened beverages.
However, people with prediabetes should focus on comprehensive lifestyle modifications rather than relying solely on artificial sweeteners. This includes adopting a balanced diet rich in whole foods, engaging in regular physical activity, and maintaining a healthy weight.
Working with Healthcare Providers
Making informed decisions about flavored waters and artificial sweeteners should involve collaboration with healthcare professionals who understand your individual health status, diabetes management goals, and potential risk factors.
Questions to Discuss with Your Doctor
When meeting with your healthcare provider, consider discussing:
- Whether artificial sweeteners are appropriate for your specific type of diabetes and overall health status
- Any medications you’re taking that might interact with artificial sweeteners or their effects
- Your current blood glucose control and whether dietary changes might help
- Any digestive issues or other symptoms you’ve experienced with artificial sweeteners
- Recommended limits for artificial sweetener consumption based on your individual needs
- Alternative strategies for reducing sugar intake if artificial sweeteners aren’t suitable for you
Working with a Registered Dietitian
Registered dietitians, particularly those who are certified diabetes care and education specialists, can provide valuable guidance on incorporating flavored waters into a diabetes-friendly eating plan. They can help you:
- Develop a comprehensive meal plan that includes appropriate beverage choices
- Understand how different artificial sweeteners might affect your individual health goals
- Learn to read and interpret food labels effectively
- Create strategies for reducing sugar intake while maintaining satisfaction with your diet
- Monitor and adjust your dietary approach based on blood glucose responses
- Address any concerns about weight management and overall nutrition
Regular Monitoring and Follow-Up
Diabetes management requires ongoing monitoring and adjustment. Regular follow-up appointments with your healthcare team allow for:
- Assessment of blood glucose control through HbA1c testing
- Evaluation of weight management progress
- Discussion of any new research or recommendations regarding artificial sweeteners
- Adjustment of diabetes medications if needed
- Screening for diabetes-related complications
- Review of dietary patterns and their effectiveness
The Future of Artificial Sweeteners and Diabetes Research
The field of artificial sweetener research continues to evolve, with new studies regularly contributing to our understanding of these compounds and their effects on health, particularly for people with diabetes.
Ongoing Research Areas
This comprehensive review highlights the importance of a nuanced approach to understanding the implications of artificial sweeteners in diabetes management, and given the mixed evidence on their health effects, there is a clear need for further research to fully elucidate the role of artificial sweeteners in metabolic health and their suitability as part of dietary interventions for diabetes.
Current research priorities include:
- Long-term studies examining the effects of artificial sweetener consumption over decades
- Investigation of individual differences in response to artificial sweeteners
- Research on gut microbiome changes and their metabolic implications
- Studies examining the effects of different artificial sweeteners in combination
- Research on potential cardiovascular effects in people with diabetes
- Investigation of effects on appetite regulation and weight management
Other research is looking at long-term use of sugar substitutes and the gut, with many focusing on how the gut and brain communicate, as researchers are checking to see if sugar substitutes affect cravings for sweets, the way people feel hunger and how the body manages blood sugar.
Emerging Sweetener Technologies
The food industry continues to develop new sweetening technologies and compounds. SGFE (Luo Han Guo/SGFE) was recently given the GRAS category status by the FDA, and another newer agent, advantame, has been approved by the FDA in 2014 for use as a sweetener and flavor enhancer, though extensive and long-term clinical data on both these agents are awaited before their safety in special populations can be determined.
Future developments may include:
- Novel sweeteners with improved taste profiles
- Compounds that provide sweetness with additional health benefits
- Better understanding of optimal sweetener combinations
- Development of sweeteners that don’t affect gut microbiome
- Personalized recommendations based on genetic or metabolic profiles
Evolving Guidelines and Recommendations
As research continues to accumulate, guidelines and recommendations from health organizations may evolve. The World Health Organization recommends limiting free sugar intake to less than 10% of total daily energy intake, with additional benefits likely at levels below 5% per day.
People with diabetes should stay informed about:
- Updates from diabetes organizations like the American Diabetes Association
- New research findings published in peer-reviewed journals
- Changes to FDA recommendations or acceptable daily intake levels
- International guidelines from organizations like the WHO
- Emerging consensus on best practices for artificial sweetener use in diabetes management
Making Informed Choices: A Balanced Perspective
The question of whether flavored waters with artificial sweeteners are safe for diabetics doesn’t have a simple yes or no answer. The evidence suggests that for most people with diabetes, these products can be consumed safely in moderation as part of a comprehensive diabetes management plan.
Key Takeaways for People with Diabetes
When considering flavored waters with artificial sweeteners, remember these important points:
- Artificial sweeteners generally do not cause immediate blood sugar spikes, making them preferable to sugar-sweetened beverages
- FDA-approved artificial sweeteners have undergone safety testing and are considered safe for most people when consumed within acceptable daily intake levels
- Individual responses to artificial sweeteners can vary, making personal monitoring important
- Moderation is key – artificial sweeteners should be part of a balanced diet, not consumed in unlimited quantities
- Some people may experience digestive side effects or other sensitivities to specific sweeteners
- Ongoing research continues to explore long-term effects, particularly on gut health and metabolic function
- Plain water remains the optimal choice for hydration, with flavored waters serving as occasional alternatives
- Consultation with healthcare providers is essential for personalized recommendations
Weighing Benefits and Risks
The decision to consume flavored waters with artificial sweeteners involves weighing potential benefits against possible risks:
Potential Benefits:
- Reduced calorie intake compared to sugar-sweetened beverages
- No immediate impact on blood glucose levels
- Increased variety in beverage choices, potentially improving adherence to dietary recommendations
- May help reduce overall sugar consumption
- Can support weight management efforts when used appropriately
- Provides hydration with added flavor for those who struggle to drink plain water
Potential Concerns:
- Possible effects on gut microbiome with long-term use
- Potential impact on appetite regulation and food cravings
- Digestive side effects in some individuals
- Ongoing questions about long-term cardiovascular and metabolic effects
- May not address underlying habits related to sweet taste preferences
- Could provide false sense of security about overall diet quality
Practical Recommendations
Based on current evidence and expert recommendations, people with diabetes considering flavored waters with artificial sweeteners should:
- Start with small amounts and monitor individual blood glucose response
- Choose products with artificial sweeteners that have been well-studied and FDA-approved
- Read labels carefully to understand exactly what sweeteners and other ingredients are present
- Stay within recommended acceptable daily intake levels for specific sweeteners
- Consider alternating between artificially sweetened and naturally flavored waters
- Maintain plain water as the primary source of hydration
- Be aware of total daily consumption across all foods and beverages containing artificial sweeteners
- Pay attention to any digestive symptoms or other side effects
- Discuss consumption patterns with healthcare providers during regular check-ups
- Stay informed about new research and evolving recommendations
- Focus on overall dietary quality rather than relying on artificial sweeteners as a primary strategy
- Consider individual health factors, including any digestive conditions or medication interactions
Conclusion: An Individualized Approach to Diabetes Management
Flavored waters with artificial sweeteners can be a safe and useful tool for many people with diabetes when consumed thoughtfully and in moderation. They offer a way to enjoy flavorful beverages without the blood sugar spikes associated with sugar-sweetened drinks, potentially supporting both diabetes management and weight control efforts.
However, they are not a magic solution, and their use should be considered within the context of a comprehensive diabetes management plan that includes a balanced diet, regular physical activity, appropriate medication management, and ongoing monitoring. The key is finding an approach that works for your individual circumstances, preferences, and health goals.
As research continues to evolve our understanding of artificial sweeteners and their effects on health, staying informed and maintaining open communication with your healthcare team will help you make the best decisions for your diabetes management. Whether you choose to incorporate flavored waters with artificial sweeteners into your routine, opt for naturally flavored alternatives, or stick primarily with plain water, the most important factor is finding a sustainable approach that supports your overall health and well-being.
Remember that diabetes management is highly individualized, and what works well for one person may not be ideal for another. By staying informed, monitoring your individual responses, and working closely with your healthcare providers, you can make confident decisions about whether flavored waters with artificial sweeteners have a place in your diabetes management strategy.
For more information about diabetes management and nutrition, visit the American Diabetes Association, consult with a registered dietitian nutritionist, or discuss your specific concerns with your healthcare provider. Additional resources can be found through the Centers for Disease Control and Prevention, Mayo Clinic, and Cleveland Clinic.