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Eating Disorders

Last reviewed: September 2024

Eating Disorders

Eating Disorders are characterized by eating behaviors that are physically and psychologically unhealthy. They can occur in individuals throughout their lifespan, but adolescence and young adulthood are particularly vulnerable periods for development. Typically, eating disorders disproportionately affect girls and women; however, any gender may be affected. The recognition of an eating disorder is a collaborative process between the patient, family and primary care provider, Furthermore, management of eating disorders often requires a care team that includes mental health providers.

Eating disorders are associated with potentially life-threatening medical complications that can affect all major organ systems. Most complications will improve and ultimately reverse with nutritional rehabilitation. However, some complications (such as low bone mineral density, growth retardation, and structural brain changes) may not fully normalize after prolonged disease. Early recognition and treatment are vital to improve recovery and reduce the likelihood of serious complications.

Myths vs. Facts

Fact: The causes of an eating disorder are complex. Eating disorders are caused by both genetic and environmental factors; they are bio-sociocultural diseases. A societal factor (like the media-driven thin body ideal) is an example of an environmental trigger that has been linked to increased risk of developing an eating disorder. Environmental factors also include physical illnesses, childhood teasing and bullying, and other life stressors. Eating disorders may run in families, as there are biological predispositions that make individuals vulnerable to developing an eating disorder.

Fact: Roughly 1 in 20 people with eating disorders die because of their illness and not just due to the severe calorie restriction seen in Anorexia. Individuals who abuse laxatives or diuretics or force themselves to vomit are at significantly higher risk of sudden death from heart attacks due to electrolyte imbalances. Excessive exercise also can increase the risk of death in individuals with eating disorders by increasing the amount of stress on the body.

Fact: Difficulty with accurate self-awareness is one of the hallmarks of eating disorders, so your loved one may not have the self-awareness required to recognize a problem. The individual struggling may also genuinely believe they are fine when they are acutely ill or may deny the presence of an eating disorder because they are afraid of treatment. Regardless of the reason, it is important to insist on treatment by a trained mental health professional, and regular medical follow-up with a physician who is well-versed in eating disorders.

Fact: What appears to be a strict diet on the surface may be the beginning of an eating disorder. Even if the symptoms do not meet the criteria for a clinical eating disorder diagnosis, disordered eating can have serious medical consequences, such as anemia and bone loss. Individuals dealing with serious disordered eating may benefit from intervention and treatment to address concerns before it becomes a full-blown eating disorder. Chronic dieting has been associated with the later development of an eating disorder, so addressing these issues right away may aid in prevention.

Clinical Pearl: Cycle of Malnutrition

The strong resistance to taking in adequate nutrition that individuals with anorexia nervosa may display, and the strength of inaccurate beliefs about their eating or body shape and size (“eating disorder cognitions”), is exacerbated by malnutrition. This means that patients with anorexia who are in “starvation state” may be incapable of breaking out of dangerous restricting or purging behaviors without help from friends, family, and professionals. Care providers can help caregivers to understand that taking positive steps to improve nutritional status, even though it is necessary to do, may cause significant distress in the patient.

 

Role of Primary Care Practitioner

  • Early detection: Primary care practitioners (PCPs) are in a unique position to detect eating disorders early and interrupt their progression at annual well visits and sports examinations.
  • Arranging appropriate care: This includes urgent referral to a hospital for patients who are medically unstable. Early response is associated with better outcomes.
  • Ongoing management: A vital role of the PCP is to offer guidance regarding eating, and to manage the physical aspects of the illness. If patients do not promptly respond to treatment, more intensive care may be needed (such as day-treatment or residential care).
  • Education: Share resources with families (see Resources).

Prevention

The American Academy of Pediatrics clinical report, “Preventing Obesity and Eating Disorders in Adolescents | American Academy of Pediatrics (aappublications.org)” describes strategies to prevent eating disorders. These strategies focus on healthy habits rather than weight.

1. Discourage dieting, skipping meals, or the use of diet pills; instead, encourage and support healthy eating and physical activity behaviors.

2. Promote a positive body image and discourage talk about body dissatisfaction.
3. Encourage more frequent family meals.
4. Encourage families to focus on healthy eating and physical activity rather than weight
5. Inquire about a history of mistreatment or bullying in overweight and obese teenagers and address this issue with patients and their families.
6. Carefully monitor weight loss in an adolescent who needs to lose weight to ensure the adolescent does not develop the medical complications of semi starvation.

 

Screening and Assessment

Patients or family members may raise concerns about an eating disorder during a visit, or the primary care provider may detect signs and symptoms while taking one’s history or during physical examination. Primary care providers less commonly use a validated screening instrument to detect and characterize an eating disorder than they do for conditions such as depression or anxiety, but they may find it helpful to recall five screening domains represented by the mnemonic “SCOFF”: Sick, Control, One, Fat, and Food.

 

  1. Do you make yourself Sick (vomit) because you feel uncomfortably full?
  2. Do you worry you have lost Control over how much you eat?
  3. Have you recently lost One stone (14 pounds) in a 3-month period?
  4. Do you believe yourself to be Fat when others say you are too thin?
  5. Would you say that Food dominates your life?

1

Meet Ava

Ava is a 15-year-old female who presents to the PCP's office for weight loss and low appetite. Upon assessment, it is noted that Ava has crossed three percentile lines on her growth curve and her BMI is now 16. Ava’s mom reports that she started dancing this year and has really “gotten in to” exercise. Her mom is worried about her low mood, self-isolation, and chronic fatigue. Furthermore, Ava reports not having a period for three months despite having regular monthly menses prior. When talking with Ava alone she admits to wanting to be thinner, being unhappy with her body size, and frequently going most of the day without eating. She knows that her mom is worried, so she will wake up in the middle of the night and exercise for hours without anyone knowing. Ava’s vital signs during the visit are BP 95/70, HR 50, and temperature 97.0. Orthostatic vitals done in the office were normal. Ava also screened positively on the SCOFF.

1

Meet Charlotte

Charlotte is a 14-year-old female who presents to the PCP’s office for diarrhea. Charlotte’s mom reports that she goes to the bathroom immediately after eating, which she finds concerning. Recently, she found an empty package of chocolate laxatives in the garbage as well. She states that she frequently observes Charlotte eating large meals in one sitting, and often finds snack food wrappers hidden in Charlotte’s room. When interviewed alone, Charlotte expresses that she is unhappy with her body size. She also shares that she eats until she feels overly full three to four times per week. Due to guilt, she will then make herself vomit and use laxatives to prevent weight gain. Furthermore, Charlotte complains of frequent dizziness and heartburn. She is in the 75th percentile for weight, with a BMI of 23. Her vital signs during the visit are BP 100/76, HR 74, and temperature 98.1. Her orthostatic vitals were also normal.

Clinical Pearl: Eating Disorder Terminology

Although some patients with or without an eating disorder may bring up concerns about being fat, it may be best to avoid using the potentially pejorative word “fat” at all, instead asking about body shape and size. For instance, “Do you have concerns about your body shape and size?” or “Do you spend a lot of time and energy thinking about your body shape and size, and about your eating habits?” A positive response, which could indicate either an eating disorder or normative attitudes to eating, dieting, and body image, should trigger additional questions.

Three eating disorders that providers should be familiar with are anorexia nervosa, bulimia nervosa, and binge eating disorder. Individuals with anorexia and bulimia are preoccupied with food, have distorted body image, and engage in unhealthy behaviors related to controlling their body shape and size. In anorexia, the pattern involves severe restriction of food intake, compensatory measures to prevent weight gain from eating, such as purging through vomiting, or excessive exercise, or both. In bulimia, behavior involves eating an amount of food that is larger than normal over a short period of time (binging), followed by purging behaviors to prevent gaining weight from binges. In binge eating disorder, binges occur without accompanying clinically significant purging behaviors.

 

Psychosocial Assessment

An open-ended interview that encourages the patient, in a nonjudgmental way, to describe their eating, exercise habits, and any extreme methods used to prevent weight gain, along with concerns about body image and time spent thinking about food or body shape and size is crucial to characterizing the presence and severity of eating disorder symptoms. Questions aimed at eliciting symptoms of an eating disorder from the patient or caregiver can be incorporated into the provider’s standard psychosocial assessment, such as the commonly used mnemonic interview prompt “HEADSSS”. Topics specific to eating disorders include body dissatisfaction, use of supplements, excessive exercise, strict and rigid “healthy” eating, body image, self-esteem, stress management, mood, and eating patterns.

HEADSSS assessment  A mnemonic tool used commonly by providers to assess domains of psychosocial functioning that contain risk factors and protective factors for adolescent medical and mental health. These domains are as follows: Home, Education/employment, Activities, Drugs, Sexuality, Suicide/depression, and Safety). Questions about satisfaction with/preoccupation with body shape and size and eating and exercise behaviors may be incorporated into this wide-ranging psychosocial assessment to help detect and characterize eating disorder symptoms.

 

Physical Examination

An assessment of physical symptoms should be conducted to monitor symptoms associated with eating disorders and identify serious risk factors.

  • Menstrual patterns to identify amenorrhea (hypothalamic dysfunction, low estrogen state).
  • Targeted questions for differential diagnoses of conditions including malignancy, diabetes mellitus,; thyroid, celiac, inflammatory bowel disease.
  • Assessment of cardiac symptoms, such as dizziness, (pre-) syncope, exercise intolerance, palpitations, chest pain, which may signal cardiac injury, malnutrition, or orthostasis.
  • Abdominal symptoms such as constipation, delayed gastric emptying, decreased intestinal mobility, or pancreatitis.
  • Body mass index and height compared to standard growth charts (www.cdc.gov/growthcharts) and sexual maturity (adolescents), which may signal rapid weight loss, stunted growth and delayed puberty.
  • Height, including trends and percentiles (may signal stunted growth).
  • Blood pressure, including hypotension (may signal malnutrition or dehydration).
  • Heart rate, including bradycardia (may signal heart muscle wasting, metabolic changes).
  • Temperature, including presence of hypothermia (may signal thermoregulatory dysfunction).
  • Hair loss at scalp, including presence of lanugo.
  • Mouth, including presence of dental erosion, changes to salivary glands.
  • Skin and extremities for signs of self-harm and ,muscle wasting.
  • Laboratory testing may include Aamylase, basic metabolic panel, calcium, cholesterol, complete blood county, magnesium, phosphorus, prealbumin, and thyroid testing.

 

Clinical Pearl: Blinded Weights

Patients with eating disorders, especially anorexia nervosa, have frequent weight checks as a part of appropriate care. However, the process of being weighed and knowing one’s weight can cause significant distress and worsen eating disordered behavior. To minimize this, it is important for primary care providers to obtain blinded weights, where the displayed or recorded patient weight measured by the scale is visible to the provider, but not the patient. There should also be a process for providers and their staff to make this adjustment to care during appointments. Examples can include turning the patient away from the scale before weighing and covering the output display on digital scales.

 

Clinical Pearl: BMI Concerns

Concern for anorexia nervosa, prompting additional evaluation, should be higher both in patients with extremely low weight and BMI and in individuals with dramatic reduction in weight starting from an initially normal or high BMI, as seen by crossing several percentile curves on a standard growth chart. Individuals with binge eating disorder and bulimia do not typically have the extremely low BMI often seen in individuals with anorexia.

 

Clinical Pearl: Athletics and Eating Disorders

There is a relationship between athletic activities and eating disorders. There may be overlapping personality characteristics such as perfectionism and competitiveness. Certain athletic activities have a higher than usual correlation to eating disordered behaviors. Examples include judged (rather than refereed) sports like gymnastics and diving, sports such as wrestling where athletes must “weigh in” to a weight class, and activities such as ballet where individuals may associate leanness with aspects of both performance and aesthetics. Some activities, such as running, have a low correlation, but because those activities are very common, the number of individuals with an eating disorder who engage in those activities is significant.

 

Clinical Pearl: Weight Fluctuation

Other reasons for shifts in weight and BMI include gastrointestinal disease, thyroid dysfunction, and substance use.

 

Clinical Pearl: Obese Patients

Obese patients may still have an eating disorder, in particular binge eating disorder.

 

Clinical Pearl: Missing a Diagnosis

Patients who are at a normal weight or even overweight can also meet criteria for anorexia nervosa, but they may be missed because losing weight is considered healthy and it is not questioned.

For more information about screenings and assessments for eating disorders see What All Medical Professionals Should Know About Eating Disorders | National Eating Disorders Association.

Diagnostic Features

Common Diagnostic Features of Eating Disorders in Children and Adolescents include the following. For the full diagnostic criteria, see DSM-5 Eating Disorder Diagnosis Diagnostic Features.

Anorexia nervosa (AN)

Restricted caloric intake relative to energy requirements, leading to significant low body weight for age, sex, and projected growth. Intense fear of gaining weight and altered perception of one’s weight or shape.

Bulimia nervosa (BN)

Repeated episodes of binge eating include episodes of eating an amount of food that is clearly larger than most individuals would eat is accompanied by a feeling that one is unable to control overeating. Use of inappropriate compensatory behaviors (e.g., vomiting, fasting, misuse of laxatives) to prevent weight gain. It occurs at least once a week for three months.

Binge-eating disorder (BED)

Recurrent episodes of binge eating and three or of the following: eating much more quickly than normal in one sitting, eating until uncomfortably full, eating large amounts of food when not feeling hungry, eating alone because of embarrassment at how much one is eating, and feeling guilty, disgusted, or depressed after binging.

Avoidant/restrictive food intake disorder (ARFID)

A disrupted eating pattern (e.g., loss of interest or avoidance) and failure to meet nutritional and energy needs that leads to any of the following: significant weight loss, failure to achieve expected growth and/or weight gain, marked nutritional deficiency, reliance on enteral feeding or oral nutritional supplements, significant interference with psychosocial functioning

 

Clinical Pearl: Compensatory Mechanisms

Compensatory behaviors to prevent weight gain are a hallmark of anorexia and bulimia, including excessive exercise and purging. Self-induced vomiting is the most widely known type of purging behavior, but others can include misuse of diuretics, laxatives, enemas, and even intentionally forgoing or under-dosing insulin in individuals with type 1 diabetes. In addition to these compensatory behaviors, individuals with eating disorders may also misuse medications such as psychostimulants to reduce appetite and intake, thereby facilitating restricting behaviors.

2

Ava

Ava’s PCP sent her to receive STAT labs. CBC with differential showed that she had mild leukopenia. Her CMP indicated significant levels of hypernatremia and hypokalemia. The urine pregnancy test was negative, and urinalysis showed high specific gravity. Ava’s TSH was elevated, and her ECG showed sinus bradycardia. LH, FSH, estradiol, and prolactin were still pending at the time of re-evaluation. Ava was referred to a dietician and a psychologist who specializes in treating eating disorders.

2

Charlotte

Charlotte was sent for labs following her doctor's appointment. Her CMP levels were significant for hypokalemia, and urinalysis showed high specific gravity. Her CBC, TSH, and ECG were within normal limits. Charlotte was referred to a dietician and a psychologist who specializes in treating eating disorders.

Clinical Pearl: Limiting Physical Activity

Limitations on exercise and physical activity in patients with anorexia are appropriate, because excessive exercise as a compensatory behavior may be a problem at baseline and may increase if restricting behaviors are curtailed during treatment. Limitations are particularly urgent for those who display signs such as bradycardia, orthostatic hypotension, QTc prolongation, or electrolyte abnormalities, who may need medical stabilization prior to resuming significant physical activity.

Treatment

Non-Medication Management 

Psychotherapy is the most important component of treatment for eating disorders. Eating disorders treatment is often provided by a specialized multi-disciplinary treatment team and may not be within the skill set of all mental health practitioners. Timely referral to a practitioner who specializes in this type of treatment is recommended, if available.

Evidence-Based Treatments Include:

  • AN - Family-based therapy (FBT) is an evidence-based treatment and strongly preferred for adolescents with anorexia nervosa. FBT, also known as the Maudsley approach, engages family members to support healthy food choices and weight restoration until patients can resume independent eating. More intensive inpatient or community-based treatment may be necessary for patients who are medically unstable or require a more immediate level of care.
  • BN - Cognitive behavioral therapy (CBT), to address negative thought and behavior patterns is considered the most effective treatment for bulimia nervosa. Patients may initially require a more intensive treatment program to help them break the pattern of binge-purge behaviors.
  • BED - Psychotherapeutic approaches for patients with binge-eating disorders include CBT and dialectic behavioral therapy (DBT), which combines principles of CBT with techniques to gain insight and regulate emotions. In obese patients, psychotherapy should be coupled with weight loss treatment to address the physical and medical consequences of the disorder.

 

Clinical Pearl: Nutritional Needs

In anorexia nervosa, the nature of the disorder is that patients struggle to overcome their eating disordered thoughts and behaviors. For this reason, appropriate care often involves strict adherence to appropriate intake (to curtail restricted eating) and restriction from activities until nutrition is adequate; the patient may be ambivalent or outright against these steps. The degree of resistance, the response to limit-setting by family and providers, and the ability of a patient’s family to navigate this are likely to determine what level of care – from conventional outpatient care to intensive outpatient or partial hospitalization, all the way to inpatient care – is necessary to stabilize anorexia nervosa.

 

Clinical Pearl: Screening for Comorbidity

In some cases, the distress caused when eating disordered behaviors are interrupted is so great that a patient may express suicidal ideation. Screening for comorbid disorders such as depression and planning for safety is appropriate. In some cases, suicidal ideation is fleeting, and statements are an expression of severe distress right now, but the risk of suicide is low. In other cases, hopelessness and suicidal thoughts due to the severe distress persist, which is one reason that inpatient hospitalization to address the eating disorder and suicidal ideation may be necessary.

 

If resources do not exist locally, clinicians may partner with a health expert to manage patients with mild nutritional, medical, and psychological dysfunction. A multidisciplinary team may include a nutritionist and therapist who can guide parents to ensure that their children eat a sufficient diet and adjust portion size and caloric intake based on weight progress. For BN and BED, the primary goal of treatment is to re-establish regular eating patterns. The urge to binge can be minimized by eating regularly throughout the day.

For additional clinical guidance see:

 

Clinical Pearl: Resistance to Treatment

In anorexia nervosa, patients often both deny the seriousness of their illness and strongly resist treatment. These are common features of the condition, underscoring the importance for patients to be referred to specialty interdisciplinary teams that address eating disorders and have experience with patients whose care journey takes them through different treatment settings, including outpatient care and inpatient medical stabilization for malnourished patients who are medically unstable.

 

Medication Management Principles

Pharmacotherapy is not recommended as a monotherapy for eating disorders. Prescribing medications that affect electrolytes, QT interval, or heart rate should be prescribed with caution. While there are no FDA approved medications for Anorexia Nervosa, Selective Serotonin Reuptake Inhibitors (SSRIs) do have limited evidence for improving symptoms. SSRIs are approved to treat comorbid conditions such as anxiety, obsessive compulsive disorder (OCD), and depression.

An FDA approved medication in adolescents and adults for BN is the SSRI Fluoxetine (Prozac).

Pharmacotherapy may have more benefits in binge-eating disorder. Evidence supports the use of imipramine, topiramate, or selective serotonin reuptake inhibitors, particularly sertraline or citalopram, to reduce binge eating. For patients older than 18 years, lisdexamfetamine (30 mg daily, orally) was recently approved by the US Food and Drug Administration for treatment of binge-eating disorder.

When to Consider Medical Admission

Consider Medical admission if any of the following are present
<75% of ideal body weight or ongoing weight loss despite intensive management
Refusal to eat in the presence of other concerning finding
Heart rate <45 BPM during the day or <40 BPM at night
Systolic pressure <90 mm Hg
Orthostatic changes in pulse (>20 BPM) or blood pressure (>10 mmg Hg)
Core body temperature of <96° F
Arrhythmia, including prolonged QTc
Syncope
Serum potassium <3.3 mmol/L
Serum chloride <88 mmol/L
Esophageal tears or hematemesis
Intractable vomiting
Suicide Risk
Failure to respond to outpatient treatment

 

Ongoing Management

Recovery from eating disorders, and especially anorexia nervosa, can be a challenge, and partial recovery rather than full recovery is common. Furthermore, relapse is also common, especially in the first year of treatment of anorexia (Khalsa et al., 2017; Herzog et al., 1999).

Major roles for the primary care provider in ongoing management include:

  1. Monitoring (of weight, vital signs, laboratory studies, and signs and symptoms of malnutrition) for continued worsening of nutrition and associated complications over time.
  2. Encouraging patients and families to access specialty care for eating disorders despite ambivalence about treatment, lack of access, or other barriers to care.
  3. Detection of comorbid conditions over time which also may require clinical attention (particularly anxiety and depression, including suicidality).

3

Ava

Ava returns to her PCP's office four weeks after starting family-based therapy. She is much more interactive, and her mood is brighter. Her mom reports that she is doing much better with eating, though at first it was very difficult. She is now eating at least six small meals per day and continues to be seen by a dietician. She is also monitored for excessive exercise. Ava’s weight is up, and her BMI is now 17. Her vitals during today’s visit are BP 100/75, HR 60, and temperature 98.0.

3

Charlotte

Charlotte has a follow-up with her PCP six weeks after starting therapy. Her mom reports that she is no longer using laxatives and has significantly reduced her self-induced vomiting to less than once per week. Her family is monitoring the size of her meals and the time that she spends in the bathroom. When interviewed alone, Charlotte states that she has not used laxatives in four weeks. She is also no longer dizzy, and her heartburn has improved. She shares that she is currently working on body acceptance and negative patterns of thinking in therapy. Charlotte’s BMI is now 24. Her vital signs at today’s visit are BP 110/78, HR 76, and temperature is 98.2. She received repeat labs, which showed a resolution of her hypokalemia.

Resources

Educating young people and their parents about the physiologic and psychological effects of food restriction and the perpetuating nature of the restriction-binge-purge cycle is an early component of care (see Resources).

English: Treating Eating Disorders - HealthyChildren.org

Spanish: Tratamiento para los trastornos alimentarios - HealthyChildren.org

The UK's Eating Disorder Charity - Beat (beateatingdisorders.org.uk)

 

English: Is Your Teen at Risk for Developing an Eating Disorder? - HealthyChildren.org

Spanish: ¿Corre riesgo su adolescente de sufrir de un trastorno alimentario? - HealthyChildren.org

 

English: Boys and Eating Disorder - Child Mind Institute

Spanish: Niños varones y trastornos alimentarios- Child Mind Institute

 

Lock J, Le Grange D. Help Your Teenager Beat an eating disorder, 2nd ed. New York, NY: Guilford Press; 2015

Frequently Asked Questions (FAQs)

No. You cannot determine if an individual is struggling with an eating disorder by looking at their weight or body size.

Yes. Eating disorders have the second highest fatality rate among all mental illnesses.

Overeating at a special occasion, event or holiday is normal. Binge eating is a frequent loss of control, is usually secretive, and accompanied by shame, embarrassment, depression and guilt.

Yes. 10% of those with anorexia nervosa and bulimia are men, with 1/3 or more men with binge eating disorder.

References

  1. Herzog, D.B., Dorer, D.J., Keel, P.K., Selwyn, S.E., Ekeblad, E.R., Flores, A.T., Greenwood, D.N., Burwell, R.A., & Keller, M.B. (1999). Recovery and relapse in anorexia and bulimia nervosa: a 7.5-year follow-up study. Journal of the American Academy of Child Adolescent Psychiatry, 38(7):829-837. https://doi.org/10.1097/00004583-199907000-00012
  2. Hornberger, L., Lane, M., The Committee on Adolescence, Breuner, C., Alderman, E., Grubb, L., Powers, M., Upadhya, K., Wallace, S., Loveless, M., Menon, S., Zapata, L., Hua, L., Smith, K., & Bamberger, J. (2021). Identification and management of eating disorders in children and adolescents. Pediatrics, 147(1). https://doi.org/10.1542/peds.2020-040279
  3. Khalsa, S.S., Portnoff, L.C., McCurdy-McKinnon, D., & Feusner, J.D. (2017). What happens after treatment? A systematic review of relapse, remission, and recovery in anorexia nervosa. Journal of Eating Disorders, 5. https://doi.org/10.1186/s40337-017-0145-3
  4. Klein, D. A., Sylvester, J. E., & Schvey, N. A. (2021). Eating disorders in primary care: Diagnosis and management. American Family Physician, 103(1), 22–32.
  5. Morgan, J. F., Reid, F., & Lacey, J. H. (1999). The SCOFF questionnaire: Assessment of a new screening tool for eating disorders. BMJ (Clinical Research Ed.), 319. https://doi.org/10.1136/bmj.319.7223.1467
  6. National Eating Disorders Association. (2021). What all medical professionals should know about eating disorders. https://www.nationaleatingdisorders.org/blog/what-all-medical-professionals- should-know-about-eating-disorders
  7. Rome, E. S., & Strandjord, S. E. (2016). Eating disorders. Pediatrics in Review, 37(8), 323–336. https://doi.org/10.1542/pir.2015-0180