Continuing Education Activity

Constipation, a common gastrointestinal ailment, is a condition that affects individuals of all ages, from newborns to older individuals, transcending gender, race, and socioeconomic backgrounds. Characterized by infrequent and often difficult bowel movements, constipation is more than just a symptom. It can significantly impact an individual's quality of life and, if left unmanaged, may lead to various health complications. Constipation contributes substantially to healthcare use in the United States and globally. The condition encompasses various subtypes, including functional constipation, chronic idiopathic constipation, and secondary constipation, each with distinct underlying factors and clinical features. It is essential to understand the clinical evaluation of a patient with constipation. This activity reviews the multifaceted nature of constipation, shedding light on its causes, symptoms, prevalence, and the importance of effective management for maintaining overall well-being. It also emphasizes the critical role of the interprofessional team in coordinating the care of the patient with constipation.

Objectives:

• Identify the various etiologies of constipation.
• Select appropriate diagnostic tests to identify underlying conditions contributing to constipation.
• Implement evidence-based interventions for constipation management, including lifestyle modifications, dietary changes, and pharmacological options.
• Collaborate with an interprofessional team to provide and coordinate comprehensive care for patients with constipation.

Introduction

Constipation is a symptom or condition characterized by difficult and infrequent bowel movements, typically 3 or fewer times a week. It is one of the most common gastrointestinal complaints in the United States and a common reason for referral to colorectal surgeons and gastroenterologists.[1][2] Constipation is a prevalent condition that often remains unrecognized until the patient starts having sequelae, such as anorectal disorders. 

Constipation encompasses several subtypes, each with its unique characteristics and underlying factors. Functional constipation, a common subtype, often affects children and adults and is marked by infrequent and difficult bowel movements without any evident structural or organic cause. Functional constipation is common in childhood, with about 29.6% prevalence worldwide. It comprises 3% to 5% of pediatric visits in the United States and represents a high annual healthcare cost. Most patients do not have an etiological factor, and one-third continue to have issues beyond adolescence. Up to 84% of functionally constipated children suffer from fecal incontinence, while more than one-third of children present with behavioral problems due to constipation. The pathophysiology underlying functional constipation is multifactorial and not well understood. Factors contributing to functional constipation include pain, fever, dehydration, dietary and fluid intake, psychological issues, toilet training, medicines, and a family history of constipation.[3][4][5]

Chronic idiopathic constipation is another common subtype characterized by irregularity in defecation and difficulty in passing stool. Unlike functional constipation, where underlying factors may be apparent, chronic idiopathic constipation lacks a clear physiological or anatomical explanation for the persistent discomfort and irregularity in defecation. An underlying cause is identified in <5% of cases. This subtype is defined by its chronic nature, often lasting for an extended period and its primary symptom of infrequent and challenging bowel movements. Management typically involves a combination of lifestyle modifications, dietary changes, and, in some cases, pharmacological interventions to alleviate symptoms and improve the patient's quality of life.

Secondary constipation, a third subtype of constipation, can be linked to specific causes such as medications, certain medical disorders, dietary issues, or structural abnormalities in the gastrointestinal tract. The treatment approach for secondary constipation often involves addressing the root cause, including adjusting medications, managing underlying health conditions, or making dietary modifications. Proper identification and management of these underlying factors are essential in effectively alleviating constipation symptoms.

Understanding these subtypes is pivotal for healthcare professionals as it guides tailored approaches to diagnosis and treatment, optimizing patient care and outcomes.

Etiology

Causes of constipation can be divided into the following broad categories:

Primary or Idiopathic

A diagnosis of exclusion, this category includes constipation due to fecal withholding behaviors. Organic causes have been ruled out. It can generally be divided into the following:

1. Normal-transit constipation (NTC) - although the transit of the stool through the colon is at a normal rate, it is difficult for patients to evacuate their bowels.
2. Slow-transit constipation (STC) - is characterized by infrequent bowel movements, diminished urgency, or straining to defecate. In addition, these patients have impaired phasic colonic motor activity.
3. Pelvic floor dysfunction - is distinguished by impaired musculature of the pelvic floor. Patients often report a feeling of incomplete evacuation, prolonged or excessive straining, or the use of perineal pressure during defecation.

Dietary Causes

Dietary issues that cause constipation include inadequate fiber intake, inadequate water intake, and overuse of coffee, tea, or alcohol. Reduced levels of exercise may also play a role.[6]

Anatomic Causes

Structural causes of constipation include anal stenosis or atresia, anal fissure, anteriorly displaced anus, imperforate anus, thrombosed hemorrhoids, intestinal stricture, obstructing tumors, and anal stricture.[7]

Abnormal Musculature

These disorders include prune belly syndrome, gastroschisis, Down syndrome, and muscular dystrophy.[8]

Neurologic Causes

Disorders with issues in the neurological structure of the intestine include Hirschsprung disease, pseudo-obstruction, intestinal neuronal dysplasia, spinal cord defects, tethered cord, and spina bifida. Other neurological disorders that could lead to constipation include stroke, Parkinson disease, multiple sclerosis, Chagas disease, and familial dysautonomia.[9]

Drugs

Medications contributing to constipation include anticholinergics, narcotics, antidepressants, lead, iron, bismuth, calcium channel blockers, nonsteroidal anti-inflammatory drugs, psychotropic drugs, and vitamin D intoxication.[10]

Metabolic and Endocrine Causes

Metabolic or endocrinologic disorders that cause constipation include hypokalemia, hypercalcemia, hypothyroidism, diabetes mellitus (DM), and diabetes insipidus.

Miscellaneous Causes

Other causes of constipation include celiac disease, cow milk protein allergy, cystic fibrosis, inflammatory bowel disease, and scleroderma.

Epidemiology

Chronic constipation is excessively prevalent and affects about 15% of the population in the United States.[11] In 2006, the number of visits to healthcare professionals for constipation reached 5.7 million, and 2.7 million visits listed constipation as the primary diagnosis.[12] Approximately 12% of people worldwide report self-defined constipation; people in the Asian Pacific and the Americas suffer twice as much as the European population.

Constipation can occur in any age group, from newborns to older individuals; overall, it is seen more commonly in females than males. An age-related increase in the prevalence of constipation has been seen, with 30% to 40% of adults over 65 citing constipation as a problem.[13] Also, the nonwhite population has been reported to have a 30% higher prevalence than the white population.[14][15][16]

In children, the pattern and frequency of defecation depends on age. During the neonatal period and early infancy, bowel movements can occur more than 4 times per day, eventually trending to 1 to 2 per day by toddler age. At this point, children usually have achieved voluntary control of their sphincters. 

Pathophysiology

The pathophysiology of constipation is multifaceted and not entirely understood. It involves a complex interplay of factors affecting the gastrointestinal tract, nervous system, and pelvic muscles. Common contributors include reduced colonic motility, delayed transit of stool, impaired rectal sensation, and ineffective coordination of pelvic floor muscles during defecation.

These issues can result from a variety of causes, including:

• Low fiber diet
• Poor dietary habits
• Lack of fluid intake
• Caffeine abuse
• Overuse of alcohol
• Medications
• Sedentary lifestyle
• Endocrine disorders (hypothyroid)
• Neurologic disease (neuropathy)
• Psychological issues [17][18]

History and Physical

The diagnosis of constipation should not rely simply on asking the patient whether they are constipated, as this limited inquiry is associated with significant underreporting in patients with physical evidence of constipation, including hemorrhoidal disease.[19] Therefore, a thorough history should be obtained, including the history of medications, previous colonoscopies, surgeries, and underlying or pertinent medical issues. A detailed history of the patient's usual pattern of defecation and the frequency of altered defecation patterns compared to the usual pattern, such as 'missing a day.' The patients should also be asked about the perceived hardness of the stools, any other symptoms the patient may be experiencing, and whether the patient strains to defecate.

Concerning historical features include the following:

• Rectal bleeding
• Abdominal pain
• Vomiting
• Loss of appetite
• Unexplained weight loss
• Family history of gastrointestinal malignancy
• Inability to pass flatus
• Abdominal mass
• A feeling of incomplete evacuation
• Digital extraction
• Straining
• Tenesmus
• Enema retention

The physical examination begins with the patient's weight and overall nutritional status. The patient's abdomen is examined for distention, high-pitched or absent bowel sounds, tenderness, or masses. The rectal examination includes careful inspection and palpation for masses, hemorrhoids, anal and perianal fissures, inflammation, rectal prolapse, and hard stool in the ampulla. Evidence of fecal soiling and the color and consistency of the stool should be noted. A focused neurologic examination should be performed, and the patient should also be evaluated for signs of depression, anxiety, and somatization.

A thorough history is particularly significant as part of a complete evaluation of a child with constipation. Important information includes the time after the birth of the first bowel movement, the period the condition has been present, the incidence of bowel movements, consistency and the size of the stools, whether defecation is painful, whether blood is present on the stool or toilet paper, and if defecation is associated with abdominal pain. Also, it is essential to inquire about soiling, which can be mistaken for diarrhea in some patients. Medications can be related to constipation, such as opiates, sucralfate, and antacids.[20] A psychosocial history is essential to evaluate the family structure, the number of members living at home and the child's relationship to them, interaction with his peers, and the possibility of abuse.

The physical exam of an infant or child should include an assessment of concerning features or 'alarm' signs. For example, bloody diarrhea in an infant with constipation could indicate a diagnosis of Hirschsprung disease.[21] On abdominal examination, distention or a palpable "mass" may be appreciated in the lower abdomen. A rectal exam should be performed to identify the presence of impacted stool or an intrarectal mass. Visual and digital anal inspection should be carried out to ensure normal size and positioning of the anal opening and to assess for rectal prolapse.

 Adult and pediatric Rome IV criteria are helpful in making the diagnosis of functional constipation (see below for an outline of Rome IV criteria).

Evaluation

An extensive workup of the patient with constipation should be performed on an outpatient basis. Usually, the workup starts after 3 to 6 months of failed medical management. It is worthwhile to repeat rectal and perineal examinations at this point, even if it has been previously performed. Anorectal tests help distinguish defecatory disorders if over-the-counter options do not relieve constipation.[2] Laboratory investigations do not play a significant role in the initial evaluation of constipation.

Routinely using any specific imaging or laboratory test in diagnosing pediatric functional constipation is not recommended. However, when symptoms fail to improve with a conventional medical approach, further diagnostic evaluation may clarify possible causes and help guide therapy. Such diagnostic tests include anorectal manometry, colonic manometry, colonic transit studies, and imaging such as x-ray and ultrasonography.[22][23][24] Regional colonic transit pattern does not conclusively identify evacuation disorders in constipated patients with delayed colonic transit.[25]

Laboratory Studies

Due to rectal bleeding, patients can develop anemia, appearing on a complete blood cell (CBC) count. Fecal occult blood testing in patients with constipation should be carried out to rule out the possibility of an obstructing neoplasm of the colon.[26] The white blood cell count is helpful in patients with fever or abdominal pain, as it could indicate an underlying ileus. This could lead to further, more aggressive investigations. Thyroid function tests could also be helpful as hypothyroidism is one of the recognized causes.[27] Thyroid-stimulating hormone (TSH) levels should be checked to rule out hypothyroidism in patients whose constipation is refractory to dietary management. A metabolic profile may include causative factors, such as hypokalemia and hypercalcemia.

Radiography

In patients with symptoms suggesting systemic or intra-abdominal pathology, imaging studies help rule out causes of sepsis or intra-abdominal issues. Therefore, an upright chest radiograph and a flat and upright abdominal x-ray are appropriate investigations. The abdominal film can reveal fecal loading in the colon. Differentiation could also be made between fecal impaction, bowel obstruction, and fecalith. Diagnosing fecaliths is essential due to the dreaded complication of stercoral ulcers, leading to colonic perforation.

Abdominal computed tomography (CT) can establish the diagnosis of an abdominal abscess. Acute constipation with an empty rectal vault and a dilated proximal colon with air or stool indicates large bowel obstruction, which needs further evaluation via a Gastrografin enema or lower gastrointestinal endoscopy.

Anorectal Manometry

Anorectal manometry evaluates motor and sensory anorectal function to identify potential causes of constipation or fecal incontinence. This test aids in the Hirschsprung disease diagnosis, but the gold standard test is a rectal suction biopsy.

Colonic manometry consists of the colonoscopic insertion of a catheter throughout the length of the colon to measure segmental pressures. This diagnostic modality helps identify neurogenic and myogenic causes of constipation. However, there is no specific motility pattern that is diagnostic of idiopathic constipation.

Colonic Transit Studies

These studies use radiopaque markers to assess the speed of intestinal transit. This evaluation can help identify anatomic sites of fecal retention and slow transit.

Defecography

This should be carried out if an obstruction is possible at the anal canal level. In this technique, the rectosigmoid is filled with barium paste, and the process of defecation is observed fluoroscopically. This test may demonstrate changes in the anorectal angle during defecation, transient rectal prolapse, intussusception, or pelvic floor weakness.[28]

Treatment / Management

The treatment of adults with constipation involves a comprehensive approach that addresses the underlying causes and focuses on promoting regular bowel movements and symptom relief. Initially, dietary and lifestyle modifications play a crucial role, emphasizing increased fiber intake from fruits, vegetables, whole grains, and adequate hydration to soften stools. Scheduled bathroom time and regular physical activity further aid in improving bowel regularity. For patients with pelvic floor dysfunction, physical therapy focusing on the pelvic floor can be helpful. Biofeedback therapy, or cognitive-behavioral therapy, can be beneficial, particularly when stress or anxiety exacerbates symptoms. Over-the-counter medications such as bulk-forming agents, stool softeners, or osmotic agents may provide short-term relief, but their extended use should be monitored. 

When these measures prove insufficient, prescription medications may be considered. Multiple options exist. A bicyclic fatty acid derived from prostaglandin E1, lubiprostone, a chloride channel activator, increases intestinal fluid and accelerates GI transit. Lubiprostone is FDA-approved for the indications of chronic idiopathic constipation and IBS-C. It can be utilized in conjunction with or instead of over-the-counter medications. Nausea is a dose-dependent adverse effect that can be minimized by taking it with food. The dose for chronic idiopathic constipation is 24 μg 2 times daily. Lubiprostone is contraindicated in patients with known or suspected mechanical GI obstruction and should be used at a lower dose in patients with hepatic insufficiency.[29]

Linaclotide, a guanylate cyclase-C agonist, is also FDA-approved for treating chronic idiopathic constipation at 72 μg or 145 μg daily doses. Patients should take linaclotide without food at least 30 minutes before the first meal of the day. A known or suspected mechanical GI obstruction is a contraindication, and diarrhea is a possible adverse effect.[29]

Another prescription alternative approved for chronic idiopathic constipation is plecanatide, a pH-dependent guanylate cyclase-C agonist. A dose of 3 mg daily, taken with or without food, is recommended. Plecanatide increases luminal chloride and bicarbonate secretion, thereby increasing intestinal fluid and accelerating GI transit. Diarrhea may occur, leading to a discontinuation of the medication.[29]

An additional option, prucalopride, a selective agonist of serotonin 5-HT₄ receptors, induces and increases the amplitude of colonic high-amplitude propagated contractions, thereby increasing bowel movement frequency and relieving constipation symptoms. The recommended dose is 2 mg once daily in adults and 1 mg daily in individuals with significant renal impairment. Side effects include headache, abdominal pain, nausea, and diarrhea. Prucalopride is contraindicated in patients with Crohn's disease, ulcerative colitis, intestinal perforation or obstruction, and toxic megacolon.[29]

Patients with disorders such as colonic inertia may require total abdominal colectomy with ileorectal anastomosis.

Treating adults with secondary constipation involves addressing the underlying causes or contributing factors that have led to this condition. Primary among these is medication review and adjustment, as many drugs can disrupt normal bowel function. Healthcare professionals may consider switching medications or altering dosages when possible. Managing medical conditions responsible for secondary constipation, such as thyroid disorders or neurological issues, is crucial. Depending on the specific cause, additional treatments may be necessary, including interventions for structural abnormalities in the gastrointestinal tract. In all cases, a personalized approach that targets the root cause while managing symptoms ensures effective treatment and improved quality of life.

Management of pediatric constipation includes medical supervision, dietary instructions, behavioral changes, and instructions regarding toilet training. A normal fiber intake, fluid intake, and physical activity level are recommended, and the routine use of prebiotics or probiotics is not recommended in treating childhood constipation. The non-pharmacological intervention consists of demystification, explanation, and guidance for toilet training in those children with a developmental age of at least 4 years.[30][31][32]

Laxatives represent first-line treatment for childhood constipation; if an adequate regimen is implemented, they often have a symptomatic improvement. Consensus guidelines recommend daily polyethylene glycol (PEG) of 1 to 1.5 g/kg per day for 3 to 6 days for initial fecal disimpaction, followed by a daily maintenance dose of 0.4 g/kg per day for at least 2 months to prevent reaccumulation. A stimulant laxative should be added if PEG alone does not cause disimpaction after 2 weeks of treatment. Other pharmacological agents used for treating constipation include the following:

• Bulk-forming agents (fiber)
• Emollient stool softeners
• Rapidly acting lubricants
• Prokinetics
• Laxatives
• Prosecretory drugs
• Osmotic agents

Polyethylene glycol is reported to be effective in some cases. The FDA has also approved prucalopride and lubiprostone for chronic idiopathic constipation. However, there continues to be a debate about the safety of these agents in the long run, and caution is advised against starting patients on these drugs. FDA approved linaclotide in 2012 for chronic idiopathic constipation and for constipation associated with IBS in adults.[33] Chronic constipation that does not respond well to laxatives could be due to using medications, such as opioids, defecation disorders, and colonic dysmotility.[34] Peripherally acting mu-opiate antagonists, such as methylnaltrexone, naldemedine, and naloxegol, could help treat opioid-induced constipation.[35]

Biofeedback has improved defecation dynamics but does not affect constipation. Hence, this approach has not been supported for managing idiopathic constipation in children.

Sacral nerve stimulation is a modality that has been used to treat refractory constipation, helping extrinsic neural control of the large bowel and modulating inhibitory reflexes. This has improved the defecation frequency in some children with functional constipation, but effects were found to last less than 6 months in a large group of patients.

Surgical management is reserved for patients refractory to medical interventions. At least 10% of children with functional constipation referred to a pediatric surgeon will require an operation. The surgical treatment goal is to produce symptom alleviation. Surgical options may include anal procedures, antegrade enemas, colorectal resection, and intestinal diversion. Benign outlet obstruction because of prolapse may be managed via stapled transanal rectal resection or anopexy.[36][37] Laparoscopic ventral rectopexy has also been advocated for this problem, although this may be more invasive.

Differential Diagnosis

Differential diagnosis of constipation is extensive and inclusive of:

• Abdominal hernias
• Anal fissure
• Anorectal malformations
• Anxiety disorders 
• Appendicitis
• Chagas disease (American trypanosomiasis)   
• Colorectal cancer 
• Colonic obstruction
• Crohn disease 
• Depression 
• Diverticulitis 
• Dysfunctional voiding 
• Hirschsprung disease
• Hypopituitarism (Panhypopituitarism)   
• Hypothyroidism  
• Ileus
• Internal anal sphincter hypertonicity or achalasia
• Intestinal motility disorders
• Intestinal obstruction
• Irritable bowel syndrome (IBS)    
• Large bowel obstruction 
• Multiple endocrine neoplasia type 2 (MEN 2)
• Ogilvie syndrome
• Pelvic floor dyssynergia
• Pelvic/rectal masses
• Peritonitis and abdominal sepsis
• Rectal prolapse
• Rectocele 
• Toxic megacolon

In addition to the above disorders, consideration should be given to the following:

• Psychosocial issues
• Medications
• Spinal cord anomalies
• Cystic fibrosis
• Connective tissue disorders
• Celiac disease
• Cow’s milk protein allergy
• Parkinson disease

Prognosis

Most patients with constipation are managed well with holistic treatment, and most improve. A small percentage of adult patients are severely debilitated due to constipation. At least 30% of children with constipation will remain symptomatic until adulthood. 

Factors associated with a worse prognosis are female gender, older age of onset, longer time between symptom presentation and starting therapy, and longer colonic transit time. In some cases, treatments do not work; even when they work, the benefits are short-lived.

In many patients, recurrence of constipation is common, chiefly due to a lack of compliance with the diet. For the significant number of people who become disabled because of chronic constipation, their quality of life can be poor. A few patients who fail to respond to medical management may need to undergo total abdominal colectomy; however, patient selection is vital for a good outcome. The most difficult patients are those addicted to laxatives, who will not change their lifestyle and continue to use a variety of laxatives.[4][38]

Complications

The effect of constipation on a patient's life depends on the severity of the constipation and the underlying diagnosis. Some of the more common complications of constipation include the following: 

• Abdominal discomfort or cramps
• Poor quality of life
• Hemorrhoids
• Anal fissures
• Damage to the pelvic floor
• Fecal incontinence
• Urinary retention
• Stercoral perforation
• Rectal prolapse
• Volvulus
• Fistula-in-ano

Deterrence and Patient Education

Patient education about constipation is a crucial component of its management. It empowers individuals to understand their condition and actively participate in their well-being. Patients should be educated about the common causes of constipation, such as dietary factors, inadequate fluid intake, and sedentary lifestyles. Individuals with constipation should also learn the importance of a balanced fiber-rich diet, regular physical activity, and vigorous hydration to promote healthy bowel movements. Dietary deficiency often requires excess fluid and fiber supplementation for life. Education on the importance of adherence to treatment plans, recognizing constipation symptoms, and when to seek medical attention is essential for patient empowerment and management. By providing patients with this knowledge and practical strategies, healthcare professionals can help prevent constipation, improve patients' quality of life, and reduce the risk of complications associated with this common gastrointestinal issue.

Pearls and Other Issues

A diagnosis of functional constipation can be made using Rome IV diagnostic criteria revised in 2016. 

Adult Rome IV criteria establish a functional constipation diagnosis when a patient has experienced 2 or more of the following over the preceding 6 months:

• Fewer than 3 spontaneous bowel movements per week
• Straining for more than 25% of defecation attempts
• Lumpy or hard stools for at least 25% of defecation attempts
• Sensation of anorectal obstruction or blockage for at least 25% of defecation attempts
• Sensation of incomplete defecation for at least 25% of defecation attempts
• Manual maneuvering required to defecate for at least 25% of defecation attempts

Additionally, the patient must rarely have loose stools present without using a laxative and must not meet Rome IV criteria for irritable bowel syndrome (IBS).

Pediatric Rome IV criteria are met when at least 2 of the following are present for at least 1 month in infants and children up to 4 years. For children older than 4 years of age, symptoms should last for at least 2 months:

• Fewer than 3 spontaneous bowel movements per week
• At least 1 episode of fecal incontinence per week after the child has acquired complete bowel control
• History of extensive fecal retention or withholding behavior by the child
• Hard and painful stools 
• Large fecal mass on digital rectal examination
• Large diameter of stools causing rectal outlet obstruction or that obstruct the toilet [39]  

Enhancing Healthcare Team Outcomes

Constipation is seen in patients of all ages, and the causes are diverse. The condition affects millions of people, and the treatment is overall unsatisfactory. An interprofessional team best manages the disorder with a multidisciplinary approach.

Healthcare professionals must develop expertise in assessing and managing constipation. This includes proficiency in taking comprehensive patient histories, performing physical examinations, and interpreting diagnostic tests. Collaborative strategies involve a patient-centered approach. Healthcare professionals should individualize care plans, considering the patient's age, gender, underlying conditions, and medication history. A strategic approach may include dietary and fluid recommendations, medications, physical therapy, and behavioral interventions.

A diet high in fiber is essential. A dietary consult may be necessary to educate the patient on what foods to eat. In addition, the patient must be told to refrain from using laxatives, avoid drugs that cause constipation, and exercise regularly. Drinking ample water and avoiding too much alcohol and coffee may also help. For those habituated to laxatives, a gastroenterology consult is necessary.[40][41]

If laxatives are prescribed, the pharmacist should assist the team by educating the patient regarding the risks and benefits. If constipation persists, patients may be tried on pharmacological therapy. Pharmacists should be knowledgeable about various medications and their potential impact on bowel function, while nurses need proficiency in administering these medications. Clinicians should be aware of the potential adverse effects of constipation medications, monitor for complications, and promptly address any concerns.

Constipation may be a chronic condition requiring long-term management. An interprofessional team must coordinate care over time, monitor treatment effectiveness, and adjust strategies as needed. Care coordination helps prevent gaps in care, reduces unnecessary interventions, and ensures continuity of care. Communication about changes in the patient's condition is crucial to ensuring prompt interventions if needed.

A tailored therapeutic approach aims to enhance the quality of life by achieving regular, comfortable, and sustainable bowel movements for patients with constipation. A collaborative approach executed by an interprofessional team promotes a more holistic and effective response to this common and potentially debilitating condition.

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Disclosure: Sorangel Diaz declares no relevant financial relationships with ineligible companies.

Disclosure: Khaled Bittar declares no relevant financial relationships with ineligible companies.

Disclosure: Muhammad Hashmi declares no relevant financial relationships with ineligible companies.

Disclosure: Magda Mendez declares no relevant financial relationships with ineligible companies.