What causes increased fussiness in a 3-month-old infant without fever or changes in bowel habits?

Differential Diagnosis of Increased Fussiness in a 3-Month-Old Infant Without Fever

In a 3-month-old male with increased fussiness, normal feeding patterns, no fever, and no otitis media, the primary differentials to consider are gastroesophageal reflux with possible aspiration, urinary tract infection (particularly in uncircumcised males), and benign paroxysmal conditions of infancy.

Immediate Assessment Priorities

Urinary Tract Infection (UTI)

• UTI remains a critical consideration even without fever, as approximately 5% of febrile infants without an apparent source have UTI, and irritability can be a presenting symptom 1
• Uncircumcised males have a 4-20 times higher UTI rate than circumcised males 1
• Obtain urine specimen via catheterization or suprapubic aspiration if clinical suspicion exists, as bag specimens are unreliable 1
• Diagnosis requires both pyuria/bacteriuria on urinalysis AND ≥50,000 CFU/mL on culture 1
• The absence of fever does not exclude UTI; irritability and fussiness may be the predominant symptoms in young infants 1

Gastroesophageal Reflux with Aspiration

• Consider swallowing dysfunction and aspiration in infants with persistent fussiness, particularly if feeding is intermittent ("on and off") 1
• Swallowing dysfunction is detected in 10-15% of infants with respiratory or feeding symptoms 1
• Sandifer syndrome should be suspected in young children with paroxysmal head tilt or abnormal posturing after eating, secondary to gastroesophageal reflux 1
• Video-fluoroscopic swallowing study can identify aspiration, with feeding modifications reducing aspiration by >90% 1

Age-Specific Benign Paroxysmal Conditions

Benign Myoclonus of Early Infancy (BMEI)

• Occurs between 4-7 months of age with myoclonic jerks mimicking spasms, but consciousness is preserved 1
• Episodes occur in clusters, triggered by excitement, frustration, or postural changes 1
• Normal interictal examination and EEG are required for diagnosis 1
• Resolves by age 2 years without treatment 1

Transient Dystonia of Infancy

• Onset typically 5-10 months with paroxysmal abnormal upper limb postures 1
• Normal interictal examination and neuroimaging 1
• Resolves between 3 months to 5 years without developmental abnormalities 1

Benign Paroxysmal Torticollis (BPT)

• Onset usually before 3 months of age with recurrent episodes of painless head tilt 1
• Episodes last minutes to days, alternating sides 1
• Associated with later development of migraines, suggesting age-dependent migraine disorder 1

Less Common but Important Considerations

Metabolic Disturbances

• Hypercalcemia can present with extreme irritability and fussiness, particularly in conditions like Williams syndrome 2
• Check serum calcium (total and ionized), albumin, and intact PTH if clinical suspicion exists 2
• Symptoms are often reversible with treatment (low-calcium diet, increased water intake) 2

Drug Withdrawal

• If maternal substance use history exists, consider neonatal withdrawal syndrome 1
• Opioid withdrawal develops in 55-94% of exposed neonates, presenting with irritability, hyperactivity, tremors, and excessive crying 1
• SSRI exposure causes crying, irritability, tremors, and feeding difficulty with onset in hours to days 1

Clinical Approach Algorithm

1. First, rule out serious bacterial infection:

   • Obtain catheterized urine for urinalysis and culture if infant appears uncomfortable or irritable 1
   • Consider UTI even without fever, especially in uncircumcised males 1

2. If feeding is truly "on and off" with fussiness:

   • Evaluate for gastroesophageal reflux and aspiration 1
   • Consider video-fluoroscopic swallowing study if symptoms persist despite conservative management 1
   • Look for Sandifer syndrome (head tilt after feeding) 1

3. If paroxysmal episodes are present:

   • Characterize timing, triggers, and duration of fussiness episodes 1
   • Consider benign paroxysmal conditions based on age and semiology 1
   • Ensure normal interictal examination 1

4. If persistent unexplained irritability:

   • Check serum calcium, albumin, and electrolytes 2
   • Obtain detailed maternal medication/substance use history 1

Critical Pitfalls to Avoid

• Do not dismiss UTI based solely on absence of fever; irritability may be the primary manifestation in young infants 1
• Avoid bag urine specimens as they have unacceptably high contamination rates; always use catheterization or suprapubic aspiration for culture 1
• Do not attribute all fussiness to "colic" without systematic evaluation for treatable causes 1
• Recognize that "feeding on and off" may indicate aspiration rather than simple feeding intolerance 1
• At 3 months of age, asymptomatic C. difficile colonization is common (up to 70%), so testing is not indicated without diarrhea 1