What is the differential diagnosis for a 33‑week preterm newborn who completed a course of antibiotics five days ago and is now experiencing non‑bloody, non‑bilious vomiting?

Differential Diagnosis for Non-Bloody, Non-Bilious Vomiting in a 33-Week Preterm Infant Five Days Post-Antibiotics

The most likely diagnoses in this clinical scenario are gastroesophageal reflux disease (GERD), necrotizing enterocolitis (NEC), or late-onset sepsis, with GERD being most common but NEC requiring urgent exclusion given the recent antibiotic exposure and prematurity. 1, 2

Primary Differential Considerations

Gastroesophageal Reflux Disease (GERD)

• GERD is the most common cause of recurrent non-bilious vomiting in infants, particularly in premature infants with immature lower esophageal sphincter function 1
• The vomiting is characteristically non-forceful regurgitation rather than projectile, and infants typically maintain adequate weight gain if this is the sole etiology 3, 1
• This diagnosis becomes more likely if the infant is tolerating feeds between episodes and showing no signs of systemic illness 1

Necrotizing Enterocolitis (NEC)

• Recent antibiotic exposure significantly increases NEC risk in preterm infants, making this a critical diagnosis to exclude despite the non-bilious nature of vomiting 2
• NEC can present with non-bilious vomiting initially before progressing to bilious emesis, abdominal distension, and bloody stools 4, 5
• The timing (5 days post-antibiotics) is particularly concerning, as prolonged antibiotic exposure disrupts the developing gut microbiome and increases NEC susceptibility 2
• Examine specifically for abdominal distension, feeding intolerance, lethargy, and temperature instability 1, 4

Late-Onset Sepsis

• Preterm infants remain at high risk for late-onset sepsis, which commonly presents with non-specific symptoms including vomiting 6
• Assess for fever, hypothermia, lethargy, poor perfusion, and increased oxygen requirements 1, 6
• The recent completion of antibiotics does not eliminate this risk, particularly in a 33-week preterm infant 6

Secondary Differential Considerations

Hypertrophic Pyloric Stenosis (HPS)

• While HPS typically presents between 2-8 weeks of age in term infants, it remains a consideration if vomiting becomes progressively forceful or projectile 7, 8
• Palpate for an epigastric "olive" mass in the right upper quadrant, though this is present in only 60-80% of cases 7
• The non-bilious nature fits HPS, but the timing and prematurity make this less likely than GERD or NEC 7

Malrotation with Intermittent Volvulus

• Malrotation can present at any age, not just in newborns, and may cause intermittent non-bilious vomiting before progressing to bilious emesis 3, 7
• This represents a surgical emergency if vomiting becomes bilious, as midgut volvulus can cause intestinal necrosis within hours 7, 8
• Maintain high vigilance for any change to bilious vomiting 7, 8

Metabolic Disorders

• Inborn errors of metabolism can present with vomiting and altered mental status in the neonatal period 3
• Assess specifically for lethargy, poor feeding, and abnormal neurologic examination 1

Infectious Gastroenteritis

• Viral gastroenteritis remains possible, though less common in hospitalized preterm infants 1
• Consider if there are other affected infants in the unit or recent exposure history 1

Critical Diagnostic Approach

Immediate Clinical Assessment

• Determine hydration status by evaluating capillary refill, urine output (should be ≥4 wet diapers per 24 hours), and mucous membranes 8
• Perform abdominal examination specifically assessing for distension, tenderness, visible bowel loops, and absent bowel sounds 4, 5
• Verify the vomiting remains non-bilious, as any green/bilious component immediately escalates urgency and changes the differential to surgical obstruction 7, 4, 5

Initial Imaging

• Obtain plain abdominal radiographs (supine and cross-table lateral or left lateral decubitus) to assess for dilated bowel loops, pneumatosis intestinalis (NEC), or obstruction patterns 3, 4
• If clinical suspicion for HPS develops (progressive projectile vomiting), abdominal ultrasound is the diagnostic modality of choice, looking for pyloric muscle thickness >3-4 mm and channel length >15-17 mm 7, 8

Laboratory Evaluation

• Consider complete blood count, C-reactive protein, and blood culture if sepsis is suspected based on clinical presentation 6
• Electrolytes to assess for metabolic alkalosis (seen in HPS) or metabolic acidosis (seen in NEC or sepsis) 7

Management Priorities

Immediate Interventions

• Place nasogastric or orogastric tube for gastric decompression if abdominal distension is present or NEC is suspected 4
• Initiate oral rehydration therapy with small, frequent volumes (5 mL every minute initially) if dehydration is present and no obstruction suspected 1, 8
• Make infant NPO (nothing by mouth) if NEC, obstruction, or surgical pathology is suspected pending definitive diagnosis 8, 4

Conservative Management Trial (if no red flags)

• If examination is benign and imaging unremarkable, consider a 2-4 week trial of smaller, more frequent feeds with positional therapy (upright positioning after feeds) 1, 8
• Continue full-strength formula or breast milk; do not dilute feeds 8

Critical Red Flags Requiring Urgent Escalation

• Bilious (green) vomiting at any point = surgical emergency until proven otherwise 7, 4, 5
• Abdominal distension with decreased or absent bowel sounds suggests intestinal obstruction or NEC 1, 4
• Blood in stool or vomit indicates mucosal injury and possible NEC or intussusception 1, 4
• Lethargy, temperature instability, or altered mental status suggests sepsis or metabolic disorder 1, 6
• Poor weight gain or weight loss distinguishes pathologic GERD from benign reflux 1, 7

Common Pitfalls to Avoid

• Do not dismiss non-bilious vomiting as benign reflux in a preterm infant with recent antibiotic exposure without excluding NEC 2
• Do not delay imaging if abdominal examination is abnormal or infant appears systemically ill 4, 5
• Always reassess for progression to bilious vomiting, which fundamentally changes the diagnosis to surgical obstruction 7, 4, 5
• Antiemetics are generally NOT indicated in preterm infants and may mask important clinical deterioration 8