What are the differential diagnoses for leukocytosis (elevated white blood cell count) in a newly born neonate?

Differential Diagnoses of Neonatal Leukocytosis

Leukocytosis in a newly born neonate is most commonly caused by bacterial sepsis (particularly Group B Streptococcus and Escherichia coli), but must be differentiated from physiologic stress responses, maternal factors, and rare congenital disorders.

Infectious Causes

Early-Onset Bacterial Sepsis (Most Common)

• Group B Streptococcus (GBS) is the leading cause of early-onset neonatal sepsis, particularly in term infants born to mothers with chorioamnionitis 1, 2
• Escherichia coli is the second most common pathogen, especially prevalent in preterm infants and cases with maternal chorioamnionitis 2
• Other gram-negative organisms including Klebsiella and Pseudomonas species should be considered 2
• Leukocytosis with an elevated band/total neutrophil ratio (I/T ratio ≥0.2) is highly predictive of sepsis, with 93% sensitivity when combined with other abnormal tests 3

Fungal Sepsis

• Candida species (particularly C. albicans and C. parapsilosis) cause invasive candidiasis in 3-10% of very low birth weight neonates 1
• Thrombocytopenia and elevated C-reactive protein accompany leukocytosis but are nonspecific for candidiasis 1

Maternal and Perinatal Factors

Chorioamnionitis

• Maternal chorioamnionitis significantly increases risk of neonatal sepsis and associated leukocytosis 1, 2
• All infants born to mothers with chorioamnionitis should undergo limited evaluation including CBC with differential and platelets 1, 2

Amniotic Fluid Infection Risk Factors

• Multiple risk factors (prolonged rupture of membranes >24 hours, maternal fever, preterm labor) increase sepsis risk to 10% compared to 1.3% with single factors 4
• An I/T ratio ≥0.2 identifies 21% of at-risk neonates with actual sepsis 4

Physiologic and Stress-Related Causes

Normal Neonatal Stress Response

• Birth stress, crying, and immediate postnatal adaptation can cause transient leukocytosis
• This typically resolves within 24-48 hours without other signs of sepsis 1

Leukemoid Reaction

• Severe bacterial infection can trigger extreme leukocytosis (WBC ≥100,000/µL) mimicking leukemia 5
• Sepsis-induced leukemoid reactions respond to appropriate antibiotic therapy with gradual WBC normalization 5

Congenital and Hematologic Disorders

Leukocyte Adhesion Deficiency

• Rare immunodeficiency presenting with persistent severe leukocytosis and fulminant sepsis 6
• Diagnosed by flow cytometry showing absent or reduced CD11/CD18 expression 6
• Should be suspected when leukocytosis persists despite appropriate antibiotic therapy 6

Congenital Leukemia (Rare)

• Down syndrome-associated transient myeloproliferative disorder presents with leukocytosis in 5% of newborns with trisomy 21 1
• GATA1 mutations characterize these cases, which usually resolve spontaneously 1

Diagnostic Approach

Initial Laboratory Evaluation

• CBC with differential and platelet count at birth and repeated at 6-12 hours of life provides optimal sensitivity 1
• Blood culture before antibiotic initiation is essential 1, 7
• I/T ratio ≥0.2 combined with leukopenia (<5,000/µL) has 100% sensitivity for sepsis 4, 3

"Sepsis Screen" Criteria

• Two or more abnormal tests from: I/T ratio ≥0.2, WBC <5,000/µL, positive C-reactive protein, elevated ESR, or positive haptoglobin 3
• When ≥2 tests positive: 39% have proven sepsis, additional 23% have "very probable" infection 3
• When <2 tests positive: 99% probability sepsis is absent 3

Common Pitfalls to Avoid

• Do not delay antibiotics while awaiting culture results in symptomatic neonates; initiate ampicillin plus gentamicin immediately after obtaining cultures 7, 2
• Do not rely solely on maternal GBS screening; infants can develop GBS disease despite negative maternal screening 2
• Do not start antibiotics based on risk factors alone without laboratory evaluation, as this leads to indiscriminate antibiotic use 4
• Do not assume leukocytosis alone indicates infection; combine with I/T ratio and clinical signs for accurate assessment 4, 3