Neonatal Sepsis

Definition & Overview

• Tintinalli's Emergency Medicine, p. 773
• Miller's Anesthesia, p. 11455

Classification: Early-Onset vs. Late-Onset

• Tintinalli's Emergency Medicine, p. 773

Causative Organisms

• Group B Streptococcus (GBS) - most common bacterial pathogen; causes severe cardiorespiratory instability and meningitis in 30% of cases. By 2-3 weeks of age, more commonly associated with meningitis than pulmonary disease.
• Escherichia coli - second most common, especially in preterm neonates
• Listeria monocytogenes - causes early-onset sepsis (in utero infection, diagnosed within 48h) and late-onset meningitis (~2 weeks of age, full-term infants)
• Klebsiella spp., Enterobacter spp., Haemophilus influenzae
• Gram-positive cocci (beta-hemolytic streptococci)
• Herpes simplex virus - particularly fulminant; active lesions in the birth canal are an indication for caesarean section
• TORCH pathogens - can mimic bacterial sepsis when CNS depression, circulatory collapse, or thrombocytopenia occurs
• Miller's Anesthesia, p. 11455
• Rosen's Emergency Medicine, p. 1714

Clinical Features

• Temperature instability - fever (rectal ≥38°C/100.4°F) or hypothermia (<36.5°C/97.7°F)
• CNS dysfunction - lethargy, irritability, seizures
• Respiratory distress - apnea, tachypnea, grunting
• Feeding disturbance - vomiting, poor feeding, gastric distension, diarrhea
• Jaundice
• Rashes or petechiae
• Metabolic - hypoglycemia, metabolic acidosis
• Circulatory - poor cutaneous perfusion, hypotension

Differential Diagnosis

• Congenital heart disease (ductal-dependent lesions presenting in the first week with shock as the duct closes - easily mistaken for sepsis)
• Inborn errors of metabolism
• Congenital adrenal hyperplasia
• Intracranial hemorrhage
• Abdominal catastrophe (malrotation/volvulus, NEC)
• Tintinalli's Emergency Medicine, p. 773

Risk Factors for EOS

• Maternal GBS colonization (positive vaginal swabs)
• Maternal fever / chorioamnionitis
• Prolonged rupture of membranes
• Fetal distress
• Prematurity (≤34 weeks especially high risk)
• Preterm labor, cervical insufficiency, prelabor ROM
• Inadequate intrapartum antibiotic prophylaxis (IAP)

• Red Book 2021, p. 1103-1104

Investigations

• Blood cultures (only ~50% of suspected septic neonates have positive cultures)
• Urine culture
• CSF analysis and culture - lumbar puncture is part of the standard workup; should be considered in clinically ill infants when GBS EOS is highly suspected (unless procedure would compromise clinical condition)
• CBC with differential (neutropenia is a marker of early-onset disease)
• CRP, metabolic panel, glucose

Treatment

Antibiotic Therapy

• Ampicillin 50-100 mg/kg IV (covers GBS, Listeria, Enterococcus)
• Gentamicin (aminoglycoside) 2.5-4 mg/kg IV (covers E. coli and other gram-negatives)

• If gram-negative meningitis is strongly suspected: replace gentamicin with cefotaxime or ceftazidime 50 mg/kg (better CNS penetration)
• Avoid ceftriaxone in neonates - can displace bilirubin from albumin and cause kernicterus
• Add IV acyclovir if: maternal history of herpes, suspicious CSF findings (lymphocyte and RBC predominance on non-traumatic LP), or any ill-appearing neonate

• Tintinalli's Emergency Medicine, p. 774
• Rosen's Emergency Medicine, p. 1714

GBS Prevention (Intrapartum Antibiotic Prophylaxis)

• Creasy & Resnik's Maternal-Fetal Medicine

Recent Evidence (2025)

• A 2025 meta-analysis (PMID 40555905) reviewed antibiotic strategies for neonatal sepsis, highlighting efficacy concerns and emerging antimicrobial resistance patterns - an important clinical consideration when selecting empiric regimens.
• A 2025 Cochrane review (PMID 40105375) assessed molecular (PCR) assays for neonatal sepsis diagnosis, providing updated data on their diagnostic accuracy as alternatives to blood culture.

Summary Points

1. Sepsis is the most common cause of neonatal cardiorespiratory distress; fever OR hypothermia should prompt evaluation
2. Early-onset (<7 days) is fulminant and maternally acquired; late-onset (>7 days) is more insidious and more commonly causes meningitis
3. GBS and E. coli are the dominant pathogens; Listeria requires ampicillin coverage
4. Clinical signs are non-specific - maintain a low threshold for full workup and empiric treatment
5. Standard empiric therapy: ampicillin + gentamicin; avoid ceftriaxone; add acyclovir when herpes is possible
6. Only ~50% of suspected cases yield positive cultures

Neonatal Seizures

Overview

• Bradley and Daroff's Neurology in Clinical Practice, p. 2854

Pathophysiology

• In adult neurons, GABA-A receptor activation causes chloride influx → membrane hyperpolarization → inhibition
• In immature neurons, there is net chloride efflux with GABA-A activation → membrane depolarization → excitation
• This is because the chloride exporter KCC2 (which maintains low intracellular Cl⁻) is immature. The importer NKCC1 dominates instead, keeping intracellular chloride high.
• As the neonate matures, KCC2 expression becomes dominant, reversing this effect.

• Neuronal injury via disturbances in cerebral energy metabolism and excitotoxicity
• Recurrent shorter seizures → long-term morphological/physiological deficits including suppression of neuronal stem cells
• Independent association with further hypoxic-ischemic brain injury (MR spectroscopy) and later neurodevelopmental impairment

• Bradley and Daroff's Neurology in Clinical Practice, p. 2854-2855

Etiology

1. Hypoxic-Ischemic Encephalopathy (HIE) - accounts for ~50% of neonatal seizures in term newborns; ~30% in preterm (where intracranial hemorrhage is equally common)
2. Intracranial hemorrhage - accounts for ~30% in preterm newborns
3. Metabolic:
   • Hypoglycemia (most frequent metabolic cause)
   • Hypocalcemia (tetany; now less common)
   • Hyponatremia, hypomagnesemia
   • Pyridoxine (B6) deficiency - rare but treatable; responds to IV pyridoxine 100 mg; may even cause in utero seizures
   • Biotinidase deficiency
   • Nonketotic hyperglycinemia, maple syrup urine disease, other inborn errors
4. CNS infection - meningitis (GBS, E. coli, Listeria), HSV encephalitis
5. Structural/Congenital CNS abnormalities - 5-10% of cases; dysplasia (seizures often refractory)
6. Perinatal stroke - focal clonic seizures in a term newborn are most commonly associated with focal cerebral infarction
7. Drug withdrawal - maternal narcotics
8. Non-accidental trauma

• Bradley and Daroff's Neurology in Clinical Practice, p. 2855-2856
• Adams and Victor's Principles of Neurology, p. 352

Neonatal Epilepsy Syndromes

• Benign Familial Neonatal Epilepsy (BFNE) - autosomal dominant; mutations in voltage-gated K⁺ channels KCNQ2, KCNQ3 (also SCN2A); onset first week of life; seizures remit within first year; normal neurodevelopment
• Benign Neonatal Seizures ("fifth-day fits") - clonic convulsions starting days 2-7; discontinuous theta on EEG; good prognosis, rarely recur
• Ohtahara Syndrome - severe epileptic encephalopathy; intractable tonic seizures + burst-suppression on EEG; caused by increasing number of genetic mutations; may evolve into West or Lennox-Gastaut syndromes
• Early Myoclonic Encephalopathy - erratic focal myoclonus shifting asynchronously, burst suppression on EEG
• Pyridoxine-dependent epilepsy (antiquitin/ALDH7A1 deficiency) - responds to pyridoxal phosphate + folinic acid; biomarkers: elevated urinary α-aminoadipic semialdehyde (AASA) and CSF pipecolic acid
• Bradley and Daroff's Neurology in Clinical Practice, p. 2855

Clinical Features and Semiology

• Bradley and Daroff's Neurology in Clinical Practice, p. 2857
• Tintinalli's Emergency Medicine
• Adams and Victor's Principles of Neurology

Distinguishing Seizures from Non-Epileptic Events

Electroencephalography

1. Sudden electrographic change
2. Repetitive waveforms evolving in morphology, frequency, and/or location
3. Amplitude ≥2 μV
4. Duration ≥10 seconds

• Bradley and Daroff's Neurology in Clinical Practice, p. 2857

Investigations

• Blood glucose (treat hypoglycemia immediately)
• Electrolytes: Na⁺, K⁺, Cl⁻, HCO₃⁻, BUN, creatinine
• Calcium, magnesium
• CBC with differential
• Lactic acid, ammonia, serum amino acids, urine organic acids (for inborn errors of metabolism)

• Blood, urine, CSF cultures
• CSF: cell count, protein, glucose, HSV PCR
• LP should be performed (meningitis is not clinically reliable to exclude in young infants)

• Head CT if non-accidental trauma, hemorrhage, or infarction suspected
• MRI is preferred for structural assessment once stabilized
• Bedside head ultrasound if neonate is unstable (to screen for neurosurgical emergency)

• Rosen's Emergency Medicine, p. 1262
• Tintinalli's Emergency Medicine, p. 2678

Treatment

Step 1: Treat Reversible Causes Immediately

• Hypoglycemia: IV dextrose (D10W 2-4 mL/kg)
• Hypocalcemia: IV calcium gluconate
• Hypomagnesemia: IV magnesium sulfate
• Hyponatremia: Correct cautiously

Step 2: Antiepileptic Drugs

• Standard first-line agent for neonatal seizures
• Loading dose IV; maintenance dosing follows
• Limitation: Growing evidence of phenobarbital-induced neuronal apoptosis even with a single dose, and evidence of memory/learning difficulties in animal models. This has prompted investigation of alternatives.

• If seizures continue after phenobarbital loading

• Benzodiazepine infusion (lorazepam, midazolam)
• Levetiracetam (see note below)

• Pyridoxine 15-30 mg/kg/day (max 500 mg/day) IV, can repeat over 30 minutes - with concurrent EEG monitoring (can induce apnea)
• Alternatively: folinic acid + pyridoxal phosphate for 3 days pending genetic results
• Stop if no improvement; continue if clinical response

• Sodium channel blockers (phenytoin, carbamazepine) are particularly effective

Antimicrobials

• Start empiric parenteral antibiotics (ampicillin + aminoglycoside/cefotaxime) if infection suspected
• Add IV acyclovir if HSV encephalitis is possible (maternal herpes history, skin/mucosal lesions, CSF RBCs, no other clear cause)
• Rosen's Emergency Medicine, p. 1268-1270
• Tintinalli's Emergency Medicine, p. 2687
• Bradley and Daroff's Neurology in Clinical Practice, p. 2856

Recent Evidence: Phenobarbital vs. Levetiracetam

• A systematic review and meta-analysis (PMID 37938514) compared levetiracetam vs. phenobarbital for neonatal seizures.
• A second meta-analysis (PMID 40975024) evaluated efficacy and safety of levetiracetam vs. phenobarbital.

Prognosis

• Neonatal seizures within 24-48h of a difficult birth (usually HIE): severe cerebral damage; many infants succumb; ~50% of survivors are severely disabled
• Seizures with onset days-weeks after birth (metabolic, hereditary): more often treatable if identified early; better prognosis with specific therapies (pyridoxine, biotin)
• Benign familial neonatal epilepsy: good prognosis, seizures remit by first year of life
• "Fifth-day fits": good prognosis, normal development, rarely recur
• Ohtahara / early myoclonic encephalopathy: poor; often evolves to West or Lennox-Gastaut syndromes
• Early myoclonic jerks with burst-suppression EEG pattern = particularly ominous
• Seizures associated with HIE → independently associated with later neurodevelopmental impairment
• Adams and Victor's Principles of Neurology, p. 352
• Bradley and Daroff's Neurology in Clinical Practice, p. 2855

Key Summary Points

1. Neonatal seizures are almost always acute symptomatic; HIE is the most common cause in term neonates
2. Seizures are often subtle (lip-smacking, bicycling, eye deviation) - full tonic-clonic is uncommon
3. EEG is mandatory - clinical detection is unreliable in both directions
4. The GABA/NKCC1-KCC2 developmental imbalance explains why phenobarbital may be less effective
5. Workup must include glucose, electrolytes (Ca, Mg), LP with HSV PCR, and neuroimaging
6. Treat immediately: correct metabolic causes, start phenobarbital (first-line), add acyclovir if HSV is possible
7. Consider pyridoxine empirically in seizures of unknown etiology
8. All neonates with seizures require hospital admission and neurological evaluation