Recurrent Hypoglycaemia in the Newborn

Definition

• <45-50 mg/dL (point-of-care) within the first 48 hours of life
• <70 mg/dL beyond 48 hours of life

Pathophysiology of Glucose Homeostasis in the Newborn

Causes of Recurrent / Persistent Neonatal Hypoglycaemia

1. Hyperinsulinism (Most Common Cause Beyond Day 7)

A. Transient Hyperinsulinism

• IDM hypoglycaemia is driven by fetal hyperinsulinism from prolonged intrauterine hyperglycaemia; it usually resolves within 1-2 days with feeds. If it persists, further evaluation is mandatory.
• Perinatal stress-induced hyperinsulinism: neonates have high glucose utilisation, inappropriately normal or elevated insulin at the time of hypoglycaemia, suppressed beta-hydroxybutyrate, and a glucagon-responsive glucose rise of ~30 mg/dL. Responds well to diazoxide.

B. Congenital Hyperinsulinism (CHI)

• Incidence: 1/50,000 live births (up to 1/2,500 in consanguineous populations)
• Infants are typically large-for-gestational-age, with severe hypoglycaemia requiring glucose infusion rates >10 mg/kg/min

• KATP mutations are the most common and most severe form; most require pancreatectomy
• Focal vs. diffuse CHI can be distinguished by 18F-DOPA PET scan - focal disease may be cured by limited pancreatectomy

2. Counter-regulatory Hormone Deficiencies

Hypopituitarism / GH + ACTH deficiency

• Incidence of hypoglycaemia in hypopituitarism: ~20%
• Key clinical clues: midline defects (septo-optic dysplasia, cleft palate), micropenis (gonadotropin deficiency), cholestatic jaundice
• In the neonatal period, beta-hydroxybutyrate is NOT elevated (unlike older children)
• Low GH and cortisol at the time of hypoglycaemia confirm the diagnosis

Isolated GH deficiency or cortisol deficiency (CAH, Addison)

• CAH (21-hydroxylase): hypoglycaemia + salt-wasting + ambiguous genitalia

3. Inborn Errors of Metabolism

4. Other Causes

• Beckwith-Wiedemann syndrome (macroglossia, omphalocele, macrosomia, ear creases) - due to islet cell hyperplasia/CHI
• Kabuki syndrome - CHI documented
• Costello syndrome (HRAS mutations) - recurrent hypoglycaemia
• SGA/IUGR - depleted glycogen stores + hormonal immaturity

Diagnostic Approach to Recurrent Neonatal Hypoglycaemia

"Critical sample" at the time of hypoglycaemia (plasma glucose <45-50 mg/dL)

Glucagon stimulation test

• Rise ≥30 mg/dL = glycogenolytic response intact, suggests hyperinsulinism (glycogen stores full due to high insulin)
• Blunted rise = glycogen depletion, GSD, or gluconeogenic defect

Glucose infusion rate (GIR)

• Normal newborn: 4-6 mg/kg/min
• >8 mg/kg/min needed to maintain normoglycaemia = strong indicator of hyperinsulinism
• >10 mg/kg/min = congenital hyperinsulinism until proven otherwise

Profile interpretation

Management

Immediate (any neonatal hypoglycaemia)

1. Enteral feeds (breast or formula) - first-line if clinically stable
2. Buccal dextrose gel (40%) - 200 mg/kg; effective in at-risk term neonates
3. IV dextrose - 10% dextrose, 2 mL/kg bolus (200 mg/kg), then continuous infusion titrated to maintain glucose

Treatment Goals

• Suspected congenital hypoglycaemia disorder: maintain plasma glucose >70 mg/dL
• High-risk neonate, no congenital disorder: >45-50 mg/dL at <48 hours; >60 mg/dL at >48 hours

For Persistent / Recurrent Hypoglycaemia (Hyperinsulinism)

• Mechanism: opens beta-cell ATP-sensitive K+ channels (KATP), hyperpolarises membrane, inhibits insulin release
• Dose: 5-15 mg/kg/day in 2-3 divided doses
• Requires concurrent chlorothiazide to counteract fluid retention
• Black box warning: rarely associated with pulmonary hypertension in neonates (requires echocardiogram before and during use)
• Effective in: perinatal stress hyperinsulinism, GDH/GLUD1, SCHAD, HNF4A/1A mutations
• NOT effective in: KATP channel mutations (ABCC8/KCNJ11)

• Second-line; inhibits insulin secretion via Gi-protein
• Used when diazoxide fails or is contraindicated
• Risk of necrotising enterocolitis, tachyphylaxis

• Useful as a bridge while establishing diagnosis or preparing for surgery
• 0.01-0.02 mg/kg/hour IV

• For diazoxide-unresponsive CHI
• Focal lesion (KATP mutation): localised resection after 18F-DOPA PET - potentially curative
• Diffuse disease: near-total pancreatectomy (>95-98%) - risk of diabetes and exocrine insufficiency

For Counter-regulatory Deficiencies

• GH deficiency: recombinant GH
• Cortisol deficiency / CAH: hydrocortisone replacement

For Metabolic Disorders

• Disease-specific dietary management (e.g. avoid fasting in MCAD, restrict galactose in galactosaemia)

Neurodevelopmental Consequences

Summary Algorithm

Recurrent/Persistent Neonatal Hypoglycaemia
            |
   Obtain Critical Sample at nadir
            |
    ┌───────┴────────┐
 Insulin         Insulin
 detectable      undetectable
    |                 |
Hyperinsulinism   ┌──┴──────────────┐
    |            Low BHB/FFA    High BHB/FFA
  GIR >8?       (FA Oxidation)   (GH/Cortisol
    |            Defect)         deficiency)
 Diazoxide
 trial
    |
 Responsive? → Yes: Perinatal stress / GDH / HNF
 No? → Genetic testing + 18F-DOPA PET
       → Surgery if focal CHI

• The Harriet Lane Handbook (23rd ed.), Chapter 10 - Neonatal Hypoglycaemia Evaluation
• Henry's Clinical Diagnosis and Management by Laboratory Methods - Hypoglycaemia in Infancy and Childhood (Congenital Hyperinsulinism)
• Creasy & Resnik's Maternal-Fetal Medicine - Neonatal Hypoglycaemia
• Recent reviews: Garg & Devaskar, Eur J Pediatr 2025 (PMID 40119223) on long-term impacts and safe glucose thresholds

Seizures in the Newborn (Neonatal Seizures)

Why Neonatal Seizures Are Different

1. Clinical presentation is often subtle

• Lip-smacking or chewing
• Eye deviation or blinking
• Bicycling or pedalling leg movements
• Apnoeic episodes with colour change (pallor/cyanosis)
• Tonic posturing of a limb
• Stiffening of the body

2. GABA is excitatory, not inhibitory, in the immature brain

• NKCC1 (Na-K-Cl cotransporter 1) drives Cl- into the cell, keeping intracellular Cl- high
• KCC2 (K-Cl cotransporter 2) - which extrudes Cl- - is underexpressed at birth

Etiology - By Day of Presentation

Day 1 (Most Common Causes)

Days 2-3

Days 3-7+

Seizure Types (Neonatal Classification)

Neonatal Epilepsy Syndromes

Benign

• Benign familial neonatal epilepsy (BFNE): autosomal dominant mutations in KCNQ2, KCNQ3, or SCN2A (voltage-gated K+/Na+ channels); onset first week; remit within first year; good neurodevelopment
• "Fifth-day fits": non-familial; onset days 4-6; partial seizures, discontinuous EEG theta; good prognosis

Severe (Epileptic Encephalopathies)

• Ohtahara syndrome / Early Infantile Epileptic Encephalopathy (EIEE): intractable tonic seizures + burst-suppression EEG; genetic aetiology; may evolve into West syndrome
• Early Myoclonic Encephalopathy (EME): erratic shifting myoclonus + burst-suppression; often metabolic (non-ketotic hyperglycinaemia)
• KCNQ2 encephalopathy: neonatal seizures with EEG burst-suppression; responds to sodium channel blockers

Treatable Metabolic Epileptic Encephalopathies (Must Not Miss)

Diagnosis

Clinical Assessment

• Full birth history (asphyxia, prematurity, instrumental delivery)
• Maternal history (diabetes, drug use, infection, medications - beta-blockers)
• Family history (genetic epilepsy syndromes)
• Physical exam: dysmorphic features (genetic syndrome), anterior fontanelle (raised ICP), skin lesions (HSV, tuberous sclerosis), microcephaly

Immediate Investigations (Emergency)

Second-Line Investigations

EEG - the Gold Standard

• Continuous video-EEG monitoring is the definitive tool to detect and quantify seizures - especially electrographic-only seizures
• Amplitude-integrated EEG (aEEG): bedside tool; useful for monitoring but may miss focal seizures
• Neonatal EEG findings include discontinuous theta activity, focal sharp waves, and burst-suppression patterns

Management

Step 1: Treat the Cause First

• Hypoglycaemia: 10% dextrose 2 mL/kg IV bolus
• Hypocalcaemia: Calcium gluconate 10% - 1-2 mL/kg IV slowly
• Hypomagnesaemia: Magnesium sulphate 50% - 0.2 mL/kg IV/IM
• Infection: Empiric IV antibiotics (ampicillin + gentamicin) + acyclovir (for HSV)
• Pyridoxine trial: 100 mg IV if seizures refractory to 2nd-line agents, with EEG monitoring

Step 2: Anti-Seizure Medications (ASMs)

First-Line: Phenobarbital

• Dose: 20 mg/kg IV loading dose; may repeat 10 mg/kg x1-2 if seizures persist (max 40 mg/kg)
• Maintenance: 3-5 mg/kg/day in 1-2 divided doses
• Effective in ~50% of neonatal seizures
• Mechanism: enhances GABA-A, inhibits glutamate
• Limitation: GABA is excitatory in immature neurons (reduced efficacy); respiratory depression risk
• Exception: If channelopathy suspected (family history of genetic epilepsy), use phenytoin or carbamazepine (sodium channel blockers) as first line

Second-Line Options (if phenobarbital fails)

Pyridoxine (Vitamin B6)

• 100 mg IV with EEG monitoring - seizure cessation within minutes supports pyridoxine-dependent epilepsy
• A trial should be attempted in any neonate with seizures unresponsive to second-line ASMs

Step 3: When to Stop ASMs

• After acute provoked seizures resolve and there is no evidence of neonatal-onset epilepsy - stop ASMs before discharge, regardless of MRI or EEG findings
• This applies even if MRI shows brain injury - maintenance ASMs do not improve outcomes in this context

Therapeutic Hypothermia

• In HIE, therapeutic hypothermia (33-34°C for 72 hours) reduces seizure burden and improves neurodevelopmental outcome
• An evidence-based ILAE recommendation

Prognosis

• Further hypoxic-ischaemic brain injury (MR spectroscopy evidence)
• Suppression of neuronal stem cell proliferation
• Later neurodevelopmental impairment (cognitive, motor, epilepsy)

Summary Algorithm

Neonate with suspected seizure
          |
   Confirm on EEG (video-EEG or aEEG)
          |
   Immediate: Check glucose, electrolytes (Ca, Mg, Na)
   Treat reversible cause FIRST
          |
   Blood/CSF cultures → Empiric antibiotics + acyclovir
          |
   Imaging: cranial US → MRI brain
          |
   Still seizing?
          |
   PHENOBARBITAL 20 mg/kg IV (1st line)
          |
   No response → Phenytoin OR Levetiracetam OR Midazolam
          |
   Still refractory?
          → Pyridoxine 100 mg IV (with EEG)
          → PLP, folinic acid
          → Genetic testing (gene panel)
          |
   Seizures resolved - stop ASMs before discharge
   (if no ongoing epilepsy)

• Bradley and Daroff's Neurology in Clinical Practice - Neonatal Seizures (Chapter 110)
• Adams and Victor's Principles of Neurology, 12th ed. - Neonatal Seizures
• Tintinalli's Emergency Medicine - Neonatal Seizures
• Henry's Clinical Diagnosis and Management by Laboratory Methods
• 2023 ILAE Task Force Guidelines: Pressler RM et al., Epilepsia 2023 - Treatment of seizures in the neonate (evidence-based recommendations)
• Cochrane Review: Abiramalatha T et al., Cochrane Database Syst Rev 2023 (PMID 37873971) - Anti-seizure medications for neonates