10.3 Neonatal Hypoglycaemia, Hyperbilirubinaemia & Neonatal Sepsis (NICE NG195)

Neonatal Hypoglycaemia, Hyperbilirubinaemia & Neonatal Sepsis (NICE NG195)

Following birth, the newborn must achieve independent metabolic, haematological, and immunological equilibrium. Failure of physiological adaptation during the early postnatal period can manifest as life-threatening metabolic collapse, neurotoxic jaundice, or fulminant septic shock. Midwives play a vital frontline role in early risk stratification, bedside physiological monitoring, and initiating time-critical clinical bundles. Clinical practice across the United Kingdom is governed by guidelines from the British Association of Perinatal Medicine (BAPM) and the National Institute for Health and Care Excellence (NICE guideline NG195 [Neonatal infection] and CG98 [Jaundice in newborn babies under 28 days]).

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Part 1: Neonatal Hypoglycaemia

Transition & Glucose Homeostasis

In utero, the fetus receives a continuous transplacental supply of maternal glucose via facilitated diffusion, maintaining fetal blood glucose concentrations at approximately 70% to 80% of maternal levels. Immediately upon umbilical cord clamping at birth, this exogenous glucose supply ceases abruptly. The healthy term infant undergoes an orchestrated endocrine surge: circulating insulin levels plummet, while glucagon, epinephrine, and cortisol surge, activating hepatic glycogenolysis and gluconeogenesis alongside adipose tissue lipolysis (generating free fatty acids and ketone bodies as alternative cerebral substrates).

• All healthy neonates experience a transient, physiological nadir in blood glucose concentration between 1 and 2 hours of life, which typically recovers spontaneously above 2.0 to 2.5 mmol/L by 4 to 6 hours as enteral feeds are established.

At-Risk Neonatal Populations

Routine universal blood glucose screening in healthy, asymptomatic, term infants with no risk factors is unnecessary and harmful. However, targeted surveillance is mandatory in defined high-risk cohorts:

1. Infants of Diabetic Mothers (IDM): Maternal hyperglycaemia drives excess glucose across the placenta, stimulating fetal pancreatic beta-cell hyperplasia. The resulting fetal hyperinsulinaemia persists postnatally, suppressing hepatic gluconeogenesis and lipolysis, causing profound rebound hypoglycaemia within 2 to 4 hours of birth.
2. Preterm Infants (<37 weeks): Born with blunted hepatic glycogen stores, minimal subcutaneous fat reserves, and immature gluconeogenic enzyme pathways.
3. Small for Gestational Age (SGA) & Intrauterine Growth Restriction (IUGR): Birth weight <10th centile; suffering from antenatal placental insufficiency with depleted glycogen and adipose tissue stores.
4. Large for Gestational Age (LGA): Birth weight >90th centile; often associated with undiagnosed maternal gestational glucose intolerance and transient hyperinsulinaemia.
5. Stressed / Compromised Neonates: Infants with intrapartum hypothermia (<36.0°C), perinatal asphyxia/hypoxia, or neonatal sepsis, which dramatically accelerate metabolic glucose consumption.

Clinical Presentation

Midwives must recognize that clinical signs of neonatal hypoglycaemia are often subtle and non-specific:

• Neurological: Jitteriness / fine tremors (crucially, tremulousness from hypoglycaemia is stimulus-sensitive and suppressible by gently flexing or holding the infant's limb, unlike non-suppressible clonic epileptic seizures), hypotonia ("floppiness"), lethargy, high-pitched or abnormal cry, poor feeding, irritability, and in severe cases, frank neonatal seizures or coma.
• Cardiorespiratory & Autonomic: Tachypnoea (respiratory rate >60 breaths/min), apnoea, cyanotic episodes, hypothermia, diaphoresis, and pallor.

                    ┌──────────────────────────────────────────────┐
                    │   BAPM 2024 HYPOGLYCAEMIA PATHWAY (TERM)     │
                    └──────────────────────┬───────────────────────┘
                                           │
         ┌─────────────────────────────────┴─────────────────────────────────┐
         ▼                                                                   ▼
┌──────────────────────────────────┐               ┌──────────────────────────────────┐
│ AT-RISK BABY, NO ABNORMAL SIGNS  │               │  BG <1.0, OR <2.5 WITH SIGNS     │
│ • Feed within first hour         │               │ • Urgent medical review          │
│ • BG before the second feed      │               │ • Admit to Neonatal Unit         │
│ • If BG 1.0–1.9 mmol/L:          │               │ • IV 10% glucose 2.5 mL/kg       │
│   - 40% oral gel 200 mg/kg       │               │ • Then IV 10% glucose infusion   │
│     (about 0.5 mL/kg)            │               │   starting at 60 mL/kg/day       │
│   - Support a feed               │               │ • Gel or IM glucagon only while  │
│   - Recheck before next feed     │               │   IV access is being obtained    │
└──────────────────────────────────┘               └──────────────────────────────────┘

Operational Thresholds & Management Framework

The British Association of Perinatal Medicine (BAPM) 2024 framework for term babies (birth to 72 hours) uses operational thresholds at which clinicians should act:

• Operational Thresholds: a blood glucose below 1.0 mmol/L at any time; a single value below 2.5 mmol/L in a baby with abnormal clinical signs; or more than two measurements below 2.0 mmol/L in an at-risk baby without signs.
• At-Risk Baby without Abnormal Signs: feed within the first hour and measure blood glucose before the second feed (at 2 to 4 hours of age).
• Blood Glucose 1.0 to 1.9 mmol/L (no abnormal signs):
  • Give 40% oral glucose gel 200 mg/kg (about 0.5 mL/kg) massaged into the buccal mucosa, alongside feeding support (up to two doses 30 minutes apart per episode, and no more than six doses in 48 hours).
  • Support an immediate breastfeed, or give expressed breast milk or formula as part of a feeding plan.
  • Recheck glucose as the pathway directs. If more than two measurements are below 2.0 mmol/L, inform the neonatal team and look for causes such as sepsis.
  • Oral gel raises glucose without separating mother and baby, protecting breastfeeding.
• Blood Glucose below 1.0 mmol/L, or below 2.5 mmol/L with Abnormal Signs:
  • Arrange urgent medical review, admit to the Neonatal Unit and take hypoglycaemia screening bloods before treatment if this causes no delay.
  • Give IV 10% glucose 2.5 mL/kg, then start an IV 10% glucose infusion at 60 mL/kg/day, adjusted by the neonatal team.
  • If IV access is delayed, give oral gel (200 mg/kg) or IM glucagon 200 micrograms/kg as an interim measure only.
  • Hyperinsulinism is suspected if glucose stays low despite adequate feeding or needs more than 8 mg/kg/min of glucose.

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Part 2: Neonatal Hyperbilirubinaemia & Jaundice

Bilirubin Metabolism

Neonates produce bilirubin at more than twice the adult rate (6–8 mg/kg/day) owing to their elevated circulating haematocrit (50%–60%) and shorter red blood cell lifespan (70 to 90 days, compared to 120 days in adults). Reticuloendothelial breakdown of haemoglobin produces lipid-soluble, unconjugated (indirect) bilirubin, which binds reversibly to circulating serum albumin.

• Unconjugated bilirubin is transported to the liver, where it is taken up by hepatocytes and conjugated into water-soluble conjugated (direct) bilirubin by the enzyme uridine diphosphoglucuronosyltransferase (UGT1A1).
• Conjugated bilirubin is excreted via bile into the intestine. However, the sterile neonatal bowel contains the mucosal enzyme beta-glucuronidase, which deconjugates direct bilirubin back into unconjugated bilirubin, allowing it to be reabsorbed into the portal circulation via the enterohepatic circulation.

Physiological vs. Pathological Jaundice

Prolonged Jaundice & Biliary Atresia

Prolonged jaundice is defined as jaundice persisting beyond 14 days in term infants or 21 days in preterm infants. While frequently benign (breast milk jaundice, caused by beta-glucuronidase and epidermal growth factors in human milk that enhance enterohepatic reabsorption):

• The midwife must ensure an urgent split bilirubin measurement (conjugated vs. unconjugated fractions) is performed.
• If conjugated bilirubin is >25 micromol/L, it signifies obstructive cholestatic hepatobiliary disease, most critically biliary atresia (fibro-obliterative destruction of the extrahepatic biliary tree).
• Biliary atresia demands immediate paediatric surgical referral for a Kasai portoenterostomy (hepatoportoenterostomy), which must be executed before 60 days of life to prevent irreversible biliary cirrhosis, liver failure, and death.

Clinical Assessment & Measurement (NICE Guidelines)

• Visual Inspection: Jaundice progresses in a cephalocaudal direction (Kramer's zones: Zone 1 face ~100 mcmol/L; Zone 5 palms and soles >250–300 mcmol/L). Visual estimation is notoriously subjective and inaccurate, especially in infants with deeply pigmented skin, in artificial fluorescent lighting, or following phototherapy.
• Transcutaneous Bilirubinometer (TcB): A non-invasive multi-wavelength optical sensor placed against the sternum or forehead. Recommended by NICE for infants ≥35 weeks' gestation and >24 hours of age.
• Serum Bilirubin (SBR): Gold standard blood test. An SBR must be performed if:
  • Jaundice develops within the first 24 hours of life;
  • TcB reads >250 micromol/L;
  • TcB reading is within 50 micromol/L of the phototherapy treatment threshold on the gestational age-specific NICE chart; or
  • The infant is currently receiving or has received phototherapy.

Phototherapy & Kernicterus

• Mechanism of Phototherapy: Exposes the infant's skin to narrow-spectrum blue-green light (wavelength 460 to 490 nm). The light penetrates subcutaneous tissue, converting neurotoxic lipid-soluble unconjugated 4Z,15Z-bilirubin via structural photo-isomerisation into lumirubin, a stable, water-soluble structural isomer that bypasses the liver and is excreted directly into bile and urine without requiring conjugation.
• Phototherapy Nursing Care: Fit protective opaque eye shields to prevent retinal phototoxicity; maximize naked skin exposure; maintain a neutral thermal environment; promote frequent milk feeds (every 2 to 3 hours) to prevent dehydration and stimulate bowel motility; monitor fluid balance and stool consistency (transient loose green stools are common).
• Kernicterus (Chronic Bilirubin Encephalopathy): When unbound unconjugated bilirubin exceeds albumin-binding capacity, it crosses the blood-brain barrier and deposits selectively within the basal ganglia (globus pallidus), subthalamic nuclei, and auditory brainstem pathways. Early acute signs include lethargy, hypotonia, and poor suck, progressing to high-pitched crying, retrocollis, and opisthotonos (severe hyperextension of neck and spine). Chronic kernicterus results in permanent choreoathetoid cerebral palsy, upward gaze palsy, and sensorineural deafness.

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Part 3: Early-Onset Neonatal Sepsis (NICE NG195)

Early-onset neonatal sepsis (EOS) is defined as invasive bacterial infection occurring within the first 72 hours of life. It typically results from vertical transmission of maternal vaginal or gastrointestinal microflora ascending into the amniotic cavity or during passage through the birth canal.

Pathogens

• Group B Streptococcus (GBS / Streptococcus agalactiae): The primary causative organism, responsible for ~50% of EOS cases in the UK. Causes fulminant neonatal pneumonia, septic shock, and meningitis.
• Escherichia coli (E. coli): The primary Gram-negative coliform (~20% of cases), carrying high mortality and common in preterm infants.
• Listeria monocytogenes, Staphylococcus aureus, and Enterococci.

NICE NG195 Risk Stratification: Red Flags vs. Other Risk Factors and Indicators

NICE guideline NG195 (updated 2026) separates risk factors (box 1, mostly maternal) from clinical indicators (box 2, observations in the baby), and marks some of each as red flags:

                    ┌──────────────────────────────────────────────┐
                    │      NICE NG195 EARLY-ONSET INFECTION        │
                    └──────────────────────┬───────────────────────┘
                                           │
         ┌─────────────────────────────────┴─────────────────────────────────┐
         ▼                                                                   ▼
┌──────────────────────────────────┐               ┌──────────────────────────────────┐
│          ANY RED FLAG            │               │  ≥2 NON-RED-FLAG FACTORS/SIGNS   │
│ • Infection in co-twin/multiple  │               │ • ROM >18 h before preterm birth │
│ • Apnoea                         │               │ • ROM >24 h before term birth    │
│ • Seizures                       │               │ • GBS, preterm labour <37 weeks  │
│ • Needs CPR                      │               │ • Chorioamnionitis or sepsis     │
│ • Needs mechanical ventilation   │               │ • Respiratory distress, tone,    │
│ • Signs of shock                 │               │   feeding, temperature <36/>38°C │
└─────────────────┬────────────────┘               └─────────────────┬────────────────┘
                  │                                                  │
                  └────────────────────────┬─────────────────────────┘
                                           ▼
                    ┌──────────────────────────────────────────────┐
                    │  INVESTIGATE & START ANTIBIOTICS (NO WAIT)   │
                    │ • Blood culture (+ CRP)                      │
                    │ • IV Benzylpenicillin + Gentamicin           │
                    │   WITHIN 1 HOUR OF THE DECISION TO TREAT     │
                    └──────────────────────────────────────────────┘

Red Flags

Any baby with a single red flag is investigated and started on antibiotics without waiting for results:

• Red flag risk factor: suspected or confirmed infection in another baby in a multiple pregnancy.
• Red flag clinical indicators: apnoea; seizures; need for cardiopulmonary resuscitation; need for mechanical ventilation; signs of shock.

Other (Non-Red-Flag) Risk Factors & Clinical Indicators

Antibiotics are started if the baby has two or more of the following risk factors or clinical indicators:

• Risk Factors: invasive GBS infection in a previous baby, or maternal GBS colonisation, bacteriuria or infection in this pregnancy; preterm birth after spontaneous labour before 37 weeks; confirmed rupture of membranes for more than 18 hours before a preterm birth or more than 24 hours before a term birth (2026 update); suspected or confirmed maternal sepsis in labour or the early postpartum period; suspected or confirmed chorioamnionitis.
• Clinical Indicators: altered behaviour or responsiveness; altered muscle tone (floppiness); feeding difficulties or feed intolerance; abnormal heart rate; signs of respiratory distress (grunting, recession, tachypnoea); hypoxia; persistent pulmonary hypertension; jaundice within 24 hours; neonatal encephalopathy; temperature below 36°C or above 38°C unexplained by the environment; unexplained bleeding or abnormal coagulation; altered glucose homeostasis; metabolic acidosis (base deficit of 10 mmol/L or more).
• If there is only one risk factor or clinical indicator and no red flags, clinical judgement decides whether antibiotics can be withheld; if the baby is monitored, observations continue for at least 12 hours using a newborn early warning system.

Empirical Antimicrobial Protocol & The Golden Hour

When sepsis investigation is triggered:

1. Diagnostic Workup: Inoculate a blood culture (minimum 0.5 to 1.0 mL of blood) and measure baseline C-reactive protein (CRP) and full blood count. A lumbar puncture is performed if neurological symptoms or seizures are present, but antimicrobial therapy must never be delayed waiting for a lumbar puncture.
2. The Golden Hour: Administer the first dose of empirical intravenous antibiotics strictly within 1 hour of the decision to treat.
3. Empirical First-Line Regimen:
   • Intravenous Benzylpenicillin: 25 mg/kg 12-hourly (or 50 mg/kg 12-hourly if high suspicion of GBS meningitis). Highly bactericidal against Group B Streptococcus and Listeria.
   • Intravenous Gentamicin: 5 mg/kg once every 36 hours (adjusted for gestation and renal clearance). Aminoglycoside delivering potent Gram-negative bactericidal coverage against E. coli.
4. Therapeutic Drug Monitoring (TDM): Gentamicin requires strict monitoring. A trough serum concentration is drawn immediately prior to the second dose; the trough must be <1 to 2 mg/L to prevent irreversible ototoxicity (vestibulocochlear nerve damage) and nephrotoxicity.
5. 36-Hour Review: NICE NG195 advises stopping antibiotics at 36 hours if the blood culture is negative, the initial suspicion of infection was not strong, the baby is clinically well and CRP levels are reassuring. From 2026, babies of 35+0 weeks or more who need a full course may be considered for a switch to oral antibiotics at 36 hours. If these conditions are met, antibiotics are discontinued.