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Background
  • Hyperbilirubinaemia is a bilirubin concentration >95th percentile for gestation length and postnatal age (>300 μmol/L in full term infants >72 h old). Phototherapy is usually commenced at the 95th or 98th percentile, depending on risk factors for neurotoxicity. 
  • Unconjugated bilirubin has not been metabolised and hence cannot be excreted via the normal pathways in the urine and bowel. It crosses the blood-brain barrier and can cause neurotoxicity. Conjugated bilirubin has been metabolised and accumulates in the blood usually due to hepatic dysfunction or biliary obstruction. A conjugated fraction >20% is abnormal. 
  • Jaundice refers to deposition of unconjugated bilirubin in dermis, subcutaneous tissues and sclera is usually evident at plasma bilirubin concentrations >80 μmol/L, typically with cephalocaudal progression. 
  • Severe and/or prolonged unconjugated hyperbiliurbinaemia can cause acute bilirubin encephalopathy (lethargy, hypotonia and poor feeding, progressing to hypertonia, opisthotonus and seizures), which may lead to chronic bilirubin encephalopathy (athetoid cerebral palsy, intellectual disability, sensorineural hearing loss, oculomotor disturbances). Kernicterus refers to permanent neurological injury due to accumulation of unconjugated bilirubin in the brain, especially basal ganglia, and can be demonstrated on MRI.  
  • The aetiological role of hyperbilirubinaemia in other subtle neurodevelopmental abnormalities is unclear. 
  • Early jaundice (<24 hours), conjugated bilirubinaemia, prolonged jaundice (>14 days term, >21 days preterm) and severe hyperbilirubinaemia ("intensive range") require urgent assessment to exclude underlying pathology.        

Management 

Phototherapy thresholds

Late preterm (35 weeks) and term infants

Postnatal age (hours)

Start phototherapy

Admit to NICU for intensive phototherapy, consider exchange if not responding

Prepare for exchange transfusion 

≥38 weeks without risk factors

≥38 weeks with risk factors

35-37 weeks without risk factors

35-37 weeks with risk factors

25-48

260

220

220

180

>340

>430

49-72

310

260

260

230

>430

>510

>72

350

310

310

260

>430

>510

Risk factors for neurotoxicity: isoimmunisation, haemolysis, hypoalbuminaemia, sepsis, hypoxic ischaemic encephalopathy, seizures, severe respiratory distress, intraventricular haemorrhage.

Stop phototherapy when bilirubin concentration is ≥50 μmol/L below thresholds or at consultant discretion. Phototherapy may not be required if hyperbilirubinaemia is predominantly conjugated (discuss with SMO).

Preterm infants (<34 weeks) infants

Postnatal age (hours)

Start phototherapy

<27 weeks

27-30 weeks

31-32 weeks

33-34 weeks

12-24

90

110

120

130

25-36

110

140

155

165

37-48

125

160

175

190

49-72

140

175

195

210

>72

150

190

220

240


Postnatal age (hours)

Consider exchange if not responding to phototherapy

<27 weeks

27-30 weeks

31-32 weeks

33-34 weeks

12-24

180

200

225

210

25-36

205

230

255

240

37-48

220

250

275

260

49-72

235

270

295

295

>72

250

290

320

340

Stop phototherapy when bilirubin concentration is ≥20 μmol/L below thresholds or at SMO discretion.

Investigation 

All infants commencing phototherapy should have a Coombs test (direct agglutination test, DAT) and blood group. Additional investigations should be performed as follows:

Early jaundice or severe hyperbilirubinaemia: Full blood count, blood film and reticulocyte count. Consider screening for G6PD, sepsis and haemoglobinopathies.

Prolonged jaundice: Unconjugated and conjugated plasma bilirubin, blood group, full blood count, blood film, reticulocyte count, thyroid function, liver function tests. Consider urine culture, G6PD screen, galactosaemia blood screen (galactose-1-PO4 uridyl transferase activity), and red cell membrane, enzyme defect and haemoglobinopathy screen.

Conjugated hyperbilirubinaemia: Prolonged intravenous nutrition is the most common cause. Consider further investigation at SMO discretion using the Starship guideline for Investigation of Prolonged Jaundice. Acholic (white) stool indicates complete extrahepatic obstruction but may not be present in the first weeks of life. Presence of a gall bladder does not exclude biliary atresia.

Fluid management

  • Breastfed infants should not be given artificial feeding simply because of jaundice; clinical trials show that this has no impact on treatment of hyperbilirubinaemia. The need for supplementary artificial feeding should be determined by hydration status, plasma sodium concentration and lactation.

  • For infants admitted with severe HDN (intensive phototherapy range), there is some evidence that adding 30 ml/kg/d to normal fluid intake may reduce in the need for exchange transfusion and the duration of phototherapy.

Adjunctive therapy

  • Albumin priming may improve the effectiveness of exchange transfusion. Give 20% albumin (200 g/L) 5 ml/kg over 1h (1 g/kg).

  • There is insufficient evidence to support the use of intravenous immunoglobulin.

Maternal isoimmunisation

The Australia and New Zealand Society of Blood Transfusion (ANZSBT) classifies erythrocyte antibodies according to the risk of HDN as follows:

  • High risk: Rhesus (Rh) (D, c, C, e, E, Ce, cE), Kell (K, k), Duffy (Fya).

  • Low risk: Rh (Cw), Duffy (Fyb), Kidd (Jka, Jkb, Jk3), MNS (S, s), Gernich (Ge3).

  • Not significant: MNS (N), Lewis (lea, leb, Lea+b), Lutheran (Lua, lub), Sda, H, P.

High risk: collect cord bilirubin, FBC, DAT, blood group

  • Cord bilirubin <50 μmol/L and Hb >110 g/L: admit to PNW and repeat bilirubin in 6 hours, start phototherapy if >100 μmol/L at 6 h or rate of rise >8.5 μmol/L.h, otherwise repeat bilirubin in ~12 hours

  • Cord bilirubin 50-70 μmol/L and Hb >110 g/L: start prophylactic phototherapy on PNW (1 overhead unit plus bilibed); repeat bilirubin in 6 hours, then after 6-12 hours

  • Cord bilirubin >70 μmol/L or Hb <110 g/L: consider admission to NNU for intensive phototherapy

Low risk: admit to the postnatal ward for clinical monitoring and if jaundice develops, test bilirubin every 6 to 12 hours.

If the risk is unknown and the maternal red cell IgG antibody titre is ≥1:16, manage as for high risk. Babies exposed to non-significant maternal antibodies can receive routine care.   

Vitamin supplements for cholestasis

In prolonged cholestasis, consider fat soluble vitamin supplements. Continue for several weeks until after resolution of jaundice.

  • Vitamin K: Konakion K1 (IV preparation 10 mg/ml), give 0.2 ml daily orally (2 mg); increase as required according to INR
  • Vitamin A: Optimus Vitamin A drops (666.7 mcg per 2 drops), give 2 ml daily orally (vitamin A 7400 IU). Special Authority form required
  • Vitamin D: Puria (cholecalciferol 400 IU/drop), 0.5 ml daily orally (3750 IU); titrate according to vitamin D concentrations
  • Vitamin E: Micel E (156 IU/mL), 0.5 ml once daily orally (78 IU Vitamin E). Special Authority form required.

Ursodeoxycholic acid (URSO) may be used at consultant discretion (20-30 mg/kg/day orally in 2 divided doses). This medicine is restricted under the Pharmac HML criteria, hence an NPPA Rapid Assessment application may be required in some cases (discuss with pharmacist).

Other nursing considerations

  • Sending a blood gas in a capillary tube in the first 6 weeks of life will automatically include a plasma-equivalent total bilirubin.  
  • Two types of phototherapy unit are available: overhead blue light emitting diodes (LED) and fibreoptic blankets. Both have low heat output. Blankets cover less surface area than overhead lights, and are used as adjuncts to overhead light sources and during feeding. LED units should always be set to "double". Eye covering is required during phototherapy. Intensive phototherapy should include three overhead LED units and a fibreoptic blanket.  

Other information

Aetiology of pathological hyperbilirubinaemia

Early jaundice

  • Haemolysis:
    1. Isoimmunisation ("haemolytic disease of the newborn")
    2. Hereditary spherocytosis and other red cell membrane defects
    3. Erythrocyte enzyme defects: pyruvate kinase deficiency
    4. Micro-angiopathic: disseminated intravascular coagulation, Kasabach-Merrit syndrome
    5. Alpha and gamma globulin chain structural abnormalities (thalassaemia does not cause neonatal jaundice)
  • Sepsis
  • UGT1A1 defects: Crigler Najjar syndrome, Gilbert syndrome
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency

 Prolonged unconjugated hyperbilirubinaemia

  • Haemolysis
  • Congenital hypothyroidism
  • G6PD deficiency
  • UGT1A1 defects
  • Urinary tract infection
  • Metabolic: galactosaemia
  • Breast milk jaundice

Conjugated hyperbilirubinaemia

  • Hepatitis / hepatocellular dysfunction:
    1. Congenital / viral infection: syphilis, toxoplasmosis, rubella, CMV, EBV, HSV, HIV, enteroviruses (hepatitis viruses are symptomatic in neonates)
    2. Metabolic: galactosaemia, tyrosinaemia
    3. Gestational alloimmune liver disease (“neonatal haemochromatosis”)
    4. Idiopathic neonatal hepatitis
  • Inherited defects of bilirubin excretion
    1. Dubin-Johnson syndrome
    2. Rotor syndrome
  • Biliary obstruction:
    1. Intrahepatic: intravenous nutrition, severe Rh haemolytic disease, inspissated bile syndrome/cystic fibrosis, inborn errors of bile acid biosynthesis, Alagille syndrome, Caroli disease, Progressive familial intrahepatic cholestasis
    2. Extrahepatic: biliary atresia, biliary cysts

Exchange transfusion

This is a high-risk procedure that is performed infrequently. Therefore, the SMO on duty must be present to oversee the procedure. See here for Exchange Transfusion Equipment.

Blood request

  • Use irradiated O- Kell-, CMV negative, leucocyte depleted, fresh (<5 days) resuspended red cells, with haematocrit <0.6.
  • Perform double exchange 160 ml/kg + 30 ml for priming.
  • Irradiation takes 1-2 hours and is performed at Auckland Hospital so discuss with blood bank early if exchange is being considered.
  • Irradiated blood must be used within 24 hours.
  • Consider albumin priming prior to exchange; give 20% albumin (200 g/L) 5 ml/kg over 1h (1 g/kg).

General measures

  • Place on heat table with radiant warmer on servo control.
  • Measure HR and Sp02 continuously; automated blood pressure every 15 minutes.
  • Continue intensive phototherapy throughout and afterwards.
  • Ensure resuscitation equipment is at hand and ventilator is ready to use.

Medical management during exchange

  • Consider giving FFP 10 ml/kg mid-way and at the end, over 15-20 min. Use separate line (UVC, peripheral IV) or pause maintenance fluid for administration.
  • Routine calcium replacement is not required and may actually increase the risk of bradycardia.
  • Empty the stomach before starting and give maintenance fluids (40 ml/kg/day dextrose 10%). Delay feeding for 24 h (risk of necrotising enterocolitis).
  • Consider prophylactic antibiotics.
  • Baseline bloods: FBC, coagulation screen, gas, creatinine, calcium, magnesium, phosphate. Ensure any required metabolic, genetic, haematological & serological tests are sent prior to exchange.
  • Repeat gas every ~100 ml of blood exchanged.
  • Repeat baseline bloods post-exchange.

Blood removal

  • Sample from UAC, UVC or femoral vein.
  • Attach 20 ml syringe to the end of the 3-way tap and a discard bag to the side port.
  • Withdraw and discard aliquots (see table below) every 5 minutes via the 3-way tap. Record each aliquot discarded and the accumulating total blood removed. Continue the procedure until 160 ml/kg of blood has been withdrawn.
  • Removal line system should be assembled using sterile technique. Once the line is closed, use of sterile gloves and clean local field is sufficient for blood removal.
  • The exchange should not commence until lines have been thoroughly checked by nursing and medical staff.

Blood return

  • Infuse replacement blood continuously via UVC or peripheral vein until all aliquots have been withdrawn.
  • Blood must be warmed.

See table for infusion rates (total volume 160 ml/kg).

Weight (kg)

Aliquot volume (ml)

Total number of aliquots

Duration of exchange (min)

Total exchange volume (ml)

Return infusion rate (ml/h)

1.0-1.4

10

16

80

160

120

1.5-1.9

10

24

120

240

120

2.0-2.4

15

21

105

320

180

2.5-2.9

15

27

135

400

180

3.0-3.4

15

32

160

480

180

3.5-3.9

20

28

140

560

240

4.0-4.5

20

32

160

640

240

Recommended reading

  • American Academy of Pediatrics. Management of hyperbilirubinaemia in the newborn infant 35 weeks or more of gestation. Pediatrics. 2004;114(1):297–316.
  • Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. NEJM. 2008;358:920-8.
  • Zwiers C, Scheffer-Rath ME, Lopriore E, de Haas M, Liley HG. Immunoglobulin for alloimmune hemolytic disease in neonates. Cochrane Database Syst Rev. 2018;3(3):CD003313.

Disclaimer

This documents provides general guidance for care of neonates in Kidz First Neonatal Care NICU and SCBU, including medical, nursing and allied health management. Individual clinician judgment is required when applying these guidelines.  

This document is only valid for the day on which it is accessed. 

Administration

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Review date:  

Contact: Kidz First Neonatal Care Guidelines Group

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