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Prolonged Neonatal Guidelines

No of pages: 9 Author(s): Dr Gemma Macey Author(s) title: Consultant Paediatrician Glan Clwyd Hospital (Main Author)

Consultant Neonatologist, Dr Manjunath Shetthalli Glan Clwyd Hospital

Responsible dept / Children’s and Young People director: Neonatal Department Approved by: Neonatal Steering Group March 2019 Date approved: March 2019 Date activated (live): 29/08/2019 Review date March 2022

Date EQIA completed: Documents to be read 1. alongside this policy: Purpose of Issue/Description of current changes:

First operational: 29/08/2019 Previously reviewed: date date date date date Changes made yes/no: Yes/no Yes/no Yes/no Yes/no Yes/no

PROPRIETARY INFORMATION This document contains proprietary information belonging to the Betsi Cadwaladr University Health Board. Do not produce all or any part of this document without written permission from the BCUHB.

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Table of Contents Page 1 Introduction, Definitions and 3 2 Causes of Unconjugated hyperbilirubinemia 4 3 Causes of Conjugated hyperbilirubinemia 4 4 Clinical Assessment 5 5 Investigations 6 6 Management 7 7. References 8 8. Appendix: Conjugated Jaundice: Summary of Investigations sheet 9

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Prolonged Neonatal Jaundice Guidelines

1. Introduction

Jaundice is one of the most commonly occurring problems in newborn babies – approximately 60% of term babies and 80% of preterm babies develop jaundice in the first week of life.1

Breakdown of red blood cells produces unconjugated . Most of this is bound to albumin but some is free in the circulation. Unconjugated bilirubin is metabolised in the to produce conjugated bilirubin. This then passes into the gut and is largely excreted in the stools, giving them a dark pigmentation. A small amount is converted into which is excreted in urine.

Hyperbilirubinaemia results in accumulation of bilirubin in the skin and mucous membranes, causing yellow discoloration of the skin and sclera and is called as Jaundice.

2. Prolonged Jaundice - Definitions

Prolonged jaundice is defined as visible jaundice persisting beyond 14 days in term babies (37 weeks or more gestation) and 21 days in preterm babies (born at <37 weeks gestation).1

Unconjugated hyperbilirubinaemia is defined as when >80% of total bilirubin is unconjugated

Conjugated hyperbilirubinaemia is defined by conjugated bilirubin ≥25 μmol/L1 OR >20% of total bilirubin

3. Differential Diagnosis

The vast majority of cases of prolonged hyperbilirubinaemia are due to jaundice, which resolve spontaneously and cause no harm. In a small number of cases there is a pathological cause.

Early identification of with cholestatic is critical in ensuring a correct diagnosis is made and prompt appropriate therapy is instituted.

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3.1 Unconjugated hyperbilirubinaemia

Breast milk jaundice Peaks at 2-3 weeks and can take 2-3 months to resolve ~10% of breastfed babies are jaundiced at 1 month

Haemolysis Coombs positive: ABO incompatibility Rhesus incompatibility Anti-Kell, anti-Duffy

Coombs negative: Red cell membrane defects e.g. /elliptocytosis Red cell enzyme defects e.g. G6PD, pyruvate kinase deficiency Haemoglobinopathy Disseminated intravascular coagulation (DIC)

Increased enterohepatic circulation Bowel obstruction

Decreased conjugation Prematurity Galactosaemia Gilbert’s disease Hypopituitarism Crigler-Najjar syndrome Hypoadrenalism Table 1 - Causes of unconjugated hyperbilirubinaemia

3.2 Conjugated hyperbilirubinaemia If conjugated jaundice is present, liver disease must be excluded. The causes are extensive and listed below.

Extrahepatic biliary duct disorders hypoplasia syndromes Choledochal cyst Gallstones

Neonatal hepatitis Endocrine Idiopathic syndrome Hypothyroidism Intrauterine infections Hypopituitarism

Metabolic α-1 antitrypsin deficiency Neonatal haemochromatosis Galactosaemia Glycogen storage disorders Peroxisomal disorders Fatty acid oxidation disorders Tyrosinaemia Mitochondrial disorders Niemann-Pick Disease Type C

Sepsis UTI

Chromosomal disorders Turner’s syndrome Trisomy 13, 18, 21

Toxic/drugs Fetal alcohol syndrome Chloral hydrate, rifampicin, erythromycin Table 2 - Causes of conjugated hyperbilirubinaemia

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4. Clinical Assessment

All infants with prolonged jaundice require clinical assessment by an appropriately trained professional.

If the baby has any potential life-threatening features, senior staff should be notified and emergency treatment initiated.

Assessment of a baby with prolonged jaundice should include a comprehensive history:

 Antenatal history o Maternal blood group (ABO/Rh/other antibodies) o Scan results (congenital/genetic abnormalities) o Infections (risk of or congenital infection) o Medication & substance use history (alcohol, teratogenic medications)  Postnatal history o Method of feeding and weight gain (include birth and current weight) o Urine and stool colour o Delayed passage of meconium (cystic fibrosis) o Lethargy (hypoglycaemia, endocrine & metabolic disorders) o and abnormal movements (hypoglycaemia, sepsis) o /bruising (signs of from liver disease)  Family history o Blood, liver and metabolic disorders o Cystic fibrosis

A full systemic examination should be performed:

 Weight & head circumference - plot on a growth chart & compare to Red Book  Appearance o Pallor (haemolysis, sepsis, cardiac failure) o Hydration status o Dysmorphic features (endocrine, metabolic, genetic) o (galactosaemia, congenital infection) o Petechiae/purpura (galactosaemia, severe liver disease)  Cardiorespiratory o Murmur o Tachypnoea, increased work of breathing o Focal or widespread crackles o Femoral pulses o Review previous chest X-rays for butterfly vertebrae (Alagille’s syndrome)  Gastrointestinal o o Abdominal mass o Bowel sounds  Neurological o , encephalopathy, abnormal reflexes

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An important step is to ensure that the urine is pale and stools are pigmented, indicating normal liver function in bilirubin metabolism.

Pale stools and dark urine indicate significant liver disease – most commonly biliary atresia. Any with these signs should be discussed with the consultant on call and may require discussion/transfer to a gastroenterologist or specialist liver unit.

Investigation of prolonged jaundice

Initial investigations for a well baby aim to confirm that the jaundice is unconjugated with no evidence of haemolysis, hypothyroidism or infection:

 Split bilirubin (total & conjugated)  Thyroid function tests  FBC  Blood group & DAT  Urine MC&S – ideally by clean catch method to avoid contamination  Routine metabolic screening – confirm Guthrie card has been performed & parents are not aware of any abnormalities

Any child requiring further investigations should be discussed with the patient’s consultant or the consultant on call.

Further investigations for unconjugated hyperbilirubinaemia depend on what is felt to be the most likely cause. Some differential diagnoses can be reasonably excluded on the basis of the history or examination, while others require blood tests or imaging.

Haemolysis: Pyloric stenosis: Galactosaemia: FBC, reticulocyte count Blood gas, U&E, chloride GAL-1-PUT Blood film Abdominal ultrasound LDH Gilbert’s/Crigler-Najjar: Red blood cell G6PD Bowel obstruction: Specific genetic testing screen Abdominal X-ray Pyruvate kinase screen

If hypopituitarism or hypoadrenalism are suspected, discuss with the patient’s local consultant as to whether advice from Endocrinology at Alder Hey Children’s Hospital is required.

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Bwrdd Iechyd Prifysgol Betsi Cadwaladr University Health Board

Further investigation of conjugated hyperbilirubinaemia should be discussed with the Liver Team at Birmingham Children’s Hospital. Advice from liver team at Birmingham Children’s Hospital is available via email [email protected]. The first line investigations on the conjugated hyperbilirubinaemia results sheet3 can be completed whilst awaiting specialist advice.

Management

If the baby is well and there are no concerning features on history/examination, the baby can be discharged home pending the results. If the baby appears unwell, has pale stools & dark urine or has significant problems identified on history/examination, this should be discussed urgently with the consultant on call that day.

If the baby is being seen on the Paediatric ward, please ensure you have taken a working contact number for the parents and warned them that the call will be from a withheld number. They should expect a call within the following 3 days with the results and a management plan.

Total SBR <200 μmol/L AND conjugated fraction <25 μmol/L: Reassure parent(s)/guardian(s) Repeat SBR after 1 week – if falling, no further tests are required.

Total SBR >200 μmol/L AND conjugated fraction <25 μmol/L: Discuss with the patient’s consultant as further investigations for unconjugated hyperbilirubinaemia may be required.2

Cases of conjugated hyperbilirubinaemia will require admission, further investigations and discussion with the Liver Team at Birmingham Children’s Hospital. Advice from liver team at Birmingham Children’s Hospital is available via email [email protected]. These infants require regular monitoring of pre-feed blood glucose levels for the first 24 hours of admission. Treatment of conjugated hyperbilirubinaemia is dependent on the underlying cause.

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Bwrdd Iechyd Prifysgol Betsi Cadwaladr University Health Board

References

1. NICE Clinical Guideline CG98 – Neonatal Jaundice, May 2010 (updated October 2016). http://www.nice.org.uk/nicemedia/live/12986/48578/48578.pdf (accessed 01/04/2017)

2. Children’s Liver Disease Foundation Yellow Alert Jaundice Protocol – Early identification and referral of liver disease in infants. https://www.yellowalert.org/For-Professionals (accessed 01/04/2017)

3. BSPGHAN Investigation of Neonatal Conjugated Hyperbilirubinaemia, Feb 2012. https://bspghan.org.uk/guidelines (accessed 01/04/2017)

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Bwrdd Iechyd Prifysgol Betsi Cadwaladr University Health Board Appendix 1 Conjugated Jaundice: Summary of Investigations Sheet

Test Date Result Stool Colour

Haematology FBC Reticulocytes Group and Coombs INR / PT APTT / fibrinogen

Biochemistry Blood sugar / BM U&E, albumin, bicarb Bone profile Ca PO4 ALP Bilirubin Total conjugated Liver enzymes ALT AST GGT Lipid profile Cholesterol triglycerides

Metabolic Galactosaemia Alpha-1-antitrypsin Plasma amino acids Urine amino acids Urine organic acids Ward test protein

Endocrine Thyroid function Cortisol Short Synacthen test*

Microbiology Blood culture Urine culture TORCH serology Hepatitis serology Urine CMV

Imaging Fasting US scan (liver, spleen, ascites, gallbladder & biliary tree) Isotope scan* CXR / spine X ray*

Ophthalmology*

Other* * Second line as appropriate

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