Guideline for Management of Haemolytic Disease of the Newborn and Coombs’ Positive Baby

• Summary of guideline
• Introduction
• Interpreting the cord blood result
• Haemolytic Disease of the Newborn (HDN)
• Late Anaemia
• Management
• Discharge
• Discharge advice
• Discharge Medication
• Follow up

Summary of guideline

• Rhesus isoimmunisation has the most risk of morbidity and mortality associated with HDN
• Anti-K alloantibodies can cause late-onset anaemia. Follow-up is recommended.
• Send Cord blood for urgent full blood count (FBC), serum bilirubin, blood group and Direct Coombs’ Test (DCT) and chase within 2 hours.
• Interpret the DCT in the context of maternal immunisation, other lab results and the neonate’s clinical condition.
• Neonates with HDN needing treatment should be discharged on folic acid and reviewed in the clinic.
• If the five golden rules are met, the baby can be discharged home at 24 hours of age.

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Introduction

Coombs’ test (direct Coombs’ test [DCT] or direct antiglobulin test [DAT]) is a simple and elegant test invented by Robin Coombs, Professor of Immunology in Cambridge, in 1945.

A positive Coombs’ test means an antibody is attached to the baby’s red blood cells. The antibody will have come from the maternal circulation. In some cases, the antibody will lead to fetal and neonatal haemolytic disease.

The most important cause of neonatal haemolytic disease is Rhesus D alloimmunisation. The key to the prevention of this condition is avoidance of maternal sensitisation. Mothers known to be Rhesus D negative are now given passive immunisation with anti-D globulin during any pregnancy. It is normal to have small feto-maternal blood leaks during pregnancy, particularly during delivery. This fetal blood may sensitise the mother to Rhesus D. Passive immunisation of the mother will removefetal Rhesus D positive from the mother without the mother showing an active immunological response. This management has almost eradicated the previously severe condition of Rhesus D haemolytic disease of the newborn.

However, the anti-D administered to the mother will cross the placenta, and if the fetus is Rhesus positive, small amounts will attach to the fetal red blood cells. This does not lead to fetal haemolytic disease, but it will give a positive Coombs’ test in the newborn infant. This can make the interpretation of a positive Coombs’ test difficult.

It follows that:

• Most infants with a positive Coombs’ test have no risk of haemolysis, as this is simply the result of passive maternal immunisation.
• Babies with haemolytic disease of the newborn have a positive Coombs’ test.

It is essential for a newborn baby with a positive Coombs’ test to make an assessment. Is the baby’s positive Coombs’ test simply the result of passive maternal immunisation? Is this a baby with a positive Coombs’ test because of maternal alloimmunisation to the Rhesus D antigen, one of the other rhesus antigens or one of the other red blood cell antigens?

For babies born to mothers who are Rhesus D negative or have abnormal red cell antibodies, an urgent cord blood sample for FBC, serum bilirubin, and blood group should be sent alongside the DCT. This should ideally be chased and reviewed within 2 hours.1

NB:

• Transcutaneous bilirubinometer should not be used to check for jaundice in the 1st 24 hours of life, in babies < 35 weeks or in babies who have had phototherapy.
• DCT negative babies are unlikely to have HDN. Other causes of pathological jaundice should be investigated.

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Interpreting the cord blood result

The following baseline is expected from the urgent cord sample

• Hb ≥120
• DCT negative or positive (weakly positive in maternal passive immunisation)
• Serum bilirubin <100μmol/L in term babies and <40μmol/L in preterm babies

Plot the bilirubin on the appropriate chart for gestational age and manage following the NICE recommendation for Jaundice in newborn babies under 28 days¹.

Bilirubin from the blood gas result can be used to make a decision regarding phototherapy while awaiting investigation results.

A blood film may be requested if there is doubt about the cause of a positive DCT test2. In the DCT positive test result, due to passive immunisation of the mother, spherocytes, nucleated red blood cells (RBC) and RBC fragments will not be present in excessive amounts. Discuss with a senior or the lab if there is any doubt.

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Haemolytic Disease of the Newborn (HDN)

HDN is a cause of a Coombs’ positive test and can cause anaemia and hyperbilirubinaemia in the newborn. HDN due to ABO incompatibility is currently the most common neonatal haemolytic disease in the Western world, and it occurs in 15% - 25% of pregnancies. It tends to be less severe than HDN caused by rhesus isoimmunization.³

Rhesus isoimmunisation has the highest risk of fetal mortality and morbidity. Passive immunisation has reduced its incidence.

There are other alloantibodies which can cause varying degrees of haemolysis. Anti K alloantibodies has a higher risk for severe HDN compared to other maternal red cell alloantibodies.4 in anti-K, there is a poor correlation between antibody titre and the severity of the disease. Therefore, obstetric history is not a good indicator of risk for HDN. Anaemia (usually late onset) is a prominent feature of this condition, rather than haemolysis and hyperbilirubinaemia⁵. There is suppression of the foetal erythropoiesis and immune destruction of early erythroid progenitor cells in anti-K antibodies⁶. This can persist until three months of age.

The coexistence of anti-c and anti-E is also high risk for HDN. While anti-c can cause mild haemolysis, anti-E potentiates the severity of fetal anaemia due to anti-c antibodies.

Coombs’ test is a poor positive predictor of newborns that will require treatment7. In addition to DCT testing, other laboratory and clinical features must be reviewed while deciding the appropriate management plan.

In haemolytic disease of the newborn, red blood cells are destroyed, leading to anaemia. Folic acid is a B vitamin which is needed to produce the haem component of haemoglobin. It also aids the maturation of red blood cells. The body cannot make folic acid. There is a need, therefore, to give folic acid supplements to babies with haemolytic anaemia of the newborn.

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Late Anaemia

Late anaemia may develop due to transient suppression of neonatal erythropoiesis due to transfusion or immune destruction of erythroid cells. Babies who have required several intrauterine transfusions (IUTs) or have maternal anti-K antibodies have increased risk for late-onset anaemia.

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Management

Baby can be managed on the post natal ward (PNW) unless there is a need for more than single phototherapy, intravenous fluids or anaemia.

History.

1. Review maternal notes for history of IUTs, previous sibling with HDN requiring phototherapy or top-up transfusion.
2. Ask about the frequency and adequacy of feeds. Dehydration can worsen jaundice.

Examination.
Examine the baby and take care to look for signs of anaemia. As a minimum, the following should be documented:

1. Presence/absence of pallor, jaundice, oedema.
2. Hydration status.
3. Spleen and liver size.

Ongoing Management.

• If significant jaundice occurs within the 1st 24 hours of age, babies should be screened for sepsis and commenced on antibiotics. Investigation for other causes of pathological jaundice should be done.
• Where the serum bilirubin level is above the phototherapy line, then single phototherapy should be commenced as soon as possible. The phototherapy light should be optimised to ensure it is as close to the baby as possible and covering as much surface area as possible. Time out of the lights for feeds should be kept to a minimum.
• In babies with bilirubin >50μmol/L below the treatment line, a biliflash can be done at 24 hours of age before discharge (provided phototherapy has not already been warranted).
• In babies with initial bilirubin less than the treatment threshold but <50μmol/L below the treatment line and a positive DCT, a repeat serum bilirubin should be done within 4 - 6 hours to monitor the rate of increase.
• Bilirubin increasing >8.4μmol/L/hr indicates severe jaundice and the need for urgent review. This should be managed with as much surface exposure as possible (two or three lights may be required) and no time out from the lights unless the jaundice level has improved. Intravenous immunoglobulin may also be indicated.
• In babies with evidence of haemolysis on a blood film, full blood count should be done daily, reducing the frequency when the trend is stable.
• In babies at severe risk of HDN, the blood bank should be informed as soon as possible as blood used for exchange blood transfusion (EBT) is of lower Packed Cell Volume (PCV) and has a shorter half-life. It needs to be specially prepared.

Further management is according to the NICE guidance for Jaundice in newborn babies under 28 days.

• In babies with Coombs’ positive jaundice requiring treatment, check the serum bilirubin at 12 hours and 24 hours after stopping treatment and only discharge if bilirubin has plateaued or is falling. If bilirubin is rising, the baby should be monitored as an inpatient with repeat serum bilirubin done. In exceptional circumstances and following discussion with the Consultant of the week, the baby may be discharged with safety netting advice and a clear plan for repeat bilirubin 24 hours later.

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Discharge

Early discharge is not advisable. The baby must have established feeds before discharge8. If medical review or treatment has not already been indicated, then the baby should be reviewed at 24 hours of age, and the decision to discharge will depend on meeting the five golden rules criteria.

Golden rules
The baby with a positive Coombs’ test is most unlikely to have haemolytic disease, and no further action is needed if all the following apply.

1. Mother has had anti-D antibody passive immunisation before birth.
2. Mother has no rising titre of anti-D antibody during pregnancy.
3. Mother has no antibody titre against other red cell antigens (e.g., c, E, Kell).
4. Baby is not jaundiced or has mild physiological jaundice or jaundice controlled by single phototherapy at more than 24 hours of age (jaundice requiring phototherapy within the first 24 hours should be assumed to be pathological and may be due to haemolysis).
5. Baby is not clinically anaemic or has normal haemoglobin on testing.

If all five rules are met, no further investigation is required, reassurance can be given, and we can explain that it is most unlikely but possible that jaundice will occur. If a baby develops jaundice, it will be necessary to have blood tests to look for anaemia. The mother or midwife noting jaundice should refer to the neonatal service.

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Discharge advice

Safety netting advice should be given before discharge. Parents should be counselled that increased sleepiness, poor feeding, increasing yellowness of the skin, appearing pale, and fast or difficult breathing can be features of jaundice and anaemia. Their baby would need a medical review if this were noted. Clear advice regarding regular feeding should be given to the parents. Parents should be counselled that there may be late onset anaemia up to 3 months after birth.

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Discharge Medication

Babies requiring IUT, high maternal titres, and evidence of haemolysis or HDN requiring treatment should be commenced on folic acid supplements following a discussion with a senior and continued until 3 – 4 months of age⁸.

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Follow up

In babies with HDN, a repeat blood test (FBC, blood film, reticulocyte count and bilirubin) should be done at 10 – 14 days as there may be on-going haemolysis and suppression of erythropoiesis. This can be done at the phlebotomy clinic at LGI. This should be added to the PNW job list, and the result should be discussed with the consultant of the week and a further plan for bloods made if required. Consider G6PD assay in high-risk population.

Follow-up appointments in ANNP clinic should be planned following a discussion with the Consultant of the week (usually requiring an early appointment ~ 6-8 weeks).

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