Neonatal Alloimmune Thrombocytopaenia (NAIT)

Background

• Caused by maternal IgG alloantibodies to human platelet antigens (HPAs).
  • Most-common is anti-HPA-1a (80%, complicates 1:347 Caucasian pregnancies).
  • Second most-common is anti-HPA-5b (15%).
• HPA antibodies cross the placenta, causing fetal platelet destruction and potentially, suppression of megakaryopoiesis.
• May cause severe neonatal thrombocytopaenia (plt < 50×10⁹/L), with an estimated incidence of 1:1000 in the first pregnancy.
• Intracranial haemorrhage may be fatal or result in permanent neurological disability:
  • Most ICH occur in utero – 54% before 28 weeks gestation.
  • ICH occurs in 0.02-0.1 in 1000 live births.
• NAIT should be suspected if a pregnancy is complicated by:
  • Bleeding in utero (ICH, ventriculomegaly or cerebral cysts) or in a newborn.
  • Hydrops fetalis.
  • Neonatal thrombocytopaenia.
  • Any family history of NAIT.
  • Any infant with widespread petechiae. 
• Once it has been determined that the mother has HPA antibodies, management of subsequent pregnancies requires specialised care.

Investigation

• Diagnosis: demonstration of anti-HPA antibodies in maternal plasma that react against paternal and fetal platelet-specific antigens.
  • Detection of HPA antibodies is carried out by indirect platelet immunofluorescence (PIFT) and monoclonal antibody immobilisation of platelet antigens (MAIPA) assay using a panel of HPA-typed platelets.
  • In the UK, parents and infants are genotyped for HPA-1, 2, 3, 4, 5, 6, 9 and 15 antigens.
  • HPA antibodies may be undetectable in up to 30% of cases of NAIT. In some cases, increasing the serum:cell ratio may help to detect low levels of antibody.
• For relatives of women affected by NAIT who are HPA 1b/1b, determination of HLA DRB3*01:01 genotype can be useful in predicting the risk of NAIT. Absence of the genotype is associated with a very low risk of alloimmunisation.
• Fetal risk-stratification:
  • Determine paternal HPA genotype for subsequent pregnancies.
  • If the father is heterozygous for the antigen, then there is a 50% chance his offspring will be affected.
    • Determination of fetal HPA group can be done using PCR amplification of DNA from cultured amniocytes from 14 weeks gestation.
  • If the father is homozygous for the antigen, there is a 100% chance that the offspring will be affected.

Management of Neonates

• If there is a clinical suspicion of NAIT, manage as for NAIT without waiting for laboratory diagnostic confirmation.
• The goal of treatment is to prevent major haemorrhage with prophylactic platelet transfusions.
• Indications for platelet transfusion:
  • Major bleeding (ICH or GI bleeding): transfuse to keep platelets >100×10⁹/L initially, then above 50×10⁹/L for at least 7 days.
  • Asymptomatic neonates: keep platelets >30×10⁹/L
• The dose of platelets is a single unit (1/4 the adult dose). 20-30% of cases will require more than one transfusion to maintain platelet counts above 30.
• If platelet transfusion is indicated, HPA-selected platelets should be used if available.
  • NHSBT has HPA-1a and HPA-5b platelets available on request within one working day.
  • HPA-matched platelets have a longer half-life (1.9 days) compared with unmatched platelets (1 day).
  • Maternal platelets (irradiated) may also be used as a source of HPA-negative platelets if no other appropriate donor products are available. The plasma must be removed and platelets suspended in platelet suspension media.
• If platelet transfusion is required but HPA-matched platelets are not available, transfuse unselected platelets.
• If ICH is suspected, do not delay platelet transfusion pending confirmation via imaging studies.
• All neonates with suspected NAIT should have a cranial ultrasound within 24h of delivery to exclude ICH.
• Neonates should be monitored until the platelet count normalises.
• IVIG is not recommended as a first-line treatment. However, it can be considered in protected thrombocytopaenia or major bleeding or when platelets are unavailable. Increments may take 24-72hrs.

Antenatal Management 

• Women who have a previous pregnancy affected by NAIT, or a sister with a pregnancy complicated by NAIT should be referred for specialist, multi-disciplinary management.
• The management of a pregnancy in a HPA-alloimmunised mother is dependent upon:
  • The outcome of previous pregnancies
  • The previous neonatal fetal counts (if a previous child has plt <50 then successive fetuses likely to be equally or more severely affected).
  • Specificity of the HPA antibody
  • Zygosity of the father (see risk assessment above)
• Fetal HPA typing should be performed when the father is unknown or heterozygous for the implicated HPA antigen.
• HPA-1a antibody titres may be useful in predicting the risk of NAIT.
• General measures:
  • Avoid NSAIDs and aspirin.
  • Inform the blood centre about the risk of a thrombocytopaenic neonate.
  • Arrange to have HPA-compatible platelets available at the local blood centre.
• Antenatal IVIG 1g/kg weekly should commence at 12-16 weeks gestation in all women who have had a previous fetus/neonate with NAIT-associated ICH.
  • The recurrence rate of ICH in successive pregnancies is reported to be 72%.
  • A beneficial effect of IVIG on fetal platelet counts occurs in 67% of cases.
• For all other pregnancies, IVIG should be discussed; if required, IVIG should start between 20-22 weeks.
• Fetal blood sampling for platelet count can be considered at 28 weeks (usually after 8 weeks of IVIG).
  • Alternatively this can be avoided altogether, with planned delivery at 34-36 weeks.
• If platelet counts fail to respond to IVIG:
  • Consider doubling IVIG dose
  • Add prednisolone 0.5mg/kg
  • Consider weekly intrauterine platelet transfusion if the above measures fail. However there is significant risk of fetal morbidity and mortality.
  • IUT uses hyperconcentrated platelets (2-4×10¹²/l, standard neonatal dose 1-2×10¹²/l) which are negative for the antigen in question. They are not standard products and require 7 days notice for donor sourcing. They contain < 2.5 x 10⁶ leucocytes/unit, are CMV seronegative, require irradiation and expire 24 hrs after collection.
• Delivery should be planned.
  • Delivery should be planned.
  • Caesarean section should be considered if a severely affected fetus is anticipated or if the platelet count is unknown.
  • If a woman goes into labour spontaneously, operative vaginal delivery, fetal blood sampling and fetal scalp electrodes must be avoided.
• Post-delivery:
  • A cord blood sample should be sent for a platelet count immediately after delivery. If the platelet count is <100, a venous sample should be sent.
  • Inspect the neonate for skin or mucosal bleeding.
  • Management is for neonates as above.
• Patients should be transfused with HPA-compatible red cells and platelets, as long as these are available and will not delay urgent transfusion. This is to reduce the risk of PTP.