Foetal/neonatal alloimmune thrombocytopenia (FAIT/NAIT) 1 or foeto-maternal alloimmunisation thrombocytopenia (FMAIT) 2.

Foetal/neonatal alloimmune thrombocytopaenia (NAIT) is a disorder caused by foetomaternal platelet incompatibility that usually presents as severe isolated thrombocytopaenia in otherwise healthy newborns. It results from destruction of the foetal platelets by maternal immunoglobulin G (IgG) antibodies elicited during pregnancy and directed against foetus-specific platelet antigens that are inherited from the father and are different from those present in the mother 1.

Clinically, the diagnosis is suspected when an otherwise healthy neonate, born after an uneventful pregnancy and delivery, exhibits petechiae or widespread purpura at birth or a few hours after birth. Visceral haemorrhages are less common. The mother is typically healthy, with no previous history of thrombocytopaenia, auto-immune disorders or ingestion of drugs. The infant has no clinical signs of infection or malformations (see Differential diagnosis). Approximately 20% of these infants show evidence of intracranial haemorrhage (ICH) leading to death or neurological sequelae (see Prognosis). The platelet count is low at birth and may be associated with anaemia, secondary to bleeding. Platelet immunological investigations will confirm the maternal specific alloimmunisation (see Diagnostic methods).

NAIT is the commonest cause of severe isolated thrombocytopaenia in the foetus and newborn. Prospective studies showed that it occurs in about 1 in 800 or 1000 live births 34. Unselected cohort of neonates reported 0.9% frequency of neonatal thrombocytopaenia 5. Immune aetiology was demonstrated in one third of these cases. As thrombocytopaenia when moderate (whatever its cause) is often silent, systematic neonatal blood sampling for a platelet count is the only possible way to detect neonatal thrombocytopaenia and to provide better management of the infant and subsequent pregnancies 5.

In the foetus, alloimmune thrombocytopaenia is considered to be the most severe thrombocytopaenia. It may occur very early during pregnancy, and in several studies, ICH has been documented before 20 weeks of gestation 678. In utero, ICH accounts for approximately 50% of the reported cases of ICH in NAIT. Therefore, NAIT should be considered as a potential aetiological factor in all cases where porencephaly, ventriculomegaly and, in fact, any type of ICH is discovered during the foetal life.

In the neonate, purpura or haematoma are the most common clinical manifestations. Visceral haemorrhages, such as gastrointestinal bleeding or haematuria, occur less frequently. ICH has been reported in NAIT (whatever the platelet antigen involved, see Aetiology) and is usually present at birth. ICH may also occur later, if the thrombocytopaenia persists. Mildly affected infants may be asymptomatic.

Anti HPA-1a and -3a immunisation induce severe neonatal thrombocytopaenia (see Aetiology) 9. NAIT linked to HPA-5b incompatibility seems to be less severe than HPA-1a NAIT 10. However, the infant may be symptomless, with thrombocytopaenia discovered incidentally, even in case of HPA-1a alloimmunisation. Therefore, unexpected or unexplained neonatal thrombocytopaenia or early onset of severe thrombocytopaenia in both pre-term and term babies should raise the possibility of NAIT and guide investigations accordingly.

NAIT results from maternal immunisation against foetus-specific platelet antigens. The exact mechanism underlying maternal sensitisation remains unknown. A prospective study detected antibodies at 16 weeks of gestation in primipara primigravida women 3. The maternal IgG alloantibodies can cross the placenta as early as the 14^th week of pregnancy. The foetal alloantigens are fully expressed as early as the 18^th week of gestation 1112. In these circumstances, foetal thrombocytopaenia (platelet counts below 150.10⁹/L) can occur very early during pregnancy and there is no spontaneous correction 3.

Although platelets express human leukocyte antigen (HLA) Class I and ABO blood group antigens at their surface, NAIT is mainly due to alloantibodies directed against platelet-specific alloantigens. A prospective study analysis showed that HLA antibodies did not cause thrombocytopaenia 14, unless there is an association with neutropaenia 15. Casual observations suggest that NAIT is sometimes due to ABO incompatibility, although the particular features of these cases are not well established.

The so-called platelet-specific alloantigens, conventionally defined by their exclusive presence on the megakaryocyte lineage, have a phenotype frequency that varies between ethnic groups 1617. Since 1990, the Human Platelet Antigen (HPA) nomenclature has been adopted 1819. The platelet-specific antigen systems have been numbered chronologically in order of publication, and the allelic antigens designated alphabetically in order of frequency in the population: 'a' designating the higher frequency allele, 'b' the lower frequency allele. Polymorphism responsible for several of the platelet allotypes has been identified and a new nomenclature proposed 20. Among the platelet-specific alloantigens, HPA-1a antigen is the form most commonly involved in NAIT in Caucasians 21, followed (at much lower frequency) by HPA-5b 10. In Asians, NAIT is essentially linked to the HPA-4 system. Maternal immunisation against 'rare' or 'private' alloantigens has been reported 2223242526.

Retrospective and prospective studies highlighted the importance of immunogenetic factors in platelet alloimmunisation. The HLA class II DRB3*0101 allele in mothers could be implicated in anti HPA-1a immunisation 272829, whereas anti HPA-5b alloimmunisation was reported to be associated with a cluster of HLA DR molecules, sharing a particular polymorphic amino-acid sequence at position 69–70 in the DRβ1 chain 30. A better understanding of the immune response to platelet alloantigens would allow for a better definition and thus appropriate management of pregnant women at high risk.

The first step in the diagnosis is to confirm the isolated thrombocytopaenia in the newborn, and the absence of thrombocytopaenia in the mother. The platelet count is variable, usually as low at birth as <50. 10⁹/L. Anaemia occurs secondary to bleeding. Platelet immunological tests require expertise in the field. The therapy should be started as soon as a provisional diagnosis has been made. Any difficulties in confirming the diagnosis should not delay the therapy.

Testing involves the detection of maternal circulating antibodies and identification of the targeted platelet antigen, with determination of the platelet phenotype and genotype of both parents. Antibodies are usually detected with antigen capture enzyme-linked immunosorbent assay (ELISA) and the microplate enzyme-linked assay 31. Molecular techniques are used for genotyping 32. If the father is heterozygous for the considered antigen or if the paternity is uncertain, the platelet typing of the infant should be performed to confirm the diagnosis. Diagnosis is certain when parental antigen incompatibility with a corresponding maternal antibody is demonstrated. The biological diagnosis is unclear in the absence of such an antibody (in this case, a repeat testing may substantiate the diagnosis), or when a new, rare or private antigen is involved. Diagnosis should be unequivocally established before a subsequent pregnancy for a better management.

Diagnosis of foetal ICH is made by ultrasonography and magnetic resonance imaging (MRI).

Careful examination of the infant and consideration of the maternal history should exclude most of the other causes of neonatal thrombocytopaenia 33. However, NAIT may also be associated with other causes of thrombocytopaenia, especially maternal antiplatelet autoimmunity 5.

The recurrence of thrombocytopaenia is very high and its severity usually increases in subsequent pregnancies. The risk depends on whether the father's platelet genotype is homozygous or heterozygous for the targeted antigen. Therefore, in case of heterozygosity or if the paternity is uncertain, the foetus platelet genotype must be determined with molecular biology techniques using amniocytes, microvilli or foetal blood sampling. Noninvasive typing from maternal blood is under investigation.

Platelet typing can be proposed to the sisters of an affected woman, in order to detect high-risk pregnant women. In our experience, antenatal management for the first affected pregnancy depends on the detection of maternal alloantibodies.

In cases of women already identified as at risk of having or developing HPA alloimmunisation (first child with NAIT or previous history of NAIT in the family), foetal genotyping may be performed either on chorionic villi or on amniotic cells.

Alloimmune thrombocytopaenia can be suspected in case of foetal ICH. Foetomaternal alloimmune thrombocytopaenia presenting antenatally as hydrops foetalis 34 has also been reported as a complication of foetomaternal platelet alloimmunisation. Recurrent miscarriages should be taken into account.

When incidental, thrombocytopaenia is discovered by foetal blood sampling and careful determination of contamination with amniotic fluid should be included. Considerations in the differential diagnosis of foetal alloimmune thrombocytopaenia include both maternal and foetal factors, among which thrombocytopaenia in foetuses small for date with the risk of intraventricular haemorrhage 35 and foetal hypoxia 36, infection, chromosomal abnormalities, but associations should not be ignored. In other causes of thrombocytopaenia, alloimmunisation should be studied when thrombocytopaenia is atypically severe.

• Mechanism of maternal sensitisation

• Modulation of the maternal immunisation

• Real incidence of ICH

• Best antenatal management

• Setting up of the routine antenatal screening