**4.1 Haemolytic disease of foetus/newborn (HDFN)**

 Alloantibodies against the Rh antigen are the most common reason for intensive haemolytic disease in the neonates. Although the rate at which clinically significant HDFN occurs is relatively low viz. 3/100,000–80/100,000 live births [51]. In comparison to Rh antigen, alloantibodies to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNSs (M, N, S, and s) antigens, are also known to lead severe haemolytic disease in the foetus [52]. Although over 50 different non-ABO red cell surface antigens are thought to be involved in leading to HDFN, but the most relevant and significant alloantibodies causing HDFN are anti-RhD [44], anti-Rhc, and anti-Kell (K1) [53]. HDN due to Kell alloimmunization results in haemolysis and direct inhibition of erythropoiesis by Kell antibodies, as the Kell antigen is expressed on the surface of erythroid progenitor [6, 54]. Alloimmunization due to anti-Kell antibodies results in critical foetal disease even at lower maternal antibody titre than in Rhesus disease [6]. ABO incompatibility also causes HDN, but it occurs exclusively in mother with type-O blood with foetus having type-A or type-B blood. 1% of the type-O mothers possess a high titre of IgG antibodies against both A and B antigens. They cross the placental barrier and lead to haemolysis. Mothers with type-A or type-B antigen have the occurrence of IgM antibodies which are incapable of crossing the placental barrier thus have no role in alloimmunization during pregnancy [6].

 A neonate delivered by an alloimmunized mother displays clinical indication based on the severity of the disease. General indications are jaundice, pallor, hepatosplenomegaly, and foetal hydrops in severe cases. Neonates with HDN very frequently suffer anaemia due to destruction of RBCs by reticuloendothelial system and in some due to intravascular destruction. Rarely conjugated hyperbilirubinemia is suffered by the neonate due to placental or hepatic dysfunction with severe haemolytic disease.

Foetal anaemia can be diagnosed using ultrasound, cardiotocography and cordocentesis [48]. High resolution ultrasonography has supported in early diagnosis of early hydrops and has also lowered the foetal trauma and fatality rate to approximately 2% while performing percutaneous umbilical blood sampling (PUBS) and placental trauma during amniocentesis. Rh and ABO alloimmunization can be diagnosed using indirect Coombs test and direct antibody test [6]. Currently in order to prevent alloimmunization in mothers having maternal and foetal Rh

### *Alloimmunization and Role of HLA in Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.84211*

 incompatibility Rh immunoglobulin (RhIG) is administered at the 28th week of pregnancy. This has critically helped in reducing the instances of HDFN due to anti-D alloantibody [6, 55]. Postnatal HDFN treatment consists of intensive phototherapy and exchange transfusions to treat severe hyperbilirubinemia and top-up transfusions to treat early and late anaemia [56].

### **4.2 Foetal/neonatal alloimmune thrombocytopenia (FNAIT)**

Maternal alloantibodies against foetal human platelet antigens (HPA) cause FNAIT. It is comparatively an infrequent condition occurring in 1–800/2000 live new born. The alloantibodies are IgG antibodies against the paternal HPA antigens and are responsible for destruction of platelets in the foetus or the newborn. Almost 80% of the instances of FNAIT are a consequence of maternal and foetal incompatibility to HPA-1a, the rest 20% results from incompatibility to HPA-5b on GPIa and other HPAs [57]. In addition to HPA antigens, antibodies against CD36 glycoprotein a member of class B scavenger receptor family [58] is also implicated in the causal of FNAIT. A case study reported, maternal deficiency in expression of CD36 protein lead to maternal immunization against CD36 protein (anti-NAK) [59]. The clinical impact of NAIT is related with maternal immunization against CD36 is analogous to that observed in infants affected by HPA specific antibodies [60].

Alloantibody production by maternal immune system requires the presentation of antigen to maternal T-cell through HLA class II molecules. It was reported that HPA-1a alloimmunization is mediated by interaction of HPA-1a peptides to HLA DRB3\*01:01 molecule [57, 61]. This may be a consequence of feto-maternal haemorrhage, which can happen during delivery or abortion, as a consequence of platelet leakage into maternal circulation [62]. Maternal IgG alloantibody thus formed is progressively transported to the foetus through the neonatal Fc receptor, whereas the IgA and IgM are not transported as there are no specific receptors for them. Once through the placenta, the maternal alloantibody opsonises the foetal platelets thereby resulting in their destruction and leading to thrombocytopenia [62–64].

 The clinical indication of FNAIT differs from asymptomatic thrombocytopenia to life threatening intracranial haemorrhage (ICH) [57]. Intraparenchymal haemorrhage in the temporal lobe is also most often noticed in FNAIT [65]. Studies have also shown that antibodies against HPA-1a antigen or thrombocytopenia may also result in decreased birth weight and a very low weight for gestational age which presents a health risk later in life [66]. In many of the FNAIT instance, the illness presents as, petechiae, hematomas, haemoptysis, retinal bleeding and haematuria [57, 67]. Occasionally, the bleeding due to FNAIT is diagnosed during foetal life in ultrasound abnormalities [68]. Without routine screening for HPA antibodies the disease is mostly detected after the delivery of the first affected child. Thus, making antenatal treatment and diagnosis possible only for subsequent pregnancies in order to prevent recurrence of severe FNAIT [69]. FNAIT may be diagnosed using antibody detection methods using serological or ELISA based techniques or by platelet typing using PCR-based assays.

 The immediate treatment for thrombocytopenia in case of severe bleeding is platelet transfusion [68, 70]. In addition to transfusion intravenous immunoglobulin IVIG can be provided to prolong the survival of incompatible platelets and reduce the overall impact of thrombocytopenia [71, 72]. The most favourable antenatal treatment in order to prevent bleeding complications in pregnancies with FNAIT is non-invasive IVIG treatment on weekly basis [68]. In FNAIT resulting due to anti-CD36 glycoprotein intrauterine transfusions with compatible RBC and CD36 null platelets are useful in preventing the hazardous clinical effect of the disease [73].

## **4.3 Neonatal alloimmune neutropenia (NAN)**

Neonatal alloimmune neutropenia (NAN) is a very rare disorder, but is a life threatening disorder of the neonates. The occurrence of NAN has been estimated to be 1 in 1000/6000 live births. NAN occurs due to maternal sensitization to incompatible paternal foetal granulocyte antigens. The maternal alloantibodies formed against the foetal granulocytes are transported through the placenta which thereby causes the destruction of foetal granulocytes [74].

Maternal alloantibodies against granulocyte-specific antigens HNA-1a and HNA-1b have been accounted widely to cause NAN. Antibodies to Fc gamma RIIb (CD16) and HNA-2a granulocyte antigen are infrequently involved in neonatal neutropenia, if mother is HNA-1 null phenotype [74, 75]. A case study has also reported the involvement of HNA-4b as a causative of severe NAN [76].

Neutropenia in neonates is a self-limiting disorder and lasts for only few weeks, but in some instances, it can prevail for as long as 6 months. In the course of this period, neonates are at severe risk of acquiring infection [75]. Symptomatic neonate suffering NAN frequently present with retarded umbilical cord separation, skin infections, otitis media, or pneumonia within 15 days of life. Most of the infections that occur are mild, but it may at times turn severe. The fatality rate because of NAN has been noted to be around 5%. The severity of NAN is dependent on concentration and the subclass of IgG present [74].

The immune neutropenia correlates with granulocytes specific antibodies present in the serum and can be diagnosed [75] using the granulocyte agglutination test (GAT), the granulocyte immunofluorescence test (GIFT), the monoclonal antibody immobilization of granulocyte antigens assay (MAIGA), an assay called as extracted granulocyte immunofluorescence assay (EGIFA) measures the anti-HNA-1a, -1b, and/or -2 antibodies in the sera. The use of EGIFA assay has been reported to improve the diagnosis and clinical management of patient suspected to have NAN [77]. The treatment for NAN is still a matter of discussion, but the options used for the management of NAN include antibiotics, intravenous immunoglobulin (IVIG), corticosteroids, and human granulocyte colony-stimulating factor (rhG-CSF) [78].

## **5. Conclusions**

**Table 1** summarizes the implication of HLA antigens in complications related to pregnancy. Though it is now well identified that the HLA plays major role in pregnancy, placentation and immune modulation to maintain an immune-tolerance



*Alloimmunization and Role of HLA in Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.84211* 

### **Table 1.**

*Role of HLA in pregnancy disease/disorders.* 

state. This in turn results in foetus being well accepted by the maternal immune system. Alloimmunization and other pregnancy complications result due to maladapted immune system when the maternal immune system is unable to maintain an immune tolerance state towards the foetus.

*Complications of Pregnancy* 
