What Is Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT)?

Overview

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs when a mother makes antibodies that destroy her baby’s platelets, causing low levels of platelets in the fetus or newborn. The main clinical feature is thrombocytopenia (low platelet count) in newborns, which may cause bleeding. A complication of FNAIT is intracranial haemorrhage (ICH) in the fetus or neonate (newborns), which may lead to death or lifelong neurologic complications.

What is fetal and neonatal alloimmune thrombocytopenia?

Fetal and neonatal alloimmune thrombocytopenia (FNAIT), also known as Fetomaternal alloimmune thrombocytopenia (FMAIT) or neonatal alloimmune thrombocytopenia (NAIT), occurs when a mother makes antibodies that destroy her baby’s platelets, which leads to low levels of platelets (thrombocytopenia) in the fetus or newborn. Usually, the mother’s antibodies attack the platelet antigens the fetus inherited from the father.¹

Understanding platelets and antibodies

The role of platelets in blood clotting

Platelets, also called thrombocytes, are the smallest blood component and are crucial in preventing bleeding and promoting clotting. Platelets play a role in hemostasis. Hemostasis is a physiological process that leads to the cessation of bleeding from a blood vessel.²

Whenever you have a cut, hemostasis prevents you from bleeding out. You will notice a patch on your injury that stops you from bleeding further. That patch is called a clot, and platelets play a role in forming that clot. So whether you’re bleeding internally or externally, platelets are involved in a process that prevents you from bleeding out.

Antibodies and their role in the immune system

Your immune system is your body’s defence system that protects you from threats such as diseases causing organisms (pathogens), toxins and unwanted foreign substances. When the body has an infection, the immune system fights the infection. Your immune system does so by producing antibodies in response to the infection.³

Antibodies are proteins produced by your immune system that protect you from foreign substances that enter your body. Antibodies bind to these unwanted substances to eliminate them from your system.

Every foreign substance that enters your body has an antigen. These antigens are specific markers that let the immune system know the foreign substance isn’t from the body. Examples are bacteria, viruses, fungi, allergens, venom, and toxins. Antibodies attack and fight off these pathogens by binding to the antigensand activating other components of the immune system.⁴.

Cause and mechanism of fetal and neonatal alloimmune thrombocytopenia

Alloimmunization is an immune response against foreign antigens. Alloimmunization commonly happens when the body develops an immune response against foreign antigens in blood components, such as red blood cells and platelets.⁵ The body can be exposed to these foreign antigens during a blood transfusion or pregnancy.⁶

FNAIT occurs when a woman becomes immunized against fetal platelet antigens inherited from the fetus’s father, which leads to fetal thrombocytopenia (low platelet levels). In FNAIT, there is an incompatibility between the mother’s platelet antigen and the fetus’ platelet antigen. The mother recognizes the fetus’ platelets as foreign and produces antibodies that attack it. The destruction of the fetus’ platelets is what leads to thrombocytopenia.^1,7

During pregnancy, although unlikely, fetal platelets may enter the maternal circulation and cause an immune reaction, leading to the maternal production of antibodies against the fetus’ platelet antigen, which subsequently crosses the placenta and leads to fetal thrombocytopenia.^7,8

In first pregnancies, neonates may not show FNAIT because the mother becomes sensitized by producing antibodies against the platelet antigen when exposed to the neonate’s blood at birth. This maternal antibody production may not affect the first child but will affect the next child who has the incompatible platelet antigen. As a result, the maternal antibodies will attack the fetus’ platelet cells, leading to fetal thrombocytopenia.⁹

About 36 antibodies against Human Platelet Antigens (HPAs) are associated with FNAIT⁷, but in white populations, the Human Platelet Antigen 1a (HPA-1a) in the fetus is the most common cause of FNAIT.^1,7,8 The mother produces anti-HPA-1a (an antibody) against HPA-1a, which attacks the fetus’s platelets, leading to fetal thrombocytopenia. The marked severity of thrombocytopenia in FNAIT could also be due to an inhibition of fetal megakaryocyte (precursor cell of platelets found in the bone marrow) production by the maternal anti-platelet antibodies.⁸

Clinical presentation

FNAIT may present no symptoms and can go undetected.⁹ Your doctor may suspect FNAIT if there is neonatal thrombocytopenia or clinical manifestations of haemorrhage (bleeding) or if you have a previously affected child.¹

The following are the clinical presentations of FNAIT:^8,10

• Bleeding into the skin - The bleeding may be mild or widespread petechiae (coloured pinpoint, round spots on the skin), purpura (purple spots on the skin), or bruises (ecchymoses) within a few hours after birth or, in some cases, with hematoma (blood pooling) formation at injection sites or bleeding after circumcision
• Internal bleeding - bleeding into the major organs, such as gastrointestinal, lung and Intracranial haemorrhage (ICH)
• Haematuria - blood in the urine
• Thrombocytopenia - an abnormally low platelet count

Intracranial haemorrhage

Intracranial haemorrhage (bleeding in the brain) affects less than 26% of all cases of FNAIT, and most cases occur within the uterus (during intrauterine life).^1,8,9 Intracranial haemorrhage (ICH) is the most severe complication of FNAIT. ICH can lead to the death of the fetus or neonate (perinatal death) or lifelong neurologic complications such as mental retardation, cerebral palsy, cortical blindness and seizures.^9,10

Risk factors

The highest risk for FNAIT-related complications in subsequent pregnancies is among those infants with siblings who experienced antenatal ICH. Severe thrombocytopenia in a newborn with FNAIT is a risk factor in subsequent pregnancies. However, the problem in using obstetric history as a risk factor is that the first affected child may go undetected during pregnancy and receive no attention.⁹

The first affected child may go undetected during pregnancy because there may be no symptoms of FNAIT in the first pregnancy. Another is that the mother produces antibodies against the platelet antigen when exposed to the neonate’s blood at birth. This antibody production may not affect the first child but can affect the next child who has the incompatible platelet antigen, leading to the maternal antibodies attacking the fetus’ platelet cells.

Another risk factor is if the father has an incompatible platelet antigen with the mother, especially if the father’s platelet antigen is the common HPA-1a antigen known to cause FNAIT¹¹.

Diagnosis and screening

FNAIT is an underdiagnosed condition. Treatment is usually available to those who have previously had a child with FNAIT, which means many children do not have the advantage of early diagnosis and follow-up.⁹

If there is no screening during pregnancy, FNAIT is only diagnosed after the birth of a symptomatic neonate. Your doctor will look out for neonatal bleeding and the typical clinical manifestations of FNAIT (low platelet levels). Your doctor may occasionally diagnose FNAIT by chance when testing neonatal blood for other reasons^10. Cranial ultrasound may also be performed to screen for ICH in all neonates at risk of FNAIT within 24 hours of delivery.¹²

Maternal antibody screening during pregnancy

If a pregnant woman has a risk of FNAIT, the doctor may carry out maternal serum testing for antibody formation. This test detects the presence of the HPA antibodies that cause FNAIT in the pregnant woman’s serum.^10,12

Maternal and fetal HPA-typing

Another way to screen for FNAIT during pregnancy is by HPA-typing. HPA-typing is a test that detects the presence of the HPA antigen causing FNAIT. The most common HPA antigen implicated is HPA-1a. HPA-typing can be done on the mother or fetus’ blood sample.^10,12

For maternal HPA-typing, the pregnant woman’s blood is tested for the HPA antigen. Fetal HPA-typing may be conducted by getting a sample of the fetus’ blood or using free fetal DNA in maternal plasma. There is a risk of fetal loss when acquiring fetal blood for HPA-typing. However, HPA-typing using free fetal DNA in maternal plasma is a much safer option for fetuses.¹⁰

Treatment and management

Treatment of FNAIT in newborns is through platelet transfusion, especially using (HPA)-selected platelets if immediately available.¹²

If there are no maternal or fetal screenings for FNAIT, the disease is only diagnosed after the birth of symptomatic neonates. As a result, antenatal treatment is provided only for women with a previously affected child by infusing intravenous immunoglobulins (IVIG) weekly.¹⁰ Administering IVIG reduces the risk of ICH and provides better outcomes for FNAIT.¹³

An early diagnosis of FNAIT during pregnancy can help prevent the complications of FNAIT.

Summary

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) occurs when a mother makes antibodies that destroy her baby’s platelets, which leads to low levels of platelets in the fetus or newborn. Platelets play a role in preventing bleeding and promoting clotting, and low levels cause bleeding problems.

Your immune system protects your body from threats such as infections, toxins and unwanted foreign substances by producing antibodies to fight these threats. Every foreign substance has an antigen (a specific marker for identification). The body’s antibodies attack and fight these foreign substances by binding to their antigens.

In FNAIT, there is an incompatibility between the mother’s platelet antigen and the fetus’ platelet antigen. The mother recognizes the fetus’ platelets as foreign and produces antibodies that attack it. The destruction of the fetus’ platelets leads to the clinical features of thrombocytopenia (low platelet count).

FNAIT may present no symptoms and is only suspected when there is neonatal thrombocytopenia or bleeding. FNAIT may also be suspected in women with a previously affected child. Intracranial haemorrhage (bleeding in the brain) is the most severe complication of FNAIT and can lead to the death of the fetus or neonate, or lifelong neurologic complications.

If a mother once had a newborn with FNAIT, she may be at risk of FNAIT in subsequent pregnancies. Diagnosis of FNAIT is by observing for clinical features in neonates, HPA antibody screening in mothers, and HPA-typing in mother and fetus to detect the HPA antigen responsible for FNAIT.

Treatment is by platelet transfusion in neonates, but if a mother is at risk of FNAIT, the doctor will infuse intravenous immunoglobulins (IVIG), which reduces the risk of ICH in the fetus.