• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
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Fetal and Neonatal Alloimmune Thrombocytopenia

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Last updated: July 12, 2022
Years published: 2022


Acknowledgment

NORD gratefully acknowledges John M. Thorp Jr., MD, Hugh McAllister Distinguished Professor of Obstetrics and Gynecology, Professor, Maternal & Child Health, School of Public Health, University of North Carolina, for assistance in the preparation of this report.


Disease Overview

Summary

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare immune disorder. FNAIT occurs when the baby’s platelets are attacked and destroyed by the mother’s immune cells in her blood stream. This occurs when platelets from the baby are identified as foreign and the mother develops an antibody response against them. This immune response can develop when the mother’s blood is exposed to her baby’s blood, either during development of the fetus in the womb or when the baby is being born. FNAIT can occur in a woman’s first pregnancy and/or in subsequent pregnancies.

A mother’s immune system attacks her baby’s platelets if they are recognized as foreign. A baby’s platelets may be recognized as foreign when they’re different from the mother’s platelets because of genes inherited from the father. Platelets are a type of blood cell that helps blood clot. An abnormally low level of platelets (thrombocytopenia) can lead to easy bleeding and rupture of blood vessels.

Introduction

FNAIT was first reported in the medical literature in 1953. Antigens, or targets for the immune system on platelet cells, were first described in the 1950s and 1960s. As of 2022, 35 different platelet-specific antigens in FNAIT have been described. FNAIT is the leading cause of severe thrombocytopenia in newborns.

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Synonyms

  • FNAIT
  • neonatal alloimmune thrombocytopenia (NAIT)
  • fetomaternal alloimmune thromobocytopenia (FMAIT)
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Signs & Symptoms

Signs and symptoms of FNAIT vary depending on how low the platelet levels drop in the baby due to increased platelet destruction and reduced platelet production. Signs and symptoms may occur before birth or up to four weeks after birth.

Many babies with FNAIT have mild symptoms and some babies may have no signs of the disease other than low platelet levels. The most common sign is skin discolorations called petechiae and purpura, which occur from bleeding under the skin. Petechiae are pinpoint spots on the skin that are often redder in color than purpura, which are larger areas of skin discoloration that tend to be more purple in color. These skin discolorations may occur on much of the body and typically appear within a few hours after birth. Easy formation of severe bruises, or hematomas, may also occur. When symptoms are mild, they will eventually disappear with time and after treatment.

Babies with a severe case of FNAIT may have bleeding in major organs, such as the brain, gastrointestinal tract, lungs or eyes. Bleeding in the brain is known as intracranial hemorrhage (ICH). Severe symptoms can cause death or lead to life-long disability.

Typically, babies with a severe case also have signs of petechiae or purpura along with cephalohematoma, a condition where blood collects under the scalp, resulting in a bulge on the baby’s head. Cephalohematoma is associated with an increased risk for ICH, which can lead to long-term neurological abnormalities due to brain damage. Neurological deficits can include cerebral palsy, intellectual disability, seizures and a type of hearing loss known as bilateral sensorineural hearing loss that occurs in both ears. Cerebral palsy includes permanent disorders of posture and movement that do not worsen with time. This is the same as a hemorrhagic stroke in an adult.

The severity of thrombocytopenia does not accurately predict whether a baby will develop ICH. Only a small portion of babies with severely low platelet levels develop ICH and ICH may develop in some babies with only moderately low platelet levels.

Without treatment, ICH is estimated to affect up to 26% of babies with FNAIT. Most of these cases are thought to occur before birth and in firstborn children, before a mother is aware of FNAIT. When a mother has one child with FNAIT with ICH as a symptom, her next child with FNAIT has a high risk of ICH as well.

The gastrointestinal tract is the second most common body system where bleeding occurs. Signs can include bloody stools. Bleeding can also occur in the lungs and eyes. Bleeding in the eyes can lead to blindness.

Mothers of children with FNAIT may have a higher risk for miscarriage.

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Causes

FNAIT occurs when a mother makes antibodies that destroy her baby’s platelets. A mother’s immune system may target her child’s platelets when they contain an antigen inherited from the child’s father that the mother does not have. An antigen is an identifying tag on a cell that all individuals have. The presence of the tag signals the immune system to make antibodies specific to the tag. Those antibodies then turn on the immune system to destroy the foreign cell. When this is the case, the mother’s immune system recognizes her child’s platelets as foreign and mounts an immune response against them. Common platelet antigens in Caucasians with FNAIT are human platelet antigen (HPA)-1a and HPA-5b. Other platelet antigens exist and may include HPA-2, HPA-3, HPA-4 and HPA-15. The mother’s antibodies that attack these antigens are known as anti-HPA antibodies. The HPA-1 antigen is involved in 80-90% of FNAIT cases, and FNAIT associated with anti-HPA-1a antibodies is usually more severe.

Babies who develop FNAIT inherited the human platelet antigen from their father in an autosomal dominant pattern. For mothers who already produce anti-HPA antibodies, this means that their children will have a 50% chance of developing FNAIT if the father has one copy of the gene that encodes for the targeted human platelet antigen. If the father has two copies of the gene that encodes for the targeted HPA antigen, the child has a 100% chance of developing FNAIT. The risk is the same regardless of the baby’s sex.

It is not known why a mother’s immune system begins to attack her child’s platelets when they’re different from her own. The presence of platelet antigens involved in FNAIT doesn’t mean FNAIT will develop. For instance, only 10% of mothers without HPA-1a on their platelets will develop anti-HPA-1 antibodies to their baby.

A mother’s immune system forms these alloantibodies after her immune system has been exposed to the fetus or newborn’s platelets. For HPA-1a-associated FNAIT, alloantibodies are estimated to form during pregnancy 25% of the time and during delivery 75% of the time.

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Affected populations

FNAIT is the most frequent cause of thrombocytopenia in newborns with an estimated incidence of 1 in 1,500 pregnancies. Fetal intracranial hemorrhage (ICH) associated with FNAIT is estimated to occur in 1 in 10,000 pregnancies.

In Caucasians, FNAIT is usually associated with anti-HPA-1a antibodies and estimated to occur in 1/1000 Caucasian births. In African Americans, FNAIT is more likely to occur in babies with HPA-2 and HPA-5 antigens. In Japanese populations, HPA-4 and HPA-5 antigens in babies with FNAIT are more common.

FNAIT may appear in first pregnancies and/or subsequent pregnancies. In subsequent pregnancies where the baby has the same human platelet antigens targeted in a previous pregnancy, FNAIT will occur early. In first pregnancies, although FNAIT is more likely to occur at birth, it can also occur early in pregnancy. FNAIT occurs in first pregnancies in 50% of cases and has a 90% chance of recurring in subsequent pregnancies.

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Diagnosis

FNAIT is not routinely screened for during pregnancy and is thought to be underdiagnosed. Babies are screened for FNAIT when they have older siblings who have had it, but for firstborn children with FNAIT, diagnosis is not made until further testing after birth, usually after the baby has developed widespread skin petechiae and thrombocytopenia.

Diagnostic tests are available for FNAIT. They include testing the mother’s blood for anti-HPA antibodies and HPA genotyping of the mother, father and newborn. Genotyping of human platelet antigens (HPA) is done to check for the presence or absence of HPA genes that would further support the diagnosis. If common alloantibodies are not found in the mother’s blood, a test that examines how the mother’s blood interacts with the father’s platelets can be performed to look for less common alloantibodies to HPA.

When FNAIT is suspected in a fetus, blood samples are taken from only the mother and father due to the risk for complications in attempting to get a blood sample from a fetus. HPA genotyping of the fetus based on the mother’s blood samples is available for HPA-1a antigens only.

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Standard Therapies

Treatment differs depending on the timing of diagnosis (fetus or newborn). Because of the risk of severe complications like ICH, treatment in a newborn found to have severe thrombocytopenia should begin before diagnostic test results confirm FNAIT.

In a newborn suspected to have FNAIT, treatment includes a platelet transfusion. When there is no ICH, the baby is likely to recover, and platelet levels should increase to a normal level.

When a fetus is suspected to be at risk for FNAIT, treatment may include giving the mother intravenous immunoglobulin (IVIG), steroids or serial intrauterine platelet transfusions (IUPT). IVIG is the delivery of antibodies from donors into the mother’s blood. IVIG and steroids are used to suppress the mother’s immune response against the fetus’s platelets. IUPT is used to increase platelet counts in the fetus to prevent hemorrhages. IUPT, however, is considered invasive and risky to the fetus and may be reserved for cases that don’t respond to IVIG or steroids. Early delivery via C-section is also thought to reduce the likelihood of ICH.

After birth, a baby with FNAIT should undergo a cranial ultrasound to make sure there is no intracranial hemorrhage. Newborns with FNAIT may need platelet transfusions or IVIG to raise their platelet counts.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Bussel JB, Vander Haar EL and Berkowitz. New developments in fetal and neonatal alloimmune thrombocytopenia. Am J Obstet Gynecol. 2021 Aug;225(2):120-127. doi: 10.1016/j.ajog.2021.04.211. Epub 2021 Apr 8.

de Vos TW, Winkelhorst D, de Haas M, et al. Epidemiology and management of fetal and neonatal alloimmune thrombocytopenia. Transfusion and Apheresis Science. Dec 31, 2019; 59(1). doi: https://doi.org/10.1016/j.transci.2019.102704

Tiller H, Husebekk A, Ahlen MT, Stuge TB, Skogen B. Current perspectives on fetal and neonatal alloimmune thrombocytopenia – increasing clinical concerns and new treatment opportunities. Int J Womens Health. 2017;9:223-234. Published 2017 Apr 19. doi:10.2147/IJWH.S90753

Brojer E, Husebekk A, Dębska M, et al. Fetal/neonatal alloimmune thrombocytopenia: pathogenesis, diagnostics and prevention. Arch Immunol Ther Exp (Warsz). 2016;64(4):279-290. doi:10.1007/s00005-015-0371-9

Espinoza JP, Caradeux J, Norwitz ER, Illanes SE. Fetal and neonatal alloimmune thrombocytopenia. Rev Obstet Gynecol. 2013;6(1):e15-e21.

Peterson JA, McFarland JG, Curtis BR, Aster RH. Neonatal alloimmune thrombocytopenia: pathogenesis, diagnosis and management. Br J Haematol. 2013;161(1):3-14. doi:10.1111/bjh.12235

Constantinescu S, Zamfirescu V, Vladareanu PR. Fetal and neonatal alloimmune thrombocytopenia. Maedica (Bucur). 2012;7(4):372-376.

INTERNET
Paidas MJ. Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management. UpToDate. Last updated: May 03, 2022. Available at: https://www.uptodate.com/contents/fetal-and-neonatal-alloimmune-thrombocytopenia-parental-evaluation-and-pregnancy-management. Accessed June 21, 2022.

Fetal and neonatal alloimmune thrombocytopenia. Orphanet. Last update: March 2022. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=853. Accessed June 21, 2022.

Fetal and neonatal alloimmune thrombocytopenia. Genetic and Rare Diseases Information Center. Last Updated: Nov. 8, 2021. Available at: https://rarediseases.info.nih.gov/diseases/2295/fetal-and-neonatal-alloimmune-thrombocytopenia. Accessed June 21, 2022.

Disseminated Intravascular Coagulation (DIC). Cleveland Clinic. Reviewed 09/28/2021. Available at: https://my.clevelandclinic.org/health/diseases/21836-disseminated-intravascular-coagulation-dic#:~:text=Disseminated%20intravascular%20coagulation%20(DIC)%20is,who%20have%20cancer%20or%20sepsis. Accessed June 21, 2022.

Testing and management of fetal and neonatal alloimmune thrombocytopenia. Canadian Blood Services. May 2020. Available at: https://professionaleducation.blood.ca/en/transfusion/best-practices/testing-and-management-fetal-and-neonatal-alloimmune-thrombocytopenia#:~:text=Diagnostic%20testing%20for%20FNAIT%20includes,of%20platelet%20antigens%20(MAIPA)%20assay. Accessed June 21, 2022.

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