Practice Essentials
Thrombocytopenia is common in mothers and newborns and usually is caused by an increased rate of platelet destruction. The reference range of a normal platelet count in nonpregnant women and newborns is 150,000-400,000/µL; however, mean platelet counts in pregnant women generally are lower.
Thrombocytopenia in pregnancy has many common causes, including gestational thrombocytopenia, viral and bacterial infections, and preeclampsia complicated by hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome. [1] This article focuses on immune thrombocytopenia (ITP) and neonatal alloimmune thrombocytopenia (NAIT). Although relatively rare, these immunologic causes of thrombocytopenia are important, as neonatal outcomes can be significantly impaired and subsequent pregnancies can be affected (See images below.)
Immune thrombocytopenia. An infant born with neonatal lupus syndrome and severe thrombocytopenia. Note extensive bruising and petechiae.
ITP occurs in approximately 1 to 3 in 10,000 pregnancies; this rate is 10-fold greater than the incidence of ITP in the general population. The increased frequency in pregnancy could be due to frequent blood testing and unmasking of asymptomatic mild thrombocytopenia in pregnancy. [2] ITP can occur during any trimester, or the diagnosis may be known prior to the pregnancy.
Compared with ITP in the general population, ITP in pregnant women is associated with greater risk of bleeding at platelet counts < 20,000 to 30,000/μL. [3] Platelet counts typically decrease modestly in the course of a normal pregnancy, and almost all women with ITP have a decrease in the platelet count during gestation, with many requiring treatment in preparation for delivery. However, most women return to their previous ITP status after delivery and pregnancy has not been shown to be a risk for worsening ITP. [4]
Pathophysiology
ITP is a rare autoimmune disease due to an abnormal T-cell response, notably supported by splenic T follicular helper cells, that stimulates the proliferation and differentiation of autoreactive B cells. The antiplatelet autoantibodies they produce facilitate platelet phagocytosis by macrophages, essentially in the spleen. These autoantibodies can cross the placenta; thus, both mother and newborn can be affected. Macrophages contribute to the perpetuation of the autoimmune response as the main antigen-presenting cell during ITP. CD8+ T cells also contribute to thrombocytopenia by increasing platelet apoptosis. [5]
Besides this peripheral platelet destruction, inappropriate bone marrow production also exacerbates thrombocytopenia, due to an immune response against megakaryocytes. Moreover, the level of circulating thrombopoietin, the main growth factor of megakaryocytes, is low. [5]
NAIT is caused by maternal immunization against fetal paternally derived platelet-specific antigens (similar to rhesus [Rh] disease). The mother has a normal platelet count, while the fetus can be severely thrombocytopenic. The foreign antigens promote the production of immunoglobulin by the mother. This is initially immunoglobulin M, whose large size prevents transplacental passage. Subsequently, the mother produces immunoglobulin G. The smaller size of this molecule permits passage across the placenta, resulting in the destruction of fetal platelets and neonatal thrombocytopenia.
Epidemiology
ITP occurs in 1 to 2 of every 1,000 pregnancies, which in the United States represents about 3,000 to 6,000 cases of ITP in pregnancy per year. [6] Although ITP accounts for less than 3% of all cases of thrombocytopenia during pregnancy, it is the most common cause of a platelet count below 50 × 109/L detected in the first and second trimesters. [7] The frequency of NAIT is estimated at 1-2 cases per thousand deliveries.
In Helsinki, Finland, the frequency of ITP is 1.8 cases per 1,000 deliveries. [8] The frequency of NAIT was reported as 0.5 cases per 1,000 and 1.5 cases per 1,000 liveborn neonates in England [9] and France, [10] respectively. In Japan, the frequency of NAIT was 0.3 cases per 1,000 liveborn neonates, and incompatibility for human platelet antigen (HPA)-4 was the cause of 80% of those cases. [11]
The recurrence risk for NAIT is extremely high (nearly 100% of subsequent pregnancies are affected if the sibling carries the significant paternally derived antigen). [12] In general, siblings with the platelet antigen will be as severely affected or more severely affected than the preceding affected child. [12]
ITP occurs in all races. However, more than 50% of all cases of NAIT have been reported in whites. Most cases of alloimmune thrombocytopenia (and the most severe cases) occur in white mothers homozygous for the P1A2 allele (HPA-1b). [13] The prevalence of homozygous HPA-1b in whites is estimated at 2.5%. [14] Multiple other platelet-specific antigens exist that can cause alloimmune thrombocytopenia; the prevalence of these varies in different ethnic groups.
In the general population, ITP is diagnosed more commonly in females than males (ratio 3:1). [15] NAIT occurs in newborns of both sexes. ITP commonly is diagnosed in the second or third decade of life. NAIT develops in fetal life, with 25-50% of fetal intracranial hemorrhages detectable on prenatal ultrasound prior to the onset of labor. [16]
Prognosis
Women with ITP generally do well in pregnancy. ITP is an autoimmune disease, and exacerbations and remissions are common. Pregnancy does not appear to affect the course of the disease. ITP is not an absolute contraindication to pregnancy but in unusually severe or refractory cases or for women taking potentially teratogenic medications, deferring pregnancy may be indicated. [7] Duration of maternal ITP is a risk factor for preterm birth and women with chronic ITP experience more adverse outcomes than those with a pregnancy-related diagnosis of ITP. [6]
Fetuses and newborns with NAIT can experience permanent neurologic sequelae, organ damage, and death from intracranial and intra-abdominal bleeds due to severe thrombocytopenia. However, after birth, maternal antibodies are fairly rapidly degraded and the thrombocytopenia resolves.
Women and newborns with severe thrombocytopenia can experience intracranial and intra-abdominal bleeding. This can result in significant morbidity, including neurologic damage and/or death. Women requiring long-term steroid therapy can develop complications from the medication exposure.
Transfusion of blood products can result in transfusion reactions in the recipient. With current blood bank crossmatching, significant transfusion reactions are rare. Additionally, transfusions pose the rare risk of transmission of viral infections, especially hepatitis and human immunodeficiency virus. Monteith et al reported that pregnant women infected with hepatitis C virus had a significantly higher frequency of thrombocytopenia and significantly lower platelet counts compared with controls. [17]
Maternal hemorrhage at time of birth is a risk in women with ITP, particularly if the platelet count falls below 20,000/µL, however, severe bleeding is rare. [18] and a meta-analysis of 15 articles and 1043 pregnancies found no maternal deaths. [19]
Neonatal thrombocytopenia due to the active transport of antiplatelet antibodies through the placenta is a clinically more significant problem, and it occurred in 9 of 66 (13.6%) pregnancies complicated by ITP in a review by Yamada et al. [20] Of those infants, 5 of 66 (7.5%) had severe thrombocytopenia, with platelet counts less than 50,000/µL. Splenectomy prior to pregnancy was the only risk factor associated with the development of neonatal thrombocytopenia by logistic regression analysis.
Severe neonatal thrombocytopenia places the infant at risk for intracranial or visceral hemorrhage. None of the 9 thrombocytopenic infants in the Yamada trial had intracranial hemorrhage documented on clinical neurologic examination or ultrasound. Neonatal intracranial hemorrhage previously has been reported to have a very low incidence (0-2.3%) in newborns of mothers with ITP. [21]
Neonatal morbidity is far more common in NAIT, with 10% of affected newborns dying and 20% experiencing neurological sequelae secondary to intracranial hemorrhage. [14] Affected infants can have generalized petechiae, hemorrhage into abdominal viscera, and excessive bleeding after venipuncture or circumcision.
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Immune thrombocytopenia. Nonstress test 1 week before delivery showing a normal reactive fetal heart rate pattern.
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Immune thrombocytopenia. Nonstress test 4 days before delivery showing a reactive fetal heart rate with an unusual pseudosinusoidal pattern that lasted 9 minutes.
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Immune thrombocytopenia. Neonatal brain at autopsy showing extensive subdural hemorrhage.
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Immune thrombocytopenia. Neonatal spine at autopsy showing extensive hemorrhage at base of spine.
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Immune thrombocytopenia. An infant born with neonatal lupus syndrome and severe thrombocytopenia. Note extensive bruising and petechiae.
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Immune thrombocytopenia. An infant born with a cephalohematoma.
