Fetal Effects of Autoimmune Disease

Immune Thrombocytopenic Purpura

Immune thrombocytopenic purpura in adults is often a chronic disease mediated by autoantibodies directed against cell surface components (glycoproteins) of platelets (IIb/IIIa or Ib/IX). Thrombocytopenia occurs when the platelet-antibody complexes are destroyed by the reticuloendothelial system. A low platelet count raises suspicion for ITP, but the diagnosis is reached after exclusion of other causes of thrombocytopenia by history, physical examination, blood count, peripheral blood smear, and autoimmune profile. A spuriously low platelet count should be evaluated by examining a blood smear to exclude pseudothrombocytopenia caused by ethylene diaminetetra-acetic-acid–dependent platelet agglutination. The normal range of platelet counts in nonpregnant women and neonates is 150,000-400,000/µL; however, the mean counts tend to be lower during pregnancy. The prevalence of maternal ITP is one to two cases per 1000 deliveries. The potential risk of a low platelet count for the mother is bleeding; however, the risk becomes significant only when the platelet count becomes less than 20,000/µL. A maternal platelet count of greater than 50,000/µL is considered to be hemostatic during vaginal or cesarean birth.

Thrombocytopenia of the fetus or newborn is caused by active transplacental transport of the antiplatelet antibodies; however, no significant correlation has been observed between neonatal thrombocytopenia and maternal autoimmune antibodies. A low platelet count increases the risk for hemorrhage, but this seems to be more theoretical than real because intrauterine fetal hemorrhage has not been reported in patients with ITP. The concern is for the potential trauma at birth and the potential risk for cerebral hemorrhage in the neonate. This serious complication is rare because the prevalence of fetal or neonatal ITP is about 10% that of maternal ITP, and less than half of these infants have platelet counts less than 20,000/µL. In the past, obstetricians performed antepartum cordocentesis (percutaneous umbilical vein blood sampling [PUBS]) or fetal scalp blood sampling to identify a fetus with a platelet count less than 50,000/µL and to deliver the fetus by the abdominal route. The current view holds that PUBS and fetal scalp sampling are unnecessary in pregnant women with known ITP even with platelet counts of 40,000/µL. Generally, when the maternal platelet count is greater than 50,000/µL, and the fetal platelet count (or the platelet count of previous offspring) is unknown, cesarean section is not indicated; a vaginal delivery is allowed, and the cesarean option is reserved for obstetric indications. If the fetal platelet count is known to be less than 20,000/µL, cesarean section is appropriate.

Treatment of ITP during pregnancy follows the guidelines published in 1996 and mainly reaffirmed later. Pregnant patients with ITP and platelet counts greater than 50,000/µL throughout gestation and patients with platelet counts of 30,000-50,000/µL in the first or second trimester do not routinely require treatment. Treatment in the form of glucocorticoids or intravenous immune globulin (IVIG) is indicated in patients with platelet counts less than 10,000/µL and patients with platelet counts of 10,000-30,000/µL who are in their second or third trimester or are bleeding. Intravenous immune globulin is an appropriate initial treatment for patients with platelet counts less than 10,000/µL in the third trimester and for patients with platelet counts of 10,000-30,000/µL who are bleeding. When glucocorticoid and IVIG therapy have failed, splenectomy is appropriate in the second trimester in women with platelet counts less than 10,000/µL who are bleeding. Splenectomy should not be performed in asymptomatic pregnant women with platelet counts greater than 10,000/µL. Platelet transfusion is indicated for patients with counts less than 10,000/µL before a planned cesarean section and for those who are bleeding and expected to deliver vaginally. Prophylactic transfusions are unnecessary when the platelet count is greater than 30,000/µL and there is no bleeding.

Immune thrombocytopenic purpura does not preclude breastfeeding. The use of IVIG during pregnancy may improve platelet counts in the mother, but the treatment may not prevent fetal thrombocytopenia because the placental transfer of IVIG is inconsistent and mostly insufficient to reach fetal therapeutic levels. A retrospective study examined the morbidity of 92 obstetric patients with ITP during 119 pregnancies over an 11-year period. The authors found that most of these patients had thrombocytopenia during pregnancy. At delivery, 89% had platelet counts less than 150,000/µL. For many patients, the pregnancy was uneventful; however, 21.5% of the women had moderate to severe bleeding. In 31.1% of the pregnancies, treatment was required to increase the platelet counts. Most deliveries (82.4%) were vaginal. Platelet counts of less than 150,000/µL were found in 25.2% of the infants, including 9% with platelet counts less than 50,000/µL. Treatment for hemostatic impairment was necessary in 14.6% of the infants. During the study period, two fetal deaths occurred, including one caused by hemorrhage.

After birth, the platelet count of newborns whose mothers have ITP-mediated thrombocytopenia may continue to decrease, and careful follow-up of the thrombocytopenia should be performed during the first week of life. Ultrasound imaging of the brain seems to be indicated if the count is less than 50,000/µL, even in the absence of neurologic findings. Neonates who exhibit severe thrombocytopenia (<20,000/µL) should be treated with platelet transfusion or IVIG or both. Neonates with platelet counts of 20,000-50,000/µL do not require IVIG treatment; however, careful platelet count monitoring is needed. Neonates with intracranial hemorrhage or any other bleeding manifestation should be treated with combined platelet transfusion and IVIG or glucocorticoid therapy, especially if the platelet count is less than 20,000/µL. Neonatal thrombocytopenia usually resolves within 4-6 weeks.

Neonatal Alloimmune Thrombocytopenia

The pathogenesis of neonatal alloimmune (also known as isoimmune) thrombocytopenia is similar to Rh disease. A mother with antigen-negative platelets is sensitized by antigen-positive fetal platelets gaining access to the maternal circulation via breaches in the placental barrier. As a result, the mother produces antiplatelet antibodies, and these IgG antibodies cross the placenta and destroy the fetal platelets. In contrast to Rh disease, 50% of neonatal alloimmune thrombocytopenia cases occur during the first pregnancy of an at-risk couple. This difference is explained by the higher immunogenicity of the platelet antigen and the smaller size of the platelets, which may facilitate their fetomaternal transfusion.

Of the several types of platelet antigens, the human platelet antigen 1a (HPA-1a) is involved in 80%-90% of neonatal alloimmune thrombocytopenia cases in whites, and HPA-5b is responsible for a further 5%-15% of the cases. Among people of color (e.g., Asians), HPA-1a incompatibility is a rare cause of neonatal alloimmune thrombocytopenia, and other alloantigens (e.g., HPA-4b) are implicated. The fetus acquires the antigen from the father. When the father is heterozygous, 50% of the fetuses would be affected, whereas all fetuses of a homozygous father would be HPA positive.

The prevalence of neonatal alloimmune thrombocytopenia is 0.5-2 cases per 1000 deliveries. Fetomaternal platelet incompatibility is much more frequent. The discrepancy is explained by the facilitating role of certain human leukocyte antigen (HLA) types that are associated with the development of neonatal alloimmune thrombocytopenia. HLA-DR3 is associated with a 10- to 30-fold risk for HPA-1a antibody production.

In the usual scenario, an asymptomatic woman delivers an otherwise normal infant in an otherwise uncomplicated birth. Most neonates are asymptomatic, and the thrombocytopenia is detected by a blood count performed for other perinatal causes. In some cases, neonates present with generalized petechiae, hemorrhage into abdominal viscera, excessive bleeding after venipuncture or circumcision, or, in extreme cases, abnormal neurologic manifestations secondary to intracranial hemorrhage. The platelet count commonly decreases further during the first week after birth.

The diagnosis of neonatal alloimmune thrombocytopenia involves typing platelet antigens in the newborn and in the parents to show that the mother lacks a platelet antigen that is present on the platelets of the father and the neonate. A more sophisticated test is to establish the existence of the antiplatelet antibody in the mother's serum that is directed against a platelet antigen in the father. Testing the infant is generally unnecessary if the father is available for testing.

Human platelet antigen genotyping is now available as a routine laboratory technique and can be used to identify HPA incompatibilities between mother and child. Several techniques are known, and the polymerase chain reaction with sequence-specific primers is used. New microarray technologies are expected to support routine genotyping of all known HPAs, which allows detection of incompatibilities for low-frequency antigens, increasing the sensitivity for the detection of antibodies against low-frequency antigens.

Older methods that measure the antibody associated with platelets lack adequate specificity, but newer enzyme-linked immunosorbent assays specifically detect the antiplatelet antibody. In antigen capture immunoassays, monoclonal antibodies directed against platelet antigens are used to identify various known platelet antigens individually, although these may be negative in maternal blood 2-4 weeks after delivery in 30% of the cases. Flow cytometry and polymerase chain reaction assays can also be used to identify the patient's platelet antigens. Establishing the diagnosis of neonatal alloimmune thrombocytopenia has immediate importance and implications for future pregnancies.