Thrombocytopenia in pregnant women may be inherited or idiopathic. The eighteen potential causes of thrombocytopenia are shown in Table 70-1. In this chapter, we focus on thrombocytopenia due to pregnancy itself (gestational thrombocytopenia), immune thrombocytopenic purpura (ITP), alloimmune thrombocytopenia (ATP), thrombotic thrombocytopenia (TTP), and hemolytic uremic syndrome (HUS).
TABLE 70-1. Potential Causes of Thrombocytopenia in Pregnancy
Gestational thrombocytopenia is defined as a platelet count of less than 150,000/μL and occurs in 4 to 7 percent of pregnant women. Approximately 1 percent of pregnant women will have platelet counts of less than 100,000/μL. Gestational thrombocytopenia is a diagnosis of exclusion, and secondary causes of thrombocytopenia such as hypertensive disorders of pregnancy or immuno-logical disorders must be ruled out.
These characteristics of gestational hypertension are summarized as follows:
• The thrombocytopenia is relatively mild, with platelet counts usually remaining greater than 70,000/μL.
• Women are asymptomatic with no history of bleeding. The thrombocytopenia usually is detected as part of routine prenatal screening.
• Women have no history of thrombocytopenia prior to pregnancy (except in previous pregnancies).
• Platelet counts usually return to normal within 2 to 12 weeks following delivery.
• There is an extremely low risk of fetal or neonatal thrombocytopenia.
IMMUNE THROMBOCYTOPENIC PURPURA
The entity long referred to as idiopathic thrombocytopenic purpura (ITP) is usually the consequence of an immune process in which antibodies are directed against platelets. Antibody-coated platelets are destroyed prematurely in the reticuloendothelial system, especially the spleen. The mechanism of production of these platelet-associated immunoglobulins (PAI)—PAIgG, PAIgM, and PAIgA—is not known, but most investigators consider them to be autoantibodies.
Acute ITP is most often a childhood disease that follows a viral infection. Most cases resolve spontaneously, although perhaps 10 percent become chronic. Conversely, in adults ITP is primarily a chronic disease of young women and rarely resolves spontaneously. There is no evidence that pregnancy increases the risk of relapse in women with previously diagnosed ITP, nor does it make the condition worse in women with active disease.
There are no pathognomonic signs, symptoms, or diagnostic tests for ITP; it is a diagnosis of exclusion. However, four findings have been traditionally associated with the condition:
• Persistent thrombocytopenia (platelet count less than 100,000/μL with or without accompanying megathrombocytes on the peripheral smear)
• Normal or increased number of megakaryocytes determined from bone marrow
• Exclusion of other systemic disorders or drugs that are known to be associated with thrombocytopenia
• Absence of splenomegaly
Treatment in Pregnancy
Treatment is considered if the platelet count is less than 50,000/μL. Corticosteroids in a dose of 1 mg/kg/day may be required for improvement, and most likely treatment will have to be continued throughout pregnancy. Corticosteroid therapy usually produces amelioration, but in refractory disease, high-dose immunoglobulin is given intravenously. In women with no response to steroid or immunoglobulin therapy, splenectomy may be effective. Late in pregnancy, the procedure technically is more difficult, and cesarean delivery may be necessary to improve exposure.
Fetal and Neonatal Effects
Platelet-associated IgG antibodies can cross the placenta and cause thrombocytopenia in the fetus-neonate. The severely thrombocytopenic fetus is at increased risk for intracranial hemorrhage as the consequence of labor and delivery. Approximately 12 percent of newborns born to mothers with ITP will have severe thrombocytopenia (less than 50,000/μL). Approximately 1 percent of all infants born to women with ITP will have an intracranial hemorrhage and half of these infants have initial platelet counts of 50,000/μL or greater.
There is no clinical characteristic or laboratory test that will accurately predict fetal platelet count, and there is no correlation between fetal and maternal platelet counts. Intrapartum platelet determinations can be made on blood obtained from the fetal scalp once the cervix is 2 to 3 cm dilated and the membranes ruptured. In the past, an immediate cesarean delivery was performed whenever the platelet count in scalp blood was identified as being less than 50,000/μL. Percutaneous umbilical cord blood sampling for fetal platelet quantification has also been performed in women with ITP. This procedure, however, is associated with a high complication rate (4.6 percent).
Prophylactic cesarean delivery does not appear to reduce the risk of fetal or neonatal hemorrhage, cesarean delivery is usually reserved for obstetric indications.
ISOIMMUNE (ALLOIMMUNE) THROMBOCYTOPENIA (ATP)
This type of thrombocytopenia differs from immunological thrombocytopenia in several important ways. Because it is caused by maternal isoimmunization to fetal platelet antigens in a manner similar to Rh-antigen isoimmunization, the maternal platelet count is always normal. Thus, alloimmunization is not suspected until after the birth of an affected child. Another important difference is that the fetal thrombocytopenia associated with ATP is frequently severe and can cause intracranial hemorrhage even before 20 weeks.
Fetal thrombocytopenia follows maternal isoimmunization against fetal platelet antigens. The most common antibody is against PLA1 platelet-specific antigen. Based on the incidence of HPA-1a negativity, 1 in 50 pregnancies is at risk. The rarity of the condition (from 1 in 5000 to 1 in 10,000 live births) results from the fact that fetal-to-maternal hemorrhage significant enough to provoke an immune response must occur, and only occurs in 5 to 10 percent of such pregnancies. Other antibodies are important and alloimmunization to HPA-5b, HPA-3a, and HPA-1b have been reported. Fortunately, weekly maternal infusions of immunoglobulin usually result in fetal platelet levels high enough to allow vaginal delivery. The diagnosis often can be made correctly on clinical grounds if the mother has a normal platelet count with no evidence of any immunological disorder, and her infant has thrombocytopenia without evidence of other disease. The first pregnancy is affected in about half of cases. Fetal thrombocytopenia recurs in 70 to 90 percent of subsequent pregnancies. It is often severe and occurs earlier with each successive pregnancy. Because of severe thrombocytopenia in fetuses in subsequent pregnancies, invasive therapies are problematic; however, weekly maternal intravenous infusions of immunoglobulin (IVIG), 1 mg/kg/week, usually result in fetal platelet levels high enough to prevent spontaneous hemorrhage.
THROMBOTIC MICROANGIOPATHIES (TTP AND HUS)
TTP is characterized by the pentad of thrombocytopenia, fever, neurological abnormalities, renal impairment, and hemolytic anemia. HUS is similar to TTP but with more profound renal involvement and fewer neurological aberrations. Idiopathic postpartum renal failure is characterized by acute irreversible renal failure that develops within the first 6 weeks postpartum, associated with micro-angiopathic hemolytic anemia and thrombocytopenia. Although it is likely that there are different etiologies to account for the variable findings within these syndromes, they are clinically indistinguishable in adults.
The frequency of thrombotic microangiopathy in pregnancy is 1 in 25,000 and is not greater than that in the general hospital population. It is not surprising that severe preeclampsia and eclampsia complicated further by thrombocytopenia and overt hemolysis have been confused with TTP and vice versa. Differentiating between preeclampsia, especially atypical preeclampsia, and these syndromes can be difficult, especially at the outset. One constant feature of thrombotic microangiopathies is hemolytic anemia, which is rarely severe with preeclampsia, even with the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Although delivery leads to resolution of preeclampsia with HELLP syndrome, there is no evidence that thrombotic microangiopathy is improved by delivery. Importantly, 64 percent of women with thrombotic microangiopathy have recurrent disease either when not pregnant or within the first trimester of a subsequent pregnancy.
Thrombotic microangiopathies are characterized by thrombocytopenia, fragmentation hemolysis, and variable organ dysfunction. Thrombocytopenia is usually severe. Fortunately, even with very low platelet counts, spontaneous severe hemorrhage is uncommon. Microangiopathic hemolysis is associated with moderate-to-marked anemia, and transfusions are frequently necessary. The blood smear is characterized by erythrocyte fragmentation with schistocytosis. The reticulocyte count is high, and nucleated red blood cells are numerous. Consumptive coagulopathy, although common, is usually subtle and clinically insignificant. A viral prodrome may precede up to 40 percent of cases. Neurological symptoms are present or develop in up to 90 percent of patients and include headache, altered consciousness, convulsions, or stroke. Because renal involvement is common, HUS and TTP are difficult to separate. Renal failure is thought to be more severe with HUS, and in half of the cases, dialysis is required. Recently it has been demonstrated that different defects in the ADAMTS13 gene that encodes the endothelial-derived metalloproteinase responsible for cleaving von Willebrand factor are associated with several clinical presentations of TTP.
Unless the diagnosis is unequivocally one of these thrombotic microangiopathies, rather than severe preeclampsia or eclampsia, the response to pregnancy termination should be evaluated before resorting to plasmapheresis and exchange transfusion, massive-dose glucocorticoid therapy, or other therapy. Plasmapheresis is not indicated for preeclampsia–eclampsia complicated by hemolysis and thrombocytopenia. Transfusions with red blood cells are imperative for life-threatening anemia. Those with minimal neurological symptoms may be given predinose, 200 mg daily, if there are neurological symptoms or rapid clinical deterioration plasmapheresis and plasma exchange may be performed daily. In our experiences from Parkland Hospital, 63 percent of women treated by plasmapheresis had a dramatic salutary response.
Recent observations indicate that pregnant women with thrombotic micro-angiopathy have a number of long-term complications, which include multiple recurrences; renal disease requiring dialysis or transplantation, or both; severe hypertension; blood-borne infectious diseases; and death. Although it is not possible to ascertain whether the guarded prognosis in these women is different from the natural history, clearly, development of thrombotic microangiopathy during pregnancy has severe immediate and long-term mortality.
For further reading in Williams Obstetrics, 23rd ed.,
see Chapters 29, “Diseases and Injuries of the Fetus and Newborn,” 48, “Renal and
Urinary Tract Disorders,” and 51, “Hematological Disorders.”