Hemolytic Anemia in PregnancyPregnancy-induced Hemolytic AnemiaTable 42.2 Features of Idiopathic Pregnancy-induced Hemolytic Anemia

A variety of hemolytic anemia syndromes can occur in pregnant women just as in nonpregnant women. In fact, pregnancy can exacerbate underlying autoimmune hemolytic anemia.90 Thus, hemolytic anemia is not particularly uncommon in obstetric practice. However, a rare entity has been described in which an idiopathic hemolytic anemia occurs during pregnancy, resolves completely after pregnancy, and recurs during subsequent pregnancy (Table 42.2). The pathogenesis of this anemia is not known. Terms for the condition include idiopathic autoimmune hemolytic anemia of pregnancy, unexplained hemolytic anemia associated with pregnancy, and pregnancy-induced hemolytic anemia. The condition is not homogeneous. In the cases reported by Ng et al. from Kuala Lumpur and Benraad et al. from The Netherlands,91,92 women had immunoglobulin G warm antibodies and were successfully treated with glucocorticoids. In some cases, a positive direct antiglobulin (Coombs) test is not found. 93,94,95 The majority of cases have no identifiable immune mechanisms and have a variable response to glucocorticoids.96,97,98

This pregnancy-induced hemolytic anemia becomes apparent in the third trimester of pregnancy and in most cases remits completely within 2 months of delivery, sometimes taking as long as 4 or 5 months. The anemia is usually very severe, even life threatening to mother and fetus. Corticosteroids and intravenous immunoglobulin (IVIG) have been reported to be successful in some cases, but many of the women have been treated with repeated erythrocyte transfusions. Generally, the transfused donor cells have a shortened survival. Neonates born to women with pregnancy-induced hemolytic anemia generally have transient hemolysis, lasting 1 to 2 months; severe jaundice requiring neonatal exchange transfusion has not been reported.

Autoimmune Hemolytic Anemia during PregnancyIn cases of autoimmune hemolytic anemia during pregnancy, whether idiopathic or of an identified variety, the degree of hemolysis is generally more severe in the mother than that in the fetus.99 However, therapy that ameliorates the maternal disease (such as corticosteroids or IVIG) often does not protect the fetus. This is in contrast to autoimmune thrombocytopenia during pregnancy, in which maternal and fetal platelet counts are likely to be concordant.

HELLP SyndromeTable 42.3 Major Clinical Characteristics of Hellp Syndrome, TTP, and HUS Modified from Saphier CJ…

Preeclampsia is characterized by gestational hypertension and proteinuria or pathologic edema; eclampsia is complicated by the additional occurrence of seizures.100,101 Preeclampsia and

eclampsia are systemic diseases involving the kidney, liver, heart, and central nervous system. Hematologic complications have been recognized for some time and include microangiopathic hemolytic anemia with characteristic fragmented red blood cells (RBCs) in the peripheral blood, thrombocytopenia, and well-defined abnormalities of the coagulation system.102,103 This subset of patients with severe preeclampsia/eclampsia is considered to have HELLP syndrome, characterized by hemolysis (H), elevated liver (EL) enzymes, and low platelet (LP) counts (Table 42.3).104,105

It is thought that RBC fragmentation and thrombocytopenia associated with HELLP are a result of a number of interrelated, largely mechanical factors, including endothelial damage, vasoconstriction coupled with hypertension, and the deposition of fibrin in injured vessels. Women with preeclampsia have abnormalities in coagulation, including signs of chronic intravascular coagulation,106 shortened platelet lifespan,103,107 decreased plasma antithrombin III activity,108,109 abnormalities in circulating fibrinogen multimers110 and increased fibrin deposition within the kidney and the liver.111,112 Increased rates of factor VIII consumption have been reported by some although not all investigators.113,114,115 Patients with preeclampsia have decreased hemopexin relative to healthy pregnant mothers.116 Women with preeclampsia also have higher circulating levels of the endogenous vasoconstrictor endothelin and other abnormalities of endothelial function.117,118,119,120 Patients with preeclampsia have an imbalance of placental prostacyclin and thromboxane production that favors vasoconstriction.121

HELLP syndrome reportedly occurs in 20% of women with severe preeclampsia and 10% of women with eclampsia.122 The median gestational age at presentation is 32 to 34 weeks, with a range of 24 to 39 weeks.123 Clinical findings at presentation include malaise, right upper quadrant tenderness, hypertension, and edema. Most women with HELLP syndrome are not anemic at presentation, although they may drop their hemoglobin out of proportion to the volume of blood lost at delivery.123

Laboratory features include elevated liver enzymes (i.e., alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), thrombocytopenia with <100,000/μl in most patients, and evidence of compensated hemolysis. The latter is probably the most specific abnormality associated with HELLP syndrome, but sometimes difficult to detect. The peripheral blood smear usually reveals schistocytes and there also may be burr cells and polychromatophilia.123 In one study, however, schistocytes were seen in only a small fraction of patients and it was proposed that the fragmented cells may have been removed by the spleen.124 Hemoglobinemia and hemoglobinuria occur in <10% of cases. The one consistent abnormality noted in women with HELLP syndrome is a decreased serum haptoglobin in virtually all patients, and this may be considered to be a highly sensitive test to detect this RBC abnormality when only a few schistocytes are present on smear.124 Patients with HELLP syndrome have been reported to have mild to moderate reduction in the von Willebrand factor cleaving protease ADAMTS-13 compared to nonpregnant women or women experiencing an uncomplicated pregnancy. These reduced levels were not due to inactivating antibodies.125 Severely reduced ADAMTS-13 levels would suggest a diagnosis of thrombotic thrombocytopenic purpura (TTP) rather than HELLP.126

TTP is also distinguished from HELLP by an increased lactate dehydrogenase (LDH)/AST ratio.127

The management of pre-eclampsia with HELLP syndrome is a matter of some obstetric debate, and is beyond the scope of this chapter. In general, the issues relate to immediate delivery or close observation, and these in turn are governed by maternal clinical status and fetal gestational age.123,128 The most common approach is to deliver the fetus as soon as possible or, if it is likely that there is fetal lung immaturity because of gestational age, steroids are administered to the mother for 2 to 3 days, and then the infant is delivered. It is intriguing that a small but significant fraction of women (30% in one study) spontaneously improves without more aggressive intervention.129 In contrast to TTP, there currently are no data indicating a role for plasmapheresis.

One of the most serious complications is hepatic rupture, with 50% maternal and 60% to 70% fetal mortality. Other complications include disseminated intravascular coagulation, renal failure, pulmonary edema, and placental abruption.105 Overall, maternal mortality ranges from 0% to 4% in different series.123 Hematologic and chemical abnormalities resolve within a few days of delivery. Neonatal mortality is 5% to 20%,105,123 and this is more a reflection of fetal age rather than any specific complication of maternal HELLP issues.

Pregnancy-associated Thrombotic Thrombocytopenic Purpura and Hemolytic-uremic SyndromeIn most reported studies of thrombotic microangiopathy with pregnancy, TTP and hemolytic-uremic syndrome (HUS) have been distinguished on the basis of the predominant symptomatology, neurologic or renal. TTP most commonly occurs antepartum, with a significant majority of cases presenting before 24 weeks’ gestation. Postpartum TTP is uncommon.130 HUS, on the other hand, typically occurs after a normal delivery and a symptom-free interval, and is characterized by acute-onset renal failure and microangiopathic hemolytic anemia.106,128 Hypertension is almost always found. A small fraction (10% to 15%) of HUS and TTP patients have signs of preeclampsia. Sometimes TTP/HUS is not correctly diagnosed until the patient, thought to have preeclampsia, has an atypical prolonged recovery in the