Hemolytic Anemia in Pregnancy

Pregnancy-induced Hemolytic Anemia

Table 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 Pregnancy

In 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 Syndrome
Table 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/l 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 Syndrome
In most reported studies of thrombotic microangiopathy with pregnancy, TTP and hemolyticuremic 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