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Routine supplementation with folic acid and, if indicated (following
Pregnancy-induced hemolytic anemia This extremely rare con-
assessment of serum ferritin), iron is necessary in order to ensure
dition presents as hemolytic anemia during the third trimester
effective erythopoiesis. In the rare event of severe anemia, splenect-
and remits spontaneously postpartum. The anemia is severe and
omy may be required. As anemia may worsen during episodes of
may become life-threatening, such that some women require
infection (due to increased hemolysis and possibly suppressed
transfusion. Corticosteroids and intravenous immunoglobulin
hematopoiesis) these patients require frequent monitoring.
(IVIG) have been tried but without uniform success. To date no
Other membrane abnormalities include hereditary elliptocyto-
cause has been found and treatment is empirical.59
sis and hereditary stomatocytosis; neither of these are improved
by splenectomy and most patients have a mild chronic hemolytic
anemia, which is unaffected by pregnancy.
Miscellaneous causes of hemolysis
Hemolysis may occur in patients with normal RBCs, secondary to
Red cell enzyme deficiencies The most common hereditary
trauma from prosthetic heart valves or secondary to fibrin deposi-
deficiencies are those of glucose-6-phosphate dehydrogenase
tion in the microvasculature (microangiopathic anemia). In the
and pyruvate kinase. Both of these enzyme deficiencies make
former situation, chronic hemolysis during pregnancy will be
the RBC susceptible to oxidant stress leading to an increased
associated with a raised LDH, possibly mild icterus, reticulocyto-
susceptibility to hemolysis. The degree of hemolysis varies, with
sis, and hemosiderinuria with decreased plasma haptoglobin.
more severe episodes often triggered by oxidant drugs including
Supplementation with folic acid and iron is usually necessary to
some antibiotics and nonopioid analgesics.
allow the bone marrow to compensate for ongoing loss.
Microangiopathic hemolytic anemia is associated with acute
DIC, preeclampsia, or acute vasculititis and treatment of the
Acquired disorders of the RBC leading to hemolysis
underlying disorder is essential.
Autoimmune hemolytic anemias These hemolytic anemias
result from the development of warm (IgG) or cold (IgM) reactive
red cell autoantibodies. These disorders can occur at all ages but
Abnormalities of the bone marrow
are more common in adults, particularly women. Autoimmune
hemolytic anemia is usually idiopathic but may occur secondary
Bone marrow failure syndromes
to drugs such as a-methyl dopa or in association with an under-
lying disease (about 25% of patients) such as systemic lupus
Aplastic anemia
erythematosus (SLE), rheumatoid arthritis, inflammatory bowel
Aplastic anemia is a primary bone marrow disorder caused by
disease, or a lymphoproliferative disease (e.g. chronic lympho-
hypocellularity of the marrow with resulting pancytopenia in the
cytic leukemia, non-Hodgkin lymphoma).
peripheral blood. The etiology of marrow hypoplasia is varied and
Patients with IgG autoantibodies (warm, reactive) are more
aplastic anemia has been associated with exposure to radiation,
common and present with anemia, mild icterus, and splenomegaly.
organic solvents, various drugs, immune lesions and viral disease,
Laboratory findings include reticulocytosis, and the presence
particularly the hepatitis viruses. Other more unusual defects
of spherocytes on the peripheral smear. If immune thrombocy-
may involve only one cell line such as anemia due to RBC aplasia,
topenia is present in conjunction with autoimmune hemolytic
anemia the condition is known as Evan syndrome.58 Patients or neutropenia due to white blood cell (WBC) aplasia. In the past,
aplastic anemia was associated with a dismal prognosis but bone
with idiopathic, immune hemolytic anemia usually respond
marrow transplantation from a matched sibling donor has a
well to corticosteroid therapy at a 1 mg/kg dose of prednisone.
reported success rate of 90%. Supportive therapy is often required
IgG autoantibodies have the potential to cross the placenta and
and immunosuppression is another treatment modality.60 Blood
cause fetal anemia. Transfusion should be avoided unless the
counts in nonpregnant patients who respond to immuno-
patient is very symptomatic or the fetus is compromised by
suppression may never become completely normal, and these
severe maternal anemia. Cross matching of blood may be difficult
patients are at risk for relapse of aplasia or development of par-
due to the presence of other alloantibodies.
oxysmal nocturnal hemoglobinuria (PNH), a myelodysplastic
In patients with immune hemolysis due to cold-reactive anti-
syndrome, or acute leukemia.61
bodies (IgM), the pathophysiology of hemolysis is different,
Approximately 50% of cases of aplastic anemia are idiopathic in
resulting largely from the fixation of complement on the red cell
origin. There are sporadic case reports of refractory hypoplastic
membrane with resultant hemolysis in the intravascular space.



297
5 Other disorders


Diamond-Blackfan anemia
anemia, which appear to be related to pregnancy and which
regress postpartum.62,63,64,65,66,67 However, the majority of Diamond-Blackfan anemia is an autosomal dominant congenital
women affected in pregnancy have become pregnant during the RBC aplasia resulting from failure of a single hematopoietic cell
course of chronic aplastic anemia.68 Due to increased plasma line. Treatment generally consists of RBC transfusion with iron
chelation and oral corticosteroids.78 Bone marrow transplanta-
volume and the inability of bone marrow to respond it is common
for peripheral cytopenia to worsen during pregnancy and to tion is also successful. There are isolated reports of pregnancy
improve postpartum. in women with this disorder and the associated risks include C/S,
low birth weight, and premature delivery.79,80 There are a few
Pregnancy in women with aplastic anemia is considered high
risk due to the high incidence of perinatal morbidity and mortal- reports of nonimmune hydrops occurring in the infants of
ity.69,70 To date, there is conflicting evidence as to the effect that mothers with Diamond-Blackfan anemia.81,82
pregnancy has on aplasia and vice versa. Aplasia has been dis-
Shwachman-Diamond (SD) syndrome
covered during pregnancy and occasionally aplasia may comple-
tely resolve postpartum. One retrospective study describes This is a very rare disorder. In 1999 there were approximately 200
pregnancy in 36 women who received immunosuppressive ther- reported cases of SD and most had not lived to age 16. There is a
apy for aplastic anemia.61 Twenty-two pregnancies were uncom- single report of successful pregnancy (delivery by C/S) in this
autosomal recessive inherited bone marrow failure syndrome.80
plicated, but seven women (19%) had a relapse of aplasia and
three of these had remission of their disease while three more Women with this disorder have evidence of pancreatic insuffi-
recovered after treatment. One who did not have a remission ciency (steatorrhea, malabsorption), neutropenia, anemia and
died. Complications were related to low platelet counts and thrombocytopenia, short stature, and bony abnormalities.
PNH-associated aplastic anemia. Women who had a relapse Supportive therapy is essential throughout pregnancy.
during pregnancy or had progressive thrombocytopenia had an
operative delivery. Anesthetic management is not discussed.61
Paroxysmal nocturnal hemoglobinuria
The major risks of aplastic anemia during pregnancy are severe
anemia, hemorrhage due to thrombocytopenia, and infection Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired
associated with neutropenia.71 In the past, women with aplastic clonal disorder of bone marrow, which may affect young adults. An
anemia were advised not to become pregnant or, if pregnancy abnormal clone at the stem cell level produces RBCs, platelets, and
granulocytes that are abnormally sensitive to complement.4 This
occurred, to terminate the pregnancy. With transfusion support,
particularly platelets, this may not be appropriate advice for those leads to acute and chronic intravascular hemolysis, intermittent
with mild to moderate disease.68,72 However, some authors still hemoglobinuria, and a thrombotic tendency. Thrombocytopenia
debate this.70 The best outcome from pregnancy is achieved with often occurs, while granulocytopenia (increased risk of infection)
a multidisciplinary approach involving obstetricians, hematolo- is less common. Some patients present with a picture indistin-
gists, and anesthesiologists.73 guishable from aplastic anemia. Bone marrow transplantation
has been successful in curing PNH.
Venous thrombosis is frequent in PNH and is attributed
Congenital red cell aplasias
to intravascular hemolysis with inappropriate activation of
Primary red cell aplasia thrombin. Patients who have had episodes of thrombosis may
Primary red cell aplasia (PRCA) is a rare disease associated with be on long-term oral anticoagulation, which, in pregnancy, would
progressive anemia, marked reticulocytopenia, and almost com- be switched to therapeutic, subcutaneous heparin (unfraction-
ated [UFH] or low-molecular-weight [LMWH]).83 There is
plete absence of RBC precursors in the marrow. Production of
WBCs and platelets is normal. The congenital form is known as limited experience with this disorder in pregnancy; however,
Diamond-Blackfan syndrome or anemia and it usually presents several reports describe severe thrombotic complications in unu-
in infancy (see below). Acquired PRCA has been associated with sual sites (maternal hepatic vein, cerebral venous sinus) and fetal
loss.84,85,86,87
thymoma, chronic lymphocytic leukemia, renal failure, preg-
nancy, and various autoimmune disorders.74,75 Washed RBCs should be given when transfusion is needed to
correct anemia or during episodes of hemolysis.85 Prophylactic
Fanconi anemia transfusions may decrease the incidence of thrombotic compli-
Fanconi anemia is a rare congenital RBC aplasia, which is inherited cations, but this remains speculative because of the small number
as an autosomal recessive trait. Characteristics are progressive of patients with PNH and the inability to undertake properly
bone marrow failure, skeletal defects, reduced fertility, and in- structured research trials. Steroids are useful in approximately
creased susceptibility to malignancy. There is a report of a pregnant 50% of patients during acute hemolytic episodes.
woman with Fanconi anemia who received ˜˜washed™™ RBCs during
pregnancy, was induced at term for preeclampsia, and delivered
Sideroblastic anemia
by C/S. The postpartum period was complicated by anemia,
thrombocytopenia, epistaxis, and superficial wound hemor- This is a descriptive term for a variety of disorders that have a
rhage.76 Successful pregnancies have been reported following defect in heme biosynthesis and defective iron use. They are
bone marrow transplantation in women with Fanconi anemia.77 inherited in either an autosomal recessive or sex-linked pattern



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Chapter 17


or acquired in association with certain diseases (myelodysplastic It is important to provide adequate analgesia during labor
syndromes, malignancy), drugs, or toxins. Ringed sideroblasts in as pain-induced hypertension could lead to intracranial hemor-
the bone marrow are diagnostic. Medical management during rhage in patients with severe thrombocytopenia. As regional
pregnancy is similar to the patient with hypoplastic anemia. anesthesia is contraindicated in the severely thrombocytopenic
However, since this disorder is associated with significant dys- parturient, intravenous patient-controlled analgesia (PCA) with
erythropoiesis, administration of exogenous iron is contraindic- an opioid is an acceptable option. The neutropenia associated
ated unless the serum ferritin suggests iron deficiency, which is with marrow hypoplasia places the patient at increased risk
highly unlikely. There are few reports of pregnancy in patients with of infection so appropriate precautions should be undertaken
sideroblastic anemia. In one successful pregnancy the hematocrit during invasive procedures, including surgery. Special considera-
was maintained throughout pregnancy by periodic transfusion of tions for bone marrow recipients are noted later in this chapter.
washed RBCs.88 A woman with twin pregnancy required periodic There are few reports of the anesthetic management of women
transfusion when she had a relapse during pregnancy.89 with primary marrow disorders. There is a report of the anesthetic
management of C/S in a woman with hypoplastic anemia and
preeclampsia.91 Immediately preoperatively her hemoglobin was
Anesthesia for parturients with bone
6.4 g/l, WBC count 4.33 ‚ 109/l, and platelet count 10 ‚ 109/l.
marrow failure disorders
She received ten units of platelets prior to induction of general
The principles of management for these patients relate primarily anesthesia for C/S and four units intraoperatively. Hydralazine
to ensuring adequate oxygen-carrying capacity, prevention of 5 mg was administered intravenously 20 minutes before induc-
infection, and, more importantly, adequate hemostasis.90 A multi- tion, and alfentanil was administered prior to thiopental and
disciplinary approach is necessary for optimal management of succinylcholine in order to prevent a hypertensive response.
The intraoperative course was uneventful.89 Another report
their labor and delivery.
Patients who had previous transfusions or previous pregnan- concerned a woman with myelodysplastic syndrome who had
uneventful general anesthesia for C/S twice.92
cies are often refractory to platelet transfusions due to the pre-
sence of human leukocyte antigen (HLA) antibodies. Human Anesthetic considerations in women with PNH include strict
leukocyte antigen typing of the patient in advance, and collection asepsis, peripartum anticoagulation to prevent thrombosis, and
of HLA-matched platelets for support during delivery, is neces- prompt intervention in the event of hemorrhage, as well as main-
sary. Similarly, patients who have received previous RBC trans- tenance of normothermia, normovolemia, acid-base balance,
fusions may have red cell alloantibodies. Advance warning to the and avoidance of stress and medications that may activate com-
blood bank helps ensure availability of RBCs. Patients who have plement release. Regional and general anesthesia have been
described in patients with PNH.87,93,94 Concerns with respect to
never had blood products and are potential candidates for bone
marrow transplant require consultation with a hematologist general anesthesia include the risk of cerebral hemorrhage during
and transplantation team to ensure that appropriate products induction in those with thrombocytopenia. Kjaer reported the use
are used in order not to compromise chances for a successful of general anesthesia in a parturient with PNH whose platelet
count was 52 ‚ 109/l.94 Corticosteroids and blood products were
transplant.
Neuraxial anesthesia is contraindicated in the presence of severe administered after delivery of the placenta to avoid a hemolytic
thrombocytopenia, but there is little in the literature to guide one crisis. Heparin for antithrombosis prophylaxis was initiated
postpartum.94
with respect to a ˜˜safe™™ platelet count in women with primary
marrow disorders. A platelet count >50 ‚ 109/l is adequate for Although regional anesthesia has been described in patients
an uncomplicated vaginal delivery. However, in our opinion, a with PNH, one must ensure there is an adequate platelet count,
platelet count of 75“80 ‚ 109/l is required for adequate hemostasis probably >75 ‚ 109/l. A report describes uneventful epidural
labor analgesia in a woman whose platelet count was 64 ‚ 109/l
prior to neuraxial anesthesia, episiotomy, or C/S in women with
primary marrow disorders. This differs from the situation with at the time of insertion. Epidural analgesia was used to reduce
labor stress.93 Paech and Pavy described the use of PCA intrave-
idiopathic/immune thrombocytopenic purpura (ITP) where the
platelets are young and healthy, as the thrombocytopenia is due nous fentanyl for labor analgesia in a woman with PNH followed
by general anesthesia for removal of a retained placenta.95
to platelet destruction. In primary marrow disorders there is a
mixture of old and young platelets in the circulation “ the older
platelets being less functional than young platelets.
Primary marrow malignant disorders
In patients requiring transfusion of platelets to achieve ade-
quate levels for delivery, a one-hour posttransfusion platelet
Philadelphia negative myeloproliferative
count is essential to ensure that the target range has been reached.
diseases (MPD)
Failure to achieve a rise in platelet count of 5“10 ‚ 109/l per
random donor unit of platelets transfused is suggestive of immune Most of these diseases occur in the 6th and 7th decades but
refractoriness, related to human leukocyte antigen (HLA) anti- they have been reported in younger women and in concurrence
bodies. The level of hemoglobin that is appropriate varies and with pregnancy. The myeloproliferative disorders include, in
depends on the degree of maternal compensation, fetal well- order of appearance in the obstetric population: essential throm-
being, and projected blood loss. bocythemia (ET) (also known as essential thrombocytosis),



299
5 Other disorders


polycythemia rubra vera (PRV), chronic myelogenous or granu- 1600
locytic leukemia, and myelofibrosis with myeloid metaplasia.
All arise from clonal stem cell defects and these disorders are
characterized by autonomous proliferation of the stem cell lines.
1400
Clinical features include thrombosis, hemorrhage, progression to
myelofibrosis, and acute myeloid leukemia.96 Management issues
during pregnancy include maintenance of normal uterine blood
flow and adequate placental development. The risk of thrombosis




Platelet count — 109/l
1200
in the placenta and maternal circulation is high. Strategies during
pregnancy include aspirin and/or heparin (LMWH or UFH) to
prevent thrombosis, phlebotomy to reduce RBC or platelet mass,
and possible use of cytoreductive agents such as interferon a and
1000
hydroxyurea. Occasionally, plateletpheresis is used.96

Essential thrombocythemia (ET)
This is the most common of the myeloproliferative disorders seen 800
in pregnancy. These patients present with thrombocytosis that is
often asymptomatic, particularly in the range below 1000 ‚ 109/l.
The criteria for diagnosis of ET is a platelet count consistently
>600 ‚ 109/l, hematocrit <40, stainable iron in the marrow, a 600
normal serum ferritin level, no Philadelphia chromosome, no
evidence of marrow fibrosis, no cytogenic or morphological
evidence of myelodysplastic syndrome, and no cause for reactive
400
thrombocytosis.97,98 At presentation, only 50% have splenomegaly 50
40
30
20
0 10
and a sustained elevation of platelet count, usually >1000 ‚ 109/l.
Weeks™ Gestation
The platelet smear may be normal or show giant platelets and
Figure 17.2 Platelet count of three patients with essential thrombocythemia
hypogranular platelets. Anemia is rare unless there has been
demonstrating the physiological decrease in platelet count that occurred
hemorrhage or iron deficiency. The major causes of morbidity
during pregnancy.
and mortality are thromboses (arterial and venous) and hemor-
rhage.99 Stroke and transient ischemic attacks are common and
placental abruption. Although thrombosis is common, mainly in
are related to inappropriate platelet activation in the microvascu-
the postpartum period, hemorrhage also occurs (approximately
lature. Symptoms requiring therapy are erythromelalgia (burning
4“5%). In one review, two women with ET and acquired von
pain in the fingertips), headaches, easy bruising or mucous
Willebrand (VW) disease had major bleeding events.102
membrane hemorrhage. Interestingly, both thrombotic and
Randi et al. reported on six normal pregnancies in five untreated
hemorrhagic complications are usually controlled by lowering
patients concluding that many patients do not warrant therapy
the platelet count. Platelet function studies fail to uncover a con-
during pregnancy.103 In our experience, the platelet count
sistent pattern and there is no laboratory assay that predicts a
decreases gradually during pregnancy, usually reaching its nadir
predisposition to either bleeding or thrombosis. Some patients
at 32“36 weeks, coinciding with completion of plasma volume
have spontaneous in vitro platelet aggregation or platelet hyper-
expansion (see Figure 17.2). Low-dose aspirin (81 mg daily)
aggregability, while others lose platelet responsiveness to
epinephrine.100 Other platelet function abnormalities include is reported to minimize placental compromise from platelet
thrombosis. At the present time, there is no indication for routine
platelet membrane abnormalities, acquired storage pool defici-
heparin prophylaxis unless there is a preceding history of venous
ency, and metabolic abnormalities.
thrombosis. Women with very high platelet counts may be on
In patients with evidence of platelet-associated thrombosis
interferon alpha (IFNa), which may reduce complications in any
without impaired hemostasis, and a platelet count in the range
of 1500 ‚ 109/l or less, the use of low-dose aspirin is often suffi- woman with ET. As IFNa is excreted in breast milk, breast-feeding
cient to control symptoms.98 Two major therapeutic options for is contraindicated in women receiving this therapy.
ET are to lower the platelet count using antiproliferative agents,
Polycythemia vera (PV, erythrocytosis)
such as hydroxyurea or myleran (busulfan), or in the more acute
This chronic myeloproliferative disorder, with an estimated
situation, plateletpheresis. There is no concensus on the use of
hydroxyurea or myleran during pregnancy.100,101 incidence of 1:50 000 in the general population, is occasionally
seen in pregnancy.104 It is characterized by an increase in RBC
There have been over 280 pregnancies reported in 147 patients
mass, usually associated with a pancytosis and splenomegaly.
with ET. Essential thrombocythemia is accompanied by an
Symptoms are related primarily to the increased blood volume
increased risk of fetal complications, with early and late fetal
and viscosity, and these patients are at risk from bleed-
loss rates approximately double that in the normal population.
ing and thrombosis. These problems are well controlled
Other complications include IUGR, preterm delivery, and



300
Chapter 17


with phlebotomy.104 Diagnosis is based on an elevated RBC but this is debated. By 2005 only four pregnancies in two patients
had been reported.96 There were two live births at 34 and 36
mass, normal arterial oxygen saturation, and splenomegaly.
If there is no splenomegaly two other criteria are required weeks™ gestation and two stillbirths due to placental infarction
(leukocytosis >12 ‚ 109l, thrombocytosis >400 ‚ 109/l, leukocyte at 27 and 30 weeks™ gestation.96 Anesthetic management is not
reported.112
alkaline phosphatase >100 U, serum B12 >900 pg/ml or
unbound B12 binding capacity >2200 pg/ml).104 Erythrocytosis
may be primary (PV) or secondary (congenital, acquired).
Lymphoma
Since PV is more common in men and older individuals, PV in
pregnancy is uncommon. As of 2005, there were reports of 36 preg- Hodgkin disease is the most common lymphoproliferative
nancies in 18 patients with a neonatal survival rate of 50%. disorder in young people and overall, lymphoma is the fourth
most frequent cancer diagnosis among pregnant women.113
Complications included one maternal death after elective
termination of pregnancy, two postpartum pulmonary emboli, The prevalence of non-Hodgkin lymphoma is unknown.
and one large PPH. Four pregnancies were complicated by Pregnancy does not appear to affect the natural history of
preeclampsia.96 Hodgkin disease114 and vice versa. However, high grade lym-
Pregnant women with PV are at risk for poor obstetrical out- phomas, including Burkitt lymphoma, are rapidly progressive
come because of placental compromise. Due to the autonomous and require aggressive intervention and treatment in pregnant
nature of erythropoiesis in this disorder, the plasma volume women. Extra-dural presentations of non-Hodgkin lymphoma
expansion of pregnancy will result in a fall in hematocrit through- have been reported, including one that resulted in paraparesis
out the first 34 weeks with a nadir late in the third trimester.96 following delivery.115 Mediastinal non-Hodgkin lympomas
Phlebotomy is safe during pregnancy and can be used to further have been reported during pregnancy causing cardiorespiratory
compromise.116,117
reduce hematocrit, minimizing maternal and fetal risk. Iron
stores will be diminished and careful limited supplementation
may be necessary to ensure adequate iron delivery to the fetus.
Multiple myeloma
There is an increased risk of cardiac failure due to increased
cardiac output associated with PV and pregnancy. Heparin may This hematological malignancy results from proliferation of a
be used to reduce risk of thrombosis.96 single clone of neoplastic plasma cells and is rare in preg-
nancy.118,119,120,121,122 Clinically these patients may present
Leukemia with a spectrum of complaints including a mild unresponsive
Acute leukemia affects a younger population than does chronic anemia, bone pain, pathologic fractures, neurologic deficits,
leukemia. The incidence of acute leukemia is one in 75“100 000 and recurrent infections. Recurrent infections result from sup-
pregnancies.105 The majority of cases that occur during pression of normal B cell function by the malignant clone.
pregnancy are diagnosed during routine prenatal care. If acute Spinal cord compression secondary to vertebral collapse with
leukemia presents during pregnancy, chemotherapy is generally paraplegia occurs in approximately 14% of nonpregnant patients.
started and is considered safe during the second and third Anemia occurs secondary to marrow infiltration and renal
trimesters,106,107 but potential complications include hemor- failure in the latter stages of the disease. An increased bleeding
rhage and sepsis.108 Remission rates are high following treat- tendency may occur secondary to thrombocytopenia or through
ment of acute myelogenous and acute lymphocytic leukemia, monoclonal protein interference with platelet function or coagu-
but relapse is common within a year. Breast-feeding is con- lation factors. As well, these patients can develop a hypervis-
traindicated when the mother is receiving cytotoxic drugs.109 cosity syndrome with stroke, myocardial compromise, and skin
Many parturients with leukemia have thrombocytopenia, hypo- infarction.
fibrinogenemia, or DIC and so are at risk for hemorrhage. The cases reported in pregnancy had diverse presentations
such as, threatened miscarriage,121 anemia during a routine
However, hemorrhage has rarely been reported possibly
antenatal visit,116 bilateral leg weakness and back pain post-
because these women tolerate low platelet counts well.
partum,118 and pathologic fracture.122 The offspring were
Infection may be secondary to leukopenia from the leukemia, or
from chemotherapy. unaffected.
There is no evidence that pregnancy alters the incidence or
prognosis of acute or chronic leukemia.110 The commonest
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