C H A P T E R 151 
HEMATOLOGIC CHANGES IN PREGNANCY
Hematologic conditions are often seen during pregnancy. These range
from the simple to the complex. The primary physiologic hematologic
changes during pregnancy relate to the expansion of plasma volume.1
In addition to physiologic changes of pregnancy, a prothrombotic
state develops as the pregnancy advances that is thought to prepare
the mother and fetus for eventual placental separation.2 All require
proper planning, anticipation, and discussion with the treating physi-
cians as well as the patient. The effect of the condition on the
pregnancy, and conversely the effect of the pregnancy on the condi-
tion, should be considered. The evolving clinical picture as the
pregnancy progresses must also be taken into account. Multidisci-
plinary planning and communication are essential.
Anemia and thrombocytopenia are common hematologic condi-
tions seen for a variety of reasons during pregnancy and are addressed
in this chapter. Inherited and acquired bleeding disorders affect
pregnant women, and coagulation parameters must be monitored
during pregnancy and delivery. Venous thromboembolism (VTE)
during pregnancy remains a high-morbidity, high-risk situation
that is challenging for clinicians. These more common hematologic
problems and dilemmas in management are discussed in this
chapter.
ANEMIA IN PREGNANCY
Anemia in pregnancy affects approximately half of all pregnancies
worldwide. It is more prevalent in underdeveloped countries.
The World Health Organization classifies anemia in pregnancy as
hemoglobin below 11 g/dL, although in developing countries it is
clinically defined as hemoglobin below 10 g/dL.1 Physiologic anemia
occurs during pregnancy as the blood volume increases to a greater
proportion than the red blood cell (RBC) mass, resulting in a dilu-
tional anemia. Total circulatory volumes increase by approximately
50% greater than the prepregnancy volume. Plasma volume and RBC
mass return to baseline during the first and second postpartum
months. Common maternal signs of anemia include pallor, tachy-
pnea, fatigue, and headache. Hemoglobin levels less than 6 g/dL in
pregnant women can be associated with significant maternal and fetal
complications. At these levels, tissue oxygenation decreases and may
lead to high-output congestive heart failure in the mother.2–4 Multiple
studies have shown a correlation between maternal anemia and
increased rates of both preterm (<37 weeks of gestation) and low-
birth-weight deliveries.5–13 There are varied etiologies behind anemia
in pregnancy.
Iron-Deficiency Anemia
Iron-deficiency anemia is the most common cause of anemia in
pregnancy. It has been identified as a risk factor for preterm delivery
and low birth weight. Iron requirements increase during pregnancy
because of maternal and fetal erythropoiesis. Generally, hemoglobin
levels decrease throughout pregnancy and then may increase during
the last month of pregnancy. Ferritin levels also increase in the last
month of pregnancy because it is an acute-phase reactant. Erythro-
poietin levels increase throughout pregnancy. The clinical symptoms
of iron deficiency are similar to those in nonpregnant patients and
include fatigue, pallor, tachycardia, and poor exercise tolerance. The
diagnosis and treatment of iron-deficiency anemia are generally
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Caroline Cromwell and Michael Paidas
similar to those in nonpregnant patients. Anemia and low ferritin
levels are considered diagnostic.
Because the typical diet in the United States provides only 50%
of daily iron requirements for pregnant women and because of the
relatively high prevalence of iron deficiency among women of child-
bearing age, routine iron supplementation in pregnancy is recom-
mended.14 Currently, the Centers for Disease Control and Prevention,
the American Dietetic Association, and the American College of
Obstetrics and Gynecology recommend 15 to 30 mg/day of elemen-
tal iron to prevent adverse outcomes from iron-deficiency anemia.14–18
Treatment should be from the beginning of gestation to 3 months
postpartum. On the basis of results of a study by Casanueva et al,19
weekly therapy with 120 mg of iron appears to be a safe and effective
alternative to daily therapy. The side effects associated with iron
therapy—constipation, diarrhea, nausea—are well known.
Intravenous iron is appropriate in certain circumstances; evidence
from a recently published randomized trial by Al et al supports the
use of intravenous iron therapy to replenish iron stores in appropri-
ately selected patients, including those who have not tolerated a trial
of oral iron therapy and those with severe iron deficiency.20
Multiple studies have shown that routine iron supplementation
in pregnancy decreases the incidence of iron-deficiency anemia. In a
randomized, double-blind study in which 275 iron-replete pregnant
women received either a daily iron supplement or placebo from the
time of enrollment (all women were enrolled before week 20) to 28
weeks of gestation, the incidence of both low-birth-weight and
preterm low-birth-weight infants was lower among women who
received daily iron.21 Nonetheless, there are limits to the effectiveness
of routine iron supplementation. After all, the recommendation by
prominent public health organizations for universal iron supplemen-
tation has not led to a commensurate decrease in the incidence of
iron-deficiency anemia in pregnancy22,23 or an increase in maternal
hemoglobin levels.24,25 Compliance is an important factor in this
discussion. A large, multicenter, randomized, controlled trial on the
benefits of iron supplementation during pregnancy in the United
States is needed to draw more definitive conclusions.
Other Nutritional Deficiencies
Folate deficiency and, less commonly, vitamin B12 deficiency are the
next most common causes of anemia in pregnancy. Cobalamin and
folate are critical for fetal growth because they are necessary for the
production of tetrahydrofolate. Tetrahydrofolate is key in the DNA
synthesis pathway.
Folate deficiency accounts for 95% of megaloblastic anemias in
pregnancy.26 Folate deficiency complicates between 1% and 4% of
pregnancies in the United States and affects approximately one-third
of pregnancies worldwide.27 Similar to iron-deficiency anemia, the
incidence of megaloblastic anemia in pregnancy is increased in ado-
lescents, women of low socioeconomic status, and women with
multiple closely spaced births.28 The folic acid requirement for
nonpregnant women is 50 to 100 µg/day, but this increases to 150 µg
during pregnancy as RBC mass in the mother increases and as fetal
demands for folate grow with cell proliferation.29
Diagnosis of folate deficiency is best based on RBC folate levels.
An elevated homocysteine level also helps confirm the diagnosis.
Pregnant women should at least receive 400 µg of folic acid per day.
Vitamin B12 deficiency is much less common during pregnancy.
2203
 2204 Part XIII  Consultative Hematology
Diagnosis of vitamin B12 deficiency can be aided by the assessment
of homocysteine and methylmalonic acid. If a woman is found to be
deficient in vitamin B12 during pregnancy, vitamin B12 injections are
indicated. These are usually injected weekly for 4 to 8 weeks and then
monthly.
HEMOGLOBINOPATHIES AND PREGNANCY
Sickle Cell Disease
Every year more than 300,000 children are born with either sickle
cell disease or thalassemia. Prenatal counseling now exists in many
countries. In the United States, all newborns are screened for sickle
cell disease (see Chapters 42 and 43). Management of pregnant
patients with sickle cell disease requires coordination of care between
the hematologist and obstetrician. Many women with sickle cell
disease experience more frequent vasoocclusive crises and other sickle
cell–related complications during pregnancy.30 The increased fre-
quency of vasoocclusive crises, particularly during the latter half of
pregnancy, likely results from heightened metabolic requirements in
pregnancy, increased venous stasis, as well as the physiologic pro-
thrombotic and inflammatory state associated with pregnancy. In
addition, pathophysiologic changes in the renal and immune func-
tion of patients with sickle cell disease increase their susceptibility to
urinary tract infections and pyelonephritis. By causing tissue hypoxia,
sickling of RBCs within the placental vasculature may cause deleteri-
ous effects on the fetus.31
Additional significant complications occur in pregnant women
with sickle cell disease. The incidence of preeclampsia, thromboem-
bolic events, placental abruption, intrauterine growth retardation,
low birth weight, and postpartum infections are higher among
women with hemoglobin SS, SC, and S β-thalassemia than among
women without sickle cell disease. One study noted a higher inci-
dence of stillbirths and perinatal mortality among patients with sickle
cell disease,32 but another study revealed an increased risk of preterm
labor and premature rupture of membranes in women with hemo-
globin SS disease.33 Despite advances made in sickle disease, a recent
meta-analysis highlights that risks for pregnancy in patients with SS
genotype remains high with regard to mortality, a fourfold higher risk
of stillbirth and a 2.43 higher relative risk of preeclampsia. These risks
were amplified in low-income countries. Because of the increased risk
for such complications, women with sickle cell disease should receive
close medical attention throughout the prenatal period. This includes
counseling about intrauterine diagnosis of sickle cell disease when
appropriate. Pregnant women can undergo chorionic villi sampling
as early as the ninth week of gestation or amniocentesis in the 15th
to 16th weeks. A reticulocyte count along with hemoglobin, iron,
and folate levels should be obtained to assess for deficiency states and
bone marrow suppression. Urinalysis with urine culture is performed
as often as every trimester to monitor for asymptomatic bacteriuria.
Finally, beginning around 28 weeks of gestation, patients should have
weekly clinic visits and begin serial ultrasonography.
Treatment of sickle cell disease during pregnancy warrants careful
consideration. Hydroxyurea should be avoided. If pregnancy is being
considered it should be discontinued. Women should receive 5 mg/
day of supplemental folic acid. Studies examining the benefit of
prophylactic blood transfusions or exchange transfusions have not led
to definitive conclusions.34 Although they may lead to alloimmuniza-
tion, prophylactic transfusions appear to decrease the incidence of
vasoocclusive crises and decrease maternal and fetal morbidity and
mortality.35 A conservative approach reserves transfusions for patients
whose hemoglobin levels fall below 6 g/dL, patients who develop
progressive complications related to sickle cell disease, and patients
with obstetric complications.36 Following this approach, 60% to 75%
of women with sickle cell disease will require transfusion therapy
during pregnancy. Patients with a sickle cell crisis during pregnancy
should receive aggressive analgesic therapy, hydration, and oxygen
while undergoing evaluation for infection or other precipitating
influences.
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At the time of delivery, pregnant women with sickle cell disease
are managed in a manner similar to those with high cardiac output
anemia. Supplemental oxygen, hydration, and adequate oxygenation
during anesthesia should be given to prevent sickling of RBCs and
the associated complications. During the postpartum period, hemo-
globin levels are followed closely, and prophylaxis for VTE is admin-
istered unless contraindications preclude it.
Thalassemias
Pregnant women with an underlying thalassemia typically have
β-thalassemia minor or α-thalassemia trait—conditions with a rela-
tively benign clinical phenotype—rather than β-thalassemia major or
hemoglobin H disease (see Chapter 41). Because of delayed pubertal
growth or hypogonadism with associated anovulation, women with
β-thalassemia major and hemoglobin H disease rarely become preg-
nant. Case reports indicate that when it does occur, pregnancy in
women with hemoglobin H disease can be complicated by severe
hemolytic anemia and hepatosplenomegaly. However, in the setting
of widespread transfusion and iron chelation therapy, pregnancy is
more frequent in the thalassemia population. Pregnancy outcomes
among women with β-thalassemia major were recently examined in
10 patients with homozygous β-thalassemia. Of 15 pregnancies, there
were 14 live births, a 20% incidence of intrauterine growth restriction
(IUGR), and 21% were low-birth-weight children. In patients with
β-thalassemia intermedia, approximately 50% of pregnancies are
complicated by preterm delivery, third-trimester stillbirth, or IUGR.37
Pregnancy is a common setting for the diagnosis of β-thalassemia
minor or α-thalassemia trait in previously asymptomatic women who
are found to be anemic on routine laboratory evaluation during
pregnancy. Several studies indicate that the physiologic anemia of
pregnancy may be exacerbated in women with thalassemia minor,
although findings from at least one study suggest otherwise.38
β-Thalassemia minor and α-thalassemia traits do not have an adverse
effect on fetal development, fetal morbidity and mortality, or mater-
nal morbidity and mortality.39
Similar to those with sickle cell disease, women with thalassemia
require vigilant follow-up throughout their pregnancies. This includes
interval monitoring of maternal vital signs and fetal heart rate,
maternal hemoglobin levels, and fetal growth as assessed by ultraso-
nography beginning around the 24th week of gestation. Patients are
screened for folate and iron deficiency. They should also be assessed
for iron overload, which can develop in individuals with thalassemia
as a result of increased intestinal iron absorption, frequent blood
transfusions, and rapid turnover of plasma iron.40 Prenatal genetic
testing can be performed if desired, with results used to counsel
parents of the child and guide optimal care of the fetus. In terms of
therapy, there are no specific treatment recommendations for women
with thalassemia during pregnancy, aside from folate supplementa-
tion and supportive care. In pregnant women with evidence of iron
overload, chelation therapy using deferoxamine has been used safely,
although the potential for teratogenicity associated with the agent
must be considered in this setting.41
OTHER HEMOLYTIC ANEMIAS
Hereditary Spherocytosis
Hereditary spherocytosis is the most common inherited hemolytic
anemia among people of northern European descent (see Chapter
46).42 Few cases of pregnancy in individuals with hereditary sphero-
cytosis have been reported. Published reports indicate there may be
an increased incidence of first trimester fetal loss in patients with
hereditary spherocytosis.43 Because some patients have only low levels
of hemolysis under normal conditions, the disease may not become
clinically apparent until pregnancy. Pregnant women with hereditary
spherocytosis can exhibit a variety of clinical manifestations. These
include folate deficiency related to the increased requirements of

pregnancy superimposed on chronic hemolysis, hemolytic crisis, and
aplastic crisis.44,45 The results of two small series suggest that preg-
nancy outcomes for women with hereditary spherocytosis are gener-
ally good, with improvements in outcomes for splenectomized
patients.46 Care is primarily supportive.
Glucose 6-Phosphate Dehydrogenase Deficiency
Favorable pregnancy outcomes observed in women with hereditary
spherocytosis and pyruvate kinase deficiency stand in contrast to
those in women with glucose 6-phosphate dehydrogenase (G6PD)
deficiency. The deficiency of G6PD leads to hemolytic anemia in the
face of oxidative stress (see Chapter 45). The condition increases the
risk of spontaneous abortion, low-birth-weight fetuses, and neonatal
jaundice.47 Women with G6PD deficiency should be instructed to
strictly avoid medications with oxidative potential. Complications
after the ingestion of oxidative drugs can even occur in a carrier of
the G6PD deficiency gene if her male fetus has inherited the disease.48
Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder
caused by somatic mutation in the membrane-anchoring protein
PIGA (see Chapter 32). PIGA mutation leads, in turn, to deficient
function of critical membrane proteins that in wild-type individuals
are anchored by the gene product of PIGA. Features of the clinical
phenotype include hemolysis, thrombosis, and bone marrow failure.
Hemolysis results from deficiency in the membrane proteins CD55
and CD59, which renders affected individuals susceptible to
complement-mediated intravascular hemolysis.
The clinical manifestations of PNH can have a devastating impact
on pregnancy. Reported cases highlight the significant pregnancy-
associated morbidity and mortality in women with this condition.
Complications include severe anemia, thrombocytopenia, thrombotic
events, preterm delivery, low-birth-weight infants, neonatal death,
and maternal death.49,50 A study by Ray and colleagues50 reviewed
pregnancy outcomes in 24 women with PNH and found a 20%
maternal mortality rate.
Owing to the high-risk nature of these pregnancies, women with
PNH require close medical attention in the antenatal, perinatal, and
postnatal periods. Prophylactic anticoagulation is recommended
because of the high incidence of thrombotic events during pregnancy.
Warfarin is contraindicated because of its teratogenicity. Low-
molecular-weight heparin (LMWH) is favored over unfractionated
heparin (UFH) because it less frequently causes heparin-induced
thrombocytopenia (HIT). Anticoagulation should be interrupted
during the perinatal period but, in the absence of contraindications,
reinitiated thereafter and continued for 6 weeks postpartum.51
Results of a phase III trial by Hillmen and colleagues52 demon-
strated that eculizumab, a humanized monoclonal antibody against
the terminal complement protein C5, can reduce levels of hemolysis,
stabilize hemoglobin, minimize transfusion requirement, and improve
quality of life in patients with PNH. There are case reports describing
success in patients chronically receiving eculizumab throughout
pregnancy with uncomplicated deliveries. However, a large random-
ized trial has not been performed. Supportive care is used as needed
throughout pregnancy. RBC transfusions are used in the treatment
of anemia. In the setting of thrombocytopenia and bleeding, platelet
transfusions may also be necessary.
Autoimmune Hemolytic Anemia
Autoimmune hemolysis can occur during pregnancy and lead to
anemia (see Chapter 47). The relatively small size of immunoglobulin
(Ig)G immunoglobulin molecules allows them to cross the placenta;
thus the IgG subtype of autoimmune hemolytic anemia can adversely
affect fetuses. In contrast, the larger IgM antibodies do not cross the
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Chapter 151  Hematologic Changes in Pregnancy 2205
placenta. Patients with autoimmune hemolytic anemia are treated
with glucocorticoids and, if necessary, intravenous immunoglobulin
(IVIg). Supportive transfusions are administered when needed.53 In
rare instances, pregnancy appears to precipitate the development of
autoimmune hemolytic anemia in a previously unaffected woman.
The etiology of this phenomenon is not known.54 Women in this
circumstance have been treated in the standard fashion with favorable
results.
THROMBOCYTOPENIA
Thrombocytopenia during pregnancy is quite common. It occurs in
approximately 10% of pregnancies.55 Although there is not one clear
value to define thrombocytopenia in pregnancy, generally a platelet
count less than 100,000 is considered cause for concern. There is
some physiologic thrombocytopenia that occurs during pregnancy.
Gestational thrombocytopenia (GT) is the most common cause of
thrombocytopenia in pregnancy followed by preeclampsia and
immune thrombocytopenia. Much rarer causes include disseminated
intravascular coagulation (DIC), thrombotic thrombocytopenic
purpura (TTP) and hemolytic uremic syndrome (HUS), and medica-
tion induced. The evaluation of thrombocytopenia is essential to rule
out any systemic disorders that may affect pregnancy management
Gestational Thrombocytopenia
GT is quite common during pregnancy. The platelet count is gener-
ally never lower than 70,000/µL. This occurs mainly in the third
trimester. Patients are asymptomatic and have no history of throm-
bocytopenia. The platelet count normalizes within 3 months of
delivery but often normalizes within 1 week. The etiology of GT
remains unclear, but it is thought in part to be autoimmune in nature
and demonstrates a clear overlap with mild idiopathic thrombocyto-
penic purpura (ITP).
The management of patients with GT is uncomplicated. Typi-
cally, they can receive epidural anesthesia. However, practice varies at
each institution in terms of platelet threshold for epidural anesthesia.
Platelet counts greater than 100,000/µL are considered safe for epi-
dural anesthesia. There are studies demonstrating safe administration
of epidural anesthesia in pregnant patients with platelet counts as low
as 70,000/µL.56
Immune Thrombocytopenia
ITP is responsible for pregnancy-associated thrombocytopenia in
approximately 3% of cases (Chapter 132). It is the most common
cause of thrombocytopenia during the first two trimesters of preg-
nancy.57 ITP can recur in women with previously documented disease
or can develop de novo during pregnancy.
ITP is usually not diagnosed during pregnancy. Pregnant patients
with ITP usually have a long-standing history of thrombocytopenia.
ITP may be difficult to distinguish from GT because patients with
these conditions can present with similar clinical and laboratory
findings. Elevated levels of platelet-associated IgG and antibody titers
can be found in both conditions.58 Furthermore, assays that detect
antibodies against the glycoprotein receptors IIb/IIIa and Ib/IX are
not specific for ITP.59 Whereas thrombocytopenia in the first trimester
or early portion of the second trimester should raise suspicion for
ITP, thrombocytopenia that develops later in pregnancy should raise
suspicion for GT. A preconception platelet count can also be helpful
in distinguishing between the two. It is important to attempt to
distinguish between ITP and GT because there is a small but signifi-
cant risk of neonatal thrombocytopenia in the setting of ITP.60
In terms of diagnostic evaluation, human immunodeficiency
virus, hepatitis, and lupus should be tested for if clinically indicated.
Platelet antibody testing is not considered helpful. The peripheral
smear may demonstrate an increased platelet size but should otherwise
 2206 Part XIII  Consultative Hematology
TABLE Initiation of Treatment in Pregnant Patients With
151.1 Idiopathic Thrombocytopenic Purpura
Platelet Count Treatment
<10,000/µL Platelet transfusion for life-threatening bleeding
10,000-30,000/µL Consider monitoring in first trimester; treat in
second or third trimester
>30,000/µL Clinically monitor
be normal. Bone marrow biopsy and aspirate are not indicated unless
there are other hematologic abnormalities present.
Treatment options are generally similar to those for nonpregnant
patients with ITP (Table 151.1). Platelet transfusions are reserved for
life-threatening bleeding because the lives of transfused platelets are
usually short in ITP. Glucocorticoids are considered first-line treat-
ment; prednisone is usually initiated at 1 mg/kg based on the patient’s
baseline weight. Side effects of prednisone should be discussed with
the patient and include weight gain, bone loss, hypertension, and
gestational diabetes. IVIg can also be used. It is a means of rapid
increase in platelet count. It is particularly used to help increase
platelet counts a few days before delivery.61 It is usually administered
at a dose of 2 g/kg over 2 days. However, the improvement in platelet
count is fairly transient. Splenectomy is also an option indicated for
refractory thrombocytopenia; it is best performed during the second
trimester.
Other agents such as danazol, cyclophosphamide, and vinca
alkaloids, although used in the management of ITP in nonpregnant
individuals, are teratogenic and should be avoided during pregnancy.62
Use of cyclophosphamide has been associated with birth defects.
Danazol may cause clitoral enlargement and labial fusion in female
fetuses when given in the first trimester.63,64 The use of rituximab has
never been studied systematically in this setting and is considered a
pregnancy class C drug. Although case reports of its use exist, it is
not generally recommended in this case. Animal data indicate that
thrombopoietin mimetics may cause fetal harm, and little is known
about their use in pregnant patients. A registry has been developed
for pregnant patients treated with thrombopoietin mimetics.
As discussed previously, maternal antiplatelet IgG can cross the
placenta and cause thrombocytopenia in fetuses. Percutaneous
umbilical blood sampling is the most accurate means to obtain the
fetal platelet count. However, the procedure is associated with a high
complication rate and 1% fetal mortality.65 Intrapartum fetal scalp
sampling represents an alternative, but the accuracy of this technique
is only 50% to 70%.66 The maternal platelet count and antiplatelet
antibody level do not accurately predict the fetal platelet count.67
Overall, 10% of babies born to mothers with ITP have a platelet
count less than 50,000/µL, but less than 5% have a platelet count
less than 20,000/µL.68 Treatment of pregnant women with IVIg or
steroids does not appear to affect the platelet count of fetuses.68,69
Thrombocytopenia places neonates at risk for bleeding events,
including intracranial hemorrhage, although this complication is
rare.70
In terms of delivery, at present, available guidelines on the subject
suggest that obstetric factors, rather than hematologic ones, should
guide the manner of delivery.71 After the delivery of a child, the cord
blood platelet count is checked and the newborn platelet count fol-
lowed because thrombocytopenia is often most severe 4 to 6 days
after delivery and resolves as maternal antiplatelet IgG is cleared.
Preeclampsia and HELLP Syndrome
Thrombocytopenia in pregnant woman also occurs in association
with preeclampsia and HELLP syndrome (hemolysis, elevated liver
enzymes, low platelet count), potentially severe multisystem disor-
ders associated with pregnancy. In previously healthy nulliparous
women, the incidence of preeclampsia is between 2% and 7%.72
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Thrombocytopenia is observed in 15% to 50% of patients with this
condition.73,74 Clinical manifestations include a maternal syndrome
characterized by hypertension, proteinuria, and systemic abnormali-
ties as well as a fetal syndrome characterized by fetal growth restric-
tion, preterm delivery, and hypoxia-induced neurologic damage.72,74
In most instances, preeclampsia occurs during a woman’s first
pregnancy, but it can recur in a subsequent pregnancy or occur for
the first time in a woman with one or more previously unaffected
pregnancies. Risk factors for the disorder include, but are not limited
to, preeclampsia in a previous pregnancy, a family history of pre-
eclampsia, chronic hypertension, obesity, multifetal gestation, rheu-
matic disease, and preexisting thrombophilia.72 With respect to
thrombophilia, a case–control study by Mello and colleagues75 sug-
gests that the prevalence of an underlying thrombophilia is signifi-
cantly higher among women who develop preeclampsia during
pregnancy than among those who have uneventful pregnancies.
HELLP syndrome represents a severe variant of preeclampsia. In
the majority of cases, patients who develop the syndrome are white
and multiparious.76 The median age of affected patients is 25 years.
The time of presentation during pregnancy ranges from the midtri-
mester (15%) to term (18%). In 30% of patients who develop
HELLP, it develops within 2 days after delivery.77 Patients typically
exhibit vague symptoms such as malaise, fatigue, epigastric or right
upper quadrant pain, nausea, vomiting, and flulike symptoms.
Because of the nonspecific nature of these symptoms, diagnosis is
often delayed; one study found an average time to diagnosis of 8 days
in women with HELLP syndrome.78 Clinical findings at the time of
diagnosis (weight gain or edema, hypertension, and proteinuria) are
similar to those observed in preeclampsia.77
Although various criteria have been used in diagnosing HELLP
syndrome, they generally share the following features: signs of micro-
angiopathic hemolytic anemia, serum lactate dehydrogenase greater
than 600 U/L or serum total bilirubin greater than 1.2 mg/dL,
aspartate aminotransferase greater than 70 IU/L, and a platelet count
lower than 100,000/µL.79 Martin and colleagues77 further defined
HELLP syndrome on the basis of platelet count. According to this
classification, patients with class 1 HELLP syndrome have a platelet
count lower than 50,000/µL, those with class 2 disease have a platelet
count between 50,000 and 100,000/µL, and individuals with class 3
HELLP syndrome have a platelet count higher than 100,000/µL. As
might be expected, women with class 1 HELLP syndrome required
a recovery period in the aftermath of their illness.
Although the precise mechanism through which preeclampsia
develops is uncertain, research in the field continues to advance
understanding of the underlying pathophysiology. Endothelial cell
dysfunction after placentation appears to play a central role in the
pathogenesis of the disease. During development of the placenta,
placental trophoblast cells interface with the epithelial layer of the
uterus, forming the decidua. Penetration and remodeling of maternal
spiral arteries beginning at week 9 during pregnancy increase placental
perfusion and improve oxygenation for the developing fetus under
normal conditions.80
Cellular abnormalities such as those described impair placental
implantation and vasculogenesis, leading to fetal hypoxia and the
release of vasoactive compounds such as endothelin, nitric oxide, and
prostaglandins. High levels of endothelin, a potent vasoconstrictor,
are seen in preeclamptic patients, and injection of endothelin into
rabbits produces a syndrome similar to HELLP syndrome.81,82 The
activity of endothelin, nitric oxide, and prostaglandins leads to
hypertension and platelet activation. Angiogenic factors such as
vascular endothelial growth factor 1 (VEGF 1) are elevated in pre-
eclampsia compared with normal pregnancy. Injury to the vascular
endothelium results in fibrin deposition, further platelet activation,
and the release of additional vasoactive agents such as serotonin and
thromboxane A2. The etiology of thrombocytopenia in preeclampsia
is likely related to increased antiplatelet IgG levels83 or to activation
of the coagulation cascade with subsequent consumption of
platelets.84,85
These events lead to the multisystem dysfunction seen in patients
with HELLP syndrome. Fibrin deposition in the hepatic sinusoids
 Chapter 151  Hematologic Changes in Pregnancy 2207

causes hepatocellular injury. Patients can develop right upper quad-
rant pain if intraparenchymal or subcapsular hemorrhage occurs.
DIC was observed in 21% of patients with HELLP in one series, and
placental abruption was seen in 16% of patients.86 Other manifesta-
tions of HELLP syndrome include acute renal failure, pulmonary
edema, shock, cerebrovascular accident (CVA), eclampsia, retinal
detachment, diabetes insipidus, and an increased incidence of cesar-
ean section.
HELLP syndrome is associated with high maternal and neonatal
mortality rates. Maternal mortality rates range from 1.1% to 24.2%.87
The immediate cause of death is most often rupture of the liver, DIC,
acute renal failure, pulmonary edema or acute respiratory distress
syndrome (ARDS), shock, or CVA. Perinatal deaths resulting from
placental abruption, asphyxia, or extreme prematurity occur in 10%
to 15% of patients. After delivery, infants born to women with pre-
eclampsia or HELLP can develop a self-limited neonatal thrombocy-
topenia. Uncertainty exists regarding whether infant thrombocytopenia
in these instances results from preeclampsia or HELLP itself or from
a related complication such as neonatal sepsis.88–90 HELLP recurs in
subsequent pregnancies of affected women in 3% to 27% of cases.
There is also an increased risk of preeclampsia, placental abruption,
and preterm delivery in these pregnancies.91–100
In caring for a patient with preeclampsia or HELLP syndrome,
the clinician’s primary concerns are the mother’s health and safety.
The clinician must also consider the stage of pregnancy at time of
diagnosis, the condition of the fetus, and desires of the patient in
making management decisions. Definitive treatment for preeclampsia
and HELLP involves delivery of the fetus; it is indicated for women
who present after 34 weeks of gestation and those with evidence of
multisystem dysfunction. However, conservative, supportive care
without immediate delivery can be pursued for women who are rela-
tively asymptomatic, hemodynamically stable, at less than 32 to 34
weeks of gestation, and without evidence of abnormal coagulation
parameters.100,101 Magnesium sulfate, which reduces cerebral vasocon-
striction and ischemia, should be administered for seizure prophy-
laxis.102 Parenteral labetalol or hydralazine is given for blood pressure
control. Systemic corticosteroids appear to lessen the risk of maternal
ARDS and reduce neonatal complications when administered to
women who present at less than 34 weeks of gestation.103 In addition
to these measures, volume status is closely monitored to prevent
plasma volume expansion and ensure adequate urine output.
Persistent right upper quadrant pain, which may herald a liver
hematoma or rupture, hemodynamic instability, coagulation profile
abnormalities, or a decline in clinical status, should prompt delivery
by cesarean section. As mentioned previously, delivery is also indi-
cated if the fetus is at least 32 to 34 weeks of gestation at the time
when signs and symptoms of preeclampsia or HELLP develop. In a
clinically stable woman, vaginal delivery can be attempted.104 When
cesarean section is required, transfusion of RBCs, platelets, and fresh
frozen plasma (FFP) is performed as necessary before and during
surgery. Severe hypofibrinogenemia should be treated with
cryoprecipitate.
Patients are monitored closely in the postpartum period. Magne-
sium should be continued for 12 to 48 hours after delivery and blood
pressure controlled appropriately. Although hypertension typically
resolves within 6 weeks after delivery, some women require long-term
antihypertensive therapy.102 Coagulation and platelet abnormalities
tend to resolve within 24 to 48 hours after delivery. Some patients,
however, experience an ongoing decline in platelet count and should
be followed until counts normalize. Postpartum eclampsia can
occur for up to 48 hours after delivery; thus patients and health
care providers should remain vigilant in monitoring for suggestive
signs and symptoms.105 Treatment options in the setting of severe
postpartum preeclampsia and HELLP include corticosteroids and
plasmapheresis.106,107
In light of the morbidity and mortality associated with preeclamp-
sia and HELLP, considerable research has been focused on prevention
of these conditions. The efficacy of various preventive strategies,
including magnesium supplementation, low-dose aspirin, zinc supple-
mentation, antihypertensive drugs, and heparin therapy, among
others, has been the focus of observational studies, systematic reviews,
and randomized trials. Initial small studies suggested that low-dose
aspirin reduces the risk of preeclampsia, although patients who
received aspirin had a higher incidence of placental abruption and
bleeding.108–115 Larger, randomized trials failed to confirm the benefit
of low-dose aspirin.109,110
Thrombotic Thrombocytopenic Purpura–
Atypical Hemolytic Uremic Syndrome
TTP and HUS/atypical HUS are also important considerations in
the evaluation of pregnant women with thrombocytopenia (Chapter
135). Similar to preeclampsia and HELLP syndrome, they are
multisystem disorders associated with high morbidity and mortality
rates in the absence of appropriate therapy. Microvascular injury and
platelet agglutination with resulting thrombocytopenia and microan-
giopathic hemolytic anemia are pathologic hallmarks of TTP and
HUS (Fig. 151.1). They are rare conditions overall, but the incidence
of both increases in pregnancy.116 In the case of TTP, in fact, estimates
suggest that approximately 10% of cases occur in pregnant or post-
partum women.117

A B
Fig. 151.1  MICROANGIOPATHIC HEMOLYTIC ANEMIA. Microangiopathic hemolytic anemia in
pregnancy, peripheral blood smear (A, B). Evidence of microangiopathy with the formation of schistocytes,
fragmented forms and spherocytes, associated with polychromasia and nucleated red blood cells (A, B, detail).

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 2208 Part XIII  Consultative Hematology
Because they share many common clinical features, TTP and
aHUS are often categorized as a single entity, TTP-HUS. However,
the pathophysiologies underlying the two conditions are distinctive.
TTP is associated with unusually large multimers of circulating von
Willebrand factor (vWF), which foster platelet aggregation and
thrombus formation. Under normal circumstances, a vWF-cleaving
protease referred to as ADAMTS13 (a disintegrin and metallopro-
teinase with a thrombospondin type 1 motif, member 13) cleaves
these multimers into smaller multimers of normal size. In TTP, func-
tion of the cleaving protease is impaired. ADAMTS13 deficiency
characterizes familial TTP. Inhibition of ADAMTS13 protease activ-
ity by an autoantibody characterizes the acquired form of TTP. An
inhibitory autoantibody can be found in 70% to 85% of patients
with TTP.118 On the other hand, impaired vWF-cleaving protease
activity does not appear to play a role in the pathogenesis of a HUS.119
Our understanding of the pathogenesis of atypical HUS has evolved
in recent years as this disorder has been recognized to be associated
as a complement-mediated disorder. With this dysregulation of
complement, a picture of profound inflammation evolves. In contrast
to TTP, there is typically more severe renal involvement with less
severe thrombocytopenia. There can be some similarity found
between the features of TTP-HUS and HELLP syndrome. It can be
difficult to distinguish TTP and HUS from HELLP syndrome
because they both have signs of microangiopathy. TTP tends to occur
earlier in pregnancy, with a mean onset at 23.5 weeks, although it
can occur at any point from the first trimester through the postpartum
period.120 HUS primarily occurs after delivery; 90% of cases occur
in the postpartum period, with a mean onset at 26 days after deliv-
ery.121 TTP and HUS do not cause hypertension or liver necrosis.
Furthermore, TTP and HUS frequently persist after delivery, but
HELLP syndrome typically resolves in the postpartum period.
Treatment of TTP-HUS involves emergent plasmapheresis within
24 to 48 hours of diagnosis. The response rate among pregnant
women treated with plasmapheresis for TTP is approximately 75%.
By comparison, the overall response rate in patients with TTP is
approximately 80% to 90%.122–125 Long-term sequelae in surviving
patients include chronic renal failure, hypertension, and recurrence
of TTP-HUS. TTP-HUS recurs in approximately 50% of subsequent
pregnancies.126 Infusion of FFP represents an alternative to plasma-
pheresis, although plasmapheresis is the preferred treatment modality.
The response rate after FFP infusion is 64%.127 Corticosteroids have
also been used successfully in the treatment of pregnancy-associated
TTP-HUS, with a response rate of 26%.125 Conversely, antiplatelet
agents such as aspirin do not play a role in the treatment of pregnancy-
associated TTP-HUS.128
Disseminated Intravascular Coagulation
DIC in pregnant women can occur in various clinical settings, includ-
ing HELLP syndrome, TTP-HUS, placental abruption, amniotic
fluid embolism, uterine rupture, intrauterine fetal demise, sepsis,
elective abortion, and acute fatty liver of pregnancy (AFLP).
Severe placental abruption sufficient to cause fetal death occurs in
0.12% of all pregnancies.129 This condition leads to a consumptive
hypofibrinogenemia, and (when fibrinogen levels fall below 100 to
150 mg/dL) bleeding may ensue. Maintenance of adequate urine
output and a hematocrit level greater than 30% are important
components of care for women who have had a placental abruption.
Either vaginal delivery or cesarean section is appropriate in the
context of severe placental abruption. In a woman undergoing
cesarean section after abruption, the platelet count should be main-
tained at 50,000/µL or above through platelet transfusion and
fibrinogen replaced with FFP or cryoprecipitate.
Amniotic fluid embolism is a rare but often lethal condition with
a mortality rate of approximately 80%.130 About 10% to 15% of these
patients develop a coagulopathy. DIC in this setting most likely
follows the release of thromboplastin-rich material into the maternal
circulation. DIC seen in association with uterine rupture and
intrauterine fetal demise presumably occurs through a similar
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mechanism.131 On the contrary, bacterial endotoxin or exotoxin
mediates sepsis-associated DIC in pregnant women with pyelone-
phritis, chorioamnionitis, endometritis, or septic abortion.132 On rare
occasions, elective abortions that use hypertonic solution and those
complicated by hemorrhage can be associated with DIC.133
AFLP, or acute yellow atrophy, occurs in 1 of every 5000 to 10,000
pregnancies, most often in the third trimester of primiparous
women.134 Maternal and fetal mortality are 5% and 15%, respectively.
Although the pathogenesis of AFLP is not clear, microvesicular fatty
infiltration of the liver’s central zone is observed and presumably plays
a central role in the development of this disease.135 In some cases,
fatty infiltration can be detected by ultrasonography or computed
tomography (CT).136 Patients present with a variety of symptoms,
including malaise, fatigue, right upper quadrant pain, dyspnea, and
mental status changes. Laboratory findings include abnormal liver
function test results consistent with cholestatic disease, elevated
ammonia, low fibrinogen and antithrombin levels, and elevated
prothrombin time, with evidence of DIC. Hepatic dysfunction can
impair gluconeogenesis. Diabetes insipidus may be present. The
clinical course of AFLP resembles those of HELLP syndrome, TTP,
and HUS, although the microangiopathy and thrombocytopenia are
not as severe.137 With supportive care, the condition typically resolves
within 10 days after delivery.
LEUKEMIA AND LYMPHOMA
The diagnosis of hematologic malignancy during pregnancy can be
incredibly traumatic for a pregnant patient and her family, and it is
a treatment challenge for the physician. Although great strides have
been made in the treatment of this heterogeneous group of diseases,
the treatment of pregnant patients is limited because of the lack of
research in this area and limited pregnancy safety data. The need to
treat the patient and risk to the fetus must both be taken into
account. Diagnosis can be difficult because many of the nonspecific
signs that accompany these disorders, including fatigue, anemia, loss
of appetite, and weight loss, can occur at various times during a
normal pregnancy. Diagnostic imaging is limited mainly to ultraso-
nography and magnetic resonance imaging (MRI). Although the
radiation dose from a CT scan is considered low, it is usually avoided.
Diagnostic procedures such as bone marrow or lymph node biopsy
can usually be performed safely during pregnancy.
In terms of treatment, the risk of teratogenicity from treatment
appears highest during fetal organogenesis, which occurs mainly
during the first trimester of pregnancy.138 Ideal dosing is unknown,
but dosing is usually based on the woman’s prepregnancy weight.
In the largest study of its kind, Aviles and Neri139 followed 84
children born to mothers with hematologic malignancies, including
29 women with acute leukemia and 38 who received treatment
during the first trimester. Assessing growth and development, hema-
tologic parameters, psychological characteristics, and cognitive func-
tion over 19 years, the authors found no significant, long-term,
deleterious consequences related to treatment. The risk of childhood
malignancies was not increased. In a retrospective report following
the outcome of 54 newborns of women treated with chemotherapy
specifically during the first trimester, long-term development was
found to be normal. However, this is in contrast to general incidence
of congenital malformations found by others for treatment given
during this time period.
Hodgkin Lymphoma
That hematologic malignancies are among the most commonly
diagnosed cancers during pregnancy reflects to a large extent the rela-
tively high incidence of Hodgkin lymphoma in women between the
ages of 15 and 24 years.140 On the basis of results of several retrospec-
tive studies, Hodgkin lymphoma diagnosed during pregnancy appears
to have no significant effect on pregnancy outcome.141 A single-
institution experience published by Dilek and colleagues,142 however,

highlights complications that may occur in pregnant women with
Hodgkin disease because children born to three of five women with
the disease had complications, including death. Remission rates and
20-year overall survival rates among women diagnosed with Hodgkin
disease during pregnancy are reportedly similar to those observed in
nonpregnant women with the disease.143,144 In rare instances, Hodgkin
lymphoma metastasizes to the placenta, so the placenta and newborn
infant should be examined for evidence of malignancy.145 Staging
during pregnancy can be performed with CT, but MRI is preferred
to reduce to exposure of the fetus to radiation.
Similar to other malignancies managed during pregnancy, treat-
ment of women with Hodgkin disease is challenging. Generally,
chemotherapy at any point in pregnancy increases the risk of an
unfavorable outcome.142 The teratogenic effects of chemotherapy and
radiation during pregnancy are a primary concern. However, the
standard regimen of Adriamycin (doxorubicin), bleomycin, vinblas-
tine, and dacarbazine does not appear to increase teratogenic risk
when given in the second or third trimester.
Non-Hodgkin lymphoma (NHL) rarely occurs during pregnancy.
There are case reports and case series of women with NHL who have
been treated successfully with chemotherapy during the second and
third trimesters of pregnancy.145 In a review of 121 cases of pregnancy-
associated NHL, 75% had stage IV disease at diagnosis, and repro-
ductive organ involvement was found in half the cases. Placental and
fetal involvement were uncommon.146,147
Alkylating agents given during the first trimester can result in fetal
malformations or death, although there are reports of children who
received chemotherapy during the first trimester with no subsequent
deficits.148 On the basis of available data, response and recurrence
rates among women treated for NHL during pregnancy are similar
to those seen in the treatment of pregnant women with Hodgkin
disease.
Acute and Chronic Leukemias
Treatment of acute myeloid leukemia cannot be delayed. Minimal
data are available on the treatment of patients with acute leukemia,
but in patients treated with chemotherapy during the first trimester,
outcomes were poor. For patients in the first trimester, planned
abortion should be discussed, followed by treatment with standard
induction chemotherapy.149
Patients in the second and third trimesters should be treated
immediately. There is an association of preterm delivery, IUGR, and
spontaneous abortion with treatment in the second and third trimes-
ters.150 In terms of treatment options, daunorubicin is preferred
because idarubicin has increased placental transfer. Amphotericin B
is considered the antifungal of choice in pregnancy because there have
been no reports of teratogenicity.151,152 If treatment is not delayed,
pregnant women can have outcomes similar to those of nonpregnant
patients.
Among acute leukemias arising within the myeloid lineage, acute
promyelocytic leukemia is unique in terms of clinical features, par-
ticularly DIC and associated bleeding complications, and therapy,
which involves all-trans retinoic acid (ATRA) in conjunction with
traditional chemotherapy. Concern regarding the teratogenic effects
of ATRA is warranted. In the 1980s, Lammer and colleagues153 noted
an increased risk of fetal malformation after in utero exposure to the
retinoid isotretinoin. In a recent case report, Carradice et al154
described a bleeding complication that occurred after ATRA initia-
tion in a pregnant woman with acute promyelocytic anemia. However,
authors of a review of 13 women treated during pregnancy with
ATRA administration for acute promyelocytic anemia found no
evidence that the agent led to fetal malformation when used in the
treatment of pregnant women.155
Similar concerns regarding toxicity of therapy arise in managing
pregnancies conceived before and during treatment of chronic
myeloid leukemia (CML). Imatinib, a small-molecule inhibitor
against the BCR-ABL tyrosine kinase, is the standard of care
for treatment of CML. In animal studies, imatinib exhibited
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Chapter 151  Hematologic Changes in Pregnancy 2209
Imatinib Therapy
A 38-year-old woman with a history of chronic-phase chronic myeloid
leukemia on imatinib therapy for 5 years becomes pregnant. She has
had a complete cytogenetic response. She asks what to do about her
imatinib therapy.
Imatinib is teratogenic and should not be used during pregnancy. It
has been linked to spontaneous abortions and to fetal malformations,
including skeletal abnormalities, hydrocephalus, and exophthalmos.
Although there are case reports documenting fetal exposure at various
stages of pregnancy without harm, it is not recommended. Case reports
suggest that patients who have achieved maximal response to therapy
fare better when their treatment is held for pregnancy, as opposed to
patients who have not achieved best response.
teratogenicity in rats and impaired spermatogenesis in dogs, monkeys,
and rats.156 In a series of 19 pregnancies involving a mother or father
undergoing imatinib-based therapy for CML, three pregnancies
resulted in a spontaneous abortion, and two others produced children
with minor malformations.157 The remaining 13 pregnancies resulted
in the delivery of a healthy child. Among mothers in this study who
had previously achieved a complete hematologic remission with
imatinib and interrupted therapy during pregnancy, a majority (five
of nine) lost the hematologic remission. These findings highlight the
important therapy-related implications for mother and fetus, which
must be weighed carefully in determining an appropriate course of
management (see box on Imatinib Therapy). Currently, it is recom-
mended by specialists in the field that patients undergoing treatment
with imatinib for CML use proper contraception.157
The Myeloproliferative Neoplasms:
Essential Thrombocythemia, Polycythemia
Vera, and Myelofibrosis
Essential thrombocythemia (ET) has a bimodal peak of distribution,
so it is the most common myeloproliferative neoplasm (MPN) in
women of childbearing age (see Chapters 69, 70, and 71). Although
evidenced-based guidelines do not exist for the management of
pregnancy in this setting, more and more information regarding this
topic is being reported.158 Although some variation is seen in the rates
of complications among various studies, overall, all of the studies
noted a consistent increase in the rate of complications compared
with pregnant women without MPN.158 Pregnancy alone is a risk
factor for thrombosis, and pregnancy confers a sixfold increase in the
rate of thrombosis in pregnant patients without MPN. Thrombosis
is a major source of morbidity and mortality in patients with MPN.
It is thought that the prothrombotic state that exists in MPN is
behind a majority of the morbidity that can develop during preg-
nancy. Thrombotic occlusion of the placental circulation has been
observed.
In a study documenting 103 pregnancies occurring in 62 patients
with MPN, the rate of live births was 60%, and the first trimester
abortion rate was 32%. Fetal complications occurred in 40% of cases
and maternal complications in 9%. The risk of fetal loss for patients
with ET was 3.4-fold higher than for those in the aged-matched
control population.159
A pooled outcome analysis of 461 pregnant patients with ET
demonstrated that first-trimester loss occurred in 25% to 40% of
patients with a live birth rate of 50% to 70%. Late pregnancy loss
occurred in 10% of cases.160 Postpartum thrombotic complications
occurred in 5.2% of patients. In a recent analysis of all publications
of pregnant patients with ET that had more than 30 patients per
study, a mean rate of live birth obtained from the literature was
60.6% (range, 50%–75.4%).161
Studies of pregnancy in the setting of polycythemia vera (PV) are
much fewer and consist mainly of case reports. One of the largest
studies to date consisted of 18 pregnancies. There were 11 live births
 2210 Part XIII  Consultative Hematology
and 7 miscarriages.162 First trimester loss is the most frequent com-
plication in patients with PV.161 Information regarding pregnancy in
primary myelofibrosis is even sparser, with overall fewer than 20 cases
reported in the literature. However, on the basis of these, fetal loss is
common.163 In women of childbearing age with an MPN, a discus-
sion when the patient is not pregnant should occur, outlining preg-
nancy management and risks. Women should be informed if they are
taking a drug with teratogenic potential, and the risk of unplanned
pregnancy should be recognized.
Continuing aspirin is considered standard if there is no clear
contraindication, extrapolating from the results of the European
Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP)
study, which confirmed the importance of aspirin in the management
of MPNs.164 Certain features may confer a patient at more risk of
maternal or fetal complications during pregnancy. These include
cardiovascular risk factors, prior thrombosis, and prior pregnancy-
related complications that may have been caused by MPN or for
which no other cause can be identified. In these settings, cytoreduc-
tive therapy or LMWH can be considered. There are no clear
evidence-based management guidelines in these settings, but local
practice is to use LMWH. Six weeks of postpartum LMWH should
be considered in the postpartum setting if there is no contraindica-
tion. It is clear that management of these patients requires close
collaboration with a hematologist and high-risk obstetrician.
BLEEDING DISORDERS
von Willebrand Disease
Affecting approximately 1% of the population, von Willebrand
disease (vWD) is the most common inherited disorder of coagulation
(see Chapter 139). By mediating platelet adhesion and functioning
as a carrier for circulating factor VIII (FVIII), vWF plays a vital role
in hemostasis. According to the most widely used classification by
Sadler,165 there are three types of vWD: type 1 (partial deficiency of
vWF); type 3 (severe deficiency of vWF); and type 2, which includes
four subtypes that involve qualitative defects in vWF. FVIIIc, vWF
antigen (vWF:Ag), and the ristocetin cofactor activity (vWF:Rco) are
important components of the laboratory diagnosis. vWD does not
impair fertility or increase the likelihood of miscarriage.166 Thus the
management of pregnancy in patients with the condition is an
important feature of the overall care for these individuals.
For pregnant women with vWD, bleeding at parturition and in
the postpartum period is of primary concern. Related concerns
include the administration of anesthesia, perineal hematoma, episi-
otomy blood loss and healing, and bleeding at surgical sites. Approxi-
mately 75% of women with moderate to severe vWD experience
significant peripartum bleeding.167 Overall there is a 20% risk of
postpartum hemorrhage in women with vWD. In a normal preg-
nancy, FVIIIc and vWF levels increase, beginning in the second tri-
mester.168 They peak as the pregnancy nears term. Among many
pregnant women with vWD, particularly those with type 1 disease,
a similar increase in FVIII and vWF levels is observed. FVIIIc levels
in pregnant women with vWD peak at 29 to 32 weeks of gestation,
but vWF:Ag levels peak at approximately 35 weeks of gestation.169
The risk of peripartum bleeding is related to the level of these
factors.170 In most instances, vWF:Ag, FVIIIc, and vWF:RCo levels
should be assessed during the first and third trimesters to determine
the bleeding risk for individuals with vWD. However, this may be
less relevant for patients with type 3 vWD, in whom levels tend to
remain low throughout pregnancy. Patients without a documented
bleeding disorder who have bleeding complications during pregnancy
should be evaluated for vWD because many with the disorder have
a mild clinical course and remain undiagnosed for a long period.171
As a general rule, therapy can be rendered either in the setting
of a spontaneous bleeding event or in a prophylactic context for
the high-risk individual. Mainstays of therapy for pregnant women
with vWD include DDAVP (1-deamino-8-D-arginine-vasopressin;
desmopressin), a synthetic analogue of vasopressin, and vWF-FVIII
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concentrates (Humate-P, Alphanate). Cryoprecipitate can be used on
an emergent basis if vWF-FVIII concentrates are unavailable, but it
is avoided if possible during pregnancy because it poses a small risk
of bloodborne infection.172 Although antifibrinolytic therapy plays a
role in the management of individuals with vWD, it is also generally
avoided during pregnancy and lactation because of its potential tera-
togenicity and effects on newborns. Data concerning the toxicity of
antifibrinolytic therapy in pregnancy are limited.
Exerting its effect through the type 2 vasopressin receptors,
DDAVP rapidly and transiently increases levels of FVIII and vWF.173
It is administered by continuous intravenous infusion over 30 minutes
in the setting of an acute bleeding event. On a prophylactic basis, it
can be given subcutaneously or inhaled nasally.174 Although highly
effective when used in an appropriate clinical context, DDAVP does
have limitations. Patients who have never received DDAVP therapy
should be tested for responsiveness to the agent during the second
trimester. Because of its potential oxytocic effect, DDAVP is preg-
nancy risk category B.175 Owing to its antidiuretic effect, DDAVP
can cause fluid retention and hyponatremia. Finally, DDAVP has
uncertain utility in the management of women with type 2 and type
3 vWD because of an underlying genetic defect in these individuals.
VWF-FVIII concentrate is indicated for these patients.
Multidisciplinary care by an experienced obstetrician and hema-
tologist should be provided for pregnant women with vWD. This
becomes particularly important as parturition nears. In providing care
for this population of patients, clinicians aim to control the conse-
quences of the disease in pregnant and postpartum mothers. FVIIIc
and vWF:RCo levels, partial thromboplastin time (PTT), type and
crossmatch, and a complete blood count are obtained at the time of
hospital admission. Women with vWD should be monitored for
bleeding at the time of delivery, with blood cell products and DDAVP
available for use as needed. vWF:RCo and FVIIIc levels of 50 IU/dL
generally serve as a target at parturition and in the postpartum period;
expert opinion suggests that women with levels below this should
receive replacement products.175
In the management of pregnant women with vWD, the provision
of regional anesthesia during delivery is an important topic. Some
anesthesiologists use epidural anesthesia in patients with mild disease
with or without the use of DDAVP.176,177 For patients with moderate
to severe disease, an alternative form of analgesia may be considered.
If epidural analgesia is used in a patient with moderate to severe
disease, prophylactic factor replacement therapy is indicated. The
epidural catheter should be removed soon after delivery because
falling factor levels in the postpartum period increase the bleeding
risk.173
The route of delivery is also an important matter in patients with
vWD. To minimize the risk of neonatal hemorrhage, some obstetri-
cians recommend cesarean delivery for patients with type 2, type 3,
and clinically moderate type 1 disease. However, neonatal bleeding
occurs in the setting of cesarean delivery as well, and delivery methods
have not been rigorously compared.167,176
Prenatal testing is a challenge in women with vWD. The specific
mutations involved in the pathogenesis of type 1 and type 3 vWD
are not known. Multiple mutations are involved in the pathogenesis
of type 2 vWD. Fetal blood vWF levels can be obtained if necessary,
but inherent risks are associated with the procedure.178 Expectant
mothers should be informed of these risks in making decisions about
prenatal genetic testing.
HEMOPHILIAS
The hemophilias (A and B) are X-linked recessive diseases character-
ized by hemarthrosis and subcutaneous and intramuscular bleeding
(see Chapter 136).179 Hemophilia A results from deficient production
of FVIII, and hemophilia B from deficient production of FIX. As
X-linked disorders, hemophilia A and B occur most often in men,
but they can occur in women under several circumstances, including
X-chromosome inactivation (lyonization), X hemizygosity, and
double heterozygosity as can occur in the female offspring of an

affected father and carrier mother.179 In the United States, women
account for 1.7% of patients with hemophilia A and 3.2% of patients
with hemophilia B.180 Fifty percent of male offspring from a female
carrier inherit the disorder, whereas 100% of male offspring from an
affected mother inherit the disease. Female carriers in both disorders
can be detected through laboratory screening and pedigree analysis.181
Women with hemophilia and pregnant women with an affected fetus
must be monitored closely during pregnancy for bleeding events that
compromise the well-being of either the mother or the fetus. Fetal
umbilical blood sampling can be used to check FVIII and FIX levels.
Chorionic villus sampling may also be used.182
At parturition, women with hemophilia A whose FVIIIc level lies
below 50% of the normal range should receive purified FVIII. Levels
should be greater than 80% for surgery and maintained at 30% to
40% for 3 to 4 days postoperatively. Rarely, thrombosis can occur in
the aftermath of FVIII replacement therapy.183 Among neonates with
hemophilia, 6% to 10% have hemorrhagic complications in the
perinatal period, including intracranial hemorrhage. Vacuum extrac-
tors, forceps delivery, and scalp electrodes should be avoided. To date,
no studies have rigorously compared the outcomes of vaginal and
cesarean delivery in this patient population. Neonatal blood should
be assayed for FVIIIc levels and PTT immediately after birth. Neo-
nates with low FVIIIc levels may require serial cranial ultrasounds to
rule out bleeding.184
Hemophilia B is treated in a similar fashion. However, it should
be noted that cryoprecipitate contains low levels of FIX and should
not be used as replacement therapy in the management of this condi-
tion. Purified FIX is the agent of choice for patients with hemophilia
B. Meanwhile, individuals with other clotting factor deficiencies
should receive FFP or specific clotting factor products to maintain
factor levels at greater than 25%.185 One exception to this pertains to
the management of patients with FXIII deficiency; the occurrence of
spontaneous recurrent abortions and uterine bleeding in these indi-
viduals necessitates regular infusions of FFP or FXIII concentrate to
maintain pregnancy.186
VENOUS THROMBOEMBOLIC DISEASE AND PREGNANCY
VTE disease is a leading cause of maternal morbidity and mortality.186
The risk of VTE increases two- to fourfold during pregnancy and the
early postpartum period.187 In women who have had a previous VTE
event, pregnancy appears to increase the risk of a recurrent thrombo-
embolic event.188 Various factors account for the prothrombotic state
associated with pregnancy. Increased estrogen levels early in pregnancy
increase venous distention and contribute to venous stasis.189 Increased
plasma volume and compression of the inferior vena cava by the
gravid uterus contribute to venous stasis as well.190 In addition,
studies have demonstrated decreased blood flow velocity in pregnant
women, particularly in the left leg when pregnant women lie in a
Prolonged PPT Postpartum
A 22-year-old woman presents to the emergency department (ED) 4
days postpartum. Her delivery was uncomplicated, and her hemoglobin
at delivery was 9.9 g/dL with a partial thromboplastin time (PTT) 37
seconds. She returns to the ED 4 days later with complaints of weak-
ness and vaginal bleeding and is found to have a large hematoma at
the episiotomy site. It is surgically drained but immediately recurs,
and persistent bleeding is noted. Her hemoglobin decreases to 5.9 g/
dL. Repeat laboratory evaluation reveals her PTT to be 66 seconds.
Acquired hemophilia should be considered in the postpartum patient
with bleeding and prolonged PTT. It is an uncommon disorder, thought
to be immune mediated, with development of autoantibodies against
factor VIII. Treatment must be targeted at inhibitor eradicator and
control of bleeding. For acute bleeding, activated prothrombin complex
concentrates or recombinant FVIIa should be used.
Franchini, M. (2006), Am J Hematol, 81:768–773.
CMAJ August 14, 2007 vol. 177(4): 339–340.
Santoro RC, et al. Blood Coagul Fibrinolysis, 20:461, 2009.
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Chapter 151  Hematologic Changes in Pregnancy 2211
supine position. This phenomenon likely explains the increased risk
of left leg thrombosis among pregnant women.191 Furthermore,
whereas the concentration of coagulation factors changes during
pregnancy, the concentration of vWF, fibrinogen, and prothrombin,
along with factors V, VII, VIII, IX, X, and XII increase, and the
concentration of factor XI and protein S decrease (Table 151.2).192–194
Finally, fibrinolytic activity decreases during pregnancy as the levels
of plasminogen activator inhibitors 1 and 2 increase.195 Other factors,
including high body mass index, smoking, immobilization, and age
older than 35 years, should also be considered when assessing the
thrombotic risk of a pregnant woman (see box on Bleeding Associated
With Factor XI Deficiency).
Because of the prothrombotic physiology associated with preg-
nancy, a clinician’s concern for VTE in a pregnant woman should
prompt immediate evaluation. To assess for lower extremity throm-
bosis, venous compression ultrasonography remains the initial test of
choice. Ultrasonography poses no threat to the fetus and can detect
thrombosis of the proximal common femoral and popliteal veins with
a sensitivity of 95% and specificity of 96%. Despite the efficacy of
ultrasonography, limitations to its use do exist. The test is less effec-
tive for the diagnosis of calf vein thrombosis, with a sensitivity and
specificity in the 60% to 70% range.196 For this reason, a woman
with suspected lower extremity deep venous thrombosis should
undergo serial ultrasonography if the initial evaluation is nondiag-
nostic.197 Similarly, thrombus in the common iliac vein can evade
diagnosis by venous compression ultrasonography.
In such cases, other modalities, such as contrast venography and
magnetic resonance venography, can be considered. Although con-
trast venography exposes the fetus to radiation and should thus be
used with caution during pregnancy, its use may be warranted when
clinical suspicion for an underlying thrombotic event is high.196
Serum D-dimer tests are often used in conjunction with imaging
studies to assess for thrombosis in nonpregnant patients. The sensitiv-
ity of D-dimer tests for the presence of thrombus ranges from 85%
TABLE
Hemostatic Changes in Pregnancy
151.2
Factor XIII ↑/↓
Protein C, antithrombin =
Protein S ↓
Factor XI ↓/=
Factors V, VII, VIII, IX, X, XII ↑
von Willebrand factor, fibrinogen ↑
Tissue plasminogen activator ↓
Prothrombin, D-dimer ↑
Bleeding Associated With Factor XI Deficiency
A 25-year-old woman is referred for prolonged partial thromboplastin
time (PTT) discovered during pregnancy. Evaluation reveals severe
factor XI deficiency. She has no history of easy bruising or bleeding.
She is at 30 weeks of gestation and is presenting for evaluation before
delivery.
Bleeding associated with factor XI deficiency can be quite variable,
ranging from no bleeding symptoms to bleeding associated with trauma
or surgery. For a patient without a history of bleeding, prophylaxis is
not necessary but fresh frozen plasma (FFP) should be available if
needed. Epidural is usually contraindicated in patients with severe
factor XI deficiency, and women should be advised to speak with the
treating anesthesiologist before delivery in order to plan alternative
strategies. If consideration for regional block anesthesia is made, it
is usually administered with FFP prior and with documentation of
normalization of the PTT.
In patients with a bleeding history, FFP should be administered
before delivery, as well as 2 to 3 days later to reduce the risk of delayed
hemorrhage.
 2212 Part XIII  Consultative Hematology
to 95%.198 However, several pregnancy-associated conditions elevate
D-dimer levels, including preterm labor, placental abruption, and
hypertension of pregnancy, thus undermining the utility of the test
somewhat in pregnant women by decreasing its specificity.195 None-
theless, when normal, the D-dimer assay provides the clinician with
useful information.
When lower extremity imaging reveals no evidence of thrombus
in a pregnant woman with suspected pulmonary embolism (PE), the
clinician has several options. Helical CT has become the standard
modality for the diagnosis of PE in nonpregnant individuals at many
centers. However, even with abdominal shielding, the procedure
results in fetal radiation exposure (approximately 16 mrad) because
of internal scatter.199 Although this low level of radiation exposure
probably does not cause harm to the fetus, repeated imaging during
the course of pregnancy is to be avoided.197 Ventilation/perfusion
(V/Q) scanning is frequently used in the evaluation of pregnant
women with suspected PE but has limitations as well. Results of a
prospective study indicate that when used in this patient population,
V/Q scanning infrequently yields a conclusively positive result (1.8%
of cases) and is often nondiagnostic (24.8% of cases).200 Finally,
pulmonary angiography can be used in the evaluation of PE in rare
instances when the previously described diagnostic tests yield nondi-
agnostic results in the face of a high clinical suspicion.
VTE in pregnancy is treated with heparin. Until LMWH was
introduced in the late 1980s, UFH was the anticoagulant of choice
for treatment of pregnant women with VTE. Because it does not cross
the placenta, UFH is nonteratogenic. However, drawbacks to UFH
therapy, including heparin-associated osteoporosis, HIT, and the
drug’s unpredictable pharmacokinetics, are well documented.186
Heparin-associated osteoporosis can develop in women who receive
at least 1 month of therapy; it is likely related to a toxic effect of
heparin on osteoblasts.201 Because of its more favorable side effect
profile, reliable pharmacokinetics, and equal efficacy in treating VTE,
LMWH now represents the most commonly used anticoagulant for
treatment of VTE in pregnancy.202 The risk of osteoporosis and HIT
appears to be less with LMWH-based anticoagulation than with
UFH-based anticoagulation.203,204 Although practice patterns vary, it
is reasonable to base the initial dose of LMWH on early pregnancy
(rather than current) weight.204 Because clearance of LMWH increases
during pregnancy, twice-daily dosing regimens are preferred to once-
daily regimens.205 In terms of duration of therapeutic anticoagulation,
many clinicians continue therapy at full dose through the entire
pregnancy and puerperium based on the rationale that pregnancy
itself represents a risk factor for recurrent VTE.202 In contrast, other
clinicians advocate initial anticoagulation with full-dose LMWH for
a designated period followed by conversion to an intermediate dose.
This approach may be beneficial for individuals susceptible to side
effects of anticoagulation such as bleeding or osteoporosis.186 The risk
of significant bleeding with LMWH during pregnancy is estimated
to be around 2%.
Warfarin is contraindicated in pregnant women. It crosses the
placenta and can cause both fetal hemorrhage and nervous system
abnormalities and other teratogenic effects.206 Warfarin can be used
in the postpartum period after initiating therapy with concurrent
heparin and in this setting does not appear to increase the risk of
bleeding in children of lactating mothers.196
Anticoagulation should be discontinued at the time of parturition.
UFH and LMWH should, in most circumstances, be stopped 12 to
24 hours before delivery. If the risk of recurrent VTE is particularly
high in a woman receiving LMWH, the clinician can convert to
intravenous UFH and treat until 4 to 6 hours before delivery, mini-
mizing the time off anticoagulation.
The risks of regional anesthesia must be weighed carefully in
women receiving anticoagulation because therapy increases the likeli-
hood of bleeding, hematoma formation, and potential neurologic
compromise. In a woman undergoing elective delivery with discon-
tinuation of anticoagulation 12 to 24 hours prior, epidural anesthesia
may be used. UFH or LMWH may be reinitiated 6 to 12 hours after
delivery or after removal of the epidural catheter. Then, after thera-
peutic levels of UFH or LMWH have been achieved, warfarin may
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be initiated. The newer target specific oral anticoagulant should not
be used during pregnancy until safety data in this population have
been established.
PROPHYLACTIC ANTICOAGULATION
DURING PREGNANCY
Given the prothrombotic state associated with pregnancy itself, pro-
phylactic anticoagulation should be considered in pregnant women
with a history of VTE. Recurrence rates for VTE during pregnancy
may be as high as 12% based on the results of retrospective studies.207
Conversely, Brill-Edwards and colleagues208 prospectively studied
125 pregnant women with prior VTE in a study that excluded
women with known thrombophilia. Study subjects did not receive
prophylactic anticoagulation during the antenatal period, but they
did receive anticoagulation therapy for 4 to 6 weeks postpartum. The
authors documented a VTE recurrence rate of 2.4%. Women who
had a temporary risk factor at the time of their initial VTE event
and lacked laboratory evidence of an underlying hypercoagulable
disorder at the time of study enrollment experienced no recurrences
during pregnancy. On the basis of the results of this study, routine
prophylactic anticoagulation for women with a single previous
VTE event is not recommended. However, patients with a known
hypercoagulable state, those with multiple previous VTE events,
and those considered high risk for recurrent VTE should receive
prophylactic anticoagulation during pregnancy and for 4 to 6 weeks
postpartum. As previously discussed, prophylactic anticoagulation
can be discontinued at parturition and reinitiated 6 to 12 hours
postpartum.
The management of pregnant women with prosthetic heart valves
is controversial and deserves special attention, although a full review
of the topic is beyond the scope of this review. Coupled with the
prothrombotic physiology of pregnancy, the presence of a prosthetic
valve places such women in an ultra-high-risk category. Before the
introduction of LMWH, options for anticoagulation in this patient
population included (1) warfarin throughout pregnancy; (2) warfarin
with UFH during weeks 6 to 12, the period of major organogenesis;
and (3) UFH throughout pregnancy.186 More recently, LMWH has
been used in this setting, although its safety and efficacy have been
questioned on the basis of several studies. Overall, a lack of rigorous,
comparative studies hinders evidence-based management of women
with prosthetic heart valves. Current recommendations allow for one
of three therapeutic strategies, initiated after a thorough discussion
of risks and benefits with the patient: (1) warfarin, with LMWH or
UFH substituted during weeks 6 to 12; (2) dose-adjusted UFH
throughout pregnancy; or (3) dose-adjusted LMWH throughout
pregnancy.186
THROMBOPHILIA AND PREGNANCY
Thrombophilias, inherited and acquired, increase the risk of VTE in
pregnant women and adversely affect pregnancy outcomes. Included
within this category of diseases are factor V Leiden, prothrombin
gene polymorphisms, antiphospholipid antibody syndrome, anti-
thrombin deficiency, and protein S and C deficiency. In addition,
hyperhomocysteinemia and methylenetetrahydrofolate reductase
C677T mutation have been studied. There are varied results when
assessing the literature in regard to the risk of pregnancy-associated
VTE in the setting of an inherited thrombophilia. Authors of a 2005
meta-analysis reviewed the risk of VTE during pregnancy by the
specific thrombophilia present. The inherited thrombophilias (with
the exception of MTHFR mutation) were associated with a statisti-
cally significant increase in the risk of VTE during pregnancy.209
Because the overall incidence of VTE in pregnancy is low, however,
in women without a history of thrombosis, the absolute risk conferred
by thrombophilias is generally low. The positive predictive value of
factor V Leiden heterozygosity was 1 in 500. Prothrombin heterozy-
gosity was 1 in 200. Women with homozygosity for these mutations,

double heterozygosity, and antithrombin III deficiency were at
highest risk. Given the increased risk of VTE, prophylactic anticoagu-
lation is warranted.
Screening for inherited thrombophilia in patients with recurrent
miscarriage or pregnancy complications such as preeclampsia or
placental abruption is not indicated. Thrombophilia screening is
indicated only in patients with a prior thromboembolic event or a
high likelihood of thrombophilia. Selective screening based on per-
sonal and family history is recommended (see box on The TIPPS
(Thrombophilia in Pregnancy Prophylaxis Study) Trial and box on
Thrombophilia During Pregnancy).
Prophylactic treatment of carriers of low-risk mutations with any
personal or family history of VTE is not indicated. In patients with
The TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) Trial
The TIPPS trial was the first large randomized controlled trial in which
researchers examined the effect of low-molecular-weight heparin
(LMWH) in pregnant patients with thrombophilia and a history of on
adverse pregnant outcomes or venous thromboembolism (VTE). The
TIPPS investigators studied 292 pregnant women who were randomly
assigned to dalteparin or no dalteparin. The primary objective of the
study was to identify if LMWH prophylaxis in thrombophilic pregnant
women results in a greater than 33% relative risk reduction in the
composite outcome measure of severe or early-onset preeclampsia,
small-for-gestational-age infants (<10th percentile), pregnancy loss, or
VTE. Dalteparin did not reduce the incidence of the primary composite
outcome in both intention-to-treat analysis (dalteparin, 25 [17.1%] of
146; 95% confidence interval [CI], 11.4%–24.2%; vs. no dalteparin,
27 [18.9%] of 143; 95% CI, 12.8%–26.3%; risk difference, –1.8%;
95% CI, −10.6% to 7.1%) and on-treatment analysis (dalteparin 28
[19.6%] of 143 vs. no dalteparin 24 [17.0%] of 141; risk difference,
+2.6%; 95% CI, –6.4% to 11.6%). Major bleeding did not differ. More
minor bleeding was seen in the dalteparin group (28 [19.6%] of 143)
than in the no-dalteparin group (13 [9.2%] of 141; risk difference,
10.4%; 95% CI, 2.3–18.4; p = .01).
The conclusion from the study was that prophylactic dalteparin did
not reduce the occurrence of venous thromboembolism, pregnancy
loss, or placenta-mediated pregnancy complications in pregnant
women with thrombophilia.
Some debate and controversy exist regarding the trial and its
conclusions.
Cons: It took 12 years to randomize 292 women from 21 referral
centers. Some physicians raised concern over the amount of time
it took to accrue the number of patients and the accuracy of the
patient base it represents. Others argued that eligibility criteria
were based on a rationale that had already changed by the time
the study was concluded.
Pros: The article confirms that women who are at low risk of
thrombosis should not be treated with low-molecular-weight
heparin and that this widespread practice should be stopped.
Cons: Many of these women were women who would be placed in
“lower-risk” categories to begin with, such as women who were
heterozygous for thrombophilic mutations such as factor V Leiden
mutation with one family member with a history of thrombosis.
Thrombophilia During Pregnancy
A 25-year-old woman wishes to become pregnant. Her mother expe-
rienced a deep vein thrombosis at the age of 70 years, underwent
thrombophilia evaluation, and was found to be heterozygous for the
factor V Leiden mutation. She herself has never had a thrombotic
episode, just recently discontinued her birth control, and was told to
see a hematologist before she became pregnant. Her primary care
physician tested her for factor V Leiden, and she was found to be
heterozygous for the mutation. She is asking if she should be on
anticoagulation during her pregnancy.
Every case of thrombophilia during pregnancy needs to be assessed
on a case-by-case basis. Asymptomatic women who harbor thrombo-
philic conditions but have never manifested clinical manifestations do
not require anticoagulation.
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Chapter 151  Hematologic Changes in Pregnancy 2213
recurrent miscarriage, anticoagulation has been used in efforts to
improve rates of live birth. There have been varied results in clinical
trials using anticoagulation in the setting of recurrent miscarriage.
However, in the large, multicenter, randomized, placebo-controlled
study examining the use of aspirin or aspirin plus heparin in women
with unexplained miscarriage, there was no improvement in the live
birth rate compared with placebo.210
Antiphospholipid Antibody Syndrome
The antiphospholipid antibody syndrome (Table 151.3) is the most
common form of acquired thrombophilia.211 Antiphospholipid
antibodies include lupus anticoagulant antibodies and anticar-
diolipin antibodies. They can occur as a manifestation of various
conditions, such as systemic lupus erythematosus (SLE) and other
rheumatic diseases, infection, and drug reactions. Antiphospho-
lipid antibodies exert their prothrombotic effect through several
mechanisms. For example, they inhibit the activity of anticoagulants
thrombomodulin, protein S, protein C, β2-glycoprotein I, and
prostacyclin.212–214 They interact with phospholipids on the surface
of platelets, increasing platelet adhesiveness and production of von
Willebrand mulitmers.215,216 In pregnant patients, antiphospholipid
antibodies decrease levels of annexin V, a potent vascular endothelial
anticoagulant produced by placental trophoblasts.217 Nonpregnant
individuals with antiphospholipid antibody syndrome can develop
arterial and venous thromboses. In pregnant women, antiphos-
pholipid antibody syndrome can manifest as thrombotic events,
spontaneous abortion, preeclampsia, and HELLP syndrome, as well
as IUGR.218–221
Antiphospholipid antibodies can be detected in 5% of healthy
pregnant women and 37% of pregnant women with SLE.222
Thrombotic events occur in approximately 5% of pregnant women
with antiphospholipid antibodies.221 All pregnant women with SLE
should undergo testing for antiphospholipid antibodies. Women who
sustain recurrent spontaneous abortions or a thromboembolic event
during pregnancy should also undergo evaluation for the disorder. A
history of either vascular thrombosis or fetal loss coupled with the
presence of either lupus anticoagulant antibodies or anticardiolipin
antibodies establishes the diagnosis of antiphospholipid antibody
syndrome.223
False-negative laboratory results do occur and do so more fre-
quently in pregnant than in nonpregnant women. This may be
because of the increased concentration of clotting factors observed in
pregnancy.224 Women with antiphospholipid antibody syndrome who
have sustained prior thrombotic events receive therapeutic anticoagu-
lation during pregnancy. Those with antiphospholipid antibodies but
no manifestations of the clinical syndrome should receive prophylac-
tic anticoagulation.
TABLE
Antiphospholipid Antibody Syndrome
151.3
Vascular Thrombosis
One or more episodes of arterial or venous thrombosis confirmed by
imaging
Pregnancy morbidity
Death of a fetus beyond 10 weeks of gestation with normal fetal
morphology
Premature birth before 34 weeks of gestation
Three or more consecutive spontaneous abortions before 10 weeks of
gestation
Laboratory criteria (all measured on two or more occasions at least
12 weeks apart)
Lupus anticoagulant on two or more occasions at least 12 weeks apart
Anticardiolipin antibody
Anti-B2 glycoprotein IgM or IgG
Ig, Immunoglobulin.
 2214 Part XIII  Consultative Hematology
FUTURE DIRECTIONS
Management of the hematologic complications of pregnancy contin-
ues to be a challenge. The physicians and patient involved all benefit
from a multidisciplinary approach. In certain disorders, the manage-
ment is clear and will likely remain unchanged in the future. In other
disorders, treatment paradigms may shift as new treatments are dis-
covered for the nonpregnant patient. In all instances, further well-
designed studies will continue to advance evidence-based management
of the pregnant patient.
SUGGESTED READINGS
Al RA, Unlubilgin E, Kandamir O, et al: Intravenous verses oral iron for
treatment of anemia in pregnancy: a randomized trial. Obstet Gynecol
106:1335, 2005.
Allen LH: Nutritional supplementation for the pregnant woman. Clin Obstet
Gynecol 37:587, 1994.
Bothwell TH: Overview and mechanisms of iron regulation. Nutr Rev
53:237, 1995.
Casanueva E, Viteri FE, Mares-Galindo M, et al: Weekly iron as a safe
alternative to daily supplementation for nonanemic pregnant women.
Arch Med Res 12:674, 2006.
Centers for Disease Control and Prevention (CDC): CDC criteria for anemia
in children and childbearing-aged women. MMWR Morb Mortal Wkly
Rep 38:400, 1989.
Centers for Disease Control and Prevention (CDC): Recommendations to
prevent and control iron deficiency in the United States. MMWR Recomm
Rep 47(RR-3):1, 1998.
Chanarin I: Folate and cobalamin. Clin Haematol 14:729, 1985.
Chanarin I, MacGibbon BM, O’Sullivan WJ, et al: Folic acid deficiency
in pregnancy—the pathogenesis of megaloblastic anemia of pregnancy.
Lancet 2:634, 1959.
Chanarin I, Rothman D: Further observations on the relation between iron
and folate status in pregnancy. Br Med J 2:81, 1971.
Cogswell ME, Parvanta I, Ickes L, et al: Iron supplementation during
pregnancy, anemia, and birth rate: a randomized trial. Am J Clin Nutr
78:773, 2003.
Council on Foods and Nutrition Committee on Iron Deficiency: Iron
deficiency in the United States. JAMA 203:119, 1968.
Crowley JP: Coagulopathy bleeding in the parturient patient: recent informa-
tion has helped in the identification of individuals at special risk. R I Med
J 72:135, 1989.
Galloway R, McGuire J: Determinants of compliance with iron supplementa-
tion: supplies, side effects, or psychology? Soc Sci Med 39:381, 1994.
Garn SM, Ridella SA, Petzold AS, et al: Maternal hematologic levels and
pregnancy outcomes. Semin Perinatol 5:155, 1981.
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Hiss RG: Evaluation of the anemic patient. In Laros RK, editor: Blood
disorders in pregnancy, Philadelphia, 1986, Lea & Febiger, p 1.
Hytten F: Blood volume changes in normal pregnancy. Clin Haematol
14:601, 1985.
Institute of Medicine: Nutrition services in perinatal care, Washington, DC,
1992, National Academy Press.
Klebanoff MA, Shiono PH, Selby JV, et al: Anemia and spontaneous preterm
birth. Am J Obstet Gynecol 164:59, 1991.
Lieberman E, Ryan KJ, Monson RR, et al: Association of maternal hematocrit
with premature labor. Am J Obstet Gynecol 159:107, 1988.
Lu ZM, Goldenberg RL, Oliver SP, et al: The relationship between maternal
hematocrit and pregnancy outcome. Obstet Gynecol 77:190, 1991.
Milman N: Iron and pregnancy—a delicate balance. Ann Hematol 85:559,
2006.
Milman N, Agger AI, Nielson OJ: Iron status markers and serum erythropoi-
etin in 120 mothers and newborn infants: effect of iron supplementation
and normal pregnancy. Acta Obstet Gynecol Scand 73:200, 1994.
Murphy JF, O’Riordan J, Newcombe RG, et al: Relation of haemoglobin
levels in first and second trimesters to outcome of pregnancy. Lancet
1:992, 1986.
Perry GS, Yip R, Zyrkowski C: Nutritional risk factors among low-income
pregnant US women: the Centers for Disease Control and Prevention
(CDC) Pregnancy Nutrition Surveillance System, 1979 through 1993.
Semin Perinatol 19:211, 1995.
Romslo I, Haram K, Sagen N, et al: Iron requirement in normal pregnancy
as assessed by serum ferritin, serum transferring saturation, and eryth-
rocyte protoporphyrin determinations. Br J Obstet Gynaecol 90:101,
1983.
Rothman D: Folic acid in pregnancy. Am J Obstet Gynecol 108:149, 1970.
Scholl TO, Hediger ML: Anemia and iron-deficiency anemia: compilation
of data on pregnancy outcome. Am J Clin Nutr 59(2 Suppl):492S, 1994.
Scholl TO, Hediger ML, Fischer RL, et al: Anemia vs iron deficiency:
increased risk of preterm delivery in a prospective study. Am J Clin Nutr
55:985, 1992.
Singh K, Fong YF, Arulkumaran S: Anaemia in pregnancy—a cross-sectional
study in Singapore. Eur J Clin Nutr 52:65, 1998.
World Health Organization: The prevalence of anaemia in women: a tabulation
of available information, ed 2, Geneva, 1992, World Health Organization.
Zhou LM, Yang WW, Hua JZ, et al: Relation of hemoglobin measured at
different times in pregnancy to preterm birth and low birth weight in
Shanghai, China. Am J Epidemiol 148:998, 1998.
REFERENCES
For the complete list of references, log on to www.expertconsult.com.

REFERENCES
1. World Health Organization: The prevalence of anaemia in women: a
tabulation of available information, ed 2, Geneva, 1992, World Health
Organization.
2. Crowley JP: Coagulopathy bleeding in the parturient patient: recent
information has helped in the identification of individuals at special
risk. R I Med J 72:135, 1989.
3. Hytten F: Blood volume changes in normal pregnancy. Clin Haematol
14:601, 1985.
4. Centers for Disease Control and Prevention (CDC): CDC criteria
for anemia in children and childbearing-aged women. MMWR Morb
Mortal Wkly Rep 38:400, 1989.
5. Garn SM, Ridella SA, Petzold AS, et al: Maternal hematologic levels
and pregnancy outcomes. Semin Perinatol 5:155, 1981.
6. Singh K, Fong YF, Arulkumaran S: Anaemia in pregnancy—a cross-
sectional study in Singapore. Eur J Clin Nutr 52:65, 1998.
7. Klebanoff MA, Shiono PH, Selby JV, et al: Anemia and spontaneous
preterm birth. Am J Obstet Gynecol 164:59, 1991.
8. Lu ZM, Goldenberg RL, Oliver SP, et al: The relationship between
maternal hematocrit and pregnancy outcome. Obstet Gynecol 77:190,
1991.
9. Murphy JF, O’Riordan J, Newcombe RG, et al: Relation of haemoglo-
bin levels in first and second trimesters to outcome of pregnancy. Lancet
1:992, 1986.
10. Lieberman E, Ryan KJ, Monson RR, et al: Association of maternal
hematocrit with premature labor. Am J Obstet Gynecol 159:107, 1988.
11. Scholl TO, Hediger ML: Anemia and iron-deficiency anemia: compila-
tion of data on pregnancy outcome. Am J Clin Nutr 59(2 Suppl):492S,
1994.
12. Scholl TO, Hediger ML, Fischer RL, et al: Anemia vs iron deficiency:
increased risk of preterm delivery in a prospective study. Am J Clin Nutr
55:985, 1992.
13. Zhou LM, Yang WW, Hua JZ, et al: Relation of hemoglobin measured
at different times in pregnancy to preterm birth and low birth weight
in Shanghai, China. Am J Epidemiol 148:998, 1998.
14. Centers for Disease Control and Prevention (CDC): Recommendations
to prevent and control iron deficiency in the United States. MMWR
Recomm Rep 47(RR-3):1, 1998.
15. Institute of Medicine: Nutrition services in perinatal care, Washington,
DC, 1992, National Academy Press.
16. Galloway R, McGuire J: Determinants of compliance with iron supple-
mentation: supplies, side effects, or psychology? Soc Sci Med 39:381,
1994.
17. Chanarin I, Rothman D: Further observations on the relation between
iron and folate status in pregnancy. Br Med J 2:81, 1971.
18. Bothwell TH: Overview and mechanisms of iron regulation. Nutr Rev
53:237, 1995.
19. Casanueva E, Viteri FE, Mares-Galindo M, et al: Weekly iron as a safe
alternative to daily supplementation for nonanemic pregnant women.
Arch Med Res 12:674, 2006.
20. Al RA, Unlubilgin E, Kandamir O, et al: Intravenous versus oral
iron for treatment of anemia in pregnancy: a randomized trial. Obstet
Gynecol 106:1335, 2005.
21. Cogswell ME, Parvanta I, Ickes L, et al: Iron supplementation during
pregnancy, anemia, and birth rate: a randomized trial. Am J Clin Nutr
78:773, 2003.
22. Perry GS, Yip R, Zyrkowski C: Nutritional risk factors among low-
income pregnant US women: the Centers for Disease Control and
Prevention (CDC) Pregnancy Nutrition Surveillance System, 1979
through 1993. Semin Perinatol 19:211, 1995.
23. Council on Foods and Nutrition Committee on Iron Deficiency: Iron
deficiency in the United States. JAMA 203:119, 1968.
24. Milman N, Agger AI, Nielson OJ: Iron status markers and serum
erythropoietin in 120 mothers and newborn infants: Effect of iron
supplementation and normal pregnancy. Acta Obstet Gynecol Scand
73:200, 1994.
25. Romslo I, Haram K, Sagen N, et al: Iron requirement in normal
pregnancy as assessed by serum ferritin, serum transferring saturation,
Downloaded for FK Unisba (mahasiswa17fkunisba@unisba.ac.id) at Bandung Islamic University from ClinicalKey.com by Elsevier on May 17, 2019.
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Chapter 151  Hematologic Changes in Pregnancy 2214.e1
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Chapter 151  Hematologic Changes in Pregnancy 2214.e5
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