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C H A P T E R 151 


Caroline Cromwell and Michael Paidas

Hematologic conditions are often seen during pregnancy. These range similar to those in nonpregnant patients. Anemia and low ferritin
from the simple to the complex. The primary physiologic hematologic levels are considered diagnostic.
changes during pregnancy relate to the expansion of plasma volume.1 Because the typical diet in the United States provides only 50%
In addition to physiologic changes of pregnancy, a prothrombotic of daily iron requirements for pregnant women and because of the
state develops as the pregnancy advances that is thought to prepare relatively high prevalence of iron deficiency among women of child-
the mother and fetus for eventual placental separation.2 All require bearing age, routine iron supplementation in pregnancy is recom-
proper planning, anticipation, and discussion with the treating physi- mended.14 Currently, the Centers for Disease Control and Prevention,
cians as well as the patient. The effect of the condition on the the American Dietetic Association, and the American College of
pregnancy, and conversely the effect of the pregnancy on the condi- Obstetrics and Gynecology recommend 15 to 30 mg/day of elemen-
tion, should be considered. The evolving clinical picture as the tal iron to prevent adverse outcomes from iron-deficiency anemia.14–18
pregnancy progresses must also be taken into account. Multidisci- Treatment should be from the beginning of gestation to 3 months
plinary planning and communication are essential. postpartum. On the basis of results of a study by Casanueva et al,19
Anemia and thrombocytopenia are common hematologic condi- weekly therapy with 120 mg of iron appears to be a safe and effective
tions seen for a variety of reasons during pregnancy and are addressed alternative to daily therapy. The side effects associated with iron
in this chapter. Inherited and acquired bleeding disorders affect therapy—constipation, diarrhea, nausea—are well known.
pregnant women, and coagulation parameters must be monitored Intravenous iron is appropriate in certain circumstances; evidence
during pregnancy and delivery. Venous thromboembolism (VTE) from a recently published randomized trial by Al et al supports the
during pregnancy remains a high-morbidity, high-risk situation use of intravenous iron therapy to replenish iron stores in appropri-
that is challenging for clinicians. These more common hematologic ately selected patients, including those who have not tolerated a trial
problems and dilemmas in management are discussed in this of oral iron therapy and those with severe iron deficiency.20
chapter. 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
ANEMIA IN PREGNANCY women received either a daily iron supplement or placebo from the
time of enrollment (all women were enrolled before week 20) to 28
Anemia in pregnancy affects approximately half of all pregnancies weeks of gestation, the incidence of both low-birth-weight and
worldwide. It is more prevalent in underdeveloped countries. preterm low-birth-weight infants was lower among women who
The World Health Organization classifies anemia in pregnancy as received daily iron.21 Nonetheless, there are limits to the effectiveness
hemoglobin below 11 g/dL, although in developing countries it is of routine iron supplementation. After all, the recommendation by
clinically defined as hemoglobin below 10 g/dL.1 Physiologic anemia prominent public health organizations for universal iron supplemen-
occurs during pregnancy as the blood volume increases to a greater tation has not led to a commensurate decrease in the incidence of
proportion than the red blood cell (RBC) mass, resulting in a dilu- iron-deficiency anemia in pregnancy22,23 or an increase in maternal
tional anemia. Total circulatory volumes increase by approximately hemoglobin levels.24,25 Compliance is an important factor in this
50% greater than the prepregnancy volume. Plasma volume and RBC discussion. A large, multicenter, randomized, controlled trial on the
mass return to baseline during the first and second postpartum benefits of iron supplementation during pregnancy in the United
months. Common maternal signs of anemia include pallor, tachy- States is needed to draw more definitive conclusions.
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 Other Nutritional Deficiencies
lead to high-output congestive heart failure in the mother.2–4 Multiple
studies have shown a correlation between maternal anemia and Folate deficiency and, less commonly, vitamin B12 deficiency are the
increased rates of both preterm (<37 weeks of gestation) and low- next most common causes of anemia in pregnancy. Cobalamin and
birth-weight deliveries.5–13 There are varied etiologies behind anemia folate are critical for fetal growth because they are necessary for the
in pregnancy. production of tetrahydrofolate. Tetrahydrofolate is key in the DNA
synthesis pathway.
Folate deficiency accounts for 95% of megaloblastic anemias in
Iron-Deficiency Anemia pregnancy.26 Folate deficiency complicates between 1% and 4% of
pregnancies in the United States and affects approximately one-third
Iron-deficiency anemia is the most common cause of anemia in of pregnancies worldwide.27 Similar to iron-deficiency anemia, the
pregnancy. It has been identified as a risk factor for preterm delivery incidence of megaloblastic anemia in pregnancy is increased in ado-
and low birth weight. Iron requirements increase during pregnancy lescents, women of low socioeconomic status, and women with
because of maternal and fetal erythropoiesis. Generally, hemoglobin multiple closely spaced births.28 The folic acid requirement for
levels decrease throughout pregnancy and then may increase during nonpregnant women is 50 to 100 µg/day, but this increases to 150 µg
the last month of pregnancy. Ferritin levels also increase in the last during pregnancy as RBC mass in the mother increases and as fetal
month of pregnancy because it is an acute-phase reactant. Erythro- demands for folate grow with cell proliferation.29
poietin levels increase throughout pregnancy. The clinical symptoms Diagnosis of folate deficiency is best based on RBC folate levels.
of iron deficiency are similar to those in nonpregnant patients and An elevated homocysteine level also helps confirm the diagnosis.
include fatigue, pallor, tachycardia, and poor exercise tolerance. The Pregnant women should at least receive 400 µg of folic acid per day.
diagnosis and treatment of iron-deficiency anemia are generally Vitamin B12 deficiency is much less common during pregnancy.

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2204 Part XIII  Consultative Hematology

Diagnosis of vitamin B12 deficiency can be aided by the assessment At the time of delivery, pregnant women with sickle cell disease
of homocysteine and methylmalonic acid. If a woman is found to be are managed in a manner similar to those with high cardiac output
deficient in vitamin B12 during pregnancy, vitamin B12 injections are anemia. Supplemental oxygen, hydration, and adequate oxygenation
indicated. These are usually injected weekly for 4 to 8 weeks and then during anesthesia should be given to prevent sickling of RBCs and
monthly. the associated complications. During the postpartum period, hemo-
globin levels are followed closely, and prophylaxis for VTE is admin-
istered unless contraindications preclude it.
Sickle Cell Disease Thalassemias
Every year more than 300,000 children are born with either sickle Pregnant women with an underlying thalassemia typically have
cell disease or thalassemia. Prenatal counseling now exists in many β-thalassemia minor or α-thalassemia trait—conditions with a rela-
countries. In the United States, all newborns are screened for sickle tively benign clinical phenotype—rather than β-thalassemia major or
cell disease (see Chapters 42 and 43). Management of pregnant hemoglobin H disease (see Chapter 41). Because of delayed pubertal
patients with sickle cell disease requires coordination of care between growth or hypogonadism with associated anovulation, women with
the hematologist and obstetrician. Many women with sickle cell β-thalassemia major and hemoglobin H disease rarely become preg-
disease experience more frequent vasoocclusive crises and other sickle nant. Case reports indicate that when it does occur, pregnancy in
cell–related complications during pregnancy.30 The increased fre- women with hemoglobin H disease can be complicated by severe
quency of vasoocclusive crises, particularly during the latter half of hemolytic anemia and hepatosplenomegaly. However, in the setting
pregnancy, likely results from heightened metabolic requirements in of widespread transfusion and iron chelation therapy, pregnancy is
pregnancy, increased venous stasis, as well as the physiologic pro- more frequent in the thalassemia population. Pregnancy outcomes
thrombotic and inflammatory state associated with pregnancy. In among women with β-thalassemia major were recently examined in
addition, pathophysiologic changes in the renal and immune func- 10 patients with homozygous β-thalassemia. Of 15 pregnancies, there
tion of patients with sickle cell disease increase their susceptibility to were 14 live births, a 20% incidence of intrauterine growth restriction
urinary tract infections and pyelonephritis. By causing tissue hypoxia, (IUGR), and 21% were low-birth-weight children. In patients with
sickling of RBCs within the placental vasculature may cause deleteri- β-thalassemia intermedia, approximately 50% of pregnancies are
ous effects on the fetus.31 complicated by preterm delivery, third-trimester stillbirth, or IUGR.37
Additional significant complications occur in pregnant women Pregnancy is a common setting for the diagnosis of β-thalassemia
with sickle cell disease. The incidence of preeclampsia, thromboem- minor or α-thalassemia trait in previously asymptomatic women who
bolic events, placental abruption, intrauterine growth retardation, are found to be anemic on routine laboratory evaluation during
low birth weight, and postpartum infections are higher among pregnancy. Several studies indicate that the physiologic anemia of
women with hemoglobin SS, SC, and S β-thalassemia than among pregnancy may be exacerbated in women with thalassemia minor,
women without sickle cell disease. One study noted a higher inci- although findings from at least one study suggest otherwise.38
dence of stillbirths and perinatal mortality among patients with sickle β-Thalassemia minor and α-thalassemia traits do not have an adverse
cell disease,32 but another study revealed an increased risk of preterm effect on fetal development, fetal morbidity and mortality, or mater-
labor and premature rupture of membranes in women with hemo- nal morbidity and mortality.39
globin SS disease.33 Despite advances made in sickle disease, a recent Similar to those with sickle cell disease, women with thalassemia
meta-analysis highlights that risks for pregnancy in patients with SS require vigilant follow-up throughout their pregnancies. This includes
genotype remains high with regard to mortality, a fourfold higher risk interval monitoring of maternal vital signs and fetal heart rate,
of stillbirth and a 2.43 higher relative risk of preeclampsia. These risks maternal hemoglobin levels, and fetal growth as assessed by ultraso-
were amplified in low-income countries. Because of the increased risk nography beginning around the 24th week of gestation. Patients are
for such complications, women with sickle cell disease should receive screened for folate and iron deficiency. They should also be assessed
close medical attention throughout the prenatal period. This includes for iron overload, which can develop in individuals with thalassemia
counseling about intrauterine diagnosis of sickle cell disease when as a result of increased intestinal iron absorption, frequent blood
appropriate. Pregnant women can undergo chorionic villi sampling transfusions, and rapid turnover of plasma iron.40 Prenatal genetic
as early as the ninth week of gestation or amniocentesis in the 15th testing can be performed if desired, with results used to counsel
to 16th weeks. A reticulocyte count along with hemoglobin, iron, parents of the child and guide optimal care of the fetus. In terms of
and folate levels should be obtained to assess for deficiency states and therapy, there are no specific treatment recommendations for women
bone marrow suppression. Urinalysis with urine culture is performed with thalassemia during pregnancy, aside from folate supplementa-
as often as every trimester to monitor for asymptomatic bacteriuria. tion and supportive care. In pregnant women with evidence of iron
Finally, beginning around 28 weeks of gestation, patients should have overload, chelation therapy using deferoxamine has been used safely,
weekly clinic visits and begin serial ultrasonography. although the potential for teratogenicity associated with the agent
Treatment of sickle cell disease during pregnancy warrants careful must be considered in this setting.41
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 OTHER HEMOLYTIC ANEMIAS
prophylactic blood transfusions or exchange transfusions have not led
to definitive conclusions.34 Although they may lead to alloimmuniza- Hereditary Spherocytosis
tion, prophylactic transfusions appear to decrease the incidence of
vasoocclusive crises and decrease maternal and fetal morbidity and Hereditary spherocytosis is the most common inherited hemolytic
mortality.35 A conservative approach reserves transfusions for patients anemia among people of northern European descent (see Chapter
whose hemoglobin levels fall below 6 g/dL, patients who develop 46).42 Few cases of pregnancy in individuals with hereditary sphero-
progressive complications related to sickle cell disease, and patients cytosis have been reported. Published reports indicate there may be
with obstetric complications.36 Following this approach, 60% to 75% an increased incidence of first trimester fetal loss in patients with
of women with sickle cell disease will require transfusion therapy hereditary spherocytosis.43 Because some patients have only low levels
during pregnancy. Patients with a sickle cell crisis during pregnancy of hemolysis under normal conditions, the disease may not become
should receive aggressive analgesic therapy, hydration, and oxygen clinically apparent until pregnancy. Pregnant women with hereditary
while undergoing evaluation for infection or other precipitating spherocytosis can exhibit a variety of clinical manifestations. These
influences. include folate deficiency related to the increased requirements of

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Chapter 151  Hematologic Changes in Pregnancy 2205

pregnancy superimposed on chronic hemolysis, hemolytic crisis, and placenta. Patients with autoimmune hemolytic anemia are treated
aplastic crisis.44,45 The results of two small series suggest that preg- with glucocorticoids and, if necessary, intravenous immunoglobulin
nancy outcomes for women with hereditary spherocytosis are gener- (IVIg). Supportive transfusions are administered when needed.53 In
ally good, with improvements in outcomes for splenectomized rare instances, pregnancy appears to precipitate the development of
patients.46 Care is primarily supportive. 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
Glucose 6-Phosphate Dehydrogenase Deficiency results.

Favorable pregnancy outcomes observed in women with hereditary

spherocytosis and pyruvate kinase deficiency stand in contrast to THROMBOCYTOPENIA
those in women with glucose 6-phosphate dehydrogenase (G6PD)
deficiency. The deficiency of G6PD leads to hemolytic anemia in the Thrombocytopenia during pregnancy is quite common. It occurs in
face of oxidative stress (see Chapter 45). The condition increases the approximately 10% of pregnancies.55 Although there is not one clear
risk of spontaneous abortion, low-birth-weight fetuses, and neonatal value to define thrombocytopenia in pregnancy, generally a platelet
jaundice.47 Women with G6PD deficiency should be instructed to count less than 100,000 is considered cause for concern. There is
strictly avoid medications with oxidative potential. Complications some physiologic thrombocytopenia that occurs during pregnancy.
after the ingestion of oxidative drugs can even occur in a carrier of Gestational thrombocytopenia (GT) is the most common cause of
the G6PD deficiency gene if her male fetus has inherited the disease.48 thrombocytopenia in pregnancy followed by preeclampsia and
immune thrombocytopenia. Much rarer causes include disseminated
intravascular coagulation (DIC), thrombotic thrombocytopenic
Paroxysmal Nocturnal Hemoglobinuria purpura (TTP) and hemolytic uremic syndrome (HUS), and medica-
tion induced. The evaluation of thrombocytopenia is essential to rule
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder out any systemic disorders that may affect pregnancy management
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 Gestational Thrombocytopenia
are anchored by the gene product of PIGA. Features of the clinical
phenotype include hemolysis, thrombosis, and bone marrow failure. GT is quite common during pregnancy. The platelet count is gener-
Hemolysis results from deficiency in the membrane proteins CD55 ally never lower than 70,000/µL. This occurs mainly in the third
and CD59, which renders affected individuals susceptible to trimester. Patients are asymptomatic and have no history of throm-
complement-mediated intravascular hemolysis. bocytopenia. The platelet count normalizes within 3 months of
The clinical manifestations of PNH can have a devastating impact delivery but often normalizes within 1 week. The etiology of GT
on pregnancy. Reported cases highlight the significant pregnancy- remains unclear, but it is thought in part to be autoimmune in nature
associated morbidity and mortality in women with this condition. and demonstrates a clear overlap with mild idiopathic thrombocyto-
Complications include severe anemia, thrombocytopenia, thrombotic penic purpura (ITP).
events, preterm delivery, low-birth-weight infants, neonatal death, The management of patients with GT is uncomplicated. Typi-
and maternal death.49,50 A study by Ray and colleagues50 reviewed cally, they can receive epidural anesthesia. However, practice varies at
pregnancy outcomes in 24 women with PNH and found a 20% each institution in terms of platelet threshold for epidural anesthesia.
maternal mortality rate. Platelet counts greater than 100,000/µL are considered safe for epi-
Owing to the high-risk nature of these pregnancies, women with dural anesthesia. There are studies demonstrating safe administration
PNH require close medical attention in the antenatal, perinatal, and of epidural anesthesia in pregnant patients with platelet counts as low
postnatal periods. Prophylactic anticoagulation is recommended as 70,000/µL.56
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 Immune Thrombocytopenia
heparin (UFH) because it less frequently causes heparin-induced
thrombocytopenia (HIT). Anticoagulation should be interrupted ITP is responsible for pregnancy-associated thrombocytopenia in
during the perinatal period but, in the absence of contraindications, approximately 3% of cases (Chapter 132). It is the most common
reinitiated thereafter and continued for 6 weeks postpartum.51 cause of thrombocytopenia during the first two trimesters of preg-
Results of a phase III trial by Hillmen and colleagues52 demon- nancy.57 ITP can recur in women with previously documented disease
strated that eculizumab, a humanized monoclonal antibody against or can develop de novo during pregnancy.
the terminal complement protein C5, can reduce levels of hemolysis, ITP is usually not diagnosed during pregnancy. Pregnant patients
stabilize hemoglobin, minimize transfusion requirement, and improve with ITP usually have a long-standing history of thrombocytopenia.
quality of life in patients with PNH. There are case reports describing ITP may be difficult to distinguish from GT because patients with
success in patients chronically receiving eculizumab throughout these conditions can present with similar clinical and laboratory
pregnancy with uncomplicated deliveries. However, a large random- findings. Elevated levels of platelet-associated IgG and antibody titers
ized trial has not been performed. Supportive care is used as needed can be found in both conditions.58 Furthermore, assays that detect
throughout pregnancy. RBC transfusions are used in the treatment antibodies against the glycoprotein receptors IIb/IIIa and Ib/IX are
of anemia. In the setting of thrombocytopenia and bleeding, platelet not specific for ITP.59 Whereas thrombocytopenia in the first trimester
transfusions may also be necessary. 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
Autoimmune Hemolytic Anemia in distinguishing between the two. It is important to attempt to
distinguish between ITP and GT because there is a small but signifi-
Autoimmune hemolysis can occur during pregnancy and lead to cant risk of neonatal thrombocytopenia in the setting of ITP.60
anemia (see Chapter 47). The relatively small size of immunoglobulin In terms of diagnostic evaluation, human immunodeficiency
(Ig)G immunoglobulin molecules allows them to cross the placenta; virus, hepatitis, and lupus should be tested for if clinically indicated.
thus the IgG subtype of autoimmune hemolytic anemia can adversely Platelet antibody testing is not considered helpful. The peripheral
affect fetuses. In contrast, the larger IgM antibodies do not cross the smear may demonstrate an increased platelet size but should otherwise

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2206 Part XIII  Consultative Hematology

TABLE Initiation of Treatment in Pregnant Patients With Thrombocytopenia is observed in 15% to 50% of patients with this
151.1 Idiopathic Thrombocytopenic Purpura condition.73,74 Clinical manifestations include a maternal syndrome
characterized by hypertension, proteinuria, and systemic abnormali-
Platelet Count Treatment ties as well as a fetal syndrome characterized by fetal growth restric-
<10,000/µL Platelet transfusion for life-threatening bleeding tion, preterm delivery, and hypoxia-induced neurologic damage.72,74
In most instances, preeclampsia occurs during a woman’s first
10,000-30,000/µL Consider monitoring in first trimester; treat in
pregnancy, but it can recur in a subsequent pregnancy or occur for
second or third trimester
the first time in a woman with one or more previously unaffected
>30,000/µL Clinically monitor 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
be normal. Bone marrow biopsy and aspirate are not indicated unless thrombophilia, a case–control study by Mello and colleagues75 sug-
there are other hematologic abnormalities present. gests that the prevalence of an underlying thrombophilia is signifi-
Treatment options are generally similar to those for nonpregnant cantly higher among women who develop preeclampsia during
patients with ITP (Table 151.1). Platelet transfusions are reserved for pregnancy than among those who have uneventful pregnancies.
life-threatening bleeding because the lives of transfused platelets are HELLP syndrome represents a severe variant of preeclampsia. In
usually short in ITP. Glucocorticoids are considered first-line treat- the majority of cases, patients who develop the syndrome are white
ment; prednisone is usually initiated at 1 mg/kg based on the patient’s and multiparious.76 The median age of affected patients is 25 years.
baseline weight. Side effects of prednisone should be discussed with The time of presentation during pregnancy ranges from the midtri-
the patient and include weight gain, bone loss, hypertension, and mester (15%) to term (18%). In 30% of patients who develop
gestational diabetes. IVIg can also be used. It is a means of rapid HELLP, it develops within 2 days after delivery.77 Patients typically
increase in platelet count. It is particularly used to help increase exhibit vague symptoms such as malaise, fatigue, epigastric or right
platelet counts a few days before delivery.61 It is usually administered upper quadrant pain, nausea, vomiting, and flulike symptoms.
at a dose of 2 g/kg over 2 days. However, the improvement in platelet Because of the nonspecific nature of these symptoms, diagnosis is
count is fairly transient. Splenectomy is also an option indicated for often delayed; one study found an average time to diagnosis of 8 days
refractory thrombocytopenia; it is best performed during the second in women with HELLP syndrome.78 Clinical findings at the time of
trimester. diagnosis (weight gain or edema, hypertension, and proteinuria) are
Other agents such as danazol, cyclophosphamide, and vinca similar to those observed in preeclampsia.77
alkaloids, although used in the management of ITP in nonpregnant Although various criteria have been used in diagnosing HELLP
individuals, are teratogenic and should be avoided during pregnancy.62 syndrome, they generally share the following features: signs of micro-
Use of cyclophosphamide has been associated with birth defects. angiopathic hemolytic anemia, serum lactate dehydrogenase greater
Danazol may cause clitoral enlargement and labial fusion in female than 600 U/L or serum total bilirubin greater than 1.2 mg/dL,
fetuses when given in the first trimester.63,64 The use of rituximab has aspartate aminotransferase greater than 70 IU/L, and a platelet count
never been studied systematically in this setting and is considered a lower than 100,000/µL.79 Martin and colleagues77 further defined
pregnancy class C drug. Although case reports of its use exist, it is HELLP syndrome on the basis of platelet count. According to this
not generally recommended in this case. Animal data indicate that classification, patients with class 1 HELLP syndrome have a platelet
thrombopoietin mimetics may cause fetal harm, and little is known count lower than 50,000/µL, those with class 2 disease have a platelet
about their use in pregnant patients. A registry has been developed count between 50,000 and 100,000/µL, and individuals with class 3
for pregnant patients treated with thrombopoietin mimetics. HELLP syndrome have a platelet count higher than 100,000/µL. As
As discussed previously, maternal antiplatelet IgG can cross the might be expected, women with class 1 HELLP syndrome required
placenta and cause thrombocytopenia in fetuses. Percutaneous a recovery period in the aftermath of their illness.
umbilical blood sampling is the most accurate means to obtain the Although the precise mechanism through which preeclampsia
fetal platelet count. However, the procedure is associated with a high develops is uncertain, research in the field continues to advance
complication rate and 1% fetal mortality.65 Intrapartum fetal scalp understanding of the underlying pathophysiology. Endothelial cell
sampling represents an alternative, but the accuracy of this technique dysfunction after placentation appears to play a central role in the
is only 50% to 70%.66 The maternal platelet count and antiplatelet pathogenesis of the disease. During development of the placenta,
antibody level do not accurately predict the fetal platelet count.67 placental trophoblast cells interface with the epithelial layer of the
Overall, 10% of babies born to mothers with ITP have a platelet uterus, forming the decidua. Penetration and remodeling of maternal
count less than 50,000/µL, but less than 5% have a platelet count spiral arteries beginning at week 9 during pregnancy increase placental
less than 20,000/µL.68 Treatment of pregnant women with IVIg or perfusion and improve oxygenation for the developing fetus under
steroids does not appear to affect the platelet count of fetuses.68,69 normal conditions.80
Thrombocytopenia places neonates at risk for bleeding events, Cellular abnormalities such as those described impair placental
including intracranial hemorrhage, although this complication is implantation and vasculogenesis, leading to fetal hypoxia and the
rare.70 release of vasoactive compounds such as endothelin, nitric oxide, and
In terms of delivery, at present, available guidelines on the subject prostaglandins. High levels of endothelin, a potent vasoconstrictor,
suggest that obstetric factors, rather than hematologic ones, should are seen in preeclamptic patients, and injection of endothelin into
guide the manner of delivery.71 After the delivery of a child, the cord rabbits produces a syndrome similar to HELLP syndrome.81,82 The
blood platelet count is checked and the newborn platelet count fol- activity of endothelin, nitric oxide, and prostaglandins leads to
lowed because thrombocytopenia is often most severe 4 to 6 days hypertension and platelet activation. Angiogenic factors such as
after delivery and resolves as maternal antiplatelet IgG is cleared. 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,
Preeclampsia and HELLP Syndrome and the release of additional vasoactive agents such as serotonin and
thromboxane A2. The etiology of thrombocytopenia in preeclampsia
Thrombocytopenia in pregnant woman also occurs in association is likely related to increased antiplatelet IgG levels83 or to activation
with preeclampsia and HELLP syndrome (hemolysis, elevated liver of the coagulation cascade with subsequent consumption of
enzymes, low platelet count), potentially severe multisystem disor- platelets.84,85
ders associated with pregnancy. In previously healthy nulliparous These events lead to the multisystem dysfunction seen in patients
women, the incidence of preeclampsia is between 2% and 7%.72 with HELLP syndrome. Fibrin deposition in the hepatic sinusoids

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Chapter 151  Hematologic Changes in Pregnancy 2207

causes hepatocellular injury. Patients can develop right upper quad- when signs and symptoms of preeclampsia or HELLP develop. In a
rant pain if intraparenchymal or subcapsular hemorrhage occurs. clinically stable woman, vaginal delivery can be attempted.104 When
DIC was observed in 21% of patients with HELLP in one series, and cesarean section is required, transfusion of RBCs, platelets, and fresh
placental abruption was seen in 16% of patients.86 Other manifesta- frozen plasma (FFP) is performed as necessary before and during
tions of HELLP syndrome include acute renal failure, pulmonary surgery. Severe hypofibrinogenemia should be treated with
edema, shock, cerebrovascular accident (CVA), eclampsia, retinal cryoprecipitate.
detachment, diabetes insipidus, and an increased incidence of cesar- Patients are monitored closely in the postpartum period. Magne-
ean section. sium should be continued for 12 to 48 hours after delivery and blood
HELLP syndrome is associated with high maternal and neonatal pressure controlled appropriately. Although hypertension typically
mortality rates. Maternal mortality rates range from 1.1% to 24.2%.87 resolves within 6 weeks after delivery, some women require long-term
The immediate cause of death is most often rupture of the liver, DIC, antihypertensive therapy.102 Coagulation and platelet abnormalities
acute renal failure, pulmonary edema or acute respiratory distress tend to resolve within 24 to 48 hours after delivery. Some patients,
syndrome (ARDS), shock, or CVA. Perinatal deaths resulting from however, experience an ongoing decline in platelet count and should
placental abruption, asphyxia, or extreme prematurity occur in 10% be followed until counts normalize. Postpartum eclampsia can
to 15% of patients. After delivery, infants born to women with pre- occur for up to 48 hours after delivery; thus patients and health
eclampsia or HELLP can develop a self-limited neonatal thrombocy- care providers should remain vigilant in monitoring for suggestive
topenia. Uncertainty exists regarding whether infant thrombocytopenia signs and symptoms.105 Treatment options in the setting of severe
in these instances results from preeclampsia or HELLP itself or from postpartum preeclampsia and HELLP include corticosteroids and
a related complication such as neonatal sepsis.88–90 HELLP recurs in plasmapheresis.106,107
subsequent pregnancies of affected women in 3% to 27% of cases. In light of the morbidity and mortality associated with preeclamp-
There is also an increased risk of preeclampsia, placental abruption, sia and HELLP, considerable research has been focused on prevention
and preterm delivery in these pregnancies.91–100 of these conditions. The efficacy of various preventive strategies,
In caring for a patient with preeclampsia or HELLP syndrome, including magnesium supplementation, low-dose aspirin, zinc supple-
the clinician’s primary concerns are the mother’s health and safety. mentation, antihypertensive drugs, and heparin therapy, among
The clinician must also consider the stage of pregnancy at time of others, has been the focus of observational studies, systematic reviews,
diagnosis, the condition of the fetus, and desires of the patient in and randomized trials. Initial small studies suggested that low-dose
making management decisions. Definitive treatment for preeclampsia aspirin reduces the risk of preeclampsia, although patients who
and HELLP involves delivery of the fetus; it is indicated for women received aspirin had a higher incidence of placental abruption and
who present after 34 weeks of gestation and those with evidence of bleeding.108–115 Larger, randomized trials failed to confirm the benefit
multisystem dysfunction. However, conservative, supportive care of low-dose aspirin.109,110
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 Thrombotic Thrombocytopenic Purpura–
parameters.100,101 Magnesium sulfate, which reduces cerebral vasocon- Atypical Hemolytic Uremic Syndrome
striction and ischemia, should be administered for seizure prophy-
laxis.102 Parenteral labetalol or hydralazine is given for blood pressure TTP and HUS/atypical HUS are also important considerations in
control. Systemic corticosteroids appear to lessen the risk of maternal the evaluation of pregnant women with thrombocytopenia (Chapter
ARDS and reduce neonatal complications when administered to 135). Similar to preeclampsia and HELLP syndrome, they are
women who present at less than 34 weeks of gestation.103 In addition multisystem disorders associated with high morbidity and mortality
to these measures, volume status is closely monitored to prevent rates in the absence of appropriate therapy. Microvascular injury and
plasma volume expansion and ensure adequate urine output. platelet agglutination with resulting thrombocytopenia and microan-
Persistent right upper quadrant pain, which may herald a liver giopathic hemolytic anemia are pathologic hallmarks of TTP and
hematoma or rupture, hemodynamic instability, coagulation profile HUS (Fig. 151.1). They are rare conditions overall, but the incidence
abnormalities, or a decline in clinical status, should prompt delivery of both increases in pregnancy.116 In the case of TTP, in fact, estimates
by cesarean section. As mentioned previously, delivery is also indi- suggest that approximately 10% of cases occur in pregnant or post-
cated if the fetus is at least 32 to 34 weeks of gestation at the time partum women.117

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 mechanism.131 On the contrary, bacterial endotoxin or exotoxin
aHUS are often categorized as a single entity, TTP-HUS. However, mediates sepsis-associated DIC in pregnant women with pyelone-
the pathophysiologies underlying the two conditions are distinctive. phritis, chorioamnionitis, endometritis, or septic abortion.132 On rare
TTP is associated with unusually large multimers of circulating von occasions, elective abortions that use hypertonic solution and those
Willebrand factor (vWF), which foster platelet aggregation and complicated by hemorrhage can be associated with DIC.133
thrombus formation. Under normal circumstances, a vWF-cleaving AFLP, or acute yellow atrophy, occurs in 1 of every 5000 to 10,000
protease referred to as ADAMTS13 (a disintegrin and metallopro- pregnancies, most often in the third trimester of primiparous
teinase with a thrombospondin type 1 motif, member 13) cleaves women.134 Maternal and fetal mortality are 5% and 15%, respectively.
these multimers into smaller multimers of normal size. In TTP, func- Although the pathogenesis of AFLP is not clear, microvesicular fatty
tion of the cleaving protease is impaired. ADAMTS13 deficiency infiltration of the liver’s central zone is observed and presumably plays
characterizes familial TTP. Inhibition of ADAMTS13 protease activ- a central role in the development of this disease.135 In some cases,
ity by an autoantibody characterizes the acquired form of TTP. An fatty infiltration can be detected by ultrasonography or computed
inhibitory autoantibody can be found in 70% to 85% of patients tomography (CT).136 Patients present with a variety of symptoms,
with TTP.118 On the other hand, impaired vWF-cleaving protease including malaise, fatigue, right upper quadrant pain, dyspnea, and
activity does not appear to play a role in the pathogenesis of a HUS.119 mental status changes. Laboratory findings include abnormal liver
Our understanding of the pathogenesis of atypical HUS has evolved function test results consistent with cholestatic disease, elevated
in recent years as this disorder has been recognized to be associated ammonia, low fibrinogen and antithrombin levels, and elevated
as a complement-mediated disorder. With this dysregulation of prothrombin time, with evidence of DIC. Hepatic dysfunction can
complement, a picture of profound inflammation evolves. In contrast impair gluconeogenesis. Diabetes insipidus may be present. The
to TTP, there is typically more severe renal involvement with less clinical course of AFLP resembles those of HELLP syndrome, TTP,
severe thrombocytopenia. There can be some similarity found and HUS, although the microangiopathy and thrombocytopenia are
between the features of TTP-HUS and HELLP syndrome. It can be not as severe.137 With supportive care, the condition typically resolves
difficult to distinguish TTP and HUS from HELLP syndrome within 10 days after delivery.
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 LEUKEMIA AND LYMPHOMA
period.120 HUS primarily occurs after delivery; 90% of cases occur
in the postpartum period, with a mean onset at 26 days after deliv- The diagnosis of hematologic malignancy during pregnancy can be
ery.121 TTP and HUS do not cause hypertension or liver necrosis. incredibly traumatic for a pregnant patient and her family, and it is
Furthermore, TTP and HUS frequently persist after delivery, but a treatment challenge for the physician. Although great strides have
HELLP syndrome typically resolves in the postpartum period. been made in the treatment of this heterogeneous group of diseases,
Treatment of TTP-HUS involves emergent plasmapheresis within the treatment of pregnant patients is limited because of the lack of
24 to 48 hours of diagnosis. The response rate among pregnant research in this area and limited pregnancy safety data. The need to
women treated with plasmapheresis for TTP is approximately 75%. treat the patient and risk to the fetus must both be taken into
By comparison, the overall response rate in patients with TTP is account. Diagnosis can be difficult because many of the nonspecific
approximately 80% to 90%.122–125 Long-term sequelae in surviving signs that accompany these disorders, including fatigue, anemia, loss
patients include chronic renal failure, hypertension, and recurrence of appetite, and weight loss, can occur at various times during a
of TTP-HUS. TTP-HUS recurs in approximately 50% of subsequent normal pregnancy. Diagnostic imaging is limited mainly to ultraso-
pregnancies.126 Infusion of FFP represents an alternative to plasma- nography and magnetic resonance imaging (MRI). Although the
pheresis, although plasmapheresis is the preferred treatment modality. radiation dose from a CT scan is considered low, it is usually avoided.
The response rate after FFP infusion is 64%.127 Corticosteroids have Diagnostic procedures such as bone marrow or lymph node biopsy
also been used successfully in the treatment of pregnancy-associated can usually be performed safely during pregnancy.
TTP-HUS, with a response rate of 26%.125 Conversely, antiplatelet In terms of treatment, the risk of teratogenicity from treatment
agents such as aspirin do not play a role in the treatment of pregnancy- appears highest during fetal organogenesis, which occurs mainly
associated TTP-HUS.128 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
Disseminated Intravascular Coagulation children born to mothers with hematologic malignancies, including
29 women with acute leukemia and 38 who received treatment
DIC in pregnant women can occur in various clinical settings, includ- during the first trimester. Assessing growth and development, hema-
ing HELLP syndrome, TTP-HUS, placental abruption, amniotic tologic parameters, psychological characteristics, and cognitive func-
fluid embolism, uterine rupture, intrauterine fetal demise, sepsis, tion over 19 years, the authors found no significant, long-term,
elective abortion, and acute fatty liver of pregnancy (AFLP). deleterious consequences related to treatment. The risk of childhood
Severe placental abruption sufficient to cause fetal death occurs in malignancies was not increased. In a retrospective report following
0.12% of all pregnancies.129 This condition leads to a consumptive the outcome of 54 newborns of women treated with chemotherapy
hypofibrinogenemia, and (when fibrinogen levels fall below 100 to specifically during the first trimester, long-term development was
150 mg/dL) bleeding may ensue. Maintenance of adequate urine found to be normal. However, this is in contrast to general incidence
output and a hematocrit level greater than 30% are important of congenital malformations found by others for treatment given
components of care for women who have had a placental abruption. during this time period.
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- Hodgkin Lymphoma
tained at 50,000/µL or above through platelet transfusion and
fibrinogen replaced with FFP or cryoprecipitate. That hematologic malignancies are among the most commonly
Amniotic fluid embolism is a rare but often lethal condition with diagnosed cancers during pregnancy reflects to a large extent the rela-
a mortality rate of approximately 80%.130 About 10% to 15% of these tively high incidence of Hodgkin lymphoma in women between the
patients develop a coagulopathy. DIC in this setting most likely ages of 15 and 24 years.140 On the basis of results of several retrospec-
follows the release of thromboplastin-rich material into the maternal tive studies, Hodgkin lymphoma diagnosed during pregnancy appears
circulation. DIC seen in association with uterine rupture and to have no significant effect on pregnancy outcome.141 A single-
intrauterine fetal demise presumably occurs through a similar institution experience published by Dilek and colleagues,142 however,

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Chapter 151  Hematologic Changes in Pregnancy 2209

highlights complications that may occur in pregnant women with

Imatinib Therapy
Hodgkin disease because children born to three of five women with
the disease had complications, including death. Remission rates and A 38-year-old woman with a history of chronic-phase chronic myeloid
20-year overall survival rates among women diagnosed with Hodgkin leukemia on imatinib therapy for 5 years becomes pregnant. She has
disease during pregnancy are reportedly similar to those observed in had a complete cytogenetic response. She asks what to do about her
nonpregnant women with the disease.143,144 In rare instances, Hodgkin imatinib therapy.
lymphoma metastasizes to the placenta, so the placenta and newborn Imatinib is teratogenic and should not be used during pregnancy. It
infant should be examined for evidence of malignancy.145 Staging has been linked to spontaneous abortions and to fetal malformations,
during pregnancy can be performed with CT, but MRI is preferred including skeletal abnormalities, hydrocephalus, and exophthalmos.
to reduce to exposure of the fetus to radiation. Although there are case reports documenting fetal exposure at various
stages of pregnancy without harm, it is not recommended. Case reports
Similar to other malignancies managed during pregnancy, treat- suggest that patients who have achieved maximal response to therapy
ment of women with Hodgkin disease is challenging. Generally, fare better when their treatment is held for pregnancy, as opposed to
chemotherapy at any point in pregnancy increases the risk of an patients who have not achieved best response.
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 teratogenicity in rats and impaired spermatogenesis in dogs, monkeys,
when given in the second or third trimester. and rats.156 In a series of 19 pregnancies involving a mother or father
Non-Hodgkin lymphoma (NHL) rarely occurs during pregnancy. undergoing imatinib-based therapy for CML, three pregnancies
There are case reports and case series of women with NHL who have resulted in a spontaneous abortion, and two others produced children
been treated successfully with chemotherapy during the second and with minor malformations.157 The remaining 13 pregnancies resulted
third trimesters of pregnancy.145 In a review of 121 cases of pregnancy- in the delivery of a healthy child. Among mothers in this study who
associated NHL, 75% had stage IV disease at diagnosis, and repro- had previously achieved a complete hematologic remission with
ductive organ involvement was found in half the cases. Placental and imatinib and interrupted therapy during pregnancy, a majority (five
fetal involvement were uncommon.146,147 of nine) lost the hematologic remission. These findings highlight the
Alkylating agents given during the first trimester can result in fetal important therapy-related implications for mother and fetus, which
malformations or death, although there are reports of children who must be weighed carefully in determining an appropriate course of
received chemotherapy during the first trimester with no subsequent management (see box on Imatinib Therapy). Currently, it is recom-
deficits.148 On the basis of available data, response and recurrence mended by specialists in the field that patients undergoing treatment
rates among women treated for NHL during pregnancy are similar with imatinib for CML use proper contraception.157
to those seen in the treatment of pregnant women with Hodgkin
The Myeloproliferative Neoplasms:
Acute and Chronic Leukemias Essential Thrombocythemia, Polycythemia
Vera, and Myelofibrosis
Treatment of acute myeloid leukemia cannot be delayed. Minimal
data are available on the treatment of patients with acute leukemia, Essential thrombocythemia (ET) has a bimodal peak of distribution,
but in patients treated with chemotherapy during the first trimester, so it is the most common myeloproliferative neoplasm (MPN) in
outcomes were poor. For patients in the first trimester, planned women of childbearing age (see Chapters 69, 70, and 71). Although
abortion should be discussed, followed by treatment with standard evidenced-based guidelines do not exist for the management of
induction chemotherapy.149 pregnancy in this setting, more and more information regarding this
Patients in the second and third trimesters should be treated topic is being reported.158 Although some variation is seen in the rates
immediately. There is an association of preterm delivery, IUGR, and of complications among various studies, overall, all of the studies
spontaneous abortion with treatment in the second and third trimes- noted a consistent increase in the rate of complications compared
ters.150 In terms of treatment options, daunorubicin is preferred with pregnant women without MPN.158 Pregnancy alone is a risk
because idarubicin has increased placental transfer. Amphotericin B factor for thrombosis, and pregnancy confers a sixfold increase in the
is considered the antifungal of choice in pregnancy because there have rate of thrombosis in pregnant patients without MPN. Thrombosis
been no reports of teratogenicity.151,152 If treatment is not delayed, is a major source of morbidity and mortality in patients with MPN.
pregnant women can have outcomes similar to those of nonpregnant It is thought that the prothrombotic state that exists in MPN is
patients. behind a majority of the morbidity that can develop during preg-
Among acute leukemias arising within the myeloid lineage, acute nancy. Thrombotic occlusion of the placental circulation has been
promyelocytic leukemia is unique in terms of clinical features, par- observed.
ticularly DIC and associated bleeding complications, and therapy, In a study documenting 103 pregnancies occurring in 62 patients
which involves all-trans retinoic acid (ATRA) in conjunction with with MPN, the rate of live births was 60%, and the first trimester
traditional chemotherapy. Concern regarding the teratogenic effects abortion rate was 32%. Fetal complications occurred in 40% of cases
of ATRA is warranted. In the 1980s, Lammer and colleagues153 noted and maternal complications in 9%. The risk of fetal loss for patients
an increased risk of fetal malformation after in utero exposure to the with ET was 3.4-fold higher than for those in the aged-matched
retinoid isotretinoin. In a recent case report, Carradice et al154 control population.159
described a bleeding complication that occurred after ATRA initia- A pooled outcome analysis of 461 pregnant patients with ET
tion in a pregnant woman with acute promyelocytic anemia. However, demonstrated that first-trimester loss occurred in 25% to 40% of
authors of a review of 13 women treated during pregnancy with patients with a live birth rate of 50% to 70%. Late pregnancy loss
ATRA administration for acute promyelocytic anemia found no occurred in 10% of cases.160 Postpartum thrombotic complications
evidence that the agent led to fetal malformation when used in the occurred in 5.2% of patients. In a recent analysis of all publications
treatment of pregnant women.155 of pregnant patients with ET that had more than 30 patients per
Similar concerns regarding toxicity of therapy arise in managing study, a mean rate of live birth obtained from the literature was
pregnancies conceived before and during treatment of chronic 60.6% (range, 50%–75.4%).161
myeloid leukemia (CML). Imatinib, a small-molecule inhibitor Studies of pregnancy in the setting of polycythemia vera (PV) are
against the BCR-ABL tyrosine kinase, is the standard of care much fewer and consist mainly of case reports. One of the largest
for treatment of CML. In animal studies, imatinib exhibited studies to date consisted of 18 pregnancies. There were 11 live births

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2210 Part XIII  Consultative Hematology

and 7 miscarriages.162 First trimester loss is the most frequent com- concentrates (Humate-P, Alphanate). Cryoprecipitate can be used on
plication in patients with PV.161 Information regarding pregnancy in an emergent basis if vWF-FVIII concentrates are unavailable, but it
primary myelofibrosis is even sparser, with overall fewer than 20 cases is avoided if possible during pregnancy because it poses a small risk
reported in the literature. However, on the basis of these, fetal loss is of bloodborne infection.172 Although antifibrinolytic therapy plays a
common.163 In women of childbearing age with an MPN, a discus- role in the management of individuals with vWD, it is also generally
sion when the patient is not pregnant should occur, outlining preg- avoided during pregnancy and lactation because of its potential tera-
nancy management and risks. Women should be informed if they are togenicity and effects on newborns. Data concerning the toxicity of
taking a drug with teratogenic potential, and the risk of unplanned antifibrinolytic therapy in pregnancy are limited.
pregnancy should be recognized. Exerting its effect through the type 2 vasopressin receptors,
Continuing aspirin is considered standard if there is no clear DDAVP rapidly and transiently increases levels of FVIII and vWF.173
contraindication, extrapolating from the results of the European It is administered by continuous intravenous infusion over 30 minutes
Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) in the setting of an acute bleeding event. On a prophylactic basis, it
study, which confirmed the importance of aspirin in the management can be given subcutaneously or inhaled nasally.174 Although highly
of MPNs.164 Certain features may confer a patient at more risk of effective when used in an appropriate clinical context, DDAVP does
maternal or fetal complications during pregnancy. These include have limitations. Patients who have never received DDAVP therapy
cardiovascular risk factors, prior thrombosis, and prior pregnancy- should be tested for responsiveness to the agent during the second
related complications that may have been caused by MPN or for trimester. Because of its potential oxytocic effect, DDAVP is preg-
which no other cause can be identified. In these settings, cytoreduc- nancy risk category B.175 Owing to its antidiuretic effect, DDAVP
tive therapy or LMWH can be considered. There are no clear can cause fluid retention and hyponatremia. Finally, DDAVP has
evidence-based management guidelines in these settings, but local uncertain utility in the management of women with type 2 and type
practice is to use LMWH. Six weeks of postpartum LMWH should 3 vWD because of an underlying genetic defect in these individuals.
be considered in the postpartum setting if there is no contraindica- VWF-FVIII concentrate is indicated for these patients.
tion. It is clear that management of these patients requires close Multidisciplinary care by an experienced obstetrician and hema-
collaboration with a hematologist and high-risk obstetrician. 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-
BLEEDING DISORDERS quences of the disease in pregnant and postpartum mothers. FVIIIc
and vWF:RCo levels, partial thromboplastin time (PTT), type and
von Willebrand Disease crossmatch, and a complete blood count are obtained at the time of
hospital admission. Women with vWD should be monitored for
Affecting approximately 1% of the population, von Willebrand bleeding at the time of delivery, with blood cell products and DDAVP
disease (vWD) is the most common inherited disorder of coagulation available for use as needed. vWF:RCo and FVIIIc levels of 50 IU/dL
(see Chapter 139). By mediating platelet adhesion and functioning generally serve as a target at parturition and in the postpartum period;
as a carrier for circulating factor VIII (FVIII), vWF plays a vital role expert opinion suggests that women with levels below this should
in hemostasis. According to the most widely used classification by receive replacement products.175
Sadler,165 there are three types of vWD: type 1 (partial deficiency of In the management of pregnant women with vWD, the provision
vWF); type 3 (severe deficiency of vWF); and type 2, which includes of regional anesthesia during delivery is an important topic. Some
four subtypes that involve qualitative defects in vWF. FVIIIc, vWF anesthesiologists use epidural anesthesia in patients with mild disease
antigen (vWF:Ag), and the ristocetin cofactor activity (vWF:Rco) are with or without the use of DDAVP.176,177 For patients with moderate
important components of the laboratory diagnosis. vWD does not to severe disease, an alternative form of analgesia may be considered.
impair fertility or increase the likelihood of miscarriage.166 Thus the If epidural analgesia is used in a patient with moderate to severe
management of pregnancy in patients with the condition is an disease, prophylactic factor replacement therapy is indicated. The
important feature of the overall care for these individuals. epidural catheter should be removed soon after delivery because
For pregnant women with vWD, bleeding at parturition and in falling factor levels in the postpartum period increase the bleeding
the postpartum period is of primary concern. Related concerns risk.173
include the administration of anesthesia, perineal hematoma, episi- The route of delivery is also an important matter in patients with
otomy blood loss and healing, and bleeding at surgical sites. Approxi- vWD. To minimize the risk of neonatal hemorrhage, some obstetri-
mately 75% of women with moderate to severe vWD experience cians recommend cesarean delivery for patients with type 2, type 3,
significant peripartum bleeding.167 Overall there is a 20% risk of and clinically moderate type 1 disease. However, neonatal bleeding
postpartum hemorrhage in women with vWD. In a normal preg- occurs in the setting of cesarean delivery as well, and delivery methods
nancy, FVIIIc and vWF levels increase, beginning in the second tri- have not been rigorously compared.167,176
mester.168 They peak as the pregnancy nears term. Among many Prenatal testing is a challenge in women with vWD. The specific
pregnant women with vWD, particularly those with type 1 disease, mutations involved in the pathogenesis of type 1 and type 3 vWD
a similar increase in FVIII and vWF levels is observed. FVIIIc levels are not known. Multiple mutations are involved in the pathogenesis
in pregnant women with vWD peak at 29 to 32 weeks of gestation, of type 2 vWD. Fetal blood vWF levels can be obtained if necessary,
but vWF:Ag levels peak at approximately 35 weeks of gestation.169 but inherent risks are associated with the procedure.178 Expectant
The risk of peripartum bleeding is related to the level of these mothers should be informed of these risks in making decisions about
factors.170 In most instances, vWF:Ag, FVIIIc, and vWF:RCo levels prenatal genetic testing.
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 HEMOPHILIAS
remain low throughout pregnancy. Patients without a documented
bleeding disorder who have bleeding complications during pregnancy The hemophilias (A and B) are X-linked recessive diseases character-
should be evaluated for vWD because many with the disorder have ized by hemarthrosis and subcutaneous and intramuscular bleeding
a mild clinical course and remain undiagnosed for a long period.171 (see Chapter 136).179 Hemophilia A results from deficient production
As a general rule, therapy can be rendered either in the setting of FVIII, and hemophilia B from deficient production of FIX. As
of a spontaneous bleeding event or in a prophylactic context for X-linked disorders, hemophilia A and B occur most often in men,
the high-risk individual. Mainstays of therapy for pregnant women but they can occur in women under several circumstances, including
with vWD include DDAVP (1-deamino-8-D-arginine-vasopressin; X-chromosome inactivation (lyonization), X hemizygosity, and
desmopressin), a synthetic analogue of vasopressin, and vWF-FVIII double heterozygosity as can occur in the female offspring of an

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Chapter 151  Hematologic Changes in Pregnancy 2211

affected father and carrier mother.179 In the United States, women supine position. This phenomenon likely explains the increased risk
account for 1.7% of patients with hemophilia A and 3.2% of patients of left leg thrombosis among pregnant women.191 Furthermore,
with hemophilia B.180 Fifty percent of male offspring from a female whereas the concentration of coagulation factors changes during
carrier inherit the disorder, whereas 100% of male offspring from an pregnancy, the concentration of vWF, fibrinogen, and prothrombin,
affected mother inherit the disease. Female carriers in both disorders along with factors V, VII, VIII, IX, X, and XII increase, and the
can be detected through laboratory screening and pedigree analysis.181 concentration of factor XI and protein S decrease (Table 151.2).192–194
Women with hemophilia and pregnant women with an affected fetus Finally, fibrinolytic activity decreases during pregnancy as the levels
must be monitored closely during pregnancy for bleeding events that of plasminogen activator inhibitors 1 and 2 increase.195 Other factors,
compromise the well-being of either the mother or the fetus. Fetal including high body mass index, smoking, immobilization, and age
umbilical blood sampling can be used to check FVIII and FIX levels. older than 35 years, should also be considered when assessing the
Chorionic villus sampling may also be used.182 thrombotic risk of a pregnant woman (see box on Bleeding Associated
At parturition, women with hemophilia A whose FVIIIc level lies With Factor XI Deficiency).
below 50% of the normal range should receive purified FVIII. Levels Because of the prothrombotic physiology associated with preg-
should be greater than 80% for surgery and maintained at 30% to nancy, a clinician’s concern for VTE in a pregnant woman should
40% for 3 to 4 days postoperatively. Rarely, thrombosis can occur in prompt immediate evaluation. To assess for lower extremity throm-
the aftermath of FVIII replacement therapy.183 Among neonates with bosis, venous compression ultrasonography remains the initial test of
hemophilia, 6% to 10% have hemorrhagic complications in the choice. Ultrasonography poses no threat to the fetus and can detect
perinatal period, including intracranial hemorrhage. Vacuum extrac- thrombosis of the proximal common femoral and popliteal veins with
tors, forceps delivery, and scalp electrodes should be avoided. To date, a sensitivity of 95% and specificity of 96%. Despite the efficacy of
no studies have rigorously compared the outcomes of vaginal and ultrasonography, limitations to its use do exist. The test is less effec-
cesarean delivery in this patient population. Neonatal blood should tive for the diagnosis of calf vein thrombosis, with a sensitivity and
be assayed for FVIIIc levels and PTT immediately after birth. Neo- specificity in the 60% to 70% range.196 For this reason, a woman
nates with low FVIIIc levels may require serial cranial ultrasounds to with suspected lower extremity deep venous thrombosis should
rule out bleeding.184 undergo serial ultrasonography if the initial evaluation is nondiag-
Hemophilia B is treated in a similar fashion. However, it should nostic.197 Similarly, thrombus in the common iliac vein can evade
be noted that cryoprecipitate contains low levels of FIX and should diagnosis by venous compression ultrasonography.
not be used as replacement therapy in the management of this condi- In such cases, other modalities, such as contrast venography and
tion. Purified FIX is the agent of choice for patients with hemophilia magnetic resonance venography, can be considered. Although con-
B. Meanwhile, individuals with other clotting factor deficiencies trast venography exposes the fetus to radiation and should thus be
should receive FFP or specific clotting factor products to maintain used with caution during pregnancy, its use may be warranted when
factor levels at greater than 25%.185 One exception to this pertains to clinical suspicion for an underlying thrombotic event is high.196
the management of patients with FXIII deficiency; the occurrence of Serum D-dimer tests are often used in conjunction with imaging
spontaneous recurrent abortions and uterine bleeding in these indi- studies to assess for thrombosis in nonpregnant patients. The sensitiv-
viduals necessitates regular infusions of FFP or FXIII concentrate to ity of D-dimer tests for the presence of thrombus ranges from 85%
maintain pregnancy.186

Hemostatic Changes in Pregnancy
Factor XIII ↑/↓
VTE disease is a leading cause of maternal morbidity and mortality.186
Protein C, antithrombin =
The risk of VTE increases two- to fourfold during pregnancy and the
early postpartum period.187 In women who have had a previous VTE Protein S ↓
event, pregnancy appears to increase the risk of a recurrent thrombo- Factor XI ↓/=
embolic event.188 Various factors account for the prothrombotic state Factors V, VII, VIII, IX, X, XII ↑
associated with pregnancy. Increased estrogen levels early in pregnancy
increase venous distention and contribute to venous stasis.189 Increased von Willebrand factor, fibrinogen ↑
plasma volume and compression of the inferior vena cava by the Tissue plasminogen activator ↓
gravid uterus contribute to venous stasis as well.190 In addition, Prothrombin, D-dimer ↑
studies have demonstrated decreased blood flow velocity in pregnant
women, particularly in the left leg when pregnant women lie in a

Bleeding Associated With Factor XI Deficiency

Prolonged PPT Postpartum
A 25-year-old woman is referred for prolonged partial thromboplastin
A 22-year-old woman presents to the emergency department (ED) 4 time (PTT) discovered during pregnancy. Evaluation reveals severe
days postpartum. Her delivery was uncomplicated, and her hemoglobin factor XI deficiency. She has no history of easy bruising or bleeding.
at delivery was 9.9 g/dL with a partial thromboplastin time (PTT) 37 She is at 30 weeks of gestation and is presenting for evaluation before
seconds. She returns to the ED 4 days later with complaints of weak- delivery.
ness and vaginal bleeding and is found to have a large hematoma at Bleeding associated with factor XI deficiency can be quite variable,
the episiotomy site. It is surgically drained but immediately recurs, ranging from no bleeding symptoms to bleeding associated with trauma
and persistent bleeding is noted. Her hemoglobin decreases to 5.9 g/ or surgery. For a patient without a history of bleeding, prophylaxis is
dL. Repeat laboratory evaluation reveals her PTT to be 66 seconds. not necessary but fresh frozen plasma (FFP) should be available if
Acquired hemophilia should be considered in the postpartum patient needed. Epidural is usually contraindicated in patients with severe
with bleeding and prolonged PTT. It is an uncommon disorder, thought factor XI deficiency, and women should be advised to speak with the
to be immune mediated, with development of autoantibodies against treating anesthesiologist before delivery in order to plan alternative
factor VIII. Treatment must be targeted at inhibitor eradicator and strategies. If consideration for regional block anesthesia is made, it
control of bleeding. For acute bleeding, activated prothrombin complex is usually administered with FFP prior and with documentation of
concentrates or recombinant FVIIa should be used. normalization of the PTT.
Franchini, M. (2006), Am J Hematol, 81:768–773. In patients with a bleeding history, FFP should be administered
CMAJ August 14, 2007 vol. 177(4): 339–340. before delivery, as well as 2 to 3 days later to reduce the risk of delayed
Santoro RC, et al. Blood Coagul Fibrinolysis, 20:461, 2009. hemorrhage.

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2212 Part XIII  Consultative Hematology

to 95%.198 However, several pregnancy-associated conditions elevate be initiated. The newer target specific oral anticoagulant should not
D-dimer levels, including preterm labor, placental abruption, and be used during pregnancy until safety data in this population have
hypertension of pregnancy, thus undermining the utility of the test been established.
somewhat in pregnant women by decreasing its specificity.195 None-
theless, when normal, the D-dimer assay provides the clinician with
When lower extremity imaging reveals no evidence of thrombus DURING PREGNANCY
in a pregnant woman with suspected pulmonary embolism (PE), the
clinician has several options. Helical CT has become the standard Given the prothrombotic state associated with pregnancy itself, pro-
modality for the diagnosis of PE in nonpregnant individuals at many phylactic anticoagulation should be considered in pregnant women
centers. However, even with abdominal shielding, the procedure with a history of VTE. Recurrence rates for VTE during pregnancy
results in fetal radiation exposure (approximately 16 mrad) because may be as high as 12% based on the results of retrospective studies.207
of internal scatter.199 Although this low level of radiation exposure Conversely, Brill-Edwards and colleagues208 prospectively studied
probably does not cause harm to the fetus, repeated imaging during 125 pregnant women with prior VTE in a study that excluded
the course of pregnancy is to be avoided.197 Ventilation/perfusion women with known thrombophilia. Study subjects did not receive
(V/Q) scanning is frequently used in the evaluation of pregnant prophylactic anticoagulation during the antenatal period, but they
women with suspected PE but has limitations as well. Results of a did receive anticoagulation therapy for 4 to 6 weeks postpartum. The
prospective study indicate that when used in this patient population, authors documented a VTE recurrence rate of 2.4%. Women who
V/Q scanning infrequently yields a conclusively positive result (1.8% had a temporary risk factor at the time of their initial VTE event
of cases) and is often nondiagnostic (24.8% of cases).200 Finally, and lacked laboratory evidence of an underlying hypercoagulable
pulmonary angiography can be used in the evaluation of PE in rare disorder at the time of study enrollment experienced no recurrences
instances when the previously described diagnostic tests yield nondi- during pregnancy. On the basis of the results of this study, routine
agnostic results in the face of a high clinical suspicion. prophylactic anticoagulation for women with a single previous
VTE in pregnancy is treated with heparin. Until LMWH was VTE event is not recommended. However, patients with a known
introduced in the late 1980s, UFH was the anticoagulant of choice hypercoagulable state, those with multiple previous VTE events,
for treatment of pregnant women with VTE. Because it does not cross and those considered high risk for recurrent VTE should receive
the placenta, UFH is nonteratogenic. However, drawbacks to UFH prophylactic anticoagulation during pregnancy and for 4 to 6 weeks
therapy, including heparin-associated osteoporosis, HIT, and the postpartum. As previously discussed, prophylactic anticoagulation
drug’s unpredictable pharmacokinetics, are well documented.186 can be discontinued at parturition and reinitiated 6 to 12 hours
Heparin-associated osteoporosis can develop in women who receive postpartum.
at least 1 month of therapy; it is likely related to a toxic effect of The management of pregnant women with prosthetic heart valves
heparin on osteoblasts.201 Because of its more favorable side effect is controversial and deserves special attention, although a full review
profile, reliable pharmacokinetics, and equal efficacy in treating VTE, of the topic is beyond the scope of this review. Coupled with the
LMWH now represents the most commonly used anticoagulant for prothrombotic physiology of pregnancy, the presence of a prosthetic
treatment of VTE in pregnancy.202 The risk of osteoporosis and HIT valve places such women in an ultra-high-risk category. Before the
appears to be less with LMWH-based anticoagulation than with introduction of LMWH, options for anticoagulation in this patient
UFH-based anticoagulation.203,204 Although practice patterns vary, it population included (1) warfarin throughout pregnancy; (2) warfarin
is reasonable to base the initial dose of LMWH on early pregnancy with UFH during weeks 6 to 12, the period of major organogenesis;
(rather than current) weight.204 Because clearance of LMWH increases and (3) UFH throughout pregnancy.186 More recently, LMWH has
during pregnancy, twice-daily dosing regimens are preferred to once- been used in this setting, although its safety and efficacy have been
daily regimens.205 In terms of duration of therapeutic anticoagulation, questioned on the basis of several studies. Overall, a lack of rigorous,
many clinicians continue therapy at full dose through the entire comparative studies hinders evidence-based management of women
pregnancy and puerperium based on the rationale that pregnancy with prosthetic heart valves. Current recommendations allow for one
itself represents a risk factor for recurrent VTE.202 In contrast, other of three therapeutic strategies, initiated after a thorough discussion
clinicians advocate initial anticoagulation with full-dose LMWH for of risks and benefits with the patient: (1) warfarin, with LMWH or
a designated period followed by conversion to an intermediate dose. UFH substituted during weeks 6 to 12; (2) dose-adjusted UFH
This approach may be beneficial for individuals susceptible to side throughout pregnancy; or (3) dose-adjusted LMWH throughout
effects of anticoagulation such as bleeding or osteoporosis.186 The risk pregnancy.186
of significant bleeding with LMWH during pregnancy is estimated
to be around 2%.
Warfarin is contraindicated in pregnant women. It crosses the THROMBOPHILIA AND PREGNANCY
placenta and can cause both fetal hemorrhage and nervous system
abnormalities and other teratogenic effects.206 Warfarin can be used Thrombophilias, inherited and acquired, increase the risk of VTE in
in the postpartum period after initiating therapy with concurrent pregnant women and adversely affect pregnancy outcomes. Included
heparin and in this setting does not appear to increase the risk of within this category of diseases are factor V Leiden, prothrombin
bleeding in children of lactating mothers.196 gene polymorphisms, antiphospholipid antibody syndrome, anti-
Anticoagulation should be discontinued at the time of parturition. thrombin deficiency, and protein S and C deficiency. In addition,
UFH and LMWH should, in most circumstances, be stopped 12 to hyperhomocysteinemia and methylenetetrahydrofolate reductase
24 hours before delivery. If the risk of recurrent VTE is particularly C677T mutation have been studied. There are varied results when
high in a woman receiving LMWH, the clinician can convert to assessing the literature in regard to the risk of pregnancy-associated
intravenous UFH and treat until 4 to 6 hours before delivery, mini- VTE in the setting of an inherited thrombophilia. Authors of a 2005
mizing the time off anticoagulation. meta-analysis reviewed the risk of VTE during pregnancy by the
The risks of regional anesthesia must be weighed carefully in specific thrombophilia present. The inherited thrombophilias (with
women receiving anticoagulation because therapy increases the likeli- the exception of MTHFR mutation) were associated with a statisti-
hood of bleeding, hematoma formation, and potential neurologic cally significant increase in the risk of VTE during pregnancy.209
compromise. In a woman undergoing elective delivery with discon- Because the overall incidence of VTE in pregnancy is low, however,
tinuation of anticoagulation 12 to 24 hours prior, epidural anesthesia in women without a history of thrombosis, the absolute risk conferred
may be used. UFH or LMWH may be reinitiated 6 to 12 hours after by thrombophilias is generally low. The positive predictive value of
delivery or after removal of the epidural catheter. Then, after thera- factor V Leiden heterozygosity was 1 in 500. Prothrombin heterozy-
peutic levels of UFH or LMWH have been achieved, warfarin may gosity was 1 in 200. Women with homozygosity for these mutations,

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Chapter 151  Hematologic Changes in Pregnancy 2213

double heterozygosity, and antithrombin III deficiency were at recurrent miscarriage, anticoagulation has been used in efforts to
highest risk. Given the increased risk of VTE, prophylactic anticoagu- improve rates of live birth. There have been varied results in clinical
lation is warranted. trials using anticoagulation in the setting of recurrent miscarriage.
Screening for inherited thrombophilia in patients with recurrent However, in the large, multicenter, randomized, placebo-controlled
miscarriage or pregnancy complications such as preeclampsia or study examining the use of aspirin or aspirin plus heparin in women
placental abruption is not indicated. Thrombophilia screening is with unexplained miscarriage, there was no improvement in the live
indicated only in patients with a prior thromboembolic event or a birth rate compared with placebo.210
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 Antiphospholipid Antibody Syndrome
Thrombophilia During Pregnancy).
Prophylactic treatment of carriers of low-risk mutations with any The antiphospholipid antibody syndrome (Table 151.3) is the most
personal or family history of VTE is not indicated. In patients with common form of acquired thrombophilia.211 Antiphospholipid
antibodies include lupus anticoagulant antibodies and anticar-
diolipin antibodies. They can occur as a manifestation of various
The TIPPS (Thrombophilia in Pregnancy Prophylaxis Study) Trial conditions, such as systemic lupus erythematosus (SLE) and other
rheumatic diseases, infection, and drug reactions. Antiphospho-
The TIPPS trial was the first large randomized controlled trial in which lipid antibodies exert their prothrombotic effect through several
researchers examined the effect of low-molecular-weight heparin mechanisms. For example, they inhibit the activity of anticoagulants
(LMWH) in pregnant patients with thrombophilia and a history of on thrombomodulin, protein S, protein C, β2-glycoprotein I, and
adverse pregnant outcomes or venous thromboembolism (VTE). The prostacyclin.212–214 They interact with phospholipids on the surface
TIPPS investigators studied 292 pregnant women who were randomly of platelets, increasing platelet adhesiveness and production of von
assigned to dalteparin or no dalteparin. The primary objective of the Willebrand mulitmers.215,216 In pregnant patients, antiphospholipid
study was to identify if LMWH prophylaxis in thrombophilic pregnant
women results in a greater than 33% relative risk reduction in the
antibodies decrease levels of annexin V, a potent vascular endothelial
composite outcome measure of severe or early-onset preeclampsia, anticoagulant produced by placental trophoblasts.217 Nonpregnant
small-for-gestational-age infants (<10th percentile), pregnancy loss, or individuals with antiphospholipid antibody syndrome can develop
VTE. Dalteparin did not reduce the incidence of the primary composite arterial and venous thromboses. In pregnant women, antiphos-
outcome in both intention-to-treat analysis (dalteparin, 25 [17.1%] of pholipid antibody syndrome can manifest as thrombotic events,
146; 95% confidence interval [CI], 11.4%–24.2%; vs. no dalteparin, spontaneous abortion, preeclampsia, and HELLP syndrome, as well
27 [18.9%] of 143; 95% CI, 12.8%–26.3%; risk difference, –1.8%; as IUGR.218–221
95% CI, −10.6% to 7.1%) and on-treatment analysis (dalteparin 28 Antiphospholipid antibodies can be detected in 5% of healthy
[19.6%] of 143 vs. no dalteparin 24 [17.0%] of 141; risk difference, pregnant women and 37% of pregnant women with SLE.222
+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)
Thrombotic events occur in approximately 5% of pregnant women
than in the no-dalteparin group (13 [9.2%] of 141; risk difference, with antiphospholipid antibodies.221 All pregnant women with SLE
10.4%; 95% CI, 2.3–18.4; p = .01). should undergo testing for antiphospholipid antibodies. Women who
The conclusion from the study was that prophylactic dalteparin did sustain recurrent spontaneous abortions or a thromboembolic event
not reduce the occurrence of venous thromboembolism, pregnancy during pregnancy should also undergo evaluation for the disorder. A
loss, or placenta-mediated pregnancy complications in pregnant history of either vascular thrombosis or fetal loss coupled with the
women with thrombophilia. presence of either lupus anticoagulant antibodies or anticardiolipin
Some debate and controversy exist regarding the trial and its antibodies establishes the diagnosis of antiphospholipid antibody
conclusions. syndrome.223
Cons: It took 12 years to randomize 292 women from 21 referral
centers. Some physicians raised concern over the amount of time
False-negative laboratory results do occur and do so more fre-
it took to accrue the number of patients and the accuracy of the quently in pregnant than in nonpregnant women. This may be
patient base it represents. Others argued that eligibility criteria because of the increased concentration of clotting factors observed in
were based on a rationale that had already changed by the time pregnancy.224 Women with antiphospholipid antibody syndrome who
the study was concluded. have sustained prior thrombotic events receive therapeutic anticoagu-
Pros: The article confirms that women who are at low risk of lation during pregnancy. Those with antiphospholipid antibodies but
thrombosis should not be treated with low-molecular-weight no manifestations of the clinical syndrome should receive prophylac-
heparin and that this widespread practice should be stopped. tic anticoagulation.
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.
Antiphospholipid Antibody Syndrome
Vascular Thrombosis
Thrombophilia During Pregnancy One or more episodes of arterial or venous thrombosis confirmed by
A 25-year-old woman wishes to become pregnant. Her mother expe- Pregnancy morbidity
rienced a deep vein thrombosis at the age of 70 years, underwent Death of a fetus beyond 10 weeks of gestation with normal fetal
thrombophilia evaluation, and was found to be heterozygous for the morphology
factor V Leiden mutation. She herself has never had a thrombotic Premature birth before 34 weeks of gestation
episode, just recently discontinued her birth control, and was told to Three or more consecutive spontaneous abortions before 10 weeks of
see a hematologist before she became pregnant. Her primary care gestation
physician tested her for factor V Leiden, and she was found to be
Laboratory criteria (all measured on two or more occasions at least
heterozygous for the mutation. She is asking if she should be on
anticoagulation during her pregnancy. 12 weeks apart)
Every case of thrombophilia during pregnancy needs to be assessed Lupus anticoagulant on two or more occasions at least 12 weeks apart
on a case-by-case basis. Asymptomatic women who harbor thrombo- Anticardiolipin antibody
philic conditions but have never manifested clinical manifestations do Anti-B2 glycoprotein IgM or IgG
not require anticoagulation. Ig, Immunoglobulin.

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2214 Part XIII  Consultative Hematology

FUTURE DIRECTIONS Hiss RG: Evaluation of the anemic patient. In Laros RK, editor: Blood
disorders in pregnancy, Philadelphia, 1986, Lea & Febiger, p 1.
Management of the hematologic complications of pregnancy contin- Hytten F: Blood volume changes in normal pregnancy. Clin Haematol
ues to be a challenge. The physicians and patient involved all benefit 14:601, 1985.
from a multidisciplinary approach. In certain disorders, the manage- Institute of Medicine: Nutrition services in perinatal care, Washington, DC,
ment is clear and will likely remain unchanged in the future. In other 1992, National Academy Press.
disorders, treatment paradigms may shift as new treatments are dis- Klebanoff MA, Shiono PH, Selby JV, et al: Anemia and spontaneous preterm
covered for the nonpregnant patient. In all instances, further well- birth. Am J Obstet Gynecol 164:59, 1991.
designed studies will continue to advance evidence-based management Lieberman E, Ryan KJ, Monson RR, et al: Association of maternal hematocrit
of the pregnant patient. 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.
SUGGESTED READINGS Milman N: Iron and pregnancy—a delicate balance. Ann Hematol 85:559,
Al RA, Unlubilgin E, Kandamir O, et al: Intravenous verses oral iron for Milman N, Agger AI, Nielson OJ: Iron status markers and serum erythropoi-
treatment of anemia in pregnancy: a randomized trial. Obstet Gynecol etin in 120 mothers and newborn infants: effect of iron supplementation
106:1335, 2005. and normal pregnancy. Acta Obstet Gynecol Scand 73:200, 1994.
Allen LH: Nutritional supplementation for the pregnant woman. Clin Obstet Murphy JF, O’Riordan J, Newcombe RG, et al: Relation of haemoglobin
Gynecol 37:587, 1994. levels in first and second trimesters to outcome of pregnancy. Lancet
Bothwell TH: Overview and mechanisms of iron regulation. Nutr Rev 1:992, 1986.
53:237, 1995. Perry GS, Yip R, Zyrkowski C: Nutritional risk factors among low-income
Casanueva E, Viteri FE, Mares-Galindo M, et al: Weekly iron as a safe pregnant US women: the Centers for Disease Control and Prevention
alternative to daily supplementation for nonanemic pregnant women. (CDC) Pregnancy Nutrition Surveillance System, 1979 through 1993.
Arch Med Res 12:674, 2006. Semin Perinatol 19:211, 1995.
Centers for Disease Control and Prevention (CDC): CDC criteria for anemia Romslo I, Haram K, Sagen N, et al: Iron requirement in normal pregnancy
in children and childbearing-aged women. MMWR Morb Mortal Wkly as assessed by serum ferritin, serum transferring saturation, and eryth-
Rep 38:400, 1989. rocyte protoporphyrin determinations. Br J Obstet Gynaecol 90:101,
Centers for Disease Control and Prevention (CDC): Recommendations to 1983.
prevent and control iron deficiency in the United States. MMWR Recomm Rothman D: Folic acid in pregnancy. Am J Obstet Gynecol 108:149, 1970.
Rep 47(RR-3):1, 1998. Scholl TO, Hediger ML: Anemia and iron-deficiency anemia: compilation
Chanarin I: Folate and cobalamin. Clin Haematol 14:729, 1985. of data on pregnancy outcome. Am J Clin Nutr 59(2 Suppl):492S, 1994.
Chanarin I, MacGibbon BM, O’Sullivan WJ, et al: Folic acid deficiency Scholl TO, Hediger ML, Fischer RL, et al: Anemia vs iron deficiency:
in pregnancy—the pathogenesis of megaloblastic anemia of pregnancy. increased risk of preterm delivery in a prospective study. Am J Clin Nutr
Lancet 2:634, 1959. 55:985, 1992.
Chanarin I, Rothman D: Further observations on the relation between iron Singh K, Fong YF, Arulkumaran S: Anaemia in pregnancy—a cross-sectional
and folate status in pregnancy. Br Med J 2:81, 1971. study in Singapore. Eur J Clin Nutr 52:65, 1998.
Cogswell ME, Parvanta I, Ickes L, et al: Iron supplementation during World Health Organization: The prevalence of anaemia in women: a tabulation
pregnancy, anemia, and birth rate: a randomized trial. Am J Clin Nutr of available information, ed 2, Geneva, 1992, World Health Organization.
78:773, 2003. Zhou LM, Yang WW, Hua JZ, et al: Relation of hemoglobin measured at
Council on Foods and Nutrition Committee on Iron Deficiency: Iron different times in pregnancy to preterm birth and low birth weight in
deficiency in the United States. JAMA 203:119, 1968. Shanghai, China. Am J Epidemiol 148:998, 1998.
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. REFERENCES
Galloway R, McGuire J: Determinants of compliance with iron supplementa-
tion: supplies, side effects, or psychology? Soc Sci Med 39:381, 1994. For the complete list of references, log on to www.expertconsult.com.
Garn SM, Ridella SA, Petzold AS, et al: Maternal hematologic levels and
pregnancy outcomes. Semin Perinatol 5:155, 1981.

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Chapter 151  Hematologic Changes in Pregnancy 2214.e1

and erythrocyte protoporphyrin determinations. Br J Obstet Gynaecol

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2214.e2 Part XII  Hemostasis and Thrombosis

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