Anemias in Pregnancy

Ramus RM1, Rigby FB2

American College of Obstetricians and Gynecologists, Society for Maternal-Fetal
Medicine

Abstract
With normal pregnancy, blood volume increases, which results in a concomitant
hemodilution. Although red blood cell (RBC) mass increases during pregnancy, plasma
volume increases more, resulting in a relative anemia. This results in a physiologically
lowered hemoglobin (Hb) level, hematocrit (Hct) value, and RBC count, but it has no effect
on the mean corpuscular volume (MCV). In an iron-replete population, anemia defined as
a value less than the fifth percentile is a hemoglobin level of 11 g/dL or less in the first
trimester, 10.5 g/dL or less in the second trimester, and 11 g/dL or less in the third
trimester.
Many centers define anemia in a patient who is pregnant as an Hb value lower
than 10.5 g/dL, as opposed to the reference range of 14 g/dL in a patient who is not
pregnant. Treatment with 1 mg folic acid and daily iron is helpful when deficiencies are
noted. [1]
The simplest approach to the differential diagnoses of anemia is to differentiate
anemias by the mean corpuscular volume (MCV), measured in fL.
MCV less than 80 fL or microcytic anemia etiologies are as follows:
Iron deficiency
Thalassemia
Anemia of chronic disease
Sideroblastic anemia
Anemia associated with copper deficiency
Anemia associated with lead poisoning
MCV 80-100 fL or normocytic anemia etiologies are as follows:
Hemorrhagic anemia
Early iron deficiency anemia
Anemia of chronic disease
Anemia associated with bone marrow suppression
Anemia associated with chronic renal insufficiency
Anemia associated with endocrine dysfunction
Autoimmune hemolytic anemia
Anemia associated with hypothyroidism or hypopituitarism
Hereditary spherocytosis
Hemolytic anemia associated with paroxysmal nocturnal hemoglobinuria
MCV greater than 100 fL or macrocytic anemia etiologies are as follows:
Folic acid deficiency anemia
Vitamin B-12deficiency anemia
Drug-induced hemolytic anemia (eg, zidovudine)
Anemia associated with reticulocytosis
Anemia associated with liver disease
Anemia associated with ethanol abuse
Anemia associated with acute myelodysplastic syndrome
Iron deficiency anemia
Iron deficiency anemia accounts for 75-95% of the cases of anemia in pregnant
women. A woman who is pregnant often has insufficient iron stores to meet the demands
of pregnancy. Pregnant women are encouraged to supplement their diet with 60 mg of
elemental iron daily. An MCV less than 80 mg/dL and hypochromia of the RBCs should
prompt further studies, including total iron-binding capacity, ferritin levels, and Hb
electrophoresis if iron deficiency is excluded.
Clinical symptoms of iron deficiency anemia include fatigue, headache, restless
legs syndrome, and pica (in extreme situations). Treatment consists of additional
supplementation with oral iron sulfate (320 mg, 1-3 times daily). Once-daily
administration is preferable because more frequent iron supplementation can cause
constipation.
The clinical consequences of iron deficiency anemia include preterm delivery, perinatal
mortality, and postpartum depression. Fetal and neonatal consequences include low birth
weight and poor mental and psychomotor performance. [2]

Folate and vitamin B-12 deficiency anemia

Folate deficiency is much less common than iron deficiency; however, taking 0.4
mg/d to reduce the risk of neural tube defects is recommended to all women
contemplating pregnancy. Patients with a history of a prior fetus with a neural tube defect
should take 4 mg/d. An increased MCV (typically >100 fL) can be suggestive of folate
and/or B-12 vitamin deficiency; in this case, determine serum levels of vitamin B-12 and
folate. If the levels are low, the patient may require oral folate at a dose of 1 mg 3 times
daily.
Patients with vitamin B-12 deficiency need further workup to determine the level of
intrinsic factor to exclude pernicious anemia. The Schilling test is not recommended
during pregnancy, because of the radionuclide used in testing. Treatment of vitamin B-12
deficiency includes 0.1 mg/d for 1 week, followed by 6 weeks of continued therapy to
reach a total administration of 2 mg.
Infectious causes of anemia
Infectious cause of anemia are more common in nonindustrialized
countries. [3]Anemia can be caused by infections such as parvovirus B-19,
cytomegalovirus (CMV), HIV, hepatitis viruses, Epstein-Barr virus (EBV), malaria,
babesiosis, bartonellosis, hookworm infestation, and Clostridium toxin. If the patients
history suggests exposure to any of these infectious agents, appropriate laboratory
studies should be performed.
Diamond-Blackfan anemia
Diamond-Blackfan anemia is a rare (7 per 1 million) autosomal dominant disorder
of pure red cell aplasia necessitating life-long transfusion. Women who are contemplating
or who are pregnant require the consultation and care of a hematologist in conjunction
with a maternal-fetal medicine specialist. Concerns during pregnancy include maintaining
adequate hemoglobin while decreasing the risk of fetal exposure to the iron chelating
agent (deferoxamine) used during transfusions. [2]
Sickle Cell Hemoglobinopathies in Pregnancy
Sickle cell hemoglobinopathies include those abnormalities resulting from an
alteration in the structure, function, or production of hemoglobin (Hb). Hemoglobin S
(HbS) results from substitution of thymine for adenine in the beta-globin gene, which leads
to the substitution of the neutral amino acid valine for the negatively charged glutamic
acid at the sixth position from the N terminus in the beta chain. Hemoglobin C (HbC)
results from substitution of lysine for glutamic acid.
HbAS is also known as sickle cell trait and occurs in 1 in 12 African Americans.
HbS is also found in other populations, such as Greeks, Italians (particularly Sicilians),
Turks, Arabs, Southern Iranians, and Asian Indians.
Major sickle disorders with severe clinical symptoms include sickle cell
anemia (HbSS), sickle cell hemoglobin C (HbSC) disease, and sickle cell beta-
thalassemia (HbS beta-Thal). HbSS is the most common of these, occurring in 1 in 625
African Americans. Minor disorders include hemoglobin C disease (HbAC), hemoglobin
SE (HbSE), hemoglobin SD (HbSD), and hemoglobin S-Memphis (HbS-Memphis).
Heterozygosity for hemoglobin A and hemoglobin S (HbAS) is the most common disorder.
These hemoglobinopathies are diagnosed by hemoglobin electrophoresis.
Anemia occurs as a result of the sickle hemoglobinopathies. Deoxygenation of the
abnormal red blood cells (RBCs) results in sickling. These permanently damaged RBCs
are then removed by the reticuloendothelial system, with the average RBC lifespan
reduced to 17 days. The result is a chronic compensated anemia, with Hb typically
measured between 6.5 and 9.5 g/dL.
The sickle shape also results in altered motion through the microvasculature. This altered
motion can predispose the patient to vascular stasis, hypoxia, acidosis, and increased
2,3-diphosphoglycerate, which perpetuates the cycle by resulting in further
deoxygenation and, thus, more sickling. The microvascular injury can result in ischemic
necrosis and end-organ infarction.
Organs affected by chronic sickling include the spleen, lungs, kidneys, heart, and
brain. Patients with sickle cell anemia are functionally asplenic. Therefore, immunization
for encapsulated organisms (pneumococcus and meningococcus) is recommended.
Likewise, aggressive treatment should be instituted when encapsulated bacterial
infections are diagnosed in sickle cell disease.
Maternal and fetal morbidity
In general, treating a pregnant woman who has sickle cell disease requires close
observation. Obtain blood cell counts frequently because anemia can worsen quickly.
Folic acid supplementation is recommended because of the quick turnover of
erythrocytes. One should monitor the pregnancy with serial sonograms for assessment
of fetal growth, and implementation of fetal surveillance in the third trimester is
reasonable. Pneumococcal and meningococcal vaccines should be provided.
Prophylactic RBC transfusions, once standard in patients who were pregnant and had
sickle cell disease, is no longer routinely advised. In 1988, a National Institutes of Health
(NIH)sponsored, multicenter, randomized, controlled trial of 72 patients with HbSS
disease showed no significant difference in overall maternal or perinatal outcome of
patients who received transfusions and those who did not, except for a lower incidence
of painful crises in patients who received transfusions. [4]
The risks incurred with multiple blood transfusions include infection and
alloimmunization, which have their own implications for pregnancy. Similar findings have
been reported in a more heterogenous group of patients from the United Kingdom
(including patients with HbSS, HbSC, and HbS beta-Thal), although some evidence
indicates that the subset of women with sickle hemoglobinopathies carrying twins or
higher-order multiples may benefit from prophylactic transfusion.
A woman who is pregnant is at risk of developing sickle cell crisis (SCC). These
crises typically are vasoocclusive and may be precipitated by infection. They may be
associated with thrombophlebitis or preeclampsia. Commonly, a pattern of sudden
recurrent attacks of pain involving the abdomen, chest, vertebrae, or extremities occurs.
These crises are more common in HbSS disease than in HbSC and HbS beta-Thal
disease.
Laboratory tests that may be helpful to distinguish between SCC and other possible
etiologies of pain include a white blood cell (WBC) count with differential and lactic
dehydrogenase (LDH) determinations. An elevated WBC count may be observed in cases
of SCC, but a left shift should not be observed unless triggered by an underlying infection.
Patients with SCC have elevated LDH levels. Other laboratory tests that should be
ordered upon patient admission include a complete blood count (CBC) count, type and
cross-match, and arterial blood gas determinations as indicated.
Therapeutic measures for SCC are primarily supportive, with the initiation of
intravenous (IV) fluid administration to decrease blood viscosity and pain control as
standard pillars of care. If a sudden drop in hematocrit (Hct) occurs, therapeutic
transfusion may be advisable. Identification and treatment of any underlying infection is
of paramount importance. If the fetus is viable, fetal heart rate monitoring is necessary if
maternal oxygenation is compromised. If clinical evidence of hypoxia is present, mother
and fetus may benefit from supplemental oxygen.
During a sickle cell crisis, fetal heart rate tracings may be nonreactive and the
blood pressure and pulse may be abnormal; blood pressure and pulse typically revert to
normal when the crisis resolves. Umbilical artery Doppler study findings have also been
noted as frequently being normal during crisis, even in the setting of abnormal uterine
artery Doppler study results.
Overall, improvement has occurred in maternal and fetal outcome in patients with sickle
cell disease. A widely quoted study from West Africa in the early 1970s reported an 11.5%
mortality rate in mothers who are homozygous. [5] Other investigators noted a decrease in
maternal death rates at Los Angeles County Hospital, from 4.1% in the era before 1972
to 1.7% from 1972-1982, with all deaths occurring in patients with HbSS or HbS beta-
Thal disease. [6]
A decade later, the NIH-sponsored Cooperative Study of Sickle Cell Disease
reported 2 deaths in 445 (0.6%) pregnancies; both of these deaths occurred in patients
with HbSS. [7] Few reported maternal deaths have been associated with HbSC disease in
the past 2 decades.
The Cooperative Study also found earlier gestational ages at delivery, smaller birth
weights, and an increased rate of stillbirths (0.9%) in the HbSS group, as well as a greater
rate of painful crises (50%). [7] No difference in the rates of preeclampsia existed among
the different genotypes, and surprisingly pyelonephritis occurred infrequently (< 1%). First
trimester miscarriage occurred in approximately 6% of women with HbSS; however,
correctly ascertaining this rate in the modern era is difficult, because many women with
this disease electively terminate their pregnancies.
The most recent data on sickle cell disease in pregnancy come from a 2008 study
by Chakravarty et al and Villers et al, who examined Nationwide Inpatient Sample data.
They found increased risks of antenatal hospitalization, hypertensive disorders,
intrauterine growth restriction (IUGR), and cesarean delivery among women with sickle
cell disease. [8] The following odds ratios were significantly increased for women with
sickle cell disease: pneumonia (9.8), sepsis (6.8), cerebral venous thrombosis (4.9),
eclampsia (3.2), IUGR (2.9), DVT (2.5), stroke (2.0), pulmonary embolism (1.7),
postpartum infection (1.4), and pyelonephritis (1.3). The mortality rate for women with
sickle cell disease was 6 times that for women without sickle cell disease. [9]
Acute chest syndrome can occur in 10% of sickle cell patients in sickle cell crisis.
This presents with pleuritic chest pain, fever, cough, lung infiltrates, and hypoxia. Up to
15% of patients require intubation, and it has up to a 3 % mortality rate. [10]
The improvement in both maternal and fetal survival notwithstanding, it is important
to remember that patients with the sickle hemoglobinopathies remain at risk for renal
insufficiency, cerebrovascular accidents, cardiac dysfunction, leg ulcers, and sepsis,
particularly from encapsulated organisms.

Thalassemias in Pregnancy
Thalassemia is a disease with many forms, all of which are characterized by
impaired production of one of the normal globin peptide chains found in hemoglobin (Hb).
Healthy adults should have more than 95% hemoglobin A (HbA), which consist of 2 alpha
and 2 beta peptide chains. Other polypeptide chains are gamma, delta, epsilon, and zeta.
Hemoglobin F (fetal hemoglobin, HbF) consists of 2 alpha chains and 2 gamma chains.
HbA2 consists of 2 alpha chains and 2 delta chains. Depending on the hemoglobinopathy,
some of these other types of hemoglobin may be found on electrophoresis. Presence of
these less common adult forms should signal the need for further investigation of a
hemoglobinopathy.
The 2 major thalassemias, alpha-thalassemia and beta-thalassemia, result from
decreased production of one or more of these peptide chains. The clinical consequences
can be ineffective erythropoiesis, hemolysis, and anemia of varying degrees. Consultation
with a maternal-fetal medicine specialist is often prudent.
Inheritance is autosomal recessive. A lethal homozygous state can result when an
individual inherits mutant genes for the alpha and beta chains from both parents. Various
defects that may be responsible for the different thalassemia syndromes have been
implicated on a molecular level. In most populations, the gene loci for the alpha-globin
chains are located on the short arm of chromosome 16. The beta chain gene is located
on the short arm of chromosome 11.
The disease is found throughout the world, but its highest prevalence is in areas
endemic for malaria, where it may confer a protective advantage. These regions include
the Mediterranean, central Africa, and parts of Asia. Geographical variation exists with
the various syndromes. Hemoglobin Barts (HbBart) and hemoglobin B (HbB) principally
affect people of Asian descent.
Alpha-thalassemia
Alpha-thalassemia disorders involve a loss of at least one of the 4 alpha-globin
genes. Deletion of 1 alpha-globin gene causes a silent carrier state, and laboratory values
remain in the normal range. Deletion of more than one gene causes the clinical
syndromes described below.
The homozygous condition results when all 4 genes for the alpha-globin chain are
deleted and the fetus is unable to synthesize HbF, or any other adult hemoglobin. This
condition results in HbBarts in the fetus (also known as alpha-thalassemia major), which,
without alpha chains, is a tetramer of gamma chains as the dominant Hb. Because of its
high oxygen affinity, little oxygen is released to the tissues. The fetus develops
nonimmune hydrops and typically dies in utero or shortly after birth. Preeclampsia can
develop in the patient carrying a fetus with alpha-thalassemia major.
Hemoglobin H (HbH) disease is a compound heterozygous state that is due to the
deletion of 3 of the 4 alpha-globin genes. With only one active alpha gene, there is an
excess of beta chains, resulting in tetramers of beta chains or HbH. The abnormal red
cells at birth consist of both HbH and HbBarts. The neonate typically appears healthy at
birth but then develops a hemolytic anemia. Ultimately, the HbBarts is replaced with HbH.
This results in anemia, which varies in severity and can worsen significantly during
pregnancy.
Alpha-thalassemia minor or alpha-thalassemia trait exists when 2 alpha chain
genes are missing. It is common in people of African, Southeast Asian, West Indian, and
Mediterranean decent. Two alpha globin genes are present on each chromatid of
chromosome 16. With 2 dysfunctional alpha globin genes, both may occur on the same
chromatid a cis configuration (--/alpha, alpha)that is, 1 chromosome without any copies
and 1 with 2 copiesor may occur one on each chromatid or a trans configuration
(alpha,-/alpha,-). A fetus whose parents with alpha-thalassemia in the cis configurations
(more common in Southeast Asia) is at greater risk of HbBarts than the parents with
the trans configuration (more common in African Americans).
Alpha-thalassemia minor causes a mild-to-moderate hypochromic microcytic
anemia. Patients with this condition typically do well during pregnancy.
An article published by Leung et al describes the use of ultrasonographic markers
during pregnancy to predict fetuses at risk for alpha-thalassemia major. [11] This may
prove to be a useful and attractive option for some patients.
Beta-thalassemia
The beta-thalassemias are the consequence of point mutations that cause
absence of or reduction in beta-chain production. HbA is usually absent in these
individuals. Elevated levels of HbF can often be found.
Beta-thalassemia major, or Cooley's anemia, occurs when both beta genes are
missing. It is characterized by precipitation of the excessive alpha chains that results in
ineffective erythropoiesis and hemolysis. The fetus is protected from this because of high
levels of HbF; however, after birth, as HbF levels fall, the infant becomes anemic.
Although transfusion can prolong life, especially when combined with iron chelation
therapy, females with this disorder historically have been infertile. However, the number
of successful pregnancies in these patients has been increasing. These patients require
frequent transfusions and deferoxamine iron chelation therapy throughout pregnancy.
Beta-thalassemia minor occurs in individuals who are heterozygous for this gene
mutation and therefore have variable production of the beta-globin chain. As a
consequence, beta-thalassemia minor has variable clinical effects, depending on the rate
of beta-chain production. It may be unmasked during pregnancy or uncovered after a
patient has delivered a homozygous infant.
Hb electrophoresis characteristically shows an adult hemoglobin, which consists of 2
alpha and 2 delta chains (known as Hb A2), to be increased to greater than 3.5%. In the
presence of iron deficiency anemia, the amount of HbA2 may be falsely normal. These
patients do not have impaired fertility or pregnancy outcome; however, they may become
disproportionately anemic and require iron or folate supplementation during pregnancy.
The obstetric emphasis with these patients who are heterozygous is on prenatal
diagnosis.
Like the alpha-thalassemias, the beta-thalassemias are common in individuals of
Mediterranean, Asian, Middle Eastern, and West Indian descent. Hispanics have a higher
prevalence for thalassemia than Caucasians; therefore, these disorders should be
considered in the differential diagnosis for anemia in Hispanic patients as well.
In a retrospective analysis of 60 pregnancies in 34 Greek women with TI over 2
decades, Voskaridou et al reported that, despite complications (eg, spontaneous
abortions, neonatal intensive care for infants with birth weights of 2-3 kg), successful
maternal-fetal outcomes are achievable with close and frequent hematologic and
obstetric monitoring. [12]

Screening and Genetic Testing for Hemoglobinopathies

Advances in genetic research that allow precise identification of mutations of the
hemoglobin (Hb) genes make the process of identifying couples at risk for having
offspring with the hemoglobinopathies increasingly important for obstetrician-
gynecologists. [13]
Although universal screening for a hemoglobinopathy is not recommended,
complete blood counts (CBCs) with red blood cell (RBC) indices for all pregnant women
at the initiation of prenatal care is appropriate. In patients from Southeast Asia, the
Mediterranean, or of African descent, Hb electrophoresis to evaluate for sickle
hemoglobin and thalassemia is recommended.
Pregnant women with microcytic (MCV < 80 fL) anemia not attributable to iron
deficiency based on normal iron studies should also undergo Hb electrophoresis to
evaluate for thalassemias. One should inquire about previous pregnancies and a family
history of adverse pregnancy outcomes.
Increased HbA2 would suggest a beta-thalassemia. Normal HbA2 with significant
microcytic anemia and normal iron studies should prompt testing for alpha thalassemia.
One should offer to test the partner of any carrier of sickle hemoglobinopathies and any
patient with elevated (>3.5%) HbA2 to assess the risk to the fetus. If both partners are
identified as carriers, offer DNA-based tests for the fetus.
Tests for prenatal diagnosis of sickle cell anemia and thalassemia now include
polymerase chain reaction (PCR) of fetal DNA extracted from amniotic cells, of
trophoblasts from chorionic villus sampling, and of erythroblasts obtained from
cordocentesis.
In many hemoglobinopathies, including sickle cell disease and most beta-
thalassemias, point mutations exist for which specifically designed oligonucleotide probes
can be used, especially in combination with knowledge of the patients ethnicity. For some
thalassemias, performing indirect DNA testing by linkage analysis is still necessary.
Efforts to reduce the risks to the fetus incurred with invasive tests such as
amniocentesis, chorionic villus sampling, and cordocentesis have been made by
acquisition of fetal cells from the maternal circulation using magnetic cell sorting;
however, this procedure is not standard. This technique can only work in
hemoglobinopathies in which the mutation has been identified, because only a small
amount of fetal cells can be purified. Pyrophosphorolysis-activated polymerization (PAP)
is also being used when a previously born child is available for analysis. [14] Digital PCR
is also being tested to detect abnormal fetal cells in maternal plasma, although more work
is need to perfect this technique. [15] Many couples elect to continue an affected
pregnancy.
Preimplantation genetics can be offered to assure the placement of an unaffected
embryo in utero.
One more genetic test should be considered in patients with anemia who are of
African, Mediterranean, Indian, and Southeast Asian descent: a test for glucose-6-
phosphate dehydrogenase (G6PD) deficiency. This deficiency appears to be common in
these populations because G6PD deficiency seems to confer relative protection
from Plasmodium falciparum malaria.
The G6PD gene is on the X chromosome and therefore follows a sex-linked
pattern. Because of lyonization in red blood cells, a variable proportion of RBCs are
affected in women who are heterozygous for the deficiency. Therefore, heterozygous
women can have mild, moderate, or severe anemia. With the common G6PD mutations,
anemia may occur with exposure to specific drugs, infections, and other sources of stress.
Less commonly, G6PD mutations may result in a shortened life span of the red blood cell,
resulting in a nonspherocytic hemolytic anemia.

Anemias From Drug and Medication Use in Pregnancy

Various medications and drug exposures can lead to anemia (see the Table
below).[22] Most pregnant women and their obstetricians are careful about what medicines
are administered or ingested during pregnancy. On occasion, drugs that can cause
anemia are required. A good example is the pregnant woman who is diagnosed with
breast cancer in early pregnancy and requires chemotherapy, which is an increasingly
common clinical scenario. Table 1. Drugs and Possible Underlying Causes of Anemia

Drug/Medication Potential Etiology for Anemia

Penicillin, cephalosporin, procainamide,
Drug-induced hemolytic anemia
quinidine, quinine, sulfonamide

Oxidant-induced hemolysis (glucose-6-

Fava beans, dapsone, naphthalene phosphate dehydrogenase [G6PD]
deficiency)

Bone marrow suppression, oxidant

Cancer chemotherapeutic medications damage, fluid retention/dilutional
anemia

Chloramphenicol, gold salts,

Bone marrow hypoplasia
sulfonamides, anti-inflammatory drugs

Ethanol, chloramphenicol Acute reversible bone marrow toxicity

Methotrexate, azathioprine,
Bone marrow aplasia/hypoplasia,
pyrimethamine, trimethoprim, sulfa
megaloblastic anemia
drugs, zidovudine, hydroxyurea

Bone marrow suppression, acute

Past chemotherapy drugs
myeloid leukemia, myelodysplasia

Unexplained Maternal Anemias

Unexplained maternal anemia can be a highly vexing problem for obstetricians and
other medical specialists. In such cases, it is prudent to consider all potential causes for
anemia, including (but not limited to) pharmacologic, infectious, and immunologic causes.
Supportive measures for the pregnant woman should be instituted while pursuing the
etiology for anemia.
Besides the use of drugs and medications, as discussed earlier (see above),
alcohol consumption should be considered. There is a population of pregnant women
who have alcoholism and consume alcohol without revealing this to their obstetricians.
Women should be carefully queried regarding their alcohol use.
An example of unexplained anemia was cited in 2008 by Katsuragi et al, who described
a Japanese woman with severe hemolytic anemia who had negative results on direct and
indirect Coombs tests. [23] Immunoglobulin G (IgG) levels on the patients red blood cells
(RBCs) were increased during her pregnancy and resolved post partum. All other
antibody test results were likewise negative; screening test results for all
hemoglobinopathies were also negative. The patient was successfully treated
with prednisolone and RBC transfusions and delivered at 35 weeks gestation.
 Infectious causes, though rare, include viral etiologies such as HIV,
cytomegalovirus (CMV), Epstein-Barr virus (EBV), parvovirus B-19, and the hepatitis
viruses. Other infectious causes include brucellosis and tuberculosis.

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