Anemia in Pregnancy: Alfred Ian Lee,, Maureen M. Okam
Anemia in Pregnancy: Alfred Ian Lee,, Maureen M. Okam
Anemia in Pregnancy: Alfred Ian Lee,, Maureen M. Okam
a b,
Alfred Ian Lee, MD, PhD , Maureen M. Okam, MD, MPH *
KEYWORDS
Anemia Pregnancy Iron deficiency Folate B12 deficiency
“A person, ordinarily in good health . suddenly becomes pale, the surface of the
body being waxy and bloodless; she is faint and fatigued; capable of great bodily
efforts which, however, produce palpitations and distress; she has pain in the
head, impatience of light, throbbing at the temples, and sometimes an universal
throbbing, slight confusion in the mind, and a sense of total and extreme prostra-
tion. At the same time the pulse is frequent, large, strong and hard; at least, an
observer who should not see the pallid face and miserable look of the patient,
would pronounce it to be hard.. Still every surface which can be examined
during life, is destitute of blood. And after death, the only remarkable appearance
is the bloodlessness of the tissues.”
Walter Channing, 1842
In 1842, Walter Channing, Dean of Harvard Medical School, published the first docu-
mented account of puerperal anemia in his narrative of Mrs H, who developed a fatal
nonhemorrhagic anemia shortly after delivery.1 Addison soon followed with his report
of idiopathic anemia, later renamed pernicious anemia owing to its grim prognosis,
with the term “pernicious anemia of pregnancy” coined to describe the Channing
disease. Landmark advances in the early part of the twentieth century uncovered
the pathologic basis of classic pernicious anemia, demonstrating the therapeutic
potential of parenteral liver extract and the central role of gastric intrinsic factor in
cobalamin (vitamin B12) absorption.2 Pernicious anemia of pregnancy was shown to
be primarily caused by a deficiency of folate rather than vitamin B12, based on the
observations that affected women lacked gastric achlorhydria and exhibited a slow
or absent response to liver supplementation.
Anemia of pregnancy is currently recognized as a major global health problem,
affecting nearly half of all pregnant women worldwide.3 The pernicious anemia of
Channing, once regarded as a model for puerperal and gestational anemia, has
been shown to be rare, accounting for only 1 of 200 to 1 of 1000 cases. Hydremia
of pregnancy, a gestational decrease in hemoglobin levels because of
IRON HOMEOSTASIS
Dietary iron is absorbed by intestinal epithelial cells in the duodenum and jejunum.8,9
Absorption depends on gastric acid, which maintains iron in its soluble ferrous (Fe21)
form rather than the insoluble ferric (Fe31) form. Intracellular iron within macrophages
is liberated from senescent erythrocytes during erythrophagocytosis. Iron from both
intestinal epithelial cells and macrophages is transported, via ferroportin channels,
to the circulation, where it is bound to serum transferrin, which carries the bound
iron to target cells (Fig. 1). Transferrin receptors on the surfaces of erythroid progen-
itors, lymphocytes, and other proliferating cells bind and internalize the transferrin-iron
complex, releasing iron intracellularly through the transferrin cycle. Ferritin, an intracel-
lular protein that binds and sequesters iron, is leaked into the circulation in small levels;
serum ferritin levels are an accurate indicator of total body iron stores, although the
function of intracellular ferritin is unknown.
Anemia in Pregnancy 243
Fig. 1. Iron metabolism. Absorption of dietary iron by duodenal and jejunal epithelial cells is
dependent on gastric acid, which maintains iron in its soluble ferrous (Fe21) form rather
than the insoluble ferric (Fe31) form. Intestinal ferric reductase reduces any remaining
ferrous iron before intestinal epithelial cell uptake. Ferric iron is transported into intestinal
epithelial cells via divalent metal transporter (DMT-1) receptors. Within the intestinal
epithelial cell, some iron becomes bound by intracellular ferritin, whereas the remainder
is secreted via ferroportin channels into the circulation and bound by serum transferrin.
Hepcidin (not shown) regulates iron metabolism by binding ferroportin, inducing its endo-
cytosis and degradation in lysosomes.
The primary regulator of iron use is hepcidin, which binds ferroportin and induces its
endocytosis and degradation in lysosomes.8,9 High hepcidin levels cause intracellular
accumulation of iron and impairment of iron use, as seen in anemia of inflammation; by
contrast, hepcidin deficiency, seen in hemochromatosis, results in uncontrolled
release of iron into the circulation. Transferrin, ferritin, and hepcidin are produced by
the liver. The latter 2 are acute phase reactants, and their levels may be elevated
during infection, inflammation, or stress.
Clinicians long recognized that hydremia alone could not account for the hemoglobin
levels of less than 7 g/dL in 10% to 70% of pregnant women reported in the early
twentieth century studies. A central role for iron deficiency in anemia of pregnancy
was demonstrated in the 1950s by the frequent finding of hypochromia, microcytosis,
and anisocytosis in the blood smears of pregnant women with anemia, and the reso-
lution of such abnormalities following iron supplementation.15 Iron deficiency has
since been recognized as the most common cause of anemia of pregnancy world-
wide, manifesting predominantly in the third trimester, when iron is maximally accu-
mulated to accommodate erythropoiesis in the growing fetus.16
Risk Factors
In addition to poor nutritional intake, factors that impair iron absorption may precipi-
tate iron deficiency in pregnancy, including bariatric surgery, antacids, and defi-
ciencies of micronutrients such as vitamin A, vitamin C, zinc, and copper.17,18
Clinical Manifestations
Fatigue, pallor, light-headedness, tachycardia, dyspnea, poor exercise tolerance, and
suboptimal work performance have all been reported in pregnant or postpartum
women with iron deficiency, as have postpartum depression, poor maternal/infant
behavioral interactions, impaired lactation, low birth weight, premature delivery, intra-
uterine growth retardation, and increased fetal and neonatal mortality.19–23 Although
supplemental iron improves the hematologic abnormalities of iron deficiency in preg-
nancy, the therapeutic benefits to neonatal mortality, infant morbidity, and child devel-
opment are uncertain.11,19,21,22
Diagnosis
By either the CDC or WHO criteria, the presence of anemia in combination with a low
ferritin level (<15–20 mg/L) is considered diagnostic of iron deficiency in pregnancy.24
Diagnosis is complicated by the increase in ferritin levels during the third trimester,
when iron deficiency is most likely to be present. If ferritin levels are normal or
elevated, hypochromia, microcytosis, or a reduced red cell MCV may support a picture
of iron deficiency.11 C-reactive protein is an alternate measure of inflammation;
a normal or elevated ferritin level with a normal C-reactive protein level should prompt
investigation for alternate causes of anemia, such as hemoglobinopathies.24 Soluble
transferrin receptor (sTfR) concentration, released into the circulation by transferrin
receptor–expressing cells, correlates inversely with total body iron content and
exhibits high sensitivity and specificity in the diagnosis of iron deficiency during
pregnancy.25 Because sTfR is not an acute phase reactant, its levels do not increase
with inflammation, although they can be influenced by red cell mass or erythropoietic
activity and are often low in early pregnancy, when erythropoiesis is reduced.
246 Lee & Okam
Prevention
The WHO, CDC, and US Food and Drug Administration (FDA) recommend that all
pregnant women receive oral iron supplementation from the beginning of gestation
to 3 months post partum, at doses of 27 mg/d (FDA), 30 mg/d (CDC), or 60 mg/d
(WHO), although doses as low as 20 mg/d may be effective.3,11,19,21,26 The major
side effects of oral iron supplementation are gastrointestinal symptoms, which occur
in a dose-dependent manner, primarily at doses of 200 mg/d or more.
Treatment
Patients with mild anemia (hemoglobin level, 9.0–10.5 g/dL) should receive oral iron at
160 to 200 mg of elemental iron daily, with an expected increase in hemoglobin levels
of 1 g/dL after 14 days of therapy.24 Compared with oral iron, parenteral iron demon-
strates faster hematologic recovery, likely because of variations in oral iron tolerability,
absorption, and compliance. Parenteral iron may be administered in the second
or third trimester to patients who have moderate to severe anemia (hemoglobin <9
g/dL), who are intolerant to oral iron, or who fail to respond appropriately to oral
therapy.11,19,21,27–29 Four preparations of parenteral iron are available in the United
States: iron dextran (low–molecular-weight InFeD and high–molecular-weight DexFer-
rum), sodium ferric gluconate (Ferrlecit), iron sucrose (Venofer), and ferumoxytol (Fer-
aheme). Among pregnant women who received parenteral iron in published studies,
15% to 20% developed thrombosis, although the relationship between these factors
is uncertain.21 Administration of recombinant human erythropoietin, in combination
with parenteral iron, may be an alternate therapy for pregnant women with anemia,
who are refractory to oral iron.30,31 Darbepoietin has been similarly used in a single
case report of a pregnant woman with chronic kidney disease.32 Larger studies are
needed to confirm the appropriateness, safety, and feasibility of erythropoietic stimu-
lating agents in anemia of pregnancy.
Fig. 2. Physiology and biochemistry of folate metabolism. (A) In the stomach, pepsin
releases vitamin B12 from ingested food, and R proteins (eg, haptocorrin, secreted by the
salivary gland) bind vitamin B12 and carry it to the duodenum, where pancreatic proteases
degrade the R proteins, releasing vitamin B12 for binding by intrinsic factor (IF). The complex
is carried to the terminal ileum, and vitamin B12 is transported into intestinal epithelial cells
via the transcobalamin II (TCII) receptor. (B) Within cells, folate and vitamin B12 are required
for synthesis of tetrahydrofolate (THF), which itself is required for the conversion of
deoxyuridyl monophosphate to deoxythymidyl monophosphate, an essential precursor for
DNA synthesis. DHFR, dihydrofolate reductase.
Most pregnant women with folate or vitamin B12 deficiency do not exhibit
erythrocyte macrocytosis, although 2% to 5% of pregnant women with normocytic
anemia have mild megaloblastic changes in the bone marrow that resolve with folic
acid supplementation.15 Elevation in homocysteine or methylmalonic acid levels
248 Lee & Okam
Hookworm Infection
Among pregnant women with hookworm infection, the burden of infection is a strong
predictor of maternal iron stores, with severity of anemia correlating with the number
of hookworm eggs isolated from stool.46–48 The WHO recommends universal
deworming of pregnant women in hookworm-endemic areas with antihelminthic medi-
cations (eg, albendazole or mebendazole), in conjunction with iron and folate supple-
mentation, although the hematologic benefits of deworming are uncertain.48,49
Malaria
In malaria-endemic regions, chronic malaria can cause acute hemolytic anemia during
pregnancy, particularly in patients with coexisting nutritional deficiencies or hemoglo-
binopathies (eg, sickle cell disease).50 Primigravidas are particularly prone, with
a strong association of Plasmodium falciparum with severe anemia (defined as
a hemoglobin level of <7 g/dL) and maternal death.51 The relationship between
Anemia in Pregnancy 249
Fig. 3. Human a- and b-globin gene loci, located on chromosomes 16 and 11, respectively.
Expression of both loci is regulated by enhancer elements known as locus control regions
(LCRs). Embryonic hemoglobin is the first hemoglobin expressed in fetal development and
is composed of z- and e-globin chains. Beginning at 6 weeks of gestation and continuing
into the first few weeks after delivery, fetal hemoglobin is synthesized, consisting of
a- and g-globin chains. Two forms of adult hemoglobin are synthesized shortly before birth:
hemoglobin A, the major adult hemoglobin, consisting of a- and b-chains, and hemoglobin
A2, consisting of a- and d-chains.
b-Thalassemia
More than 200 mutations in the b-globin gene have been described for b-thalassemia,
which affects primarily the people of Mediterranean, African, Middle Eastern, East
Asian, South Asian, and Latin American descent.63,66 Mutations causing a reduction
in b-chain synthesis are designated as b1, whereas those causing a complete
absence of b-chain expression are designated b0. The b-thalassemias are classified
as b-thalassemia minor, b-thalassemia intermedia, and b-thalassemia major, based
on variations in phenotypic severity that arise from different combinations of b1, b0,
and wild-type b. Heterozygosity for bS and b-thalassemia leads to the S/b-Thal pheno-
type, which can be severe, particularly if the b allele is b0.
Anemia in Pregnancy 251
Hemoglobin E thalassemia
Hemoglobin E (HbE) arises from a missense (G-to-A) mutation in the 26th codon of the
b-globin gene, encoding an unstable b-globin synthesized at reduced levels because
of an abnormal messenger RNA splice site.67 HbE thalassemia is one of the most
common b-thalassemias, occurring in patients of East and South Asian descent.
Similar to bC, HbE trait and homozygous HbE (HbEE) are mild diseases, whereas
heterozygosity for bS and HbE (HbSE) produces a severe phenotype.
a-Thalassemia
More than 40 different deletions and other mutations in the a-globin locus have been
described for a-thalassemia.68,69 Genotypes are classified as a1 or a0, based on
whether a-globin gene expression is present or absent, respectively, in each of the
4 a genes. Phenotypic severity reflects the number of a genes expressed, with dele-
tion of 1 a gene designated as a silent carrier state (a-thalassemia-2, or a-thalassemia
trait); deletion of 2 a genes, a-thalassemia minor (a-thalassemia-1); deletion of 3
a genes, hemoglobin H (HbH) disease, characterized by accumulation of tetramers
of b globin (b4); and deletion of all 4 a genes, hemoglobin Bart’s hydrops fetalis,
with fatal accumulation of tetrameric fetal g globin (g4) in utero.
Thalassemias in Pregnancy
For pregnant and nonpregnant patients with a- or b-thalassemia, hemolytic anemia
caused by ineffective erythropoiesis is the major complication.82 Imbalanced nonstoi-
chiometric production of a- and b-globin chains leads to disruptions in red cell phys-
iology, causing intramedullary destruction of erythroid precursors and hemolysis of
circulating red blood cells. Extramedullary hematopoiesis occurs when anemia is
severe. In an attempt to maintain erythropoietic needs, iron use is increased through
reduction in hepcidin levels, leading to hemochromatosis independent of transfusion
therapy.83 Splenectomy can be helpful in improving anemia but confers an increased
risk of thrombosis, particularly in patients with HbE thalassemia.66,67,69
Anemia in Pregnancy 253
HbH disease
HbH is an unstable tetramer of b-chains (b4) with high oxygen affinity and impaired
oxygen delivery.69,79,84 Precipitation of b4 in erythrocytes disrupts red cell metabolism
and impairs membrane deformability, leading to shortened erythrocyte survival. Clin-
ical manifestations of HbH disease include microcytic anemia, hepatosplenomegaly,
cholelithiasis, growth defects, thrombosis, and hemochromatosis; the last manifesta-
tion is associated with hepatic and cardiac dysfunction. Hemolytic crises occur in
10% of patients with HbH disease, sometimes in conjunction with parvovirus B19
infection.85 In pregnant women with HbH disease, anemia can be profound with
hemoglobin levels of less than 6 to 7 g/dL, particularly in the second and third trimes-
ters. Pregnancy in HbH disease is associated with increased risks of preeclampsia,
congestive heart failure, miscarriage, premature births, intrauterine growth restriction,
low birth weight, and perinatal deaths compared with patients without thalassemia.86
Rarely, fatal HbH hydrops fetalis can occur because of a specific a gene mutation.87
Pregnant women with HbH disease may receive blood transfusions to maintain hemo-
globin levels more than 7 g/dL. Recombinant human erythropoietin has been success-
fully used in a single case report of a pregnant patient with HbH disease and
symptomatic anemia.88
Multiple cases of aplastic anemia associated with pregnancy and a few cases of preg-
nancy-induced aplastic anemia seen with or mimicking immune thrombocytopenia
254 Lee & Okam
have been reported in patients presenting with petechiae or pallor during the second
or third trimester of pregnancy.96–99 Pathologically, pregnancy may induce aplastic
anemia through erythropoietic inhibitory effects of estrogens and other hormones,
although in some cases, pregnancy may uncover a preexisting aplastic anemia.
Maternal death occurs in 20% to 50% of cases, usually from fatal hemorrhage or
infection. Fetal complications include in utero death in up to one-third of cases and
preterm labor from chorioamnionitis. Women with a preexisting diagnosis of aplastic
anemia may have a more favorable prognosis than those with pregnancy-
associated aplastic anemia, although prenatal management is the same and consists
of blood transfusions to maintain a platelet count of more than 20 109/L and admin-
istration of growth factors (eg, granulocyte/monocyte colony stimulating factor) and, in
select cases, cyclosporine. Hematopoietic cell transplant, the mainstay of treatment
of aplastic anemia in nonpregnant patients, is contraindicated during pregnancy.100
Among women who survive pregnancy-associated aplastic anemia, 50% to 70%
achieve spontaneous remission, whereas the remainder require therapy with antithy-
mocyte globulin, immunosuppression, and/or stem cell transplantation.
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