Anemia and Thrombocytopenia in Pregnancy

Updated: Jan 20, 2022
  • Author: Fidelma B Rigby, MD; Chief Editor: Ronald M Ramus, MD  more...
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Anemias in Pregnancy

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. In its most recent guidelines on anemia in pregnancy, the American College of Obstetricians and Gynecologists eliminated different hemoglobin level thresholds to define iron-deficiency anemia in Black and White pregnant persons. [1, 2]

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. [3]

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-12–deficiency 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

Go to Anemia, Emergent Management of Acute Anemia, and Chronic Anemia for complete information on these topics.

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. [4]  In a Swedish study, Wiegersma et al found that iron deficiency anemia diagnosed at 30 weeks’ gestation or earlier increased the risk of autism spectrum disorder, attention-deficit/hyperactivity disorder, and intellectual disability in children. [5]

Go to Iron Deficiency Anemia for complete information on this topic.

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.

Go to Pernicious Anemia for complete information on this topic.

Infectious causes of anemia

Infectious cause of anemia are more common in nonindustrialized countries. [6] 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 patient’s 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. [4]


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. [7]

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. [8] 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. [9]

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. [10] 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%). [10] 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. [11] 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. [12]

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. [13]

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.

Go to Sickle Cell Anemia for complete information on this topic.


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 Bart’s (HbBart) and hemoglobin B (HbB) principally affect people of Asian descent.


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 copies—or 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. [14] This may prove to be a useful and attractive option for some patients.


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. [15]


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. [16]

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 patient’s 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. [17] Digital PCR is also being tested to detect abnormal fetal cells in maternal plasma, although more work is need to perfect this technique. [18] 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.


Thrombocytopenias in Pregnancy

Thrombocytopenia in pregnancy is common and is diagnosed in approximately 7% of pregnancies. It is typically defined as a platelet count lower than 150,000/µL. The most common cause of thrombocytopenia during pregnancy is gestational thrombocytopenia, which is a mild thrombocytopenia with platelet levels remaining above 70,000/µL. Patients who are affected usually are asymptomatic and have no history of thrombocytopenia before pregnancy. Their platelet levels should return to normal within several weeks following delivery.

An extremely low risk of fetal or neonatal thrombocytopenia is associated with gestational thrombocytopenia. Gestational thrombocytopenia may result from increased platelet consumption and can be associated with antiplatelet antibodies. Gestational thrombocytopenia can be hard to distinguish from immune thrombocytopenia purpura (ITP) presenting during pregnancy.

Immune thrombocytopenic purpura

Acute immune thrombocytopenic purpura (ITP) is a disorder occurring in childhood; it has few implications for women who are pregnant, because it resolves spontaneously. Chronic ITP may occur in the second or third decade of life, affecting females 3 times as frequently as males. This condition is characterized by immunologically mediated platelet destruction. Antiplatelet antibodies (immunoglobulin G) attack platelet membrane glycoproteins and destroy platelets at a rate that cannot be compensated by the bone marrow.

ITP is usually associated with persistent thrombocytopenia (< 100,000/µL), normal or increased megakaryocytes on bone marrow aspirate, exclusion of other disorders associated with thrombocytopenia, and the absence of splenomegaly. Patients may report a history of easy bruising and petechiae or epistaxis and gingival bleeding preceding the pregnancy.

Although worsening of the disease is not typical during pregnancy, when it occurs, the mother is at risk for bleeding complications at the time of delivery. Therapies aimed at improving the maternal platelet count in anticipation of delivery include intravenous immunoglobulin (IVIg) and steroids. The patient may require platelet transfusion during delivery if the platelet count drops below 20,000/µL. Splenectomy is reserved for severe cases only.

Some controversy exists regarding the threat of intracranial hemorrhage (ICH) in neonates born to mothers with ITP. Although as many as 12-15% of infants born to mothers with ITP may develop platelet counts less than 50,000/µL, the risk of ICH is estimated at less than 1% in 2 recent prospective studies.

Neonatal alloimmune thrombocytopenia

In contrast to ITP, neonatal alloimmune thrombocytopenia may pose a serious risk to the newborn. [19] It may occur in 1 in 1000 live births and often is unanticipated when it occurs in first pregnancies. The presentation may be in the setting of an unremarkable pregnancy and delivery.

Like Rhesus (Rh) disease, neonatal alloimmune thrombocytopenia results from maternal alloimmunization against fetal platelet antigens. The most commonly affected antigen is human platelet antigen-1a, which has been described in approximately 50% of cases in Caucasians. A high risk of recurrence of neonatal alloimmune thrombocytopenia exists, and it tends to worsen with subsequent gestations in a manner similar to Rh disease.

Clinical manifestations in the neonate include generalized petechiae, ecchymoses, hemorrhage into viscera, increased bleeding at the time of circumcision or venipuncture, or, most gravely, ICH. ICH may occur in utero in as many as 25% of cases.

For patients who have a history of the disease and are experiencing their first pregnancy, referral to a maternal-fetal medicine specialist skilled in cordocentesis may be warranted because the fetus may need to have platelet counts or a transfusion while in utero. IVIg has been shown to improve fetal thrombocytopenia. Cesarean delivery is the preferred route of delivery for infants with platelet counts less than 50,000/µL to reduce the risk of ICH secondary to trauma incurred during labor.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) may also arise in pregnancy and requires careful diagnosis, close monitoring, and treatment for successful pregnancy outcomes. [20] Data from 35 women obtained from a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry indicate that the risk of TTP is greatest in the third trimester or the postpartum period, but fetal loss is highest in the second trimester (42% occurred before congenital TTP was diagnosed but none in 15 subsequent managed pregnancies). In cases of acquired TTP, fetal loss occurred in nearly 28% of affected pregnancies and there were two terminations due to the disease. [20]


Coagulation Disorders in Pregnancy

von Willebrand disease

von Willebrand disease is the most common inherited bleeding abnormality, with a prevalence rate of 0.8-1.3%. This disorder is secondary to a decrease or defect in the von Willebrand portion of the factor VIII complex, which plays a significant role in platelet aggregation.

Type I, which is inherited in an autosomal dominant fashion, is the most common subtype (>70% of cases). Patients may present with menorrhagia, easy bruising, gingival bleeding, and epistaxis or with abnormal bleeding following surgery or trauma. Laboratory findings in patients with type I disease typically show a prolonged bleeding time from decreased platelet aggregation, decreased von Willebrand factor (vWF), decreased factor VIII:C, and sometimes, a prolonged activated partial thromboplastin time. Mild thrombocytopenia may occur.

In patients with type II disease, normal amounts of abnormally functioning vWF may exist. Type III disease is very rare and is characterized by very low vWF. Type III disease tends to have a more severe course.

During pregnancy, a patient with type I disease may have improvement in the bleeding time secondary to an increase in factor VIII:C, although these beneficial effects are not seen until after the first trimester. Thus, patients are at the highest risk of bleeding problems early in pregnancy and in the puerperium.

In a series from the United Kingdom, 33% of patients had first trimester bleeding, and the miscarriage rate was 21%–comparable to rates observed in the healthy population. [21] However, patients had increased rates of postabortal transfusion, persistent bleeding, and an increased need for repeat dilatation and curettage.

In patients with von Willebrand disease it is recommended that one measure factor VIII:C levels and a bleeding time at their first prenatal visit and in the third trimester, prior to delivery. Historically, cryoprecipitate has been advised when factor levels fall below 80% of the reference level (approximately 50 IU/dL) or when anything but an uncomplicated vaginal delivery is anticipated.

Because of the concern of infection risk with products from pooled donors, deamino-8-D-arginine vasopressin (DDAVP) is now used in many patients, particularly those with type I disease. Another product that can be used at the time of anticipated bleeding is Humate-P, a concentrate of many high molecular proteins needed to replace vWF. A woman with mild disease may not need these measures in cases of an uncomplicated vaginal delivery.

Recent studies have suggested that it is possible to offer women with von Willebrand disease the option of regional anesthesia, providing the coagulation defects have normalized (spontaneously or with pharmacological methods). [22] Patients are at increased risk of postpartum hemorrhage; one should monitor levels of factor VIII:C and bleeding as necessary. Because type I disease is autosomal dominant (although with variable penetrance), avoid fetal scalp electrodes during labor and evaluate the neonate before circumcision.

Hemophilia A

Hemophilia A is an X-linked recessive disorder characterized by a decrease in factor VIII:C. Women who are homozygous are extremely rare and require fresh frozen plasma or cryoprecipitate at the time of delivery to prevent postpartum hemorrhage. The main obstetric concern is the risk to the offspring. The risk to a male fetus is 50%. Chorionic villus sampling or amniocentesis can determine if the fetus is at risk by determining fetal sex and providing tissue for DNA analysis. [23] Scalp electrodes, fetal scalp sampling, and instrumental deliveries should be avoided in fetuses at risk for hemophilia A. [24]

Hemophilia B

Hemophilia B disease, also known as Christmas disease, is an X-linked recessive disorder caused by multiple molecular defects in the factor IX gene. Carriers typically have no clinical manifestations. Prenatal diagnosis can be accomplished via chorionic villus sampling or amniocentesis in fetuses in which the familial genetic mutation is known. Invasive fetal monitoring and instrumental delivery, as with hemophilia A fetuses, should be avoided. [24]


Anemias From Drug and Medication Use in Pregnancy

Various medications and drug exposures can lead to anemia (see the Table below). [25] 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. Drugs and Possible Underlying Causes of Anemia

Table. (Open Table in a new window)


Potential Etiology for Anemia

Penicillin, cephalosporin, procainamide, quinidine, quinine, sulfonamide

Drug-induced hemolytic anemia

Fava beans, dapsone, naphthalene

Oxidant-induced hemolysis (glucose-6-phosphate dehydrogenase [G6PD] deficiency)

Cancer chemotherapeutic medications

Bone marrow suppression, oxidant damage, fluid retention/dilutional anemia

Chloramphenicol, gold salts, sulfonamides, anti-inflammatory drugs

Bone marrow hypoplasia

Ethanol, chloramphenicol

Acute reversible bone marrow toxicity

Methotrexate, azathioprine, pyrimethamine, trimethoprim, sulfa drugs, zidovudine, hydroxyurea

Bone marrow aplasia/hypoplasia, megaloblastic anemia

Past chemotherapy drugs

Bone marrow suppression, acute 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. [26] Immunoglobulin G (IgG) levels on the patient’s 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.