Hematologic Disorders in Pregnancy PDF

Vanderbilt - School of Nursing | Hematologic Disorders in Pregnancy This lecture provides an overview of hematologic disorders in pregnancy specifically related to the antenatal care period. We'll cover each of the following topics as an overview of potential hematologic complications in pregnancy....

Vanderbilt - School of Nursing | Hematologic Disorders in Pregnancy This lecture provides an overview of hematologic disorders in pregnancy specifically related to the antenatal care period. We'll cover each of the following topics as an overview of potential hematologic complications in pregnancy. The lecture begins with RHD and other red cell aloimmunizations, examining the risk, preventive care, and midwifery management. We'll then shift to inherited anemias of pregnancy, first reviewing the effect of anemia on pregnancy from a physiologic standpoint and then discussing the genetic basis for heritable forms of hemolytic anemia. Things like G6PD deficiency, spherocytosis, and elliptocytosis. We'll also look at non hemolytic anemias, those that result from genetic variants of hemoglobin molecules, better known as hemoglobinopathies. This includes things like thalassemias and sickle cell anemia. Our final topics will focus on conditions whereby there are alterations in platelets and/or clotting factors, best known as thrombocytopenia and thrombophilia, respectively. As you will recall from reproductive physiology, red blood cell isoimmunization of the mother is a concern in pregnancy. Exposure to red blood cell antigens can result in immunologic production of antibodies that are capable of crossing the placenta and affecting fetal health. There are many types of red blood cell antigens each named after the person who first identified them or particular letters of the alphabet. The most common red blood cell antigen is RHD, from which Rh positive and negative blood type status is derived. While RHD is the antigen most common and of utmost concern during pregnancy, certain other red blood cell antigens are also of concern in childbearing women. Isoimmunization is the term used to describe immunologic response to red blood cell antigens. Risk factors for red blood cell isoimmunization include a history of blood transfusion, pregnancy, transplantation of organs or tissue, and traumatic injuries where there's a potential for mixing of blood from others. Rh factor isoimmunization is the most prevalent due to high rates of Rh negative individuals in the general population. The good news is that there's a very effective prophylactic treatment against RHD antibody production known as RhoD immunoglobulin. As a review, RhoD immunoglobulin is a blood based product. It goes by various names in the United States, such as Rhophylac and Rhogam. Those are the most common trade names, but many others exist. RhoD immunoglobulin is used routinely in pregnant women who have an Rh negative blood type. It's given routinely in the late second trimester or early third trimester, usually between 26 and 28 weeks estimated gestational age. The woman may need a second dose following birth if her newborn is confirmed to have an Rh positive blood type. Birth is the most common instance of maternal fetal blood mixing, but other situations also call for RhoD immunoglobulin use. For example, abdominal trauma in pregnancy and certain procedures such as amniocentesis and chorionic villi sampling both have the potential to disrupt the maternal fetal placental interface and cause blood mixing. Also, spontaneous miscarriages and pregnancy terminations at any gestational age beyond four weeks are also at risk for maternal fetal transfusion and Rhogam should be used. The standard dose of RhoD immunoglobulin is 300 micrograms via an intramuscular injection in the deltoid. A 300 microgram dose is sufficient to provide protection against up to 30 milliliters of fetal blood. Since maternal fetal transfusions are usually relatively small in volume, this dose is usually sufficient for most clinical situations. A mini dose formulation is also available and ranges from 150 to 200 micrograms depending on the actual brand name. These formulations are known as half dose or mini dose RhoD products and are rarely used, as they tend to be more expensive and there is no risk in using a larger dose. Megadoses are multiple doses of RhoD prophylaxis are sometimes required if the maternal fetal transfusion is determined to be large. A standard blood test known as the Kleinhauer-Betke or KB is available to quantify the volume of fetal red blood cells in the maternal circulation. Based on the result of the KB, additional doses of RhoD immunoglobulin can be correlated with the estimated amount of red blood cells needing to be treated. An exception to RhoD immunoglobulin administration in pregnancy is if both reproductive partners are RH negative. This is due to the inheritance pattern of RH status, which is autosomal recessive. That means all RH negative phenotypes have homozygous genotypes for RH negative and their offspring will always be RH negative. RhoD prophylaxis must be provided within 72 hours of a potential exposure event to be most effective. This is related to the time it takes for a woman's immune system to mount a response to the foreign red blood cells from the fetus. Doses of rhophylacs given after the 72 hour window may still be reasonable, but serial antibody screens would be needed to monitor closely and watch for antibody production in the mother. If a mother is not treated with RhoD immunoglobulin or if the treatment is inadequate, such as in cases of larger maternal fetal transfusions or late doses, then serious sequela are possible. Primary instances of isoimmunization rarely affect current pregnancies. This is due to the lag time needed for women to mount those antibodies and the fact that most isoimmunization events occur during birth. It's subsequent pregnancies, those following an isoimmunization event that are at most risk for poor fetal outcomes. The standard of care for providers is to perform an antibody screen on all women at the initiation of prenatal care. This aids an early detection of possible antibodies to red blood cells and antibody screens should always be negative, but can be affected by RhoD immunoglobulin administration. In such instances, the antibody screen generally flags as a weak positive any time it's drawn within the 14 weeks following RhoD prophylaxis. Antibody screens both detect and identify particular red blood cell antibodies. All known red blood cell antibodies are incorporated into the standard antibody screening test with an upwards of 25 plus red blood cell antigens currently known to exist. Identification of specific antibodies is important, as there are several clinically significant antibodies of concern during pregnancy. Besides the RhD antigen, Kell, Lewis, and Duffy antigens are the next most common antibody producing red blood cell antigens. Kell and Duffy have both been associated with severe fetal hemolytic anemia. Other lesser antigens can result in antibody formation but rarely do maternal antibodies to these lesser antigens cause significant fetal sequelae. Some sources advocate for a repeat antibody screen at the time of RhoD prophylaxis between 26 and 28 weeks estimated gestational age. There is no strong evidence suggesting that this practice is necessary, as current rates of RH related isoimmunization are extremely low due to undetected early maternal fetal transfusion events. Again, the greatest risk of transfusion is during labor and birth, thus the 26 to 28 week dose of RH prophylaxis is timed to provide protection during any possible third trimester events and the postpartum dose is given within 72 hours of birth to provide additional coverage when there's a confirmed RH positive baby. The presence of red blood cell antibodies at any time during pregnancy warrants a physician consultation for midwife providers. Red cell isoimmunization is not a normal finding and even maternal antibodies to lesser antigens sometimes will warrant close fetal monitoring. Fetal effects of isoimmunization usually present as recurrent early spontaneous miscarriage, abnormal fetal growth, or fetal immune hydrops. Hydrops fetalis is a condition characterized by an accumulation of fluid within fetal tissues and body compartments. Fetal hydrops stems directly from fetal anemia. Hydrops can occur in response to a handful of conditions, only one of which is isoimmunization. Hydrops occurs as the fetal red blood cells are attacked by the maternal antibodies and the fetal red blood cells become lysed, leaking their fluid into the circulatory system. The decreased number of red blood cells viable as a result of this lysing can cause cardiac and circulatory overload and eventually mass accumulation of fluid in the fetal tissues. The prognosis for fetuses affected by immune related hydrops is very grim. In milder cases, fetal red blood cell transfusion is sometimes performed using percutaneous umbilical blood sampling and transfusion until the baby can reach a level of maturity compatible with extrauterine life. Even then, the sequela of deoxygenation from a reduced amount of available hemoglobin and thereby oxygen in the fetal circulatory system still tends to have very grim prognosis for intact neurologic growth and development in the baby. In an earlier week of this course, we discussed the most common form of anemia during pregnancy, iron deficiency anemia. But another type of hematologic complication in pregnancy stems from forms of inherited anemias. The next section reviews the most common forms of heritable anemias that obstetric care providers should be familiar with. As a review, let's begin by looking at how anemia is defined in the pregnant woman. According to the CDC, lab value thresholds for diagnosing anemia during pregnancy varies from non-pregnant levels as well as by trimester. The lowest hemoglobin values can be expected during the second trimester when a state of physiologic hemodilution is common due to rapid increases in plasma volume and lagging increases in red blood cell production. Hemoglobin and hematocrit are standard serum measures that reflect the amount of functional iron in the body. These tests are low cost and relatively easy to perform. However, because changes in lab values occur only at later stages in iron deficiency, both are considered late indicators of oxygen carrying capacity changes for red blood cells when iron deficiency is suspected. On the other hand, heritable anemias are chronic conditions that can be exacerbated by the physiologic adaptation of the woman's body to pregnancy. Hemoglobin and hematocrit values in women affected by chronic heritable anemic conditions tend to be low at baseline and worsen in later stages of pregnancy as physiologic adaptations become superimposed. Heritable anemias are most commonly diagnosed during childhood, but occasionally milder forms may not present until early adulthood. It's also quite common for initial diagnosis of heritable anemias to occur during pregnancy, especially in individuals who may be immigrants to the United States or did not receive routine medical care during childhood. As we discussed earlier in this course, there are several variables which can affect hemoglobin and hematocrit values. Long term residency at high altitudes and cigarette smoking may cause a generalized upward shift in hemoglobin and hematocrit values. In terms of race and ethnicity, the distribution of hemoglobin concentration values are similar among white, Asian, and American Indians but lower among African-Americans. While there are no changes in interpretation of values based on race and ethnicity in clinical practice, a general awareness of these differences is very prudent. Of note, hemoglobin and hematocrit values can be obtained either through capillary blood sampling or through serum venipuncture. Note however, that squeezing the finger excessively during capillary blood based testing methods can affect specimen quality. Serum specimens are slightly more reliable, but more resource expensive. Anemia manifest as low hemoglobin and hematocrit levels but high hemoglobin and hematocrit values are not necessarily reassuring. For pregnant women, a test result greater than three standard deviations higher than the mean of the reference population, that is a hemoglobin value of greater than 15 grams per deciliter or a hematocrit value greater than 45% in most individuals, specifically during the second trimester likely indicates poor blood volume expansion. High hemoglobin and hematocrit values may be associated with hypertension, dehydration, and have been correlated with poor perinatal outcomes. Anemia of any type affects the oxygen carrying capacity of the maternal blood and thereby has potential to reduce the amount of oxygen available to the fetus. While there is some controversy in the literature about how much of an impact anemia has on perinatal outcomes, several studies have shown an increase in poor perinatal outcomes among women who are affected by anemia during pregnancy. In pregnancies affected by anemia, especially heritable anemias, fetal growth restriction during the second and third trimesters can be an issue. Additionally, some forms of heritable anemia can result in recurrent early pregnancy loss as tissue oxygenation can disrupt early implantation and placental bed vascularization. It's estimated by the World Health Organization that up to 40% of maternal deaths in third world countries can be attributed to anemia in general. While this statistic is mostly related to blood loss anemia and rates of postpartum hemorrhage at the time of birth, prenatal anemia can also play a role. Iron deficiency anemia represents the largest portion of anemias, but it's important to remember that heritable anemias have similar physiologic sequelae and their impact on perinatal health should not be overlooked. There have also been correlations between anemia and a woman's risk for preterm birth. Reduced oxygen in the form of chronic tissue hypoxia and hypoxemia can lead to inflammation and early initiation of the labor cascade. Likewise, fetuses who are not well oxygenated are subjected to physiologic stress that can cause early activation of fetal hypothalamic pituitary adrenal axis as an additional contribution to the labor onset. We mentioned that high hemoglobin and hematocrit values are problematic as well. Specifically, fetal growth abnormalities, such as intrauterine growth restriction have been associated with not only low hemoglobin levels, but also abnormally high hemoglobin and hematocrit levels. Anemia is classified as either acquired or hereditary. Most acquired forms of anemia are related to either nutritional deficiencies or acute blood loss. Hereditary anemias include genetic susceptibilities that can be influenced by drugs and the environment as well as genetic disease states. The focus of this week's content is to review the hereditary forms of anemia and the related clinical screening and management. There are also many forms of anemia related to chronic diseases, however. Things such as renal failure, malignancies, HIV, and chronic inflammatory conditions such as lupus and rheumatoid arthritis. Since midwives do not tend to care for women with chronic diseases independently, this lecture will omit these more complicated clinical forms of anemia in favor of focusing on those hereditary anemias that may be more common to midwifery practice. The first hereditary form of anemia that we'll examine is glucose 6 phosphate dehydrogenase deficiency or G6PD deficiency. This is just one of more than 20 hereditary red blood cell enzyme defects. G6PD is x-linked and the most common. G6PD anemia is a drug induced hemolytic anemia that results from genetic susceptibility to hemolysis of red blood cells. It's believed that G6PD deficiency probably confers some degree of protection against malarial infection and explains which populations it's most commonly found in. Mediterranean descent, Sephardic and Asiatic Jewish heritage and African subgroups are most commonly found to have the G6PD genetic defect. According to Creasy and Resnik, greater than 10% of African-American males are carrier of the G6PD gene. Approximately 400 million people worldwide are affected by G6PD deficiency. Anemia due to this deficiency, however, is episodic. That means that the anemia symptoms come and go as a result of their particular exposures to drugs or various nutritional components. In women who are heterozygous for the G6PD defect, symptoms can vary between normal G6PD activity and no symptoms all the way to clinical features that are similar to affected males. This means a few women with G6PD may be severely affected, but most only exhibit very mild forms of the disorder. It's estimated that 2% to 3% of African-American women in the United States are homozygous for G6PD defect, while approximately 10% to 25% of those women are heterozygous. Greeks, Sardinians, Sephardic Jews are the most common populations to carry the G6PD Mediterranean version of the disorder, a more severe form in which hemolysis is usually severe and favism occurs. Favism is a form of hemolytic disease that occurs in response to the consumption of fava beans. The G6PD deficient African-American population has not been reported to experience favism, however. Drugs that invoke the G6PD enzyme and contribute to hemolytic anemia in G6PD susceptible individuals include sulfonamides, nitrofurantoins, antipyretics, some analgesics, and some anti-malarial compounds. Aside from drugs and nutritional factors, surgery and infection can also trigger clinical anemia symptoms related to G6PD deficiency. The clinical features of G6PD deficiency in pregnancy is characterized by intermittent episodes of anemia related to when the woman has been exposed to a drug or nutritional agent that invokes G6PD enzymatic activity. Hemolysis presents as a reduction in the amount of functional hemoglobin and low serum hemoglobin and hematocrit values would be expected. In fact, 2/3 of cases presenting with G6PD hemolytic anemia will have a hemoglobin value lower than 10 grams per deciliter. Women affected by G6PD deficiency are at increased risk for UTIs. This has a duplicative effect on the risk of UTI in pregnancy due to normal physiologic adaptation. Just like with other forms of hemolytic anemia, women may report feeling fatigued or experience episodes of dizziness and fainting as a result of G6PD induced anemia. Clinically, we may see signs of tachycardia, jaundice, and hemoglobinuria indicative of G6PD deficiency. Severity of symptoms depends on the genetic makeup of the individual woman, whether she's homozygous or heterozygous and the quantity and duration of exposure to the provoking agent. Women may present during pregnancy with a new or established diagnosis of G6PD deficiency. If it is a new or suspected diagnosis, then the first step is to advise discontinuation of the provoking drug or food and obtain a physician consultation. It's also important to rule out other potential causes of anemia, such as iron deficiency or hemoglobinopathy. These conditions can co-exist with G6PD deficiency or may be important differential diagnoses to rule out. Given the increased risk of UTI with G6PD deficiency, it's important to screen regularly for asymptomatic bacteriuria and G6PD disease process. Standard care usually calls for at minimum a urinalysis and urine culture and sensitivity each trimester. More frequently, obviously if symptoms warrant. If bacterial infections occur in women with G6PD deficiency, prescribers should avoid use of oxidant medications, sulfonamides and nitrofurantoin specifically. Pre-existing G6PD deficiency would still warrant a physician consultation for a midwife unless the midwife is working in a population where G6PD deficiency is common and there are standing guidelines for clinical care that have been previously developed in conjunction with a physician consultant. Since G6PD hemolytic anemia is episodic in nature and can be prevented by avoidance of certain substances, affected women should be counseled about how to reduce their risk of G6PD related anemia. Fetal growth abnormalities would only be expected if a woman has a new diagnosis in pregnancy or if she is not compliant with avoiding provoking agents. Screening for G6PD deficiency is not routinely performed during pregnancy, but in women with a known diagnosis of G6PD it is reasonable to offer partner carrier testing to help predict the potential risk of the fetus being affected. Remember that G6PD inheritance follows an x-link pattern with more males than females being affected with severe disease. In women who present with anemia symptoms not explained by the common contributing factors of pregnancy or iron deficiency, further testing to rule out G6PD deficiency as a cause is recommended. However, midwives should be alert to notify pediatric providers of potential newborn heritable conditions any time a woman affected by G6PD deficiency gives birth. Spherocytosis is another heritable form of hemolytic anemia, but it differs from G6PD in that it's symptoms and sequela are not dependent on consumption of a provoking agent. Spherocytosis is a purely heritable anemia and it's fairly common. It affects two to three individuals out of 10,000, approximately 1,000 pregnancies each year. It is transmitted to offspring through an autosomal dominant inheritance pattern, but spherocytosis has a variable penetrance rate in the general population. So its inheritance is not always as easily predictable. Spherocytosis results from a genetic defect that causes structural changes in the erythrocyte membrane and instead of maintaining a biconcave disk shape, the red blood cell's membrane becomes more fragile and spherical in shape. These morphological changes result in a loss of red blood cell volume and a reduction in oxygen carrying capacity. Clinically, spherocytosis presents as a hemolytic crisis usually precipitated by infection, trauma, or pregnancy and diagnosis is based on a combination of factors. Family history, the presence of hyper proliferative anemia, which is demonstrated by changes to the complete blood cell count, specifically the reticulum sites. Diagnosis of spherocytosis is based on a confirmatory osmotic fragility test. In terms of prenatal care for women affected by spherocytosis, it really involves vigilant monitoring for acute hemolytic crisis. The folate supplementation is recommended and as long as the anemia is not severe, then there's not really has not been demonstrated an increase in perinatal morbidity or mortality. But as always, genetic counseling may be helpful and it may help to inform care planning for these clients. Elliptocytosis is another heritable form of hemolytic anemia, but it differs from spherocytosis in that it's symptoms and sequela tend to be much milder. The prevalence of elliptocytosis is difficult to estimate, as most forms of the disorder are mild in nature and often go undiagnosed. Rates appear highest among individuals of Mediterranean and African descent, however. Elliptocytosis results from a genetic defect that causes abnormal polarization of the hemoglobin molecule. Instead of maintaining a biconcave disk shape, the red blood cell membranes become distorted and elongated in shape. These morphological changes result in reduced hemoglobin binding capacity. Clinically, elliptocytosis presents similarly to spherocytosis, however, it's usually in a much less severe form. Diagnosis is also similar and heavily based on a combination of family history and anemia demonstrated by CBC abnormalities. Diagnosis for elliptocytosis can be confirmed by the presence of greater than 25% elliptocytes on a peripheral blood smear or an abnormal osmotic fragility test. Prenatal care for women affected by elliptocytosis is similar to spherocytosis and involves baseline evaluation of red blood cell indices and q trimester monitoring. M.D. Consultation and folate supplementation are also recommended for midwives providing care to women with elliptocytosis. Anemia generally remains mild for women affected and perinatal sequelae are rare when it comes to elliptocytosis. The next section of this lecture reviews hemoglobinopathies, another hematologic condition that can affect pregnancy health. Hemoglobinopathies are hereditary, but they differ in that not all of these conditions result in pathology. Hemoglobinopathies arise as a result of inheritance of abnormal hemoglobin variants. Some hemoglobin variants cause disease, others are considered non pathological. There are many normal hemoglobin variants. For this lecture, we'll be focusing on those important to consider when caring for pregnant women. A large number of genetic mutations have been described in the globin genes. These are found on chromosome 16. Genetic mutations of the globin genes can be divided into two distinct types, those that cause quantitative abnormalities, the thalassemias, and those that cause qualitative abnormalities, things like sickle cell anemia. Taken together, these disorders are referred to as the hemoglobinopathies. Thalassemia syndromes are the result of normal hemoglobin being synthesized at an abnormally slow rate, thus the title quantitative changes. Whereas structural hemoglobinopathies occur because the genetic alteration affects amino acid content in the hemoglobin molecule. The effect of structural changes can range from no effect to very profound effects in terms of hemoglobin function. When these conditions are compounded by physiologic adaptation of pregnancy, the concern is that pathologic hemoglobinopathies could negatively impact normal fetal growth and development. The image on this slide is provided as a review of the molecular structure of the hemoglobin molecule. Alterations in the various chains are the basis for hemoglobinopathies. You'll recall that hemoglobin is made up of four sub chains named by the Greek letters alpha and beta. There are two alpha chains and two beta chains. The alpha chains are responsible for producing most of the adult type hemoglobin, while the beta chains produce a smaller percentage. The heme molecule is the oxygen carrying component and is made up in part by iron. The maps on this slide show the distribution of various hemoglobinopathies throughout the world. At the top left, hemoglobin variants are shown by region of the world, whereas on the bottom right, the world distribution of thalassemias is depicted. As you can see, Mediterranean, African, Middle Eastern, and Southeast Asian populations have the highest prevalence of these disorders. Before we examine the specific types of hemoglobinopathies in more depth, let's review the types of human hemoglobin. Due to the developmental pattern of globin gene expression, different forms of hemoglobin are present at different times during the embryonic fetal and adult lifespans. The predominant embryonic forms are referred to as hemoglobin Gower one and hemoglobin Gower two. The fetal forms are identified as hemoglobin Portland and hemoglobin F, with hemoglobin F being the most abundant form during the fetal period. You'll recall, fetal hemoglobin has a slightly higher affinity for oxygen as compared to adult hemoglobin. In adults, the mature hemoglobin form is referred to as hemoglobin A. Hemoglobin A1 is the most prevalent with minor amounts of hemoglobin A2 formed from the alpha and delta globin proteins. There's almost always a small amount of hemoglobin F remaining in adults and can represent as much as one half of 1% of the total hemoglobin panel for the normal adult. Understanding the various types of hemoglobin across the lifespan and the expected ratio of each is important to understanding hemoglobinopathies. The thalassemias are the result of abnormalities in hemoglobin synthesis. Thalassemia syndromes are named and classified by the type of peptide sub chain that is inadequately produced in the hemoglobin molecule. The two most common types are alpha and beta thalassemia, both of which affect the synthesis of hemoglobin A. Deficiencies in A globin synthesis results in alpha thalassemia, whereas deficiencies in B globin synthesis result in beta thalassemia. Thalassemias are autosomal recessive, meaning that an offspring must inherit two abnormal gene variants in order to be affected. Thalassemias are further classified by their level of pathology, that is both alpha and beta thalassemias can be further described as having major or minor features. The severity of thalassemias depends on how many of the genes are defective. Alpha thalassemia is so named because of the genetic errors that affect hemoglobin production from the alpha chains of the hemoglobin molecule. Diagnosis of alpha thalassemia is presumptive and usually based on exclusion of iron deficiency and beta thalassemia. Most clients affected by alpha thalassemia will present with abnormal red blood cell indices, particularly a low MCV. In clients with alpha thalassemia, one or more hemoglobin production genes are physically absent from the genome. The various alpha thalassemia genotypes are summarized on the image here. With alpha thalassemia, the level of alpha globin production can range from none to very nearly normal levels. This is due in part to the fact that there are two identical alpha globin genes on chromosome 16, alpha globin gene one and globin gene two. Thus, the alpha thalassemias involve inactivation or deletion of one, two, three, or all four alpha globin genes. If only one gene is inactive, individuals are completely asymptomatic. This situation is also referred to as a silent carrier state or alpha thalassemia 2. If two of the four genes are inactive, individuals are designated as alpha thalassemia trait, also known as alpha thalassemia minor or alpha thalassemia 1. This results in mild hypothermic microcytic anemia that can be difficult to differentiate from iron deficiency without hemoglobin electrophoresis studies and genotyping. Alpha thalassemia 1 varies in how it manifests across ethnicities and races, shown here in the left versus right column of genotype depictions. In Africans, the most common two gene deletion state consist of one gene missing on each of the chromosomes. In Asians, however, it's more common that both genes are missing from the same chromosome. The most severe form of alpha thalassemia that's compatible with extrauterine life is called hemoglobin H disease. This results from an inactivation of three alpha globin genes. In these patients, abnormally high quantities of both hemoglobin H and hemoglobin Barts accumulate. Finally, in the homozygous state, all four genes of the alpha globin are inactive and no hemoglobin A chains will ever be produced. These cases usually result in stillbirth, as the fetus is unable to synthesize normal hemoglobin F or any of the adult hemoglobins. Prenatally, this deficiency manifests as a high output cardiac failure in the fetus along with fetal hydrops and then stillbirth. This condition is completely incompatible with extrauterine life. Beta thalassemia is so named because of genetic errors that affect hemoglobin production from the beta chains of the hemoglobin molecule. Whereas the primary cause of alpha thalassemia was deletion or inactivation of globin genes, beta thalassemia involves subtle mutations in these genes. A large number of mutations have been identified as leading to decreased or absent production of beta globin chains. In the most severe situation, both the maternal and paternal beta globin genes lead to a loss of normal amounts of beta globin protein. There may be a complete lack of hemoglobin A production or a reduced quantity of hemoglobin A produced. This depends on the pervasiveness of the mutations on the four globin genes. Diagnosis of beta thalassemia is presumptive and usually based on the exclusion of iron deficiency and findings from the hemoglobin electrophoresis. Most clients affected by beta thalassemia will present with abnormal red blood cell indices that are unresponsive to iron supplementation. And again, a low MCV, or mean corpuscular volume, less than 80 is usually a key clinical feature. In clients with beta thalassemia, one or more hemoglobin production genes are mutated. Severity of the disorder depends on whether the client is homozygous or heterozygous for the mutated gene. Homozygous mutation is referred to as beta thalassemia major and also sometimes called Cooley's anemia after the physician who first described the disorder. Affected individuals suffer from severe anemia beginning in the first year of life. This leads to the need for blood transfusions. As a consequence of the anemia, the bone marrow dramatically increases its effort at blood production and the overproduction results in thinned cortexes of bones that can result in fractures and facial and skull bone distortion. There's usually marked hepatosplenomegaly as the liver and spleen act as additional sites of blood production. Without intervention, individuals affected with beta thalassemia major usually die within the first couple decades of life. On the other hand, individuals who are heterozygous for beta thalassemia mutations are referred to as having beta thalassemia minor. Affected individuals harbor one or more normal beta globin genes and then one gene that harbors a mutation. The mutated gene leads to a production of beta globin that is reduced or absent. Beta thalassemia minor clients are generally asymptomatic. The most common thalassemia encountered by midwives in clinical practice is beta thalassemia minor. Clinical diagnosis is based on red blood cell indices and hemoglobin electrophoresis. Initial diagnosis usually follows the finding of a low serum hemoglobin, sometimes as low as 8 grams per deciliter, and a mean corpuscular volume less than 80. Beta thalassemia minor presents as chronic microcytic anemia. Hemoglobin electrophoresis of the hemoglobin types will reveal a hemoglobin A2 percentage greater than 3.5 and a hemoglobin F percentage greater than 2. Both of these hemoglobin types are usually much smaller in percentage in a normal adult. In terms of management of pregnancies affected by thalassemia, most clients with severe cases of alpha or beta thalassemia are either infertile or are managed by perinatology. General principles for prenatal care include routine antenatal fetal assessment in the second and third trimesters monitoring for intrauterine growth restriction and oligohydramnios, as the incidence of these features have a two-fold increase in thalassemia. Usually iron supplementation is needed and should be started prophylactically even if red blood cell indices are normal or low normal in early pregnancy. Folate supplementation is also recommended, as the addition of folate helps to increase available hemoglobin chains oxygen carrying capacity. Due to the heritable nature of thalassemias, genetic counseling is warranted and prenatal genetic diagnosis is available for the fetus. Also note that compound inheritance is possible with some forms of thalassemia. For example, individuals can be heterozygous for both alpha thalassemia and beta thalassemia or they could inherit both sickle cell trait and beta thalassemia trait. These compound inheritance patterns make for a much more complex genetic and clinical picture. The later situation is referred to as sickle cell beta thalassemia. This slide summarizes perinatal outcomes for each of the thalassemia types. Alpha major affects women by making them sterile and affects fetuses severely. Fetuses are generally unable to make fetal hemoglobin if they're affected by alpha major. This usually results in severe fetal hydrops and/or stillbirth. Alpha thalassemia minor shows clinically as affected women who tolerate pregnancy rather well as long as they have iron supplementation. Affected fetuses usually do equally as well, but need to be monitored for signs and symptoms of fetal hydrops, especially if their genotype is not known. Other genetic consequences include that if an infected individual mates with a reproductive partner who is missing a single allele, then their offspring could be affected by hemoglobin H disease. In terms of beta thalassemia major, females who are fortunate enough to survive beyond childhood usually are sterile and life expectancy even with transfusion therapy is much shortened. Affected fetuses are usually healthy at birth, but as their hemoglobin F level falls and adult hemoglobins prevail, the infant will become severely anemic and begin to fail to thrive. Beta thalassemia minor is usually associated with good outcomes for both affected women and affected fetuses. And in terms of who is actually a carrier of thalassemia, it's estimated that the incidence of thalassemia traits in pregnant women is approximately 1 in 300 to 1 in 500 for all races. So it's quite likely that in your career as a midwife you will see some cases of thalassemia, either as an initial diagnosis or as management of an ongoing chronic diagnosis. Beta thalassemia trait is most prevalent among Greeks, Italians, some Arabs, and Sephardic Jews. Alpha thalassemia trait is more common among Chinese, Vietnamese, Cambodians, and Laotians. Both alpha and beta thalassemia traits can be quite common in African-Americans. The algorithm on this slide is a suggested clinical approach for maternal screening for alpha and beta thalassemia. Routine screening of all women is not recommended in pregnancy, but rather women who present with low hemoglobin levels that are unresponsive to iron supplementation or for whom there are abnormal red blood cell indices on the initial CBC warrant further follow up. The most common clinical presentation in pregnancy is a low serum hemoglobin and a low mean corpuscular volume. From there, the recommended workup is for iron studies including serum ferritin and a total iron binding capacity or transferrin saturation. Also, hemoglobin electrophoresis. The results of iron studies helped to rule out Iron deficiency anemia but also help build the case for whether thalassemia is present. Prenatal fetal diagnosis including pre-implantation genetic diagnosis is now available for alpha and beta thalassemia using fetal blood or fetal DNA obtained from amniocentesis or chorionic villa sampling. This may be a consideration if the genetic history of the woman and/or her reproductive partner suggests a risk of thalassemia inheritance for the baby. We've talked a lot about hemoglobin electrophoresis. As clinicians, we use a hemoglobin electrophoresis to determine an individual's hemoglobin makeup. Interpretation of the hemoglobin electrophoresis aids in identification of the predominant hemoglobin type and helps to rule in or out the various hemoglobinopathies. The overall hemoglobin composition in normal adults is made up of hemoglobin A and hemoglobin F. It's the expected balance of these types of hemoglobin that we compare when interpreting electrophoresis results. In normal adults, there are two types of hemoglobin A, hemoglobin A1 and hemoglobin A2. Hemoglobin A1 should make up the largest proportion of hemoglobin. It should be present and represent at least 95% of the total hemoglobin in the adult. The actual percentage of hemoglobin A1 will vary between 95 and 98% based on the presence and percentage of other hemoglobin types. Hemoglobin A2 is usually also present, but in normal adults it's percent contribution to total hemoglobin should be less than 3%. We mentioned that hemoglobin F, the fetal hemoglobin, is also present in adults but it is present in very small amounts. Hemoglobin F should be less than 2%, but it can range from 0.5% to 2% normally. The values on this slide are typical of a standard hemoglobin electrophoresis report for a normal adult. Whereas thalassemia syndromes caused changes in the amount of normal hemoglobin produced, structural hemoglobinopathies such as sickle cell disease are the result of abnormal hemoglobin structure. Several hundred variants of hemoglobin chains have been identified. Most differ from normal chains by a single amino acid. The nomenclature and frequency of the most common structural hemoglobinopathies are on this slide. Confirmation of a diagnosis of specific hemoglobin variant requires hemoglobin electrophoresis. Sickle cell disease is an inherited autosomal recessive disorder expressed as sickle cell anemia, sickle cell hemoglobin C disease, or sickle cell beta thalassemia disease. Sickle cell disease is characterized by the production of abnormal hemoglobin S within the urethra sites and is the most common of all inherited anemias. Hemoglobin S causes red blood cells to morph from a biconcave disk to a curved elliptical shape similar to a cutting blade known as a sickle. Individuals who are homozygous for the gene variant that produces hemoglobin S are referred to as having the SS genotype, whereas both s's are capitalized. This occurs in approximately 1 in 400 to 1 in 500 live African-American births in the United States. For women affected with sickle cell disease, there are high rates of maternal mortality during pregnancy. Additionally, more than a third of these pregnancies will end in miscarriage, stillbirth, or neonatal death. Individuals who are heterozygous for the gene variant that produces hemoglobin S are referred to as having sickle cell trait and represented by the genotype SS, whereby there is a single capital S and a single lowercase s. This occurs in approximately 1 in 12 live African-American births that translates to a prevalence rate of approximately 7 to 13% of African-Americans in the United States having sickle cell trait. East African descendants are particularly high prevalences approaching 45% at the latest World Health Organization estimate. Again, hemoglobin S is believed to be a protective factor against lethal forms of malaria, a genetic advantage to those carriers who reside in endemic regions for malaria such as the Mediterranean and African zones. But there's no such advantage to carriers living in the United States. As previously mentioned during the thalassemia slides, compound inheritance of both sickle cell and beta thalassemia can occur. The prevalence of this is estimated at 1 in 2,000 live births. Sickle cell inheritance can also be combined with something known as hemoglobin C disease which occurs in a similar prevalence to sickle cell beta thalassemia disease. Sickle cell trait combined with hemoglobin C trait is known as sickle cell C disease and is denoted by the genotype capital S capital C. This condition usually presents much milder symptoms than that of true sickle cell hemoglobin S disease. In non-pregnant women, there's less morbidity and mortality, as well as fewer than half of women will ever be symptomatic prior to pregnancy. Pregnancy is different, however. In an 18 year research study from Parkland Hospital in Dallas, Texas, maternal mortality with sickle cell hemoglobin C disease, that maternal mortality rate was 2%. That rate alone makes maternal death from sickle cell C disease as common as with sickle cell S disease. Sickle cell beta thalassemia has the mildest clinical manifestations of all sickled cell diseases. The normal hemoglobin, particularly hemoglobin F, helped to inhibit sickling. In addition, the erythrocytes tend to be small, microcidic and they contain relatively little hemoglobin, making them hypochromic. These characteristics make these erythrocytes much less likely to occlude the microcirculation, even if they are in a sickled state. Given the high prevalence of sickle cell trait in the US population, midwives often find themselves caring for these women during pregnancy. In terms of perinatal risk for women affected by sickle cell trait, there is no increase in the risk of miscarriage, perinatal mortality, low birth weight, or gestational hypertension. Some studies have shown an increase in the risk of pre-eclampsia, however, with rates as high as 25% in those women affected with sickle cell trait as compared to rates of pre-eclampsia in non sickle cell trait women, quoted around 10%. Sickle cell trait doubles the woman's risk for asymptomatic bacteriuria and urinary tract infection. This translates to the need for every trimester urine culture insensitivity and a low threshold for clinical screening of infection when dysuria symptoms are present. Pyelonephritis is also more common, not only due to normal pregnancy adaptations, but also biochemical alterations related to the presence of abnormal hemoglobin variants. Aside from clinical management of risk, there's also concern for fetal inheritance of sickle cell trait or disease. Genetic counseling and partner carrier screening are important hallmarks of clinical practice when it comes to caring for women with sickle cell trait. Midwives may be involved in the care of women with sickle cell disease as part of co-management or when employed in high risk perinatal settings. As a reminder, hemoglobin S is formed by a genetic mutation and becomes the predominant type of hemoglobin in women with sickle cell disease. Hemoglobin S reacts to deoxygenation and dehydration by solidifying and stretching the erythrocyte into an elongated sickle shape. This produces a hemolytic anemia. All signs and symptoms of sickle cell anemia are secondary to hemolysis, vaso occlusive disease, and the increased susceptibility to infection. A daily supplement of folic acid is recommended for women with sickle cell disease. And the clinical risk manifest in terms of increased risk of preterm labor and birth as well as fetal growth restriction. Inheritance is again a concern and there are both prenatal fetal diagnostics and pre-implantation genetic test available for fetal diagnosis of sickle cell disease. Midwives occasionally are called to evaluate and provide care to pregnant women who are in sickle cell crisis. Sickle cell crisis is a serious obstetrical and medical problem that causes not only anemia, but also severe pain. Hallmarks of care during these situations are for close observation of both maternal fetal status, particularly evaluation of fetal oxygenation. During an acute crisis, IV fluids, supplemental oxygen, supportive therapy, and pain management are central. Ongoing fetal assessment with continuous electronic fetal monitoring and other tests of fetal well-being may be necessary. And these modalities are often used in serial assessments over time during sickle crisis. Hemoglobin S is the most common and most significant hemoglobin variant. There are, however, other variant hemoglobin that may show up on a hemoglobin electrophoresis. Specifically, hemoglobin C and hemoglobin E. As with other hemoglobin inheritance patterns, individuals who are heterozygous are usually asymptomatic because they have hemoglobin A in their repertoire. But for those individuals who are homozygous for hemoglobin C or hemoglobin E production, then there may be a disease state present. Notably, hemoglobin C and E disease states are usually significantly milder than hemoglobin S disease states. In fact, there has been shown to be no increased morbidity or mortality associated with either hemoglobin C or hemoglobin E in pregnant women. The next section of this lecture reviews platelet and clotting disorders that can affect pregnancy health. These conditions can be either hereditary or acquired. Thrombocytopenia is a condition characterized by low serum platelet counts. In general, the accepted clinical diagnostic threshold is less than 150,000 platelets per microliter. Of note, bleeding times in adults are rarely altered from normal until platelet counts reach less than 50,000, however. Thrombocytopenia can be either pregnancy related or a chronic pre-existing condition. There are several possible causes, mostly immune, autoimmune, or hypertensive in nature. Although there are some drugs that can reduce platelet activity and quantity, these drugs are rarely given during pregnancy. Thrombocytopenia has significant implications for antenatal and intrapartum care. Route of birth may need to be altered to help control blood loss or to optimally time birth. Invasive procedures such as amniocentesis or chorionic villa sampling may need to be avoided and the use of spinal and regional anesthesia such as epidurals may be contraindicated due to the risk of subdural hematoma formation. Midwives typically care for women with thrombocytopenia in consultation with physicians or through collaborative management arrangements. Antiphospholipid syndrome is a condition whereby antibodies are produced in response to phospholipid bound blood proteins. These antibody complexes contribute to an increased risk of blood clots and poor pregnancy outcomes. The clinical presentation of antiphospholipid syndrome is usually characterized by one or more of the following, recurrent unexplained early miscarriage, recurrent stillbirth, abnormal fetal growth for which there's no other explanation, severe early onset pre-eclampsia, or unexplained blood clot formation. Diagnosis of antiphospholipid syndrome involves both genetic studies as well as clotting time studies. Intrapartum care for women affected by antiphospholipid syndrome usually includes multiple anticoagulation therapies such as heparin or low molecular weight heparin in addition to low dose aspirin. Fetal surveillance is important with monthly growth ultrasounds and twice weekly fetal testing beginning at term usually recommended. Midwives may find themselves providing care for women with antiphospholipid syndrome, but usually that care is provided in consultation with physicians or via collaborative management situations. Thrombophilias are inherited conditions characterized by genetic mutations that predispose individuals to venous clot formation. There are various types of thrombophilias, each depending on the underlying gene alteration. The most common and influential of these on pregnancy outcomes are factor V Leiden and protein S and protein C deficiencies. It's estimated that up to 50% or 60% of thromboembolic events in pregnancy can be attributed to thrombophilias. Thrombophilia testing is available, but it tends to be very expensive and is usually reserved for retrospective application following a clotting event. Evidence on prenatal care of women with thrombophilias is rapidly evolving. Current evidence suggests that anticoagulation therapy be reserved for women who are either compound heterozygotes, for multiple thrombophilia mutations, or for women who have personal or family histories of unexplained blood clots. Fetal surveillance is generally recommended starting at near term gestational ages such as 36 weeks, and midwives routinely provide care for these women with uncomplicated thrombophilias. In instances of complicated thrombophilias, consultation, collaboration, or referral may be indicated depending on the individual circumstances of the woman. Thromboembolism refers to venous blood clots that are either stable or migratory. Normal pregnancy physiology increases the risk of venous thrombolic events and symptoms of these conditions can be masked by common discomforts of pregnancy. Symptoms of thromboembolism vary depending on the location of the clot, with most common sites for clotting being either deep vein thrombosis of the lower extremities or pulmonary embolism. DVT's are more common during the prenatal period, whereas pulmonary embolism is more likely during labor, birth, and the postpartum period. Symptoms of DVT include unilateral swelling, pain, and discoloration of the affected extremity. Pulmonary embolism usually presents as chest pain, difficulty breathing, or sudden cardiac and respiratory arrest. Diagnosis of embolism is based on lab studies and imaging of the affected areas and most commonly requires specialty level consultation and collaboration for interpretation. If a woman has a history of unexplained DVT or PE, then prophylactic anticoagulation may be warranted during pregnancy. And if a DVT or PE occurs during pregnancy, treatment consists of anticoagulation and supportive therapy. Midwives may find themselves involved in the screening, diagnosis, and treatment of thromboembolism during pregnancy, but generally an interdisciplinary approach is warranted for these situations. This lecture has covered the spectrum of most common hematologic disorders that can affect pregnancy. It's important to remember that midwifery management of most of these conditions should include at minimum physician consultation. While in some cases, independent midwifery management may be warranted such as cases of simple iron deficiency anemia, other more serious hematologic disorders may rely on collaborative care or referral outside of the midwifery practice.