Obstentrics_Williams

Obstentrics_Williams. Although commonly regarded as a hemolytic anemia, this hemopoietic stem cell disorder is characterized by formation of defective platelets, granulocytes, and erythrocytes. Paroxysmal nocturnal hemoglobinuria is acquired and arises from one abnormal clone of cells, much like a neoplasm (Luzzatto, 2015). One mutated X-linked gene responsible for this condition is termed PIG-A because it codes for phosphatidylinositol glycan protein A. Resultant abnormal anchor proteins of the erythrocyte and granulocyte membrane make these cells unusually susceptible to lysis by complement (Provan, 2000). The most serious complication is thrombosis, which is heightened in the hypercoagulable state of pregnancy.


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Obstentrics_Williams. Chronic hemolysis has an insidious onset, and its severity ranges from mild to lethal. Hemoglobinuria develops at irregular intervals and is not necessarily nocturnal. Hemolysis may be initiated by transfusions, infections, or surgery. Almost 40 percent of patients sufer venous thromboses and may also experience renal failure, hypertension, and Budd-Chiari syndrome. Because of the thrombotic risk, prophylactic anticoagulation is recommended (Parker, 2005). The treatment of choice is eculizumab, an antibody that inhibits complement activation (Kelly, 2015). Median survival after diagnosis is 10 years, and bone marrow transplantation is the deinitive treatment.


Obstentrics_Williams

Obstentrics_Williams. During pregnancy, paroxysmal nocturnal hemoglobinuria can be serious and unpredictable. Complications have been reported in up to three fourths of afected women, and the maternal mortality rate in the past was 10 to 20 percent (De Gramont, 1987; de Guibert, 2011). Complications more often develop postpartum, and half of afected women develop venous thrombosis (Fieni, 2006; Ray, 2000). Kelly and colleagues (2015) described 75 pregnancies in 61 afected women treated with eculizumab. In half of these, the dose was increased during pregnancy. They described no maternal deaths but 4 percent stillbirths.


Obstentrics_Williams

Obstentrics_Williams. he most fulminant acquired hemolytic anemia encountered during pregnancy is caused by the exotoxin of Clostridium petingens or by group A J-hemolytic streptococcus (Chap. 47, p. 922). Endotoxin of gram-negative bacteria, that is, lipopolysaccharide, may be accompanied by hemolysis and mild-to-moderate anemia (Cox, 1991). For example, anemia often accompanies acute pyelonephritis. With normal erythropoietin production, red cell mass is restored following infection resolution as pregnancy progresses (Cavenee, 1994; Dotters-Katz, 2013).


Obstentrics_Williams

Obstentrics_Williams. he normal erythrocyte is a lexible biconcave disc that allows numerous cycles of reversible deformations. Several genes encode expression of erythrocyte structural membrane proteins or intraerythrocytic enzymes. Various mutations of these genes may result in inherited membrane defects or enzyme deiciencies that destabilize the lipid bilayer. The loss of lipids from the erythrocyte membrane causes a surface area deficiency and poorly deformable cells that undergo hemolysis. Anemia severity depends on the degree of rigidity or decreased distensibility. Erythrocyte morphology similarly is dependent on these factors, and these disorders are usually named after the most dominant red-cell shape characteristic of the disorder. hree examples are hereditary spherocytosis) pyropoikilocytosis, and ovalocytosis.


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Obstentrics_Williams. Hereditary Spherocytosis. Hemolytic anemias that compose this group of inherited membrane defects are among the most common hemolytic anemias found in gravidas. Mutations are usually an autosomally dominant, variably penetrant spectrin deiciency. Others are autosomally recessive or de novo gene mutations that result from deiciency of ankyrin) protein 4.2, moderate band 3, or combinations of these (Gallagher, 2010; Rencic, 2017; Yawara, 2000). The degrees of anemia and jaundice vary, and diagnosis is conirmed by identiication of spherocytes on peripheral smear and increased osmotic fragility.


Obstentrics_Williams

Obstentrics_Williams. Spherocytic anemias may be associated with a so-called crisis that is characterized by severe anemia from accelerated hemolysis, and it develops in patients with an enlarged spleen. Infection can also accelerate hemolysis or suppress erythropoiesis to worsen anemia. An example of the latter is infection with parvovirus B19 (Chap. 64, p. 1216). In severe cases, splenectomy reduces hemolysis, anemia, and jaundice.


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Obstentrics_Williams. Pregnancy. In general, women with inherited red-cell membrane defects do well during pregnancy. Folic acid supplementation of 4 mg daily is given orally to sustain erythropoiesis. Women with hereditary spherocytosis cared for at Parkland Hospital had hematocrits ranging from 23 to 41 volumes percent mean 31 (Maberry, 1992). Reticulocyte counts ranged from 1 to 23 percent. Among 50 pregnancies in 23 women, eight women miscarried. Four of 42 infants were born preterm, but none was growth restricted. Infection in four women intensified hemolysis, and three of these required transusions. Similar results were reported by Pajor and coworkers (1993). Because these disorders are inherited, the newborn may be afected. Celkan and Alhaj (2008) report prenatal diagnosis via cordocentesis at 18 weeks' gestation and testing for osmotic fragility. Newborns with hereditary spherocytosis may manifest hyperbilirubinemia and anemia shortly after birth.


Obstentrics_Williams

Obstentrics_Williams. n intraerythrocytic deficiency of enzymes that permit anaerobic glucose metabolism may cause hereditay nonspherocytic anemia. Most of these mutations are autosomal recessive traits. As discussed earlier (p. 1078), most episodes of severe anemia with enzyme deficiencies are induced by drugs or infections. Pyruvate kinase deficiency is associated with variable anemia and hypertensive complications (Wx, 2007). Due to recurrent transfusions in homozygous carriers, iron overload is frequent, and associated myocardial dysfunction should be monitored (Dolan, 2002). The fetus that is homozygous for this mutation may develop hydrops ttalis from anemia and heart failure (Chap. 15, p. 309).


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Obstentrics_Williams. Glucose-6-phosphate dehydrogenase (G6PD) deiciency is complex because there are more than 400 known enzyme variants. he most common are caused by a base substitution that leads to an amino acid replacement and a broad range of phenotypic severity (Luzzatto, 2015; Puig, 2013). In the homozygous or A variant, both X chromosomes are afected, and erythrocytes are markedly deicient in G6PD activity. Approximately 2 percent of African-American women are afected, and the heterozygous variant is found in 10 to 15 percent (Mockenhaupt, 2003). In both instances, random X-chromosome inactivation-yonization-results in variable enzyme activity.


Obstentrics_Williams

Obstentrics_Williams. During pregnancy, infections or drugs can induce hemolysis in G6PD deficiency heterozygotes or homozygotes, and severity is related to enzyme activity. Anemia is usually episodic, although some variants induce chronic nonspherocytic hemolysis. Because young erythrocytes contain more enzyme activity, anemia ultimately stabilizes and is corrected soon after the inciting cause is eliminated. Newborn screening for G6PD deiciency is not recommended by the American College of Obstetricians and Gynecologists (20 16b).


Obstentrics_Williams

Obstentrics_Williams. Aplastic anemia is a grave complication that is characterized by pancytopenia and markedly hypocellular bone marrow (Young, 2015). There are multiple etiologies, and at least one is linked to autoimmune diseases (Stalder, 2009). he inciting cause can be identified in approximately a third of cases. These include drugs and other chemicals, infection, irradiation, leukemia, immunological disorders, and inherited conditions such as Fanconi anemia and Diamond-Backon syndrome (Green, 2009; Lipton, 2009). The functional defect appears to be a marked decrease in committed marrow stem cells.


Obstentrics_Williams

Obstentrics_Williams. Hematopoietic stem-cell transplantation is optimal therapy in a young patient (Killick, 2016). Immunosuppressive therapy is given, and in some nonresponders, eltrombopag has been successful (Olnes, 2012; Townsley, 2017). Deinitive treatment is bone marrow transplantation, and approximately three fourths of patients have a good response and long-term survival (Rosenfeld, 2003). Umbilical cord blood-derived stem cells can also serve as a potential transplant source (Moise, 2005; Pinto, 2008). Previous blood transfusions and even pregnancy enhance the risk of graft rejection (Young, 2015).


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Obstentrics_Williams. Hypoplastic or aplastic anemia complicating pregnancy is rare. A study of 60 pregnancies complicated by aplastic anemia found that half were diagnosed during pregnancy (Bo, 2016). There are a few well-documented cases of pregnancy-induced hypoplastic anemia, and the anemia and other cytopenias improve or remit following delivery or pregnancy termination (Bourantas, 1997; Choudhry, 2002). In some cases, anemia recurred in a subsequent pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Diamond-Blackon anemia is a rare form of pure red-cell hypoplasia. Approximately 40 percent of cases are familial and have autosomal dominant inheritance (Orfali, 2004). The response to glucocorticoid therapy is usually good. Continuous treatment is necessary, and most become at least partially transfusion dependent (Vlachos, 2008). In 64 pregnancies complicated by this syndrome, Faivre and associates (2006) reported that two thirds had problems related to placental vascular etiologies that included miscarriage, preeclampsia, preterm birth, fetal-growth restriction, or stillbirth.


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Obstentrics_Williams. Gaucher disease is an autosomally recessive lysosomal enzyme deficiency characterized by deficient activity of acid >-glucosidase. Afected women have anemia and thrombocytopenia that is usually worsened by pregnancy (Granovsky-Grisaru, 1995). Elstein and colleagues (1997) described six pregnant women whose disease improved when they were given alglucerase enzyme replacement. Imiglucerase therapy, which is human recombinant enzyme replacement therapy, has been available since 1994. European guidelines recommend treatment in pregnancy, whereas the Food and Drug Administration states it may be given with "clear indications" (Granovsky-Grisaru, 2011).


Obstentrics_Williams

Obstentrics_Williams. he major risks with hypoplastic anemia are hemorrhage and infection. Rates of preterm labor, preeclampsia, fetal-growth restriction, and stillbirth are increased (Bo, 2016). Management depends on gestational age, and supportive care includes continuous infection surveillance and prompt antimicrobial therapy. Granulocyte transfusions are given only during infections. Red cells are transfused to improve symptomatic anemia and routinely to maintain the hematocrit at or above 20 volumes percent. Platelet transfusions may be needed to control hemorrhage. Maternal mortality rates reported since 1960 have averaged nearly 50 percent, however, better outcomes have been reported more recently (Choudhry, 2002; Kwon, 2006).


Obstentrics_Williams

Obstentrics_Williams. Several reports describe successful pregnancies in women who have undergone bone marrow transplantation (BorgnaPignatti, 1996; Eliyahu, 1994). In their review, Sanders and coworkers (1996) reported 72 pregnancies in 41 women who had undergone transplantation. In the 52 pregnancies resulting in a liveborn neonate, almost half were complicated by preterm delivery or hypertension. Our experiences with a few of these women indicate that they have normal pregnancy-augmented erythropoiesis and total blood volume expansion. Excessive erythrocytosis during pregnancy is usually related to chronic hypoxia from maternal congenital cardiac disease or a chronic pulmonary disorder. Unusually heavy cigarette smoking can cause polycythemia. We have encountered otherwise healthy pregnant women who were heavy smokers, had chronic bronchitis, and had hematocrits ranging from 55 to 60 volumes percent! If polycythemia is severe, the probability of a successful pregnancy outcome is low.


Obstentrics_Williams

Obstentrics_Williams. This is a primary clonal myeloproliferative hemopoietic stemcell disorder characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic precursors (Spivak, 2015; Vannucchi, 2015). Virtually all patients have either aJA2V617F or aJA2 exon 12 gene mutation (Harrison, 2009). Symptoms are related to increased blood viscosity, and thrombotic complications are common. Treatment of nonpregnant patients is with hydroxyurea or ruxolitinib (Vannucchi, 2015). Fetal loss rates are high in women with polycythemia vera, and pregnancy outcome may be improved with aspirin therapy (Griesshammer, 2006; Robinson, 2005; Teferi, 2000). Women with a history of venous thrombosis are given prophylaxis with low-molecular-weight heparin. If cytoreduction is required during pregnancy, interferon alpha may be considered (Kreher, 2014).


Obstentrics_Williams

Obstentrics_Williams. Hemoglobin A is the most common hemoglobin tetramer and consists of two .-and two 3-chains. In contrast, sickle hemoglobin (hemoglobin S) originates from a single 3-chain substitution of glutamic acid by valine, which stems from an A-for-T substitution at codon 6 of the 3-globin gene. Hemoglobinopathies that can result in clinical features of the sickle-cell syndrome include sickle-cell anemia (Hb SS); sickle-cell hemoglobin C disease (Hb SC); sickle-cell 3-thalassemia disease (either Hb SI or Hb S/B+); and sickle-cell E disease (Hb SE) (Benz, 2015). All are also associated with increased pregnancy morbidity.


Obstentrics_Williams

Obstentrics_Williams. Sickle-cell anemia results from the inheritance of the gene for S hemoglobin from each parent. In the United States, 1 of 12 African-Americans has sickle-cell trait, which results from inheritance of one gene for hemoglobin S and one for normal hemoglobin A. he computed incidence of sickle-cell anemia among frican-Americans is 1 in 576 (1112 X 1112 X 114 = 11576). But, the disease is less common in adults because of earlier mortality. Hemoglobin C originates from a single 3-chain substitution of glutamic acid by lysine, which stems from a T -forC substitution at codon 6 of the 3-globin gene. Approximately 1 in 40 African-Americans has the gene for hemoglobin C. Thus, the theoretical incidence for co inheritance of the gene for hemoglobin S and an allelic gene for hemoglobin C in an frican-American child is about 1 in 2000 (1/12 X 1140 X 114). 3-halassemia minor is approximately 1 in 40, thus S-3-thalassemia also is found in approximately 1 in 2000 (1/12 X 1140 X 114).


Obstentrics_Williams

Obstentrics_Williams. Red cells with hemoglobin S undergo sickling when they are deoxygenated, and the hemoglobin aggregates. Constant sickling and unsickling cause membrane damage, and the cell may become irreversibly sickled. Events that slow erythrocyte transit through the microcirculation include adhesion to endothelial cells, erythrocytic dehydration, and vasomotor dysregulation. Clinically, the hallmarks of sickling episodes are periods during which there is ischemia and infarction in various organs. The sickle-cell crisis produces clinical symptoms, predominately pain, which is often severe. There may be aplastic, megaloblastic, sequestration, and hemolytic crises.


Obstentrics_Williams

Obstentrics_Williams. Chronic and acute changes from sickling include bony abnormalities such as osteonecrosis of femoral and humeral heads, renal medullary damage, autosplenectomy in homozygous SS patients and splenomegaly in other variants, hepatomegaly, ventricular hypertrophy, pulmonary infarctions, pulmonary hypertension, cerebrovascular accidents, leg ulcers, and a propensity for infection and sepsis (Benz, 2015; Gladwin, 2004). Other sequelae are cerebrovascular aneurysms and sickle-cell vasculopathy (Buonanno, 2016). Pulmonary hypertension can develop and is found in 20 percent of adults with SS hemoglobin (Gladwin, 2008).


Obstentrics_Williams

Obstentrics_Williams. Good supportive care is essential to prevent mortality. Speciic therapies are evolving, and many are still experimental. One treatment is hemoglobin F induction with drugs that stimulate gamma-chain synthesis. This increases hemoglobin F, which inhibits hemoglobin S polymerization. One example is hydroyurea, which augments hemoglobin F production and reduces the number of sickling episodes (Platt, 2008). Hydroxyurea is teratogenic in animls, although a preliminary 17 -year surveillance of antenatally exposed children was reassuring (Ballas, 2009; Briggs, 2015; Italia, 2010). A randomized trial showed no benefit from treatment with prasurel, a platelet inhibitor (Henney, 2016). Treatment with crianlizumab, an antibody against P-selectin, signiicantly lowered the incidence of adverse events (Ataga, 2017).


Obstentrics_Williams

Obstentrics_Williams. Various forms of hemopoietic cell transplantation are emerging as "cures" for sicle-cell syndromes and severe thalassemias (Hsieh, 2009). Oringanje and coworkers (20l3) performed a Cochrane review and found that only observational studies have been reported. Bone marrow transplantation has 5-year survival rates that exceed 90 percent (DaIle, 20l3). Cord-blood stem-cell transplantation from related donors also shows great promise (Shenoy, 2013). Finally, successful gene therapy has been accomplished by lentiviral vector-mediated addition of a beta globin gene into stem cells (Ribeil, 2017). only after all other possible causes have been excluded. Pain TABLE 56-2. Pregnancy Morbidity with Hemoglobin SS with sickle-cell syndromes is caused by intense sequestration of sickled erythrocytes and infarction in various organs, especially Odds Ratios Oukome Hb.SS Hb.SC bone marrow. These episodes may develop acutely, especially


Obstentrics_Williams

Obstentrics_Williams. Odds Ratios Oukome Hb.SS Hb.SC bone marrow. These episodes may develop acutely, especially Preeclampsia 2-3.1 late in pregnancy, during labor and delivery, and early in the 2.0 puerperium. Stillbirth 6.5 3.2 Preterm delivery 2-2.7 1.5 Growth restriction 2.8-3.9 1.5 Data from metaanalyses by Boafor, 201n6; Oteng-Ntim, 2015.


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Obstentrics_Williams. Stillbirth 6.5 3.2 Preterm delivery 2-2.7 1.5 Growth restriction 2.8-3.9 1.5 Data from metaanalyses by Boafor, 201n6; Oteng-Ntim, 2015. Pregnancy is a serious burden to women with any of the major sickle hemoglobinopathies, particularly those with hemoglobin SS disease. Several large studies have defined this relationship. Villers and colleagues (2008) studied 17,952 births in women with sickle-cell syndromes. Chakravarty and associates (2008) studied 4352 pregnancies. A more recent cohort study of 1526 women was reported by Boulet and coworkers (2013). Last, a cohort study taken from more than 2 million women compared those with sickle-cell disease to normal controls (Kuo, 2016). Common obstetrical and medical complications and their relative risks from a composite of most of these studies are shown in Table 56-2.


Obstentrics_Williams

Obstentrics_Williams. Maternal morbidity common in pregnancy includes ischemic necrosis of multiple organs, especially bone marrow that causes episodes of severe pain. Pyelonephritis, pneumonia, and pulmonary complications are frequent. Although the maternal mortality rate has improved, perinatal morbidity and mortality rates remain formidable (Boga, 2016; Lesage, 2015; Yu, 2009). Perinatal outcomes include increased risks for preterm birth, fetal-growth restriction, and perinatal mortality. In nonpregnant women, morbidity and mortality rates from SC disease are appreciably lower than those from sickle-cell anemia. Indeed, fewer than half of these women have symptoms before pregnancy. In our experiences, afected gravidas sufer attacks of severe bone pain and episodes of pulmonary infarction and embolization more commonly than when they are not pregnant (Cunningham, 1983). Some adverse pregnancy outcomes are shown in Table 56-2.


Obstentrics_Williams

Obstentrics_Williams. Women with sickle-cell hemoglobinopathies require close prenatal observation. Any factor that impairs erythropoiesis or increases red cell destruction aggravates the anemia. Prenatal folic acid supplementation with 4 mg daily is needed to support rapid red blood cell turnover. One danger is that a symptomatic woman may categorically be considered to be sufering from a "sickle-cell crisis." As a result, serious obstetrical or medical problems that cause pain, anemia, or both may be overlooked. Examples are ectopic pregnancy, placental abruption, pyelonephritis, or appendicitis. Thus, a diagnosis of sickle-cell crisis should be applied


Obstentrics_Williams

Obstentrics_Williams. Guidelines for care of these women have been appropriately stressed by Rees and colleagues (2003). !vIarti-Carvajal and coworkers (2009) performed a Cochrane review and reported that no randomized trials have evaluated treatment during pregnancy. At minimum, intravenous luids are given, and opioids are administered promptly for severe pain. Oxygen via nasal cannula may decrease the intensity of sickling at the capillary level. We have found that red cell transfusions after the onset of severe pain do not dramatically improve pain intensity and may not shorten its duration. Conversely, as discussed later, prophylactic transfusions almost always prevent further vasoocclusive episodes and pain crises. Recent reports suggest benefits from epidural analgesia (Verstraete, 2012; Winder, 2011). Long term, afected women can become habituated to narcotics. his problem is highlighted by the increased rates of neonatal abstinence syndrome, which is a constellation of withdrawal symptoms (Shirel,


Obstentrics_Williams

Obstentrics_Williams. term, afected women can become habituated to narcotics. his problem is highlighted by the increased rates of neonatal abstinence syndrome, which is a constellation of withdrawal symptoms (Shirel, 2016).


Obstentrics_Williams

Obstentrics_Williams. Rates of covert bacteriuria and acute pyelonephritis are elevated substantively, and screening and treatment for bacteriuria are essential. If pyelonephritis develops, sickle cells are extremely susceptible to bacterial endotoxin, which can cause dramatic and rapid red cell destruction while simultaneously suppressing erythropoiesis. Pneumonia, especially due to Streptococcus pneumoniae, is common. he Centers for Disease Control and Prevention recommends specific vaccination for those with sickle-cell disease and all asplenic patients (Kim, 2016). hese are polyvalent pneumococcal, Haemophilus inluenzae type B, and meningococcal vaccines, and administration guidelines are found in Table 9-7 (p. 172).


Obstentrics_Williams

Obstentrics_Williams. Pulmonary complications are frequent. Of these, acute chest syndrome is characterized by pleuritic chest pain, fever, cough, lung infiltrates, and hypoxia, and usually also by bone and joint pain (Vichinsky, 2000). In addition to symptoms, radiographs show a new pulmonary infiltrate. There are four precipitants: infection, marrow emboli, thromboembolism, and atelectasis (Medof, 2005). Bacterial or viral infection causes approximately half of cases. When acute chest syndrome develops, the mean duration of hospitalization is 10.5 days. Mechanical ventilation is required in approximately 15 percent, and the mortality rate approximates 3 percent (Gladwin, 2008). At least for nonpregnant adults, some recommend rapid simple or exchange transfusions to remove the "trigger" for acute chest syndromes (Gladwin, 2008). In a study of nonpregnant patients, Turner and colleagues (2009) reported that there were no increased beneits of exchange versus simple transfusions, and the former were


Obstentrics_Williams

Obstentrics_Williams. syndromes (Gladwin, 2008). In a study of nonpregnant patients, Turner and colleagues (2009) reported that there were no increased beneits of exchange versus simple transfusions, and the former were associated with fourfold increased blood usage.


Obstentrics_Williams

Obstentrics_Williams. Women with sickle-cell disease usually have some degree of cardiac dysfunction from ventricular hypertrophy. Chronic hypertension worsens the dysfunction (Gandhi, 2000). During pregnancy, the basal hemodynamic state characterized by high cardiac output and increased blood volume is augmented (Veille, 1994). Although most women tolerate pregnancy with out problems, complications such as severe preeclampsia or ham, 1986). Heart failure caused by pulmonary hypertension must also be considered (Chakravarty, 2008). In 4352 pregnancies in women with sickle-cell syndromes, pregnancy complication rates. Compared with controls, women with sickling disorders had a 63-percent rate of nondelivery related admissions. hey had a 1.8-fold greater incidence of hypertensive disorders-19 percent; a 2.9-fold higher rate of fetal-growth restriction-6 percent; and a 1.7-fold increased cesarean delivery rate-45 percent.


Obstentrics_Williams

Obstentrics_Williams. Prophylactic Red Cell Transfusions. Chronic transfusion therapy prevents strokes in high-risk children (DeBaun, 2014). During pregnancy, the most dramatic beneit of prophylactic transfusions has been on maternal morbidity rates (Benites, 2016). In an observational 10-year prospective study at Parkland Hospital, we ofered prophylactic transfusions to all pregnant women with sickle-cell syndromes. Transfusions were given throughout pregnancy to maintain the hematocrit above 25 volumes percent and the portion of hemoglobin S <60 percent (Cunningham, 1979). Maternal morbidity was minimal, and erythropoiesis suppression was not problematic. Their outcomes were compared with historical controls who were not routinely transfused. Overall, morbidity and hospitalization rates were signiicantly reduced in the transfused group (Asma, 2015; Cunningham, 1983; Grossetti, 2009). Still, adverse perinatal outcomes are prevalent (Ngo, 2010).


Obstentrics_Williams

Obstentrics_Williams. In a multicenter trial, Koshy and coworkers (1988) randomly assigned 72 pregnant women with sickle-cell syndromes to prophylactic or indicated transfusions. They reported a signiicant decline in the incidence of painful sickle-cell crises with prophylactic transfusions but no diferences in perinatal outcomes. Because of risks inherent with blood administration, they concluded that prophylactic transfusions were not indicated. A metaanalysis of 12 studies found prophylactic transfusions improved rates of some adverse maternal and neonatal outcomes, including maternal mortality, pulmonary complications, and perinatal mortality (Malinowski, 2015).


Obstentrics_Williams

Obstentrics_Williams. Undoubtedly, morbidity from multiple transfusions is significant. Up to 10 percent of women had a delayed hemolytic transfusion reaction, and infections are major concerns. Garratty (1997) reviewed 12 studies and found alloimmunization developed in a fourth of women. Finally, in liver biopsies in these women, we found no evidence of transfusion-related iron overload, hemochromatosis, or chronic hepatitis (Yeomans, 1990). Because of what some consider marginal benefits, routine prophylactic transfusions during pregnancy remain controversial (American College of Obstetricians and Gynecologists, 2015; Okusayna, 2013). Current consensus is that their use should be individualized. Fetal Assessment. Because of the high incidence offetal-growth restriction and perinatal mortality, serial fetal assessment with sonography and antepartum surveillance is recommended (American College of Obstetricians and Gynecologists, 2015).


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Obstentrics_Williams. Anyaegbunam and colleagues (1991) reported nonreactive stress tests during sickling crises, which resumed reactivity with crisis resolution. They concluded that transient efects of sicklecell crisis do not compromise umbilical blood flow. Management is essentially identical to that for women with cardiac disease (Chap. 49, p. 953). Women should be kept comfortable, but not oversedated. Conduction analgesia is ideal (Camous, 2008). Compatible blood should be available. If a diicult vaginal or cesarean delivery is contemplated, and the hematocrit is <20 volumes percent, then packed erythrocyte transfusions are administered. There is no categorical contraindication to vaginal delivery, and cesarean delivery is reserved for obstetrical indications (Rogers, 2010).


Obstentrics_Williams

Obstentrics_Williams. Many clinicians do not recommend combination hormonal contraception because of potential adverse vascular and thrombotic efects. In their systematic review, however, Haddad and coworkers (2012) found that complication rates were not higher with their use in women with sickle-cell syndromes. he Centers for Disease Control and Prevention categorizes combination hormonal contraception, intrauterine devices, implants, and progestin-only contraception as having no risk or as having advantages that generally outweigh theoretical or proven risks (Curtis, 2016).


Obstentrics_Williams

Obstentrics_Williams. The frequency of sickle-cell trait among African-Americans averages 8 percent. Carriers have occasional hematuria, renal papillary necrosis, and hyposthenuria, which is urine of low specific gravity (Tsaras, 2009). And although controversial, sickle-cell trait does not appear to be associated with increased rates of abortion, perinatal mortality, low birthweight, or pregnancy-induced hypertension (Pritchard, 1973; Tita, 2007; Tuck, 1983). One unquestioned relationship is the twofold increased incidence of asymptomatic bacteriuria and urinary infection. Sickle-cell trait should not be considered a deterrent to pregnancy or to hormonal contraception. Inheritance is a concern for the fetus of a mother with sickle-cell trait whenever the father carries a gene for abnormal hemoglobins that include S, C, and D or for 3-thalassemia trait. Prenatal diagnosis is discussed in Chapter 14 (p. 290).


Obstentrics_Williams

Obstentrics_Williams. Approximately 2 percent of African-Americans are heterozygous for hemoglobin C, but even if homozygous, hemoglobin C is innocuous (Nagel, 2003). Only when coinherited with sickle-cell trait to yield hemoglobin SC is the trait problematic. Pregnancy in women with homozygous hemoglobin CC disease or C-3-thalassemia carries relatively benign associations. Table 56-3 shows our experiences from Parkland Hospital (Maberry, 1990). Other than mild-to-moderate anemia, pregnancy outcomes were not abnormal. Supplementation with folic acid and iron is indicated. Data from Maberry, 1990.


Obstentrics_Williams

Obstentrics_Williams. Although uncommon in the United States, hemoglobin E is the second most frequent hemoglobin variant worldwide. The heterozygous E trait is common in Southeast Asia. Hurst and coworkers (1983) identified homozygous hemoglobin E, hemoglobin E plus 3-thalassemia, or hemoglobin E trait in 36 percent of Cambodians and 25 percent of Laotians. Hemoglobin EE is associated with little or no anemia, hypochromia, marked microcytosis, or erythrocyte targeting. Kemthong and colleagues (2016) studied 1073 women and 2146 controls and found that hemoglobin E trait does not increase pregnancy risks other than asymptomatic bacteriuria. Conversely, doubly heterozygous E-3-thalassemia is a common cause of severe childhood anemia in Southeast Asia (DeLoughery, 2014). In a cohort study of 54 women with singleton pregnancies, Luewan and associates (2009) reported a threefold greater risk of preterm birth and fetal-growth restriction in afected women. It is unclear if hemoglobin SE disease is ominous during


Obstentrics_Williams

Obstentrics_Williams. pregnancies, Luewan and associates (2009) reported a threefold greater risk of preterm birth and fetal-growth restriction in afected women. It is unclear if hemoglobin SE disease is ominous during pregnancy.


Obstentrics_Williams

Obstentrics_Williams. • Hemoglobinopathy in the Newborn Neonates with homozygous SS, SC, and CC disease can be identiied accurately at birth by cord blood electrophoresis. The United States Preventive Services Task Force recommends that all newborns be tested for sickle-cell disease (Lin, 2007). In most states, such screening is mandated by law and performed routinely (Chap. 32, p. 614). Many tests are available to detect sickle-cell disease ante natally. Most are DNA based and use chorionic villus samples or amnionic fluid specimens (American College of Obstetricians and Gynecologists, 2015). Several mutations that encode hemoglobin S and other abnormal hemoglobins can be detected by targeted mutation analysis and polymerase chain reaction-based techniques (Chap. 13, p. 270).


Obstentrics_Williams

Obstentrics_Williams. Hundreds of mutations afect genes that control hemoglobin production. Some of these impair synthesis of one or more of the normal globin peptide chains and may result in a clinical syndrome characterized by varying degrees of inefective erythropoiesis, hemolysis, and anemia (Benz, 2015). Thalassemias are classiied according to the globin chain that is deficient. The two major forms involve impaired production or instability of a-peptide chains to cause a-thalassemia or of 3-chains to cause 3-thalassemia. hese may form from point mutations, deletions, or translocations involving the .-or non-a-globin gene (Leung, 2012). Because there are four a-globin genes, the inheritance of a-thalassemia is more complicated than for 3-thalassemia (Piel, 2014). Possible genotypes and phenotypes are shown in


Obstentrics_Williams

Obstentrics_Williams. Because there are four a-globin genes, the inheritance of a-thalassemia is more complicated than for 3-thalassemia (Piel, 2014). Possible genotypes and phenotypes are shown in Table 56-4. Clinical severity closely correlates with the degree of a-globin chains synthesis impairment. In most populations, the a-globin chain "cluster" or gene loci are doubled on chromosome 16. Similarly, ther, chains are duplicated. Thus, the normal genotype for diploid cells can be expressed as ../.. and "r /,,. here are two main groups of a-thalassemia determinants: .0-thalassemia is the deletion of both loci from one chromosome (--/..), whereas .+ -thalassemia is the loss of a single locus from one allele (-./.. heterozygote) or a loss from each allele (-./-.homozygote). here are two major phenotypes. he deletion of all four a-globin chain genes (--/--) characterizes homozygous a-thalassemia. Because a-chains are contained in fetal hemoglobin, the fetus is afected. When none of the four genes


Obstentrics_Williams

Obstentrics_Williams. TABLE 56-4. Genotypes and Phenotypes of .-Thalassemia Syndromes Normal ../.. Normal .+-Thalassemia heterozygote -'/.. } Normal; silent carrier ../-. .+-Thalassemia homozygotea -./-. } a-Thalassemia minor-mild .°-Thalassemia heterozygoteb --/.. hypochromic microcytic anemia Compound heterozygous .0/.+ --/-. Hgb H (34) with moderate-to severe hemolytic anemia Homozygous .-thalassemia --/--Hgb Bart ('4) disease, hydrops fetalis African Americans. bMore common in Asian Americans. are expressed, no a-globin chains are produced, and instead hemoglobin Bart (14) and hemoglobin H (34) are formed as abnormal tetramers that cannot transport oxygen (Chap. 7, p. 131). he relative frequency of a-thalassemia minor, hemoglobin H disease, and hemoglobin Bart disease varies remarkably among racial groups. All of these variants are encountered in Asians.


Obstentrics_Williams

Obstentrics_Williams. he relative frequency of a-thalassemia minor, hemoglobin H disease, and hemoglobin Bart disease varies remarkably among racial groups. All of these variants are encountered in Asians. In those of African descent, although a-thalassemia minor has a frequency approximating 2 percent, hemoglobin H disease is rare and hemoglobin Bart disease is unreported. This is because Asians usually have .0-thalassemia minor inherited with both gene deletions typically from the same chromosome (--/..), whereas blacks usually have .+-thalassemia minor in which one gene is deleted from each chromosome (-xl-x). Diagnosis of 3-thalassemia minor and a-thalassemia major in the fetus can be accomplished by DNA analysis using molec ular techniques (Piel, 2014). Fetal diagnosis of hemoglobin yakul, 2009; Srivorakun, 2009). Molecular genetic testing for HBAl and HBA2 identifies 90 percent of deletions and 10 percent of point mutations in afected individuals (Galanello, 2011 b).


Obstentrics_Williams

Obstentrics_Williams. Important obstetrical aspects of some a-thalassemia syndromes depend on the number of gene deletions in a given woman. he silent carrier state with one gene deletion is of no consequence. Deletion of two genes resulting in a-thalassemia minor is characterized by minimal-to-moderate hypochromic micro cytic anemia. This is due to either .r_ or .+-thalassemia trait, and thus genotypes may be -xla or --la.. Diferentiation is possible only by DNA analysis (Piel, 2014). Because no other clinical abnormalities accompany either form of a-thalassemia minor, it often goes unrecognized and is usually of no maternal consequence (Hanprasertpong, 2013). The fetus with these forms of thalassemia minor will have hemoglobin Bart at birth, but as its levels drop, it is not replaced by hemoglobin H. Red cells are hypochromic and microcytic, and the hemoglobin concentration is normal to slightly depressed.


Obstentrics_Williams

Obstentrics_Williams. Hemoglobin H disease (34) results from the compound heterozygous state for .0_ plus .+-thalassemia with deletion of three of four alpha genes (--I-x). With only one functional a-globin gene per diploid genome, the newborn will have abnormal red cells containing a mixture of hemoglobin Bart (14), hemoglobin H (34)' and hemoglobin A. The neonate appears normal but soon develops hemolytic anemia as most of the hemoglobin Bart is replaced by hemoglobin H. In adults, anemia is moderate to severe and usually worsens during pregnancy. Inheritance of all four abnormal a genes causes homozygous a-thalassemia with predominant production of hemoglobin Bart, which has an appreciably increased ainity for oxygen. This is incompatible with extended survival. Hsieh and colleagues (1989) reported that blood obtained by funipuncture from 20 hydropic fetuses contained 65 to 98 percent Bart hemoglobin. These fetuses are stillborn, or they are hydropic and usually die very soon after birth.


Obstentrics_Williams

Obstentrics_Williams. Sonographic measurement of the fetal cardiothoracic ratio at 12 to 13 weeks' gestation can be used to identiy afected fetuses (Lam, 1999; Zhen, 2015). Sonographic assessment of myocardial performance-the Tei index-in the irst half of pregnancy has been evaluated. Changes predate hydrops in afected fetuses (Luewan, 2013). Severe anemia can be detected using Doppler velocimetry of the middle cerebral artery. ment (Galanello, 201r1a). he 3-thalassemias are the consequences of impaired 3-globin chain production or a-chain instability. Genes that encode con trol of 3-globin synthesis are in the r3-gene "cluster" located on chromosome 11 (Chap. 7, p. 131). More than 150 point mutations in the 3-globin gene have been described (Weather all, 2010). In 3-thalassemia, 3-chain production is decreased, and excess a-chains precipitate to cause cell-membrane dam age. Other forms of3-thalassemias are caused by a-chain insta bility (Kihm, 2002).


Obstentrics_Williams

Obstentrics_Williams. he heterozygous trait is 3-thalassemia minor, and those Az levels. his hemoglobin is composed of two .-and two 6-globin chains, and concentrations are usually more than 3.5 percent. Hemoglobin F-composed of two .-and two I-globin chains-also usually has increased concentrations that exceed 2 percent. Some patients with heterozygous 3-thalassemia minor do not have anemia, and others have mild-to-moderate anemia characterized by hypochromia and microcytosis.


Obstentrics_Williams

Obstentrics_Williams. Homozygous 3-thalassemia-also called 3-thalassemia major or Cooley anemia-is a serious and frequently fatal disorder. Hemolysis is intense and leads to severe anemia. Many patients become transfusion dependent, and the subsequent iron load, along with abnormally increased gastrointestinal iron absorption, leads to hemochromatosis, which is fatal in many cases. Stem cell transplantation has been used to treat 3-thalassemia major Gagannath, 2014). A heterozygous form of 3-thalassemia that clinically manifests as thalassemia intermedia produces moderate anemia. During pregnancy, women with 3-thalassemia minor may have mild anemia (Charoenboon, 2016). Iron and folate supplements are given. In some women, anemia will worsen because normal plasma volume expansion may be accompanied by slightly subnormal erythropoiesis.


Obstentrics_Williams

Obstentrics_Williams. Thalassemia major and some of the other severe forms were uncommonly encountered during pregnancy before the advent of transfusion and iron chelation therapy. With such management, 63 pregnancies were reported and sufered no serious complications (Aessopos, 1999; Daskalakis, 1998). Pregnancy is considered reasonably safe if maternal cardiac function is normal. Transfusions are given throughout pregnancy to maintain the hemoglobin concentration at 10 g/dL. This is coupled with surveillance of fetal growth (American College of Obstetricians and Gynecologists, 2015; Sheiner, 2004).


Obstentrics_Williams

Obstentrics_Williams. Because 3-thalassemia major is caused by numerous mutations, prenatal diagnosis is diicult. For a given individual, targeted mutation analysis is done that requires prior identification of the familial mutation. The analysis is done using chorionic villus sampling and other techniques discussed in Chapter 14 (p. 293). Noninvasive testing of circulating fetal nucleic acids in maternal plasma for the diagnosis of 3-thalassemia has been described (Leung, 2012; Xiong, 2015).


Obstentrics_Williams

Obstentrics_Williams. Platelet abnormalities may precede pregnancy, develop during pregnancy coincidentally, or be induced by pregnancy. hrombocytopenia-deined by a platelet count < 150,000/�L-is identified in nearly 10 percent of gravidas (American College of Obstetricians and Gynecologists, 2016c). Of these cases, 75 percent are gestational thrombocytopenia, whereas 25 percent are due to other various causes. One other common cause is HELLP syndrome. Thrombocytopenia may be inherited or idiopathic, acute or chronic, and primary or associated with other disorders. Examples are shown in Table 56-5.


Obstentrics_Williams

Obstentrics_Williams. Burrows and Kelton (1993) reported that 6.6 percent of 15,471 pregnant women had a platelet count < 150,000/�L, and in 1.2 percent, it was <100,000/�L. hey further noted that almost 75 percent of 1027 women whose platelet counts were < 150,000/�L were found to have normal-variant incidental thrombocytopenia. Of the remainder, 21 percent had a hypertensive disorder of pregnancy, and 4 percent had an immunological disorder. A platelet count of <80,000/�L should trigger TABLE 56-5. Some Causes of Thrombocytopenia in Pregnancy APAS = antiphospholipid antibody syndrome; DIC = disseminated intravascular coagulopathy; HELLP = hemolysis, elevated liver enzyme levels, low platelet count; MTP = massive transfusion protocol. Data from American College of Obstetrics and Gynecologists, 2016c; Aster, 2007; Diz-Ku:ukkaya, 2016. an evaluation for etiologies other than incidental or gestational thrombocytopenia, which is unlikely to have a platelet count <50,000/�L (Gernsheimer, 2013).


Obstentrics_Williams

Obstentrics_Williams. an evaluation for etiologies other than incidental or gestational thrombocytopenia, which is unlikely to have a platelet count <50,000/�L (Gernsheimer, 2013). he physiological decline in platelet concentration seen with gestational thrombocytopenia is usually evident in the third trimester and is thought to be predominantly due to hemodilution. The normal increased splenic mass characteristic of pregnancy may also be contributory (Maymon, 2006). Most evidence shows that platelet life span is unchanged in normal pregnancy (Kenny, 2015).


Obstentrics_Williams

Obstentrics_Williams. Benard-Soulier yndrome is characterized by lack of platelet membrane glycoprotein (GPIb/IX) and causes severe dysunction. Moreover, women exposed to fetal platelets carrying this glycoprotein can develop antibodies against this fetal GPIb/IX antigen to cause lloimmune fetal thrombocytopenia (Fujimori, 1999; Peng, 1991). A systematic review of 30 pregnancies in 18 women reported a 33-percent rate of primary postpartum hemorrhage, and half of women with bleeding required blood transfusion (Peitsidis, 2010). he reviewers also described six cases of neonatal lloimmune thrombocytopenia and two perinatl deaths. Close monitoring throughout pregnancy and 6 weeks postpartum is critical due to the possibility of life-threatening hemorrhage (Prabu, 2006).


Obstentrics_Williams

Obstentrics_Williams. May-Heglin anomay is an autosomal dominant disorder characterized by thrombocytopenia, giant platelets, and leukocyte inclusions (Chatwani, 1992). Urato and Repke (1998) described such a woman who was delivered vaginally. Despite a platelet count of 16,000/�L, she did not bleed excessively. he neonate inherited the anomaly but also had no bleeding despite a platelet count of35,000/�L. A systematic review of26 studies containing 75 pregnancies in 40 women reported four cases of postpartum hemorrhage, 34 cases of neonatal thrombocytopenia, and two fetal deaths (Hussein, 2013).


Obstentrics_Williams

Obstentrics_Williams. The primary form-also termed idiopathic thrombocytopenic purpura (ITP)-is usually caused by a cluster of IgG antibodies directed against one or more platelet glycoproteins (Konkle, 2015). Antibody-coated platelets are destroyed prematurely in the reticuloendothelial system, especially the spleen. Although not proven, the disorder is probably mediated by autoantibodies directed at platelet-associated immunoglobulins-P AlgG, P AIgM, and P lA.In adults, immune thrombocytopenia most often is a chronic disease that rarely resolves spontaneously.


Obstentrics_Williams

Obstentrics_Williams. As shown in Table 56-5, secondary forms of immunemediated chronic thrombocytopenia appear in association with systemic lupus erythematosus, lymphomas, leukemias, and several systemic diseases. Approximately 2 percent of thrombocytopenic patients have positive serological tests for lupus, and in some cases, levels of anticardiolipin antibodies are high. Finally, approximately 10 percent of HIV -positive patients have associated thrombocytopenia (Scaradavou, 2002). Diagnosis and Management. Only a few adults with primary immune thrombocytopenia recover spontaneously, and for those who do not, platelet counts usually range from 10,000 to 100,000/�L (George, 2014). Evidence does not suggest that pregnancy increases the risk of relapse in women with women with active disease. hat said, it is certainly not unusual years to have recurrent thrombocytopenia during pregnancy. Although this may be from closer surveillance, hyperestrogen emia has also been implicated.


Obstentrics_Williams

Obstentrics_Williams. Although this may be from closer surveillance, hyperestrogen emia has also been implicated. Therapy is considered if the platelet count is below 30,000 to 50,000/�L (American College of Obstetricians and Gyne cologists, 20 16c). Primary treatment includes corticosteroids or intravenous immune globulin (lYlG) (Neunert, 201r1). Initially, prednisone, 1 mg/kg daily, is given to suppress the phagocytic activity of the splenic monocyte-macrophage sys tem. IYlG given in a total dose of 2 g/kg during 2 to 5 days is also efective.


Obstentrics_Williams

Obstentrics_Williams. In pregnant women with no response to corticosteroid or IVIG therapy, open or laparoscopic splenectomy may be efective. In late pregnancy, cesarean delivery may be necessary for surgical exposure. Improvement usually follows splenectomy in 1 to 3 days and peaks at approximately 8 days. Cytotoxic agents are typically avoided in pregnancy due to teratogenicity risks. Azathioprine and rituximab, however, which are used in nonpregnant persons with ITP, have been used for other conditions in pregnancy. Finally, the thrombopoietin agonist romplostim has stimulated responses in some patients (Decrooq, 2014; Imbach, 2011; Kuter, 2010).


Obstentrics_Williams

Obstentrics_Williams. Fetal and Neonatal Efects. Pregnancy complications that are increased with ITP include stillbirth, fetal loss, and preterm birth (Wyszynski, 2016). Platelet-associated IgG antibodies cross the placenta, and fetal death from hemorrhage occurs occasionally (Webert, 2003). he severely thrombocytopenic fetus is at increased risk for intracranial hemorrhage with labor and delivery, but fortunately this is unusual. Payne and associates (1997) reviewed studies of maternal ITP published since 1973. Of 601 newborns, 12 percent had severe thrombocytopenia with counts <50,000/�L. Six infants had intracranial hemorrhage, and in three, their initial platelet count was >50,000/�L. his is consistent with a study of 127 pregnancies in women with ITP in which 10 to 15 percent of neonates had transient ITP (Koyama, 2012).


Obstentrics_Williams

Obstentrics_Williams. Investigators concut that fetal and maternal platelet counts lack strong correlation (George, 2009; Hachisuga, 2014). Because of this, maternal IgG free platelet antibody levels and platelet-associated antibody levels have been evaluated to predict fetal platelet counts. Again, however, there is little concurrence with these.


Obstentrics_Williams

Obstentrics_Williams. Investigators have also examined the association between the speciic cause of thrombocytopenia and risk of a thrombocytopenic fetus. Four researched causes include gestational th ro m bocyto penia, hypertension -associa ted thro m bocyto penia, immune thrombocytopenia, and alloimmune thrombocytopenia. Burrows and Kelton (1993) reported neonatal umbilical cord platelet counts measuring <50,000/�L in 19 of 15,932 consecutive newborns (0.12 percent). Only one of756 mothers with gestational thrombocytopenia had an afected newborn. Of 1414 hypertensive women with thrombocytopenia, five neonates had thrombocytopenia. In contrast, of 46 mothers with immunological thrombocytopenia, four infants had thrombocytopenia. Alloimmune thrombocytopenia was associated with profound thrombocytopenia and cord platelet counts <20,000/�L. One of these fetuses died, and two others had intracranial hemorrhage.


Obstentrics_Williams

Obstentrics_Williams. Detection of Fetal Thrombocytopenia. Because no test accurately predicts fetal platelet counts, direct fetal blood sampling is necessary. Scott and coworkers (1983) obtained intrapartum scalp blood samples and recommended cesarean delivery for fetuses with platelet counts <50,000/�L. Dafos and colleagues (1985) reported that percutaneous umbilical cord blood sampling (PUBS) for this indication had a high complication rate (Chap. 14, p. 294). Conversely, Berry and associates (1r997) reported no complications and described poor reliability to predict severe thrombocytopenia, but noted a high negative-predictive value. Payne and coworkers (1r997) summarized six studies in which fetal blood sampling was done for platelet estimation. Of the total of 195 fetuses, severe neonatal thrombocytopenia <50,000/�L was found in 7 percent. But, serious complications from cordocentesis were noted in 4.6 percent. Because of the low incidence of severe neonatal thrombocytopenia and morbidity, fetal


Obstentrics_Williams

Obstentrics_Williams. <50,000/�L was found in 7 percent. But, serious complications from cordocentesis were noted in 4.6 percent. Because of the low incidence of severe neonatal thrombocytopenia and morbidity, fetal platelet determinations and cesarean delivery are not recommended (N eunert, 2011).


Obstentrics_Williams

Obstentrics_Williams. Alloimmune Thrombocytopenia. Disparity between maternal and fetal platelet antigens can stimulate maternal production of antiplatelet antibodies. Such platelet alloimmunization can be severe, and its pathophysiology is identical to that caused by red cell antigens (Chap. 15, p. 307).


Obstentrics_Williams

Obstentrics_Williams. Also called thrombocythemia, thrombocytosis generally is deined as persistent platelet counts >450,000/�L. Common causes of seconday or reactive thrombocytosis are iron deficiency, infection, inflammatory diseases, and malignant tumors (Deutsch, 2013). Platelet counts seldom exceed 800,000/�L in these secondary disorders, and prognosis depends on the underlying disease. On the other hand, primary or essential thrombocytosis accounts for most cases in which platelet counts exceed 1 millionl �L. It is a clonal disorder frequently due to an acquired mutation in the fAQ gene (Konkle, 2015). Thrombocytosis usually is asymptomatic, but arterial and venous thromboses may develop, and thrombosis is associated with pregnancy complications (Rabinerson, 2007; Randi, 2014). hese cases must be diferentiated from the sticky platelet syndrome, which is also associated with thromboses (Rac, 2011).


Obstentrics_Williams

Obstentrics_Williams. Normal pregnancies have been described in women whose mean platelet counts werer> 1.25 million/�L (Beard, 1991; Randi, 1994). Others report more adverse outcomes. Niittyvuopio and associates (2004) described 40 pregnancies in 16 women with essential thrombocythemia. Almost half had a spontaneous abortion, fetal demise, or preeclampsia. In 63 pregnancies in 36 women cared for at the Mayo Clinic, a third had a spontaneous miscarriage, but other pregnancy complications were uncommon (Gangat, 2009). In this observational study, aspirin therapy was associated with a signiicantly lower abortion rate than that in untreated women-1 versus 75 percent, respectively. Suggested treatments during pregnancy include aspmn, low-molecular-weight heparin, and interferon-a (Finazzi, 2012). Interferon-a therapy during pregnancy was successful in 11 women in the review by Delage and coworkers (1996). One of these women had transient blindness at midpregnancy when her platelet count was 2.3 million/�L.


Obstentrics_Williams

Obstentrics_Williams. Although not a primary platelet disorder, some degree of thrombocytopenia accompanies the thrombotic microangiopathies, which include thrombotic thrombocytopenic purpura (TTP) and hemoytic uremic syndrome (HUS). hese syndromes have an incidence of2 to 6 per million persons per year (Miller, 2004). heir similarities to HELLP syndrome allude to their obstetrical ramiications (George, 2014). Although diferent causes account for the variable findings within these syndromes, clinically, they frequently are indistinguishable. Most cases of TTP are thought to be caused by antibodies to or a plasma deficiency of ADAMTS13 (Ganesan, 201r1; Sadler, 2010). his endothelium-derived protease cleaves von Willebrand factor (vWF) to decrease its activity. Conversely, HUS is usually due to endothelial damage incited by viral or bacterial infections and is seen primarily in children (Ardissino, 2013; George, 2014).


Obstentrics_Williams

Obstentrics_Williams. With TTP, intravascular platelet aggregation stimulates a cascade of events leading to end-organ failure. There is endothelial activation and damage, but it is unclear whether this is a consequence or a cause. Elevated levels of unusually large multimers of vWF are identiied with active TTP. Various defects in the ADAMTS13 gene create difering clinical presentations of thrombotic microangiopathy (Camilleri, 2007; Moake, 2002, 2004). In another scheme, antibodies raised against ADAMTS13 neutralize its action to cleave vWF multimers during an acute episode. he end result is micro thrombi of hyaline material consisting of platelets and small amounts of ibrin within arterioles and capillaries. When suicient in number or size, these aggregates produce ischemia or infarctions in various organs.


Obstentrics_Williams

Obstentrics_Williams. hrombotic microangiopathies are characterized by thrombocytopenia, fragmentation hemolysis, and variable organ dysfunction. TTP is characterized by the pentad of thrombocytopenia, fever, neurological abnormalities, renal impairment, and hemolytic anemia. HUS typically has more profound renal involvement and fewer neurological aberrations. hrombocytopenia is usually severe, but fortunately, even with very low platelet counts, spontaneous severe hemorrhage is uncommon. Microangiopathic hemolysis is associated with moderate-to-marked anemia, and erythrocyte transfusions are frequently necessary. he blood smear is characterized by erythrocyte fragmentation with schizocytosis. Reticulocytes and nucleated red blood cells are increased, lactate dehydrogenase (LDH) levels are high, and haptoglobin concentrations are decreased. Consumptive coagulopathy, although common, is usually subtle and clinically insignificant.


Obstentrics_Williams

Obstentrics_Williams. The cornerstone of treatment is plasmapheresis with freshfrozen plasma replacement. Plasma exchange removes inhibitors and replaces the ADAMTS13 enzyme (George, 2014; Michael, 2009). Treatment with caplacizumab, the anti-vWF immunoglobulin, inhibits the interaction between ultralarge vWF multimers and platelets (Peyandi, 2016). hese treatments have remarkably improved outcomes in patients with these formerly fatal syndromes. Red cell transfusions are imperative for life-threatening anemia. Treatment is usually continued until the platelet count is > 150,OOO/�L. Unfortunately, relapses are common. Additionally, there may be long-term sequelae such as renal impairment (Dashe, 1998; Vesely, 2015). Treatment for pregnancy-associated HUS, which is complement mediated, uses the anti-C5 humanized monoclonal antibody eculizumab (Ardissino, 2013; Caiigral, 2014; Fakhouri, 2016).


Obstentrics_Williams

Obstentrics_Williams. As shown in the Appendix (p. 1256), ADAMTS13 enzyme activity decreases across pregnancy by up to 50 percent (S8nchez-Luceros, 2004). Levels drop even further with the preeclampsia syndrome. his is consonant with prevailing opinions that TTP is more commonly seen during pregnancy. he Parkland Hospital experiences were described by Dashe and coworkers (1998), who identified 11 pregnancies complicated by these syndromes among nearly 275,000 obstetrical patients-a frequency of 1 in 25,000.


Obstentrics_Williams

Obstentrics_Williams. I t seems likely that some of the disparately higher incidence in pregnancy reported by others is because of inclusion of women with severe preeclampsia and eclampsia (Hsu, 1995; Magann, 1994). Diferences that usually allow appropriate diagnosis are listed in Table 56-6. For example, moderateto-severe hemolysis is a rather constant feature of thrombotic microangiopathies. But, this is seldom severe with the preeclampsia syndrome, even when complicated by HELLP syndrome (Chap. 40, p. 719). And, although there is deposition of hyaline micro thrombi within the liver with thrombotic microangiopathy, hepatocellular necrosis with elevated serum hepatic aminotransferase levels characteristic of preeclampsia is not a common feature (Ganesan, 2011; Sadler, 2010). Importantly, whereas delivery is imperative to reverse the preeclampsia syndrome, no evidence shows that thrombotic microangiopathy is improved by delivery (Dashe, 1998; Letsky, 2000). Finally, microangiopathic syndromes are usually


Obstentrics_Williams

Obstentrics_Williams. imperative to reverse the preeclampsia syndrome, no evidence shows that thrombotic microangiopathy is improved by delivery (Dashe, 1998; Letsky, 2000). Finally, microangiopathic syndromes are usually recurrent and frequently unassociated with pregnancy. For example, seven of 11 women described by Dashe and colleagues (1998) had recurrent disease either when not pregnant or within the first trimester of a subsequent pregnancy. George (2009) reported recurrent TTP in only five of 36 subsequent pregnancies. That said, the risk for preeclampsia in these women is increased Giang,r2014).


Obstentrics_Williams

Obstentrics_Williams. Unless the diagnosis is unequivocally one of these thrombotic microangiopathies, rather than severe preeclampsia, the TABLE 56-6. Some Differential Factors between HELLP Syndrome and Thrombotic Microangiopathiesa Thrombocytopenia Mild/mod. Mod/severe ADAMTS 1 3 def. Mild/mod. Severe (AST, ALT) hemolytic uremic syndrome (HUS). ADAMTS 13 = ADAM metallopeptidase with thrombospondin type 1 motif, 13; AST = aspartate transaminase; ALT = alanine transaminase; def. = deficiency; DIC = disseminated intravascular coagulopathy; HELLP = hemolysis, elevated liver enzyme levels, low platelet count; Mod. = moderate.


Obstentrics_Williams

Obstentrics_Williams. response to pregnancy termination should be evaluated before resorting to plasmapheresis and exchange transfusion, massivedose glucocorticoid therapy, or other therapy. Unfortunately, recall that determination of ADAMTS13 enzyme activity may be diicult to interpret with HELLP syndrome (Franchini, 2007). Plasmapheresis is not indicated or preeclampsia-eclampsia complicated by hemoysis and thrombocytopenia. During the past two decades, and coincidental with plasmapheresis and plasma exchange, maternal survival rates from thrombotic micro angiopathy have improved dramatically (Dashe, 1998). Although previously fatal in up to half of mothers, with such treatment, Egerman and coworkers (1996) reported two maternal and three fetal deaths in 11 pregnancies. Hunt and associates (2013) reported that TTP accounted for 1 percent of maternal deaths in the United Kingdom from 2003 to 2008.


Obstentrics_Williams

Obstentrics_Williams. Women who are diagnosed with thrombotic micro angiopathy during pregnancy are at risk for serious long-term complications (Egerman, 1996). he Parkland experiences included a mean 9-year surveillance period (Dashe, 1998). hese women had multiple recurrences; renal disease requiring dialysis, transplantation, or both; severe chronic hypertension; and transfusion-acquired infectious diseases. Two women died remote from pregnancy-one from dialysis complications and one from transfusion-acquired HIV infection. In nonpregnant women who have recovered from thrombotic microangiopathies, persistent cognitive defects and physical disabilities have been reported (Kennedy, 2009; Lewis, 2009). Interestingly, as discussed in Chapter 40 (p. 745), these cognitive defects are very similar to those found in long-term surveillance studies of women who had eclampsia (Aukes, 2009,r2012; Wiegman, 2012).


Obstentrics_Williams

Obstentrics_Williams. Obstetrical hemorrhage may infrequently be the consequence of an inherited defect in a protein that controls coagulation. Both types of hemophilia are examples. Severity reflects plasma factor levels and is categorized as mild-levels of 6 to 30 per cent; moderate-2 to 5 percent; or severe-less than 1 percent (Arruda, 2015).


Obstentrics_Williams

Obstentrics_Williams. Hemophilia A is an X-linked recessively transmitted disorder characterized by a marked deiciency of factor VIII. It is rare among women compared with men, in whom the heterozygous state is responsible for the disease. Heterozygous women have diminished factor VIII levels, but almost invariably, the homozygous state is requisite for hemophilia A. In a few instances, it appears in women spontaneously from a newly mutated gene. Pregnancy-associated acquired hemophilia A from antibodies may result in severe bleeding-related morbidity (Tengborn, 2012). Christmas disease or hemophilia B is caused by severe deiciency of factor IX and has similar genetic and clinical features.


Obstentrics_Williams

Obstentrics_Williams. he risk of obstetrical bleeding with these is directly related to factor VIII or IX levels. Afected women have a range of activity that is determined by random X-chromosome inactivation-Iyonization-although activity is expected to average 50 percent (Letsky, 2000). Levels below 10 to 20 percent pose hemorrhage risks. If levels fall to near zero, this risk is substantial. Pregnancy does aford some protection, however, because concentrations of both these clotting factors rise appreciably during normal pregnancy (Appendix, p. 1256). Treatment with desmopressin may also stimulate factor VIII release. Risks are further reduced by avoiding lacerations, minimizing episiotomy use, and maximizing postpartum uterine contractions. Operative vaginal deliveries should be avoided. here are few published experiences during pregnancy.


Obstentrics_Williams

Obstentrics_Williams. here are few published experiences during pregnancy. Kadir and coworkers (1997) reported that 20 percent of carriers had postpartum hemorrhage. Guy and associates (I992) reviewed five pregnancies in women with hemophilia B, and in all, outcomes were favorable. They recommended factor IX administration if levels are below 10 percent. Desmopressin has been shown in selected cases to reduce obstetrical bleeding complications (Trigg, 2012). If a male fetus has hemophilia, the risk of hemorrhage increases after delivery in the neonate. his is especially true if circumcision is attempted. If a mother has hemophilia A or B, all of her sons will have the disease, and all of her daughters will be carriers. If she is a carrier, half of her sons will inherit the disease, and half of her daughters will be carriers. Prenatal diagnosis of hemophilia is possible in some families using chorionic villus biopsy (Chap. 14, p. 293).


Obstentrics_Williams

Obstentrics_Williams. Preimplantation genetic diagnosis for hemophilia was reviewed by Lavery (2009). Rarely, antibodies directed against factor VIII or IX are acquired and may lead to life-threatening hemorrhage. Patients with hemophilia more commonly develop antibodies, and their acquisition in patients without hemophilia is extraordinary. It has been identified rarely in women during the puerperium (Santoro, 2009). he prominent clinical feature is severe, protracted, repetitive hemorrhage from the reproductive tract starting a week or so after an apparently uncomplicated delivery (Gibson, 2016). he activated partial thromboplastin time is markedly prolonged. Treatment has included multiple transfusions of blood component, immunosuppressive therapy, and attempts at various surgical procedures, especially curettage and hysterectomy. A recombinant activated factor VII (NovoSeven) stops bleeding in up to 75 percent of patients with these inhibitors (Arruda, 2015; Gibson, 2016).


Obstentrics_Williams

Obstentrics_Williams. here are at least 20 heterogeneous clinical disorders involving aberrations of factor VIII complex and platelet dysfunctioncollectively termed von Willebrand disease (vWD). hese abnormalities are the most frequently inherited bleeding disorders, and their prevalence is as high as 1 to 2 percent (Arruda, 2015; Pacheco, 2010). Most von Willebrand variants are inherited as autosomal dominant traits, and types I and II are the most common. Speciically, type I accounts for 75 percent of von Willebrand variants. Type III, which is the most severe, is a recessive trait. lthough most cases of acquired vWD develop after age 50 years, some have been reported in pregnant women (Lip kind, 2005).


Obstentrics_Williams

Obstentrics_Williams. he von Wilebrand actor is a series of large plasma multimeric glycoproteins that form part of the factor VIII complex. It is essential for normal platelet adhesion to subendothelial collagen and formation of a primary hemostatic plug. It also plays a major role in stabilizing the coagulant properties of factor VIII. he procoagulant component is factor VIII, a glycoprotein synthesized by the liver. Conversely, von Willebrand precursor, which is present in platelets and plasma, is synthesized by endothelium and megakaryocytes. he von Willebrand factor antigen (vWF:Ag) is the antigenic determinant measured by immunoassays.


Obstentrics_Williams

Obstentrics_Williams. Symptomatic patients typically present with easy bruising, epistaxis, mucosal hemorrhage, and excessive bleeding with trauma, including surgery. he classic autosomal dominant forms usually cause symptoms in the heterozygous state. With vWD, laboratory features often include a prolonged bleeding time, prolonged partial thromboplastin time, decreased vWF antigen levels, decreased factor VIII immunological and coagulation-promoting activity, and inability of platelets from an afected person to react to various stimuli.


Obstentrics_Williams

Obstentrics_Williams. During normal pregnancy, maternal levels of both factor VIII and vWF antigen increase substantively (Appendix, p. 1256). Because of this, pregnant women with vWD often develop normal levels of factor VIII coagulant activity and vWF antigen, although their measured bleeding time still may be prolonged. If factor VIII activity is very low or if there is bleeding, treatment is recommended. Desmopressin by infusion transiently increases factor VIII and vWF levels (Arruda, 2015; Kujovich, 2005). With signiicant bleeding, 15 or 20 units of cryoprecipitate are transfused every 12 hours. Alternatively, factor VIII concentrates (Alfanate, Hemate-P) may be given that contain high-molecular-weight vWF multimers. Lubetsky and colleagues (1999) described continuous infusion with Hemate-P in a woman during a vaginal delivery. According to Chi and coworkers (2009), conduction analgesia can be provided safely if coagulation defects have normalized or if hemostatic agents are administered


Obstentrics_Williams

Obstentrics_Williams. a woman during a vaginal delivery. According to Chi and coworkers (2009), conduction analgesia can be provided safely if coagulation defects have normalized or if hemostatic agents are administered prophylactically.


Obstentrics_Williams

Obstentrics_Williams. Pregnancy outcomes in women with vWD are generally good, but postpartum hemorrhage is encountered in up to half of cases. In a fourth of 38 cases summarized by Conti and associates (1986), bleeding was reported with abortion, with delivery, or in the puerperium. Kadir and coworkers (1998) reported their experiences with 84 pregnancies. They described a 20-percent incidence of immediate postpartum hemorrhage and another 20-percent incidence of late hemorrhage. Most cases were associated with low vWF levels in untreated women, and none given treatment peripartum had hemorrhage. More recently, Stoof and colleagues (2015) reviewed 185 deliveries in 154 afected women and found the risk for postpartum hemorrhage to be highest in deliveries with lowest factor levels.


Obstentrics_Williams

Obstentrics_Williams. Although most patients with vWD have heterozygous variants and associated minor bleeding complications, the disease can be severe. Moreover, homozygous ofspring develop serious clotting dysfunction. Chorionic villus sampling with DNA analysis to detect the missing genes has been described. Some authorities recommend cesarean delivery to avoid trauma to a possibly afected fetus if the mother has severe disease. In general, the activity of most procoagulant factors rises across pregnancy (Appendix, p. 1256). Factor VII deiciency is a rare autosomal recessive disorder. Levels of this factor normally increase during pregnancy, but these may rise only mildly in women with factor VII deficiency (Fadel, 1989). A systematic review of 94 births found no diference in postpartum hemorrhage rates with or without prophylaxis with recombinant factor VIla (Baumann Kreuziger, 2013).


Obstentrics_Williams

Obstentrics_Williams. Factor X or Stuart-Prower actor deiciency is rare and is inherited as an autosomal recessive trait. Factor X levels typically rise by 50 percent during normal pregnancy. Konje and colleagues (1994) described a woman who had 2-percent factor activity. She was given prophylactic treatment with plasmaderived factor X, which raised her plasma levels to 37 percent. Despite this, she sufered an intrapartum placental abruption. plasma to a woman with less than I-percent factor X activity. She delivered spontaneously without incident. Beksa: and asso ciates (20r10) described a woman with severe factor X deiciency who was successfully managed with prophylactic prothrombin complex concentrate. Nance and colleagues (2012) reported on 24 pregnancies, of which 18 resulted in a healthy baby.


Obstentrics_Williams

Obstentrics_Williams. Factor I-plasma thromboplastin antecedent-diciency is inherited as an autosomal trait. It manifests as severe disease in homozygotes but only as a minor defect in heterozygotes. It is most prevalent in Ashkenazi Jews and is rarely seen in pregnancy. Musclow and coworkers (1987) reported 41 deliveries in 17 afected women, and none required transfusion. In 105 pregnancies from 33 afected women, Myers and colleagues (2007) reported an uneventful pregnancy and delivery in 70 percent. hey recommended peripartum treatment with factor XI concentrate if cesarean delivery is performed and advised against epidural analgesia unless factor XI is given. From their review, Martin-Sakes and associates (2010) found that factor XI levels and bleeding severity correlated poorly in women with severe deiciency. Wiewel-Verschueren and colleagues (2015) performed a systematic review of 27 studies with 372 women and reported that 18 percent had postpartum hemorrhage.


Obstentrics_Williams

Obstentrics_Williams. Factor II diciency is another autosomal recessive disorder that rarely complicates pregnancy. A greater incidence of thromboembolism is encountered in nonpregnant patients with this deficiency. Lao and coworkers (1991) reported an afected pregnant woman in whom placental abruption developed at 26 weeks' gestation. Factor III diciency is an autosomal recessive trait and may be associated with maternal intracranial hemorrhage (Letsky, 2000). In their review, Kadir and associates (2009) cited an increased risk of recurrent miscarriage and placental abruption. It has also been reported to cause umbilical cord bleeding (Odame, 2014). Treatment is fresh frozen plasma. Naderi and colleagues (2012) described 17 successful pregnancies in women receiving weekly prophylaxis with Factor XIII concentrate.


Obstentrics_Williams

Obstentrics_Williams. Fibrinogen abnormalities-either qualitative or quantitativealso may cause coagulation abnormalities. Autosomally inherited abnormalities usually involve the formation of a functionally defective ibrinogen-commonly referred to as dyibrinogenemia (Edwards, 2000). Familial hypoibrinogenemia and sometimes aibrinogenemia are infrequent recessive disorders. In some cases, both are found-hypodysibrinogenemia (Deering, 2003). Our experience suggests that hypoibrinogenemia represents a heterozygous autosomal dominant state. he thrombinclottable protein level in these patients typically ranges from 80 to 110 mg/ dL when nonpregnant, and this increases by 40 or 50 percent in normal pregnancy. Those pregnancy complications that give rise to acquired hypoibrinogenemia, such as placental abruption, are more common with ibrinogen deiciency. Trehan and Fergusson (1991) and Funai and coworkers (1997) described successful outcomes in two afected women in whom ibrinogen or plasma inusions were given


Obstentrics_Williams

Obstentrics_Williams. are more common with ibrinogen deiciency. Trehan and Fergusson (1991) and Funai and coworkers (1997) described successful outcomes in two afected women in whom ibrinogen or plasma inusions were given throughout pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Conduction Analgesia with Bleeding Disorders Most serious bleeding disorders would logically preclude the use of epidural or spinal analgesia for labor or delivery. If the bleeding disorder is controlled, however, conduction analgesia may be considered. Chi and colleagues (2009) reviewed intrapartum outcomes in 80 pregnancies in 63 women with an inherited bleeding disorder. These included those with factor XI deiciency, hemophilia carrier status, vWD, platelet disorders, or a deiciency of factor VII, Xl, or X. Regional block was used in 41. Of these, 35 had spontaneously normalized hemostatic dysfunction, and others were given prophylactic replacement therapy. The reviewers reported no unusual complications. Singh and associates (2009) reviewed 13 women with factor XI deiciency. Nine received neuraxial analgesia without complications, but only after fresh-frozen plasma was transfused to most to correct the activated partial thromboplastin time.


Obstentrics_Williams

Obstentrics_Williams. Several important regulatory proteins act as inhibitors at strategic sites in the coagulation cascade to maintain blood fluidity. Inherited deiciencies of these inhibitory proteins are caused by gene mutations. Because they may be associated with recurrent thromboembolism, they are collectively referred to as thrombophilias. These are discussed in Chapter 52 (p. 1005) and reviewed by the American College of Obstetricians and Gynecologists (2017b). Aessopos A, Karabatsos F, Farmakis D, et al: Pregnancy in patients with welltreated 3-thalassemia: outcome for mothers and newborn infants. Am J Obstet Gynecol 180:360, 1999 American College of Obstetricians and Gynecologists: Hemoglobinopathies in pregnancy. Practice Bulletin No. 78, January 2007, Reairmed 2015 American College of Obstetricians and Gynecologists: Neural tube defects. Practice Bulletin No. 44, July 2003, Reairmed 2016a


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Obstentrics_Williams. American College of Obstetrics and Gynecologists: Prenatal diagnostic testing for genetic disorders. Practice Bulletin No. 162, May 2016b American College of Obstetricians and Gynecologists: hrombocytopenia in pregnancy. Practice Bulletin No. 166, September 20t16c American College of Obstetricians and Gynecologists: Anemia in pregnancy. Practice Bulletin No. 95, July 2008, Reairmed 2017a American College of Obstetricians and Gynecologists: Inherited thrombophilias in pregnancy. Practice Bulletin No. 138, September 2013, Reaffirmed 20t17b Anyaegbunam A, Morel MI, Merkatz IR: Antepartum fetal surveillance tests during sickle cell crisis. Am J Obstet Gynecol 165:1081, 1991 Ardissino G, Ossola MW, Bafero GM, et al: Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol 122(2):487,t2013


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Obstentrics_Williams. Ardissino G, Ossola MW, Bafero GM, et al: Eculizumab for atypical hemolytic uremic syndrome in pregnancy. Obstet Gynecol 122(2):487,t2013 Arruda VR, High A: Coagulation disorders. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal Medicine, 19th ed. New York, McGraw-Hill Education, 2015 Asma S, Kozanoglu I, Tarim E, et al: Prophylactic red blood cell exchange may be beneficial in the management of sickle cell disease in pregnancy. Transfusion 55(1):36, 2015 Aster RH, Bougie DW: Drug-induced immune thrombocytopenia. N Engl J Med 357:580, 2007 Ataga U, Kutlar A, Kanter J, et al: Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 376: 1796, 2017 Aukes AM, de Groot JC, Aarnoudse JG, et al: Brain lesions several years after eclampsia. Am J Obstet Gynecol 200:504.e1, 2009 Aukes AM, de Groot Jc, Wiegman MJ, et al: Long-term cerebral imaging after preeclampsia. BJOG 119(9):1117,t2012


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Obstentrics_Williams. Aukes AM, de Groot Jc, Wiegman MJ, et al: Long-term cerebral imaging after preeclampsia. BJOG 119(9):1117,t2012 Azulay CE, Pariente G, Shoham-Vardi I, et al: Maternal anemia during pregnancy and subsequent risk for cardiovascular disease. J Matern Fetal Neonatal Med 28(15):1762, 2015 Ballas SK, McCarthy WF, Guo N, et al: Multicenter study of hydroxyurea in sickle cell anemia. Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia. J Natl Med Assoc 101t(10):1046,t2009 Baumann Kreuziger LM, Morton CT, Reding MT: Is prophylaxis required for delivery in women with factor VII deficiency? Haemophilia 19(6):827, 2013 Beard J, Hillmen P, Anderson CC, et al: Primary thrombocythaemia in pregnancy. Br J Haematol 77:371, 1991 Beksa: 'IS, Atak Z, Ozlii T: Severe factor X deiciency in a twin pregnancy. Arch Gynecol Obstet 281(1):151,s2010


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Obstentrics_Williams. Beksa: 'IS, Atak Z, Ozlii T: Severe factor X deiciency in a twin pregnancy. Arch Gynecol Obstet 281(1):151,s2010 Benites BD, Benevides TC, Valente IS, et al: he efects of exchange transfusion for prevention of complications during pregnancy of sickle hemoglobin C disease patients. Transfusion 56(1):119, 2016 Benz EJ: Disorders of hemoglobin. In: Kasper DL, Fauci AS, Hauser SL, et al (eds): Harrison's Principles of Internal l1edicine, 19th ed. New York, McGraw-Hill Education, 2015 Berry SM, Leonardi MR, Wolfe HM, et al: Maternal thrombocytopenia. Predicting neonatal thrombocytopenia with cordocentesis. J Reprod Med 42:276, 1997 Bo L, Mei-Ying L, Yang Z, et al: Aplastic anemia associated with pregnancy: mater nal and fetal complications. J Matern Fetal Neonatal Med 29(7):1120,s2016 Boafor TK, Olayemi E, Galadanci N, et al: Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis. BJOG 123(5):691,2016


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Obstentrics_Williams. Boafor TK, Olayemi E, Galadanci N, et al: Pregnancy outcomes in women with sickle-cell disease in low and high income countries: a systematic review and meta-analysis. BJOG 123(5):691,2016 Bofill JA, Young A, Perry KG J r: Successful pregnancy in a woman with severe factor X deficiency. Obstet Gynecol 88:723, 1996 Boga C, Ozdogu H: Pregnancy and sickle cell disease: a review of the current literature. Crit Rev Oncol Hematol 98:364, 2016 Borgna-Pignatti C, Marradi P, Rugolotto S, et al: Successful pregnancy ater bone marrow transplantation for thalassaemia. Bone Marrow Transplant 18:235, 1996 Boulet SL, Okoroh EM, Azonobi I, et al: Sickle cell disease in pregnancy: maternal complications in a Medicaid-enrolled population. Matern Child Health J 17(2):200,2013 Bourantas K, Makrydimas G, Georgiou I, et al: Aplastic anemia: report of a case with recurrent episodes in consecutive pregnancies. J Reprod Med 42:672, 1997


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Obstentrics_Williams. analgesia and anaesthesia in women with inherited bleeding disorders. Thromb Haemost 101(6):1104, 2009 Choudhry P, Gupta S, Gupta M, et al: Pregnancy associated aplastic anemia-a series of 10 cases with review of literature. Hematology 7(4):233, 2002


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Obstentrics_Williams. Conti M, Mari D, Conti E, et al: Pregnancy in women with diferent types of vonWillebrand disease. Obstet Gynecol 68:282, 1986 Cox SM, Shelburne P, Mason R, et al: Mechanisms of hemolysis and anemia associated with acute antepartum pyelonephritis. Am J Obstet Gynecol 164:587, 1991 Cunningham FG, Cox SM, Harstad W, et al: Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 163:453, 1990 Cunningham FG, Nelson DB: Disseminated intravascular coagulation syndromes in obstetrics. Obstet GynecoIs126(5):999, 2015 Cunningham FG, Pritchard JA: Prophylactic transfusions of normal red blood cells during pregnancies complicated by sickle cell hemoglobinopathies. Am J Obstet Gynecol 135:994, 1979 Cunningham FG, Pritchard JA, Hankins GDV, et al: Idiopathic cardiomyopathy or compounding cardiovascular events. Obstet Gynecol 67: 157, 1986


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Obstentrics_Williams. Cunningham FG, Pritchard JA, Hankins GDV, et al: Idiopathic cardiomyopathy or compounding cardiovascular events. Obstet Gynecol 67: 157, 1986 Cunningham FG, Pritchard JA, Mason R: Pregnancy and sickle hemoglobinopathy: results with and without prophylactic transfusions. Obstet Gynecol 62:419, 1983 Curtis\1, Tepper NK, Jatlaoui TC, et al: U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR 65(3):1, 2016 Cyganek A, Pietrzak B, Kociszewska-Najman B, et al: Anemia treatment with erythropoietin in pregnant renal recipients. Transplant Proc 43(8):2970, 2011 Dafos F, Capella-Pavlovsky M, Forestier F: Fetal blood sampling during pregnancy with the use of a needle guided by ultrasound: a study of 606 consecutive cases. Am J Obstet GynecoIs153:655, 1985 Dalle JH: Hematopoietic stem cell transplantation in SCD. C R Bioi 336(3):148,s2013


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Obstentrics_Williams. Dalle JH: Hematopoietic stem cell transplantation in SCD. C R Bioi 336(3):148,s2013 Daru J, Cooper NA, Khan KS: Systematic review of randomized trials of the efect of iron supplementation on iron stores and oxygen carrying capacity in pregnancy. Acta Obstet Gynecol Scand 95(3):270, 2016 Dashe JS, Ramin SM, Cunningham FG: he long-term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy. Obstet Gynecol 91:662, 1998 Daskalakis GJ, Papageorgiou IS, Antsaklis AJ, et al: Pregnancy and homozygous beta thalassaemia major. BJOG 105:1028, 1998 DeBaun MR, Gordon M, McKinstry RC, et al: Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 371 :699,2014 Decrooq J, Marcellin L, Le Ray C, et al: Rescue therapy with romiplostim for refractory primary immune thrombocytopenia during pregnancy. Obstet Gynecols124(2 pt 2 Suppl1):481, 2014


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Obstentrics_Williams. Edwards Z, Rijhsinghani A: Dysibrinogenemia and placental abruption. Obstet Gynecol 95: 1 043, 2000 Egerman RS, Witlin AG, Friedman SA, et al: hrombotic thrombocytopenic purpura and hemolytic uremic syndrome in pregnancy: review of 11 cases. Am J Obstet Gynecol 195:950, 1996 Eliyahu S, Shalev E: A successful pregnancy after bone marrow transplantation for severe aplastic anaemia with pretransplant conditioning of total Iymphnode irradiation and cyclophosphamide. Br J HaematoI86:649, 1994 Elstein D, Granovsky-Grisaru S, Rabinowitz R, et al: Use of enzyme replacement therapy for Gaucher disease during pregnancy. Am J Obstet Gynecol 177:1509,s1997 Fadel HE, Krauss JS: Factor VII deiciency and pregnancy. Obstet Gynecol 73:453, 1989 Faivre L, Meerpohl J, Da Costa L, et al: High-risk pregnancies in DiamondBlackfan anemia: a survey of 64 pregnancies from the French and German registries. Haematologica 91 :530, 2006


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Obstentrics_Williams. Harrison C: Do we know more about essential thrombocythemia because of JAK2V617F? Curr Hematol Malig Rep 4(1):25, 2009 Henney MM, Hoppe Cc, Abboud MR, et al: A multinational trial of prasugrel for sickle cell vaso-occlusive events. N Engl] Med 374:625, 2016 Hesdorfer CS, Longo DL: Drug-induced megaloblastic anemia. N Englt] Med 373:1649,t2015 Hsieh F], Chang FM, Ko TM, et al: The antenatal blood gas and acid-base status of normal fetuses and hydropic fetuses with Bart hemoglobinopathy. Obstet Gynecol 74:722, 1989 Hsieh MM, Kang EM, Fitzhugh CD, et al: Allogenic hematopoietic stem-cell transplantation for sickle cell disease. N Engl] Med 361(24):2309, 2009 Hsu HW, Belfort MA, Vernino S, et al: Postpartum thrombotic thrombocytopenic purpura complicated by Budd-Chiari syndrome. Obstet Gynecol 85:839, 1995 Huhta ]C, Linask K: When should we prescribe high-dose folic acid to prevent congenital heart defects? Curr Opin Cardiol 30(1):125, 2015


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