Blood Disorders Among Women

Implications for Preconception Care

      Abstract

      The objectives of preconception care for women with blood disorders are to provide women and their partners with information on the implications of blood disorders for pregnancy; reproductive choices; and the management of potential or future pregnancies. Advances in hematology have led to improved diagnosis and treatment of blood disorders, thereby contributing to longevity and quality of life for women who are either affected by or are carriers of blood disorders. Women with blood disorders pose unique challenges: physiologic events such as pregnancy and menstruation influence the manifestations of blood disorders; blood disorders are a risk factor for adverse pregnancy outcomes; pregnancy imposes the risk of potential genetic transmission of the blood disorder to the offspring;and medications used for treatment of blood disorders pose additional challenges to conception and pregnancy. Hence, it is crucial that women of childbearing age with blood disorders be provided proper care for their conditions and be counseled before they become pregnant, in time to prevent complications to mothers and infants related to blood disorders. The purpose of this paper is to provide a brief overview of the current knowledge related to blood disorders in women of reproductive age, the interventions needed to manage these conditions, and the implications of these conditions and their management for the health of women and their infants.

      Introduction

      Women and infants often disproportionately bear the burden of inadequate prevention services and interventions. Preconception care and counseling may serve as a vehicle for further improving general wellness and perinatal outcomes. Preconception care is preventive medicine for maternal and child health. In the U.S., preconception care was first envisioned as a public health strategy in 1989 by a U.S. Public Health Service expert panel.
      U.S. Public Health Service Expert Panel on the Content of Prenatal Care
      Caring for our future: the content of prenatal care.
      Subsequent conceptual advancements and experience with preconception care were reviewed and summarized by a federal panel of experts and published in the form of recommendations by the CDC in 2006.
      CDC
      Recommendations to improve preconception health and health care—U.S..
      The expert panel suggested that preconception care aims to achieve four goals: (1) to improve the knowledge, attitudes, and behaviors of men and women related to preconception health; (2) to ensure that all women of childbearing age in the U.S. receive preconception care services that will enable them to enter pregnancy in optimal health; (3) to reduce risks indicated by a previous adverse pregnancy outcome through interventions during the interconception period; and (4) to reduce disparities in adverse pregnancy outcomes.
      CDC
      Recommendations to improve preconception health and health care—U.S..
      The expert panel further defined preconception care as “a set of interventions that aim to identify and modify biomedical, behavioral, and social risks to a woman's health or pregnancy outcome through prevention and management.”
      CDC
      Recommendations to improve preconception health and health care—U.S..
      These renewed discussions on preconception care have underscored the need to improve the evidence base in several areas and promote the use of the evidence base to improve preconception health. Beyond these policy recommendations, primary care providers have indicated the need to expand relevant information on issues of general interest to clinical care providers.
      In resource-poor countries, survival to adulthood for people with certain blood disorders is not common, whereas in established market economies, advances in the recognition and treatment of blood disorders have led to improvements in both the longevity and quality of life of patients with blood disorders.
      • Weatherall D.
      • Hofman K.
      • Rodgers G.
      • et al.
      A case for developing North–South partnerships for research in sickle cell disease.
      • Makani J.
      • Williams T.N.
      • Marsh K.
      Sickle cell disease in Africa: burden and research priorities.
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      • Darlison M.
      Global epidemiology of hemoglobin disorders and derived service indicators.
      • Soucie J.M.
      • Evatt B.
      • Jackson D.
      Occurrence of hemophilia in the U.S..
      Further, as people with blood disorders live longer and become fully integrated into society, it is more likely that they will raise families and pass some of the genetically mediated blood disorders on to their children. Because of this increased longevity, healthcare providers in public and private settings are more likely to encounter women with blood disorders who are of reproductive age and plan to become pregnant.
      Pregnancy has been associated with the exacerbation of pre-existing blood disorders, such as sickle cell disease (SCD), and can place women, especially those with sickle cell anemia, at an increased risk for obstetric complications.
      • Philipp C.
      • Faiz A.
      • Dowling N.
      • et al.
      Age and the prevalence of bleeding disorders in women with menorrhagia.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      The presence of a thrombophilia, whether inherited or acquired, predisposes pregnant women to an increased risk for maternal and fetal adverse pregnancy outcomes, including recurrent miscarriage, unexplained fetal death, placental thrombosis, infarcts, abruptions, intrauterine growth retardation, preeclampsia, and maternal cerebrovascular ischemic events or stroke. Thus, for women who have blood disorders or carry risk genes for blood disorders, preconception care is critical for ensuring optimal health for themselves and their children.
      The current paper summarizes information on blood disorders relevant to preconception care; it provides a description of the hematologic changes related to pregnancy and a description of the effect of common hematologic conditions on pregnancy and relevant preconception care issues. As the focus is on preconception care, general clinical management aspects of blood disorders, including during pregnancy, are not covered. A few of the blood disorders commonly addressed in public health and clinical settings are highlighted, and the discussion is restricted to common and hereditary conditions. Several other blood-related clinical issues—including emerging pathogens and transfusion safety of blood and blood products, adverse effects of medications, and blood-related cancers—are important but lie beyond the scope of this paper.

      Blood Disorders Among Women and Their Relevance to Preconception Care

      Blood disorders affect both men and women. Despite the same disease severity as men, women often are more symptomatic because of regular hemostatic challenges during menstruation, pregnancy, and childbirth. Because of the many reproductive events (including pregnancy), physiologic and pathologic changes in blood have special significance for women. Sometimes, blood disorders are initially diagnosed during a reproductive event.
      Pregnancy is of particular relevance to hematology practice; normal hematologic changes that occur during pregnancy alter the expression of blood disorders, and influence the health of the woman and fetus.
      • Philipp C.
      • Faiz A.
      • Dowling N.
      • et al.
      Age and the prevalence of bleeding disorders in women with menorrhagia.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      In spite of major advancements in access to and utilization of early prenatal care, further improvements in pregnancy outcomes among women with blood disorders may be realized only through the delivery of interventions in the preconception period. Thus, hematology is of high relevance to preconception care because most blood disorders can be diagnosed or managed prior to pregnancy. Blood disorders include common conditions such as anemia, and some rare, inherited blood disorders. Although data on prevalence are limited, obstetric and gynecologic conditions disproportionately affect women with blood disorders.

      Hematologic Changes During Pregnancy

      Pregnancy is accompanied by several changes that contribute to the hypercoagulable state of pregnancy and to improved hemostasis.
      • Philipp C.
      • Faiz A.
      • Dowling N.
      • et al.
      Age and the prevalence of bleeding disorders in women with menorrhagia.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      • Allen L.H.
      Anemia and iron deficiency: effects on pregnancy outcome.
      Such changes include increased concentrations of fibrinogen; factor VII (FVII); factor VIII (FVIII); factor X (FX); and von Willebrand factor (VWF), particularly during the last trimester, with decline to baseline 2–7 weeks after delivery; reduced fibrinolytic activity resulting from increased plasminogen activator inhibitor type 1 (PAI-1); and a decrease in the free protein S secondary to an increase in its binding protein, the complement component C4B. However, despite improved hemostasis, women with factor deficiencies do not achieve the same factor levels as women without deficiencies.
      During a normal pregnancy, both maternal red cell mass and plasma volume increase to enhance oxygen delivery to the fetus. Blood volume expands by 50% (1000 mL) and red cell mass by 25% (300 mL), resulting in a net decrease in hemoglobin to as low as 10.5 gm/dL. Iron requirements increase during pregnancy to support the red cell mass and placental and fetal growth.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 95: Anemia in pregnancy.

      Types and Burden of Blood Disorders Among Women of Childbearing Age

      Because of the complexity of steps and organs involved in the production and use of blood, and the variety of disorders associated with blood, classification of blood disorders is challenging.
      • Modell B.
      • Darlison M.
      Global epidemiology of hemoglobin disorders and derived service indicators.
      • Soucie J.M.
      • Evatt B.
      • Jackson D.
      Occurrence of hemophilia in the U.S..
      • Philipp C.
      • Faiz A.
      • Dowling N.
      • et al.
      Age and the prevalence of bleeding disorders in women with menorrhagia.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      • Allen L.H.
      Anemia and iron deficiency: effects on pregnancy outcome.
      Blood disorders range from anemias to inherited disorders and cancers. Similarly, blood disorders do not present with a single clinical feature or related clinical features; instead they present as multisystem clinical conditions and are managed by several clinical specialties. Some conditions such as anemias are not considered disorders per se, but rather second- or third-order consequences of underlying abnormalities. Further, some medications that are used for blood disorders, and some procedures (e.g., dialysis and transfusion), pose additional challenges to conception and pregnancy but are not categorized as diseases. For these reasons, the population-level burden from all blood disorders and their consequences is unavailable.
      • Modell B.
      • Darlison M.
      Global epidemiology of hemoglobin disorders and derived service indicators.
      • Soucie J.M.
      • Evatt B.
      • Jackson D.
      Occurrence of hemophilia in the U.S..
      • Philipp C.
      • Faiz A.
      • Dowling N.
      • et al.
      Age and the prevalence of bleeding disorders in women with menorrhagia.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      • Allen L.H.
      Anemia and iron deficiency: effects on pregnancy outcome.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 95: Anemia in pregnancy.
      CDC
      Iron deficiency—U.S., 1999–2000.
      • Anderson Jr, F.A.
      • Wheeler H.B.
      • Goldberg R.J.
      • et al.
      A population-based perspective of the hospital incidence and case–fatality rates of deep vein thrombosis and pulmonary embolism The Worcester DVT Study.
      • Cusick S.E.
      • Mei Z.
      • Freedman D.S.
      • et al.
      Unexplained decline in the prevalence of anemia among U.S. children and women between 1988–1994 and 1999–2002.
      In general, blood disorders can be grouped into three broad categories: red blood cell disorders, clotting disorders, and other blood disorders.

      Implications of Selected Blood Disorders for Pregnancy and Preconception Care

      Disorders of Red Cells

      Anemia

      Anemia is an important health concern among women of childbearing age and can have serious consequences for both the woman and her offspring.
      • Allen L.H.
      Anemia and iron deficiency: effects on pregnancy outcome.
      American College of Obstetricians and Gynecologists
      ACOG Practice Bulletin No. 95: Anemia in pregnancy.
      CDC
      Iron deficiency—U.S., 1999–2000.
      • Anderson Jr, F.A.
      • Wheeler H.B.
      • Goldberg R.J.
      • et al.
      A population-based perspective of the hospital incidence and case–fatality rates of deep vein thrombosis and pulmonary embolism The Worcester DVT Study.
      • Cusick S.E.
      • Mei Z.
      • Freedman D.S.
      • et al.
      Unexplained decline in the prevalence of anemia among U.S. children and women between 1988–1994 and 1999–2002.
      • Cogswell M.E.
      • Kettel-Khan L.
      • Ramakrishnan U.
      Iron supplement use among women in the U.S.: science, policy and practice.
      • Newman B.
      Iron depletion by whole-blood donation harms menstruating females: the current whole-blood-collection paradigm needs to be changed.
      Anemia often results in reduced physical capacity. Maternal iron deficiency is associated with the risk of low birth weight, preterm delivery, and perinatal and neonatal mortality and morbidity.
      The various kinds of anemia that a woman might encounter during the preconception period are nutritional anemias (iron-deficiency anemia (IDA); and macrocytic anemias, such as B12 and folate deficiencies); inherited hemolytic blood disorders; hemoglobinopathies; bone marrow failure syndromes, and anemias resulting from blood loss from inherited and acquired blood disorders. Physiologic changes during pregnancy can complicate the diagnosis of anemia.
      Anemia of any kind exaggerates the drop in hemoglobin and, therefore, of oxygen delivery to the fetus.

      Prevalence of anemia among women of reproductive age

      Data from the National Health and Nutrition Examination Survey (NHANES) during the years 1988–1994 and 1999–2002 indicated that the prevalence of anemia among women declined from 10.8% to 6.9%.
      CDC
      Iron deficiency—U.S., 1999–2000.
      • Cusick S.E.
      • Mei Z.
      • Freedman D.S.
      • et al.
      Unexplained decline in the prevalence of anemia among U.S. children and women between 1988–1994 and 1999–2002.
      Although promising, this decline in anemia prevalence remains largely unexplained. Also of concern is the fact that many potential causes of anemia, such as iron deficiency, inflammation, and high blood lead, showed little change in prevalence during these periods. The decline in folate deficiency among women accounted for little of the overall decline in anemia. The study also indicated that, although anemia prevalence declined across all ethnic groups, minority women were much more likely to be anemic than white women. Results showed that 24.4% of African-American women and 8.7% of Hispanic women were anemic, compared with 3.3% of white women.

      Iron-deficiency anemia

      Iron is an essential nutrient of all cells in the body and is a major component of hemoglobin, the oxygen-carrying protein within red cells.
      • Allen L.H.
      Anemia and iron deficiency: effects on pregnancy outcome.
      • Newman B.
      Iron depletion by whole-blood donation harms menstruating females: the current whole-blood-collection paradigm needs to be changed.
      Smaller amounts are found in myoglobin and intracellular respiratory enzymes. Approximately 70% of iron is found in hemoglobin, whereas 15%–20% is stored as ferritin and hemosiderin. The total body content is 2 g among women and 6 g among men. Iron balance is determined by dietary intake, supplementation, and salvage of red-cell iron, by losses through menstruation, gastrointestinal tract absorption, and increased needs during breastfeeding. The adverse clinical effects related to iron deficiency among nonpregnant women include increased prevalence of fatigue, decreased physical endurance, and restless leg syndrome (RLS).
      • Newman B.
      Iron depletion by whole-blood donation harms menstruating females: the current whole-blood-collection paradigm needs to be changed.
      Iron-deficiency anemia accounts for 75%–95% of all cases of anemia among pregnant women.
      • Allen L.H.
      Anemia and iron deficiency: effects on pregnancy outcome.
      The clinical consequences of IDA among pregnant women include preterm delivery, perinatal mortality, and postpartum depression; it also can have clinical consequences for their offspring, including low birth weight and poor mental and psychomotor performance. The prevalence of RLS is as high as 20%–30% among pregnant women with IDA. Restless leg syndrome occurs during the last trimester of pregnancy and disappears within 4 weeks after delivery.
      • Newman B.
      Iron depletion by whole-blood donation harms menstruating females: the current whole-blood-collection paradigm needs to be changed.
      The American College of Obstetricians and Gynecologists recommends
      • Cogswell M.E.
      • Kettel-Khan L.
      • Ramakrishnan U.
      Iron supplement use among women in the U.S.: science, policy and practice.
      screening for anemia for all pregnant women and treatment of those with IDA with supplemental iron and further evaluation of anemia of other origins.

      Macrocytic anemias

      Folic acid and vitamin B12 deficiencies are the most common causes of megaloblastic anemias that often present with macrocytic anemias. During pregnancy, folic acid requirements increase from 50 μg/day to 400 μg/day, and nutritional deficiency is the primary etiology. Deficiency of folic acid is associated with the occurrence of neural tube defects (NTDs) in the fetus and other adverse pregnancy outcomes such as preeclampsia, stillbirth, and fetal growth restriction. Further, the reduction of NTDs by folic acid supplementation has been proven in many trials.
      • Wheeler S.
      Assessment and interpretation of micronutrient status during pregnancy.
      Both B12 and folate deficiencies are associated with adverse pregnancy outcomes such as miscarriage, low birth weight, and premature birth.
      • Wheeler S.
      Assessment and interpretation of micronutrient status during pregnancy.

      Diamond Blackfan anemia

      Diamond Blackfan anemia (DBA) is an inherited disorder of pure red cell aplasia often diagnosed in the first year of life and requires lifelong transfusions.
      • Vlachos A.
      • Ball S.
      • Dahl N.
      • et al.
      Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference.
      • Faivre L.
      • Meerpohl J.
      • Da Costa L.
      • et al.
      High-risk pregnancies in Diamond Blackfan anemia: a survey of 64 pregnancies from the French and German registries.
      It affects seven per million live births; 40% of those affected will have congenital anomalies. Recent data show that 40%–45% of the cases are familial with an autosomal dominant pattern.
      • Vlachos A.
      • Ball S.
      • Dahl N.
      • et al.
      Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference.
      Mutations of the gene encoding a ribosomal protein (RPS19) and elevated erythrocyte adenosine deaminase activity often are seen in this disorder. A recent study of 64 pregnancies among women with DBA showed complications such as fetal loss, preeclampsia, hydrops fetalis, and intrauterine growth restriction, as well as congenital anomalies among the offspring.
      • Faivre L.
      • Meerpohl J.
      • Da Costa L.
      • et al.
      High-risk pregnancies in Diamond Blackfan anemia: a survey of 64 pregnancies from the French and German registries.
      Management of pregnancies is difficult in the face of the transfusion requirements of these patients. Deferoxamine, an iron-chelating agent often used among patients with chronic transfusion, is embryopathic. It is recommended that chelation should cease when a patient is pregnant or plans to become pregnant. Most of these patients are anemic, and hemoglobin should be maintained above 10 g/dL. Periconception use of aspirin for up to 37 weeks' gestation to prevent recurrent vascular placental complications has been recommended.
      • Faivre L.
      • Meerpohl J.
      • Da Costa L.
      • et al.
      High-risk pregnancies in Diamond Blackfan anemia: a survey of 64 pregnancies from the French and German registries.
      Patients should be referred to a high-risk obstetrics clinic and work in close cooperation with a DBA center.
      There are rare reports of pregnancy associated with other bone marrow failure syndromes. Alter et al.
      • Alter B.P.
      • Frissora C.L.
      • Halpérin D.S.
      • et al.
      Fanconi's anaemia and pregnancy.
      reported worsening of anemia and thrombocytopenia in 26 pregnancies in 17 cases. Seven of these patients subsequently died from cancer.

      Hemoglobinopathies

      Inherited hemoglobin disorders are perhaps the most common genetic blood disorders worldwide and encompass sickling and nonsickling disorders.

      Thalassemias

      Thalassemias are a heterogeneous group associated with mutations in the alpha and beta globin chains of the hemoglobin. Although they are rare in the U.S., the influx of immigrants from countries where thalassemias are relatively common, such as Southeast Asia, has given rise to a substantial increase in hemoglobinopathies such as hemoglobin H disease. Changing demographics in the U.S. caused by the influx of migrants, especially in states such as California, New York, and Florida, require knowledge and awareness of issues of preconception care in this population. There are currently no standard guidelines related to thalassemia, and research is needed to develop evidence-based guidelines.
      In women with hemoglobinopathies, there are two issues regarding preconception care that should be taken into consideration. These include: (1) care of the woman affected with thalassemia; and (2) prenatal screening for pregnancy at risk.
      Although fertility is compromised in most cases of transfusion-dependent thalassemia major, with advances in care of thalassemia, including iron chelation therapy and early detection of iron overload, pregnancy is possible. Hypogonadotropic hypogonadism and higher prevalence of fetal and maternal complications have been reported.
      • Skordis N.
      • Petrikkos L.
      • Toumba M.
      • et al.
      Update on fertility in thalassemia major.
      Pregnant women with thalassemia intermedia (TI) are at increased risk of abortion, preterm delivery, intrauterine growth restriction, and thromboembolism.
      • Nassar A.H.
      • Naja M.
      • Cesaretti C.
      • Eprassi B.
      • Cappellini M.D.
      • Taher A.
      Pregnancy outcome in patients with beta-thalassemia intermedia at two tertiary care centers, in Beirut and Milan.
      A recent Italian study of 58 pregnancies in 46 women with thalassemia major and 17 pregnancies in 11 women with thalassemia intermedia reported successful delivery in 91% of the pregnancies, with the high rate of preterm deliveries (32.7%) related to multiple pregnancies. Gestational diabetes, preeclampsia, placental abruption, and urinary tract infection were rare. All but one had normal pre-pregnancy cardiac function that remained normal. Thirty-three pregnancies required gonadotropin-induced ovulation. Women with TI were at risk for severe alloimmune anemia if blood transfusions were required. There was a high rate of cesarean deliveries in 52 pregnancies, of which 48% were elective as a precaution.
      • Origa R.
      • Piga A.
      • Quarta G.
      • et al.
      Pregnancy and {beta}-thalassemia: an Italian multicenter experience.

      Prenatal Screening

      Although newborn screening for SCD is mandated in all the states in the U.S., screening for nonsickling disorders such as beta thalassemia and hemoglobin H is not routinely done. Although European countries advocate for prenatal screening as an effective means to prevent births of affected infants, studies in the U.S. have failed to show widespread acceptance of prenatal diagnosis among pregnant women at risk by prenatal screening.
      • Hoppe C.
      Newborn screening for non-sickling hemoglobinopathies Hematology 2009.
      It would be ideal to integrate prenatal and neonatal screening to maximize identification of at-risk newborns and offer maximum benefits in terms of prenatal counseling, parental options, and education. According to Oliver et al.,
      • Oliver S.
      • Dezateux C.
      • Kavanagh J.
      • Lempert T.
      • Stewart R.
      Disclosing to parents newborn carrier status identified by routine blood spot screening.
      knowledge of newborn status can often lead to testing of parents with identification of one or both as carriers, which may be helpful in education and future pregnancy planning. However, there is a possibility of such testing revealing that the putative father is not the biological father; raising concerns about the child's future reproductive choices; and creating unjustified anxiety about the health of the carrier newborn. There is an urgent need to develop clear guidance as to how to respond.
      • Oliver S.
      • Dezateux C.
      • Kavanagh J.
      • Lempert T.
      • Stewart R.
      Disclosing to parents newborn carrier status identified by routine blood spot screening.

      Sickle Cell Disease

      Sickle cell disease (SCD) includes an array of disorders in which defective hemoglobin is unable to carry oxygen around the body as it should
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      • Korenbrot C.
      • Steinberg A.
      • Bender C.
      • Newberry S.
      Preconception care: a systematic review.
      • Letsky E.A.
      Blood disorders in pregnancy.
      ; it is one of the most prevalent genetic disorders of hemoglobin. The gene mutation that causes the disease is recessive. Many women who might not have the disease might unknowingly be carriers. Although many women might experience no adverse effects, they should be monitored closely throughout pregnancy. Potential maternal complications among women with SCD include tissue hypoxia that results in acute painful crisis, severe anemia, infections, and preterm loss.
      • Korenbrot C.
      • Steinberg A.
      • Bender C.
      • Newberry S.
      Preconception care: a systematic review.
      • Letsky E.A.
      Blood disorders in pregnancy.
      The primary preconception interventions for women with SCD are genetic testing and counseling.
      • Levitt C.
      Preconception health promotion Primary care.
      For women not desiring to become pregnant, testing should assess their current health status, and counseling should address family planning choices and contraception options. For women desiring to become pregnant, testing should identify which hemoglobin disease variant each woman has, and counseling should ensure that each woman or couple is fully apprised of the potential risks pregnancy might pose to the woman and fetus and what steps can be taken to mitigate those risks. During the preconception period, women in high-risk ethnic groups should be screened to determine their carrier status. If they are found to carry the mutated gene, their potential spouse or mate also should be tested. Assessments of the mother's and father's health should be performed and their family history obtained. Women with sickle cell anemia might be at an increased risk of having a baby with an NTD and should continue taking 5 mg folic acid daily.
      • Levitt C.
      Preconception health promotion Primary care.
      Health Canada
      Family-centered maternity and newborn care: national guidelines.
      Women who are carriers should receive 400 mcg of folic acid daily.
      The ultimate goal of preconception counseling should be informed decision making.
      • Levitt C.
      Preconception health promotion Primary care.
      Health Canada
      Family-centered maternity and newborn care: national guidelines.
      Care should be taken not to induce undue anxiety or stress, which itself could adversely affect the health of the mother and fetus. Counseling should provide information appropriate to each individual's or couple's level of understanding and equip recipients to identify risks specific to the mother and to the fetus.

      Hemostatic Disorders

      Clotting disorders (venous thromboembolism and thrombophilia)

      Venous thromboembolisms (VTE; includes deep-vein thrombosis [DVT] and pulmonary embolism [PE]) are estimated to affect up to 600,000 Americans each year.
      U.S. Census Bureau News. Nation's population to reach 300 million on Oct. 17.
      • Anderson Jr, F.A.
      • Wheeler H.B.
      • Goldberg R.J.
      • et al.
      A population-based perspective of the hospital incidence and case–fatality rates of deep vein thrombosis and pulmonary embolism The Worcester DVT Study.
      Thrombophilia is an inherited blood clotting disorder caused by one or more genetic risk factors or mutations that make a person susceptible to venous thrombosis.
      • Seligsohn U.
      • Griffin J.H.
      Hereditary thrombophilia.
      These factors include mutations in the factor V and prothrombin genes, which result in factor V Leiden and prothrombin G20210A, respectively, and deficiencies in the anticoagulation factors protein C, protein S, and antithrombin.
      • Seligsohn U.
      • Griffin J.H.
      Hereditary thrombophilia.
      Over one third (35%) of VTE patients have at least one of these five factors.
      • Rosendaal F.R.
      Venous thrombosis: the role of genes, environment, and behavior.
      • Cushman M.
      Inherited risk factors for venous thrombosis.
      The risks of VTE are much greater for those individuals with thrombophilia compared with the population at large, particularly for those who also have another risk, such as surgery, hospitalization, or a prolonged bed stay.
      • Heit J.A.
      • Silverstein M.D.
      • Mohr D.N.
      • Petterson T.M.
      • O'Fallon W.M.
      • Melton 3rd, L.J.
      Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case–control study.
      • Geerts W.H.
      • Pineo G.F.
      • Heit J.A.
      • et al.
      Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
      • Baglin T.P.
      • White K.
      • Charles A.
      Fatal pulmonary embolism in hospitalized medical patients.
      However, an individual with such a genetic mutation will not necessarily develop these conditions, and fewer than 10% of those who carry the most common mutations will develop a detectable blood clot each year.
      • Vossen C.Y.
      • Conard J.
      • Fontcuberta J.
      • et al.
      Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect The European Prospective Cohort on Thrombophilia (EPCOT).

      Risk among women

      Although most studies report the overall risk of VTE to be similar among women and men, there are several reports of specific trends related to gender.
      • Anderson Jr, F.A.
      • Wheeler H.B.
      • Goldberg R.J.
      • et al.
      A population-based perspective of the hospital incidence and case–fatality rates of deep vein thrombosis and pulmonary embolism The Worcester DVT Study.
      • Di Minno G.
      • Mannucci P.
      • Tufano A.
      • et al.
      The first ambulatory screening on thromboembolism: a multicenter, cross-sectional, observational study on risk factors for venous thromboembolism.
      The risk of VTE among women is influenced inherently by age, race, weight, and inherited predisposition to clotting, with the risk varying chronologically throughout a woman's life, in large part because of exposure to estrogen.
      • Rathburn S.
      Venous thromboembolism in women.
      Early in life, a woman could be exposed to oral contraceptive therapy, and later pregnancy; finally, with menopause, a woman might choose to receive hormone replacement therapy.
      • Rathburn S.
      Venous thromboembolism in women.
      In addition, this risk is influenced by the formulation, dose, and duration of estrogen and progestin administration. Taken together, these factors can pose a substantial risk of VTE throughout a woman's life and should be considered thoughtfully as an important women's health issue.
      • Rathburn S.
      Venous thromboembolism in women.

      Thrombophilia and pregnancy

      During pregnancy and the postpartum period, women are five times more likely to suffer from VTE than when they are not pregnant.
      • Rathburn S.
      Venous thromboembolism in women.
      Moreover, several studies have demonstrated an association between thrombophilias and adverse pregnancy outcomes.
      • James A.
      • Brancazio L.R.
      • Ortel T.L.
      Prevention of venous thromboembolism NIH Consensus Development.
      Maternal effects of thrombophilias include an increased risk of venous thromboembolism (including DVT, PE, and cerebral vein thrombosis); arterial thrombosis (peripheral and cerebral); and severe preeclampsia. Placental and fetal effects include thrombosis and infarcts, placental abruption, recurrent miscarriage, fetal growth restriction, fetal stroke, and death.
      Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy.
      • Lockwood C.J.
      Inherited thrombophilias in pregnant patients: detection and treatment paradigm.
      • Silver R.M.
      • Warren J.E.
      Preconception counseling for women with thrombophilia.
      • Wu O.
      • Robertson L.
      • Twaddle S.
      • et al.
      Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.
      • Lin L.
      • August P.
      Genetic thrombophilias and preeclampsia: a meta-analysis.
      Our ability to predict pregnancy outcomes based solely on the presence of thrombophilia is poor, and our ability to predict whether thromboprophylaxis will prevent these adverse outcomes is equally controversial.
      Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy.
      Therefore, at this time, routine screening for thrombophilia is not recommended. However, screening for thrombophilia is recommended for women with a personal or family history of thrombosis.
      • Rey E.
      • Kahn S.R.
      • David M.
      • Shrier I.
      Thrombophilic disorders and fetal loss: a meta-analysis.
      Testing for thrombophilia also should be considered for women who have no personal history of thrombosis but have a strong family history and an inherited thrombophilia, and those who have a history of recurrent adverse pregnancy outcomes (severe preeclampsia, fetal growth restriction, or abruptio placenta).
      • Rey E.
      • Kahn S.R.
      • David M.
      • Shrier I.
      Thrombophilic disorders and fetal loss: a meta-analysis.
      American College of Obstetrics and Gynecology
      Thromboembolism in pregnancy.
      Women planning pregnancy should avoid the use of warfarin. They also should be offered genetic counseling and preconception care to allow them to optimize control of their condition prior to pregnancy and to transition to a medication regimen that is safer for the fetus. Women who are not planning pregnancy should be offered genetic counseling and effective contraception. The American College of Chest Physicians recommends
      • Prins M.H.
      • Raskob G.E.
      • Büller H.R.
      • Agnelli G..
      • Hull R.D.
      • Hyers T.M.
      Thromboembolic disease antithrombotic therapy for venous.
      that women with recurrent early pregnancy loss or unexplained pregnancy should be screened for antiphospholipid antibodies.

      Bleeding disorders

      The most common congenital coagulopathies are von Willebrand disease (VWD); hemophilia A, and hemophilia B. Of these, VWD is mostly autosomal dominant, whereas hemophilia A and B are X-linked recessive.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      • Dunlop A.L.
      • Jack B.W.
      • Bottalico J.N.
      • et al.
      The clinical content of preconception care: women with chronic medical conditions.
      About 5%–32% of women with menorrhagia have a bleeding disorder.
      The most common congenital coagulopathy affecting women is VWD; it constitutes a heterogenous group of hemorrhagic disorders.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      • Kadir R.
      • Chi C.
      • Bolton-Maggs P.
      Pregnancy and rare bleeding disorders.
      The prevalence of menorrhagia among women with VWD is 74%–92%. Among women presenting with menorrhagia or excess menstrual periods, approximately 11%–13 % have VWD. Severe forms of VWD, such as type3 VWD, are easy to diagnose, milder forms do occur and can be difficult to diagnose. Some of the milder forms, such as type 1 and type 2, might become apparent only following a major hemostatic challenge. Clinical features include menorrhagia, epistaxis, easy bruising, gastrointestinal bleeding, and post-operative and postpartum hemorrhage. In the absence of genetic analysis, VWD is diagnosed by the combination of clinical and laboratory features. However, the diagnosis of mild forms of VWD is difficult and complex because the clinical expression of VWD is variable. The laboratory tests can fluctuate to normal levels with time in any given individual. Although the bleeding time and activated Partial Thromboplastin Time (aPTT) are prolonged among patients with severe VWD, they might be normal among those with mild disease. Repeat testing and restriction of sampling times to Days 5–7 of the menstrual cycle have been suggested
      • Chi C.
      • Kadir R.A.
      Management of women with inherited bleeding disorders in pregnancy.
      to minimize intra-individual variation.
      In obstetrics, von Willebrand disease is also important.
      • James A.H.
      • Kouides P.A.
      • Abdul-Kadir R.
      • et al.
      Von Willebrand disease and other bleeding disorders in women: consensus on diagnosis and management from an international expert panel.
      Although there is no increased risk of hemorrhage during the antenatal period, women with VWD are at increased risk for postpartum hemorrhage. This is due to the rapid fall in levels of factor VIII and VW factor following delivery. One particular situation in which hemorrhage can occur is after a first- or second-trimester miscarriage. The concentrations of FVIII coagulant (FVIIIC) activity seem to peak at around 38 weeks of gestation. Thus, the protective effect of pregnancy on FVIII might not be sufficient at the time of miscarriage to offer hemostatic protection. Regarding rare bleeding disorders, the prevalence of menorrhagia among women with FV, FVII, FX, and fibrinogen deficiencies is as high as 50%.
      Hemophilia A and hemophilia B are characterized by low circulating plasma levels of factor VIIIC and IX, respectively. With the increasing life expectancy of people with hemophilia, it is more likely that they will raise families and transmit the hemophilia gene to their daughters, thus raising the frequency of women with hemophilia seen in obstetric practice. One third of cases of hemophilia arise in families with no family history, reflecting new mutations. The clinical picture of hemophilia is dependent on the degree of deficiency of the coagulation factor in the blood: severe hemophilia is associated with a level that is less than 1% of normal. Because platelet functions are unaffected, people with hemophilia have normal bleeding time. People with hemophilia experience deep tissue bleeding, hemarthrosis, and post-operative bleeding, but not mucocutaneous bleeding episodes. The hallmark of severe hemophilia is recurrent and spontaneous bleeding into joints, particularly the knees, elbows, and ankles. Such repeated bleeding in the absence of treatment can lead to arthritis. The severity of hemophilia in a given family remains constant.
      There is very little information on obstetric and gynecologic problems of obligate carriers of hemophilia A and hemophilia B. Because these carriers have FVIII or FIX levels within the normal range, severe bleeding is unlikely. Factor levels can remain low among women with low nonpregnant values, and few reports have indicated menorrhagia and postpartum bleeding. This uncertainty underscores the need to monitor these women. In contrast to carriers of hemophilia A, carriers of hemophilia B seem to have much less of an increase in factor-IXc levels with pregnancy and might be more susceptible to postpartum hemorrhage.
      Overall, women with bleeding disorders are at increased risk of developing hemorrhagic ovarian cysts and other conditions that present as bleeding, such as fibroids, endometrial hyperplasia, and polyps. They also are more likely to undergo a hysterectomy at a younger age. During pregnancy, they are at increased risk of miscarriage and bleeding complications.
      Pregnancy is not contraindicated among patients with bleeding disorders. Because women with diagnosed bleeding disorders are likely to have frequent contact with hematology services, efforts to achieve a safer pregnancy would be more meaningful, and compliance and outcome much greater, if the hematologic service is complemented by preconception care. Similarly, a high index of suspicion among gynecology service providers, who might be the first contact for women with undiagnosed bleeding disorders, will help ensure referral and diagnosis of more women with bleeding disorders.
      To allow appropriate preconception counseling and early pregnancy management, identification of affected or carrier status ideally should be carried out before pregnancy for women in families with inherited bleeding disorders.
      • Dunlop A.L.
      • Jack B.W.
      • Bottalico J.N.
      • et al.
      The clinical content of preconception care: women with chronic medical conditions.
      • Chi C.
      • Kadir R.A.
      Management of women with inherited bleeding disorders in pregnancy.
      This identification is most important for women who are carriers of hemophilia and couples with FXI deficiency or type 3 VWD. Carrier detection for hemophilia is based on four different methods:
      • 1
        Pedigree analysis, using the knowledge of X-linked recessive inheritance, to assess a woman's risk from her position on the family tree. Daughters of a man with hemophilia are obligate carriers.
      • 2
        Phenotypic assessment, based on assays of plasma FVIII and FIX and, in some cases, VWF.
      • 3
        Direct gene mutation detection.
      • 4
        Indirect gene analysis involving the use of linked polymorphic markers to track heredity of a hemophilia gene within a pedigree when the mutation is not known.
      The preconception period is important if a trial of desmopressin is being considered.
      • Lethagen S.
      • Harris A.S.
      • Sjorin E.
      • Nilsson I.M.
      Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility.
      Preconception counseling should be offered to women with VWD, carriers of hemophilia, and other blood disorders to discuss suitable reproductive options and methods of prenatal diagnosis. Prenatal diagnosis is not required for the majority of women with VWD, whereas it is recommended for women with hemophilia. A substantial percentage of women with idiopathic hemorrhage have an underlying bleeding disorder, the most common being VWD, and testing should be considered. A personal and family history of bleeding symptoms should be obtained. Adolescents presenting with acute menorrhagia should be investigated for bleeding disorders. Finally, women with inherited bleeding disorders should be informed about the increased risks they face during pregnancy and childbirth and the effect these disorders can have on the fetus.

      Thrombocytopenia

      The normal platelet count among nonpregnant women is 150–400,000/μL; there is a 10% decrease in platelet count toward the end of pregnancy.
      • Verdy E.
      • Bessous V.
      • Dreyfus M.
      • Kaplan C.
      • Tchernia G.
      • Uzan S.
      Longitudinal analysis of platelet count and volume in normal pregnancy.
      There are a number of causes of thrombocytopenia during pregnancy. Gestational thrombocytopenia is a common and asymptomatic cause, resulting in platelet counts as low as 70,000/μL and occurring late in gestation; it has no fetal effect. The platelet count returns to normal 2–12 weeks following delivery. Other causes include hemolysis elevated liver enzyme and low platelet (HELLP) syndrome; disseminated intravascular coagulopathy; systemic lupus erythematosis; thrombotic thrombocytopenic purpura; infections; and drug-induced thrombocytopenias.
      Neonatal alloimmune thrombocytopenia (NAIT), a disorder caused by feto–maternal platelet incompatibility, occurs when the mother is exposed to paternally derived fetal platelet antigens. Maternal platelet counts are normal; however, the fetus or newborn can experience bleeding episodes, including intracranial hemorrhage due to low platelet counts.
      Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by low platelet counts in the mother and mucocutaneous bleeding. It is more common among young adults, especially women. The incidence of ITP among the general population is 1/10,000 and among pregnant women it is 1/1000–1/10,000. Pregnancy does not increase the risk of developing ITP or exacerbate pre-existing ITP.
      • Sukenik-Halevy R.
      • Ellis M.H.
      • Fejgin M.D.
      Management of immune thrombocytopenic purpura in pregnancy.
      However, maternal antibodies can cross the placenta and produce bleeding, although fetal effects are less severe than with NAIT. During pregnancy, frequent monitoring of the maternal platelet count is indicated. Treatment of ITP often involves the use of intravenous immunoglobulin or steroids. Immunosuppressive drugs are avoided because of potential teratogenic effects on the fetus.

      Summary

      Common blood disorders, such as hemophilia, thrombosis, SCD, and thalassemia pose unique challenges for women of reproductive age because of the relationship of these disorders to adverse pregnancy outcomes. Evidence from countries with a high burden of hereditary blood disorders, such as Middle Eastern countries, indicates that preconception genetic screening and counseling can be important tools in reducing adverse events among women with known or suspected genetic disorders.
      • Serjeant G.R.
      Geographic heterogeneity of sickle cell disease.
      • Gelpi A.P.
      Benign sickle cell disease in Saudi Arabia: survival estimates and population dynamics.
      For example, preconception diagnosis of a thrombophilia can significantly reduce the risk of adverse pregnancy outcomes through thromboprophylaxis, early treatment, or other risk-reduction strategies.
      Preconception counseling has two objectives. The main objective is to provide women and their partners with adequate information on the implications of their disorders; their reproductive choices; and the management of their pregnancies, including options of prenatal diagnosis. The second objective is to allow planning for pregnancy and to perform appropriate treatment or management procedures to minimize adverse events.
      Although substantial knowledge gaps exist with respect to the management and prevention of blood disorders during pregnancy, management of blood disorders requires providers and patients to tailor management and treatment and use the best available strategies to minimize adverse events. Clinicians providing hematology services would benefit from (1) guidelines and continuing medical education on preconception genetic counseling for women with blood disorders such as thalassemia, sickle cell anemia, hemophilia, and thrombosis; (2) information on the evidence and current guidelines regarding preconception care for women with common blood disorders; and (3) information on the potential effect of preconception care on maternal and fetal complications for women with common blood disorders such as SCD. It is generally suitable for women with a bleeding disorder to have shared preconception care between their local obstetric unit and a tertiary center allied to a hematology center, with the delivery planned at their local unit.
      Several preconception care interventions have reduced risk and improved health outcomes. By increasing support for provision of preconception care, policymakers have the opportunity to promote broad-based programs and services for women with blood disorders aimed at improving the health of women, children, and families.
      The views expressed in this report are those of the authors and do not necessarily represent the official position of the CDC.
      No financial disclosures were reported by the authors of this paper.

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