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Hematologic changes in pregnancy

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					Haematological Changes
    in Pregnancy
        Physiologic Anemia
            Neutrophilia
      Mild Thrombocytopenia
   Increased Procoagulant Factors
      Diminished Fibrinolysis.
                Anemia in Pregnancy

   PLASMA VOLUME — Plasma volume increases by 10 to 15 percent at 6 to
    12 weeks of gestation , expands rapidly until 30 to 34 weeks, after which there
    is only a modest rise . The total gain at term averages 1100 to 1600 mL and
    results in a plasma volume of 4700 to 5200 mL, 30 to 50 percent above that
    found in nonpregnant women .

   RED BLOOD CELLS — Red blood cell mass begins to increase at 8 to 10
    weeks of gestation and steadily rises by 20 to 30 percent (250 to 450 mL)
    above nonpregnant levels by the end of pregnancy in women taking iron
    supplements .
    Among women not on iron supplements, the red cell mass may only increase
    by 15 to 20 percent .
    Erythrocyte life span is slightly decreased during normal pregnancy .
            Anemia in Pregnancy

   Erythropoietin levels increase by 50 percent in normal
    pregnancies and vary according to the presence of pregnancy
    complications .
    The increased plasma erythropoietin induces the rise in red
    cell mass, which partially supports the higher metabolic
    requirement for oxygen during pregnancy .
    Mean corpuscular volume (MCV) decreases during
    pregnancy and averages 80 to 84 fL in the third trimester.
            Anemia in Pregnancy
   Anemia — A greater expansion of plasma volume relative to
    the increase in hemoglobin mass and erythrocyte volume is
    responsible for the modest fall in hemoglobin levels (ie,
    physiological or dilutional anemia of pregnancy)
    observed in healthy pregnant women. The greatest
    disproportion between the rates at which plasma and
    erythrocytes are added to the maternal circulation occurs
    during the late second to early third trimester (lowest
    hematocrit is typically measured at 28 to 36 weeks .
    Nearer to term, hemoglobin concentration increases due to
    cessation of plasma expansion and continuing increase in
    hemoglobin mass .
    Conversely, the absence of physiologic anemia appears to be a
    risk factor for stillbirth.
             Anemia in Pregnancy
   Determining a good definition of anemia in pregnant women is
    not straightforward, given the pregnancy associated changes in
    plasma volume and red cell mass, normal differences in
    hemoglobin concentrations between women and men, ethnic
    variation between white and black women, and the frequent use
    of iron supplementation in pregnancy.
    The Centers for Disease Control and Prevention has defined
    anemia as hemoglobin levels of less than 11 g/dL (hematocrit
    less than 33 percent) in the first and third trimesters and less
    than 10.5 g/dL (hematocrit less than 32 percent) in the second
    trimester . Since hemoglobin and hematocrit levels are lower in
    African-American adults, the Institute of Medicine recommends
    lowering the hemoglobin cut-off level by 0.8 g/dL in this
    population .
          Anemia in Pregnancy

   Women with hemoglobin values below these levels
    can be considered anemic and should undergo a
    standard evaluation .
    Sixteen to 29 percent of pregnant women become
    anemic in the third trimester . If the evaluation is
    negative, a hemoglobin as low as 10 g/dL can be
    attributed to physiologic anemia since a wide
    variety of factors affect the normal level of
    hemoglobin in a specific individual.
             Anemia in Pregnancy

   Chronic severe anemia is most common in women in developing
    countries.
   Maternal hemoglobin below 6 g/dL has been associated with
    reduced amniotic fluid volume, fetal cerebral vasodilation, and
    nonreassuring fetal heart rate patterns .
    Increased risks of prematurity, spontaneous abortion, low birth
    weight, and fetal death have also been reported . In addition,
    severe anemia (hemoglobin less than 7 g/dL) increases the risk
    of maternal mortality.
             Anemia in Pregnancy

   Chronic severe anemia is usually related to (1) inadequate iron
    stores due to nutritional deficiency and intestinal helminthic
    infections, (2) folate deficiency due to poor intake, and (3)
    chronic hemolytic states.
    Ideally, severe anemia could be prevented and pregnancy
    outcome improved with nutritional supplementation and
    infection control measures. However, 40 percent of women
    were still anemic in the third trimester.
    It is probably prudent to treat severe anemia aggressively, as
    with red cell transfusion, if there are signs suggestive of fetal
    hypoxemia.
                   Iron Deficiency
   In both the industrialized and the developing world, iron-
    deficiency anemia is the commonest cause of anemia. On
    average approximately 1 g of iron is required during a normal
    pregnancy; 300 mg of iron are required by the fetus and the
    placenta, whereas expansion of the maternal red blood cell
    (RBC) mass requires 500 mg, and 200 mg are lost via
    excretion.
   These requirements exceed the iron storage ( 300 mg) of most
    young women, and in general cannot be met by the diet.
   Even in cases of maternal iron deficiency, the fetal
    requirements for iron are always met, thus there is no
    correlation between the hematocrit of the fetus and that of the
    mother.
                 Iron Deficiency
   Iron-deficiency anemia during the first two trimesters
    of pregnancy is associated with a twofold increased
    risk for preterm delivery and a threefold increased
    risk for delivery of a low-birth-weight infant.
   However, a large randomized trial comparing routine
    iron prophylaxis in pregnancy versus iron
    supplementation given only as needed demonstrated
    no significant differences in adverse maternal or fetal
    outcomes.
    As in nonpregnant individuals, iron-deficiency
    anemia can generally be diagnosed using laboratory
    values such as serum ferritin, and transferrin levels .
                 Iron Deficiency
    Pica, the ingestion of nonnutritive substances, is said
    to be more common among iron-deficient pregnant
    women than among other populations with iron
    deficiency.
    Ice, clay or dirt, and starch are the most frequent
    substances ingested ; to some extent, however, the
    choice appears to be cultural and much more
    widespread than most practitioners realize.
    Folate and Vitamin B12 Deficiency
   Apart from iron deficiency, folate deficiency is the next most
    frequent nutritional deficiency leading to anemia in pregnant
    women.
   In the United States, where foodstuffs are supplemented with
    folate and the level of awareness of the association between
    folate deficiency and neural tube defects is high, folate
    deficiency is relatively unusual.
    Folate requirements in pregnancy are roughly twice those in the
    nonpregnant state (800 µ g/day vs. 400 µ g/day), and if diet is
    insufficient may exceed the body's stores of folate (5-10 mg) in
    short order.
   Anemia related to folate deficiency most often presents in the
    third trimester and responds to folate supplementation with
    reticulocytosis within 24 to 72 hours.
    Folate and Vitamin B12 Deficiency
   Vitamin B12 deficiency during pregnancy is rare, in
    part because deficiency of this vitamin leads to
    infertility.
   Serum cobalamin levels are known to fall during
    pregnancy.
    A shift from the serum to tissue stores is proposed to
    account for the drop in serum B12 levels. However,
    values less than 180 pmol/liter are not observed in
    healthy women, and these low normal levels are not
    accompanied by increased levels of methylmalonic
    acid.
                Red Cell Aplasia
   A rarer, but well-recognized cause of anemia in
    pregnancy is pure red cell aplasia .
    In pure red cell aplasia, anemia tends to occur early
    in pregnancy and often resolves within weeks of
    delivery.
    The anemia does not appear to be transferred to the
    fetus, but does tend to recur in subsequent
    pregnancies.
   Conservative treatment, if feasible, is probably best
    until delivery; successful prenatal treatments with
    steroids and with intravenous immunoglobulin have
    been reported.
             Hemoglobinopathies
   Sickle Syndromes
   Although pregnancy in patients with sickle cell trait is
    typically uneventful, these patients probably have an
    increased risk for urinary tract infection.
    Earlier studies suggested an increased risk for
    preeclampsia in patients with sickle cell trait, but a
    recent large study demonstrated that sickle cell trait is
    not an independent risk factor for preeclampsia .
                 Sickle Syndromes
   Women with sickle cell anemia and their fetuses have an
    increased risk of complications during pregnancy. In a
    retrospective review of 127 deliveries of women with sickle
    cell disease, nearly 50 percent of women with SS disease
    experienced pain crises during pregnancy.
   As compared with deliveries among women with hemoglobin
    AA, deliveries among women with sickle cell disease were at
    increased risk for intrauterine growth restriction, low birth
    weight, prematurity, and preterm labor. In general, these risks
    were lower for patients with SC disease than with SS disease.
              Sickle Syndromes
   Although the incidence of cesarean section in sickle
    cell patients is reported to be as high as 36 percent,
    delivery can generally be accomplished vaginally.
    Most experts recommend avoiding induction of labor
    as this can lead to sickle crisis.
    Epidural anesthesia is reported to be safe and to
    decrease the risk of peripartum painful crises.
          Thalassemia Syndromes
   βThalassemia Syndromes :
   Preconception evaluation of patients with β -thalassemia
    syndromes is recommended and should include assessment of
    transfusion needs, chelation therapy, body iron status and
    organ function, and the presence of antibodies to red cell
    antigens.
    Patients with β -thalassemia minor generally tolerate
    pregnancy well; however, doses of at least 4 mg of folate per
    day are recommended in the preconception period and the first
    trimester as there is some data to suggest an increased risk of
    neural tube defects in their offspring.
         βThalassemia Syndromes
   Transfusion and iron chelation therapy has improved both life
    expectancy and fertility in patients with - β thalassemia
    intermedia and major, and successful pregnancies have been
    reported in both disorders. During pregnancy, regular
    transfusions are recommended to keep the hemoglobin level at
    10 mg/dl.
    Iron-chelation therapy with deferoxamine in pregnancy is
    controversial and most authorities recommend a hiatus during
    pregnancy; however, no fetal abnormalities have been reported
    in pregnancies in which it was continued.
         α-Thalassemia Syndromes
   Patients with the silent carrier state or α -thalassemia trait have no
    increase in pregnancy complications; however, identification of
    patients with heterozygous α -thalassemia trait is important in
    assessing the risk of having a fetus that has hemoglobin H or
    hemoglobin Bart's.
   Although women with hemoglobin H are generally able to have
    successful pregnancies, the chronic anemia often worsens,
    requiring blood transfusion.
    Patients with hemoglobin H are sensitive to oxidizing
    compounds and medications, which should be borne in mind,
    particularly during pregnancy .
Thrombocytopenia in pregnancy
   NORMAL PREGNANCY — Platelet counts
    are within the normal range of 150,000 to
    450,000/microL in women during normal
    pregnancies, however they may be slightly
    lower than in healthy, nonpregnant women.
            GESTATIONAL
         THROMBOCYTOPENIA
    Incidental thrombocytopenia of pregnancy, also termed
    gestational thrombocytopenia, is defined by the following five
    criteria :
    Mild and asymptomatic thrombocytopenia
    No past history of thrombocytopenia (except possibly during
    a previous pregnancy)
    Occurrence during late gestation
   No association with fetal thrombocytopenia
   Spontaneous resolution after delivery
                     Etiology


    Many, if not all, of the features of gestational
    thrombocytopenia are similar to those of mild ITP,
    suggesting a possible immunologic etiology.
    Several observations support the hypothesis that
    gestational thrombocytopenia may be a mild and
    transient manifestation of ITP.
          Differential diagnosis
    The possibility of preeclampsia should be
    considered in pregnant women.
   Whether gestational thrombocytopenia is truly
    distinct from ITP remains unknown and, in
    women with mild thrombocytopenia, the
    distinction from ITP is impossible, except
    possibly in retrospect.
             Differential diagnosis
   If the mother's thrombocytopenia is not severe and only occurs
    during late pregnancy or at term, if her platelet count returns to
    normal following delivery, and if the infant's platelet count is
    normal, gestational thrombocytopenia is an appropriate
    diagnosis.
   ITP is the more likely diagnosis if thrombocytopenia occurs
    early during pregnancy or if the platelet count is very low (ie,
    <50,000/microL).
    Accordingly, for women with mild thrombocytopenia who do
    not need treatment, the distinction from ITP may not be
    important during the pregnancy.
                    Management
    For both mother and infant, routine obstetric management is
    appropriate .
   Epidural anesthesia is considered to be safe in women with
    gestational thrombocytopenia who have platelet counts above
    50,000 to 80,000/microL and, of the many women who have
    epidural anesthesia at delivery with no platelet count
    performed, some will predictably be mildly thrombocytopenic.
   Women with documented thrombocytopenia should be
    followed with platelet counts to determine if spontaneous
    resolution occurs after delivery.
      ITP DURING PREGNANCY AND
              DELIVERY
   Early in pregnancy the management of ITP is the same as if
    the patient were not pregnant, using prednisone as initial
    therapy to treat patients whose platelet counts are less than
    30,000 to 50,000/microL, depending upon the presence or
    absence of symptoms (ie, bleeding).
    Patients with chronic ITP who have persistent platelet counts
    less than 30,000 to 50,000/microL and who are not being
    treated prior to their pregnancy may need no treatment during
    their pregnancy, except in preparation for delivery.
                     Management
   Splenectomy should be deferred if possible, because the
    severity of thrombocytopenia may spontaneously improve
    after delivery.
   Furthermore, splenectomy may increase the risk of fetal death
    and premature labor in early pregnancy and uterine
    enlargement presents technical problems in performing a
    splenectomy later during pregnancy.
    Rituximab is increasingly being used to treat ITP in non-
    pregnant patients.
   However, there is insufficient experience to know the safety of
    rituximab administered during pregnancy.
   It is therefore recommended to avoid rituximab during
    pregnancy unless the mother's health is critically dependent
    upon use of this medication.
                     Management
   Intravenous immune globulin (IGIV, IVIG) is an alternative
    TEMPORARY therapy that may help to delay splenectomy,
    although splenectomy remains the most effective treatment for
    severe, symptomatic ITP.
    The greatest concern for ITP during pregnancy comes as term
    approaches and the risks of thrombocytopenia in the newborn
    infant must be considered. Although published data vary
    widely on the risk of thrombocytopenia in infants born to
    mothers with ITP, a summary of published case series suggests
    that there is an approximately 10 and five percent risk that the
    newborn infant will have a platelet count of <50,000 or
    <20,000/microL, respectively .
                   Management
   It is important to emphasize that platelet counts of
    infants born to mothers with ITP may decrease
    sharply during the several days AFTER birth .
    This occurs because infants have minimal splenic
    function at the time of birth, as evidenced by the
    presence of Howell-Jolly bodies and pitted red cells .
    As splenic function improves within the first few
    days after birth, destruction of antibody-sensitized
    platelet in the infant's spleen can increase sharply.
                         Management
   Percutaneous umbilical cord blood sampling — Some authors had
    suggested use of percutaneous umbilical blood sampling at 38 weeks
    gestation to determine the fetal platelet count followed by cesarean section
    delivery if the fetal platelet count is <50,000/microL. This procedure is no
    longer recommended, since it has a risk for fetal hemorrhage and death of
    approximately two percent, which is greater than the risk of severe neonatal
    intracerebral hemorrhage (<1 percent).
   Fetal scalp blood sampling — some authors had recommended fetal scalp
    sampling in order to evaluate the platelet count of the fetus. Performance of
    this procedure requires ruptured membranes, a dilated cervix, and an
    engaged fetal head. This procedure has been abandoned as it is technically
    difficult and frequently results in spuriously low platelet counts.
                     Management
   Accordingly, current recommendations are to manage the
    delivery in a conventional manner, without fetal platelet count
    determinations (by either cordocentesis or scalp sampling),
    and a cesarean delivery reserved only for standard obstetrical
    indications.
   Neonatal thrombocytopenia may be predicted by the following
    situations:
   The mother has had a splenectomy
   The mother's platelet count has been <50,000/microL at some
    time during the pregnancy
   An older sibling has had neonatal thrombocytopenia
                 PREECLAMPSIA
    Preeclampsia refers to the otherwise unexplained and gradual
    development of hypertension and proteinuria in pregnancy.
    These findings typically become apparent in the latter part of
    the third trimester and progress until delivery. However, in
    some patients symptoms begin in the latter half of the second
    trimester, while in other women the signs of preeclampsia may
    not occur until after delivery.
   The estimated incidence is 5 to 10 percent of all pregnancies (3
    to 4 percent in the United States), with a higher risk in
    primiparas under the age of 20.
                   PREECLAMPSIA
   Degree of thrombocytopenia — Platelet counts are lower in preeclamptic
    women than in women with uncomplicated pregnancies, with an estimated
    incidence of thrombocytopenia of approximately 15 percent.
   If 4 percent of pregnant women develop preeclampsia in the United States
    and 15 percent become thrombocytopenic, then thrombocytopenia due to
    preeclampsia will occur in about 6 of every 1000 deliveries (0.6 percent).
   Severe thrombocytopenia with platelet counts <50,000/microL probably
    occurs in <5 percent of preeclamptic women. However, the frequency and
    severity of thrombocytopenia increase with the severity of preeclampsia,
    and are further increased in patients with the HELLP (hemolysis, elevated
    liver enzymes, and low platelets) syndrome or those with full-blown
    eclampsia in whom disseminated intravascular coagulation may be a
    contributing factor .
                PREECLAMPSIA
   Differential diagnosis — The systemic signs of preeclampsia
    typically resolve within hours to a few days following
    delivery.
    However, in some patients, the hematologic manifestations of
    preeclampsia first develop in the immediate postpartum
    period. In severe preeclampsia (including HELLP syndrome)
    and eclampsia, thrombocytopenia and microangiopathic
    hemolytic anemia can combine with seizures and other organ
    dysfunction to produce a disorder that may be clinically
    indistinguishable from TTP-HUS, which can follow a normal
    pregnancy or be preceded by findings similar to preeclampsia.
                 PREECLAMPSIA
   Symptoms and signs of liver disease, including right upper
    quadrant abdominal pain, may predominate in the HELLP
    syndrome, which may cause confusion with acute fatty liver of
    pregnancy.
    The latter disorder is not typically associated with
    thrombocytopenia unless there is supervening DIC.
    Additionally, marked hypoglycemia can be seen with acute
    fatty liver. There is, however, suggestive evidence that, in at
    least some cases, the HELLP syndrome and acute fatty liver of
    pregnancy may be pathogenetically related although
    phenotypically different .
                            Treatment
    Delivering the fetus is the most effective method of treating preeclampsia,
    eclampsia, and the HELLP syndrome.
    In most patients with preeclampsia, hematologic recovery begins promptly
    following delivery. However, the nadir of thrombocytopenia and the peak
    serum LDH levels may occur postpartum .
    Recovery within three days following delivery is consistent with the
    diagnosis of preeclampsia. If severe thrombocytopenia and hemolysis
    persist for longer than three days, the clinical picture becomes
    indistinguishable from TTP-HUS.
   Infants born to mothers with preeclampsia are not at increased risk for
    thrombocytopenia, except as related to complications of prematurity .
    Management of the delivery is guided by obstetrical, not hematologic,
    considerations .
                            Treatment
   For patients with severe thrombocytopenia and microangiopathic hemolytic
    anemia, plasma exchange may be indicated if the fetus cannot be delivered
    or if improvement does not follow delivery. The third postpartum day is
    often considered the limit for only supportive therapy or glucocorticoids
    without plasma exchange in anticipation of a spontaneous recovery.
   If thrombocytopenia and hemolysis (as assessed by serum LDH levels)
    continue to worsen beyond 3 post-partum days, intervention with plasma
    exchange is appropriate for the presumed diagnosis of TTP-HUS .
    Although TTP-HUS occurring at day three or four may not be
    distinguishable from "atypical preeclampsia/eclampsia/HELLP syndrome",
    plasma exchange treatment may also be beneficial in the latter disorder.
    Earlier intervention with plasma exchange may be indicated for more
    severe clinical problems, such as neurologic abnormalities or acute, anuric
    renal failure.
     TTP-HUS ASSOCIATED WITH
           PREGNANCY
   In many case series of TTP-HUS, 10 to 25 percent of
    patients were pregnant or in the postpartum period.
    However, the incidence of TTP-HUS among all
    pregnancies is only 1 in 25,000.
   In addition to de novo disease, TTP-HUS that
    initially occurred in nonpregnant women may relapse
    during a subsequent pregnancy and recurrent TTP-
    HUS has developed during successive pregnancies.
    The time of onset of TTP-HUS in pregnancy is
    variable.
      TTP-HUS ASSOCIATED WITH
            PREGNANCY
   The primary therapy for TTP-HUS related to pregnancy is plasma
    exchange as it is in nonpregnant patients. Renal failure requires supportive
    care with dialysis and transfusion, as needed.
   If the disease is severe and the fetus is viable, delivery should be induced
    since this will resolve preeclampsia which may be confused with TTP-
    HUS.
    Although delivery does not generally cause resolution of TTP-HUS, there
    is anecdotal evidence that it may do so in selected patients.
    However, termination of the pregnancy is usually not required .
   There has been no report of transmission of TTP to the infant. However,
    intrauterine fetal death may occur due to placental infarction caused by
    thrombosis of the decidual arterioles.