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.