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Maternal adaptations to pregnancy Hematologic changes INTRODUCTIONNormal pregnancy is characterized by profound changes in almost every organ system to accommodate the growing and developing fetoplace[.]
Maternal adaptations to pregnancy: Hematologic changes INTRODUCTIONNormal pregnancy is characterized by profound changes in almost every organ system to accommodate the growing and developing fetoplacental unit The major hematologic changes during pregnancy include expanded plasma volume, physiologic anemia, mild neutrophilia in some individuals, and a mildly prothrombotic state The clinician must be able to distinguish these anticipated physiologic changes from those caused by pregnancy-related complications This topic discusses physiologic changes in blood volume, blood cells, and hemostasis during pregnancy Cardiovascular and vascular changes associated with pregnancy and hematologic complications of pregnancy are discussed in separate topic reviews: ●(See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".) ●(See "Anemia in pregnancy".) ●(See "Approach to the adult with unexplained neutropenia".) ●(See "Thrombocytopenia in pregnancy".) OVERVIEWThe most significant hematologic changes during pregnancy include the following and are detailed in the table (table 1): ●Expanded plasma volume (in excess of the increase in red blood cell mass) and resultant physiologic anemia ●Mild neutrophilia ●Mild thrombocytopenia ●Increased procoagulant factors and decreased natural anticoagulants ●Diminished fibrinolysis FINDINGS OF CONCERNThe following findings are not consistent with normal, physiologic adaptation to pregnancy and should prompt additional evaluation, and possibly additional interventions In general, more severe abnormal findings require more prompt consultation by a hematologist ●Nonphysiologic anemia or polycythemia, especially when associated with symptoms out of proportion to the stage of pregnancy Hemoglobin levels less than 10 g/dL or greater than 16 g/dL should prompt hematologic evaluation unless the etiology is known or the abnormalities are related to a preexistent chronic condition (See "Anemia in pregnancy" and "Clinical manifestations and diagnosis of polycythemia vera".) ●Evidence of iron deficiency (eg, new microcytosis, which is a late finding of iron deficiency, or iron studies showing reduced iron stores) The demand for iron is increased in pregnancy (figure 1); iron deficiency is therefore common However, approximately one-third of pregnant women with iron deficiency not manifest microcytosis Furthermore, pregnant women can have iron deficiency anemia with ferritin levels in the low-normal reference range While oral iron supplementation in prenatal vitamins is standard, this may not be sufficient for women with iron deficiency, and oral iron supplements are often poorly tolerated because of gastric irritation and/or constipation Thus, parenteral iron administration should be considered in women with iron deficiency anemia who not respond to or cannot tolerate oral iron supplementation (See "Anemia in pregnancy", section on 'Management'.) ●Thalassemia is another major cause of microcytic anemia In some cases, it is not diagnosed until pregnancy (See "Anemia in pregnancy" and "Microcytosis/Microcytic anemia".) ●Leukocytosis or leukopenia Leukocytosis due to an excess of neutrophils can occur in some women during pregnancy in the absence of infection or inflammatory conditions Findings prompting hematology consultation include a white blood cell (WBC) count >20,000/microL in the absence of labor or infection, or a WBC differential showing immature myeloid or lymphoid forms or a marked excess of lymphocytes Leukopenia in association with an absolute neutrophil count 500,000/microL should prompt hematologic evaluation Platelet counts >1,000,000/microL require urgent evaluation (See "Approach to the patient with thrombocytosis" and "Diagnosis and clinical manifestations of essential thrombocythemia".) PLASMA VOLUMEPlasma volume increases by 10 to 15 percent at to 12 weeks of gestation, expands rapidly until 30 to 34 weeks, and then plateaus or decreases slightly through term (figure 2) [1-3] The total gain at term averages 1100 to 1600 mL and results in a total plasma volume of 4700 to 5200 mL, which is 30 to 50 percent above that in nonpregnant women [1,4,5] The expanded plasma volume is thought to meet the increased metabolic demands of the uterus and placenta, facilitate delivery of nutrients to the developing fetus and removal of waste, protect against the effects of impaired venous return when the mother is supine or standing, and protect the mother from excessive blood loss during delivery [6] During pregnancy, plasma renin activity tends to be increased and atrial natriuretic peptide levels are slightly reduced [7,8] These changes suggest that the rise in plasma volume is in response to an underfilled vascular system caused by systemic vasodilatation and the rise in vascular capacitance The converse picture (low plasma renin activity and elevated natriuretic peptide, suggestive of a vascular response to expanded plasma volume) are not seen The hypothesis that vascular changes precede expansion of the plasma volume is also supported by the observation that increasing sodium intake does not lead to further volume expansion [9] Of note, total plasma volume expansion is accompanied by retention of 900 to 1000 mEq of sodium and to L of water, which is distributed among the fetus, amniotic fluid, and extracellular and intracellular spaces [9,10] There are no specific measures available to expand the plasma volume in pregnant women, and there is no evidence that the expansion of plasma volume would reverse or prevent associated poor pregnancy outcomes associated with low plasma volume In theory, increasing dietary protein could improve colloid oncotic pressure (COP), which would shift extravascular fluid to the intravascular space For dehydrated women, increasing maternal hydration may also act synergistically with a higher COP to improve intravascular volume RED BLOOD CELLS Increased mass — Red blood cell (RBC) mass begins to increase at to 10 weeks of gestation, steadily rises, and reaches levels 20 to 30 percent higher than in nonpregnant women by the end of pregnancy [4,11-14] This is accompanied by a slight increase in the mean corpuscular volume (MCV) (table 1) in healthy pregnant women [15] However, as noted above, the increase in RBC mass is smaller than the increase in plasma volume, which contributes to the physiologic anemia of pregnancy (See 'Dilutional or physiologic anemia' below.) The increase in RBC mass requires sufficient iron, folate, and vitamin B12; thus, women with deficiencies of iron or these vitamins will have blunted increases in RBC mass and are likely to develop more severe anemia As an example, in a series of 69 women not receiving iron supplements, the RBC mass was estimated to increase by 15 to 20 percent rather than the normal 20 to 30 percent and the MCV decreased to an average value of 80 to 84 fL in the third trimester [16,17] The major mediator of increased RBC mass is an increase in erythropoietin, which stimulates RBC production [6] Erythropoietin levels increase by 50 percent in normal pregnancies and vary according to the presence of pregnancy complications [18] RBC lifespan is also slightly decreased during normal pregnancy [19] The increased RBC mass partially supports the higher metabolic requirement for oxygen during pregnancy [20] In addition, levels of RBC 2,3 bisphosphoglycerate (2,3-BPG, also called 2,3-diphosphoglycerate [2,3-DPG]) remain elevated during pregnancy, which leads to a decrease in oxygen affinity (ie, a shift of the hemoglobin-oxygen dissociation curve to the right) (figure 3) [21] This lower oxygen affinity, combined with low pCO2 of the maternal blood due to increased minute ventilation, facilitates transport of oxygen across the placenta and to the fetal RBCs, which have greater oxygen affinity due to fetal hemoglobin The function of fetal hemoglobin is reviewed elsewhere (See "Fetal hemoglobin (hemoglobin F) in health and disease", section on 'Biology of fetal hemoglobin'.) Iron requirements — In a typical singleton gestation, maternal iron requirements average close to 1000 mg over the course of pregnancy (figure 1): approximately 300 mg for the fetus and placenta and approximately 500 mg, if available, for the expansion of the maternal RBC mass [6] An additional 200 mg is shed through the gut, urine, and skin Since most women not have adequate iron stores to meet the demands of pregnancy, iron is commonly prescribed as part of a prenatal multivitamin or as a separate supplement In general, women taking iron supplements have a mean hemoglobin concentration that is g/dL greater than that of women not taking supplements Reference ranges for iron indices in pregnancy are listed in the table (table 2) Recommended iron intake and treatment of iron deficiency in pregnancy are presented in detail separately (See "Anemia in pregnancy", section on 'Prevention of iron deficiency'.) Folate requirements — The increase in RBC production during pregnancy creates an increased demand for folate and an increased risk of folate deficiency The increased folate demand for RBC creation is more than met by the higher daily intake (400 to 800 mcg) already recommended for prevention of neural tube defects [22,23] (See "Folic acid supplementation in pregnancy" and "Nutrition in pregnancy".) Dilutional or physiologic anemia — In normal pregnancies, greater expansion of plasma volume relative to the increase in RBC mass is associated with a modest decrease in hemoglobin concentration, which is referred to as physiologic or dilutional anemia of pregnancy (see 'Plasma volume' above and 'Increased mass' above) The greatest disproportion between the rates at which plasma and RBCs are added to the maternal circulation occurs during the late second to early third trimester; thus, the lowest hemoglobin concentration is typically measured at 28 to 36 weeks [17] Nearer to term, hemoglobin concentration increases due to cessation of plasma expansion and continuing increase in RBC mass (figure 2) Determining a precise laboratory value that defines anemia in pregnant women is not straightforward because of normal pregnancy-associated changes in plasma volume and RBC mass as well as variation between White and Black women The Centers for Disease Control and Prevention, National Academy of Medicine, and the World Health Organization thresholds for diagnosing anemia in pregnancy are: ●Centers for Disease Control and Prevention – Anemia in pregnant women is defined as a hemoglobin level