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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2016. | This topic last updated: Aug 10, 2016.
While these changes facilitate healthy pregnancy, they also increase the risks of some conditions (eg,
venous thromboembolism). In addition, physiologic changes in blood cell counts must be distinguished
from pregnancy complications that require specific treatments.
This topic discusses physiologic changes in blood cells and hemostasis during pregnancy. Hematologic
complications of pregnancy are discussed in separate topic reviews.
OVERVIEW The most significant hematological changes during pregnancy include the following (table
1):
Physiologic anemia
Neutrophilia
Mild thrombocytopenia
Increased procoagulant factors
Diminished fibrinolysis
During pregnancy, plasma renin activity tends to be increased and atrial natriuretic peptide levels are
slightly reduced. This suggests that the rise in plasma volume is in response to an underfilled vascular
system caused by systemic vasodilatation and the rise in vascular capacitance. If expansion of blood
volume was the initial event, renal and atrial volume sensors would respond, leading to the opposite
hormonal profile (low plasma renin activity, elevated atrial natriuretic peptide) [5,6]. This hypothesis is also
supported by the observation that increasing sodium intake does not lead to further volume expansion [7].
Postpartum, plasma volume decreases immediately after delivery, then increases again two to five days
later, possibly because of a rise in aldosterone secretion, which occurs at this time. Plasma volume then
decreases; it is still elevated by 10 to 15 percent above nonpregnant levels at three weeks postpartum,
but is usually at normal nonpregnant levels at six weeks postpartum.
RED BLOOD CELLS Red blood cell (RBC) mass begins to increase at 8 to 10 weeks of gestation and
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steadily rises by 20 to 30 percent (250 to 450 mL) above nonpregnant levels by the end of pregnancy in
women taking iron supplements [4,8-11]. Among women not on iron supplements, the red cell mass may
only increase by 15 to 20 percent [12]. RBC life span is slightly decreased during normal pregnancy [13].
The major mediator of increased RBC mass is an increase in levels of erythropoietin, which stimulates
RBC production. Erythropoietin levels increase by 50 percent in normal pregnancies and vary according to
the presence of pregnancy complications [14]. The resulting increased RBC mass partially supports the
higher metabolic requirement for oxygen during pregnancy [15].
In women not taking iron supplements, mean corpuscular volume (MCV) decreases during pregnancy and
averages 80 to 84 fL in the third trimester [16]. However, MCV increases approximately 4 fL in healthy
pregnant women and those with only mild iron deficiency [17].
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 of maternal RBCs (figure 2) [18].
This lower oxygen affinity, combined with low pCO 2 of the maternal blood due to increased minute
ventilation, facilitates transport of oxygen across the placenta.
Anemia Healthy pregnancy is associated with a modest decrease in hemoglobin levels (ie,
physiological or dilutional anemia of pregnancy). This decrease is due to a greater expansion of plasma
volume relative to the increase in RBC mass. 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 (lowest hemoglobin is typically measured at 28 to 36 weeks [16]). Nearer to term, hemoglobin
concentration increases due to cessation of plasma expansion and continuing increase in hemoglobin
mass (figure 1). Conversely, the absence of physiologic anemia appears to be a risk factor for stillbirth
[19].
Determining a precise definition of anemia in pregnant women is not straightforward, given the pregnancy
associated changes in plasma volume and RBC mass, ethnic variation between white and black women,
and the frequent use of iron supplementation in pregnancy.
The Centers for Disease Control and Prevention (CDC) 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 [20]. 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 [21].
The World Health Organization (WHO) defines anemia in pregnant women as hemoglobin <110 g/L
(11 g/dL) or hematocrit <6.83 mmol/L or 0.33 L/L (33 percent) [22]. Severe anemia in pregnancy is
defined as hemoglobin <70 g/L (7 g/dL) and requires medical treatment. Very severe anaemia is
defined as hemoglobin <40 g/L (4 g/dL) and is a medical emergency due to the risk of congestive
heart failure.
Women with hemoglobin values below these levels can be considered anemic and should undergo a
standard evaluation (eg, complete blood count, review of peripheral smear, reticulocyte count, serum
Fe/TIBC, and ferritin) [23]. Sixteen to 29 percent of pregnant women in the United States become anemic
in the third trimester [24]. 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 affects the normal level of hemoglobin in a specific
individual. (See "Approach to the adult patient with anemia" and "Causes and diagnosis of iron deficiency
and iron deficiency anemia in adults", section on 'Pregnant women'.)
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 [25]. Increased risks of prematurity, spontaneous abortion, low birth
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weight, and fetal death have also been reported [26]. In addition, severe anemia (hemoglobin less than 7
g/dL) increases the risk of maternal mortality [27]. There is no evidence that maternal anemia increases
the risk of congenital anomalies in offspring.
Chronic severe anemia is usually related to (1) inadequate iron stores due to nutritional deficiency and
intestinal helminthic infections, (2) folate deficiency due to inadequate intake, and (3) chronic hemolytic
states, such as malaria. Ideally, severe anemia could be prevented and pregnancy outcome improved with
nutritional supplementation and infection control measures [28,29]. As an example, a randomized trial in
rural China found an iron-folic acid supplement (60 mg iron plus 400 mcg folic acid) was associated with
higher maternal hemoglobin levels, fewer births before 34 weeks of gestation, and fewer early neonatal
deaths than folate alone [29]. However, 40 percent of women were still anemic in the third trimester. A
similar trial found that an iron-folic acid supplement given to pregnant Nepalese women in an area where
iron deficiency was common appeared to be associated with improvement in some aspects of intellectual
and motor function in offspring evaluated at age 7 to 9 years [30].
Where safe blood transfusion is available, it is probably prudent to treat severe anemia aggressively, as
with red cell transfusion, if there are signs suggestive of fetal hypoxemia [23].
Physiologic anemia of pregnancy should resolve by six weeks postpartum since plasma volume has
returned to normal by that time. (See 'Plasma volume' above.)
Iron requirements In a typical singleton gestation, maternal iron requirements average close to 1000
mg over the course of pregnancy: approximately 300 mg for the fetus and placenta and approximately 500
mg, if available, for the expansion of the maternal hemoglobin mass. Two hundred milligrams is shed
through the gut, urine, and skin. Since most women do not have adequate iron stores to handle 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 1
g/dL greater than that of women not taking supplements. Reference ranges for iron indices in pregnancy
are listed in the table (table 2). (See "Nutrition in pregnancy", section on 'Iron'.)
A detailed discussion on the diagnosis, prevention, and management of iron deficiency anemia in
pregnant women can be found separately. (See "Treatment of iron deficiency anemia in adults", section on
'Pregnancy' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on
'Pregnant women'.)
Folate requirements In nonpregnant individuals, the daily folic acid requirement is 50 to 100 mcg. The
increase in RBC production during pregnancy necessitates an increase in the folic acid requirement, but
this is more than met by the increased daily intake (400 to 800 mcg) already recommended for prevention
of neural tube defects. (See "Folic acid supplementation in pregnancy" and "Nutrition in pregnancy".)
WHITE BLOOD CELLS Pregnancy is associated with leukocytosis, primarily related to increased
circulation of neutrophils. The neutrophil count begins to increase in the second month of pregnancy and
plateaus in the second or third trimester, at which time the total white blood cell counts range from 9000 to
15,000 cells/microL [31]. Data from two series reported mean white blood cell counts in laboring patients
of 10,000 to 16,000 cells/microL, with an upper level as high as 29,000 cells/microL [32,33]; the mean
count increased linearly with the duration of elapsed labor [33]. The white blood cell count falls to the
normal nonpregnant range by the sixth day postpartum.
Normal pregnant women can have a small number of myelocytes or metamyelocytes in the peripheral
circulation. Some studies have observed an increase in the percent of bands as pregnancy advances
[34-36]. Dohle bodies (blue staining cytoplasmic inclusions in granulocytes) are a normal finding in
pregnant women. (See "Evaluation of the peripheral blood smear", section on 'Neutrophil series' and
"Evaluation of the peripheral blood smear", section on 'Granulation'.)
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In healthy women with normal pregnancies, there is no change in the absolute lymphocyte count and no
significant changes in the relative numbers of T and B lymphocytes [37]. The monocyte count is generally
stable, the basophil count may slightly decrease and the eosinophil count may slightly increase.
PLATELETS AND COAGULATION SYSTEM Hemostasis involves complex interactions between the
coagulation system (figure 3), platelets, and the vascular endothelium. The fibrinolytic system has a
complementary role in preventing excessive coagulation, via removal of fibrin and clot dissolution (table 3
and figure 4). These processes interact to ensure that the circulating blood flows freely in the vascular bed
and that bleeding is quickly arrested following trauma. (See "Overview of hemostasis".)
In pregnancy, however, the demands on the hemostatic and fibrinolytic systems change in order to
prevent excessive hemorrhage during placental separation. A relative hypercoagulable state compared
with non-pregnant individuals is caused by a marked increase in some coagulation factors, reduced
fibrinolysis, and increased platelet activity.
Changes in vascular tone that enhance uteroplacental blood flow also occur. These changes are due to a
variety of factors (eg, nitric oxide, endothelin, renin-angiotensin, estrogen, progesterone, prostacyclin).
Platelets Although platelet counts remain in the normal nonpregnant range in most women during
uncomplicated pregnancies [38], mean platelet counts of pregnant women may be slightly lower than in
healthy nonpregnant women (table 2) [39]. Serial platelet counts during uncomplicated pregnancies may
[40] or may not [41] decrease, but the mean values in groups of women do not necessarily reflect changes
in individual women [42].
Mild decreases in platelet count occur in about 5 percent of pregnancies (ie, gestational
thrombocytopenia, incidental thrombocytopenia of pregnancy). Gestational thrombocytopenia is
characterized by mild asymptomatic thrombocytopenia occurring in the third trimester in a patient without
any history of thrombocytopenia (other than in a prior pregnancy). It is not associated with maternal, fetal,
or neonatal sequelae and spontaneously resolves postpartum [43-45]. Platelet counts are typically
>70,000/microL, with about two-thirds being 130,000 to 150,000/microL. Diagnosis and management of
gestational thrombocytopenia are discussed in detail separately. (See "Thrombocytopenia in pregnancy".)
The platelet count begins to rise soon after delivery and continues to increase for three to four weeks
before returning to baseline. In one study of 50 presumably normal pregnant/postpartum women followed
with serial platelet counts, the mean platelet count predelivery and 3, 7, 15, 25, and 42 days after delivery
was 219,000; 267,000; 349,000; 363,000; 279,000; and 254,000 per microL, respectively [46].
A variety of changes occur in procoagulant and anticoagulant pathways, which on balance increase
coagulation potential on a background of reduced anticoagulation and fibrinolysis. While these changes
increase the risk of thrombosis, they are not in and of themselves an indication for intervention.
The following changes occur in circulating levels of coagulation factors, inhibitors, and fibrinolytic markers
(table 2):
The physiological anticoagulant protein S decreases (measured as total protein S, free protein S, and
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protein S activity).
Levels of the anticoagulant antithrombin (AT) are 20 percent lower during pregnancy compared with
baseline levels [58]. Immediately after birth, AT levels fall to 30 percent below baseline level, with a
nadir reached approximately 12 hours after delivery. AT levels return to baseline by 72 hours
postpartum. The relatively large and rapid changes in the postpartum levels of AT have not been
consistently documented, likely in part because both the reduction and resolution are swift
[53,57,59-63].
Procoagulant factors fibrinogen, factors II, VII, VIII, X, XII, and XIII increase by 20 to 200 percent
[57,64].
Activity of fibrinolytic inhibitors increases, including thrombin activatable fibrinolytic inhibitor (TAFI),
plasminogen activator inhibitor-1 (PAI-1), and PAI-2 [65]. PAI-1 levels increase markedly derived from
the placenta and decidua.
Thrombin cleavage products increase, suggesting ongoing coagulation. Changes include increases in
fibrin D-dimer, fibrin monomers, and fibrinopeptides A and B [66-73]. Products of fibrinolysis also
increase, including plasminogen and tissue type plasminogen activator [74].
Other anticoagulant and procoagulant proteins (eg, protein C, factor V and factor IX) remain
unchanged or increase slightly [57,75].
Resistance to activated protein C (a biochemical test used to diagnose the prothrombotic factor V
Leiden mutation) increases in the second and third trimesters when evaluated by a test using plasma
that is not factor V deficient; however, this type of first generation test is rarely performed clinically
and is primarily of historical interest. (See "Factor V Leiden and activated protein C resistance",
section on 'Diagnosis'.)
The net effect of these changes is to increase the tendency for thrombus formation and extension, which,
along with myometrial contractions and high levels of decidual tissue factor expression, protect the mother
from excessive bleeding at the time of placental separation and delivery. These changes also increase the
risk of venous thromboembolism during pregnancy and especially the postpartum period.
Laboratory tests of coagulation are not routinely done (or required) during pregnancy. In a study of 117
normal pregnant women, the activated partial thromboplastin time (aPTT) remained in the normal range
during pregnancy, but decreased slightly near term [59]. The prothrombin time (PT) shortened in some.
(See "Clinical use of coagulation tests".)
The D-dimer lacks utility to evaluate the likelihood of venous thromboembolism during pregnancy, due to
changes in this parameter and a lack of normal reference ranges during pregnancy. (See "Pulmonary
embolism in pregnancy: Epidemiology, pathogenesis, and diagnosis", section on 'Laboratory studies'.)
Postpartum, normalization of coagulation parameters and factor levels varies depending on the factor, but
all should return to baseline by six to eight weeks after delivery [46]. Hemostasis probably should not be
evaluated earlier than three months following delivery and after terminating lactation to exclude
pregnancy-related effects [57].
The role of prophylactic anticoagulation or other interventions to reduce thromboembolic risk in specific
settings (eg, inherited thrombophilias, cesarean delivery) is discussed separately. (See "Inherited
thrombophilias in pregnancy" and "Cesarean delivery: Preoperative issues", section on
'Thromboembolism prophylaxis'.)
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POSTPARTUM Pregnancy-related hematological changes return to baseline by six to eight weeks after
delivery [46]. Within this range, the rate and pattern of resolution of pregnancy-related changes of specific
hematological parameters vary and are described above in the section on each parameter.
The major hematological changes during pregnancy are physiologic anemia, neutrophilia, mild
thrombocytopenia, increased procoagulant factors, and diminished fibrinolysis (table 1). (See
'Introduction' above.)
Plasma volume increases by 10 to 15 percent at 6 to 12 weeks of gestation, and then expands rapidly
until 30 to 34 weeks, after which there is only a modest rise (figure 1). (See 'Plasma volume' above.)
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. 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 Centers for Disease Control and Prevention (CDC) has defined anemia
as hemoglobin levels of less than 11 g/dL in the first and third trimesters and less than 10.5 g/dL in
the second trimester. (See 'Red blood cells' above.)
The neutrophil count begins to increase in the second month of pregnancy and plateaus in the
second or third trimester, at which time the total white blood cell counts range from 9000 to 15,000
cells/microL. There is no change in the absolute lymphocyte count. (See 'White blood cells' above.)
The circulating levels of several coagulation factors change during pregnancy (table 2), resulting in a
relative prothrombotic state. (See 'Coagulation and fibrinolysis' above.)
Mean platelet counts of pregnant women may be slightly lower than in healthy nonpregnant women,
but most pregnant women have normal platelet counts (table 2). (See 'Platelets' above.)
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71. Bellart J, Gilabert R, Fontcuberta J, et al. Fibrinolysis changes in normal pregnancy. J Perinat Med
1997; 25:368.
72. Chabloz P, Reber G, Boehlen F, et al. TAFI antigen and D-dimer levels during normal pregnancy and
at delivery. Br J Haematol 2001; 115:150.
73. Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new
diagnostic thresholds are needed. Clin Chem 2005; 51:825.
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74. Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and pregnancy. Br Med J 1969;
3:387.
75. Clark P, Brennand J, Conkie JA, et al. Activated protein C sensitivity, protein C, protein S and
coagulation in normal pregnancy. Thromb Haemost 1998; 79:1166.
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GRAPHICS
Erythropoietin Increases
Fibrinogen, factors II, VII, VIII, X, XII, XIII Increases 20 to 200 percent
D-dimer Increases
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Data from Shnider SM, Levinson G. Anesthesia for Obstetrics, 3rd ed, Williams &
Wilkins, Baltimore, p. 8.
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Depicted here is the oxyhemoglobin dissociation curve for normal adult hemoglobin
(hemoglobin A, solid line). Note that at a partial pressure of oxygen of 27 mm Hg on
the X axis, hemoglobin is 50% saturated with oxygen (the P50 is 27 mm Hg), and at an
arterial partial pressure of oxygen of 100 mm Hg, hemoglobin is 100% saturated. At
the typical mixed venous oxygen tension of approximately 40 mm Hg, the oxygen
saturation of hemoglobin is approximately 75%. Shifting the curve to the right (red
line) can reduce oxygen saturation to 50 to 60% for the partial oxygen pressure of 40
mm Hg, meaning that less oxygen is bound to hemoglobin and more oxygen is
delivered to the tissues. The opposite occurs with left shifts (blue line). A high
proportion of fetal hemoglobin, which has high oxygen affinity, shifts this curve to the
left in newborns. The effect of right- or left-shifting of the curve is most pronounced at
low partial pressures of oxygen.
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Hematology
White blood cell count 3.5-9.1 5.7-13.6 5.6-14.8 5.9-16.9 5, 6, 13, 14,
(x10 3 /mm 3 ) 18
Coagulation
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Plasminogen activator 9.3 +/ 1.9 9.0 +/ 0.8 Not reported 31.4 +/ 3.0 87
inhibitor-1 (PAI-1)
activity (arbitrary units)
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Sex hormones
Lipids
Cardiac function
Cardiac output (L/min) 4.8-6.8 5.6-9.7 5.5-9.9 4.8-8.7 64, 65, 66, 67,
68
Echocardiography
Intraventricular septal 0.7-0.9 0.63-0.83 0.65-0.85 0.66-0.9 68, 69, 70, 91,
dimension (cm) 92
Posterior ventricular 0.75-0.9 0.56-0.8 0.59-0.9 0.59-0.9 68, 69, 70, 91,
wall dimension (cm) 92
Left ventricular mass 116-143 108-167 115-150 128-162 68, 70, 91, 92
(g)
Left ventricular mass 40-78 53-79 58-82 60-88 68, 70, 91, 92
index
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Atrial natriuretic peptide Not reported Not reported 28.1-70.1 Not reported 73
(pg/mL)
B-type natriuretic <167 (age- and 18.4 13.5-29.5 15.5-46 71, 72, 73
peptide (pg/mL) gender-specific)
Blood gas
7.39-7.45
(arterial)
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* Unless otherwise specified, all normal reference values are from the seventeenth edition of Harrison's Principles of
Internal Medicine [84].
Range includes references with and without iron supplementation.
Normal reference range is specific range for females.
Reference values are from Cerneca et al: Coagulation and fibrinolysis changes in normal pregnancy increased levels
of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a
reactive fibrinolysis [19].
References values are from Cerneca et al and Choi et al: Tissue plasminogen activator levels change with plasma
fibrinogen concentrations during pregnancy [17,19].
Reference values are from Mannuci et al: Changes in health and disease of the metalloprotease that cleaves von
Willebrand factor [28].
Reference values are from Bacq Y et al: Liver function tests in normal pregnancy: a prospective study of 102
pregnant women and 102 matched controls [29].
Reference values are from the fifteenth edition of Harrison's Principles of Internal Medicine [85].
** The American Thyroid Association recommends these TSH ranges if individual laboratories do not determine their
own trimester-specific reference ranges.
Range is for premenopausal females and varies by menstrual cycle phase.
Reference values are from Leiserowitz GS et al: Creatine kinase and its MB isoenzyme in the third trimester and
the peripartum period [74].
Reference values are from Dunlop W: Serial changes in renal haemodynamics during normal human
pregnancy [79].
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Molecular weight
Activity
(d)
TPA 70,000 (one/two chain) Enzyme present in tissues that coverts plasminogen to plasmin
PAI-1 40,000 (single chain) Fast-acting inhibitor of tPA (and UPA) secreted by endothelial
cells)
d: Daltons; TPA: tissue plasminogen activator; UPA: urokinase-like plasminogen activator; 2PI: alpha-2 plasmin
inhibitor; PAI-1: plasminogen activator inhibitor-1.
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