Hematologic changes in pregnancy

Author
Kenneth A Bauer, MD
Section Editor
Charles J Lockwood, MD, MHCM
Deputy Editors
Kristen Eckler, MD, FACOG
Jennifer S Tirnauer, MD
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All topics are updated as new evidence becomes available and our peer
review process is complete.
Literature review current through: Jul 2016. | This topic last updated:
Aug 10, 2016.
NEWER VERSION OF TOPIC MESSAGE
INTRODUCTION Normal pregnancy is characterized by profound
changes in almost every organ system to accommodate the demands of the
fetoplacental unit. The hematologic system must adapt in a number of ways,
such as provision of vitamins and minerals for fetal hematopoiesis (iron,
vitamin B12, folic acid), which can exacerbate maternal anemia, and
preparation for bleeding at delivery, which requires enhanced hemostatic
function.
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

PLASMA VOLUME Plasma volume increases by 10 to 15 percent at 6 to

12 weeks of gestation [1-3], expands rapidly until 30 to 34 weeks, after
which there is only a modest rise (figure 1). 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 [1,4].
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 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 2,3diphosphoglycerate [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 pCO2 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 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'.)
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".)
It is important to distinguish gestational thrombocytopenia from other causes
of thrombocytopenia, including severe preeclampsia, hemolysis elevated
liver function tests and low platelets (HELLP) syndrome, thrombotic
thrombocytopenic purpura (TTP), immune thrombocytopenia (ITP),
antiphospholipid syndrome, and drug-induced thrombocytopenia. Most of
these conditions are associated with more severe thrombocytopenia and/or
other hematologic changes. These other conditions 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].
Coagulation and fibrinolysis Normal pregnancy is a prothrombotic state
[47-57].
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 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].

The pro-hemostatic factor von Willebrand factor increases.

Activity of fibrinolytic inhibitors increases, including thrombin activatable

fibrinolytic inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1), and PAI2 [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'.)
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.
SUMMARY AND RECOMMENDATIONS

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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