Chuyên đề huyết học (tiếng anh)

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".)
1


●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 do
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 do 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 <1000/microL that is unexplained also requires hematologic
evaluation. (See "Approach to the patient with neutrophilia" and "Approach to

the adult with unexplained neutropenia".)
●Severe thrombocytopenia or thrombocytopenia with bleeding. Gestational
thrombocytopenia with a reduced platelet count (typically, between 80,000 and
149,000/microL) is common during pregnancy. Levels below this level should
prompt hematologic consultation. (See "Thrombocytopenia in pregnancy".)
●Thrombocytosis. The new onset of thrombocytosis is unusual during
pregnancy, and platelet counts >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 6 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
2


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 6 to 8 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 8 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].
3

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 do 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 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).
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
4


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 <11 g/dL (approximately equivalent to a
hematocrit <33 percent) in the first and third trimesters and <10.5 g/dL
(hematocrit <32 percent) in the second trimester [24].

●The World Health Organization – Anemia in pregnant women is defined as a
hemoglobin level <110 g/L (<11 g/dL) or a hematocrit <6.83 mmol/L (<33
percent) [25]. Severe anemia in pregnancy is defined as a hemoglobin level <70
g/L (<7 g/dL). Very severe anemia is defined as hemoglobin <40 g/L (<4 g/dL).
However, a hemoglobin as low as 10 g/dL can be attributed to physiologic
anemia after pathologic causes of anemia have been excluded since a wide
variety of factors can affect the normal level of hemoglobin in a specific
individual. (See "Anemia in pregnancy".)
WHITE BLOOD CELLSPregnancy is associated with leukocytosis (increased
white blood cell [WBC] count). The neutrophil count begins to increase in the
second month of pregnancy and plateaus in the second or third trimester, at
which time WBC counts range from 9000 to 15,000 cells/microL [26]. Data
from two series reported mean WBC counts in laboring patients of 10,000 to
16,000 cells/microL, with an upper level as high as 29,000 cells/microL [27,28];
the mean count increased linearly with the duration of elapsed labor [28]. As
noted above, we advise hematologic evaluation of women with a WBC count
greater than 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. (See 'Findings of concern' above.)
Some studies have observed an increase in the percent of bands as pregnancy
advances [29-31]. Normal pregnancy can also result in a small number of
myelocytes or metamyelocytes in the peripheral circulation. Dohle bodies (blue5


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'.)
However, an increase in WBC associated with fever, a large number of
immature WBC forms, or any blasts in the peripheral blood are not normal and

should be evaluated promptly. (See "Approach to the patient with neutrophilia".)
In normal pregnancy, there is no change in the absolute lymphocyte count and
no significant change in the relative numbers of T and B lymphocytes [32]. The
monocyte count is generally stable; the basophil count may slightly decrease;
and the eosinophil count may slightly increase. Alterations in the function of the
immune system during pregnancy are presented in detail separately.
(See "Immunology of the maternal-fetal interface".)
PLATELETSPlatelet counts decline as pregnancy progresses, but they remain
in the normal nonpregnant range (approximately 150,000 to 450,000/microL)
[33]. In the vast majority of uncomplicated pregnancies, the platelet count
remains ≥100,000/microL and returns to the prepregnancy baseline level by
several weeks postpartum. The most common cause is a normal physiologic
response referred to as gestational thrombocytopenia (GT; also called incidental
thrombocytopenia of pregnancy). GT is a diagnosis of exclusion and may recur
in subsequent pregnancies. We generally do not evaluate women with a mild
decrease in platelet count during pregnancy as long as they are asymptomatic
and their platelet count is ≥100,000/microL. (See "Thrombocytopenia in
pregnancy", section on 'Gestational thrombocytopenia (GT)'.)
Moderate to severe thrombocytopenia (platelet count <100,000/microL) is rare
in pregnancy, but when it occurs, it may be a medical emergency. Possible
causes include immune thrombocytopenia, severe preeclampsia, sepsis with
disseminated intravascular coagulation; HELLP syndrome (hemolysis, elevated
liver enzymes, and low platelets); thrombotic thrombocytopenic purpura;
antiphospholipid syndrome; and drug-induced thrombocytopenia. Evaluation
and management of moderate to severe thrombocytopenia in pregnancy are
discussed in detail separately; early involvement of the consulting hematologist
is advised. (See "Thrombocytopenia in pregnancy", section on 'Acutely ill,
platelets <100,000/microL, bleeding, thrombosis, or other major findings'.)
COAGULATION AND FIBRINOLYSISThe hemostatic system ensures
appropriate clot formation via complex interactions between coagulation factors

(figure 4), platelets, and the vascular endothelium. The fibrinolytic system
prevents excessive coagulation via removal of fibrin and clot dissolution (table
3 and figure 5). (See "Overview of hemostasis".)
6


Normal pregnancy is a prothrombotic state [34-44]. The shift in the balance
between the hemostatic and fibrinolytic systems serves to prevent excessive
hemorrhage during placental separation. Compared with nonpregnant women,
pregnant women have a marked increase in some coagulation factors, reduced
fibrinolysis, and increased platelet reactivity. As a consequence, there is
increased risk for thromboembolic complications. While these changes increase
the risk of thrombosis, they are not themselves an indication for intervention.
Laboratory tests of coagulation are not routinely performed (or required) during
pregnancy. The following changes occur in circulating levels of coagulation
factors, inhibitors, and fibrinolytic markers (table 2):
●Increased procoagulant factors
•Procoagulant factors fibrinogen, factors II, VII, VIII, X, and XII increase by 20
to 200 percent [44].
•The prohemostatic von Willebrand factor (VWF) can increase substantially
from baseline during pregnancy. Studies have reported that VWF increases by
two- to fourfold during pregnancy, peaks within 24 hours postpartum, and
returns to baseline by one month postpartum [45].
●Reduced anticoagulant factors
•The anticoagulant protein S decreases physiologically in nearly all pregnant
women, such that they appear protein S deficient based on reference ranges
established for normal populations (measured as total protein S, free protein S,
and protein S activity) [46]. If a pregnant woman has a venous
thromboembolism (VTE) during pregnancy and concern for an inherited
thrombophilia, testing of protein S levels should be deferred until after delivery.

However, most pregnant women with VTE do not require thrombophilia testing.
•Several studies have found that antithrombin (AT) levels are unchanged or
slightly increased antepartum. One study, however, reported that AT decreases
by approximately 20 percent [47]. Immediately after birth, AT levels fall to 30
percent below baseline level, with a nadir reached approximately 12 hours after
delivery, likely due to consumption. 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 [40,44,48-52].
●Reduced fibrinolysis
•Activity of fibrinolytic inhibitors increases, including thrombin activatable
fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1), and PAI-2 [53].

7


PAI-1 levels increase markedly since it is partly derived from the placenta and
decidua.
There is evidence of ongoing coagulation, including increased thrombin
cleavage products, increased fibrin D-dimer, increased fibrin monomers, and
increased fibrinopeptides A and B [54-61]. Products of fibrinolysis also
increase, including plasminogen and tissue type plasminogen activator [62].
Factor XIII levels normally decrease by 20 to 30 percent during the second and
third trimesters [63]. The mechanism is unclear; hypotheses include a potential
role for factor XIII in anchoring the cytotrophoblast of the placenta to the
uterine lining. Other anticoagulant and procoagulant proteins (eg, protein C,
factor V, and factor IX) remain mostly unchanged [44,64].
The activated partial thromboplastin time remains in the normal range during
pregnancy but decreases (shortens) slightly near term, and the prothrombin time
may decrease (shorten) [48].

It is worth noting that certain tests for prothrombotic states may be inaccurate
during pregnancy. As an example, the D-dimer lacks utility to evaluate the
likelihood of venous thromboembolism during pregnancy (ie, sensitivity and
specificity are low). (See "Pulmonary embolism in pregnancy: Epidemiology,
pathogenesis, and diagnosis", section on 'Laboratory studies'.)
POSTPARTUM RESOLUTIONPregnancy-related hematologic changes
return to baseline by six to eight weeks after delivery [65]. Within this range, the
rate and pattern of resolution of pregnancy-related changes of specific
hematological parameters vary.
●Plasma volume – Plasma volume decreases immediately after delivery, then
increases again two to five days later, possibly because of a rise in aldosterone
secretion. 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.
●White blood cells – The white blood cell count falls to the normal nonpregnant
range by the sixth day postpartum.
●Physiologic anemia – Physiologic anemia should resolve by six weeks
postpartum since plasma volume has returned to normal by that time.
●Platelets – For most pregnant women, the platelet count remains within the
normal range during pregnancy and does not change postpartum. For women
with gestational thrombocytopenia, mild thrombocytopenia begins to resolve
soon after delivery and is no longer present at three to four weeks postpartum.

8


●Coagulation and fibrinolysis – Postpartum normalization of coagulation
parameters and return to baseline thromboembolic risk generally occur by six to
eight weeks after delivery [65]. For women who require thrombophilia testing,
we suggest delaying testing until three months following delivery and after

lactation has been completed [44].
Failure of an abnormal laboratory test to normalize within these time frames
indicates that further evaluation is needed.
SOCIETY GUIDELINE LINKSLinks to society and government-sponsored
guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Anemia in adults".)
SUMMARY AND RECOMMENDATIONS
●The major hematologic changes during pregnancy include expanded plasma
volume, physiologic anemia, mild neutrophilia in some individuals, and a mildly
prothrombotic state that does not require intervention (table 1). More severe
changes may warrant additional testing and/or interventions.
(See 'Overview' above and 'Findings of concern' above.)
●Physiologic (dilutional) anemia occurs because plasma volume increases to a
greater extent than red blood cell mass. (See 'Plasma volume' above.)
●The Centers for Disease Control and Prevention have defined physiologic
anemia as hemoglobin levels <11 g/dL in the first and third trimesters and <10.5
g/dL in the second trimester. More severe anemia is most commonly due to iron
deficiency. (See 'Dilutional or physiologic anemia' above and "Anemia in
pregnancy".)
●The white blood cell (WBC) count begins to increase in the second month of
pregnancy and plateaus in the second or third trimester (typical WBC range:
9000 to 15,000 cells/microL). This results in mild neutrophil leukocytosis in
some individuals. There is no change in the absolute lymphocyte count.
(See 'White blood cells' above.)
●The platelet count may be slightly lower in pregnancy (eg, below the normal
range or below the woman's baseline), but most pregnant women have normal
platelet counts (table 2). The most common cause of mild thrombocytopenia is
gestational thrombocytopenia (typical platelet count range, 100,000 to
149,000/microL), which does not require any intervention and resolves after
delivery. More severe thrombocytopenia typically requires further evaluation

and treatment. (See 'Platelets' above and "Thrombocytopenia in pregnancy".)
●Pregnancy is a prothrombotic state due to changes in several procoagulant and
anticoagulant factors (table 2). Most pregnant women do not require coagulation

9


testing, but if testing is performed, the prothrombin time (PT) and activated
partial thromboplastin time (aPTT) are typically normal or slightly decreased
(shortened). Certain tests of coagulation such as the D-dimer lack sensitivity and
specificity during pregnancy. (See 'Coagulation and fibrinolysis' above.)
●Pregnancy-related hematologic changes generally return to baseline by six to
eight weeks after delivery. Failure to do so indicates the need for additional
evaluation. (See 'Postpartum resolution' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Lund CJ, Donovan JC. Blood volume during pregnancy. Significance of
plasma and red cell volumes. Am J Obstet Gynecol 1967; 98:394.
2. Bernstein IM, Ziegler W, Badger GJ. Plasma volume expansion in early
pregnancy. Obstet Gynecol 2001; 97:669.
3. Whittaker PG, Lind T. The intravascular mass of albumin during human
pregnancy: a serial study in normal and diabetic women. Br J Obstet
Gynaecol 1993; 100:587.
4. Pritchard JA. Changes in the blood volume during pregnancy.
Anesthesiology 1965; 26:393.
5. de Haas S, Ghossein-Doha C, van Kuijk SM, et al. Physiological
adaptation of maternal plasma volume during pregnancy: a systematic
review and meta-analysis. Ultrasound Obstet Gynecol 2017; 49:177.
6. Maternal physiology. In: Williams Obstetrics, 24th ed, Cunningham FG,
Leveno KJ, Bloom SL, et al (Eds), McGraw-Hill Education, 2014. p.55.

7. Schrier RW. Pathogenesis of sodium and water retention in high-output
and low-output cardiac failure, nephrotic syndrome, cirrhosis, and
pregnancy (2). N Engl J Med 1988; 319:1127.
8. Nadel AS, Ballermann BJ, Anderson S, Brenner BM. Interrelationships
among atrial peptides, renin, and blood volume in pregnant rats. Am J
Physiol 1988; 254:R793.
9. Lindheimer MD, Katz AI. Sodium and diuretics in pregnancy. N Engl J
Med 1973; 288:891.
10.Brown MA, Whitworth JA. The kidney in hypertensive pregnancies-victim and villain. Am J Kidney Dis 1992; 20:427.

10


11.Metcalfe J, Stock MK, Barron DH. Maternal physiology during gestation.
In: The Physiology of Reproduction, Knobil K, Ewing L (Eds), Raven
Press, New York 1988. p.2145.
12.McLENNAN CE. Plasma volume late in pregnancy. Am J Obstet
Gynecol 1950; 59:662.
13.Campbell DM, MacGillivray I. Comparison of maternal response in first
and second pregnancies in relation to baby weight. J Obstet Gynaecol Br
Commonw 1972; 79:684.
14.Ueland K. Maternal cardiovascular dynamics. VII. Intrapartum blood
volume changes. Am J Obstet Gynecol 1976; 126:671.
15.Haram K, Nilsen ST, Ulvik RJ. Iron supplementation in pregnancy-evidence and controversies. Acta Obstet Gynecol Scand 2001; 80:683.
16.Hytten FE, Lind T. Indices of cardiovascular function. In: Diagnostic
Indices in Pregnancy, Hytten FE, Lind T (Eds), Documenta Geigy, Basel
1973.
17.Whittaker PG, Macphail S, Lind T. Serial hematologic changes and
pregnancy outcome. Obstet Gynecol 1996; 88:33.
18.Harstad TW, Mason RA, Cox SM. Serum erythropoietin quantitation in

pregnancy using an enzyme-linked immunoassay. Am J Perinatol 1992;
9:233.
19.Lurie S, Mamet Y. Red blood cell survival and kinetics during pregnancy.
Eur J Obstet Gynecol Reprod Biol 2000; 93:185.
20.Milman N, Graudal N, Nielsen OJ, Agger AO. Serum erythropoietin
during normal pregnancy: relationship to hemoglobin and iron status
markers and impact of iron supplementation in a longitudinal, placebocontrolled study on 118 women. Int J Hematol 1997; 66:159.
21.Bille-Brahe NE, Rørth M. Red cell 2.3-diphosphoglycerate in pregnancy.
Acta Obstet Gynecol Scand 1979; 58:19.
22. (Accessed on
October 03, 2017).
23.Cheschier N, ACOG Committee on Practice Bulletins-Obstetrics. ACOG
practice bulletin. Neural tube defects. Number 44, July 2003. (Replaces
committee opinion number 252, March 2001). Int J Gynaecol Obstet
2003; 83:123.

11


24.Centers for Disease Control (CDC). CDC criteria for anemia in children
and childbearing-aged women. MMWR Morb Mortal Wkly Rep 1989;
38:400.
25.World Health Organization. Iron deficiency anaemia: Assessment,
prevention, and control. A guide for programme managers.
/>control.pdf (Accessed on September 06, 2011).
26.KUVIN SF, BRECHER G. Differential neutrophil counts in pregnancy. N
Engl J Med 1962; 266:877.
27.Molberg P, Johnson C, Brown TS. Leukocytosis in labor: what are its
implications? Fam Pract Res J 1994; 14:229.
28.Acker DB, Johnson MP, Sachs BP, Friedman EA. The leukocyte count in

labor. Am J Obstet Gynecol 1985; 153:737.
29.Siegel I, Gleicher N. Peripheral white blood cell alterations in early labor.
Diagn Gynecol Obstet 1981; 3:123.
30.Fernández-Suárez A, Pascual VT, Gimenez MT, Hernández JF. Immature
granulocyte detection by the SE-9000 haematology analyser during
pregnancy. Clin Lab Haematol 2003; 25:347.
31.Pramanik SS, Pramanik T, Mondal SC, Chanda R. Number, maturity and
phagocytic activity of neutrophils in the three trimesters of pregnancy.
East Mediterr Health J 2007; 13:862.
32.Kühnert M, Strohmeier R, Stegmüller M, Halberstadt E. Changes in
lymphocyte subsets during normal pregnancy. Eur J Obstet Gynecol
Reprod Biol 1998; 76:147.
33.Reese JA, Peck JD, Deschamps DR, et al. Platelet Counts during
Pregnancy. N Engl J Med 2018; 379:32.
34.Paidas MJ, Ku DH, Arkel YS. Screening and management of inherited
thrombophilias in the setting of adverse pregnancy outcome. Clin
Perinatol 2004; 31:783.
35.Greer IA. Epidemiology, risk factors and prophylaxis of venous thromboembolism in obstetrics and gynaecology. Baillieres Clin Obstet Gynaecol
1997; 11:403.
36.Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet
1999; 353:1258.
37.Lindqvist P, Dahlbäck B, Marŝál K. Thrombotic risk during pregnancy: a
population study. Obstet Gynecol 1999; 94:595.
12


38.Andersen BS, Steffensen FH, Sørensen HT, et al. The cumulative
incidence of venous thromboembolism during pregnancy and
puerperium--an 11 year Danish population-based study of 63,300
pregnancies. Acta Obstet Gynecol Scand 1998; 77:170.

39.Hellgren M, Blombäck M. Studies on blood coagulation and fibrinolysis
in pregnancy, during delivery and in the puerperium. I. Normal condition.
Gynecol Obstet Invest 1981; 12:141.
40.Stirling Y, Woolf L, North WR, et al. Haemostasis in normal pregnancy.
Thromb Haemost 1984; 52:176.
41.Comp PC, Thurnau GR, Welsh J, Esmon CT. Functional and
immunologic protein S levels are decreased during pregnancy. Blood
1986; 68:881.
42.Cumming AM, Tait RC, Fildes S, et al. Development of resistance to
activated protein C during pregnancy. Br J Haematol 1995; 90:725.
43.Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin
Haematol 2003; 16:153.
44.Hellgren M. Hemostasis during normal pregnancy and puerperium. Semin
Thromb Hemost 2003; 29:125.
45.Sood SL, James AH, Ragni MV, et al. A prospective study of von
Willebrand factor levels and bleeding in pregnant women with type 1 von
Willebrand disease. Haemophilia 2016; 22:e562.
46.Paidas MJ, Ku DH, Lee MJ, et al. Protein Z, protein S levels are lower in
patients with thrombophilia and subsequent pregnancy complications. J
Thromb Haemost 2005; 3:497.
47.James AH, Rhee E, Thames B, Philipp CS. Characterization of
antithrombin levels in pregnancy. Thromb Res 2014; 134:648.
48.Cerneca F, Ricci G, Simeone R, 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. Eur J Obstet Gynecol Reprod
Biol 1997; 73:31.
49.Dahlman T, Hellgren M, Blombäck M. Changes in blood coagulation and
fibrinolysis in the normal puerperium. Gynecol Obstet Invest 1985; 20:37.
50.Gerbasi FR, Bottoms S, Farag A, Mammen E. Increased intravascular

coagulation associated with pregnancy. Obstet Gynecol 1990; 75:385.

13


51.Sánchez-Luceros A, Meschengieser SS, Marchese C, et al. Factor VIII
and von Willebrand factor changes during normal pregnancy and
puerperium. Blood Coagul Fibrinolysis 2003; 14:647.
52.Wickström K, Edelstam G, Löwbeer CH, et al. Reference intervals for
plasma levels of fibronectin, von Willebrand factor, free protein S and
antithrombin during third-trimester pregnancy. Scand J Clin Lab Invest
2004; 64:31.
53.Ku DH, Arkel YS, Paidas MP, Lockwood CJ. Circulating levels of
inflammatory cytokines (IL-1 beta and TNF-alpha), resistance to activated
protein C, thrombin and fibrin generation in uncomplicated pregnancies.
Thromb Haemost 2003; 90:1074.
54.Francalanci I, Comeglio P, Alessandrello Liotta A, et al. D-dimer plasma
levels during normal pregnancy measured by specific ELISA. Int J Clin
Lab Res 1997; 27:65.
55.Senent M, Bellart J, Zuazu-Jausoro I, et al. [Markers of
hypercoagulability during pregnancy: thrombin-antithrombin-III
complexes and D dimer]. Sangre (Barc) 1991; 36:21.
56.van Wersch JW, Ubachs JM. Blood coagulation and fibrinolysis during
normal pregnancy. Eur J Clin Chem Clin Biochem 1991; 29:45.
57.Mercelina-Roumans PE, Ubachs JM, van Wersch JW. Coagulation and
fibrinolysis in smoking and nonsmoking pregnant women. Br J Obstet
Gynaecol 1996; 103:789.
58.Bremme K, Ostlund E, Almqvist I, et al. Enhanced thrombin generation
and fibrinolytic activity in normal pregnancy and the puerperium. Obstet
Gynecol 1992; 80:132.

59.Bellart J, Gilabert R, Fontcuberta J, et al. Fibrinolysis changes in normal
pregnancy. J Perinat Med 1997; 25:368.
60.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.
61.Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in
normal pregnancy: new diagnostic thresholds are needed. Clin Chem
2005; 51:825.
62.Bonnar J, McNicol GP, Douglas AS. Fibrinolytic enzyme system and
pregnancy. Br Med J 1969; 3:387.
63.Sharief LT, Lawrie AS, Mackie IJ, et al. Changes in factor XIII level
during pregnancy. Haemophilia 2014; 20:e144.
14


64.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.
65.Saha P, Stott D, Atalla R. Haemostatic changes in the puerperium '6
weeks postpartum' (HIP Study) - implication for maternal
thromboembolism. BJOG 2009; 116:1602.

Maternal adaptations to pregnancy: Cardiovascular and hemodynamic
changes
INTRODUCTIONThe major pregnancy-related hemodynamic changes include
increased cardiac output, expanded blood volume, and reduced systemic
vascular resistance and blood pressure. These changes contribute to optimal
growth and development of the fetus and help to protect the mother from the
risks of delivery, such as hemorrhage. Knowledge of these cardiovascular
adaptations is required to correctly interpret hemodynamic and cardiovascular
tests in the gravida, to predict the effects of pregnancy on the woman with

underlying cardiac disease, and to understand how the fetus will be affected by
maternal cardiac disorders.

15


The cardiovascular changes associated with normal pregnancy will be reviewed
here. The management of specific cardiac disorders, such as acquired and
congenital heart disease, heart failure, and arrhythmias, are discussed separately.
●(See "Acquired heart disease and pregnancy".)
●(See "Pregnancy in women with congenital heart disease: General principles".)
●(See "Pregnancy in women with congenital heart disease: Specific lesions".)
●(See "Management of heart failure during pregnancy".)
CHANGES RELATED TO PREGNANCY
Timeline of cardiovascular changes — These changes begin early in
pregnancy, reach their peak during the second and early third trimester, and then
remain relatively constant until delivery (figure 1 and figure 2) [1].
●First trimester (conception to 13+6 weeks of gestation) – Maternal systemic
vasodilation begins at approximately 5 weeks of gestation [2]. Systemic vascular
resistance (SVR) progressively drops by approximately 35 to 40 percent and
nadirs in the mid-second trimester while cardiac output begins to rise.
●Second trimester (14 to 27+6 weeks of gestation) – The reduction in SVR that
began in the first trimester ends in a plateau in the middle of the second
trimester [2]. Cardiac output continues to rise, but in a nonlinear fashion.
●Third trimester (28 weeks of gestation to delivery) – Cardiac output peaks in
the early third trimester [2]. Heart rate, which rises throughout gestation, peaks
in the late third trimester at an average of 16 beats per minute (bpm; 24 percent)
above nonpregnant values. Supine positioning reduces cardiac output and stroke
volume and increases heart rate due to compression of the aorta and vena cava
from the enlarging uterus. Placing the woman in the left lateral decubitus

position shifts the uterus off the aorta and vena cava, which in turn increases
blood flow to the heart and results in increased cardiac output and stroke
volume. Blood pressure (BP) returns to prepregnancy levels during the third
trimester.
●Intrapartum – Cardiac output increases by 15 percent above prelabor levels
in early labor and 25 percent during the active phase. During pushing in the
second stage, cardiac output rises by 50 percent (figure 3). With epidural
anesthesia, the baseline increase in cardiac output is attenuated; however, the
increases associated with uterine contractions persist. Position changes from
supine to lateral decubitus during labor increases cardiac output. This effect is
more pronounced during labor, suggesting that cardiac output during labor may
be more dependent on preload.

16


●Postpartum – Following birth, heart rate and BP returns to nonpregnant
values and remains unchanged throughout the postpartum period [2].
Changes in blood volume
Timeline — Expansion of the plasma volume and an increase in red blood cell
mass begin as early as the fourth week of pregnancy, peak at 28 to 34 weeks of
gestation, and then plateau until parturition [3-5]. Plasma volume expansion is
accompanied by a lesser increase in red cell volume (figure 4) [6]. As a result,
there is a modest reduction in hematocrit, with peak hemodilution occurring at
24 to 26 weeks. Compared with the blood volume (65 to 70 mL/kg) in
nonpregnant women, the blood volume in pregnant women at term is increased
to 100 mL/kg [7].
Plasma volume — Plasma volume increases by 10 to 15 percent at 6 to 12
weeks of gestation [8-10], expands rapidly until 30 to 34 weeks, and then
plateaus or falls slightly (figure 4). The mechanisms of plasma expansion are

presented in detail in a related topic review. (See "Maternal adaptations to
pregnancy: Hematologic changes", section on 'Plasma volume'.)
Red blood cell mass — Red blood cell mass begins to increase at 8 to 10 weeks
of gestation and steadily rises, in women taking iron supplements, by 20 to 30
percent (250 to 450 mL) above nonpregnant levels by the end of pregnancy
[5,11-14]. Among women not on iron supplements, the red cell mass may only
increase by 15 to 20 percent [15]. Increased plasma erythropoietin induces the
rise in red cell mass, which partially supports the higher metabolic requirement
for oxygen during pregnancy [16]. (See "Maternal adaptations to pregnancy:
Hematologic changes", section on 'Red blood cells'.)
Physiologic anemia — A greater increase in intravascular volume compared
with red cell mass results in the dilutional or physiologic anemia of pregnancy.
This becomes most apparent at 30 to 34 weeks of gestation when plasma volume
peaks in relation to red cell volume. Assuming normal renal function, blood
volume and constituents return to nonpregnant values by eight weeks
postpartum, a result of diuresis. Hemoglobin begins to increase from the third
postpartum day [7].
The physiologic effects of hypervolemia and anemia during pregnancy have
several benefits:
●Decreased blood viscosity (from greater increases in plasma volume than red
cell volume) results in reduced resistance to flow, facilitating placental perfusion
and lowering cardiac work.
●Total intravascular volume increases to approximately 50 percent above
nonpregnant values near term to provide some reserve against the normal blood
17


loss during parturition (approximately 300 to 500 mL for vaginal delivery, 600
to 1000 mL for cesarean delivery) and peripartum hemorrhage [4,5]. During
delivery, as much as 500 mL of blood sequestered in the uteroplacental unit is

autotransfused to the maternal circulation, thereby minimizing adverse
circulatory effects from blood loss at delivery.
●Most of the increase in cardiac output is distributed to the placenta, kidneys,
and skin to provide nutrients to the fetus, excrete maternal and fetal waste
products, and assist maternal temperature control, respectively. The increases in
renal blood flow and glomerular filtration rate during pregnancy are largely
mediated by the ovarian hormone relaxin, the release of which is increased by
human chorionic gonadotropin [17]. (See "Maternal adaptations to pregnancy:
Renal and urinary tract physiology".)
The absence of physiologic anemia appears to be harmful [18,19]. A populationbased, case-control study using data from the Swedish Medical Birth Register
reported that women with a hemoglobin concentration of 14.6 g/dL or higher at
the first prenatal visit were at increased risk of stillbirth (odds ratio [OR] 1.8),
antepartum stillbirth without malformations (OR 2.0), and preterm and small for
gestational age nonmalformed stillbirth (OR 2.7 and 4.2, respectively) [18]. The
elevated risk persisted despite a subsequent fall in hemoglobin concentration and
after excluding women with preeclampsia. It is hypothesized that high blood
viscosity increases the risk of thrombosis in the uteroplacental circulation.
Changes in systemic hemodynamics — Maternal and fetal metabolic
requirements increase as pregnancy progresses. A change in cardiac output (the
product of stroke volume and heart rate) occurs during pregnancy to meet these
demands (figure 5).
Heart rate — During normal pregnancy, the resting heart rate begins to rise in
the first trimester, with an average increase of 10 to 30 bpm (71±10 bpm) having
been reported [20-22]. In a three-center, prospective, longitudinal cohort study,
the median heart rate at 12 weeks was 82 bpm (3rd to 97th centiles: 63 to 105
bpm) and rose progressively until 34 weeks of gestation to a maximum of 91
bpm (3rd to 97th centiles: 68 to 115 bpm) [23]. Heart rate then decreased slightly
at 40 weeks to a median of 89 bpm (3rd to 97th centiles: 65 to 114 bpm). Thus, the
upper limit of the resting heart rate is typically not greater than 115 bpm, and
those exceeding 115 bpm warrant evaluation.

Cardiac output
●Physiology – The cardiac output, calculated as the heart rate x the stroke
volume, rises 30 to 50 percent (1.8 L/min) above baseline during normal
pregnancy. The elevation in cardiac performance results in part from changes in
three important factors that determine cardiac output [20]:
18


•Preload is increased due to the associated rise in blood volume
•Afterload is reduced due to the decline in systemic vascular resistance
•Maternal heart rate rises (see 'Heart rate' above)
In early pregnancy, increased cardiac output is primarily related to the rise in
stroke volume; one meta-analysis reported an 8 percent increase (6 mL) in
stroke volume in the first trimester [2]. In late pregnancy, heart rate change is
the major factor contributing to increased cardiac output. The ejection fraction is
unchanged from normal nonpregnant values, making it a reliable indicator of left
ventricular function during pregnancy, although the direct effect of pregnancy
on left ventricular contractility remains controversial [24]. Although changes in
blood volume during pregnancy affect right ventricular preload, central venous
pressure remains in the normal nonpregnant range throughout pregnancy due to
the reduction in cardiac afterload induced by the substantial decrease in both
systemic vascular resistance and pulmonary vascular resistance (ie, afterload to
the left and right heart, respectively) [25].
Regardless of the mechanism, the stress induced by the increase in cardiac
output can cause women with underlying and, in some cases, asymptomatic
heart disease to decompensate during the latter half of pregnancy.
(See "Management of heart failure during pregnancy".)
●Cardiac function – The inherent contractility of the myocardium is stable to
slightly improved in pregnancy [26,27]. This stable to improved function may
be a result of increased left ventricular mass, with the greatest change, an

increase of an average of 40 g (34 percent) above baseline, noted in the early
third trimester [2]. Pulmonary capillary wedge pressure and pulmonary artery
systolic and diastolic pressures remain in the normal nonpregnant range since
the hypervolemia of pregnancy is balanced by the fall in pulmonary vascular
resistance.
●Timing – Approximately one-half of the increase in cardiac output occurs by
eight weeks of gestation [20,28-31]. The slope of increase in cardiac output
slows in the late second trimester and drops in the late third trimester, although
it remains above prepregnancy levels until postpartum [2]. Increased vena caval
compression by the uterus, increased blood flow to the uteroplacental
circulation, or both have been a proposed as the cause of the late third trimester
drop.
●Impact of maternal posture – The degree of change is acutely influenced by
posture, as the cardiac output is higher when the pregnant woman is in the left
lateral decubitus position, particularly after 20 weeks of gestation [6,32,33]. By
comparison, assumption of the supine position can lower the cardiac output by

19


as much as 25 to 30 percent due to compression of the inferior cava by the
gravid uterus, leading to a substantial reduction in venous return to the heart.
Changes in maternal heart rate, stroke volume, and cardiac output during
pregnancy measured in the lateral and supine positions are demonstrated in the
figure (figure 5). (See 'Postural hypotensive syndrome' below.)
●Multiple gestation – The cardiovascular changes in women carrying twins are
greater than those described above for singleton pregnancies. Two-dimensional
and M-mode echocardiography of 119 women (in the left lateral position) with
twins suggested that cardiac output was 20 percent higher than in women
carrying singletons, and peaked at 30 weeks of gestation [34]. This increase was

due to a 15 percent increase in stroke volume and 3.5 percent increase in heart
rate.
Blood pressure and vascular resistance — Systolic and diastolic BP typically
fall early in gestation. A three-center, prospective cohort study suggests the fall
in BP is less than what has been previously thought [23]. In this report:
●Systolic BP decreased from 12 weeks of gestation (median 114 mmHg; 3rd to
97th centiles: 95 to 138 mmHg) to reach a nadir at 18.6 weeks (median 113
mmHg; 3rd to 97th centiles: 95 to 136 mmHg).
Systolic BP then rose progressively to 40 weeks to a maximum median of 121
mmHg (3rd to 97th centiles: 102 to 144 mmHg). The 3rd centile for systolic BP
was never less than 94 mmHg and was greater than 96 mmHg in all groups.
●Diastolic BP decreased from 12 weeks of gestation (median 70 mmHg; 3rd to
97th centiles: 56 to 87 mmHg) to its nadir at 19.2 weeks (median 69 mmHg;
3rd to 97th centiles: 55 to 86 mmHg).
Diastolic BP then increased to 40 weeks to a maximum median of 78 mmHg
(3rd to 97th centiles: 62 to 95 mmHg).
The fall in BP is induced by a reduction in systemic vascular resistance (SVR),
which in pregnancy appears to parallel changes in afterload [35]. A metaanalysis of 39 studies reported that the SVR progressively dropped throughout
pregnancy, with the lowest value (396 dyne s/cm6) being 30 percent below the
nonpregnant baseline and occurring in the early third trimester [2]. Both creation
of a high flow, low-resistance circuit in the uteroplacental circulation and
vasodilatation contribute to the decline in vascular resistance [20]. The factors
responsible for the vasodilatation are incompletely understood, but one of the
major findings is decreased vascular responsiveness to the pressor effects of
angiotensin II and norepinephrine [36-38]. Several additional mechanisms for
the fall in vascular resistance have been proposed:
●Increased endothelial prostacyclin [39]
20