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Maternal adaptations to pregnancy: Hematologic changes

Maternal adaptations to pregnancy: Hematologic changes
Author:
Kenneth A Bauer, MD
Section Editors:
Charles J Lockwood, MD, MHCM
Lawrence LK Leung, MD
Deputy Editors:
Vanessa A Barss, MD, FACOG
Jennifer S Tirnauer, MD
Literature review current through: Aug 2021. | This topic last updated: Aug 12, 2020.

INTRODUCTION — Normal 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".)

OVERVIEW — The 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 CONCERN — The following findings are not consistent with normal, physiologic adaptation to pregnancy and should prompt additional evaluation, and possibly additional interventions. In general, more severe abnormal findings require more prompt consultation by a hematologist.

Nonphysiologic anemia or polycythemia, especially when associated with symptoms out of proportion to the stage of pregnancy. Hemoglobin levels less than 10 g/dL or greater than 16 g/dL should prompt hematologic evaluation unless the etiology is known or the abnormalities are related to a preexistent chronic condition. (See "Anemia in pregnancy" and "Clinical manifestations and diagnosis of polycythemia vera".)

Evidence of iron deficiency (eg, new microcytosis, which is a late finding of iron deficiency, or iron studies showing reduced iron stores). The demand for iron is increased in pregnancy (figure 1); iron deficiency is therefore common. However, approximately one-third of pregnant women with iron deficiency 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 VOLUME — Plasma 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 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].

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 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 CELLS — Pregnancy 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 (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'.)

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".)

PLATELETS — Platelet 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 FIBRINOLYSIS — The 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".)

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]. 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 "Diagnosis of pulmonary embolism in pregnancy", section on 'Laboratory studies'.)

POSTPARTUM RESOLUTION — Pregnancy-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.

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 LINKS — Links 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 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.)

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  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.
Topic 429 Version 36.0

References

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65 : Haemostatic changes in the puerperium '6 weeks postpartum' (HIP Study) - implication for maternal thromboembolism.