Test
Reference intervals
Change in pregnancy
CBC
WBC
3.00–10.5×109/L
↑to 10–16×109/L
Hb
115–155 g/L
↓to 100–130 g/L
Platelet count
100–400×109/L
↓near term to as low as 100 x10 9/L
PTT
24–36 s
↔
INR
0.9–1.2
↔
Fibrinogen
>2.0 g/L
↑↑
vWF
Group O: 0.40–1.75 Um/L
Nongroup 0: 0.70–2.10 U/mL
↑
Factor Vlll
0.6–1.95 U/mL
↑
D-dimer
<300 μg/L
↑
Protein C
Functional: 0.75–1.60 U/mL
Antigen: 0.70–1.20 U/mL
↔
Protein S
Functional: 0.50–1.00 U/mL
Antigen: 0.57–1.20 U/mL
↓
AT
0.80–1.25 U/mL
↔
Homocysteine
<10 μmol/L
↓
Ferritin
↑
ESR
↑
Anemia
In pregnancy, anemia is generally well tolerated. The Centers for Disease Control and Prevention defines anemia in pregnancy as a hemoglobin of less than 11 g/dL in the first and third trimesters and less than 10.5 g/dL in the second trimester [4]. For women with adequate iron stores, the hemoglobin should return to normal around 1 to 6 weeks after delivery [5]. A hemoglobin of less than 10 g/dL should prompt a work-up for a pathological cause. Severe anemia, defined as a hemoglobin below 6 g/dL, has been associated with reduced amniotic fluid volume, fetal cerebral vasodilation, and nonreassuring fetal heart rate tracings [6]. There have also been reports of increased risk of prematurity, spontaneous abortion, low birth weight, and fetal death [7]. A hemoglobin of less than 7 g/dL increases the risk of maternal mortality as well [8]. Current recommendations are for all pregnant women to have a baseline complete blood count prior to pregnancy or at the first prenatal visit and again in the third trimester.
Iron Deficiency Anemia
Iron deficiency anemia accounts for the majority (>90 %) of nonphysiologic anemias. During a normal singleton pregnancy, a woman loses 1000 mg of iron to the fetus and placenta, expansion of red blood cells, and insensible losses [9]. Studies of the efficacy of iron supplementation on pregnancy outcomes are lacking. Transferrin is usually elevated with pregnancy. Serum ferritin is a useful screening test for iron deficiency in pregnancy with a sensitivity of 90 % and specificity of 85 % [10]. Iron repletion recommendations are generally the same for pregnant patients as nonpregnant patients and current recommendations suggest 15 to 30 mg daily of supplemental elemental iron for all pregnant women. Parental iron can be used for patients who do not absorb or are intolerant of oral iron. Iron sucrose in pregnancy has better safety data and is preferred over iron dextran. Recombinant erythropoietin has been shown to be of some benefit in patients with an inadequate response to iron but may cause a hypertensive effect [11]. However, in patients refractory to standard iron repletion, another cause of anemia should be investigated.
Macrocytic Anemias
Macrocytic anemias are most commonly due to folate deficiency and rarely vitamin B12 deficiency. Accurate diagnosis of both folate and B12 deficiency in pregnancy usually requires measuring plasma homocysteine and methylmalonic acid levels. Folate deficiency is caused by both increased demands of the fetus and erythropoiesis from the expansion of red cell mass. Hormonal changes of pregnancy can decrease folate absorption and increase urine losses [12]. Folate requirements increase from 50 μg/day in the nonpregnant patient to 150 μg/day in pregnant patients. Current recommendations are for pregnant women to take 1 mg daily of folate to prevent neural tube defects, which is also adequate for prevention and treatment of folic acid deficiency. Higher doses of folate are recommended in patients on antiepileptic drugs and in patients with a previously effected child with a neural tube defect. Repletion for both vitamin B12 and folate deficiency is the same as for nonpregnant patients. Other less common causes of macrocytic anemia include alcohol use, medications, hypothyroidism, and liver disease.
Hemoglobinopathies
For the majority of women with hemoglobinopathies, pregnancy is possible and successful with increased monitoring to avoid maternal and fetal complications.
Sickle Cell Disease
Sickle cell syndrome is caused by an inherited single nucleotide (GAG/GTG) mutation in the β-globin gene. Heterozygosity for Hb S (sickle cell trait) does not cause disease, but homozygous inheritance or compound heterozygous inheritance with another mutant β-globin gene does result in sickle cell disease. At least 17 hemoglobinopathies resulting in sickle cell disease variants exist. The more common types are listed in Table 7.2 [13]. Some risks to the mother and fetus are caused by pregnancy. Pregnancy-related increases in adhesion and coagulation proteins such as von Willebrand factor, fibrinogen, and factor VIII may exacerbate RBC adhesion and ultimately occlusion [14]. This results in occlusion of the vessels and a vaso-occlusive event, which may be more frequent during pregnancy. The frequency of obstetric complication in women with sickle cell disease can be found in Table 7.3 [13]. Sickle cell disease carries approximately a 6.5 % risk of spontaneous abortion according to the Cooperative Study of Sickle Disease [15]. Rates of intrauterine growth restriction may be increased in women with sickle cell disease especially those with acute complications of sickle cell disease during pregnancy [15, 16]. Preterm labor, placental abruption, and preeclampsia may be more common in patients with Hb SS disease compared to healthy African American females without sickle cell disease [15, 17].
Table 7.2
Characteristics of common sickle cell diseases compared with sickle cell trait
Disease | Baseline Hb(g/dL) | MCV | Baseline reticulocyte (%) | Relative clinical severity |
|---|---|---|---|---|
HbSS | 6.0–9.0 | Normal | 5–30 | ++++ |
HbS-βO-thalassemia | 6.0–9.0 | Low | 5–30 | ++++ |
HbSC | 10.0–13.0 | Normal | 3–4 | +++ |
HbS-β+-thalassemia | 10.0–14.0 | Low | 3–4 | ++ |
HbAS | 14.0–16.0 | Normal | 0–1 | 0 |
Table 7.3
Frequency of obstetric complications in women with sickle cell disease
Transfusion study, 1978–1986 [22] | |||||
|---|---|---|---|---|---|
Control | SS | SC | Sβthal | Cooperative study, 1979–1986 [12] | |
Number of pregnancies | 8981 | 100 | 66 | 23 | 225 |
Gestational age at delivery (week) | 40 | 37.5 | 38.6 | 37.1 | 37.7 |
Preterm labor (%) | 17 | 26 | 15 | 22 | 9 |
Placenta previa (%) | 0.4 | 1 | 2 | 4 | _ |
Abruptio placentae (%) | 0.5 | 3 | 2 | 4 | _ |
Toxemia (%) | 4 | 18 | 9 | 13 | 11 |
Cesarean section (%) | 14 | 29 | 30 | 26 | _ |
Patients should be followed in a high-risk clinic in conjunction with a healthcare provider familiar with the care of patients with sickle cell disease, ideally at 2-week intervals. A complete blood count, reticulocyte count, urinalysis, and blood pressure check are recommended with each visit. A prenatal vitamin without iron and additional folate should be prescribed [18]. During the first trimester preventing nausea and dehydration may decrease sickle cell-related complications. Close monitoring for the development of sickle cell pain events such as acute chest syndrome, acute sequestration or splenic infarct, and acute multiorgan failure is recommended during pregnancy, labor, and postpartum period. Pain crises are treated similar to nonpregnant patients and are outlined in Table 7.4 [13]. Adequate hydration and oxygenation should be maintained during labor. Analgesia doses may exceed those usually required for obstetrical pain due to increased tolerance of pain medications used for pain crises [19]. Indications for cesarean section are obstetric and the same as for patients without sickle cell disease.
Table 7.4
Management of acute sickle cell pain episodes in pregnant women
IV fluids: correct dehydration, then maintain euvolemia | |
Oxygen therapy: maintain normal oxygen saturation | |
Investigation and treatment of infection | |
Pain control: IV on a regular schedule ( not prn) | |
Monitor for complications of sickle cell disease: | |
Daily complete blood count and reticulocyte count | |
Baseline chemistry profile: repeat as needed for clinical deterioration | |
Frequent pulse oximetry | |
Narcotics (IV) | Nonnarcotic adjuncts (first–second trimester) |
Morphine sulfate | Nonsteroidal anti-inflammatory drugs |
Hydromorphone | Diphenhydramine |
Fentanyl | |
Chronic anemia associated with sickle cell disease is exacerbated by the usual dilution effect of pregnancy. Iron repletion will not correct the anemia and should be avoided, as many patients are already iron overloaded due to repeat transfusions. The use of prophylactic blood transfusions is not supported by the literature [20, 21]. Simple or exchange transfusions should be instituted for the same indications as nonpregnant patients: stroke, ocular events, severe acute chest syndrome, splenic sequestration, symptomatic aplastic crisis, and cerebrovascular accident [22].
Thalassemia
Thalassemias are a result of quantitative disorders of hemoglobin production. This is a result of decreased or imbalanced production of generally structurally normal globins. In β-thalassemia, a mutation in β-globin leads to decreased production and an excess of α-globins and the reverse for mutations in α-globins in α-thalassemias. These mutations result in membrane damage and red cell fragility causing microcytosis with target cell morphology and a chronic hemolytic anemia with compensatory reticulocytosis and splenomegaly. α-Thalassemias are more common in persons of Asian, African, or Mediterranean descent. β-Thalassemias occur more commonly in persons of Mediterranean and African descent. The more common types of thalassemias are described in [13].
Table 7.5
Recommended indications for transfusion in pregnant women with sickle cell disease
Toxemia |
|---|
Severe anemia (drop of 30 % below or Hb ≤ 6.0 g/dL) |
Acute renal failure |
Septicemia/bacteremia |
Acute chest syndrome with hypoxia or other severe sickle cell complication |
Anticipated surgery |
In general, women with α- or β-thalassemia trait tolerate pregnancy well. These patients have a mild baseline microcytic anemia, and despite increased iron absorption characteristic of thalassemia, iron deficiency can develop and iron studies may need to be checked during pregnancy [13]. Patients with severe α- and β-thalassemia intermedia have compromised fertility and few pregnancies have been reported. Approximately 50 % of pregnancies result in stillbirth, intrauterine growth restriction, and/or preterm delivery [24]. However, successful pregnancies have been achieved in patients with severe thalassemia with adequate cardiac function, good chelation regimens, and transfusion support with a goal HB of 10 g/dL during pregnancy as well as careful maternal and fetal monitoring [25].
Thrombocytopenia
Thrombocytopenia affects 10 % of pregnancies and can be isolated or part of a systemic disorder, and causes may be specific to or unrelated to pregnancy. The major causes of thrombocytopenia in pregnancy are presented in Table 7.6 (see attached table). A 10 % decrease in platelets can commonly be seen in pregnancy. For general management, most women can continue routine obstetrical care. The mode of delivery for patients with thrombocytopenia should be determined by obstetrical indications. No studies have been conducted to determine the optimal platelet count, but observational data indicate that a platelet count above 50 is adequate for epidural anesthesia, vaginal delivery, and cesarean section [26, 27]. Per current guidelines [28], vaginal deliveries are felt to be safe with a platelet count of 50,000. While the ASH guidelines also use a platelet count of 50,000 as appropriate for cesarean deliveries, concerns regarding bleeding from epidural anesthesia and possible neurologic complications led the The British Committee for Standards in Haematology (BCSH) [26] to recommend a platelet count of 80,000 for epidural anesthesia and for cesarean sections. Given that recommendations vary by institution, the treating team and the anesthesiologist should individualize each patient’s care.
Table 7.6
Differential diagnosis of thrombocytopenia in pregnancy
Incidence | Timing of incidence | Degree of thrombocytopenia | Microangiopathic hemolytic anemia | Hyper tension | Coagulopathy | Liver disease | Renal disease | CNS disease | |
|---|---|---|---|---|---|---|---|---|---|
ITP | 3–4 % | Most common in 1st trimester, anytime | Mild to severe | None | None | None | None | None | None |
Gestational/incidental thrombocytopenia | 75–80 % | Second–third trimester | Mild | None | None | None | None | None | None |
Preeclampsia | 15–20 % | Late 2nd to 3rd trimester | Mild to moderate | Mild | Moderate to severe | None to mild | None | Proteinuria | Seizures with preeclampsia |
HELLP | Late 2nd to 3rd trimester | Moderate to severe | Moderate to severe | None to severe | Absent to mild | Moderate to severe | None to moderate | None to moderate | |
DIC | Rare | Anytime | Moderate to severe | Mild to moderate | None | Mild to severe | Variable | Variable | None |
AFLP | Rare | 3rd trimester | Mild | Mild | None to mild | Severe | Severe | None to mild | None to mild |
TTP | Rare | 2nd to 3rd trimester | Severe | Moderate to severe | None | None | None | None to moderate | None to severe |
HUS | Rare | Postpartum | Moderate to severe | Moderate to severe | None to mild | None | None | Moderate to severe | None to mild |
Gestational thrombocytopenia, a benign condition initially diagnosed in the second or third trimester, is usually mild and is often difficult to differentiate from idiopathic thrombocytopenia (ITP). The former is typically mild with platelet counts rarely below 70,000/uL. ITP is found in approximately 1 in 10,000 pregnancies and usually presents in the first trimester. Whereas gestational thrombocytopenia has no affect on the neonate, there have been isolated cases of ITP that appeared to cause thrombocytopenia in the neonate. No correlation has been found between maternal and fetal/neonatal platelet counts, and most cases of severe fetal or neonatal thrombocytopenia are related to alloimmune thrombocytopenia (see below). Antiplatelet antibody testing has not been shown to be of value in predicting the risk of a thrombocytopenic infant or complications related to delivery. Current guidelines from the American Society of Hematology (ASH) and the British Committee for Standards in Haematology (BCSH) do not recommend the use of antiplatelet antibody testing for ITP in pregnancy [28, 29].
There is no evidence to support the need for intrapartum fetal platelet counts in patients with ITP. Women with preexisting ITP are less likely to have complications during pregnancy or require treatment. A clinical presentation of bleeding rather than an absolute platelet count directs the need for treatment remote from term. ITP in pregnancy is generally treated with either corticosteroids or IVIG for similar indications as in nonpregnant patients, with an attempt to keep platelet counts above 50–75,000 u/L toward term (Table 7.7 and 7.8) [30]. Although rituximab use in pregnancy has not been formally evaluated, rituximab has been used successfully during pregnancy for non-Hodgkin lymphoma, Crohn’s disease, and other indications in a limited number of patients and is pregnancy class C [31, 32]. Thrombopoietic agents’ romiplostim and eltrombopag are pregnancy class C, and there are no data to recommend use in pregnancy.
Table 7.7
Medical management of immune thrombocytopenic purpura in pregnancy: American Society of Hematology guidelines
Treatment indications | Platelets < 10,000/μl in |
Platelets 10–30,000/μl in Second or third trimester | |
Bleeding | |
Intravenous immunoglobulin | Initial treatment: third trimester Platelets < 10,000/μl |
Initial treatment: platelets 10–30,000 /μl and bleeding | |
After steroid failure: platelets < 10,000/μl | |
After steroid failure: platelets 10–30,000/μl | |
After steroid failure: third trimester, platelets 10–30,000/μl, asymptomatic | |
Splenectomy | Second trimester, platelets < 10,000/μl, bleeding |
Safe platelet count for delivery | 50,000/μl |
Table 7.8
Maternal management of immune thrombocytopenic purpura in pregnancy: British Committee for Standards in Haematology guidelines
Treatment indications | Platelets < 20,000/μl, unless delivery imminent |
Intravenous immunoglobulin | Oral corticosteroids and IVlg have similar responses as in nonpregnant state |
Splenectomy | If essential, in the second trimester, laparoscopic advantageous |
Safe platelet count | 50,000 /μl, vaginal |
For delivery | 80,000/μl cesarean section or epidural |
Preeclampsia affects 6 % of first pregnancies and about 50 % of these patients will have thrombocytopenia. The pathophysiology is not well understood, but accelerated platelet consumption is felt to contribute. HELLP (hemolysis, elevated liver function tests, and low platelets) syndrome (see Liver chapter), which affects between 0.1 % and 0.89 % of pregnancies, shares many clinical features with preeclampsia and is often considered a variant of severe preeclampsia. HELLP has a higher rate of maternal and fetal mortality than preeclampsia making correct diagnosis and treatment imperative. Patients with HELLP typically have a microangiopathic hemolytic anemia (schistocytes on peripheral blood smear) and an elevated lactate dehydrogenase (LDH), serum levels of aspartate aminotransferase greater than 70 unit/L, and platelets less than 100,000/uL. HELLP is often difficult to differentiate from thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). While TTP-HUS can occur throughout pregnancy and in the postpartum period, HELLP is most likely seen in the third trimester. Initial clinical symptoms appear nonspecific including gastrointestinal symptoms such as right upper quadrant or midepigastric tenderness, nausea and vomiting, and malaise. It is presumed that these symptoms are secondary to hepatic sinusoid blood flow obstruction. 75 % of patients have associated proteinuria: hypertension is seen in 50–60 % [33, 34]. In contrast to TTP, the presence of schistocytes on peripheral smear is seen to a minor degree and ADAMTS-13 deficiency is rarely seen.
Treatment of preeclampsia and HELLP consists of stabilization of the mother followed by expeditious delivery, which usually results in resolution of the disorder within 3 to 4 days in the majority of patients. However, occasionally both syndromes, especially HELLP, can worsen or develop postpartum. There is limited data from several, small randomized studies looking at the use of corticosteroids in the pre- or postnatal setting. Corticosteroids for HELLP are felt to hasten the resolution of thrombocytopenia and laboratory abnormalities and may be continued for 5 to 7 days after delivery for worsening thrombocytopenia or other signs of clinical decline, but the efficacy of corticosteroids for this indication has not been established [35].
The risk of TTP during pregnancy is increased and pregnant women comprise 10 % to 20 % of TTP patients. TTP typically develops in the second or third trimester. TTP-HUS may be confused with severe preeclampsia as common signs and symptoms may occur. Treatment is plasmapheresis. The risk of HUS also increases with pregnancy and the majority of cases develop 3 to 4 weeks postpartum. Atypical HUS with renal failure as the predominant manifestation is the most common. The prognosis of postpartum HUS is poor with more than 25 % of patients with persistent renal failure. Plasmapheresis is recommended despite low response rates due to the difficulty discerning HUS from TTP. Although in the past prompt delivery had been advocated, there is no level 1 data demonstrating that delivery alters the natural history of this disorder. It is likely that previous recommendations were confounded by mixing of cases of preeclampsia with TTP-HUS.
Disseminated intravascular dissemination (DIC) may accompany preeclampsia and may also result from retained fetal products, sepsis, placental abruption, or amniotic fluid embolization. In general, the thrombocytopenia is milder and the degree of microangiopathic hemolysis is less. DIC in pregnancy can be abrupt, severe, and fatal if not addressed appropriately. Treatment is aimed at treating the underlying condition that precipitated the DIC. BCSH has published guidelines for the management of DIC [36]. Transfusion support should be based on the presence of bleeding such as from low platelets or a prolonged prothrombin time. Cryoprecipitate may be used for severe hypofibrinogenemia (fibrinogen <100 g/dL) that persists after plasma therapy. Low doses of heparin may be indicated for patients with significant thrombosis.
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