Obstetrics and Gynecology

Thrombocytopenia in pregnancy

Thrombocytopenia in pregnancy

1. What every clinician should know

Thrombocytopenia, defined as a platelet count less than 150 x 109/L, is second only to anemia as the most common hematologic abnormality encountered during pregnancy,occurring in 7% to 10% of pregnancies. Platelet counts less than 100 x109/L are observed in only 1% of pregnant women, which is the definition adopted by an International Working Group published in Blood in 2010.

In normal pregnancy, platelet count is approximately 10% lower than in the nonpregnant state and decreases as gestation progresses. Despite this, most women will still have platelets within the normal level. In the majority of cases of thrombocytopenia in pregnancy, the thrombocytopenia is mild and not associated with significant morbidity for the mother or the fetus or neonate.

Occasionally, thrombocytopenia may be part of a serious medical disorder with significant morbidity for mother and fetus, and the challenge facing clinicians is to determine the level of risk it poses to the mother and fetus.

2. Diagnosis and differential diagnosis

Pregnancy-related versus nonpregnancy-related

Causes of thrombocytopenia may be specific complications of pregnancy, be associated with an increased frequency in pregnancy, or have no relationship to pregnancy.

Pregnancy-specific complications

Gestational thrombocytopenia, also known as incidental thrombocytopenia of pregnancy, is the commonest cause of thrombocytopenia in pregnancy occurring in approximately 75% of cases. It is a diagnosis of exclusion, no confirmatory tests are available. It generally causes mild thrombocytopenia with the majority of cases having platelet counts of 130 to 150 x 109/L. Most experts consider this diagnosis unlikely if the platelet count falls below 70 x 109/L.

It occurs in the middle of the second trimester and the third trimester and is not associated with maternal bleeding. During pregnancy, it is not possible to differentiate between the more severe form of gestational thrombocytopenia and primary immune thrombocytopenia (ITP) as both are diagnoses of exclusion. For the thrombocytopenia to be consistent with gestational thrombocytopenia, women should have no history of thrombocytopenia (except during a previous pregnancy), the thrombocytopenia should resolve spontaneously (usually shortly after delivery) within 1 to 2 months in all cases and the fetus/neonate should not be affected by thrombocytopenia.

Preeclampsia is the second most frequent cause of thrombocytopenia developing in the late second and third trimester and accounts for 21% of the cases of thrombocytopenia at delivery. Thrombocytopenia may be the only initial manifestation of preeclampsia. Platelet counts of in less than 50 x 109/L are rare in preeclampsia, occurring in less than 5% of cases. Intravascular hemolysis and elevated LDH and transaminases are less severe than seen in HELLP syndrome.

HELLP syndrome is characterized by hemolysis (abnormal peripheral blood film, LDH >600 U/L or bilirubin >1.2mg/dL), elevated liver enzymes (aspartate aminotransferase >70 U/L) and low platelets (<100 x 109/L). HELLP occurs in 10% to 20% of cases of severe preeclampsia. One, two, or three components of the disease have been described as a partial form of severe preeclampsia. The risk of severe morbidity correlates in general with increasingly severe thrombocytopenia. Disseminated intravascular coagulation (DIC) complicates up to 80% of severe cases.

Acute fatty liver of pregnancy (AFLP) is a disorder seen in 1 in 7000 to 20,000 pregnancies with a 15% maternal mortality. It has a significant clinical and biochemical overlap with preeclampsia and HELLP. Laboratory findings include normochromic normocytic anemia, with no or mild evidence of microangiopathic hemolysis and low platelets, which can occasionally be less than 20 x109/L. Elevated levels of transaminases are a constant feature. Low prothrombin time, fibrinogen and antithrombin levels are seen along with raised bilirubin levels (usually >5 mg/dL).

Pregnancy-associated conditions

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition characterized by microangiopathic hemolytic anemia, thrombocytopenia, fever, neurologic abnormalities, and renal dysfunction. It occurs due to a deficiency of VWF cleaving protein ADAMTS13. TTP is more common in women (3:2) and occurs in 1 in 25,000 pregnancies. It is not specific to pregnancy but is found with increased frequency in association with pregnancy in 5% to 25% of cases. Laboratory findings reveal microangiopathic hemolytic anemia, negative direct antiglobulin test, and normal coagulation tests (prothrombin time, activated partial thromboplastin time (APTT), fibrinogen, and D-dimers). Renal impairment is usually mild.

Hemolytic uremic syndrome (HUS) is a microangiopathy similar to TTP but with predominantly renal involvement. A useful clinical feature in distinguishing atypical HUS from TTP is the timing of onset; most cases of HUS occur a number of weeks postpartum. Complement abnormalities are present in 90% of cases with pregnancy-related disease.

Disseminated intravascular coagulation presenting in pregnancy often has a dramatic clinical onset due to the underlying causal obstetric events. Placental abruption, amniotic fluid embolism, and uterine rupture all lead to profound activation of the clotting system and serious consumption of clotting factors. Maternal sepsis and retained fetal tissue can lead to DIC in a more insidious way with thrombocytopenia being the presenting feature.

Nonpregnancy associated

Primary immune thrombocytopenia (ITP) is found in approximately 3% of women who are thrombocytopenic in pregnancy, with an incidence of 1 in 1000 to 10,000. It is the most common cause of an isolated low platelet count in the first and second trimesters. Without a prepregnancy platelet count or a history of ITP, differentiation from gestational thrombocytopenia may be impossible during pregnancy as they are both diagnoses of exclusion.

Systemic lupus erythematosus (SLE) or the antiphospholipid antibody syndrome can cause thrombocytopenia, which is usually less severe than that associated with ITP.

Inherited thrombocytopenias may first come to light during pregnancy. Type 2B Von Willebrand disease (type 2B VWD) is a rare subtype of VWD with increased affinity for platelet receptor glycoprotein 1b. This results in spontaneous platelet aggregation and accelerating platelet clearance leading to thrombocytopenia. May-Hegglin anomaly is an autosomal dominant platelet disorder characterized by thrombocytopenia, large platelets, and inclusion bodies in white blood cells. Recent studies have linked it to the MYH9 gene.

Malignant hematologic disorders are a very rare cause of thrombocytopenia in pregnancy and include metastatic infiltrative bone disease and bone marrow syndromes, such as myelodysplasia.

Viral infection

Severe folate or B12 deficiency may cause low platelet counts, usually accompanied by a low red and white cell count. The frequent use of periconceptual folic acid has significantly reduced the incidence of this as a cause of thrombocytopenia in pregnancy.

Drugs are used less frequently in pregnancy than outside of pregnancy but should be considered as a possible cause of thrombocytopenia. Unfractionated heparin can cause heparin-induced thrombocytopenia (HIT).

Viral infections are a common temporary cause of thrombocytopenia in pregnancy. Cytomegalovirus, Epstein-Barr virus, HIV, hepatitis B, and C all can cause thrombocytopenia.

Diagnostic approach

A pregnant woman with a new presentation of thrombocytopenia should have a full diagnostic assessment including history, physical examination, and laboratory testing to try and identify the likely underlying cause, narrowing down the cause based on the possible differentials described above.

The history should ascertain the presence of a prepregnancy low platelet count if known, any prescribed or over-the-counter drugs, and whether there is a personal or family history of bleeding disorders or autoimmune phenomena.

The key initial laboratory assessment at all gestational ages is a peripheral blood smear to confirm that low platelet count is genuine and to rule out microangiopathy. Following this, the level of thrombocytopenia at which to perform additional tests is a matter of debate, with many using a level of less than 100 x 109/L as a cut-off point below which further investigations should be carried out.

Screening for coagulation abnormalities (prothrombin time, antithrombin, fibrinogen, APTT, D-dimers) should be performed, being aware that APTT shortens during pregnancy. Liver function test abnormalities (bilirubin, albumin, total protein, transferases, and alkaline phosphatase) and screening for infectious causes are recommended and antiphospholipid antibodies, lupus anticoagulant, and serology for SLE are also recommended. Thyroid dysfunction is commonly seen in association with pregnancy and with ITP and should be done routinely. A direct antiglobulin test is required to rule out autoimmune hemolysis.

If there is a family history of bleeding or of thrombocytopenia, laboratory investigation for type 2B VWD should be carried out and included in VWF activity, ristocetin-induced platelet aggregation, and multimeric analysis of VWF.

Bone marrow examination is rarely indicated in pregnancy and suspicion of malignancy is one of its few indications. It is not required for the diagnosis of ITP. As in the nonpregnant patient, antiplatelet antibodies are of no value in the diagnosis of ITP in pregnancy.

ITP

Platelet count of:

>30 x 109/L - no treatment required in 1st and 2nd trimesters

>50 x 109/L - procedures safe

>80 x 109/L - regional anesthesia possible

In general, in women with platelet counts more than 100 x 109/L, monthly monitoring is appropriate in the first and second trimesters. Monitoring should become more frequent as gestation advances, if the platelet count drops below 80 to 100 x 109/L, or if there is development of unexplained bleeding or extensive bruising, consultation with hematology colleagues is advised.

The aim of antenatal management of ITP in pregnancy is to achieve and maintain a safe, rather than a normal, platelet count to minimize the risk of bleeding complications. Expert opinion and retrospective studies suggest that in the first and second trimester of pregnancy, asymptomatic patients with platelet counts less than30 x 109/L do not need treatment. If the patient is symptomatic, if the platelets are less than 30 x 109/L, or if a procedure is necessary, then treatment is required. Counts of more than50 x 109/L are usually adequate for procedures.

Treatment

  • First line — IVIg/corticosteroids

  • Other options — Anti-D; azathioprine; high-dose methylprednisolone; splenectomy; cyclosporine; rituximab

  • Contra-indicated — danazol; vinca alkaloids; cyclophosphamide

First-line therapy is similar to that of a nonpregnant patient, intravenous gammaglobulin (IVIg), and oral corticosteroids. By starting at a lower dose than outside of pregnancy, and adjusting to the minimum dose that achieves the required level depending on gestation, will reduce the risks. Anti-D has been used in Rh (D) positive patients but is not recommended as a first-line agent due to risks of acute hemolysis and neonatal risks of jaundice, anemia, and direct antiglobin positivity.

If a patient is refractory to first-line treatments, the balance of risk between bleeding and potential toxic effects of treatment must be considered. Splenectomy is best performed by the end of the second trimester as risks to the fetus and technical difficulty due to uterine size are less after 20 weeks ofgestation. The risk of neonatal thrombocytopenia is not altered by a splenectomy. There is limited data on the use of rituximab during pregnancy. It is known to cross the placenta and may cause a delay in neonatal B-cell maturation. Data from use in renal transplant patients has shown little toxicity associated with the use of both azathioprine and cyclosporine in pregnancy.

Perinatal management

General measures include avoidance of nonsteroidal medications. However, the antenatal use of aspirin can be allowed if the indication is appropriate and the platelet count is not too low. The cutoff level should be individualized based on the individual's indication and platelet count. Intermuscular injections can be considered depending on platelet count and should be avoided if less than 50 x 109/L. An anesthetic consult should be sought prenatally to discuss options for delivery. Most anesthetists would consider an epidural with platelet counts of 80 x 109/L or more in the absence of other risk factors or conditions associated with platelet function disorders.

ITP is not an indication for cesarean delivery and the mode of delivery should be based on obstetric considerations. To safely proceed with vaginal delivery, a platelet count of at least 50 x 109/L is advised. Procedures that increase the hemorrhagic risk to the fetus (e.g., vacuum, forceps, and fetal scalp sampling/electrodes) should be avoided. Determination of fetal platelet count by cordocentesis is associated with a potential hemorrhagic risk to the fetus and the fetal platelet count may be inaccurate. The risk of complications is 1% to 2%, which is similar to the risk of intracranial hemorrhage. Therefore, prenatal fetal platelet count measurement is not recommended in this circumstance.

Preeclampsia, HELLP, and AFLP

Mainstay of management of thrombocytopenia in preeclampsia/HELLP and AFLP is delivery of the fetus. Reversal of coagulopathy through transfusion of red cells, cryoprecipitate, plasma, and platelets may be required before delivery. The safe threshold of platelets for delivery by cesarean section is 50 x 109/L. Apart from delivery, the other main aspects of management are prevention of seizures with magnesium sulfate and treatment of hypertension, but further discussion of this is beyond the scope of this. Intensive postpartum monitoring is essential in women with HELLP as laboratory abnormalities frequently worsen 24 to 48 hours postdelivery. The platelet count should begin to rise by the fourth postpartum day. A Cochrane meta-analysis showed that platelet counts rose significantly more in patients receiving high dose steroids for the treatment of HELLP, but without a beneficial effect on maternal or fetal morbidity or mortality.

AFLP usually resolves following delivery with most patients improving by day 2 to 3. However, if ongoing liver dysfunction, coagulopathy, and neurologic impairment continue, supportive management in an intensive care setting may be required for more than 1 week. In severe cases, liaison with regional liver unit must take place as transplantation may be required in refractory cases.

Plasma exchange has been used in the treatment of severe HELLP/AFLP, particularly when it is hard to distinguish it from TTP/HUS.

TTP/HUS

The initial management of TTP/HUS during pregnancy does not differ from that of the nonpregnant patient. Delivery does not usually cause resolution of TTP, though it may need to be considered if there is co-existing preeclampsia. Early diagnosis of TTP/HUS is essential to institute treatment as soon as possible as most fatal events occur within 24 hours from presentation. Plasma exchange is the first-line treatment and regular plasma exchange may enable pregnancy to continue successfully. The optimal frequency of plasma exchange in pregnancy is unknown. Serial fetal monitoring with a uterine artery Doppler should be instituted to assess fetal growth and placental blood flow. In acquired TTP, prophylactic plasma exchange should be carried out if the ADAMTS13level is <10% or the blood smear shows evidence of hemolysis.

4. Complications

Maternal Risks

Maternal risks of steroid treatment for ITP include gestational diabetes, maternal hypertension, weight gain, osteoporosis, and psychosis. High doses of prednisolone have the potential to cause premature rupture of membranes, adrenal suppression, and a small increase in fetal cleft following use in the first trimester.

Hemorrhage is the main maternal concern at delivery. Major obstetric hemorrhage following vaginal delivery is uncommon even with severe thrombocytopenia. Platelets should be available on standby at the time of delivery but timing of their use is dependent on progression of labor and ultimate mode of delivery.

Fetal risks

ITP

Gestational thrombocytopenia and ITP can be difficult to separate until after pregnancy. Gestational thrombocytopenia is considered completely benign for the neonate, whereas ITP may result in the transplacental passage of antibodies leading to fetal/neonatal thrombocytopenia. The main concern for women with ITP is the risk of neonatal thrombocytopenia and intercranial hemorrhage. Platelet counts of less than 50 x 109/L occur in approximately 10% of neonates whose mothers have ITP and platelet counts of less than 20 x 109/L occur in 5%. The correlation between maternal and neonatal platelet count is poor but some studies have shown that the relative risk of neonatal thrombocytopenia increases with decreased maternal platelet counts. The best predictor of a low platelet count at birth is an older sibling with thrombocytopenia at birth. Maternal response to treatment does not automatically protect the neonate from development of thrombocytopenia.

A neonatal platelet count should be obtained at delivery and intermuscular injection of vitamin K should be deferred until platelet count is known. Neonatal platelet counts are rarely less than 10 x 109/L. The risk of intracranial hemorrhage is up to1.5%. Most neonatal hemorrhagic events occur 24 to 48 hours postdelivery when the platelet count is at its lowest point. If the platelet count is normal, there is no need for repeat counts. In neonates with low platelet counts, transcranial ultrasound is recommended. As severe (<10 x 109/L)

HUS/TTPp

Risk of IUGR, prematurity and fetal death is significant for the fetus due to extensive placental ischemia. Early plasma exchange may be helpful in reducing this risk. Some studies have shown a live birth rate of 67% with successful treatment.

5. Prognosis and outcome

Gestational thrombocytopenia—resolves spontaneously within a maximum of 1 to 2 months in all cases. There is a risk of recurrence in future pregnancies.

ITP — up to one third of women require treatment in subsequent pregnancies. ITP may worsen or relapse in subsequent pregnancies, but it is hard to predict in whom this will occur.

TTP — In inherited TTP, the risk of relapse is up to 100% in subsequent pregnancies. Prophylactic plasma exchange therapy may significantly reduce the risk of recurrence. With acquired TTP associated with severe ADAMTS13 deficiency, the risk of relapse is around 20%. Due to the rarity of the condition, precise figures are difficult to verify.

6. What is the evidence for specific management and treatment recommendations

Burrows, R, Kelton, JG. "Fetal thrombocytopenia and its relation to maternal thrombocytopenia". N Engl J Med . vol. 329. 1993. pp. 1463-6.

(A landmark cross sectional study of over 5,000 mother and infant pairs, describing the relationship of fetal thrombocytopenia to maternal thrombocyotpenia, outlining the rarity of severe fetal thrombocytopenia, and describing its relationship to mothers with antiplatelet alloantibodies.)

Jensen, JD, Wiemeier, SE, Henry, E, Silver, RM, Christensen, RD. "Linking maternal platelet counts with neonatal platelet counts and outcomes using data repositories of a multihospital health care system". Am J Perinatalol. vol. 28. 2011. pp. 97-604.

(A retrospective study which used a large data source with almost 12,000 mother-infant pairs to estimate the likelihood of a low neonatal platelet count with a predelivery maternal platelet count. Among Its strengths are the large patient numbers.)

Gernsheimer, TB. "Thrombocytopenia in pregnancy: is this immune thrombocytopenia or...". Hematology Am Soc Hematol Educ Program. vol. 2012. 2012. pp. 198-202.

(An excellent, comprehensive review of the investigation and management of thrombocytopenia in pregnancy.)

Myers, B. "Diagnosis and management of maternal thrombocytopenia in pregnancy". Br J Haematol. vol. 158. 2012. pp. 3-15.

(Another excellent, evidenced-based guideline for the diagnosis and management of thrombocytopenia in pregnancy, with helpful algorithms and tables.)

Provan, D, Stasi, R, Newland, AC, Blanchette, VS, Bolton-Maggs, P. "International consensus report on the investigation and management of primary immune thrombocytopenia". Blood . vol. 115. 2010. pp. 168-86.

(An international consensus statement on primary immune thrombocytopenia in the general population, with an in-depth section on pregnancy.)
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