Immune Thrombocytopenia and Pregnancy 

Updated: Aug 19, 2019
Author: Muhammad A Mir, MD, FACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP 

Overview

Practice Essentials

Thrombocytopenia is common in mothers and newborns and usually is caused by an increased rate of platelet destruction. The reference range of a normal platelet count in nonpregnant women and newborns is 150,000-400,000/µL; however, mean platelet counts in pregnant women generally are lower.

Thrombocytopenia in pregnancy has many common causes, including gestational thrombocytopenia, viral and bacterial infections, and preeclampsia complicated by hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome.[1]  This article focuses on the immune thrombocytopenias, immune thrombocytopenic purpura (ITP) and neonatal alloimmune thrombocytopenia (NAIT). These relatively rare causes of thrombocytopenia are important, as neonatal outcomes can be significantly impaired and subsequent pregnancies can be affected. (See images below.)

Immune thrombocytopenia. An infant born with neona Immune thrombocytopenia. An infant born with neonatal lupus syndrome and severe thrombocytopenia. Note extensive bruising and petechiae.
Immune thrombocytopenia. An infant born with a cep Immune thrombocytopenia. An infant born with a cephalohematoma.

Pathophysiology

Immune thrombocytopenia is a rare autoimmune disease due to an abnormal T cell response, notably supported by splenic T follicular helper cells, that stimulates the proliferation and differentiation of autoreactive B cells. The antiplatelet autoantibodies they produce facilitate platelet phagocytosis by macrophages, essentially in the spleen. Macrophages contribute to the perpetuation of the auto-immune response as the main antigen-presenting cell during ITP. CD8+ T cells also participate to thrombocytopenia by increasing platelet apoptosis. Besides this peripheral platelet destruction, inappropriate bone marrow production also exacerbates thrombocytopenia, due to an immune response against megakaryocytes. Moreover, the level of circulating thrombopoietin, the main growth factor of megakaryocytes, is low. These autoantibodies can cross the placenta; thus, both mother and newborn can be affected.[2]  

NAIT is caused by maternal immunization against fetal paternally derived platelet-specific antigens (similar to rhesus [Rh] disease). The mother has a normal platelet count, while the fetus can be severely thrombocytopenic. NAIT occurs when the mother is exposed to fetal platelets with incompatible paternally derived cell surface antigens. The mother's response to the foreign antigens is to produce immunoglobulin. This is initially immunoglobulin M, and the large size of this molecule prevents transplacental passage. Subsequently, the mother produces immunoglobulin G. The smaller size of this molecule permits passage across the placenta, resulting in the destruction of fetal platelets and neonatal thrombocytopenia.

Epidemiology

ITP occurs in 1 to 2 of every 1000 pregnancies, which in the United States represents about 3000 to 6000 cases of ITP in pregnancy per year.[3]  Although ITP accounts for less than 3% of all cases of thrombocytopenia during pregnancy, it is the most common cause of a platelet count below 50 × 109/L detected in the first and second trimesters.[4]  The frequency of NAIT is estimated at 1-2 cases per thousand deliveries.

The frequency of ITP is 1.8 cases per 1000 deliveries in Helsinki, Finland.[5]  The frequency of NAIT was reported as 0.5 cases per 1000 and 1.5 cases per 1000 liveborn neonates in England[6] and France,[7] respectively. In Japan, the frequency of NAIT was 0.3 cases per 1000 liveborn neonates, and incompatibility for human platelet antigen (HPA)-4 was the cause of 80% of these cases.[8] The recurrence risk for NAIT is extremely high (nearly 100% of subsequent pregnancies are affected if the sibling carries the significant paternally derived antigen).[9] In general, siblings with the platelet antigen will be as severely affected or more severely affected than the preceding affected child.[9]

ITP occurs in all races. However, more than 50% of all cases of NAIT have been reported in whites. Most cases of alloimmune thrombocytopenia (and the most severe cases) occur in white mothers homozygous for the P1A2 allele (HPA-1b).[10]  The prevalence of homozygous HPA-1b in whites is estimated at 2.5%.[11]  Multiple other platelet-specific antigens exist that can cause alloimmune thrombocytopenia; the prevalence of these varies in different ethnic groups.

ITP is diagnosed more commonly in females than males (ratio 3:1).[12]  NAIT occurs in newborns of both sexes.  ITP commonly is diagnosed in the second or third decade of life. NAIT develops in fetal life, with 25-50% of fetal intracranial hemorrhages detectable on prenatal ultrasound prior to the onset of labor.[13]

Prognosis

Women with ITP generally do well in pregnancy. ITP is an autoimmune disease and exacerbations, and remissions are common. Pregnancy does not appear to affect the course of the disease. ITP is not an absolute contraindication to pregnancy but in unusually severe or refractory cases or for women taking potentially teratogenic medications, deferring pregnancy may be indicated.[4]   Duration of maternal ITP is a risk factor for preterm birth and women with chronic ITP experience more adverse outcomes than those with a pregnancy-related diagnosis of ITP.[3]  

Fetuses and newborns with NAIT can experience permanent neurologic sequelae, organ damage, and death from intracranial and intra-abdominal bleeds due to severe thrombocytopenia. However, after birth, maternal antibodies are fairly rapidly degraded and the thrombocytopenia resolves.

Women and newborns with severe thrombocytopenia can experience intracranial and intra-abdominal bleeding. This can result in significant morbidity, including neurologic damage and/or death. Women requiring long-term steroid therapy can develop complications from the medication exposure.

Transfusion of blood products can result in transfusion reactions in the recipient. With current blood bank crossmatching, significant transfusion reactions are rare. Additionally, a risk of transmission of viral infections, especially hepatitis and human immunodeficiency virus, exists.[14]

Maternal hemorrhage at time of birth is a risk in women with ITP, particularly if the platelet count decreases to less than 20,000/µL. However, no maternal deaths have been reported in the last 20 years,[9]  and maternal morbidity is minimal if appropriate therapy is administered during pregnancy and childbirth.

Neonatal thrombocytopenia due to the active transport of antiplatelet antibodies through the placenta is a clinically more significant problem, and it occurred in 9 of 66 (13.6%) pregnancies complicated by ITP in one review.[15]  Of these infants, 5 of 66 (7.5%) had severe thrombocytopenia, with platelet counts less than 50,000/µL. Splenectomy prior to pregnancy was the only risk factor associated with the development of neonatal thrombocytopenia by logistic regression analysis.

Severe neonatal thrombocytopenia places the infant at risk for intracranial or visceral hemorrhage. None of the 9 thrombocytopenic infants in the Yamada trial had intracranial hemorrhage documented on clinical neurological examination or ultrasound. Neonatal intracranial hemorrhage previously has been reported to have a very low incidence (0-2.3%) in newborns of mothers with ITP.[16]

Neonatal morbidity is far more common in NAIT, with 10% of affected newborns dying and 20% experiencing neurological sequelae secondary to intracranial hemorrhage.[11]  Affected infants can have generalized petechiae, hemorrhage into abdominal viscera, and excessive bleeding after venipuncture or circumcision.

 

Presentation

History

Pregnant women with immune thrombocytopenic purpura (ITP) can be asymptomatic or can present with a history of easy bruisability, bleeding into the mucous membranes (epistaxis or gingival bleeding), or petechiae. They may have a history of menorrhagia or menometrorrhagia prior to pregnancy.

A maternal history of delivering a term newborn with thrombocytopenia, visceral or intracranial hemorrhage, or spontaneous or prolonged bleeding after venipuncture or circumcision raises suspicion for neonatal alloimmune thrombocytopenia (NAIT). However, about 50% of neonates with NAIT are first-born children and thus are delivered to women whose risk for the disorder is previously unrecognized and unknown.[17, 18]

Case history

A woman is 24 years old. She has been pregnant four times and given birth once (G4 P1). She has had zero spontaneous abortions (SAB0) and two elective abortions (EAB2). She is part Hawaiian and part Samoan and was referred for twice-weekly antepartum testing due to a prior stillbirth at 31 weeks' estimated gestational age. A specific cause of her fetal demise was never determined. Chromosome analysis revealed a normal male (46, XY) pattern. Placental pathology was normal, and an autopsy was not performed.

Her pregnancy and antepartum testing results are normal until 35 and 5/7 weeks' estimated gestational age (see images below). This woman is admitted for prolonged fetal monitoring, the findings of which are completely normal. She is discharged home later that day.

Immune thrombocytopenia. Nonstress test 1 week bef Immune thrombocytopenia. Nonstress test 1 week before delivery showing a normal reactive fetal heart rate pattern.
Immune thrombocytopenia. Nonstress test 4 days bef Immune thrombocytopenia. Nonstress test 4 days before delivery showing a reactive fetal heart rate with an unusual pseudosinusoidal pattern that lasted 9 minutes.

She presents 4 days later with 2 days of decreased fetal movement. Fetal heart tones cannot be auscultated, and an ultrasound confirms an intrauterine fetal demise. Labor is induced, and she delivers a 2729-g male fetus. Autopsy demonstrates a large subdural hemorrhage surrounding the brain and spinal cord (54 g) (see images below).

Immune thrombocytopenia. Neonatal brain at autopsy Immune thrombocytopenia. Neonatal brain at autopsy showing extensive subdural hemorrhage.
Immune thrombocytopenia. Neonatal spine at autopsy Immune thrombocytopenia. Neonatal spine at autopsy showing extensive hemorrhage at base of spine.

The woman's blood is sent for platelet antigen typing. Her platelet-associated immunoglobulins are high, at 7.5 (reference range 0-4.3). She tests positive for HPA-1a, the platelet-specific antigen implicated in most cases of NAIT (in whites). The father of the baby declines to have his blood drawn; therefore, platelets from the father cannot be tested with the mother's serum. Thus, these studies do not support a diagnosis for NAIT, but they do not exclude it either because many different platelet antigens exist. This mother is of Hawaiian, Samoan heritage, and different platelet antigens (not HPA-1a) probably are significant in nonwhite ethnic groups. HPA-4 has been shown to be important in NAIT in Japanese women.

Therefore, when the woman presents 2 years later pregnant with a new partner, the new father's platelets are tested against the mother's serum to verify that no antibodies in the maternal serum will react to paternal platelets. No antiplatelet antibodies are present, and she has an uncomplicated pregnancy delivering a full-term healthy infant.

Physical

Most women with ITP have normal findings on physical examination (splenomegaly is absent). Petechiae can be identified in the presence of severe thrombocytopenia.

Newborns with NAIT may have normal findings on physical examinations, or they may have a cephalohematoma, ecchymoses over the presenting part, and generalized petechiae (see images below).

Immune thrombocytopenia. An infant born with neona Immune thrombocytopenia. An infant born with neonatal lupus syndrome and severe thrombocytopenia. Note extensive bruising and petechiae.
Immune thrombocytopenia. An infant born with a cep Immune thrombocytopenia. An infant born with a cephalohematoma.
 

DDx

Diagnostic Considerations

Thrombocytopenia is extremely common in mothers and newborns, affecting 7-8% of all women during pregnancy[10] and 15-20% of newborns admitted to neonatal intensive care units [NICUs].[19] Particular attention must be paid to the peripheral smear to rule out macrothrombocytopenia, which may occasionally occur in the absence of other disorders associated with the MYH9 gene (deafness, cataracts, and nephritis).[20] Immune thrombocytopenias are relatively rare causes of thrombocytopenia, but they always must be considered in the differential diagnosis because neonatal outcomes can be impaired significantly and subsequent pregnancies can be affected.

Immune thrombocytopenic purpura

Other problems to consider in the differential diagnosis include the following:

  • Gestational thrombocytopenia
  • Preeclampsia
  • Systemic lupus erythematosus
  • Hemolytic-uremic syndrome
  • Thrombotic thrombocytopenic purpura (TTP)
  • Antiphospholipid syndrome
  • Disseminated intravascular coagulation (DIC)
  • Hereditary thrombocytopenias (eg, May Hegglin anomaly)
  • Thrombocytopenia secondary to drug exposure (eg, heparin, sulfonamides)
  • Other miscellaneous medical conditions that can cause thrombocytopenia (eg, leukemia, viral infection)

Gestational thrombocytopenia occurs in the last half of pregnancy and accounts for three quarters of all cases of thrombocytopenia in pregnancy. A platelet count of less than 50,000/µL makes this diagnosis very unlikely. These women typically do not have a history of ITP, except during previous pregnancies, which usually resolves 4-8 weeks after delivery. The neonates of these women are not thrombocytopenic.[21] ​

Neonatal alloimmune thrombocytopenia

Other problems to consider in the differential diagnosis include the following:

  • Sepsis
  • Congenital infections (eg, cytomegalovirus or HIV)
  • Stress (in premature newborns in the NICU)
  • Hypoxia secondary to perinatal asphyxia or aspiration
  • Congenital genetic syndrome
  • Congenital leukemia
  • Cyanotic congenital heart disease
  • Maternal preeclampsia (particularly in infant is growth restricted)
  • Maternal drug ingestion
  • Intracranial vascular abnormality

Differential Diagnoses

 

Workup

Laboratory Studies

No laboratory test can differentiate immune thrombocytopenic purpura (ITP) from other causes of maternal thrombocytopenia. Therefore, the diagnosis of ITP is based on a personal history of bleeding, a low platelet count prior to pregnancy, and/or a family history that excludes hereditary thrombocytopenia (HT).[4]  Platelet counts less than 70,000/µL are suspicious for the disorder if no other etiology for thrombocytopenia is identified.[22]

Bone marrow aspiration demonstrates normal or increased numbers of megakaryocytes. Guidelines from the American Society of Hematology state that a bone marrow examination is not required in adults younger than 60 years who have a classic presentation for ITP. However, the bone marrow should be assessed prior to proceeding with splenectomy.

Antiplatelet antibodies can be detected in the serum of women with ITP. The direct assay for the measurement of platelet-bound autoantibodies has an estimated sensitivity of 49-66% and an estimated specificity of 78-92%. A negative test does not exclude the diagnosis.[23] Additionally, many women with gestational thrombocytopenia have high levels of circulating platelet-associated immunoglobulin. Therefore, current antiplatelet antibody assays cannot be used to differentiate between ITP and gestational thrombocytopenia.

In newborns, a platelet count less than 150,000/µL is consistent with thrombocytopenia. Consider neonatal alloimmune thrombocytopenia (NAIT) in the differential diagnosis of any significantly thrombocytopenic newborn (platelet count <  50,000/µL) or in newborns with intracranial hemorrhages (platelet count <  100,000/µL) in whom other illnesses commonly associated with thrombocytopenia have been excluded, as follows[19] :

  • Platelet antigen typing can determine the genotype of the mother and father of the baby to determine if they are discordant.

  • Test the maternal sera for the presence of a platelet antibody that binds paternal, but not maternal, platelets.

  • A lack of antiplatelet antibody does not exclude the diagnosis of NAIT because, in a number of cases, no antiplatelet antibody could be detected when fetuses were profoundly thrombocytopenic due to NAIT.[9]

Other laboratory tests are as follows:

  • Complete blood cell count (CBC) with differential
  • Peripheral blood smear
  • Thyroid-stimulating hormone (TSH)
  • Prothrombin time/activated partial thromboplastin time (PT/aPTT)
  • Liver function tests
  • Hepatitis B and C and HIV serologies
  • Antinuclear antibody
  • Antiphospholipid antibodies
 

Treatment

Approach Considerations

Pregnant women with significant thrombocytopenia should deliver at a facility where blood products, including platelets, are available. Pregnant women at risk to deliver a newborn with severe thrombocytopenia should deliver at an institution capable of caring for the newborn. In general, a hospital with a level III neonatal intensive care unit (NICU) is necessary to provide an appropriate level of care.

Medical Care

In pregnancy, treatment for immune thrombocytopenic purpura (ITP) and neonatal alloimmune thrombocytopenia (NAIT) involves two patients: the mother and the fetus.

In cases of ITP, care of the mother centers on minimizing her risk of bleeding during pregnancy and childbirth. Check platelet counts regularly throughout gestation to verify that they are in an acceptable range. Conservatively, platelet counts should be checked monthly during pregnancy (platelet counts should be checked at least every trimester even in completely stable patients).

Spontaneous bleeding seldom occurs if the maternal platelet count is greater than 20,000/µL; therefore, treatment is not indicated in the absence of bleeding unless the platelet count falls below this level. Intraoperative or intrapartum bleeding complications are unusual if the platelet count is greater than 50,000/µL; therefore, administer treatment if the platelet count is less than that prior to delivery.[24] A history of ITP in a mother or ITP in a previous pregnancy is not a contraindication to future pregnancies.[25]

One trial evaluated the safety of breastfeeding in women with ITP and did not document thrombocytopenia developing in any breastfed infants.[19] IgG antiplatelet antibodies are transmitted through the breast milk, so consider monitoring the platelet counts in breastfed newborns of mothers with ITP.

The major neonatal concern in ITP is the risk of fetal or newborn intracranial or visceral hemorrhage due to severe thrombocytopenia. Newborn thrombocytopenia is difficult to predict because newborn platelet counts do not always correlate with maternal platelet counts[5] or antiplatelet antibody titers.[16]  The newborn platelet count does correlate with the platelet count of previous first and second siblings at birth.[26]

Maternal platelet counts that fall within the reference range after previous splenectomy or corticosteroid treatment do not guarantee a fetal platelet count within the reference range. In fact, splenectomy prior to pregnancy has been reported as a risk factor for the development of newborn thrombocytopenia.[27] Splenectomy possibly increases the amount of free antiplatelet antibody in the maternal sera due to the removal of the platelet/antibody destruction site.[28]

Fetal platelet counts can be obtained by fetal scalp sampling during labor or cordocentesis at 38-39 weeks' estimated gestational age; however, neither is reliable at predicting thrombocytopenia at birth. Fetal scalp sampling is technically difficult and often unreliable.[29] Owing to the risk of hemorrhage in the fetus and possible inaccuracy of the fetal platelet count, it is best avoided.[30] In a clinical trial, platelet counts were obtained by cordocentesis in 42 women with ITP. Two of the 42 newborns had severe thrombocytopenia at birth; neither case was detected with cordocentesis.[31] At present, no reliable method of determining which newborns are at risk for severe thrombocytopenia exists.

A platelet count at birth is recommended. Peripheral blood is preferred over heel sticks or cord samples because of better accuracy. A cranial ultrasound should be considered if the platelet count is less than 50,000/µL, even in the absence of symptoms. Intramuscular injections such as vitamin K are best avoided.[21]

Some investigators have recommended performing a cesarean delivery in all women with ITP to minimize the trauma to the newborn during the birth process. Cesarean delivery has not been demonstrated to prevent bleeding complications in thrombocytopenic newborns. In a review of 474 newborns born to mothers with ITP, 29% of newborns born vaginally experienced a bleeding complication, compared with 30% of newborns born via cesarean delivery.[32] Reviews published to date comparing vaginal birth with cesarean delivery in women with ITP are retrospective studies; none are randomized controlled trials. However, in the absence of any clear benefit to the neonate (given the low rate of intracranial hemorrhage in infants born to mothers with ITP), cesarean delivery should be reserved for the usual obstetrical indications.

In women with a history of delivering a significantly thrombocytopenic newborn (platelet < 50,000/µL) or a newborn with an intracranial hemorrhage (platelet count < 100,000/µL) in whom other illnesses commonly associated with thrombocytopenia have been excluded,[33] test for NAIT. Perform maternal platelet antigen typing and confirm the presence of maternal antiplatelet antibodies with specificity for paternal platelets. Perform antigen typing and zygosity testing on the father of the baby to determine if platelet antigen incompatibility between the parents exists and if all potential offspring will be at risk for NAIT. If the father is a heterozygote, each subsequent fetus has only a 50% chance of being affected. Fetal platelet typing can be performed on a chorionic villous sample, amniocytes, or fetal blood to determine if the fetus carries the significant paternally derived antigen.

Prospective screening programs have demonstrated that NAIT usually develops in babies born to women with detectable antiplatelet antibody.[11] Some investigators have suggested all pregnant women presenting for prenatal care be typed for platelet alloantigen to determine if they are at risk for NAIT. Women at risk can be tested for the presence of platelet alloantibodies twice during gestation (similar to current screening programs for Rh disease). A comparison of the effectiveness of this type of screening program estimated a cost of $45,000 per case of alloimmunization diagnosed in whites.[11] The cost would be higher if testing were initiated in women of other ethnic groups because the rate of NAIT is lower in nonwhite women. At present, universal prenatal screening is not recommended because a clear clinical benefit has not been demonstrated.[10, 34]

Surgical Care

Splenectomy is an appropriate treatment for women with ITP who have severe thrombocytopenia that is refractory to medical therapy. Approximately two thirds of patients have a positive response to splenectomy, generally within a few days. Splenectomy is seldom performed during pregnancy because most patients can be managed medically.

If splenectomy is indicated, it should be performed in the second trimester. Surgical interventions requiring general anesthesia are avoided in the first trimester if possible to prevent fetal medication exposure during embryogenesis. Splenectomy is technically difficult in the third trimester because the enlarging uterus limits exposure to the spleen. Successful splenectomy has been reported during cesarean delivery.[35]

Women with splenectomies should be immunized against pneumococcus, meningococcus, and Haemophilus influenzae.[10]

Consultations

Consulting a surgeon may be appropriate if splenectomy is indicated in a pregnant woman with ITP. A hematologist can be consulted if a patient with ITP or NAIT is not responding to standard therapies or requires transfusions.

Prevention

Some investigators have suggested that all pregnant women presenting for prenatal care be typed for platelet alloantigen to determine if they are at risk for NAIT. A comparison of the effectiveness of this type of screening program estimated a cost of $45,000 per case of alloimmunization diagnosed in whites. The cost would be higher if testing were initiated in women in other ethnic groups because the rate of NAIT is lower in nonwhite women. At present, universal prenatal screening is not recommended because a clear clinical benefit has not been demonstrated.

 

Guidelines

Guidelines Summary

The following organizations have issued guidelines for the management of immune thrombocytopenia (ITP) during pregnancy:

  • American College of Obstetricians and Gynecologists (ACOG)
  • American Society of Hematology (ASH)

In 2016, the American College of Obstetricians and Gynecologists (ACOG) published a practice bulletin on thrombocytopenia in pregnant women, which included the following key recommendations[36] :

  • Given the very low risk of serious neonatal hemorrhage, the mode of delivery in pregnancies complicated with ITP should be determined based upon obstetric considerations alone.
  • In pregnancies with high risk of intracranial hemorrhage (fetal platelet counts by umbilical cord blood sampling at 20 weeks of gestation of  < 20 x 10 9/L or a sibling with a perinatal intracranial hemorrhage), maternal intravenous immunoglobulin (IVIG) combined with prednisone is more effective than IVIG alone in eliciting a satisfactory fetal platelet response.
  • In pregnancies at standard risk (no history of intracranial hemorrhage in a previously affected sibling and initial fetal platelet counts > 20 x 10 9/L at 20 weeks of gestation), IVIG or prednisone therapy is beneficial, with no significant advantage of one therapy over another.
  • Epidural or spinal anesthesia is considered acceptable in patients with platelet counts ≥ 80 x 10 9/L, provided that the platelet level is stable, there is no other acquired or congenital coagulopathy, the platelet function is normal, and the patient is not on any antiplatelet or anticoagulant therapy.
  • Fetal–neonatal alloimmune thrombocytopenia should be suspected in cases of otherwise unexplained fetal or neonatal thrombocytopenia, hemorrhage, or ultrasonographic findings consistent with intracranial bleeding.

The American Society of Hematology (ASH) published an updated evidence-based practice guideline for ITP in 2011. The next update of the guideline is expected in 2019.[37] The guideline comprises recommendations (grade 1B) and suggestions (grade 2C). Recommendations and suggestions are provided separately for pediatric and adult patients. In 2013, ASH issued a clinical practice guide on the treatment of thrombocytopenia in pregnancy, based in part on the 2011 guideline.[38]

ASH recommends the following tests for diagnosis of thrombocytopenia in pregnant patients[38] :

  • Complete blood count
  • Reticulocyte count
  • Peripheral blood smear
  • Liver function tests
  • Viral screening (HIV, HCV, HBV)

Tests to consider if clinically indicated include the following[38] :

  • Antiphospholipid antibodies
  • Antinuclear antibody (ANA)
  • Thyroid function tests
  • H pylori testing
  • Disseminated intravascular coagulation testing—prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, fibrin split products
  • Von Willebrand disease type IIB testing*
  • Direct antiglobulin (Coombs) test
  • Quantitative immunoglobulin levels

The following studies are not recommended[38] :

  • Antiplatelet antibody testing
  • Bone marrow biopsy
  • Thrombopoeitin (TPO) levels

Treatment considerations include the following[38] :

  •  Women with no bleeding manifestations and platelet counts ≥30 x 10 9/L do not require any treatment until 36 weeks’ gestation (sooner if delivery is imminent)
  •  If platelet counts are < 30 x 10 9/L or clinically relevant bleeding is present, first-line therapy is oral corticosteroids or intravenous immunoglobulin (IVIg)
  • The recommended starting dose of IVIg is 1 g/kg
  • Prednisone and prednisolone are preferred to dexamethasone, which crosses the placenta more readily.
  • Recommended starting doses of prednisone by different experts vary from 0.25 to 0.5 to1 mg/kg daily; no evidence exists that a higher starting dose is better
  • Medications are adjusted to maintain a safe platelet count

Expected responses to first-line therapy are as follows[38] :

  • Oral corticosteroids—initial response 2-14 days, peak response 4-28 days
  • IVIg—initial response 1-3 days, peak response 2-7 days

Second-line therapy for refractory ITP is with combined corticosteroids and IVIg or, in the second trimester, splenectomy.  For third-line therapy, anti-D immunoglobulin and azathioprine are relatively contraindicated. Agents that are not recommended, but whose use in pregnancy has been described, include the following[38] :

  • Cyclosporine
  • Dapsone
  • Thrombopoietin receptor agonists
  • Campath-1H
  • Rituximab

Contraindicated agents include the following[38] :

  • Mycophenolate mofetil
  • Cyclophosphamide
  • Vinca alkaloids
  • Danazol

Management at the time of delivery

ASH recommendations are as follows[38] :

  • Because of the possible need for cesarean delivery, the recommended target platelet count prior to labor and delivery is ≥50 x 10 9/L
  • A woman whose platelet count is < 80 x 10 9/L but who has not required therapy during pregnancy can be started on oral prednisone (or prednisolone) 10 days prior to anticipated delivery at a dose of 10-20 mg daily and titrated as necessary
  • The mode of delivery should be determined by obstetric indications
  • Although the minimum platelet count for the placement of regional anesthesia is unknown and local practices may differ, many anesthesiologists will place a regional anesthetic if the platelet count is ≥80 x 10 9/L
  • While platelet transfusion alone is generally not effective in ITP, its use in conjunction with IVIg can be considered if an adequate platelet count has not been achieved and delivery is emergent
  • Percutaneous umbilical blood sampling (PUBS) or fetal scalp blood sampling is not recommended, as it is not helpful in predicting neonatal thrombocytopenia and is potentially harmful
  • In the newborn, the nadir platelet count reaches its nadir 2-5 days after delivery and rises spontaneously by day 7
  • Postpartum thromboprophylaxis should be considered, as women with ITP are at increased risk of venous thromboembolism
 

Medication

Medication Summary

Immune thrombocytopenic purpura (ITP)

Treatment for ITP in pregnancy is well established and effective.[39, 40, 41, 1] Medical therapy is initiated if the maternal platelet count decreases to less than 20,000/µL, if spontaneous bleeding occurs and the platelet count is less than 50,000/µL, or if surgery or delivery is anticipated and the platelet count is less than 50,000/µL.

Patients with ITP and platelet counts greater than 50,000/µL with active bleeding need to be evaluated for other causes of hemorrhage. If no other etiology of bleeding can be identified, then the patient with ITP and active bleeding should be treated medically for ITP until her platelet count increases to greater than 100,000/µL.

Prednisone (1-2 mg/kg/d) usually is first-line therapy in stable patients. An increase in platelet count usually is observed within 3-5 days, and maximal effect occurs in 2-3 weeks. The optimal duration of prednisone therapy is unknown. Steroids are not entirely benign during pregnancy and orofacial fetal abnormalities such as cleft palate occur 3-fold more commonly in infants exposed in the first trimester.[42] Maternal hyperglycemia and hypertension may also result.

Opinions vary concerning the minimal platelet count required for epidural anesthesia; however, many anesthesiologists are hesitant to utilize epidural anesthesia for labor with a patient whose platelet count is less than 100,000/µL. Thus, patients with platelet counts below this level often are treated with prednisone at 36-37 weeks' gestation.

Intravenous immunoglobulin (IVIG) can be used in women who do not respond to prednisone. Because patients respond more quickly to IVIG than prednisone (a response can be observed as quickly as 6 h), IVIG is a good choice for first-line therapy in women with platelet counts less than 10,000/µL or in association with perioperative or postpartum bleeding. IVIG (usual prescription 0.4 mg/kg/d for 3-5 d) is costly and of limited availability, thus it should be used judiciously.[43] A retrospective study of 67 neonates with thrombocytopenia born to mothers with ITP suggested benefit of starting IVIG when the platelet count is below 50 x 109/L, after the first platelet transfusion to avoid multiple transfusions.[44]

Intravenous anti-D (WinRho, WinRho SD) has been utilized in both children and adults to treat ITP. Children have a better response than adults; overall, approximately 70% of treated individuals respond to intravenous anti-D with increasing platelet counts.[45] Doses utilized have ranged from 25-200 mcg/kg/d. Some studies administered intravenous anti-D daily for 5 days, others administered a single dose. Toxicity was minimal, and infusions were completed in less than 5 minutes.[45, 46] Anti-D is effective in Rh-positive individuals only and may be associated with immune hemolysis.[47]

Experience with intravenous anti-D in pregnancy to treat ITP has been limited. This is likely because of concerns of possible fetal hemolysis from transplacental passage of the IgG molecules. Significant fetal hemolysis from maternal antepartum prophylaxis has not been reported[48] ; however, doses of intravenous anti-D used for prophylaxis to prevent Rh disease are much lower than those used to treat ITP. Thus, IVIG tends to be used more commonly in pregnancy.

Platelet transfusions should be used sparingly because maternal antiplatelet antibodies result in rapid destruction of transfused platelets.[49] Administer platelet transfusions to women with hemorrhage or platelet counts less than 10,000/µL. Generally, at time of delivery or just prior to cesarean delivery, 6-10 units of platelets are administered if the maternal platelet count is less than 50,000/µL to prevent intrapartum or postpartum bleeding.

The safety and efficacy of thrombopoietin mimetics is not established in pregnant women with ITP. In one case report, in which romiplostim was used during pregnancy in addition to steroids and IVIG, the newborns still experienced intraventricular hemorrhage, although there was no developmental delay at 10 months.[50]

Rituximab crosses the placenta, and data are insufficient to recommend use in ITP during pregnancy.[51]

Cyclophosphamide, mycophenolate, vincristine, and danazol are contraindicated during pregnancy.

Neonatal alloimmune thrombocytopenia

The goal of treatment in NAIT is to prevent intracranial or visceral bleeds in the fetus and newborn. Prenatal diagnosis and treatment is important because 25-50% of fetal intracranial hemorrhages occur while the fetus is in utero.[13] The only reliable method of determining the fetal platelet count is to perform cordocentesis and check the fetal blood directly because fetal platelet counts do not correlate with maternal antibody levels. Cordocentesis is associated with a 1-2% chance of emergent cesarean delivery for fetal indications.[10] Thus, a risk for fetal loss exists with each cordocentesis procedure performed.

Platelet membrane specific antigens are present in the fetus at 18 weeks' gestation; therefore, cordocentesis commonly is initiated in human platelet antigen–1b (HPA-1b) mothers with platelet alloantibodies at 20 weeks' gestation. Continued monitoring and treatment for NAIT is quite controversial. Controversy exists because NAIT is rare and only small numbers of successfully treated patients are reported in the literature.

European authors have advocated weekly platelet transfusions and have demonstrated that this therapy is effective in increasing the fetal platelet count.[52, 53, 54] Brussel et al have advocated a less invasive management and treatment plan, reporting on a total of 73 patients with NAIT.[55, 56] Mothers of fetuses determined to be thrombocytopenic at initial cordocentesis were treated with IVIG 1 g/kg/wk. A repeat cordocentesis was performed after 4-6 weeks to assess efficacy of treatment.

In their randomized controlled trial, some mothers were treated with IVIG, others with IVIG and dexamethasone.[56] The addition of dexamethasone did not enhance the effect of IVIG. At least 62% of patients responded to IVIG alone. Patients failing to respond either were delivered early or were continued on IVIG plus prednisone (60 mg/d). This salvage therapy was effective in 50% of cases that failed to respond to IVIG alone. None of the mothers treated according to this management plan had a fetus with an intracranial hemorrhage. These authors advocate administering platelet transfusions if the fetal platelet count is less than 20,000/µL at the time of cordocentesis because they noted an increased rate of fetal exsanguination secondary to cordocentesis when the platelet count was in this range.

Other authors have advocated using IVIG as a primary treatment, particularly in patients who are at risk for NAIT and have no history of a previous child affected with intracranial hemorrhage.[57] Fetuses that fail to respond to IVIG receive weekly platelet transfusions for the duration of the pregnancy.[22]

Results of a meta-analysis of 26 studies found comparable outcomes regarding the occurrence of intracranial hemorrhage, regardless of the antenatal management strategy: serial fetal blood sampling (FBS), intrauterine platelet transfusions (IUPT), or weekly IVIG, with or without corticosteroids. There was no consistent evidence for benefit for the addition of steroids to IVIG.[58]

The fetus should be delivered as soon as fetal lung maturity is documented, to minimize the risk of hemorrhage in utero. Usually, if the fetal platelet count is less than 50,000/µL, a cesarean delivery is performed, although no clear evidence in the literature supports this.

Management of the newborn with NAIT is fairly straightforward. Because of the significant risk of intracranial hemorrhage, an immediate cranial ultrasound should be performed. Severely thrombocytopenic newborns (< 10,000/µL) or newborns with intracranial or visceral hemorrhages should receive a matched platelet transfusion (maternal or homozygous HPA-1b donor) as soon as possible. If maternal platelets are utilized, they must be processed to remove platelet alloantibodies. Reserve random platelets for life-threatening hemorrhage when matched platelets are not immediately available because reports exist of worsening thrombocytopenia and disseminated intravascular coagulation (DIC) following random platelet transfusion in cases of NAIT.[9]

IVIG (1 g/kg/d) has been demonstrated to increase newborn platelet counts in most cases of NAIT. A substantial increase is observed in 24-72 hours, which is adequate for newborns who are stable and without evidence of bleeding.

Exchange transfusions can be performed to remove antiplatelet antibody and shorten the course of neonatal disease.[9] Approximately 30% of available immunoglobulin G antiplatelet antibodies are estimated to be removed per double volume procedure.

In a retrospective study, Giers et al concluded that in the treatment of fetal alloimmune thrombocytopenia, there was equal clinical effectiveness in the intrauterine transfusion of either maternal platelets or HPA-matched donor platelets.[59] No procedure-related fetal or neonatal loss resulted from the use of either maternal (15 fetuses) or donor (42 fetuses) platelets, and both types of treatment reliably increased fetal platelet counts.

Glucocorticoids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone (Sterapred)

Inhibits phagocytosis of antibody-covered platelets. Used to increase platelet count.

Blood products

Class Summary

Used to increase platelet count.

Intravenous immune globulin (Gammagard S/D, Gammar-P, Gamunex, Carimune, Polygam S/D)

Has rapid onset of action and is DOC (used in conjunction with platelet transfusion) when severe thrombocytopenia or life-threatening hemorrhage occurs.