Immune Thrombocytopenia and Pregnancy Treatment & Management

Women who have been diagnosed with immune thrombocytopenia (ITP) prior to pregnancy should be offered preconception counseling. For the counseling session, it is necessary to obtain details of her case, including the presentation of ITP, prior medical treatment, whether splenectomy was performed, and response to treatment. In addition, an obstetric history should be obtained; in women who have previously given birth, this should include the neonatal platelet count.

The patient should be educated about the need for additional blood tests and followup during pregnancy and the potential need to consider treatment for ITP, which is the case in one-third of pregnant women with ITP. The small risk of maternal and fetal complications should be discussed. However, most of these women can safely proceed with pregnancy, as the risk of complications is low if they receive appropriate care, so they should not be discouraged from pregnancy. ^[30]  A history of ITP in a mother or ITP in a previous pregnancy is not a contraindication to future pregnancies. ^[31]

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.

Immune thrombocytopenia

Treatment for ITP in pregnancy is well established and effective. ^{[32, 33, 34, 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, the patient should be treated medically for ITP until her platelet count increases to greater than 100,000/µL.

When therapy is indicated, most hematologists use a glucocorticoid as initial therapy. High-dose dexamethasone, 40 mg daily for 4 days without taper, or prednisone 1- 2 mg/kg/day are both effective. A meta-analysis showed better overall response with high-dose dexamethasone compared with prednisone (79% versus 59%) and better complete response (64% versus 36%) at 2 weeks and fewer bleeding events (12% versus 24%) at 10 days, as well as fewer adverse effects. However, there was no difference in overall response or complete response at 6 months. These researchers concluded that high-dose dexamethasone might be preferable to prednisone for patients with severe ITP who require a rapid rise in platelet count. ^[35]

 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. ^[36]  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, so it should be used judiciously. ^[37]  A retrospective study of 67 neonates with thrombocytopenia born to mothers with ITP suggested a benefit of starting IVIG when the platelet count is below 50 × 10⁹/L after the first platelet transfusion, to avoid multiple transfusions. ^[38]

Intravenous (IV) 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 IV anti-D with increasing platelet counts. ^[39]  Doses utilized have ranged from 25-200 mcg/kg/d. In some studies, IV anti-D was administered daily for 5 days; in others, it was given as a single dose. Toxicity was minimal, and infusions were completed in less than 5 minutes. ^{[39, 40]}  Anti-D is effective in Rh-positive individuals only and may be associated with immune hemolysis. ^[41]

Experience with IV 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 ^[42] ; however, doses of IV 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.

Timing of response with the various agents is as follows ^[43] :

• IVIG: 1-3 days for initial reponse and 2-7 days for peak response
• Dexamethasone:  2-14 days for initial response and 4-28 days for peak response
• Prednisone: -  4 -14 days for initial response and 7-28 days for peak response

Platelet transfusions should be used sparingly because maternal antiplatelet antibodies result in rapid destruction of transfused platelets. ^[44]  Administer platelet transfusions to women with hemorrhage or platelet counts less than 10,000/µL. 

The platelet count threshold for a non-bleeding pregnant woman nearing delivery or a procedure depends on the expected mode of delivery or type of procedure. In the absence of bleeding, transfuse to a platelet counts of 30,000/µL for vaginal delivery and transfuse to 50,000/µL if plan for cesarean delivery.

The safety and efficacy of thrombopoietin mimetics are 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. ^[45]

Thrombopoietin-receptor agonists are not approved by the US Food and Drug Administration or the European Medicines Agency for use in pregnancy. However, published case reports have reported on the efficacy of thrombopoietin-receptor agonists given in the third trimester to increase platelet counts before delivery. ^[18]  

Rituximab crosses the placenta, and data are insufficient to recommend use in ITP during pregnancy. ^{[46, 47]}

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

Neonatal alloimmune thrombocytopenia (NAIT)

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 NAIT-related intracranial hemorrhages occur while the fetus is in utero. ^[16]  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. ^[13]  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 mothers with human platelet antigen–1b (HPA-1b) 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. ^{[48, 49, 50]}  Brussel et al have advocated a less invasive management and treatment plan, reporting on a total of 73 patients with NAIT. ^{[51, 52]}  Mothers of fetuses found 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. ^[52]  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. ^[53]  Fetuses that fail to respond to IVIG receive weekly platelet transfusions for the duration of the pregnancy. ^[28]

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. ^[54]

In a retrospective study, Giers et al concluded that in the treatment of fetal NAIT, the intrauterine transfusion of either maternal platelets or HPA-matched donor platelets had equal clinical efficacy. ^[55]  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.

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. ^[12]

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. ^[12]  Approximately 30% of available immunoglobulin G antiplatelet antibodies are estimated to be removed per double volume procedure.

Management of maternal ITP

Clinical management of pregnancy-associated ITP is a complex task requiring close collaboration by the obstetrician, hematologist, and anesthetist. Pregnant women with ITP should be seen monthly in the first and second trimester, every 2 weeks after 28 weeks, and weekly after 36 weeks. Visits should involve routine obstetric care with emphasis on blood pressure, urine dipstick analysis for protein, weight, and serial platelet counts. ^[56]  However, the need for additional care will vary depending on the patient's platelet count and clinical condition.

The goal is to treat when required to maintain an adequate platelet count to avoid maternal hemorrhagic complications in the antenatal, intrapartum, and postnatal period. The current International Consensus Report considers that in the absence of symptoms or any planned intervention, a platelet count of 20 - 30 × 10⁹/L is safe during most of pregnancy and patients can often be managed by observation only. ^[57]

Preparation for delivery

At week 34 to 36, there should be a review of whether or not treatment needs to be commenced to minimize the risk of hemorrhage around the time of delivery. The review should take into account individual clinical features, obstetric factors, the trend in platelet count, and the patient's personal wishes. Considerations include the following:

• If the patient is asymptomatic and platelet counts are stable and greater than 50 ×10 ⁹/L, no treatment is generally required.
• If the platelet counts are less than 50 × 10 ⁹/L, treatment should be considered.
• If the platelet count is between 50 and 70 × 10 ⁹/L, treatment should be considered if neuraxial anesthesia is desired for delivery or cesarean delivery is planned because of an obstetric indication.

The platelet threshold deemed safe for administering spinal or epidural anesthesia remains controversial due to the theoretical risk of epidural hematoma formation and neurological damage. There is a paucity of data for a specific platelet count predictive of neuraxial anesthetic complication. A systematic review of neuraxial techniques for anesthesia included 14 papers reporting 326 neuraxial techniques in 325 patients diagnosed with ITP. All but one were obstetric patients, of which nine had a platelet count < 50 × 10⁹/L  and 19 had a platelet count of 50 - 70 × 10⁹/L. There were no hemorrhagic complications associated with neuraxial techniques.

Archived British Committee for Standards in Haematology (BCSH)  ITP guidance from 2003 recommended a  platelet count of > 80 ×10⁹/L if epidural anesthesia is to be used for cesarean delivery. ^[58] The 2019 International Consensus Report suggests that regional axial anesthesia can be safely performed/L at a platelet count ≥70 × 10⁹/L, if no other hemostatic abnormalities are present. ^[57] This assumes the absence of bruising, bleeding, and history of anticoagulation and the presence of a normal international normalized ratio, activated partial thromboplastin time, and fibrinogen level.

In these cases, an anesthetist should counsel the patient regarding the risk and benefit of regional anesthesia versus general anesthesia.  

In addition to the known prothrombotic state of pregnancy, some women may have risk factors (eg, anti-cardiolipin antibody syndrome) requiring venous thromboembolism prophylaxis. A platelet count > 50 × 10⁹/L is generally recommended for such patients receiving anticoagulation. ^[57]

Management of neonate born to women with ITP

One trial evaluated the safety of breastfeeding in women with ITP and did not document thrombocytopenia developing in any breastfed infants. ^[25] 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 or antiplatelet antibody titers. ^{[8, 21]}  The newborn platelet count does correlate with the platelet count of previous first and second siblings at birth. ^[59]

Maternal platelet counts that fall within the reference range after pre-pregnancy 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. ^[60] Splenectomy possibly increases the amount of free antiplatelet antibody in the maternal sera due to the removal of the platelet/antibody destruction site. ^[61]

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. ^[62] Owing to the risk of hemorrhage in the fetus and possible inaccuracy of the fetal platelet count, it is best avoided. ^[63] 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. ^[64] At present, no reliable method of determining which newborns are at risk for severe thrombocytopenia exists.

Procedures during labor that may be associated with increased hemorrhagic risk to the fetus should be avoided, specifically the use of fetal scalp electrodes, fetal scalp blood sampling, vacuum extraction, and rotational forceps ^[57]

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. ^[27]

Some investigators have recommended performing a cesarean delivery in all women with ITP to minimize the trauma to the newborn during the birth process. However, 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. ^[65] Reviews published to date comparing vaginal birth with cesarean delivery in women with ITP are retrospective studies; none are randomized controlled trials. 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 obstetric indications.

In women with a history of delivering a significantly thrombocytopenic newborn (platelet count < 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, ^[66] test for neonatal alloimmune thrombocytopenia (NAIT), also referred to as fetal and neonatal alloimmune thrombocytopenia (FNAIT). 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. ^[14] 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. 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. ^[14] 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. ^{[13, 67]}

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. ^[68]

Women with splenectomies should be immunized against pneumococcus, meningococcus, and Haemophilus influenzae. ^[13]

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