Neonatal immune-mediated thrombocytopenia

INTRODUCTION — Immune-mediated processes are among the most common causes of thrombocytopenia in neonates. Autoantibodies, drug-dependent antibodies, or maternal antibodies mediate platelet destruction through interaction with platelet membrane antigens or by forming immune complexes, which can bind to reticuloendothelial cell Fc receptors leading to platelet clearance from the circulation.

The various forms of immune-mediated thrombocytopenia will be discussed here. An overview of the causes, evaluation, and general management of neonatal thrombocytopenia are discussed separately. (See "Neonatal thrombocytopenia: Etiology" and "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management".)

DEFINITIONS — Neonatal thrombocytopenia is defined as a platelet count <150,000/microL. Severity of thrombocytopenia is defined by the following:

●Mild – Platelet count 100,000 to 150,000/microL.

●Moderate – Platelet count 50,000 to 99,000/microL.

●Severe – Platelet count <50,000/microL. Severe thrombocytopenia is associated with an increased risk of bleeding resulting in morbidity or death.

NEONATAL ALLOIMMUNE THROMBOCYTOPENIA — Neonatal alloimmune thrombocytopenia (NAIT), also referred to as fetal and neonatal alloimmune thrombocytopenia (FNAIT), is caused by maternal antibodies directed towards fetal and neonatal platelets.

Pathogenesis — NAIT occurs when fetal platelets contain an antigen inherited from the father (most commonly human platelet antigen [HPA]-1a) that the mother lacks. The mother forms immunoglobulin G (IgG) class antiplatelet antibodies against the "foreign" antigen, which cross the placenta and destroy fetal and neonatal platelets that express the paternal antigen. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Pathogenesis' and "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Commonly involved platelet antigens'.)

Incidence — The incidence of NAIT has been estimated at 1 in 1000 to 10,000 births [1-3]. A 2014 systematic review of prospective studies reported that the incidence of severe thrombocytopenia (platelet count <50,000/microL) was 0.15 percent in the general newborn population, and NAIT was diagnosed in one-quarter of these patients [4]. In this analysis, a quarter of the infants with NAIT had evidence of intracranial hemorrhage.

Risk factors affecting the severity of neonatal thrombocytopenia for infants with NAIT include (see "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Factors affecting severity of thrombocytopenia'):

●Later pregnancy compared with first pregnancy

●High and rising maternal HPA-1a antibody level

●Fetal/neonatal intracranial hemorrhage in previous pregnancy

●HPA-1a is the antigen associated with the most severe disease

Clinical features

Maternal history — The mother of a newborn with NAIT is asymptomatic, although she or a sister may have a history of previously affected pregnancies. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Clinical presentation'.)

Neonatal findings — Clinical findings in affected newborns, who otherwise look well, are dependent on the severity of thrombocytopenia. In neonates with moderate (platelet count 50,000 to 99,000/microL) to severe (platelet count <50,000/microL) thrombocytopenia, petechiae, bruising, and bleeding may be observed. The most serious complication is intracranial hemorrhage.

In a case series of 123 live-born infants with NAIT, the relative frequency of bleeding symptoms were as follows [5]:

●No bleeding − 34 percent

●Cutaneous bleeding only − 47 percent

●Intracranial hemorrhage − 14 percent

●Other major organ bleeding (gastrointestinal, lung, retina) − 2 percent

Intracranial hemorrhage — The most serious complication of NAIT is intracranial hemorrhage. Reported rates of intracranial hemorrhage among neonates with NAIT range from 10 to 25 percent; approximately 25 to 50 percent of these occur in utero [2,4,6]. Risk factors for intracranial hemorrhage in this setting include [4,7]:

●Severity of thrombocytopenia (the risk is highest for those with platelet count <50,000/microL)

●Multigravida (ie, infants born to mothers with prior pregnancies)

●Having an affected older sibling with intracranial hemorrhage

Platelet count — At birth, neonatal platelet counts are usually <100,000/microL. The platelet count typically falls in the first few days after birth, then rises over the next one to four weeks as the antibody level declines [8].

Diagnosis

When to suspect NAIT — The diagnosis should be considered in any otherwise well-appearing term infant who presents with unexplained thrombocytopenia in the first 24 to 48 hours of life or if there is evidence of fetal intracranial hemorrhage. NAIT also needs to be considered in ill-appearing infants, especially if severe thrombocytopenia is present, the thrombocytopenia appears to be out of proportion to the clinical illness, or persists when the clinical illness improves. In a case series of 220 thrombocytopenic neonates, one-third of 110 cases that were diagnosed as NAIT occurred in infants who were clinically ill and in whom other causes were first being entertained [6].

Laboratory confirmation — The diagnosis of NAIT is made by serologic testing that demonstrates the presence of a maternal antibody that binds to paternal, but not maternal, platelets and is directed against a specific human platelet antigen incompatible between the mother and father (algorithm 1). Antigen typing of the mother's and father's platelets is performed, and the mother's serum is tested for antiplatelet alloantibodies, and if present, the diagnosis of NAIT is confirmed. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Screening' and "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Evaluation of couples at risk for FNAIT'.)

Additional testing: Cranial ultrasound — Because of the high rate of intracranial hemorrhage in newborns with NAIT, a cranial ultrasound examination should be performed in any affected infant with a platelet count <50,000/microL [8,9]. The imaging should be obtained as soon as possible after delivery (ideally within the first 24 hours). If an intracranial hemorrhage is present, early postnatal imaging can help determine whether bleeding occurred in utero or postnatally. Evidence of fetal intracranial hemorrhage is a criterion for suspected NAIT. The presence of intracranial hemorrhage has significant implications for the management of the subsequent pregnancy as it increases the risk of bleeding in future offspring. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Diagnostic criteria' and "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Management of other clinical scenarios'.)

Management

Platelet count monitoring — During the first days of life, the platelet count is closely monitored in anticipation of the expected decline. In our practice, if immune-mediated thrombocytopenia is suspected or anticipated, platelet counts are obtained at a minimum daily and more frequently (every six to eight hours) if there are clinical concerns for bleeding or the platelet count is <50,000/microL. Once a trend showing an increase in platelet count is observed, the interval between testing is increased until the count is stable. The infant may be discharged, with appropriate outpatient follow-up, if the infant is asymptomatic once the platelet counts are stable, not decreasing, and above 30,000/microL.

Platelet transfusion

Indications — Decisions regarding platelet transfusions are based largely on clinical experience, as high-quality data are lacking to guide these decisions. In our practice, we use the following thresholds for platelet transfusion in infants with NAIT (algorithm 2):

●Otherwise healthy term infants ‒ For term infants with NAIT who are not acutely ill and have no active bleeding or risk factors for hemorrhage (eg, traumatic delivery), we suggest platelet transfusion if the platelet count is <30,000/microL [10-14].

●Intracranial hemorrhage and other major bleeding ‒ Major bleeding is defined as intracranial hemorrhage, pulmonary hemorrhage, frank rectal bleeding, or life-threatening bleeding requiring emergency fluid therapy or red blood cell transfusion. For infants with NAIT who have major bleeding, we suggest platelet transfusion if the platelet count is <100,000/microL [15,16].

●Ill-appearing infants ‒ For infants who are ill-appearing or clinically unstable (eg, poor perfusion, lethargy, respiratory distress, and/or apnea), we suggest platelet transfusion if the platelet count is <50,000/microL since these infants are at increased risk of major bleeding, particularly intracranial hemorrhage [15].

As discussed below, we typically administer intravenous immune globulin (IVIG) immediately following platelet transfusion in patients with NAIT, although data supporting this practice are limited. (See 'Other interventions' below.)

Platelet counts should be maintained above these thresholds during the first 72 to 96 hours because the risk of intracranial hemorrhage is highest during this period. In general, we maintain a platelet threshold >30,000/microL (or higher as noted above if there is evidence of intracranial bleeding, other major bleeding, or additional risk factors) until there is evidence that the platelet count is beginning to rise. After the infant has reached 96 hours of age, the decision to transfuse platelets depends upon clinical circumstances.

Additional details regarding platelet transfusion thresholds in neonates are provided separately. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)

Procedure — In infants with NAIT who require urgent platelet transfusion (eg, those with active hemorrhage), random donor platelets should be used initially as this is an effect way to acutely increase the platelet count [11,17]. However, the transfused platelets will not survive very long due to the presence of maternally derived antiplatelet antibodies.

In the meantime, arrangements can be made to acquire maternal platelets for future transfusions, which are preferred because they will not react with the maternally derived antiplatelet antibodies. The use of concentrated maternal platelets (reduces the amount of serum that contains antiplatelet antibodies) may delay the transfusion process, as it may take up to 12 to 24 hours to collect and properly process the cells. Concentrating platelets is preferred to washing platelets, as washing damages the donor platelets [18]. The platelets should be irradiated to avoid graft-versus-host disease.

Alternatively, donor platelets that are typed and matched to the mother's cells in order to exclude the offending platelet antigen can be used. However, it is unlikely that matched platelets will be available in an emergency setting, unless the infant has a sibling who had NAIT and this was anticipated. If ABO-incompatible platelets need to be transfused, the plasma component should be reduced to avoid potential hemolysis.

Another option includes administration of "universal" platelet concentrates that are HPA-1a-negative/HPA-5b-negative [5]. However, these are expensive interventions and are not generally available off-the-shelf (except in the United Kingdom and a few other countries [15]).

Other interventions

●Intravenous immune globulin (IVIG) – In our practice, we administer high-dose IVIG (400 mg/kg per day for three to four days or 1 gm/kg per day for one to three days) to patients with NAIT immediately following platelet transfusion. It is thought that IVIG may prolong survival of transfused platelets in this setting; however, there are limited data to support this practice [14,19,20]. In a systematic review of 14 observational studies that included 754 neonates with NAIT, IVIG was used in 33 percent of those who received platelet transfusions and in 8 percent of those managed without platelet transfusions [20]. The studies were not able to determine if IVIG had any benefit in these patients. (See "Overview of intravenous immune globulin (IVIG) therapy".)

●Glucocorticoid therapy – We do not routinely use glucocorticoids in the management of NAIT except in rare instances of life-threatening thrombocytopenia that persists despite platelet transfusions and IVIG. In this setting, intravenous methylprednisolone is given at a dose of 1 mg/kg per day in three divided doses for one to three days [21]. There are limited data to support this practice [14,19,20]. In a systematic review of 14 observational studies that included 754 neonates with NAIT, glucocorticoids were used in only 6 percent of patients [20]. The studies were not able to determine if glucocorticoids had any benefit in these patients.

Management of subsequent pregnancy — In families with an affected fetus/infant, there is a risk of recurrence depending on the zygosity of the father. If the father is homozygous, the risk is 100 percent for the subsequent pregnancies; if heterozygous, only 50 percent. In the latter instance, fetal genotyping (at 18 to 20 weeks gestation) or chorionic villus sampling (at 8 to 10 weeks) can be done to determine the risk for the fetus. Thrombocytopenia in the second affected child is always as or more severe than in the previous infant. As noted above, in our center, the threshold for platelet transfusion is higher for infants with a previous sibling with NAIT and ICH [15]. Prenatal management for subsequent pregnancies is discussed separately. (See 'Indications' above and "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management", section on 'Severity-based treatment approach'.)

NEONATAL AUTOIMMUNE THROMBOCYTOPENIA — Neonatal autoimmune thrombocytopenia is mediated by maternal autoantibodies that react with both maternal and fetal platelets. This occurs in maternal autoimmune disorders, including immune thrombocytopenia and systemic lupus erythematosus (SLE).

Clinical features — Most affected infants appear healthy since the degree of thrombocytopenia is typically mild (platelet count 100,000 to 150,000/microL) [22]. However, approximately 10 to 25 percent of affected infants develop severe thrombocytopenia (platelet count of <50,000/microL) [22,23].

When bleeding symptoms are present, they are typically mild (eg, petechiae) [22,24]. Uncommonly, infants with severe thrombocytopenia may have signs of mucosal bleeding (eg, pulmonary hemorrhage, gross hematuria, gastrointestinal bleeding).

Intracranial hemorrhage is rare. In a meta-analysis of 14 observational studies involving 887 pregnancies complicated by maternal ITP, there were 5 reported cases (0.6 percent) of neonatal intracranial hemorrhage [23]. The platelet count was <10,000/microL in four of the five cases.

Platelet counts of infants born to mothers with ITP often decrease sharply during the several days after birth [24,25]. The nadir typically occurs between two and five days after birth [8,22,23].

Persistent neonatal thrombocytopenia beyond four months was observed in breastfed infants of mothers with ITP [26]. Thrombocytopenia appears to be due to the transfer of antiplatelet antibodies of the immunoglobulin A (IgA) type in the milk of affected mothers and resolved when breastfeeding was discontinued.

Risk factors — The following are risk factors that impact on the severity of neonatal autoimmune thrombocytopenia:

●Maternal splenectomy

●The mother's platelet count has been less than 50,000/microL at some time during the pregnancy [22,25,27]

●An older sibling has had neonatal thrombocytopenia [22,27]

Diagnosis — The diagnosis of neonatal autoimmune thrombocytopenia usually is apparent from the mother's medical history and the presence of maternal thrombocytopenia. However, the platelet count of affected mothers may be normal after a splenectomy or if there is sufficient compensatory thrombopoiesis. Mothers of infants with unexplained neonatal thrombocytopenia should be investigated for the presence of an autoimmune disorder because neonatal thrombocytopenia can be the presenting sign [28]. (See "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)

Antenatal management — The maternal management of ITP during pregnancy is discussed separately. (See "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)

Postnatal management

Monitoring — During the first days of life, the platelet count needs to be closely monitored in anticipation of the expected decline. In our practice, platelet counts are obtained at a minimum daily and more frequently if there are clinical concerns for bleeding or the counts are below 50,000/microL. Once a trend showing an increase in platelet count is observed, the interval between testing is increased. The infant may be discharged, with appropriate outpatient follow-up, if the infant is asymptomatic once the platelet counts are stable, not decreasing, and above 30,000/microL.

Interventions — Postnatal management depends upon the severity of thrombocytopenia and the infant's clinical status and risk of bleeding. Most affected patients do not require any intervention since the degree of thrombocytopenia is typically mild.

●Platelet transfusions are given to infants with clinically significant bleeding (ie, intracranial hemorrhage, pulmonary hemorrhage, gross hematuria, gastrointestinal bleeding) and/or platelet count <20,000/microL. Clinicians should be aware that platelet transfusions may be less effective in this setting than in infants with thrombocytopenia from other causes because the autoantibodies usually will react with all donor platelets, including those of the mother. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)

●Intravenous immune globulin (IVIG) is suggested for infants with clinically significant bleeding and/or with platelet count <20,000/microL. IVIG is given at a dose of 1 g/kg and can be repeated if necessary. This typically produces a rapid response [29]. Neonatal thrombocytopenia secondary to maternal ITP may last for weeks to months. Occasionally, repeat treatment of the infant is required at four to six weeks after birth [29].

●Glucocorticoid therapy is an option for the rare instances of severe thrombocytopenia that is refractory to IVIG therapy. Data supporting this approach are limited. A small case series reported that infants who were refractory to IVIG responded to a short course of methylprednisolone (1 mg/kg twice a day by mouth for five days) [19]. A short course of prednisone (2 mg/kg per day) has also been used in this setting [22].

DRUG-INDUCED IMMUNE THROMBOCYTOPENIA — Drug-induced immune thrombocytopenia is typically caused by platelet destruction from maternal drug-dependent antibodies and, rarely, by neonatal antibodies. Bone marrow suppression also can result in thrombocytopenia due to decreased platelet production. (See "Drug-induced immune thrombocytopenia".)

Pathogenesis — Neonatal drug-induced immune thrombocytopenia is usually caused by maternal drug-dependent antibodies formed after drug exposure to the mother during pregnancy. Maternal antibodies can cross the placenta and affect fetal and neonatal platelets. This mechanism is similar to that seen in mothers with primary immune thrombocytopenia. Drugs associated with maternal drug-mediated platelet destruction include quinidine and antiepileptic agents (eg, carbamazepine, phenytoin, and valproic acid) [30]. (See "Thrombocytopenia in pregnancy", section on 'Other causes of thrombocytopenia'.)

Rarely, platelet destruction can be caused by neonatal drug-dependent antibodies, such as seen in heparin-induced thrombocytopenia. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

Diagnosis — The diagnosis of drug-induced thrombocytopenia is a clinical diagnosis made by excluding other causes and documenting resolution of thrombocytopenia after the drug is discontinued. Although testing for drug-dependent antibodies can be helpful when the diagnosis is unclear, this testing generally is not performed for diagnosis when the suspected drug has a well-established role in causing drug-induced immune thrombocytopenia. In addition, laboratory testing for drug-dependent antiplatelet antibodies takes several days and is not routinely available in hospital laboratories. (See "Drug-induced immune thrombocytopenia", section on 'Diagnosis'.)

Management — If drug-associated thrombocytopenia is suspected, the offending agent should be withdrawn. Transfusions should be given for low platelet counts (<20,000/microL) or major bleeding. Intravenous immune globulin (IVIG) can be used after platelet transfusion similar to the approach used to treat infants with neonatal alloimmune thrombocytopenia. (See 'Other interventions' above.)

SUMMARY AND RECOMMENDATIONS

●Introduction – Immune-mediated processes are among the most common causes of thrombocytopenia in neonates. Autoantibodies, drug-dependent antibodies, or maternal antibodies mediate platelet destruction through interaction with platelet membrane antigens or by forming immune complexes, which can bind to reticuloendothelial cell Fc receptors leading to platelet clearance from the circulation. (See 'Introduction' above.)

●Neonatal alloimmune thrombocytopenia – Neonatal alloimmune thrombocytopenia (NAIT), also referred to as fetal and neonatal alloimmune thrombocytopenia (FNAIT), is due to maternal antibodies directed towards an antigen inherited from the father that is expressed on fetal and neonatal platelets. (See 'Neonatal alloimmune thrombocytopenia' above.)

•Clinical findings ‒ Clinical findings for the neonate are dependent on the severity of the thrombocytopenia and may range from no symptoms to serious bleeding including intracranial hemorrhage, whereas the mother is asymptomatic. (See 'Clinical features' above.)

•Diagnosis ‒ The clinical diagnosis of NAIT should be considered in term infants who present with unexplained thrombocytopenia in the first 24 to 48 hours of life or if there is evidence of fetal intracranial hemorrhage without another explanation. The diagnosis is confirmed by serologic testing that demonstrates the presence of a maternal antibody directed against a specific human platelet antigen for which there is parental incompatibility (algorithm 1). (See 'Diagnosis' above.)

•Management – Our suggested approach to managing patients with NAIT is as follows (algorithm 2):

-Monitoring – During the first days after birth, the platelet count is monitored at least once daily in anticipation of the expected decline. (See 'Platelet count monitoring' above.)

-Platelet transfusions – Patients with NAIT who experience major bleeding (intracranial hemorrhage, pulmonary hemorrhage, frank rectal bleeding, or other life-threatening bleeding) in the setting of platelet count <100,000/microL require urgent platelet transfusion. In addition, we suggest platelet transfusion for clinically unstable neonates (eg, poor perfusion, lethargy, respiratory distress, and/or apnea) if the platelet count <50,000/microL (Grade 2C). For term infants with NAIT who are not acutely ill and have no active bleeding, we suggest platelet transfusion if the platelet count is <30,000/microL (Grade 2C). (See 'Platelet transfusion' above.)

-Intravenous immune globulin (IVIG) – For patients receiving platelet transfusion, we suggest administration of IVIG after the transfusion (Grade 2C). It is thought that IVIG may prolong survival of transfused platelets in this setting. (See 'Other interventions' above.)

●Neonatal autoimmune thrombocytopenia – Neonatal autoimmune thrombocytopenia is mediated by maternal autoantibodies that react with both maternal and fetal platelets. This occurs in maternal autoimmune disorders, including immune thrombocytopenia and systemic lupus erythematosus (SLE). (See 'Neonatal autoimmune thrombocytopenia' above.)

•Clinical features ‒ Most affected infants appear healthy since the degree of thrombocytopenia is usually mild (platelet count 100,000 to 150,000/microL). Patients with severe thrombocytopenia may have bleeding symptoms such as petechiae, purpura, melena, or hematuria. The risk of intracranial hemorrhage is lower than for NAIT. (See 'Clinical features' above.)

•Diagnosis ‒ The diagnosis usually is apparent from the mother's medical history and the presence of maternal thrombocytopenia. (See 'Diagnosis' above and "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)

•Management ‒ Most affected patients do not require any treatment since the degree of thrombocytopenia is typically mild. Platelet transfusion may be required for patients with severe thrombocytopenia and clinically significant bleeding. We also suggest platelet transfusion if the platelet count <20,000/microL, even in the absence of bleeding (Grade 2C). In addition, we suggest IVIG for any patient with clinically significant bleeding and/or platelet count <20,000/microL (Grade 2C). (See 'Postnatal management' above.)

●Drug-induced immune thrombocytopenia – In neonates, drug-induced immune thrombocytopenia is typically caused by platelet destruction from maternal drug-dependent antibodies, and rarely by neonatal antibodies. If drug-associated thrombocytopenia is suspected, the offending agent should be withdrawn. Otherwise, management is similar to that of infants with neonatal autoimmune thrombocytopenia. (See 'Drug-induced immune thrombocytopenia' above.)