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, clinical presentations and their relative frequency included the following [5]:
●Skin bleeding only − 47 percent
●No bleeding − 34 percent
●Intracranial hemorrhage − 14 percent
●Other major organ bleeding (gastrointestinal, lung, retina) − 2 percent
Intracranial hemorrhage — The most serious complication is intracranial hemorrhage. The risk of intracranial hemorrhage increases with the severity of thrombocytopenia, for infants born to multiparous women, and especially for infants who have had an older affected sibling with intracranial hemorrhage [4,6]. The reported risk ranges from 10 to 25 percent of newborns with NAIT, and one-quarter to one-half of these incidences take place in utero [2,4]. The risk of intracranial hemorrhage is greater in alloimmune than in autoimmune thrombocytopenia [7]. The risk is greater in NAIT with infants born of multigravidas compared with primigravidas [6].
Platelet count — At birth, neonatal platelet counts often are less than 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 [7].
Diagnostic imaging — Because of the high rate of intracranial hemorrhage, 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 within the first 24 hours to attempt to determine whether bleeding (if present) occurred pre- 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'.)
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'.)
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 counts are below 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 — Current management decisions regarding platelet transfusions are based on clinical experience, as data are insufficient to be able to establish an evidence-based management approach. In our practice, we use the following management approach for infants with NAIT and thrombocytopenia (platelet count <150,000/microL) based on the clinical setting:
●Healthy term infants ‒ Term infants who are not ill and have no other risk factors for hemorrhage (eg, traumatic delivery) are transfused if the platelet count is <30,000/microL or if there are signs of major bleeding [10-14]. Major bleeding is defined as intracranial hemorrhage, pulmonary hemorrhage, frank rectal bleeding, life-threatening bleeding requiring emergency fluid therapy, or red blood cell transfusion.
●Ill-appearing infants ‒ The threshold for transfusion is higher (<50,000/microL) in infants who are ill or have additional risk factors (such as a previous sibling with NAIT and ICH [15] or presence of intracranial hemorrhage on a postnatal head ultrasound) [15,16].
●Intracranial hemorrhage ‒ Our initial evaluation includes a cranial ultrasound examination to detect hemorrhage. If an intracranial hemorrhage is present, a higher threshold is used for platelet transfusion (<50,000/microL rather than <30,000/microL). If a platelet transfusion is administered, the platelet count should be maintained above 50,000/microL to 100,000/microL in infants who have evidence of intracranial hemorrhage [9].
Adequate platelet counts should be maintained 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 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. (See "Neonatal thrombocytopenia: Clinical manifestations, evaluation, and management", section on 'Platelet transfusion'.)
Procedure — In an infant with severe thrombocytopenia or hemorrhage, random donor platelets should be used initially as they have been shown to be effective in rapidly increasing the platelet count, even though survival of incompatible platelets may be short [11,17].
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 certain European countries, such as the United Kingdom [15]).
Other interventions — It is uncertain whether administration of high-dose intravenous immune globulin (IVIG) (400 mg/kg per day for three to four days or 1 gm/kg per day for one to three days) prolongs the survival of transfused platelets [19-22]. Nevertheless, in our practice, it is given to patients with NAIT immediately following platelet transfusion. There is limited evidence that IVIG should be used alone [14,23]. For infants with stable platelet count >30,000/microL who do not have significant bleeding, IVIG may be considered as a sole intervention based on consensus agreement reached by the neonatal and pediatric hematology teams. (See "Overview of intravenous immune globulin (IVIG) therapy".)
Intravenous methylprednisolone (1 mg every eight hours for one to three days) has been used by some as an adjunctive therapy [24]; however, studies on its efficacy are lacking. We currently do not use steroids as routine therapy for NAIT, but would consider it in instances where life-threatening thrombocytopenia persists despite platelet transfusions and IVIG.
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 purpura (ITP) and systemic lupus erythematosus (SLE).
Clinical features — The majority of affected infants appear healthy, as more than half of infants born to mothers with ITP will have either mild thrombocytopenia (platelet count 100,000 to 150,000/microL) or normal platelet counts (platelet count ≥150,000/microL) [25]. However, a significant minority number of infants will develop severe thrombocytopenia (platelet count of <50,000/microL) with reported risks ranging from 10 to 30 percent [25,26]. However, clinical findings are uncommon and primarily consistent of evidence of mild bleeding (eg, petechiae) [25,26].
The risk of intracranial hemorrhage is unclear. In a 1993 summary of published case series of mothers with ITP, there were five reports of intracranial hemorrhage from 552 pregnancies (1 percent). Three percent of infants had additional evidence of bleeding (petechiae, purpura, melena, or hematuria). In a subsequent 2013 study of 67 neonates (30 percent with severe thrombocytopenia), there were no reports of intracranial hemorrhage. However, in this cohort, prenatal treatment (splenectomy before pregnancy, intravenous immune globulin [IVIG], corticosteroids, and cyclosporine) was provided to about one-third of mothers. Thus, in more contemporary series, the risk of intracranial hemorrhage is most likely lowered due to interventions provided to the mothers during pregnancy.
Platelet counts of infants born to mothers with ITP often decrease sharply during the several days after birth [26,27]. The nadir typically occurs between two and five days of age [8,25].
Persistent neonatal thrombocytopenia beyond four months was observed in breastfed infants of mothers with ITP [28]. 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 [25,27,29]
●An older sibling has had neonatal thrombocytopenia [25,29]
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 [30]. (See "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)
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:
●Platelet transfusions are given to infants if the platelet count is less than 20,000/microL or with clinical bleeding (ie, bleeding from intravenous puncture sites, bleeding from mucosal surfaces [pulmonary, gastric, rectal or vesical hemorrhage], intracranial hemorrhage, or suspected intra-abdominal bleeding causing hypotension). However, transfusions may not be as effective as in infants with thrombocytopenia due to 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) should be administered to infants with platelet counts <20,000/microL or with clinical bleeding at a dose of 1 g/kg (repeated if necessary), which typically produces a rapid response [31]. Neonatal thrombocytopenia secondary to maternal ITP may last for weeks to months. Occasionally, a second dose of IVIG is required at four to six weeks after birth [31].
●Corticosteroids may be administered to the rare cases of infants with severe thrombocytopenia that remains persistent after IVIG therapy in some centers but the efficacy of this approach has not been proven. In our center, we do not routinely use corticosteroids. If the decision is made to use corticosteroids, a small case series has 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) [21]. A short course of prednisone (2 mg/kg per day) has also been used in this setting [25].
Perinatal management — The maternal management of ITP during pregnancy is discussed separately. (See "Thrombocytopenia in pregnancy", section on 'Immune thrombocytopenia (ITP)'.)
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 purpura (ITP). Drugs associated with maternal drug-mediated platelet destruction include quinidine and antiepileptic agents (eg, carbamazepine, phenytoin, and valproic acid) [32]. (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 for bleeding (algorithm 2). 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 any infant who presents 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
-Indications for platelet transfusion for infants with thrombocytopenia (platelet count <150,000/microL) are dependent on the presence of major bleeding and platelet count (algorithm 3). (See 'Platelet transfusion' above.)
-We suggest that intravenous immunoglobulin (IVIG) is given to all patients who received platelet transfusion (Grade 2C). (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 purpura (ITP) and systemic lupus erythematosus (SLE). (See 'Neonatal autoimmune thrombocytopenia' above.)
•Clinical features ‒ The majority of affected infants appear healthy, as more than half of infants born to mothers with ITP will have either mild thrombocytopenia (platelet count 100,000 to 150,000/microL) or normal platelet counts (platelet count ≥150,000/microL). Patients with severe thrombocytopenia will have a range of findings (petechiae, purpura, melena, or hematuria). The prevalence of intracranial hemorrhage is lower than infants with NAIT but it remains uncertain to what degree the risk is lower and whether this is related to interventions that the mother received during pregnancy. (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 ‒ Management decisions, including IVIG administration and platelet transfusion, are based on the presence or absence of major bleeding and platelet count. (See '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. Management is similar to that of infants with neonatal autoimmune thrombocytopenia. (See 'Drug-induced immune thrombocytopenia' above.)
