Obstetrics and Gynecology

Neonatal Alloimmune Thrombocytopenia (NAIT)

Neonatal alloimmune thrombocytopenia (NAIT)

1. What every clinician should know

Neonatal alloimmune thrombocytopenia (NAIT) can occur when a fetus inherits a paternal Human Platelet Antigen (HPA) that differs from the maternal antigen. Due to the fetal-maternal mixing of platelets, a specific antibody is formed that crosses the placenta, which may result in severe fetal thrombocytopenia.

Incidence varies based on ethnicity, with the highest at 0.2-1.0 of every 1,000 live births. Unlike Rhesus disease, the antibodies can cause severe fetal thrombocytopenia even in the first affected pregnancy. Though several polymorphic, diallelic platelet antigens exist, the severity of NAIT depends on the antigen involved.

The HPA-1a antigen, which accounts for the majority of cases, is responsible for 75-90% of cases in Caucasians. Although 1 in 42 pregnancies is incompatible for HPA-1a, the disorder can remain subclinical, as there appears to be a need for an immunologic susceptibility to HPA-1a sensitization. The human leukocyte antigen (HLA) class II determinant can modulate the severity of the disease and may be required for the development of antibodies against HPA-1a.

2. Diagnosis and differential diagnosis

The spectrum of the disease in both the fetus and newborn varies widely, from asymptomatic mild thrombocytopenia to severe thrombocytopenia with spontaneous intracranial hemorrhage. In a typical affected pregnancy, the mother is generally healthy, has a normal platelet count, and the pregnancy, labor, and delivery are usually without incident. However, the affected neonate can either be born with evidence of profound thrombocytopenia or manifest generalized petechia or ecchymoses within hours after birth.

The most severe consequence is intracranial hemorrhage, occurring in 10-20% of cases, which may result in intrauterine or neonatal demise or survival with lifelong disability. In a published case series examining 123 neonates with untreated NAIT, clinical presentation included superficial bleeding in 47%, intracerebral hemorrhage in 14%, bleeding within another major organ in 2%, and no signs in 34%. The platelet count at birth will typically drop in the first few days of life and then rise over the next 1-4 weeks as the level of maternal antibodies decline in the neonate. Fetal intracranial hemorrhage can also occur with detection of a hematoma, porencephalic cysts, or obstructive hydrocephalus on ultrasound.

The differential diagnosis for fetal and neonatal alloimmune thrombocytopenia includes idiopathic thrombocytopenic purpura (ITP). Similar to NAIT, maternal IgG antiplatelet antibodies are transported into the fetal circulation, occasionally resulting in fetal or neonatal thrombocytopenia. This can cause minor clinical bleeding, such as purpura, ecchymoses, hematuria, or melena, but rarely results in fetal or intracranial hemorrhage. The best predictor of fetal or neonatal thrombocytopenia for a woman with ITP is an affected neonate in a prior pregnancy.

The goal of obstetric management is to identify pregnancies at risk for NAIT and to prevent intracranial hemorrhage. Although screening for HPA-1a antibodies would detect all at-risk pregnancies, it is not cost effective due to the low prevalence of this disorder. Maternal platelet antigen testing is recommended if a maternal sister had a pregnancy with diagnosed NAIT, or if the mother or her sister have had an obstetrical history suggesting NAIT, a fetal intracranial hemorrhage observed sonographically, or neonatal thrombocytopenia of <50,000/ml3, regardless of the presumed etiology.

A diagnosis of NAIT is made by testing the blood of both parents and confirming a suspected diagnosis with fetal or neonatal blood. If a platelet antigen incompatibility exists in the couple, screening for maternal anti-HPA antibodies specific for paternal or neonatal platelet antigens should be performed. Antibody titers are poorly predictive and are therefore not necessary. The recurrence risk in subsequent pregnancies is 100% if the father is homozygous for the responsible HPA. If the father is heterozygous for the antigen, fetal HPA typing can be obtained by amniocentesis. Chorionic villus sampling should be avoided, as it may exacerbate the alloimmune reaction.

3. Management

Antepartum

In contrast to Rh alloimmunization, NAIT will often develop in the first pregnancy with worsening thrombocytopenia as the pregnancy progresses. With each subsequent pregnancy, thrombocytopenia can occur earlier in gestation and tends to be more severe, with a history of antenatal intracranial hemorrhage in a prior pregnancy being most predictive of early-onset disease in the next pregnancy. In one study of 107 fetuses identified due to an affected older sibling, the initial platelet count at the time of fetal blood sampling was less than 20,000/ml3 in 50%, including many that were sampled prior to 24 weeks’ gestation. Since thrombocytopenia uniformly worsens in untreated fetuses, and the majority of intracranial hemorrhages occur in utero, treatment should be initiated antenatally rather than simply avoiding labor or waiting to treat the disorder until after birth.

Antenatal treatment has evolved over the past 25 years based on published case series detailing the outcomes of different regimens. Initial treatment included weekly in utero platelet transfusions, requiring serial cordocenteses. This approach has been largely abandoned because of the risk of fetal morbidity from repeated invasive procedures.

The administration of IVIG directly to the fetus has also been attempted but it has not consistently raised fetal platelet counts and carries a risk of pregnancy loss or significant fetal morbidity similar to that of serial platelet transfusions. Subsequent studies have focused on maternal medical management as a safer alternative. Currently, the mainstay of therapy includes maternal administration of intravenous immunoglobulin (IVIG), with or without steroids.

Intravenous human immunoglobulin (IVIG) has proven to be the most successful treatment for fetal and neonatal alloimmune thrombocytopenia. Its mechanism of action is unclear, but it may suppress maternal antibody production and/or reduce the placental transfer of antibodies. The dosage of this pooled blood product is 1 gm/kg/week, infused over 4-5 hours once or twice a week.

Studies have clearly shown that IVIG is effective in reducing the risk of intracranial hemorrhage when compared to cases not treated in utero. The most common side effect reported is mild to severe headache. Other side effects include fatigue, flushing, back pain, myalgia, nausea, fever/chills, and hypotension. Premedication with acetaminophen, diphenhydramine, and in refractory cases, methylprednisolone, will decrease adverse events. Rare side effects include aseptic meningitis, acute kidney injury, thrombosis, hemolytic anemia, and stroke. Anaphylactic reactions are uncommon; however, it is recommended that the first infusion be performed in a hospital or medical office for close monitoring.

Corticosteroids can be administered in conjunction with IVIG. Low-dose dexamethasone has been studied, but it failed to improve platelet counts beyond the effect achieved with IVIG alone. Oral prednisone is now recommended in doses between 0.5-1mg/kg/day. Side effects include hyperglycemia, acne, hypertension, emotional lability, immunosuppression, fluid retention, and osteoporosis. Due to these common side effects, patients treated with long-term steroids should be repeatedly screened for gestational diabetes and supplemented with calcium and vitamin D. This medication is not effective in treating AIT when given alone, and, whenever possible, should be administered in association with IVIG.

A parallel-group randomized trial stratified patients based on risk for severe thrombocytopenia and ICH. Forty women who had previously had an infant with peripartum ICH or who currently carried a fetus with a platelet count less than 20,000 ml3 were randomized to receive either IVIG alone or in combination with prednisone. In the group that received both therapies, the mean platelet count increased by 67,000 ml3, compared with 17,300 ml3 in those receiving only IVIG.

In utero salvage therapy for NAIT was initially recommended in cases that failed to respond to treatment as determined at the time of follow-up fetal blood sampling. An adequate response was defined in one study as a platelet increase of 10,000 ml3 compared with the first cordocentesis, or a subsequent platelet count of greater than 30,000 ml3. If this was not achieved with the initial therapy, additional interventions were employed, including increasing the initial IVIG dose or adding prednisone. Follow up studies have proposed empiric use of salvage therapy based on risk category.

Previous treatment plans recommended serial cordocentesis to determine the fetal platelet count prior to initial IVIG therapy, after several weeks of IVIG therapy in order to assess response, and before deciding on the mode of delivery. However, fetal blood sampling is not without risk, and serious complications have been reported in 1-8% of cases. The risk of complications associated with fetal blood sampling is higher in NAIT than in other disorders due to the risk of exsanguination from the cord puncture site in severely thrombocytopenic fetuses.

Management algorithm

Most recently, a management algorithm was published that recommends stratification of risk with modification of treatment based on stratum. This will minimize overall cost and significant side effects, while reserving cordocentesis for those patients that desire a trial of labor.

Low risk - History of a prior fetus or newborn with thrombocytopenia or intracranial hemorrhage of unknown etiology without evidence of an anti-HPA antibody in the maternal circulation.

Although paternal incompatibility for human platelet antigens may be present in this group, a specific anti-HPA antibody is not. As a maternal antibody has not been detected, the fetus is probably not affected with NAIT, but is at risk for developing the disorder as the pregnancy continues if a parental HPA discordance exists. These women do not need empiric treatment, but should be followed with maternal anti-HPA antibody screening along with cross-matching with the father of the fetus' platelets at 12, 24, and 32 weeks of gestation. This will ensure that rare platelet antigens are detected as well. If the studies remain negative, the fetus is very unlikely to be affected and no therapy is needed during the pregnancy. If anti-HPA antibodies are subsequently detected in the maternal serum, the pregnancy must be stratified in the medium-risk category.

In cases where there is no incompatibility with the father's HPA antigens, there may be a risk of a rare HPA antigen incompatibility that is not detected by the current screening methods. For that reason, a single antibody screen involving cross-matching of maternal and paternal platelets is recommended at 30 weeks’ gestation in this group. If that remains negative, no further testing or treatment is needed.

Medium risk - History of a previous fetus or newborn with serologically confirmed fetal and neonatal alloimmune thrombocytopenia having only thrombocytopenia; i.e., no evidence of an intracranial hemorrhage.

Once the diagnosis is serologically confirmed, therapy should be empirically started at 20 weeks’ gestation with either IVIG 1 gm/kg/week and prednisone 0.5 mg/kg/day or IVIG 2 gm/kg/week. This regimen should be continued until 32 weeks’ gestation, when IVIG should be empirically increased to 2 gm/kg/week with prednisone 0.5 mg/kg/day until delivery.

High risk - History of serologically confirmed fetal and neonatal alloimmune thrombocytopenia AND previous fetus/newborn with intracranial hemorrhage after 28 weeks’ gestation.

Empiric therapy should begin at 12 weeks’ gestation with IVIG 1 gm/kg/week. At 20 weeks’ gestation, either the IVIG should be increased to 2 gm/kg/week, or treatment should continue with 1 gm/kg/week and prednisone 0.5 mg/kg/day should be added to the regimen. At 28 weeks’ gestation, therapy should be increased to IVIG 2 gm/kg/week and prednisone 0.5 mg/kg/ day until delivery.

A previously published series reported intracranial hemorrhage in 2 of 12 patients whose prior infant had an ICH after 28 weeks and who started treatment at 20 weeks. In a follow up study of the patients who started IVIG at 12 weeks’ gestation, all neonates did well and had platelet counts > 50,000/ml3 at birth.

Extreme high risk -History of serologically confirmed fetal and neonatal alloimmune thrombocytopenia AND previous fetus with intracranial hemorrhage at <28 weeks.

This group represents the highest risk category, as a previous pregnancy involved a severely affected infant prior to 28 weeks’ gestation. High dose IVIG at 2 gm/kg/week is recommended at 12 weeks’ gestation. At 20 weeks’ gestation, prednisone 1 mg/kg/day should be added, and both medications continued until delivery.

Of 8 women previously treated using this approach, there was 1 intracranial hemorrhage that occurred at 19 weeks’ gestation, but that patient had only been receiving IVIG 1 gm/kg/week since 12 weeks. In the remaining 7 patients that received the full protocol recommended above, all the neonates had platelet counts >50,000/ml3 and normal postnatal cranial ultrasounds.

Intrapartum

Delivery by elective cesarean section is generally recommended and should occur between 37-38 weeks gestation for those in the medium-risk category or between 35-36 weeks for those in the high-risk or extreme high-risk categories. Antenatal betamethasone administration is recommended prior to indicated delivery in the late preterm period under 37 weeks' gestational age. Amniocentesis should not be considered as a routine component of decision-making for the timing of delivery in affected pregnancies.

In patients highly motivated for a trial of labor, fetal blood sampling could be performed within a few days prior to planned delivery. With a fetal platelet count greater than 80,000 ml3, labor induction is reasonable. If the fetal platelet count is between 30,000 and 80,000 ml3, the patient should consider caesarean delivery. Alternatively, immediate induction of labor after fetal transfusion of antigen-negative platelets is an option for those rare patients who remain resistant to caesarean delivery. Cesarean delivery is recommended for platelet counts under 30,000 ml3.

The mother can serve as a platelet donor for the fetus or neonate and should donate platelets 3 days prior to planned delivery or fetal blood sampling. If the mother is used as a donor, however, her platelets must be appropriately prepared prior to administration in order to remove or greatly reduce the anti-HPA antibodies in her circulation. Alternatively, donor platelets that are negative for the offending HPA antigen can be used. In either case, platelets should be ready at the time of delivery for those neonates who have demonstrated unacceptable platelet counts by cordocentesis.

4. Prognosis and outcome

Follow-up of children treated with IVIG or with serial platelet transfusions suggest normal neurological and physical development. Those who receive antenatal IVIG appear to have normal immunological development. When compared to older siblings not treated antenatally, children who received treatment in utero, with either IVIG alone or in conjunction with corticosteroids, have better long-term developmental and behavioral outcomes.

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

Although fetal and neonatal alloimmune thrombocytopenia is rare, it can be a devastating disorder. The appropriate identification of at-risk women and timely implementation of therapy can prevent intracranial hemorrhage in the vast majority of patients. Treatment should be based on risk stratification, and the algorithms presented in this chapter reflect a shift from invasive to noninvasive strategies. This approach reduces the risk of fetal morbidity and mortality, maximizing therapy for those most affected while minimizing cost and exposure to lower risk patients.

References

Bussel, JB, Zabusky, MR, Berkowitz, RL, McFarland, JG. "Fetal alloimmune thrombocytopenia". N Engl J Med. vol. 337. 1997. pp. 22-26.

Pacheco, LD, Berkowitz, RL, Moise, KJ, Bussel, JB, MacFarland, JG, Saade, G.. "Fetal and neonatal alloimmune thrombocytopenia: A management algorithm based on risk stratification". Obstet and Gynecol.. vol. 118. 2011. pp. 1157-11632.

Gramatges, MM, Fani, P, Nadeau, K, Pereira, S, Jeng, MR. "Neonatal alloimmune thrombocytopenia and neutropenia associated with maternal human leukocyte antigen antibodies". Pediatr Blood Cancer. vol. 53. 2009. pp. 97.

Ghevaret, C, Campbell, K, Walton, J, Smith, GA. "Management and outcome of 200 cases of fetomaternal alloimmune thrombocytopenia". Transfusion. vol. 47. 2007. pp. 901.

Bussel, JB, Berkowitz, RL, Lynch, L. "Antenatal management if alloimmune thrombocytopenia with intravenous-Y-globulin: A randomized trial of the addition of low dose steroid to intravenous-Y-globulin". Am J Obstet Gynecol. vol. 174. 1996. pp. 1414.a.

Provan, D, Stasi, R, Newland, AC. "International consensus report on the investigation and management of primary immune thrombocytopenia". Blood. vol. 115. 2010. pp. 168.

Berkowitz, RL, Bussel, JB, McFarland, JG.. "Alloimmune thrombocytopenia: state of the art 2006". Am J Obstet Gynecol.. vol. 195. 2006. pp. 907.

Overton, TG, Duncan, KR, Jolley, M. "Serial platelet transfusion for fetal alloimmune thrombocytopenia: Platelet dynamics and perinatal outcome". Am J Obstet Gynecol. vol. 186. 2002. pp. 826-831.

Nicolini, U, Tannirandorn, Y, Gonzalez, P. "Continuing controversy in alloimmune thrombocytopenia: Fetal hyperimmunoglobulinemia fails to prevent thrombocytopenia". Am J Obstet Gynecol. vol. 163. 1990. pp. 1144.

Bussel, JB, Berkowitz, RL, Hung, C, Kolb, EA, Wissert, M, Primiani, A, Tsaur, FW, McFarland, JG.. "Intracranial hemorrage in alloimmune thrombocytopenia: stratified management to prevent recurrence in the subsequent affected fetus". Am J Obstet Gynecol.. vol. 203. 2010. pp. 135.e1.

Berkowitz, RL, Kolb, A, McFarland, JG. "Parallel randomized trials of risk-based therapy for fetal alloimmune thrombocytopenia". Obstet Gynecol. vol. 107. 2006. pp. 91-6.

Berkowitz, RL, Lesser, ML, McFarland, JG. "Antepartum treatment without early cordocentesis for standard-risk alloimmune thrombocytopenia". Obstet Gynecol.. vol. 110. 2007. pp. 249-255.

Ward, MJ, Pauliny, J, Lipper, EG, Bussel, JB.. "Long-term effects of fetal and neonatal alloimmune thrombocytopenia and its antenatal treatment on the medical and developmental outcomes of affected children". Am J Perinatol.. vol. 23. 2006. pp. 487.

Gyamfi-Bannerman, C, Thom, EA, Blackwell, SC. "Antenatal betamethasone for women at risk for late preterm delivery". NEJM. vol. 374. 2016. pp. 1311-20.

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