NEONATAL ALLOIMMUNE THROMBOCYTOPENIA Jason K Baxter KEY POINTS Neonatal alloimmune thrombocytopenia (NAIT) is a fetal/neonatal thrombocytopenia (<150000/mm3) due

ue to maternal sensitization to incompatible fetal platelet antigens. The most significant complication of NAIT is the 1030% fetal/neonatal risk of intracranial hemorrhage (VT-fl. of which 45% occurs antenatally, most Often in the third irirnestei at around 3035 weeks, but as early as 20 weeks. There is also a 5 13% risk of neonatal mortality. Only HPA-la antigen and a more severe thrombocytopenia. The goal of management fetus and neonate. > 20 000/Lmm3 achieves this goal. a past history of ICH predict in the platelets

is to Keeping

prevent ICH fetal/neonatal

Routine universal maternal screening is in general not recommended. Intravenous immunoglobulin (IVIG) is associated with a 75% response rate, and a very rare risk of ICH, with half of non-responders improved with the addition of highdose prednisone. Fetal blood sampling (FBS) is associated with a 12% risk of fetal loss per procedure, and 510% cumulative. Management is usually based on IVIG therapy, with FBS as needed, as determined by prior history of ICH (or not), and its timing (Figure 48.1). An alternative approach, using FBS at 20 weeks for all pregnancies, is described in Figure 48.2. There is insufficient evidence to compare these two approaches, but this second approach may be associated with a higher risk of fetal loss and preterm birth from early FBS.

DEFINITION Neonatal alloimmune thrombocytopenia (NAIT) is fetal/neonatal thrombocytopenia due to maternal sensitization to incompatible fetal platelet antigens. It is also called alloimmune thrombocytopenia (AlT), or fetal maternal alloimmune thrombocytopenia (FMAIT).

EPIDEMIOLOGY/INCIDENCE The incidence of NAIT is 1:10001500 births. NAIT is the most common reason for severe thrombocytopenia and/or intracranial iiefrrrhage (ICH) in term newborns.

ETIOLOGY/BASIC PATHOPHYSIOLOGY Maternal alloimmunization occurs against fetal platelet antigen (Ag) lacked by the mothers own platelets. Platelet Disease similar to RBC Rh disease Like red blood cells (RBCs), platelets have specific surf ace proteins called antigens Mother lacks platelet antigen possessed by father Mother is exposed to antigen by fetal platelets Maternal sensitization to incompatible fetal (platelet) antigens Transplacental transfer of maternal antiplatelet antibody to the fetus Subsequent antibody-coating and sequestration of platelets in the fetal reticuloendothelial system.

Different from Rh disease Firstborn children are often affected (primiparas account for 2060% of cases) Maternal antibody titers are not predictive of outcome Antiplatelet irnmunoglobulin G (IgG) production can occur in first pregnancy.

Maternal platelet count and function is normal (although 10% of women with NAIT may have gestational thrombocytopenia). Most incompatibilities will not become sensitized. GENETICS

HPA-lb is due to a single base pair change of cytosine to thymine at position 196 (proline to leucine) in platelet glycoprotein IIIA.

CLASSIFICATION

There are five major biallelic systems of platelet-specific antigens (which differ by single amino acids). The new nomenclature is described in Table 48.1. Whites: 97% HPA-ia+:68% homozygotes (HPA-. I a/HPA- Ia), 29% heterozygotes (HPA- 1 a/HPA- I b); 23%HPA-lb/HPA-lb. HLA class 11 determinant DRW52a (HLA-DR3) or HLA-B8 are more likely to develop antibodies vs HPAI a; 1/42 pregnancies have platelet Ag incompatibility, but only 1/30 of these get NAIT. Other rare causes of NAIT are HLA class I (but not class II) antigens, which are also expressed by platelets. Gov (HPA- 15) is unstable, making serological testing difficult.

NATURAL WSTORY/COMPLICATIONS

The fetus/neonate develops decreased platelets. This can lead to: 90% affected neonates have diffuse petechiae 1030% ICH, often in third early as 20 weeks: of which trimester at 45% around occur 3035 antenatally, most weeks, but as

o mostly intraparenchyrnal, leading to encephalomalacia o may result in porencephalic cysts (which may be seen by ultrasound) o sometimes intraventricular hemorrhage (IVH), leading to arachnoiditis hydrocephalus. 513% neonatal mortality first case in family usually detected shortly after birth (due to petechiae, bleeding, or incidentally).

RECURRENCE RISK o Clinical history of affected sibling is best indicator of risk in current/future pregnancy. o Recurrence in subsequent pregnancy is generally of greater severity. It is about 100% for HPA-la (usually worst Ag). o There is no correlation between plateet count at cordoc entesis and degree of thrombocytopenia in previously o Neonatal alloimmune thrombocytopenia affected infant. How severe NAIT was in the last pregn ancy is not as predictive. o Only HPA-la antigen and past history of ICH predict a more severe thrombocytopenia. o Prior severity. ICH: greatest risk, only true predictor of

o Fetal platelets in first monitored pregnancy: 70% <50000/mm at first percutaneous umbilical blood sampling (PUBS); 50% <20 000/mm3 50% <24 weeks. If > 50000/mm3 on first PUBS, still possible decrease later (in HPA-la, fetal platelets decrease as much as about 23000/mm3 per week). MANAGEMENT Principles Goal: prevent hemorrhage, specifically ICH, in fetus and neonate. ICH is rare with platelets >20 000/mm3; therefore, goal is to keep platelets >20000/mm3. The normal platelet count of fetus 18 weeks is 150000/mm3, as in an adult. Fetal cord blood sampling (PBS) with direct measurem ent of fetal platelet count is the only method to assess disease severity. Optimal management of NAIT has not been determined by any randomized trial, and no one therapy is proven 100% effective.

Prevention

Some clinicians have advocated routine universal maternal serological screening for platelet antigens for identifying pregnancies at risk for NAIT, before it occurs in the first pregnancy without warning.

Rationale against routine maternal serological screening o About 25% of NAIT is not caused by the most common antigen. o Maternal immune response is influenced by other fact ors (e.g. HLA type). o Only a minority of infants of mothers negative for platelet antigen will develop significant thrombocytopenia. o Many false negatives and false positives. o No adequate risk/benefit ratio or cost-effectiveness analys es have been performed. The incidence of ICH is low. Screening by maternal ultrasound is futile, as fetal thromb ocytopenia cannot be detected by ultrasound, and when it is so severe as to cause fetal ICH, it is too late for effective intervention. Since there is no consensus regarding utility of screening unaffected women for alloimmune antiplatelet antibodies, active management of the disease is usually confined to women who have had a previously affected fetus.

Workup for suspected NAIT Indications for testing o Neonate with petechiae and ecchymosis, unexplained thrombocytopenia o Fetus with unexplained ICH, hydrocephalus, or porencephalic cyst. o Woman incidentally found to be HPA-la negative o Family history of NAIT.

NAIT serological testing o Test parents in a reference laboratory (e.g. Blood Center of Southeastern Wisconsin) o Initial testing: maternal platelet antibody; paternal antigen typing (usually HPA-1, 3, 5)if maternal antibody positive.

Diagnosis o The mother is antibody positive (specific to father and fetal platelet antigen) and antigen negative. o The, fathers antigen zygosity and neonatal antigen determines the risk of recurrence in subsequem pregnancies: 100% if father is homozygous, 50% if heterozygous.

o This documentation of maternal, paternal, and neonatal serological diagnosis should always be reviewed to guide management in the next pregnancy.

Counseling Prognosis, natural history and complications, and mana gement criteria should all be reviewed with the family. All patients should be advised that the optimal management of alloimmune thrombocytopenia has not been determined and that no one therapy has proven 100% effective.

Investigations and consultations

With a heterozygous father, consider amniocentesis to determine fetal antigen status by polymerase chain reaction (PCR). Chorionic villus sampling (CVS) should be conside red only if mother would terminate affected fetus. Multidisciplinary management should involve a hematolog ist and the blood bank.

Fetal therapy There are insufficient data to assess different types of interv entions for the pregnancy with NAIT. There are two main antenatal treatments (IVIG and intrauterine transfusion). Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) (>51000/dose) is most common in North America: o Pooled blood product, increasing hepatitis and HIV risks (donor screening and viral inactivation procedures decrease risk. o Usually, given as a weekly infusion over 6 - 12 hours. o WIG has an unclear mechanism of action, but is theor ized to work via: o Fc-receptor saturation in the placenta with a reducz ion of antibody transfer across the planta (most pobable main mechanism). o Fc-receptor blockade on macrophages, leading to inhibition of uptake of the antibody-coated platelets by fetal macrophages. Endothelial stabilization prev ents damage by maternal platelet antibodies (low platelets are not a cause of ICH). o Suppression of maternal IgG antibody production.

o IVIG not only can prevent/improve thrornbocytopenia in the majority of cases but also prevents ICH. There are only very rare (possibly only two in the literature) reports of IVIG failures to prevent ICH. o Side effects headaches and febrile reactions: pretreat with Benadryl (diphenhydramine) and acetaminophen. o Only FBS. way to monitor efficacy of IVIG treatment is via

o Seventy-five percent respond to weekly IVIG, half of non-responders being improved with addition of high- dose prednisone (I mg/kg = 60mg/day).4 Dexamethasone has been associated with oligohydramnios and. fetal growth restriction (FGR). o When the IVIG dose is 2 g/kg/week, it car be infused at doses of 1 g/kg twice a week. o If this fails, consider weekly in-utero platelet transfus ions via FBS until birth.

Intrauterine transfusion

Repeated intrauterine transfusion of antigen-compatible platelets via FBS is more popular in Europe: Weekly in-utero transfusion of platelets via FBS may be required from 20 weeks until delivery. Risk of increasing sensitization due to fetomaternal hemorrhage. Risk of fetal hemorrhage is at least 12% per procedure, and 510% cumulative loss for each pregnancy. To minimize fetal hemorrhage at FBS, always begin transfusing platelets immediately after obtaining platelet sample. Transfuse maternal platelets (antigen negative), obtained by plasmapheresis a day or two earlier (packed, washed, and irradiated). (Estimated fetoplacental volume) x Volume Infused = (Desired increase in platelet count) Platelet Infusion Concentration Goal: keep platelets >50 000/mm3 if being treated conc urrently (usually 310 ml required). Due to risk of emergent delivery, corticosrerojds for fetal lung maturity before PBS are suggested at> 2434 weeks. In fetuses with platelets > 80 000/mm3 at first PBS and not treated, follow-up FBS showed decreases of at least 10 000/mm3 per week.

Many centers use WIG as initial treatment, with FBS to monitor response, with the addition of oral steroids for refractory cases, as suggested in Figure 48.1. Management depends on history of prior ICH or not. This is an empirical approach, which tries to avoid a 20-week PBS, associated with significant complications as just discussed.

Previous sibling without in-utero ICH In cases where previous siblings did not have in-utero ICH (Figure 48.1): A. Begin IVIG at 1 g/kg/week at 20 weeks. Some advoc ate also adding prednisone 0.51.0 mg/kg/day, or a higher dose of IVIG (2 g/kg/week), but there is insufficient evidence to assess the effectiveness of these approaches. B. Assess adequacy of therapy by FBS at 3032 weeks: (a) have platelets ready at any FBS, with slow transfusion started after sampling even before platelet count (PC) available; (b) compatible (mothers preferred) platelets; (c) transfusion volume aim for 200000400000 platelets, by using following equation: Transfusion volume = Estimated fetal blood volume x ((Final PC initial PC)/Donor PC]: 1. If adequate (platelet count 30000/mm), continue IVIG weekly to term. If the first fetal platelet count is >20000/mm3 while on IV1G, the chance of platelet count >20000/mm3 at a later sampling is 89%, while if the first count is 20000/mm3, this chance is only 51%. Therefore, if the response is adequate (>20000/mm3), a second FBS may not be required, provided IVIG is continued, given the risks of FBS. 2. If inadequate fetal platelet count (<20000), start IV1G 2 g/kg/week (some suggest adding prednisone at this point, too). The chance that this initial platelet count is <20 000/mm3 is <20%. 3. Resample after 4 weeks of therapy. If inadequate, add prednisone 0.51 mg/kg/day to term. 4. Resample after 4 weeks of therapy. If inadequate, intensify therapy to IVIG 2 g/kg/week and prednisone 1.5 mg/kg/day and resample in 2 weeks. If response occurs, prednisone can be tapered. 5. If above salvage therapy fails, continue IVIG, stop prednisone, begin weekly in-utero platelet transfusions and deliver early with mature amniocentesis.

C. Follow with serial (every 24 weeks) ultrasound assessments. D. Delivery mode management options: 1. Cesarean section (no evidence it decreases incid ence of ICH).

2. FBS. If platelet count >50000/mm3, vaginal delivery is considered safe.

Previous sibling with in-u tero ICH In cases where previous sibling had in-utero ICH (see Figure 48.1):

a. b.

Begin IVIG at 12 g/kg/week at 1214 weeks (see Figure 48.1: if prior ICH <28 weeks: suggest IVIG 2 g/kg/week). Assess adequacy of therapy by FBS at 20 weeks. A. If adequate ( 30000/mm), continue IVIG (platelet count falls if IVIG stopped).

B. If inadequate (<30000/mm): IVIG 2 g/kg/ week and resample in 4 weeks. If still inadequate, add prednisone 0.51.5 mg/kg/day (see Figures 48.1 and 48.2). If medical management fails, offer weekly in-utero platelet tthsfusidns (half-life is 57 days). C. Follow with serial (every 24 weeks) ultrasound assessments. D. Delivery early with mature amniocentesis. E. Delivery mode management options: 1. Cesarean section (no evidence it decreases incid ence of ICH). 2. FBS. If platelet count >S0000/mm3, vaginal delivery is considered safe. Early FBS An alternative approach, using FBS at 20 weeks for all pregn ancies, is described in Figure 48.2. This approach has the benefit of knowing the fetal platelet count early in pregnancy, and therefore offers more directed therapy; however, it is associated with the complications of an early FBS. General issues regarding therapy Patients should be instructed to avoid activities (i.e. sports) that could result in potential trauma. External cephalic versions and non-steroidal anti- inflammatory drugs (NSAIDs) are contraindicated. Patients should receive IVIG and antenatal steroids see ral days prior to each PBS to maximize beneficial effects. Fetal IVIG therapy is not efficacious, since it increases antibody levels, but it does not always increase the fetal platelet count. There are reported cases of ICH while receiving IVIG treatment,37 so that IV1G should be considered a highly ffctve but not perfect therapy to prevent ICH (and therefore FBS and possible transfusions are still necessary). Women with prior IIG administration should have their serum checked for human T cell lymphotropic virus types I and II and hepatitis C antibodies.

Fetal monitoring/testing

FBS is indicated in certain cases, as shown in Figures 48.1 and 48.2. Ultrasound can help detect ICH, but when this is detected it is too late for intervention to prevent severe sequelae.

Anesthesia

No special precautions, since maternal platelets are usually normal. Delivery Avoid fetal trauma: avoid maternal abdominal trauma, external cephalic version, fetal scalp lead, and vacuum or forceps. Delivery is confirmed. should occur once fetal lung maturity

Cesarean delivery is indicated if platelet count is <50000/mm3; consider FBS to confirm adequate platelet count ( 50000/mm3), which is safe for trial of labor and attempt at vaginal delivery.

Neonatology management Maternal platelets (Ag negative, obtained by plasmaphoresis, plasma depleted, washed, irradiated, and packed) should always be available for transfusion after delivery. Neonatal treatment is with IVIG,IV steroids, and antigen-compatible platelets until platelet count recovers, usually by710 days of age. The volume of platelets transfused = Blood volu mex[(Desired increase in platelet countActual platelet count)/Platelet concentration)]. For the term neonate, this usually equates to 1 ml pit = increase platelet count by 5000/mm3 (10 ml = 50000, 20 ml = 100000). Often the neonatologist chooses to transfuse 10 ml of platelets per neonatal weight (kg).

Future pregnancy preconception counseling Management, events, and outcome of the pregnancy should be reewed with the family postpartum (after disc harge ofhe rseori.ate. As stated above, the natural history of NAIT is that, if it recurs (depending on FOB [father of baby] zygocity), it is more severe than in the previous pregnancy.