Thrombocytopenia In Newborns

Introduction

Thrombocytopenia is one of the common hematological problems encountered in the neonatal period particularly in sick newborns, premature babies and neonates admitted in neonatal intensive care units and usually indicates an underlying pathologic process. Platelet count and mean platelet volume in the newborn are similar to those in adults and in children and range from 150,000/uL to 450,000/uL and 7.5/fl respectively. They are 14 times smaller than erythrocytes. However, premature infants on an average have slightly lower platelet count than full-term infants but practically within the normal range. Fetal platelet count increases linearly with the gestation from a mean of 187,000/uL at 15 weeks to 274,000/uL at 40 weeks. Postnatally, mean platelet volume increase slightly, over the first 2 weeks of life concomitant with an increase in platelet count. Platelet survival in the newborn is not likely to differ significantly from those in adults i.e. 7-10 days^1-9.

Thrombocytopenia in Newborns

Thrombocytopenia is defined as a platelet count less than 150,000/uL and platelet count less than 100,000/uL is considered as definitely abnormal at any gestational age and deserves further evaluation. However, the significance of platelet count between 100,000 to 150,000/uL in the neonate is not clear but needs further follow-up^6,7,8,10,11. Further investigations depend upon the infant's condition and subsequent platelet count.

Incidence of Thrombocytopenia In Neonates

The incidence of neonatal thrombocytopenia varies depending upon:

• Definition of thrombocytopenia <1,00,000/cmm Vs 1,50,000/cmm.

• Timing of neonatal platelet count.

Few studies are available about the incidence of neonatal thrombocytopenia in non-selected population. Reported incidence of thrombocytopenia less than 100,000/ul in cord blood is around 0.7 to 0.9% and thrombocytopenia less than 50,000 count is around 0.12 to 0.14% and severe thrombocytopenia - platelet count less than 20,000 were seen in 0.01 to 0.08%. However, the incidence increases to 0.28% if infants are included who had dropped the platelet count during first few weeks of life^{6,7,8,11,12,13, 15}.

Of the 4 million birth annually occurring in the United States, about 36,000 can be expected to have congenital thrombocytopenia and 11,000 of these can be expected to have severe thrombocytopenia^16,17.

Thrombocytopenia is the most common hemostatic abnormality in newborn admitted to the Neonatal Intensive Care Unit. Thrombocytopenia is an indication of the presence of an underlying pathologic process. In contrast to healthy infants, approximately 20-50% of infants admitted to tertiary Neonatal Intensive Care Units develop thrombocytopenia.^17,18,19 38% of affected infants have platelet count <100,000/uL and 20% of infants have platelet count <50,000/uL.¹⁸ Mehta et al¹⁹ reported an incidence of thrombocytopenia of 35% among the infants admitted to the NICU. Despite intensive investigations, 60% of these infant's cause could not be obtained^1,19. Thrombocytopenia in sick neonates usually present by day 2 of life in 15 to 75% of infants and reaches nadir by day 4 in 75% of infants and recovers to more than 150,000/uL by day 10 of life in 86% of infants. H. Oren²⁰ reported thrombocytopenia in 0.8% of term infants and 18.2% of preterm infants during their stay in intensive care units. Prematurity was an important risk factor and sepsis, hypoxia, intrauterine growth retardation, DIC, narcotizing enterocolitis (NEC), asphyxia, maternal hypertension, intrauterine growth retardation, congenital infection, drug effects, etc. played an important role in the etiology of thrombocytopenia. The early diagnosis of Neonatal Thrombocytopenia and assessment of the underlying primary pathologic process play an important role in reducing the risk of life-threatening complications of neonatal thrombocytopenia^{13,14,16,19,20}.

Mechanisms that are responsible for thrombocytopenia in a newborn, particularly premature infant are:

• Fetal and neonatal megakaryocytes are smaller and have lower ploidy than megakaryocytes of adult and hence may produce fewer platelets.

• Inadequate production of thrombopoietin in response to thrombocytopenia in neonates as compared to adult leading to limited ability to increase platelet production in response to increased platelet consumption.

• Thrombocytopenic premature neonates have fewer circulating megakaryocytes progenitors than do their non-thrombocytopenic counterparts^{10,16,21,22,23}.

Classification of Thrombocytopenia

Thrombocytopenia in neonates, as in adults can be caused by decreased production, increased platelet destruction, and platelet pooling in the enlarged spleen or by a combination of these mechanisms. Characterization of the mechanism responsible for thrombocytopenia has practical implications in the management of these patients. For example, transfusion of platelets into an infant with consumptive coagulopathy or peripheral destruction may be of limited or no benefit, since the platelets transfused will be destroyed in a very short time. Most infants in whom thrombocytopenia develops are ill, are premature, or associated with other disorders that will contribute to thrombocytopenia including bacteremia, sepsis, DIC, etc. Usually, the thrombocytopenia is caused by maternal factors such as antiplatelet-all or autoantibodies that have crossed the placenta. However, the commonest cause of low platelet count is improper collection of blood or inadequate anticoagulants and hence it is wise to confirm the laboratory reports of low platelet count with peripheral blood smear examination which will show clumps of platelet when platelet count and functions are normal.

On the basis of pathophysiological factors, neonatal thrombocytopenia can be classified as:

• Immune-mediated

• Associated with infection - Bacterial or Non-bacterial

• Drug-Related

• Increased peripheral consumption of platelets: Disseminated Intravascular Coagulation, Necrotizing enterocolitis, hypersplenism

• Genetic and Congenital Anomalies

• Miscellaneous

Immune-mediated Thrombocytopenia

Immune mediated neonatal thrombocytopenia could be due to:

• Neonatal allo-immune thrombocytopenia (NAIT)

• Incidental thrombocytopenia of pregnancy or Gestational thrombocytopenia

• Autoimmune thrombocytopenic purpura

Neonatal allo-immune thrombocytopenia (NAIT)

When there is incompatibility within the parental platelet antigen, the mother can become sensitized to an antigen expressed on fetal platelet. This mechanism resembles that of erythroblastosis fetalis associated with Rh-incompatibility. Maternal antibody is formed in response to fetal platelet antigen inherited from the father which is not present on the mother's platelet, crosses the placenta, and binds to fetal platelet which is then removed from circulation by the fetal reticuloendothelial system. Platelet antigen appears in the fetus early in gestation and maternal antibodies can cross the placenta early in 2nd trimester thereby inducing severe thrombocytopenia. In the study of 110 fetuses with a history of sibling allo-thrombocytopenia, Bussel et al²⁹ reported thrombocytopenia in 50% of fetuses with initial platelet < or = 50,000/ul at a gestational age of 25 ± 4 weeks. The exact incidence of Feto-Maternal Allo-Immune Thrombocytopenia (FMAIT) is not known but is reported in the range of 1 in 1000 to 1 in 5000 births. This is due to incompatibility for human platelet antigen (HPA), most frequently HPA-IA. Immune thrombocytopenia can occur during first pregnancy in more than 50% cases of NAIT and there are no routine screening tests being done^27-35.

Multiple antigens are expressed on the platelets, which include Class I Antigen (HLA), ABO antigen, and several bi-allelic platelet alloantigens. Recently the platelet antigens nomenclature has been changed to Human Platelet Antigen (HPA) and different allelic forms are distinguished "a" or "b". "a" indicated more common and "b" indicated a more rare allele. Following table 1 give various types of antigen along with previous old names¹⁶.

Table 1: Platelet antigen systems

HPA = Human Platelet Antigens, W = Workshops (refers to systems that are still under evaluation). Adapted from the American Medical Association Manual of Style, ed 9. Baltimore, Williams, and Wilkins, 1998, p. 343.

Autoimmune thrombocytopenia

Autoimmune thrombocytopenic purpura in the neonate is mediated by the transplacental passage of maternal antiplatelet antibodies. However, antibodies responsible for these cases bind both maternal and fetal platelets leading to thrombocytopenia in both mother and neonate¹.

Studies done on neonatal thrombocytopenia caused by maternal factors are few^{7,11,12,24,25,42,43,44,45}.

The main causes of thrombocytopenia in mother have been reported to be due to:

• incidental or gestational thrombocytopenia of pregnancy (74%)

• hypertensive diseases of pregnancy (21%)

• immune thrombocytopenic disorders during pregnancy like - idiopathic thrombocytopenic purpura and systemic lupus erythematosis (4%)

Moderate thrombocytopenia (cord platelet count is 50,000 to 25,000/cmm) or severe thrombocytopenia (<20,000/cmm) is distinctly uncommon event occurring in less than 0.2% of all the deliveries.

The conditions leading to thrombocytopenia in pregnancy are:

• Gestational or incidental thrombocytopenia was seen in healthy women without ITP or any other autoimmune process. Usually, this condition leads to a mild decrease in platelet count, which is first detected in pregnancy and resolves after the delivery. This condition, however, is associated with very low risk of thrombocytopenia in the newborn^12,24,36,40. However, differentiation between ITP during pregnancy and gestational thrombocytopenia is difficult.

• In most recent studies on ITP in pregnancy, severe fetal thrombocytopenia in utero is distinctly uncommon. These studies also indicated neonatal morbidity and mortality that can occur can be prevented by early recognition and therapeutic intervention. Incidence of neonatal thrombocytopenia (platelet count <150,000/ml) with maternal ITP ranges from 13-64% and severe neonatal thrombocytopenia - platelet count <50,000/cmm from 5-20%^{39,40,41,42,43}.

• Most studies have reported a very low rate of significant bleeding complication particularly intracranial hemorrhage (ICH) around 3%²⁵. In addition, they found no significant association between the mode of delivery - caesarian Vs vaginal and the rate of intracranial hemorrhage^{25,39,40,41, 45}.

• Inspite of extensive study no factors predictive of the severity of neonatal or fetal thrombocytopenia are available. Maternal platelet count, history of splenectomy, titers of PAIgG, or serum platelet-bindable IgG and platelet counts of older siblings have not been found to be useful. Absence of history of ITP and negative results on circulating antibody testing were associated with minimal risk of severe neonatal thrombocytopenia. The measurement of antiplatelet antibody titer unfortunately has not been useful in predicting the likelihood of a fetus being affected. Lack of uniform predictive factors has complicated obstetric management and pregnant women with ITP^42,43,45.

Neonatal Immune Thrombocytopenia Due to Maternal Idiopathic Thrombocytopenia

Bleeding is rarely severe in the newborn and is usually confined to the first few days. Any baby with significant bleeding or a very low platelet count of less than 20,000/cmm should be given IVIgG 500-1000 mg/kg for 2 days. In contrast to the management of NAIT, platelet transfusion is seldom useful as transfused platelets are destroyed rapidly within few minutes and transfused platelets do not produce a sustained rise in platelet counts. However, in life-threatening hemorrhage random donor platelets may have a role in tiding over the crisis and hence may be given. Maternally administered intravenous immunoglobulin (IVIgG) has been reported to be useful in preventing fetal thrombocytopenia. Caesarian section is usually recommended in all cases where the mother has active ITP to prevent severe bleeding in the baby due to trauma of delivery³⁸.

Neonatal Thrombocytopenia Associated with Infection

With the recent advances in the management of neonates and premature babies particularly in intensive neonatal care unit and survival of more and more preterm babies and more and more prolonged hospitalization, systemic infection in neonates is seen more frequently. Thrombocytopenia commonly accompanies systemic infection in neonates. The incidence of thrombocytopenia is 55-65%, if the definition of thrombocytopenia is taken as <100,000/cmm, whereas if platelet count <150,000/cmm is taken as criteria, then thrombocytopenia is seen in practically 80% of the neonates^{16,44, 45, 46}.

Initial complete blood count (CBC) changes are leucocyte left shift with increased immature cells and band cells and increased I: T ratio. It is soon followed by a drop in platelet counts. In general by the time child develops the sepsis, clinically about 25% of neonates and by 36-48 hours majority of them develop thrombocytopenia and the average duration of thrombocytopenia is around 6 days^{16,44,45,47,48,49,50}. Another factor responsible for thrombocytopenia in a neonate with sepsis is due to clinical or subclinical DIC. However, often they may have thrombocytopenia without evidence of DIC. The mechanism responsible for thrombocytopenia in these infected neonates has accelerated platelet destruction due to:-

• Endothelial damage that occurs during sepsis with platelet adhesion and aggregation or due to platelet lysis or removal of platelets by the reticuloendothelial system^44,45,50. Reticuloendothelial hyperplasia is often associated with infection.

• Decreased platelet production also has been proposed as contributing factor^{49, 50}. Increased thrombopoietin level (>1000 pg/ml) in some neonates with sepsis suggest that decrease in marrow megakaryocytes mass⁴³.

• Many infections are associated with DIC, a common cause of platelet consumption.

Clinical bleeding abnormalities because of thrombocytopenia of bacterial infection are rare as low platelet counts are usually not severe 50-100,000/ul respectively. However, when septic neonate develops thrombocytopenia as a manifestation of DIC, the platelet count is commonly less than 20,000/uL and bleeding is common and in such cases, platelet transfusion is helpful⁴³. All bacterial organisms capable of causing sepsis in neonates are also capable of inducing thrombocytopenia⁴³.

Fungal Infection

Secondary fungal infections are increasing particularly in very low birth weight babies <1500 gms and extremely very low birth weight babies <1000 gms. Thrombocytopenia is one of the most consistent laboratories finding seen in many of the neonates with fungal sepsis in as much as in 73% cases. Some have even recommended empirical fungal treatment while waiting for culture results particularly in extremely low birth weight babies who are clinically septic with nosocomial infection and associated with thrombocytopenia^{17, 53, 54}. Fungal infections have been reported in very low birth weight babies receiving intravenous lipid emulsions⁵⁵.

Viral Infection

Congenital viral infections are important causes of thrombocytopenia in the neonatal period and early infancy. All TORCH groups of organisms particularly cytomegalovirus, toxoplasmosis, rubella, and herpes simplex can cause severe thrombocytopenia. Though thrombocytopenia is fairly common in HIV positive women either due to disease progression or due to antiviral therapy, however, thrombocytopenia is rare in HIV infected neonates of these women. Other viral infections like coxsackievirus B along with thrombocytopenia can cause the involvement of multi-organ leading to myocarditis, hepatitis, and CNS involvement. Other viruses leading to thrombocytopenia are echovirus 11, parvovirus 19, Epstein Barr virus, mumps, adenovirus, etc. and may be associated with hydrops, anemia, and thrombocytopenia. These infections lead to thrombocytopenia due to various mechanisms like diminished production or destruction in the spleen and reticuloendothelial damage due to viral function leading to platelet adhesion and aggregates.

Thrombocytopenia Associated With Genetic And Congenital Abnormalities

Thrombocytopenia due to decreased platelet production is usually associated with other congenital abnormalities or evidence of systemic disease.

Genetic causes of thrombocytopenia in neonates¹⁷

• Thrombocytopenia with absent radii (TAR)

• Fanconi's anemia

• Congenital amegakaryocytic thrombocytopenic purpura

• Congenital hypoplastic thrombocytopenia with microcephaly.

• Familial thrombocytopenias:-

• Bernard Soulier syndrome

• May-Hogglin anomaly

• Paris-Trousseau thrombocytopenia

• X-linked recessive thrombocytopenia

Chromosomal anomalies

• Trisomy 13

• Trisomy 18

• Trisomy 21 (Mongol)

• Turner's syndrome

Associated with genetic disorders

• Wiskott-Aldrich syndrome (WAS)

• Noonan syndrome

• Alpert's syndrome

Inherited metabolic disorders

• Methylmalonic acidemia

• Ketotic glycinemia

• Isovaleric acidemia

• Holocarboxylase synthetase deficiency

Thrombocytopenia with Absent Radii Syndrome (TAR)

Thrombocytopenia with absent radius (TAR) is a congenital syndrome characterized by severe thrombocytopenia with bilateral absent radii and may be associated with other skeletal abnormalities⁵⁷. By now more than 100 cases have been reported in the literature^58,59,60. Other skeletal abnormalities are usually present. Limbs are more involved than the trunk. Hypoplasia, aplasia or malformation of ulna seen in 78% of cases, hand 75%, and humerus 40% cases. However, thumbs and digits are almost always present which distinguishes TAR from Fanconi's anemia^60,61. It may be associated with congenital heart defects like tetralogy of Fallot and ASD present in 1/3rd of cases⁵⁷. Pregnancies are usually uncomplicated and there is no maternal history of exposure to drugs, radiation, and the environment. It is transmitted in an autosomal recessive fashion, and consanguinity is not a feature⁶⁰.

Various mechanisms responsible for thrombocytopenia include:

• Decreased platelet production as a consequence of reduced megakaryocytes in the marrow.

• Impaired platelet production from the megakaryocytes.

• These patients have an elevated concentration of thrombopoietin (TPO) and TPO receptors on the surface of the platelet. However, platelet induced tyrosine phosphorylation of platelet protein is completely absent or markedly reduced suggesting lack of response to TPO in signal transduction, the pathway of its receptors (u-PL)^68,69.

Sekine and colleagues⁶⁹ could grow megakaryocytic colonies from patients with TAR syndrome in the presence of TPO. However, colonies grown appeared smaller suggesting a decreased proliferative response to TPO.

Bleeding manifestation and severe thrombocytopenia, platelet count less than 10-30,000/uL have been reported in more than 50% of cases at birth or before the age of 1 week and 90% of patients by 4 months age⁶⁰. Approximately 25% of affected individuals die due to intracranial hemorrhage (ICH)⁵⁶. If they survive through this period, the thrombocytopenia generally resolves over a period, and normal platelet count is usually achieved by school age⁶⁴. First-year of life is a period of high risk and over 90% of death from hemorrhage occurs during this time, over 40% of death occurs in the first 4 months of life⁶⁰.

Other hematologic abnormalities include leukemoid reactions with a white cell count of 100,000 or more seen in 63% cases, eosinophilia, anemia secondary to iron deficiency. Bone marrow examination reveals absent or reduced or immature hypoplastic megakaryocytes. Bone marrow cellularity is normal with normal or increased myeloid and erythroid series^{56, 57}. Results of platelet function tests are variable and are difficult to interpret in thrombocytopenic individuals⁶⁵.

Evaluation of therapeutic intervention is difficult in view of spontaneous remission and exacerbation of thrombocytopenia. Corticosteroids have been tried with beneficial results⁶⁰. Judicious use of platelet transfusion given particularly during an acute bleeding episode or prophylactically before surgery is the treatment of choice. Most children tolerate orthopedic procedures well. Prenatal diagnosis of TAR by the demonstration of absent radii using fetal radiography at 16-20 weeks has been reported.

Prognosis depends upon the severity and duration of thrombocytopenia with an overall mortality of 40%⁶⁰. Children who survive do not appear to be at increased risk for developing leukemia or aplastic anemia.

Fanconi's Anemia (FA)

Fanconi's anemia (FA) is familial aplastic anemia associated with a number of congenital anomalies and inherited by autosomal recessive patterns⁵⁷. Usually presents during middle childhood (4-11 years) and is characterized by progressive persistent anemia, skeletal anomalies with the absent or hypo-plastic or bifid thumb (66%), abnormal skin pigmentation (64-77%), microcephaly (25-40%), renal anomalies (34-40%), hypogonadism, growth retardation, short stature, and mental subnormalities. Since Fanconi's description of three brothers with pancytopenia and physical anomalies in 1927,⁵⁶ more than 700 cases have been reported. Pancytopenia usually does not manifest until childhood (median age 7 yrs). These children rarely experience hemato-logical problems in the neonatal period^{77, 71, 73, 74}.

Diagnosis of Fanconi's anemia is based on clinical features along with pancytopenia on the peripheral smear and the presence of chromosomal abnormalities, breaks, gaps, rearrangements, and exchanges and Endo-reduplications in baseline culture and more so when clastogenic agents like diepoxybutane used^{75, 76, 77}.

Ultrasound abdomen or intravenous pyelography may reveal kidney anomalies like horseshoe kidney, double ureter, bifid pelvis, ectopic kidney, etc.

Fetal characteristics of RBC is demonstrated by macrocytosis, increased fetal hemoglobin, and increased I antigen^{72, 74}. 25% of affected individuals may be structurally normal and may not have dysmorphic features⁵⁷.

Treatment of this condition includes androgen therapy, bone marrow transplantation⁷⁸, and regular supportive therapy with packed red cell blood transfusion^{56, 61, 71, 72}, Butterini et al⁷⁷ reported 388 patients with Fanconi's anemia and 35% of these patients died at the median age of 13 years. They may develop leukemia - myeloid leukemia or myelodysplastic syndrome, other malignancies, and hepatic disease^{66, 72}. Several reports of successful umbilical cord blood-derived stem cell transplantation from histocompatible siblings are the new therapeutic alternative. Recombinant hematopoietic growth factors also have been tried⁷⁷

Congenital Amegakaryocytic Thrombocytopenia

Congenital amegakaryocytic thrombocytopenic purpura is a rare disorder characterized by isolated, moderate to severe thrombocytopenia in the first year of life in the absence of other physical abnormalities. Platelet count at the time of diagnosis ranges from 0-80,000/cmm. The bone marrow examination reveals absent or extremely scarce and small megakaryocytes with normal marrow cellularity. Alter et al⁵⁶ reported 21 cases, out of which 12 presented in the first week of life and the remainder in the first 9 years. The male to female ratio was 2:3 suggestive of x-linked transmission in some cases. Half of the patients initially diagnosed as congenital amegakaryocytic thrombocytopenia eventually develop aplastic anemia at a median age of 3-5 years.

Chromosomal analysis has been normal⁷⁶. Elevated fetal Hb and I antigen also have been reported in some cases^{70, 74}.

Mortality from this disorder is high, usually because of hemorrhage or infection. Some patients also develop leukemia or preleukemia or pancytopenia, which develop between 5 months and 12 years of age⁵⁶.

Pathophysiology has been studied recently and Muraoka and Co-workers⁷⁹ found that serum thrombopoietin (TPO) level increased significantly higher than normal controls but response of bone marrow progenitors in vitro was defective. They did not detect the expression of the TPO receptors mRNA in the marrow mononuclear cells, suggesting the defect responsible for thrombocytopenia might be an impaired expression of the TPO receptors. Guinan et al's(64) in vitro studies demonstrated IL3, GM-CSF or a combination of both increased the number of CFU-MK derived colonies and IL3 administration resulted in improved platelet count and decreased bleeding and transfusion requirement.

Bone marrow transplantation has been curative in some patients. Megakaryocytic thrombocytopenia with microcephaly is a rare condition. However, to differentiate it from congenital rubella syndrome, thrombocytopenia in this condition persists beyond 1 year of life and is not associated with other anomalies.

Thrombocytopenia Due to Chromosomal Disorders

Various chromosomal disorders present with neonatal thrombocytopenia in addition to characteristic physical features of the syndrome. The commonest syndromes encountered are Trisomies of chromosomes 13, 18, or 21 and infants with Turner's syndrome.

Hohlfeld et al⁸⁰ in a study of 5194 fetal blood samples (17 to 41 weeks) reported 4.7% samples (247 samples) with thrombocytopenia less than 150,000/ul, out of which 17% (43 samples) were due to chromosomal anomalies including Trisomy 13, Trisomy 18, Trisomy 21, Turner's syndrome and Triploidy. Hord and associates⁸² in their study of 25 neonates with Down's syndrome reported thrombocytopenia (less than 100,000) in 28% of cases. Thrombocytopenia in these cases was mild to moderate (platelet count >40,000/ul).

Neonatal thrombocytopenia is also associated with other genetic disorders like Wiskott-Aldrich syndrome, Noonan's syndrome, Alport's syndrome, and other inherited metabolic disorders like methylmalonic acidemia, ketotic glycemia, isovaleric aciduria, holocarboxylase synthetase deficiency.

Wiskott-aldrich Syndrome (WAS)

It is an x-linked immunodeficiency characterized by eczema, recurrent infection, and thrombocytopenia leading to severe bleeding tendency. Laboratory investigations in addition to thrombocytopenia reveal very small-sized platelets, not in clumps in the peripheral smear, and have impaired aggregation to ADP, epinephrine, ristocetin, and collagen. Bone marrow examination shows normal megakaryocytes and there is impairment of cellular and humoral immunity. Prognosis is poor and children die of severe infection during the first year of life (85,86). Splenectomy though improves platelet count, should be avoided in children for the fear of the increased risk of overwhelming infections due to capsulated organisms and gram-negative organisms like pneumococcus, H.influenza, meningococcus, etc. particularly among the children below the age of 5-6 years. Bone marrow transplantation nowadays is considered as the treatment of choice.

Bernard Soulier syndrome is a rare autosomal incompletely recessive disorder of moderate clinical severity characterized by giant platelets of the near size of lymphocytes on peripheral smear, mild to moderate thrombocytopenia, and clinical manifestation of cutaneous bleeds or bleeding tendency. Platelet adhesiveness and platelet aggregation by ristocetin are abnormal and they lack the receptor site for factor VIII related antigen⁶³.

Drugs That Produce Thrombocytopenia In Mother, Fetus And Neonate

Certain drugs administered to pregnant women have been reported to cause thrombocytopenia in women and in their fetuses and newborns. However, it is difficult to statistically differentiate the apparent association between drug ingestion and the development of thrombocytopenia in a given case. Mechanisms by which drug produce idiosyncratic thrombocytopenia in mother and fetus is unclear but may involve immune reaction. Antibodies are formed against the drug HEPTRAN complex that cross-reacts with a platelet antigen. When such antibodies are IgG type, in addition to getting attached to maternal platelet, it crosses the placenta and simultaneously attaches to fetal platelets. The drugs that have been implicated are quinine, thiazides, diuretics, hydralazine, tolbutamide, indomethacin, heparin, vancomycin, and intravenous lipid infusion.

Drugs are given to neonate like aspirin, phenylbutazone, promethazine, indomethacin, carbenicillin, etc. have all been shown to produce platelet dysfunction presumably by inhibiting the cyclo-oxygenase enzyme. Though these disorders usually lead to minor bleeds and do not require any active treatment, in an emergency, after injury, or before operation they may have to be given platelet concentration judiciously.

Miscellaneous causes of thrombocytopenia include:

• Caused by thrombosis like renal vein thrombosis, NEC (narcotizing enterocolitis), other vascular thrombosis.

• Intrauterine growth retardation

• Pregnancy induced hypertension

• Perinatal asphyxia

• Idiopathic

As many as 60% of cases with neonatal thrombocytopenia fall in this group of idiopathic variety with platelet count varying from 50,000 to 100,000 and may persist for many weeks. Associated conditions with this group are pulmonary hypertension, phototherapy, preterm babies, and placental insufficiency.

Clinical Features Suggestive of Immune Thrombocytopenia In Thrombocytopenic Neonates

Clinical manifestations reflect the severity of thrombocytopenia. Infants may be born with severe, generalized petechiae, rash, or purpura or may appear normal at birth and may develop symptoms and signs of thrombocytopenia any time during 2-3 days post-partum and are rarely associated with other disorders or factors that account for thrombocytopenia. Usually, they are otherwise healthy infants born to healthy mothers with normal platelet count and neonates often associated with thrombocytopenia <50,000/u/L.

The most severe complication is intracranial hemorrhage which is seen in approximately 10-15% cases and half of these occurs in utero as early as 20 weeks of pregnancies³¹ and the majority of them have a neuro-developmental sequel and hence USG skull should be performed to all neonates with Feto-Maternal Neonatal Allo-Immune Thrombocytopenia (FMNAIT) before discharge^31-33.

Confirmation of diagnosis ideally requires demonstration of maternal and fetal platelet incompatibility and absence of antigen in the mother's serum, which is present in the child. When tested against a panel of platelets of known antigenicity, specific antigen involved (usually PLA1) can be demonstrated to be lacking on the mother's platelet but is present in newborns and father's platelets. However, laboratory facilities may not be available in the majority of centers^32,33.

Treatment

Neonatal alloimmune thrombocytopenia may be associated with fetal thrombocytopenia (as early as 20 weeks of gestation) and neonatal thrombocytopenia. The most serious complication of this hyper-thrombocytopenia is intracranial hemorrhage, which occurs in 10-20% of neonates, and half of these occur in utero, increasing the likelihood of similar complications in subsequent pregnancies³¹.

Fetal scalp platelet count during the labor, fetal blood sampling during the antenatal period helps in deciding the type of delivery to be conducted. If fetal blood platelet count >50,000/uL vaginal delivery may be allowed. However, if these criteria are not met, a cesarean section is usually recommended^{32, 34, 35, 37, 38}.

No treatment is required for the mildly affected neonates. However, those with count <30,000 u/L should receive washed maternal platelets. If the birth of such an infant is anticipated maternal plateletpheresis should be done in advance so as to have non-immunized platelet available for transfusion. Administration of random donor platelets is not effective as 98% of the population has PLA1 antigen and hence these platelets are susceptible to antibody-mediated destruction.

Intravenous immunoglobulin has been used successfully when antigen-negative platelets are not available. Steroids and exchange transfusion have found to be not much of clinical benefit in the management of NAIT. Intravenous immunoglobulin 500-1000 mg/kg/day for 2 days have been used successfully when antigen-negative platelets are not readily available. Platelet count in the neonate may remain low, till the maternally derived antibody is completely cleared, which may even take 4-8 weeks. Steroids in dose 1-2 mg/kg/day can be given to those neonates who continue to have low platelet count or bleeding^{32, 34, 35, 37, 38}.