Inherited bone marrow failure syndromes (IBMFS) are a rare but important consideration in the differential diagnosis of cytopenias in childhood [1]. However, diagnosis of IBMFS in the newborn period can be challenging because many of the manifestations considered typical for a specific disorder may not yet be present, and in many cases children will not be recognized until later in life. Young children with IBMFS may have one or more cytopenias, congenital anomalies, both, or neither. A high index of suspicion for an IBMFS is required in order to establish the correct diagnosis, determine appropriate clinical management and follow up plans, and provide the family with genetic counseling. Some IBMFS predispose to leukemia or solid tumors; while the development of cancer is uncommon in the newborn period, this risk is an important determinant of subsequent follow up for the child and any affected family members.

Eosinophilia in neonates is identified when the blood concentration of eosinophils exceeds the upper reference range limit. To avoid the potential pitfall of laboratory or technician error, perhaps the definition should be two subsequent eosinophil counts above the upper reference limit. The 95th percentile for blood concentration of eosinophils increases slightly over the first month following birth. Initially a count ≥1,200/µL would exceed the upper range, and by about four weeks a count of above 1,500/µL would exceed the upper limit [1]. This latter value is similar to that generally used to define eosinophilia in adults [2]. Adults with persistent eosinophilia are well advised to have the situation evaluated, because an association has been seen between persistent eosinophilia and end-organ damage [2]. Some adults with persistent eosinophilia have elevated blood Interkeukin-5 (IL-5) concentrations [3]. Some with hypereosinophilic syndrome have an eosinophilic leukemia involving a translocation in the tyrosine kinase gene [4].

Leukemia in the neonatal period is very rare and can present as early as the day of birth [1, 2]. Acute leukemia arises from clonal changes in hematopoietic precursor cells. In neonatal leukemia, defined as leukemia presenting in the first month after birth, these clonal abnormalities initiate during fetal development [3]. A backtracking molecular study of infants and young children who developed leukemia beyond the neonatal period demonstrated that the same clonal mutations found in the leukemia were also present in neonatal blood spots [4]. Though some epidemiologic studies have suggested that maternal intake of certain foods may contribute, the genetic and environmental risk factors for infant leukemia are not well understood [5–7]. One exception is the observation that an identical twin of an infant with acute lymphoblastic leukemia has a nearly 100% chance of developing the same type of leukemia [8, 9]. In contrast, the genetic risk factors associated with myeloproliferative neoplasms among neonates are better defined [10]. Neonates with Down syndrome are at risk of transient myeloproliferative disorder (TMD) [11) and neonates with Noonan syndrome or related Ras pathway disorders may present with juvenile myelomonocytic leukemia (JMML) [10]. Both TMD and JMML have the potential to be serious and life-threatening. Recognition of the presenting features of neonatal leukemia is important, as early initiation of therapy may prevent rapid progression of disease.

Bleeding symptoms presenting in the neonatal period usually present a diagnostic and therapeutic challenge for treating physicians. Bleeding disorders may be due to either congenital or acquired coagulation disorders, and may be related to mortality or long term morbidity when not appropriately and timely diagnosed. While severe congenital coagulation defects usually present in the first hours to days of life with distinct symptoms in otherwise well newborns, acquired coagulation disorders usually present in sick newborns with a variety of presentations and distinct etiologies that differ from older children and adults. In newborns, the diagnosis of coagulation abnormalities based upon plasma concentrations of components of the hemostatic system requires age-appropriate reference ranges because plasma concentrations of several procoagulant and inhibitor proteins are physiologically decreased at birth. The aim of this chapter is to discuss clinical presentation, diagnosis, and management of the most common congenital and acquired bleeding disorders in newborns, excluding platelet disorders.

In this chapter, we will focus exclusively on acquired thrombocytopenias that present in the neonatal period. We will discuss the mechanisms underlying some of the most common varieties of neonatal thrombocytopenia, and how the biological differences between neonatal and adult megakaryocytes might contribute to the susceptibility of neonates to develop thrombocytopenia. We will then review the presentation, pathophysiology, and management of the most common etiologies of neonatal early- and late-onset thrombocytopenia, including autoimmune neonatal thrombocytopenia. Alloimmune and congenital causes of neonatal thrombocytopenia will be discussed in detail in Chapters 14 and 15, respectively.

Over the last decades, as the survival of neonates admitted to the neonatal intensive care unit (NICU) improved, thrombocytopenia became an increasingly important problem in the care of sick term and particularly preterm neonates. In this population, the majority of thrombocytopenias are due to acquired processes, and most resolve with time and/or treatment of the underlying illness. Frequently, however, the etiology of the thrombocytopenia poses a diagnostic dilemma, and – if severe enough – may place the affected neonate at risk of bleeding.

Ancient concepts of the blood were described by Hippocrates and Galen 2000 years ago in their doctrine of “humors.” It was believed that the body was made up of four humors – blood, phlegm, black bile, and yellow bile – and that these four components had the qualities of heat (hot-blooded!), cold, moist, and dry. The Galenic concept of the blood prevailed through the Middle Ages. Health or disease were a result of an imbalance, between these humors. This was the basis of the practice of therapeutic bloodletting (which, fortunately, was performed infrequently on children) through the mid nineteenth century as a way to rid the body of the imbalance of humors believed to cause a wide variety of diseases.

The newborn screening (NBS) program is a well-established comprehensive public health initiative with the main goal of identifying newborns affected by genetic disorders, for whom early interventions may prevent disease morbidity and mortality. The early-in-life screening for genetic conditions not only permits early institution of specific therapeutic measures for those affected, but also creates the opportunity for genetic counselling for carriers (e.g., parents). Several hematologic conditions have benefited from NBS, most notably hemoglobinopathies, particularly sickle cell disease (SCD), for which early diagnosis with preemptive penicillin initiation has substantively reduced pediatric mortality [1, 2]. The inclusion of severe combined immune deficiency (SCID) in the panel of screened genetic disorders has allowed for early referral to hematopoietic stem cell transplantation and the soon-to-be scaled up, gene therapy [3, 4].

The fetal–placental–maternal unit can produce significant abnormalities in the neonate’s hematologic health at birth. A newborn can have disorders of white blood cells, red blood cells, or platelets, or any combination thereof. Neonatal cytopenias can result from dilution, peripheral destruction, or a defect in cellular production [1]. Maternal illness can be the cause of such abnormalities (Table 23.1). Close communication between the obstetrical provider and the pediatrician is important. This can allow for anticipation of a problem in order to mitigate the consequences, or to discover the cause if an unexpected cytopenia is detected.

Neonatal transfusion therapy requires an understanding of the dynamic interactions of the fetomaternal unit, the physiologic changes that accompany the transition from fetus to neonate to infant, and the underlying pathophysiology of different hematologic disorders. Guidelines for neonatal transfusions remain controversial, since most have been extrapolated from evidence in adults or based on small studies in neonates with marginal statistical validity. Compared to older children and adults, neonates have small total blood volumes but high blood volume per body weight. Because of the limited capacity to expand their blood volume to compensate for their rapid growth, many sick and/or premature infants require significant blood component support, especially within the first weeks of life. Immaturity of many organ systems predisposes them to metabolic derangements from blood products and their additive solutions, and to the infectious and immunomodulatory hazards of transfusion, such as transfusion-acquired CMV (TA-CMV) infection and transfusion-associated graft versus host disease (TA-GVHD). Therefore, component modifications are often required to compensate for the infant’s small blood volume, immunologic immaturity, and/or compromised organ function, and constitute the uniqueness of neonatal transfusion therapy.

Over the last decades, as the survival of neonates admitted to the neonatal intensive care unit (NICU) improved, thrombocytopenia became an increasingly important problem in the care of sick term and particularly preterm neonates. In this population, the majority of thrombocytopenias are due to acquired processes, and most resolve with time and/or treatment of the underlying illness. Frequently, however, the etiology of the thrombocytopenia poses a diagnostic dilemma, and – if severe enough – may place the affected neonate at risk of bleeding.

Introduction

Over the last decades, as the survival of neonates admitted to the neonatal intensive care unit (NICU) improved, thrombocytopenia has become an increasingly important problem in the care of sick term and particularly preterm neonates. In this population, the majority of thrombocytopenias are due to acquired, non-immune processes, and most resolve with time and/or treatment of the underlying illness. Frequently, however, the etiology of the thrombocytopenia poses a diagnostic dilemma, and – if severe enough – places the affected neonate at risk of bleeding.

In this chapter, we will focus exclusively on acquired, non-immune thrombocytopenias that present in the neonatal period. First, we will review the incidence of neonatal thrombocytopenia, and will propose a classification based on timing and clinical presentation. We will then discuss the mechanisms underlying some of the most common varieties of neonatal thrombocytopenia, and how the biological differences between neonatal and adult megakaryocytes might contribute to the susceptibility of neonates to develop thrombocytopenia. Finally, we will offer recommendations for the management of non-immune thrombocytopenia in neonates, and will discuss the risks and benefits associated with platelet transfusions and with the potential future use of novel thrombopoiesis-stimulating factors in this population. Immune and congenital causes of neonatal thrombocytopenia are discussed in detail in Chapters 10 and 12, respectively.