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.

This chapter focuses on the recognition and management of hemolysis in newborn infants (). Some of the common hemolytic anemias of childhood first appear in the newborn period, while others do not present until several months of age, and a few rare hemolytic disorders occur only in the neonatal period. These variations in the age that hemolytic anemia first presents reflect differences in neonatal erythropoiesis, hemoglobin synthesis, and the metabolism of newborn erythrocytes. When approaching an infant with a potential hemolytic disorder, the first issue to be addressed is whether there is evidence of increased red-cell destruction and accelerated production. If yes, then the next question to consider is whether the cause of neonatal hemolysis is due to extracellular (acquired) factors or an intrinsic (genetic) red-cell defect. Acquired disorders are those that are immune mediated, associated with infection, or accompany some other underlying pathology. Inherited red-cell disorders are due to defects in the cell membrane, abnormalities in red blood cell (RBC) metabolism, or a consequence of a hemoglobin defect.

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].

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.

Thrombocytopenia occurs in less than 1% of all newborns. However, thrombocytopenia is a common finding in the intensive-care nursery where it is present in 25–35% of admitted infants [1, 2]. See Chapters 12 and 13 for a discussion of the approach to thrombocytopenia as well as acquired causes of thrombocytopenia in newborns. This chapter will focus primarily on the diagnosis and initial management of inherited thrombocytopenia disorders that present in infancy.

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].

Fetal and neonatal alloimmune thrombocytopenia (AIT) is the most common cause of severe thrombocytopenia in fetuses and neonates [1]. Maternal IgG alloantibodies against paternally derived fetal platelet antigens cross the placenta early in pregnancy and commonly result in severe thrombocytopenia. While the reported incidence varies somewhat with the assigned threshold of thrombocytopenia (50, 100, or 150 × 109/L), in most unselected populations AIT affects 1 in 1,000 live births. Table 14.1 displays the studies of AIT in unselected populations, systematically screened. In its severe form, AIT has the potential for significant morbidity (including intracranial hemorrhage in utero) and mortality. In milder forms, there are either antibodies with no thrombocytopenia, or mild to moderate thrombocytopenia, which is identified only by a complete blood count obtained for another indication or in a screening study. While there have been extensive efforts made in the diagnosis and characterization of the disease, strategies for early detection and intervention remain controversial.

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.

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.

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].

Solid tumors in neonates can arise anywhere in the body and present unique challenges to clinicians. Benign tumors are most common [1], and are typically less amenable to chemotherapy or radiation and more in need of surgical approaches. Radiation’s role in childhood cancer is diminishing as better chemotherapeutic approaches are developed and its use in neonates is rare due to its devastating long-term toxicity. Finally, differences in neonatal physiology imparts a variable upon chemotherapy pharmacokinetics that is difficult to fully control and frequently results in greater toxicity. These factors, combined with the biology of the tumors uniquely seen in the neonate, worsen the survival for neonates with cancer. This chapter acquaints the clinician with the array of tumors most commonly found in the infant <28 days of age (Table 22.1).

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.

Hemolytic disease of the fetus and newborn (HDFN) is the immune mediated destruction of fetal and neonatal red blood cells by maternal antibody. HDFN occurs when the fetal red blood cells express a paternally inherited antigen not present on maternal red blood cells. The spectrum of illness ranges from clinically insignificant to that of a critically ill, anemic, hydropic, and jaundiced infant at risk for bilirubin-induced brain damage (kernicterus).

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.

Polycythemia of the newborn is first mentioned in the Bible as Esau and Jacob are described at the time of their birth. Esau appears to be the recipient of a twin-to-twin transfusion (Genesis 25:25: “The first one emerged red …”). There is little in the modern medical literature concerning polycythemia in the newborn until the early 1970s [1–5]. During this time, there were a number of case reports and small series of infants with various symptoms that were thought to be secondary to an elevated hematocrit and blood viscosity. It was not until the 1980s that several investigators systematically examined the association between polycythemia, hyperviscosity of the blood, and organ-system dysfunction. These studies have done much to enlighten our understanding of the relationships between abnormalities of the hematocrit, blood viscosity, organ blood flow, and organ function. The dissemination of this knowledge has provided a clinical approach that is based on well-defined data and has clarified the role of polycythemia as an etiologic factor for organ dysfunction in the neonate.

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.