Understanding the development of specific components of the neonatal immune system is critical to the understanding of the susceptibility of the neonate to specific pathogens [1]. With the increasing survival of extremely premature infants, neonatologists and other physicians caring for these newborns need to be aware of the vulnerability of this population. Furthermore, it is important for neonatologists to be able to differentiate between immune immaturity and the manifestations of a true primary immunodeficiency that present during the neonatal period. Failure to properly identify primary or acquired immunodeficiency diseases can result in delayed diagnosis and treatment, adversely affecting outcomes. This chapter will briefly define the immune immaturity of the neonate and a diagnostic approach for primary immune deficiency diseases that may present in the neonatal period.

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.

Hematopoiesis refers to the continuous production and release of blood cells into the circulation. As blood cells become old or injured, self-renewing hematopoietic stem cells (HSC) proliferate and differentiate to replenish multiple hematopoietic lineages. This process produces nearly 200 billion red blood cells, 10 billion white blood cells, and 400 billion platelets every day. In addition to the requirement for high cell production, the concentration of individual blood cell lineages is precisely regulated in the peripheral blood and tissues. The production and use of circulating blood cells increase during periods of altered homeostasis such as defense against infection or replenishment of circulating red cells after hemorrhage. When the tightly regulated production of blood cells fails, the host may encounter life-threatening anemia or other cytopenias or suffer from excessive neoplastic growth of blood cells manifesting as leukemia.

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].

Thromboembolism (TE) in pediatrics is relatively rare compared with adults, with an estimated venous thromboembolism (VTE) incidence of 0.07–0.14/10,000 children [1, 2]. A bimodal age distribution has been well demonstrated in the pediatric VTE population and children less than 1 year of age, especially those less than 1 month of age, are most commonly affected [1, 2]. The incidence of VTE in this very young population, particularly when hospitalized, is increasing [3–6]. Between 1997 and 2018, up to a 13-fold increase in neonatal TE incidence has been described in all live births and a greater than six-fold increase in neonatal TE incidence has been described for neonatal intensive care unit (NICU) admissions [4–7]. This increase has been attributed to improving survival rates in critically ill and/or premature neonates, the increased utilization of central venous catheters (CVC), and a much greater awareness of VTE and the associated risk factors in this population [3, 6, 8, 9]. The aim of this chapter is to review the congenital and acquired risk factors associated with neonatal TE and to discuss the clinical presentation, diagnosis, and management of this rare complication that has been shown to significantly impact the morbidity and mortality rates of those afflicted [1–3, 8].

“Normal ranges” for hematologic values of neonates are not available. This is because blood is not drawn on healthy normal neonates to establish such ranges, as is done with the consent of healthy adult volunteers. Instead, neonatal hematology utilizes “reference intervals.” These consist of 5th to 95th percentile values compiled from laboratory tests that were performed on neonates thought to have minimal pathology relevant to the specific laboratory test under consideration, or with pathology unlikely to significantly affect that test result. The premise on which the reference interval concept is based is that these values approximate normal ranges, although they were admittedly obtained for a clinical reason and not from healthy volunteers. Basically, reference intervals are the best tools we have to interpret a neonate’s complete blood count (CBC), and they likely will continue to be the best we will have for several years to come [1].

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.

In addition to quantitative neutrophil abnormalities, innate immunity, and thus risk of infection in a neonate, may be negatively impacted by qualitative phagocyte defects. The term phagocyte stems from the Greek “phagein” meaning “to eat or devour” and “cyte” meaning “cell” and refers to hematopoietic derived cells, namely monocytes, macrophages and neutrophils capable of engulfing and digesting microorganisms, foreign particles, and cellular debris. Neutrophils are also classified as granulocytes, given the characteristic presence of granules in their cytoplasm that play a key role in neutrophil function.

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.

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.

Diagnosing anemia in a neonate is only a first step in a process that includes: clarifying the pathology responsible for the anemia, instituting the best-known therapy (if indeed a treatment is warranted), and then evaluating whether the therapy administered was effective in alleviating the anemia. Chapters 4, 6–10 and 20 focus on the principal varieties of anemia that occur in the neonatal period. The purpose of this chapter is not to repeat material detailed there, but to provide a method for navigating the somewhat unique process of diagnosing neonatal anemia and then discovering its cause. To accomplish this purpose, the chapter is organized into two parts: (1) making the diagnosis of anemia in neonates using reference intervals appropriate for gestational and postnatal age, and (2) following an evaluative algorithm to identify the underlying cause of the anemia in a neonatal patient.

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.

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.

Anemia of prematurity is a multifactorial anemia, characterized by relatively low plasma erythropoietin (EPO) levels, iatrogenic blood loss, low circulating blood volumes and insufficient erythropoiesis. This anemia has been long characterized as nutritionally insensitive, but nutrition may influence its clinical course. Anemia of prematurity is treated with erythrocyte transfusions. However, delaying umbilical cord clamping may increase initial hematocrit percentages, improve infant iron status, prevent erythrocyte transfusions, decrease necrotizing enterocolitis (NEC), and decrease intraventricular hemorrhage (IVH). Many published studies have examined the potential of therapy with recombinant human EPO or other erythropoietic stimulating agent (ESA). Although EPO therapy is associated with statistically lower number of total erythrocyte transfusions, most early transfusions are not eliminated. However, early erythropoietic EPO dosing may also decrease NEC and IVH as well as improve neurocognitive outcomes. A recent systematic review refuted previous concerns that early administration of EPO was associated with increased retinopathy of prematurity (ROP). Early high dose EPO regimens are currently being studied for neuroprotection in premature infants. Iron deficiency in EPO treatment is also of potential concern, but long-term iron status of EPO treated premature infants is similar to controls.