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Introduction
Anemia is a term typically used to describe either a low hemoglobin (Hb) or hematocrit (Hct). Although the word anemia is loosely used in clinical medicine, the exact meaning is difficult to define as it is not binary. Instead, the meaning of an individual Hb or Hct value is relative, requiring interpretation in contemporaneous clinical context.
Although oxygen dissolves in the fluid-based plasma compartment of blood, the amount dissolved is inadequate at standard pressure and temperature to satisfy the needs of aerobic metabolism. Hemoglobin, an iron-containing tetrameric protein located in the red cell, overcomes this problem and is used for transport of molecular oxygen from the lung to the cell.
Commencing late in gestation and continuing throughout the first postnatal months of life, the molecular form of hemoglobin changes from a fetal to an adult configuration. This changes the protein globin structure, altering its affinity for oxygen. Physiologically, the unique characteristic of fetal hemoglobin is that it has a high affinity for oxygen. This allows the fetus, who is in a hypoxemic in utero environment, to draw oxygen away from maternal, adult Hb at the maternal–fetal interface in the placenta. Following birth, in a relatively normoxic milieu, the newborn red cell lineage is programmed to change to producing lower affinity adult Hb. A developmental abnormality of globin chain synthesis (such as thalassemia) can be unmasked during this transition if the infant is genetically at risk.
All newborns, regardless of gestation, develop a physiologic transitional anemia. This reflects an initial failure of the bone marrow to respond to signaling from renal-derived erythropoietin. For the preterm—as opposed to the full-term—newborn this anemia typically commences earlier and is both deeper and longer in duration. Termed anemia of prematurity, this process is almost universal in the premature newborn, frequently prompting a red cell transfusion. Characteristically, this transfusion is triggered by commonly accepted clinical signs. Though it would be preferable to use indications tested by large randomized trials, these are, unfortunately, not yet available. This pattern of anemia in the preterm newborn should be differentiated from “pathologic anemia,” the result of either abnormalities of production or consumption (including bleeding and hemolysis).
Anemia is usually well tolerated in the newborn, particularly if it is a gradual process, until a critical level or threshold is reached. By contrast, a more rapid, acute fall in Hb concentration with hypovolemia (anemic shock) is much less well tolerated and typically requires an emergent response.
The chapter begins with the physiology of oxygen handling, including developmental transition from an intra to extrauterine environment and changes to Hb–oxygen affinity before setting out an etiologic basis of anemia. Lastly, the chapter will separate hypovolemic anemia (a reduction in the total circulating blood and plasma volume) from euvolemic anemia (a constant or normal circulating blood volume but with a low red cell volume and often an increased plasma volume). We then provide an outline of available therapeutic options, including both exogenous erythropoietin and allogeneic adult red cell transfusion.
Clinical questions and case reports are added to frame important principles in the approach to anemia in the newborn.
How to approach anemia in newborn
Beginning in clinical context lets us frame a common clinical situation. What if the junior resident informs you that baby Michael has an Hb of 8.5 g/dL? How can this clinical concern be approached systematically?
Although the Hb value is important, it is only relevant in a clinical context. Thus further information is required before the implications of this single Hb value can be understood and addressed by the treating team.
Both gestation and chronologic age are important, as are the clinical signs of anemic hypovolemia, such as relative tachycardia, low BP, and elevated lactate. In addition, the timing of presentation often provides clues as to the likely diagnosis. Early anemia, at the time of birth, is typically the result of hemorrhage or hemolysis (typically isoimmunization). A blood film will usually differentiate these conditions, and a reticulocyte or nuclear red cell count will separate subacute/chronic from acute hemorrhage. Presentation in the first week is typically related to ex utero hemolysis (though both in utero and ex utero hemolysis may coexist) and/or hemorrhage. In the preterm baby, the hemorrhage may be clinically apparent (pulmonary) or not (brain, liver capsular, etc.). Later anemia, after the second week, is usually the result of upstream conditions (as mentioned earlier) though in the preterm may be anemia of prematurity, whereas in the term newborn it is more typical of physiologic anemia. Persistent anemia after this time is usually either nutritional or genetic ( Fig. 8.1 ).
Understanding the physiology of oxygen handling is particularly important, as Hb is a single constituent part of a complex physiologic process. For this reason, we have begun the chapter with a short section on physiology to provide a foundation that will be helpful throughout the chapter.
Physiology of oxygen delivery
The movement of oxygen from the atmosphere to the cell flows down a well-maintained concentration gradient from the alveolus to the mitochondrion. This carefully choreographed process has many checks and balances but relies on the following physiologic processes: alveolar ventilation, hemoglobin binding to oxygen, blood flow, and passive diffusion.
The pathway ensures oxygen delivery from the lung to the tissues. Oxygen is essential for aerobic metabolism and energy production. Although glucose can be metabolized without oxygen, it is far less efficient. For example, a molecule of glucose generates 1270 kJ in aerobic conditions versus 67 kJ in anaerobic conditions ( ). The cascade in partial pressure of oxygen concentration from a high level in the atmosphere/lung to a much lower (yet adequate) level at the tissue is summarized schematically by Nunn ( Fig. 8.2 ).
Step one: The alveolar–endothelial interface
According to Fick’s law of diffusion, the rate of transfer of a gas across a permeable membrane is directly proportional to the tissue area and the pressure gradient and inversely related to the tissue thickness ( ). This important relationship highlights potential pathology. A likely impairment to diffusion from a widened pulmonary interstitium may occur with alveolar exudate in the setting of primary surfactant deficiency in a preterm newborn.
Step two: From the alveolus to the bloodstream
Once in the fluid plasma compartment, oxygen diffuses rapidly across the red blood cell (RBC) membrane and is taken up by Hb located within the cytoplasm of the red cell. Normal hemoglobin is a tetramer consisting of four protein subunits (globin), each with a heme moiety comprising an iron atom within a porphyrin ring. This complex structure is of itself important for red cell shape, which undergoes conformational changes in response to oxygen binding. In total, each gram of Hb molecule can bind 4 moles or 16 grams of oxygen, which is the equivalent of approximately 1.39 ml.g −1 . The affinity of hemoglobin for oxygen varies as a result of developmental changes to several important variables. These include the structure of Hb, the influence of organic phosphate (2,3 diphosphoglyceric acid DPG), and other exogenous factors, such as temperature, pH, and carbon dioxide (Bohr effect). The key to these complex interactions is the effect of each factor on the sigmoid (nonlinear) shape of the relationship between oxygen and Hb. The Hb–oxygen dissociation curve is particularly relevant in normoxic conditions ensuring uptake of oxygen in an oxygen-abundant environment and subsequent release of oxygen in an oxygen poor setting ( Fig. 8.3 ). The long, flat upper section enables high oxygen saturation over a wide range of alveolar partial pressures. In contrast, the steep middle section at lower partial pressures is more likely encountered in the smaller capillaries where oxygen is unloaded and the Bohr effect (rightward shift in dissociation curve) becomes important.
2,3 DPG is an organic phosphate that binds to the globin chain thereby altering Hb–oxygen affinity. The intraerythrocyte concentration of 2,3 DPG is in flux, dependent on pH.
Step 3: Oxygen transport to the tissue
Blood flow, hemoglobin concentration, and hemoglobin oxygen saturation are the principal determinants of systemic oxygen delivery. Tissue oxygen delivery also depends on the oxygen gradient and distance between the capillary and the cell. However, in the microvasculature, where distance is reduced and the pressure gradient is the highest ( ), the latter two factors do not greatly alter the system and are of minor importance. A value known as the critical mixed venous oxygen threshold—defined as the value before the onset of anaerobic respiration—is conceptually important, though particularly difficult to measure, especially in newborns ( ).
The combination of Hb concentration with oxygen saturation is termed the oxygen content (CaO 2 (arterial) and CvO 2 (venous)). See equation:
The oxygen content value represents the body’s oxygen store located in both venous and arterial compartments. The oxygen balance within each newborn is in a constant flux, as oxygen consumption is balanced by delivery and extraction. This dynamic relationship is often represented theoretically by a simple figure ( Fig. 8.4 ).
At rest, almost all humans operate with an excess of delivery over consumption, resulting in aerobic conditions. As delivery falls (e.g., in hypoxic conditions), consumption increases (e.g., in disease states including fever), or both occur in combination, oxygen extraction increases ( ).
However, the increase in oxygen extraction is limited both by the maintenance of a minimum concentration gradient (as shown in Fig. 8.5 ) and by the amount of oxygen stored on Hb. Eventually, if tissue demand exceeds this threshold of compensation with consumption being restricted or limited by delivery (so-called dependence on oxygen supply), this heralds the onset of anaerobic metabolism and subsequent lactic acidosis.
The complexity and dynamic balance between oxygen delivery and consumption make it evident that there can be no single Hb threshold that consistently results in anemic hypoxia. Moreover, this value need not be stable within an infant over time. In fact, oxygen delivery and consumption will vary within and between newborns. For this reason, the Hb or Hct thresholds used in most clinical trials are based on population-derived best guesses rather than individual physiology. Ideally an individualized approach would be more scientific, though this is currently not feasible in practice ( ).
Flow of RBC in the circulation
Nitric oxide is one of the key determinants of vascular tone in the microcirculation balancing local vasodilation with vasoconstriction. The red cell uses nitric oxide (NO) signaling in a paracrine method to alter the local dynamics of the microcirculation. Whereas free Hb scavenges NO avidly, Hb located within the red cell acts much more slowly. This has important clinical consequences in conditions of intravascular hemolysis, such as might occur in sickle cell disease. In such conditions, free Hb “mops” up NO, reducing vasodilation, and therefore becomes an additional disadvantage to oxygen delivery. In contrast, deoxyHb reduces nitrite to NO, thereby promoting hypoxic dilatation ( ).
Normal hematological values
Hemoglobin
Hemoglobin is a complex structure located in the red cell. The hemoglobin tetramer consists of four globin chains, each surrounding a heme moiety. The heme moiety is the active site of oxygen binding and comprises an iron atom within a porphyrin ring. There are six known globin chain variants. Fetal Hb, designated HbF, comprises two alpha and two gamma chains. It is alkali resistant and has a high affinity for oxygen. Fetal Hb makes up between 50% to 85% of hemoglobin in the newborn but in healthy individuals will disappear by 3 to 4 years of age.
Ontogeny of hemoglobin and globin chains
Hb concentrations gradually increase with advancing gestation (see Fig. 8.5 ). Epsilon (or embryonic) globin is the first globin chain produced. This is quickly followed by α- and γ-globin. Fetal hemoglobin (HbF [α 2 γ 2 ]) is produced from 4 to 5 weeks gestation and depending on gestational age accounts for up to 70% to 90% of the total erythrocyte hemoglobin ( Fig. 8.6 ). Adult hemoglobin (Hb A [α 2 β 2 ] and Hb A 2 [α 2 δ 2 ]), is produced from 6 to 8 weeks but remains in low concentrations until the third trimester. In the postnatal period, the relative concentrations of HbF and HbA change with HbF concentrations falling to approximately 2% by 1 year of age. By 10 weeks’ gestation, hemoglobin concentration is approximately 9 g/dL, increasing throughout gestation until reaching a plateau over the last 6 to 8 weeks of pregnancy. As a result, Hb concentrations at term are typically between 16 to 17 g/dL. In addition, it should be noted that Hb may rise by 1 to 2 g/dL from the effect of placental transfusion and as a result of relative dehydration in the early neonatal interval.
Hemoglobin vs. hematocrit
Hemoglobin is typically expressed as a concentration per unit volume, that is, the amount in grams per liter or deciliter of whole blood. Hematocrit is the volume of red blood cells as a proportion of total blood volume. Both are used interchangeably in definitions of anemia and in trials of transfusion thresholds. A mathematical conversion is set out here.
Erythrocyte maturation is regulated by growth factors produced by the fetus. Erythropoietin (Epo), a 30 to 39 kDa glycoprotein that binds to specific cell surface receptors on erythroid precursors, is the primary regulator of fetal erythropoiesis ( ). Epo does not cross the placenta and is produced by the fetus in the liver ( ). During the first and second trimester, cells of monocyte/macrophage origin produce Epo with manufacture regulated by an oxygen-sensing mechanism involving hypoxia inducible factor (HIF-1). As such, the primary stimulus for Epo production is hypoxia with or without anemia. Fetal Epo increases until birth with serum concentrations normally ranging between 5 and 100 mU/mL compared with 0 to 25 mU/mL observed in healthy adults. However, in comparison to mature newborns, preterms have a poorer bone marrow response, which is one of the important factors resulting in anemia of prematurity ( ). Nonetheless, Epo therapy may still have a therapeutic role. (See later discussion.)
Physiology of red cell production
Several factors are involved, of which the principal components are erythropoietin and iron balance.
Erythropoietin (Epo)
Although the function of erythropoietin has been well described, the mechanism translating changes in tissue oxygen to red cell production has only been defined recently. This is understood to be mediated by a family of transcription factors called hypoxia inducible factors (HIFs), with HIF-A being the most important. In tissue hypoxia, HIF-A rises and in turn stimulates Epo. Knock-in experiments confirm a potential role of HIF-A and its mediators in pathology of polycythemia. Moreover, HIF-A also induces the expression of vascular endothelial growth factor (VEGF), important for angiogenesis and lung alveolarization.
The rapid release of RBCs in response to hypoxia may result in still immature RBCs (nucleated) being circulated. This has been proposed as a biomarker of extent and timing of fetal hypoxia ( ). The time response is over 24 hours duration, making this a potential “timer” of the degree of relatively chronic fetal hypoxia ( ). There have been many attempts made to use the physiology of hypoxia as a guide to transfusion. Direct measures of Epo ( ) and VEGF ( ) have been tried. More complex methods of measuring either available oxygen in vitro, p 50 ( ), or oxygen tissue saturation in the brain ( ) have also been tested. As of yet, none have been found robust, diagnostically useful, and practical viable.
Iron balance
Iron is a key component of the molecule of hemoglobin and thus is the pivot around which the molecule can bind oxygen. For this reason, the body’s iron balance is important for modifying the circulating RBC mass. Because free iron reacts quickly with oxygen (the Fenton reaction) to produce reactive oxygen species (ROS), it is bound to the protein transferrin in the blood, whereas in the cell it is bound to ferritin. The liver senses the amount of iron-transferrin product and will secrete the hormone hepcidin in response, which will in turn raise the protein ferroportin. This regulates small bowel and spleen release of iron into the bloodstream. If iron deficient, the liver releases erythroferrone, which blocks hepcidin and stimulates release of iron from the duodenum and spleen and liver. This is summarized in Fig. 8.7 .
Other controllers of erythroblastosis
Although a detailed review of these is outside the scope of this chapter, the reader should be aware that a host of other transcription factors apart from HIFs are likely to be named as important in the near future. Of these, the forkhead box 03 protein (FOX03) is likely the most important. This is known to regulate the final stages of erythroid maturation in the bone marrow.
Range of normal red blood cell indices in the fetus and neonate
The effect of gestational age on hematocrit, hemoglobin, mean corpuscular volume, and reticulocytosis in shown in Table 8.1 ( ). Erythrocyte indices vary across gestation and continue to change through the first year of life. Hematocrit (Hct) increases from 30% to 40% during the second trimester before reaching 50% to 63% at term. As the practice of deferred umbilical cord clamping has become routine, much higher hematocrit levels are frequently observed ( ). Lastly, Hct and Hb vary according to the sampling site with higher levels from capillary samples.
TABLE 8.1
Changes in Hematocrit, Hemoglobin, Mean Corpuscular Volume, and Reticulocyte Count With Advancing Gestational Age
From Christensen RD: Expected hematologic values for term and preterm neonates. In Christensen RD, editor: Hematologic problems of the neonate, Philadelphia, 2000, Saunders, p 120.
| Gestational Age (wk) | Hematocrit (%) a | Hemoglobin (g/dL) | MCV (fl) | Reticulocytes (%) |
|---|---|---|---|---|
| 18–20 b | 36 ± 3 | 11.5 ± 0.8 | 134 ± 9 | NR |
| 21–22 b | 38 ± 3 | 12.3 ± 0.9 | 130 ± 6 | NR |
| 22–23 b | 38 ± 3 | 12.4 ± 0.9 | 125 ± 1 | NR |
| 24–25 | 63 ± 3 | 19.4 ± 1.5 | 135 ± 0 | 6.0 ± 0.5 |
| 26–27 | 62 ± 3 | 19.0 ± 2.5 | 132 ± 14 | 9.6 ± 3.2 |
| 28–29 | 60 ± 3 | 19.3 ± 1.8 | 131 ± 14 | 7.5 ± 2.5 |
| 30–31 | 60 ± 3 | 19.1 ± 2.2 | 127 ± 13 | 5.8 ± 2.0 |
| 32–33 | 60 ± 3 | 18.5 ± 2.0 | 123 ± 10 | 5.0 ± 1.9 |
| 34–35 | 61 ± 3 | 19.6 ± 2.1 | 122 ± 10 | 3.9 ± 1.6 |
| 36–37 | 64 ± 3 | 19.2 ± 1.7 | 121 ± 12 | 4.2 ± 1.8 |
| Term | 61 ± 3 | 19.3 ± 2.2 | 119 ± 9 | 3.2 ± 1.4 |
MCV, Mean corpuscular volume; NR, not reported.
With advancing gestation, erythrocyte size and volume decrease. This continues in the postnatal period with values reaching those commonly seen in adults by 1 year of age. Mean corpuscular volume (MCV) decreases from over 180 fL in the embryo, to 130 to 140 fL by midgestation, and, finally, 115 fL by the end of pregnancy. A low MCV (values below the fifth percentile) at birth is most commonly seen in α-thalassemia trait or hereditary spherocytosis but may also be caused by fetal iron deficiency as a result of chronic feto-maternal hemorrhage (FMH) or twin-to-twin transfusion syndrome. In the postpartum period, MCV continues to fall, more quickly in preterm infants, such that by 1 year of age mean MCV is typically 82 fL.
There is also marked variability in erythrocyte shape and deformability. Neonatal erythrocytes have higher mean corpuscular hemoglobin concentrations (MCHC) remaining constant at 33 to 34 g/dL from approximately 32 weeks’ gestation through to adulthood. Several conditions affect RBC volume because of compression of hemoglobin, such as in hereditary spherocytosis, ABO incompatibility, or microangiopathic hemolytic anemia. These are all associated with elevated MCHC as the surface area of the RBC decreases while the hemoglobin concentration remains stable (thus being relatively more concentrated).
In the preterm newborn, erythrocyte life span is typically 35 to 50 days compared with 60 to 90 days in the term newborn and 120 days in adults ( ). Red cell deformability is a particularly important determinant of red cell life span in vivo. This is principally governed by three factors: the surface-area/volume relationship, the viscosity of the cytoplasm of the cell, and intrinsic differences in the fetal and neonatal erythrocyte membrane. Fetal and neonatal erythrocytes are also at increased susceptibility to oxidative injury from differences in glycolytic and pentose phosphate pathways ( ). Oxidative injury will result in increased glutathione instability, Heinz body formation, methemoglobinemia (MetHb), and ultimately hemolysis in situations of severe hypoxia and/or acidosis ( ).
Rates of hemoglobin synthesis and erythrocyte production are low in the immediate postnatal period due to the dramatic increase in tissue oxygenation. This is further compounded by a shortened red cell life span and plasma dilution with an increase in blood volume related to growth. Whereas the reticulocyte count is elevated at birth, the postnatal period is typically characterized by a significant fall in erythropoiesis. This results in an Hb nadir between 9 and 11.2 g/dL in full-term infants at approximately 4 to 8 weeks of age ( ). Reticulocyte counts subsequently increase in response to the Hb nadir as a result of erythropoiesis. For the preterm or very low birth weight newborn, this postnatal fall is exaggerated. This occurs for a variety of reasons, including significant phlebotomy losses in addition to the down regulation of endogenous erythropoiesis from the effect of “top up” transfusions ( ). These factors together lead to a significantly greater fall in hemoglobin concentration in the first few weeks of life in the preterm compared with term newborn. [ ]). Conversely, newborns exposed to in utero hypoxemia, such as those born small for gestational age or those born at higher altitudes, tend to have a higher high red cell mass, or polycythemia.
Disorders of anemia
Let us return to the original clinical story. What if the junior resident informs you that baby Michael has a Hb of 8.5 g/dL? The cause of anemia can be sort by sequential reasoning. An example follows.
If Michael is a newly born baby and
- 1.
the cord SBR is elevated, the blood film shows fragmentation, and the DCT is positive, then baby Michael likely has blood group incompatibility.
- 2.
the cord SBR is not elevated, the blood film shows reticulocytosis, and the DCT is negative, then baby Michael likely has had a subacute hemorrhage, probably feto–maternal.
This simple approach will allow the reader to develop a list of likely causes that will require confirmation with further investigation. In addition to a method to sort diagnosis, a further approach to therapy is dependent on the clinical circumstance.
For example if baby Michael has:
- 1.
hypovolemic anemia with commensurate hemodynamic instability (or shock) and raised HR, low BP, and clinically poor circulation with elevated lactate, then he requires prompt RBC transfusion.
- 2.
normovolemic anemia with a normal HR and BP for gestational age and clinically sound circulation with normal lactate concentration, then transfusion can be deferred.
Definition of anemia
There are a number of approaches to the definition of anemia in the newborn. Statistically, anemia can be defined as the red cell number, Hct or Hb less than 2 SD below the mean value. This approach, however, is likely to include a small percentage of values in normal, normoxic, stable newborns. An example of this approach is shown in Table 8.2 . Alternatively, anemia can be defined by a physiology-based approach. An example would be to define the Hb value adjacent to the onset of anaerobic respiration. This can be identified from either a change in the slope (steeper) of the oxygen delivery–consumption curve or accumulation of lactate ( ). Although this physiologic approach to the definition of anemia may be the ideal, it is too impractical for general application.
TABLE 8.2
Normal Hematologic Values in Healthy Term Infants a During the First Year of Life
From Saarinen UM, Slimes MA; Developmental changes in red blood cell counts, and indices of infants after exclusion of iron deficiency by laboratory criteria and continuous iron supplementation, J Pediatr 92;414, 1978.
| Age(mo) b | |||||||
|---|---|---|---|---|---|---|---|
| 0.5 (n = 232) | 1 (n = 240) | 2 (n = 241) | 4 (n = 52) | 6 (n = 52) | 9 (n = 56) | 12 (n = 56) | |
| Hemoglobin (mean ± SE) −2 SD |
|||||||
| 16.6 ± 0.11 | 13.9 ± 0.1 | 11.2 ± 0.06 | 12.2 ± 0.14 | 12.6 ± 0.1 | 12.7 ± 0.09 | 12.7 ± 0.09 | |
| 13.4 | 10.7 | 9.4 | 10.3 | 11.1 | 11.4 | 11.3 | |
| Hematocrit (mean ± SE) −2 SD |
|||||||
| 53 ± 0.4 | 44 ± 0.3 | 35 ± 0.2 | 38 ± 0.4 | 36 ± 0.3 | 36 ± 0.3 | 37 ± 0.3 | |
| 41 | 33 | 28 | 32 | 31 | 32 | 33 | |
| RBC count (mean ± SE) −2 SD + 2 SD |
|||||||
| 4.9 ± 0.03 | 4.3 ± 0.03 | 3.7 ± 0.02 | 4.3 ± 0.06 | 4.7 ± 0.05 | 4.7 ± 0.04 | 4.7 ± 0.04 | |
| 3.9 − 5.9 | 3.3 − 5.3 | 3.1 − 4.3 | 3.5 − 5.1 | 3.9 − 5.5 | 4.0 − 5.3 | 4.1 − 5.3 | |
| MCH (mean ± SE) −2 SD |
|||||||
| 33.6 ± 0.1 | 32.5 ± 0.1 | 30.4 ± 0.1 | 28.6 ± 0.2 | 26.8 ± 0.2 | 27.3 ± 0.2 | 26.8 ± 0.2 | |
| 30 | 29 | 27 | 24 | 24 | 25 | 24 | |
| MCV (mean ± SE) −2 SD |
|||||||
| 105.3 ± 0.6 | 101.3 ± 0.3 | 94.8 ± 0.3 | 86.7 ± 0.8 | 76.3 ± 0.6 | 77.7 ± 0.5 | 77.7 ± 0.5 | |
| 88 | 91 | 84 | 76 | 68 | 70 | 71 | |
| MCHC (mean ± SE) −2 SD |
|||||||
| 314 ± 1.1 | 318 ± 01.2 | 318 ± 1.1 | 327 ± 2.7 | 350 ± 1.7 | 349 ± 1.6 | 343 ± 1.5 | |
| 281 | 281 | 283 | 288 | 327 | 324 | 321 | |
MCH, Mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell; SD, standard deviation; SE, standard error of the mean.
a These values were obtained from a selected group of 26 healthy term infants followed up at the Helsinki University Central Hospital who were receiving continuous iron supplementation and who had normal values for transferrin saturation and serum ferritin.
b Values at the ages of 0.5, 1, and 2 months were obtained from the entire group, and those at the later ages were obtained from the iron-supplemented infant group after exclusion of iron deficiency.
Usually, anemia is defined more loosely, using a mix of clinical criteria and expert opinion ( ). In preterm newborns, the Hb or Hct values so compiled form the basis of comparison in randomized trials ( ; ) (a high or a low transfusion threshold). Regardless of definition, the etiology of anemia can be considered under the broad headings of reduced production, hypovolemia, or bleeding.
Reduced production
Neonatal anemia in term newborns secondary to decreased erythrocyte production is quite rare. Of known causes, congenital infections with a marrow suppression of erythrocyte production are most common. Other causes include genetically determined abnormalities, bone marrow replacement syndromes, and maternal nutritional deficiencies.
Congenital infection may lead to bone marrow failure and hemolysis. There are a number of bacterial and viral infections that result in hemolysis and subsequent anemia. Parvovirus B 19 , however, selectively infects erythroid precursors and inhibits both growth and maturation. Infection in children and adults is benign, often characterized by fever, vomiting, diarrhea, and a maculopapular exanthem of the face (slapped-cheek syndrome). However, infection in pregnant women may result in profound fetal anemia and nonimmune hydrops. Although the fetal anemia and hydrops may resolve, the fetus is at significant risk of demise. In utero transfusions are not infrequently used to successfully treat this reversible condition in affected fetuses. Other infections associated with neonatal anemia include congenital malaria and human immunodeficiency virus (HIV), either the result of primary infection or secondary to maternal antiviral therapy.
Nutritional anemia
In developed countries, nutritional anemia is infrequent in the newborn, and yet it is the most common cause of anemia after the first 3 to 6 months and in the first year of life. Iron deficiency, characterized by hypochromic, microcytic red cells with a low hematocrit, is rare at birth. If present, it is commonly the result of either acute prenatal or significant chronic blood loss, for instance in the context of chronic feto–maternal hemorrhage or twin-to-twin transfusion syndrome. More commonly however, it develops over the first weeks and months of life with preterm neonates at particular risk from with inadequate nutritional (iron) supplementation. The use of Epo to prevent and treat anemia in preterm infants can also result in iron deficiency when iron supplementation is inadequate. There is an interaction between total iron stores and the weaning from milk with possible inadequate iron supplementation. This is further influenced by the movement toward deferred cord clamping and the likelihood of adverse intellectual development ( ). Worldwide, avoiding iron deficiency in infancy is the most important reason to employ deferred cord clamping.
Red cell folate concentrations represent total body folate stores. Folate deficiency can result in a megaloblastic anemia, with the MCV generally greater than 110 fL. Folate deficiency can result from a folate-poor diet (as is the case with weaned infants fed goat’s milk) or from congenital folate malabsorption, defective cellular folate uptake, and inborn errors of folate metabolism. Supplementation is particularly important in situations of increased erythropoiesis.
Vitamin B12 deficiency anemia is also rare in the newborn. It can occur in breastfed infants of deficient mothers. B 12 deficiency may also be the result of malabsorption in newborns with short-gut syndrome and with inborn errors of metabolism, including deficiency of haptocorrin and transcobalamin ( ). Other less frequent deficiencies in the newborn include vitamin E deficiency, which results in a hemolytic anemia. This hemolysis is related to the vitamin’s actions as an antioxidant, inhibiting peroxidation of polyunsaturated fatty acids (PUFAs).
Finally, copper deficiency, characterized by sideroblastic, hypochromic anemia, may occur in low birth weight premature infants when enteral or parenteral nutrition is poor in quality or in conditions associated with chronic diarrhea with severe malnutrition.
Genetic syndromes
Congenital syndromes may primarily diminish or inhibit red cell production or secondarily alter the red cell mass through hemolysis. Syndromes associated with anemia in the neonatal period and infancy is outlined in Table 8.3 .
TABLE 8.3
Congenital Syndromes Associated with Anemia
| Syndrome | Genetic Characteristics | Hematologic Phenotype |
|---|---|---|
| Diamond Blackfan anemia | Autosomal recessive (AR); sporadic mutations and autosomal dominant (AD) inheritance have been described | Steroid responsive hypoplastic anemia, macrocytic after 5 months of age |
| Shwachman Diamond syndrome | AR – mutations in Shwachman Bodian Diamond syndrome (SBDS) gene, chromosome 17q11 | Neutropenia most common, anemia and thrombocytopenia can occur |
| Fanconi pancytopenia | AR – multiple gene abnormalities (at least 5 genetic subtypes) | Steroid responsive hypoplastic anemia, reticulocytopenia, some macrocytic RBCs, shortened RBC life span |
| Aase syndrome | AR, possible AD | Steroid responsive hypoplastic anemia that improves with age |
| Pearson’s syndrome | Mitochondrial DNA abnormalities, X-linked or AR | Hypoplastic sideroblastic anemia unresponsive to pyridoxine |
| Osteopetrosis | AR – defective resorption of immature bone | Hypoplastic anemia caused by marrow suppression |
| Congenital dyserythropoietic anemias (CDA) | AR | Type I: megaloblastic erythroid hyperplasia and nuclear chromatin bridges between cells Type II: erythroblastic multinuclearity and positive acidified serum test result |
| Peutz Jeghers syndrome | AD | Iron deficiency anemia from chronic blood loss |
| Dyskeratosis congenita | X-linked recessive, locus Xq28, some cases AD | Hypoplastic anemia usually presenting between 5–15 years of age |
| X-linked α-thalassemia/mental retardation (ATR-X and ATR-16) syndromes | ATR-X: X-linked recessive, mapped to Xq13.3 ATR-16: mapped to 16p13.3, deletions of α-globin locus |
ATR-X: hypochromic, microcytic anemia; mild form of hemoglobin H disease ATR-16: more significant hemoglobin H disease |
| Thrombocytopenia-absent radius syndrome (TAR) | AR | Hemorrhagic anemia, possibly hypoplastic anemia as well |
| Osler hemorrhagic telangiectasia syndrome | AD, mapped to 9q33–34 | Hemorrhagic anemia |
Fetal and neonatal hemorrhage
Hemorrhage occurring before birth or during delivery is usually a transplacental process from abnormalities of placentation, such as twin-to-twin transfusion or feto–maternal hemorrhage (FMH), or as a result of antepartum hemorrhage and vasa previa.
Feto–maternal hemorrhage
FMH is almost universal in pregnancy but of little consequence if small in volume ( ). However, in a very small number, FMH can have a significant clinical impact, including hydrops fetalis and even in utero death. Typically, the hemorrhage is slow and subacute, although occasionally newborns may present with anemia from combined subacute or chronic blood loss in addition to an acute process. This may result in biventricular heart failure with persistent pulmonary hypertension, hypovolemic shock, and subsequent neurologic injury. Lastly, FMH (from an Rh-positive newborn) may sensitize an antigen-negative mother, resulting in isoimmunization in future pregnancies.
The Kleihauer-Betke laboratory test is frequently used to detect fetal red blood cells in the maternal circulation. Quantitative estimation of the volume of the FMH is possible using the formula: 2400 × the ratio of fetal to maternal cells = 1 mL of fetal blood. Caution is required in conditions that elevate maternal HbF production.
Case 1
Baby Ezekiel is born at term by emergency cesarean section after a history, from his mother, of reduced fetal movements in the previous 24 hours. The cardiotocograph (CTG) showed a sinusoidal trace. He is in fair condition at birth, breathing spontaneously, although he is noted to be slightly grunting and pale by clinical attendants. He is assigned Apgar scores of 5 and 8 before being taken to the neonatal nursery.
On arrival he has a HR 140, systolic BP 40 mm Hg, and an Sa o 2 88% in 21% inspired oxygen but 98% with 30% inspired oxygen. On further examination the liver and spleen are slightly enlarged.
Exercise 1
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