NEONATAL ERYTHROPOIESIS AND RED CELLS
Hemoglobin, Hematocrit, and Indices
The mean hemoglobin level in cord blood at term is 16.8 g/dL, with 95 percent of the values falling between 13.7 and 20.1 g/dL.73 This variation reflects perinatal events, particularly asphyxia,74 and also the amount of blood transferred from the placenta to the infant after delivery. Early cord clamping appears to heighten the occurrence of anemia at 2 months and to impair cardiopulmonary adaptation.75 Delay of cord clamping may increase the blood volume and red cell mass of the infant by as much as 55 percent.76,77 This results in fewer transfusions and fewer days requiring oxygen and ventilation in preterm infants.75 The mean total blood volume after birth is 86 mL/kg for the term infant and 89 mL/kg for the premature infant.78 The blood volume per kilogram decreases over the ensuing weeks, reaching a mean value of approximately 65 mL/kg by 3 to 4 months of age.
Normally the hemoglobin and hematocrit values rise in the first several hours after birth because of the movement of plasma from the intravascular to the extravascular space.79 A venous hemoglobin concentration of less than 14 g/dL in a term infant and/or a fall in hemoglobin or hematocrit level in the first postnatal day are abnormal. Table 7–2 shows the normal red cell values from capillary blood samples for term infants in the first 12 weeks after birth.80 Capillary hematocrit values in newborns are higher than those in simultaneous venous samples, particularly during the first postnatal days, and the capillary-to-venous ratio is approximately 1.1:1.81 This difference reflects circulatory factors and is greater in preterm and sick infants.
Table 7–2.Red Cell Values for Term Infants during the First 12 Weeks after Birth* ||Download (.pdf) Table 7–2. Red Cell Values for Term Infants during the First 12 Weeks after Birth*
|Age ||Hbg, g/dL ± SD ||RBC × 1012/L ± SD ||Hematocrit, % ± SD ||MCV, fL ± SD ||MCHC, g/dL ± SD ||Reticulocytes, % ± SD |
|DAYS || || || || || || |
|1 ||19.3 ± 2.2 ||5.14 ± 0.7 ||61 ± 7.4 ||119 ± 9.4 ||31.6 ± 1.9 ||3.2 ± 1.4 |
|2 ||19.0 ± 1.9 ||5.15 ± 0.8 ||60 ± 6.4 ||115 ± 7.0 ||31.6 ± 1.4 ||3.2 ± 1.3 |
|3 ||18.8 ± 2.0 ||5.11 ± 0.7 ||62 ± 9.3 ||116 ± 5.3 ||31.1 ± 2.8 ||2.8 ± 1.7 |
|4 ||18.6 ± 2.1 ||5.00 ± 0.6 ||57 ± 8.1 ||114 ± 7.5 ||32.6 ± 1.5 ||1.8 ± 1.1 |
|5 ||17.6 ± 1.1 ||4.97 ± 0.4 ||57 ± 7.3 ||114 ± 8.9 ||30.9 ± 2.2 ||1.2 ± 0.2 |
|6 ||17.4 ± 2.2 ||5.00 ± 0.7 ||54 ± 7.2 ||113 ± 10.0 ||32.2 ± 1.6 ||0.6 ± 0.2 |
|7 ||17.9 ± 2.5 ||4.86 ± 0.6 ||56 ± 9.4 ||118 ± 11.2 ||32.0 ± 1.6 ||0.5 ± 0.4 |
|WEEKS || || || || || || |
|1–2 ||17.3 ± 2.3 ||4.80 ± 0.8 ||54 ± 8.3 ||112 ± 19.0 ||32.1 ± 2.9 ||0.5 ± 0.3 |
|2–3 ||15.6 ± 2.6 ||4.20 ± 0.6 ||46 ± 7.3 ||111 ± 8.2 ||33.9 ± 1.9 ||0.8 ± 0.6 |
|3–4 ||14.2 ± 2.1 ||4.00 ± 0.6 ||43 ± 5.7 ||105 ± 7.5 ||33.5 ± 1.6 ||0.6 ± 0.3 |
|4–5 ||12.7 ± 1.6 ||3.60 ± 0.4 ||36 ± 4.8 ||101 ± 8.1 ||34.9 ± 1.6 ||0.9 ± 0.8 |
|5–6 ||11.9 ± 1.5 ||3.55 ± 0.2 ||36 ± 6.2 ||102 ± 10.2 ||34.1 ± 2.9 ||1.0 ± 0.7 |
|6–7 ||12.0 ± 1.5 ||3.40 ± 0.4 ||36 ± 4.8 ||105 ± 12.0 ||33.8 ± 2.3 ||1.2 ± 0.7 |
|7–8 ||11.1 ± 1.1 ||3.40 ± 0.4 ||33 ± 3.7 ||100 ± 13.0 ||33.7 ± 2.6 ||1.5 ± 0.7 |
|8–9 ||10.7 ± 0.9 ||3.40 ± 0.5 ||31 ± 2.5 ||93 ± 12.0 ||34.1 ± 2.2 ||1.8 ± 1.0 |
|9–10 ||11.2 ± 0.9 ||3.60 ± 0.3 ||32 ± 2.7 ||91 ± 9.3 ||34.3 ± 2.9 ||1.2 ± 0.6 |
|10–11 ||11.4 ± 0.9 ||3.70 ± 0.4 ||34 ± 2.1 ||91 ± 7.7 ||33.2 ± 2.4 ||1.2 ± 0.7 |
|11–12 ||11.3 ± 0.9 ||3.70 ± 0.3 ||33 ± 3.3 ||88 ± 7.9 ||34.8 ± 2.2 ||0.7 ± 0.3 |
The red cells of the newborn are macrocytic, with an MCV in excess of 110 fL/cell. The MCV begins to fall after the first week, reaching adult values by the ninth week (see Table 7–2).80,82 The blood film from a newborn infant shows macrocytic normochromic cells, polychromasia, and a few nucleated red blood cells. Even in healthy infants there may be mild anisopoikilocytosis.83 Three to 5 percent of the red cells may be fragments, target cells, or otherwise distorted. By 3 to 5 days after birth, nucleated red blood cells are not found normally in the blood of term or premature infants, but they may be present in markedly elevated numbers in the presence of hemolysis or hypoxic stress. As expected from these findings, the red cell distribution width (RDW) is markedly elevated in the newborn period.84
There are significant numbers of circulating progenitor cells in cord blood.85,86,87 Cord blood BFU-E and colony-forming unit–erythroid (CFU-E) differentiate more rapidly than their adult counterparts.88 Furthermore, the proportion of cord blood hematopoietic progenitors in the mitotic cycle is approximately 50 percent, intermediate between the proportions found in fetal and adult progenitor cells.72,86
In several,89,90 but not all,91 studies, premature infants at birth had lower hemoglobin levels, higher reticulocyte counts, and higher nucleated red cell counts than did the term infants. The reticulocyte counts of premature infants are inversely proportional to their gestational age, with a mean of 8 percent reticulocytes evident at 32 weeks’ gestation and 4 to 5 percent at term.92 Infants who are small for their gestational ages have higher red cell counts, hematocrit levels, and hemoglobin concentrations as compared with infants whose size is appropriate for their gestational age.90,93
Erythropoietin and Physiologic Anemia of the Newborn
Erythropoietin is the primary regulator of erythropoiesis (Chaps. 32 and 33). Although erythropoietin is present in cord blood, it falls to undetectable levels after birth in healthy infants.94 Subsequently, the reticulocyte count falls to less than 1 percent by the sixth day after birth.80,95 The red cell, hemoglobin, and hematocrit values decrease only slightly during the first week, but decline more rapidly in the following 5 to 8 weeks (see Table 7–2),80 producing the physiologic anemia of the newborn. The lowest hemoglobin values in the term infant occur at approximately 2 months of age.82 When the hemoglobin concentration falls below 11 g/dL, erythropoietic activity begins to increase. Erythropoietin can be measured after the 60th postnatal day,96 corresponding to the recovery from physiologic anemia. If there is sufficient stimulus, such as hemolytic anemia or cyanotic heart disease, the newborn infant is able to produce erythropoietin prior to the 60th postnatal day.94
The fall in hemoglobin level is more pronounced in the premature infant. In one study of premature infants, the mean hemoglobin level at 2 months was 9.4 g/dL, with a 95 percent range of 7.2 to 11.7 g/dL.97 In healthy premature infants erythropoietin becomes detectable when the hemoglobin level falls to approximately 12 g/dL. In infants with a lower percentage of Hgb F (as from transfusion) and, consequently, better oxygen delivery, erythropoietin does not rise until the hemoglobin falls to approximately 9.5 g/dL.98 The mean values for iron-sufficient premature infants reached those of term infants by 4 months for red cell count, 5 months for hemoglobin level, and 6 months for mean corpuscular volume and mean corpuscular hemoglobin.97
The viscosity of blood increases logarithmically in relation to the hematocrit.99,100 Hyperviscosity was found in 5 percent of infants,101 and in 18 percent of infants who were small for gestational age.102 Newborn infants with hematocrit values of greater than 65 to 70 percent may become symptomatic because of increased viscosity.103 In one study of infants with documented hyperviscosity and a mean hematocrit greater than 65 percent, 38 percent displayed symptoms of irritability, hypotonia, tremors, or poor suck reflex.104 Partial plasma exchange transfusion reduced blood viscosity, improved cerebral blood flow, and relieved the symptoms. However, cerebral blood flow was normal in the asymptomatic infants with hyperviscosity, and, consequently, there was no benefit from exchange transfusion.104 Studies of neurodevelopmental status do not show any clear long-term benefits for the use of partial exchange transfusions in asymptomatic neonates.105
The blood group antigens on neonatal red cells differ from those of the older child and adult. The i antigen is expressed strongly, whereas the I antigen and the A and B antigens are expressed only weakly on neonatal red cells. The i antigen is a straight-chain carbohydrate that is replaced by the branched-chain derivative, I antigen, as a result of the developmental acquisition of a glycosyltransferase.106 By 1 year of age the i antigen is undetectable, and the ABH antigens increase to adult levels by age 3 years (Chap. 136). The ABH, Kell, Duffy, and Vel antigens can be detected on the cells of the fetus in the first trimester and are present at birth.107 The Lua and Lub antigens also are detectable on fetal red cells and are more weakly expressed at birth, increasing to adult levels by age 15 years.107 The Xg antigen is variably expressed in the fetus and is weaker on newborn than on adult red cells. Moreover, particularly poor expression of Xg has been noted in newborns with trisomy 13, 18, and 21.107 The Lewis group (Lea/Leb) antigens are adsorbed on the red cell membrane and become detectable within 1 to 2 weeks after birth as the receptor sites develop. Anti-A and anti-B isohemagglutinins develop during the first 6 postnatal months, reaching adult levels by 2 years of age.
The life span of the red cells in the newborn infant is shorter than that of red cells in the adult (Chap. 33). The average of several studies of mean half-life of newborn red cells is 60 to 80 days.108 The reasons for this shortened survival are unclear, but the known susceptibility to oxidant injury of newborn red cells may be a contributing factor.
The serum iron level in cord blood of the normal infant is elevated compared to maternal levels. The mean value is approximately 150 ± 40 mcg/dL (1 SD).109 Infants on an iron-supplemented diet have a median serum iron level of 125 mcg/dL at 1 month of age and of approximately 75 mcg/dL at 6 months of age. The total iron-binding capacity rises throughout the first year. The median transferrin saturation falls from almost 65 percent at 2 weeks to 25 percent at 1 year, and saturations as low as 10 percent may be observed in the absence of iron deficiency.110 The mean serum ferritin levels in iron-sufficient infants are high at birth, 160 mcg/L, rise further during the first month, and then fall to a mean of 30 mcg/L by 1 year of age.111 The amount of stainable iron in the marrow at birth is small but increases in both term and premature infants during the first weeks after birth. Stainable marrow iron begins to decrease after 2 months and is gone by 4 to 6 months in term infants and earlier in premature infants.112 Iron is preferentially allocated to erythropoiesis if the availability of iron is limited.113 This makes the availability of adequate iron particularly important to avoid iron lack in the brain, heart, and skeletal muscle.
The oxygen affinity of cord blood is greater than that of maternal blood, because the affinity of Hgb F for 2,3-bisphosphoglycerate (2,3-BPG) is less than that of Hgb A.114 Levels of 2,3-BPG are lower in newborn red cells than in adult cells and even more decreased in the red cells of premature infants,115 and this low 2,3-BPG level further heightens the oxygen affinity of newborn red cells. Consequently, the red cell oxygen equilibrium curve of the newborn is shifted to the left of that of the adult (Fig. 7–3). The mean partial pressure of oxygen (pO2) at which hemoglobin is 50 percent saturated with oxygen at 1 day of age in term infants is 19.4 ± 1.8 torr, as compared with the normal adult value of 27.0 ± 1.1 torr.116 This results in a decrease in the oxygen released at the tissue level, as shown in Fig. 7–3. As the partial pressure of oxygen (Po2) falls from 90 torr in arterial to 40 torr in the venous blood, 3.0 mL/dL of oxygen are released from newborn blood, whereas 4.5 mL/dL are released from adult Hgb A-containing blood. The shift to the left of the oxygen equilibrium curve is even more pronounced in the premature infant, requiring a larger fall in Po2 to release an equivalent amount of oxygen. After birth the oxygen equilibrium curve shifts gradually to the right, reaching the position of the adult curve by 6 months of age. The position of the curve in the premature infant correlates with gestational age rather than with postnatal age,116 and its shift to the adult position is more gradual.
The oxygen equilibrium curves are based on the assumption that the Hgb concentration is 15 g/dL and that there is full O2 saturation of Hgb at a partial pressure of arterial oxygen (Pao2) of 100 torr. The O2 released is the difference in O2 content between a Pao2 of 90 torr and the mixed venous Pao2 of 40 torr. The O2 available is the difference in O2 content between a Pao2 of 90 torr and a mixed venous Pao2 of 20 torr. This is the maximum O2 available without evoking compensatory mechanisms such as increased cardiac output.
Many differences have been found between the metabolism of the red cells of newborn infants and that of adults.117,118 Some of the differences may be explained by the younger mean cell age in the newborn, but others seem to be properties of the fetal cell. The glucose consumption in newborn red cells is lower than that in adult red cells.119 Elevated levels of glucose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase beyond those explainable by the young cell age have been found in neonatal cells.115,120 The level of phosphofructokinase is low in red cells of term and premature infants.115,120,121 The pentose phosphate shunt is active in red cells of term and premature infants,122 but glutathione instability leads to a heightened susceptibility to oxidant injury. The result of oxidant stress is depletion of adenosine triphosphate (ATP) and adenine nucleotides leading to iron release, denaturing of membrane proteins, and hemoglobin and membrane peroxidation.123 The levels of ATP and adenosine diphosphate (ADP) are higher in the red cells of term and preterm infants,121 but may merely reflect the younger age of the erythrocyte population. Finally, lower-than-adult activities have been found for several other red cell enzymes, including cytochrome B5 reductase124 and glutathione peroxidase.125
The membrane of the newborn red cell also is different from that of the adult red cell. Ouabain-sensitive adenosine triphosphatase (ATPase) is decreased,126 and active potassium influx is significantly less in neonatal red cells.127 Newborn cells are more sensitive to osmotic hemolysis and to oxidant injury than are adult cells. Newborn red cell membranes have higher total lipid, phospholipid, and cholesterol per cell than adult red cells.128,129 The patterns of phospholipid and phospholipid fatty acid composition also differ from those in adult red cells. Red cells of newborns have the same pattern of membrane proteins on polyacrylamide gel electrophoresis130 and the same rate of mobility in an electric field131 as do red cells from adults. After trypsin treatment of newborn and adult cells, however, there is a difference in electrophoretic mobility, indicating that the surface trypsin-resistant proteins are different.131 The relationship of the metabolic and membrane alterations in neonatal red cells to their shorter life span is not clear.
Granulocytopoiesis and Monocytopoiesis
Colony-Stimulating Factors and Granulomonopoiesis
The absolute number of neutrophils in the blood of term and premature infants usually is greater than that found in older children (Table 7–3).132 The neutrophil count tends to be lower in the premature than in the term infant, and the proportion of myelocytes and band neutrophils is higher.133 Serum and urinary colony-stimulating activity are elevated during the period of neutrophilia.134 When granulopoiesis was studied in cord blood, blood, and marrow of infants, the macrophage colony-forming unit was predominant despite the clinical neutrophilia, and this pattern was not altered by different sources of colony-stimulating factors.135,136 The endogenous cytokines produced by mononuclear cells from cord or systemic venous blood support the growth of neutrophil colonies in assays using marrow from adults.135 However, there is diminished GM-CSF, G-CSF, and IL-3 production in stimulated newborn compared to adult mononuclear cells,137,138,139 which may limit the response to bacterial infection in the newborn. Furthermore, preterm infants have a reduced neutrophil storage pool and a restricted capacity to increase their progenitor proliferation, and their neutrophil count may fall precipitously with neonatal bacterial infection.140 Dysregulation, as well as diminished capacity of neonatal granulopoiesis, may impair the neonatal response to infection.141 Smaller numbers of CFU-GM colonies were observed in the blood of sick infants, who also have diminished endogenous production of colony-stimulating factors in culture.136 The clinical use of cytokines to treat neonatal sepsis remains controversial,142 but circulating neutrophils are increased in preterm infants treated with recombinant G-CSF, and the infants’ length of stay in the neonatal intensive care unit is shortened.143
Table 7–3.The White Cell Count and the Differential Count during the First 2 Weeks after Birth* ||Download (.pdf) Table 7–3. The White Cell Count and the Differential Count during the First 2 Weeks after Birth*
| || ||Neutrophils || || || || |
|Age ||Leukocytes ||Total ||Segmented ||Bands ||Eosinophils ||Basophils ||Lymphocytes ||Monocytes |
|BIRTH || || || || || || || || |
|Mean ||18.0 ||11.0 ||9.4 ||1.6 ||0.40 ||0.10 ||5.5 ||1.05 |
|Range ||9.0–30.0 ||6.0–26.0 ||— ||— ||0.02–0.85 ||0–0.64 ||2.0–11.0 ||0.4–3.1 |
|Mean % ||— ||61 ||52 ||9 ||2.2 ||0.6 ||31 ||5.8 |
|7 DAYS || || || || || || || || |
|Mean ||12.2 ||5.5 ||4.7 ||0.83 ||0.50 ||0.05 ||5.0 ||1.1 |
|Range ||5.0–21.0 ||1.5–10.0 ||— ||— ||0.07–1.1 ||0–0.25 ||2.0–17.0 ||0.3–2.7 |
|Mean % ||— ||45 ||39 ||6 ||4.1 ||0.4 ||41 ||9.1 |
|14 DAYS || || || || || || || || |
|Mean ||11.4 ||4.5 ||3.9 ||0.63 ||0.35 ||0.05 ||5.5 ||1.0 |
|Range ||5.0–20.0 ||1.0–9.5 ||— ||— ||0.07–1.0 ||0–0.23 ||2.0–17.0 ||0.2–2.4 |
|Mean % ||— ||40 ||34 ||5.5 ||3.1 ||0.4 ||48 ||8.8 |
White Cell and Differential Counts
Table 7–3 gives the values for the white cell and differential counts during the first 2 weeks after birth. The absolute number of segmented neutrophils rises in both term and premature infants in the first 24 hours.144 In term infants, the mean value increases from 8 × 109/L to a peak of 13 × 109/L and then falls to 4 × 109/L by 72 hours of age, remaining at this level through the following 7 days. In the premature infant, the mean values for neutrophils are 5 × 109/L at birth, 8 × 109/L at 12 hours, and 4 × 109/L at 72 hours. The mean count then falls gradually to 2.5 × 109/L by the 28th postnatal day. The level after the first 72 hours is very stable for an individual infant, whether term or premature. Immature forms, including an occasional promyelocyte and blast cell, may be seen in the blood of healthy infants in the first few days after birth and are more frequent in premature infants than in term infants.144 Segmented granulocytes are the predominant cells in the first few days after birth. As their number decreases, the lymphocyte becomes the most numerous cell and remains so during the first 4 years of life. An absolute eosinophil count of greater than 0.7 × 109/L was found in 76 percent of premature infants at 2 to 3 weeks of age. The onset of the eosinophilia coincided with the establishment of steady weight gain in the infants.145 It is increased by the use of total parenteral nutrition, endotracheal intubation, and blood transfusions.
Bacterial infections are a major cause of morbidity and mortality in the newborn period.146 The infections frequently are caused by organisms of low virulence in normal children and adults, including Staphylococcus and Lancefield group B β-hemolytic streptococci, but, also, by Pseudomonas, and other Gram-negative bacilli. Cellular defense mechanisms and humoral immunity of the newborn differ from those found later in life, and these undoubtedly contribute to the unusual susceptibility to infection noted in the neonatal period.146
Engulfment and destruction of bacteria by neutrophils depend on opsonic activity of the plasma and on chemotaxis, phagocytosis, and the bacteriocidal capacity of the leukocyte. The serum factors necessary for optimal phagocytosis (opsonins) include the immunoglobulins and complement components. In term infants, opsonic activity is normal for Staphylococcus aureus,147,148 but it is low for yeast149 and Escherichia coli.147,148 Diminished opsonic antibody is associated with group B streptococcal infection and represents one risk factor for neonatal infection.150
In premature infants, opsonic activity is low for S. aureus and Serratia marcescens,147 but is normal for Pseudomonas aeruginosa.151 When serum concentrations of fibronectin and IgG subclasses C3 and C4 were measured at birth, 1 month, 3 months, and 6 months, early gestational age was correlated with lower initial levels.152 The decreased opsonic activity for some organisms in premature infants is attributed to diminished IgG levels, because additional IgG will correct the opsonic defect both in vivo and in vitro.147 The added IgG improves bacterial opsonization by serum of premature infants in part because complement consumption and deposition of C3 on the bacterial surface are augmented.153,154
Complement components appear in fetal blood before 20 weeks’ gestation and increase markedly during the third trimester. However, in many newborns both the classical and alternative complement pathways are decreased in activity and in levels of individual components.155 The mean level of C3, the first common component of the two pathways of complement activation, is approximately 65 percent of that in normal adults.156,157,158 There is no transplacental transfer of this protein, and levels in infants are lower than those in their mothers.156 Total serum hemolytic complement (CH50) and alternative pathway activity (PH50) in newborns are lower than in adults, as are mean levels of C1q, C2–C9, properdin, and factors B, I, and H.157,158,159 In general, the mean levels in full-term infants are greater than 50 percent of those in normal adult controls and may be somewhat less in premature infants. There is considerable overlap, however, between levels in infants and in controls. A functional deficiency in the alternative pathway has been detected in infants.160
Fibronectin mediates more efficient interactions between phagocytes and infectious agents. Fibronectin, a 450-kDa glycoprotein found in plasma and in the intercellular matrix, promotes the attachment of staphylococci to neutrophils161 and enhances opsonic activity of antibodies against group B streptococci.162 Because both these bacteria are common pathogens for neonates, the deficiency in fibronectin observed in neonates163 may further compromise opsonic capacity and hence bactericidal activity in the neonate.
The administration of intravenous IgG may be useful in the treatment or prophylaxis of infection in preterm infants based on the reduced placental transfer of maternal antibody and the restricted endogenous synthesis of IgG.164 IgG administered to septic neonates appears to enhance serum opsonic capacity as well as to increase the quantity of circulating neutrophils.165 In premature neonates, added IgG heightens granulocyte phagocytosis.165,166 Intravenous IgG has been reported to effectively treat infected premature neonates, but these reports involved small numbers of subjects.167,168 The clinical efficacy of IgG prophylaxis against neonatal pathogens is not firmly established.169,170 New IgG preparations with consistent, adequate levels of antibodies directed against neonatal pathogens can be achieved by selection of sera with high levels of functional antibodies,171 or potentially by the addition of monoclonal antibodies, and these may prove more effective.
Chemotactic function of leukocytes is low in neonates, whereas random motility is normal.172,173,174 Neonatal serum does not generate as much chemotactic factor as does adult serum, even after the addition of purified C3. The defect in chemotaxis may be related to decreased granulocyte deformability and impaired capping of cell surface receptors.175 The role of observed cyclic adenosine monophosphate (cAMP) and membrane potential alterations in the defective chemotaxis is not clear.175 The ability of neutrophils to roll along the blood vessel endothelium also is impaired in neonates. Diminished upregulation and surface migration of β2 integrins and fewer L-selectin receptors reduce the ability of neonatal neutrophils to interact with adhesion molecules on the endothelium.139
The densities of the C3bi receptor (CD11b/CD18) and of the low-affinity receptor for immunoglobulin, FcRIII (CD16), are decreased on neutrophils of premature infants, whereas term infants’ cells show a lesser impairment.176,177,178 The deficient upregulation of C3bi correlates with decreased adherence and chemotaxis by neonatal neutrophils.179 Low FcRIII is associated with impaired chemotaxis of neonatal neutrophils,180 although decreased FcRIII might also be responsible for subtle defects in adherence and subsequent phagocytosis of opsonized171 and unopsonized181 organisms by neutrophils.
Neutrophil cell adhesion molecules are central to the bonding of neutrophils to the vascular endothelium, and reduction of these molecules diminishes the capacity of neonatal neutrophils to properly adhere and migrate (Chap. 19).182 Although L-selectin, a key adhesion molecule, is expressed at high levels on hematopoietic progenitor cells, it decreases markedly during the first 3 days of life and remains low compared to adult levels during the first weeks, impairing the neutrophil’s ability to “roll” as part of the adhesion process. Also, there are defects in expression of CD18/CD11b, which are members of the β2-integrin family of adhesion molecules.183 These characteristics likely contribute to the newborn susceptibility to bacterial infections.
Phagocytic and Bactericidal Activity
Phagocytosis of bacteria and latex granules by neutrophils from premature and term infants is normal.147,151,184 Bactericidal activity varies according to the conditions of testing and the clinical status of the neonates. The intracellular killing of S. aureus and S. marcescens in cells from most term and low-birth-weight infants is normal,147,185 as is that of E. coli in term infants.148 Similar studies have shown defective bactericidal activity against S. aureus in some infants in the first 12 hours after birth,183 P. aeruginosa in cells from premature infants,151 and Candida albicans in granulocytes from term and premature infants.186 With bacteria-to-neutrophil ratios of 1:1, newborn cells kill S. aureus and E. coli as effectively as controls; however, at the higher ratio of 100:1, killing and oxidative responses as measured by chemiluminescence are markedly depressed, although phagocytosis is normal.184 Depressed activity also has been found in cells from newborns who have had clinical stress, either from infection or other disorders, shown both as decreased chemiluminescence and impaired bactericidal activity against S. aureus, E. coli, and group B streptococci.187,188,189 The decreased granulocyte function shown in these studies also is found in liquid culture, where neutrophils from newborns do not survive as long as those from adults, perhaps because of decreased resistance to autoxidation.188 Although superoxide dismutase levels are normal and superoxide production is normal or increased in neutrophils from newborns, glutathione peroxidase and catalase levels are decreased.189,190 The relationship of these in vitro cellular defects to bacterial infections in the newborn is still not clear.
Antimicrobial proteins and peptides are present in neutrophil cytoplasmic granules. Bacterial permeability-increasing protein (BPI), located in the primary granules, is markedly lower in newborns, particularly preterm newborns.191,192 BPI is an antimicrobial protein that binds and neutralizes endotoxin. Other granule components, such as myeloperoxidase (bacterial killing) and defensins (antimicrobial proteins), are not diminished.
Monocytes from newborn infants have normal nitroblue tetrazolium (NBT) reduction,193 normal antibody-dependent cellular cytotoxicity,194 and normal in vitro killing of S. aureus and E. coli.195 However, they are slower than monocytes from adults in phagocytosis of polystyrene spheres,196 and they have reduced ATP production.197 Furthermore, chemotaxis to serum-derived factors is decreased, as is monocyte appearance in skin windows.198 These functional aspects may contribute to the observed susceptibility of newborns to a variety of infectious agents.
Cytokine Effects on Neonatal Phagocytic Function
There is a complex interaction between cytokines produced by lymphocytes and macrophages, and the activation status of neutrophils during infection. There is decreased production of interferon-γ by neonatal leukocytes.199,200 Interferon-γ causes the upregulation of the C3bi receptor and induces the surface expression of the high-affinity immunoglobulin receptor FcRI (CD64)201 on neutrophils. C3bi is required for adherence and efficient chemotaxis by neutrophils. Low levels of this receptor also impair complement-mediated phagocytosis and oxidative metabolism. FcRI also mediates oxidative responses, and appears on neutrophils of adults during infection. The diminished production of G-CSF and GM-CSF by neonatal mononuclear cells137,138,139 may not only limit progenitor colony growth, but may also impair neonatal neutrophil functions, including chemotaxis, superoxide production, and C3bi expression, which are enhanced by these factors.202,203 Tumor necrosis factor (TNF)-α and IL-4, cytokines that modulate neutrophil functions, also may be produced at lower levels in neonates.204
THROMBOPOIESIS AND PLATELETS
The platelet counts in term and preterm infants are between 150 and 400 × 109/L (150,000 to 400,000/μL), comparable to adult values.205,206 Thrombocytopenia of fewer than 100 × 109/L (100,000/μL) may occur in high-risk infants with respiratory distress or sepsis,207 small-for-date infants,208 and newborns with trisomy syndromes.209 Even normal newborns are unable to regulate thrombopoiesis and myelopoiesis in a wholly effective manner.210 Although committed megakaryocyte progenitors (colony-forming unit–megakaryocyte [CFU-Meg]) are increased in the marrow and cord blood of newborns, they are less able to produce adequate numbers of platelets when severely stressed. Reduced levels of G-CSF, GM-CSF, and IL-3 may play a role in the impaired response.211 Thrombopoietin (TPO) is a major regulator of platelet production in adults. TPO transcripts have been detected as early as 6 weeks postconception and the primary source of TPO in the fetus and neonate is thought to be the liver.212 Serum TPO levels are higher in preterm and term neonates compared to adults. However, thrombocytopenic newborns do not increase serum TPO levels as robustly as thrombocytopenic adults, which may contribute to the high incidence of thrombocytopenia seen in sick infants.212
Bleeding Time and Closure Time
The expected inverse relationship between the platelet count and bleeding time has been described in term and preterm newborns.213 However, the bleeding time often is longer than would be predicted by the platelet count because of sepsis or respiratory distress resulting in impaired platelet function, aggravating the effects of thrombocytopenia.
The bleeding time reflects platelet function and capillary integrity, as well as the platelet count, and traditionally has been used to assess these parameters. However, there are technical difficulties in applying a technique for measuring bleeding time to neonates or preterm infants because of the need for venous occlusion of the forearm, where the test normally is performed, and for a minimal incision to avoid scarring of the skin. Bleeding times were measured using an automatic device to minimize trauma in normal neonates, with venous occlusion of 20 torr for infants who weigh less than 1000 g, 25 torr for those who weigh 1000 to 2000 g, and 30 torr for those who weigh more than 2000 g. In 82 observations, 97 percent of the measurements were below 3.5 minutes, which was suggested as the upper limit for normal in these infants.214 A similar upper limit (200 seconds) for the bleeding time of normal infants has been obtained using an automated device and vertical incisions.215 Generally, newborn infants have shorter bleeding times than do children and adults, which may reflect their higher hematocrit, increased concentration of von Willebrand factor, and higher proportion of high-molecular-weight multimers of von Willebrand factor.216 Children have longer bleeding times than either adults or newborns,217 and the upper limit measured with an automated pediatric device may be as high as 13 minutes before age 10 years, compared to an upper limit of 7 minutes in adults measured with the same device.217
The bleeding times in newborns may be prolonged for a variety of reasons, including neonatal infection and respiratory distress syndrome, which do not necessarily result in thrombocytopenia.218 Platelets from healthy newborns are relatively deficient in phospholipid metabolism, granule secretion, and aggregation,219 but there is heightened platelet adhesion because of increased large von Willebrand multimers. The result of these differences is shortened bleeding and closure times in normal neonates (see below).
The use of indomethacin for treatment of patent ductus arteriosus in preterm infants has been questioned because this agent interferes with prostaglandin metabolism and the production of thromboxane A2, an important initiator of platelet aggregation. Although bleeding times are prolonged from a normal 3.5 minutes to approximately 9 minutes in indomethacin-treated patients,220 indomethacin did not result in an increase in periventricular or intraventricular hemorrhage in preterm infants treated for patent ductus arteriosus.
The closure time to assess platelet function may replace the bleeding time, particularly for neonates and young children in whom bleeding times are difficult to perform and interpret. Newborn infants have closure times that are shorter than those of adults, likely related to their higher hematocrits, increased von Willebrand multimers and hence ristocetin cofactor, and higher leukocyte counts.221,222,223 The normal adult value for collagen-epinephrine closure time is less than 164 seconds, and for collagen-ADP closure time is less than 116 seconds. However, each laboratory must determine its own normal range for these tests.
Platelet Aggregation and Metabolism
A variety of differences have been described in the platelet function of neonates. These include decreases in ADP release, in platelet factor 3 activity, in platelet adhesiveness, and in platelet aggregation in response to ADP, epinephrine, collagen, or thrombin.224,225 These defects result from intrinsic differences in neonatal compared to adult platelets.226 Paradoxically, these insufficiencies have little effect on the bleeding time of neonates. The in vitro findings do not appear related to a significant defect in prostaglandin synthesis or to storage pool deficiency of adenine nucleotides.224 Furthermore, electron micrographs of neonatal platelets do not differ from those of platelets from normal adults.227 This leaves unexplained the in vitro observations in neonatal platelets, which may be related to platelet membrane immaturity. These in vitro abnormalities may aggravate the impairment in platelet function and the predisposition to bleeding that result from neonatal diseases, particularly respiratory distress syndrome and sepsis.
Maternal aspirin ingestion also results in abnormalities in platelet aggregation in the newborn in response to collagen.228,229 However, aspirin has been studied extensively in patients with preeclampsia, and there is no significant bleeding in the fetus or newborn.230,231
Newborn infants commonly have petechiae, particularly on the head, neck, and shoulders, after vertex deliveries. They are presumably caused by trauma associated with passage through the birth canal and disappear within a few days. Petechiae usually are not present in infants delivered by cesarean section.
Platelet Antigens and Glycoproteins
The glycoprotein complex GPIIb/IIIa represents approximately 15 percent of platelet surface protein and exhibits two allelic forms, PlA1 and PlA2.232 The PlA1 antigen can be identified on fetal platelets by 16 weeks’ gestation.233 PlA1 antigen is observed in a higher percentage of fetuses between 18 and 26 weeks’ gestation than in adults. Approximately 2 percent of the population in the United States of European descent is homozygous for PlA2 and thus are PlA1-negative. The complete expression of the PlA1 antigen during early gestation likely permits sensitization in women who are PlA1-negative even during their first pregnancy.233 The membrane glycoprotein GPIb, as well as the GPIIb/IIIa complex, is expressed by 18 weeks of gestation.233 The difference between PlA1 and PlA2 is a leucine 33–proline 33 amino acid polymorphism in glycoprotein IIIA.232 Prenatal diagnosis of the glycoprotein genotype using DNA from amniocytes and the polymerase chain reaction can establish the potential for neonatal alloimmune thrombocytopenia,234 as well as the diagnosis of Glanzmann thrombasthenia. Rarely, other fetal platelet antigens, such as PlE2, DUZOa, Koa, and Baka have caused maternal sensitization and neonatal alloimmune thrombocytopenia.235 The gestational ages for expression of these antigens have not been defined but are sufficiently early to permit sensitization.
T-Lymphocyte Functions—Cellular Immunity
The absolute number of lymphocytes in the newborn is equivalent to that in older children, ages 6 months to 2 years, with lower values in premature infants at birth. Thymus-derived cells (T cells) develop early in gestation.236 Tables 7–4 and 7–5 show the various lymphocyte subsets in infants and children.237,238 The absolute number of CD3+ and CD4+ (helper/inducer phenotype) T-cell subsets in blood of newborns is higher than in adults.239 This is a result of an increased total lymphocyte count in neonates (and older children) as compared with adults.240 The percentages of major lymphoid subsets (CD2, CD3, CD4, CD8, CD19) and natural killer (NK) cells are not markedly different in neonates, children, and adults when measured by flow cytometry methods.241,242 However, functional defects are present in the NK cell population.242 Furthermore, the responses of T-helper type 1 (Th1 cell-mediated immunity) and T-helper type 2 (Th2-assisted humoral immunity) differ in newborns and adults in response to various antigens such as vaccines, infectious agents, and environmental antigens.243 The numbers of T and B lymphocytes are sustained or increased during the first 2 postnatal months.244 There is a trend toward increased CD4 and decreased CD8 lymphocytes in newborns and children, resulting in an increased CD4:CD8 ratio.245,246 In spite of this, T-cell suppressor activity may be increased in newborns.247 Most responses of the cellular immunity system, such as antigen recognition and binding, antibody-dependent cytotoxicity, and graft-versus-host reactivity are present in the newborn,247 although some are decreased in comparison with adults.248 The in vitro response to phytohemagglutinin of cord blood lymphocytes is increased,249,250 but the response of the newborn to 2,4-dinitrofluorobenzene, a potent inducer of delayed hypersensitivity, is not as consistent as that seen in older children.251 Impaired T-cell production of interferon-γ and other lymphokines may be related to immature macrophage rather than to T-lymphocyte function, because intercellular cooperation is a requisite for these processes.252 Furthermore, cord blood T lymphocytes form a functional IL-2 receptor complex and have normal IL-2 receptors, but they do not upregulate interferon-γ in response to IL-2.253
Table 7–4.Blood Lymphocyte Subsets: Infants Age 1 to 3 Days ||Download (.pdf) Table 7–4. Blood Lymphocyte Subsets: Infants Age 1 to 3 Days
| ||Median (10th–90th percentile range) |
|Lymphocyte Subsets ||Infants (1–3 Days) ||Adults |
|Lymphocytes × 109/L ||3.1 × 109/L (3.1–6.8) ||___ |
|CD3+ % of lymphocytes ||83% (72–90) ||77 (69–84) |
|Count × 109/L ||3.7 (2.6–5.8) ||___ |
|CD3–/CD19+ % of lymphocytes ||14% (6–22) ||14 (8–18) |
|Count × 109/L ||0.58 (0.23–1.2) ||___ |
|NK (CD3–/CD16+ or CD56+) % of Lymphocytes ||4% (2–8) ||11 (6–17) |
|Count × 109/L ||0.2 (0.06–0.38) ||___ |
|CD3+/CD4+ % of lymphocytes ||63% (52–72) ||46 (37–55) |
|Count × 109/L ||2.7 (2.0–4.4) ||___ |
|CD3+/CD8+ % of lymphocytes ||23% (16–29) ||28 (20–34) |
|Count × 109/L ||1.1 (0.55–1.9) ||___ |
Table 7–5.Blood Lymphocyte Subsets: Infants and Children to Age 18 Years ||Download (.pdf) Table 7–5. Blood Lymphocyte Subsets: Infants and Children to Age 18 Years
|Lymphocyte Subsets ||0–3 Months ||3–6 Months ||6–12 Months ||1–2 Years ||2–6 Years ||6–12 Years ||12–18 Years |
|WBC × 109/L ||10.60 (7.20–18.00) ||9.20 (6.70–14.00) ||9.10 (6.40–13.00) ||8.80 (6.40–12.00) ||7.10 (5.20–11.00) ||6.50 (4.40–9.50) ||6.00 (4.40–8.10) |
|Lymphocytes × 109/L ||5.40 (3.40–7.60) ||6.30 (3.90–9.00) ||5.90 (3.40–9.00) ||5.50 (3.60–8.90) ||3.60 (2.30–5.40) ||2.70 (1.90–3.70) ||2.20 (1.40–3.30) |
CD3+ % of lymphocytes
Count × 109/L
|73% (53–84) ||66% (51–77) ||65% (49–76) ||65% (53–75) ||66% (56–75) ||69% (60–76) ||73% (56–84) |
|3.68 (2.50–5.50) ||3.75 (2.50–5.60) ||3.93 (1.90–5.90) ||3.55 (2.10–6.20) ||2.39 (1.40–3.70) ||1.82 (1.20–2.60) ||1.48 (1.00–2.20) |
CD19+ % of lymphocytes
Count × 109/L
|15% (06–32) ||25% (11–41) ||24% (14–37) ||25% (16–35) ||21% (14–33) ||18% (13–27) ||14% (06–23) |
|0.73 (0.30–2.00) ||1.55 (0.43–3.00) ||1.52 (0.61–2.60) ||1.31 (0.72–2.60) ||0.75 (0.39–1.40) ||0.48 (0.27–0.86) ||0.30 (0.11–0.57) |
CD16+/CD56+ % of lymphocytes
Count × 109/L
|8% (04–18) ||6% (03–14) ||7% (03–15) ||7% (03–15) ||9% (04–17) ||9% (04–17) ||9% (03–22) |
|0.42 (0.17–1.10) ||0.42 (0.17–0.83) ||0.40 (0.16–0.95) ||0.36 (0.18–0.92) ||0.30 (0.13–0.72) ||0.23 (0.10–0.48) ||0.19 (0.07–0.48) |
CD4+ % of lymphocytes
Count × 109/L
|52% (35–64) ||46% (35–56) ||46% (31–56) ||41% (32–51) ||38% (28–47) ||37% (31–47) ||41% (31–52) |
|2.61 (1.60–4.00) ||2.85 (1.80–4.00) ||2.67 (1.40–4.30) ||2.16 (1.30–3.40) ||1.38 (0.07–2.20) ||0.98 (0.65–1.50) ||0.84 (0.53–1.30) |
CD8+ % of lymphocytes
Count × 109/L
|18% (12–28) ||16% (12–23) ||17% (12–24) ||20% (14–30) ||23% (16–30) ||25% (18–35) ||26% (18–35)0 |
|0.98 (0.56–1.70) ||1.05 (0.59–1.60) ||1.04 (0.50–1.70) ||1.04 (0.62–2.00) ||0.84 (0.49–1.30) ||0.68 (0.37–1.10) ||0.53 (0.33–0.92) |
B-Lymphocyte Functions–Humoral Immunity
Humoral (B-cell) immunity also develops early in gestation,236 but it is not fully active until after birth. In the newborn, approximately 15 percent of lymphocytes have immunoglobulin on their surface, with all immunoglobulin isotypes represented.254 A percentage of these cells are CD5+ B cells (B-1 cells), which produce polyreactive autoantibodies whose function is yet unclear.255 The proportion of CD5+ B cells is markedly higher in the fetus compared to adults. The percentages of B cells expressing specific immunoglobulin isotypes are not related to the plasma levels of those isotypes. Variation in antibody response to specific antigens relates to the interaction of macrophages, T cells, and B cells. B lymphocytes are well represented in newborns, but T-lymphocyte–independent B-lymphocyte responses are limited during the first year.256 T-lymphocyte–dependent B-lymphocyte antibody production matures much earlier.256
Fetal lymphocytes synthesize little immunoglobulin, presumably because of the sheltered environment in utero. Animals kept germ-free after birth have few plasma cells and markedly decreased production of immunoglobulins.257 IgG levels of term infants are similar to maternal levels because of transplacental transfer.258 IgM, IgD, and IgE do not cross the placenta,258,259 and the levels of these immunoglobulins and of IgA are low or not detectable at birth. Breastfeeding provides some transfer of antibodies, particularly secretory IgA, lysozyme, and lactoferrin. Large numbers of lymphocytes and monocytes (106 cells/mL) are found in colostrum and milk during the first 2 months postpartum.260 These may provide local gastrointestinal protection against infection,261,262 and there is some evidence for absorption of immunoglobulin and transfer of tuberculin sensitivity to the infant.
Although the newborn infant can produce specific IgG antibody,263 only small amounts of IgG are usually produced by the fetus. IgG levels in premature infants are reduced in relation to gestational age because of the low placental transport early in pregnancy.264,265,266 The ability of the fetus to produce IgM and IgA with appropriate stimuli is indicated by the presence of these antibodies in many newborn infants who have had prenatal infections267 and by the presence of IgM isohemagglutinins in more than half of term newborn infants.268 In human newborns and in fetal animals, the IgM response is predominant, and the appearance of IgG after exposure to specific antigens is delayed. These differences from the adult may relate to functional immaturity of B and T lymphocytes,269,270,271 to increased activity of suppressor T cells,258,269 and perhaps to altered macrophage function.272
Newborns also may have relative splenic hypofunction, suggested by the large number of “pocked” red cells seen in the blood films of neonates, particularly premature infants. These “pocks” represent residual intraerythrocyte inclusions, which remain because of monocyte and macrophage hypofunction.273,274
COAGULATION IN THE NEONATE
Plasma Coagulation Factors
When the term newborn is compared to older children and adults, several differences in the coagulation and fibrinolytic systems are apparent.275,276,277,278,279,280,281 A comprehensive evaluation of the developmental changes in the levels of clotting factors and coagulation tests in preterm and term infants has been published.282,283 The term newborn has reduced mean plasma levels (<60 percent of adult levels) of factors II, IX, X, XI, XII, prekallikrein, and high-molecular-weight kininogen (Table 7–6). This is not a result of impaired mRNA expression, at least in the case of factors II and X.284 In contrast, the plasma concentration of factor VIII is similar and von Willebrand factor is increased compared to that of older children and adults. In spite of the lower levels of factors, the functional tests (prothrombin and partial thromboplastin times) are only slightly prolonged compared to adult normal values (Table 7–6). Although different coagulation factors show different postnatal patterns of maturation, near-adult values are achieved for most components by 6 months of age.278
Table 7–6.Reference Values for Coagulation Tests in Preterm and Full-Term Infants* ||Download (.pdf) Table 7–6. Reference Values for Coagulation Tests in Preterm and Full-Term Infants*
| ||Preterm 28–31-Week Infants ||Preterm 30–36-Week Infants ||Full-Term Infants || |
|Coagulation Test ||Day 1 ||Day 1 ||Day 30 ||Day 180 ||Day 1 ||Day 30 ||Day 180 ||Adults |
|PT(s) ||15.4 (14.6–16.9) ||13.0 (10.6–16.2) ||11.8 (10.0–13.6) ||12.5 (10.0–15.0) ||13.0 (10.1–15.9) ||11.8 (10.0–14.3) ||12.3 (10.7–13.9) ||12.4 (10.8–13.9) |
|INR || ||1.0 (0.61–1.70) ||0.79 (0.53–1.11) ||0.91 (0.53–1.48) ||1.00 (0.53–1.62) ||0.79 (0.53–1.26) ||0.88 (0.61–1.17) ||0.89 (0.64–1.17) |
|APTT(s) ||108(80.0–168) ||53.6(27.5–79.4) ||44.7(26.9–62.5) ||37.5(27.2–53.5) ||42.9(31.3–54.5) ||40.4(32.0–55.2) ||35.5(28.1–42.9) ||33.5(26.6–40.3) |
|TCT(s) ||24.8 (19.2–30.4) ||24.4 (18.8–29.9) ||25.2 (18.9–31.5) ||23.5 (19.0–28.3) ||24.3 (19.4–29.2) ||25.5 (19.8–31.2) ||25.0 (19.7–30.3) || |
|Fibrinogen (g/L) ||2.56 (1.60–5.50) ||2.43 (1.50–3.73) ||2.54 (1.50–4.14) ||2.28 (1.50–3.60) ||2.83 (1.67–3.99) ||2.70 (1.62–3.78) ||2.51 (1.50–3.87) ||2.78 (1.56–4.00) |
|II (U/mL) ||0.31(0.19–0.54) ||0.45(0.20–0.77) ||0.57(0.36–0.95) ||0.87(0.51–1.23) ||0.48(0.26–0.70) ||0.68(0.34–1.02) ||0.88(0.60–1.16) ||1.08(0.70–1.46) |
|V (U/mL) ||0.65(0.43–0.80) ||0.88(0.41–1.44) ||1.02(0.48–1.56) ||1.02(0.58–1.46) ||0.72(0.34–1.08) ||0.98(0.62–1.34) ||0.91(0.55–1.27) ||1.06(0.62–1.50) |
|VII (U/mL) ||0.37(0.24–0.76) ||0.67(0.21–1.13) ||0.83(0.21–1.45) ||0.99(0.47–1.51) ||0.66(0.28–1.04) ||0.90(0.42–1.38) ||0.87(0.47–1.27) ||1.05(0.67–1.43)0 |
|VIII (U/mL) ||0.79(0.37–1.26) ||1.11(0.50–2.13) ||1.11(0.50–1.99) ||0.99(0.50–1.87) ||1.00(0.50–1.78) ||0.91(0.50–1.57) ||0.73(0.50–1.09) ||0.99(0.50–1.49) |
|VWF (U/mL) ||1.41(0.83–2.23) ||1.36(0.78–2.10) ||1.36(0.66–2.16) ||0.98(0.54–1.58) ||1.53(0.50–2.87) ||1.28(0.50–2.46) ||1.07(0.50–1.97) ||0.92(0.50–1.58) |
|IX (U/mL) ||0.18(0.17–0.20) ||0.35(0.19–0.65) ||0.44(0.13–0.80) ||0.81(0.50–1.20) ||0.53(0.15–0.91) ||0.51(0.21–0.81) ||0.86(0.36–1.36) ||1.09(0.55–1.63) |
|X (U/mL) ||0.36(0.25–0.64) ||0.41(0.11–0.71) ||0.56(0.20–0.92) ||0.77(0.35–1.19) ||0.40(0.12–0.68) ||0.59(0.31–0.87) ||0.78(0.38–1.18) ||1.06(0.70–1.52) |
|XI (U/mL) ||0.23(0.11–0.33) ||0.30(0.08–0.52) ||0.43(0.15–0.71) ||0.78(0.46–1.10) ||0.38(0.10–0.66) ||0.53(0.27–0.79) ||0.86(0.49–1.34) ||0.97(0.67–1.27) |
|XII (U/mL) ||0.25(0.05–0.35) ||0.38(0.10–0.66) ||0.43(0.11–0.75) ||0.82(0.22–1.42) ||0.53(0.13–0.93) ||0.49(0.17–0.81) ||0.77(0.39–1.15) ||1.08(0.52–1.64) |
|PK (U/mL) ||0.26(0.15–0.32) ||0.33(0.09–0.57) ||0.59(0.31–0.87) ||0.78(0.40–1.16) ||0.37(0.18–0.69) ||0.57(0.23–0.91) ||0.86(0.56–1.16) ||1.12(0.62–1.62) |
|HK (U/mL) ||0.32(0.19–0.52) ||0.49(0.09–0.89) ||0.64(0.16–1.12) ||0.83(0.41–1.25) ||0.54(0.06–1.02) ||0.77(0.33–1.21) ||0.82(0.36–1.28) ||0.92(0.50–1.36) |
|XIIIa (U/mL) || ||0.70(0.32–1.08) ||0.99(0.51–1.47) ||1.13(0.65–1.61) ||0.79(0.27–1.31) ||0.93(0.39–1.47) ||1.04(0.46–1.62) ||1.05(0.55–1.55) |
|XIIIb (U/mL) || ||0.81(0.35–1.27) ||1.07(0.57–1.57) ||1.15(0.67–1.63) ||0.76(0.30–1.22) ||1.11(0.39–1.73) ||1.10(0.50–1.70) ||0.97(0.57–1.37) |
Factors II (prothrombin), VII, IX, and X require vitamin K for the final γ-glutamyl carboxylation step in their synthesis.285 These factors decrease during the first 3 to 4 days after birth. This fall may be lessened by administration of vitamin K,286 effectively preventing classic, early occurring (first few days after birth) hemorrhagic disease of the newborn. Inactive prothrombin molecules have been found in the plasma of some newborns, but they disappear after administration of vitamin K.287 Early occurring hemorrhagic disease is most often associated with maternal administration of medications such as phenytoin (Dilantin)288 and warfarin,289 which reduce the vitamin K–dependent factors. In rare cases, no contributing factor is found.
A hemorrhagic diathesis also may occur later, 2 to 12 weeks after birth, as a result of lack of vitamin K, and is called late hemorrhagic disease of the newborn or acquired prothrombin complex deficiency.290,291 The etiology of the vitamin K lack is unclear but may result from poor dietary intake, particularly related to breastfeeding, alterations in liver function with cholestasis and decreased vitamin K absorption, or a toxic or infectious impairment of hepatic utilization.290 Unfortunately, intracranial hemorrhage frequently is the presenting event in this condition. This problem can be prevented by parenteral or oral vitamin K, but the preferred route of administration remains controversial.292 The parenteral route may result rarely in neuromuscular complications,293 and an association of intramuscular vitamin K prophylaxis and cancer in infancy was suggested but not substantiated. Oral administration, however, appears less reliable and may require repeated doses.290 The current recommendation of the American Academy of Pediatrics suggests that vitamin K1, 0.5 to 1.0 mg, be administered intramuscularly at birth.294 Even the lower (0.5 mg) parenteral dose may be excessive for preterm (<32 weeks’ gestation) infants, although no toxic effects have been reported as a result of very high plasma values.295 Recent data suggest that 0.2 mg vitamin K may be appropriate prophylaxis for infants delivered at fewer than 32 weeks’ gestation, but additional oral supplementation is needed when feeding is established.296 A mixed micellar vitamin K1 preparation is particularly well absorbed and may permit prophylaxis with a single oral dose,297 but the efficacy and safety of oral prophylaxis require further study.
Table 7–6 shows the values for coagulation factors in healthy 30 to 36 weeks’ gestation premature infants. More prominent decreases in factors IX, XI, and XII are noted, which tend to prolong the partial thromboplastin time. Table 7–6 also shows the values for coagulation factors in 28 to 31 weeks’ gestation infants. All of the coagulation factors are lower at earlier gestational ages.
There are no significant differences in mean prothrombin time determinations between 30 and 36 weeks’ gestation premature and full-term infants who have not received vitamin K.298 Premature infants given vitamin K have a longer mean prothrombin time than do term infants similarly treated. In some small infants there is no improvement in prothrombin time or levels of prothrombin, and factors VII and X after the intramuscular administration of vitamin K.286,299 These results suggest a greater degree of “immaturity” of the liver in the small infants.
Significant bleeding occurs more often in low-birth-weight infants than in term newborn infants. Increased capillary fragility is frequently found in premature infants in the first 2 days after birth and is not associated with thrombocytopenia.286 Bleeding under the scalp or in other superficial areas may be caused by trauma at birth coupled with increased capillary fragility. The more serious disorders of periventricular–intraventricular hemorrhage and pulmonary hemorrhage probably are not caused by coagulation disorders, although such disorders may increase the bleeding.300 Hypoxia seems to affect the clotting status of low-birth-weight infants.301 Many infants with markedly abnormal prothrombin times have had hypoxia during delivery or shortly thereafter.296 Cardiovascular collapse seen with episodes of cardiac arrest or with profound shock may cause disseminated intravascular coagulation and generalized bleeding. In many sick premature infants, a combination of shock, sepsis, liver immaturity, hypoxia, and other factors may contribute to the pathogenesis of coagulation abnormalities.
Arterial and venous thromboses are relatively frequent in newborns as compared to other age groups, but greater than 90 percent of arterial and greater than 80 percent of venous clots are related to catheters. Spontaneous thromboses are much less common, and most involve the renal veins or, rarely, the pulmonary vasculature.302 Relative hypercoagulability in the newborn could result from a difference in the vascular endothelium, activation of the coagulation cascade, diminished coagulation inhibitor activity, or a defect in fibrinolysis. Inhibitors of coagulation include antithrombin, heparin cofactor II, protein C, and protein S.283,303 The levels of proteins C and S, which are vitamin K dependent, as well as antithrombin and heparin cofactor II, are low in the newborn; they are in a range associated with thrombotic episodes in adults with inherited deficiencies.303 In addition, the presence of factor V Leiden may occur in as many as 6 percent of newborns.304 This produces resistance to the action of protein C and may heighten the susceptibility to thrombosis (Chap. 130). Hyperprothrombinemia caused by the 20210A allele prothrombin gene may affect 1 percent of the population,305 but the elevated prothrombin level predisposing to thrombosis occurs in older patients.306 The combined deficiency of these anticoagulant proteins may further intensify the thrombotic risk. However, the precise role of these inhibitors of coagulation in newborn hypercoagulability is uncertain because a proportionate decrease in vitamin K–dependent procoagulant factors (II, VII, IX, X) also is present, and an additional inhibitor, α2-macroglobulin, is increased (Chap. 130). Table 7–7 shows the values for plasma inhibitors of coagulation in premature and term infants.
Table 7–7.Reference Values for Inhibitors of Coagulation in Preterm and Full-Term Infants* ||Download (.pdf) Table 7–7. Reference Values for Inhibitors of Coagulation in Preterm and Full-Term Infants*
|Inhibitor Levels ||Day 1 ||Day 30 ||Day 180 ||Day 1 ||Day 30 ||Day 180 ||Adults |
|AT (U/mL) ||0.38 (0.14–0.62) ||0.59 (0.37–0.81) ||0.90 (0.52–1.28) ||0.63 (0.39–0.87) ||0.78 (0.48–1.08) ||1.04 (0.84–1.24) ||1.05 (0.79–1.31) |
|α2M (U/mL) ||1.10 (0.56–1.82) ||1.38 (0.72–2.04) ||2.09 (1.10–3.21) ||1.39 (0.95–1.83) ||1.50 (1.06–1.94) ||1.91 (1.49–2.33) ||0.86 (0.52–1.20) |
|C1E-INH (U/mL) ||0.65 (0.31–0.99) ||0.74 (0.40–1.24) ||1.40 (0.96–2.04) ||0.72 (0.36–1.08) ||0.89 (0.47–1.31) ||1.41 (0.89–1.93) ||1.01 (0.71–1.31) |
|α1AT (U/mL) ||0.90 (0.36–1.44) ||0.76 (0.38–1.12) ||0.82 (0.48–1.16) ||0.93 (0.49–1.37) ||0.62 (0.36–0.88) ||0.77 (0.47–1.07) ||0.93 (0.55–1.31) |
|HCII (U/mL) ||0.32 (0.10–0.60) ||0.43 (0.15–0.71) ||0.89 (0.45–1.40) ||0.43 (0.10–0.93) ||0.47 (0.10–0.87) ||1.20 (0.50–1.90) ||0.96 (0.66–1.26) |
|Protein C (U/mL) ||0.28 (0.12–0.44) ||0.37 (0.15–0.59) ||0.57 (0.31–0.83) ||0.35 (0.17–0.53) ||0.43 (0.21–0.65) ||0.59 (0.37–0.81) ||0.96 (0.64–1.28) |
|Protein S (U/mL) ||0.26 (0.14–0.38) ||0.56 (0.22–0.90) ||0.82 (0.44–1.20) ||0.36 (0.12–0.60) ||0.63 (0.33–0.93) ||0.87 (0.55–1.19) ||0.92 (0.60–1.24) |
HEMATOLOGIC EFFECTS OF MATERNAL DRUGS ON THE FETUS AND NEWBORN
A number of maternally administered pharmacologic agents have been implicated in hematologic abnormalities of the fetus or newborn (Table 7–8). Maternal aspirin ingestion results in impaired platelet aggregation but does not foster neonatal bleeding. Other agents taken by the mother, including diazoxide and thiazides, might be associated with neonatal thrombocytopenia.307,308,309
Table 7–8.Hematologic Effects of Maternal Drugs on the Fetus and Newborn ||Download (.pdf) Table 7–8. Hematologic Effects of Maternal Drugs on the Fetus and Newborn
|Drug ||Effect ||Certainty* ||Mechanism ||Reference |
|Antiretroviral agents in combination ||Decreased hemoglobin ||Established ||Unknown—only seen with combination of zidovudine, lamivudine + nelfinavir ||318 |
|Aspirin ||Bleeding; kernicterus ||Established; potential ||Interference with platelet function ||123,224,228 |
|Displacement of bilirubin from albumin ||317 |
|Diazoxide ||Bleeding ||Questionable ||Thrombocytopenia ||307 |
|Nalidixic acid ||Hyperbilirubinemia ||Potential ||Oxidant damage to hemoglobin ||315 |
|Nitrofurantoin ||Hyperbilirubinemia ||Potential ||Oxidant damage to hemoglobin ||314,316 |
|Phenytoin (Dilantin/phenobarbital) ||Bleeding ||Suspected ||Depletion of vitamin K–dependent coagulation factors by hepatic enzyme induction and factor degradation ||288 |
|Rifampin/isoniazid ||Bleeding ||Suspected ||Depletion of vitamin K–dependent coagulation factors ||313 |
|Sulfonamides ||Kernicterus ||Established ||Displacement of bilirubin from albumin ||317 |
|Thiazides ||Bleeding ||Suspected ||Thrombocytopenia ||308,309 |
|Warfarin (Coumadin) ||Bleeding ||Established ||Known depletion of vitamin K–dependent coagulation factors by blocking carboxylation ||288,289 |
The newborn’s plasma coagulation factors may be depressed by maternal warfarin ingestion.289 This drug is best avoided during pregnancy because it is teratogenic (first trimester) and may cause growth retardation of the fetus as well as bleeding.289 In contrast, heparin does not cross the placenta, and maternal treatment with heparin appears to be safe for the fetus.310
Phenytoin (Dilantin) and/or phenobarbital also may reduce the newborn’s vitamin K–dependent factors, possibly by microsomal enzyme induction, which enhances their degradation.287 Furthermore, phenytoin may depress the platelet count as a result of prenatal exposure311 and cause teratogenic effects, for example, the fetal hydantoin syndrome.312 The decision to use this agent during pregnancy should reflect an assessment of the need for this specific drug, and also the risk of maternal seizures to the fetus and mother versus the potential side effects of treatment. Newborns of mothers taking rifampin and isoniazid also may have depressed vitamin K–dependent factors.313
Hyperbilirubinemia and Kernicterus
Nitrofurantoin and nalidixic acid may cause oxidant injury to the red cell membrane and hemoglobin.314,315 If there is glucose-6-phosphate dehydrogenase deficiency, or if reduced glutathione is diminished, as in newborn red cells, these drugs have the potential to induce hemolysis and heighten neonatal hyperbilirubinemia (Chap. 47). Although this problem has not been documented by transplacental transfer of nitrofurantoin or nalidixic acid, hemolysis has occurred in glucose-6-phosphate dehydrogenase-deficient infants who acquired the drugs from breast milk.315,316 Alternatively, sulfonamides may cause displacement of bilirubin bound to albumin and heighten the risk of kernicterus.317 Salicylates, phenylbutazone, and naproxen may have a similar effect at very high plasma concentrations.317 Ideally, all these medications should be avoided during pregnancy unless their indication outweighs the potential risk to the fetus and newborn.