122: Polycythemia and Hyperviscosity

Polycythemia is an increased total red blood cell (RBC) mass. Polycythemic hyperviscosity is an increased viscosity of the blood resulting from, or associated with, increased numbers of RBCs.

1. Polycythemia of the newborn. Defined as a central venous hematocrit >65%. The clinical significance of this value results from the curvilinear relationship between the circulating RBC volume (hematocrit) and whole-blood viscosity. Above a hematocrit of 65%, blood viscosity, as measured in vitro, rises exponentially.

2. Hyperviscosity. Defined as a viscosity >14 cP at a shear rate of 11.5/s measured by a viscometer. Serum viscosity is reported as centipoises [cP]. Hyperviscosity is the cause of clinical symptoms in infants presumed to be symptomatic from polycythemia. Many polycythemic infants are also hyperviscous, but this is not invariably the case. The terms polycythemia and hyperviscosity are not interchangeable.

1. Polycythemia. Polycythemia occurs in 2–4% of the general newborn population. Half of these patients are symptomatic, although it is not at all certain whether their symptoms are caused by polycythemia.

2. Hyperviscosity. Hyperviscosity without polycythemia occurs in 1% of normal (nonpolycythemic) newborns. In infants with a hematocrit of 60–64%, a fourth have hyperviscosity.

Clinical signs attributed to hyperviscosity may result from the regional effects of hyperviscosity, including tissue hypoxia, acidosis, and hypoglycemia, and from the formation of microthrombi within the microcirculation. An important caveat, however, is that the same clinical signs may result from coexisting perinatal circumstances in the presence or absence of hyperviscosity. Potentially affected organs include the central nervous system, the kidneys and adrenal glands, the cardiopulmonary system, and the gastrointestinal tract. Blood viscosity depends on the interaction of frictional forces in whole blood. These forces are defined as shear stress (refers to frictional forces within a fluid) and shear rate (a measure of blood flow velocity). The shear rate in the aorta is 230/s and only 11.5/s in the small arterioles and venules. As the viscosity increases, such as in the microcirculation, blood with a high hematocrit may virtually cease flowing. The frictional forces identified within whole blood and their relative contributions to hyperviscosity in the newborn include the following:

1. Hematocrit. An increase in the hematocrit is the most important single factor contributing to hyperviscosity in the neonate. An increased hematocrit results from either an absolute increase in circulating RBC volume or a decrease in plasma volume.

2. Plasma viscosity. A direct linear relationship exists between plasma viscosity and the concentration of plasma proteins, particularly those of high molecular weight, such as fibrinogen. Term infants and, to a greater degree, preterm infants have low plasma fibrinogen levels compared with adults. Consequently, except for the rare case of primary hyperfibrinogenemia, plasma viscosity does not contribute to an increased whole-blood viscosity in the neonate. Under normal conditions, low plasma fibrinogen levels and, correspondingly, low plasma viscosity actually may protect the microcirculation of the neonate by facilitating perfusion and contributing to low whole-blood viscosity.

3. RBC aggregation. Occurs only in areas of low blood flow and is usually limited to the venous microcirculation. Because fibrinogen levels are typically low in term and preterm infants, RBC aggregation does not contribute significantly to whole-blood viscosity in newborn infants. There is some concern that the use of adult fresh-frozen plasma for partial exchange transfusion in neonates might critically alter the concentration of fibrinogen and paradoxically raise whole-blood viscosity within the microcirculation.

4. Deformability of RBC membrane. There are apparently no differences among term infants, preterm infants, and adults in terms of the membrane deformability of erythrocytes. RBC deformability is increased in preterm neonates as compared with term neonates and in term neonates as compared with adults. The increase in deformability is presumed to reduce blood viscosity and to reduce the likelihood that polycythemia will cause hyperviscosity. Because infants of diabetic mothers are thought to have RBCs with reduced deformability, hyperviscosity may be more likely at polycythemic hematocrits than in unaffected neonate.

1. Conditions that alter incidence

   1. Altitude. There is an absolute increase in RBC mass as part of physiologic adaptation to high altitude.

   2. Neonatal age. The normal pattern of fluid shifts during the first 6 hours of life is away from the intravascular compartment. The period of maximum physiologic increase in the hematocrit occurs at 2–4 hours of age.

   3. Obstetric factors. A delay in cord clamping beyond 30 seconds or stripping of the umbilical cord, if that is the prevailing practice, results in a higher incidence of polycythemia.

   4. High-risk delivery. A high-risk delivery is associated with an increased incidence of polycythemia, particularly if precipitous or uncontrolled.

2. Perinatal processes

   1. Enhanced fetal erythropoiesis. Elevated erythropoietin levels result from a direct stimulus, usually related to fetal hypoxia, or from an altered regulation of erythropoietin production.

      1. Placental insufficiency

         1. Maternal hypertensive disease (preeclampsia/eclampsia) or primary renovascular disease

         2. Abruptio placentae (chronic recurrent)

         3. Postmaturity

         4. Cyanotic congenital heart disease

         5. Intrauterine growth restriction (IUGR)

         6. Maternal cigarette smoking

      2. Endocrine disorders. Increased oxygen consumption is the suggested mechanism by which hyperinsulinism or hyperthyroxinemia creates fetal hypoxemia and stimulates erythropoietin production.

         1. Infant of a diabetic mother (>40% incidence of polycythemia)

         2. Infant of a mother with gestational diabetes (>30% incidence of polycythemia)

         3. Congenital thyrotoxicosis

         4. Congenital adrenal hyperplasia

         5. Beckwith-Wiedemann syndrome (secondary hyperinsulinism)

      3. Genetic trisomies. Trisomies 13, 18, and 21.

   2. Hypertransfusion. Conditions that enhance placental transfusion at birth may create hypervolemic normocythemia, which evolves into hypervolemic polycythemia as the normal pattern of fluid shift occurs. A larger transfusion may create hypervolemic polycythemia at birth, with signs present in the infant. Conditions associated with hypertransfusion include the following:

      1. Delay in cord clamping. Placental vessels contain up to a third of the fetal blood volume, half of which is returned to the infant within 1 minute after birth. The risks associated with delayed cord clamping are probably negligible compared with the benefits that are in the term infant: reduction in the rate of iron deficiency in the first 2 years of life and in the sick preterm, decreased need for blood transfusions, inotrope support, and intraventricular hemorrhage. Representative blood volumes for term infants with a variable delay in cord clamping are as follows:

         1. 15-second delay, 75–78 mL/kg.

         2. 60-second delay, 80–87 mL/kg.

         3. 120-second delay, 83–93 mL/kg.

      2. Gravity. Positioning the infant below the placental bed (>10 cm below the placenta) enhances placental transfusion via the umbilical vein. Elevation of the infant >50 cm above the placenta prevents placental transfusion.

      3. Maternal use of medications. Drugs that enhance uterine contractility— specifically oxytocin—do not significantly alter the gravitational effects on placental transfusion during the first 15 seconds after birth. With further delay in clamping of the cord, however, blood flow toward the infant accelerates to a maximum at 1 minute of age.

      4. Cesarean delivery. In cesarean delivery, there is usually a lower degree of placental transfusion if the cord is clamped early because of the absence of active uterine contractions in most cases and because of gravitational effects.

      5. Twin–twin transfusion. Interfetal transfusion (parabiosis syndrome) is observed in monochorionic twin pregnancy with an incidence of 15%. The recipient twin, on the venous side of the anastomosis, becomes polycythemic, and the donor, on the arterial side, becomes anemic. Simultaneous venous hematocrits obtained after delivery differ by >12–15%, and both twins have a high risk of intrauterine or neonatal death and increased neurologic morbidity.

      6. Maternal-fetal transfusion. Approximately 10–80% of normal newborn infants receive a small volume of maternal blood at the time of delivery. The “reverse” Kleihauer-Betke acid elution technique documents maternal RBC “ghosts” on a neonatal blood smear. With large transfusions, the test is positive for several days. Because various conditions may lead to a false-negative test result, new and more accurate flow cytometry techniques can be used when the index of suspicion for maternal-fetal transfusions is elevated.

      7. Intrapartum asphyxia. Prolonged fetal distress enhances the net umbilical blood flow toward the infant until cord clamping occurs, and acidosis may encourage capillary leak, reduced plasma volume, and decreased red blood cell deformability.

Clinical signs observed in polycythemia are nonspecific and reflect the regional effects of hyperviscosity within a given microcirculation. The conditions listed next may occur independently of polycythemia or hyperviscosity and must be considered in the differential diagnosis.

1. Central nervous system. There may be an altered state of consciousness, including lethargy and decreased activity, hyperirritability, proximal muscle hypotonia, vasomotor instability, and vomiting. Seizures, thromboses, and cerebral infarction are extraordinarily rare.

2. Cardiopulmonary system. Respiratory distress and tachycardia may be present. Congestive heart failure with cardiomegaly may be seen but is rarely clinically prominent. Pulmonary hypertension may occur but is not usually severe unless other predisposing factors are present.

3. Gastrointestinal tract. Feeding intolerance occurs occasionally. Necrotizing enterocolitis has been reported but rarely without other factors (eg, IUGR), which casts doubt on the primary cause.

4. Genitourinary tract. Oliguria, acute renal failure/acute kidney injury, renal vein thrombosis, or priapism may occur.

5. Metabolic disorders. Hypoglycemia, hypocalcemia, or hypomagnesemia may be seen.

6. Hematologic disorders. There may be hyperbilirubinemia, thrombocytopenia, or reticulocytosis (with enhanced erythropoiesis only).

1. Venous (not capillary) hematocrit. Polycythemia is present when the central venous hematocrit is ≥65%.

2. The following screening studies may be used:

   1. A cord blood hematocrit >56% suggests polycythemia.

   2. A warmed capillary hematocrit ≥65% suggests polycythemia.

(See also Chapter 71). Clinical management of the polycythemic infant is more expectant now than a decade ago. Studies and reviews have created much doubt about any long-term benefits of partial exchange transfusion (PET). Consequently, PET should probably be performed only on infants in whom significant morbidity is in question.

1. Asymptomatic infants. Only expectant observation is required for virtually all asymptomatic infants. The possible exception is an infant with a central venous hematocrit of >75%, but even in this group the risks of central catheter insertion probably outweigh the benefits of PET.

2. Symptomatic infants. When the central venous hematocrit is ≥65%, PET with normal saline may ameliorate acute signs of polycythemia or hyperviscosity. Whether treatment of a self-limited problem justifies the risks of central catheter insertion and an exchange procedure is debatable, however. For the procedure for partial exchange transfusion, see Chapter 30.

The long-term outcome of infants with polycythemia or hyperviscosity and response to PET is as follows:

1. A causal relationship exists between PET and an increase in gastrointestinal tract disorders and necrotizing enterocolitis.

2. Older randomized controlled prospective studies of polycythemic and hyperviscous infants indicate that PET may reduce but not eliminate the risk of neurologic sequelae. More recent data suggest that no benefits accrue from PET.

3. Infants with “asymptomatic” polycythemia have an increased risk for neurologic sequelae, but normocythemic controls with the same perinatal histories have a similarly increased risk.