Differential diagnosis and management of polycythemia

Pediatr Clin N Am 51 (2004) 1063 – 1086

Differential diagnosis and management of polycythemia Athina Pappas, MDa, Virginia Delaney-Black, MD, MPHa,b,* a

Division of Neonatal-Perinatal Medicine, Wayne State University School of Medicine, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201, USA b Health Services Research, Children’s Research Center of Michigan, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201, USA

One percent to 5% of all newborns in the United States are polycythemic. As the venous hematocrit rises above 65%, the thickness or viscosity of whole blood also increases, potentially compromising blood flow to a variety of organs. Hypoxia, acidosis, and a reduction in nutrient supply may ensue. Fortunately, relatively few infants who have neonatal polycythemia or hyperviscosity develop complications attributable to their thick blood; however, controversy and the need for continued research envelop the issue of which infants are at risk and need to be treated. This article reviews the differential diagnosis, clinical presentation, and treatment of neonatal polycythemia.

Defining polycythemia and hyperviscosity The terms neonatal polycythemia and hyperviscosity are often used interchangeably. Though this is not accurate, it represents an understandable simplification. In many cases, infants who have hyperviscosity are polycythemic, and vice versa [1,2]. Nonetheless, polycythemia refers to an abnormal increase in red cell mass (hematocrit), whereas hyperviscosity refers to an increase in the internal friction of blood or the force required to achieve flow. The viscosity of whole blood is affected by numerous factors, including the red cell mass, the plasma components, and the interaction of cellular elements with the vessel wall.

* Corresponding author. Division of Neonatal-Perinatal Medicine, Wayne State University School of Medicine, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201. E-mail address: [email protected] (V. Delaney-Black). 0031-3955/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pcl.2004.03.012

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Diagnosis Polycythemia

Hematocrit %

The multiplicity of definitions used in the literature to define polycythemia has complicated the discussion of the incidence and outcome of this condition. The most widely accepted definition is a venous hematocrit of 65% or greater. Still, variability in sampling site, timing, and technique determine the incidence and perhaps the outcome of infants who have polycythemia/hyperviscosity. Studies have suggested that the hematocrit at term will rise from cord blood levels to a peak at 2 hours of age and then drop slowly over the next 12 to 18 hours [3]. When considering sampling procedures for newborn hematocrit, it is important to recognize this natural variation (Fig. 1). Hematocrit testing in the well infant is best done after the peak hematocrit at 6 to 8 hours of age. In the symptomatic infant, the timing of initial hematocrit sampling should be determined by clinical signs. A common error in the diagnosis of neonatal polycythemia is the use of a capillary hematocrit without a confirming venous sample. Peripheral capillary sampling will overestimate the venous hematocrit in many newborns [1,4]. The difference between central and peripheral hematocrits may be minimal if the extremity is warm and peripheral perfusion is good; however, there is often very poor correlation [4]. Although peripheral hematocrits may be used to screen for suspected polycythemia, venous samples should be obtained for confirmation. In addition to timing and the site of specimen collection, instrumentation and screening technique may contribute to variability in neonatal hematocrit values. Most of the literature regarding symptomatic polycythemia has relied upon spun hematocrits. These values are higher than values obtained by automated counter techniques and show better correlation with viscosity. In a study of 10 symptomatic infants who had polycythemia conducted by Villalta and colleagues [5], 8 of the 10 infants had spun hematocrits greater than 65%, whereas none had automated counter-calculated hematocrits above this value. Still, many nurseries

62 60 58 56 54 52 50

2hrs 6hrs 15mins cord blood

0

2

12-18hrs range

4

6

8

10

12

14

16

Time (hrs) Fig. 1. Mean hematocrit levels according to age from cord clamping (50 infants). (Adapted from Shohat M, Merlob P, Reisner SH. Neonatal polycythemia: I. Early diagnosis and incidence relating to time of sampling. Pediatrics 1984;73(1):8; with permission.)

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Table 1 Screening guidelines for high-risk infants with suspected polycythemia/hyperviscosity Age

Screening technique

Birth

Dextrostix for all high-risk infants (eg, IUGR, infants of diabetic mothers, Down’s syndrome, congenital adrenal hyperplasia, hypo- and hyperthyroidism, Beckwith-Wiedemann syndrome, etc) Peripheral Hct determination in symptomatic infants > 34 weeks’ gestation. Venous hematocrit determination when peripheral Hct is significantly elevated (> 70%). When available, evaluate viscosity for symptomatic infants with moderately elevated Hct (> 55 – 64%). In the absence of viscosity measurements, estimate viscosity by assessing total protein and red cell smear for abnormalities in RBC shape.

6 – 8 hours

Any time

Adapted from Black VD. Neonatal hyperviscosity syndromes. Curr Probl Pediatr 1987;17(2):75 – 130; with permission.

employ automated hematology analyzers. With this method, mean cell volume and hemoglobin concentration are measured and the hematocrit is calculated. The American Academy of Pediatrics Committee on Fetus and Newborn [6] does not recommend universal screening of hematocrit for all term newborns. Nonetheless, selective screening for high-risk infants is warranted, and neonatal intensive care units should adopt individualized guidelines for sampling site, timing, and technique (Table 1). Hyperviscosity Blood viscosity is dependent on hematocrit, red cell characteristics, platelets, plasma components, and their interaction with the vessel wall. Although viscosity measurements are not available routinely, they may be important because elevated viscosity correlates well with symptoms in neonatal polycythemia/ hyperviscosity [7– 9]. Most neonatal studies employ rotational viscometers, such as the Wells-Brookfield cone plate microviscometer, to measure whole blood viscosity. These instruments measure the ratio of shear stress over shear rate; Black [10] describes them in detail in another publication. Researchers measure viscosity at different shear rates. Low shear rates are thought to represent capillary and arteriolar blood flow, whereas high shear rates are thought to represent arterial and large-vessel blood flow. Environmental temperature is an important factor as well; viscosity measurements vary with temperature. Normal ranges for whole blood viscosity in the newborn and prospective studies examining clinical manifestations of neonatal hyperviscosity are available from several authors. Gross and colleagues [7] determined the viscosity of 102 healthy full-term neonates using cord blood samples run on the Wells-Brookfield microviscometer at shear rates of 2 to 212 seconds
1 (temperature = 37
C). They defined hyperviscosity as a viscosity value above two standard deviations from the mean (Fig. 2). Drew et al [11] determined cord whole-blood viscosity and hematocrit values for 2461 live born infants using an

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Fig. 2. Shaded area represents viscosity at shear rates from 2 to 212 sec
1 for healthy, full-term AGA infants (±2 SD). Hematocrit values range from 41% – 63%. Viscosity for 18 symptomatic infants is plotted at shear rates of 11 sec
1. Hematocrit values range from 63% – 77%. Hct, hematocrit. (Adapted from Gross GP, Hathaway WE, McGaughey HR. Hyperviscosity in the neonate. J Pediatr 1973; 82(6):1006; with permission.)

Australian-designed coaxial narrow-gap covette viscometer. Normal viscosity measurements were determined for every week of gestation above 34 weeks. Once again, hyperviscosity was defined as a viscosity value above two standard deviations from the mean. Hyperviscosity was more common in growth retarded infants than in appropriately grown infants. Other studies on high-risk populations exist as well [8,12].

Incidence of neonatal polycythemia and hyperviscosity The incidence of neonatal polycythemia and hyperviscosity ranges from 1% to 5% in the total newborn population (Table 2) [1,13 – 17]. It is also influenced by birth weight, gestational age, and altitude. Infants who are small or large for gestational age and infants born at high altitudes have a higher incidence of polycythemia. Premature infants, especially those born after less than 34 weeks’ gestation, rarely have polycythemia or hyperviscosity.

Conditions that predispose to the development of neonatal polychythemia Erythropoiesis in the human fetus is acclimated to the relatively hypoxic fetal environment. Compared with older infants and children, fetal hematocrit is elevated and allows for an increased oxygen carrying capacity. Factors that interfere with placental oxygen concentration may increase fetal hematocrit even

Study

Location

N

Definition

Method

Site

Symptoms

Incidence

Tudehope et al [13] Wirth et al [1]

San Francisco, CA Denver, CO

4083 790

Hct > 66% Hct  65%

Venous Venous

48.8% —

Polycythemia 2.1% Polycythemia 4% Hyperviscosity 5%

Stevens et al [14]

Norfolk, VA

405

Hct  65%

Venous

0%

Polycythemia 1.8% Hyperviscosity 2.9%

Host et al [15] Wiswell et al [16]

Odense, Denmark Hawaii

635 7133

Hct  65% Hct  65%

Not stated Microhematocrit Microviscometer run at shear rates of 5 – 212/s Microhematocrit Microviscometer run at shear rates of 5.75/s and 230,000/sec Coulter Counter Microhematocrit

Venous Venous

20% 70%

Bada et al [17]

Memphis, TN

2400

Hct  63%, Visc  13.5cps at 11.25/s

Microviscometer run at 2.25, 4.5, 11.25, 22.5, 45, 90, 225, and 450/s

Arterial

—

Polycythemia 4.7% Polycythemia 1.14% SGA 5.67% AGA 0.95% LGA 2.08% Polycythemia 0.4% Hyperviscosity 0.4%

Abbreviations: AGA, average for gestational age; LGA, large for gestational age; AGA, average for gestational age.

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Table 2 Incidence of neonatal polycythemia/hyperviscosity in prospective hematocrit screening studies

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further, resulting in a pathologically high neonatal red cell mass. Examples include high altitude [1], maternal diabetes [18], hypertension [19], intrauterine growth retardation [20], smoking [21,22], advanced maternal age [23], use of propranolol [24], and maternal cardiac, respiratory, or renal diseases [23]. Placental factors that may influence fetal hematocrit include placental infarction, placenta previa and viral infections, especially TORCH infections (toxoplasma infection, also called toxoplasmosis; other infections, such as hepatitis B, syphilis, and herpes zoster, the virus that causes chickenpox; rubella, the virus that causes German measles; cytomegalovirus, or CMV; and herpes simplex virus, the cause of genital herpes) [23]. These all have been associated with an increased risk of neonatal polycythemia. Still, not all infants exposed to adverse intrauterine conditions will develop polycythemia. At sea level, only 1% to 2% of infants may be affected [14]; at

Box 1. Factors that place an infant at risk for neonatal polycythemia Intrauterine hypoxia Intrauterine growth retardation Maternal diabetes Maternal hypertension Maternal smoking Maternal use of propranolol Placental transfusion Delayed cord clamping Cord stripping Twin-twin transfusion Maternal-fetal transfusion Fetal risk factors Trisomy 13, 18, 21 Congenital adrenal hyperplasia Hypothyroidism Hyperthyroidism Beckwith-Wiedemann syndrome Perinatal asphyxia Delivery Unattended out-of-hospital births Water births with delayed cord clamping

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1061 meters above sea level, as many as 4% to 5% may have elevated hematocrit values at birth [1]. Conversely, not all newborns who have neonatal polycythemia will be exposed to prolonged oxygen deprivation. Many may have acute or chronic placental transfusions from delayed cord clamping or from arterialvenous malformations. Still others may have fetal conditions contributing to the development of polycythemia. In the vast majority of infants, there is no identifiable cause. Risk factors for neonatal plycythemia are listed in Box 1.

Fetal hypoxia Intrauterine growth retardation A multitude of fetal and intrauterine environmental factors can lead to aberrant fetal growth and intrauterine growth retardation (IUGR). Environmental factors such as maternal hypertension, diabetes, and smoking suggest that fetal hypoxia may play a pivotal role in the development of IUGR. Kramer et al [20] studied a large cohort of 8719 singleton infants who did not have any evidence of congenital infection, chromosomal anomalies, or other major malformations, while controlling for severity of growth retardation. Fetal polycythemia, defined as a maximum capillary hemoglobin 21 g/dL, was noted in 7.5% of non-IUGR neonates, compared with 41.5% of severe IUGR neonates (Table 3). Maternal diabetes Diabetic pregnancies are associated with an increased risk of in-utero hypoxemia. Their infants have a high prevalence of polycythemia, elevated erythropoietin concentrations, and decreased serum iron and ferritin concentrations at birth [25,26]. In a large prospective longitudinal study by Hod et al [18], the prevalence of polycythemia in infants of diabetic mothers was 13.3%, significantly higher than that in controls (only 4.9%). Maternal hypertension Maternal pre-eclampsia and hypertension pose a significant risk for neonatal polycythemia. In a study conducted by Kurlat and Sola [19], the risk of

Table 3 Neonatal polycythemia with increasing severity of IUGR

Non-IUGR Mild IUGR Moderate IUGR Severe IUGR

All gestations

Term births

7.5% 9.5% 13.8% 41.5%

6.2% 8.2% 12.5% 36.2%

Adapted from Kramer MS, Olivier M, McLean FH, Willis DM, Usher RH. Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome. Pediatrics 1990;86(5): 707 – 13; with permission.

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polycythemia was 12.6 times greater in appropriate-for-gestational-age (AGA) infants of hypertensive mothers, compared with nonhypertensive mothers. Maternal smoking Maternal tobacco smoking is an important modifiable risk factor for intrauterine hypoxia. Smoking results in increased maternal blood levels of carbon monoxide that readily cross the placenta and compete with oxygen for fetal hemoglobin binding sites. In a recent study by Al-Alawi and Jenkins [21], cordblood hemoglobin and hematocrit were significantly higher in infants born to smoking mothers than in those born to nonsmoking mothers. In addition, there was a statistically significant dose – response relationship. The mean cord hematocrit for infants of smoking mothers was 55.4%, compared with 48.3% for that of infants of nonsmoking mothers. A cord hematocrit above 55% places an infant at higher risk for polycythemia, because hematocrit naturally rises from cord blood levels [27]. In fact, term neonates of mothers who smoked were 2.5 times more likely to be treated for neonatal polycythemia than infants of nonsmoking mothers [22]. Maternal use of propranolol In-utero exposure to propranolol also has been linked to neonatal polycythemia; however, it is difficult to differentiate the contribution of drug-related effects from that of maternal disease-related effects [24]. Placental transfusion During the first few minutes after birth, a substantial transfer of blood can occur between the placenta and the newborn. Important factors that may lead to placental transfusion include delayed cord clamping, positioning of the infant below the level of the introitus, and stripping or milking the umbilical cord toward the infant. Delayed cord clamping/cord stripping In 1977, Saigal and Usher first raised the concern that delayed cord clamping may contribute to the development of polycythemia [28]. Data from more recent randomized clinical trials demonstrated that late-clamped term and preterm infants have higher hematocrit levels than do infants clamped early (30s) [29]. Nonetheless, very few infants whose cords are clamped between 3 and 10 minutes of age go on to develop polycythemia [29]. Still, there is concern regarding cord clamping delayed beyond a few minutes. In at least one case report, severe symptomatic polycythemia occurred after a water birth in which the cord was clamped at 40 minutes [30]. Moreover, Linderkamp and colleagues [31] related a marked rise in viscosity in infants whose cords were clamped late. Stripping or milking the umbilical cord toward the neonate after delivery or holding the newborn below the level of the placenta can lead to significant placental transfusion as well.

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Twin-twin transfusion Placental transfusion also can occur as a result of arteriovenous communications between placental blood vessels of monozygotic twins. Twin –twin transfusions occur in 15% to 30% of monochorionic twins, and often result in anemia in the donor twin and polycythemia with circulatory overload in the recipient [32,33]. New treatments such as laser coagulation or septostomy are being offered, but improvement in maternal-fetal outcomes has not been demonstrated conclusively [34]. Maternal –fetal transfusion Placental transfusion between the mother and the fetus is known as maternalfetal transfusion. In this type of placental transfusion, a bleb within the placenta breaks, allowing maternal blood volume to enter the fetal circulation. This may lead to polycythemia and blood incompatibilities in the fetus [35]. Fetal risk factors Fetal risk factors associated with polycythemia/hyperviscosity include chromosomal abnormalities (Trisomy 13, 18, 21), congenital adrenal hyperplasia, hypo- and hyperthyroidism, Beckwith-Wiedemann syndrome, hemoglobin alterations (especially b chain alterations), erythropoietin receptor defects, cyanotic congenital heart disease, and perinatal asphyxia [36 – 40]. Risk factors related to type of delivery Out-of-hospital unattended births have been associated with a significantly higher incidence of neonatal polycythemia. In a study on outcome of unattended out-of-hospital births in Harlem, polycythemia occurred in 14% (8 of 59) newborns [41]. In addition, delivery under water with delayed cord clamping was associated with severe neonatal polycythemia in at least one case report [30].

Clinical features and complications Infants who have polycythemia often show increased whole blood viscosity. As the hematocrit rises above 65%, there may be an increased tendency for diminished blood flow, especially in the cerebral, hepatic, renal, and mesenteric microcirculations. Clinical symptoms may include lethargy, cyanosis, respiratory distress, jitteriness, hypotonia, feeding intolerance, hypoglycemia, and hyperbilirubinemia. Symptoms are outlined in Box 2. Several organ systems may be involved. Central nervous system Polycythemia and hyperviscosity may have lasting effects on neonatal neurodevelopment. Ratrisawadi and colleagues [55] found global developmental delay

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Box 2. Neonatal findings and diagnoses associated with neonatal polycythemia and hyperviscosity Central nervous system Hypotonia (7% – 9%) [42,43] Tremulousness (7%) [42,43] Irritability (13%) [42] Lethargy (14.5%) [43] Seizures (1.2%) [16] Stroke (rare) [44] One or more central nervous system (CNS) signs (27%) [42] Cardiopulmonary Tachypnea (16% – 27%) [13,16,42] Respiratory distress (9%) [43] Cyanosis (7% –14.5%) [42,43] Plethora (4.9% – 20%) [16,43] Apnea (4%) [42] Pleural effusions [45] Cardiomegaly and increased pulmonary vascularity [45] Endocrine Hypoglycemia (11% –40%) [13,16,42,43] Hypocalcemia (1% –11%) [40] Gastrointestinal Poor feeding (7% –20.7%) [16,42] Feeding problems (22%) [43] Necrotizing enterocolitis (1% – 3.7%) [16,42,43,46 – 48] Renal Renal vein thrombosis [48] Proteinuria [49] Renal tubular damage [50,51] Hematologic Thrombocytopenia (1% – 30%) [43,52,53] Hyperbilirubinemia (2% –22%) [13,42,43] Elevated reticulocytes and nucleated red blood cells (RBCs) [54]

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at 1.5 to 2 years of age following neonatal polycythemia. Black et al [56,57] found more gross motor delays, neurologic findings, fine motor abnormalities, and speech delays in 2-year-olds who had a history of neonatal polycythemia compared with age-matched controls. Neonatal hyperviscosity has been linked to neurologic and cognitive impairment in older children as well. In a study of 7-year-olds who had a history of hyperviscous cord blood, Drew et al [9] found a higher likelihood for an abnormal neurologic exam and motor index as assessed by the McCarthy Scales of Children’s Abilities. Delaney-Black et al [58] found lower achievement and IQ scores in school age children who had a history of polycythemia as neonates when compared with controls. Finally, polycythemia has been associated with stroke [37,44] and acquired neonatal paraplegia [59]. In a retrospective review of 30 newborns who had acquired paraplegia, seven (22%) had neonatal polycythemia [59]. These disturbing results may be tempered by the findings of Bada and colleagues [42]. Multivariate analysis revealed that other perinatal risk factors and race may possibly mediate long-term neurodevelopmental sequelae in infants who had polycythemia. Important risk factors included fetal distress, asphyxia, hypoglycemia, uncontrolled precipitous delivery, and maternal pre-eclampsia. Furthermore, the initiating intrauterine events that lead to polycythemia are likely to be the causes of both the polycythemia and developmental problems. Cardiopulmonary In contrast to the central nervous system, there is no evidence of lasting cardiopulmonary complications from neonatal polycythemia. Short-term pulmonary problems may include tachypnea, respiratory distress, pulmonary vascular congestion, pleural effusions, and pulmonary hypertension [16,42,45]. In animal models of neonatal polycythemia, rising hematocrit was associated with increasing pulmonary vascular resistance and right-to-left shunting through the ductus arteriosus and patent foramen ovale [60]. Elevated pulmonary vascular resistance was observed in polycythemic human newborns as well. In a study of 19 asymptomatic polycythemic newborns studied with M-mode echocardiography, Murphy and colleagues [61] demonstrated elevated right ventricular pre-ejection period to right ventricular ejection time ratios. Elevated systemic vascular resistance and decreased cardiac output may be observed as well. In a study on newborn dogs conducted by Kotagal and Kleinman [62], there was a 98% increase in total vascular resistance and a 40% fall in cardiac output when puppies received an exchange transfusion to induce neonatal polycythemia. LeBlanc and colleagues [63] examined two additional parameters: oxygen transport and oxygen consumption. In a study examining 16 puppies who had induced hypervolemic polycythemia, peripheral vascular resistance increased by 170%, cardiac output decreased by 50%, O2 consumption decreased by 13%, and O2 transport remained unchanged. No difference was noted on these parameters in hypervolemic control puppies.

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Polycythemia affects the human neonate in a similar fashion. Murphy et al [64] demonstrated that the peak rate of left ventricular emptying was lower in a group of polycythemic infants compared with age-matched controls. In addition, polycythemic infants had evidence of decreased stroke volume and decreased cardiac output [61,65]. Clinical manifestations related to these changes may include cyanosis, tachycardia, heart murmurs, and signs of congestive heart failure [42,43,45,49,65]. Endocrine and metabolic Hypoglycemia and hypocalcemia are the most common metabolic abnormalities seen in infants who have neonatal polycythemia and hyperviscosity. Hypoglycemia occurs in 12% to 40% of polycythemic infants [7,42,43,49]. It may be mediated by such contributing factors as maternal diabetes, at least in part. The pathogenesis for the hypocalcemia observed in polycythemic infants is less clear. Saggese and colleagues [66] proposed that it may be related to elevated levels of calcitonin gene related peptide (CGRP). CGRP is a 37 –amino acid polypeptide with putative vasoactive effects. In a study of 43 polycythemic newborns and 20 healthy controls, CGRP values were significantly elevated in the polycythemic group, both at birth and at 16 to 36 hours of extrauterine life. Interestingly, the CGRP levels were highest in the 5 polycythemic infants who had hypocalcemia. Lower levels of the renal metabolites of cholecalciferol also have been described in infants who had polycythemia/hyperviscosity. Both 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D were significantly lower in polycythemic infants compared with healthy controls [67]. Gastrointestinal Experiments in puppies have shown that polycythemia may significantly decrease gastrointestinal (GI) blood flow [68]. A similar reduction in GI blood flow may occur in human neonates. Mandelbaum and colleagues [65] demonstrated significantly reduced Doppler flow velocities in the celiac arteries of polycythemic infants compared with age-matched controls. Theoretically, this may explain the association between polycythemia and necrotizing enterocolitis. Animal models have been developed to study this association. In newborn puppies, LeBlanc et al [69] induced necrotizing enterocolitis (NEC) under conditions of normovolemic and hypervolemic polycythemia. In rats made hyperviscous by serial transfusion and diuresis, Dunn et al [70] demonstrated increased mortality related to hypoxic gut injury. Among human neonates who have NEC, the link to polycythemia is more elusive. Though early studies revealed a high incidence of polycythemia in term infants who have NEC [71 –74], more recent data suggest little or no association [75] (Table 4). Neonatal polycythemia may affect GI function as well. Boehm and colleagues [76] demonstrated altered enterohepatic circulation of bile acids and delayed postnatal development of trypsin and lipase activity in

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Table 4 Percentage of infants with NEC who also had polycythemia (Hct > 65%) Study

N

Patient description

%

Wilson et al [71] Thilo et al [72] Wiswell et al [73] Andrews et al [74] Martinez-Tallo et al [75]

11 13 43 10 24

Weight > 2500g Onset first 24 h Term infants Term infants, weight > 2100 g Term infants, weight > 2000 g

45% 31% 16.3% 10% 4%

polycythemic newborns. This may explain some of the feeding intolerance observed in these infants. Renal Relatively few studies have examined the renal effects of polycythemia. When polycythemia was induced in puppies, renal blood flow was preserved, despite a dramatic drop in cardiac output [62]. Nonetheless, renal plasma flow and glomerular filtration were significantly reduced (Fig. 3). In addition, urine output (Fig. 4), urine sodium, and urine potassium excretion (Fig. 5) were decreased, resulting in water and salt retention. In the human newborn, renal dynamics may be modified as well. Polycythemic newborns have lower glomerular filtration rates, lower urine volumes, and lower urinary sodium excretion [77]. On conventional urinalysis, Goldberg et al [49] demonstrated an increased risk of proteinuria. In addition, polycythemia may contribute to renal tubular damage. A marker of such injury, urinary N-acetyl-bD-glucosaminidase, was significantly elevated in the urine of polycythemic newborns soon after birth [50,51].

RENAL PLASMA FLOW (ml/gmmin) 1.00 0.90 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0.10 0.00

GFR per g KIDNEY WEIGHT 0.30 0.25 0.20 0.15

BEFORE

AFTER p<0.01

0.10

BEFORE AFTER p<0.0!

0.05 0.00 1

2

1

2

Fig. 3. Renal plasma flow and glomerular filtration rate before (not shaded) and after (shaded) polycythemia. Mean ± SE. GFR, glomular filtration. (Adapted from Kotagal UR, Kleinman LI. Effect of acute polycythemia on newborn renal hemodynamics and function. Pediatr Res 1982;16:150; with permission.)

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URINE OUTPUT (ml/min) 0.09

0.06

BEFORE

0.03 AFTER p<0.01

0.00

1

2

Fig. 4. Urine ouput before (not shaded) and after (shaded) polycythemia. Mean ± S.E. (Adapted from Kotagal UR, Kleinman LI. Effect of acute polycythemia on newborn renal hemodynamics and function. Pediatr Res 1982;16:150; with permission.)

Renal cholecalciferol metabolites also are altered in neonatal polycythemia. Levels of 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D were lower in the sera of polycythemic infants when compared with healthy controls [67]. Alkalay and colleagues [67] suggested that hyperviscosity may interfere with the kidneys’ ability to convert 25-hydroxyvitamin D to its dihydroxylated metabolites. Hematologic Hematologic manifestations of neonatal polycythemia include thrombocytopenia, hyperbilirubinemia, and elevated reticulocytes and nucleated red blood cell

URINE Na EXCRETION ( Eq/min)

URINE K EXCRETION ( Eq/min) 3.00

5.00 4.00

2.00

3.00

BEFORE

BEFORE

2.00

1.00

1.00

AFTER p<0.01

AFTER p<0.01

0.00

0.00 1

2

1

2

Fig. 5. Urine Na (sodium) and urine K (potassium) excretion before (not shaded) and after (shaded) polycythemia. Mean ± S.E. (Adapted from Kotagal UR, Kleinman LI. Effect of acute polycythemia on newborn renal hemodynamics and function. Pediatr Res 1982;16:150; with permission.)

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counts [42,43,54]. Erythropoietin levels at birth are also elevated [78]. Ruth and colleagues [78] demonstrated increased cord venous erythropoietin in infants who had neonatal polycythemia. Postnatally, these levels declined within a few hours of life. Thrombocytopenia is detected in approximately 20% to 30% of polycythemic infants [49,52,53]. Though the exact mechanism for this is unknown, it is thought to be related to an increase in platelet adhesion and aggregation, and a decrease in platelet life span. Some researchers suggest an association between thrombocytopenia (a platelet count < 150,000/mL) and increased clinical severity of polycythemia [53].

Peripheral and capillary blood flow Clinical evidence of poor peripheral blood flow has been associated with polycythemia and hyperviscosity. Case reports link polycythemia to neonatal priapism [79] and gangrene in the distal extremities [80,81]. Norman and colleagues [82] studied capillary perfusion via a television microscopy technique. Compared with control subjects, capillary blood flow velocity was significantly reduced in polycythemic newborns on the first day of life (0.11 mm/s in polycythemic infants, compared with 0.30 mm/s in healthy control infants). This study suggests that an insufficient microcirculation may be involved in the pathophysiology responsible for some of the clinical manifestations of neonatal polycythemia.

Treatment Treatment of neonatal polycythemia and hyperviscosity remains controversial. Although partial exchange transfusion is recommended for symptomatic infants, outcome data do not show clear long-term benefits. Undoubtedly, infants who have clinical manifestations should receive care aimed at alleviating their symptoms. The debate lies in whether this care should involve symptomatic therapy or routine partial exchange transfusion (PET) to replace the infant’s blood with a plasma substitute.

Patient selection criteria Recently, Upadhyay and colleagues [83] proposed a useful algorithm for the management of neonates with polycythemia (Fig. 6). They suggested examining a central venous hematocrit and the infant’s hydration status for all infants who have suspected polycythemia. PET was recommended for all symptomatic infants. Hydration with intravenous fluids was recommended for all stable, asymptomatic infants.

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Algorithm for the Management of Neonates with Polycythemia Capillary hematocrit >65%

Confirm with venous hematocrit

Exclude dehydration Check weight loss

Asymptomatic

Symptomatic

Hematocrit 65-70%

PET

Hematocrit >70% ?

Consider hydration in stable baby

Consider PET

PET= Partial Exchange Transfusion

Fig. 6. Algorithm for the management of neonates with polycythemia. (Adapted from Upadhyay A, Aggarwal R, Deorari AK, Paul VK. Polycythemia in the newborn. PET, partial exchange transfusion. Indian J Pediatr 2002;69:82; with permission.)

Partial exchange transfusion The goal of a PET is to reduce the infant’s hematocrit and viscosity while maintaining circulatory volume. Though a variety of techniques have been described (Table 5), umbilical venous catheterization with a commercial plasma exchanger is the most efficient and safe modality. Alternative techniques, such as peripheral venous exchange and umbilical venous-peripheral venous exchange, require considerably more expertise and are associated with a higher number of complications. Nonetheless, alternative routes for exchange transfusion are im-

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Table 5 Techniques used for partial exchange transfusion Type of Exchange

Comments

Umbilical venous exchange Umbilical venous-peripheral venous exchange Peripheral venous exchange

Technically simple procedure, ‘‘push-pull technique’’ Concomitant withdrawl of blood from venous catheter and infusion of blood via peripheral IV Requires considerable expertise and ability to perform cutdown. May be employed in cases of omphalitis, inability to cannulate the umbilical vein or other GI disorders.

portant and may be employed in cases of omphalitis, inability to cannulate the umbilical vein, or other serious GI disorders such as necrotizing enterocolitis [84]. In the polycythemic newborn, the total exchange volume is generally calculated using the following formula: Total exchange volume ¼ Circulating blood volume   Hct current
Hct desired  Hct current In this equation, the circulating blood volume refers to the infant’s weight in kilograms times the expected intravascular volume in mL per kilogram of body weight. In term infants, intravascular volume is usually estimated at 80 to 90 mL/kg; in preterm infants, intravascular volume is usually estimated at 100 mL/kg [10]. Maertzdorf and colleagues [85] recommended calculating the exchange volume in small-for-gestational-age (SGA) infants using a circulating volume of 106 mL/kg. In a simple but elegant study, they calculated the circulating blood volume of 31 polycythemic infants treated with PET using a regression line between the number of exchange steps and central hematocrit values obtained at onset and after every exchange step. Based on their results, they suggested using a circulating volume of 86 mL/kg in AGA infants and 106 mL/kg in SGA infants, regardless of gestational age. The current hematocrit in the aforementioned equation is obtained from a free flowing venous sample drawn from the infant. Typically, the desired hematocrit is 50% to 55% [10,86]. In infants who have hyperviscosity, a desired hematocrit of 50% can be chosen [10]. Hematocrit and viscosity, if clinically available, can be reassessed after the PET. In clinical practice, the exchange procedure is performed in steps of 5 to 10 mL aliquots, depending on the infant’s weight and response to treatment. Careful planning is important and can reduce the number of complications and adverse reactions. Attention to thermoregulation, glucose homeostasis, and vital signs is imperative. Resuscitation equipment and intravenous (IV) dextrose and medications should be readily available. Following PET, feedings should be withheld for 2 to 4 hours [10]. In addition, monitoring should be continued until the infant is asymptomatic.

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Saline versus colloid A variety of crystalloid and colloid solutions have been used as replacement fluid for PET in neonates who have polycythemia. They include fresh frozen plasma (FFP) [46,87,88], 5% albumin [86], plasmanate [59,86], isotonic saline [47], and Ringer’s lactate [89,90]. Randomized controlled trials have demonstrated that crystalloid solutions are as effective as colloids in reducing neonatal hematocrit and viscosity [47,88,89]. In addition to being cheaper, crystalloids are less allergenic and are less likely to promote infection. Moreover, they may be less likely to promote NEC. In a study conducted by Black et al [46], the use of Ffp was associated with a high incidence of NEC (Table 6). Controversy on outcome Clinical studies reveal some measurable benefits following PET. In a study of 13 polycythemic infants conducted by Swetnam et al [91], heart rate, Dopplerderived cardiac index, left ventricular stroke volume, systemic oxygen transport, and laser-Doppler peripheral (cutaneous) blood flow were all increased after partial exchange. Other researchers have documented improved left ventricular (LV) function [64], decreased pulmonary [61] and peripheral vascular resistance, and improved cerebral and mesenteric blood flow [17,65,91] in infants treated with partial exchange. Still, such treatment is not without risk. Complications may include vessel perforation, vasospasm, thrombosis, infarction, electrolyte abnormalities, arrhythmias, bleeding, infection, hypo- and hyperthermia, and necrotizing enterocolitis. Moreover, the replacement fluid selected may impact the procedure’s risk. If Ffp is used, there is increased chance of viral and bacterial infections and anaphylactic reactions. Also, controversy exists with respect to the long-term benefits to infants treated with partial exchange transfusion. Most studies demonstrate little effect on physical growth, neurologic sequelae, or mental development (Table 7) [42,49,57,58,92]. In one of the earliest randomized-controlled clinical studies

Table 6 Percentage of infants with polycythemia that developed NEC Study

%

Comment

van der Elst et al [48]

N 49

2%

The one infant that developed NEC received a partial exchange transfusion using Ffp.

Wiswell et al [16] Black et al [46]

82 93

3.7% 8.6%

Wiswell et al [43] Hein et al [47]

932 204

1.4% 0%

All infants that developed NEC were treated with partial exchange transfusions using FFP (via umbilical catheter). No polycythemic infants treated with supportive care developed NEC. 185 patients received partial exchange transfusions using plasmanate.

Table 7 Randomized controlled trials examining neurodevelopmental outcome of infants treated for polycythemia/hyperviscosity with PET or symptomatic care N

Definition

van der Elst et al [48] 49 Venous Hct > 65%

Goldberg et al [49]

Black et al [57]

Delaney-Black et al [58]

Bada et al [42]

± Symptoms No or only mild symptoms

Outcome measured

Developmental score (locally devised) Neurologic examination No neurological symptoms Bayley Scales of 20 Venous Hct  64% Viscosity > 2 SD above Infant Development Neurologic examination mean as described by Milani-Comparetti postural Gross et al (1973) reflex examination 93 Venous Hct  65% Symptomatic & asymptomatic Mental delay rate Viscosity > 2 SD above Motor delay rate mean as described by Neurologic examination Gross et al (1973) and fine motor abnormalities 93 Venous Hct  65% Symptomatic & asymptomatic Slosson IQ Test Viscosity > 2 SD above Wide Range mean as described by Achievement Test Gross et al [7] Charlop-Atwell Scale of Motor Coordination PANESS 28 Radial Hct  63% Asymptomatic Mental developmental Viscosity  13 cps at index/ IQ shear rate 11.25/s Mental retardation rate

Key results

Follow-up

No significant difference

8 months follow-up 86% follow-up rate

No significant difference No significant difference

8 months follow-up 80% follow-up rate

No significant difference No significant difference Reduced by PPET (25% v 55%), P < 0.05

2 years follow-up 67% follow-up rate

No significant difference No significant difference

7 years follow-up 53% follow-up rate

No significant difference No significant difference No significant difference

27.5 months mean follow-up Borderline higher retardation 71% follow-up rate rate in treated group

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Study

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on treatment of polycythemia, van der Elst and colleagues [48] found indistinguishable long-term outcomes among infants treated with symptomatic care and those offered PET. They studied 49 polycythemic infants who had no symptoms or only mild symptoms and performed neurologic and developmental testing on these infants at 8 months of age. There was no significant difference in outcome among treatment groups. In fact, all infants were normal at follow-up. Similarly, Goldberg et al [49] found no significant difference in neurologic and developmental testing between infants offered PET or routine medical care. They studied 20 newborn infants who had neonatal polycythemia/hyperviscosity and performed follow-up assessments at 8 months of age. Testing included the Bayley Scales of Infant Development, the Milani-Comparetti Postural Reflex Examination, a standardized neurologic examination, a medical history, and a physical examination. Neurologic symptoms and developmental delay were observed in 4 of 6 untreated infants and in 5 of 10 infants treated who had PET. In contrast to van der Elst’s study, abnormal neurologic and developmental findings were impressive in both treatment groups. Black et al [57] conducted one of the largest randomized-controlled clinical trials on outcome of infants treated for neonatal polycythemia. They studied 93 infants who had polycythemia and hyperviscosity (randomized to partial plasma exchange transfusion or symptomatic care) and conducted neurodevelopmental testing on these infants at 2 years of age. There were no significant differences in speech, mental and motor delays, or in the incidence of clonus between the two treatment groups. In a follow-up study of this population, Delaney-Black and colleagues [58] located 49 of their original 93 children who had polycythemia. Of these, 21 received a partial plasma exchange transfusion and 28 received symptomatic care. The children underwent neurodevelopmental testing at 7 years that included the Slosson IQ Test, the Wide Range Achievement Test (WRAT), the Charlop-Atwell Scale of Motor Coordination and the Physical and Neurological Examination for Subtle Signs (PANESS—a scored examination designed to evaluate neurologic soft signs). There were no significant differences between treatment groups for IQ, WRAT, or gross motor or visual-motor scores. Bada and colleagues [42] examined 45 infants who had polycythemia. Seventeen patients had symptomatic polycythemia and underwent PET. Twenty-eight patients had asymptomatic polycythemia; half were randomized to PET and the remainder received supportive care. There was no difference in long-term growth (physical height, weight, or head circumference) or mental development index (MDI) and rate of mental retardation between the two treatment groups. Because no randomized-controlled clinical trial shows clear long-term benefits for asymptomatic infants offered PET, the risks of the procedure should be weighed carefully.

Prognosis The diversity of follow-up data on neonatal polycythemia suggests that the outcome of these infants is variable. In part, this may result from other associated

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conditions, the severity of these conditions, and their underlying etiology. Still, the diagnosis of polycythemia raises many questions and concerns. For example, which infants will develop symptoms, how should they be treated, and what care will improve their short- and long-term outcomes? Polycythemia/hyperviscosity is an intriguing neonatal diagnosis that deserves continued research.

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