Neonatal polycythemia

INTRODUCTION — Neonatal polycythemia is characterized by a venous hematocrit (HCT) that greatly exceeds normal values for gestational and postnatal age. This condition affects approximately 1 to 5 percent of newborns. Although many affected infants are asymptomatic, the characteristic clinical features are thought to result from hyperviscosity and/or the metabolic effects of an increased red blood cell mass.

DEFINITIONS

Polycythemia — Polycythemia is defined as hematocrit (HCT) or hemoglobin (HGB) level above the upper limit of normal (>2 standard deviations) for gestational and postnatal age [1].

In term newborns, the upper limits for HCT and HGB values differ depending upon the type of blood sample:

●For peripheral venous blood samples, the upper limit for HCT is 65 percent and for HGB is 22 g/dL [2-5]

●For capillary blood samples, the upper limit for HCT is 75 percent and for HGB is 23.7 g/dL [6]

There is considerable variability in measurements obtained from capillary samples. HCT of blood from venous samples may be as much as 15 percent lower than those obtained from capillary samples. (See 'Laboratory testing' below.)

For this reason, the diagnosis of polycythemia is based upon peripheral venous samples. A term newborn infant is considered to be polycythemic if the HCT from a peripheral venous sample is >65 percent or the HGB is >22 g/dL [2-5]. By convention, the definition typically is based upon the HCT rather than HGB. (See 'Diagnosis' below.)

Hyperviscosity — Polycythemia must be distinguished from hyperviscosity, which is defined as a blood viscosity >12 centipoise, measured at a shear rate of 11.5 per second; or >6 centipoise, measured at a shear rate of 106 per second [7]. A minority of infants with polycythemia have measurable hyperviscosity [8]. Conversely, some infants with hyperviscosity are not polycythemic. However, measurement of viscosity is not widely available in many clinical settings and thus clinical decisions are based on HCT.

INCIDENCE — Polycythemia occurs in 1 to 2 percent of healthy newborns born at sea level and up to 5 percent of infants born at high altitude [3,4,6,9,10]. The incidence of polycythemia is influenced by the practice of delayed cord clamping since the amount of placental transfusion is increased when cord clamping is delayed [11]. This is discussed separately. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Early versus delayed cord clamping'.)

The incidence of hyperviscosity is considerably less than that of polycythemia. In studies that detected polycythemia by routine capillary screening, only 3 to 5 percent of polycythemic infants had abnormal viscosity [4,12,13]. In a separate study that used cord blood samples, hyperviscosity was detected in approximately one-half of infants with polycythemia [14]. No matter how one measures it, neonatal hyperviscosity is a fairly uncommon clinical entity.

PATHOPHYSIOLOGY — Compared with older infants and children, term newborns have an increased red cell mass caused by the fetal response of increased hemoglobin production to a relatively hypoxic intrauterine environment and possibly vasomotor instability and venous pooling in the newborn immediately after birth.

The hematocrit (HCT) increases after birth, reaching a maximum at approximately two hours of age, then decreases to levels in cord blood by 18 hours of age [8,15,16].

The increased red cell mass in newborns can significantly increase blood viscosity [17]. Whole blood viscosity can also be affected by other elements of blood, including white cells, platelets, plasma proteins, immunoglobulins, or clotting factors. Nevertheless, red cell mass is the main contributor to viscosity in newborns.

Blood viscosity and HCT have a linear relationship when the HCT is <60 percent [5,12,18]. This relationship becomes exponential when the HCT exceeds 65 percent, such that a small increase in HCT is associated with a dramatic increase in viscosity. The relationship is less predictable for intermediate values [5]. In one report, for example, hyperviscosity was present in 23 percent of infants with HCTs in the range of 60 to 64 percent [5].

Even for HCT values >65 percent, the relationship between HCT and hyperviscosity is somewhat inconsistent. This was examined in a study of cord blood in 2461 infants of >34 weeks gestation [14]. Among infants with HCT >65 percent, only approximately one-half were found to have abnormal viscosity (defined as >2 standard deviations above the mean for viscosity at each week of gestation).

Hyperviscosity is thought to be the main pathologic mechanism resulting in neurologic sequelae from polycythemia [19]. At high levels of viscosity blood flow to critical organs becomes impaired, leading to poor tissue perfusion. However, studies in newborn lambs suggest that decreased cerebral blood flow in polycythemia may be due in part to a vascular response to increased arterial oxygen content related to the increased hemoglobin concentration, rather than to hyperviscosity. When polycythemia was maintained in these lambs but the oxygen delivery was reduced by infusing sodium nitrite, brain blood flow increased to baseline values [20].

Blood flow is determined by resistance to flow, which varies directly with the viscosity of the blood. However, the size (diameter) of the blood vessel affects resistance to flow more strongly than does viscosity. Thus, an increase in viscosity will reduce blood flow only if the vessel size remains constant.

CAUSES — The causes of polycythemia are multifactorial but are due to two major mechanisms: passive (erythrocyte transfusion) and active (increased intrauterine erythropoiesis) (table 1) [21].

●Delayed cord clamping – The most common cause of polycythemia in otherwise healthy term infants is the practice of delaying umbilical cord clamping, which results in increased transfer of placental blood to the infant [22,23]. The usual practice is to delay cord clamping for at least 30 to 60 seconds after birth if the newborn is vigorous. This rarely results in clinically significant polycythemia. However, if there is a longer delay (eg, >2 minutes), polycythemia is more likely to occur, particularly if the baby is held at a level below the mother immediately following birth, before clamping of the cord. Polycythemia can also result from unintentionally delayed cord clamping (eg, at an unattended delivery).

In a meta-analysis of five trials involving 1025 mother-infant pairs, polycythemia occurred more frequently in infants randomized to delayed cord clamping compared with early clamping (2.5 versus 0.7 percent); however, the findings were not statistically significant (relative risk 2.56, 95% CI 0.79-8.3) [11]. Hemoglobin levels were higher among newborns in the delayed cord clamping group than in the early clamping group at 24 to 48 hours but not at subsequent assessments. More infants in the delayed cord clamping group required phototherapy for jaundice than in the early cord clamping group. There were no apparent differences between early and late clamping in neonatal mortality or long-term neurodevelopmental outcome. Additional data on delayed versus early cord clamping are presented separately. (See "Labor and delivery: Management of the normal third stage after vaginal birth", section on 'Early versus delayed cord clamping'.)

●Other causes of passive transfusion – Other associations include:

•Twin-to-twin transfusion, which occurs in 10 to 15 percent of monochorionic twins (see "Twin-twin transfusion syndrome: Screening, prevalence, pathophysiology, and diagnosis")

•Maternal-fetal transfusion, which is uncommon [24]

•Precipitous delivery (see "Precipitous birth not occurring on a labor and delivery unit")

●Causes due to increased intrauterine erythropoiesis – Increased intrauterine erythropoiesis usually results from placental insufficiency and chronic intrauterine hypoxia [10,13]. Neonatal polycythemia due to this mechanism can be seen in the following settings (table 1):

•Infants who are small for gestational age (see "Infants with fetal (intrauterine) growth restriction")

•Maternal preeclampsia or other hypertensive or vascular disorders (see "Preeclampsia: Clinical features and diagnosis" and "Gestational hypertension")

•Pregnancies complicated by chronic maternal hypoxemia due to cardiac or pulmonary disorders, drugs such as propranolol, smoking, or high altitude (see "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate" and "Asthma in pregnancy: Clinical course and physiologic changes")

•Infants of diabetic mothers (see "Infants of mothers with diabetes (IMD)")

•Post-term infants (see "Postterm infant")

•Infants who are large for gestational age, including those with Beckwith-Wiedemann syndrome (see "Large for gestational age (LGA) newborn" and "Beckwith-Wiedemann syndrome")

•Other endocrine abnormalities, such as congenital adrenal hyperplasia [25], hypothyroidism [26], or hyperthyroidism [27] (see "Genetics and clinical manifestations of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Clinical features and detection of congenital hypothyroidism" and "Evaluation and management of neonatal Graves disease")

•Chromosomal anomalies, such as trisomy 21, 18, and 13 [28] (see "Down syndrome: Clinical features and diagnosis" and "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome' and "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome')

CLINICAL FEATURES

Signs and symptoms — Most affected newborns are asymptomatic. Among symptomatic neonates, the most common signs and symptoms are gastrointestinal symptoms (poor feeding or vomiting) and cyanosis/apnea [29,30].

●Asymptomatic (most common) – Most polycythemic infants have no associated signs or symptoms, other than, perhaps, plethora [21]. However, plethora is a subjective finding and may not be detected in neonates with darker skin pigmentation. In asymptomatic patients, polycythemia may be noted as an incidental finding when a complete blood cell count is obtained for other reasons. In two large prospective studies of infants with polycythemia, 74 to 90 percent of affected patients were asymptomatic [29,30].

●Cardiorespiratory findings – Cardiorespiratory signs, such as cyanosis and tachycardia, are uncommon, with reported occurrence of <15 percent in prospective studies [29,30]. Respiratory symptoms, including tachypnea, develop in <5 percent of patients [29,30].

●Gastrointestinal symptoms – Gastrointestinal symptoms may include abdominal distension, vomiting, and poor feeding. These symptoms occur in 15 to 20 percent of affected patients [29-31].

●Other findings – Other findings that have been attributed to polycythemia in retrospective studies and small case series include abnormal cry, lethargy, jitteriness, hematuria, renal vein thrombosis, priapism, gallstones, hypotonia, irritability, seizures, and persistent pulmonary hypertension [3,8,32-34].

Symptoms, when present, often begin by two hours after birth, after fluid shifts have occurred and the hematocrit (HCT) is at its peak [12]. Onset may be delayed to the second or third day of life in some infants who develop polycythemia because of excessive extracellular fluid loss. In this case, the volume depletion likely exaggerates the expression of an already increased red cell mass. Infants with no symptoms by 48 to 72 hours of age are likely to remain asymptomatic [15,35].

Symptoms associated with polycythemia are thought to be due to reduced tissue perfusion or associated metabolic abnormalities, but causality has not been established [20]. These signs and symptoms are nonspecific and can occur with many other neonatal disorders.

Associated laboratory abnormalities

Hypoglycemia — Hypoglycemia is a common metabolic problem in newborns with polycythemia. It occurs in 12 to 40 percent of cases [3,29,33,36]. The mechanism may involve increased glucose utilization by the increased number of circulating red cells. However, there are no data to support a causal relationship, and hypoglycemia in these infants may be related to underlying causes of polycythemia (eg, polycythemia commonly occurs in infants of diabetic mothers who are at risk for hypoglycemia due to increased insulin production). (See "Infants of mothers with diabetes (IMD)", section on 'Hypoglycemia'.)

Hyperbilirubinemia — At least one-third of infants with polycythemia develop hyperbilirubinemia [3], most likely due to the breakdown of an increased number of circulating red cells. This may occasionally lead to the development of gallstones [21]. The actual effect of polycythemia on hyperbilirubinemia is difficult to quantify since interventions for polycythemia, such as exchange transfusion and hydration, also mitigate the hyperbilirubinemia. These treatment effects may explain why some studies do not show an association between polycythemia and hyperbilirubinemia [29]. (See "Unconjugated hyperbilirubinemia in neonates: Risk factors, clinical manifestations, and neurologic complications" and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

DIAGNOSIS

Who to test — The hematocrit (HCT) should be measured in infants who have signs or symptoms that may be due to polycythemia, including cyanosis, tachypnea, poor feeding, and vomiting. We do not routinely measure the HCT in term infants who are well-appearing (including those with growth restriction without other concerning findings), because asymptomatic newborns with polycythemia do not appear to benefit from treatment [32,37]. (See 'Management' below.)

Laboratory testing

●Pitfalls of testing – HCT values can vary substantially depending upon the type of blood sample used, age of the neonate, and method of HCT measurement:

•Type of blood sample – HCT values are highest in capillary samples, intermediate in peripheral venous samples, and lowest in samples drawn from the umbilical vein [5]. In one study of newborns with peripheral venous HCTs ≥65 percent, the mean values for capillary, peripheral venous, and umbilical venous HCTs were 75, 71, and 63 percent, respectively [8].

•Age at the time of sampling – The HCT increases after birth, reaching a maximum at approximately two hours of age, then decreases to levels in cord blood by 18 hours of age [8,15,16].

•Method of HCT measurement – Values obtained from centrifuged samples are higher than those using cell counters and correlate better with blood viscosity [38].

●Approach to testing – The best laboratory tool to confirm the diagnosis and determine the need for intervention is a HCT measured on a peripheral venous blood sample. However, because capillary blood samples are generally easier to obtain, the HCT is often first measured on a capillary blood sample, usually taken from a warmed heel. If the capillary HCT is ≤65 percent, no further testing is needed. If the capillary HCT is >65 percent, testing should be repeated on a peripheral venous blood sample. The venous HCT usually will be 5 to 15 percent lower than the capillary HCT.

●Confirming the diagnosis – The diagnosis of polycythemia is confirmed if the venous HCT is >65 percent.

A minority of infants with polycythemia have hyperviscosity [8]. Conversely, some infants with hyperviscosity are not polycythemic. However, measurement of viscosity is not widely available and is generally not performed in the clinical setting. (See 'Hyperviscosity' above.)

●Additional testing – Infants with confirmed polycythemia should have blood glucose and bilirubin levels measured since hypoglycemia and hyperbilirubinemia are common complications of polycythemia. (See 'Associated laboratory abnormalities' above.)

The frequency of subsequent blood glucose and bilirubin testing depends on the initial results. Management of hypoglycemia and hyperbilirubinemia are discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Timing of glucose screening' and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening".)

In most infants with polycythemia, the underlying etiology is readily apparent based upon the history and physical examination (eg, delayed cord clamping, maternal diabetes, preeclampsia, macrosomia) (table 1). However, if the etiology is uncertain, it may be reasonable to evaluate for an underlying endocrine abnormality (eg, congenital adrenal hyperplasia or thyroid disease), particularly if there are other concerning findings.

DIFFERENTIAL DIAGNOSIS — The symptoms associated with polycythemia (eg, cyanosis, tachycardia, tachypnea, poor feeding, vomiting) are nonspecific and can occur in many neonatal disorders. Thus, other possible causes of the symptoms should be investigated. These include:

●Respiratory disorders (eg, pneumonia). (See "Overview of neonatal respiratory distress and disorders of transition" and "Neonatal pneumonia".)

●Cardiovascular abnormalities (eg, congenital heart disease, persistent pulmonary hypertension). (See "Identifying newborns with critical congenital heart disease" and "Persistent pulmonary hypertension of the newborn (PPHN): Clinical features and diagnosis".)

●Neonatal sepsis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

●Neurologic disorders (eg, intracranial hemorrhage, stroke, intracranial anomalies, or metabolic abnormalities). (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Stroke in the newborn: Classification, manifestations, and diagnosis" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features".)

●Dehydration – The possibility of dehydration can be evaluated by comparison of birth weight and current weight; loss of >7 percent of birth weight during the first five days of life may suggest dehydration (table 2). (See "Overview of the routine management of the healthy newborn infant", section on 'Weight loss'.)

If the symptoms are not severe, these possibilities usually can be excluded by reviewing the maternal labor and delivery course, performing a thorough physical examination, and closely observing the infant. Infants with severe or progressive symptoms generally warrant additional evaluation, which may include:

●Pulse oximetry and chest radiograph if there are respiratory symptoms or cyanosis, with additional testing determined by results of these tests. (See "Approach to cyanosis in the newborn", section on 'Evaluation' and "Overview of neonatal respiratory distress and disorders of transition", section on 'Diagnostic approach'.)

●Detailed cardiovascular examination (including four extremity blood pressure measurement). (See "Identifying newborns with critical congenital heart disease", section on 'Physical examination'.)

●Blood culture to evaluate for neonatal sepsis. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests'.)

●Metabolic panel (eg, serum electrolytes, calcium, blood urea nitrogen, creatinine) if the clinical picture is suggestive of dehydration.

●Neuroimaging (eg, head ultrasound) if there are concerning neurologic findings (eg, seizures, extreme lethargy, focal deficits). (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis", section on 'Cranial ultrasound'.)

MANAGEMENT — All polycythemic infants should be observed closely for neurologic and cardiovascular symptoms and monitored for common complications, such as hypoglycemia and hyperbilirubinemia. Interventions aimed at lowering the hematocrit (HCT) include intravenous (IV) hydration and partial exchange transfusion (PET). These interventions are generally reserved for symptomatic and/or severely polycythemic neonates.

The management approach outlined below is based largely on expert opinion. Evidence supporting the long-term benefits of PET is generally lacking. Limited observational evidence suggests that there may some short-term benefits; however, there also are known risks.

Treat associated abnormalities

●Hypoglycemia – Once the clinician makes the diagnosis of polycythemia, careful monitoring of blood glucose should be undertaken; if hypoglycemia is discovered, adequate glucose supplementation should be given, as discussed separately. (See "Management and outcome of neonatal hypoglycemia".)

●Hyperbilirubinemia – Serum bilirubin should be followed and hyperbilirubinemia should be treated accordingly, as discussed separately. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Initial management".)

Approach to treating polycythemia

Asymptomatic infants — In asymptomatic infants, polycythemia may be noted as an incidental finding when a complete blood cell count is obtained for other reasons. Management of asymptomatic infants is usually guided by the hematocrit (HCT) (algorithm 1) (in this context, plethora is not considered a symptom):

●HCT ≤70 percent – Infants who are asymptomatic and have a peripheral venous HCT ≤70 percent should be observed. Adequate hydration and glucose intake should be ensured by monitoring oral intake, body weight, and urine output. The venous HCT should be repeated in 12 to 24 hours, while monitoring closely for the development of symptoms. If the HCT remains ≤70 percent and the infant remains asymptomatic, supportive care is continued for 24 hours and the HCT rechecked.

●HCT >70 percent – If the HCT is >70 percent, management options include:

•Many centers (including the author's institution) manage such infants with continued observation, with or without IV hydration (see 'Intravenous hydration' below)

•Some centers perform PET in asymptomatic infants only if the venous HCT is >75 percent [39,40] (see 'Partial exchange transfusion' below)

•Some centers perform PET for any infant with a venous HCT >70 percent, even if the infant is asymptomatic (this approach is uncommon) [41-43] (see 'Partial exchange transfusion' below)

Symptomatic infants — The optimal management of polycythemic infants (ie, peripheral venous HCT >65 percent) with associated signs and symptoms (cyanosis, apnea, poor feeding, vomiting, hypoglycemia) has not been established and varies among centers (algorithm 1).

●Nonsevere symptoms – For infants with nonsevere symptoms, our preferred approach is to provide IV hydration and continued observation (see 'Intravenous hydration' below). Other centers may perform PET in this setting [40].

●Severe symptoms – Infants with severe signs and symptoms (eg, significant cyanosis/apnea, severe gastrointestinal symptoms, severe hypoglycemia) should undergo a thorough evaluation for other causes of these symptoms, as discussed above (see 'Differential diagnosis' above). If another cause is identified, management focuses on addressing the primary cause.

If the symptoms appear to be attributable to polycythemia, we initially manage the infant with IV hydration (see 'Intravenous hydration' below). If symptoms persist or worsen despite adequate IV hydration, we proceed with PET. When the decision is made to perform PET, it should be done as soon as possible because the neonatal HCT and blood viscosity peak between two and four hours after birth [41]. (See 'Partial exchange transfusion' below.)

Interventions

Intravenous hydration — The primary rationale for administering IV fluids in newborns with polycythemia is to prevent and treat hypoglycemia, which is a common complication of polycythemia (see 'Hypoglycemia' above). IV fluid is provided for the first 24 to 48 hours of age at a rate of at least 100 mL/kg per day, including glucose (dextrose) at a rate of 6 to 8 mg/kg per minute, while the infant is closely monitored. The goal is to maintain normal blood glucose and adequate hydration. Additional details regarding IV dextrose for treatment of neonatal hypoglycemia are provided separately. (See "Management and outcome of neonatal hypoglycemia", section on 'IV dextrose infusion'.)

Partial exchange transfusion — Isovolumetric PET reduces the HCT without causing hypovolemia. There is some evidence that PET has beneficial short-term effects on measures of perfusion. However, a long-term benefit of PET in infants with polycythemia has not been demonstrated. (See 'Outcome' below.)

Efficacy

●Short-term effects – In clinical studies, PET has been found to have beneficial effects on physiologic measures related to viscosity (eg, cerebral blood flow, cardiac index, oxygen transport) [7,37,44-48]; however, PET has not been demonstrated to alter the symptoms associated with polycythemia [41].

●Long-term effects – Based on the available evidence, PET does not appear to improve long-term outcomes. Several small clinical trials and two meta-analyses have found that long-term neurodevelopmental outcomes are similar among infants managed with and without PET [29,30,32,33,37,49-51]. In addition, the risk of gastrointestinal injury may be increased with PET [50,51]. (See 'Complications' below and 'Outcome' below.)

In most studies evaluating PET, the intervention was usually performed after six hours of life, so the effect of earlier intervention is unknown.

Technique — PET can be performed in several ways. The procedure is generally similar to exchange transfusion used in management of neonatal hyperbilirubinemia with two key distinctions: PET involves a smaller exchange volume, and it uses normal saline for replacement rather than reconstituted blood. (See "Unconjugated hyperbilirubinemia in term and late preterm newborns: Escalation of care", section on 'Exchange transfusion'.)

PET involves removing blood from an intravascular catheter (typically an umbilical venous catheter [UVC]) and infusing normal saline through a peripheral intravenous (PIV) catheter [52,53].

The usual exchange volume is 15 to 20 mL/kg. Alternatively, it can be calculated using the following formula:

The desired HCT is usually set at 55 percent. Blood volume is estimated at 80 to 100 mL/kg body weight. Higher volumes may be appropriate in infants with lower gestational ages and/or those who have polycythemia due to delayed cord clamping.

For example, for a term neonate weighing 3 kg whose HCT is 75 percent, the exchange volume would be calculated as follows:

Blood can be withdrawn from the UVC while simultaneously infusing saline continuously via the PIV (isovolumetric technique). This technique is preferred in unstable infants. Alternatively, the process can be accomplished using serial aliquots of 10 mL/kg.

Complications — The risk of necrotizing enterocolitis may be increased in infants with polycythemia who are treated with PET [50,51]. In a small clinical trial, necrotizing enterocolitis developed in 8 of 43 patients with hyperviscosity who underwent PET and in none of the controls [54]. Treated infants also had significantly more gastrointestinal symptoms (eg, abdominal distension, bloody stools, emesis). In contrast, in a retrospective analysis of 185 polycythemic term infants treated with PET, the prevalence of gastrointestinal symptoms did not appear to differ before or after the procedure (8 versus 7 percent, respectively) [31]. No patients in this study had severe gastrointestinal injury. The conflicting findings might be explained by differences between the PET techniques used in the two studies. The clinical trial used serial aliquots to perform the PET whereas the second study used an isovolumetric technique (ie, simultaneously replacing volume through a peripheral catheter as blood was withdrawn from an umbilical venous catheter). In addition, because the second study did not test and select patients for hyperviscosity, the population studied may have been at lower risk for complications. The study is also limited by its retrospective nature and lack of a control group. (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

In addition, there are risks attributable to placement of the UVC (eg, thrombosis). (See "Vascular (venous) access for pediatric resuscitation and other pediatric emergencies", section on 'Umbilical vein access' and "Neonatal thrombosis: Clinical features and diagnosis", section on 'Catheter-associated thrombosis'.)

OUTCOME — Whether neonatal polycythemia or its treatment affect long-term outcome is uncertain. The available evidence suggests that the clinical outcome may depend more upon associated conditions (eg, hypoglycemia), or the underlying disorder (eg, placental insufficiency), than on polycythemia itself. As previously discussed, partial exchange transfusion (PET) has not been shown to impact long-term outcomes [50,51]. (See 'Efficacy' above.)

Studies evaluating the effects of polycythemia and hyperviscosity on long-term neurodevelopmental outcomes have produced conflicting results. Some studies have found associations between hyperviscosity and neurologic sequelae, such as motor and speech delays, intellectual disability, and lower academic achievement [29,30,33,49], while others have not found an association [32,37].

A study evaluating three-year outcomes of 111 newborns with hyperviscosity (of whom 42 received PET) compared with 110 nonpolycythemic neonates who were matched for birthweight and gestational age controls found that infants with hyperviscosity had more motor and neurologic abnormalities compared with controls (38 versus 11 percent). These findings did not differ according to treatment [30]. Maternal preeclampsia and neonatal hypoglycemia were more common in the hyperviscosity group than in the control group. In addition, many infants in both groups were lost to follow-up, including approximately one-third of the patients with hyperviscosity.

A similar study compared neurodevelopmental outcomes of 93 infants with hyperviscosity, one-half of whom were randomly assigned to receive PET, with 93 controls [29]. Hyperviscosity was associated with delays in speech and fine motor development at one and two years of age, and persistent effects on intelligence quotient (IQ) scores and academic achievement also were seen in the patients available for follow-up at seven years of age (53 percent of the original cohort) [49]. Among the infants with hyperviscosity, treatment with PET was not associated with effects on any of these neurodevelopmental outcomes, except for neurologic diagnoses and fine motor abnormalities at two years of age; no differences were noted at seven years.

By contrast, in a study of 71 infants with neonatal polycythemia identified by routine screening, of whom 46 were available for follow-up at an average age of 30 months, neurodevelopmental outcomes were similar among infants with symptomatic hyperviscosity, asymptomatic hyperviscosity, and asymptomatic infants with normal viscosity [37]. Another study reported normal neurologic and developmental achievement at eight months and at two years of age among 49 infants with polycythemia and hyperviscosity treated with and without PET [32].

There are important limitations to these studies that preclude a clear understanding of the effects of polycythemia or a firm answer on the clinical benefits of PET. Most reports include patients with polycythemia detected by routine screening who also had documented hyperviscosity. Thus, the results may not apply to infants with polycythemia alone or those in whom polycythemia was detected, because they were symptomatic. Most studies did not control for pre-existing confounders such as maternal diabetes, smoking, or intrauterine growth retardation, so the observed differences in neurodevelopmental outcomes may not be caused by the polycythemia. In studies evaluating PET, the intervention was usually performed after six hours of life, so the effect of earlier intervention is unknown.

SUMMARY AND RECOMMENDATIONS

●Definition and incidence – Neonatal polycythemia is characterized by a venous hematocrit (HCT) that greatly exceeds normal values. A term newborn infant is considered to be polycythemic if the HCT from a peripheral venous sample is >65 percent or the hemoglobin is >22 g/dL. The condition affects approximately 1 to 5 percent of newborns. (See 'Definitions' above and 'Incidence' above.)

●Etiology and pathophysiology – The most common cause of polycythemia in an otherwise healthy term infant is delayed clamping of the umbilical cord. Other causes include twin-twin transfusion, placental insufficiency, maternal hypoxemia or diabetes, and infant risk factors including macrosomia and endocrine abnormalities (table 1). Clinical manifestations of polycythemia are thought to result from hyperviscosity and/or the metabolic effects of an increased red blood cell mass. (See 'Causes' above and 'Pathophysiology' above.)

●Clinical features

•Signs and symptoms – Most infants with polycythemia are asymptomatic, other than, perhaps, plethora. Associated symptoms may include cyanosis, apnea, vomiting, or poor feeding. When present, symptoms often begin by two hours after birth but may be delayed to the second or third day in some infants. (See 'Signs and symptoms' above.)

•Associated laboratory abnormalities – Hypoglycemia and hyperbilirubinemia are commonly associated with polycythemia. (See 'Clinical features' above.)

●Diagnosis

•Who to test – HCT should be measured in infants who have signs or symptoms that may be due to polycythemia (cyanosis, tachypnea, poor feeding, vomiting). We do not routinely measure the HCT in infants who are well-appearing (including those with growth restriction without other concerning findings). (See 'Who to test' above.)

•Approach to testing – The HCT is often first measured on a capillary blood sample, usually taken from a warmed heel. If the capillary HCT is ≤65 percent, no further testing is needed. If the capillary HCT is >65 percent, testing should be repeated on a peripheral venous blood sample. The diagnosis of polycythemia is confirmed if the venous HCT is >65 percent. (See 'Laboratory testing' above.)

•Additional testing – Infants with confirmed polycythemia should have blood glucose and bilirubin levels measured since hypoglycemia and hyperbilirubinemia are commonly associated with polycythemia. Management of hypoglycemia and hyperbilirubinemia are discussed. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Timing of glucose screening' and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening".)

●Differential diagnosis – Signs and symptoms associated with polycythemia (eg, cyanosis, tachycardia, tachypnea, poor feeding, vomiting) are nonspecific and can occur in many neonatal disorders. Thus, other possible causes of the symptoms should be investigated, including respiratory disorders (eg, pneumonia), cardiovascular abnormalities (eg, congenital heart disease, persistent pulmonary hypertension), sepsis, neurologic disorders (eg, intracranial hemorrhage, stroke), and dehydration. (See 'Differential diagnosis' above.)

●Management – Management of neonatal polycythemia depends upon the degree of symptoms (algorithm 1):

•Asymptomatic patients – For asymptomatic newborns, we suggest supportive care alone rather than partial exchange transfusion (PET) (Grade 2C). Supportive care consists of monitoring oral intake, body weight, and urine output to ensure adequate hydration and glucose intake. The venous HCT should be repeated in 12 to 24 hours, while monitoring closely for the development of symptoms.

Supportive care alone is generally sufficient for asymptomatic patients. However, some centers may use PET in asymptomatic patients, particularly if the HCT is >75 percent. (See 'Asymptomatic infants' above.)

•Symptomatic patients – For most infants with symptomatic polycythemia, we suggest initial treatment with supportive care (including intravenous [IV] hydration with dextrose) rather than PET (Grade 2C). Management also includes close monitoring of urine output and evaluation for other possible reasons for the symptoms. PET is a reasonable alternative treatment based on limited data on short-term beneficial effects. However, the available evidence suggests that PET does not improve long-term neurodevelopmental outcome and PET is associated with known risks. We generally limit use of PET to patients with severe progressive symptoms despite initial management with IV hydration. (See 'Symptomatic infants' above and 'Partial exchange transfusion' above.)

●Outcome – Whether neonatal polycythemia or its treatment affect long-term outcome is uncertain. The available evidence suggests that the clinical outcome may depend more upon associated conditions, such as hypoglycemia, or on the underlying disorder (eg, placental insufficiency), than on polycythemia itself. (See 'Outcome' above.)