OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal polycythemia? What are the typical findings for this disease?

Polycythemia in the term newborn is defined as a hematocrit value = or > 65%. The blood sample should be from a large freely flowing blood vessel. Samples from small vessels or capillary samples will yield falsely elevated values. Automated analysis (Coulter Counter) will yield lower values than those that are spun. From a practical point, an appropriate blood sample run in a hospital laboratory is adequate.

The most common clinical features include ruddy appearance, poor capillary refill and peripheral perfusion.

Other clinical features include lethargy, tachypnea, cyanosis, jitteriness, poor feeding, feeding intolerance, hypoglycemia.

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Most common presentation:

The majority of newborn infants with polycythemia are asymptomatic. They can only be identified by performance of a hematocrit. It is not recommended that all newborns have screening hematocrits as an elevated hematocrit generally does not result in symptoms or organ dysfunction that requires intervention. This approach has been endorsed by the American Academy of Pediatrics.

What other disease/condition shares some of these symptoms?

The following are common symptoms associated with polycythemia and other diseases that should be considered in the differential diagnosis before attributing the symptom to polycythemia.

  • Respiratory distress and cyanosis. Other causes include RDS, TTN, PPHN, cyanotic heart disease.

  • Neurologic abnormalities including lethargy and jitteriness. Other causes include hypoglycemia, hypocalcemia, perinatal hypoxia, other CNS or peripheral neuromuscular disease, genetic syndromes, infant of a diabetic mother, infant with high magnesium level secondary to maternal administration.

  • Poor oral feeding or feeding intolerance. Other causes of poor oral feeding include CNS or peripheral neuromuscular disease, genetic syndromes, infant of a diabetic mother, infant with high magnesium level secondary to maternal administration. Feeding intolerance may be due to bowel obstruction, NEC, intolerance of component of formula, poor bowel motility.

  • Poor urine output or renal failure. Other causes include ATN, obstruction of the urinary tract such as posterior urethral valves, dehydration, renal dysplasia or absence of the kidneys.

  • Hypoglycemia. Other causes include intrauterine growth retardation, infant of a diabetic mother, inborn error of metabolism, nesidioblastosis, abnormalities of insulin or cortisol production, Beckwith-Wiedemann syndrome, infection.

What caused this disease to develop at this time?

  • Chronic intrauterine fetal hypoxia

    Results in increased erythropoietin production. This leads to increased RBC production and hematrocrit to compensate and correct the fetal hypoxia. Common clinical entities related to chronic intrauterine fetal hypoxia include

    PIH with placental dysfunction or other pathology resulting in placental dysfunction

    Maternal diabetes

    Maternal smoking

    Fetal hyperthyroidism

  • Acute fetal hypoxia. Results in a shift in blood volume from the placenta to the fetus. It is a compensatory mechanism to maintain fetal oxygenation and cardiac output to vital organs such as the brain

  • Delayed cord clamping or stripping of the umbilical cord. This results in an infusion of blood that results in polycythemia, increased blood volume and red blood cell mass

  • Genetic syndromes. Beckwith-Wiedemann syndrome, Trisomy 13, 18 and 21

  • Twin to Twin transfusion syndrome (recipient twin)

Most of these underlying causes can be determined by an adequate maternal, pregnancy and delivery history as well as a full physical examination of the infant. Genetic causes should be confirmed with appropriate DNA analysis.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A hematocrit is the sole laboratory test needed to confirm the diagnosis. The sample of blood to be analyzed should be from a large blood vessel with the blood freely flowing. Capillary blood samples will give a falsely elevated hematocrit value. Discussions of polycythemia in the literature are based on blood samples in which the hematocrit is based on a spun or centrifuged sample. Most clinical laboratories use automated methods (e.g., Coulter Counter) which give a lower value, however they are quite acceptable for clinical diagnosis and management.

Hyperviscosity

Many practitioners continue to believe that the elevated blood viscosity associated with polycythemia is responsible for the neurologic dysfunction observed in affected infants. While most clinical laboratories are not able to analyze the viscosity of blood, it may be assumed to be elevated when the hematocrit is ≥ 65%. A thorough review of the literature shows the following relationships between organ dysfunction, polycythemia, and hyperviscosity of the blood.

  • Neurological dysfunction. In randomized studies, infants with polycythemia have a poorer outcome compared to infants with a normal hematocrit. The neurological dysfunction appears to be related to the underlying problems of the fetus responsible for the polycythemia and not the elevated hematocrit or blood viscosity. The most common underlying etiology is chronic and/or acute hypoxia.

  • Hypoglycemia. There have been few studies examining the cause of low blood sugar in affected infants. Most likely the low blood sugar is related to the reduced plasma volume and increased extraction of glucose at the organ level.

  • Respiratory distress. This is due to the elevated blood viscosity. The increased blood viscosity reduces pulmonary blood flow and results in cyanosis, tachypnea, vascular congestion and pulmonary hypertension.

  • Renal failure. Renal blood flow is normal. As noted above, plasma volume is reduced. This results in a lower GFR. As such, urine output may be reduced and BUN and creatinine elevated.

  • Necrotizing enterocolitis. There is no evidence that polycythemia or hyperviscosity have a role in the development of necrotizing enterocolitis. However the perinatal events that result in polycythemia are also risk factors for necrotizing enterocolitis. Therapy for polycythemia (partial exchange transfusion) may lead to the development of necrotizing enterocolitis as noted below.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not needed for the diagnosis or care of the infant with polycythemia. They may be needed for the infant with polycythemia and an associated problem such as respiratory distress or necrotizing enterocolitis.

Confirming the diagnosis

Obtain a hematocrit in the infant who is at risk as described above. If the blood sample was not from a large, free flowing vessel, then obtain such a sample for confirmation.

The need for appropriate sampling has been discussed above. If one only obtains a capillary sample for diagnosis, then infants with a normal hematocrit will be inappropriately diagnosed as having polycythemia and potentially have unnecessary therapy.

Screening hematocrits on all newborn infants was once an accepted practice. This is no longer appropriate due to the low yield and limited number of infants who will need any intervention should the hematocrit be found to be elevated.

If you are able to confirm that the patient has polycythemia, what treatment should be initiated?

The treatment for polycythemia is a partial exchange transfusion (PET) to lower the hematocrit. The fluid for the PET may be saline or a 5% protein solution such as Plasmanate® or 5% albumin. Note that all three solutions are equivalent for reducing the hematocrit and blood viscosity. However, saline is cheaper and does not pose any infectious risk. Fresh frozen plasma (FFP) should be avoided as it has been associated with the development of necrotizing enterocolitis in this population.

The volume of the PET is calculated as follows:

Volume = Blood volume of infant x (observed HCT – desired HCT) / Observed HCT

Blood volume = 80 – 90 cc/kg

Desired HCT = 50-55%

The exchange transfusion should be performed in a sterile manner using the umbilical vein similar to the technique for the classic exchange transfusion for hyperbilirubinema except that the transfused solution is saline, not blood. The aliquot for each ‘pass’ should be 5 cc/k. Supportive therapy should be provided until the PET is performed. This would include appropriate respiratory support for infant in infant with respiratory distress or provision of intravenous glucose solution for hypoglycemia.

PET should not be routinely used. Most infants with polycythemia are asymptomatic and require no therapy. Therapy is reserved for the infant whose symptoms are directly related to the increased hematocrit and blood viscosity. This includes:

Respiratory distress and cyanosis related to changes in pulmonary blood flow and pressure (PPHN).

Hypoglycemia that is not responding to usual provision of intravenous dextrose and other causes of hypoglycemia have been excluded.

Renal failure in which other causes have been excluded.

PET should not be performed solely based on the hematocrit alone. It should not be used with the expectation of preventing or improving neurologic function, gastrointestinal function or prevention of NEC. There is no evidence that it will improve the short or long term function of either the brain or GI tract.

Provision of intravenous fluids to dilute or lower the hematocrit has not been shown to be effective. Some affected infants are IUGR. They may have a decreased body water content but the intravascular volume is normal.

It is the practice of some NICUs to provide treatment as follows:

HCT between 65% and 70%, no symptoms – observe or treat with IV fluids

HCT between 70%-75%, treat with IV fluids or PET

HCT greater than 75%, treat all infants

This type of staged provision of therapy is not based on clinical outcomes in randomized clinical trials or known pathophysiology.

There is no need for any type of long term treatment. Whether the infant is treated with PET or observed, the hematocrit will become lower over time. The polycythemia is an acute problem of the newborn and will not recur unless the child develops some other non-related illness that causes elevation of the hematocrit such dehydration or polycythemia vera in adulthood. Children with polycythemia, especially those who had evidence of fetal distress in the perinatal period, should have close neurologic follow up as they are at risk for developmental delay and neurologic dysfunction. This risk is not changed by PET.

What are the adverse effects associated with each treatment option?

The risks of PET for the treatment of polycythemia include:

infection

thromboembolic episode

perforation of the umbilical vein, portal vein, ductus venosus, right atrium

necrotizing enterocolitis associated with catheterization of the umbilical vein

What are the possible outcomes of polycythemia?

In discussions with the family of the infant, it is important to discuss what is known about polycythemia and its affect on their newborn. If one discusses possible concerns that are not backed by evidence, that should be made clear. Important points to share with the family include:

Polycythemia in the infant is not due to something that the mother did or did not do.

Polycythemia is a common finding (2-5%) of term newborns.

Polycythemia is associated with changes in organ blood flow. However some of these changes are a physiologic response to the elevated HCT and not associated with short or long term organ dysfunction while others may cause acute problems in the newborn period. As reviewed above polycythemia is associated with acute and long term neurologic dysfunction but is not causative. The brain dysfunction appears to be related to perinatal events that directly cause brain injury as well as an elevation in the HCT. However the vast majority of the newborns will have normal brain function and neurodevelopment. PPHN, hypoglycemia and renal failure may be related to the polycythemia and may respond to PET. Once these problems are resolved by the PET, there should not be any long term problems.

The family should know what problems the infant is having and whether or not supportive therapy or PET is the most appropriate therapy. They should be made aware of the risk of PET as described above but that these complications are very rare.

What causes this disease and how frequent is it?

The overall incidence of polycythemia on studies in the United States is 2-5%. It is at the higher range in infants born at higher elevations, likely due to the lower partial pressure of oxygen with higher elevation, resulting in lower PaO2 in the mother and fetus. Polycythemia develops in the fetus as reviewed below. The incidence outside the United States is not well documented but likely to be higher due to the pregnancy complications outlined below that result in fetal/neonatal polycythemia. It may be as high as 17-33% in those infants with trisomies.

The primary etiologies for polycythemia are given above in the section entitled “What caused the disease to develop at this time?” Infants with Beckwith-Wiedemann syndrome or Trisomy 13, 18 and 21 have an increased risk for polycythemia. It appears to be due to chronic hypoxia and associated elevated erythropoietin.

How do these pathogens/genes/exposures cause the disease?

As reviewed above, the underlying problems in prenatal or perinatal period responsible for polycythemia may be classified into two general categories. The first is chronic elevation of erythropoietin secondary to chronic fetal hypoxia or genetic syndrome. The second is an acute transfusion of blood either from the placenta due to acute hypoxia or delayed cord clamping or stripping of the cord towards the newborn prior to clamping of the cord.

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

N/A

Are additional laboratory studies available; even some that are not widely available?

N/A

How can polycythemia be prevented?

Polycythemia may be associated with conditions that cause chronic intrauterine hypoxemia as outlined above. In these situations polycythemia in the newborn is an incidental condition and requires no preventive management in and of itself. Polycythemia in association with maternal diabetes may be prevented by rigorous maternal glycemic control. Avoidance of delayed cord clamping or stripping of the umbilical cord will prevent polycythemia in those infants with normal intrauterine hematocrits. Other causes including chronic intrauterine hypoxia secondary to placental dysfunction (as seen in preeclampsia), fetal trisomy or twin to twin transfusion syndrome are not preventable.

What is the evidence?

There are several reviews of polycythemia of the newborn that include information on etiology, physiology, pathophysiology, clinical care and outcome:

Rosenkrantz, TS. “Polycythemia and Hyperviscosity in the Newborn”. Seminars in Thrombosis and Hemostasis.. vol. 29. 2003. pp. 515-5272.

Sarkar, S, Rosenkrantz, TS. “Neonatal Polycythemia and Hyperviscosity”. Seminars in Fetal and Neonatal Medicine. vol. 13. 2008. pp. 248-255.

The following article reviews the frequency of symptoms in newborn infants with polycythemia. Infants with polycythemia were identified by screening hematocrits of all infants born at two different medical centers:

Wiswell, TE, Cornish, JD, Northam, RS. “Neonatal Polycythemia: Frequency of Clinical Manifestations and Other Associated Findings”. Pediatrics. vol. 78. 1986. pp. 26-30.

The following are articles of original work examining the etiology of polycythemia as well as the definition as it affected by timing:

Oh, W, Lind, J. “Venous and capillary hematocrit in newborn infants and placental transfusion”. Acta Paediatr Scand. vol. 55. 1966. pp. 38-40.

Oh, W, Blankenship, W, Lind, J. “Further study of neonatal blood volume in relation to placental transfusion”. Ann Paediatr. vol. 207. 1969. pp. 147-159.

Flod, NE, Ackerman, BD. “Perinatal asphyxia and residual placental blood volume”. Acta Paediatr Scand. vol. 60. 1971. pp. 433-436.

Oh, W, Omori, K, Emmanouilides, GC, Phelps, DI. “Placenta to lamb fetus transfusion in utero during acute hypoxia”. Am J Obstet Gynecol. vol. 122. 1975. pp. 316-321.

Shohat, M, Teisner, SH, Mimoini, F, Merlob, P. “Neonatal polycythemia: II. Definition related to time of sampling”. Pediatrics. vol. 73. 1984. pp. 11-13.

The following are articles of original work examining the relationship of blood viscosity and blood flow:

Wells, RE, Penton, R, Merrill, EW. “Measurements of viscosity of biologic fluids by core plate viscometer”. J Lab Clin Med. vol. 57. 1961. pp. 646-656.

Wells, RE, Merrill, EW. “Influence of flow properties of blood upon viscosity-hematocrit relationships”. J Clin Invest. vol. 41. 1961. pp. 1591-1598.

Fahraeus, R, Lindqvist, T. “The viscosity of the blood in narrow capillary tubes”. Am J Physiol. vol. 96. 1931. pp. 562-568.

The following are articles of original work examining the function of various organs in newborns with polycythemia:

Nowicki, P, Oh, W, Yao, A, Hansen, NB, Stonestreet, B. “Effect of polycythemia on gastrointestinal blood flow and oxygenation in piglets”. Am J Physiol. vol. 247. 1984. pp. G220-G225.

LeBlanc, MH, Kotagal, VR, Kleinman, LI. “Physiological effects of hypervolemic polycythemia in newborn dogs”. J Appl Physiol. vol. 53. 1982. pp. 865-872.

Le Blanc, MH, D’Cruz, C, Pate, K. “Necrotizing enterocolitis can be caused by polycythemic hyperviscosity in the newborn dog”. J Pediatr. vol. 105. 1984. pp. 804-809.

Black, VD, Rumack, CM, Lubchenco, LO, Koops, BL. “Gastrointestinal injury in polycythemic term infants”. Pediatrics. vol. 76. 1985. pp. 225-31.

Oh, W, Oh, MA, Lind, J. “Renal function and blood volume in newborn infant related to placental transfusion”. Acta Paediatr Scand. vol. 56. 1966. pp. 197-210.

Kotagal, VR, Kleinman, LI. “Effect of acute polycythemia on newborn renal hemodynamics and function”. Pediatr Res. vol. 16. 1982. pp. 148-151.

Rosenkrantz, TS, Oh, W. “Cerebral blood flow velocity in infants with polycythemia and hyperviscosity. Effects of partial exchange transfusion with Plasmanate”. J Pediatr. vol. 101. 1982. pp. 94-98.

Rosenkrantz, TS, Stonestreet, BS, Hansen, NB, Nowicki, P, Oh, W. “Cerebral blood flow in the newborn lamb with polycythemia and hyperviscosity”. J Pediatr. vol. 104. 1984. pp. 276-280.

Rosenkrantz, TS, Philipps, AF, Skrzypczak, PS, Raye, JR. “Cerebral metabolism in the newborn lamb with polycythemia”. Pediatr Res. vol. 23. 1988. pp. 329-333.

The following are articles that examine polycythemia and neurologic outcome. These articles include populations that were treated with partial exchange transfusion or observed. Treatment decisions were made by the treating clinicians in some studies while others are reports on infants who were randomized to therapy or observation. The duration of follow-up is variable.

Höst, A, Ulrich, M. “Late prognosis in untreated neonatal polycythemia with minor or no symptoms”. Acta Paediatr Scand. vol. 71. 1982. pp. 629-633.

Goldberg, K, Wirth, FH, Guggenheim, MA, Murphy, JR, Braithwaite, WR, Lubchenco, LO. “Neonatal hyperviscosity. II. Effect of partial plasma exchange transfusion”. Pediatrics. vol. 69. 1982. pp. 426-431.

Black, VD, Lubchenco, LO, Luckey, DW. “Developmental and neurologic sequelae of neonatal hyperviscosity syndrome”. Pediatrics. vol. 69. 1982. pp. 426-431.

Black, VD, Luchenco, LO, Koops, BL, Poland, RL, Powell, DP. “Neonatal hyperviscosity: Randomized study of effect of partial plasma exchange on long-term outcome”. Pediatrics. vol. 75. 1985. pp. 1048-1053.

Black, VD, Lubchenco, LO, Luckey, DW, Koops, BL, McGuinness, GA, Powell, DP, Tomlinson, AL. “Neonatal hyperviscosity is associated with lower achievement and IQ scores at school age”. Pediatr Res. vol. 23. 1988. pp. 442A

Bada, HS, Korones, SB, Pourcyrous, M, Wong, SP, Wilson, WM, Kolni, HW, Ford, DL. “Asymptomatic syndrome of polycythemic hyperviscosity: effect of partial plasma exchange transfusion”. J Pediatr. vol. 120. 1992. pp. 579-585.

Ongoing controversies regarding etiology, diagnosis, treatment

The current body of information concerning the various aspects of newborn polycythemia appears to be comprehensive and complete. Recent investigations into the subject have added no major changes in our understanding but rather continue to confirm what is currently known.

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