Neonatal Polycythe

miaDr. vijay

Moderator : Dr. Sanjeev

OBJECTIVES Definition

factors that potentially influence neonatal hematocrit

Major causes of polycythemia

Effects (signs and symptoms) and complications

Clinical trials that studied the effects of partial exchange transfusion (PET)

Recommendations - diagnosis & management of NP

DEFINITION

Neonatal polycythemia defined in most neonatology textbooks as a venous HCT >65%

This cutoff has been chosen based on the observation that blood viscosity exponentially increases above a Hct of 65%

or hemoglobin concentration higher than 22.0 g/dl

a statistical definition of infants at risk

neither based upon the risk for symptoms or for complications

MEASURE HEMATOCRIT OR BLOOD VISCOSITY?

How to define hyperviscosity ?

Viscosity depends on Hematocrit, plasma proteins (especially fibrinogen), deformability of erythrocytes, erythrocyte aggregation , interaction of cell components with vessel walls

The gold standard - measurement of viscosity is a whole blood viscometer that can accurately measure the viscosity of blood (expressed in centipoise)

whole blood viscometers are not universally available

Because the erythrocyte number is the most important factor affecting viscosity, measurement of the neonatal Hct has been suggested as the best clinical screening test for identifying infants with presumed hyperviscosity

factors influence normally HCT

1. Gestational age

HCT increases progressively with increasing gestational age, thus NP may occur at much higher rates in post term than in preterm infants (Due to normal variation of Hct)

2. Degree of placental transfusion

At term, the total fetoplacental blood volume is about 115 ml/kg fetal weight, and is distributed in the "normal" full-term infant after birth as approximately 70 ml/kg

in the infant, with 45 ml/kg remaining in the placenta. This distribution may vary considerably, as more or less blood may remain in the placenta.

The main factors influencing placental transfusion are time of cord clamping, position of the delivered infant in relation to the placenta, onset of respiration, presence or not of intrauterine hypoxia, and presence or not of cord compression

A. Time of cord clamping

Within 30 to 45 seconds following birth, the umbilical arteries are functionally closed, while blood flow from placenta to fetus through the umbilical vein may continue for a few additional minutes . When the infant is delivered at or below the introitus level, if the cord is not clamped, her/his blood volume will increase in a stepwise manner, reaching 55% additionalvolume after 3 minutes

B. Position of the delivered infant in relation to the placenta

In vaginally delivered infants who are kept 50 to 60 cm above the placenta, placental transfusion does not occur (7). In contrast, if they are maintained 40 cm below the placenta, placental transfusion is hastened

C. Onset of respiration

onset of respiration (through generating a negative intrathoracic pressure and presumably increasing the placental-fetal transfusion process

Polycythemia

Study Level of Evidence Inclusion/Exclusion Intervention Outcomes Statistics/NotesMcDonald & Middleton, 2008 Cochrane Review; Cord

clamping effects in mothers and term infants. 11 trials.

Term infants >= 37 weeks gestation. Excluded breech presentation & multiple pregnancies.

Variable timing of cord clamping in the various trials;1-5 minutes, cessation of pulsation, after placentaldescent, etc.

Polycythemia, Hgb/Hct (@ birth, 24-48hrs, 2-4 months, 4 months, & 6 months).

No statistically significant differences found for polycythemia.

Hutton and Hassan, 2007 Meta-analysis (15 controlled trials (8 randomized, 7 not randomized) of Late vs Early clamping in full tern neonates

15 controlled trials (1912 newborns). 37 or greater wks.

ICC vs. late (at least 2 minutes, as defined by this meta-analysis).

Noted increased risk of asymptomatic polycythemia >65%

No treatment was needed for noted asymptomatic polycythemia.

Kugelman et al, 2007 RCT. 35 neonates. 24-34 6/7 wks. Exluded: vaginal bleeding (abruption, previa, placental tear), major anomaly, severe IUGR < 3%, MGDM w/ insulin, twin-twin or discordant (>20% wt), maternal drug abuse.

Hold baby as low as possible without creating tension on cord (20-30cm below vaginal introitus, or below incision if C/S). ICC (5-10”) vs. DCC (30-45”)

Primary: Initial Hct, MAPduring 1st 24 hours.

No significant increase in polycythemia.

Ultee et al, 2006 RCT 41 infants, 34 wks to 36 6/7 wks; Caucasian mothers. Excluded DM, GDM, PIH, twins, congenital abnls.

Infants placed on mother’s abd at neutral position.ICC < 30 seconds vs. DCC at3 minutes.

Primary: Hct at 1 hour & 10 weeks of life; polycythemia (defined as Hct > 0.7)

Hct higher w/ DCC compared to ICC @ 1 hr & 10 wks (P <0.05)

No significant differences found between the two groups in regards to polycythemia.

Chaparro et al, 2006 RCT 476 normal birthweight infants between 36-42 weeksgestation. Exclude: multiple gestation, PreE or Eclamp,hemorrhage, placental abnl, Trisomy, congenital abnl, any type of diabetes, HTN,

Early (10 seconds; mean <20”)) vs. DCC (2 minutes; mean > 90”). Timed from delivery of shoulders. Maintained @ level of uterus.

Secondary: Percentage of infants w/ capillary Hct > 70%

Did not see significantly increased risk of polycythemia

Delayed Cord Clamping

Clinical bottom line: Delayed cord clamping does not increase the risk of polycythemia, especially in preterm neonates. Most studies found no clinically or statistically significant increases in polycythemia for babies who received delayed cord clamping. Studies of term infants were also included; any polycythemia seen in these children was asymptomatic/not clinically significant and required no therapy.

cardiopathies, chronic renal dz,+ tobacco use, not planning to breastfeed for @ least 6months.

Cernadas et al, 2006 RCT 2 obstetrical units in Argentina. 276 neonates with uneventful pregnancies >= 36 wks. Included those with uneventful cephalic vaginal or C/S delivery, singletons. Excluded if > singleton, complicated course, cliinca ldz (DM, PreE, HTN, etc.), evidence of congenital malformations, IUGR (<10th%ile).

CC within first 15 seconds (group 1; mean 12.7 sec), within 1 minute (group 2; mean 59.8 sec), or at 3 minutes (group 3; mean 169.5 sec).

For vaginal deliveries, babies held in mother’s arms. C/S, placed on mother’s lap. Babies received ICC if nospontaneous respiratory effort in first 10 seconds, or ifdiscovered congenital malformation, unexpectedly low birthweight, tight nuchalcord.

Primary: Hct at 6hrs of life.

Secondary: Hct @ 24 & 48 hrs, bili levels, neonatal morbidity/mortality, maternal hemorrhage/Hct, etc.

Prevalence of Hct < 45% significantly less in grps 2&3 vs. 1.

Prevalence of Hct > 65%significantly increased in grp3 (14.1%) vs. grps 1 (4.4%)&2 (5.9%).

No babies w/ Hct > 65 were symptomatic.

Van Rheenen et al, 2007 RCT. 91 term babies. Exclusions: Twins, history of post-partum hemorrhage, GDM, PreE, placental separation before delivery, C/S, tight nuchal cord necessitating early cutting,need for resuscitation, major congenital anomalies.

Vaginal births; held 10 cm below introitus. ICC within20 seconds (mean 15”) vs. DCC done after cessation ofcord pulsation (mean 305 seconds, with SD of 136”).

Secondary: Included possible side effects (neonatal polycythemia/hyperviscosity, maternal blood loss, etc.)

No statistically significant differences were found.

RCT in malaria-endemic area. Partially blinded RCT. Not intention to treat.

Ibrahim et al, 2000 RCT 32 infants with bwt 501-1250 grams and gestational ages of24 to less than 29 weeks. Excluded major congenitalanomalies, twin to twin transfusion, maternal diabetes, placenta previa/abruption, or maternal history of drug abuse.

DCC (20 seconds). Timing started once baby completely out of birth canal in VD. Held supine at level of introitus.

Primary: Initial Hct/Hgb. No polycythemia seen.

D. Presence or not of intrauterine hypoxia

Acute intrapartum and intrauterine asphyxia can be accompanied by anincrease in hematocrit (presumably through increased transcapillary escape ofplasma)

E. Presence or not of cord compression

Because the umbilical vein is more compressible than theumbilical arteries, infants born with a tight nuchal cord may actually have lowblood volume at birth

F. Dehydration

Relative loss of water from body

3. Site of blood sampling

Capillary HCT is generally higher than venous HCT which in turn is higherthan "central" HCT (from umbilical vein) . Capillary HCT from warmed heelscorrelates well with venous HCT

4. Time of blood sampling

Hematocrit rises from values obtained at birth (from cord venous or arterial

sampling) to reach a peak at 2 hours of age, staying at a plateau for 2 additional hours,

then decreases to go back to values close to cord blood values by 12 to 18 hours of age.

CAUSES OF POLYCYTHEMIA

Classified as

Normovolemic

hypervolemic

Hypovolemic

1. Normovolemic Polycythemia

condition where normal intravascular volume is present despite an increase in red cell mass. It results from increased RBC production due to placental insufficiency and/or chronic intrauterine hypoxia

Intrauterine Growth Restriction

Maternal Pregnancy Induced Hypertension

Discordant Twins

Maternal Diabetes Mellitus Prolonged Intrauterine Tobacco Exposure

Postmaturity

2. Hypervolemic polycythemia

occurs when higher than average blood volume is accompanied by an increased red cell mass

acute transfusion to the fetus such as maternal-fetal transfusion

twin-to-twin transfusion

3. Hypovolemic polycythemia

occurs secondary to a relative increase in number of erythrocytes to plasma volume

intravascular dehydration

EFFECTS AND COMPLICATIONS OF POLYCYTHEMIA

A. Hyperviscosity

leads to a reduction in cerebral blood flow

decreased blood flow to the brain→ decrease supply to the brain of other substances carried by plasma, such as glucose, amino acids

B. Decreased cerebral blood flowglucose delivery and utilization in the brain decreases

C. Increased cellular breakdown of the increased red cell massIncreased breakdown of red cells in NP may be a significant contributing factor ofneonatal hyperbilirubinemia

D. Hemodynamic effects of hypervolemia or of hypovolemia

hypervolemia may lead to congestive heart failure, pulmonary edema, and cardiorespiratory failure

hypovolemia can lead to hypoxic-ischemic injury to vital organs.

A. Central nervous system (CNS). Poor feeding, lethargy, hypotonia, apnea, tremors,jitteriness,seizures, cerebral venous thrombosis.

B. Cardiorespiratory. Cyanosis, tachypnea, heart murmur, congestive heart failure,cardiomegaly, devated pulmonary vascular resistance, prominent vascular markings on chest x-ray.

C. Renal.Decreased glomerular filtration, decreased sodium excretion, renal vein thrombosis, hematuria, proteinuria.

D. Other. thrombocytopenia, poor feeding,increased jaundice,persistent hypoglycemia, hypocalcemia, testicular infarcts, necrotizing enterocolitis (NEC), priapism, disseminated intravascular coagulation.

The long-term neurodevelopmental outcome controversial.

higher risk for development delays

Speech and fine motor abnormalities

lower spelling and arithmetic achievement test results and gross

motor skills

Indications for polycythemia screening

Do not routinely screen well term newborns for this syndrome, because there are few data showing that treatment of asymptomatic patients with partial exchange transfusion is beneficial in the long term

Small for gestational age (SGA) neonates

Large for gestational age (LGA) neonates

Infants of diabetic mothers (IDM)

Newborns with morphological features of growth restriction

Monochorionic twins especially the recipient twin

How to screen

Hematocrit at 2nd- 4th HOL

Hematocrit > 65% Hematocrit < 65%. No symptoms

No further evaluation

With symptoms Without symptoms

PET

repeat -12 & 24 HOL

MANAGEMENT

A. Once other causes of illness have been considered and excluded (e.g., sepsis,

pneumonia, hypoglycemia), any child with symptoms that could be due to

hyperviscosity should be considered for partial exchange transfusion if the

peripheral venous hematocrit is >65%.

B. Asymptomatic infants with a peripheral venous hematocrit between 60% and

70% can usually be managed by increasing fluid intake and repeating the

hematocrit in 4 to 6 hours.

C. exchange transfusion when the peripheral venous hematocrit is >70% in the absence of symptoms, but this is a controversial

D. The following formula can be used to calculate the exchange with normal saline that will bring the hematocrit to 50% to 60%. In infants with polycythemia, the bloodvolume varies inversely with the birth weight

TECHNICAL ASPECTS OF PET

Which Diluting Fluid Should Be Used?

Plasma, 5% Albumin, Ns, Or Ringer Solution

PET Is Efficient In Relieving Immediate Symptoms And Reducing HCT.

It Did Not Find Clinically Differences

Thus NS Is The Optimal Fluid (Cheapest, With Less Potential Side-effects)

How much to exchange?

Aim for a target, post PET HCT of 55%

CONCLUSIONS

1. PCT is a venous hematocrit of at least 65%. Such a number is much more likely to be significant in an infant >6 hours than it is at 2-4 hours of age.

2. Symptoms/complications of polycythemia are unlikely to be related to a hematocrit of < 65%.

3. The need for PET and its efficacy have not been demonstrated when PET was conducted after 6 hours of life in asymptomatic infants (regardless of their hematocrit). There is no evidence that PET alters the neurologic or developmental outcomes of asymptomatic polycythemic neonates.

Outcome of PET

Polycythemia

HyperviscosityChonic intrauterine

hypoxia

Chronic uterine hypoxia +

polycythemia

PET will help

PET will not help

PET partially

helps

Malan et al1980

RCT, 49 neonates Venous HCT>65 No or mild symps

o PET> 12 hrso Follow up at 8 mo

No Diff

Goldberg et al 1982

RCT, 20 neonates Capillary HCT>68% + presence of hyperviscosity on venous blood nil symp

o PET was performed at > 12 hrs

o Follow up at 8 mo

No diff

Black's et al1985

RCT, 93 neonates heel stick screening HCT > 65%, a repeat venousHCT>65%, and a venous blood viscosity increased, all neonates

o PET performed at 8-12 hrso Follow up at 2 yrso addnl follow up at 7 yrs

No diff in mental delay rate, motor delay improved

Bada et al1992

RCT, 28 neonates cord blood HCT>57+ arterial blood HCT >62%+ presence ofhyperviscosity

o PET at >6hrs(av 10 hrs)o Follow up at 2 yrs

No diff in MDI and IQ

The clinical trials conducted to date do not allow to reach a practical conclusion, because of the following inherent flaws in design:

1) CNS "damage" may have already occurred before PET was conducted, because PET was performed too late.

2) Confounding variables that may have affected the outcome (such as number of IDM’s, infants of pre eclamptic mothers, smokers, intrauterine growth restriction (IUGR), in whom CNS “damage” may have occurred in utero, unrelated to the polycythemia), were not taken into account in any study

3) the small sample size of all studies

4) follow up of infants was very partial, and did not included all of them. Thus this working group concludes that PET performed after 6 hours of life (after the peak hematocrit/viscosity) is not likely to significantly alter the neurologic or developmental outcomes of asymptomatic polycythemic neonates

5) the effect of PET in symptomatic infants has not been systematically studied

RECOMMENDATIONS

1. Routine screening for polycythemia is not recommended.

2. Routine performance of PET in asymptomatic infants is not recommended.

3. Screening for symptoms should be performed carefully and documented in all infants with polycythemia.

4. Normality of blood glucose should be documented in all infants found to have polycythemia.

5. PET causes a prompt relief of symptoms. the presence of symptoms (or of hypoglycemia) should lead to perform PET

6. PET should be performed as early as possible whenever symptoms are present, in view of the potential for more severe symptoms and complications to develop. Before proceeding with PET, it appears that there is a need for thorough, timely, clinical and physical assessment of the newborn.

7. If performed, PET should be done with normal saline.