Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia

Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia

Skip sharing on social media links
Share this:

Authors

Eren Özek1, Roger Soll2, Michael S Schimmel3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Pediatrics / Division of Neonatology, Maramara University Medical Center, Istanbul, Turkey [top]
2Division of Neonatal-Perinatal Medicine, University of Vermont, Burlington, Vermont, USA [top]
3Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel
[top]

Citation example: Özek E, Soll R, Schimmel MS. Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No.: CD005089. DOI: 10.1002/14651858.CD005089.

Contact person

Roger Soll

Division of Neonatal-Perinatal Medicine
University of Vermont
Fletcher Allen Health Care, Smith 552A
111 Colchester Avenue
Burlington Vermont 05401
USA

E-mail: Roger.Soll@vtmednet.org

Dates

Assessed as Up-to-date: 02 November 2009
Date of Search: 01 October 2009
Next Stage Expected: 02 November 2011
Protocol First Published: Issue 1, 2005
Review First Published: Not specified
Last Citation Issue: Issue 1, 2005

What's new

Date / Event Description

History

Date / Event Description
24 October 2008
Amended

Converted to new review format.

Abstract

Background

Hyperviscosity of blood results in increased resistance to blood flow and decreased oxygen delivery. In the neonate, hyperviscosity can cause abnormalities of central nervous system function, hypoglycemia, decreased renal function, cardiorespiratory distress, and coagulation disorders. Hyperviscosity has been reported to be associated with long-term motor and cognitive neurodevelopmental disorders. Blood viscosity exponentially increases when an infant has polycythemia (hematocrit greater than/or equal to 65%). Partial exchange transfusion (PET) is traditionally used as the method to lower the hematocrit and treat hyperviscosity.

Objectives

To evaluate the effect of PET on mortality and neurodevelopmental outcome in infants with neonatal polycythemia.

Search methods

Electronic databases searched included: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (1966 to October 2009), EMBASE (1980 to October 2009) and CINAHL (1982 to October 2009).

Selection criteria

Randomized controlled clinical trials or quasi-randomized trials comparing partial exchange transfusion to control (non-treatment) in infants with neonatal polycythemia

Data collection and analysis

Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group.

Results

One study (Kumar 2004) reported no demonstrable effect on the risk of neonatal mortality (RR 5.23, 95% CI 0.66, 41.26).

Four studies reported on neurodevelopmental assessment at 18 months or older. The completeness of follow-up differed widely between the studies. Overall, no difference was seen in developmental delay when all trials are analysed based on available cases (typical RR 1.45, 95% CI 0.83 to 2.54) and when only the randomized controlled trials are analysed (typical RR 1.35, 95% CI 0.68 to 2.69). A best case/worst case analysis of developmental delay is consistent with large benefit or harm from PET.

Two studies reported on necrotizing enterocolitis (Van der Elst 1980; Black 1985). An increase in the risk of NEC was noted in infants receiving PET (typical RR 11.18, 95% CI 1.49, 83.64; typical RD 0.14, 95% CI 0.05, 0.22). No differences in short-term complications including hypoglycemia (two studies) and thrombocytopenia (one study) were noted.

Authors' conclusions

There are no proven clinically significant short or long-term benefits of PET in polycythemic newborn infants who are clinically well or who have minor symptoms related to hyperviscosity. PET may lead to an increase in the risk of NEC. The data regarding developmental follow-up is extremely imprecise due to the large number of surviving infants who were not assessed and, therefore, the true risks and benefits of PET are unclear.

Plain language summary

Partial exchange transfusion to prevent neurodevelopmental disability in infants with polycythemia

Polycythemia is a condition in which there are too many red blood cells in the blood circulation. Polycythemia may occur with many different conditions. Some of the babies affected by polycythemia include those born after 42 weeks (post-term), small for gestational age (SGA )/intrauterine growth restriction (IUGR ), identical twins who share the same placenta and develop twin to twin transfusion, infants of diabetic mothers, and those with chromosomal abnormalities. Mild polycythemia may not cause problems. However, too many red blood cells can make the blood "viscous', making it harder to circulate through the vessels and to the organs and cause complications.

The accepted treatment of polycythemia is partial exchange transfusion (PET). PET involves slowly removing some of the blood volume and replacing the withdrawn blood with fluids to help dilute the red blood cell concentration.Treatment of polycythemia with PET is controversial. It may be associated with earlier improvement of symptoms.This review of trials found that there is no evidence of long-term benefit from PET in polycythemic infants, but the estimates of these effects are extremely imprecise due to the large number of surviving infants who were not assessed.

[top]

Background

Description of the condition

Hyperviscosity of blood results in increased resistance to blood flow and decreased oxygen delivery. Hyperviscosity in the neonate can cause abnormalities of central nervous system function, hypoglycemia, decreased renal function, cardiorespiratory distress, and coagulation disorders. Hyperviscosity has been reported to be associated with long term motor and cognitive neurodevelopmental disorders (Delaney-Black 1989; Drew 1997).

The "gold standard" measurement of viscosity uses a whole blood viscometer that can accurately measure the viscosity of blood at the low shear rates that occur naturally in the capillary circulation. Unfortunately, whole blood viscometers are not universally available in the clinical setting. Since erythrocyte number is the single most important factor affecting viscosity, the measurement of the neonatal hematocrit has been suggested as the best screening test for identifying infants with presumed hyperviscosity (Gross 1973).

Traditionally, polycythemia has been defined as a venous hematocrit over 65%. This cut off was chosen based on the observation that blood viscosity exponentially increased above a hematocrit of 65% (Nelson 1976). It is unclear if this is an appropriate clinical threshold. Gross measured whole blood viscosity in 102 normal and 18 symptomatic infants (Gross 1973). All symptomatic infants had hyperviscosity. The hematocrit of these infants ranged from 63% to 77%. However, factors other than erythrocyte number contribute to the degree of blood viscosity. Drew reported that only 47% of infants with hematocrit over 65% had hyperviscosity and 23% of the hyperviscous infants were polycythemic (Drew 1997).

The reported incidence of neonatal polycythemia in term newborns varies from 0.4% to 12% (Wiswell 1986; Reisner 1983; Shohat 1984). This wide variation may be due to different screening techniques, sampling sites (capillary versus peripheral or central venous), varied patient populations, mode of delivery, methodology of measuring (Coulter counter or centrifuged capillary blood), and sampling time. Sampling time is the most important source of this variation. The hematocrit normally rises after birth, reaching a peak at two hours postpartum and then slowly decreases over the next 12 hours (Shohat 1984). At two hours of life the upper limits (2 S.D.) of a normal capillary hematocrit is 71%.

Whole blood viscosity is influenced primarily by three factors: red cell number, plasma proteins, and erythrocyte deformity (Muller 1981; Gross 1973). In addition, blood flow is also affected by the radius of the vessels, endothelial characteristics, blood pressure and end capillary pressure.

The causes of hyperviscosity/polycythemia in the neonate are varied. The entity "polycythemia" can be subdivided based on underlying etiology:

  1. increased red cell mass and plasma volume, secondary to "blood transfusion" (delayed cord clamping, twin to twin or maternal-fetal transfusion) or maternal diabetes;
  2. increased red cell mass and normal plasma volume associated with a congenital syndrome (Trisomy 13, 18, 21);
  3. increased red cell mass with normal or decreased plasma volume secondary to intrauterine growth retardation, placental insufficiency, maternal hypertension or smoking (al-Alawi 2000).

Description of the intervention

Partial exchange transfusion (PET) is traditionally used as the method to lower the hematocrit and treat hyperviscosity. PET is performed with either crystalloid (normal saline) or colloid (5% albumen) solutions. The volume to be exchanged is based on the observed and desired hematocrit (usually 55%) [volume to be exchanged = infant's blood volume x (observed Hct - desired Hct)/observed Hct]. Usually, the total volume exchanged will be in the range of 50 to 80 mL.

How the intervention might work

PET has been shown to reduce pulmonary vascular resistance (Murphy 1985), and increase cerebral blood flow velocity (Rosenkrantz 1982; Maertzdorf 1989). Bada has noted that PET normalized cerebral hemodynamics and improved the clinical status of infants with polycythemia (Bada 1992). PET is a relatively simple procedure, but has numerous potential complications. Unfortunately, there are no data regarding the incidence of complications of PET; one can only extrapolate from the data on full exchange transfusions performed for neonatal hyperbilirubinemia. Reported complications in whole blood exchange include infections, cardiac arrhythmia, thrombosis, emboli, vessel perforation, necrotizing enterocolitis, accidental hemorrhage, air embolus, hypothermia, reduction in blood pressure and cerebral blood flow fluctuation and even death (Merchant 1986). Full exchange transfusion is expected to have a higher incidence of complications than PET, since the amount of blood to be exchanged is almost nine times higher and the product utilized for the exchange is donor's blood. Most of these complications can be avoided by performing the procedure carefully, while monitoring vital signs and adjusting to a standard protocol. The relevance of this data in calculating the magnitude of the risk of performing PET is unclear.

Why it is important to do this review

The statement of the American Academy of Pediatrics Committee on Fetus and Newborn regarding the treatment of neonatal polycythemia with PET reflects both the concern and uncertainty regarding this condition: "The accepted treatment of polycythemia is partial exchange transfusion (PET). However there is no evidence that exchange transfusion affects the long-term outcome. Universal screening for polycythemia fails to meet the methodology and treatment criteria and also, possibly the natural history criterion" (AAP Committee 1993). Despite this ambivalent statement, standard practice in most nurseries is to perform PET in symptomatic babies with a hematocrit greater than 65% or in asymptomatic babies with a hematocrit greater than 70% (Roithmaier 1995; Acunas 2000).

Objectives

To evaluate the effect of partial exchange transfusion (PET) on mortality and neurodevelopmental outcome (motor delays, speech abnormalities, fine-motor abnormalities, abnormal neurologic findings, MDI, IQ and school grade level) in infants with neonatal polycythemia.

Secondary objectives included the evaluation of the effect of partial exchange transfusion (PET) on symptoms associated with neonatal polycythemia [hypoglycemia, thrombocytopenia, hyperbilirubinemia, feeding intolerance, respiratory distress, necrotizing enterocolitis (NEC), CNS depression, seizure activity, thrombotic complications] and rehospitalization (for feeding intolerance, hyperbilirubinemia - prolonged hyperbilirubinemia, infection) in infants with neonatal polycythemia.

Proposed subgroup analyses included various subpopulations (IUGR; IDM; post-term, symptomatic infants, infants with documented hyperviscosity), method of PET (using crystalloid or colloid solutions) and trial methodology (randomized controlled trials or quasi-randomized controlled trials).

Post hoc, a best case/worst case analysis was done to determine the effect of the large number of surviving infants not evaluated for developmental delay.

[top]

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled clinical trials or quasi-randomized trials comparing partial exchange transfusion to control (non-treatment) in infants with neonatal polycythemia

Types of participants

Post-term (> 42 weeks gestation), term (38 to 42 weeks gestation) or late preterm infants (36 to 38 weeks gestation) with neonatal polycythemia (defined as a venous hematocrit greater than or equal to 65%) with or without symptoms of hyperviscosity.

Types of interventions

Infants randomly allocated to receive either partial exchange transfusion (using crystalloid or colloid solutions) or control (non-treatment).

Types of outcome measures

Primary outcomes
  • Neonatal mortality
  • Mortality at hospital discharge
  • Neurodevelopmental status at two years of age, neurodevelopmental status at school age. This will include both a combined and separate analyses of the components of severe neurodevelopmental delay defined as an MDI < 70, cerebral palsy, vision loss, and hearing loss.
Secondary outcomes
  • Hypoglycemia (blood glucose < 35 mg %)
  • Thrombocytopenia (platelet count < 100, 000)
  • Hyperbilirubinemia (total bilirubin > 15 mg %)
  • Respiratory distress
  • Proven bacterial infection
  • Feeding intolerance
  • Necrotizing enterocolitis (Bell's Stage two or greater)
  • Clinical seizures
  • Cerebral infarction
  • Other thrombotic complications
  • Rehospitalization for infection and hyperbilirubinemia

Search methods for identification of studies

The standard search strategy of the Neonatal Review Group, as outlined in The Cochrane Library, was used.

Electronic searches

We searched the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (1966 to October 2009), EMBASE (1980 to October 2009) and CINAHL (1982 to October 2009). We did not limit the search to any language. We used the following search terms: (MeSH terms: polycythemia, hyperviscosity, partial exchange transfusion; limits; age groups, newborn infants; publication type, clinical trial as well as review articles and guidelines). From the resulting studies, we manually extracted randomized controlled studies that fulfilled the inclusion criteria. In addition, in order to identify reports of long-term neurodevelopmental sequelae, we performed a separate search using the following keywords: (outcome OR sequelae OR follow-up OR mental retardation OR cerebral palsy OR hearing OR visual OR motor OR mental OR psychological) AND (partial exchange transfusion) not limited to any age group or language. We searched the list of articles cited in each publication obtained, in order to identify additional relevant articles.

We used a similar modified search strategy for searching EMBASE and CINAHL.

Searching other resources

Published abstracts: The abstracts of the Society for Pediatric Research (USA) (published in Pediatric Research) for the years 1985 to 1999 were searched by hand using the following key words: partial exchange transfusion OR polycythemia OR hyperviscosity. Abstracts from 2000 to 2009 were searched electronically through the PAS web site (abstractsonline). For abstract books that do not include keywords, the search was limited to relevant sections such as hematology and neonatology.

Clinical trials registries were also searched for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

We used the standard method for the Cochrane Collaboration described in the Cochrane Collaboration Handbook.

Selection of studies

We included randomized controlled trials and quasi-randomized trials fulfilling the inclusion criteria. Two review authors separately selected the studies for inclusion (EO and RFS). Any disagreement was resolved by discussion.

Data extraction and management

For each included trial, information was collected regarding the method of randomization, blinding, intervention (colloid or crystalloid solution), stratification, and whether or not the trial was single or multicenter. Information collected regarding trial participants included birth weight or gestational age, postnatal age, and disease severity (asymptomatic or asymptomatic). Two review authors separately assessed each study (EO and RFS). Any disagreement was resolved by discussion.

Two review authors separately extracted, assessed and coded all data for each study using a form that was designed specifically for this review. Any disagreement was resolved by discussion. For each study, final data was entered into RevMan by one reviewer (RFS) and then checked by a second reviewer (EO).

Information on clinical outcomes was analysed including the incidence of neurodevelopmental status until two years of age, neurodevelopmental status at school age, hypoglycemia, thrombocytopenia, hyperbilirubinemia, respiratory distress, infection, necrotizing enterocolitis, seizures, thrombotic complications (central nervous system and others), and mortality.

Assessment of risk of bias in included studies

Two review authors (EO and RFS) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreement was resolved by discussion or by involving MS as a third assessor.

The methodological quality of the studies was assessed and entered into the Risk of Bias table using the following criteria:
  1. Was there adequate sequence generation (checking for possible selection bias):
    The method used to generate the allocation sequence in each included study was described as: adequate (any truly random process e.g. random number table, computer random number generator); inadequate (any nonrandom process e.g. odd or even date of birth, hospital or clinic record number); unclear.
  2. Was there adequate allocation concealment (checking for possible selection bias):
    The method used to conceal the allocation sequence in each included study was described as: adequate (e.g. telephone or central randomization, consecutively numbered sealed opaque envelopes); inadequate (open random allocation, unsealed or non-opaque envelopes, alternation, date of birth); unclear.
  3. Was there adequate blinding (checking for possible performance bias):
    The methods used to blind study participants and personnel from knowledge of which intervention a participant received were described. Blinding was assessed separately for different outcomes or classes of outcomes. We assessed the methods as: adequate, inadequate or unclear for participants; adequate, inadequate or unclear for personnel; adequate, inadequate or unclear for outcome assessors.
  4. Were incomplete outcome data addressed (checking for possible attrition bias through withdrawals, dropouts, protocol deviations):
    Ifattrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes were reported.Where sufficient information was reported or could be supplied by the trial authors, we re-included missing data in the analyses that we undertook. We assessed methods as: adequate (< 20% missing data); inadequate (greater than/or equal to 20% missing data); unclear.
  5. Was there selective reporting bias:
    The possibility of selective outcome reporting bias was investigated. We assessed the methods as: adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported); inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported); unclear.
  6. Were there any other sources of potential bias:
    Any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process) were described. We assessed whether each study was free of other problems that could put it at risk of bias as: yes; no; unclear.

Measures of treatment effect

We used the standard method of the Cochrane Neonatal Review Group. In assessing the treatment effects for dichotomous outcomes we used the relative risk (RR), risk difference (RD), and the number needed to treat (NNT) with 95% confidence intervals (95% CI). For outcomes measured on a continuous scale, we used mean difference (MD) or, if the scale of measurement differs across trials, standardized mean difference (SMD), each with its 95% CI.

Dealing with missing data

For the primary outcome measure "Developmental Delay" a post hoc analysis was done to determine a best case/worst case scenario. These estimates reflect the most extreme impact of the missing data: i.e. the best case scenario imputes the favorable outcome to all missing in the treatment group, and the adverse outcome to all missing in the control group; the reverse for worst case scenario. In situations where there is a great deal of missing data, the best-worst case analysis gives an estimate of the treatment effect that is very wide. In addition to the "best case/worst case" scenario, we calculated the uncertainty interval using the methods of Gamble and Hollis (Gamble 2005; courtesy of Dr. J. Sinclair). The uncertainty interval incorporates both sampling error and the potential impact of missing data and gives a more conservative estimate of the impact of the missing data (Gamble 2005).

Assessment of heterogeneity

The decision to perform a meta-analysis was based on whether there was sufficient similarity between the eligible studies in their design features and clinical features (population, interventions) to make pooling of the data for meta-analysis reasonable. If the studies were sufficiently similar, a meta-analysis was performed; if not, the results of individual trials were described separately.

The amount of heterogeneity of treatment effect across trials in a meta-analysis was estimated using the I2 statistic. If substantial heterogeneity was present, the potential source of this heterogeneity was explored including exploring differences in trial design or clinical features of trial subjects.

Data synthesis

Meta-analysis was done using RevMan 5. For estimates of typical relative risk and risk difference, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed effect model. When meta-analysis was judged to be inappropriate, individual trials were analyzed and interpreted separately.

Subgroup analysis and investigation of heterogeneity

Planned subgroup analyses: colloid or crystalloid solutions for partial exchange transfusion, symptomatic or asymptomatic infants, etiology of polycythemia.

Sensitivity analysis

Post hoc, a best case/worst case analysis was done to determine the effect of the large number of surviving infants not evaluated for developmental delay. These estimates represent the most extreme impact of the missing cases. A more reasonable estimate is derived by calculating the pooled uncertainty interval using the methods of Gamble and Hollis (Gamble 2005; courtesy of Dr. J. Sinclair) (see discussion on "Missing Data" above).

[top]

Results

Description of studies

Results of the search

The review includes the following six studies: Van der Elst 1980; Goldberg 1982; Black 1985; Bada 1992; Ratrisawadi 1994; Kumar 2004. The methods of randomization, description of interventions, and outcomes reported are summarized in the table "Characteristics of Included Studies".

Included studies

Van der Elst 1980:
Van der Elst and coworkers studied infants who had a central venous hematocrit of 65% or greater. The infants were clinically well or had minor signs of hyperviscosity. The postnatal age at randomization is not clear. Forty nine infants were randomly assigned to receive either an umbilical PET using plasma (n = 24, gestational age of 38.3 ± 3.3 weeks) or supportive care (n = 25, gestational age of 38.8 ± 3.8 weeks). Thirty normal infants (gestational age of 38.8 ± 1.weeks) were also reported for purposes of comparison. No distinction was made between the mildly symptomatic and asymptomatic infants. BNBAS and neurological assessment of Prechtl was performed at 10 days. At eight months of age, the neurodevelopmental status of the infants was assessed using a score similar to Griffith. The examiner was masked to intervention status.

Hakanson 1981:
Hakanson reported a trial of PET in hyperviscous infants born at or near term (range 36 to 40 weeks gestation). Few details are available, as this trial is only presented in abstract form. Twenty-four infants diagnosed with hyperviscosity before 12 hours of age were randomly assigned to receive PET with FFP or supportive care. It is unclear from the abstract whether these infants were symptomatic or asymptomatic. All infants were appropriate for gestational age. All infants were seen at follow-up at eight months of age for BSID and neurological assessment.

Goldberg 1982:
Goldberg and coworkers conducted a randomized controlled trial to determine the effect of PET. Twenty term infants with a central hematocrit of 64% or greater and a blood viscosity greater than 2 SD above the mean were randomly assigned to observation (n = 10) or umbilical PET with plasma (n = 10). Enrollment occurred within the first eight hours after birth. No distinction was made between symptomatic and asymptomatic infants. BNBAS at 8 hours, 24 hours, 72 hours and two weeks and BSID and neurological assessment at eight months were performed. Examiners were masked to intervention status.

Black 1985:
Black and coworkers studied 94 term infants with polycythemia (defined as a venous hematocrit of 65% or greater) and hyperviscosity (defined as a viscosity measurement more than 2 SD above the mean). The infants were enrolled into the study at four to six hours of age. Infants were randomly assigned to receive umbilical PET using plasma or symptomatic care by drawing a card from a deck generated by a random number table. No distinction was made between symptomatic and asymptomatic infants. One infant was dropped from control group by the attending physician after the diagnosis of structural heart disease. Neonatal course and neurodevelopmental outcome at one and two years by using BSID and neurological assessment were evaluated.

Bada 1992:
Bada and coworkers evaluated the effect of PET using Plasmanate or supportive care in four groups of infants. Polycythemia was defined as an arterial hematocrit of 63% or greater and hyperviscosity as an increase in viscosity of 13 centipoises or greater at a shear rate of 11.2 seconds-1. Only asymptomatic term and late preterm infants were randomized (n = 28). Infants with hyperviscosity who were free of symptoms were randomly selected to receive PET (n = 14) or to be observed (n = 14) until nursery discharge. The infants underwent cerebral artery doppler measurements. BSID or Stanford Binet and neurological assessment were evaluated at 30 months.

Ratrisawadi 1994:
Ratrisawadi and coworkers followed 147 polycythemic infants. Forty-two of these infants were symptomatic and received PET and supportive care. An unknown number were dropped from the analysis because of congenital malformations. The asymptomatic infants with polycythemia were alternately assigned to treatment with partial plasma exchange transfusion or observation to assess the effect of PET on developmental outcome. Polycythemia was defined as central hematocrit of 65% or greater during age 12 to 24 hours. The gestational age of the study group is not clearly stated. The route of exchange is not stated. After discharge, the infants were followed for the developmental outcome until the age one and one-half to two years. The authors state that the "Gasel developmental test" was done. The meaning of this statement is unclear; perhaps the authors were referring to the "Gesell Preschool Test", which is usually administered to children between the ages of two and one-half to six years. The masking of examiners was not clear. The score below 100 on the "Gasel" test was considered abnormal. Only a fraction of the subjects entered in the study are reported at follow-up (partial plasma exchange transfusion n = 25; observation n = 15).

Kumar 2004:
Kumar and coworkers conducted a randomized controlled trial of PET in asymptomatic polycythemic infants. Polycythemia was defined as a peripheral venous hematocrit of 70% or greater at six to eight hours of age. Forty-five asymptomatic infants were randomized either to peripheral PET using isotonic saline (n = 22) or to routine medical management (n = 23). The birth weights ranged from 1000 to 2000 g for the treatment group and 1250 to 2000 g for the control group. The gestational age of the treatment and observed group were 36.7 ± 3.3 weeks and 37.2 ± 2.4 weeks respectively. Given the range in gestational age and birth weight, it is clear that some of these infants may have fallen below the gestational age cutoff set for this review (36 weeks gestation). However, given that the majority of infants in the study met the gestational criteria, it was decided to include this study. Outcome measures were neonatal morbidity (hypoglycemia, apnea, jaundice and neurological alterations) and neonatal mortality. Developmental delays using DDST-II, neurological deficits, tone and DTR abnormalities were assessed over 18 months follow-up period. The developmental status of study subjects was only ascertained on eight PET subjects and five control subjects.

Excluded studies

The following studies were excluded as they compare different types of partial exchange to each other: Supapannachart 1999; Wong 1997; Krishnan 1997; Deorari 1995; Roithmaier 1995. Details of these studies are included in the table "Characteristics of Excluded Studies".

Risk of bias in included studies

Methodological quality of included studies:

Selection bias: Five of the trials are stated to be randomized controlled trials (Van der Elst 1980; Goldberg 1982; Black 1985; Bada 1992; Kumar 2004). However, only the studies of Black and coworkers (Black 1985) and Kumar and coworkers (Kumar 2004) state the specific method of randomization. The study of Ratrisawadi and coworkers (Ratrisawadi 1994) utilized a quasi-randomized design.

Performance bias: None of the included studies note that there were efforts to mask the intervention.

Attrition bias: Follow-up was less than optimal in the studies of Bada 1992 (71% follow-up), Black 1985 (74% treated, 85% control), Goldberg 1982 (60% untreated group), Kumar 2004 (28.2% at 18 months), and Van der Elst 1980 (86%). Only a small fraction of the infants discussed in the paper of Ratrisawadi and coworkers (Ratrisawadi 1994) were evaluated at follow-up.

Detection bias: Evaluation for long-term outcome in studies was performed by individuals unaware of treatment assignment.

Further details are noted in the table "Characteristics of Included Studies" and in the "Risk of Bias" table.

Effects of interventions

Partial exchange tranfusion vs. non treatment in infants with polycythemia (Comparison 1):

Primary Outcomes

Neonatal mortality (Outcome 1.1): One study (Kumar 2004) presented data on neonatal mortality. There was no demonstrable effect on the risk of neonatal mortality in this one study (RR 5.23, 95% CI 0.66, 41.26).

Developmental delay at 18 months of age or older (available case analysis) (Outcome 1.2): In the original protocol, severe neurodevelopmental delay was defined as an MDI < 70, cerebral palsy, vision loss and hearing loss. None of the studies reported on neurodevelopmental status using these specific criteria.

A post hoc analysis was done on neurodevelopmental delay as reported by the study authors. Four studies (Bada 1992; Black 1985; Kumar 2004; Ratrisawadi 1994) reported on the neurodevelopmental assessment at 18 months or older. The completeness of follow-up differed widely between the studies. Overall, no difference was seen in developmental delay as defined by the investigators when all trials are analyzed (typical RR 1.45, 95% CI 0.83 to 2.54).

Van der Elst 1980 reports that there was no difference between the three groups of infants followed in his trial (hyperviscous infants given PET, hyperviscous infants given no treatment, and normal control infants without hyperviscosity) regarding abnormal neurological examination at eight months. Goldberg 1982 reported no difference in abnormal neurological findings at eight months (5/10 PET, 4/6 Control).

When only the higher quality randomized controlled trials are included in the analysis, there is still no demonstrable effect of PET on developmental outcome (typical RR 1.35, 95% CI 0.68, 2.69).

The estimate of these effects is extremely imprecise due to the large number of surviving infants who failed to be evaluated for developmental delay. In order to explore this issue, a "best case/worst case" analysis was done (see Comparison 2 below).

Secondary Outcomes

Many studies reported the expected change in hematocrit and viscosity associated with the dilutional effects of PET (Van der Elst 1980; Kumar 2004; Bada 1992). Few clinical outcomes are reported in the trials.

Necrotizing enterocolitis (Outcome 1.3): Two studies (Van der Elst 1980; Black 1985) reported on the incidence of NEC. In Van der Elst and coworkers study, one of the 24 patients in the exchanged group developed NEC 24 hours after PET, whereas none of the control patients had NEC (Van der Elst 1980). In Black and colleagues study (Black 1985), eight of 43 infants in the PET group developed NEC compared to none of the 50 control infants. The typical RR for the development of NEC is 11.18 (95% CI 1.49, 83.64) and the typical RD is 0.14 (95%CI 0.05, 0.22).

Black and coworkers also reported that the risk of gastrointestinal symptoms after umbilical PET was increased (18/43 (42%) in the treated vs.1/50 (2%) in the observed group) (Black 1985).

Hypoglycemia (Outcome 1.4): Two studies (Black 1985; Kumar 2004) reported on hypoglycemia. No clinically important difference is found between treated and observed groups (typical RR 1.02, 95% CI 0.55, 1.91).

Thrombocytopenia (Outcome 1.5): Only one study (Goldberg 1982) reported on thrombocytopenia. No difference was found between exchanged and non-exchanged group (RR 1.00, 95% CI 0.17, 5.77).

Jaundice (Outcome 1.6): Kumar and coworkers (Kumar 2004) reported on clinical jaundice. No specific definition regarding bilirubin level was given. No differences were seen regarding the risk of clinical jaundice (RR 2.09, 95% CI 0.20, 21.45).

Partial exchange transfusion vs. non treatment in infants with polycythemia: Sensitivity Analysis (best case/worst case scenario) (Comparison 2):

Developmental delay at 18 months of age or older (best case/worst case scenario) (Outcome 2.1):

Four studies (Bada 1992; Black 1985; Kumar 2004; Ratrisawadi 1994) reported on neurodevelopmental assessment at 18 months or older. The completeness of follow-up differed widely between the studies. Overall, no difference was seen in developmental delay as defined by the investigators when all trials are analyzed based on the available cases (typical RR 1.45, 95% CI 0.83 to 2.54; typical RD 0.10, 95% CI -0.04, 0.25) (see discussion above).

The estimate of these effects is extremely imprecise due to the large number of surviving infants who failed to be evaluated for developmental delay. In order to explore this issue, a "best case/worst case" analysis was done. Given the large number of subjects that were not evaluated for developmental delay, the results vary greatly in this analysis.

In the "worst case" analysis, the typical relative risk demonstrates an extremely increased risk of developmental delay (typical RR 6.10, 95% CI 3.67, 10.14; RD -0.47, 95% CI -0.57, -0.37) associated with PET, compared with a "best case" scenario that would suggest that PET is extremely effective in reducing the risk of developmental delay (typical RR 0.29, 95% CI 0.20, 0.42; typical RD 0.53, 95% CI 0.43, 0.62).

To quantitate these extreme differences, we calculated the pooled uncertainty interval using the methods of Gamble and Hollis (Gamble 2005; courtesy of Dr. J. Sinclair). The uncertainty interval reflects the amount of information in each trial and the potential impact of missing data. Regarding developmental delay at 18 months or older in infants known not to have died, the pooled uncertainty interval for the risk difference is -0.23 to 0.43, representing a more conservative and realistic estimate compared to the "best case/worst case" scenario. Even with this more conservative estimate, the impact of missing data is large and consistent with either clinically significant benefit or harm. (Table 1)

Other subgroup analyses:

Other proposed subgroup analyses included various subpopulations (IUGR; IDM; post-term, symptomatic infants, infants with documented hyperviscosity) and method of PET (using crystalloid or colloid solutions). Insufficient information is available on the subpopulations of interest. Colloid solutions were used in four trials (Van der Elst 1980; Goldberg 1982; Black 1985; Bada 1992) and saline solution in one trial (Kumar 2004). The type of fluid used for PET in the trial of Ratrisawadi 1994 is unclear. Given the large degree of uncertainty noted in the primary analysis above (Comparison 2), these subgroup analyses were not undertaken.

Discussion

Polycythemia in the newborn leads to hyperviscosity and impaired end organ perfusion, which may cause serious complications.The main concern is that polycythemia may be associated with adverse long-term neurological sequelae. Partial exchange transfusion (PET) has been used to treat hyperviscosity; however, it is unclear whether this is an effective approach in preventing long-term neurologic consequences.

Previous meta-analyses have addressed this issue (Dempsey 2006). These authors did not include data from the study of Hakanson and coworkers because it has only been published in abstract form and they considered the data inadequate (Hakanson 1981). However, the results of both analyses are consistent in their findings.

In our review, six randomized controlled trials of PET in the treatment of polycythemic newborn were identified. The studies differed in whether infants were symptomatic or asymptomatic at the time of study entry. Bada and coworkers (Bada 1992), Ratrisawadi and coworkers (Ratrisawadi 1994) and Kumar and coworkers (Kumar 2004) randomized only asymptomatic polycythemic infants. Black and coworkers (Black 1985), Goldberg and coworkers (Goldberg 1982) and Van der Elst and coworkers (Van der Elst 1980) made no distinction between symptomatic and asymptomatic newborns. It is hard to understand any potential differences in effect based on this important clinical variable. There are no randomized trials of PET that include only symptomatic polycythemic infants, thus it is impossible to determine the effect of PET in this group of infants. The study of Kumar and coworkers (Kumar 2004) undoubtedly included some infants below 36 weeks gestation, though these were clearly the minority.

None of the studies included in this review provided long-term follow-up data based on symptomatology or underlying etiology of hyperviscosity, thus the possibility remains that particular patients with severe neurological symptoms may have long-term benefit from PET.

Four studies (Bada 1992; Black 1985; Kumar 2004; Ratrisawadi 1994) reported on the neurodevelopmental assessment at 18 months or older. The completeness of follow-up differed widely between the studies, with all studies having a poor rate of follow-up. In particular, the quasi-randomized study of Ratrisawadi and coworkers is of concern (Ratrisawadi 1994). The quality of this study and, therefore, the concern regarding the precision of the estimate and the possibility of bias is greater based on the method of allocation and low follow-up rate (38% at two years). In the higher quality studies, the summary estimate of the RR for the presence of developmental delay in available cases was 1.35 (95% CI 0.68 to 2.69). These studies were unable to show any benefit of PET on long-term neurodevelopmental outcome. In the sensitivity analysis, the best case/worst case scenario demonstrates a wide and imprecise estimate of the risk or benefit of PET on developmental outcome.

One study (Kumar 2004) presented data on neonatal mortality.The estimate of the RR is 5.23 (95% CI 0.66 to 41.26). The wide confidence interval suggests poor precision. The authors stated that the early neonatal deaths of two babies in the exchanged group due to sepsis cannot be ascribed due to PET, which was performed by peripheral route.These babies were also very low birth weight preterm babies and susceptible to infection. Late neonatal mortality was unlikely due to PET.

Two studies (Van der Elst 1980; Black 1985) reported on the incidence of NEC. The combined analysis of these two studies suggests a possible increase in the risk of NEC (typical RR 11.18, 95% CI 1.49 to 83.64).These data suggest a relationship between NEC and umbilical PET, though confidence intervals for this effect are very wide, suggesting poor precision.

Only one study (Goldberg 1982) reported on thrombocytopenia. No difference was found between exchanged and non-exchanged group (RR 1.00, 95% CI 0.17, 5.77).Two studies (Black 1985; Kumar 2004) reported on hypoglycemia. No clinically important difference is found between treated and observed groups (typical RR 1.02, 95% CI 0.55, 1.91) suggesting no short-term clinically important benefit of PET in polycythemic newborn.

Kumar and coworkers (Kumar 2004) reported on clinical jaundice. No differences were seen regarding the risk of clinical jaundice between treatment and non-treatment groups (RR 2.09, 95% CI 0.20, 21.45).

These data support that there is no clinically significant short and long-term benefit of PET in polycythemic newborn infants who are clinically well or who have minor symptoms and the risk of gastrointestinal injury is increased. There is no data to address the question of whether infants with severe neurological symptoms and those having certain underlying etiologic factors for polycythemia might benefit from PET.

Authors' conclusions

Implications for practice

There are no proven clinically significant short or long-term benefits of PET in polycythemic newborn infants who are clinically well or who have minor symptoms related to hyperviscosity. PET may lead to an increase in the risk of NEC. The data regarding developmental follow-up is extremely imprecise due to the large number of surviving infants who were not assessed and, therefore, the true risks and benefits of PET are unclear.

Implications for research

Due to the imprecision of the estimate of the effect of PET on developmental delay (including the possibility of great benefit or harm) and the lack of data in important clinical subgroups (such as infants with intrauterine growth restriction) the practice should be subject to appropriate trials of sufficient sample size to evaluate the impact on important short-term outcomes (such as NEC) and developmental outcome in infants at risk.

Acknowledgements

We would like to acknowledge Susan Hayward for preparation of the manuscript and Dr. John Sinclair for his suggestions and calculations regarding the sensitivity analysis and uncertainty interval for the outcome "developmental delay".

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

EO helped rewrite the protocol, excerpt the data, analyze the data and write the review.

RS helped write the protocol, excerpt the data, analyze the data and write the review.

MS helped write the protocol, analyze the data and edit the review.

Declarations of interest

  • None noted.

Differences between protocol and review

Additional outcomes added. Subgroup based on methodological quality of trial added. Post hoc definition of neurodevelopmental outcome included. A sensitivity analysis was performed due to the large number of surviving infants who failed to be evaluated for developmental delay. In order to explore this issue, a "best case/worst case" analysis was done.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Bada 1992

Methods

Randomized controlled trial

Single center

Blinding of Randomization: not clearly stated

Blinding of Intervention: not clearly stated

Complete Follow-up: 20/28 (71.4%) asymptomatic-treated and observed

Blinding of outcome measurement: yes

Participants

Gestational age: treated 38.6 ± 1.7 weeks

Observed: 38.2 ± 2.0 weeks

Asymptomatic hyperviscosity cases (hct greater than/or equal to63%; increase in viscosity of 13 CPS or greater at a shear rate of 11.2 seconds-1)

8-18 hours

Interventions

PET treatment ( n=14 ) or observed ( n= 14 )

Mode of exchange: route not stated

Plasmanate

Outcomes

Short-term: Cerebral artery Doppler measurements

Long-term: at 30 ± 7.7 months BSID or Stanford Binet and neurological assessment

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Blinding of Randomization: not clearly stated

Allocation concealment? Unclear

Not clearly stated

Blinding? (Short term outcomes) Unclear
Blinding? (Long term outcomes) Yes

Evaluation of developmental status done by investigators unaware of treatment assignment

Incomplete outcome data addressed? No

20/28 (71.4%) asymptomatic-treated and observed

Free of selective reporting? Yes
Free of other bias? Yes

Black 1985

Methods

Randomized controlled trial

Single center

Blinding of Randomization: yes

Blinding of Intervention: not clearly stated

Completeness of Follow-up:

One infant dropped from control group for all analyses by attending physician s/p diagnosis of structural heart disease

Follow-up at 1 year: 21 PET; 33 control

Follow-up at 2 years: 30 PET; 32 controls

Blinding of Outcome Measurement: not clearly stated

Participants

Term

No distinction made between symptomatic and asymptomatic

Htc 65% and viscosity > 2 SD above the mean

4-6 hours

Interventions

PET (n=43) and observed (n=51) group

Mode of exchange umbilical vein, FFP

Outcomes

Short-term: Neonatal symptoms, Brazelton Behavioral Assessment

Long-term: BSID and neurological assessment at 1 and/ or 2 years

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Drawing a card from deck generated by a random- number table

Allocation concealment? Yes
Blinding? (Short term outcomes) No
Blinding? (Long term outcomes) Unclear
Incomplete outcome data addressed? No

One infant dropped from control group for all analyses by attending physician s/p diagnosis of structural heart disease

Follow-up at 1 year: 21 PET; 33 control

Follow-up at 2 years: 30 PET; 32 controls

Free of selective reporting? Yes
Free of other bias? Yes

Goldberg 1982

Methods

Randomized controlled trial

Single center

Blinding of Randomization: not clearly stated

Blinding of Intervention: not clearly stated

Complete Follow-up:

Treated group: yes

Untreated group 60%

Blinding of outcome measurement: Yes

Participants

Term (n=20)

No distinction made between symptomatic and asymptomatic

Central Htc 64% and a blood viscosity > 2 SD above the mean

4-6 hours

Interventions

PET treatment (n=10) or no treatment (n=10)

Mode of Exchange: Umblical vein, FFP

Outcomes

Short-term: BNBAS at 8h, 24h, 72h, 2 weeks

Long-term: BSID and neurological assessment at 8 months.

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Described as "randomly assigned". Methods not given

Allocation concealment? Unclear
Blinding? (Short term outcomes) Unclear
Blinding? (Long term outcomes) Yes

Examiners unaware of treatment assignment

Incomplete outcome data addressed? No

Complete Follow-up: treated group: yes; untreated group 60%

Unclear how two infants who were randomized to the control group but received PET due to neurologic symptoms prompting treatment with PET were handled.

Free of selective reporting? Yes
Free of other bias? Yes

Hakanson 1981

Methods

Randomized controlled trial

Single center

Blinding of Randomization: not stated

Blinding of Intervention: not stated

Complete Follow-up:

Treated group: yes

Untreated group: yes

Blinding of Outcome Measurement: yes

Participants

Late preterm or term infants (n=24)

Neontal hyperviscosity (no definition given)

Unclear whether infants symptomatic or asymptomatic

Age: 12 hours after birth

Interventions

PET treatment (n=12) or no treatment (n=12)

Mode of Exchange: FFP

Outcomes

Long-term: BSID and neurological assessment at 8 months.

Notes

Abstract only

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Blinding of Randomization: not stated

Allocation concealment? Unclear

Blinding of Randomization: not stated

Blinding? (Short term outcomes) Unclear

Blinding of Intervention: not stated

Blinding? (Long term outcomes) Yes
Incomplete outcome data addressed? Yes

Complete Follow-up: treated group: yes; untreated group: yes

Free of selective reporting? Yes
Free of other bias? Yes

Kumar 2004

Methods

Randomized controlled trial

Single center

Blinding of Randomization: yes

Blinding of Intervention: not clear

Complete Follow-up at 18 months: 28.8%

Blinding of Outcome Measurement: not clear

Participants

Gestational age: asymptomatic treated (n=22): 36.7 ± 3.3 weeks

Asymptomatic observed (n=23): 37.2 ± 2.4 weeks

Birth weight 1000-2000 g

Peripheral venous Htc greater than/or equal to 70%

6-8 hours

Interventions

PET treated (n=22) or observed (n=23)

Peripheral route, isotonic saline

Outcomes

Primary outcomes:

Neonatal morbidity: hypoglycemia, apnea, jaundice and neurological alterations

Neonatal mortality

Developmental delays: DDST II, neurological deficits, tone and DTR abnormalities (3, 6, 9, 12, 18 months)

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Computer generated random number sequence placed in serial numbered opaque sealed envelopes

Allocation concealment? Yes

Blinding of Randomization: yes

Blinding? (Short term outcomes) Unclear

Blinding of Outcome measurement: not clear

Blinding? (Long term outcomes) Unclear

Blinding of Outcome measurement: not clear

Incomplete outcome data addressed? No

Complete Follow-up at 18 months: 28.8%

Free of selective reporting? Yes
Free of other bias? Yes

Ratrisawadi 1994

Methods

Quasi- randomized trial

Single center

Blinding of Randomization: Alternate assignment

Blinding of Intervention: not clear

Complete Follow- up at 1.5 -2 years: no

Blinding of Outcome Measurement: not clear

Participants

Asymptomatic polycythemic babies

Birthweight :3048.95 ± 707.1 grams

Polycythemia: Central Hct greater than/or equal to 65% during age 12-24 hours

Interventions

PET treated (n=25), observed (n=15)

Mode of exchange: not stated

Outcomes

Long term: "Gasel" Developmental testing at 1.5-2 years

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Quasi- randomized trial: alternate assignment

Allocation concealment? No

Blinding of Randomization: alternate assignment

Blinding? (Short term outcomes) Unclear

Blinding of Intervention: not clear

Blinding? (Long term outcomes) Unclear

Blinding of Intervention: not clear

Incomplete outcome data addressed? No

Complete Follow- up at 1.5 -2 years: 38%

Free of selective reporting? Yes
Free of other bias? Yes

Van der Elst 1980

Methods

Randomized controlled trial

Single center

Blinding of Randomization: not clearly stated

Blinding of Intervention: not clear

Complete Follow-up: 86%

Blinding of Outcome Measurement: yes

Participants

No distinction made between symptomatic/asymptomatic

Treated: Gestational age 38.3 ± 3.3 weeks Birthweight: 2775 ± 827 grams

Observed Gestational age 38.8 ± 3.8 weeks

Birthweight: 2523 ± 682 grams

Central venous Hct greater than/or equal to 65% who are hyperviscous

Interventions

PET treated (n=24) or observed (n=25)

Mode of Exchange: Umblical vein / FFP

Outcomes

Short-term: BNBAS and neurological assessment of Prechtl at 10 days.

Long-term: Neurological, developmental assessment at 8 months (similar to the Griffith developmental score )

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Blinding of Randomization: not clearly stated

Allocation concealment? Unclear

Blinding of Randomization: not clearly stated

Blinding? (Short term outcomes) Unclear

Blinding of Intervention: not clearly stated

Blinding? (Long term outcomes) Unclear

Blinding of Outcome Measurement: yes

Incomplete outcome data addressed? Unclear

Complete Follow-up: 86%

Free of selective reporting? Yes
Free of other bias? Yes

Characteristics of excluded studies

Deorari 1995

Reason for exclusion

Conducted a prospective study to evaluate efficacy and safety of partial exchange transfusion (PET) with normal saline or plasma in 30 symptomatic polycythemic newborns. Infants were randomly assigned to receive PET either with normal saline or plasma. There was no untreated control group. A significant fall in hematocrit and viscosity was noticed at 6 hours following PET, which persisted even at 24 hours (P < 0.001). Hematocrit and viscosity were comparable in the two groups at 6 and 24 hours. The majority of the infants became asymptomatic after 24 hours of PET. No complications related to the procedure were encountered in the two groups.

Krishnan 1997

Reason for exclusion

47 babies (inborn and out born) admitted to the neonatal unit with confirmed polycythemia were randomly assigned to receive partial exchange transfusion with either normal saline (N=24) or fresh plasma (N=23). The immediate post-exchange fall in hematocrit was significant in both groups and was sustained over the following 48 hours. There was no untreated control group.

Roithmaier 1995

Reason for exclusion

Clinical trial testing whether crystalloid solutions could be used instead of colloid solutions for partial exchange transfusions (PET) in polycythemic neonates. The investigators randomly assigned 20 term neonates with venous hematocrit (Hct) > 0.65% to PET with either a serum preparation (BISEKO) or Ringer solution. PET with Ringer solution resulted in a hemodilution comparable to PET with serum. No untreated controls were included in this study.

Supapannachart 1999

Reason for exclusion

Randomized clinical trial conducted in the Neonatal Unit of Ramathibodi Hospital, Thailand. In the first phase of the study, 26 infants with polycythemia were randomized to PET using fresh frozen plasma (FFP) or Haemaccel. In the second phase of study, 38 consecutive newborn infants with polycythemia had PET using normal saline. No differences in changes of Hct were reported. No untreated control group was reported.

Wong 1997

Reason for exclusion

Performed a randomized controlled trial to compare the efficacy of using isotonic saline (crystalloid) or 5% albumin (colloid) as replacement fluid in partial exchange transfusion (PET) for the treatment of neonatal polycythemia. One hundred and two polycythemic full term infants were randomly allocated to receive PET with either isotonic saline or 5% albumin. PET with either saline (n = 53) or 5% albumin (n = 50) resulted in a significant and sustained decline in hematocrit up to 24 hours after PET. There were no untreated control infants.

Additional tables

1 Developmental delay among those not known to have died

Developmental Delay Among Those Not Known To Have Died

Study

PET

Control

Missing

Weight

Uncertainty interval, Risk difference

n(m)N

n(m)N

%

%

Bada 1992

5(5)14

5(3)14

29

27

-0.58, 0.70

Black 1985

5(15)43

4(18)48

36

40

-0.51, 0.55

Kumar 2004

3(9)17

1(17)22

67

14

-0.88, 0.89

Ratrisawadi 1994*

11(27)52

4(38)53

63

19

-0.74, 0.80

Pooled

-0.23, 0.43

Effect of partial exchange transfusion on developmental delay. For each arm of each trial, n is the number of participants with an observed event, m is the number of participants with unobserved outcome (missing data), and N is the total number of participants not known to have died. The effect estimator is Risk Difference. The uncertainty interval reflects the amount of information in each trial, taking into account not just the observed data but also the potential impact of missing data.

Shown are the uncertainty interval for risk difference for each trial and the pooled uncertainty interval. For individual trials, the uncertainty interval represents the extremes of the 95% CIs of the best case, worst case estimates. The pooled uncertainty interval was calculated using the method of Gamble and Hollis, J Clin Epidemiol 2005;58:579-88 ( Gamble 2005).

* For Ratrisawadi 1994, exact numbers for allocated and for missing were not given in the published report. These had to be inferred based on the information that was available in the report

[top]

References to studies

Included studies

Bada 1992

Bada HS, Korones SB, Pourcyrous M, Wong SP, Wilson WM 3rd et al. Asymptomatic syndrome of polycythemic hyperviscosity: effect of partial plasma exchange transfusion. Journal of Pediatrics 1992;120:579-85.

Black 1985

Black VD, Lubchenco LO, Koops BL, Poland RL, Powell DP. Neonatal hyperviscosity: randomized study of effect of partial plasma exchange transfusion on long-term outcome. Pediatrics 1985;75:1048-53.

Black VD, Rumack CM, Lubchenco LO, Koops BL. Gastrointestinal injury in polycythemic term infants. Pediatrics 1985;76:225-31.

Goldberg 1982

Goldberg K, Wirth FH, Hathaway WE, Guggenheim MA, Murphy JR, Braithwaite WR et al. Neonatal hyperviscosity. Effect of partial plasma exchange transfusion. Pediatrics 1982;69:419-25.

Hakanson 1981

Unpublished data only

Hakanson DO. Neonatal hyperviscosity syndrome: long-term benefit of partial plasma exchange transfusion (abstract). Pediatric Research 1981;15:449A.

Kumar 2004

Kumar A, Ramji S. Effect of partial exchange transfusion in asymptomatic polycythemic LBW babies. Indian Pediatrics 2004;41:366-72.

Ratrisawadi 1994

Ratrisawadi V, Plubrukarn R, Trakulchang K, Puapondh Y. Developmental outcome of infants with neonatal polycythemia. Journal of the Medical Association Thailand 1994;77:76-80.

Van der Elst 1980

van der Elst CW, Molteno CD, Malan AF, de V. Heese H. The management of polycythaemia in the newborn infant. Early Human Development 1980;4:393-403.

Excluded studies

Deorari 1995

Deorari AK, Paul VK, Shreshta L, Singh M. Symptomatic neonatal polycythemia: comparison of partial exchange transfusion with saline versus plasma. Indian Pediatrics 1995;32:1167-71.

Krishnan 1997

Krishnan L, Rahim A. Neonatal polycythemia. Indian Journal of Pediatrics 1997;64:541-6.

Roithmaier 1995

Roithmaier A, Arlettaz R, Bauer K, Bucher HU, Krieger M, Duc G, Versmold HT. Randomized controlled trial of Ringer solution versus serum for partial exchange transfusion in neonatal polycythaemia. European Journal of Pediatrics 1995;154:53-6.

Supapannachart 1999

Supapannachart S, Siripoonya P, Boonwattanasoontorn W, Kanjanavanit S. Neonatal polycythemia: effects of partial exchange transfusion using fresh frozen plasma, Haemaccel and normal saline. Journal of the Medical Association of Thailand 1999;82:S82-6.

Wong 1997

Wong W, Fok TF, Lee CH, Ng PC, So KW, Ou Y, Cheung KL. Randomised controlled trial: comparison of colloid or crystalloid for partial exchange transfusion for treatment of neonatal polycythaemia. Archives of Disease in Childhood. Fetal and Neonatal Edition 1997;77:F115-8.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

AAP Committee 1993

American Academy of Pediatrics Committee on Fetus and Newborn. Routine evaluation of blood pressure, hematocrit, and glucose in newborns. Pediatrics 1993;92:474-6.

Acunas 2000

Acunas B, Celtik C, Vatansever U, Karasalihoglu S. Thrombocytopenia: an important indicator for the application of partial exchange transfusion in polycythemic newborn infants? Pediatrics International 2000;42:343-7.

al-Alawi 2000

al- Alawi E, Jenkins D. Does maternal smoking increase the risk of neonatal polycythemia? Irish Medical Journal 2000;93:175-6.

Delaney-Black 1989

Delaney-Black V, Camp BW, Lubchenco LO, Swanson C, Roberts L, Gaherty P, et al. Neonatal hyperviscosity association with lower achievement and IQ scores at school age. Pediatrics 1989;83:662-7.

Dempsey 2006

Dempsey EM, Barrington K. Short and long term outcomes following partial exchange transfusion in the polycythaemic newborn: a systematic review. Archives of Disease in Childhood. Fetal and Neonatal Edition 2006;91:F2-6.

Drew 1997

Drew JH, Guaran RL, Cichello M, Hobbs JB. Neonatal whole blood hyperviscosity: the import factor influencing later neurologic function is the viscosity and not the polycythemia. Clinical Hemorheology and Microcirculation 1997;17:67-72.

Gamble 2005

Gamble C, Hollis S. Uncertainty method improved on best-worst case analysis in a binary meta-analysis. Journal of Clinical Epidemiology 2005;58:579-88.

Gross 1973

Gross GP, Hathaway WE, McGaughey HR. Hyperviscosity in the neonate. Journal of Pediatrics 1973;82:1004-12.

Higgins 2008

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration, 2009. Available from www.cochrane-handbook.org.

Maertzdorf 1989

Maertzdorf WJ, Tangelder GJ, Slaaf DW, Blanco CE. Effects of partial plasma exchange transfusion on cerebral blood flow velocity in polycythaemic preterm, term and small for date newborn infants. European Journal of Pediatrics 1989;148:774-8.

Merchant 1986

Merchant RH, Gupta SC. Neonatal exchange transfusions: present status. Indian Pediatrics 1986;23:459-65.

Muller 1981

Muller R. Hemorheology and peripheral vascular diseases: a new therapeutic approach. Journal of Medicine 1981;12:209-35.

Murphy 1985

Murphy DJ Jr, Reller MD, Meyer RA, Kaplan S. Effects of neonatal polycythemia and partial exchange transfusion on cardiac function: an echocardiographic study. Pediatrics 1985;76:909-13.

Nelson 1976

Nelson NM. Respiration and circulation before birth. In: Smith CA and Nelson NM, editor(s). Physiology of the Newborn Infant. 4th edition. Springfield: Charles C Thomas, 1976:17.

Reisner 1983

Reisner SH, Mor N, Levy Y, Merlob P. Incidence of neonatal polycythemia. Israel Journal of Medical Sciences 1983;19:848-9.

Rosenkrantz 1982

Rosenkrantz TS, Oh W. Cerebral blood flow velocity in infants with polycythemia and hyperviscosity: effects of partial exchange transfusion with Plasmanate. Journal of Pediatrics 1982;101:94-8.

Shohat 1984

Shohat M, Merlob P, Reisner SH. Neonatal polycythemia: I. Early diagnosis and incidence relating to time of sampling. Pediatrics 1984;73:7-10.

Wiswell 1986

Wiswell TE, Cornish JD, Northam RS. Neonatal polycythemia: frequency of clinical manifestations and other associated findings. Pediatrics 1986;78:26-30.

[top]

Data and analyses

1 Partial exchange transfusion vs. non treatment in infants with polycythemia

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Neonatal mortality 1 45 Risk Ratio (M-H, Fixed, 95% CI) 5.23 [0.66, 41.26]
1.1.1 Randomized controlled trials 1 45 Risk Ratio (M-H, Fixed, 95% CI) 5.23 [0.66, 41.26]
1.2 Developmental delay at 18 months or older 4 131 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.83, 2.54]
1.2.1 Randomized controlled trials 3 91 Risk Ratio (M-H, Fixed, 95% CI) 1.35 [0.68, 2.69]
1.2.2 Quasi randomized controlled trials 1 40 Risk Ratio (M-H, Fixed, 95% CI) 1.65 [0.64, 4.26]
1.3 Necrotizing enterocolitis 2 142 Risk Ratio (M-H, Fixed, 95% CI) 11.18 [1.49, 83.64]
1.3.1 Randomized controlled trials 2 142 Risk Ratio (M-H, Fixed, 95% CI) 11.18 [1.49, 83.64]
1.4 Hypoglycemia 2 138 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.55, 1.91]
1.4.1 Randomized controlled trials 2 138 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.55, 1.91]
1.5 Thrombocytopenia 1 20 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.17, 5.77]
1.6 Jaundice 1 45 Risk Ratio (M-H, Fixed, 95% CI) 2.09 [0.20, 21.45]

2 Partial exchange transfusion vs. non treatment: Best case / worst case scenario

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
2.1 Developmental delay at 18 months or older 4 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1.1 Available case analysis 4 131 Risk Ratio (M-H, Fixed, 95% CI) 1.45 [0.83, 2.54]
2.1.2 Best case analysis 4 263 Risk Ratio (M-H, Fixed, 95% CI) 0.29 [0.20, 0.42]
2.1.3 Worst case analysis 4 263 Risk Ratio (M-H, Fixed, 95% CI) 6.10 [3.67, 10.14]

[top]

Sources of support

Internal sources

  • Department of Neonatology, Shaare Zedek Medical Center Jerusalem, Israel
  • Ben-Gurion University, Beer-Sheva, Israel
  • Department of Pediatrics, University of Vermont College of Medicine, USA

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2010 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.