Title: Allogeneic umbilical cord red blood cell transfusion for children with
severe anaemia in a Kenyan hospital: an unmasked, single arm trial to assess
safety, harm and efficacy.
Oliver W. Hassall1,2, Johnstone Thitiri1, Greg Fegan1,3, Fauzat Hamid1, Salim
Mwarumba1, Douglas Denje4, Kongo Wambua5, Kishor Mandaliya4,5, Prof.
Kathryn Maitland1, 6, Prof. Imelda Bates2
1 Centre
for Geographic Medicine Research (Coast), Kenya Medical Research
Institute/ Wellcome Trust Research Programme, Kilifi 80108, Kenya
2
Liverpool School of Tropical Medicine, Liverpool L1 5QA, United Kingdom
3 Centre
for Clinical Vaccinology & Tropical Medicine, University of Oxford,
Oxford OX3 7LJ, United Kingdom.
4 Coast
Provincial General Hospital, Mombasa 80100, Kenya
5 Regional
Blood Transfusion Centre, Mombasa 80100, Kenya
6 Department
of Paediatrics, Imperial College London, London SW7 2AZ,
United Kingdom
Corresponding author:
Dr. Oliver Hassall (address as 2. above)
ohassall@gmail.com
+ 44 (0) 7774 354716
1
Abstract
Background
Severe anaemia requiring an urgent blood transfusion is common in
hospitalised children in sub-Saharan Africa but blood is frequently
unavailable. Where conventional blood supplies are inadequate, allogeneic
umbilical cord blood may be a feasible alternative. The aim of this trial was to
assess the safety and efficacy of cord blood transfusion in children with
severe anaemia.
Methods
Cord blood was donated at Coast Provincial General Hospital and screened
for transfusion-transmitted infections and bacterial contamination. Red cells
were produced by sedimentation during refrigerated storage. Children with
severe anaemia but without signs of critical illness were recruited at Kilifi
District Hospital and received a maximum of two group identical/compatible
cord blood units. Participants were closely monitored for adverse events and
followed up for one month. The primary outcome measure was the frequency
and nature of adverse reactions associated with the transfusion. Secondary
outcome measures were change in haemoglobin at 24 hours and one month
after transfusion compared to pre-transfusion levels. The study has been
completed. (Trial registration:ISRCTN66687527)
Findings
Fifty-five children received sedimented red cells from 74 cord blood donations.
Ten children experienced 10 serious adverse events and 43 children
experienced 94 non-serious adverse events. In none of these cases did an
independent expert panel consider cord blood transfusion to be probably or
certainly implicated (one-sided 97.5% confidence interval; 0 to 6.5%). The
median rise in haemoglobin was 2.6g/dL (IQR 2.1g/dL to 3.1g/dL) 24 hours
after transfusion, and 5.0g/dL (IQR 1.0g/dL to 6.8g/dL) 1 month after
transfusion.
Interpretation
2
The results demonstrated by this single arm trial, justify further studies
comparing the safety and efficacy of cord blood transfusion and conventional
adult-donated blood transfusion. Such trials should include operational
analyses of the availability of cord blood and conventional blood. Challenges
associated with cost, infrastructure and scale up also need exploring. Cord
blood may be an important supplementary source of blood for transfusion in
children in sub-Saharan Africa. Funding Wellcome Trust Training Fellowship
(073604)
3
Introduction
Background
Sub-Saharan Africa has the highest risk of death in the first month of life and
is one of the regions showing the least progress in reducing this high mortality
rate.1 Severe anaemia is a major public health problem in sub-Saharan Africa
and children aged less than 2 years are the most frequently affected. The
prevalence of severe anaemia in hospitalised children is reported to range
from 8-29% with case fatality rates of 8-18%.2 In children with severe,
uncompensated anaemia, blood transfusion can substantially reduce
mortality.3 Over 50% of deaths occur within 4 hours of admission and early
intervention and the ready supply of safe blood are key components of the
hospital treatment of severe anaemia in childhood.4,5 The supply of
conventional blood for transfusion in sub-Saharan Africa is insufficient with
only an estimated 52% of demand being met and a shortfall of at least 2
million units a year.6–8
Where the blood supply is limited and young children receive a significant
number of blood transfusions, umbilical cord blood is a novel and potentially
important source of blood for transfusion.9–11 Not only might cord blood
provide increased numbers of small volume transfusions but also reduce the
pressure on stocks of conventional, adult-donated blood thereby improving
the supply of blood for emergency transfusions for other vulnerable groups. In
sub-Saharan Africa, lack of blood for transfusion is implicated in 25% of
maternal deaths due to haemorrhage.12
In order to test the feasibility of cord blood transfusion, we have established a
cord blood donation programme on the labour ward at Coast General
Provincial Hospital in Mombasa, Kenya. Previously we have demonstrated the
acceptability to mothers of cord blood donation and transfusion; the feasibility
of a two-stage informed consent process for cord blood donation; and the
quality of variable volumes of whole cord blood stored in a fixed volume of
anticoagulant-preservative solution.13,14 We have also shown that, for cord
blood collected by our study team, rates of both bacterial contamination and
seroreactivity for HIV, HBV, HCV and syphilis compare favourably to that of
4
conventional adult blood donated to the Regional Blood Transfusion Centre in
Mombasa.15 Here we report the findings of, to our knowledge, the first clinical
trial of allogeneic cord blood transfusion in children with severe anaemia.
Objectives
The primary objective of the study was to assess the frequency and nature of
adverse reactions associated with umbilical cord red blood cell (UC-RBC)
transfusion. The secondary objective was to assess the haematological
efficacy of UC-RBC transfusion.
Methods
Trial design
This was an unmasked, single arm trial designed to produce preliminary data
on safety, harm and haematological efficacy of umbilical cord blood
transfusion in children with severe anaemia. The protocol was reviewed and
approved by the Kenya National Ethics Committee and the Research Ethics
Committee of the Liverpool School of Tropical Medicine. The trial is registered
as an International Standardised Randomised Controlled Trial, number
ISRCTN66687527.
Participants and study setting
Participants were recruited from children aged less than 12 years admitted for
paediatric in-patient care at Kilifi District Hospital (KDH), Kenya from 26th June
2007 to 20th May 2008. Eligibility criteria were designed to identify those
children for whom a transfusion would provide clinical benefit based on WHO
clinical guidelines but exclude those who were critically ill.16
Research staff from the KEMRI-Wellcome Trust research programme provide
24 hour clinical cover at KDH and at admission all children have a structured
clinical assessment, including anthropometry and a standard set of laboratory
investigations, including a haemoglobin concentration (Hb) estimation
(Beckman Coulter, France), a blood film examination for malaria and a blood
culture. Haemoglobin electrophoresis to detect haemoglobin S was done
retrospectively for study children aged greater than 3 months of age. Full
5
investigation of the aetiology of severe anaemia was not part of the study
protocol.
Children were eligible for inclusion in the study if they had severe anaemia
(Hb  10g/dL in children aged 3 months or less; Hb  4g/dL in children aged
greater than 3 months) and the attending clinician requested a blood
transfusion. Children with any of the following clinical features of critical illness
were excluded: coma (Blantyre Coma Scale  2), prostration, shock, deep
(acidotic) breathing, and hyperbilirubinaemia requiring exchange transfusion.
In addition children were not eligible for the study if they had had a previous
UC-RBC transfusion as part of this trial or were already enrolled in another
intervention trial. A child was only enrolled in the study if sufficient cord blood
was available and written consent was given by their caregiver.
The intervention
The intervention under investigation was the transfusion of umbilical cord red
blood cells (UC-RBC). Cord blood was collected from placentas donated at
Coast Provincial General Hospital in Mombasa and screened (for HIV,
hepatitis B and C and syphilis) as described previously.15
Screened cord blood units were transported at 2-6C 50km by road to Kilifi,
sedimented by storing vertically in racks at 2-6C and quarantined until
screened for bacterial contamination. This was done by incubation of a 4ml
sample in 40ml of brain heart infusion at 37C in the manner described
previously.15,17 Incubation was for 48 hours and screening was by microscopic
examination of a Gram stained smear.
Volume, haemoglobin concentration and blood group of cord blood units were
entered on an electronic database, which was used to ascertain whether
sufficient cord blood was available as soon as a blood transfusion was
requested for an eligible child. This was defined as at least 2.2g/kg of
haemoglobin from a maximum of two group identical and/or blood group
compatible cord blood units. Thus cord blood units were selected based on
6
estimated haemoglobin content rather than volume. In addition, no child was
transfused more than 3.5ml/kg of CPDA-1.
The hospital clinical laboratory used standard methods of blood grouping and
crossmatching. In children without severe acute malnutrition (SAM) (defined
as weight-for-height Z-score (WHZ) < -3), UC-RBC were transfused over 4
hours with no co-administration of furosemide and a maximum permitted
volume of 20ml/kg. In children with SAM, UC-RBC were transfused over 3
hours with a maximum permitted volume of 10ml/kg; and 1mg/kg of
furosemide administered intravenously at the start of the transfusion as per
clinical guidelines.16
Outcomes
The outcome measure to achieve the primary objective was the frequency
and nature of adverse reactions occurring during, or within at least one month
of, UC-RBC transfusion. Serious adverse reactions (SAR) were defined as
any serious adverse event (SAE)1 that was judged probably or certainly
related to the transfusion. Adverse reactions were defined as any adverse
event (AE)2 judged probably or certainly related to the transfusion. The
detection of adverse reactions was a two-stage process comprising the
rigorous surveillance of adverse events (monitoring of harm) and an
independent, expert judgement about their relationship to UC-RBC
transfusion (assessment of imputability).
Monitoring of harm (Figure 1)
Monitoring of harm was by both passive and active surveillance. Children
recruited to the study were admitted to a paediatric high dependency unit until
24 hours after the start of the transfusion. During the transfusion and for two
hours afterwards children had continuous physiological monitoring.
Temperature, pulse rate, respiration rate, oxygen saturation, and blood
1
Any untoward medical occurrence that is fatal, life-threatening, disabling, prolongs
hospitalisation, or results in hospitalization.18
2
Any untoward medical occurrence.18
7
pressure were recorded before the start of the transfusion, 15 minutes after
the start of a transfusion and every 30 minutes thereafter for the duration of
the transfusion and for 2 hours subsequently. Two hours after the start of the
cord blood transfusion, a blood sample was obtained for the estimation of
serum potassium (Ilyte Ion Selective Electrode Analyser; Instrumentation
Laboratory, US) and calcium (Selectra E; Vitalab, The Netherlands).
A clinician reviewed every child and performed a study-specific structured
clinical assessment designed to capture adverse events 2 hours after and 24
hours after the end of a transfusion, and at hospital discharge. For the rest of
the child’s admission, monitoring of harm was by review of the daily clinical
record kept by the attending clinicians.
At hospital discharge, carers of children recruited to the study were given the
cost of their fare home and the return fare back to the hospital and invited to
bring the child to the hospital one month after the cord blood transfusion. They
were encouraged to come back to the hospital before then if they had any
concerns about their child. In addition, details of their homestead location
were taken. Children who returned to the hospital had a structured clinical
assessment. Those who did not attend were followed up at home by a
fieldworker, who confirmed whether the child was alive and well by direct
observation of the child and/or discussion with an adult family member.
Carers were also encouraged to bring these children to the hospital for a full
review.
Assessment of imputability of adverse events
The Principal Investigator (OH) and the Local Safety Monitor (LSM; an
experienced consultant paediatrician) reviewed all serious adverse events
and prepared a case summary, which was sent to the Safety Review
Committee (SRC). The SRC comprised 3 paediatricians with extensive
experience of the clinical care of children in sub-Saharan Africa and who were
independent of the study. The SRC and the LSM came to a consensus
decision regarding the probability that an SAE was caused by the transfusion
8
of UC-RBC and assigned it an imputability score based on an established 4point scale.19
All other (non-serious) adverse events were reviewed by a study clinician and
the Principal Investigator. They were described according to an established
adverse reaction nomenclature (COSTART: Coding Symbols for a Thesaurus
of Adverse Reaction Terms)20 and the probability of a causative relationship
with UC-RBC transfusion scored according to the same 4-point scale. A
summary of these adverse events was reviewed by the LSM and SRC.
Outcome measures for the secondary objective
The outcome measure used to achieve the secondary objective was median
change in haemoglobin concentration compared with pre-transfusion levels
one day and one month after UC-RBC transfusion. A blood sample for
haemoglobin estimation (Beckman Coulter, France) was taken 24 hours after
the start of UC-RBC transfusion; unless a haemoglobin was requested for the
clinical management of the child before this time in which case this result was
used. A further blood sample for haemoglobin estimation was obtained from
those children who returned for follow-up at one month.
Sample size
It was estimated that 100 children fulfilling the eligibility criteria for the trial
would be admitted to KDH during a period of one year and that cord blood
would be available and consent to transfuse given for 40-80% of these. Thus,
during one year of study 40 to 80 children might be recruited to the trial. We
intended to run the trial for one year and these numbers were set as a
minimum and maximum sample size. The precision, as indicated by a
confidence interval, of the frequency of adverse reactions (the primary
outcome measure) at different event frequencies and sample sizes is shown
in Table 1 of the appendix.
Stopping rules
The trial was to be stopped in the event of a Suspected Unexpected Serious
Adverse Reaction (SUSAR), and not recommenced until a full review had
9
been undertaken by the SRC and their recommendations seen and approved
by the ethics committees. In addition, in the event of an SAE the SRC advised
whether they felt that the trial should continue with no change to the protocol,
continue with a change to the protocol, or be stopped.
Statistical methods
Binary data were expressed as a percentage with 95% confidence intervals
where appropriate. Where event frequencies were zero, a one-sided 97.5%
confidence interval with a lower limit of zero was calculated. Continuous data
were summarised by the median with range (minimum and maximum) and
interquartile ranges (IQR). Observed differences in continuous data were
compared for statistical significance using non-parametric statistics (Wilcoxon
rank-sum).
Role of the funding source
OH was supported by a Wellcome Trust Training Fellowship (073604). The
funder had in no role in design of the study; in the collection, analysis, and
interpretation of data; in the writing of the report; and in the decision to submit
the paper for publication.
Results
Participant flow and recruitment (Figure 1)
There were 413 transfusion episodes to children over the period of the study
and 87 children were considered eligible for the trial. In 24 cases, UC-RBC of
sufficient haemoglobin content and/or blood group were not available and
consent was declined for 6 children. Thus, 57 children were recruited to the
study but 2 were withdrawn before UC-RBC transfusion. In one case, the
laboratory made an error during compatibility testing and no further cord blood
was available. In the second case, clinical review soon after recruitment
demonstrated deep breathing (see exclusion criteria).
Demographic and clinical characteristics of participants (Table 1)
Fifty-five children received UC-RBC from 74 cord blood donations. Ages
ranged from 2 days to 5 years and 8 months (median, 12 months) with 24
10
children aged 3 months or less. Weights of children ranged from 1.1kg to
14.5kg (median, 5.3kg). WHZ-scores ranged from -4.4 to -0.9 (median, 1.9)
and 7 children had severe acute malnutrition (defined as a WHZ< -3). In those
children aged 3 months or less, pre-transfusion haemoglobin ranged from
5.5g/dL to 10g/dL (median, 8.7g/dL). In those children aged greater than 3
months, pre-transfusion haemoglobin ranged from 1.9g/dL to 4.0g/d/L
(median, 3.2g/dL). All children with SAM received 10ml/kg of UC-RBC; for
those children without SAM, the median volume transfused was 13ml/kg
(range, 10ml/kg to 20ml/kg).
Numbers analysed
In the event of an adverse event after a child had received UC-RBC from 2
units it is very unlikely that imputability could have been assigned to one of
the two units, therefore the denominator for the primary outcome measure
was the number of children transfused. Children who received subsequent
conventional blood transfusions during the follow up period were included in
the analysis of the primary outcome as these transfusions could themselves
be evidence of harm related to UC-RBC transfusion. However, these children
were not included in the analysis of haemoglobin change at 1 month as the
subsequent transfusions would have confounded the effect of UC-RBC
transfusion.
Outcomes
Of the 55 children who received UC-RBC transfusion, 10 experienced 10
serious adverse events (SAE) and 43 experienced 94 adverse events (AE)
(Table 2). In no case (0/55) was UC-RBC transfusion considered probably or
certainly implicated and thus the frequency of serious adverse reactions and
adverse reactions was 0% (One-sided 97.5% confidence interval; 0 to 6.5%).
There is, therefore, a 2.5% chance that the frequency of adverse reactions
associated with UC-RBC transfusion exceeds 6.5%.
The median change in haemoglobin on the day after UC-RBC transfusion
(median 24 hours; IQR 17 – 24 hours) was a rise of 2.6 g/dL (IQR 2.1 – 3.1)
(Table 3). In the 33 children who did not receive a further transfusion and for
11
whom a blood sample was obtained, the median change in haemoglobin at
one month (median 29 days; IQR 28 – 35) was a rise of 5.0g/dL (Table 3).
Four of the seven life-threatening SAE were new signs of critical illness (deep
breathing and/or prostration) observed after recruitment at the pre-transfusion
assessment and before the transfusion of UC-RBC. UC-RBC transfusion was
therefore excluded as a potential cause of these SAE. Of the remaining 6
SAE, one was a death, 3 were judged life-threatening and 2 resulted in
hospitalisation after discharge. These are described in detail below (see also
Table X in the appendix):
Study number: WG014
SAE severity: Fatal (Time after start of UC-RBC transfusion: approx. 7 days)
Imputability level: Unlikely
A 13-month old girl admitted with fever and cough and treated for pneumonia.
Her admission Hb was 4.6g/dL but 5 days later this had dropped to 4g/dL and
she received 100ml of UC-RBC, which raised her Hb to 6.5g/dL. Five days
later, she was diagnosed with an acute lympoblastic leukaemia by
microscopic examination of a peripheral blood film taken before UC-RBC
transfusion but reported afterwards (21% lymphoblasts). She was referred to
the local regional hospital for further management but left against medical
advice and taken by bus to her mother’s marital home in Kisumu in western
Kenya- a journey of approximately 850km. At discharge she had been noted
to be ‘pale, sick-looking and febrile’. On follow-up in the community, the child’s
grandfather reported that she died the day after arriving in Kisumu,
approximately 1 week after UC-RBC transfusion.
Study number: WG034
SAE severity: Life-threatening (26 hours)
Imputability level: Possible
A male infant with a birth weight of 1080g, delivered by emergency caesarean
section for maternal ante-partum haemorrhage at approximately 28 weeks
gestation. His initial Hb was 14.9g/dL and over the first 3 weeks of life he was
treated for neonatal sepsis and jaundice. On day 23 of life, weighing 1120g,
12
he was noted to be pale and had an Hb of 8.8g/dL. He was transfused 20ml of
UC-RBC, which increased his Hb to 15.5g/dL. Twenty-six hours after UC-RBC
transfusion, he became unwell with diarrhoea, dehydration and a metabolic
acidosis and was managed as probable neonatal sepsis. He made a full
recovery after intervention with oxygen, broad-spectrum antibiotics and
intravenous fluids.
Study number: WG044
SAE severity: Life-threatening (7 days)
Imputability level: Unlikely
A pre-term infant boy born unexpectedly while his mother was walking to work
on the family’s shamba and admitted on day 1 of life with an estimated
gestation of 30 weeks and a weight of 1440g. His admission Hb was 9.4g/dL
and he was transfused UC-RBC on day 2. Seven days after UC-RBC
transfusion, he developed abdominal distension, respiratory distress and
jaundice. This was managed as probable neonatal sepsis and he made a full
recovery after intervention with broad-spectrum antibiotics, intravenous fluid
therapy and phototherapy.
Study number: WG049
SAE severity: Life-threatening (14 hours)
Imputability level: Possible
A female infant born at home and admitted on day of birth weighing 1200g,
with an estimated gestation of 30 weeks and an Hb of 11.1g/dL. On day 9,
weighing 1180g, she was noted to be pale, her Hb was 7.6g/dL and she was
transfused 18ml UC-RBC raising her Hb to 11.0g/dL. Fourteen hours after
UC-RBC transfusion she was febrile, tachypnoeic and having apnoeas. She
was presumed septic and managed with broad-spectrum antibiotics,
intravenous fluids, supplemental oxygen and aminophylline. A chest
radiograph demonstrated right upper lobe consolidation consistent with a
diagnosis of pneumonia. She made a full recovery.
Study number: WG054
SAE severity: Hospitalisation (28 days)
13
Imputability level: Unlikely
A 4-year old boy with known sickle cell disease admitted with respiratory
distress and an Hb of 4.4g/dL. A blood transfusion was requested but he was
ineligible for UC-RBC transfusion. No adult-donated blood was available until
a replacement donor was found the following day, after which he was
transfused 20ml/kg of whole blood resulting in a post-transfusion Hb of
8.3g/dL. Over the next 10 days he was treated for sepsis and his Hb fell to
3.6g/dL over this period. He was transfused 150ml of UC-RBC from two cord
blood donations, his Hb rose to 6.2g/dL and he was discharged well with oral
haematinics 3 days later. He returned mistakenly for study follow-up at 21
days after UC-RBC transfusion and at that time had an Hb of 6.6g/dL and was
well. At his 28-day study follow-up assessment, he was found to have an Hb
of 4.1g/dL, was admitted for a conventional blood transfusion and was
discharged the following day with an Hb of 6.1g/dL.
Study number: WG056
SAE severity: Hospitalisation (28 days)
Imputability level: Possible
A female infant born in hospital and admitted to paediatric ward at 19 hours of
age with jaundice, low birth weight (2300g) and suspected prematurity, and
treated for possible sepsis. At 5 days of age was noted to be pale, had an Hb
of 9.7g/dL, and was transfused 25ml of UC-RBC which raised her Hb to
11.5g/dL. She was discharged well 3 days later fully breastfeeding and with a
weight of 2120g. At 28-day follow-up, she was found to have an Hb of 6.2g/dL
and was offered admission but her mother declined. She re-presented one
week later and was admitted. Her Hb was 8.4g/dL and a blood transfusion
was requested. No blood was available until a relative was found to donate,
after which she received 20ml/kg whole blood and was discharged well on
oral haematinics with an Hb of 14.1g/dL.
Ancillary analyses
In children aged less than 3 months, median change in haemoglobin at 1
month (median 29 days; IQR 28 – 36) was a rise of 0.5g/dL (IQR 0.2 – 1.2)
compared with a rise of 6.1g/dL (IQR 5.3 – 8.1) in children aged greater than
14
3 months (median time to follow-up, 30 days; IQR 28 – 35) (Table 5). This
difference is statistically significant (p<0.001).
In those children aged greater than 3 months, the 7 children with severe acute
malnutrition who received a maximum of 10mL/kg UC-RBC showed a median
haemoglobin rise 1 day after transfusion of 2.1g/dL (IQR 2.0 – 2.9). In 23
children aged greater than 3 months without severe acute malnutrition who
received a maximum of 15mL/kg the median rise in haemoglobin 1 day after
transfusion was 2.6g/dL (IQR 2.2 – 3.1). The difference is not statistically
significant (p=0.15, Wilcoxon rank sum). For the 5 children aged greater than
3 months with severe acute malnutrition for whom a result was available, the
median rise in haemoglobin 1 month after UC-RBC transfusion was 8.1g/dL
(IQR 7.8 – 8.2) compared to 5.9g/dL in the 15 children without severe acute
malnutrition for whom there was a haemoglobin result.
Discussion
In this study 55 children with severe anaemia were transfused sedimented red
blood cells from 74 umbilical cord blood donations. Of 10 serious adverse
events and 94 adverse events, none were certainly or probably attributable to
cord blood transfusion. Median increases in haemoglobin after transfusion
were 2.6g/dL at 24 hours and 5.0g/dL at 29 days. These findings are
consistent with the very few data concerning allogeneic cord blood transfusion
that have been reported previously.9
Although we excluded children with signs of critical illness from the study at
the time of recruitment, many children experienced adverse events which
were unrelated to the cord blood transfusion. In four children, signs of critical
illness not present at recruitment and which would have excluded them from
the study were detected at the clinical assessment undertaken just prior to
UC-RBC transfusion. To withdraw these children from the study at this stage
and to secure and crossmatch adult-donated blood would have introduced an
unacceptable delay in the management of critically ill children. This highlights
the challenge of conducting studies focusing on safety and harm in
hospitalised children in sub-Saharan Africa. Robust monitoring frameworks
15
are required to identify potential associations between the effects of the
intervention and other confounding factors. A weakness of this study is that
for those that did not attend the hospital for follow-up at 28 days there was no
full clinical assessment. However, all these children were followed up in the
community by a non-clinical fieldworker and the death of one child (WG014)
was identified in this way.
The rise in haemoglobin observed 1 day after UC-RBC transfusion seen in
this study is consistent with estimations based upon the haemoglobin content
of the transfused blood and the circulating volume of children: for a child with
a circulating volume of 80mL/kg, the transfusion of 2.2g/kg of haemoglobin
might be expected to raise the haemoglobin by 2.8g/dL. However, although
cord blood units were selected for transfusion based upon an estimation of
the unit haemoglobin content, it is not possible to ascertain from these data
how much haemoglobin was actually issued and transfused to each child.
The significant rise in haemoglobin 1 month after transfusion in children aged
greater than three months is consistent with previous data from Kilifi and other
sites in East Africa.3,4,21,22 Increases in haemoglobin over a similar time period
are also observed in children with severe anaemia who do not receive a
transfusion and survive.3,21,22 This highlights the importance of other therapies
in the management of severe anaemia such as treatment of infection, antihelminthics, haematinics and diet. The relative importance of these will
depend on the aetiology of the anaemia and this was not investigated here.
The children aged less than 3 months in this study were likely to have a very
different aetiology for their anaemia than the older children and many of them
were presumed to have anaemia of prematurity. Several of these children
required further transfusion and in those that did not the effect of a single UCRBC transfusion at one month was much more modest. Of note, however, is
the number of young infants that were eligible for UC-RBC transfusion. This is
a group of patients that carry a high burden of mortality in sub-Saharan Africa
and who may potentially benefit substantially from more evidence about the
role of transfusion in preventing the high death rates.1 These young children
16
might particularly benefit from the availability of cord blood for transfusion
because they only require small volumes of blood for transfusion.
The microbiological safety of cord blood provided by the donation programme
that we have established at Coast Provincial General Hospital in Mombasa
compares favourably to that of conventional blood from the same setting.15
Mothers who donate their infants’ umbilical cord blood are rigorously selected
(including self-reporting of antenatal testing for syphilis and HIV), and aseptic
cord blood collection undertaken by trained fieldworkers and not the midwives
managing the deliveries.13,15 Furthermore, all cord blood donations in this
study were screened for bacterial contamination. These rigorous techniques
may be difficult to replicate outside of a research setting without considerable
additional resources.
Our findings suggest that further trials of umbilical cord blood transfusions are
warranted but the challenges of conducting such trials and the barriers to
potential scale up of such an intervention should not be underestimated.
Attributing effects to the intervention is difficult in such a sick group of
children. Despite this, further clinical trials should also include children with
signs of critical illness who potentially have the most to gain from an improved
blood supply. The infrastructure and training required to set up collection and
administration of umbilical cord blood is complex and such trials would require
meticulous monitoring during and after the transfusion. Poor haemovigilance
systems in these settings means that very little is known about the harms
associated with conventional blood transfusion which would be the
comparator group in such trials.7
Other improvements and additions to the design of future trials include: better
characterisation of anaemia aetiology and assessment of any correlation with
benefits and harms of cord blood transfusion; immunological and genetic
testing to compare rates of alloimmunisation and microchimerism; and
operational analyses comparing the availability of cord blood and adultdonated blood for urgent transfusion in children, and the impact of cord blood
17
transfusion for children on the blood supply for adults requiring larger volumes
of conventional blood.
In this study, we have demonstrated that where demand for low volume
transfusions for children is high and supplies of conventional blood are limited,
umbilical cord blood may be a safe and efficacious supplementary source of
blood for transfusion. Further trials comparing cord and conventional blood
transfusion are merited.
Conflicts of interest
None of the authors have any conflicts of interest.
Acknowledgement
The authors would like to thank the following people without whom the study
could not have been undertaken: Jay Berkley, Victor Bandika, Michael Boele
van Hensbroek, Mike English, Trudie Lang, Kevin Marsh, Jennifer Othigo,
Norbert Peshu, Sophie Uyoga, Tom Williams. Also many thanks to the Wazo
Geni team, the midwives and mothers at Coast Provincial General Hospital,
and the clinical staff at Kilifi District Hospital. We are grateful to the Wellcome
Trust for funding the study.
Role of the funding source
The study funders had no role in study design; in the collection, analysis, and
interpretation of data; in the writing of the report; and in the decision to submit
the paper for publication.
Research in context
Systematic review
A review of the literature relating to cord blood transfusion was conducted
prior to this study. Allogeneic cord blood transfusion was first reported in the
1930’s before the advent of modern blood transfusion services. Subsequently,
most research and clinical activity relating to cord blood transfusion has
concerned autologous cord blood transfusion in pre-term neonates. A series
18
of about 200 mainly elderly patients with chronic and/or terminal disease has
been transfused allogeneic cord blood in India. No adverse reactions were
reported. To our knowledge, there has been no previous clinical trial of
allogeneic cord blood transfusion in African children.
Interpretation
This trial demonstrates that there is a low probability of adverse events
associated with the transfusion of sedimented red blood cells from umbilical
cord blood donations (UC-RBC) to children with severe anaemia in subSaharan Africa. Haemoglobin recovery after UC-RBC transfusion is within
expected limits. To our knowledge, this is the first time such a trial has been
undertaken and umbilical cord blood may be a safe and efficacious
supplementary source of blood for transfusion where demand for low volume
transfusions for children is high and supplies of conventional blood are limited.
Further work needs to be undertaken by clinical researchers to establish the
safety and efficacy of cord blood transfusion compared to conventional blood
transfusion. Additional research is also required on the operational aspects of
cord blood collection including costs, impact on the conventional blood supply
and scalability.
19
References
1.
United Nations Children's Fund. Levels and Trends in Child Mortality.
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2.
WHO. The prevention and management of severe anaemia in children
in malaria-endemic regions of Africa: A review of research. Geneva: WHO;
2001.
3.
Lackritz EM, Hightower AW, Zucker JR, Ruebush TK, 2nd, Onudi CO,
Steketee RW, et al. Longitudinal evaluation of severely anemic children in
Kenya: the effect of transfusion on mortality and hematologic recovery. AIDS
(London, England). 1997 Oct;11(12):1487-94.
4.
English M, Ahmed M, Ngando C, Berkley J, Ross A. Blood transfusion
for severe anaemia in children in a Kenyan hospital. Lancet. 2002 Feb
9;359(9305):494-5.
5.
Lackritz EM, Campbell CC, Ruebush TK, 2nd, Hightower AW, Wakube
W, Steketee RW, et al. Effect of blood transfusion on survival among children
in a Kenyan hospital. Lancet. 1992 Aug 29;340(8818):524-8.
6.
Allain JP, Owusu-Ofori S, Bates I. Blood transfusion in sub-Saharan
Africa Transfusion Alternatives in Transfusion Medicine. 2004;6(1):16-23.
7.
Tagny CT, Mbanya D, Tapko JB, Lefrere JJ. Blood safety in SubSaharan Africa: a multi-factorial problem. Transfusion. 2008 Jun;48(6):125661.
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Tapko JB, Sam O, Diarra-Nama AJ. Status of Blood Safety in the WHO
African Region: Report of the 2004 Survey WHO Regional Office for Africa;
2007.
9.
Bhattacharya N. Placental umbilical cord whole blood transfusion: a
safe and genuine blood substitute for patients of the under-resourced world at
emergency. J Am Coll Surg. 2005 Apr;200(4):557-63.
10.
Hassall O, Bedu-Addo G, Adarkwa M, Danso K, Bates I. Umbilical-cord
blood for transfusion in children with severe anaemia in under-resourced
countries. The Lancet. 2003;361:678-9.
11.
Khodabux CM, Brand A. The use of cord blood for transfusion
purposes: current status. Vox sanguinis. 2009 Nov;97(4):281-93.
12. Bates I, Chapotera GK, McKew S, van den Broek N. Maternal mortality in
sub-Saharan Africa: the contribution of ineffective blood transfusion services.
BJOG 2008; 115: 1331-9.
13.
Hassall O, Maitland K, Fegan G, Thitiri J, Pole L, Mwakesi R, et al. The
quality of stored umbilical cord and adult-donated whole blood in Mombasa,
Kenya. Transfusion. 2010 Nov 13;50(3):611-6.
14.
Hassall O, Ngina L, Kongo W, Othigo J, Mandaliya K, Maitland K, et al.
The acceptability to women in Mombasa, Kenya, of the donation and
transfusion of umbilical cord blood for severe anaemia in young children. Vox
sanguinis. 2008 Feb;94(2):125-31.
15.
Hassall OW, Thitiri J, Fegan G, Pole L, Mwarumba S, Denje D, et al.
The microbiologic safety of umbilical cord blood transfusion for children with
severe anemia in Mombasa, Kenya. Transfusion. 2012 Jul;52(7):1542-51.
16.
WHO. Pocket book of hospital care for children: guidelines for the
management of common illnesses with limited resources. Geneva: WHO;
2005.
20
17.
Hassall O, Maitland K, Pole L, Mwarumba S, Denje D, Wambua K, et
al. Bacterial contamination of pediatric whole blood transfusions in a Kenyan
hospital. Transfusion. 2009 Aug 4;49(12):2594-8.
18.
EMEA. ICH Guideline for Good Clinical Practice. London: The
European Agency for the Evaluation of Medicinal Products; 2002.
19.
MHRA. UK Blood Safety and Quality Regulations. Implementation of
the EU Blood Safety Directive. Background and Guidance on reporting
Serious Adverse Events & Serious Adverse Reactions. London: MHRA.
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FDA. COSTART: Coding Symbols for Thesaurus of Adverse Reaction
Terms. Rockville, MD: Public Health Service, FDA; 1995.
21.
Akech SO, Hassall O, Pamba A, Idro R, Williams TN, Newton CR, et
al. Survival and haematological recovery of children with severe malaria
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21
Figure 1 Trial participant flow
Transfusions to children
413
Age <= 3m
105
Hb > 10g/dL
12
Age > 3m
308
Hb <= 10g/dL
93
Hb <= 4g/dL
114
Hb > 4g/dL
294
Children eligible
by Hb
207
Children ineligible
by clinical criteria
120
Children eligible
by clinical criteria
87
Cord blood unavailable
Declined consent
24
6
Children enrolled
57
Withdrawn
before transfusion
2
Children transfused
55
Outpatient follow-up
Community follow-up
44
11
22
Table 1 Selected admission characteristics of trial participants (SS=
homozygous for sickle cell genotype; MPs= malaria parasites; WHZ= weightfor-height Z-score; Hb= pre-transfusion haemoglobin)
Aged <= 3
Aged > 3
months
months
N
24
31
55
Male
12
16
28
SS
-
6
6
MPs
0
6
6
WHZ< -3
-
7
7
Pre-term
14
-
14
Weight (kg)*
1.6
8.6
8.7
3.2
(5.5 to 10.0)
(1.9 to 4.0)
Hb (g/dL)*
All
5.3
(1.1 to 14.5)
-
* Median (range)
23
Table 2 Serious adverse events and adverse events experienced by children
receiving umbilical cord red cell transfusion.
Serious
Adverse Events
Adverse Events
10
10
94
43
Timing
Before transfusion
Transfusion + 24h
24h to 28d follow-up
4
1
5
4
12
78
Indicator of severity
Fatal
Life-threatening
Hospitalisation
1
7
2
N/A
N/A
N/A
Imputability level*
Not assessable
Excluded (0)
Unlikely (0)
Possible (1)
Likely/Probable (2)
Certain (3)
0
4
3
3
0
0
0
15
76
3
0
0
N
No. of children
* Numbers in parentheses refer to 4-point imputability score described in the
text
24
Table 4 Description of Serious Adverse Events occurring after umbilical cord
red cell transfusion
ID
No.
Age*
Sex
Description
(time after CBT
start)
Indicator of
severity
Comments
Imputability
level
(score)
14
1y 1m
F
Diagnosis of an acute
leukaemia- probably
acute lymphoblastic
leukaemia (N/A)
Fatal

Unlikely (0)



44
2d
M
Abdominal distension,
respiratory distress,
jaundice (7d)
Life-threatening



54
4y
M
Anaemia (28d)
Hospitalisation




34
49
24d
9d
M
F
Diarrhoea,
dehydration and
metabolic acidosis
(26h)
Life-threatening
Sepsis, peumonia,
apnoeas (14h)
Life-threatening






56
5d
F
Anaemia (28d)
Hospitalisation




Diagnosis by microscopic
examination of a peripheral blood
film; film taken before UC-RBC
transfusion but reported afterwards.
Child was referred to regional
hospital but discharged against
medical advice and taken by bus to
mother’s marital home in western
Kenya (Kisumu).
Child was noted to be ‘pale, sicklooking and febrile’ at discharge
Child reported by grandfather to
have died the day after arriving in
Kisumu, approximately 1 week after
UC-RBC transfusion.
Pre-term infant (estimated
gestation, 30 weeks; birth weight,
1440g)
Probable neonatal sepsis
Full recovery after intervention with
broad-spectrum antibiotics, nil by
mouth, intravenous fluid and
phototherapy.
Sickle cell disease
Discharged well 3 days after UCRBC transfusion (Hb 6.2) with
haematinics
Returned early (21d) for follow-up
(mistakenly) (Hb 6.6)
Hb 4.1 at 28d follow-up; admitted
for conventional blood transfusion;
discharged next day (Hb 6.1).
Pre-term infant (estimated
gestation, 28 weeks; birth weight,
1080g)
Probable neonatal sepsis
Full recovery after intervention with
oxygen, broad-spectrum antibiotics
and intravenous fluid.
Pre-term infant (estimated
gestation, 30 weeks; birth weight,
1200g)
Radiologically confirmed
pneumonia
Full recovery after intervention with
broad-spectrum antibiotics, oxygen,
aminophylline and blood
transfusion.
Low birth weight (probable
prematurity), neonatal jaundice and
possible sepsis
Discharged well 3 days after cord
blood transfusion (Hb 11.5)
Hb 6.2 at 28d follow-up; offered
admission, declined but represented 1 week later; admitted;
Hb 8.4 and transfused conventional
blood once donor found (initially no
blood available)
Discharged next day with
haematinics
* At enrolment to the study
25
Unlikely (0)
Unlikely (0)
Possible (1)
Possible (1)
Possible (1)
Table 5 Haemoglobin concentrations (median, IQR) of children receiving UCRBC stratified by age
N
Aged <= 3
Hb
months
Hb change
N
Aged > 3
months
Hb
Hb change
N
Pretransfusion
1 day
1 month
24
24
13
8.7
(7.8 – 9.2)
11.4
(10.5 – 12.4)
+2.7
(2.2 – 3.8)
9.2
(8.4 – 9.9)
+0.5
(0.2 – 1.2)
31
31
20
3.2
(2.7 – 3.8)
5.8
(5.3 – 6.2)
+2.6
(2.1 – 3.1)
9.3
(8.3 – 11.0)
+6.1
(5.3 – 8.2)
55
54*
33§
-
+2.6
(2.1 – 3.1)
+5.0
(1.0 – 6.8)
-
-
All
Hb change
* Excludes 1 child for whom consent was declined for a blood test
§
Excludes 22 children: 10 received further transfusions, 11 were followed up in the
community, 1 was not bled in error.
26