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Repeated Autologous Umbilical Cord Blood Infusions are Feasible and had No Acute Safety Issues in Young Babies with Congenital Hydrocephalus


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Babies with congenital hydrocephalus often experience developmental disabilities due to brain injury associated with prolonged increased pressure on the developing brain parenchyma. Umbilical cord blood (CB) infusion has favorable effects in animal models of brain hypoxia and stroke and is being investigated in clinical trials of brain injury in both children and adults. We sought to establish the safety and feasibility of repeated intravenous infusions of autologous CB in young babies with congenital hydrocephalus. Infants with severe congenital hydrocephalus and an available qualified autologous CB unit traveled to Duke for evaluation and CB infusion. When possible, the CB unit was utilized for multiple infusions. Patient and CB data were obtained at the time of infusion and analyzed retrospectively. From October 2006 to August 2014, 76 patients with congenital hydrocephalus received 143 autologous CB infusions. Most babies received repeated doses, for a total of two (n=45), three (n=18), or four (n=4) infusions. There were no infusion-related adverse events. As expected, all babies experienced developmental delays. Cryopreserved CB products may be effectively manipulated to provide multiple CB doses. Repeated intravenous infusion of autologous CB is safe and feasible in young babies with congenital hydrocephalus.Pediatric Research (2015); doi:10.1038/pr.2015.161.
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Copyright © 2015 International Pediatric Research Foundation, Inc.
Clinical Investigation
nature publishing group
BACKGROUND: Babies with congenital hydrocephalus often
experience developmental disabilities due to brain injury asso-
ciated with prolonged increased pressure on the developing
brain parenchyma. Umbilical cord blood (CB) infusion has
favorable effects in animal models of brain hypoxia and stroke
and is being investigated in clinical trials of brain injury in both
children and adults. We sought to establish the safety and fea-
sibility of repeated intravenous infusions of autologous CB in
young babies with congenital hydrocephalus.
METHODS: Infants with severe congenital hydrocephalus and
an available qualified autologous CB unit traveled to Duke for
evaluation and CB infusion. When possible, the CB unit was uti-
lized for multiple infusions. Patient and CB data were obtained
at the time of infusion and analyzed retrospectively.
RESULTS: From October 2006 to August 2014, 76 patients
with congenital hydrocephalus received 143 autologous CB
infusions. Most babies received repeated doses, for a total of
two (n = 45), three (n = 18), or four (n = 4) infusions. There were
no infusion-related adverse events. As expected, all babies
experienced developmental delays.
CONCLUSION: Cryopreserved CB products may be effectively
manipulated to provide multiple CB doses. Repeated intrave-
nous infusion of autologous CB is safe and feasible in young
babies with congenital hydrocephalus.
ydrocephalus results from an excessive accumulation of
cerebral spinal uid (CSF) within the ventricular system
of the brain resulting in a progressive increase in ventricular
volume and intracranial pressure. It may be caused by a block-
age within the ventricular system, overproduction of cerebral
spinal uid, or decreased absorption of cerebral spinal uid.
e incidence of congenital hydrocephalus has been esti-
mated as 0.3 to 1.5 per 1,000 live births (1,2). Congenital
hydrocephalus may occur in isolation or as a result of neural
dysgenesis, such as spina bida or a Dandy Walker malforma-
tion. ough many patients with congenital hydrocephalus are
suspected to have a genetic cause, a causal mutation is identied
in only a small portion of patients, most commonly X-linked
hydrocephalus due to a mutation in L1CAM (3). Various other
chromosomal abnormalities have been described in babies
with hydrocephalus with additional associated somatic defects.
Such genetic cases can usually be identied before or at birth.
Most cases of congenital hydrocephalus are diagnosed
inutero on routine prenatal, screening ultrasonography when
macrocephaly and/or ventriculomegaly are seen. Typically
signs of hydrocephalus are rst recognized between 15–10wk
of gestation. Options at the time of an in utero diagnosis of
severe hydrocephalus are currently limited to termination of
the pregnancy or expectant management. Fetal shunt place-
ment has been attempted, but technical issues with the shunt
and mixed patient outcomes resulted in a moratorium on fetal
percutaneous shunting in the United States since 1985 (4,5).
Current standard management of a baby with severe con-
genital hydrocephalus involves aggressive monitoring of the
third trimester of pregnancy and delivery when fetal lung
maturity is achieved. Ventriculoperitoneal shunt placement
is performed shortly aer birth to divert the ow of CSF and
decrease the intracranial pressure. In the modern era, shunt
placement is associated with very low postoperative mortality,
although there is still a moderate risk of infection in the neo-
natal period. A newer procedure called an endoscopic third
ventriculostomy along with choroid plexus coagulation is now
being performed in hopes of avoiding a shunt, although a
shunt is still most common to manage severe hydrocephalus in
the neonatal period. Survivors face the sequelae of both shunt
complications and brain injury resulting from the prolonged
hydrocephalic state in utero including motor decits (50–60%),
auditory and visual decits (25–60%), seizures (20–50%), and
impaired intelligence (50–70%) (6–13). Additional comorbidi-
ties may be present if a genetic syndrome is diagnosed post-
natally or if other anatomical abnormalities are present on
imaging, such as agenesis of the corpus callosum, colpcephaly,
holoprosencephaly, or Dandy Walker malformation.
Umbilical cord blood (CB) has been shown to lessen the clin-
ical and radiographic impact of hypoxic brain injury and stroke
Received 11 March 2015; accepted 29 May 2015; advance online publication 7 October 2015. doi:10.1038/pr.2015.161
Robertson Clinical and Translational Cell Therapy Program, Duke University, Durham, North Carolina;
Department of Neurosurgery, Stanford University, Stanford, California.
Correspondence: Jessica M. Sun (
Repeated autologous umbilical cord blood infusions are
feasible and had no acute safety issues in young babies
withcongenital hydrocephalus
, GeraldA.Grant
, ColleenMcLaughlin
, JuneAllison
, AnneFitzgerald
, BarbaraWaters-Pick
Pediatr Res
Pediatric Research
Copyright © 2015 International Pediatric Research Foundation, Inc.
CB infusion in babies with hydrocephalus
Sun et al.
Clinical Investigation
Pediatric RESEARCH 1
Copyright © 2015 International Pediatric Research Foundation, Inc.
Sun et al.
in animal models (14–18). In particular, Ballabh and colleagues
have developed a model of intraventricular hemorrhage in rab-
bit pups that is followed by the development of hydrocephalus
and subsequent white matter demyelination (19). In this model,
intraventricular administration of human CB cells 24 and 72h
aer injury failed to prevent the hydrocephalus, but did reduce
subsequent demyelination (Ballabh, personal communication,
2014). CB has also been shown to engra and dierentiate in
the brain, facilitating neural cell repair, in animal models and
human patients with inborn errors of metabolism undergo-
ing allogeneic, unrelated donor CB transplantation (20,21).
Intravenous infusion of autologous CB is currently under inves-
tigation for the treatment of acquired brain injuries including
hypoxic ischemic encephalopathy (22), cerebral palsy (23), and
spinal cord injury. A small safety trial testing CB-derived mes-
enchymal stem cells (MSCs) delivered directly into the airways
of premature babies at risk for bronchopulmonary dysplasia has
also been reported (24).
We have previously reported the safety of intravenous
autologous CB infusion in 184 children with brain injury. e
median age of infusion in that series was 2 y, and most children
received a single infusion (23). Building on this experience,
we hypothesized that autologous CB infusion might facilitate
repair of the brain subjected to the pressure injury caused by
severe congenital hydrocephalus. Prenatal diagnosis of these
infants and delivery by planned C-section allowed for optimi-
zation of CB collection and banking at birth. e small size of
the baby relative to the number of cells harvested in a typical
CB collection allowed for planning of administration of more
than one dose of CB during the rst 1–2 y of life. e purpose
of this investigation was to determine the safety and feasibil-
ity of repeated doses of autologous CB given intravenously to
very young infants with brain injury due to severe congenital
Between October 2006 and August 2014, 76 patients with con-
genital hydrocephalus were treated with 143 autologous CB
infusions. e most common etiology for hydrocephalus was
aqueductal stenosis (46%). Four patients were subsequently
diagnosed with genetic conditions: one each with Aicardi syn-
drome, Walker Warburg syndrome, and a partial duplication
and interstitial deletion of chromosome 6, and one patient
with both a partial deletion of chromosome 10 and a partial
duplication of the X chromosome. See Table 1 for patient
CB Units (CBUs)
CBUs were collected at the time of delivery by the mother’s
obstetrical provider or, when available, trained collectors from
the Carolinas Cord Blood Bank, a public CB bank housed at
Duke University. Fiy-six (74%) units were stored as directed
donors. Of these, nine patients were born and had CBUs collected
at Duke and 47 (84%) were collected remotely via a kit program
and then shipped to the Duke Stem Cell Lab for processing and
storage. e remaining 20 (26%) CBUs were stored at six dier-
ent private CB banks (four US, two international). For units in
which it was recorded (n = 68), the median collection volume
of CB was 55ml (range 5–180ml). When these units were iden-
tied as potential candidates for infusion, low resolution HLA
typing was performed on both a test sample of the CBU and
the patient for identity conrmation. Almost all CBUs (n = 73,
96%) were stored in two-compartment bags. When possible,
only one compartment or a portion of one compartment was
utilized for infusion to provide an adequate cell dose, allowing
the remainder to be stored for later infusions. e median prec-
ryopreservation total nucleated cell count (TNCC) of the CBUs
was 4.81×10
(range 0.15–18.6×10
), median viability 97%
(range 71–100%). Despite negative precryopreservation sterility
cultures, ve CBUs had positive post-thaw cultures (coagulase
negative Staphlococcus (4), Streptococcus viridans (1)). One of
the positive cultures was on a third infusion from a CBU from
which prior post-thaw cultures on the rst and second infu-
sions were negative. Since these culture results were not avail-
able until 24–72h aer the infusions, no patients were treated
with antibiotics. At the time the positive culture was reported, a
sta member communicated with the patients parents to deter-
mine whether there was any concern for post infusion infection.
No patient had concerning symptomatology and no antibiotic
treatment was initiated. ere were no clinical infections docu-
mented in any patient.
When the TNCC allowed, a portion of the CBU was utilized
for infusion. If a CBU was stored in a bag with an 80/20 con-
guration, the 20% compartment was generally used for the
rst infusion. If the 80% compartment contained an TNCC of
/kg at the time of the second infusion, then only a por-
tion of the cells in the 80% compartment were used and the
remaining thawed cells were refrozen in an 80/20 bag for future
dosing. In this study, 19 infusions were performed using cells
that had been previously thawed and refrozen. e median
post-thaw recovery of TNCC of the initial thaws of these prod-
ucts was 66% (range 41–78%). When these units were refrozen
and subsequently rethawed, the median post-thaw recovery of
TNCC was 74% (range 50–109%) of the refrozen cells and 47%
(range 21–72%) of the initial TNCC. As many of these CBUs
Table 1. Patient characteristics
(n = 76)
Age at first infusion
2 mo
6 d to 4.5 y
Gender (N, %)
39 (51%)
37 (49%)
Diagnosis (N, %)
Aqueductal stenosis
35 (46%)
10 (13%)
Other (Dandy-Walker variant, Chiari II without spina
bifida, etc)
31 (41%)
Pediatric RESEARCH
Copyright © 2015 International Pediatric Research Foundation, Inc.
CB infusion in babies with hydrocephalus
were retrieved from private CB banks, they were not tested
for CD34 content and colony forming units (CFUs) prior to
cryopreservation, making it impossible to compare recovery
aer the initial thaw. Aer refreezing, the median recovery of
CFUs was 64% (range 12 – >100%) and median recovery of
CD34+ cells was 52% (range 0 – >100%) compared to CFUs
and CD34+ cells obtained at the time of the initial thaw.
e median age at the time of the rst infusion was 2 mo (range
6 d to 4.5 y). Most babies received repeated doses, for a total
of two (n = 45), three (n = 18), or four (n = 4) infusions, as per
the timeline in Figure 1. Median cell doses per infusion were
TNC 1.9×10
/kg (range 0.1–13.3×10
/kg) and CD34 dose
/kg (range 0–6.4×10
/kg); cell doses are listed by infu-
sion number in Table 2. All babies were premedicated before
each infusion with a single dose of diphenhydramine (0.5mg/
kg IV), acetaminophen (10mg/kg PO), and methylpredniso-
lone (0.5mg/kg IV). e infusions were well tolerated, with no
acute or long-term adverse reactions noted.
Patient Follow-Up After CB Infusion
e overall survival of the patients in this study was 97% with
a median follow-up of 1.1 y (range 0.1–7.5 y). Two patients
died from issues unrelated to the CB infusion; one 4 mo aer
infusion due to complications from a surgical craniosynasto-
sis repair, and one who died in his sleep 2 mo aer infusion.
As expected, all infants had motor delays in the rst year of
life due to increased head size relative to the baby’s height and
weight. At the time of last follow-up, 42% of patients had been
diagnosed with seizures and 52% of patients had persistent
vision and/or hearing impairments.
In this report, we describe our initial clinical experience giv-
ing multiple intravenous autologous CB infusions in a hetero-
geneous group of infants with congenital hydrocephalus. As
this was a phase I, rst-in-man, proof-of-concept safety study,
there was no control group. Since ecacy of cell therapy for
congenital hydrocephalus is unknown, safety was of utmost
importance. We therefore chose to use banked CB, a cell ther-
apy product that has already had a favorable safety prole in the
clinic. In addition, given the very young age of these patients,
we felt strongly that an autologous product would pose the low-
est risk. Furthermore, theoretical concerns have been raised
about inducing aberrant immune tolerance to donor antigens
(HLA or other) if young babies are exposed to third party cells
during the early phases of immune ontogeny. Dimethyl sulfox-
ide and dextran are utilized during cryopreservation of CB, and
dextran and human serum albumin are utilized during thawing
and washing. us, the babies in this series were exposed to
residual amounts of these excipients with each infusion. Prior
to this study, only a few dozen infants <3 mo of age had been
treated with allogeneic, banked CB for correction of genetic dis-
eases, and there was no prior experience giving cryopreserved
and thawed products in single or multiple infusions to neonates
and young infants. In this series, there were no acute or long-
term adverse events related to CB infusion, indicating that the
procedure is safe and feasible in these very young babies.
Due to the young age and small size of the patients, most
(70%) CBUs were large enough to provide more than one
dose of cells and 24% of patients received three or more doses.
e safety and feasibility of multiple CB infusions were also
favorable with no increase in infusion reactions or later toxic-
ities aer subsequent infusions. It was feasible to manipulate
CB products stored in dual compartment bags so that two
to four doses could be administered at distinct and separate
time points, and products that underwent recryopreservation
and thawing demonstrated adequate cell recovery.
As the primary focus of this study was safety and feasibility,
a control group was not included. erefore, a treatment eect
cannot be established. e ecacy of this approach requires addi-
tional investigation and continues to be challenging. Congenital
hydrocephalus is a rare condition, and aected babies may have
other associated abnormalities or genetic syndromes. e causes
of congenital hydrocephalus are heterogeneous and, not surpris-
ingly, aected babies experience a wide variability of outcomes
that are not predictable based on early clinical or radiographic
characteristics. erefore, assessing the ecacy of CB infusion
on the natural history of the disease remains challenging. ere
is also a variable response to shunting in this population both
on imaging and predicting the expansion of the cortical mantle
and correlating this with overall cognitive development.
ere is increasing animal and human data to suggest that
CB may have a role in the treatment of brain injuries. In a
recent phase I trial at Duke University, 23 babies who sustained
hypoxic ischemic encephalopathy at the time of birth were
Figure 1. Timeline of shunt placement and cord blood infusions.
MedianAge 3 d2 mo 9 mo 14 mo 14 mo
Minimum 0 d6 d2 mo 7 mo 10 mo
Maximum 10 mo 4.5 y 3.6 y 3.2 y 1.9 y
Table 2. Cell doses per infusion
(n = 76)
(n = 45)
(n = 18)
(n = 4)
Post-thaw total nucleated cell count dose (×10
Median 1.95 2.08 1.15 0.56
Minimum 0.25 0.25 0.13 0.29
Maximum 13.30 5.68 2.40 3.56
Post-thaw CD34 dose (×10
Median 0.50 0.70 0.25 0.20
Minimum 0.05 0.04 0.01 0.10
Maximum 6.40 4.90 2.00 0.40
Pediatric RESEARCH 3
Copyright © 2015 International Pediatric Research Foundation, Inc.
Sun et al.
treated with a standard cooling protocol and also received
intravenous autologous CB infusions (22). CB was processed
and infused fresh, without cryopreservation, in one to four
doses within the rst 72h of life. Infusions were found to be
safe in these critically ill babies, and babies receiving cells had
increased survival rates to discharge (100 vs. 85%, P = 0.20)
and improved function at 1 y of age (74 vs. 41% with devel-
opment in the normal range, P = 0.05) compared to a con-
comitant group of babies who were treated with cooling but
did not receive cells. A phase II randomized trial is currently
in development.
In older children with cerebral palsy, Korean investigators
compared three groups of children: those who received allo-
geneic CB and erythropoietin, placebo CB and erythropoietin,
and both placebos (25). ey reported greater improvements
in cognitive and select motor functions in children who
received CB and erythropoietin vs. either control group. While
there was no CB-only group for comparison, their ndings are
encouraging and should be replicated. Our group is also cur-
rently conducting a phase II randomized, double-blind, pla-
cebo-controlled, crossover study of intravenous autologous CB
infusion in children ages 1–6 y with cerebral palsy. is study
is expected to conclude in 2015.
e mechanism by which CB cells may potentially improve
the outcome of brain injuries are multiple. In the acute setting,
such as babies with hypoxic ischemic encephalopathy, CB cells
may have the ability to deliver trophic factors that can provide
anti-inammatory and neuroprotective eects and enhance
the survival potential of host cells. In the chronic setting, such
as older children with cerebral palsy, CB cells may be able to
increase the plasticity of the injured brain by enhancing syn-
aptogenesis and angiogenesis, stimulating endogenous repair
mechanisms, and/or inducing migration and proliferation of
endogenous neural stem cells. In these scenarios, long-term
engrament of CB cells should not be required, raising the
possibility of utilizing allogeneic products. It is not yet clear
from either animal models or human studies if an ideal or
maximum therapeutic window for intervention with cell ther-
apy exists aer brain injury. If one does, it is likely to vary by
the type of injury and the age of the patient.
If cell therapies, including CB, are proven to have a role
in the treatment of neurologic injuries, the parameters of
their use will certainly require further renement. Many
issues remain unknown, including ideal cell source, route
of administration, dose and dosing regimen, timing, and
role of immunosuppression. If the intent is to modulate host
repair mechanisms, a multiple dosing regimen could be more
eective than a single dose. Although the optimal cell dose
is unknown, this case series demonstrates that a single CBU
can yield sucient cells for multiple intravenous doses in
young children, and that repeated dosing is safe and feasible
in babies with brain injuries. Data regarding the functional
outcomes of babies with congenital hydrocephalus treated
with CB infusion(s) are being collected under a separate IRB-
approved protocol. Based on the favorable safety prole and
feasibility of CB infusion in this population, a phase II trial
in children with severe hydrocephalus is under development.
In that study, diligent genetic screening and review of brain
imaging will be necessary to exclude patients with identiable
genetic conditions and brain malformations. Additional trials
using multiple dosing regimens are also planned for babies
with hypoxic ischemic encephalopathy and children with
cerebral palsy and autism.
is analysis is a retrospective data review of patients treated with
intravenous autologous CB infusion for congenital hydrocephalus by
the Duke Pediatric Blood and Marrow Transplant Program. A waiver
of authorization to conduct this study was approved by the Duke
University Medical Center Institutional Review Board. At least one
parent signed routine hospital consent for treatment as well as con-
sent for data to be collected and shared with the National Marrow
Donor Program and Center for International Blood and Marrow
Transplant Research (NMDP/CIBMTR) for entry into the Stem Cell
Transplant Outcomes Database. Charts of children infused from
3/2004 to 8/2014 were reviewed.
Infants with severe congenital hydrocephalus, diagnosed either before
or aer the child’s birth, were either self-referred or referred by their
treating physicians. Infants were eligible for autologous CB infusion if
their parents elected to bank their CB at birth and if the CB met cer-
tain technical specications enumerated below. Patients with known
genetic diseases, brain malformations, spina bida, ineligible CBUs,
or inability to travel to Duke, were excluded.
Treatment Plan
If referred prenatally, information regarding the patients diagnosis
and expected date of delivery was acquired. CB collection was then
arranged through the Stem Cell Lab, a clinical hospital laboratory
at Duke University, via a directed donor kit collection program. If
referred aer birth and if the parents had elected to bank the baby’s
CB with a private CB bank, information regarding the patients diag-
nosis, current condition, and CBU characteristics was obtained. In
either case, donor screening labs were obtained on a maternal blood
sample drawn around the time of delivery. Aer the child and their
CBU were deemed eligible, identity and potency of the CB unit were
conrmed. For units banked at private banking facilities, the CBU
was shipped to the Duke Stem Cell Lab in a dry shipper maintain-
ing temperatures <−150 °C, processed on a Sepax 1 to volume reduce
and partially red blood cell and plasma deplete, mixed with dimethyl
sulfoxide/Dextran to a nal concentration of 10% dimethyl sulfox-
ide, cryopreserved by controlled-rate freezing and stored under liq-
uid nitrogen until the time of infusion. Some parents elected to have
their babies born at Duke, so that they were able to have their CB col-
lected and receive neonatal care including their initial neurosurgery
at Duke. All patients not born at Duke traveled with their parent(s) to
Duke for a 3-d visit including: on day 1, a baseline history, physical,
and laboratory evaluation including donor screening labs (if the baby
was >30 d of age); on day 2, infusion of the autologous CB; and on day
3, follow-up by phone to screen for infusion-related toxicities.
CBU Criteria
Cryopreserved CBUs had to meet the following minimum criteria
for infusion as documented by the bank of origin: precryopreser-
vation TNCC documented and >1×10
cells/kg calculated for the
child’s current body weight, sterility cultures performed and negative,
maternal infectious history screen and infectious disease markers
(minimally HIV 1 and 2, HTLV 1 and 2, Hepatitis B and C, CMV,
West Nile virus, and syphilis) performed and negative. If not stored
by the Duke STCL, in addition to meeting the above specications,
CBU identity was conrmed via HLA typing of both a test sample of
the CBU and peripheral blood of the patient, and a test sample of the
CBU was thawed and tested for viability, CFU, and CD34 to conrm
potency before the baby was scheduled for an infusion.
4 Pediatric RESEARCH
Copyright © 2015 International Pediatric Research Foundation, Inc.
CB infusion in babies with hydrocephalus
CBU Thawing and Infusion Procedure
Cryopreserved CBUs were thawed and washed as described by
Rubinstein et al. (26) and resuspended in dextran
+ 5% human
serum albumin solution on the day of infusion. awed CBUs
were tested for enumeration of TNCC, viable CD34
cells, CFUs,
cell viability via trypan blue, and sterility cultures. On the day of
infusion, patients were admitted to the Duke Childrens Health
Center Day Hospital and IV access was established via a peripheral
vein. Aer premedication with Tylenol (10mg/kg PO), Benadryl
(0.5mg/kg IV), and Solumedrol (0.5mg/kg IV), patients received
either a portion of or their entire CBU via peripheral IV infusion
over 5–15min. e volume of the infusion was adjusted postwash
to deliver no more than 1.25 cc/kg over 15min. Intravenous uids
were administered at 1.5 times maintenance for 2–4h aer the CB
infusion. Vital signs and pulse oximetry were monitored continu-
ously during the infusion and every 30min for 1–2h postinfusion
as medically indicated.
Dosing and Multiple Infusions
e target dose per infusion was 1–5×10
cells per kilogram of
patient body weight at the time of infusion. Based on the congura-
tion in which each CBU was stored and the number of cells available,
only one compartment of the CBU bag or a portion of one compart-
ment was utilized for infusion to provide an adequate cell dose, and
the remainder was stored under liquid nitrogen for later infusions.
Generally, when the CB unit was stored in a bag with the 80/20 con-
guration, the smaller compartment was utilized for the rst infu-
sion. At the time of the second infusion, the 80% compartment was
thawed and a portion of the thawed product was administered to
deliver a targeted cell dose which was calculated based on the baby’s
weight. e remaining cells were recryopreserved in a new 80/20 bag
to allow for administration of additional 1–3 future doses. e exact
number of doses available depended on the TNCC of the initial col-
lection and the weight of the baby over time. When the CBU cell dose
was sucient for multiple infusions, patients received subsequent
doses at intervals of approximately 2–6 mo as feasible based on their
medical condition and feasibility of travel logistics.
Data Collection and Statistics
Data regarding patients (diagnosis, age, birth history, surgical history,
developmental trajectory, and symptoms at birth and at the time of
infusion), infusions, and autologous CBU characteristics (collection
volume, precryopreservation TNCC, viability, sterility, CD34 and CFU
as well as post-thaw TNCC, CD34 count, viability, sterility cultures,
and post-thaw CFUs) were obtained from both a prospectively main-
tained clinical database and retrospective review of routine medical
records. Descriptive statistics were calculated for CBU parameters.
This study was supported by The Julian Robertson Foundation, New York
City, NY.
Disclosures: The authors to not have any conicts of interest or nancial ties
to disclose.
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Pediatric RESEARCH 5
... In the CORD-SAFE study [19], two doses are being trialed (25 £ 10 6 cells/kg and 50 £ 10 6 cells/kg) based on pre-clinical data demonstrating that 50 £ 10 6 cells/kg is likely to be a neuroprotective dose [23,24]. In addition, there are pre-clinical data to suggest that multiple doses may be more efficacious than one [25], and a multiple-dose approach has now been tested in phase 1 clinical trials of UCB-derived cells in newborns [12,26]. However, as the present data demonstrate, some infants may not have adequate autologous cells for a high-or multiple-dose treatment protocol, which is where UCB cell expansion may be of use. ...
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Background aims: Umbilical cord blood (UCB)-derived cells show strong promise as a treatment for neonatal brain injury in pre-clinical models and early-phase clinical trials. Feasibility of UCB collection and autologous administration is reported for term infants, but data are limited for preterm infants. Here the authors assessed the feasibility of UCB-derived cell collection for autologous use in extremely preterm infants born at less than 28 weeks, a population with a high incidence of brain injury and subsequent neurodisability. Methods: In a prospective study at a tertiary hospital in Melbourne, Australia, UCB was collected from infants born at less than 28 weeks and processed to obtain total nucleated cells (TNCs), CD34+ cells, mononuclear cells and cell viability via fluorescence-activated cell sorting prior to cryopreservation. Feasibility was pre-defined as volume adequate for cryopreservation (>9 mL UCB collected) and >25 × 106 TNCs/kg retrieved. Results: Thirty-eight infants (21 male, 17 female) were included in the study. Twenty-four (63.1%) were delivered via cesarean section, 30 (78.9%) received delayed cord clamping before collection and 11 (28.9%) were a multiple birth. Median (interquartile range [IQR]) gestational age was 26.0 weeks (24.5-27.5) and mean (standard deviation) birth weight was 761.5 g (221.5). Median (IQR) UCB volume collected was 19.1 mL/kg (10.5-23.5), median (IQR) TNC count was 105.2 × 106/kg (57.4-174.4), median (IQR) CD34+ cell count was 1.5 × 106/kg (0.6-2.1) and median (IQR) cell viability pre-cryopreservation was 95% (92.1-96.0). Feasibility of collection volume and cell count suitable for cell cryopreservation was achieved in 27 (71%) and 28 (73.6%) infants, respectively. Conclusions: UCB-derived cell collection adequate for cryopreservation and subsequent autologous reinfusion was achieved in 70% of extremely preterm infants. Extremely preterm UCB demonstrated a higher CD34+:TNC ratio compared with published full-term values. Recruitment to demonstrate safety of UCB cell administration in extremely premature infants is ongoing in the CORD-SAFE study (trial registration no. ACTRN12619001637134).
... In a patient (S02) with available long-term follow-up assessment, meaningful developmental improvement was observed only during the 1-year study period, while the improvement was trivial before and after the study. Therefore, these results might indicate a therapeutic response in mental development during a limited period after UCB infusion and also suggest that repeated UCB administration may be effective for a longer term [46][47][48]. In the assessment of VMI and IQ derived from MFED, no significant differences were found. ...
Most pediatric patients with global developmental delay (GDD) or intellectual disability (ID) have disrupted development. Since allogeneic umbilical cord blood (UCB) may exert neurotrophic effects, a prospective clinical trial was conducted to assess the efficacy and safety of UCB therapy for GDD and ID. A total of thirteen children (aged 6 months to 15 years) with GDD and ID were enrolled and followed-up for 12 months. Under criteria of histocompatibility and cell number, allogeneic UCB units were selected and infused once intravenously, and adverse events were monitored. The Bayley Scale of Infant Development-II (BSID-II) was used as primary outcome measurement tool, and evaluations for various functional abilities were also implemented. Safety assessment did not reveal significant adverse effects. Functional improvements in mental and motor developments along with daily living activities and languages were observed at 12 months post-intervention compared with the baseline abilities (Ps <0.05). And, mental developmental quotient derived from BSID-II mental scale revealed significantly facilitated improvement during the first three months (P <0.05). In the survey conducted 80.7±13.0 months after UCB infusion to assess satisfaction and long-term safety, no long-term adverse effects were reported, and 70% of the guardians reported satisfaction with the UCB infusion. Long-term changes in two patients who were regularly followed up beyond the study completion were noticeable. One case observed for four years, showed dramatic improvement until 12 months after UCB therapy, whereas she showed insignificant improvement beyond 12 months after the therapy. Another case showed alleviation of autism with findings of anti-inflammatory response in his peripheral blood after UCB infusion. This clinical study provides support for further applications of UCB as a therapeutic avenue for children with GDD or ID owing to its safety and partial efficacy. Due to patient heterogeneity, further studies focusing on specific clinical manifestations and etiologies are required.
... prenatal onset). Based on prior studies in young babies with congenital hydrocephalus [208], a compassionate use study led by Dr. Joanne Kurtzberg at Duke University involving sibling or autologous umbilical cord blood infusions is available to children with one of seven brain disorders, including hydrocephalus. Other cell-based trials for hydrocephalus were not found in the ...
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The Hydrocephalus Association (HA) workshop, Driving Common Pathways: Extending Insights from Posthemorrhagic Hydrocephalus, was held on November 4 and 5, 2019 at Washington University in St. Louis. The workshop brought together a diverse group of basic, translational, and clinical scientists conducting research on multiple hydrocephalus etiologies with select outside researchers. The main goals of the workshop were to explore areas of potential overlap between hydrocephalus etiologies and identify drug targets that could positively impact various forms of hydrocephalus. This report details the major themes of the workshop and the research presented on three cell types that are targets for new hydrocephalus interventions: choroid plexus epithelial cells, ventricular ependymal cells, and immune cells (macrophages and microglia).
... The potential of autologous UCB-derived stem-cell therapy led a number of perinatal centers worldwide to establish protocols and conduct pilot trials for neonatal disorders such as hypoxic-ischemic encephalopathy (HIE) [5,6] and congenital hydrocephalus [7]. Despite their safety and considerable clinical promise, these studies encountered major hurdles, such as problems in preparing cells on time and in sufficient amounts to permit scalability of the approach using the patient´s own umbilical stem cells right after birth. ...
Within the fast-growing field of regenerative medicine stem-cell therapy is well established in various hematologic and immunologic diseases and has received a recent substantial boost from the introduction of gene editing and gene transfer technologies. In neonates, for example, regenerative medicine may benefit those with congenital or acquired disease due to prematurity or perinatal hypoxia-ischemia. We compare and contrast the two main approaches – autologous vs. allogeneic – and summarize the recent advances and applications of interventional stem-cell research in perinatally acquired disorders such as intraventricular hemorrhage, hypoxia-ischemia and stroke. After discussing stem-cell sources and routes of administration, we conclude by highlighting the key opportunities and obstacles in this exciting field.
... Sun et al conducted an open-label, phase I trial of autologous UCB-MNCs for congenital hydrocephalus. 65 The cells were administered in 2-4 intravenous doses of 1-5 × 10 7 /kg, at variable time points from day 6 postbirth to 4.5 years (median 2 months). The primary outcome of this study was safety and feasibility, with no serious adverse effects reported at 12 months. ...
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Cell therapies are an emerging focus for neonatal research, with benefits documented for neonatal respiratory, neurological, and cardiac conditions in pre-clinical studies. Umbilical cord blood (UCB) and umbilical cord (UC) tissue-derived cell therapy is particularly appealing for preventative or regenerative treatment of neonatal morbidities; they are a resource that can be collected at birth and used as an autologous or allogeneic therapy. Moreover, UCB contains a diverse mix of stem and progenitor cells that demonstrate paracrine actions to mitigate damaging inflammatory, immune , oxidative stress, and cell death pathways in several organ systems. In the past decade, published results from early-phase clinical studies have explored the use of these cells as a therapeutic intervention in neonates. We present a systematic review of published and registered clinical trials of UCB and cord tissue-derived cell therapies for neonatal morbidities. This search yielded 12 completed clinical studies: 7 were open-label phase I and II safety and feasibility trials, 3 were open-label dose-escalation trials, 1 was a open-label placebo-controlled trial, and 1 was a phase II randomized controlled trial. Participants totaled 206 infants worldwide; 123 (60%) were full-term infants and 83 (40%) were preterm. A majority (64.5%) received cells via an intravenous route; however, 54 (26.2%) received cells via intratracheal administration, 10 (4.8%) intraoperative cardiac injection, and 9 (4.3%) by direct intraventricular (brain) injection. Assessment of efficacy to date is limited given completed studies have principally been phase I and II safety studies. A further 24 trials investigating UCB and UC-derived cell therapies in neonates are currently registered.
Preterm birth and intrapartum related complications account for a substantial amount of mortality and morbidity in the neonatal period despite significant advancements in neonatal-perinatal care. Currently, there is a noticeable lack of curative or preventative therapies available for any of the most common complications of prematurity including bronchopulmonary dysplasia, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia and retinopathy of prematurity or hypoxic-ischemic encephalopathy, the main cause of perinatal brain injury in term infants. Mesenchymal stem/stromal cell-derived therapy has been an active area of investigation for the past decade and has demonstrated encouraging results in multiple experimental models of neonatal disease. It is now widely acknowledged that mesenchymal stem/stromal cells exert their therapeutic effects via their secretome, with the principal vector identified as extracellular vesicles. This review will focus on summarizing the current literature and investigations on mesenchymal stem/stromal cell-derived extracellular vesicles as a treatment for neonatal diseases and examine the considerations to their application in the clinical setting.
The nutrients and other factors transported by umbilical cord blood, which is vital for fetal survival, play crucial roles in fetal development. There are various communication modes between the fetal-placental system and the maternal-placental system, and these communication modes are all mediated by umbilical cord blood. During the process of umbilical cord blood transportation, the changes of some nutrients and factors may play a key role in fetal development. Exosomes, which are members of the extracellular vesicle family, are present in the umbilical cord blood and play roles in information transmission as a result of their efficient cellular communication activity. The study of umbilical cord blood-derived exosomes provides a new approach for research on the etiology of maternal–fetal diseases and they may be useful for the development of intrauterine treatments. This review summarizes specific functions and research directions regarding umbilical cord blood-derived exosomes, and their potential associations with pregnancy complications.
Unrelated cord blood (CB) units, already manufactured, fully tested and stored, are high-quality products for haematopoietic stem cell transplantation and cell therapies, as well as an optimal starting material for cell expansion, cell engineering or cell re-programming technologies. CB banks have been pioneers in the development and implementation of Current Good Manufacturing Practices for cell-therapy products. Sharing their technological and regulatory experience will help advance all cell therapies, CB-derived or not, particularly as they transition from autologous, individually manufactured products to stored, 'off-the shelf' treatments. Such strategies will allow broader patient access and wide product utilisation.
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Objective To assess the safety and feasibility of allogeneic human umbilical cord blood (hUCB)-derived mesenchymal stem cell (MSC) transplantation in preterm infants. Study design In a phase I dose-escalation trial, we assessed the safety and feasibility of a single, intratracheal transplantation of hUCB-derived MSCs in preterm infants at high risk for bronchopulmonary dysplasia (BPD). The first 3 patients were given a low dose (1 × 107 cells/kg) of cells, and the next 6 patients were given a high dose (2 × 107 cells/kg). We compared their adverse outcomes, including BPD severity, with those of historical case-matched comparison group. Results Intratracheal MSC transplantation was performed in 9 preterm infants, with a mean gestational age of 25.3 ± 0.9 weeks and a mean birth weight of 793 ± 127 g, at a mean of 10.4 ± 2.6 days after birth. The treatments were well tolerated, without serious adverse effects or dose-limiting toxicity attributable to the transplantation. Levels of interleukin-6, interleukin-8, matrix metalloproteinase-9, tumor necrosis factor α, and transforming growth factor β1 in tracheal aspirates at day 7 were significantly reduced compared with those at baseline or at day 3 posttransplantation. BPD severity was lower in the transplant recipients, and rates of other adverse outcomes did not differ between the comparison group and transplant recipients. Conclusion Intratracheal transplantation of allogeneic hUCB-derived MSCs in preterm infants is safe and feasible, and warrants a larger and controlled phase II study.
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To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE). We enrolled infants in the intensive care nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to 4 doses adjusted for volume and red blood cell content, 1-5 × 10(7) cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post-infusion vital signs. As exploratory analyses, we compared cell recipients' hospital outcomes (mortality, oral feeds at discharge) and 1-year survival with Bayley Scales of Infant and Toddler Development, 3rd edition scores ≥85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells. Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 mL. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1-year outcomes survived with scores >85. Collection, preparation, and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed.
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Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP, were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the six months treatment period: the Gross Motor Performance Measure (GMPM), Gross Motor Function Measure, and Bayley Scales of Infant Development-II (BSID-II) Mental and Motor scales. (18) F-fluorodeoxyglucose positron emission tomography ((18) F-FDG-PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID-II Mental and Motor scales at six months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. (18) F-FDG-PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain.
Hydrocephalus is a common but complex condition caused by physical or functional obstruction of CSF flow that leads to progressive ventricular dilatation. Though hydrocephalus was recently estimated to affect 1.1 in 1,000 infants, there have been few systematic assessments of the causes of hydrocephalus in this age group, which makes it a challenging condition to approach as a scientist or as a clinician. Here, we review contemporary literature on the epidemiology, classification and pathogenesis of infantile hydrocephalus. We describe the major environmental and genetic causes of hydrocephalus, with the goal of providing a framework to assess infants with hydrocephalus and guide future research.
Congenital hydrocephalus without or with associated myelomeningocoele has impaired visual function as a potential complication. The present study was embarked on to determine the frequency of optic nerve deficits and refractive errors in this group of children and document any relationship to neuroradiological measurements. All infants with congenital hydrocephalus associated with myelomeningocoele (MHC) and congenital hydrocephalus without myelomeningocoele (HC) were prospectively studied. The children underwent clinical neuro-ophthalmological evaluation and neuroimaging. Radiological confirmation and severity of hydrocephalus was by Evans ratio (frontal and occipital) and third ventricular diameter. There were 50 children (27 boys and 23 girls, median and mean age of 6 and 5.4 months, respectively) included in the study. Eighteen patients (36 %) had no or poor visual tracking and fixation, while nine (18 %) patients had optic atrophy. Optic atrophy was significantly associated with the HC group (p = 0.007), while the MHC group was significantly associated with a lower Evans ratio (occipital ratio, p = 0.000; frontal ratio, p = 0.000). Forty-nine patients had anisometropia. The refractive errors were more commonly hypermetropia (46 patients). This was not significantly associated with HC or MHC (0.309). Optic atrophy rarity in MHC is probably due to early presentation of the patients and lower Evans ratio (occipital and frontal). Evans ratio is a good predictive index for optic atrophy in infantile congenital hydrocephalus. Refractive errors frequency is not dependent on an association of myelomeningocoele with or without hydrocephalus.
Aim: To determine the prevalence, aetiology and clinical outcome in children with surgically treated hydrocephalus. Methods: A population‐based study of all 208 liveborn children with hydrocephalus, 124 with infantile hydrocephalus and 84 with hydrocephalus associated with myelomeningocoele, born during 1989–1998 in western Sweden. Aetiological and clinical information was collected from records. Results: The prevalence of hydrocephalus was 0.82 per 1000 live births, 0.49 for children with infantile hydrocephalus and 0.33 for children with myelomeningocoele. The prevalence of infantile hydrocephalus decreased during the period from 0.55 to 0.43 per 1000. In this group, the aetiology was prenatal in 55% and peri‐postnatal in 44% of the children. The origin was perinatal haemorrhage in all cases born very preterm. The mortality rate was 5% for children with either infantile hydrocephalus or myelomeningocoele. Mental retardation, cerebral palsy and epilepsy were significantly more frequent in the group with infantile hydrocephalus: 46% vs 16%, 31% vs 4% and 31% vs 10%, respectively. All children with infantile hydrocephalus born very preterm had at least one of these impairments, as did 80% of those with overt hydrocephalus at birth. Conclusion: A slightly decreasing trend for infantile hydrocephalus was observed during the 10‐y period. Children with infantile hydrocephalus had a worse outcome than those with myelomeningocoele. The need for neurosurgical revisions for two‐thirds of the children indicates the need for further development of prevention and treatment strategies.
A pilot study was conducted to determine the safety and feasibility of intravenous administration of autologous umbilical cord blood (CB) in young children with acquired neurologic disorders. Most CB units (CBUs) were electively stored in private CB banks. Unlike public banks, which utilize specific criteria and thresholds for banking, private banks generally store all collected CBUs. CBUs of eligible patients containing more than 1 × 10⁷ cells/kg were shipped to Duke from the banks of origin after confirming identity by HLA typing. On the day of infusion, CBUs were thawed and washed in dextran-albumin and infused intravenously. Patients were medicated with acetaminophen, diphenhydramine, and methylprednisolone before transfusion. Data regarding patients, infusions, and CBUs were collected retrospectively. Characteristics of CBUs were compared to existing data from CBUs publicly banked at the Carolinas Cord Blood Bank. From March 2004 to December 2009, 184 children received 198 CB infusions. Three patients had infusion reactions, all responsive to medical therapy and stopping the infusion. Median precryopreservation volume (60 mL vs. 89 mL, p < 0.0001), total nucleated cell count (4.7 × 10⁸ vs. 10.8 × 10⁸, p < 0.0001), and CD34 count (1.8 × 10⁶ vs. 3.0 × 10⁶, p < 0.0001) were significantly lower than publicly stored CBUs. Postthaw sterility cultures were positive in 7.6% of infused CBUs. IV infusion of autologous CB is safe and feasible in young children with neurologic injuries. Quality parameters of privately banked CBUs are inferior to those stored in public banks. If efficacy of autologous CB is established clinically, the quality of autologous units should be held to the same standards as those stored in public banks.