Jaundice Neonatal Clinical Trial
Official title:
The Risk of Hyperbilirubinemia in Term Newborns After Placental Transfusion: A Randomized-blinded Controlled Trial
Delayed cord clamping (DCC) has been a subject of extensive research for the last couple of
years. Based on published data, numerous neonatal benefits have been suggested such as
increased hemoglobin and ferritin levels both at birth and longer term. Available systematic
reviews of DCC versus early cord clamping (ECC) reveal that it may also contribute to other
neonatal outcomes including polycythemia and hyperbilirubinemia.
A review published nearly 10 years ago regarding late umbilical cord clamping revealed only
4 studies which as a second objective assessed whether the time of cord clamping was
associated with an increased risk of polycythemia and hyperbilirubinemia during the first
week of life. Two studies reported that neonates with DCC had bilirubin levels >15 mg/dl. No
information is provided on what hour of life the bilirubin levels were measured exactly.
In this randomized control study the investigators would like to determine if delayed cord
clamping or cord milking during labor increases the risk of hyperbilirubinaemia (requiring
phototherapy) in term infants.
The investigators feel that published results regarding 'jaundice" and "jaundice needing
phototherapy' (associated with DCC) may be misleading.
First, no information is offered about how "clinical jaundice "was assessed on examination.
The absence of jaundice is not an indication of the absence of hyperbilirubinemia.
Estimation of the degree of hyperbilirubinemia based solely on clinical examination can lead
to errors. The absence or the severity of jaundice is not predictive of subsequent severe
hyperbilirubinemia. A recent study revealed that the nurses' predischarge assessment of
jaundice extent was only moderately correlated with bilirubin concentration and was similar
in black and nonblack infants.
A review published nearly 10 years ago regarding late umbilical cord clamping revealed only
4 studies which as a secondary objective which assessed whether the time of cord clamping
was associated with an increased risk of polycythemia and hyperbilirubinemia during the
first week of life. Two studies reported that neonates with DCC had bilirubin levels >15
mg/dl. No information is provided on what hour of life the bilirubin levels were measured
exactly.
Secondly, guidelines to treat jaundice have changed over time and none of the studies
mention what threshold was used for administering phototherapy. No information is given if,
staff responsible for phototherapy administration was blinded to the type of cord clamping
intervention. Potential confounders such as isoimmune hemolytic disease, symptoms of sepsis
(significant lethargy, temperature instability), asphyxia, G6PD, acidosis, albumin <3 g/L
were not included in the analysis. Also another important factor such feeding policy at the
time of bilirubin measurement wasn't mentioned in neither of the studies.
The presence of all mentioned above confounders in available studies has lead the
investigators to conduct a blinded randomized trial.
Postnatal hyperbilirubinemia is universal and manifests as newborn jaundice in over 60-80%
of all newborns. If left untreated hyperbilirubinemia may progress to excessive levels that
can be associated with evident bilirubin neurotoxicity. Jaundice is the most common clinical
diagnosis in neonatal medicine. Elevated bilirubin concentrations may occur due to increased
bilirubin production (breakdown of heme moiety of hemoglobin) and/or delayed bilirubin
elimination (hepatic and intestinal) as well as by a unique neonatal phenomenon of
enterohepatic reabsorption of bilirubin.
Studies have shown that late cord clamping benefits expand beyond the neonatal period. A
meta -analyses estimated a significant 47% reduction in the risk of anemia and 33% reduction
in risk of having deficient iron stores at ages 2 to 3 months in the delayed cord clamping
group. These pooled results are based on two small studies, and despite a significant number
of patients lost to follow up (40%), these results agree with a large randomized trial.
It is important to understand whether evidence based benefits of DCC (such as increase of
hemoglobin, improved iron status, and decreased risk of infant anemia) may also contribute
to less favorable neonatal outcomes. This trial will aim to assess if delayed cord clamping
truly increases the risk of hyperbilirubinaemia requiring phototherapy or even exchange
transfusion.
Dose selection:
The total feto-placental blood volume is about 120 ml/kg of fetal weight. At birth, the
distribution of blood between fetus and placenta is roughly at a ratio of 2:1. Increasing
placental transfusion to at least three minutes leads to a larger infant blood volume (ratio
5:1).The rate of placental transfusion is markedly influenced by the position of the
delivered infant. From at least 10 cm above to at least 10 cm below the level of the
placenta, infants receive the maximum possible amount after at least three minutes of birth
.
The randomized and quasi-randomized controlled trials that studied delayed cord clamping in
vaginally born, healthy, term infants differed in clamping time and infant position before
clamping and there is still no consensus about the time required for a sufficient amount of
blood to be transfused from the placenta to the baby. The above mentioned trials showed that
placental-neonate blood flow significantly increases after DCC by showing higher packed cell
volume or hemoglobin concentration in the first 24 hours after birth compared with immediate
clamping.
To test the hypothesis, investigators have decided to delay cord clamping in the
intervention group to 3 minutes and place the baby 10 cm above the placental, as it seems
most efficient based on the available literature. At all births (spontaneous vaginal
deliveries and caesarian sections) a member of the recruitment team will be present. He will
inform the midwife or obstetrician about the allocated intervention and measure the time
from the delivery of the shoulders to the cord clamping. If cord milking will be the
allocated intervention, the recruiter will supervise the midwife, or obstetrician preforming
the procedure, and count out loud the number of times the cord has been milked. During
vaginal deliveries midwifes will be asked to maintain the infant at least 10 cm above the
uterus until the cord is clamped. In case of caesarian sections the baby will be placed on
the mother's laps and swaddled in sterile towels to prevent heat loss. In the early cord
clamping group, the recruiter will inform the midwife or obstetrician when 30 seconds have
passed. In the delayed clamping group, the recruiter will inform the midwife or obstetrician
after 3 minutes.
If cord milking will be applied the baby will be placed below the level of the placenta,
between the mother's thighs (during a vaginal delivery) or at the side of the mother
swaddled in sterile towels (during a caesarian delivery). Based on available literature,
before starting the trial investigators piloted this procedure[13]. They checked that about
two thirds of the umbilical cord will be present for milking both during a vaginal and
caesarian delivery. If the cord was milked once we were able to transfer approximately 10 ml
of blood to the neonate. Following this, and under the assumption that the cord vein will be
rapidly refilling itself, investigators assume that milking the cord four times will give us
40 ml of blood [13]. A member of the delivery team (vaginal delivery) or operating team
(caesarian delivery) will hold the cord at the level of the introitus or cesarean wound, and
milk the cord four times towards the neonate counting out loud. The cord will be clamped
after the forth milking.
Choice of comparator In spite of available studies which advocate for delayed cord clamping,
it is still infrequently used in labor wards throughout the world[28]. According to the new
guidelines early cord clamping-ECC is defined as cord clamping at less than 60 seconds after
the delivery. The available meta-analyses comparing early versus late cord clamping include
studies which significantly vary in defining ECC. The majority of trials define ECC as
clamping within the first 10 seconds, other describe ECC as immediate clamping. Only one
trial extended ECC to be as long as 60 seconds.
The new 2010 ILCOR (International Liaison Committee on Resuscitation) guidelines advocate
for DDC, stating that cord clamping should be delayed for at least 1 min from the complete
delivery of the baby. Investigators have chosen this definition, as the ILCOR committee
provides an international consensus and evidence based guidelines on emergency care, which
are widely accepted among neonatologist throughout the world.
ECC is part of active management of labour. Active management usually involves the clinician
intervening in the process through three interrelated processes: the administration of a
prophylactic uterotonic drug; cord clamping and cutting at ≤60 seconds after delivery; and
controlled traction of the umbilical cord. These interventions are aimed at reduction in the
risk of postpartum haemorrhage. However, ECC eliminates the possibility of additional blood
flowing from the placenta to the newborn, and deprives the baby from numerous profits such
as receiving extra amounts of iron. This potential additional amount of iron prevents iron
deficiency during the first year of life in infants born with delayed cord clamping.
Research Hypothesis Neither delayed cord clamping nor cord milking during labor does not
increase significantly the risk of hyperbilirubinaemia in comparison to early cord clamping.
Description of trial design The trail is designed as a randomized controlled, observer
blinded trial with 3 parallel groups and a primary endpoint of hyperbilirubinemia requiring
phototherapy. Randomization will be performed as block randomization with a 1:1:1
allocation. The experiment is designed to demonstrate non-inferiority of delayed cord
clamping and cord milking group in comparison to early cord clamping group regarding the
incidence of bilirubinemia treated with phototherapy in neonates.
Description of study settings The study will be carried out in the Princess Anne's Hospital
in Warsaw, Poland. This is a level III teaching hospital with approximately 3500 (1000 < 37
weeks of gestation) deliveries per year and 63 neonatal beds. It is also a referral center
for gestational and pre-gestational diabetes as well as pregnancy induced hypertension.
Having access to high risk mothers will augment the population of small for gestation
infants (SGA), and infants of diabetic mothers (IDM) in the study. SGA and IDM have an
increased risk for hyperbilirubinemia, thus the presence of the above patients will improve
the generalizability of the study population. The local protocol on cord clamping has not
yet been adjusted to the new ILCOR guidelines, but labour ward staff are willing to
implement new procedures. This should improve trail recruitment and adherence.
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