Changes You May Wish to Make in Practice

Influential Articles in Neonatal
Henry C. Lee, MD, FAAP
Lucile Packard Children’s
Stanford, CA
Steven Ringer, MD, PhD, FAAP
Brigham and Women’s Hospital
Boston, MA
Faculty Disclosure Information
In the past 12 months, I have no relevant financial relationships with the
manufacturer(s) of any commercial product(s) and/or provider(s) of commercial
services discussed in this CME activity.
I do not intend to discuss an unapproved/investigative use of a commercial
product/device in my presentation.
• Session objectives
– Discuss recent articles on evolving topics
surrounding neonatal resuscitation
– Discuss recent articles that may impact future
neonatal resuscitation guidelines and practice
• Topics to be discussed:
– Encephalopathy / hypothermia
– Periviable birth
– Oxygen concentration for resuscitation
– Cord clamping timing
• Term
• Preterm
• Encephalopathy / Hypothermia
– Hypothermia increases chance of better
• Need for awareness of identification, appropriate
diagnosis, and prompt therapy
– Neurologic care may be next frontier for
Executive summary: Neonatal Encephalopathy and Neurologic
Outcome, Second Edition, Report of the American College of
Obstetricians and Gynecologists’ Task Force on Neonatal
Encephalopathy. OB&GYN, April 2014; 123(4):896-901. PMID:
• Definition of neonatal encephalopathy – clinical syndrome of
disturbed neurologic function in the earliest days of life in an infant
born at or beyond 35 weeks gestation
– Subnormal level of consciousness or seizures
– Often accompanied by difficulty with initiating and maintaining
respirations and depression of tone and reflexes
• Signs consistent with acute peripartum or
intrapartum event
– Apgar score ≤ 5 at 5 and 10 minutes
• (≥ 7 – unlikely to be hypoxia-ischemia)
– Umbilical artery blood gas pH < 7.0 or base
deficit ≥12 mmol/L
• (> 7.20 – unlikely that intrapartum hypoxia played role)
– Multisystem organ failure consistent with hypoxicischemic encephalopathy
• Contributing factors consistent with acute
peripartum or intraparum event
– Sentinel hypoxic or ischemic event immediately
before or during labor and delivery (such as
ruptured uterus, abruption…)
– Fetal heart rate monitor patterns (such as patient
presenting with Category I pattern converting to
Category III)
• Magnetic resonance imaging /
spectroscopy preferred
– Ideal timing is between 24 and 96 hours after
– (with repeat at day 10 or later)
– Timing of injury still requires further research
• Hypothermia and Neonatal Encephalopathy. Committee on
Fetus and Newborn. Pediatrics 2014;133(6):1146-50. PMID:
– Update from 2005 workshop / COFN commentary
– Summary of randomized controlled trials of hypothermia
6 trials ~1200 infants, head or whole body cooling
> 35 or 36 weeks, < 6 hours of birth
Target temperature 33.5 to 34.5 degrees C for 72 hours
Moderate to severe encephalopathy
• Summary of large trials:
– Reduction in death or major neurodevelopmental disability
at 18 to 24 months by 24% (RR 0.76, 95%CI 0.69-0.84)
– Number needed to treat: 7
• Areas of uncertainty:
– < 35 weeks
– Cooling initiation prior to transfer to cooling center
• “Because the majority of infants who have
neonatal encephalopathy are born at
community hospitals, centers that perform
cooling should work with their referring
hospitals to implement education programs
focused on increasing the awareness and
identification of infants at risk for
encephalopathy, and the initial clinical
management of affected infants.”
• Effects of Hypothermia for Perinatal Asphyxia on Childhood
Outcomes. Azzopardi et al. (TOBY Study Group). NEJM July
10, 2014; 371(2):140-9. PMID: 25006720
– United Kingdom, original enrollment 2002 to 2006
– 325 newborns > 36 weeks
– Previous study showed reduced cerebral palsy at 18
– Current study: evaluation at 6 to 7 years of age
• Testing:
– Wechsler Scale of Intelligence (general measure of IQ)
– Other assessments of neuro / psychosocial function
• 15% loss to follow-up; 30% died
• Optimal therapy requires prompt
identification and initiation of protocols.
» Kracer JPEDS 2014; 165(2):267-273.
Changes You May Wish to Make in Practice
1. Educate others about hypothermia therapy for
moderate to severe neonatal encephalopathy.
2. Develop procedures for identification and early
clinical care for patients eligible for hypothermia.
• Periviable birth
– What is the appropriate minimum gestational
age for attempting resuscitation?
• Does GA affect neurodevelopmental
outcomes for ventilated infants who
survive to discharge home?
• 199 infants at one NICU between 23 to 28
weeks GA
• Limited to infants who required mechanical
Outcomes did
not vary by GA
for those who
• “In the US… resuscitation of infants born
at 24 weeks or below is considered
optional. Our data suggest that these
policies make sense only if “trying and
failing” in the NICU is deemed to have no
moral worth.”
JAMA 2011;306(21)
• Previous trials on antenatal steroids have been limited in
addressing the most preterm infants (22 to 25 weeks)
• Should steroids be given prior to birth before 24 weeks?
• NICHD Neonatal Research Network
• 1993 to 2009
• Born between 22 to 25 weeks, BW 4011000 grams
• 1848 total infants
• At 18 to 22 month f/u – death or
neurodevelopmental impairment was less
frequent when exposed to antenatal
– Odds ratio 0.60 (95% CI 0.53-0.69)
Death or ND impairment
Antenatal steroids
No steroids
22 weeks
90.2% -x
23 weeks
24 weeks
25 weeks
• Overall intact survival low even with
steroids (35.8%)
• Limitation – observational study – could be
biased by intentions of parents / clinicians
• Higher rate of BPD for those exposed to
antenatal steroids
Periviable Birth
Executive Summary of a Joint Workshop by the Eunice Kennedy
Shriver National Institute of Child Health and Human
Development, Society for Maternal-Fetal Medicine, American
Academy of Pediatrics, and American College of Obstetricians
and Gynecologists – May 2014
• “periviable period”
– 20 0/7 weeks – 25 6/7 weeks
• Purpose: guide management and
counseling issues
• “When counseling parents, it is appropriate to
present the data regarding the rate of survival
and long-term disabilities separately, since
the parents’ perspectives and the importance
they give these may be different. Physicians
should recognize that the parents’ views on
what is “severe” disability may be different
from those of the researchers or clinicians…”
• “Because most newborns at 24-25 weeks
of gestation will survive if resuscitated,
efforts to prolong pregnancy, intrapartum
interventions for fetal benefit, and neonatal
resuscitation should generally be offered,
if appropriate.”
Letter to Editor
Jeffrey Perlman, MB, ChB
Obstetrics & Gynecology Sept 2014
• “… concern – Table 3 particularly troubling …
omission of a parent representative group, a
critical stakeholder.”
• “All studies referenced raise serious
concerns for risk of bias for all outcomes…”
• Dr. Perlman –
– “… fetal outcomes at 23 to 23 6/7 weeks are distinctly
different from those of larger fetuses.
– Two possible recommendations:
• Recommend against routine administration of interventions
for 23 – 23 6/7 weeks except under special circumstances
• All interventions may be considered (low quality of evidence)
in accordance with parent preferences)
– Recommend GRADE (Grading of Recommendations
Assessment, Development and Evaluation) process
rather than expert opinion.
• Dr. Keith Barrington’s Neonatal Research
– “Executive Summary… overall a reasonable
reflection of our discussions, but… some
– Table 3 – cesarean delivery is not recommended
for fetal indications up to and including 22 weeks
and 6 days, but then suddenly becomes
recommended at 23 weeks and 0 days.
• Dr. Keith Barrington
– We do not know exact GA (except in IVF)
– “This recommendation must be nuanced and
take into account the particular clinical
circumstances of the mother, and her values
and desires.”
Changes You May Wish to Make in Practice
1. Discuss issues surrounding periviable birth with a
multi-disciplinary team.
2. Be able to counsel parents before and after
extremely preterm birth.
• What is the correct oxygen concentration to
initiate resuscitation for preterm infants?
• NRP 5th ed. 2005/2006
– Preference of 100% O2 with vigilance and adjustment
– Allowance of less O2 ok
– Recommend pulse oximetry
• NRP 6th ed. 2010/2011
– Titrate O2 to achieve saturation goals similar to term
– No specific oxygen concentration recommended (probably
not 100%, probably not 21%)
Targeted Pre-ductal SPO2 After Birth
1 min
2 min
3 min
4 min
5 min
10 min
• Kapadia VS, Chalak LF, Sparks JE, Allen JR, Savani RC,
Wyckoff MH. Resuscitation of preterm neonates with limited
versus high oxygen strategy. Pediatrics 2013;132(6):e148896. PMID: 24218465
• Testing initial FiO2 of 21% vs 100% and titrating
by 10% every 30 seconds to meet NRP goals
• Primary outcome: total hydroperoxide (TH),
biological antioxidant potential (BAP), BAP/TH
Protection Against Oxidative
Stress and “IGF-I Deficiency
Conditions” Munoz
Biochemistry, Genetics and
Molecular Biology 2012
• Eligible infants 24 to 34 weeks GA
• Due to equipoise, antenatal consent not
needed as long as consent obtained
• Treatment failure: HR < 60 despite 30
seconds of effective PPV  100% FiO2
• Total hydroperoxide higher in high oxygen group at first
hour after birth
• Conclusion
– May be OK to start at 21% and if needed,
gradually increase to meet goal saturations.
• Rook D, Schierbeek H, Vento M, Vlaardingerbroek H,
van der Eijk AC, Longini M, Buonocore G, Escobar J,
van Goudoever JB, Vermeulen MJ. Resuscitation of
preterm infants with different inspired oxygen fractions. J
Pediatr. 2014 Jun;164(6):1322-6.e3. PMID: 24655537
• Double blinded randomized trial
• GA < 32 weeks
• 30% vs 65%
• Written informed consent prior to delivery
– Led to some difficulty / selection bias
• Goal saturation 88%-94% at 10 minutes
– Study concentration abandoned when:
• HR < 100, SpO2 / HR drop,
– Start at 21% and manually adjusted per
• Results
– Of 781 eligible infants, 193 were analyzed
• Main reason for exclusion was imminent delivery
• No difference in glutathione concentration
or other markers of oxidative stress.
• Recommendation: starting with initial
concentration of 30% and subsequent
Starting oxygen
21% vs 100%
30% vs 65%
All eligible
Consent prior to delivery
• Rich Pediatrics 2012; 129:480
• Rich Pediatrics 2012; 129:480
Changes You May Wish to Make in Practice
1. Develop a protocol for initial oxygen concentration
for resuscitation of preterm infants (?21% / 30%)
2. Develop protocols for titrating oxygen
concentration based on oxygen saturation
Optimal timing of umbilical cord
Steven Ringer MD PhD
Harvard Medical School
•October 10, 2014
Not such a new concept
“ Another thing very injurious to the child, is the tying
and cutting of the navel string too soon; which
should always be left till the child has not only
repeatedly breathed but till all pulsation in the cord
ceases. As otherwise the child is much weaker than
it ought to be, a portion of the blood being left in the
placenta, which ought to have been in the child….”
Erasmus Darwin 1801
Arguments to clamp early
• Potential delay in resuscitation
• May interfere with cord blood banking (argued
against by ACOG)
• May cause polycythemia (never demonstrated)
• May be more of a problem in high risk pregnancies
– Maternal Diabetes
– Growth Restriction
On the other hand...
• Abrupt interruption of umbilical cord blood flow may result in
apparent need for resuscitation
• Studies in fetuses demonstrated reflex bradycardia in response to
umbilical cord occlusion
• Dawes and co-workers, in the hallmark studies on asphyxia in
Rhesus monkeys, noted that tying the cord in asphyxiated monkeys
resulted in sudden bradycardia, gasps and then apnea.
• If blood pressure was maintained, heart rate could be restored by
positive pressure ventilation
• So, does early clamping precipitate factors that then call for
resuscitation, and might a delay actually avoid the need?
Current recommendations
• 2010 International Liaison Committee on
Resuscitation (ILCOR) consensus on
Science states Cord Clamping should be
delayed for at least one minute in babies who
do not require resuscitation….Evidence is
insufficient to recommend a time for clamping
in those who require resuscitation
Fetal Circulation
Between 30 and 50% of the
combined cardiac output flows to
the placenta
Therefore, the same 30 to 50% of
cardiac venous return comes from
the placenta
About 30% ( humans) of UV blood
bypasses the liver through the
ductus venosus. Most goes
directly to left atrium
The rest of venous return is to
right ventricle but high PVR results
in shunting to aorta
Changes with cord clamping
Loss of low resistance placentaSVR increases, and venous return
to heart drops 30 to 50%
Both effects may compromise
cardiac output
Left ventricular preload and output
become largely dependent on
pulmonary blood flow and
pulmonary venous return
Respirations result in decreased
PVR and thereby improved LV
preload and output
Placental Transfusion
Most of transfusion is
in first 60-90 seconds,
amount 25-40 ml/kg
Effect on calculated blood volume in newborn and placenta
Timing of umbilical cord clamping after birth for
optimizing placental transfusion.
Raju, Tonse
Current Opinion in Pediatrics. 25(2):180-187, April
DOI: 10.1097/MOP.0b013e32835d2a9e
Clamping and respirations
• Instrumented preterm lambs, anesthetized and intubated
• Randomized to Clamp 1st (filled circles): immediate cord
clamping and ventilation at 2 minutes, or
• Vent 1st (open circles): ventilation until pulmonary blood flow
increased over 3 to 4 minutes, followed by cord clamping
• Vent 1st: Immediate drop in HR, low pulmonary blood flow ,
spike in carotid blood pressure and flow with clamping,
followed by pressure drop and flow decrease
Bhatt, et al. J Physiol 2013;591:2113-2126.
Changes with
Pulmonary blood flow increased,
but still remained lower than Vent
1st group
Carotid arterial pressure and flow
rose back to high levels
So, clamping before respirations
resulted in decreased right
ventricular output and low
pulmonary blood flow, with wide
fluctuations in carotid arterial
pressure and flow
Ventilation First, then clamp
• Heart rate remained stable before and after c lamping
• Pulmonary blood flow rose steadily, remained about
twice as high
• Carotid pressure drifted a bit lower then returned to
baseline, with steady flow
• Lung expansion before clamping results in stable
Heart Rate, progressive rise in PBF, and stable carotid
blood flow.
Clinical Impact- Term Infants
Iron deficiency in mothers and infants is a major global problem- up to 30 %
of infants born to FE- deficient mothers have anemia
In developed country, available supplements prevent this problem
A one minute delay in cord clamping results in 80 ml transfusion in a term
baby- the additional iron may prevent deficiency
Numerous studies have demonstrated higher hematocrit/hemoglobin levels
(2-3 gm/dL) which persist for 4-6 months
No increase in polycythemia, but a potential for increased jaundice and
need for phototherapy
No increase in maternal hemorrhage
McDonald SJ, Middleton P, Dowsweell T , Morris PS. Effect of timing of umbilical cord clamping of
term infants on maternal and neonatal outcomes
Improved hemoglobin and iron
Impact in term infants and mothers
• Analysis of available
• No demonstrated
maternal risk
• No increase in
• Some increase in
jaundice requiring
Benefits in
Benefits in preterm infants
• Review of studies in infants 24-36 weeks gestational age.
Cord clamping in the various trials delayed for 30-180
• Cochrane review found decreased incidence of any IVH in
7/10 trials ( 16.4% vs 28.7 %) (RR 1.90 for early clamping
(95% CI 1.27-2.84)
– Death rate similar in the two groups
• No increase in need for exchange transfusion for
polycythemia or hyperbilirubinemia
• Recent revised Cochrane review concluded that delayed
clamping results in additional benefits
Intraventricular hemorrhage – all grades
Severe IVH
Less Necrotizing Enterocolitis
No change in admission temperature
Benefits in preterm infants
• Systematic review of 10 trials in 454 preterm infants (<37 weeks) :
• No differences in
– Cord pH
– Apgar scores (RR for 5 minutes score <8 was 1.17 (95% CI 0.62-2.20)
– Admission temperature (mean difference 0.14 degrees(95% CI -.310.03)
• Many trials document higher blood pressures and higher red cell
• Systemic review showed reduced need for transfusions for
hypotension, trend to less IVH
Ghavam S, Batra D, Mercer J, Kugelman A, Hosono S, Oh W, Rabe H, Kirpalani H. Effects of placental transfusion in
extremely low birthweight infants: meta-analysis of long- and short-term outcomes.
Transfusion. 2014 Apr;54(4):1192-8.
Caution is advised
• Published randomized trials include < 200 infants < 30 weeks
gestation ( the same trials cited by Ghavam)
• Two RCTs followed 42 children at 18-24 months but used
different developmental scales and were inconclusive
• Without long term follow up and well powered studies, short
term benefits may fool us into a bad practice
• Unclear whether low grade IVH is a surrogate for long term
• These authors strongly urge caution until more data is
Tarnow-Mordi WO1, Duley L2, Field D3, Marlow N4, Morris J5, Newnham J6, Paneth N7, Soll RF8, Sweet
D9Timing of cord clamping in very preterm infants: more evidence is needed. Am J Obstet Gynecol.
2014 Aug;211(2):118-23.
Humans likely to need resuscitation
• Few trials in humans, but QI studies do add information
• Infants < 35 weeks in whom cord clamping was delayed 45
seconds were compared with historical controls:
– 77 VLBW and 172 LBW infants matched to controls
– Vaginal births, held 10-20 cm below introitus in warm towel,
gently dried. C/S births held similarly between mother’s legs
– Six babies excluded based on assessment of need for
• 1 minute Apgar scores higher in delayed group
• Fewer infants required resuscitation
• Admission temperatures similar
Is it feasible to do?
• Single center study of infants less than 33 weeks
gestation:Mean gestational age was less than 30 weeks and
mean birth weight less than 1500 g
• 480 infants, 73% (349) eligible: 236 [email protected] 45 seconds,
113 clamped early
• No difference in 1 or 5 minute Apgar scores or in need for
• Among later clamped infants, fewer had temperatures <36.3
• Incidence of NEC lower in late clamped group
What if the infant has experienced severe
acute or chronic asphyxia?
• Studies on cord clamping have generally excluded those
needing major resuscitation
• Establishing ventilation with positive pressure ventilation
does facilitate placental transfusion in experimental lambs,
but it has not been studied when severe metabolic acidosis
was present, as well as altered feto-placental blood flow, or
compromised fetal organ function(e.g, persistent pulmonary
• The mechanics of resuscitation with the cord intact are
considerable, especially during cesarean section.
What if the infant has experienced severe
acute or chronic asphyxia?
• During fetal asphyxia, blood usually shifts from placenta to fetus- the
blood volume in the delivered infant may already be as high as in
infants whose cords are clamped later.
• In these infants, pulmonary vascular resistance may be high, and
myocardial contractility may be compromised.
• One can hypothesize that a sudden increase in LV afterload and
decreased preload with early cord clamping may adversely affect
the infant, independent of placental transfusion
• At present, these are hypothetical considerations, more studies are
needed to determine whether resuscitation with the cord intact is
In stable infants, the benefits of later cord clamping among term infants relate primarily to
improved iron stores and prevention of later anemia- benefits that are primarily realized in
low resource settings
In stable preterm infants, numerous benefits may result from later cord clamping. Most
prominent among these is a marked reduction in intraventricular hemorrhage. Caution
urged before extending this practice to all low GA infants
The putative benefits of later cord clamping in infants who require resuscitation are yet to
be proven, although additional evidence is currently being accrued
Consideration of the conduct of resuscitation when the cord is intact requires a careful
evaluation of needs for team and equipment.
As with all aspects of neonatal resuscitation, team training through simulation
debriefing should play a major role as teams consider this change in practice!
The list of all of the articles discussed during this breakout session are available as a