Recent Trials in

neonatology – Part II
Dr. Keshav Kumar Pathak
DM senior resident
Department of neonatology
Dr. RML Hospital, New Delhi

01/05/2022 1
TRIALS
1. ACTION I Trial (NEJM 2020)
2. ACTION II Trial (Lancet 2022)
3. Cochrane 2020 for ACS in preterm birth
4. ASTEROID Trial(Lancet 2019)
5. HYPOEXIT Trial (NEJM 2020)
6. REACT Trial (Lancet 2021)
7. I KMC (NEJM 2021)
8. IN-REC-SUR-E (Lancet 2020)
9. HELIX Trial (Lancet 2021)
10.ULTRASURF
01/05/2022
(Eu.J.paed- 2020) 2
ACTION-I (Antenatal Corticosteroids for
Improving Outcomes in Preterm Newborns) trial

• Study design- Multi-country, multi-centre, parallel, two-arm, double-blind,

placebo-controlled trial of ACS
• Study setting : 29 secondary + tertiary hospitals across six trial sites
(Bangladesh, India,Kenya, Nigeria, and Pakistan)
• Timeline : December 2017 – November 2019
01/05/2022 3
Background
• Antenatal steroids to the mothers at risk of PT delivery (24-34 weeks)
an established practice.
• Current Evidence (Cochrane 2017)
- Tertiary hospitals (High income countries)
- Predominantly Betamethasone
• Safety and efficacy of ACS in low resource countries- not established
• ACT trial-
- increased neonatal mortality in intervention group
- increased maternal infection

01/05/2022 4
PICO
• P (population)- 2852 women having fetus between 26 week 0 days to
33 weeks 6 days of gestation at risk of preterm delivery
• I (intervention)- dexamethasone sodium phosphate 6 mg- 12hours
apart , total 4 doses
• C (control) - placebo
• O (outcomes)-
 primary outcome - neonatal death
- still birth or neonatal death
- possible maternal bacterial infection
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01/05/2022 6
Conclusion
• Dexamethasone reduced the incidence of neonatal death and
still birth or neonatal death without increasing the incidence of
maternal bacterial infection in study conducted in low resource
countries.
• Early neonatal deaths, severe respiratory distress, use of major
neonatal resuscitation and CPAP

01/05/2022 7
ACT vs ACTION trial
Act trial Action trial
• Cluster randomised • Randomised
• All levels of care • In low resource setting
• Inadequate care • With minimum standards of care
• Selected women based on LMP • Selected women GA verified by
USG
• 16% of babies exposed <5th centile
BW • >90% infants exposed born preterm
• Substantial overtreatment • Treatment received by the needed
• Inappropriate selection • Appropriate selection

01/05/2022 8
ACTION – II Trial

www.thelancet.com Vol 44 Month February, 2022

Study settings- four hospitals in India Dec-2017 to May 2021

01/05/2022 9
 PICO
• P(population)- pregnant women at risk of imminent preterm birth between 34
weeks 0 days to 36 week 0 days of gestation (782 women)
• I (intervention)- 6 mg of intramuscular dexamethasone – 4 doses 12 hours apart
• C(control)- Placebo
• O(outcome)-
Primary outcome
Neonatal deaths
Any baby death(still birth or neonatal death
Severe neonatal respiratory distress
Possible maternal bacterial infection

01/05/2022 10
 Result

No difference in neonatal death, any baby death, severe neonatal

respiratory distress and possible maternal bacterial infection
Secondary outcome –
 decreased need of major resuscitation at birth(PPV for more than 1
minute) in intervention arm
 No difference in hypoglycaemia incidence at 6 & 36 HOL
01/05/2022 11
Limitations
• Trial was stopped early as lesser number of outcomes were recorded vs
expected number
• Sample size calculation based on incidence of neonatal death prevalence
of 8%- whereas recorded incidence in this study was only 2.7%
• Lacks statistical power to detect any difference in the primary mortality
outcome
• Very few number of severe respiratory distress (outcome) recorded vs 16
% of babies requiring supplemental O2, CPAP, & mechanical ventilation

01/05/2022 12
Objectives
To assess the effects of administering a course of corticosteroids to women prior to anticipated
preterm birth (before 37 weeks of pregnancy) on fetal and neonatal morbidity and mortality,
maternal mortality and morbidity, and on the child in later life

Studies
 27 studies ( ten trials- lower or middle resource settings)
 Studies in only high resource settings were included in previous Cochrane 2017
01/05/2022 13
Primary outcomes
Neonatal/childhood outcome-
•Definite reduction
Maternal
Perinatal death- RR-0.85, CI (0.77-0.93) outcomes
Neonatal death-RR-0.78, CI (0.70-0.87)
RDS- RR-0.71, CI (0.65-0.78)
•No difference in
•Probable reduction Maternal death
IVH- RR-0.58, CI (0.45-0.75)
•Decrease in developmental delay in
Chorioamnionitis
childhood, RR-0.51, CI (0.27-0.97), no benefit Endometritis
in previous Cochrane review 2017
01/05/2022 14
 Lancet Child Adolesc Health 2019 Published Online September 12, 2019, http://dx.doi.org/10.1016/
S2352-4642(19)30292-5

Multicentre, double –blind randomised controlled trial, conducted in 14

maternity hospitals of Australia and new Zealand
Time period- Jan 2009 to feb 2013
1346 women were included in study
01/05/2022 15
Background
• Cochrane review 2013
12 trials(1557 women and 1661 infants)
Dexamethasone – reduced risk of IVH and lesser duration of
stay in NICU compared with betamethasone
No difference for RDS and neonatal deaths
But no long term results like neurodevelopment data were
available
• So RCT was planned with neurodevelopmental outcomes and
maternal outcomes

01/05/2022 16
AIMS and OBJECTIVES

To assess whether administration of antenatal dexamethasone (I) to women

at risk of preterm birth before 34 weeks of gestation (P) reduced the risk of
death or neurosensory disability in their children at age 2 years (corrected
for prematurity)—the primary outcome (O)—and whether it reduced
neonatal morbidity, had benefits for the mother, or affected childhood body
size, blood pressure, behavior, or general health, compared with
betamethasone (C).

01/05/2022 17
Results (primary outcome)

No significant difference in the primary outcome of death or

neurosensory disability in children at age 2 years (corrected for
prematurity)

01/05/2022 18
Secondary outcomes
• No difference • Dexamethasone group
Respiratory morbidities has decreased risk of
Intraventricular Hypertension at age of 2
hemorrhage year
Periventricular Decreased number of
leukomalacia cesarean section
chorioamnionitis

01/05/2022 19
 Conclusion
Antenatal dexamethasone and betamethasone use provided similar likelihoods
of survival free of neurosensory disability at age 2 years, and either can be
given to women at risk of preterm birth to improve infant and child health.

ACOG statement 2017

No sufficient evidence supports the recommendation of one corticosteroid
regimen over the other
01/05/2022 20
01/05/2022 21
 Background
•70% of all neonatal deaths occur in low birth weight babies and approx. two third of all

these deaths occur in first 3 days of life.

•Kangaroo mother care is among the most effective interventions for preventing death

in infants with low birth weight.

•Cochrane review reported 40% lower mortality in infants with a birth weight of less

than 2.0 kg who were given KMC as compared with those who were given standard

(conventional) care in hospitals at 40–41 weeks’ postmenstrual age (3.2% versus

5.3%; risk ratio (RR) 0.60, 95% confidence interval (CI) 0.39 to 0.92; eight trials, 1736

infants)
01/05/2022 22
Background

• For most studies, the median age at initiation of KMC was 3.2 to 24.5
days.

• Thus, the 40% mortality impact of KMC in enrolled infants would

translate in practice to only about 13% impact on mortality in all babies
with a birth weight of less than 2.0 kg.

• The impact of the KMC intervention could have been much larger had it
been initiated immediately after birth.
01/05/2022 23
AIM :
To evaluate the safety and efficacy of continuous KMC initiated immediately
after birth for neonates with a birth weight of 1.0 to less than 1.8 kg
compared with initiating KMC after stabilization in improving survival

Study design:
Multi-country, multi-center, non-blinded RCT
Conducted in five tertiary level hospital in Ghana, India, Malawi, Nigeria
and Tanzania between November 30,2017, and January 20, 2020;

01/05/2022 24
 PICO

Patient /population All infants born alive in the participating hospitals with
a birth weight from 1.0 to less than 1.8 kg, regardless of
their gestational age

Intervention Continuous KMC initiated immediately after birth

Comparison continuous KMC initiated after stabilization

Outcome The primary outcomes were mortality from enrollment to 28 days of

age and mortality from enrollment to 72 hours of age

01/05/2022 25
 Outcomes

Primary outcome
Secondary outcomemeasures:
measures
 Hypothermia (any axillary temperature <36°C)
Neonatal deaths between enrollment and 72 h of age measured
 Hypoglycemia (any blood glucose level of <45 mg per deciliter, measured
through vital status records every 12 h during hospital stay
when clinically indicated)

 Suspected sepsis
Neonatal deaths between enrollment and 28 days of age
 Time to clinical stabilization
measured through vital status records every 12 h during hospital
 Exclusive breast-feeding (only by suckling) at the time of discharge
 stay andbreast-feeding
Exclusive at a home at visit on day
the end of the29 of age.
neonatal period (at 28 days of age)
 Maternal satisfaction with care
 Maternal depression
01/05/2022 26
01/05/2022 27
Conclusion

In this large, multisite, multi country study conducted in low-

resource hospitals, continuous kangaroo mother care initiated
immediately after birth in infants with a birth weight between 1.0
and 1.799 kg resulted in a significantly lower risk of neonatal
death than the currently recommended initiation of kangaroo
mother care after stabilization.

01/05/2022 28
 HypoEXIT
Hypoglycemia–Expectant Monitoring versus Intensive
Treatment Trial

01/05/2022 29
Background

• Hypoglycemia, the most common metabolic problem in newborns may lead to

persistent brain injury.
• No consensus regarding the threshold glucose concentration at which treatment
for asymptomatic neonatal hypoglycemia should be initiated.
OPERATIONAL
• On the basis of expert opinion, a concept of THRESHOLD:
operational thresholds was
Glucose concentrations between 36 mg per deciliter (2.0 mmol per liter) and 47
developed.
mg per deciliter (2.6 mmol per liter) are acceptable for short periods of time.

Tin W. Defining neonatal hypoglycaemia: a continuing debate. Semin Fetal Neonatal Med 2014.
Hawdon JM. Definition of neonatal hypoglycaemia: time for a rethink? Arch Dis Child Fetal Neonatal Ed 2013.
Cornblath M, Hawdon JM, Williams AF, et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics
01/05/2022 30 2000.
Aim of the study
• Aim of this RCT was to generate evidence for cut off threshold for management
by comparing 2 accepted threshold glucose values (as yet unsupported by
evidence) for treatment of asymptomatic moderate hypoglycemia (defined as
plasma glucose concentrations of 36 to 46 mg per deciliter [2.0 to 2.5 mmol per
liter]) in four high-risk subgroups of healthy newborns.

study design- multicenter, randomized, noninferiority trial involving 689 otherwise healthy
newborns
Settings: 17 academic and teaching hospital in Netherlands
Time period- October 2007 to April 2011
01/05/2022 31
PICO
• P(population)- Newborns at risk (Late preterm, SGA, LGA, IDM) with
plasma glucose less than 47 mg/dL, > 36mg/dL

• I (intervention)- To maintain plasma glucose above 36 mg/dL in lower

threshold group

• C (control)- Newborns at risk of hypoglycemia with plasma glucose

more than 47 mg/dL

• O (outcome)- Psychomotor development at 18 months measured by

Bailey-III-NL
01/05/2022 32
Trial Outcomes
Primary outcomes Secondary outcomes

• Psychomotor development at 18 1. Related to burden included the number

months, as measured by the Bayley of glucose measurements; treatment of

Scales of Infant and Toddler hypoglycemia with supplemental oral

Development, 3rd edition, Dutch feeding, tube feeding, or intravenous

glucose; and duration of breast-feeding.
version (Bayley-III-NL) -scores range
2. Related to efficacy included glucose
from 50 to 150 (mean [±SD], 100±15),
concentrations and episodes of
with higher scores indicating more
hypoglycemia after randomization.
advanced development and 7.5 points 3. Related to the use of health care
(one half the SD) representing a resources included the duration of
clinically important difference. hospital stay and health care costs
within 18 months after randomization.
01/05/2022 33
Result
Primary outcome

• Bayley-III-NL scores at 18 months of age were similar in the

lower-threshold and traditional threshold groups
• The prespecified inferiority limit of −7.5 points was not crossed

01/05/2022 34
Secondary outcomes

• Fewer glucose measurements were performed in the lower threshold group than in the
traditional-threshold group (mean difference of −0.7 measurements, or 9% less)
• Fewer newborns in the lower threshold group received treatments for hypoglycemia.
• The durations of hospital stay of the newborns and of their mothers were similar in the
two groups, as were health care costs.

The NNT to save 1 newborn from intravenous glucose administration was 7, to save 1 newborn
from tube feeding was 12, and to save 1 newborn from supplemental oral feeding was 5.

01/05/2022 35
 Lancet Child Adolesc Health 2021; 5: 265–73
Published Online February 9, 2021 https://doi.org/10.1016/ S2352-4642(20)30367-9

13 neonatal intensive care units in the UK, Spain, and the Netherlands

01/05/2022 36
Background
• Hyperglycaemia and hypoglycemia are common in preterm infants 
• Hyperglycemia
Persistent osmotic diuresis
Metabolic acidosis
IVH
ROP Poor neurodevelopmental
outcome
• Hypoglycemia
• Occipito-parieto-temporal regions

• Attempts to treat hyperglycemia often result in hypoglycemia

01/05/2022 37
Background

• Conventionally managed with infrequent, intermittent blood glucose

measurement

• Likelihood of missing clinically silent episodes of hyper/hypoglycemia

and fail to avoid extremes of blood glucose levels

• Periods of clinically silent hypoglycemia associated with impaired

developmental outcomes

01/05/2022 38
Background
• CGM
Could allow earlier detection and prevention of exposure to
extreme glucose concentrations in preterm
Real-time CGM has been used in adult and paediatric
intensive care units
Feasible in preterm infants

No RCTs of real time CGM monitoring in preterm babies

01/05/2022 39
 Research question

• Whether real-time CGM can help improve the management of glucose

control in preterm babies in terms of efficacy, safety and clinical
acceptability

Aim

• Evaluate efficacy, safety, utility and cost-effectiveness of real-time CGM

in preterm infants in NICU

01/05/2022 40
PICOT
• Population: <33+6 weeks, < 1200g, <24 hours of life
• Intervention: Real time CGM
• Comparison : Standard clinical protocol
• Outcome:
• Primary : Proportion of time sensor glucose concentrations remaining
in target range (2·6–10 mmol/L) (~46.8-180 mg/dL)
• Secondary : Efficacy, acceptability and safety of CGM
• Time period: up to 7 days of age

01/05/2022 41
 Trial outcomes
• The primary outcome is percentage of time SG in target range of 2.6–10mmol/L
(represents internationally, clinically most widely accepted target range )
• Secondary outcomes :
• Efficacy:
• Proportion of time sensor glucose concentrations within target range of 4–8 mmol/L
• Overall mean sensor glucose concentration
• Proportion of time that sensor glucose concentrations were in the severe
hyperglycaemic range (>15 mmol/L) (~270mg/dL)
• Safety :
• Incidence of hypoglycemia (any recorded blood glucose concentration of 2·2–2·6
mmol/L or any continuous episode of sensor glucose concentration of 1 h)
• Severe hypoglycemia (any recorded blood glucose ≤2·2 mmol/L) (~40mg/dL)
• Acceptability :
• Staff and parent questionnaire
• Prospective economic evaluation
01/05/2022 42
Primary outcome
• Proportion of time that sensor glucose concentrations were 2·6–10
mmol/L

Equivalent to an increase of 13 h (95% CI 5–21) within the target range during the first 6 days of
life
01/05/2022 46
Secondary outcome

Equivalent to 17 h

Did not differ

significantly
between the
two groups

01/05/2022 47
Conclusion

• Use of CGM allowed earlier detection of and prevention of exposure to the

extremes of both hypoglycemia and hyperglycemia in preterm infants

First Multicentric RCT evaluating efficacy and safety of CGMS in

preterm neonates

Long term outcome needs to be studied

01/05/2022 48
01/05/2022 49
 Background
•IN-SUR-E (INtubate- SURfactant- Extubate)- lower incidence of need for mechanical ventilation, air

leak syndromes and BPD (Cochrane 2007)

•But the reported failure rate of IN-SUR-E by various studies – in the range of 19% to 69%(VON- DRM
Trial 50%).
•Predictors of IN-SUR-E failure-
•Young gestational age or Birth weight
•Severe disease
•Hemodynamic instability
•De-recruitment

•Surfactant administration before recruitment -> Uneven surfactant distribution -> Reduced efficacy

01/05/2022 50
Aim
To study the safety and efficacy of IN-REC-SUR-E in comparison
with IN-SUR-E in terms of need for mechanical ventilation in first
72 hours of life in spontaneously breathing preterm infants

Study design
Multi-center randomized unblinded controlled trial.
November 2015 - September 2018
35 Neonatal intensive care units in Italy

01/05/2022 51
PICO
• Population- preterm 24+0 to 27+6 week of gestation ,breathing
spontaneously with only nasal CPAP support, and met nasal
CPAP failure criteria during first 24 hours of life.
• Intervention- recruitment before surfactant administration(IN-
REC-SUR-E)
• Comparison- no recruitment before surfactant
administration(IN-SUR-E)
• Outcome- the primary outcome was the need of mechanical
ventilation within first 72hrs of life

01/05/2022 52
Inclusion criteria
• Inborn with gestation of 24+0 to 27+6 weeks (and)
• Spontaneously breathing at birth but requiring respiratory
support (CPAP or O2) at 5 mins of life (and)
• Parental consent has been obtained (and)
• Failing CPAP during the first 24 hours of life.
• FiO2 > 30 % to maintain saturation 87-94% for 30 minutes or rapid
clinical deterioration
• Respiratory acidosis: pH <7.2 and pCO2 > 65 mmHg

01/05/2022 53
Trial Outcomes
Primary outcomes Secondary outcomes

Need for mechanical ventilation  Duration of nCPAP,

within first 72 hours of life. mechanical ventilation,
 Included neonates who oxygen therapy, hospital
could not be extubated stay
within 30 minutes of  Number of doses of
surfactant administration surfactant
 Re-intubated during first  Occurrence of BPD
72 hours of life  Mortality
01/05/2022 54
 Results
Primary and
secondary
outcomes
No statistical significant differences in
various secondary outcomes

conclusion
In this trial recruitment before surfactant administration decreased the need for
mechanical ventilation in first 72 hours of life compared with no recruitment.
01/05/2022 55
• Study design – Open Label multi-country RCT
• Study site – 7 sites (5 in India, 1 in Sri Lanka and Bangladesh each)
• Duration - August 15, 2015 to February 15, 2019

01/05/2022 56
Background

• Data from HICs suggest that death or disability is reduced at 18 months

with induced hypothermia for moderate/ severe neonatal encephalopathy

• The International Liaison Committee Resuscitation guidelines in 2015

recommended therapeutic hypothermia as the standard of care in LMICs
for neonatal encephalopathy (weak level of evidence)

01/05/2022 57
 Aim

To determine whether therapeutic hypothermia that is initiated

within 6 h of birth and continued for 72 h reduces death or
disability at 18–22 months when compared with usual care, in full-
term babies with moderate or severe neonatal encephalopathy who
have been admitted to tertiary neonatal units in LMICs

01/05/2022 58
 Inclusion Criteria
Neonates born 36 weeks, birthweight of 1·8 kg, admitted within 6 h of birth
with following two criteria:

1. Need for continued resuscitation at 5 min of age or an Apgar score < 6 at 5

min of age (for babies born in a hospital), or both, or an absence of crying by
5 min of age (for babies born at home); and

2. Evidence of moderate/severe encephalopathy at any time between 1 h and 6

h of age based on a structured clinical examination using modified Sarnat
staging done by a certified examiner after admission to the neonatal unit.

01/05/2022 59
 Primary outcomes

Death or a moderate/severe disability

• Severe disability:
 Cognitive composite score < 70 based on Bayley-III, Gross motor function
classification system level 3–5, Profound hearing impairment requiring
hearing aids or Cochlear implant, or Blindness
• Moderate Disability:
 Bayley-III score of 70–84 and one or more of the following: Gross motor
function classification system level 2, hearing impairment with no
amplification, or persistent seizure disorder between 18–22 months.
01/05/2022 60
Secondary outcomes (long
term) MRI Biomarkers
Secondary outcomes (long term)

• Brain injury scores on a

• Death from any cause at 18
months conventional MRI
• Severe disability among those • Thalamic N-acetyl aspartate
who survived
(NAA) concentration
• Microcephaly, assessed at 18–22 • Lactate:NAA, NAA:creatine,
months.
and NAA:choline peak area
ratios

01/05/2022 61
Primary and secondary outcome

01/05/2022 62
Conclusion

• TH with optimal neonatal intensive care couldn’t reduce the composite

outcome of death/moderate or severe disability, but resulted in increased
mortality irrespective of the place of delivery, perinatal sentinel events,
growth restriction, or coexistent sepsis

• Secondary outcomes were worse in the cooled infants like persistent

hypotension, metabolic acidosis, thrombocytopenia, prolonged blood
coagulation and gastric bleeding
01/05/2022 63
Limitations
• 80% infants in HELIX trial had a white matter injury, suggesting a
subacute or partial prolonged hypoxia, which might explain the
absence of hypothermic neuroprotection
• Basal ganglia injury, which is suggestive of an acute intrapartum
hypoxic event, was seen only in 25% of the HELIX trial infants
• Most infants in the HELIX trial had clinical seizures within a few
hours of birth, suggesting that an intrapartum hypoxic injury might
have occurred several hours before birth

01/05/2022 64
Randomized, non-blinded clinical trial conducted in the NICU of
Hospital Joan XXIII, Tarragona, in Spain, between January
2019 and March 2020

01/05/2022 65
Background
• In recent guidelines, early therapy with surfactant in RDS if patients
requires nCPAP of 6 cmH20 and an FiO2 over 0.3.
• This cut-off can be arbitrary, as current evidence is based on
observational studies - FiO2 requirements greater than 0.3 as a predictor
of respiratory failure and may not accurately reflect patient’s
oxygenation.
• It is challenging to identify newborns who will benefit from early
surfactant treatment (within the first 3 h of life), which is known to
decrease pneumothorax and BPD and to improve survival rates
01/05/2022 66
Aim of the study
To study if lung ultrasound allows an earlier surfactant therapy (within
the first 3 hours of life) compare to FiO2 and Chest X Ray

Inclusion criteria- Exclusion criteria-

 Premature newborns  Non-acceptance of the informed
under GA of 32 weeks consent
with RDS  Chromosomal abnormalities,
 Complex congenital malformations,
 Signs of early-onset septic shock
 Mechanical ventilation and who
received surfactant in the delivery
01/05/2022 room 67
PICO
• Population- Preterm < 32weeks with RDS (total 56 babies)
• Intervention- ultrasound group, administered surfactant based on LUS
score and/or FiO2 threshold,
• Control- control group, guided by FiO2 only
• Outomes- Primary- Earlier surfactant therapy (within the first 3hr of life)
• Secondary- levels of oxygen exposure in early life, SpO2/FiO2 ratio, need
for MV (during the first 3 days of life),duration of invasive and non-invasive
mechanical ventilation, ventilator-free days, Length of stay in the NICU and
BPD
01/05/2022 68
Protocol
algorithm

01/05/2022 69
 Pie graph
representing the
proportion of
patients who
received early
surfactant
therapy
(within the first 3
h of life) in each
group

01/05/2022 70
Result
• Surfactant administration occurred earlier in the ultrasound group
than in the control group, with statistically significant differences: 1
h of life (IQR 1–2) vs. 6 h (IQR 4– 6.5), with p < 0.001.
• Patients in the ultrasound group had better oxygenation after
surfactant therapy, with lower FiO2 requirements and a better S/F.

No differences were detected regarding respiratory support (days of

non-invasive and invasive mechanical ventilation, ventilator-free days
and duration of oxygen therapy) or frequency of BPD.

01/05/2022 71
Conclusion

• This study demonstrates that the use of LUS improves the

timeliness of surfactant administration without increasing the
number of patients requiring surfactant treatment

Surfactant therapy was required in 41.3% of patients in the

ultrasound group and in 62.9% of patients in the control group
(p = 0.106).

01/05/2022 72
 Thank you
01/05/2022 73