Patterns of Preterm Brain Injury Strategies for perinatal neuroprotection steroids, Magsulf, Antibiotics Antenatal strategies Postnatal strategies Emerging therapies

1. PRETERM BRAIN
PROTECTION
STRATEGIES
Dr Mukul Mangla
Consultant
Neonatology

2. OVERVIEW
 Patterns of Preterm Brain Injury
 Strategies for perinatal neuroprotection
Antenatal strategies
Postnatal strategies
Emerging therapies

3. Preterm births constitute 12%
of live births (Blencowe et al
2012); VLBWs constitute 1.5%
of live births (Kochanek et al
2012 )
Premature birth  negative
impact on structural and
functional integrity of the brain

4.  Dysmaturational events
 Disruption of myelination
 Axonal growth
 Activity-dependent cortical
development
Long-lasting effects of very
preterm birth on brain structure
in adulthood: A systematic
review and meta-analysis.
Neuroscience and Biobehavioral
Reviews 147 (2023)

5. Magnitude of Brain injury in pre-term infants
Percentage of premature births 12%
Incidence of IVH (Fanaroff et al) 10-25%
Grade III and IV IVH 3-10%
IVH in infants 501-750 gm 25-50%
WMI and global neuronal and axonal deficit 50%
Morbidity in survivors
Spasticity/motor deficits 10%
Cognitive/behavioral deficits 25-50%
Cerebral palsy(Larroche et al) 10-20%

6. Neurodevelopmental outcome
Minor developmental impairment in preterm
children
30-40%
Major disability(Allen et al) 20%
IQ <2 SD for Gr IV IVH 100%
IQ <2 SD for Gr III IVH 60%
IQ<2 SD for Gr I and II IVH 40%
Follow up of newborns with BW<1000 gm at 8 year age
Special class room assistance >50%
Special education course 20%
Repeated at least one school grade 15%

7. ANTENATAL STRATEGIES

8. ANTENATAL STEROID

9. WHAT DO WE KNOW ABOUT ANS?
Antenatal corticosteroids were an accidental discovery while
studying preterm labor in Lambs in New Zealand

10. Antenatal Corticosteroids:
Mechanism
Single most effective antenatal pharmacological intervention
Mechanism of beneficial effects:
1. Improved cardiovascular stability, less need for blood
pressure support, decrease in placental vascular resistance
2. Stimulation of maturation of brain structures eg germinal
matrix (suppresses VEGF and elevates TGF levels, which
results in angiogenic inhibition, trimming of neovasculature,
and enhanced pericyte coverage)
3. Enhances fibronectin level by 1.5-2-fold
4. Anti-inflammatory effects

11. Antenatal steroid
 Perinatal death (RR) 0.85, 95% CI 0.77 to 0.93)
 Neonatal death (RR 0.78, 95% CI 0.70 to 0.87)
 RDS (RR 0.71, 95% CI 0.65 to 0.78)
 Intraventricular hemorrhage (Reduced odds of IVH)
 Necrotising enterocolitis/BPD/PDA/ROP – Beneficial
but no significant difference
Cochrane Database Syst Rev. 2020
Lancet 2023

12. Antenatal steroid
Maternal Outcomes: Little or no difference
 Maternal Death RR 1.19 (0.36 – 3.89)
 Chorioamnionitis RR (0.86 0.69 – 1.08)
 Endometritis RR1.14 (0.82 – 1.58)

13. ANS and CP
A single course of ANS associated with
 Reduced risk for cerebral palsy (RR 0.67, 95% CI 0.56–
0.81)
 Psychomotor development index less than 70 (RR
0.82, 95% CI 0.73–0.93)
 Severe disability (RR 0.78, 95% CI 0.72–0.85).
 Intact survival (RR 1.186, 95% CI 1.056–1.332).
Sotiriadis A .Obstet Gynecol 2015;125:1385–96

14. 2 Preparations available

15. What is celestone?
beta (acetate + phosphate)
Recent (2007 and 2009) data in sheep suggests that there may be some advantage to this
approach, with a combination of both formulations outperforming either formulation alone.
Am J Obstet Gynecol. 2007 ; 197(5): 523.e1–523.e6

16. BETA VS DEXA(COCHRANE)
Brownfoot et al. Different corticosteroids and regimens for accelerating fetal lung
maturation for women at risk of preterm birth Cochrane 2008; updated 2013
It remains unclear whether one corticosteroid has advantages over
another
Dexa
 Less IVH
 Shorter duration of NICU stay

17. Current recommendation
NIH consensus statement 1994
 Standard of care for threatened preterm birth is a single
course of antenatal steroids, either, two doses of 12mg of
betamethasone intramuscularly 24 hours apart or 4 doses of
6mg of dexamethasone intramuscularly 12 hours apart
administered to the mother with threatened preterm labor at 24
to 34 weeks of gestation
 Maximum benefits are seen if the fetus is delivered 24 hours
after and within 7 days of the last dose. Because the beneficial
effects wane off after 7 days

18. Repeat doses of prenatal corticosteroids
for women at risk of preterm birth
11 trials (4895 women and 5975 babies)
Risk of preterm birth seven or more days after an initial course of
prenatal corticosteroids with repeat dose(s) of corticosteroids,
compared with no repeat corticosteroid treatment
RDS (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.74 to 0.90)
Serious infant outcomes were probably reduced with repeat dose(s) of
corticosteroids (RR 0.88, 95% CI 0.80 to 0.97)
Severe lung disease (RR 0.83, 95% CI 0.72 to 0.97)
Severe intraventricular hemorrhage (RR 1.13, 95% CI 0.69 to 1.86)
Necrotising enterocolitis (RR 0.84, 95% CI 0.59 to 1.22; 5736 babies).
 Little or no effect on the likelihood of a cesarean birth (RR 1.03, 95%
CI 0.98 to 1.09)
 Maternal sepsis (RR 1.13, 95% CI 0.93 to 1.39)

19. The American College of Obstetrics and Gynecology
Committee on obstetric practice produced a committee opinion
statement in 2017, reaffirmed in 2020, that the use of repeat
doses of prenatal corticosteroids in the context of threatened
preterm birth should be considered for women with a
pregnancy of less than 34 weeks' gestation for whom their last
course of prenatal corticosteroids was 14 or more days prior (
ACOG 2017).

20. MAGNESIUM SULPHATE

21. Mechanism of action
Non-competitive antagonist of
the NMDA receptor
Blocking excess glutamate
release, reducing excitotoxicity
and consequently
oligodendroglial progenitor cell
death
Modulating the effects of
proinflammatory cytokines
Vasoactive properties:
Stabilisation of blood pressure
and cerebral arterial perfusion
Prevent neuronal cell death

22. •Five trials (6145 babies)
•Significant reduction in risk of cerebral palsy in their child (relative risk
(RR) 0.68; 95% CI 0.54 to 0.87)
•Significant reduction in the rate of substantial gross motor dysfunction
(RR 0.61; 95% CI 0.44 to 0.85)
•No statistically significant effect on paediatric mortality or on other
neurological impairments or disabilities in the first few years of life.
•No significant effects on combined rates of mortality with cerebral
palsy

23. Major trials of magnesium sulphate
Study Gestation Dose Key findings
MagNET
2002
<34 weeks 4 g loading 37% (11/30) had an adverse event
compared to 21% (6/29) of those
that received placebo
ACTOMgSO4
2003
<30 weeks 4 g load, then 1
g/h upto 24 h
Cerebral palsy alone: RR 0.83,
95% CI 0.64 to 1.09
PREMAG
2007
<33 weeks 4 g bolus only Death and gross motor dysfunction:
OR 0.62, 0.41 to 0.93; death,
cerebral palsy, and cognitive
dysfunction: 0.68, 0.47 to 1.00;
cerebral palsy alone: 0.63, 0.35 to
1.15
BEAM 2008 <32 weeks 6 g bolus, then 2
g/h for 12h with
retreatment
Moderate-severe cerebral palsy: RR
0.55, 0.32 to 0.95

24. Guidelines on the use of magnesium
sulfate for neuroprotection
Recommendati
ons
Gestational
age
Dosing Comments
FIGO <30 weeks
given and 32-
34 week
consider
4 g bolus then
1 g/h
for up to 24 h
Dosing to resemble current clinical
practice for
seizure prophylaxis
RCOG green
top No.73
<30 weeks 4 g bolus then
1 g/h
for up to 24 h
Endorsed Australian guideline
ANCP <30 weeks 4 g bolus then
1 g/h
for up to 24 h
Limit to <30 weeks because resources
are limited and
the effect greatest during this period
ACOG Not specified Not specified Development of a neuroprotection
protocol based on
one of the large trials is
recommended

25. PPROM AND
CHORIOAMNIONITIS

26. Chorioamnionitis and cerebral palsy: a meta-
analysis
15 studies; clinical or histological chorioamnionitis
Significant associations between clinical
chorioamnionitis or histological chorioamnionitis and
cerebral palsy
Shatrov JG et al Obstet Gynecol. 2010 Aug;116(2 Pt 1):387-92
Odds ratio Risk of cerebral
palsy
Clinical
Chorioamnionitis
2.42 (1.52-3.84) 140%
Histological
chorioamnionitis
1.83 (1.17-2.89) 80%

27. Antibiotic for PPROM
22 trials, involving 6872 women and babies
Use of antibiotics following PROM is associated with
reductions in
 Chorioamnionitis (RR) 0.66, 95% (CI) 0.46 to 0.96
 Neonatal infection (RR 0.67, 95% CI 0.52 to 0.85),
 Use of surfactant (RR 0.83, 95% CI 0.72 to 0.96),
 Oxygen therapy (RR 0.88, 95% CI 0.81 to 0.96)
 Abnormal cerebral ultrasound scan prior to discharge from hospital
(RR 0.81, 95% CI 0.68 to 0.98).
Erythromycin is recommended by RCOG
Third generation cephalosporins improve survival
(EPIPAGE – 2 France)
Kenyon S, Boulvain M, Neilson JP. Cochrane Database Syst Rev 2013;(12):CD001058

28. POSTNATAL
INTERVENTIONS

29. Delayed cord clamping (DCC)
Fifteen studies (738 infants) ,24-36 weeks gestation
Delaying cord clamping was associated with
 Fewer infants requiring transfusions for anemia (risk ratio
(RR) 0.61, 95% (CI) 0.46 to 0.81),
 Less intraventricular hemorrhage (RR 0.59, 95% CI 0.41 to
0.85) and
 Lower risk for necrotising enterocolitis ( RR 0.62, 95% CI
0.43 to 0.90)
Rabe H, Diaz-Rossello JL, Duley L, et al
Cochrane Database Syst Rev 2012;(8): CD003248

30. Delayed cord clamping
Increased blood volume and oxygenation
Prevention of iron deficiency anemia
Transfer of stem and progenitor cells with extensive
proliferative capacity  contributes to repairing tissues and
promoting immunocompetence

31. Caffeine for apnea of prematurity
Most commonly used treatment for primary apnea in preterm
Reducing the frequency of apnea
Intermittent hypoxemia
Extubation failure in mechanically ventilated preterm infants.
CAP Trial: Barbara Schmidt
2006 infants with birth weights of 500 to 1250 g during the
first 10 days of life to receive either caffeine or placebo, until
drug therapy for apnea of prematurity was no longer needed.
Caffeine therapy for apnea of prematurity reduces the rate of
bronchopulmonary dysplasia, severe retinopathy of
prematurity, and survival without disability at 18-21 months.

32. Caffeine for Apnea of prematurity
 Reduced incidence of cerebral palsy at 12–22 months (4.4% vs.
7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87)
 Cognitive delay at 18–22 months (33.8% vs. 38.3%; adjusted odds
ratio, 0.81; 95% CI, 0.66 to 0.99)
At 5 years of age
Combined outcome of death or disability was not significantly
different (21.1% vs 24.8%; odds ratio adjusted for center, 0.82; 95%
CI, 0.65-1.03)
Cognitive impairment was lower at 5 years similar in the 2 groups
(4.9% vs 5.1%; odds ratio adjusted for center, 0.97; 95% CI, 0.61-
1.55; P = .89)

33. Volume-targeted ventilation
18 RCT, all infants <37 weeks of gestation, birth wt ≤2.5kg
receiving artificial ventilation
Compared VTV vs PLV(pressure limited ventilation)
In VTV (volume targeted group)
Lower incidence of BPD at 36weeks of PMA in VTV treatment group(RR
0.61 (95% CI 0.46 to 0.82)
Lower incidence of grade 3/4 IVH (RR 0.55 (95% CI 0.39 to 0.79)
Lower incidence of PVL (RR 0.33 (95% CI 0.15 to 0.72)
Fewer episodes of hypocarbia (RR 0.56 (95% CI 0.33 to 0.96)
Peng WS, Zhu HW, Shi H, et al. Arch Dis Child Fetal Neonatal Ed 2014;99: F158–F165

34. IVH BUNDLE
 A clinical care bundle to reduce the risk of intraventricular hemorrhage
(IVH) in all preterm babies ≤28 weeks gestation
IVH: a significant complication of preterm birth (Volpe 2008). Strongly
associated with adverse neurodevelopmental and survival outcomes
Pathogenesis: linked to fragility of cerebral vasculature and fluctuations
in cerebral blood flow
First 72 hours highest risk of developing GMH-IVH in preterm infants
(Volpe 2008, Perlman 1986)
Keeping head in the midline Decrease fluctuations in cerebral blood flow
Optimise cerebral venous drainage (De Bijl-Marcus 2017)
head rotation in either side may lead to complete occlusion or
obstruction of the jugular venous-drainage system of the same side
(Cowan 1985)
Maintaining an elevated head position (Kochan2019)

38. Preventing infection
Acute
morbidity
Neurodevelopmental outcome Risk adjustment
Sepsis CP (all types—5 years) EOS—OR 1.7 (0.84–3.45) *
LOS—OR 1.71 (1.14–2.56)*
EOS+LOS—OR 2.33 (1.02–
5.33)*
Sepsis (meta-
analysis)
CP/NDI (at 18-60 month ) OR 2.09; 95%CI 1.78 to 2.45
Candida
infection
NDI at 18 months (Bayley III) OR 1.83, 95% CI 1.01-3.33**
NEC Neurological impairment (18–22 months)
both surgical NEC spontaneous intestinal
perforation
AOR—1.7 95%CI(1.2, 2.4)#
Diparetic CP at 24 months (after surgical
NEC +bacteraemia) vs Medical NEC
OR—8.4 (95% CI 1.9–39)
microcephaly OR = 9.3( 95% CI
2.2, 40) ##
*Mitha A, Foix-L’Helias L, Arnaud C, et al. Pediatrics 2013;132: E372–80
#Wadhawan R, Oh W, Hintz SR, et al. J Perinatol 2014;34:64–70
**Chapman A. J Pediatr 2013 Oct;163(4):961-7e3

39. CLABSI Prevention
Standardised care ‘bundles’
 Use of catheter checklists or “bundles”, VAP Bundle
 Hand hygiene*, sterile barrier precaution (decrease in CLABSI)
 Disinfect hubs, needleless connectors, injection ports prior to CVC use
 Remove nonessential CVCs
 Asepsis during handling CVC, sterile CVC
 Educational interventions/Specialized CVC insertion teams
Antibiotic stewardship
Prophylactic fluconazole** - decreases incidence of invasive
fungal infection (RR) 0.43, 95% (CI) 0.31 to 0.59
O'Grady NP Guidelines for prevention of intravascular catheter-related infections. Am J Infect
Control. 2011 May;39(4 Suppl 1):S1-34
*Barrera L .Am J Infect Control. 2011 Oct;39(8):633-9
**Cochrane Database Syst Rev. 2015 Oct 24

40. VAP BUNDLE
Azab et al et enrolled 143 mechanically ventilated neonates, 73
patients developed VAP (51%) throughout the study period (2500
mechanical ventilation days)
VAP bundle
Rate of VAP was significantly reduced from 67.8% (42/62to 38.2%
(31/81) (RR 0.565, 95% CI 0.4-0.7
Trend toward reduction in NICU length of stay (23.9 ± 10.3 versus
22.8 ± 9.6 days, p = 0.56) and overall mortality (25% versus 17.3%,
p = 0.215)
Azab, Seham F. A. et al. BMC Infectious Diseases 15 (2015): 314.
VAP Bundle
Head-of-bed elevation 300
-450
.
Re-enforcement of hand hygiene practice.
Sterile suction and handling of respiratory equipment.
Intubation, re-intubation and endotracheal tube (ETT) suction as
strictly indicated by unit protocol (document).
Change ventilator circuit if visibly soiled or mechanically
malfunctioning (document)
Proper timed mouth care with normal saline and suction of oro-
pharyngeal secretion.
Daily evaluation for readiness for extubation to nasal continuous
airway pressure (NCPAP)
at morning round, and sedation vacation for sedated patient.

41. BREAST MILK
Vohr et al found that ELBW babies who were exclusively breast fed
had more IQ by 5 points
Early enteral nutrition with breast milk is associated with better wt
gain, less infection, and NEC as compared to formula feed
Manea et al A Singapore Med J 2016 Nov;57(11):616-618
Exclusive formula feeding of very low birth weight infants (<1500gm)
was associated with increased risks of NEC (OR 12.6) and ROP (OR
1.80) when compared to EBM feeding
Spiegler J et al.J Pediatr. 2016 Feb;169:76-80.e4

42. EARLY TPN
Aggressive nutrition in ELBW babies during 1st
week of life associated
with better neurodevelopmental outcomes at 18 months of life
(increase of 8.2 MDI points for each 1 g/kg/day protein and 4.6 MDI
points for each 10 kcal/kg/day)
Stephens BE et al Pediatrics. 2009;123:1337
151 neonates( < 1200 gm) and gave SCAMP - Standardized,
Concentrated With Added Macronutrients Parenteral (SCAMP)
nutrition regimen nutrition to intervention group (n=76) (SCAMP 12%
glucose, 3.8 g/kg per day protein/lipid) while other received control
regimen (10% glucose, 2.8 g/kg per day protein/lipid)
SCAMP group had significantly greater means (95% confidence
interval) for ΔHC was 5 mm (2 to 8) at 28 days and 36 weeks PMA
Morgan et al Pediatrics 2014 Jan;133(1):e120-8

43. EARLY PN
8 RCTs, 13 observational studies
Early PN reduced the time to regain birth weight by 2.2 d (1.1, 3.2
d) for RCTs and 3.2 d (2.0, 4.4 d) in observational studies.
The maximum percentage weight loss with early PN was lower by
3.1 percentage points (1.7, 4.5 percentage points) for RCTs and
by 3.5 percentage points (2.6, 4.3 percentage points) for
observational studies.
Early PN improved weight at discharge or 36 wk postmenstrual
age by 14.9 g (5.3, 24.5 g) (observational studies only)
Moyses HE. Am J Clin Nutr. 2013 Apr;97(4):816-26

44. Development supportive care
Pain
protection
Protected
sleep
Activities of
daily living
Family
centered
care
Healing
environment

45. Long-term effect of early
intervention
Significantly better right hemisphere and frontal lobe function in the
experimental group
McAnulty G et al.BMC Pediatr. 2013 Feb 19;13:25
Kleberg et al found that intervention group had significant
difference in hearing and communication at 3 year of age
Kleberg et al.Early Human Development 60 (2000) 123 135
Early intervention programmes for preterm infants have a positive
influence on cognitive and motor outcomes during infancy, with
cognitive benefits persisting into preschool age
Spittle A et al. Cochrane Database of Systematic Reviews 2015,

46. KMC
At discharge or 40 to 41 weeks' PMA age
Reduction in the risk of mortality (risk ratio [RR] 0.60, 95% [CI] 0.39
to 0.92;
Nosocomial infection/sepsis (RR 0.35, 95% CI 0.22 to 0.54
 Hypothermia (RR 0.28, 95% CI 0.16 to 0.49
Increase weight gain (mean difference 4.1 g/d, 95% CI 2.3 to
5.9,length gain (MD 0.21 cm/week, 95% CI 0.03 to 0.38head
circumference gain (MD 0.14 cm/week, 95% CI 0.06 to 0.22
Exclusive breastfeeding at one to three months' follow-up (RR 1.20,
95% CI 1.01 to 1.43
Cochrane database

47. EMERGING THERAPIES

48. MAIN TARGETS FOR NEUROPROTECTION

49. MELATONIN

50. MELATONIN: MECHANISM OF ACTION
Melatonin protects the damaged developing brain by preventing abnormal
myelination and an inflammatory glial reaction, a major cause of white matter
injury

51. Melatonin as a Therapy for Preterm Brain Injury: What Is
the Evidence? Antioxidants 2023

52. STEM CELL THERAPY

53. STEM CELL-BASED INTERVENTIONS FOR THE PREVENTION
AND TREATMENT OF INTRAVENTRICULAR HEMORRHAGE
AND ENCEPHALOPATHY OF PREMATURITY IN PRETERM
INFANTS
No evidence is currently available to evaluate the benefits and
harms of stem cell-based interventions
Three ongoing studies, with a sample size range from 20 to 200.
In two studies, autologous cord blood mononuclear cells will be
administered to extremely preterm infants via the intravenous
route; in one, intracerebroventricular injection of MSCs will be
administered to preterm infants up to 34 weeks' gestational age.