what have we learned from the elgan study? - pediatrix · what have we learned from the elgan...

What Have We Learned From The ELGAN Study?

The ELGAN Study Investigators

Neonatology Update February 23, 2014

• The speaker, Michael O’Shea, MD, no financial relationships to disclose or Conflicts of Interest to resolve. Any real or apparent conflicts of interest related to the content of this presentation have been resolved.

• This presentation will not involve discussion of unapproved or off-label, experimental or investigational use of a drug.

Outline – ELGAN Study

• Background • Methods • Primary results

– Perinatal inflammation and brain dysfunctions – Antecedents and correlates of perinatal

inflammation – “Two hit” model of brain damage

• Future directions • Possible clinical implications

Infection and Perinatal Brain Damage

Chorioamnionitis associated with increased risk of cerebral palsy Sepsis associated with increased risk of neurodevelopmental impairment in extremely low birth weight infants Inflammation-related proteins (eg., TNF-α) are elevated in chorioamnionitis and sepsis Inflammation-related proteins are elevated in children who subsequently develop cerebral palsy

Shatrov JG et al. Obstet Gynecol 2010; 116:387-392; Stoll BJ et al. JAMA. 2004;292:2357-2365; Romero et al. AJOG 1992; 166:1576-87; Nelson KB et al. Ann Neurol 1998; 44:665-675

Systemic Inflammation

White Matter Damage

Perinatal Infection

Neurologic Disabilities

Chemokines Cytokines

Adhesion Molecules

Growth factors; anti-inflammatory

cytokines; hormones

Objective: to evaluate the hypothesis that perinatal inflammation contributes to structural and functional brain disorders in Elgans

ELGAN (extremely low gestational age newborn) Study

METHODS

Study Design

• Multi-site longitudinal cohort (14 U.S. hospitals) • Gestational age < 28 weeks • Enrollment: April 2002 – August 2004

Exposure measures • Inflammation-associated biomarkers • Infection-associated biomarkers

Outcomes • Neonatal: WMD on head ultrasound scans

Perinatal infection / inflammation

WMD on HUS

2-year outcomes

Adverse biomarker

profile

10-year outcomes

The ELGAN Study

• 2 years: Bayley scales (MDI & PDI), CP, microcephaly, autism risk (MCHAT) • 10 years: neurological, cognitive & behavioral deficits, neuroimaging, autism & ASD

RESULTS

* The precise number of women approached is not available, but is estimated to be 260 more than the number enrolled.

Gestational age (weeks)

Percent

23 9

24 19

25 21

26 23

27 28

Onderdonk et al. AJOG 2008; 198:e1-e7

Onderdonk et al. AJOG 2008; 198:e1-e7

Demographics Percent or Mean (range)

Age in years 28 (13-47)

Race White 55 Black 32 Asian 3 Native American 1 Mixed 4 Other 7 Hispanic 13

Medicaid eligible 44

% with IVH among those with and without WML

020

4060

80P

erce

nt w

ith in

trave

ntric

ular

hem

orrh

age

23-24 wks 25-26 wks 27 wksGestational age (weeks)

with WMLwithout WML

ELGAN Investigators

O’Shea et al. J Child Neurology 2012

Findings

Exposures White matter injury on US

Micro-cephaly

Cerebral Palsy

Maternal infections

Placental micro-organisms Placental histology

Neonatal sepsis/NEC Neonatal blood proteins

+ - +/-

+ + +

+ +/- + +/- + +

+ + +

Results Exposures Attention problem Very low MDI

Maternal infections

Placental micro-organisms Placental histology

Neonatal sepsis/NEC Neonatal blood proteins

- - + -

- -

+/- +

+ +

Persistent /Recurrent Inflammation

Leviton A et al. Cytokines 2011; 53:66-73

Gestation age (weeks)

protein 23-24 25-26 27

IL-1β 72 (0, 463) 48 (0, 234) 37 (0, 218)

IL-6 28 (6, 698) 23 (5, 21) 16 (5, 153)

TNF-α 69 (11, 240) 54 (17, 180) 42 (11, 126)

IL-8 51 (12, 265) 40 (12, 171) 28 (9, 101)

CRP 11 (1, 243) 8 (1, 225) 6 (1, 119)

Developmental Regulation of Inflammation: Median levels (10-90th percentiles) on day 1

Possible Initiators of Inflammation Maternal pre-pregnancy overweight or obesity (among infants born to mothers with preeclampsia or for fetal indications)

Van der Burg et al. Early Hum Develop 2013; 89:249-255

Possible Initiators of Inflammation • Maternal pre-pregnancy obesity (among those

born to mothers with preeclampsia or for fetal indications)

• Pregnancy disorders associated with spontaneous indications for delivery (PPROM, PTL, abruption, cervical insufficiency)

McElrath TF et al. AJOG 2011; 418.e1-12




• Fetal growth restriction




• Fetal growth restriction • Intra-uterine microorganisms

Organisms and Neonatal Inflammation

• Bacterial vaginosis-associated species (G. vaginalis, P. bivia, anaerobic Streptococcus, and Peptostreptococcus) associated with elevations of cytokines, adhesion molecules, CRP, SAA, MPO

• Placenta-derived Lactobacillus associated with lower likelihood of neonatal inflammation Fichorova RN et al. mBio 2(1):e00280-10. doi:10.1128/mBio.00280-10

Hecht J et al. Pediatr Res 2010; 69:68-73

Placenta Findings and Neonatal Inflammation




• Fetal growth restriction • Intra-uterine microorganisms/placental

inflammation • Neonatal infections (sepsis; NEC)

Neonatal infections and inflammation

• Early bacteremia associated primarily with elevations of inflammation-related proteins in first week

• Late bacteremia associated primarily with elevations of inflammation-related proteins on days 7 and/or 14

Leviton A et al. Acta Paediatr 2011; 101:355-359

Martin CR et al. Fetal and Pediatric Pathology 2012




• Fetal growth restriction • Intra-uterine microorganisms/placental

inflammation • Neonatal infections (sepsis; NEC) • Mech. ventilation and blood gas abnormalities

Low pH High CO2 Low CO2

Do Inflammation-related Protein Levels Provide Additional Risk Information

beyond Neonatal Illnesses?

O’Shea TM et al. Brain, Behavioral, and Immunity 2013.

Fetal Growth Restriction

Bose CB et al. Pediatrics 2009

Fetal Growth Restriction and Risk of Chronic Lung Disease

Patterns of Early Respiratory Function among ELGANs

FiO2 on

group days 3-7 day 14

Low FiO2 always < 0.23 ≤ 0.25

Pulmonary deterioration

< 0.23 on 1+days > 0.25

Early and persistent dysfunction

≥ 0.23 on all days > 0.25

Laughon M et al. Pediatrics 2009;123(4):1124-31.

Risk factor Multivariate Odds ratio*

BW Z score < -1 27 SNAP ≥ 30 3.3 Mechanical ventilation 1.5 Surfactant 0.2 Analgesics in weeks 2-4 3.4 Pulmonary interstitial emphysema 17

Risk Factors for Chronic Lung Disease Among Infants with Low FiO2 in the First 14 Days

*Adjusted for all risk factors listed Abbreviations: BW – birth weight; SNAP – Score for Acute Neonatal Physiology

Laughon M I et al. Pediatrics 2009;123(4):1124-31.

outcome Odds ratio* males females

MDI < 70 1.4 2.6 PDI < 70 2.6 3.2 Head circum. Z score < -2 5.0 3.2

Birth weight < 10th percentile for GA and the Risk of Adverse Outcome at 24 months

*Adjusted for gestational age, multi-fetal gestation, preeclampsia, fetal indication for delivery, and route of delivery Abbreviations: GA- gestational age; MDI – Mental Development Index; PDI – Psycho- motor development Index

Stremish IG et al. Early Human Development 2012; 88: 765-771

IUGR sensitizes immature brain to postnatal inflammation

• Small for gestational age used as indicator of fetal growth restriction

• Postnatal inflammation defined as a concentration of an inflammation-related protein in the top quartile that persisted or recurred in the first 2 weeks

Leviton A et al. Peds Res 2013; 73:362-370

Elevated protein in blood (upper quartile)

SGA

Lee JW et al. J Maternal Fetal Neonatal Med 2013.

Risk Factors for ROP as a Function of Initiator of Preterm Delivery

ELGAN Study: What have we learned?

• Perinatal inflammation is associated with brain structural and functional abnormalities later in life

• Associations stronger with recurrent/persistent inflammation than single-day inflammation

• Prenatal growth restriction appears to sensitize the fetal brain and retina to subsequent inflammation-related damage

ELGAN Study: What have we learned?

• Developmental regulation of inflammation-related proteins

• Antecedents/correlates of perinatal inflammation include: – Microorganisms in the placenta – Placental/umbilical inflammation – Early and late bacteremia – Intestinal injury – Mechanical ventilation and blood gas extremes

Future Directions – ELGAN-2

Evaluate the hypothesis that perinatal inflammation is associated at age 10 years with:

• Cognitive impairment • Epilepsy • Attention deficit • Autism spectrum disorders • Altered brain structure, assessed with MRI

Possible Implications for Prevention

• Neonatal factors that can initiate an inflammatory response already are targets for prevention: • Mechanical ventilation and blood gas

abnormalities • Sepsis • NEC and isolated intestinal perforation • Intraventricular hemorrhage

Possible Implications for Prevention

• Prenatal factors influence neonatal inflammatory responses

• Can these prenatal factors be modified to decrease inflammation and improve neonatal outcome? • Pre-pregnancy maternal obesity • Fetal growth restriction • Inflammation related to intra-uterine microbes

Interventions to Modulate Inflammation

• Therapeutic hypothermia • Glucocorticoids and indomethacin • Probiotics • Melatonin (Imperial College; ClinicalTrials.gov

identifier: NCT00649961) • N-acetyl cysteine (Yale; NCT00397735) • Stem cell therapy • Erythropoietin

↓ Inflammation ↓ Neuronal apoptosis ↓ Oligodendrocyte injury ↓ Oxidative injury ↓ Nitric oxide toxicity ↓ Glutamate toxicity ↑ Iron utilization

↑ BDNF ↑ Neurogenesis ↑ Oligodendrogenesis ↑ Glial cell proliferation ↑ Angiogenesis

Protective Growth Factor

Reviewed in: McPherson and Juul, Int J Dev Neurosci 26 (1), 103 (2008).

Non-hematopoietic Effects of Epo

Preterm Epo Neuroprotection Trial (PENUT Trial)

A randomized, placebo-controlled, 940-subject, phase-III clinical trial of

erythropoietin for the neuroprotection of extremely low gestational age neonates

(ELGANs)

Acknowledgements

• Principal Investigator for ELGAN-1: Alan Leviton, Children’s Hospital, Boston, MA

• Principal Investigator for ELGAN-2: Karl Kuban, Boston Medical Center, Boston, MA

• NINDS Program Scientist: Deborah Hirtz • 1249 participating families

Robert Dillard, Medical Director Ann Smith, NNP David Lambert, NNP Gina Lambert, NNP Corey Seidel, NNP Tiffany Martin, NNP

Thank you

Melatonin Augments Hypothermia Neuroprotection in Perinatal Asphyxia Model

• Reduced markers of proton magnetic resonance spectroscopy indicators of ischemic injury

• Reduced indicators of apoptosis in the thalamus, internal capsule, putamen and caudate

• Reduced cytoxic microglial activation in the cortex

Robertson NJ et al. Brain 2013: 136; 90–105

Robertson NJ et al. Brain 2013: 136; 90–105

Melatonin Augments Hypothermia Neuroprotection in Perinatal Asphyxia Model

• Melatonin-augmented hypothermia significantly reduced the hypoxic–ischaemic-induced increase in the

• area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in

• the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain 31P magnetic resonance spectroscopy

• nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive

• nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal

• capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia

• were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was

• decreased in the cortex at 48 h after hypoxia–ischaemia.

Multivariate odds ratio Outcome Oxygen at

36 wks Ventilator at 36 wks

MDI < 55 1.1 1.2 quadriplegia 1.6 5.7 diplegia 2.1 4.2 hemiplegia 2.7 1.2

Chronic Lung Disease and Developmental Outcome

Abbreviations: MDI – Mental Development Index

Laughon M et al. 2009; 124:637-648; Van Marter LJ et al. Arch Dis Child Fetal Neonatal Ed 2011 96: F20-F29

Hypoxia-Ischemia and Brain Dysfunctions in ELGANs

• Measures: – Score for Acute Neonatal Physiology (SNAP) – Low blood pressure – Blood gas extremes

• What do these assess: – Immaturity (paucity of endogenous protectors)? – Respiratory illness severity? – Hypoperfusion? – Inflammation?

Association of SNAP in highest decile for gestational age with indicators of brain injury

outcome MDI < 55 ventriculomegaly 2.3 echolucency 1.6 MDI < 55 2.0 PDI < 55 1.8

Dammann O et al. Neonatology 2010; 97:71-82

Data are odds ratios adjusted for gestational age

Abbreviations: SNAP – Score for Acute Neonatal Physiology; MDI – Mental Development Index; PDI – Psychomotor Development Index

Blood Pressure Variables

• Low blood pressure: – Mean blood pressure in lowest quartile for

gestational age – Mean blood pressure lower than gestational age

• Labile blood pressure: Highest quartile for quantity (highest mean arterial pressure minus lowest arterial pressure)

• Vasopressor: dopamine or dobutamine

Logan W et al. J Perinatology 2011; 31:524-534; Logan W et al. Arch Dis Child Fetal Neonatal Ed 2011; 96:F321-328

0

10

20

30

40

MDI < 70 PDI < 70 CP

BP lowBP normal

% o

f chi

ldre

n

Blood Pressure in Lowest Quartile for GA and Developmental Delay in ELGANs

05

101520253035


BP lowBP normal

% o

f chi

ldre

n

Labile Blood Pressure and Developmental Delay in ELGANs


0

10

20

30

40


vasopressorno vasopressor

% o

f chi

ldre

n

Vasopressor Treatment and Developmental Delay in ELGANs


Blood Gas Extremes

• First 3 postnatal days: – Lowest pH – Highest and lowest PaO2

– Highest and lowest PaCO2

• Extreme values: lowest or highest quintile

Leviton A et al (manuscript under review)

Blood gas quartile → Lowest PO2 (mm Hg)

Postnatal day → 1 2 3

Gestational age (wks) ↓

23-24 36 40 41

25-26 39 42 42

27 38 42 43


Blood Gas Extremes for ELGAN Cohort

Blood gas quartile → Highest PO2 (mm Hg)



23-24 175 105 113

25-26 164 108 107

27 159 98 102



Blood gas quartile → Lowest PCO2 (mm Hg)



23-24 25 30 32

25-26 27 33 33

27 26 33 34



Blood gas quartile → Highest PCO2 (mm Hg)



23-24 69 72 67

25-26 63 68 62

27 60 59 58



Blood gas quartile → Lowest pH



23-24 7.12 7.11 7.13

25-26 7.17 7.15 7.16

27 7.20 7.20 7.20



Blood Gas Extremes and the Relative Risk of Cranial Ultrasound Lesions (ORs*)

Ultrasound Abnormality Blood gas extreme Ventriculomegaly Echolucency Lowest PaO2 1.9 1.1 Highest PaO2 1.2 1.0 Lowest PaCO2 0.9 0.5 Highest PaCO2 2.5 1.4 Lowest pH 2.7 1.9

Leviton A et al. (manuscript under review)

*Odds ratios adjusted for gestational age; conception assistance, maternal fever during pregnancy, NSAID use during pregnancy, birth weight Z-score < -1, delivery for preeclampsia or fetal indications, recovery of Mycoplasma from the placenta and thrombosis of fetal stem vessels in the placenta

Blood Gas Extremes and the Relative Risk of Cerebral Palsy (ORs*)

Cerebral palsy Blood gas extreme Quadriplegia Diplegia hemiplegia Lowest PaO2 2.3 1.2 1.5 Highest PaO2 1.1 1.7 0.7 Lowest PaCO2 1.1 1.2 2.8 Highest PaCO2 1.6 0.7 5.9 Lowest pH 1.3 1.8 4.7



Blood Gas Extremes and the Relative Risk of Adverse Developmental Outcomes (ORs*)

Adverse developmental outcome Blood gas extreme MDI < 70 PDI < 70 Microcephaly Lowest PaO2 1.6 1.5 1.3 Highest PaO2 0.9 1.0 1.0 Lowest PaCO2 1.2 1.0 1.9 Highest PaCO2 1.7 1.7 1.8 Lowest pH 1.4 1.3 1.4



Cerebral Palsy is a Group of Disorders

ELGAN Algorithm for Diagnosis and Classification of Cerebral Palsy

• Algorithm to derive cerebral palsy diagnoses from individual neurological exam items

• Empiric evidence that epidemiology differs across cerebral palsy subtypes

• Classification of ultrasound findings

ELGAN Algorithm for Diagnosis and Classification of Cerebral Palsy

Kuban KCK et al J Pediatr 2008; 153:466-472

Co-occurrence of Cerebral Palsy and other developmental impairments (data are column

percents)

Quadriplegia (n=64)

Diplegia N=37)

Hemiplegia (n=19)

none

GMFCS ≥ 2 76 8 11 0.3

MDI < 70 72 34 58 22

PDI < 70 93 62 63 25

M-CHAT + 76 30 44 18

microcephaly 42 8 21 8

Kuban KCK et al. J Pediatr 2008; 153:466-472

Risk Factors for and Cerebral Palsy Diagnoses

Risk factors Cerebral palsy subtype quadriplegia diplegia Hemiplegia

> 1 micro-organisms in placenta

2 5 1

Data are adjusted odds ratios Kuban KCK et al. J Child Neurol 2009; Van Marter LJ et al. ADC-FN edition 2010




2 5 1

Echolucency 24 5 29 Ventriculomegly 17 6 17





2 5 1

Echolucency 24 5 29 Ventriculomegly 17 6 17 Severe BPD 6 4 1





2 5 1

Echolucency 24 5 29 Ventriculomegly 17 6 17 Severe BPD 6 4 1 >3 inflammation proteins elevated

2 3 4

Data are adjusted odds ratios

Kuban KCK et al. J Child Neurol 2009; Van Marter LJ et al. ADC-FN edition 2010; Kuban KCK et al. J Child Neurol 2013

what have we learned from the elgan study? - pediatrix · what have we learned from the elgan...

Documents