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The Intravenous Immunoglobulins: Current and Future Role in the NICU Could IVIG be neuro-protective?

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Title: The Intravenous Immunoglobulins: Current and Future Role in the NICU Could IVIG be neuro-protective?


1
The Intravenous Immunoglobulins Current and
Future Role in the NICU Could IVIG be
neuro-protective?
  • William Tarnow-Mordi
  • Professor of Neonatal Medicine
  • University of Sydney
  • Westmead Hospital and The Childrens Hospital at
    Westmead

2
OFF LABEL DISCLOSURE
  • William Tarnow-Mordi has documented that his
    presentation involves comments or discussion of
    unapproved or off-label, experimental or
    investigational use of
  • (a) polyclonal intravenous immunoglobulin (IVIG)
  • (b) Veronate (anti-staphylococcal
    immunoglobulin)

3
DISCLOSURE STATEMENT
  • Dr. William Tarnow-Mordi has documented that he
    has nothing else to disclose.

4
MISSION STATEMENT
  • The primary aim of clinical studies in the
    newborn is to identify interventions that
    increase disability-free survival, employing the
    most reliable evidence from RCTs.

5
  • OUTLINE

6
Current role of IVIG
  • (a) Immunomodulatory properties of IVIG
  • (b) Thrombocytopenia
  • (b) Haemolytic disease
  • (c) Infection

7
Future potential role of IVIG
  • Is IVIG neuro-protective in newborns with, or at
    risk of, infection?

8
Future role of IVIG
  • Do neonatal infections remote from the brain,
    including CONS, cause brain damage?
  • Are white matter damage and periventricular
    leukomalacia partly immune-mediated?

9
  • 3. Is multiple sclerosis (and its animal model) a
    model for PVL?
  • 4. Can IVIG promote re-myelination in multiple
    sclerosis and other CNS inflammatory states?
  • Can we do trials big enough to test reliably if
  • IVIG is neuro-protective in newborns with, or at
    risk of, infection?

10
Current role of IVIG
  • (a) Immunomodulatory properties of IVIG
  • (b) Thrombocytopenia
  • (b) Haemolytic disease
  • (c) Infection

11
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13
Pro-inflammatory
  • opsonic activity
  • fixation of complement
  • antibody dependent cytotoxicity
  • neutrophil chemiluminescence
  • phagocytosis
  • release of stored neutrophils

14
The phagocytes wont eat the microbes unless the
microbes are nicely buttered for them. Well, the
patient manufactures the butter himself alright,
but my discovery is that the manufacture of that
butter, which I call OPSONIN, goes in the system
by ups and down.There is at the bottom only one
genuinely scientific treatment for all diseases,
and that is to stimulate phagocytosis.
Dr RidgeonThe Doctors DilemmaG B Shaw
1909
15
Anti-inflammatory
  • Down-regulation of inflammatory cytokines via
  • Fc receptor blockade,
  • provision of anti-idiotype antibodies
  • interference with activation of
  • T-cells
  • B-cells
  • the cytokine network
  • complement
  • Immunomodulation of autoimmune and inflammatory
    diseases with intravenous immune globulin.
  • Kazatchkine MD,. et al. N Engl J Med 2001

16
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17
Current role of IVIG
  • (a) Immunomodulatory properties of IVIG
  • (b) Thrombocytopenia
  • (b) Haemolytic disease
  • (c) Infection

18
Neonatal alloimmune/ autoimmune thrombocytopenia
  • Incidence 1 per 1000
  • First reports of IVIG in 1980s
  • No RCTs

19
Immune-mediated thrombocytopenia (Idiopathic
thrombocytopenia - ITP)
  • Extremely rare in newborns
  • First reports of IVIG in 1981
  • Subsequently effective in RCTs
  • FDA approved

20
Current role of IVIG
  • (a) Immunomodulatory properties of IVIG
  • (b) Thrombocytopenia
  • (b) Haemolytic disease
  • (c) Infection

21
IVIG for Rhesus disease and ABO
incompatibilityTwo systematic reviews of the
same data
  • 1. Alcock GS, Liley H. Cochrane Review 2002
  • 2. Gottstein R, Cooke RW. Arch Dis Child Fetal
    Neonatal 2003
  • In 3 RCTs in 199 infants, IVIG led to
  • Fewer exchange transfusions
  • Relative Risk 0.28 (0.17 0.47)
  • Shorter phototherapy and hospital stay
  • No data on disability-free survival

22
Reduced need for exchange transfusion with IVIG
vs standard treatment for haemolytic jaundice
Number needed to treat 2.7 (95 CI 2.0 to 3.8).
23
Similar results differing conclusions
  • Alcock GS, Liley H. Cochrane Review 2002
  • Well designed studies are needed before routine
    use of IVIG can be recommended.
  • Gottstein R, Cooke RWI. Arch Dis Child Fetal
    Neonatal 2003
  • IVIG is an effective treatment.

24
Mechanisms of action of IVIG in ITP and
haemolytic jaundice
  • Similar mechanisms are postulated for effects of
    IVIG in both conditions.
  • They are incompletely understood.

25
Possible mechanisms of IVIG in ITP
Theory 1 IVIG (Fab portion fork end) binds
sensitised red cells. IVIG Fc portion (fork
handle) blocks the Fc receptor on macrophages
Macrophage
Fehr et al, 1982
26
Possible mechanisms of IVIG in ITP
Theory 2 IVIG upregulates inhibitory Fc?RIIB
receptors on macrophages. This inhibits
phagocytosis.
Fc?RIII or IIA
Plat
Macrophage
?
? Fc?RIIB expression
Samuelsson et al, 2001
27
Current role of IVIG
  • (a) Immunomodulatory properties of IVIG
  • (b) Thrombocytopenia
  • (b) Haemolytic disease
  • (c) Infection

28
(c) Infection
  • Therapeutic IVIG
  • Prophylactic polyclonal IVIG
  • Prophylactic hyper-immune IVIG (Veronate) to
    prevent staphylococcal infection

29
Therapeutic IVIG
  • Two Cochrane reviews
  • IVIG for treating sepsis and septic shock
  • Alejandria MM, Lansang MA, Dans LF, Mantaring
    JBV.
  • 2. Polyclonal IVIG for suspected or subsequently
    proven infection in neonates
  • Ohlsson A, Lacy JB.

30
1. IVIG for treating sepsis and septic shock
Alejandria MM, Lansang MA, Dans LF, Mantaring
JBV.
  • Polyclonal IVIG reduces mortality in all age
    groups combined
  • n492
  • Relative Risk 0.64 (0.64 0.80)
  • p 0.00009

31
1. IVIG for treating sepsis and septic shock
Alejandria MM, Lansang MA, Dans LF, Mantaring
JBV.
32
1. IVIG for treating sepsis and septic shock
Alejandria MM, Lansang MA, Dans LF, Mantaring
JBV.
  • No mortality reduction with anti-cytokine or
    monoclonal IVIG
  • Anti-cytokine IVIG (4 RCTs, n 4,318)
  • RR0.93 95 CI 0.86 to 1.01) NS
  • Monoclonal IVIG (5 RCTs, n 2,826)
  • RR0.97 (95 CI 0.88 to 1.07) NS

33
2. Polyclonal IVIG for suspected or subsequently
proven infection in neonatesOhlsson A, Lacy JB.
Cochrane Review 2004
  • mortality reduced in suspected infection, but
    with borderline statistical significance
  • n 318 Relative Risk 0.63 (95 CI 0.40 -
    1.00) p 0.05
  • mortality reduced in subsequently proved
    infection, but with wide confidence interval
  • n 262 Relative Risk 0.55 (95 CI 0.31, 0.98)
    p 0.04

34
2. Polyclonal IVIG for suspected or subsequently
proven infection in neonatesOhlsson A, Lacy JB.
Cochrane Review 2004
  • Insufficient evidence for routine
    IVIG.Well-designed trials to assess long term
    disability and cost effectiveness are needed.
  • One such trial is the International Neonatal
    Immunotherapy Study.

35
(c) Infection
  • Therapeutic IVIG
  • Prophylactic polyclonal IVIG
  • Prophylactic hyper-immune IVIG (Veronate) to
    prevent staphylococcal infection

36
Intravenous immunoglobulin for preventing
infection in preterm and/or low-birth-weight
infants
  • Ohlsson A, Lacy JB. Cochrane Review 2004.
  • 16 RCTs of IVIG versus placebo or no intervention
  • 5,000 infants lt 37 weeks gestation or lt2500 g
  • 3-4 reduction in sepsis or serious infection

37
Cumulative meta-analysis IVIG vs Placebo or No
Treatment
Relative Risk 0.82 (95 CI 0.74-0.92) Risk
Difference 0.04 (95 CI 0.02, 0.06)
38
Polyclonal IVIG prophylaxis
  • Reduces infection by 3-4
  • statistically significant
  • marginal clinical significance
  • No reductions in mortality, or
  • NEC, IVH
  • hospital stay
  • No short term serious side effects
  • Inconclusive on disability-free survival

39
Conclusions
  • No further RCTs of standard IVIG to prevent
    infections
  • Basic scientists and clinicians should pursue
    other avenues

40
(c) Infection
  • Therapeutic IVIG
  • Prophylactic polyclonal IVIG
  • Prophylactic hyper-immune IVIG (Veronate) to
    prevent staphylococcal infection

41
Veronatedata courtesy of Dr Seth Hetherington
  • Intravenous Immune globulin
  • Donors selected for high titers to
  • Clumping factor A S. aureus
  • Serine-aspartate repeat G protein S.
    epidermidis
  • Antibodies block attachment of bacteria to
    fibrinogen

42
Prophylactic hyperimmune anti-staphylococcal IVIG
(Veronate) 2017 infants Bwt 500- 1250 g
  • Blood Stream Infection           Control       
      Veronate n 989 n 994
  • Staph aureus      5                 
    6Probable CONS      16               
    15Definitive CONS   9                 
    11Any Infection 35 35 Mortality     
          7                  6

43
Veronate
  • No difference was statistically significant
  • Including these data may not alter the result of
    the meta-analysis of prophylactic trials
  • 3-4 reduction in sepsis with prophylactic IVIG
  • Too early for data on disability-free survival

44
Current use of IVIG in the NICU
  • Based on promising, but incomplete, evidence of
    effectiveness in
  • Thrombocytopenia
  • Haemolytic jaundice
  • Neonatal sepsis
  • with no evidence of its long-term effects.

45
Future role of IVIG
  • Do neonatal infections remote from the brain,
    including CONS, cause brain damage?
  • Are white matter damage and periventricular
    leukomalacia partly immune-mediated?

46
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47
Leviton, Gillies, Neff, Yaney 1976
  • White matter damage, or perinatal telencephalic
    leuco-encephalopathy (PTL), was more common after
    gram negative septicaemia.
  • It is hypothesized that endotoxin from
    bacteria adversely affects developing white
    matter

48
Stoll et al (JAMA) 2004
49
Stoll, Hansen, Adams-Chapman, Fanaroff, Hintz,
Vohr, Higgins, for the NICHD Neonatal Research
Network, JAMA 2004
  • 6093 infants lt 1000 g bwt assessed at 18 22
    months corrected for gestation

50
Neuro-developmental Impairment (NDI) in infected
versus uninfected infants
Category N () NDI (unadjusted) OR for NDI adjusted for 21 risk factors
uninfected 2161 (35) 29 -
Culture neg clinical infection 1538 (25) 43 1.3 (1.1-1.6)
Culture positive sepsis 1922 (32) 48 1.5 (1.2 1.7)
Sepsis and NEC 279 (5) 53 1.8 (1.4 2.5)
meningitis 193 (3) 48 1.6 (1.1 2.3)
51
Neuro-developmental impairment in infants with
different pathogens versus uninfected infants
Category N NDI (unadjusted) Adjusted OR for NDI relative to uninfected
uninfected 1976 29 -
CONS 853 44 1.3 (1.1 1.6)
Other Gm pos 256 48 1.7 (1.2 2.3)
Gram negative 185 45 1.8 (1.2 7.6)
Fungal 96 57 1.4 (0.9 2.2)
52
After adjustment for antenatal, perinatal and
postnatal factors
  • Neonatal infection, including CONS and
    culture-negative sepsis, was associated with
    increases of 30 80 in the odds of
  • poor head growth (lt 10th centile) at
  • 36 weeks
  • 18-22 months
  • neuro-developmental impairment at 18-22 months

53
  • CONS
  • although less clinically severe
  • may be associated with more disability than any
    other pathogen (n853)
  • Culture-negative clinical infection
  • potentially more important than CONS in its
    association with disability (n1538)

54
Association or causality? RCTs are needed to
prove cause and effect
  • Neonatal infection may
  • cause neuro-developmental impairment, or
  • share a common cause with NDI
  • If RCTs (e.g. of IVIG) in neonatal infection
  • show a reduction in disability
  • this would confirm infection as causal.

55
Association between cerebral palsy and
coagulase-negative staphylococci.Mittendorf et
al. Lancet 1999
  • Cultured amnion-chorion space in 107 preterm
    infants.
  • 35 grew no organisms. 28 grew CONS
  • CONS isolated in 4/5 (80) infants who later
    manifest CP vs 26/102 (25) who did not. (plt0.02)

56
Mittendorf et al. Lancet 1999
  • Small study, possible chance association
  • Consistent with hypotheses that
  • CONS may be causal in Cerebral Palsy
  • mediated by virulence factors such as
    haemolysins, deoxyribonuclease, slime and adhesins

57
Future role of IVIG
  • Do neonatal infections remote from the brain,
    including CONS, cause brain damage?
  • Are white matter damage and periventricular
    leukomalacia partly immune-mediated?

58
Zupan et al, 1996 Volpe, 1997,2001
  • Focal, cystic PVL
  • more severe, becoming less frequent
  • progressive loss of all cells in white matter.
  • Diffuse PVL
  • less severe, increasingly frequent
  • mainly affects developing oligodendrocytes

59
Nitrosative and oxidative injury to
premyelinating oligodendrocytes in PVLHaynes RL,
et al. J Neuropathol Exp Neurol 2003
  • Autopsied 17 PVL cases and 28 non-PVL controls.
  • Diffuse PVL involves injury to premyelinating
    oligodendrocytes through
  • activation of microglia
  • release of reactive oxygen and nitrogen species

60
Infection remote from the brain, neonatal white
matter damage, and cerebral palsy in the preterm
infant.Damman O, Leviton A. 1998
  • Remote infection could
  • lead to an inflammatory response that may be
    responsible for initiating and prolonging tissue
    injury
  • induce white matter damage by molecular
    mechanisms, especially cytokines.
  • .

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63
Fetal / neonatal cytokinemia and white cell
activation in WMD Duggan et al, Lancet 2001
  • 50 infants 23-29 weeks gestation cord blood
  • - for cytokines
  • - CD45RO T lymphocytes (to assess T cell
    activation)
  • Brain MRI done at median 2 days after birth
  • 18 (36) had cerebral lesions associated with
  • ? cytokines and activated T cells

64
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66
Duggan et al, Lancet 2001Immune cells might be
directly involved in injury
  • Activated CD45RO T lymphocytes express
  • activation, homing and adhesion molecules
  • migrate into tissues
  • induce apoptosis

67
Can a 500g baby mount an active inflammatory
response ?
68
YES, plasma TNF level gt 1000 pg/ml
69
The Toll-like receptor TLR4 is necessary for LPS
induced oligodendrocyte injury in the CNS
Lehnardt et al. J Neuroscience 2002
  • To exert its pathogenic effect, LPS requires
    TLR4, a receptor present on
  • circulating monocytes/ macrophages
  • other systemic immune cells
  • microglia in the CNS.

70
LPS (endotoxin) kills oligodendrocytes only when
microglia are present in culture
71
The Toll-Like Receptor TLR4 Is Necessary for
Lipopolysaccharide- induced Oligodendrocyte
Injury in CNS Lehnardt et al 2002
  • Provides a mechanism of action between
  • (1) LPS (and other microbial antigens)
  • ?
  • (2) induction of innate, non-specific immunity
  • ?
  • (2) injury to oligodendrocytes and myelin
  • (as in PVL and multiple sclerosis).

72
  • 3. Is multiple sclerosis (and its animal model) a
    model for PVL?
  • 4. Can IVIG promote re-myelination in multiple
    sclerosis and other CNS inflammatory states?
  • Can we do trials big enough to test reliably if
  • IVIG is neuro-protective in newborns with, or at
    risk of, infection?

73
Histological appearance of Multiple Sclerosis
  • Demyelination of nerve axons, mostly in white
    matter, with acute focal inflammatory changes.
  • Lesions include
  • axonal loss
  • spontaneous re-myelination
  • multifocal sclerotic plaques.

74
Spontaneous remyelination in Multiple Sclerosis
Perier O, Gregoire A. Brain 1965.
75
Premyelinating oligodendrocytes in chronic
lesions of multiple sclerosisChang et al NEJM
2002
  • Oligodendrocyte progenitor cells characterized
    in
  • developing brain
  • normal adult human brain
  • chronic lesions of multiple sclerosis.

76
Spinal cord axons in the healthy mouse
  • Normally myelinated axons.

77
Spinal cord axons after infection with Theilers
murine encephalo-myelitis virus (TMEV)
  • Extensive demyelination
  • Some spontaneous remyelination.
  • Macrophages/ microglia with ingested myelin
    debris (arrows).

78
Recruitment of T lymphocytes across Blood Brain
Barrier endothelium in MS and TME Virus
infectionEngelhardt J Neural Transmission 2006
79
  • 3. Is multiple sclerosis (and its animal model) a
    model for PVL?
  • 4. Can IVIG promote re-myelination in multiple
    sclerosis and other CNS inflammatory states?
  • Can we do trials big enough to test reliably if
  • IVIG is neuro-protective in newborns with, or at
    risk of, infection?

80
Remyelination by oligodendrocytes stimulated by
antiserum to spinal cord. Rodriguez, M. J
Neuropathol Exp Neurol. 1987
  • Produced anti-serum from mice immunized with
    homogenized spinal cord (SCH).
  • Anti-serum increased remyelination 10 fold in
    spinal cords after infection by TME virus.

81
Human monoclonal antibodies reactive
tooligodendrocytes promote remyelination in a
model of multiple sclerosisWarrington et al PNAS
2000
  • Experiments with human remyelination-promoting
    mAbs in mice using normal human IVIG (IgG) as
    control

82
Spinal cord axons in the healthy mouse
  • Normally myelinated axons not infected with
    TMEV.

83
Spinal cord axons after chronic infection with
Theilers murine encephalo-myelitis virus
  • Extensive demyelination
  • Some spontaneous remyelination.
  • Macrophages/ microglia with ingested myelin
    debris (arrows).

84
Partial remyelination after infection with TME
virus treatment with monoclonal IgM
  • Significantly greater remyelination after
    treatment with monoclonal IgM
  • Same magnification

85
Effect of IVIG on remyelination in mouse spinal
cord after TME Virus infection Warrington et al
PNAS 2000
Treatment Group Oligodendrocyte remyelination P value
Controls 6.7 -
After human IVIG IgG 14.2 lt0.05
After Human IgM mAB 23.2 lt0.001
86
Human monoclonal antibodies reactive
tooligodendrocytes promote remyelination in a
model of multiple sclerosisWarrington et al PNAS
2000
  • OL remyelination in mice was increased
  • twofold with human IgG
  • fourfold with human IgM.

87
Human monoclonal antibodies reactive
tooligodendrocytes promote remyelination in a
model of multiple sclerosisWarrington et al PNAS
2000
  • Human remyelination-promoting mAbs
  • may be a simple, effective therapy.
  • can be produced free of infectious agents
  • may alleviate the high cost of IVIg.
  • may simplify investigation of mechanisms of
    immunomodulatory therapies.

88
Anti-apoptotic signaling by a remyelination-promot
ing human antimyelin antibodyHowe CL Neurobiol
Dis 2004
  • In mice with TMEV, a recombinant hman monoclonal
    anti-myelin antibody
  • induced anti-apoptotic signaling in
    premyelinating oligodendrocytes and
  • reduced caspase-3 activation and caspase gene
    expression

89
Anti-apoptotic signaling by a remyelination-promot
ing human antimyelin antibody Howe CL,
Neurobiology of Disease 2004
  • Polyreactive autoantibodies that trigger repair
    within demyelinated lesions marked an important
    shift in our understanding of the role of
    antibodies in the CNS.
  • Recombinant monoclonal human IgM autoantibody
    rescued a pre-myelinating oligodendrocyte cell
    line from death induced by either hydrogen
    peroxide or TNF-a.

90
Anti-apoptotic signaling by a remyelination-promot
ing human antimyelin antibody Howe CL,
Neurobiology of Disease 2004
  • One mechanism by which IVIG may promote
    remyelination in CNS inflammatory conditions is
    by
  • binding oligodendrocyte progenitors and
  • preventing them from undergoing death induced by
    H2O2 of TNFa.

91
CD54 lymphocytes expressing ICAM-1 in blood from
patients before and after IVIG Créange et al. J
Neuroimmunol 2003
92
Cytokine expression by CSF monocytes in patients
with Post Polio Syndrome after IVIG.Gonzalez J
Neuroimmunol 2004
  • ? TNF-a (p lt 0.05)
  • ? IFN-? (p lt 0.001)

93
  • Is clinical evidence consistent with in vitro and
    in vivo laboratory evidence?

94
Cochrane Reviews of IVIG in neurological
inflammatory conditions
Condition No. of patients Effect
Multiple sclerosis 168 ? relapses (by 38-74)
Guillain Barre syndrome 75 speeds recovery
Multifocal neuropathy 34 ? strength
Myasthenia Gravis 60 inconclusive
Chronic demyelinating inflammatory polyneuropathy 170 ? disability
95
IVIG for the treatment of relapsing-remitting
multiple sclerosis a meta analysis.Sorensen PS,
Fazekas F, Lee M. Eur J Neurol 2002
96
Achiron et al Arch Neurol 2004
97
Achiron et al Arch Neurol 2004
  • Placebo controlled RCT of IVIG vs saline
  • within 6 weeks of first signs of MS in 91
    patients
  • 36 lower probability of developing clinically
    definite multiple sclerosis
  • Risk ratio, 0.36
  • 95 CI 0.15- 0.88
  • p 0.03.

98
Achiron et al Arch Neurol 2004
  • The IVIG group had fewer MRI lesions at 12
    months
  • reduced volume T2-weighted (P 0.01)
  • fewer T2 weighted (P 0.01) of
  • reduced volume of gadolinium enhancing lesions
    (P0.03) .

99
Achiron et al Arch Neurol 2004
  • Future studies evaluating the combined effects
    of
  • IVIG
  • interferons
  • glatiramer acetate
  • may offer additional benefit on the occurrence
    of second attack.

100
  • These studies suggest that, in animals and adult
    humans, IVIG can reduce cerebral inflammation and
    ameliorate pre-existing cerebral lesions.

101
  • 3. Is multiple sclerosis a model for PVL?
  • 4. Can IVIG promote re-myelination in multiple
    sclerosis and other CNS inflammatory states?
  • Can we do trials big enough to test reliably if
  • IVIG is neuro-protective in newborns with, or at
    risk of, infection?

102
An ideal RCT to test if IVIG increases
disability-free survival should
  • randomise neonates to prophylactic, repeated IVIG
    or placebo.
  • be large enough to detect realistically moderate
    differences with adequate power
  • include long term follow up of
  • neuro-developmental and cognitive outcomes.

103
International Neonatal Immunotherapy Study, INIS
  • Google npeu inis
  • www.npeu.ox.ac.uk/INIS.htm
  • (downloadable copy of this talk will be
    available)

104
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105
International Neonatal Immunotherapy Study, INIS
  • A randomised placebo controlled trial of IVIG in
    proven or suspected neonatal sepsis
  • Revised sample size 4,000
  • to yield 90 power to detect a 5 risk difference
    in death or major disability

106
International Neonatal Immunotherapy Study, INIS
  • 2 doses of 500 mg/ kg (total dose of 1 g/kg )
  • as an adjunct to antibiotic treatment
  • It does not therefore fulfil all the criteria
    for an ideal test of these hypotheses.

107
However,
  • Two multi-centre trials that provided more
    sustained doses of IVIG, for 2 weeks of more,
    have already been done, in a total of over 4,000
    patients.

108
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109
  • 2416 infants lt 72 hr after birth
  • stratified according to birth weight
  • (501-1000 g and 1001-1500 g)
  • randomly assigned to fortnightly
  • prophylactic IVIG (n 1204) or
  • control (n 1212).

110
  • Prophylactic IVIG failed to reduce the incidence
    of hospital-acquired infections.
  • These were 208 (17.3) in the IVIG group and 231
    (19.1) in the control group
  • (Relative Risk, 0.91 95 percent confidence
    interval, 0.77 to 1.08).

111
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113
Prophylactic hyperimmune anti-staphylococcal IVIG
(Veronate) 2017 infants Bwt 500- 1250 g
  • Blood Stream Infection           Control       
      Veronate n 989 n 994
  • Staph aureus      5                 
    6Probable CONS      16               
    15Definitive CONS   9                 
    11Any Infection 35 35 Mortality     
          7                  6

114
Speculation
  • It would be valuable to determine the rates of
    neuro-developmental impairment in these
    randomised cohort, or subsets within them
  • To test the hypothesis that sustained IVIG
    therapy is (a) safe, (b) neuro-protective in
    neonates at risk of sepsis.

115
Conclusions
  • Modulation of inflammation is a relatively new
    strategy for preventing or treating neurological
    injury.
  • New evidence is needed to evaluate IVIG as a
    non-steroidal anti-inflammatory agent that may
    reduce neonatal mortality and morbidity.

116
Sir Richard Doll and Sir Richard Peto
117
Sir Richard Doll Controlled trials the
1948 watershed BMJ 1998 317 1217-20
  • Early randomised trials (1940s) can properly be
    criticised on the grounds that they were often
    too small to have any chance of detecting
    moderate effects.
  • Small trials can be successful when the effect
    is large but this seldom occurs.

118
  • Only in the 1980s did it become possible to
    organise the groundbreaking international study
    of infarct survival (ISIS) trials
  • in tens of thousands of patients, which showed
    the value of moderate improvements in the
    treatment of common diseases.

119
The ISIS 1 Trial
  • Atenolol infusion vs placebo after heart attack
  • 16,000 patients recruited
  • Showed a 2 mortality reduction- from 13 to 11

120
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121
The ISIS 2 Trial
  • Aspirin vs placebo after heart attack
  • 17,000 patients recruited
  • Showed a 23 mortality reduction- from c. 11 to
    8.

122
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123
  • The Goddess of Chance is a capricious mistress.
    Yet, with large enough numbers, she becomes our
    obedient servant yielding up the truth.
  • Anon.

124
Sample sizes to show moderate or large
differences in disability-free survival with 90
power at 2p 0.05
Adverse outcome in controls C Adverse outcome in treated group T Absolute risk difference C-T Total sample needed (both groups combined) Number needed to treat (NNT) to prevent one case
42 40 2 20, 712 50
42 39 3 9, 168 33
42 38 4 5,134 25
42 37 5 3,270 20
42 32 10 800 10
125
  • If newborns are to benefit from evidence as
    reliable as in cardiology,
  • much larger numbers are needed
  • i.e. thousands, not hundreds

126
A challenge
  • Judged by whether sufficient evidence exists to
    exclude moderate benefits or harms, most current
    perinatal treatments remain inadequately
    evaluated.

127
A solution
  • Samples of thousands, not hundreds, where the
    research question merits it
  • Multicentre, international collaboration
  • Prospective meta-analysis
  • Simple, inexpensive modes of follow up

128
Prospective meta-analysis
  • Multiple trials with same design hypotheses
  • Pledged to combine their results in a single,
    individual patient based meta-analysis
  • New trials and hypotheses can be added before any
    results are known
  • Avoids publication bias, data driven hypotheses
  • Combines the methodological advantages of a
    single trial with pragmatic benefits of flexible
    funding arrangements and recognition needs of
    different national agencies

129
International neonatal oxygen trials NeoProm
prospective meta-analysisco-ordinator Lisa Askie
  • Australia 1200 NHMRC
  • NZ - 300 HRC
  • UK - 1200 MRC
  • Canada - 1200 - CHIR
  • US - 1500 NICHD US POST
  • US - 1300 - NICHD SUPPORT
  • Already funded. Possible total gt 6,000

130
Acknowledgments
  •  PanelistsCarol J. Baker, Baylor College of
    Medicine, Houston, TXBarbara J. Stoll, Emory
    University School of Medicine, Atlanta,
    GALeonard E. Weisman,   Baylor College of
    Medicine, Houston, TX

131
Further acknowledgments
  • Alan Leviton, Arne Ohlsson, Olaf Damman, Peter
    Brocklehurst, Khalid Haque, David Isaacs, Wendy
    Hague, John Simes, Barbara Farrell, Priya
    Duggal-Beri, Ann Cust, David Henderson-Smart, Ben
    Stenson, David Edwards, Ryszard Lauterbach, Seth
    Hetherington, Amy Morris, Iain Chalmers, The
    Cochrane Collaboration and the hundreds of
    parents, babies, nursing and medical staff in
    over 100 hospitals worldwide who are contributing
    to the International Neonatal Immunotherapy Study
    (INIS) of polyclonal IVIG.

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133
William Silverman (Fumer) 1917-2004
  • Taught his students and friends
  • to consider the long term consequences of
    neonatal care, for patients and families
  • to cultivate a habit of lifelong (un) learning
  • semper plangere (always complain) - and look
    for better evidence
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