Perinatal Infection, Inflammatory Responses

1
Perinatal Infection, Inflammatory Responses
Neurologic Sequelae
Olaf Dammann Hannover Medical School,
Germany Childrens Hospital, Boston, USA
2
Intrauterine Infection
Goldenberg et al, NEJM 2000
Chorioamnionitis
Fetal Inflammatory Response
Prematurity
Neurologic Sequelae
3
Perinatal inflammatory responses
Dammann Leviton, Early Hum Dev, 2004

• Maternal
• Chorioamnionitis
• Fetal / Neonatal
• Fetal vasculitis
• chorionic plate chorionic vasculitis
• umbilical cord funisitis
• Fetal / Neonatal cytokinemia
• Fetal neuroinflammatory response
• Fetal cell activation
• Systemic white cells
• Local (umbilical cord) endothelial cells
• Local (brain) astrocytes, microglia

4
Neurological sequelae

• Neonatal
• Brain white matter damage (US and/or MRI-defined)
• Gray matter reduction
• Longterm
• Motor limitations (e.g., Cerebral Palsy)
• Mental / Cognitive limitations
• Learning difficulty

5
Preterm birth and cerebral palsy is tumor
necrosis factor the missing link?
Prostaglandins
Preterm Birth
Low Gestational Age
Tumor Necrosis Factor
Cerebral Palsy
Intrauterine Infection
Periventricular Leukomalacia
Endotoxin
Leviton, Dev Med Child Neurol, 1993
Jun35(6)553-8
6
Increased risk of spastic diplegia among very low
birthweight children after preterm labor or
prelabor rupture of membranes

• Regional cohort, Hamburg, Germany
• N 312, six-year-old, lt1500g
• Spastic diplegia (N 29)
• N283 controls

Dammann et al, J Pediatr. 1998132531-5.
7
Increased risk of spastic diplegia among very low
birthweight children after preterm labor or
prelabor rupture of membranes

• In preterm onset of labor (POOL) or prelabor
  rupture of membranes (PROM) 12 diplegia
• In pregnancy-induced hypertension or other
  medical indications for preterm delivery 4
  diplegia
• 83 of diplegia born after POOL or PROM

Dammann et al, J Pediatr. 1998132531-5.
8
Increased risk of spastic diplegia among very low
birthweight children after preterm labor or
prelabor rupture of membranes

• Threefold increased risk of diplegia (OR 3.2,
  1.2-8.5)
• Risk ratio remained elevated after controlling
  for perinatal and neonatal variables (odds ratio
  2.4 to 2.7) in logistic regression models
• We speculate that this might be related to
  infectious processes leading to both POOL / PROM
  and diplegia

Dammann et al, J Pediatr. 1998132531-5.
9
Maternal fever at birth and non-verbal
intelligence at age 9 years in preterm infants.

• Regional cohort, N 294 infants, lt1500 g
  birthweight and lt37 completed weeks of gestation,
  age 9 years
• 47 children had a non-verbal Kaufman Assessment
  Battery for Children (K-ABC) scale standard value
  below 70, i.e. more than 2 SDs below the
  age-adjusted mean
• 247 children with a score gt or 70 served as
  controls

Dammann et al, Dev Med Child Neurol
200345148-51
10
Maternal fever at birth and non-verbal
intelligence at age 9 years in preterm infants.

• Maternal fever at birth in five cases (11) and
  eight controls (3)
• Odds ratio 3.6, 1.1-11.4
• Adjusting for potential confounders (gestational
  age, maternal education and nationality, and CP)
  left the risk estimate for maternal fever
  unchanged (3.8, 0.97-14.6)

Dammann et al, Dev Med Child Neurol 2003
45148-51
11
Intrauterine infection
Goldenberg et al, NEJM 2000
12
Congenital Toxoplasmosis
Congenital (fetal) infections

• TORCHES CLAP
• Toxoplasma gondii
• Rubella virus
• Cytomegalovirus
• Herpes simplex virus
• Enteroviruses
• Syphilis
• Chickenpox (Varicella)
• Lyme disease
• AIDS
• Parvovirus B19

Imaging
Histology
Pseudocyst containing tachyzoites
Sakaie Gonzalez, NeuroAIDS Vol.2, (7), 1999
Cand.med. Fábio Bombarda, Faculdade de Medicina 
de Marília, Brazil.
13
Remote infection no bugs in the brain!
Dammann Leviton, Semin Pediatr Neurol
19985190-201
Goldenberg et al, NEJM 2000
14
1. Intrauterine Infection, Preterm Delivery, and
Neurologic Sequelae
15
Prematurity and White Matter Damage
Larroque et al, J Pediatr 2003 143477-83
16
Prematurity and Cerebral Palsy
Western Sweden CP registry, 1991-94 (N241) and
1995-98 (N170) Gestational age 1991-94 1995-98 lt
28 wks 8.6 7.7 28-31 wks 6.0
4.0 32-36 wks 0.6 0.7 gt 36 wks 0.13
0.11
Hagberg et al, Acta Paediatr 2001 90271-7
Himmelmann et al, Acta Paediatr 2005 94287-94
17
Conclusion 1

• Intrauterine infection is associated with preterm
  birth
• Preterm birth is associated with neurologic
  sequelae

18
2. Chorioamnionitis A Maternal Inflammatory
Response
19
Histologic chorioamnionitis A Maternal
Inflammatory Response
a. Acute subchorionitis
b. Acute chorionitis
c. Acute chorioamnionitis
d. Necrotizing chorioamnionitis
e. Severe acute chorioamnionitis
e. Chronic (subacute) chorioamnionitis
Redline et al, Pediatr Dev Pathol 20036435-48
20
Histologic Chorioamnionitis and WMD / CP
cPVL 3 studies RR 1.6 (1.0 - 2.5) CP 8
studies RR 1.5 (0.9-2.5)
Wu Y, Ment Ret Dev Disabil Res Rev 2002132531-5
21
Conclusion 2

• A maternal inflammatory response
  (chorioamnionitis) is associated with neurologic
  sequelae

22
3. Umbilical vasculitis A Fetal Inflammatory
Response
23
Umbilical vasculitis
Neurological cOR 3.0 (0.9-11)1 impairment aOR
5.6 (1.2 - 25)2 Echolucency aOR 11 (1.04 - 114)3
1Redline et al., Arch Pathol Lab Med 1998
1221091-8 2Yoon et al, Am J Obstet Gynecol 2000
182675-81 3 Leviton et al., Pediatr Res 1999
46566-575
24
Cytokines in fetal/neonatal brain, circulation,
amniotic fluid and brain damage
25
Fetal / neonatal cytokinemia and white cell
activation in WMD
Duggan et al, Lancet 20013581699-1700
26
Interleukin-10 High Producer Allele and Reduced
Risk for Neonatal Disorders A Pilot Study

• We used PCR to identify a single nucleotide
  polymorphism (SNP) IL-10 (-1082 G/A) in whole
  blood from 73 children 2 yrs of age whose
  gestational age at birth had been lt32 wks.
• Infants homozygous for the high IL-10 producer
  -1082G allele (n 15) were less likely to
  develop WMD (odds ratio 0.2, 95 C.I. 0.03-0.8).
• No child with two G-alleles developed CP compared
  to 6/58 with only one or no G-allele.

Doerdelmann et al, PAS, 2005
27
Conclusion 3

• A fetal inflammatory response (fetal vasculitis,
  fetal/neonatal cytokine expression, fetal white
  cell activation) is associated with neurologic
  sequelae even more strongly than chorioamnionitis

28
4. White Matter Damage A fetal / neonatal
neuroinflammatory response ?
Human leukocyte antigen II
CD68
CD45
TNF-?
IL-1?
Kadhim et al, Neurology 2001561278-84
29
Dammann Leviton, Pediatr Res 1997421-8
Cytokines
Uterus
Fetal Circulation
?
?
Brain
Microglia
IVH
?
?
?
White Matter Damage
30
i.p. LPS d18/19
Cai et al., Pediatr Res 20004764-72
Uterus
Fetal Circulation
Brain
IL-1? TNF-?
GFAP ?
MBP ?
no macroscopic White Matter Damage
31
Do White Cells Matter in White Matter Damage?
Dammann et al., TINS 200124 320-4
32
Low-Dose i.v. endotoxin in fetal sheep,
blood-brain barrier permeability, and white
cells in white matter
Albumin immunoreactivity in white matter
LPS
Ctrl.
Macrophages and Monocytes in white matter
LPS
Ctrl.
Yan et al., Pediatr Res 200455855-863
33
Cerebral inflammatory response in focal, but not
in diffuse intrauterine infection-mediated brain
lesions
25 focal cystic white matter damage

• New Zealand White Rabbits
• Inoculation with E. coli at GD24-30
• Ceftriaxone at 24h
• C-section at 12/24/48h PI
• Controls saline C-section at 48h PI

HES
100 diffuse apoptotic cell death
Rabbit macrophage AB
E.coli
Ctrl.
iNOS
Debillon et al., Dev Brain Res 200314539-48
34
Epilogue 1
35
Epilogue 2
36
Sensitization
Epilogue 3
4 hrs
Eklind et al, Eur J Neurosci 2001131101-6
24 hrs / 50 min HI
72 hrs / 50 min HI
Eklind et al, Pediatr Res 200558112-16
37
Main Conclusions? Fetal Inflammatory response
is a stronger risk factor than Chorioamnionitis
? Fetal / Neonatal neuroinflammatory response
deserves consideration? Multi-hit studies are
crucially needed in epidemiologic research and in
the lab
38
Hamburg
1990-1995
F.J. Schulte, Norbert Veelken
Boston
Since 1995
Alan Leviton, Elizabeth N. Allred
Hannover
Since 2002
Christiane Dammann, Dorothee B. Bartels, Marjan
Moennig