Transcript Maternal Obesity - Specializzazione Pediatria

The Role of Antenatal Factors
on Neonatal Outcome
Jonathan M. Davis, MD
Vice-Chair of Pediatrics, Chief of Newborn Medicine
Floating Hospital for Children/Tufts Medical Center
Professor of Pediatrics
Tufts University School of Medicine
Boston, MA
Chair, Child Health Oversight Committee, NIH
Chair, Neonatal Advisory Committee, FDA
No relevant financial
relationships to disclose
Outpatient deck, 1906
Obesity in the US – A Major Public Health Problem
1999
1990
2009
No Data
6
<10%
10%–14
15%–19%
CDC database
20%–24%
25%–29%
≥30%
Obesity and Inflammation
Obesity is associated with marked
inflammation and immune
dysregulation
Adipocytes undergo necrosis,
promoting inflammation and
macrophage recruitment
Higher circulating levels of TNF-α,
IL-6, MCP-1, and TGF-β
Obesity in Pregnancy – Harmful to Mother and Infant
Obesity
↑CRP
↑IL-6, IL-8
↑TNFα
↑leptin,
↑adiponectin
↑macrophages
Pregnancy
↑CRP
↑macrophages
↑neutrophils
↑IL-10
↑Inflammation
Disease
Maternal Dis
Pre-eclampsia
Gestational DM
Dysfunctional Labor
Lifetime Disease Risk
Hypertension
DM
Hyperlipidemia
MI
Neonatal Dis
Low Apgars
NICU admission
Macrosomia
Prematurity
Child/Adult Disease
Obesity
DM
Metabolic Syndrome
Schmatz et al, J Perinatology, 2010.
Obesity in Pregnancy is Associated with
Increased Infections
Heslehurt et al. Obesity Reviews, 2008.
Obesity in Pregnancy
• Increased risks of antenatal, intrapartum, and
neonatal complications
• 2-5 X increased risk of:
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Diabetes
Pre-eclampsia
Induction of labor, emergency C-section
Intrapartum & postpartum hemorrhage
Chorioamnionitis
Macrosomic infants, lower Apgars, NICU admissions
Intrauterine death
Results: 1981-2005
• 219,173 pregnant women over 25 year
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•
period
Mean maternal weight increased
linearly → 139 lbs in 1981 to 161 lbs in
2005, or 22 pounds
For 27 year old mothers only, mean
weights increased 25 pounds in 25
years
Results
Medians (interquartile ranges); Kruskal-Wallis ANOVA test
Results
Major Risk Factors for Prematurity
by Multivariate Analysis
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PROM
Obesity
Pre-existing diabetes
Pre-eclampsia/hypertension
Previous preterm/SGA infant
In vitro fertilization
Obesity in Pregnancy Changes Immune Cell
Populations
Cell Populations
Obese
(n=15)
Lean
(n=15)
p value
CD4+ (%
lymphocytes)
45.8+9.4
44.3+12.7
ns
CD8+ (%
lymphocytes)
16.4+5.8
23.5+7.4
<0.05
NKT cells
22.9+6.1
27.9+4.1
<0.05
B cells
21.9+6.2
13.3+5.3
<0.05
Maternal Obesity Impairs Cytokine Production
TNF alpha
response to
to stimulation
TNFα
response
stimulation
*
geometric mean (MFU)
800
*
700
600
500
Lean
400
Obese
300
*
200
100
0
CD8+ cells
CD4+ cells
* p < 0.05
Interferon gamma response to stimulation
IFNγ response to stimulation
700
*
*
*
geometric mean (MFU)
600
*
500
400
Lean
300
Obese
200
100
0
CD8+ cells
CD4+ cells
Obese Pregnant Women Have Reduced
Micronutrients
Lean (n=15)
Obese (n=15)
RBC folate
(ng/ml)
1606+559
1131+446*
Vitamin C
(mg/dL)
1.3+0.2
0.9+0.3*
Vitamin E
(ug/dL)
1720+394
1393+282*
(1,25) OH
Vitamin D
(ng/ml)
34.8+10.2
27.4+8*
Diet Composition for Dams
Fat
(%)
Protein Carb
(%)
(%)
Kcal/g
Vit A
(g/kg)
Vit C Vit E Selenium
(g/kg) (g/kg) (g/kg)
8
16
45
3.2
4,600
0
Control+ 8
AOX
16
45
3.2
Western
16
21
50
Western
+ AOX
16
22
50
Control
86
0.165
23,000 5.6
260
0.5
4.3
4,600
86
0.165
4.3
23,000 5.6
260
0.5
0
Offspring Adiposity at 2 weeks
25
*
20
Fat Percentage
**
*
15
10
5
0
Control
Control+Aox
Western
Western+Aox
Conclusions
• Mean maternal weights have increased
significantly over time
• Obesity in pregnancy - increased
inflammation, immune dysregulation,
PPROM, chorioamnionitis, and
prematurity
• Obesity one of multiple factors that
increases the risk of prematurity
Preterm
birth
Intrauterine
infection
Fetal
Inflammatory
Response
time
Brain/Lung damage
Trimester II
Delivery
Bacterial Infection within the Uterus
Markers of Preterm Delivery
Cervix / Vagina
Amniotic Fluid
Serum
Bacterial vaginosis
 WBC
 CRP
 G-CSF
 G-CSF
 G-CSF
 TNF-a
 TNF-a
 TNF-a
 IL-1
 Glucose
 IL-6
 IL-6
 IL-6
 IL-8
Bacteria
 FFN
RISK FACTORS: INTRAPARTUM
• Fever
• Urinary tract infection
• Premature rupture of membranes
• Chorioamnionitis/funicitis (many
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organisms, e.g. ureaplasma)
Low Apgars, encephalopathy,
seizures, poor neonatal outcome
Cognitive Development
Fever
No Fever
Adj OR : 3.8 (0.97-15)
Infection in the Placenta and
Neonatal Brain Injury
• Bacteria present >80% by PCR, no correlation
with chorioamnionits/preterm labor
• Fetal inflammation needed for brain injury
• Role of endotoxin (LPS injections in rabbits),
oxidative stress (deficiency of antioxidants),
cytokines (CSF) in white matter injury
• Sensitizes fetal brain to hypoxia
• May have brain anomalies at birth
• In utero insult may continue post-partum
FIR: Role for White Cell Activation
Dammann O, et al. 2001
Pathogenetic Mechanisms in PVL
Maternal infection/
Fetal inflammation
Cytokines
Microglia
Prematurity
Ischaemia/
reperfusion
Fe++
Glutamate
Antioxidants
Reactive oxygen species
Reactive nitrogen species
Oligodendroglial death
IVH
Slide Courtesy of Alan Leviton
PVL on MRI
increased signal intensity in white
matter, volume loss in grey matter
Inflammatory
Response
Prenatal
Infection
Cytokines
Growth Factors
and Hormones
? Chemokines
Adhesion
Molecules
White Matter Damage
Lung Injury
Other poor outcomes
Long-term
Disability
Future Research
• Molecular Epidemiology
Genetic polymorphisms
Genetic susceptibility
• Directed Therapies
Protectors (antenatal steroids)
Anti-inflammatory agents (IL-10, CC10, ibuprofen)
Antioxidants (rhSOD)
• Maternal and Neonatal Conditions
Chorioamnionitis/funicitis (new FHR monitors)
BPD, PVL, ROP, NEC (salivary gene analyses)
• Laboratory Techniques (microarray, Luminex)
• Assessment Techniques (PFT, CT, MRI, EEG)
Neonatal Abstinence Syndrome
• Opioid exposure in pregnancy - 5.6
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infants/1,000 births
Incidence has tripled in the past decade
The mother may also be smoking or
taking other medications
Signs of withdrawal in 60-80% of infants
exposed to opioids
Dysfunction of the central nervous
system, gastrointestinal tract, and/or
respiratory system
Neonatal Abstinence Syndrome
• Prolonged treatment in hospital, high
healthcare costs
• Safety and efficacy of agents not well
established
• Significant variability in the incidence
and severity
• Factors influencing this variability are
unknown
Neonatal Abstinence Syndrome
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Genetic factors may be
important
Single nucleotide
polymorphisms (SNPs):
Single base pair changes
that can alter protein’s
function
SNPs influence opioid
dosing, metabolism, and
addiction in adults
No prior studies of genetic
links to NAS
Candidate Genes for NAS
• SNPs present in 40-50% of the population have
been studied in adults
• Mu Opioid Receptor (OPRM1) = Site of Action
• 118A>G SNP
• Multi-Drug Resistance Gene (ABCB1) =
Transporter
• 1236C>T SNP
• 3435C>T SNP
• 2677G/T/A SNP
• Catechol-O-methyltransferase (COMT) =
Methods
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86 opioid exposed term infants
Mothers receiving methadone or
buprenorphine
Infants treated with morphine or
methadone
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If severe - additional medications given
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A sample of blood or saliva collected from
each infant
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Incidence and severity correlated with
changes in genetic profiles
Results
DEMOGRAPHICS
White
98%
Maternal Methadone
64%
Maternal Buprenorphine
36%
Maternal Smoking
78%
Maternal Benzodiazepines
12%
LOS All Infants
Mean 22.3 days
LOS Treated Infants
Mean 31.6 days
Treatment for NAS
65%
Treated with >2 medications
24%
OPRM1 118A>G Results
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AA vs AG/GG infants compared in models
that adjust for breastfeeding and study site
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Those with the AG/GG genotype - treated
less frequently and had shorter LOS
OUTCOME
UNADJUSTED
RESULTS
ADJUSTED
RESULTS
P-VALUE
Infant
Treated
72% vs 48%
OR = 0.76
(CI 0.63, 0.96)
0.006
Mean LOS
24.1 vs 17.6 days
- 8.5 days
0.009
COMT 158A>G Results
•
AA infants vs AG/GG infants in models
that adjusted for breastfeeding and site
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AG/GG infants were treated less frequently
and had shorter LOS than AA infants
OUTCOME
UNADJUSTED
RESULTS
ADJUSTED
RESULTS
P-VALUE
Infant
Treated
88% vs 60%
OR = 0.79
(CI 0.61, 0.99)
0.02
Mean LOS
31.1 vs 20.4 days
- 10.8 days
0.005
Conclusions
• NAS is a complex disorder with many
factors contributing to the incidence and
severity
• SNPs in the OPRM1 and COMT genes -
reduced treatment and LOS
• No associations found with ABCB1 SNPs
• Combining clinical risk factors with
genetic profiling would permit
personalized genetic medicine and
targeted treatment regimens
Challenges in Neonatal Drug Development
• Most drugs used in newborn infants not
FDA approved - safety and efficacy not
established
• Small market, high liability, ethical
concerns
• Significant variability in NAS treatment
protocols
• Many NAS medications include alcohol or
propylene glycol
• Concern for adverse long-term
Future Directions
• NIH Grant – “Improving Outcomes in
Neonatal Abstinence Syndrome”
• Randomize infants to receive morphine or
methadone (determine best practice)
• Evaluate long-term neurodevelopmental
outcomes of infants treated for NAS
• Establish other genetic factors - Addiction
Array (1350 SNPs for addiction disorders)