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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: • • • • • • • 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 • • 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 • • • • • • 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 • 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 • • • • 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 • • • • 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 • • • 86 opioid exposed term infants Mothers receiving methadone or buprenorphine Infants treated with morphine or methadone • If severe - additional medications given • A sample of blood or saliva collected from each infant • 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 • AA vs AG/GG infants compared in models that adjust for breastfeeding and study site • 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 • 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)