The Role of Antenatal Factors on Neonatal Outcome

1. 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

2. No relevant financial relationships to disclose

4. Outpatient deck, 1906

6. Obesity in the US – A Major Public Health Problem 1999 1990 2009 No Data <10% 10%–14 15%–19% 20%–24% 25%–29% ≥30% CDC database 6

7. 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

8. Obesity in Pregnancy – Harmful to Mother and Infant Schmatz et al, J Perinatology, 2010.

9. Obesity in Pregnancy is Associated withIncreased Infections Heslehurt et al. Obesity Reviews, 2008.

10. 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

12. 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

14. Results Medians (interquartile ranges); Kruskal-Wallis ANOVA test

15. Results

16. Major Risk Factors for Prematurity by Multivariate Analysis • PROM • Obesity • Pre-existing diabetes • Pre-eclampsia/hypertension • Previous preterm/SGA infant • In vitro fertilization

17. Obesity in Pregnancy Changes Immune Cell Populations

18. Maternal Obesity Impairs Cytokine Production TNFα response to stimulation * * * p < 0.05 IFNγ response to stimulation * *

19. Obese Pregnant Women Have Reduced Micronutrients

20. Diet Composition for Dams

21. * * **

22. 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

23. Intrauterine infection Preterm birth Fetal Inflammatory Response Brain/Lung damage time Trimester II Delivery

25. Bacterial Infection within the Uterus

26. Markers of Preterm Delivery Cervix / VaginaAmniotic FluidSerum 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

27. 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

28. Cognitive Development Fever No Fever Adj OR : 3.8 (0.97-15)

29. 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

30. FIR: Role for White Cell Activation Dammann O, et al. 2001

31. Pathogenetic Mechanisms in PVL Maternal infection/ Prematurity Fetal inflammation Cytokines Ischaemia/ Microglia reperfusion Fe++ IVH Glutamate Antioxidants Reactive oxygen species Reactive nitrogen species Oligodendroglial death

32. Slide Courtesy of Alan Leviton

33. PVL on MRIincreased signal intensity in white matter, volume loss in grey matter

34. Inflammatory Response Prenatal Infection Chemokines ? Cytokines Adhesion Molecules Growth Factors and Hormones White Matter Damage Other poor outcomes Lung Injury Long-term Disability

35. 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) ….

36. 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

37. 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

38. 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

39. 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) = Modulator 158A>G SNP

40. 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

41. Results

42. 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

43. 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

44. 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

45. 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 developmental outcomes

46. 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)