1. Current Outcomes of Prematurity. Implications for optimal care of preterm neonates Howard W. Kilbride, MD Division Director, Neonatology Vice Chair of Perinatal Services, Department of Pediatrics Professor of Pediatrics, University of Missouri-Kansas City School of Medicine

2. Objectives Overview of epidemiology of preterm deliveries Brief review of complications of preterm birth Describe neurodevelopmental outcomes, including unique issues for extremely preterm Review factors related to neurodevelopmental impairment Discuss implications for neonatal care

3. You are counseling parents expecting a preterm delivery. What is the lowest gestational age at which you would recommend comfort care? A.<22 weeks B.22 wks C.23 wks D.24 wks E.25 wks F.26 wks

4. Your answer to Question #1 is based on: A.Likely high mortality B.Risk for severe neurodevelopmental impairment C.Low likelihood of normal neurodevelopmental outcome D.Other

5. Among ELBW survivors, cognitive outcomes are influenced equally by gestational age and socioeconomic status. A.True B.False

6. I am familiar with the online Premie Outcome Predictor. A.Yes, but don’t use it B.Yes, and I use it to assist parent counseling C.Never heard of it

7. Percentage of Preterm Births, US, 1990-2008 Ref: Norwitz et al Rev Ob Gyn, 2011

8. Epidemiology of Preterm Births 37.1% 16% 5.1% 7777.7% 13% 21.2% Davidoff, et al, Semin Perinatol 2006

9. National Center for Health Statistics, 2006-2013 Prepared by March of Dimes Perinatal Data Center, 2015

10. Neurodevelopmental Consequences of Preterm Birth Cerebral Palsy Cognitive disabilities Sensorineural impairments: hearing/vision Epilepsy Behavioral/emotional concerns Executive functioning

11. Cerebral Palsy CP worldwide 2.11/1000 live births BW 1000-1499 g 59.8/1000 > 2500 g 1.37/1000 GA < 28 wk 111.8/1000 > 36 wk 1.35/1000 Preterm birth accounts for 42-47% of Cerebral Palsy REF: Chang, BMJ, 2015

12. Effect of Preterm Birth on Cognition Bhutta AT, et al. JAMA. 2002;288:728-737

13. RISK FACTORS FOR SPECIAL EDUCATION Odds Ratio Male Gender 1.95 Parent Education <12 yr 1.63 BW <2500 g 1.48 Infants <2500 g represented 13% of non- orthopedically handicapped special education population Ref: Andrews, et al. Am J Prev Med 1995;11:55

14. Impact of preterm births on prevalence of neurocognitive impairments 27% of cognitive delay 23% of hearing loss 37% of visual impairments Estimated Cost: ~ 17 billion dollars annually (Institute of Medicine 2007) Ref: Change, BMJ 2015

15. Behavioral Effects of Prematurity Infants: less adaptable, less persistent, more withdrawn. Increased risk of ADHD Emotional/Anxiety Disorders –Variable reports Conduct Problems –Related to neurologic risk –Additional environmental effects Lower Level of Social Competence

16. Effect of Preterm Birth on Occurrence of ADHD Bhutta AT, et al. JAMA. 2002; 288:728-737

17. Late Preterms: Need for Intensive Care 17,000 NICU admissions annually > 33 wk GA Intensive care by GA 34 weeks50% 35 weeks15% 36 weeks 8% Paradox –late preterm excluded from RCT of preterm therapies (eg, surfactant, antenatal steroids) –included in term RCTs (HFOV, NO) Ref: Angus et al. AmJRCCM, 2001

18. Late Preterm Issues Acute clinical problems - increased respiratory morbidity - nutrition/feeding - glucose stability - thermal stability - hyperbilirubinemia Follow-up concerns - apnea/SIDS - ED visits/rehospitalizations - neurodevelopmental outcome

19. Late Preterm Potential for Neurodevelopmental Injury Brain weight at 34 weeks is 65% of term Approximately 50% of fetal cortical volume increase occurs 34 to 40 weeks Cerebellar volume increases 25% in last 6 weeks Developing brain tissue susceptible to hypoxic-ischemic injury (less antioxidants) Adams-Chapman, Clin Perinatol 2006

20. School-Age Outcome Florida Preschool Readiness Age (yr) Late Preterm (%) N=22,552 Term (%) N=164,628 RR (95% CI) Developmental delay 34.83.21.46 (1.4-1.5) Not ready44.74.11.09 (1.05-1.12) Special education 513.611.81.13 (1.11-1.15) Retention57.66.21.11 (1.08-1.14) Adams-Chapman, Clin Perinatol 2006

21. School Age Outcome for ELBWs, Heavier Preterms, and Terms Infants born in 1980s <750 g BW 750-1499 g BW Term Cerebral palsy 8% 6% 0 IQ <70 21% 8% 2% Limited academic skills 27% 9% 2% Poor visual-motor function 17% 5% 0 Visual impairment 24% 4% 1% Special education 45% 25% 14% Ref: Hack et al. NEJM 1994

22. Adverse Neuro Outcomes by GA Ref: Petrini et al, J Pediat 2009

23. EPIPAGE-2 France population based 2011 22-34 wks GA 23-26 wks27-31 wks32-34 wks Severe IVH12.9 %3.7%0.6% Cystic PVL2.4%1.5%0.5% BPD25.6 %4.6 %0 ROP6.0%0.3%0 NEC5.1%3.5%0.9% Ref: Ancel et al, JAMA Ped 2015, 169, 230

24. VLBW Outcomes by GA VON 2013 23 weeks24 weeks25 weeks26 weeksAll VLBW Severe ROP37.5%29.12%19.1%8.5%6.2% (0-8.3%) IVH, G3-436.2%26.3%12.7%11.9%8.1% (3.4-10.5) NEC9.5%10.5%9.0%7.7%5.1% (0-7.0) CLD75.8%64.1%58.2%44.1%24.4 (10.4-30.8)

25. Vermont Oxford Network 2013 Mortality-All VLBW Infants by GA Week

26. Survival Without Severe Neonatal Morbidity in 2011 Pierre-Yves et al, JAMA Pediatr. 2015;169(3):230-238;

27. EPICure Studies 3 year outcome for 22-25 week GA Severe Disability1995 (%) CI 2006 Cognition13 (9-18)12 (8-16) Motor11 (7-15)7 (5-14) Hearing2 (0.5-4.3)2 (0.9-4) Vision3 (0.9-6)0.9 (0.2-3) Any severe disability18 (14-24)19 (14-23) No disability59 (52-65)65 (59-70) Ref: Moore et al, BMJ, 2012, 345; e7691

28. Learning challenges in ELBWs even with normal cognitive scores

29. Factors associated with increased risk of neurodevelopmental impairments Inflammatory exposure: chorioamnionitis, sepsis, NEC In-utero/postnatal growth restriction, poor head growth Brain injury (IVH, PVL, encephalomalacia) BPD ROP Low SES

30. Date of download: 3/20/2015 Copyright © 2015 American Medical Association. All rights reserved. From: Impact of Bronchopulmonary Dysplasia, Brain Injury, and Severe Retinopathy on the Outcome of Extremely Low-Birth-Weight Infants at 18 Months: Results From the Trial of Indomethacin Prophylaxis in Preterms JAMA. 2003;289(9):1124-1129. doi:10.1001/jama.289.9.1124 Observed rates of poor 18-month outcome, with 95% confidence intervals(error bars). Solid line indicates predictions based on the fitted morbiditycount model; dotted line, the overall probability of a poor 18-month outcome(35%). Figure Legend:

32. Factors associated with improved neurodevelopmental outcomes for preterms Greater gestational maturity Antenatal steroids Improved protein nutrition and growth/breast milk Developmental NICU care Neuroprotection: ? Magnesium, caffeine, Epogen

33. Antenatal Steroids 26-34 wks GA Ref: Roberts, Cochrane review, 2006 Mortality0.69 (0.58-0.8) Moderate/Severe RDS0.55 (0.43-0.71) IVH0.54 (0.43-0.69) NEC0.46 (0.29-0.74) Systemic infection0.56-(0.38-0.85) Retrospective Review: also beneficial 23-25 weeks Carlo et al, JAMA, 2001

34. Developmental Care Individualized neurobehavioral assessments Individualized program to promote stability and self-regulation –positioning –minimize interruptions –lighting changes –noise avoidance –hammock, bunting –parental involvement

35. Journal of Perinatology, 2012

36. Evidenced Based Approach to Improving Outcomes of Preterms Delay Preterm Birth –Progesterone supplement Hx PTL: RR 0.66 (0.54-0.81) Meis et al, NEJM, 2007 Cervical shortening: RR 0.56 (0.36-0.88) Fouseca et al, NEJM 2007 Antenatal Steroids Nutrition (protein, early enteral fdg with breast milk) Conservative ventilation, judicious oxygen use Developmental NICU Care

37. Support Trial: Comparing 02 Saturation Targets Lower O2 (85-89%) Higher O2 (91-95%) P value Death Before 18-22 months 22.1 %18.2 %0.046 NDI9.5%10.5 %0.49 Death or NDI30.2 %27.5 %0.21 Bilateral blindness 1.0 %1.2%0.86 ROP (original study) 8.6%17.9%<0.001 Ref: Vaucher, NEJM 2012

38. NICHD Preemie Outcome predictor http://www.nichd.nih.gov/about/org/cdbpm/pp/prog_ epbo/epbo_case.cfm Gestational Age (Best Obstetric Estimate in Completed Weeks): Birth Weight (401 Grams to 1,000 Grams): grams Sex: Female Male Singleton Birth: Yes No Antenatal Corticosteroids (Within Seven Days Before Delivery): Yes No http://www2.aap.org/sections/perinatal/

40. Letter to Ed. NEJM 2004;351:836-837 "A girl with a birth weight of 280 g, now 14 years old"

41. Perception of Quality of Life MD/RN Parents Utility Score Hypothetical Outcomes; mean utility scores  95% CI Ref: Saigal, et al. JAMA 1999

42. Parental Rating of Quality of Life for ELBWs Ref: Saigal et al, Pediatr 2000

43. You are counseling parents expecting a preterm delivery. What is the lowest gestational age at which you would recommend comfort care? A.<22 weeks B.22 wks C.23 wks D.24 wks E.25 wks F.26 wks