1. Eric S. Shinwell, MD Kaplan Medical Center Rehovot Hebrew University Jerusalem, Israel Postnatal Steroids 2005

2. Recent History 1997-2001: Reports of adverse neurologic effects of Dexamethasone (Yeh 1997, Shinwell 1998, O’Shea 1998) 2002: Guidelines from American Academy of Pediatrics and Canadian Pediatric Society 2005: New data: Follow-up studies, The “Fear of Steroids” Era

3. 2005: Latest news Clinical Laboratory / Imaging Coping Strategies

4. Odds Ratio and 95% CI OUTCOME VARIABLE Odds Ratio ( 95% CI ) 0.51.02.04.00.2 DecreasedIncreasedRisk 0.51.02.04.00.2 EARLY 0.69 (0.60-0.80) MODERATELY-EARLY 0.62 (0.47-0.82) DELAYED 0.76 (0.58-1.00) Halliday, Ehrenkrantz, Doyle, 2003 (<4 days) (1-2 wks) (>2 wks) Steroids reduce BPD at 36 weeks

5. Odds Ratio and 95% CI OUTCOME VARIABLE Odds Ratio ( 95% CI ) 0.51.02.04.00.2 DecreasedIncreasedRisk 0.51.02.04.00.2 EARLY 1.02 (0.90-1.17) MODERATELY-EARLY 0.66 (0.40-1.09) DELAYED 1.03 (0.71-1.50) Halliday, Ehrenkrantz, Doyle, 2003 No Effect on Mortality

6. Odds Ratio and 95% CI OUTCOME VARIABLE Odds Ratio ( 95% CI ) 0.51.02.04.00.2 DecreasedIncreasedRisk 0.51.02.04.00.2 EARLY 1.69 (1.20-2.38) MODERATELY-EARLY 0.83 (0.39-1.74) DELAYED 1.20 (0.77-1.85) Halliday, Ehrenkrantz, Doyle, 2003 CEREBRAL PALSY

7. RCT, Early, 4-wks Dex F/U at 8 years Dex: –Lower Height and HC –More motor dysfunction –Lower cognition scores on WISC-II –Higher Total Impairment Scores Yeh et al, NEJM 2004 School-age Follow-up

8. Follow-up: 8 years Washburn, O’Shea, SPR 2004 Moderately-early, 42 day Dex, n = 38 dex, 30 placebo Adverse effect neuro 2 yrs 8 yrs, No effect on: – Growth – BP – Cognitive Function – Adaptive Behavior

9. Follow-up: 15 years Gross, et al. <1250 g, Ventilated at 2 weeks Dex 42 days vs 18 days vs placebo 22 of 36 survived Intact survival: – 42d: 69%; 18d:25%; Placebo: 18% – Pulmonary function best in 42d. Pediatrics 2005;115:681-687

10. Collaborative Dex Trial Dex 1/52, after age 2/52, Open-label Dex 13-17 year Follow-up (n=150) Neuro (↓), Psych, Education (↓) Growth (↓), Respiratory (↓), BP (↑) No major differences Trend to more CP (OR 1.58 0.81-3.07) Pediatrics 2005;116:370-384

11. Is there a scientific basis to steroid neurotoxicity?

12. Effect on Neurodevelopment: Animal Models Plint, et al: Systematic Review Animal models, Controlled trial, growth and neurodevelopment n = 98 Growth restriction universal Neuro results highly variable

13. Brain Growth Quantitative MRI in preterm infants at term 7 Dex, 11 Control, 14 term Dex-treated had 35% less cortical grey matter Other areas not affected Murphy, et al. Pediatrics 2001;107:217

14. Latest Volume MRI Studies Pavlovic, Inder (SPR ’05) : BW <1250, n=83, multivar. analysis Dex: Changed frontal microstructure (Apparent Diffusion Coefficient, Fractional Anisotropy) Males: regional gray matter reduction Parikh (SPR ’05) : ELBW, n=34, Dex, corrected for GA Reduced Overall Cortical Volume

15. Latest Volume MRI Studies Pavlovic, Inder (SPR ’05) : BW <1250, n=83, multivar. analysis Dex: Changed frontal microstructure (Apparent Diffusion Coefficient, Fractional Anisotropy) Males: regional gray matter reduction Parikh (SPR ’05) : ELBW, n=34, Dex, corrected for GA Reduced Overall Cortical Volume

16. Brain Volumes: Hydrocortisone Observational study of brain volumes (MRI) 8 year old former premies, n=58 +/- Hydrocortisone –low dose (5mg/kg/day, tapered over 3 weeks) No effect of Hydrocortisone on White or Grey Matter or Hippocampal size Preterm infants: lower grey and white matter volumes than term infants Lodygensky, de Vries, Huppi, 2005