Kristi Watterberg, MD Professor and Chief, Division of Neonatology Vice-chair, Department of Pediatrics

Preterm and critically ill newborns are a relatively small population in each NICU In 2007, 54 – 180 infants/network center <1000g BW ~1700 in the whole network Answering questions takes a large population Started in 1986 by NICHD with 8 centers, now 16 Purpose: to conduct multi-center clinical trials and observational studies in neonatal medicine to decrease morbidity and mortality & promote healthy outcomes

Doing the job right takes a lot of money and a lo-o-ong time!

Neonatal Research Network Protocol Development Process Concept Stage Approved by NICHD Submit Concept title to NICHD (due at least 4-5 weeks prior to Steering Committee Meeting) Submit 2-5 page Concept overview for SC review (3 weeks prior to meeting) Present at SC meeting (20-minute presentation, 40-minute discussion) Steering Committee vote (by secret ballot) Approved by ⅔ majority ( 11 / 16 sites) Rejected (½- ⅔ vote) Submit full protocol to Protocol Review Subcommittee (due within 6 months) Rejected (less than 50% vote) Rejected Approved by Subcommittee Revisions Requested (due within 6 months) Present to Steering Committee (20-30 min. presentation, min. discussion) Steering Committee members present protocol to their site faculty and staff Steering Committee vote within 6 weeks (by secret ballot) Approved by ⅔ majority ( 11 / 16 sites) Revisions Requested Rejected Development Stage Develop full protocol (form working group if needed) Can revise and resubmit Reviewed by outside advisory board and DSMC Revisions Requested Steering Committee budget vote (by secret ballot as funds become available) Prioritized for Implementation Not Prioritized Protocol Stage Rejected Subcommittee reports to SC on protocols in development and any rejections

Stanford, Utah, New Mexico, UT-Dallas, UT-Houston, Iowa, Indiana, U Alabama Birmingham, Wayne State U, Case Western Reserve, Cincinnati, Duke, Tufts, Brown, Yale

Reports of small studies often show positive results – why? Negative studies often aren’t reported Reports of negative studies are much more often rejected by journals – not exciting, harder to ‘prove a negative’ Therefore, early, small reports of new therapies or techniques are usually positive Side effects often not seen in small studies E.g., if an SAE is 1 vs. 2 in a 40 infant trial – is that going to be 50 vs. 100 in a 1000 patient trial? Or 99 vs. 100?

Good Bad NEW! Side effects Benefit - Risk Multicenter trial results

Generic Data Base: detailed information on a large prospective cohort of VLBW infant s Morbidities, mortality, outcomes at 18 – 22 months Factors associated with adverse outcomes, such as BPD, NEC, postnatal steroids Changes over time Early onset sepsis – surveillance of pathogens Early diagnosis of candidal sepsis Growth of VLBW infants Outcomes of infants born at the border of viability

IVIG to prevent nosocomial infection – no benefit Fanaroff, NEJM 1994 Indomethacin prophylaxis for improved neurodevelopment – no benefit Schmidt, NEJM 2001 Glutamine supplementation in TPN – no benefit Poindexter, Pediatrics 2004 iNO for preterm infants: no early or long term benefit Van Meurs, NEJM 2005; Hintz, J Pediatr 2007 Etc…..

iNO for term/late preterm infants with PPHN –  death or ECMO NINOS study group, NEJM 1997 Vitamin A to reduce BPD -  oxygen at 36 weeks Tyson, NEJM 1999 Hypothermia for hypoxic-ischemic encephalopathy -  death or disability at 2 years Shankaran, NEJM 2005 CPAP instead of intubation/surfactant in the delivery room Finer, NEJM 2010 Etc…

NRN member 1991 – 2001 (Papile PI) Dexamethasone: early vs. late Rx for extubation Faster extubation with early DEX, but no difference in median time to extubation More adverse effects in early DEX group Papile, NEJM 1998 Erythropoietin: effects of EPO on transfusions in preterm infants Epo  Hct, but didn’t  transfusions or improve long term outcomes Ohls, Pediatrics 2001

2006 – 2011 (Watterberg PI) Ongoing/completed: Hypotension in critically ill term and late preterm infants – Phase I, observational study (Fernandez) Ancillary – effect of ethnicity/race on cognitive and language testing at 18 – 22 months (Duncan/Lowe) Ancillary – object permanence (Lowe/Duncan) In the pipeline: RCT of hydrocortisone for extubation (Watterberg) Hydrocortisone for hypotension in term/late preterm infants – Phase II, RCT (Fernandez – concept to be presented next month)

The Neonatal Research Network has contributed unique observational data and important randomized trials to the neonatal community Fulfilling its ongoing mission of decreasing morbidity and mortality & promoting healthy outcomes in newborn infants We’re proud to be a part of this vital endeavor!