Kristi Watterberg, MDProfessor and Chief, Division of Neonatology

Vice-chair, Department of Pediatrics

Progress through collaboration: the story of the Neonatal

Research Network

Why do we need a Neonatal Network?

Preterm and critically ill newborns are a relatively small population in each NICUIn 2007, 54 – 180 infants/network center <1000g BW~1700 in the whole network

Answering questions takes a large populationStarted in 1986 by NICHD with 8 centers, now

16Purpose: to conduct multi-center clinical trials

and observational studies in neonatal medicine to decrease morbidity and mortality & promote healthy outcomes

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

Neonatal Research NetworkProtocol 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, 30-40 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 DSMCRevisions Requested

Steering Committee budget vote(by secret ballot as funds become available)

Prioritized forImplementation

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

Why do we need large RCTs?Reports of small studies often show positive

results –why?Negative studies often aren’t reportedReports 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 studiesE.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?

The life cycle of a new therapy

Good

Bad

NEW!

Side effectsBen

efit

- R

isk

Multicenter trial results

Generic Data Base: detailed information on a large prospective cohort of VLBW infants Morbidities, mortality, outcomes at 18 – 22 monthsFactors associated with adverse outcomes, such as

BPD, NEC, postnatal steroidsChanges over time

Early onset sepsis – surveillance of pathogensEarly diagnosis of candidal sepsisGrowth of VLBW infantsOutcomes of infants born at the border of

viability

Contributions of the NRN: (1) Observational studies

Benefits of the Network (2): RCTs that stopped ineffective/harmful therapies

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…..

Benefits of the Network (3): RCTs that showed a positive effect of intervention

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

extubationFaster extubation with early DEX, but no

difference in median time to extubationMore 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

Studies from New Mexico – (1st time)

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)

Studies from New Mexico (2nd time)

So in summary….The Neonatal Research Network has

contributedunique observational dataand important randomized trials to the neonatal

communityFulfilling 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!