PEDIATRICS Vol. 119 No. 1 January 2007, pp. 158-160 (doi:10.1542/10.1542/peds.2006-3095)
COMMENTARY |
The Limits of Viability and the Uncertainty of Neuroprotection: Challenges in Optimizing Outcomes in Extreme Prematurity
Kennedy Center, Section of Developmental and Behavioral Pediatrics, Institute of Molecular Pediatrics Sciences, University of Chicago, Comer and LaRabida Children’s Hospitals, Chicago, Illinois
Abbreviations: CP, cerebral palsy • IVH, intraventricular hemorrhage • ELBW, extremely low birth weight • ROP, retinopathy of prematurity
Among the 500000 infants born prematurely in 2003 in the United States, 79000 were born very prematurely.1–3 These very premature infants, defined as having been born before 32 weeks’ completed gestation, have benefited from collaborative and regional efforts of obstetrics and neonatology. In particular, among infants of extreme prematurity (defined as <28 weeks’ completed gestation), optimizing the intrauterine environment of high-risk pregnancies while concurrently using knowledge from developmental biology and multicenter translational trials has resulted in more aggressive management of respiratory, cardiac, nutritional, metabolic, and infectious-disease complications. This strategy has resulted in significant advances in survival but has come with increasing concern that current management is unable to significantly reduce the high rates of both neurosensory disability (ie, cerebral palsy [CP], blindness, and deafness) and developmental cognitive disability (Bayley mental developmental index of <70) among extremely preterm infants, especially those born between 22 and 26 weeks’ gestation.4–6 Schmidt et al7 successfully reduced rates of severe intraventricular hemorrhage (IVH) by the use of prophylactic indomethacin in extremely low birth weight (ELBW) infants. However, despite this neuroprotection, rates of death and neurodisability were not significantly different among the survivors. In a secondary analysis, 3 neonatal complications (chronic lung disease, severe retinopathy of prematurity [ROP], and sonographic parenchymal brain injury) significantly predicted short-term neurosensory and neurodevelopmental disability.8 Among the children with parenchymal brain injury (IVH grades III–IV, ventriculomegaly, and/or cystic periventricular leukomalacia), >1 (36%) in 3 had one of the CP syndromes. Among those with severe ROP, almost 1 (24%) in 4 had CP. Among those with chronic lung disease, defined as supplemental oxygen use at 36 weeks’ postmenstrual age, >1 (17%) in 6 had CP. Of most concern was that almost 9 (88%) of 10 of infants with all 3 conditions had outcomes of either death or recognized neurodisability in early childhood.
It is with this concern about the increasing rates of child neurodisability among those at the limits of viability that the article by Tommiska et al9 (in this issue of Pediatrics) is a substantial contribution. In the study they examined the outcomes of 1040 ELBW infants born in Finland in the latter part of the past decade. All infants with a birth weight of <1000 g (ELBW) were included in this study, and both perinatal and follow-up data were uniformly collected through an ELBW national registry. In addition, neurodevelopmental outcomes at 3 years of age were available through registries for children with CP and visual disability. Thus, this study meets the highest quality of epidemiologic investigations. These strengths include a very large cohort of ELBW pregnancies (with 75% having accurate early sonographic dating of gestational age before the end of the 20th gestational week), meticulous monitoring of intrauterine growth with concurrent use of up-to-date national standards, comprehensive obstetric and neonatal management data, quality improvement initiatives to lessen regional variation, and follow-up data in a country with both universal health insurance and comprehensive early childhood developmental and disability supports. In essence, this research was performed under the best possible circumstances and reflects the best outcomes using current technologies.
What were some of the findings?
- Prenatally, between 1 in 7 and 1 in 10 stillbirths had major malformations, and 1 in 4 were multiples. Thus, the first-trimester environment is far from optimal in this population.
- More than 1 (35%) in 3 experienced intrauterine growth restriction (–2 SD). In addition, almost 2 in 3 of ELBW infants of >27 weeks’ gestational age had evidence of intrauterine growth restriction.
- Cesarian section for 22 to 26 weeks’ gestation increased from 33% to 43% between the years 1996–1997 (era 1) and 1999–2000 (era 2).
- Successful regionalization was maintained, with 84% of the infants being inborn.
- Use of antenatal steroids increased from 58% to 70%.
- The survival rate of liveborn infants to term equivalent (40 weeks’ gestational age) increased from 60% to 65%. In particular, the overall survival at 22 to 25 weeks’ gestation increased from 38% to 48%. The average time to death was
6 days (median: 0.5 days) in era 1 and 5 days (median: 1 day) in era 2.
- Neonatal morbidities included an increase in respiratory distress syndrome from 75% to 83%, an increase in sepsis from 23% to 31%, and stability of severe IVH at 16% to 17%. However, between 62% and 64% of survivors had one of the morbidities of the Schmidt et al triad.
- Rates of CP among survivors of <27weeks’ gestation were between 1 in 7 and 1 in 8. In the term population, this rate is 1 in 500.
- Rates of visual disability increased from 1% to 3%. Among the survivors with gestational ages of 22 to 26 weeks, there was an increase from 2% to 4%. In the term population, this rate is 0.5%.
- Rates of survival varied by level of NICU care (level 3: 67%; level 2: 41%–59%). There were no significant differences between level 3 centers with respect to major morbidity and outcomes.
Despite aggressive treatment, there are continued high rates of neonatal deaths and high rates of neonatal morbidities at <26 weeks’ gestation. Mikkola et al10 previously examined the 5-year outcome of these 206 Finnish survivors of <1000 g from era 1 of the Tommiska et al study. At 5 years of age, 14% had CP, 9% had cognitive disability, 4% had hearing disability, and 2.6% had visual disability. Marlow et al11 demonstrated that high rates of neurodisability in early childhood are the harbingers of school-age disability. In addition, even among children who escape major neurodevelopmental disability in early childhood, a very large number (>50%) struggle in school performance and have difficulty with academic competitiveness.12,13 Most importantly, there is increased recognition in the United States of increasing rates of early childhood cognitive disability that is occurring in an era of scarce resources for community health, early childhood, and education.
With current technologies, health professionals can increasingly recognize both our limited knowledge in preventing all degrees of prematurity as well as our inability to substantially decrease major neuromotor and neurosensory disability. However, this is only the tip of the iceberg of concerns that the current generation of survivors may not be able to enter school healthy and ready to learn. It is for this reason that explicit comprehensive strategies of neuroprotection that address both white matter injury and gray matter dysfunction are required. Unraveling the complex mechanisms involved in these structural markers are crucial for preventing disorders of movement, perception, attention, and cognition.14–16 Two additional themes for enhancing developmental outcomes include prevention of severe ROP and increased attention to mechanisms that underlie ototoxicity.17 Most importantly, because of fragmentation in the accessibility of quality childhood experiences for all children, but especially for those living in poverty, eliminating missed opportunities involving critical postnatal developmental experiences is essential. Thus, our efforts require a threefold approach of reducing short-term neurodevelopmental disability, minimizing missed opportunities to optimize developmental functioning, and comprehensive supports to families who are most vulnerable. This approach will ensure not only that our technologies address the limits of viability but also that we systematically begin a multipoint approach to address our current limits of neuroprotection across all degrees of prematurity. We will know when we have succeeded when all NICU graduates have ongoing academic, vocational, and employment successes.
 |
ACKNOWLEDGMENTS |
|---|
This research was supported by grant 1U01 HD37614 from the National Institute of Child Health and Human Development Family and Child Well Being Network: "Child Disability and the Family."
Jen Park was invaluable in editing and technical assistance.
|
FOOTNOTES |
|---|
Accepted Oct 26, 2006.
Address correspondence to Michael E. Msall, MD, Kennedy Center, Section of Developmental and Behavioral Pediatrics, Institute of Molecular Pediatrics Sciences, Pritzker School of Medicine, University of Chicago, 5841 South Maryland Ave, MC09000, Chicago, IL 60637. E-mail: mmsall{at}peds.bsd.uchicago.edu
The author has indicated he has no financial relationships relevant to this article to disclose.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
|
REFERENCES |
|---|
 TOP REFERENCES |
|---|
- March of Dimes. Data Book for Policy Makers: Maternal, Infant and Child Health in the United States. Atlanta, GA: March of Dimes; 2003
- March of Dimes. PeriStats. Available at: www.marchofdimes.com/peristats. Accessed October 23, 2006
- Centers for Disease Control and Prevention, National Center for Health Statistics. National Vital Statistics System: birth data. Available at: www.cdc.gov/nchs/births.htm. Accessed October 23, 2006
- Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants <32 weeks’ gestation between 1993 and 1998.
Pediatrics. 2005;116
:635
–643
[Abstract/Free Full Text] - Wood NS, Marlow N, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extreme preterm birth. EPICure Study Group.
N Engl J Med. 2000;343
:378
–384
[Abstract/Free Full Text] - Hintz SR, Kendrick DE, Vohr BR, Poole WK, Higgins RD. Changes in neurodevelopmental outcomes at 18–22 months’ corrected age among infants of less than 25 weeks’ gestation born in 1993–1999.
Pediatrics. 2005;115
:1645
–1651
[Abstract/Free Full Text] - Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants.
N Engl J Med. 2001;344
:1966
–1972
[Abstract/Free Full Text] - Schmidt B, Asztalos EV, Roberts RS, et al. 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
:1124
–1129
[Abstract/Free Full Text] - Tommiska V, Heinonen K, Lehtonen L, et al. No improvement in outcome of nationwide extremely low birth weight infant populations between 1996–1997 and 1999–2000.
Pediatrics. 2007;119
:29
–36
[Abstract/Free Full Text] - Mikkola K, Ritari N, Tommiska V, et al. Neurodevelopmental outcome at 5 years of age of a national cohort of extremely low birth weight infants who were born in 1996–1997.
Pediatrics. 2005;116
:1391
–1400
[Abstract/Free Full Text] - Marlow N, Wolke D, Bracewell MA, Samara M; EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth.
N Engl J Med. 2005;352
:9
–19
[Abstract/Free Full Text] - Marlow N. Neurocognitive outcome after very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2004;89 :F224—F228
- Bhutta AT, Cleeves MA, Casey PH, et al. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis.
JAMA. 2002;288
:728
–737
[Abstract/Free Full Text] - Murata Y, Itakura A, Matsuzawa K, Okumura A, Wakai K, Mizutani S. Possible antenatal and perinatal related factors in development of cystic periventricular leukomalacia. Brain Dev. 2005;27 :17 –21[CrossRef][Web of Science][Medline]
- Dammann O, Leviton A. Inflammatory brain damage in preterm newborns: dry numbers, wet lab, and causal inferences. Early Hum Dev. 2004;79 :1 –15[CrossRef][Web of Science][Medline]
- Ment L, Vohr B, Allan W. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial.
Pediatrics. 2000;105
:485
–491
[Abstract/Free Full Text] - Msall M, Phelps DL, DiGaudio KM, et al. Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Behalf of the Cryotherapy for Retinopathy of Prematurity Cooperative Group.
Pediatrics. 2000;106
:998
–1005
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  C. Limperopoulos, H. Bassan, N. R. Sullivan, J. S. Soul, R. L. Robertson Jr, M. Moore, S. A. Ringer, J. J. Volpe, and A. J. du Plessis Positive Screening for Autism in Ex-preterm Infants: Prevalence and Risk Factors Pediatrics, April 1, 2008; 121(4): 758 - 765. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
