Over the past 2 decades, advances in obstetrics and neonatal medicine have resulted in a >70% survival rate of extremely preterm infants (<28 weeks' gestation) and a >90% survival rate of very preterm infants (<32 weeks' gestation).1 Although the rates of cerebral palsy (CP) may have decreased, the rate of developmental delay as measured by the Mental Developmental Index (MDI = 71–84) and cognitive disability (MDI < 70) still remains high.2–4 In addition, there are concerns that the majority (50%) of survivors will require support for deficits in attention, executive function, language, coordination, perception, and academic achievement during their school years.4
Two articles in this issue of Pediatrics provide us with important information on both the short-term and early-adolescent outcomes of these vulnerable children. In the first article, Gargus et al5 describe the correlates of unimpaired developmental outcomes at 20 months of age in the 1998–2001 National Institute of Child Health and Human Development Neonatal Network multicenter cohorts of 6090 inborn infants weighing between 401 and 1000 g. Overall, mortality rates were high, with 1 in 3 dying before NICU discharge and an additional 1.3% dying before their 18-month developmental assessment. Gargus et al describe children who weighed between 401 and 1000 g at birth, survived to NICU discharge, and were free of CP, neurosensory impairment, cognitive delay (MDI = 71–84), or cognitive disability (MDI < 70) at 18 to 22 months.
One of the strengths of the study was the large number (N = 3345) of children who were followed with a neurologic examination, reviews of visual and hearing status, developmental assessments with the Bayley II scales, and functional assessment of swallowing, self-feeding, and mobility. The central outcome of the study was that only 1 in 4 NICU survivors in this cohort were free of CP, hearing or visual impairments, mild developmental delay (MDI = 71–84), or cognitive disability (MDI < 70).
WHAT FACTORS WERE ASSOCIATED WITH UNIMPAIRED OUTCOMES IN EARLY CHILDHOOD?
Mothers of unimpaired infants had significantly higher rates of antenatal steroid use and cesarean delivery. Among unimpaired survivors, 7 in 8 received antenatal steroids and 2 in 3 were born by cesarean delivery, compared with half (56%) and one third (35%), respectively, of those who died.
Among infants without impairment, there were fewer mothers struggling with social disadvantages such as teenaged motherhood, not completing high school, being a single parent, and living in poverty, as indicated by their receiving Medicaid.
Singleton females who were more mature in gestation and heavier in birth weight had dramatically higher unimpaired survival rates.
WHAT NEONATAL COMPLICATIONS WERE ASSOCIATED WITH UNIMPAIRED OUTCOMES IN EARLY CHILDHOOD?
There were markedly decreased rates of chronic lung disease, parenchymal brain injury (intraventricular hemorrhage grade 3–4 or periventricular leukomalacia), and severe retinopathy of prematurity (stage ≥3) in unimpaired survivors, consistent with the Schmidt et al observations in the international Trial of Indomethacin Prophylaxis in Preterms (TIPP) study.6 Similarly, the rate of sepsis was significantly lower (29% vs 49%) comparing unimpaired survivors and those with neurodevelopmental disability. These observations support the hypothesis that the immature central nervous system is particularly vulnerable to infection and inflammation. Importantly, the duration of neonatal intensive care was 16.5 weeks among those with evolving neurodevelopmental disability, whereas for those who were unimpaired that figure was 11.5 weeks. In the United States, this increased length of stay would increase NICU costs by more than $80 000.
IN LIGHT OF THE AFOREMENTIONED FACTORS, WHAT WAS THE SPECTRUM OF DISABILITY AMONG EXTREMELY PREMATURELY BORN INFANTS?
Among children with mild disability, none were blind or deaf, 96% had normal swallowing, 85% walked independently (although 6% had CP) 92% could feed independently, and >90% had weight, height, or head circumference above the 10th percentile.
In contrast, among those with severe neurodevelopmental impairments, 85% had cognitive disability (MDI < 70), 2% were blind, 4% had severe bilateral hearing loss, and almost 1 in 3 had CP. In this group, 50% were able to walk independently, 80% had normal swallowing, 72% were independent in feeding, and more than half had weight, height, or head circumference below the 10th percentile.
WHAT DETERMINES DEATH OR MORE COMPLEX NEURODEVELOPMENTAL DISORDERS?
Although infant factors at birth were associated with survival, unimpaired survival was associated with decreased neonatal complications, decreased use of neonatal technology, white race, and private health insurance.
WHAT DOES THIS MEAN OVER TIME, ESPECIALLY BECAUSE THE BAYLEY SCALES AT 18 MONTHS HAVE LIMITATIONS IN PREDICTING THE FULL SPECTRUM OF SCHOOL-AGE DEVELOPMENTAL CHALLENGE?
Luu et al7 examined the trajectories of receptive language, a core cognitive competency, between ages 3 and 12 years in 355 children who weighed between 600 and 1250 g and were born at regional centers of excellence at New England between 1989 and 1991. These infants had participated in a randomized, controlled trial of indomethacin for neuroprotection. The authors used the statistical technique of growth modeling to examine the impact of indomethacin, as well as other medical and environmental factors on language trajectories. They found that boys who have the highest risk for language and developmental cognitive challenges were helped most by indomethacin. In addition, for the entire cohort, ongoing learning continued. However, factors associated with suboptimal developmental trajectories included parenchymal brain injury, low maternal education, and minority status.
HOW WERE THESE COHORTS DIFFERENT?
The cohort reported by Luu et al was heavier and more mature than the children described by Gargus et al. Among preterm children in the study reported by Luu et al, the mean (SD) birth weight and gestational age were 965 (175) g and 28 (2) weeks, respectively, compared with <850 g and <26.7 weeks' gestation in the Gargus study. However, only 1 in 3 of the Luu et al cohort received maternal steroids, because these interventions occurred before the consensus statement of maternal steroids had been disseminated. Finally, chronic lung disease occurred in 45% and severe brain injury in 6% to 7% of the Luu et al study group, higher rates than those who were unimpaired in the Gargus et al cohort.
WHAT WERE THE DEVELOPMENTAL TRAJECTORIES ACROSS PRESCHOOL AGE, MIDDLE CHILDHOOD, AND EARLY ADOLESCENCE?
Progress in learning occurred for all groups of survivors. Male children who had received indomethacin increased their standard score on the Peabody Picture Vocabulary Test from 87 to 97, whereas those who had received placebo progressed from a score of 78 to 92. Among female children, those who received indomethacin saw an increase in their standard score from 83 to 92, whereas those in the placebo group went from a score of 89 to 97.
WHAT DO 8-, 9-, 10-, AND 14-POINT IMPROVEMENT ON STANDARD SCORES OVER 9 YEARS MEAN FOR A COHORT ?
First, these are substantial effect sizes of approximately 0.53, 0.60, 0.67, and 0.93. Second, improvements in these scores decrease the risks of academic failure. Third, more factors than our neonatal interventions are taking place that are determining long-term outcome, including experiences within the family and in schools. Fourth, even among children with brain injury, progress occurs. Specifically, <10% of children in this cohort experienced severe cognitive limitations (IQ < 50), disabling CP (inability to walk, sit, or use hands), and/or severe neurosensory disability. The remainder of the children, all of whom experience a spectrum of cognitive, academic, and neighborhood challenges, make progress and learn. Fifth, just as in term children, the mother's education status is an important predictor of a preterm child's developmental success.
WHAT CAN OBSTETRICIANS, NEONATOLOGISTS, PEDIATRICIANS, AND FAMILIES LEARN FROM THESE 2 STUDIES?
First, although there are risks that affect preterm children's growth and development, there are also several optimizing factors that can counter-balance these risks. They include early intervention for the infants and supports for families.8,9 In addition to our efforts to understand interventions that reduce the rates of neonatal morbidities, we must implement quality-improvement interventions that optimize current neonatal practices and examine environmental factors that promote children's developmental and functional competencies and family well-being that are accessible to families after discharge from the NICU. Failure to address disparities for these vulnerable children (whether at highest biomedical, developmental, or social risk) will increase their chances of being left behind at kindergarten entry. Minority status and low maternal education increases the chances of suboptimal educational outcome by complex relationships on health, early childhood experiences, poor-quality preschools, and underperforming schools in neighborhoods of poverty.10,11 In an era of underfunded early intervention and challenges in accessing quality early childhood education services, health and developmental professionals must be vigilant in their assessment of growth and developmental factors beyond NICU discharge.
WHAT ARE OUR CHALLENGES AS FAMILIES STRUGGLE WITH THE CURRENT ECONOMIC CRISIS AND HEALTH PROFESSIONALS AND EDUCATORS DEAL WITH UNDERRESOURCED EDUCATIONAL SUPPORTS?
First, an overwhelming majority of extremely low birth weight survivors require quality and comprehensive early childhood interventions and proactive educational supports. Second, we need audits for our interventions that decrease the prevalence of chronic lung disease, parenchymal brain injury, and severe retinopathy of prematurity. Third, we need to acknowledge that the spectrum of child disability is mild to moderate in developmental or educational functioning and can be modulated by evidence-based interventions and family supports. Last, using the metaphor of a “2-hit hypothesis,” we fear that the current cohort of extremely low birth weight survivors are at greater risk, both physiologically from the complications of premature birth and sociologically from the complications of inadequate social support.11 This “double jeopardy” makes it that much more difficult for these vulnerable children to enter kindergarten ready to learn.12 We need to systematically link our patients to a broader range of neuroprotection strategies that include not only interventions in the NICU but also postdischarge interventions in the home and in child care.13 This way, we can optimize and understand both the successes and limits of our technologies and treatment.
This work was supported in part by the Grant Healthcare Foundation of Chicago.
William Meadows and Marilee Allen provided valuable feedback, and Jennifer Park's technical and editorial assistance was greatly appreciated.
- Accepted May 12, 2009.
- Address correspondence to Michael E. Msall, MD, University of Chicago, Pritzker School of Medicine, J.P. Kennedy Research Center on Intellectual and Developmental Disabilities, Comer Children's and LaRabida Children's Hospitals, Section of Developmental and Behavioral Pediatrics, 950 E 61st St, SSC Room 207, Chicago, IL 60637. E-mail:
Financial Disclosure: The author has indicated he has no financial relationships relevant to this article to disclose.
- ↵Marlow N. Neurocognitve outcome after very preterm birth. Arch Dis Child Fetal Neonatal Ed.2004;89 (3):F224– F228
- ↵Gargus RA, Vohr BR, Tyson JE, et al. Unimpaired outcomes for extremely low birth weight infants at 18 to 22 months. Pediatrics.2009;124 (1):112– 121
- ↵Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF; Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. 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
- ↵Luu TM, Vohr BR, Schneider KC, et al. Trajectories of receptive language development from 3 to 12 years of age for very preterm children. Pediatrics.2009;124 (1):333– 341
- ↵Spittle AJ, Orton J, Doyle LW, Boyd R. Early developmental intervention programs post hospital discharge to prevent motor and cognitive impairments in preterm infants. Cochrane Database Syst Rev.2007;(2):CD005495
- ↵Msall ME. Children at risk: social disadvantage and neurodevelopmental functioning. In: Maria B, ed. Current Management in Child Neurology. 4th ed. Shelton, CT: BC Decker; 2009
- ↵Patrianakos-Hoobler AI, Msall ME, Huo D, Marks JD, Schreiber MD. Predicting school readiness from two year neurodevelopmental assessments after respiratory distress syndrome in preterm infants. Dev Med Child Neurol.2009; In press
- ↵Heckman JJ. Skill formation and the economics of investing in disadvantaged children. Science.2006;312 (5782):1900– 1902
- Copyright © 2009 by the American Academy of Pediatrics