search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Wilson-Costello, D. Articles by Hack, M. Search for Related Content PubMed PubMed Citation Articles by Wilson-Costello, D. Articles by Hack, M. Related Collections Premature & Newborn

Improved Neurodevelopmental Outcomes for Extremely Low Birth Weight Infants in 2000–2002

Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio

	ABSTRACT

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
BACKGROUND. Neurodevelopmental impairment of extremely low birth weight infants increased in the 1990s. Modern therapeutic changes may have influenced more recent neonatal outcomes.

OBJECTIVE. We sought to compare neonatal therapies and outcomes among all extremely low birth weight infants born in 2000–2002 (period III) to 2 previous periods: 1982–1989 (period I) and 1990–1999 (period II).

METHODS. The population included 496 extremely low birth weight infants born at our perinatal center during period I, 749 during period II, and 233 during period III. Therapies, rates of death, and survival with and without impairment at 20 months' corrected age were compared.

RESULTS. Between periods I and II, survival increased from 49% to 68% as did neonatal morbidity. This resulted in increased survival without impairment but also increased survival with impairment. Changes in therapy during period III included an increase in antenatal steroid use and a decrease in postnatal steroid use, although the rate of chronic lung disease did not change. Sepsis decreased, as did severe intraventricular hemorrhage. On follow-up, the rate of cerebral palsy decreased from 13% to 5%, resulting in a decrease in neurodevelopmental impairment from 35% to 23%. As a result, during period III versus II, survival without impairment increased, whereas survival with impairment decreased.

CONCLUSION. Since 2000, neurodevelopmental impairment has decreased among extremely low birth weight infants. A variety of perinatal and neonatal factors were associated with the improved outcomes including increased antenatal steroid use and cesarean section delivery, as well as decreased sepsis, severe cranial ultrasound abnormalities, and postnatal steroid use despite no change in the rate of chronic lung disease.

Key Words: extremely preterm infants • neurologic handicap • cerebral palsy

Abbreviations: ELBW—extremely low birth weight • CA—corrected age • BSID—Bayley Scales of Infant Development • MDI—mental developmental index • PDI—psychomotor developmental index • NEC—necrotizing enterocolitis • OR—odds ratio • CI—confidence interval

The evolution of neonatal intensive care therapy has resulted in dramatic improvements in the survival of extremely low birth weight (ELBW) infants (<1000 g).¹ Although initial reports of declining mortality showed no increase in the rates of neurodevelopmental impairment,^2,3 other studies suggested an increase in neurodevelopmental problems.^4–6 Ethical concerns have been expressed that aggressive resuscitative efforts with tiny infants may result in increased rates of disability among survivors and substantial resource use.^7,8 Additional reports suggest adverse effects of modern therapies such as postnatal steroid use.⁹ Although frequently used to treat chronic lung disease during the 1990s, the use of postnatal steroids has declined dramatically based on recommendations of The American Academy of Pediatrics.¹⁰ Quality improvement endeavors based on the sharing of best practice methods to decrease sepsis rates have also been implemented.¹¹

Recently, we showed worsened neurodevelopmental outcomes for ELBW infants born in the 1990s, a period characterized by frequent postnatal steroid use and before the initiation of major efforts to decrease neonatal sepsis.¹² In light of the recent changes in care practices, we sought to compare the rates of survival, neonatal morbidity, and neurodevelopmental impairment at 20 months' corrected age (CA) among ELBW children who were born at our perinatal center during 3 eras: 1982–1989, marked by enhanced assisted ventilation; 1990–1999, associated with the introduction of surfactant and antenatal and postnatal steroid therapy; and 2000–2002, marked by routine antenatal steroid therapy with decreased postnatal corticosteroid use and sepsis prevention initiatives.

	METHODS

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The study population included all 1478 live-born infants without major congenital malformations and with birth weights between 500 and 999 g who were delivered at our perinatal center, MacDonald Hospital for Women, during 3 periods (ie, 1982–1989 [period I; n = 496], 1990–1999 [period II; n = 749], and 2000–2002 [period III; n = 233]). The study periods were selected on a priori grounds on the basis of the following factors: the availability of uniform cranial ultrasound data for all patients born from 1982 onward, the initiation of antenatal steroid and surfactant therapies after 1990, and the implementation of quality improvement measures aimed at reducing postnatal corticosteroids and late-onset sepsis in 2000. Complete neurodevelopmental assessments to 20 months' CA were available for children born through 2002.

Our perinatal center is a tertiary referral center for high-risk pregnancies. Neonatal specialists attend all preterm deliveries. Decisions concerning active treatment of extremely preterm infants are made after consultation with the family, if possible, and/or according to the condition of the infant at birth. Despite some minor variations among individual neonatologists, there was general consensus during all 3 periods regarding the criteria for active resuscitation in the delivery room. Antenatal steroid therapy to enhance fetal pulmonary maturity was initiated after 1990.¹³ Neonatal care was rendered according to established guidelines, with no significant changes in the clinical facility or care team during the 3 periods.^14,15 Maternal information included age, level of education, race and marital status, duration of gestation, antenatal steroid therapy, and mode of delivery. Gestational age was determined from the date of the last menstrual period and confirmed with obstetric measures, including ultrasonographic findings in the majority of cases. Infant birth data included birth weight, multiple birth status, Apgar scores, and use of assisted ventilation in the delivery room. Neonatal morbidity included respiratory distress, defined as need for oxygen therapy; chronic lung disease, defined as an oxygen dependence at 36 weeks' CA (CA-postmenstrual plus postnatal age)¹⁶; patent ductus arteriosus, confirmed with echocardiography; episodes of sepsis, defined as clinical signs of infection with a positive blood culture; necrotizing enterocolitis (NEC)¹⁷; intraventricular hemorrhage¹⁸; and periventricular leukomalacia. Routine cranial ultrasonographic evaluations were performed according to a similar schedule, with the initial evaluation between day of life 3 to 7 and subsequent evaluations on days of life 10, 30, 60, and before hospital discharge for all study subjects. Severe cerebral ultrasonographic abnormalities were categorized as the presence of either grade III or IV intraventricular hemorrhage, periventricular leukomalacia, or persistent of ventricular dilation at hospital discharge. Specific neonatal therapies included surfactant, duration of oxygen and ventilator therapy, indomethacin and postnatal steroids. Surfactant was used starting in 1990 for infants who required assisted ventilation and 30% ambient oxygen to maintain an arterial oxygen pressure of 50 mmHg. Postnatal steroid therapy was prescribed at the discretion of the attending neonatologist for infants with chronic lung disease and prolonged ventilator dependence. Indomethacin therapy was used to treat symptomatic patent ductus arteriosus.

Survival rates and neurodevelopmental status were measured to 18 to 20 months' CA. Measures of neurodevelopmental outcomes included neurosensory status and the Mental and Psychomotor Developmental Indices of the Bayley Scales of Infant Development (BSID).¹⁹ Children born after 1991 were tested with the revised BSID II, which has been shown to give lower scores than the original BSID used for children born 1982 through 1991. Thus, we devised a correction factor based on the published differences found in a sample of 200 children given both tests in counterbalanced order to compare the scores obtained with the BSID II with those obtained with the original BSID.²⁰ For the Bayley mental development index (MDI), the correction factor ranged from 2 points for a score of 51 to 12 points for a score of 101. For the Bayley psychomotor development index (PDI), the correction factor ranged from 13 points for a score of 51 to 7 points for a score of 101. A neurologic examination of muscle tone was performed by either of 2 trained and certified examiners.²¹ Cerebral palsy was defined as a persistent but not unchanging disorder of movement and posture appearing in early life and attributable to a nonprogressive disorder of the brain, the result of interference during its development.²² Only patients with moderate-to-severe cerebral palsy were classified as having cerebral palsy for the study. Patients with isolated findings of increased or decreased tone in the extremities were classified as hypertonia or hypotonia on the basis of specific findings. Major neurologic impairments included cerebral palsy, hypotonia, hypertonia, and shunt-dependent hydrocephalus without other neurologic abnormality. Hypotonia and hypertonia were included in the category of major neurologic abnormality, because these conditions are considered by some to represent a variant of cerebral palsy. Shunt-dependent hydrocephalus without neurologic abnormality was also considered an impairment. Neurodevelopmental impairment included any major neurologic impairment, unilateral or bilateral blindness or deafness requiring a hearing aid, and/or an MDI of <70 on the BSID. Consistent criteria for defining neurodevelopmental impairment were used throughout the 21 years of study. Thirty-five neurologically impaired children (4 from period I, 22 from period II, and 9 from period III) were not testable with the BSID because of either behavioral problems or severe impairment. They were included among those with neurologic impairment but who do not have BSID scores reported. The 4 children from period I who had isolated blindness were inadvertently not included in our previous publication on the differences between survival and morbidity rates between the 1980s and 1990s; thus, rates of blindness and overall neurodevelopmental impairment shown for period I in this article were slightly greater than those previously reported.¹² Parents provided informed consent for participation in the study, which was approved by the Institutional Review Board of University Hospitals of Cleveland.

	ANALYSIS OF DATA

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Trends in delivery room care, survival, neonatal morbidity, and outcomes at 20 months' CA were compared between the 3 periods of study. Statistical comparisons were made with unpaired t tests for continuous variables and ² analyses for categorical variables. We adjusted for gestational age via logistic regression in the examination of death and survival with and without impairment, because gestational age differed between periods (Table 1). In addition, analysis of variance was performed to compare the mean MDI scores and rates of subnormal MDI over the 3 periods, controlling for gestational age and maternal education.

	RESULTS

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

A total of 242 (49%) of 496 infants survived to 20 months' CA during period I, compared with 508 (68%) of 749 during period II (P < .001). There was no significant change in survival between periods II and III at which time 165 (71%) of 233 infants survived. Compared with periods II and III, survivors from period I were of significantly higher birth weight (826 g vs 800 and 801 g; P < .01) and gestational age (26.7 weeks vs 26.2 and 26.0 weeks; P < .001).

Cause of Death
The most common cause of death was respiratory distress syndrome, accounting for approximately one third of all infants who died during the 3 periods. (Table 2) Another one third of the infants were not offered assisted ventilation because they were not considered viable; therefore, the cause of death was defined as "immaturity." NEC as the primary cause of death occurred significantly more often during period III (P < .01). The increased mortality from NEC is unexplained in light of the overall reduction in sepsis during period III. During period I, 67% of deaths occurred before age 48 hours versus 58% and 57% during periods II and III, respectively (P = .06).

The overall rate of neurologic abnormalities was highest during period II (Table 4). Cerebral palsy, which increased from 8% in period I to 13% in period II, decreased to 5% in period III (P = .008). Blindness decreased between periods I and II, likely because of improvements in laser therapy for severe retinopathy of prematurity, but did not change between periods II and III. Deafness, which doubled between period I and II, decreased during period III.

Figure 1 illustrates the outcomes of all live-born infants. From period I to II, mortality decreased, and survival both with and without neurodevelopmental impairment increased significantly. The overall rates of death and/or impairment decreased from 67% to 57% (P < .01). Mortality did not change between periods II and III, but intact survival increased, whereas neurodevelopmental impairment decreased. The overall rate of death and/or impairment further decreased to 47% (P < .01).

View larger version (16K): [in this window] [in a new window]   FIGURE 1 Comparison of death and survival with and without neurodevelopmental impairment at 20 months' CA for 500- to 999- g birth weight infants born during 3 periods: 1982–1989; 1990–1999, and 2000–2002. a Neurosensory abnormality and/or MDI <70.

To determine the relative effect of birth period and various perinatal and neonatal factors contributing to increased survival without neurodevelopmental impairment, logistic regression analysis was performed for patients from study periods II and III who survived to age 7 days, controlling for birth weight, gender, study period, and significant factors in the univariate comparison including antenatal steroid use, mode of delivery, surfactant therapy, severe cranial ultrasound abnormality, sepsis, and postnatal steroid exposure. Patients who survived < 7 days were omitted from the analysis because they frequently lacked cranial ultrasound data and were often not eligible for postnatal steroid therapy. After adjusting for the significant factors, neurodevelopmental impairment-free survival did not differ between periods II and III (OR: 0.93; 95% CI: 0.59–1.46; P = .76). Detailed examination of these results suggested that the lower rates of impairment during period III seen in the unadjusted analyses might be explained by significant decreases in postnatal steroid therapy, severe cranial ultrasound abnormality, and sepsis. These 3 factors were all significant predictors of neurodevelopmental impairment-free survival in the multivariate logistic model. ORs and 95% CIs for impairment-free survival were 0.59 (0.41–0.85) for postnatal steroid therapy; 0.16 (0.11–0.25) for severe cranial ultrasound abnormalities and 0.64 (0.45–0.89) for sepsis, with P values of <.01, <.001, and 0.01, respectively. In contrast, a protective effect for antenatal steroids on intact survival bordered on significant (OR: 1.37; 95% CI: 0.96–2.0; P = .09). The same multivariate logistic model to predict neurodevelopmentally intact survival using significant antenatal and birth factors such as study period, birth weight, gender, cesarean section delivery, antenatal steroid treatment, and surfactant therapy was performed for the entire population of infants born during periods II and III. In this analysis, postnatal factors, such as severe cranial ultrasound abnormalities, sepsis, and postnatal steroid treatment were not included because of the lack of opportunity for exposure to these factors for infants who died before 7 days age. In this analysis, the protective effect of antenatal steroids on intact survival reached significance (OR: 2.01; 95% CI: 1.48–2.74; P < .001). Cesarean section delivery and female gender were also significantly protective (OR: 1.8; 95% CI: 1.35–2.46; P < 0001 and OR: 2.2; 95% CI: 1.62–2.94; P < .001, respectively). Surfactant did not have a protective effect on intact survival in either multivariate logistic analysis. Of interest, multivariate analysis using both prenatal and postnatal factors performed for infants surviving to follow-up suggests that although antenatal steroids, female gender, and cesarean section delivery enhanced survival, severe cranial ultrasound abnormalities, sepsis, and postnatal steroid therapy predicted neurodevelopmental outcome.

	DISCUSSION

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Our results indicate that although survival rates for ELBW infants born at our perinatal center increased during the 1990s compared with the 1980s, no additional increase in survival occurred during 2000–2002. During the 1990s, the perinatal approach to ELBW infants became more aggressive with increased use of antenatal steroids, cesarean section delivery, surfactant therapy, assisted ventilation, and postnatal steroids. The associated neonatal morbidities increased, resulting in higher rates of neurodevelopmental impairment. Between 2000 and 2002, antenatal steroid use continued to increase, but postnatal steroid use declined dramatically after reports of increased rates of cerebral palsy.^24–28 Despite this decrease in postnatal steroid use, there was no change in the rate of chronic lung disease during period III. At the same time, rates of sepsis and severe intraventricular hemorrhage also decreased. Neurodevelopmental outcomes improved for ELBW infants born during 2000–2002, with decreased rates of cerebral palsy, deafness, and overall neurodevelopmental impairment. During the 1990s, there was increased survival both with and without impairment. Since the year 2000, there have been improved neurodevelopmental outcomes, with increased survival without impairment and a decrease in survival with neurodevelopmental impairment. A variety of perinatal and neonatal factors were responsible for the improved outcomes, including decreases in postnatal steroid therapy, severe cranial ultrasound abnormalities, and sepsis.

Increasing rates of neurodevelopmental disability among ELBW infants born in the early 1990s have been previously reported.^12,29,30 However, others suggest stable or slightly improved neurodevelopmental outcomes associated with increased antenatal steroid use.^31,32 Our study, which is the first, to our knowledge, to report improved outcomes for 2000–2002 in conjunction with decreased use of postnatal steroids, suggests that the adverse neurodevelopmental outcomes during the 1990s likely relate to postnatal corticosteroid use and sepsis. Dexamethasone, the glucocorticoid most commonly used in the clinical setting, has been shown to impair cortical growth among preterm infants.^33–35 Research has demonstrated that the preferential binding of dexamethasone to the glucocorticoid receptors of the dentate gyrus induces apoptosis and neuronal cell death.³⁶

Several authors have noted an association between sepsis and cerebral palsy.^37–40 A recent report of ELBW infants identifies sepsis as an independent risk factor for neurodevelopmental impairment, including cerebral palsy and subnormal cognition.⁴¹ Inflammatory cytokines, released during intrauterine infection, are considered to be catalysts for the development of periventricular leukomalacia and subsequent cerebral palsy.^42,43 Recent neonatal quality improvement initiatives have introduced practice guidelines to minimize the risk of nosocomial sepsis.⁴⁴ Our neonatal unit now emphasizes aseptic precautions for all central line sites, use of in-line blood sampling equipment, and meticulous hand-washing. Such policies together with restriction of postnatal steroid therapy, which is associated with increased susceptibility to infections, may have contributed to our improved neurodevelopmental outcomes.^45,46

The strengths of our study include the relatively large inborn population and the high follow-up rates. The major limitation concerns the relatively short-term nature of the follow-up. Children diagnosed with cerebral palsy may "outgrow" the diagnosis in later years,⁴⁷ and cognitive scores may improve later in childhood.^48,49 The recent 3-year observational study period may not provide sufficient time to fully reveal the impact of therapeutic interventions on outcome. The presentation of outcomes by birth weight rather than gestational age will include small-for-gestational-age infants who are likely more mature. This study represents a predominantly urban population. Thus, its findings may not be generalizable to other neonatal centers with larger numbers of suburban infants.

Survival did not increase between periods II and III, as has also been shown by others.^1,50 Because additional reduction in the mortality rates of ELBW infants seems unlikely, future efforts must concentrate on reducing neonatal morbidity. Although the decrease in cerebral palsy since 2000 is encouraging, the lack of improvement in MDI is unexplained and necessitates additional research for interventions that may enhance cognitive function. Sociodemographic and environmental factors may contribute to differences in cognitive outcomes. Although maternal education was significantly higher during period II, analysis of variance controlling for maternal education did not change our outcomes. Whereas some studies on the effects of early educational intervention programs have demonstrated improved outcomes for children born to mothers of low sociodemographic status,^51,48 other reports have failed to demonstrate a sustained benefit.^52,53 The use of inhaled nitric oxide as rescue therapy to reduce death or chronic lung disease among preterm infants with respiratory failure has also been shown to decrease the rates of intraventricular bleeds and improve cognitive outcomes.^54,55 However, these findings have been tempered by studies that suggest either no improvement or worsened outcomes among ELBW infants.^56,57 Meanwhile, the iatrogenic detrimental effects of postnatal steroids caution against the premature use of new therapies for the most vulnerable infants before a thorough evaluation by randomized, controlled clinical trials.⁵⁸

	CONCLUSIONS

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Advances in perinatal care before 2000 resulted in improved survival but with either an increase or lack of reduction in neurodevelopmental impairment.^2,12 Greater numbers of disabled survivors result not only in enormous family impact but also the need for additional resources for support in school, the home, and workplace. The decreased morbidity and impairment that we have described since 2000 is a step in the right direction. However, as resuscitation and neonatal care continue to save the lives of the smallest and least mature infants, additional advances will be required to increase survival free of neonatal morbidity and neurodevelopmental impairment. Longer term follow-up of this population will be essential to evaluate the effects on quality of life for infants and their families and to help determine what constitutes appropriate care without doing harm. At the present time, prematurity cannot be prevented.⁵⁹ Emphasis on decreasing the number of multiple births resulting from infertility therapies accompanied by minimizing iatrogenesis and morbidity associated with sepsis and postnatal steroid therapy may hold promise for improved long-term outcomes.

	ACKNOWLEDGMENTS

 
This work was supported by grant M01RR00080, General Clinical Research Center, and partially supported by grant HD21364 from the National Institute of Child Health and Human Development Neonatal Research Network.

We thank Angelia Williams and Nancy Newman, RN, for help in conducting this research.

	FOOTNOTES

 
Accepted Sep 25, 2006.

Address correspondence to Deanne Wilson-Costello, MD, Division of Neonatology, Rainbow Babies & Children's Hospital, University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106-6010. E-mail: drfjcmd{at}aol.com

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT METHODS ANALYSIS OF DATA RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Fanaroff AA, Hack M, Walsh MC. The NICHD Neonatal Research Network: changes in practice and outcomes during the first 15 years. Semin Perinatol. 2003;27 :281 –287[CrossRef][ISI][Medline]
2. Doyle LW, for The Victorian Infant Collaborative Study Group. Improved outcome into the 1990s for infants weighing 500–999 g at birth. Arch Dis Child Fetal Neonatal Ed. 1997;77 :F91 –F94[Abstract/Free Full Text]
3. Robertson C, Hrynchyshyn GJ, Etches PC, Pain KS. Population-based study of the incidence, complexity and severity of neurologic disability among survivors weighing 500 through 1250 grams at birth: a comparison of two birth cohorts. Pediatrics. 1992;90 :750 –755[Abstract/Free Full Text]
4. Lorenz JM, Wookiever DE, Jetton JR, Paneth N. A quantitative review of mortality and developmental disability in extremely premature newborns. Arch Pediatr Adolesc Med. 1998;152 :425 –435[Abstract/Free Full Text]
5. Emsley HCA, Wardle SP, Sims DG, Chiswick ML, D'Souza SWD. Increased survival and deteriorating developmental outcome in 23–25 week old gestation infants, 1990–1994 compared with 1984–1989. Arch Dis Child Fetal Neonatal Ed. 1998;78 :F99 –F104[Abstract/Free Full Text]
6. Hack M, Friedman H, Fanaroff AA. Outcome of extremely low birth weight infants. Pediatrics. 1996;98 :931 –937[Abstract/Free Full Text]
7. Hack M, Taylor HG, Drotar D, et al. Chronic conditions, functional limitations, and special health care needs of school-age children born extremely low birth weight in the 1990s. JAMA. 2005;294 :1 –9
8. Marlow N, Wolke D, Bracewell MA, Samara M, for the 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]
9. Stark AE, Carlo WA, Tyson JE, et al. Adverse effects of early dexamethasone in extremely low-birth-weight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 2001;344 :95 –101[Abstract/Free Full Text]
10. American Academy of Pediatrics, Committee on Fetus and Newborn; Canadian Paediatric Society, Fetus and Newborn Committee. Postnatal corticosteroids to treat or prevent chronic lung disease in preterm infants. Pediatrics. 2002;109 :330 –338[Abstract/Free Full Text]
11. Kilbride HW, Wirtschafter DD, Powers RJ, Sheehan MD. Implementation of evidence-based potentially better practices to decrease nosocomial infections. Pediatrics. 2003;111(4) . Available at: www.pediatrics.org/cgi/content/full/111/4/SE1/e519
12. Wilson-Costello D, Friedman H, Minich N, Fanaroff A, Hack M. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics. 2005;115 :997 –1003[Abstract/Free Full Text]
13. National Institutes of Health. Effect of corticosteroids for fetal maturation on perinatal outcomes. NIH Consensus Statement. 1994;12 :1 –24[Medline]
14. Fanaroff AA, Martin RJ, eds. Neonatal-Perinatal Medicine. 7th ed. Philadelphia, PA: WB Saunders; 2001
15. American Academy of Pediatrics, American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care. 5th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2002
16. Shennan AT, Dunn MJ, Ohlsson A, Lenox K. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics. 1988;82 :527 –532[Abstract/Free Full Text]
17. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic decisions based on clinical staging. Ann Surg. 1978;187 :1 –7[ISI][Medline]
18. Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhages; a study of infants with birthweights less than 1500 grams. J Pediatr. 1978;92 :529 –534[CrossRef][ISI][Medline]
19. Bayley N. Bayley Scales of Infant Development. New York, NY: Psychological Corp; 1969
20. Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio, TX: Psychological Corp; 1993
21. Amiel-Tison C, Stewart AL. Follow-up studies in the first five years of life: a pervasive assessment of neurologic function. Arch Dis Child. 1989;64 :496 –502[ISI][Medline]
22. Bax M. Terminology and classification of cerebral palsy. Dev Med Child Neurol. 1964;6 :295 –297
23. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th rev. Geneva, Switzerland: World Health Organization; 1992
24. Kramer MS, Platt RW, Wen SW, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics. 2001;108(2) . Available at: www.pediatrics.org/cgi/content/full/108/2/e35
25. Yeh TF, Lin YJ, Lin HC, et al. Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med. 2004;350 :1304 –1313[Abstract/Free Full Text]
26. Baud O. Postnatal steroid treatment and brain development. Arch Dis Child. 2004;89 :96 –100[Free Full Text]
27. Short EJ, Klein NK, Lewis BA, et al. Cognitive and academic consequences of bronchopulmonary dysplasia and very low birth weight: 8-year-old outcomes. Pediatrics. 2003;112(5) . Available at: www.pediatrics.org/cgi/content/full/112/5/e359
28. Barrington KJ. The adverse neurodevelopmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr. 2001;1 :1[Medline]
29. Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993–1994. Pediatrics. 2000;105 :1216 –1226[Abstract/Free Full Text]
30. Hintz SR, Kendrick DE, Vohr BR, et al. Changes in neurodevelopmental outcomes at 18 to 22 months' corrected age among infants of less than 25 weeks' gestational age born in 1993–1999. Pediatrics. 2005;115 :1645 –1651[Abstract/Free Full Text]
31. Vohr BR, Wright LL, Poole K, et al. Neurodevelopmental outcomes of extremely low birth weight infants less than 32 weeks' gestation between 1993 and 1998. Pediatrics. 2005;116 :635 –643[Abstract/Free Full Text]
32. Doyle LW, Anderson PJ; Victorian Infant Collaborative Study Group. Improved neurosensory outcome at 8 years of age of extremely low birth weight children born in Victoria over 3 different eras. Arch Dis Child Fetal Neonatal Ed. 2005;90 :F484 –F485[Abstract/Free Full Text]
33. Nosarti C, Al-Asady MHS, Frangou S, Stewart AL, Rifkin L, Marray RM. Adolescents who were born very preterm have decreased brain volumes. Brain. 2002;125 :1616 –1623[Abstract/Free Full Text]
34. Abernethy LJ, Cooke RW, Foulder-Hughes L. Caudate and hippocampal volumes, intelligence, and motor impairment in 7-year-old children who were born preterm. Pediatr Res. 2004;55 :884 –893[CrossRef][ISI][Medline]
35. Lodygensky GA, Rademaker K, Zimine S, et al. Structural and functional brain development after hydrocortisone treatment for neonatal chronic lung disease. Pediatrics. 2005;116 :1 –7[Abstract/Free Full Text]
36. Hassan AH, von Rosenstiel P, Patchev VK, Holsboer F, Almeida OF. Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone. Exp Neurol. 1996;140 :43 –52[CrossRef][ISI][Medline]
37. Wu YW, Colford JM. Chorioamnionitis as a risk factor for cerebral palsy: a meta-analysis. JAMA. 2000;284 :1417 –1424[Abstract/Free Full Text]
38. Wilson-Costello D, Borawski E, Friedman H, Redline R, Fanaroff A, Hack M. Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children. Pediatrics. 1998;102 :315 –322[Abstract/Free Full Text]
39. Grether, JK, Nelson KB, Emery ES, III, Cummins SK. Prenatal and perinatal factors and cerebral palsy in very low birth weight infants. J Pediatr. 1996;128 :407 –414[CrossRef][ISI][Medline]
40. Murphy DJ, Sellers S, MacKenzie IZ, Yudkin PL, Johnson AM. Case control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet. 1995;346 :1449 –1454[CrossRef][ISI][Medline]
41. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292 :2357 –2365[Abstract/Free Full Text]
42. Dammann O, Leviton A. Maternal intrauterine infection, cytokines and brain damage in the preterm newborn. Pediatr Res. 1997;42 :1 –8[ISI][Medline]
43. Yoon BH, Jun JK, Romero R, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1B, and tumor necrosis factor-a), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997;177 :19 –26[CrossRef][ISI][Medline]
44. Aly H, Herson V, Duncan A, et al. Is bloodstream infection preventable among premature infants? A tale of two cities. Pediatrics. 2005;115 :1513 –1518[Abstract/Free Full Text]
45. Kumar P. Effect of decreased use of postnatal corticosteroids on morbidity in extremely low birthweight infants. Am J Perinatol. 2005;22 :77 –81[CrossRef][ISI][Medline]
46. Kaempf JW, Campbell B, Sklar RS, et al. Implementing potentially better practices to improve neonatal outcomes after reducing postnatal dexamethasone use in infants born between 501 and 1250 grams. Pediatrics. 2003;111(4 pt 2) . Available at: www.pediatrics.org/cgi/content/full/111/4/SE1/e534
47. Nelson KB, Ellenberg JH. Children who "outgrew" cerebral palsy. Pediatrics. 1982;69 :529 –536[Abstract/Free Full Text]
48. Ment LR, Vohr B, Allen W, et al. Change in cognitive function over time in very low-birth-weight infants. JAMA. 2003;289 :705 –711[Abstract/Free Full Text]
49. Hack M, Taylor HG, Drotar D, et al. Poor predictive validity of the Bayley Scales of Infant Development for cognitive function of extremely low birth-weight children at school age. Pediatrics. 2005;116 :333 –341[Abstract/Free Full Text]
50. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity for very low birth weight infants, 1991–1999. Pediatrics. 2002;110 :143 –151[Abstract/Free Full Text]
51. Berlin LJ, Brooks-Gunn J, McCarton C, McCormick MC. The effectiveness of early intervention: existing risk factors and pathways to enhanced development. Prev Med. 1998;27 :238 –245[CrossRef][ISI][Medline]
52. Blauw-Hosper CH, Hadders-Algram. A systematic review of the effects of early intervention on motor development. Dev Med Child Neurol. 2005;47 :421 –432[CrossRef][ISI][Medline]
53. Johnson S, Ring W, Anderson P, Marlow N. Randomized trial of parental support for families with very preterm children: outcome at 5 years. Arch Dis Child. 2005;90 :909 –915[Abstract/Free Full Text]
54. Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003;349 :2099 –2107[Abstract/Free Full Text]
55. Mestan KKL, Marks JD, Hecox K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med. 2005;353 :23 –32[Abstract/Free Full Text]
56. Field D, Elbourne D, Truesdale A, et al. Neonatal ventilation with inhaled nitric oxide versus ventilatory support without inhaled nitric oxide for preterm infants with severe respiratory failure: the INNOVO multicentre randomised controlled trial. Pediatrics. 2005;115 :926 –936[Abstract/Free Full Text]
57. Van Meurs KP, Wright LL, Ehrenkranz RA, et al. Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med. 2005;353 :13 –22[Abstract/Free Full Text]
58. Silverman WA. Personal reflections on lessons learned from randomized trials involving newborn infants from 1951 to 1967. Clin Trials. 2004;1 :179 –184[Free Full Text]
59. Goldenberg RL, Jobe AH. Prospects for research in reproductive health and birth outcomes. JAMA. 2001;285 :633 –639[Abstract/Free Full Text]

This article has been cited by other articles:

				D. Moster, R. T. Lie, and T. Markestad Long-Term Medical and Social Consequences of Preterm Birth N. Engl. J. Med., July 17, 2008; 359(3): 262 - 273. [Abstract] [Full Text] [PDF]

				S. M. Manning, D. M. Talos, C. Zhou, D. B. Selip, H.-K. Park, C.-J. Park, J. J. Volpe, and F. E. Jensen NMDA Receptor Blockade with Memantine Attenuates White Matter Injury in a Rat Model of Periventricular Leukomalacia J. Neurosci., June 25, 2008; 28(26): 6670 - 6678. [Abstract] [Full Text] [PDF]

				E. C. Eichenwald and A. R. Stark Management and Outcomes of Very Low Birth Weight N. Engl. J. Med., April 17, 2008; 358(16): 1700 - 1711. [Full Text] [PDF]

				O Khwaja and J J Volpe Pathogenesis of cerebral white matter injury of prematurity Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2008; 93(2): F153 - F161. [Abstract] [Full Text] [PDF]

				K. Kobaly, M. Schluchter, N. Minich, H. Friedman, H. G. Taylor, D. Wilson-Costello, and M. Hack Outcomes of Extremely Low Birth Weight (<1 kg) and Extremely Low Gestational Age (<28 Weeks) Infants With Bronchopulmonary Dysplasia: Effects of Practice Changes in 2000 to 2003 Pediatrics, January 1, 2008; 121(1): 73 - 81. [Abstract] [Full Text] [PDF]

				M. Ahronovich, I. S. Baron, and F. Litman Improved Outcomes of Extremely Low Birth Weight Infants Pediatrics, May 1, 2007; 119(5): 1044 - 1044. [Full Text] [PDF]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via ISI Web of Science (16) Citing Articles via Google Scholar Google Scholar Articles by Wilson-Costello, D. Articles by Hack, M. Search for Related Content PubMed PubMed Citation Articles by Wilson-Costello, D. Articles by Hack, M. Related Collections Premature & Newborn

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2007 American Academy of Pediatrics. All rights reserved.