Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California
Research Triangle Institute, Research Triangle Park, North Carolina
Women and Infants’ Hospital, Providence, Rhode Island
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
ABSTRACT
Background. Increased survival rates for extremely preterm, extremely low birth weight infants during the postsurfactant era have been reported, but data on changes in neurosensory and developmental impairments are sparse.
Objective. To compare neuromotor and neurodevelopmental outcomes at 18 to 22 months' corrected age for infants of <25 weeks' estimated gestational age (EGA) who were born in the 1990s.
Methods. This was a multicenter, retrospective, comparative analysis of infants of <25 weeks' EGA, with birth weights of 501 to 1000 g, born between January 1993 and June 1996 (epoch I) or between July 1996 and December 1999 (epoch II), in the National Institute of Child Health and Human Development Neonatal Research Network. Neurodevelopmental assessments were performed at 18 to 22 months' corrected age. Logistic-regression models were constructed to evaluate the independent risk of cerebral palsy, Mental Development Index of <70, Psychomotor Development Index of <70, and neurodevelopmental impairment.
Results. A total of 366 patients in epoch I and 473 patients in epoch II were evaluated. Prenatal steroid use, cesarean section, surfactant treatment, bronchopulmonary dysplasia, and severe retinopathy of prematurity were more likely in epoch II, whereas Apgar scores of <5 at 5 minutes, patent ductus arteriosus, and severe intraventricular hemorrhage were more likely in epoch I. The prevalences of cerebral palsy, Psychomotor Development Index of <70, and neurodevelopmental impairment were similar between epochs. The prevalences of Mental Development Index of <70 were 40% for epoch I and 47% for epoch II. Regression analysis revealed that epoch II was an independent risk factor for Mental Developmental Index of <70 (epoch I versus II: odds ratio: 0.63; 95% confidence interval: 0.45–0.87) but not for other outcomes.
Conclusions. Early childhood neurodevelopmental outcomes among infants of <25 weeks' EGA are not improving in the postsurfactant era, despite more aggressive perinatal and neonatal treatment. Later childhood follow-up assessment is needed to delineate trends in severe cognitive impairment in this extremely high-risk group.
Key Words: extremely low birth weight extremely premature surfactant neurodevelopmental cerebral palsy Bayley Scales of Infant Development II
Abbreviations: NDI, neurodevelopmental impairment BW, birth weight MDI, Mental Development Index PDI, Psychomotor Development Index ROP, retinopathy of prematurity BPD, bronchopulmonary dysplasia CI, confidence interval OR, odds ratio EGA, estimated gestational age CP, cerebral palsy NICHD, National Institute of Child Health and Human Development IVH, intraventricular hemorrhage VLBW, very low birth weight PDA, patent ductus arteriosus BSID-II, Bayley Scales of Infant Development II
Advances in perinatal and neonatal medicine in the past 2 decades, including the introduction of surfactant therapy, have resulted in improved survival rates for premature and very low birth weight (VLBW) infants.1,2 Many studies have found that this survival benefit extends to the most immature and smallest infants with extremely low birth weights (BWs)3–6 and that survival rates may be continuing to improve in the postsurfactant era2,3,7
Data on changes in rates of major morbidity and neurodevelopmental impairments are sparse but concerning. The incidence of chronic lung disease, severe intracranial hemorrhage, and/or proven necrotizing enterocolitis increased from 41% in 1991 to 56% in 1996 among infants with BWs of 501 to 750 g in the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network.2 Hack and Fanaroff8 reported that chronic lung disease increased among infants with BWs of 500 to 749 g who were born in 1993–1995, compared with 1990–1992 (63% vs 41%). Neurodevelopmental outcomes have apparently not improved among the smallest and most premature infants in the more recent era, compared with earlier time periods.1,4,9 Several reports suggest that the rates of some adverse neuromotor and cognitive outcomes may be increasing in this high-risk group.4,5,8
If resuscitation and technical interventions are successful in saving the lives of the most premature infants but have no measurable effect on long-term outcomes, increasing numbers of disabled, formerly premature infants will result, affecting the resources of family, schools, and society.10,11 Furthermore, if major in-hospital morbidities, some of which have been linked with adverse neurosensory and cognitive findings,1,12–16 are more common among these high-risk infants, then outcomes may in fact be getting worse. The degree to which improvements in neurodevelopmental outcomes can be achieved for the most premature infants is unclear, especially in the postsurfactant era. We therefore compared major neurodevelopmental outcomes at 18 to 22 months' corrected age among infants born at <25 weeks' estimated gestational age (EGA) and BW of 501 to 1000 g in the NICHD Neonatal Research Network during 2 postsurfactant time periods.
METHODS
Patient Selection and Definitions
The study compared infants born at <25 weeks' EGA, with BWs of 501 to 1000 g, and entered in the multicenter NICHD Neonatal Research Network VLBW Registry during 2 time periods in the postsurfactant era. Epoch I included infants born between January 1, 1993, and June 30, 1996. Epoch II included infants born between July 1, 1996, and December 31, 1999. These time periods were chosen for comparison of the neurodevelopmental outcomes of infants born during early and more recent postsurfactant periods; the US Food and Drug Administration approved Exosurf Neonatal (colfosceril; GlaxoSmithKline, Brentford, United Kingdom) in 1990 and Survanta (beractant; Abbott Laboratories, Abbott, IL) in 1991.
The multicenter VLBW Registry was developed to survey practices, to assess morbidity and mortality rates, and to provide information for the planning of clinical trials. Only data from centers that participated in both time periods were used in the analysis (see "Acknowledgments"). Each center's institutional review board reviewed the data collection procedures. Infants were entered in the VLBW Registry if they were born alive but died in the delivery room of a Network center or if they were admitted to a Network center within 14 days after birth. Research nurses collected demographic, perinatal, and infant data at each center, with common definitions developed by the investigators and described in previous publications.2,7,17 Timing of rupture of membranes was noted. Prenatal antibiotic treatment was defined as administration of any antibiotic to the mother during the admission that resulted in delivery. Prenatal steroid treatment was defined as administration of any corticosteroid to accelerate fetal lung maturity in the present pregnancy. EGA was determined as the best obstetric estimate based on the last menstrual period, standard obstetric parameters, and ultrasonographic findings. If there was a 2-week range of gestational ages among obstetric estimates, then the lowest estimate was used. If there was a 3-week range or if several estimates existed, then the median estimate of gestational age was used. Data were also collected pertaining to diagnoses, treatments, and in-hospital morbidities until death, discharge, or 120 days. If the patients remained in the hospital for >120 days, even if they were transferred to another facility, data were collected regarding death or date of discharge. Surfactant treatment was defined as at least 1 dose of any surfactant. Indomethacin treatment was for closure of a patent ductus arteriosus (PDA) diagnosed through clinical means or echocardiography. Prophylactic indomethacin was administration of the drug for prevention of PDA or severe intraventricular hemorrhage (IVH). IVH was reported according to the classification described by Papile et al.18 Cystic periventricular leukomalacia was defined as diagnosis through head ultrasonography performed after 2 weeks of age; if head ultrasonography was not performed after 2 weeks of age, then no report was made regarding the presence or absence of cystic periventricular leukomalacia. Early sepsis was defined as culture-proven septicemia or bacteremia at 72 hours and late sepsis as culture-proven septicemia or bacteremia at >72 hours. Necrotizing enterocolitis was defined as modified Bell's classification stage IIA or greater.19 The frequency of retinopathy of prematurity (ROP) stage 3 or greater with "plus" disease in either eye was evaluated for this analysis. Bronchopulmonary dysplasia (BPD) was defined as receiving supplemental oxygen at 36 weeks' postconceptional age (determined as the best obstetric estimate) or supplemental oxygen at hospital discharge, whichever occurred first. Postnatal steroid treatment was any steroid given for the prevention or treatment of BPD.
Neurodevelopmental Assessments
Comprehensive follow-up examinations of extremely low BW infants were performed at 18 to 22 months' postconceptional age. The Neonatal Research Network Follow-up Study included neurodevelopmental follow-up evaluations of infants with BWs of <1000 g. The institutional review board at each center approved participation in the Neonatal Research Network Follow-up Study. Waivers of consent were granted or informed consent was sought according to the specifications of each site's institutional review board. Contact to schedule the visit was made with a telephone call, postcard, or letter. The elements of the follow-up visit were described in detail previously.16 Certified developmentalists performed neurologic assessments. Neonatal Research Network Follow-up Study principal investigators were trained in the examination procedure in an annual 2-day workshop. The neurologic examination was based on the Amiel-Tison20 assessments, and the gross motor skills examination was developed from the work of Russell et al21 and Palisano et al.22 Cerebral palsy (CP) was defined as a nonprogressive central nervous system disorder characterized by abnormal muscle tone in at least 1 extremity and abnormal control of movement and posture. The Bayley Scales of Infant Development II (BSID-II)23 were administered by experienced testers at each site who had been certified by 1 of 4 master examiners. BSID-II scores of 100 ± 15 represent the mean ± 1 SD. Scores of 49 were assigned to infants whose extremely severe neurologic or developmental impairment prevented their examination. Examiners noted the reasons for unsuccessful BSID-II testing. Examiners were not able to administer the BSID-II Mental Development Index (MDI) evaluation successfully for reasons other than severe neurologic impairment or NDI for 25 patients in epoch I (acute illness, n = 4; behavioral problem, n = 6; sensory loss for a normal or suspected mildly delayed child, n = 1; other, n = 14) and 37 patients in epoch II (acute illness, n = 1; language problem, n = 1; behavioral problem, n = 10; sensory loss for a normal or suspected mildly delayed child, n = 10; other, n = 15). The BSID-II Psychomotor Development Index (PDI) evaluation was not administered successfully for 28 patients in epoch I (acute illness, n = 4; behavioral problem, n = 6; sensory loss for a suspected mildly delayed child, n = 1; other, n = 17) and 46 in epoch II (acute illness, n = 1; language problem, n = 1; behavioral problem, n = 16; sensory loss for a suspected mildly delayed child, n = 10; other, n = 18).
Deafness was defined as the use of hearing aids in both ears. Blindness was defined as no useful vision in either eye. Neurodevelopmental Impairment (NDI) was defined as 1 of the following: CP, MDI score of <70, PDI score of <70, deafness, or blindness. Neurosensory impairment was defined as 1 of the following: CP, deafness, or blindness, regardless of BSID-II scores. Unimpaired was defined as none of the following: CP, blindness, deafness, MDI score of <85, or PDI score of <85. Socioeconomic status information, including the highest level of education attained by the primary caregiver, was also obtained at the time of the follow-up visit.
Statistical Analyses
Analyses were performed with the continuity-adjusted 2 test or Fisher's exact test for categorical data and the t test, Wilcoxon rank-sum test, analysis of variance, or analysis of covariance for continuous data. Logistic-regression models were developed to evaluate epoch-related risks for CP, BSID-II MDI scores of <70, BSID-II PDI scores of <70, and NDI, with adjustment for perinatal and neonatal variables. Numerous potential maternal, perinatal, neonatal, and demographic risk factors were evaluated as predictors of these neurodevelopmental outcomes; factors included those noted above (in "Patient Selection and Definitions") and the age of the mother, mode of delivery, insurance type, educational level of the primary caregiver, and whether the infant was living with the mother at the time of the follow-up evaluation. Factors were entered into regression models and final best-fit models were constructed through stepwise, nonautomatic elimination. All final models forced inclusion of Network center, epoch, BW, EGA, gender, race, outborn status, multiple gestation, and rupture of membranes of >24 hours.
RESULTS
The progression of study patients from hospital discharge to neurodevelopmental follow-up is shown in Figure 1. For epoch I, 1170 infants of <25 weeks' EGA and 501 to 1000 g were entered in the NICHD VLBW registry, of whom 473 (40.4%) survived to discharge. For epoch II, 1260 infants were entered, of whom 544 (43.2%) survived to discharge. The survival rates were not significantly different (P = .18). Of 459 epoch I infants available for follow-up evaluations at 18 to 22 months' corrected age, 366 completed follow-up assessments (79.7% follow-up rate). Of 533 epoch II infants available for 18- to 22-month follow-up evaluations, 473 completed follow-up assessments (88.7% follow-up rate). Infants meeting inclusion criteria for this analysis in Network centers participating during the entire study period represented 12.7% of the VLBW Registry during epoch I and 13.2% during epoch II (P = .25).
Demographic and perinatal characteristics are shown in Table 1. There were significant epoch-related differences in race distribution. Prenatal antibiotic treatment, prenatal steroid treatment, and cesarean section delivery were more frequent in epoch II. Apgar scores of <5 at 5 minutes were significantly less frequent in epoch II than in epoch I.
Common in-hospital treatments and diagnoses are presented in Table 2. Surfactant, prophylactic indomethacin, BPD, and ROP of stage 3 or greater with plus disease were significantly more frequent in epoch II. Diagnoses of PDA, necrotizing enterocolitis, and grade III or IV IVH were more likely in epoch I.
Major neurosensory outcomes at 18 to 22 months are shown in Table 3. There were no differences between epochs. BSID-II MDI and PDI results are shown in Table 4. There were no significant differences between the epochs, although 47% of children in epoch II and 40% of those in epoch I had MDI scores of <70 (P = .06). Among those with MDI scores of <70 were 41 infants (12%) in epoch I and 70 infants (16%) in epoch II who were assigned scores of 49 because profound developmental impairment rendered them unable to be tested (P = .14). There were 51 infants (15%) in epoch I and 69 infants (16%) in epoch II assigned PDI scores of 49 (P = .76). Among the 108 infants in epoch I and 134 infants in epoch II with PDI scores of <70, 56 (53%) and 71 (53%), respectively, were also diagnosed as having CP. The proportions of patients who were unimpaired at 18 to 22 months (no CP, no deafness or blindness, and both MDI and PDI scores of 85) were 21% in both epochs (Table 4).
Regression analysis to determine the epoch-related risks for neurodevelopmental outcomes at 18 to 22 months' corrected age revealed that epoch was not an independent risk factor for CP, PDI scores of <70, or NDI, but a lower risk of MDI scores of <70 in epoch I, compared with epoch II, was noted (Table 5). Epoch was not an independent risk factor for neurosensory impairment (epoch I versus epoch II: odds ratio [OR]: 1.03; 95% confidence interval [CI]: 0.69–1.53). Epoch was also not an independent risk factor for unimpaired status, although being male (OR: 0.58; 95% CI: 0.38–0.89), grade III or IV IVH (OR: 0.50; 95% CI: 0.30–0.84), and postnatal steroids (OR: 0.58; 95% CI: 0.35–0.96) were significant factors.
DISCUSSION
In this analysis of infants born at <25 weeks' EGA, with BWs of 501 to 1000 g, during 2 postsurfactant time periods, adverse neuromotor and neurodevelopmental outcomes were common for both epochs at 18 to 22 months' corrected age. Although the higher rates of cesarean section delivery, prenatal antibiotic treatment, prenatal steroid treatment, and surfactant use suggested substantial changes in perinatal and neonatal management approaches in epoch II, compared with epoch I, this did not result in improved early childhood outcomes. Unadjusted comparisons of neurosensory and neurodevelopmental outcomes revealed no epoch-related differences. In multivariate regression analyses, epoch was not an independent risk factor for CP, PDI scores of <70, or NDIs, but a greater adjusted risk for MDI scores of <70 was noted in the more recent time period.
We present evidence of changing management strategies and morbidity profiles between epochs. Prophylactic indomethacin use was more frequent during epoch II. Significant decreases in the frequency of PDA and severe IVH were noted in epoch II, compared with epoch I, but were not associated with improvements in neurodevelopmental outcomes. An absence of improved neurodevelopmental outcomes was also observed in a multicenter, randomized, controlled trial of prophylactic indomethacin treatment to decrease severe IVH.24 BPD and severe ROP were more likely in epoch II. This finding could suggest greater severity of illness in the later time period, although other markers, such as mean BW and EGA, incidence of sepsis, and length of hospital stay, were not different between the epochs. Both BPD and severe ROP have been reported to be associated with adverse neuromotor, cognitive, or functional outcomes.13,16,25 Postnatal steroid use was high throughout the study period and highest in epoch II; whether this was indicative of the tenuous condition of the patient population or of routine clinical practice is not clear. It is important to note that infants in both epochs were born before the American Academy of Pediatrics and Canadian Pediatric Society statement recommending limitations on the use of postnatal corticosteroids.26
These data may seem to represent a more significant degree of adverse neurodevelopmental outcome than reported by some, but this disparity is a common challenge to comparisons of outcomes studies. Varying ages at follow-up evaluations, different definitions of impairment, and different approaches to reporting of cognitive delays are used by researchers. Many previous studies reported outcomes based on BW rather than gestational age, including small-for-gestational age infants in study cohorts. Even in studies of extremely preterm patients, the gestational age "upper limit" is frequently higher than that defined in the present analysis.5,9,14,27 However, our results do compare favorably with previous studies. Jacobs et al9 reported that 23- and 24-week EGA infants experienced 64% and 43% rates of any impairment or disability, respectively, at 18 to 24 months' corrected age. For a cohort of 23- to 25-week EGA infants born in 1990–1994, Emsley et al5 reported a 68% rate of impairment in later childhood. For a small subgroup of 24-week EGA infants within a 24- to 26-week EGA cohort, Piecuch et al14 found that 39% had "deficient" cognitive neurodevelopment and 33% were "borderline" at 32 months. Of note, and similar to our findings, Hack and Fanaroff8 reported a 48% prevalence of MDI scores of <70 at 20 months' corrected age among 500- to 749-g infants born in 1993–1995, which was more than double that in the previous postsurfactant time period (1990–1992).1 The later birth cohort also experienced a 51% prevalence of overall impairment or disability.
There are possible criticisms of this study. Infants 500 g at birth were excluded from the analysis. Recent reports suggested that the outcomes of this subcategory of "micronate" patients might be uniquely poor.28,29 The approach to resuscitation and aggressive management for these infants could differ substantially from that for larger extremely preterm infants and might be markedly inconsistent among institutions and practitioners. It is likely that the outcomes of these extraordinarily low BW infants should be analyzed separately. Follow-up rates were also different between the epochs. This finding might be explained by the fact that the Neonatal Research Network Follow-up Study had just been launched in epoch I, and mechanisms for ensuring the best possible follow-up compliance at each Network center likely improved over time. Whether there was preferential loss of ascertainment of poor cognitive performers in the first time period cannot be known absolutely, but loss to follow-up monitoring of patients in relatively intact condition would be more likely. It should also be recognized that these data do not represent a population-based cohort. Although only centers that participated in the Neonatal Research Network during both epochs were included in this analysis, subtle alterations in referral patterns or regional care plans might have occurred; such changes could also explain differences in race distributions between the time periods.
The lack of improvement and the possible shift toward worsening severe cognitive delays in the later time period are concerning. In this analysis, epoch-related differences in proportions of MDI scores of <70 could not be explained after adjustment for multiple maternal, perinatal, neonatal, and sociodemographic factors. This suggests that unmeasured or unknown factors could have affected patients in epoch II differently. Our data also suggest that a more aggressive perinatal and early neonatal management approach was taken during the later time period. It must therefore be considered that other treatments, interventions, and perhaps unconventional strategies were also applied, because survival of the most extremely preterm infants seemed increasingly attainable, and indeed expected, in the more recent time period. Many such strategies are relatively untested in the extremely preterm population and could have unforeseen iatrogenic effects.
Finally, it is crucial to remember that these data represent very early childhood outcomes. Longitudinal follow-up monitoring among infants enrolled in the Randomized Indomethacin IVH Prevention Trial demonstrated improvement in IQ scores over time, although decreased Peabody Picture Vocabulary Test-Revised scores were observed among patients with early IVH and subsequent severely abnormal neuroimaging findings.30 That report also suggested that use of special services accorded a significant benefit to children of mothers with less than high school education, with respect to verbal IQ scores. However, a recent long-term follow-up study of children born at <26 weeks' EGA revealed that moderate to severe impairment was still common at 6 years of age.31 In that study, severe disability at 30 months of age (nonambulatory CP, IQ scores 3 SD below the mean, profound hearing loss, or blindness) was a good predictor of moderate or severe disability at 6 years among extremely preterm children, but other disabilities were not. With more consistent resuscitation and intervention, improved survival rates for extremely preterm infants, and continued uncertainty regarding factors associated with adverse functional and cognitive outcomes, truly long-term neurodevelopmental follow-up monitoring of these highest-risk patients should be a priority.
ACKNOWLEDGMENTS
Members of the NICHD Neonatal Research Network were: Case Western Reserve University (U10 HD21364): Avroy A. Fanaroff, MB, BCh (principal investigator); Dee Wilson, MD (Follow-up Study principal investigator); Maureen Hack, MB, ChB; Nancy Newman, RN; University of Cincinnati (U10 HD27853): Alan Jobe, MD (chairman); Edward F. Donovan, MD (principal investigator); Jean Steichen, MD (Follow-up Study principal investigator); Marcia Mersmann, RN; Emory University (U10 HD27851): Barbara J. Stoll, MD (principal investigator); Ellen Hale, RN; Indiana University (U10 HD27856): James A. Lemons, MD (principal investigator); Anna Dusick, MD (Follow-up Study principal investigator); Scott C. Denne, MD; Diana Appel, RN; University of Miami (U10 HD21373): Charles R. Bauer, MD (principal investigator); Emmalee S. Bandstra, MD; Amy Mur Worth, RN, MSN; National Institute of Child Health and Human Development: Linda L. Wright, MD (principal investigator); Elizabeth M. McClure, MEd; University of New Mexico (U10 HD27881): Lu-Ann Papile, MD (principal investigator); Gean Lowe, PhD (Follow-up Study principal investigator); Conra Backstrom, RN; Research Triangle Institute (U01 HD36790): W. Kenneth Poole, PhD (principal investigator); Betty Hastings; Stanford University (U10 HD27880): David K. Stevenson, MD (principal investigator); Susan Hintz, MD (Follow-up Study principal investigator); Bethany Ball, BS; University of Tennessee at Memphis (U10 HD21415): Sheldon B. Korones, MD (principal investigator); Kimberly Yolton, PhD (Follow-up Study principal investigator); Henrietta Bada, MD; Tina Hudson, RN; University of Texas Southwestern Medical Center (U10 HD21373): Jon E. Tyson, MD, MPH (principal investigator); Brenda Morris, MD (Follow-up Study principal investigator); Kathleen Kennedy, MD; Susie Madison, RN; Wayne State University (U10 HD21385): Seetha Shankaran, MD (principal investigator); Yvette Johnson, MD (Follow-up Study principal investigator); Ganesh Konduri, MD; Geraldine Muran, RN; Women and Infants Hospital (U10 HD27904): William Oh, MD (principal investigator); Betty Vohr, MD (Follow-up Study principal investigator); Barbara Stonestreet, MD; Angelita Hensman, RN; Yale University (U10 HD27871): Richard A. Ehrenkranz, MD (principal investigator); Linda Mayes, MD (Follow-up Study principal investigator); Elaine Sherwonit, RN; Patricia Gettner, RN; University of Alabama at Birmingham (U10 HD34216): Waldemar A. Carlo, MD (principal investigator); Kathleen Nelson, MD (Follow-up Study principal investigator); Monica V. Collins, RN; Harvard University (U10 HD34167): Ann R. Stark, MD (principal investigator); Kerri Fournier, RN.
FOOTNOTES
Accepted Jan 20, 2005.
No conflict of interest declared.
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