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* 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
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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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.
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METHODS |
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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.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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85) were 21% in both epochs (Table 4).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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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.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address correspondence to Susan R. Hintz, MD, Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, 750 Welch Rd, Suite 315, Palo Alto, CA 94304. E-mail: srhintz{at}stanford.edu
No conflict of interest declared.
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