Objective. Extremely low birth weight (ELBW) infants are at greater risk for neurodevelopmental delay than full-term infants. Outcomes may be compromised secondary to abnormal brain development associated with complications of prematurity. Long-term cognitive outcome has also been reported to be significantly influenced by postnatal factors. The objective of this study was to clarify the effects of prematurity separate from environmental factors on growth and neurodevelopmental outcomes by comparing ELBW children with their full-term siblings.
Methods. The study consisted of 25 ELBW children, a subset selected from a larger population of infants who were <801 g birth weight and enrolled in a longitudinal follow-up project from birth and their 25 full-term, full-weight siblings. Twenty-three sets of siblings were evaluated at 5 years of age and 2 sets at 3 years of age with standardized medical, social, cognitive, motor, and language testing. Physical and neurodevelopmental outcomes were compared between groups, controlling for gender and socioeconomic status (SES).
Results. At follow-up, ELBW children were lighter, were shorter, and had smaller head circumference. The ELBW children had lower Stanford-Binet IQs (85 ± 12 [mean ± SD] and 95 ± 11), with lower Stanford-Binet subtests except short-term memory and quantitative reasoning, lower spelling scores on the Wide Range Achievement Test, and lower Peabody motor quotients (79 ± 11 and 92 ± 17). Preschool Language Scale quotients were not different, but other receptive language measures were lower for ELBW children. High SES seemed to modify the impact of preterm status on cognitive and language but not motor scores. The mean IQ for high-SES ELBW children was equivalent to that of the low-SES term siblings.
Conclusions. Preschool-age cognitive and language functioning in ELBW children seemed to be affected by both prenatal and birth influences (preterm status) and postnatal influences (SES variables). Motor scores were significantly related to preterm status but not to SES.
Despite recent improvement in survival for low birth weight infants, there has been no apparent change in likelihood of neurodevelopmental disabilities for survivors.1–3 Cognitive functioning and psychomotor disabilities are most pronounced in infants with the lowest birth weight compared with heavier preterm and term infants, suggesting a gradient effect of prematurity on outcome.4–6 When attempting to define the independent contribution of prematurity on outcome, investigators have compared preterm infants with matched “normal birth weight” or “full-term” infants.4,5,7–10 Extremely low birth weight (ELBW) children score lower on cognitive, motor, and achievement tests and are significantly more likely to require special education at school age than are term control subjects.4,9,10 In general, major neurodevelopmental disabilities are correlated with neonatal medical complications, which are inversely proportional to gestational age (GA) and birth weight (BW).8,11 In addition, preterm births are more likely to occur in families with psychosocial risks,12 and these social factors also seem to contribute to compromised outcomes for the preterm child particularly related to cognitive and language measures.7,10,13 Environmental influences on infant development are complex and difficult to control for, even with a matched cohort.14 A full-term sibling who is raised in the same home as the ELBW child would seem to provide a unique comparison for assessing independent effects of prematurity on outcome while minimizing confounding genetic and postnatal psychosocial factors.
Since 1983, we have longitudinally assessed the outcome of ELBW infants.1 In this report, the objective was to compare ELBW children with their full-term siblings in early childhood to clarify the effects of prematurity separate from environmental factors on growth and neurodevelopmental outcomes.
We previously established a database for all infants who had a BW of 450 to 800 g and were born between January 1, 1983, and December 31, 1990,1,15 at hospitals associated with the University of Missouri-Kansas City School of Medicine. At discharge, surviving infants were enrolled in a multidisciplinary research follow-up clinic, which monitored outcome longitudinally throughout early childhood. ELBW children from that study were selected for this current project when they were singleton; had previously been evaluated at 3 or 5 years of age in the developmental follow-up research clinic; and had a healthy, term gestation (≥36 weeks’ GA), full sibling (same parents as the ELBW proband) who was available for testing at 3 or 5 years of age. ELBW children with major disabilities, including blindness, cerebral palsy (CP) that interfered with locomotion, or an IQ <68, were excluded from this project because it was anticipated that these infants would have poor neurodevelopmental outcome compared with healthy siblings. Similarly, term siblings who had a medical complication or birth defect potentially affecting neurodevelopmental outcome were excluded. The null hypothesis was that preterm infants without major disabilities would have no significant differences in growth and developmental quotients in early childhood compared with full-term siblings. Families provided written consent for follow-up in accordance with the University of Missouri-Kansas City Institutional Review Board guidelines.
For infants <801 g BW, the database included obstetric and neonatal management details and complications of the neonatal course as previously described.1,15 For this study, chronic lung disease (CLD) was defined as need for supplemental oxygen at 36 weeks’ postconceptional age, and intraventricular hemorrhage (IVH) was graded according to Papile et al.16 Grades 1 to 2 IVH were considered mild, and grades 3 to 4 were considered severe. Birth records of the full-term siblings were reviewed to determine BW, GA, and pre- and postnatal complications. The study sample of ELBW children was drawn from the 179 survivors who were followed in the research clinic to 5 years of age. Of these, 154 (86%) families were not eligible for this study for the following reasons: 24 ELBW children had major disabilities; 68 had only “half siblings” or no siblings; 20 had only preterm siblings; and 9 were multiple gestations. One term sibling had a seizure disorder, and 26 others were too old or too young for evaluations in this study. Of the remaining 31 ELBW families, 6 refused term sibling follow-up.
All ELBW children were evaluated in the multidisciplinary clinic at 36 ± 3 and 60 ± 3 months of age. Twenty-three full-term siblings were assessed at 60 ± 3 months, and 2 were assessed at 36 ± 3 months. ELBW and term siblings were tested in the same clinical setting with the same instruments at equivalent ages for a clinic visit time of ∼3.5 hours.1 There was no attempt to conceal the GA category from the evaluators. At each clinic visit, current health status, previous chronic illnesses or hospitalizations, and current educational programs were documented. Visual and hearing limitations were determined by history and review of ophthalmologic or audiologic evaluations when appropriate. A standard physical examination, including neurologic examination, was performed by a developmental pediatrician or a neonatologist. Recorded growth measurements included weight, length, and head circumference. Socioeconomic status (SES) was evaluated by social worker interview with calculation of the Hollingshead Four Factor Index of Social Status.17 Evaluation tools used at 36 and 60 months of age included Stanford-Binet (SB) IQ,18 Peabody Developmental Motor Scales (psychomotor quotient [PMQ]),19 and Preschool Language Scale (PLS).20 Children who were evaluated at 60 months were additionally tested with the Goldman Fristoe Test of Articulation,21 Wide Range Achievement Test,22 Peabody Picture Vocabulary Test (PPVT),23 Test of Auditory Comprehension of Language (TACL),24 and Goodenough-Harris Drawing Test.25 For all instruments, raw scores were converted to standardized quotients for comparison. At 36 months of age, developmental quotients and growth parameters of the ELBW children were corrected for weeks of prematurity; for 60-month assessments, chronologic ages were used for all analyses, although group comparisons of 60-month IQ and PMQ were repeated using adjusted ages for ELBW children. At each visit, children were categorized as normal, abnormal, or suspect, using cognitive, motor, and language quotients and neurosensory findings as previously described.1 Briefly, a child was characterized as normal when cognitive, language, and motor quotients were >83 and the child was free of CP and neurosensory impairments.
Data analysis was conducted with SPSS for Windows (Release 10.1; SPSS, Inc, Chicago, IL) and S-plus for Windows (Release 6.1; Insightful Corporation, Seattle, WA). Growth and neurodevelopmental outcome measures were compared between ELBW and full-term siblings by paired t tests for continuous data and χ2 analysis for categorical data. Independent effects of the between-group factor (term, preterm) and within-group variables (gender and SES) on cognitive, psychomotor, and language quotients were determined using a linear mixed effects model.26 For these analyses, the SES category for the family at the time of the ELBW visit was used. A separate analysis of variance using just ELBW children examined the effects of CLD and presence and severity of IVH on IQ and PMQ. All tests were 2-sided, using an α level of .05.
By study design, BW and GA of ELBW infants were significantly lower than for full-term siblings (702 ± 76 and 3215 ± 509 g, and 26.0 ± 1.6 and 38.8 ± 1.5 weeks; both P < .0000). Four (16%) ELBW infants were small for gestational age. Neonatal complications included mild IVH (6 [24%]), severe IVH (4 [16%]), necrotizing enterocolitis (1 [4%]), and CLD (8 [32%]). Fifteen of 25 (60%) ELBW children were first-born compared with 2 (8%) of 25 term children (P = .0002); however, at the time of each child’s evaluation, the average number of children in the home was no different (2.6 ± 0.9 for ELBW and 2.7 ± 0.8 for full-term siblings). Eight (32%) ELBW and 10 (40%) term siblings were male. The mean maternal age at evaluation was not different (ELBW: 33.2 ± 4.9 years; full-term: 34.5 ± 4.7 years). Eighteen of the mothers were married and living with their spouse at the time of the ELBW evaluation, although 2 of these subsequently divorced before the full-term sibling evaluation. Twenty-four of the 25 mothers had completed high school at the time of the initial clinic visit. Fifteen (60%) were white, and 10 (40%) were black. At the time of the ELBW evaluation, 9 (36%) were high SES (Hollingshead categories 1 and 2) and 8 (32%) were low SES (Hollingshead categories 4 and 5).
At 5 years of age, full-term siblings were significantly heavier than ELBW children (24 ± 3.5 and 16.7 ± 2.2 kg; P = .0002). Ninety-two percent of full-term siblings (21 of 23) were taller (mean ± standard deviation [SD]: 111 ± 5.0 and 106 ± 3.9 cm, respectively; P = .007), and 83% (19 of 23) had a larger head circumference than the ELBW children (51.3 ± 1.3 and 49.6 ± 2.2 cm; P = .001). These relationships held true when reanalyzed excluding the 4 small for gestational age ELBW children. Three (12%) term siblings and 12 (48%) ELBW children had been rehospitalized during the first 2 years of life (P = .01). Eight (75%) of the ELBW admissions were related to CLD or pulmonary infections. By preschool age, 3 term siblings and 6 ELBW children had tympanostomy tubes placed for chronic otitis media. None of the children had sensorineural hearing loss, and 1 each had conductive loss. Four of the ELBW children and 1 term sibling used corrective lenses. One ELBW child had mild CP.
Cognitive, language, and psychomotor testing results are displayed in Tables 1 to 3. All children completed the IQ testing, but 6 ELBW children and 3 term siblings were noncompliant with 1 or more of the other tests. The mean IQ for the ELBW cohort was 10 points lower than for the full-term siblings (Table 1). SB subtest scores were significantly lower for the preterm children except for quantitative reasoning and short-term memory. There were less striking differences in the Wide Range Achievement Test scores, which were significantly different only in spelling. Nonverbal cognitive maturity assessed by the Goodenough Drawing Test was also lower for ELBW children. There were no differences in PLS receptive or expressive language quotients between ELBW and term siblings. However, the mean PPVT and TACL standard scores were significantly lower for the ELBW children (Table 2). Mean Peabody PMQ and subtest quotients were also significantly lower for the ELBW children compared with full-term siblings (Table 3). Overall, 10 (40%) of the ELBW children and 19 (76%) of the full-term siblings were considered neurodevelopmentally normal (P = .02). Within the ELBW group, neither IVH nor CLD was an independent predictor of IQ (P = .49 and P = .86, respectively) or PMQ (P = .11 and P = .87).
Data were reanalyzed using a mixed effects model to assess the independent effects of preterm/term status, controlling for gender and SES, on outcome measures. Mean IQ was significantly related to term status (F = 10.2, P = .002), SES (F = 5.7, P = .006), and borderline for gender (F = 4.0, P = .05). As noted in Fig 1, for 21 (84%) of 25 pairs, the IQ of the ELBW child was less than that of the term sibling. However, independent of GA, the mean IQ for the high-SES children (n = 18) was 12 points higher (95% confidence interval [CI]: 5–18) than those in the low-SES category (n = 16). The mean IQ for low-SES term children was not significantly different from the mean IQ of high-SES ELBW children (87 ± 10 and 91 ± 12, respectively). At the extremes, the mean IQ of the high-SES term siblings was 20% higher than that of the low-SES ELBW children (101 ± 10 and 80 ± 11, respectively).
Language skills were assessed by several tools, which provided differing results. The PLS receptive and expressive language quotients were statistically related to SES and not different by term/preterm status or gender. Mean expressive quotients were 13 points higher (95% CI: 6–20), and receptive quotients were 14 points higher (95% CI: 4–23) for high-compared with low-SES siblings (F = 17.0, P = .002; F = 4.3, P = .02, respectively). Receptive language function assessed by PPVT and TACL, however, was significantly influenced by both preterm status and SES (PPVT: preterm/term status, F = 8.1, P = .007; SES, F = 4.4, P = .019; TACL: preterm/term status, F = 5.7, P = .022; SES, F = 5.5, P = .008) but not gender. The mean PPVT and TACL standard scores for the high-SES term and the low-SES ELBW siblings were 102 ± 9, 77 ± 17, 101 ± 10, and 77 ± 9, respectively. However, there were no differences between low-SES term and high-SES ELBW children for mean scores on PPVT (88 ± 7 and 88 ± 11) or TACL (85 ± 11 and 89 ± 12). Mean motor quotients were significantly higher for full-term compared with preterm siblings (F = 9.1, P = .004); however, for this measure, there was no relationship with SES (P = .52) or gender (P = .83).
Group differences for IQ and PMQ at 60 months were reassessed using measures adjusted for GA for ELBW children. With GA adjustment, there were no significant differences between term and ELBW siblings for IQ (95 ± 11 and 89 ± 12; P = .08) and PMQ (92 ± 17 and 90 ± 14; P = .65). Despite the adjustments, the ELBW sibling still had the lower IQ in 78% (18 of 23) and lower PMQ in 61% (14 of 23) of the dyads.
For the 5-year-old children, 19 (83%) of the ELBW children and 17 (74%) of the term siblings were in preschool. Seven (30%) of the ELBW children were in a special school setting, including developmental preschool (5) or language program (2). Three term siblings were enrolled in a language program.
Multiple reports in the past 30 years have indicated a high prevalence of developmental disabilities among surviving ELBW infants.1–5,27 Compared with term cohorts, on average, extremely preterm or ELBW children have lower IQs, have lower motor quotients, and more frequently have CP and neurosensory deficits.4,5 Perinatal biological risk factors that may contribute to poor fetal growth, preterm delivery, and subsequent medical complications are likely responsible for brain injuries and long-term disabilities in some infants.28,29 However, postnatal outcome is also affected by home environment, caregiving practices, effects of poverty, and other significant psychosocial factors.14,30–32 In comparative follow-up studies, it is very difficult to control for postnatal environmental factors, many of which are not clearly delineated.
The objective of this study was to determine whether ELBW children who seemed to be free of serious neurologic injury compared with their full-term siblings would have similar growth patterns and neurodevelopmental performance at preschool age. Thirteen percent of surviving ELBW infants were excluded because of major disabilities, a rate comparable to other series.9,33 We sought to use full siblings for comparison, anticipating that they would have similar home environments as well as shared genetic backgrounds with the ELBW child. Theoretically, the full-term siblings may also be uniquely different from randomly selected term children because they will be affected by the psychosocial impact of the extreme preterm delivery on family dynamics.34 Family disruption was frequently identified in our study population. A minority of ELBW children remained in an intact family at 5 years of age. In >40% of cases, parents of the ELBW infant chose not to have another child or had a subsequent child with a different partner. Preterm delivery is a known risk factor for having a subsequent preterm child.35 Twenty (32%) of 62 families that were available for this study had only prematurely born children. As a result of study enrollment criteria, the number of ELBW children available for this follow-up project was limited. Although this selected sample offers an opportunity for a unique comparative assessment of outcome of extreme prematurity, the findings cannot be generalized to all ELBW survivors, for whom more compromised outcomes might be expected.
In comparing this cohort of ELBW children with their full-term siblings, we found no apparent differences in health status, although the ELBW children had been hospitalized more frequently in early infancy. By preschool age, the ELBW children continued to be significantly lighter and shorter than their term siblings. In >80% of sibling pairs, the ELBW child also had a smaller head circumference, which has previously been associated with lower developmental performance.36 Cognitive testing demonstrated that 84% of the ELBW children had a lower IQ than their full-term siblings, and the mean ELBW IQ was nearly 1 full SD lower (85 vs 95) than that of the term child. In addition, 30% were identified as needing specialized educational support in the preschool setting. Thus, even this select group of ELBW children seemed to have significant cognitive disadvantage near school entry age compared with their full-term siblings.
Most of the siblings were compared at the 5-year evaluation, at which time ELBW scores were no longer adjusted for GA. Reexamination of the IQ and PMQ data using adjusted quotients for the ELBW children eliminated the statistical difference between groups for these measures. However, even after adjustment for GA, nearly 80% of the ELBW children had a lower IQ than their full-term sibling. Although it has been suggested that correction for GA may continue to be appropriate at school age for developmental assessment of extremely preterm infants,37 this is not the standard practice as reflected by the literature,4–7,33 and such comparisons do not seem practical, because these children will be “competing” in the classroom setting with other children of their chronologic age. Until additional investigation determines the validity of GA correction of psychometric studies for school-aged, preterm children, we believe that it is most appropriate to assess the data using outcome by chronologic age.
Only 1 other report has compared preterm infants with sibling control subjects. Hunt et al38 evaluated 19 infants who were <1500 g and had full-term siblings at 4 years of age or greater. They found an average IQ difference of 14.6 points overall and a 10.8-point difference among the 6 pairs in which the preterm child was believed to be “normal.” These results are similar to those of this current study, although the study sample of Hunt et al was born nearly 2 decades before and included much heavier, more mature infants.
The findings of our sibling study are also consistent with more recent investigations that have used matched term control subjects. Hack et al4 found that the average performance IQ at 8 years of age was 6 points lower for infants <750 g BW, whereas Saigal et al9 found that the mean IQ for infants <1000 g BW was 13 points lower than for normal-weight control subjects. In another study involving only middle-class infants, the ELBW children’s mean IQ was 14 to 17 points lower than full-weight control subjects’.5
In our study, the SES factor seemed to mitigate the impact of prematurity on cognitive performance. The mean IQ of the high-SES ELBW child was essentially the same as the mean for the low-SES full-term child (Fig 1). However, for the ELBW child, the negative impact of low SES seemed to be additive to the risk of prematurity, so the IQ of the low-SES ELBW child was, on average, nearly 2 SDs below that of the high-SES full-term child. Similar SES effects were identified with language testing. Studies of ELBW cohorts with large SES variation have consistently identified social risk factors as important predictors of cognitive and language performance.10,30,32
Motor quotients were also significantly lower for ELBW siblings despite protocol exclusion of ELBW children with severe CP. Findings were not significantly influenced by SES, suggesting that subtle motor dysfunction was related to biological injury with less potential for modification through postnatal experience. IVH and CLD, which have previously been related to neurodevelopmental outcome,4,7 were not independent predictors in this select ELBW sample.
Koeppen-Schomerus et al,39 by analysis of monozygotic versus dizygotic twins, determined that cognitive outcome for infants at high risk (<32 weeks’ GA) was affected by environmental factors more than common genetic influences. In our study, siblings did not have common perinatal risk factors but shared elements of postnatal care and had 50% genetic overlap. In conjunction with the findings of Koeppen-Schomerus et al,39 the results of our sibling comparison study add to growing evidence that suggests that even within the ELBW population, postnatal factors may have significant influence on some aspects of long-term developmental outcome.28,30
This work was supported by a grant from the Katharine B. Richardson Research Endowment Fund and the Clinical Scholars Award at Children’s Mercy Hospital.
We thank Cynthia Jacobsen, PhD, for language interpretation; Stephen Simon, PhD, for statistical support; and Marge Ellgen for manuscript preparation and assistance.
- Received March 3, 2003.
- Accepted June 23, 2003.
- Reprint requests to (H.W.K.) Section of Neonatal-Perinatal Medicine, Children’s Mercy Hospitals & Clinics, 2401 Gillham Rd, Kansas City, MO 64108. E-mail:
- Hack M, Friedman H, Fanaroff AA. Outcomes of extremely low birth weight infants. Pediatrics.1996;98 :931– 937
- ↵Resnick MB, Gueorguieva RV, Carter RL, et al. The impact of low birth weight, perinatal conditions, and sociodemographic factors on educational outcome in kindergarten. Pediatrics.1999;104(6) . Available at: pediatrics.org/cgi/content/full/104/6/e74
- ↵McGauhey PJ, Starfield B, Alexander C, Ensminger ME. Social environment and vulnerability of low birth weight children: a social-epidemiological perspective. Pediatrics.1991;88 :943– 953
- ↵McCormick MC. The outcomes of very low birth weight infants: are we asking the right questions? Pediatrics.1997;99 :869– 876
- ↵Hollingshead AB. Hollingshead Four Factor Index of Social Status (working paper). Hartford, CT: Yale University; 1975
- ↵Thorndike RL, Hagen EP, Sattler JM. Stanford-Binet Intelligence Scales. 4th ed. Itasca, IL: Riverside Publishing Company; 1986
- ↵Folio MR, Fewell RR. Peabody Developmental Motor Scales and Activity Cards. Allen, TX: DLM Teaching Resources; 1983
- ↵Zimmerman IL, Steiner VG, Pond RE. Preschool Language Scale-Revised. New York, NY: The Psychological Corporation; 1969, 1979
- ↵Goldman R, Fristoe M. Goldman-Fristoe Test of Articulation. Circle Pines, MN: American Guidance Service; 1986
- ↵Jastak S, Wilkinson GS. Wide Range Achievement Test-Revised Level 1. Wilmington, DE: Jastak Associates; 1984
- ↵Dunn LM. Peabody Picture Vocabulary Test-Revised-Form M. Circle Pines, MN: American Guidance Service; 1981
- ↵Carrow-Woolfolk E. Test of Auditory Comprehension of Language-Revised. Allen, TX: DLM Teaching Resources; 1985
- ↵Goodenough FL, Harris DB. Goodenough-Harris Drawing Test. San Antonio, TX: The Psychological Corporation; 1963
- ↵Pinheiro JC, Bates DM. Mixed-Effects Models in S and S-PLUS. New York, NY: Springer-Verlag; 2000
- ↵Weisglas-Kuperus N, Baerts W, Smrkovsky M, Sauer PJ. Effects of biological and social factors on the cognitive development of very low birth weight children. Pediatrics.1993;92 :658– 665
- ↵Perlman JM. Neurobehavioral deficits in premature graduates of intensive care—potential medical and neonatal environmental risk factors. Pediatrics.2001;108 :1339– 1348
- ↵Whitfield MF, Grunau RV, Holsti L. Extremely premature (< or = 800 g) schoolchildren: multiple areas of hidden disability. Arch Dis Child Fetal Neonatal Ed.1997;77 :F85– F90
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