OBJECTIVES: The goal was to examine whether indomethacin use, gender, neonatal, and sociodemographic factors predict patterns of receptive language development from 3 to 12 years of age in preterm children.
METHODS: A total of 355 children born in 1989–1992 with birth weights of 600 to 1250 g were evaluated at 3, 4.5, 6, 8, and 12 years with the Peabody Picture Vocabulary Test-Revised. Hierarchical growth modeling was used to explore differences in language trajectories.
RESULTS: From 3 to 12 years, preterm children displayed catch-up gains on the Peabody Picture Vocabulary Test-Revised. Preterm children started with an average standardized score of 84.1 at 3 years and gained 1.2 points per year across the age period studied. Growth-curve analyses of Peabody Picture Vocabulary Test-Revised raw scores revealed an indomethacin-gender effect on initial scores at 3 years, with preterm boys assigned randomly to receive indomethacin scoring, on average, 4.2 points higher than placebo-treated boys. However, the velocity of receptive vocabulary development from 3 to 12 years did not differ for the treatment groups. Children with severe brain injury demonstrated slower gains in skills over time, compared with those who did not suffer severe brain injury. Significant differences in language trajectories were predicted by maternal education and minority status.
CONCLUSION: Although indomethacin yielded an initial benefit for preterm boys, this intervention did not alter the developmental trajectory of receptive language scores. Severe brain injury leads to long-term sequelae in language development, whereas a socioeconomically advantaged environment supports better language development among preterm children.
- very low birth weight
- preterm birth
- language development
- preschool outcome
- middle childhood development
- intraventricular hemorrhage
Preterm birth increases the risk of neurodevelopmental impairment. Studies have consistently shown poorer cognitive, language, and academic skills among preterm children, compared with term peers.1–4 Although some authors suggested stable neurodevelopmental function with increasing age,5 some found decreases in cognitive scores,3,6 whereas others observed the opposite trend.7–9 Studies on longitudinal neurodevelopmental outcomes generally provided broad descriptions of test findings7 or compared results across 2 distinct periods in the child's life by using statistical techniques that may be insufficient to identify changes in cognitive function.3,5,6,9,10
One of the main goals of neonatal interventions is to reduce the rates of neonatal morbidities and neurodevelopmental impairment. Prophylactic indomethacin treatment decreases the incidence and severity of intraventricular hemorrhage (IVH).11,12 Furthermore, exposure to indomethacin was associated with reductions in white matter injury on cerebral MRI scans for extremely preterm infants.13 As part of the Multicenter Randomized Indomethacin IVH Prevention Trial, preterm children were monitored longitudinally from birth to 12 years of age. A previous study involving this cohort showed an increase in median Peabody Picture Vocabulary Test-Revised (PPVT-R) standardized scores from 3 to 8 years of age.8 Among preterm children with no early brain injury, standardized scores were 89, 92, 97, and 99 at 3, 4.5, 6, and 8 years of corrected age, respectively. Another report involving this cohort indicated that preterm boys assigned to receive indomethacin performed better in cognitive and verbal tasks, compared with preterm, placebo-treated, control subjects, across time.14
Statistical analyses used in the previous studies with this cohort did not allow examination of patterns of change at the individual or group level. One way to overcome this limitation is to apply individual growth modeling for analysis of outcome data. One of the advantages of growth modeling is estimation of both the average trajectory (change at the group level) and individual trajectories (change at the individual level), which permits exploration of factors putatively involved in across-subject and within-subject variability.15,16
Taylor et al17 used growth modeling to describe the longitudinal neuropsychological findings of very low birth weight (VLBW) children from 7 to 14 years of age, compared with term control subjects. Their study demonstrated that children with birth weights of <750 g made slower cognitive progress than did their term counterparts, especially with tasks of visual-motor integration and executive function. Moreover, environmental factors seemed to modulate changes in cognitive function in certain subgroups; among children with lower socioeconomic backgrounds, those with birth weights of 750 to 1499 g exhibited some catch-up gains on the vocabulary subtest of the Wechsler Intelligence Scale for Children between 7 and 14 years of age.
The main objectives of the current study were to examine, by using growth modeling, the effect of prophylactic indomethacin treatment on receptive language development across corrected ages of 3 to 12 years among preterm children and to determine whether the effects differed according to gender. Another objective was to assess the effects of other biological and environmental factors on language trajectories. It was hypothesized that preterm male subjects assigned to receive indomethacin would demonstrate improved language development, compared with placebo-treated, male control subjects, and that preterm children with severe brain injuries on neonatal cranial ultrasound scans would exhibit slower patterns of language development, compared with preterm children without brain injuries.
Between September 1989 and August 1992, 505 infants with birth weights of 600 to 1250 g who were admitted by 6 hours of age to Women and Infants' Hospital of Rhode Island (Providence, RI), Maine Medical Center (Portland, ME), or Yale-New Haven Hospital (New Haven, CT) were enrolled, with parental consent, in a trial of prophylactic indomethacin treatment to prevent IVH. Details of the newborn protocol were described previously.11,18,19 Of the 505 infants, 431 did not have IVH by 6 hours and were assigned randomly to receive indomethacin or placebo treatment. Follow-up data for any visit from 3 to 12 years of age were available for 355 (92%) of the 385 known survivors at 3 years of age. The institutional review boards of the 3 participating centers approved all protocols related to the trial. Informed consent was obtained for each follow-up visit.
Neonatal and sociodemographic data were retrieved from the study database. Severe brain injury was defined as the presence of grade 3 or 4 IVH, periventricular leukomalacia, or moderate/severe ventriculomegaly on cranial ultrasound scans.20 Bronchopulmonary dysplasia (BPD) was defined as oxygen need at 28 days of age and chest radiographic findings consistent with BPD.
The PPVT-R21 was administered from 3 to 12 years of age by school psychologists who were blinded to the participants' perinatal histories and were trained for high interrater reliability. Participants with significant impairments were assigned a raw score of 0 when they could not be tested. The PPVT-R is a multiple-choice test that assesses receptive vocabulary, specifically, word knowledge. The examinee is asked to identify the picture associated with the spoken word. The number of correct answers gives the raw score (ie, a raw score of 50 indicates that 50 words were well understood). The raw score is then transformed into a standardized score (mean: 100; SD: 15).
The multilevel model approach to individual growth modeling (PROC MIXED in SAS 9.1; SAS Institute, Cary, NC)16,22 was used to delineate the different language trajectories. Data for all subjects were entered into the statistical model. Two main parameters were involved in growth modeling, namely, the intercept parameter, which represented initial status, and the slope parameter, which described the rate of growth. Both parameters were interpreted as regular regression coefficients. To improve the interpretability of the coefficients, the age variable was centered at 3 years (age − 3), because this was the starting point of the study period.22 Therefore, the intercept estimate corresponded to the initial PPVT-R score at 3 years of age. The slope estimate expressed the rate of change in PPVT-R scores from 3 through 12 years. In addition, growth-curve analyses yielded a random-effect component (variance component) that described the within-individual and between-individual residual variability. The variance component allowed computation of the explainable variation accounted for by a given predictor.22
An initial, unconditional, growth model that did not include any predictor variables was created to examine the effect of time on changes in PPVT-R scores. This model provided a baseline for comparison when predictors were entered into the analysis to explore interindividual variability. The following predictors were examined for their effects on the intercept, slope, and curvature parameters: indomethacin treatment, male gender, birth weight, prenatal steroid treatment, severe brain injury, BPD, maternal education (less than high school, high school graduate, or ≥1 year of college), and minority status (according to maternal report). Interaction terms were created for interactions between gender and indomethacin, between gender and BPD, and between gender and minority status. Only significant predictors (significant P set at <.15) were entered in the final step of the analysis, which involved fitting a model that controlled for all variables at all assessment points. Indomethacin treatment and gender were retained by force.
In the first step, age-standardized scores were used to compare values for preterm children as a group with standardized normative values and to determine whether catch-up gains were observed over time. The model involved only intercept and slope parameters. In the second step, to compare word knowledge between the indomethacin and placebo groups, analyses were conducted with raw scores rather than age-standardized scores, because raw scores normally increased systematically over time and therefore were more sensitive to changes. A quadratic term, (age − 3)2, was added for a better fit to the curvilinear relationship between time and PPVT-R raw scores. This quadratic change trajectory did not have a constant slope, that is, the rate of growth accelerated (positive values), remained constant, or decelerated (negative values) over time, as indicated by the curvature parameter associated with (age − 3)2.
Table 1 presents neonatal and demographic characteristics of the preterm cohort. At each assessment point, the groups were similar with respect to child and maternal factors. Attrition rates remained constant for the 5 follow-up evaluations. Table 2 presents PPVT-R standardized scores according to gender and treatment groups. For all subjects across the 5 time periods, an indomethacin-gender effect was observed, with preterm boys assigned randomly to receive indomethacin performing better than preterm boys assigned to receive placebo (P = .03). This beneficial effect was not demonstrated for girls.
Growth-curve analyses performed with PPVT-R standardized scores from 3 through 12 years suggested catch-up gains over time for the entire preterm cohort, compared with the reference population (age-standardized mean of 100). On the basis of the data displayed in Fig 1, average preterm children began with a standardized score of 84.1 (95% confidence interval: 81.8–86.5) at 3 years and gained 1.2 points per year (95% confidence interval: 1.0–1.4 points per year) across the study period.
Analysis of PPVT-R raw scores to delineate developmental trajectories within the preterm cohort indicated that, on the basis of the unconditional growth model that explored the relationship between age and outcomes (Table 3), PPVT-R raw scores increased, as expected, over baseline (age estimate: 17.4 points), although the growth rate decelerated as the child grew older (age2 estimate: −0.7 point). In other words, the increase in PPVT-R raw scores was more pronounced in the earlier years and the magnitude of growth decreased over time. The model estimated that preterm children were able to identify, on average, 12.2 pictures in the PPVT-R at age 3, which is lower than the average PPVT-R raw scores of 14 to 38 for the standard population.21 Raw scores increased by 16.7 points from 3 to 4.5 years (see Appendix for calculations). The growth rate then decreased gradually over time, with an increase in scores of 5.5 points from 11 to 12 years.
Figure 2 and Table 3 present patterns of vocabulary development for each treatment group (indomethacin versus placebo), stratified according to gender. Boys assigned randomly to receive indomethacin had higher scores at 3 years, compared with placebo-treated, male control subjects, whereas indomethacin-treated and placebo-treated girls had comparable initial PPVT-R raw scores. Stated differently, with controlling for confounders, the indomethacin effect was not significant for girls (estimate ± SE: −1.2 ± 1.8), but the significant indomethacin-gender effect (estimate ± SE: 5.4 ± 2.4; P < .05) translated into a 4.2- point advantage in PPVT-R raw scores at 3 years for indomethacin-treated boys. Furthermore, preterm boys, as a group, demonstrated lower 3-year PPVT-R raw scores than did preterm girls (estimate ± SE: −4.6 ± 1.7; P < .05). As the children grew older, rates of receptive language development were comparable between the 2 treatment groups, irrespective of gender (nonsignificant age-indomethacin and age-indomethacin-male gender interactions).
Table 4 shows the effects of selected predictors on PPVT-R raw scores, with adjustment for the other covariates. The intercept column indicates the magnitude of the effect of each predictor on initial PPVT-R raw scores at 3 years. The slope column depicts the effect of each predictor on the annual increase in PPVT-R raw scores. Finally, the curvature column describes whether the predictor was associated with acceleration, stabilization, or deceleration of growth. The intercept was influenced by gender (P < .05), presence of BPD (P < .05), level of maternal education (P < .005), and minority status (P < .005). The indomethacin-gender effect was lost with the addition of severe brain injury to the model. When indomethacin, male gender, and indomethacin-gender interaction were entered separately (as shown in the unadjusted model in Table 3), they accounted for 6% of the variance in initial PPVT-R raw scores at 3 years of age. The presence of severe brain injury, maternal education (college education versus no high school diploma), and minority status had effects on annual increases in PPVT-R raw scores. All preterm children displayed deceleration of the rate of vocabulary development, but greater deceleration was observed among children whose mothers had higher levels of education (versus no high school diploma), whereas less deceleration was found among children with severe brain injury and children from minority groups.
Figure 3 illustrates patterns of receptive language development for each level of predictive factors. Significant differences in language trajectories were predicted by severe neonatal brain injury. Although preterm children with versus without brain injury had similar PPVT-R raw scores at 3 years of age, the rate of vocabulary development was much slower for children who suffered neonatal brain injury. This complication accounted for 14% of the variability in language development observed between subjects in the cohort. The maternal level of education also affected initial status. Children whose mothers did not complete high school started with lower scores than did children whose mothers had at least a high school diploma. By the end of the study period, the predicted gap between children whose mothers had completed ≥1 year of college and the combined group of children whose mothers had not graduated from high school or had only a high school diploma increased significantly. Finally, minority status, according to maternal report, influenced initial PPVT-R raw scores at 3 years of age. White non-Hispanic children exhibited faster rates of receptive language development, compared with other children. Overall, minority status contributed 34% of the explainable difference between subjects in initial raw scores and 16% in growth rates.
This study used a growth modeling approach to determine the effects of indomethacin and various biological and sociodemographic factors on vocabulary development of preterm children from 3 through 12 years. Deficits in receptive language development are associated with poorer reading skills, which negatively affect academic achievement; this emphasizes the importance of studying vocabulary knowledge. Indomethacin yielded an advantage for boys, who displayed higher scores at 3 years, compared with placebo-treated control subjects. Over time, however, indomethacin was not associated with faster vocabulary development. Children who sustained severe neonatal brain injury showed slower gains over time, compared with those who did not have significant cerebral lesions. Finally, maternal education and minority status had the strongest effects on receptive language trajectories.
The beneficial effects of prophylactic indomethacin treatment on vocabulary and IQ test scores for boys during the early years were demonstrated previously.14 Preterm boys assigned to receive indomethacin had higher PPVT-R, verbal IQ, and full-scale IQ scores from 3 to 8 years, compared with placebo-treated control subjects. This effect was not found among girls. It was speculated that indomethacin might have prevented preterm brain injury associated with maternal inflammation, with preoligodendroglial injury and subsequent disturbances in myelination and connectivity.13,23 At 12 years, however, significant differences in neuropsychological test scores were no longer observed between the 2 treatment groups, even with gender stratification.24 Findings from the current study showed that the initial 4-point advantage in PPVT-R raw scores at 3 years among boys who received indomethacin was significant because the average raw score was 12.2 points at that age. Because indomethacin did not alter vocabulary development, this 4-point difference remained unchanged between 3 and 12 years. When preterm children reached 12 years, their mean PPVT-R raw score was 112 (Appendix⇓). These data suggested that, between 3 and 12 years, prophylactic indomethacin treatment did not alter the developmental time course for PPVT-R scores for our study subjects.
Severe brain injury had a more-sustained influence on receptive language trajectories. High-grade IVH and cystic periventricular leukomalacia on neonatal ultrasound scans are strong predictors of adverse neurodevelopmental outcomes for preterm children from infancy25–27 to school age.4,28–31 This study identified an increasing gap in PPVT-R scores between preterm children with versus without severe cerebral injury with increasing age. Koller et al32 studied developmental changes between birth and 6 years in a cohort of VLBW children and found that higher indices of neonatal morbidity were associated with lower initial developmental scores. Furthermore, neurologically impaired infants at 12 months consistently achieved lower cognitive scores, compared with VLBW children in neurologically normal condition. These findings suggest that, as cognitive demands increase in complexity with age, the injured brain has limited plasticity to compensate. Volumetric analyses of regional brain development in preterm children and adolescents with MRI showed correlations between IVH and decreased subcortical gray matter,33,34 alterations in cortical white matter volumes,34 and decreased volumes of the cerebellum and left caudate nucleus.35 Therefore, severe neonatal brain insults disrupt cerebral development, potentially leading to slower gains in certain neuropsychological functions such as receptive language, which indicates the vulnerability of the immature brain. Research on children who sustained severe traumatic brain injury at an early age showed that those patients displayed lasting cognitive sequelae.36
This study highlighted the positive impact of higher levels of maternal education and an advantaged environment (measured as the mother's race and ethnicity) on vocabulary trajectories in preterm children, in keeping with previous longitudinal research.17,32,37 Our data did not allow us to explore whether maternal education and minority status affected the outcome directly or were correlates of other sociodemographic factors associated with better outcomes, such as higher socioeconomic status,17 lower family stressors,17 a sensitive, stimulating, and less-restrictive home milieu,38,39 or living in a suburban rather than urban community, where early intervention and school services might be more widely available.40 Our findings emphasize the importance of providing continuous developmental and academic supports to children at higher social risk. A systematic review concluded that early childhood development programs were effective in improving school readiness and reducing grade retention and special education requirements among economically disadvantaged children.41
One limitation of this study was the absence of a term control group, because term subjects were enrolled at 8 years and growth modeling requires ≥3 sets of data. Therefore, we used the age-standardized, normative, PPVT-R values to evaluate catch-up gains over time. Although the average increase in PPVT-R standardized scores of 1.2 points per year is encouraging, it is possible that term control subjects would exhibit similar gains. The PPVT-R scores of our study subjects need to be monitored through adolescence and into early adulthood.
Longitudinal follow-up monitoring of preterm children revealed that, although a beneficial effect of prophylactic indomethacin treatment was observed in the early years, this pharmacologic agent did not influence the developmental trajectory of PPVT-R scores for our VLBW preterm study subjects. Although severe brain injury during the neonatal period was the most detrimental biological factor for vocabulary development, social risks had the strongest effects on this outcome. Our findings indicate the need for interventions at preschool and school ages to support preterm children from economically disadvantaged environments.
This work was supported by National Institutes of Health grant NS27116.
- Accepted January 15, 2009.
- Address correspondence to Betty R. Vohr, MD, Women and Infants Hospital, 101 Dudley St, Providence, RI 02905. E-mail:
Financial Disclosure: The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject:
Preterm children are at increased risk for cognitive, language, and behavioral impairment. Severe neonatal brain injury is associated with poor neurodevelopmental outcomes.
What This Study Adds:
This study investigated factors that modulate receptive language development in preterm children. Significant differences in rates of vocabulary learning were predicted by severe neonatal brain injury, maternal education, and minority status.
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