PEDIATRICS Vol. 105 No. 3 March 2000, pp. 485-491

Outcome of Children in the Indomethacin Intraventricular Hemorrhage Prevention Trial

Laura R. Ment, MD^*, , Betty Vohr, MD^§, Walter Allan, MD, Michael Westerveld, PhD^¶, Sara S. Sparrow, PhD^#, Karen C. Schneider, MPH^*, Karol H. Katz, MS^**, Charles C. Duncan, MD, and Robert W. Makuch, PhD^**

From the Departments of ^* Pediatrics,  Neurology, ^¶ Neurosurgery, ^# Child Study Center, ^** Epidemiology and Public Health, and  Neurosurgery, Yale University School of Medicine, New Haven, Connecticut; the ^§ Department of Pediatrics, Brown University School of Medicine, Providence, Rhode Island; and the  Departments of Pediatrics and Neurology, Maine Medical Center, Portland, Maine.

	ABSTRACT

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Background.  For preterm infants, intraventricular hemorrhage (IVH) may be associated with adverse neurodevelopmental outcome. We have demonstrated that early low-dose indomethacin treatment is associated with a decrease in both the incidence and severity of IVH in very low birth weight preterm infants. In addition, we hypothesized that the early administration of low-dose indomethacin would not be associated with an increase in the incidence of neurodevelopmental handicap at 4.5 years of age in our study children.

Methods.  To test this hypothesis, we provided neurodevelopmental follow-up for the 384 very low birth weight survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial. Three hundred thirty-seven children (88%) were evaluated at 54 months' corrected age, and underwent neurodevelopmental examinations, including the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Peabody Picture Vocabulary Test-Revised (PPVT-R), and standard neurologic examinations.

Results.  Of the 337 study children, 170 had been randomized to early low-dose indomethacin therapy and 167 children had received placebo. Twelve (7%) of the 165 indomethacin children and 11 (7%) of the 158 placebo children who underwent neurologic examinations were found to have cerebral palsy. For the 233 English-monolingual children for whom cognitive outcome data follow, the mean gestational age was significantly younger for the children who received indomethacin than for those who received placebo. In addition, although there were no differences in the WPPSI-R or the PPVT-R scores between the 2 groups, analysis of the WPPSI-R full-scale IQ by function range demonstrated significantly less mental retardation among those children randomized to early low-dose indomethacin (for the indomethacin study children, 9% had an IQ <70, 12% had an IQ of 70-80, and 79% had an IQ >80, compared with the placebo group, for whom 17% had an IQ <70, 18% had an IQ of 70-80, and 65% had an IQ >80). Indomethacin children also experienced significantly less difficulty with vocabulary skills as assessed by the PPVT-R when compared with placebo children.

Conclusions.  These data suggest that, for preterm neonates, the early administration of low-dose indomethacin therapy is not associated with adverse neurodevelopmental function at 54 months' corrected age.  Key words:  low-dose indomethacin, preterm infant, neurodevelopmental outcome, intraventricular hemorrhage.

Several recent studies have suggested that the increased survival of very low birth weight (VLBW) preterm infants is secondary not only to advances in high-risk obstetric care but also to sophisticated advances in newborn special care techniques.^1-3 The latter include changes in ventilation and feeding policies as well as pharmacologic prevention strategies. Because preterm birth is associated with a high risk for neurodevelopmental handicap,^4,5 it is important to ascertain that recently instituted pharmacologic preventive measures are not only associated with immediate neonatal benefit but do not cause long-term neurodevelopmental impairment.⁶

Intraventricular hemorrhage (IVH), or hemorrhage into the germinal matrix tissues of the developing brain, remains a major problem of preterm neonates.^7,8 Infants with IVH are at higher risk for seizures, hydrocephalus, and death in the newborn period.⁹ In addition, although most observers agree that infants with parenchymal involvement of hemorrhage are at high risk for neurodevelopmental handicap, recent data suggest that even those children with lesser hemorrhages are at risk for cognitive difficulties.⁵

Indomethacin, an inhibitor of the prostaglandin synthetic pathway, had been shown in multiple single-center studies to decrease the incidence of IVH in preterm infants.^10,11 In 1989, we began a multicenter trial to test the hypothesis that, for infants with no known hemorrhage at 6 postnatal hours, indomethacin would decrease the incidence of IVH in VLBW preterm infants. These studies demonstrated that indomethacin decreased both the incidence and severity of IVH in our study population. Infants randomized to early low-dose indomethacin also tended to have better survival than neonates randomized to placebo.¹²

In addition, because indomethacin has been shown to transiently lower cerebral blood flow in preterm infants, we hypothesized that this prevention strategy would not be associated with an increased risk for cognitive handicaps or cerebral palsy in treated children. At 36 months' corrected age (CA, ie, age from the obstetric due date), we detected no evidence for increased cognitive impairment in indomethacin-treated children.¹³ In this report, study children were reevaluated as they approached kindergarten to continue testing our hypothesis that infants exposed to early low-dose indomethacin would not be at increased risk for neurodevelopmental handicap.

	METHODS

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Patient Population

The clinical studies were conducted at Women and Infants' Hospital, Providence, RI; Maine Medical Center, Portland, ME; and Yale New Haven Hospital, New Haven, CT. The protocols and procedures described below were reviewed and approved by the institutional review boards of the 3 participating institutions.

Newborn Protocol

During the time interval September 1, 1989 through August 30, 1992, 505 infants of 600 to 1250 g birth weight were admitted by 6 hours of age to the participating institutions and, after parental consent, to a randomized prospective trial designed to determine if the early administration of low-dose indomethacin would prevent IVH in this patient population.^12,14 To evaluate the brain for hemorrhage, all infants enrolled in the study were first examined using cranial echoencephalography (ECHO) between 5 and 11 hours. Of the 505 enrolled infants, 431 did not have IVH and were randomized to the primary IVH prevention trial.

Subsequent scans to evaluate the brain for hemorrhage and/or ischemic changes were performed at 24 and 48 hours after the first cranial ECHO, and on postnatal days 4, 5, 7, 14, and 21, and at 40 weeks' conceptional age or more often if clinically indicated. Scans were interpreted first by the institutional radiologist, and later, for data verification, by a central radiologist. In cases of disagreement, the data were reexamined by all participating radiologists, and a group decision was formulated. In each case, radiologic assessment was conducted without previous knowledge of the infant's clinical condition. The grading system for hemorrhages was as previously reported¹²: grade 1, blood in the periventricular germinal matrix regions; grade 2, blood within the lateral ventricular system without ventricular dilatation; grade 3, blood within and distending the lateral ventricles; and grade 4, blood within the ventricular system and parenchymal involvement. For the purpose of our analysis, IVH was categorized into 3 groups: none, grades 1 to 2, and grades 3 to 4. Ventriculomegaly was assessed on the ECHO studies performed at 40 weeks' conceptional age (or, if not available, 21 days of age). For the purpose of our analysis, only patients with moderate and severe ventriculomegaly (ie, measurements of 1.0-1.5 and >1.5 cm, respectively, at the midbody of the lateral ventricle on sagittal scan) were included.¹⁵ The ultrasound studies were also evaluated for the presence of focal echolucencies. All cases identified as showing focal echolucencies had cystic areas consistent with periventricular leukomalacia (PVL) on the ultrasound performed at 40 weeks' conceptional age.¹⁵

As previously described, all infants underwent gestational age assessment using a modification of the Ballard scale.¹⁶ Prenatal, perinatal, and neonatal data were obtained by maternal interviews and prospective review of the maternal and neonatal charts. An infant was diagnosed as suffering from bronchopulmonary dysplasia if he/she both required oxygen supplementation and had an abnormal chest radiograph at 28 days of life, as previously defined.¹⁷ For the purpose of our analysis, bronchopulmonary dysplasia was categorized as present or absent.

Neurodevelopmental Assessments

At 54 months' CA each child was tested with the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R, 1989)¹⁸ and the Peabody Picture Vocabulary Test-Revised (PPVT-R).¹⁹ Assessments were performed by testers who were blinded with regards to the child's medication status. The WPPSI-R is an individually administered norm-referenced instrument for assessing the intellectual functioning of children (aged 3 years 0 months through 7 years 3 months) and provides 3 intelligence scores, a performance IQ (PIQ), verbal IQ (VIQ), and full-scale IQ (FSIQ). All 3 IQ scores have a mean of 100 and a standard deviation of 15. Ten subtests were administered; 5 performance subtests (object assembly, geometric design, block design, mazes, and picture completion) and 5 verbal subtests (information, comprehension, arithmetic, vocabulary, and similarities) are used for calculation of the total performance and verbal scores. IQ scores are derived from these scores. An attempt was made to administer the test to every child. If the child was severely delayed and unable to complete the test items, an IQ score of 40 was assigned for the WPPSI-R.

The PPVT-R is a multiple-choice test that measures receptive vocabulary development and listening vocabulary in a format that requires no verbal response from the child. The child is required to identify a stimulus word from a selection of 4 pictures. Raw scores are converted to standard scores with a mean of 100 and a standard deviation of 15. This test is standardized for children aged 2.5 years through adulthood. Because the PPVT-R measures receptive vocabulary and does not depend on oral expression for performance, this task provides supplemental information about language development to that provided by the WPPSI-R.

The Vineland Adaptive Behavior Scales, Survey Form²⁰ and the Child Behavior Checklist²¹ were administered to parent(s)/caregivers. The Vineland is a semistructured interview administered to parents to assess the child's adaptive functioning in the areas of communication, daily living skills, socialization, and motor skills. The Child Behavior Checklist is a widely used standardized instrument designed to assess the social competencies and behavioral problems of children aged 4 to 18 years. Parents complete questions regarding their child's performance in sports, classroom activities, chores, and the quality of relationships with friends and family.

Although all children in the study have received neurodevelopmental follow-up, those children being raised in bilingual or non-English-speaking homes were excluded a priori from the IQ data analysis, because the WPPSI-R and the PPVT-R were standardized with English-speaking persons. These tests generate valid results only within the population for which they were standardized, and preschool children from environments in which both English and another language are spoken have been shown to suffer a substantial disadvantage when they are tested only in English.^22,23 All children typically received the standard testing battery first, followed by other measures that may have been more clinically appropriate.

Routine neurologic examination was performed on all children at the 54-month CA follow-up assessment.²⁴ Assignment of the diagnosis of cerebral palsy was based on the presence of hypertonicity, hyperreflexia, and dystonic or spastic movement quality in the affected extremities. The diagnostic groups of cerebral palsy were spastic diplegia, quadriplegia, and hemiplegia.

All demographic information was obtained from the primary caregivers, and teams that performed the neurodevelopmental examinations remained blinded with regard to the study participants' previous medical histories.

Statistical Methods

We hypothesized a priori that indomethacin would not increase the incidence of cerebral palsy or cognitive disorders in children randomized to early low-dose indomethacin when compared with placebo study participants. In addition, we planned both continuous and categorical analyses at the time of our formal funding application.

Categorical data with no expectation of a linear trend among groups (eg, gender) were analyzed using Fisher's exact test. Categorical data with an a priori expectation of a linear trend among groups were analyzed by the ² test for linear trend. The 2-sample Wilcoxon rank-sum test was used for between-group comparisons of continuous-valued data. All statistical analyses were performed using SAS software (SAS Institute, Inc, Cary, NC). All P values in this report are of the 2-sided type.

	RESULTS

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We evaluated 337 of the 384 (88%) long-term survivors of our randomized clinical trial at 54 months' CA. There were no differences in the incidence of any IVH (48 of 337 [14%] vs 5 of 47 [11%], P = .65), grade 3 to 4 IVH (6 of 337 [2%] vs 1 of 47 [2%], P = .71), PVL (11 of 333 [3%] vs 0 of 45 [0%], P = .38), or ventriculomegaly at term (8 of 298 [3%] vs 0 of 41 [0%], P = .60) between the children who were evaluated and those who did not undergo our battery of neurodevelopmental testing. Of the 47 children who were not seen at 54 months' CA, the families of 14 children had withdrawn them from the study protocol, the families of 14 children had moved outside of the Continental United States or >200 miles from the testing center, and the families of the remaining 19 children were unavailable for follow-up.

Of the 337 study children evaluated, 170 had been randomized to early low-dose indomethacin therapy and 167 children had received placebo. Neurologic examinations were available for 323 (96%) of the 337 children who underwent developmental assessment. Twelve (7%) of the 165 indomethacin children and 11 (7%) of the 158 placebo children for whom neurologic examinations were available were found to have cerebral palsy (P = 1.00). As shown in Table 1, 4 indomethacin children and 3 saline children were found to have spastic diplegia; 7 indomethacin and 4 placebo children suffered spastic quadriplegia, and 1 indomethacin child and 4 placebo children had spastic hemipareses (P = .66). In addition, 1 indomethacin child and 5 placebo children had seizures for which they were being treated with anticonvulsants (P = .21), and 1 indomethacin child and 1 placebo child were blind (P = 1.00). Finally, 1 indomethacin child and 1 placebo child were deaf (P = 1.00).

Perinatal data for the 233 of 248 (94%) children residing in English-monolingual households for whom developmental data are available are shown in Table 2. These data demonstrate that although there were no differences in the birth weights or numbers of male infants between the 2 groups, the mean gestational age was significantly younger for the indomethacin infants than for the placebo group (P = .02). In addition, 7 (6%) indomethacin children and 21 (18%) placebo children had been considered small-for-gestational age (SGA, P = .004). There was a significant difference in the distribution of IVH grades between the 2 groups; for the indomethacin children, 108 (91%) had no IVH and 11 (9%) had grade 1 to 2 IVH compared with the placebo children, of whom 95 (83%) had no IVH, 16 (14%) had grade 1 to 2 IVH, and 3 (3%) had grade 3 to 4 hemorrhage (P = .03). In addition, although there was no difference in the incidence of PVL between the 2 study groups, children randomized to receive early low-dose indomethacin were also found to have a lower incidence of ventriculomegaly (P = .055) than those randomized to placebo.

The mean VIQ scores for the 233 English-monolingual children randomized to indomethacin and placebo were 91.7 ± 15.7 and 88.5 ± 16.2 (P = .21), mean PIQ scores for the 2 groups were 88.5 ± 15.4 and 86.3 ± 18.3, (P = .40), and mean FSIQ scores were 88.9 ± 15.8 and 86.0 ± 17.8 (P = .32). Analyses of the WPPSI-R subtests revealed no significant differences between groups although there was a trend for the indomethacin group to score higher on the vocabulary subtest (9.54 ± 3.19 vs 8.66 ± 3.30, P = .06).

WPPSI-R FSIQ scores were analyzed categorically to identify the percent of children in each treatment group performing within the normal range (>80), those in the borderline intelligence range (70-80) and those with mental retardation (<70) (Table 3). These data indicate a benefit for those children randomized to early low-dose indomethacin therapy with an increased incidence of mental retardation in the placebo group (FSIQ <70; 17% vs 9%, test for trend P = .035). Although there was not a marked difference in the distribution of the VIQ scores between the 2 groups (P = .13), the children randomized to early low-dose indomethacin tended to score better on the PIQ. Eleven percent of indomethacin children had PIQ values <70, 12% had PIQ 70 to 80, and 77% had PIQ scores >80, compared with the placebo children, of whom 18% had PIQ <70, 18% had PIQ 70 to 80, and 64% had PIQ values >80 (P = .06).

The association of SGA status and FSIQ was examined to determine if the study results required adjustment for SGA status. Both categorical analyses and continuous-valued analyses of FSIQ showed no significant association between SGA status and FSIQ (P = .60 and P = .29, respectively). Thus, SGA status was not an independent predictor of FSIQ and so no analyses adjusted for SGA status were performed.

PPVT-R scores were available for 226 children. Although there was no difference in mean PPVT-R scores between the indomethacin and saline groups (88.6 ± 20.2 vs 84.9 ± 26.7, P = .66), categorical analysis (Table 3) demonstrated significantly more placebo children with PPVT-R scores <70 when compared with indomethacin children (P = .02).

Finally, although we found no differences between groups on parent perception of functional status on the Vineland Scales at 54 months, data from the Child Behavior Checklist suggested that those children randomized to indomethacin had better social skills (P = .08) and were less withdrawn (P = .02) than children randomized to placebo (Table 4).

	DISCUSSION

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Preterm birth results in significant developmental disability, and several recent reports have suggested that the recent decline of >50% in mortality for this population of infants has been shown to be attributable to more aggressive newborn intensive care strategies.^1-3

In conjunction with reports of increased survival, however, are data concerning handicap in these VLBW and frequently critically ill infants. Bhushan and colleagues²⁵ have recently reported an increase in the childhood prevalence of cerebral palsy which they attribute to the increasing prevalence of preterm birth. Furthermore, 2 studies have independently demonstrated that the incidence of cognitive deficits in this population of infants has not changed during the past decade.^26,27 Depending on the birth weights of the patient cohort examined and the years in which they were born, the incidence of major neurodevelopmental handicaps in very preterm infants generally ranges from 12% to 32%.^528-31 In addition, it is these very preterm infants in whom high incidences of behavioral and school difficulties are now emerging. At age 8 years, more than half of these children require special assistance in school, almost one-fifth are educated in designated special education classrooms, and 16% have repeated at least 1 grade.³² In addition, several studies have shown that VLBW children with lower cognitive development have more evidence of behavior problems.^33,34 These data suggest that strategies for identifying and preventing causes of disability in this population of patients are essential.

In 1979, Krishnamoorthy and colleagues³⁵ demonstrated that preterm infants with parenchymal involvement of hemorrhage experience major neurodevelopmental handicaps. In the almost 2 decades since that time, many investigators have demonstrated that infants with this insult suffer high rates (45% to 86%) of mental retardation and cerebral palsy.^36-39 In addition, recent data suggest that even children with low grade hemorrhages are at cognitive disability when compared with their nonhemorrhage gestational age-matched peers.⁵ In children with both low-grade hemorrhage and those with parenchymal involvement of IVH, these cognitive difficulties are attributable in part to the profound and long-lasting alterations in cerebral blood flow which occur following hemorrhage and the secondary impact on corticogenesis and connectivity in developing brain.⁴⁰

Indomethacin is a nonspecific inhibitor of both the constitutive and inducible isoforms of the cyclooxygenase pathway of prostaglandin synthesis, COX-1 and COX-2, respectively.^41-43 Well-recognized for its pharmacologic role for closure of the patent ductus arteriosus, indomethacin has also been shown in most trials to both decrease the incidence and lessen the severity of IVH.^10,11 In Horbar's⁴⁴ meta-analysis of 10 prospective clinical trials, the overall risk for IVH was reduced by ~50% by indomethacin; in addition, low-dose indomethacin administration was highly correlated with a decrease in the incidence of parenchymal involvement of hemorrhage in VLBW preterm infants. The many side effects of indomethacin remain a concern, however, and it is therefore of note that Narayanan and colleagues⁴⁵ have just reported 4 infants of <1000 g birth weight who received a 10-fold increase in the prescribed indomethacin dose and did not experience intracranial hemorrhage, necrotizing enterocolitis, or significant deterioration of renal function.

Using 133-xenon determinations, Pryds and co-workers⁴⁶ have shown that the intravenous administration of indomethacin to newborn preterm infants results in an acute decrease in cerebral blood flow of 12% to 40%. Similarly, indomethacin has been shown to decrease cerebral blood flow velocity measured by Doppler ultrasonography for up to 2 hours after rapid intravenous infusion,⁴⁷ and near-infrared spectroscopic investigations have also demonstrated significant reductions in oxidized cytochrome oxidase concentrations and cerebral blood volume values in preterm infants after rapid infusion of indomethacin.^48,49 These changes are not replicable after subsequent doses of indomethacin and recently Hammerman and colleagues⁴⁷ have reported that they do not occur when indomethacin is administered by slow continuous intravenous infusion. In addition, the relationship between cerebral blood flow and cerebral damage in preterm infants remains unclear, and Greisen and Pryds⁵⁰ and Pryds and Edwards⁵¹ have suggested that there is no definition of a threshold cerebral blood flow value in critically ill preterm infants below which ischemic brain damage always occurs. Thus, the measurement of cerebral blood flow by any of the above referenced methods "does not currently provide a secure guide in the clinical management of sick infants."⁵¹

IVH is believed attributable to alterations in cerebral blood flow to the immature germinal matrix microvasculature, and the mechanism by which indomethacin prevents IVH remains uncertain. In both animal and clinical studies, indomethacin rapidly decreases cerebral blood flow and inhibits prostaglandin synthesis.⁵² In neonatal animal studies intravenous high-dose (1-5 mg/kg intravenously) indomethacin blunts the normal hyperemia experienced by experimental animals after insults designed to mimic asphyxia, acute hypercapnia or the sudden onset of hypertension, improves cerebral autoregulation, and produces no change in cerebral metabolic rate.^53-55 In addition, indomethacin induces basement membrane deposition in the germinal matrix microvasculature of newborn beagle pups,⁵⁶ and reduces the ischemia-induced alteration of blood-brain barrier transport in piglets.⁵⁷ In vitro, indomethacin modulates laminin cell surface receptors and reduces the production of MMP-2, an enzyme required for the degradation of basement membranes.^58-60 In addition, although COX-2 has recently been identified at postsynaptic sites in excitatory neurons in rat cerebral cortex, indomethacin does not block receptor activation in this system.⁶¹ Finally, Murohara and colleagues⁶² have recently shown that indomethacin attenuates vascular endothelial growth factor-mediated vascular permeability in experimental animals. Thus, it seems that indomethacin both modulates cerebral blood flow and induces microvascular maturation.

Our neurodevelopmental assessments of the preterm infants enrolled in the Multicenter Randomized GMH/IVH Prevention Trial demonstrate that children randomized to indomethacin demonstrate no adverse neurodevelopmental sequelae as they approach school age. For the entire sample, only 7% of the children suffered cerebral palsy, with no significant differences between the indomethacin and saline groups. However, 28% of the total sample have FSIQ values below the normal range (ie, FSIQ <80) as they approach kindergarten. Furthermore, >30% (35 of 109; 32%) of these children have PPVT-R values <80. The proportion of children with minor or no developmental handicap is significantly smaller for the indomethacin group (Table 2). In particular, the indomethacin group demonstrated relatively advanced language development in comparison with the placebo group. Receptive language development was better in the indomethacin group, as evidenced by the significantly fewer number of children with PPVT-R scores <70. This group also demonstrated a trend toward better expressive vocabulary development, showing higher WPPSI-R vocabulary scores. The better language skills of the indomethacin group may also translate into improved development of social skills, as demonstrated by the significantly higher Child Behavior Checklist scores for these children on the relevant scales (less withdrawn, fewer social problems).

The present results indicate that preterm birth remains a significant risk factor for neurodevelopmental handicap. The mean IQ score for both indomethacin-treated and placebo-treated children remains below the population mean. However, indomethacin-treated children in our sample seem to have little evidence for neurodevelopmental disadvantage as they approach school age. There are numerous antepartum, neonatal, and genetic factors that contribute to the development of both cerebral palsy and cognitive deficits,^23,3963-66 and it will be critical to continue following this cohort to determine the longitudinal effects of preterm birth and the potential influence of indomethacin on the children's continued neurocognitive development.

	ACKNOWLEDGMENTS

This work was supported by Grants NS 27116 and NS 35476 of the National Institute of Neurologic Disorders and Stroke and Grant RR 06022 of the National Center of Research Resources.

This study benefited greatly from the assistance of the following individuals: Yale University School of Medicine: Marjorene Ainley, BS; Susan DeLancy, MA; Lisa Perry, MA; Brown University: Terri Leach, MED, CAES; Beth Dingley, BA; Maine Medical Center: Alison Milne, RNC; June Gagnon, MA. We thank Giovanna Spinella, MD, and David T. Scott, PhD, for their scientific expertise.

	FOOTNOTES

Received for publication Apr 8, 1999; accepted Aug 9, 1999.

Reprint requests to (L.R.M.) Department of Pediatrics, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06511. E-mail: laura.ment{at}yale.edu

	ABBREVIATIONS

VLBW, very low birth weight; IVH, intraventricular hemorrhage; CA, corrected age; ECHO, echoencephalography; PVL, periventricular leukomalacia; WPPSI-R, Wechsler Preschool and Primary Scale of Intelligence-Revised; PPVT-R, Peabody Picture Vocabulary Test-Revised; PIQ, performance intelligence quotient; VIQ, verbal intelligence quotient; SGA, small-for-gestational age; FSIQ, full-scale IQ.

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