Relationship Between Perinatal and Neonatal Indices and Intelligence Quotient in Very Low Birth Weight Infants at the Age of 6 or 8 Years

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1 Pediatr Neonatol 2008;49(2):13 18 ORIGINAL ARTICLE Relationship Between Perinatal and Neonatal Indices and Intelligence Quotient in Very Low Birth Weight Infants at the Age of 6 or 8 Years Shu-Chi Mu 1,2,3, Cheng-Hui Lin 1, Yi-Ling Chen 1, Chia-Han Chang 1, Kuo-Inn Tsou 3,4 * 1 Department of Pediatrics, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 2 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 3 College of Medicine, Fu Jen Catholic University, Taipei, Taiwan 4 Department of Pediatrics, Catholic Tien Hospital, Taipei, Taiwan Received: Mar 15, 2007 Revised: Jan 2, 2008 Accepted: Mar 25, 2008 KEY WORDS: full scale intelligence quotient; very low birth weight; Wechsler Intelligence Scale for Children-Third Edition; Wechsler Preschool and Primary Scale of Intelligence Background: The majority of children born with very low birth weight (VLBW; < 1500 g) enter mainstream schools. They experience significant neurodevelopmental disabilities during childhood. The specific aims of our study were to evaluate the neonatal outcomes of VLBW infants and whether they would influence intelligence quotient (IQ), cognitive function and learning disabilities at the age of 6 or 8 years. Methods: We enrolled VLBW neonates who weighed less than 1500 g and who were delivered at Shin-Kong Wu Ho-Su Memorial Hospital in 1996 and The psychological assessments were applied with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) for age 6 and Wechsler Intelligence Scale for Children-Third Edition (WISC-III) for age 8. We recorded their demographic data, ventilation duration by days, length of stay, use of surfactant, respiratory distress syndrome (RDS), and other complications. Results: According to whether the full scale intelligence quotient (FSIQ) was above or below the average score (FSIQ = 90), we divided VLBW children into two groups (< 90, n = 17; 90, n = 21). The children with lower gestational age had lower FSIQ (p = 0.013). The higher FSIQ group ( 90) showed more prenatal steroid use (5/17, 29.4% vs. 14/21, 66.7%; p = 0.049). There were more boys in the lower FSIQ group (< 90, 13/17, 76.5% vs. 90, 7/21, 33.3%; p = 0.011). The average IQ scores were ± 9.05 and ± 8.89 in the FSIQ < 90 and FSIQ 90 groups, respectively. The groups were similar in ventilation duration by days, use of surfactant, frequency of sepsis, RDS, bronchopulmonary dysplasia, patent ductus arteriosus, intraventricular hemorrhage and retinopathy of prematurity. Conclusion: In our study, the children with lower gestational age had lower FSIQ. There was no significant association between small for gestational age and IQ performance. The neonatal outcomes of VLBW infants did have less impact on IQ performance later in life. * Corresponding author. College of Medicine, Fu Jen Catholic University, 510 Zhongzheng Road, Xinzhuang City, Taipei 242, Taiwan @mail.fju.edu.tw 2008 Taiwan Pediatric Association

2 14 S.C. Mu et al 1. Introduction Children born with very low birth weight (VLBW; < 1500 g) have major physical impairments that usually require special educational provision, but the majority will enter mainstream schools. 1 VLBW infants experience significant neurodevelopmental disabilities during childhood. 2,3 The incidence of major disabilities ranges from 20% to 50% in the first few years of life. 4 9 In addition, one fifth develop major cognitive disabilities by the age of 8 years, 10,11 more than 50% are reported to require special assistance in the classroom, 20% are in special education, and 15% have repeated at least one grade in elementary school These children may show learning difficulties (LD) and/or lower intelligence quotient (IQ), often associated with problems in visuospatial perception, minor motor impairments and behavioral difficulties. 15,16 The origin of these difficulties has been attributed to a delay in neurologic maturation, early cerebral injury, social factors, or poor early growth. 17 It could also be due to other factors, including hearing impairment, mental retardation, emotional disturbance, or environmental, cultural or economic disadvantages. These data suggest change in cognitive function over time in those born preterm The specific aims of our study were to evaluate the neonatal outcomes of VLBW premature infants and whether they would influence IQ, cognitive function and learning disabilities at the school ages of 6 and 8 years. 2. Materials and Methods This was a descriptive and cohort study of a group of VLBW neonates who weighed less than 1500 g and who were delivered at Shin-Kong Wu Ho-Su Memorial Hospital. Our study was performed in 2004 and Samples were collected from premature neonates born in 1996 and Demographic data were recorded, including maternal and paternal age, gravidity, parity, education, mode of delivery, multiple pregnancies, prenatal steroid use, tocolytic agent use, birth weight, gestational age, gender, Apgar scores, assisted reproductive technology, appropriate for gestational age (AGA), small for gestational age (SGA), and premature rupture of membranes (PROM). We also recorded the ventilation duration by days, length of stay, use of surfactant, respiratory distress syndrome (RDS), and other complications. RDS was diagnosed if there was a combination of three of the following: clinical signs, oxygen need greater than 30% from 12 to 72 hours, need for assisted ventilation (continuous positive airway pressure or mechanical ventilation), and typical chest X-ray appearance. The complications included bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), sepsis and necrotizing enterocolitis (NEC). The definition of BPD was oxygen dependence at 36 weeks post-conceptional age and persistent radiograph abnormality. Intraventricular hemorrhage (IVH) was graded according to the Papile classification. 23 NEC was classified as the presence of intramural gas on X-ray, perforation or evidence of intestinal necrosis at surgery or autopsy. PDA was diagnosed by clinical signs and/or echocardiography confirmation. Sepsis was defined as a positive blood culture. Gestational age was determined by menstrual history, antenatal ultrasound, and the Ballard assessment. 24 Premature neonates were younger than 36 weeks gestational age and birth weight less than 1500 g. They were either at preschool and aged 6 years or at school and aged 8 years during the period of 2004 to The psychological assessments that were applied to the children born prematurely were the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) for the age of 6 years and Wechsler Intelligence Scale for Children-Third Edition (WISC-III) for the age of 8 years. In Taiwan, we have the Chinese edition and standards. The WPPSI assessments contain 11 subtests, 8 of which (Information, Vocabulary, Arithmetic, Similarities, Comprehension, Picture Completion, Mazes, Block Design) also appear in the WISC-III, while the remaining 3 (Sentences, Animal House, Geometric Design) are unique to the WPPSI. The WPPSI employs the Deviation IQ (M = 100, SD = 15) for the Verbal, Performance, and Full Scale IQ and scaled scores (M = 10, SD = 3) for the subtests. A raw score is first obtained on each subtest and then converted to a scaled score within the examinee s own age group through use of a table in the WPPSI manual. The subtests of the WISC-III include: (1) six verbal subtests: Information, Arithmetic, Similarities, Vocabulary, Comprehension, Digit Span; and (2) seven performance subtests: Picture Completion, Coding, Picture Arrangement, Block Design, Object Assembly, Symbol Search, Maze. They can evaluate the verbal and non-verbal abilities of subjects. The full scale IQ (FSIQ) range is 90 to 109 and is based on the total standardization sample of N = 1700 in WPPSI-R and N = 2200 in WISC-III. According to the score of 90 in FSIQ, we divided the study cases into two groups of 90 and < Statistical analysis Values are expressed as mean ± standard deviation (SD) unless indicated otherwise. Independent t test was used for statistical analysis. In this study, the

3 IQ in children with VLBW 15 Mann-Whitney U test and Pearson s χ 2 test were used to compare the parameters among below- and above-mean IQ at the ages of 6 and 8 years. The statistical models fit the data remarkably well. The study was approved by the hospital s institutional review board. A p value of less than 0.05 was considered significant. Analyses were performed using the SPSS statistical package (SPSS Inc., Chicago, IL, USA). 3. Results A total of 38 children who were born preterm and VLBW were identified as having been born in the period specified. There were 20 boys (52.6%); 28 were singletons and 10 were twins. According to whether FSIQ was above or below the average range of intelligence classifications of WPPSI-R and WISC-III (FSIQ = 90), the VLBW children were divided into two groups: < 90 (n = 17) and 90 (n = 21). We can see the distribution of gestational age in Figure 1. With regard to antenatal demographic characteristics, there was a difference in prenatal steroid use between the FSIQ < 90 and FSIQ 90 groups (5/17, 29.4% vs. 14/21, 66.7%; p = 0.049). The two groups did not show any differences in maternal age, paternal age, gravidity, parity, rate of Cesarean section, and use of tocolytic agents (Table 1). The average IQ scores were ± 9.05 and ± 8.89 in the FSIQ < 90 and FSIQ 90 groups, respectively. Perinatal demographic characteristics FSIQ < 90 FSIQ Percentage >30 Gestational age 3 Figure 1 Percentage of cases with full scale intelligence quotient (FSIQ) < 90 and 90, based on gestational age in weeks. Table 1 Antenatal demographics FSIQ < 90 (n = 17) FSIQ 90 (n = 21) p Maternal age (yr) 31.4 ± ± Paternal age (yr) 34.8 ± ± Gravidity 2.8 ± ± Parity 1.8 ± ± Cesarean delivery 10 (58.8%) 19 (90.5%) Multiple pregnancy Twins 4 (23.5%) 6 (28.6%) Prenatal steroids 5 (29.4%) 14 (66.7%) 0.049* Use of tocolytic agents 8 (47.1%) 16 (76.2%) Paternal education > 9 yr 10 (58.8%) 18 (85.7%) Maternal education > 9 yr 13 (76.5%) 19 (90.5%) *p < FSIQ = full scale intelligence quotient.

4 16 S.C. Mu et al Table 2 Perinatal demographics FSIQ < 90 (n = 17) FSIQ 90 (n = 21) p Gestational age (wk) 29.0 ± ± * Birth weight (g) ± ± Apgar score (1 min) 6.5 ± ± Apgar score (5 min) 7.8 ± ± Male 13 (76.5%) 7 (33.3%) 0.011* Small for gestational age 5 (29.4%) 10 (47.6%) Premature rupture of membranes 8 (47.1%) 8 (38.1%) *p < FSIQ = full scale intelligence quotient. Table 3 Neonatal parameters FSIQ < 90 FSIQ 90 (n = 17) (n = 21) p OR (95% CI) Ventilation days (> 5) 6 (35.3%) 9 (42.9%) (0.195, 2.716) Use of surfactant 7 (41.2%) 9 (42.9%) (0.255, 3.411) Sepsis 3 (17.6%) 3 (14.3%) (0.224, 7.370) Respiratory distress syndrome 12 (70.6%) 18 (85.7%) (0.080, 1.995) Bronchopulmonary dysplasia 4 (23.5%) 9 (42.9%) (0.100, 1.690) Patent ductus arteriosus 4 (23.5%) 2 (9.5%) (0.465, ) Intraventricular hemorrhage 1 (11.1%) 0 (0.0%) Retinopathy of prematurity (all grades) 7 (41.2%) 6 (28.6%) (0.453, 6.767) Ventilation duration (d) 16.8 ± ± Length of stay (d) 63.1 ± ± FSIQ = full scale intelligence quotient; OR = odds ratio; CI = confidence interval. are shown in Table 2. There were no significant differences in Apgar scores at 1 minute and 5 minutes, SGA and PROM, but there were significant differences in gestational age (29.0 ± 2.6 weeks vs ± 2.1 weeks; p = 0.013) and male gender (13/17, 76.5% vs. 7/21, 33.3%; p = 0.011) between the FSIQ < 90 and FSIQ 90 groups. Table 3 shows the neonatal parameters of both groups. They were similar in ventilation duration by days, use of surfactant, frequency of sepsis, RDS, BPD, PDA, IVH and ROP. The lengths of stay were 63.1 ± 29.3 days and 52.7 ± 32.6 days (p = 0.391) in the FSIQ < 90 and 90 groups, respectively. All children in the VLBW group had been admitted to the neonatal intensive care unit (NICU) and had undergone the respiratory intervention of intubation. The mean age at testing in the FSIQ < 90 and FSIQ 90 groups were ± 1.63 and ± 2.29 months (p = 0.205) around 6 years, and ± 1.22 and ± 2.74 months (p = 0.178) around 8 years. 4. Discussion In our study, there were differences between the FSIQ < 90 and 90 groups in gestational age (29.0 ± 2.6 vs ± 2.1 weeks; p = 0.013), prenatal steroid use (5/17, 29.4% vs. 14/21, 66.7%; p = 0.049) and male gender (13/17, 76.5% vs. 7/21, 33.3%; p = 0.011), but no significant difference in birth weight ( ± g vs ± g; p = 0.595). The children with lower gestational age had lower FSIQ. Some studies reported the biological and environmental factors associated with neurodevelopmental outcome. 12,25 Very premature children are at risk for multiple neonatal diseases related to their immaturity, and these may leave long-lasting sequelae. Given the continuing debate on the appropriateness of offering neonatal intensive care for extremely preterm infants, it is essential that we have a continuing audit of outcomes for these infants. Neurologic sequelae and psychomotor developmental disorders are among the complications with the greatest influence on long-term quality of life. Screening for these developmental anomalies must therefore be a major objective in the follow-up of such infants, and care after discharge is now considered to be a critical part of the neonatal intensive care service. However, follow-up programs are costly, timeconsuming and might cause unnecessary anxiety to parents and children. Therefore, there is a need to precisely identify which children should be included

5 IQ in children with VLBW 17 in such programs. Many authors have examined the factors that are associated with psychomotor development in premature children, but most of the VLBW children included in population-based followup programs were born in the 1980s. 5,9 14 VLBW babies may experience cognitive and motor deficits, even if these deficits are not classified as disabilities. The disorders associated with very low birth weight may persist long past infancy, and children born with a low birth weight may experience subtle deficits in intelligence. The ages at testing in the FSIQ < 90 and FSIQ 90 groups in this study were ± 1.63 months and ± 2.29 months (p = 0.205) around 6 years and ± 1.22 months and ± 2.74 months (p = 0.178) around 8 years. The role of paternal factors in determining the risk of adverse pregnancy outcomes has received less attention than maternal factors. We were also interested in assessing the importance of paternal versus maternal factors, including age and education in relation to the cognitive function of VLBW children. In the previous studies, it was found that increasing maternal versus paternal education, growth monitoring, appropriate feeding (breastfeeding and weaning), well-baby and child follow-up and clean environment (indoor and outdoor) not only promoted physical health but also promoted the cognitive development of the new generations. Social factors and the caregiving environment were important determinants of cognitive and behavioral outcome. 26,27 We cannot neglect the impact of paternal and maternal education on performance on IQ tests and the contributing factor of maternal education on the IQ of VLBW children. In our study, there was similar distribution of maternal versus paternal age and education in both groups, and there was no significant influence of parents education on the IQ of VLBW children. Both groups were similar with regard to maternal age, paternal age, gravidity, parity, rate of Cesarean section and use of tocolytic agents. There were no differences in Apgar scores at 1 minute and 5 minutes, SGA and PROM between the FSIQ < 90 and FSIQ 90 groups. We enrolled the premature cases according to birth weight. Use of birth weight as the inclusion criterion has both advantages and disadvantages. A disadvantage is the increasing frequency of growth-retarded infants at the higher gestational ages. Intrauterine growth restriction may be associated with infants underlying disease. The frequencies of SGA were 5 (29.4%) and 10 (47.6%) in the FSIQ < 90 and FSIQ 90 groups, respectively. It seemed higher in the FSIQ 90 group. The average IQ scores of SGA children were ± 4.64 and ± 6.09 in the two groups. Several studies on the long-term outcomes of children born with low birth weight (< 2.5 kg) included both term and preterm children. The longest follow-up study was by Martyn et al, who reported on the relationship between fetal growth and cognitive function in middle and late adult life. 28 Douglas and Gear found significant differences in academic performance at 8 years of age, but no significant differences in the rates of mental or behavioral handicaps later. 29 Nilsen et al in Norway examined the outcomes of a hospital population of children born in with birth weight < 2500 g; no differences in intelligence scores were noted, although cognitive function tended to be higher with increasing birth weight. 30 The results of these studies revealed no significant association between body size or body proportion at birth and cognitive function. In our study, we concluded that similar outcomes and environmental factors in postnatal life may overshadow the effects of the intrauterine experience. In addition to preterm delivery, whether or not neonatal morbidity has an impact on IQ should be carefully evaluated. Few previous studies have mentioned this point. In our study, there was similarity in ventilation duration by days, use of surfactant, frequency of sepsis, RDS, BPD, PDA, IVH and ROP in the FSIQ < 90 and FSIQ 90 groups. The length of stay by days was 63.1 ± 29.3 and 52.7 ± 32.6 days (p = 0.391), respectively, in the two groups. All of the VLBW children had been admitted to the NICU and had undergone the respiratory intervention of intubation. From our results, the neonatal outcomes of VLBW premature infants did have less influence on IQ scores later. Due to the limitation of the small sample size in this study, a future study with a larger case number is required to conduct further informative speculations in this area. 5. Conclusion In our study, children with lower gestational age showed more severe cognitive function impairment. The higher FSIQ group ( 90) showed more prenatal steroid use. There were more boys in the lower FSIQ group (< 90). There was no significant association between SGA and IQ performance. The neonatal outcomes of VLBW prematurity did have less impact on IQ performance later. Acknowledgments This work was supervised by the Ethics Committee and Institutional Review Board of Shin-Kong Medical Center. We thank Miss Huang Sue-Hui for evaluation of the intelligence quotient test, manuscript preparation and computational analyses, Ms Li Yu-Ling for technical assistance, and Dr Bai Chyi-Huey for

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