Abstract
Neuropsychological development and the impact of postnatal head growth were studied in preschool children with asymmetrical intrauterine growth restriction. Examinees born at term with a birth weight below the 10th percentile were matched to the control group according to chronological and gestational age, gender, and maternal education. Fifty children were in each group, with a mean age of 6 years, 4 months. The Touwen neurological examination, the Čuturić developmental test, an imitative hand positions test, and a visual attention test were performed. There were significant differences (P< .03) in motor variables, the developmental quotient, and the imitative hand positions test. Fine motor skills had the most discriminative power. Relative growth of the head in relation to weight gain was positively correlated to neurocognitive outcome. Intrauterine growth–restricted children with a current head circumference ≤10th percentile had poorer outcomes. Conclusively, intrauterine growth restriction has a negative impact on neurocognitive development. Slow postnatal head growth is correlated with a poorer neuropsychological outcome.
Intrauterine growth restriction means the slowing of fetal growth and fetal inability to achieve his or her genetic growth potential due to adverse intrauterine conditions. Intrauterine growth restriction is most frequently defined by a birth weight <10th percentile for gestational age, parity, and gender or ≤2nd standard deviation for gestational age. The incidence is between 7% and 10% of births. 1 Regarding the pregnancy period, late-onset or asymmetrical intrauterine growth restriction occurs in 70% to 80% of all cases, and it is mostly caused by uteroplacental insufficiency.
Intrauterine growth restriction is related to the increasing rate of intrauterine fetal deaths. It increases perinatal mortality as well as neonatal morbidity. 2 However, intrauterine growth restriction usually has a minor impact on children’s motor development. It can rarely lead to cerebral palsy, but there are not many children with cerebral palsy in a total count of intrauterine growth–restricted children. 3 More often, children born with intrauterine growth restriction develop impairments of fine motor skills, balance and coordination, and a large amount of associated movements and have body tone disorders and clumsiness.
This is a study of the neuromotor and cognitive development of preschool children born with intrauterine growth restriction. The important aim of the study is to estimate the postnatal head growth impact on neuropsychological development. Only children with asymmetrical intrauterine growth restriction were investigated.
Intrauterine growth restriction negatively affects prenatal brain histogenesis and development, resulting in a smaller intracranial volume and reduced cerebral gray matter, especially frontal lobe volume. Intrauterine growth restriction leads to cortical selective vulnerability, decreased neuron number and migration, arborization, and dendritic growth. 4,5 These changes may result in many minor neurodevelopmental disorders, mostly in the motor skills domain, language and speech development, and cognitive functions that can disable children from sufficient learning and academic achievement later in life. 2,5
Fattal-Valevski et al 1 showed minor motor impairments in children with intrauterine growth restriction at the age of 3 years. Leitner et al 6,7 have found motor disorders in 6- to 10-year-old intrauterine growth–restricted children. They had impairments of spatial orientation, coordination, balance, graphomotor function with an increased amount of associated movements, and hypotonia. 6,7 Contrary to this, there was a study that did not find any difference in neurological outcomes of premature children with intrauterine growth restriction compared with children born with an appropriate birth weight. 8
In the cognitive domain, intrauterine growth restriction is often associated with a lower intelligence quotient, creativity and executive function disorders, working and short-term memory deficits, visuospatial and visuomotor impairments, as well as behavioral difficulties and attention deficit hyperactivity disorder. 2,9 Guellec et al 10 showed that intrauterine growth restriction in preterm children was associated with less favorable cognitive and behavioral outcomes as well as with school difficulties. These cognitive difficulties result in learning disabilities. The memory impairments are due to hippocampal vulnerability to chronic hypoxia. 10,11 Some other studies showed that children born after adverse intrauterine conditions have lower cognitive functions; however, this does not impact their academic achievement. 12
There are a few mechanisms that could explain the impact of intrauterine growth restriction on neurodevelopmental outcome. The first mechanism is the impact on brain growth. The other mechanisms are pathological development of the endocrine and other systems, increasing susceptibility to hypoxia and perinatal complications, and congenital malformations of the central nervous system. Studies have confirmed the concept of fetal programming: early developmental influences can lead to metabolic and psychological diseases during adulthood. 13,14 An insult that occurs during the developmental period can produce important structural and functional effects that lead to adult morbidities. Another process that is related to fetal programming is epigenetic programming during development. Alterations in the uterine environment could have powerful epigenetic consequences. 15 These changes could also affect the neurocognitive development.
A negative impact of prenatal growth restriction on brain development and histogenesis consequently results in reduced brain growth potential that is clinically presented as reduced head growth. Studies on prematurely born children and children with symmetrical intrauterine growth restriction have shown that prenatal slowing of head growth has a negative impact on their neurodevelopmental outcome. 2,9
When it comes to asymmetrical intrauterine growth restriction, studies have shown different results. The brain sparing process is a compensatory process taking place in late-onset intrauterine growth restriction and results in blood flow redistribution to provide nutritional and oxygen supply for the brain in conditions of impaired placental function. It results in a preserved brain size, so children born with late-onset intrauterine growth restriction have low body weights, but their head circumference is maintained. They are susceptible to perinatal complications due to chronic hypoxia in utero.
Scherjon et al 16 noticed accelerated neuromaturation in premature born children with intrauterine growth restriction. They found that children with short evoked potential latencies had greater cognitive impairments and lower intelligence quotients at the age of 5 years. Accelerated neuromaturation improves the survival outcome, but the consequence of that compensatory mechanism is poorer cognitive outcome due to a limited capacity of the brain sparing process that consequently leads to vasoconstriction and cortical vulnerability. 16
Previous studies examining the impact of postnatal head growth on the intelligence quotient and cognitive outcome have found positive correlations. 4,17 –19 Persistent microcephaly was identified as a negative predictive factor for neurodevelopmental outcome in children with intrauterine growth restriction. 4,16 Contrary to this, van Wassenaer 11 demonstrated that postnatal head growth was not predictive of school achievement in adolescence. Studies that have measured brain volume have not found differences between cerebral cortex volume in adolescence between examinees with and without intrauterine growth restriction. 20 Head growth reflects brain growth and brain volume. Accordingly, observations about head growth and neurodevelopmental outcome in children with intrauterine growth restriction could help explain a mechanism for neurological outcomes. Our hypothesis was that children born with intrauterine growth restriction would have poorer neurocognitive outcomes with a prediction of postnatal head growth.
Patients and Methods
All examinees were born at term in the maternity department of General County Hospital in Požega, Croatia, between 2002 and 2004, with a birth weight <10th percentile for gestational age, parity, and gender according to the Croatian percentile curves. 21 Gestational age was calculated according to the date of the last menstrual period. Exclusion criteria were central nervous system infections, chromosomopathies, congenital infections, major malformations, severe asphyxia, and the presence of recognizable genetic syndromes. The control group consisted of children born in the same maternity department from the year 2002 to 2004, with normal birth weights. They were matched to children restricted in intrauterine growth according to chronological and gestational age, gender, and maternal education. A total of 50 children with intrauterine growth restriction and 50 controls participated. In both groups, there were 28 (56%) girls and 22 (44%) boys. At the time of examination, children were aged between 5 years, 6 months to 7 years.
Between January 2002 and October 2004, 120 children were born with a birth weight <10th percentile for gestational age, parity, and gender. Nineteen couples of parents were not interested in participating in the study, and 29 children did not follow-up eventually. Twenty-two children were excluded from the study due to the exclusion criteria mentioned above. Antenatal ultrasound measurements showed that the remaining 50 children had middle second trimester– to third trimester–onset intrauterine growth restriction that we assumed was due to placental dysfunction.
It was ascertained by a parental questionnaire that none of the children in the study had postnatal central nervous system infections or traumatic brain injuries.
There were no statistically significant differences between the 2 groups with regard to gender (χ 2 = .04; P= .840), parity (χ 2 = 8.07; P= .152), chronological age (intrauterine growth–restricted group: median, 76 months; interquartile range, 7.0; control group: median, 77 months; interquartile range, 7.0); (Mann-Whitney, P= .699), gestational age (intrauterine growth–restricted group: median, 277 days; interquartile range, 12.0; control group: median, 279 days; interquartile range, 8.0); (Mann-Whitney, P= .353), and Apgar score (median for both groups, 10.0; interquartile range, 1.0); (Mann-Whitney, P= .165).
Children with intrauterine growth restriction were examined at the Department of Pediatrics at General County Hospital in Požega, Croatia, and children in the control group were examined at kindergarten school in Požega. Both groups were examined by a pediatrician and psychologist with parental presence. The duration of the entire examination testing was approximately 1.5 hours.
Biometric parameters collected for both groups of children were birth weight, head circumference, 22 current body weight, and current head circumference. Neurological development was evaluated by the Touwen neurological examination. 23 Cognitive development was assessed using the Čuturić developmental test, 24 imitative hand positions, and a visual attention test from a Developmental Neuropsychological Assessment (NEPSY).
Children with intrauterine growth restriction whose birth weight was <5th percentile were compared with the intrauterine growth–restricted group with a cutoff at the 10th percentile. We compared the group of intrauterine growth–restricted children with a head circumference at preschool age ≤10th percentile to the group with a head circumference at the preschool age >10th percentile as well.
The study was approved by the Ethics Review Committee of General County Hospital in Požega, Croatia, and by the Ethics Review Committee of the Medical Faculty of the University of Zagreb (Zagreb, Croatia). Informed parental consent was obtained in all cases. Parents received their child’s examination report and a recommendation for therapeutic or other diagnostic intervention as necessary. No compensation or travel fees were provided for participation.
For the statistical analysis, descriptive and inferential statistical methods were used. Nonparametric statistical methods were used to compare nonnormally distributed variables. The median was calculated as a measure of central tendency and interquartile range as a measure of variability. The Mann-Whitney test was used to compare the 2 groups on numerical variables and the Spearman test to examine the correlation between numerical variables. Differences between categorical and nominal variables were tested using the χ 2 test. Receiver operating characteristic curve analysis was used to determine discriminative variables for determining group membership. The analysis was conducted using SPSS (SPSS Inc, Chicago, Illinois). Because of multiple comparisons, a Bonferroni correction was applied, suggesting that P < .003 should be considered significant (P′ = P/19 ).
Results
The study compared children with intrauterine growth restriction (median gestational age, 277 days; interquartile range, 12.0; median body weight, 20.5 kg; interquartile range, 6.0; and median head circumference, 50.5 cm; interquartile range, 2.1) and a control group of children born with a normal birth weight (median gestational age, 279 days; interquartile range, 8.0, median body weight, 23.0 kg; interquartile range, 4.0; and median head circumference, 52.5 cm; interquartile range, 1.6). All children were born at term.
There were no statistically significant differences between groups with respect to chronological and gestational age, gender, parity, maternal education, and Apgar scores. Anthropometric parameters (weight: P= .002; height: P= .001; and head circumference: P< .001) were significantly lower in the intrauterine growth–restricted group compared with the control group.
Between-group comparisons of the motor variables indicated significant differences in posture, balance, coordination, fine motor skills, dyskinesia, quality and quantity of movements, associated movements, and visual function but not in sensorimotor function. Comparisons of the cognitive variables showed significant differences for the developmental quotient and the imitative hand positions test (both hands). Other cognitive variables were not significantly different between groups.
There were 15 children (30%) in the intrauterine growth–restricted group who were diagnosed as having developmental coordination disorder. In the control group, 2 boys were diagnosed with attention deficit hyperactivity disorder.
Receiver operating characteristic curve analysis indicated 8 statistically significant discriminative variables for determining group membership. This included fine motor skills, associated movements, posture, coordination, quality and quantity of movements, phonological help for naming (broader research), and dyskinesia. The fine motor skills variable had the most discriminative power.
When examining the influence of head growth on neurological development, motor and cognitive correlations with head growth in centimeters (difference between head circumference at birth and head circumference at preschool age) were not significant.
When the relationship between relative growth of the head [(actual head circumference – head circumference at birth)/(body weight – birth weight)] and neurocognitive development was analyzed, statistically significant correlations were found (Table 2). Posture, balance, coordination, fine motor skills, quality and quantity of movements, associated movements, muscle power, and imitative hand positions (dominant hand) were positively correlated with relative growth of the head in relation to weight gain (Table 1). The strongest correlations were observed with fine motor skills and balance. There were marginally significant differences (P> .03 and P < .05, respectively) for visual function and the developmental quotient.
Comparison Between Intrauterine Growth–Restricted (IUGR) Group and Control Group for Motor and Cognitive Variables.
Correlation Between Relative Growth of the Head and Motor and Cognitive Indicators.
Comparison Between the Group of Children With a Head Circumference at a Preschool Age ≤10th Percentile and the Group With a Head Circumference at a Preschool Age >10th Percentile.
Receiver operating characteristic curve analysis for distinguishing children with intrauterine growth restriction from the control group. The intermittent line means an absence of difference between the 2 groups.
A separate analysis comparing children with a birth weight <5th percentile (n = 37) against the intrauterine growth–restricted group with a cutoff at the 10th percentile (n = 13) showed a significant difference in posture (P = .037) and balance (P= .025).
Comparing the group of children born with intrauterine growth restriction with a head circumference at preschool age ≤10th percentile to the group with a head circumference at the preschool age >10th percentile, we found statistically significant differences on all motor variables except sensorimotor and visual functions. We also found marginally significant differences in the developmental quotient (P = .029) and visual attention: faces (recognized and missed) (P < .001). There were also marginally significant differences (P > .05 and P < .1, respectively) for imitative hand positions, with both the dominant (P =.087) and nondominant hand (P = .057).
Discussion
The hypothesis of this study was that children born with asymmetrical intrauterine growth restriction would have poorer neuropsychological outcomes with a predictive value of postnatal head growth. The results confirmed that examinees had poorer outcomes compared with the control group in many variables. These difficulties were present in posture, balance, coordination, fine motor skills, muscle power, dyskinesia, associated movements, visual function, quality and quantity of movements, the developmental quotient, and an imitative hand positions test. Fine motor skills showed the most discriminative value for distinguishing between children with intrauterine growth restriction and the control group. Lower fine motor skills were also the first and most frequent motor impairments in intrauterine growth–restricted children. Impairment in higher cortical functions manifests during tasks involving increased neurological demands. Poorer fine motor skills result in poorer graphomotor skills and writing, which have an impact on the child’s performance at school. Neuromotor impairments could also be due to slow maturation of the central nervous system. 23
There were no children with cerebral palsy in our study. Cerebral palsy is more often present in preterm children; therefore, the absence of concomitant cerebral palsy is likely due to the fact that all children in our study were born at term. Also, children with severe asphyxia who are at great risk for developing cerebral palsy were excluded from the study.
Systemic intrauterine insults incurred during the neonatal period spread through the cerebral cortex during childhood, so motor dysfunctions can be identified as higher functions develop. Asymmetrical intrauterine growth restriction especially affects the frontal cortex neural networks (Table 3). 4
Visual function is rarely impaired in children with intrauterine growth restriction, but there are studies that show disorders in visual function are more often apparent. 25 In our study, low vision and horizontal nystagmus were registered.
The intelligence quotient–related developmental quotient 24 was significantly lower in children with intrauterine growth restriction. Former studies have shown that children with intrauterine growth restriction are at greater risk for having a lower intelligence quotient, consistent with our findings. 2,4 The imitative hand positions test is used for the assessment of sensorimotor function. Poorer results of an imitative hand positions test are due to poorer visuomotor function performance and poor fine motor skills and coordination. Impairments in fine motor skills and coordination have been shown in this study as well as in previous clinical studies. 6,7
The relative growth of the head in relation to weight gain had a positive relationship with most motor variables, the developmental quotient, and imitative hand positions (dominant hand). The strongest correlations were observed for fine motor skills and balance. Postnatal head and brain growth could be important factors in predicting neurocognitive outcomes in children with intrauterine growth restriction (Figure 1). Children with slow postnatal head growth should be monitored and followed up later in childhood, so diagnostic and therapeutic interventions could be indicated if necessary.
Our results show that children with intrauterine growth restriction with a current head circumference ≤10th percentile have worse outcomes in almost all motor and cognitive variables than children whose head circumference was >10th percentile at preschool age. It also suggests that low postnatal head growth results in poorer outcomes at the preschool age.
Neuroimaging of children born prematurely with intrauterine growth restriction has shown smaller intracranial volumes and smaller cerebral cortex volumes compared with prematurely born infants with adequate birth weights for gestational age. A reduced brain volume correlates with head circumference and functional outcome at birth, especially with attention span. 26
Studies on animals have shown a decreased number of neurons, lower migration, arborization, and dendritic growth. 5 Lower brain weight and a reduced number of mature cortical astrocytes have been found when vascular intrauterine growth restriction was experimentally induced. 27 Accelerated neuromaturation in the way of accelerated myelination as an adaptation on adverse intrauterine conditions has been demonstrated by some previous studies. 16 Selective cortical vulnerability occurs because of vasoconstriction of cerebral vessels when the brain sparing process is exhausted. Especially vulnerable structures include the hippocampus, the limbic system, and the frontal lobe, which is important for appropriate neurocognitive development. 4
Brain growth is the most intensive between the 24th and 34th gestational weeks, which is the time when asymmetrical intrauterine growth restriction takes place. This is a critical time for frontal lobe development. Most aberrations in neurological outcome have their origin in frontal lobe dysfunction. 4 Although neuroimaging and animal studies have shown significant changes in the brain structure of intrauterinally restricted children, magnetic resonance spectroscopy has not found any differences in their brain metabolism and development compared with children with normal birth weights. 28
The main limitation of this study is difficulty in distinguishing between children who were intrauterine restricted in growth and those who were born small for gestational age and have constitutively lower birth weights. We tried to avoid those children by only including children who had middle second trimester– to third trimester–onset intrauterine growth restriction based on antenatal ultrasound measurements.
This study has researched the neuropsychological development of children with intrauterine growth restriction who were all born at term, so other reasons for their developmental delay, like prematurity, were excluded. Our results suggest that long-term reprogramming of the central nervous system in utero brings out slow postnatal head growth that results in changes of brain structures that are important for neurocognitive development.
Footnotes
Author Contributions
AŠK had the primary responsibility for protocol development, patient screening, enrollment, outcome assessment, preliminary data analysis, and writing the article. SG and ZK participated in the development of the protocol and analytical framework for the study and contributed to the writing of the article. VMB supervised the design and execution of the study and contributed to the writing of the article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval
The study was approved by the Ethics Review Committee of the General County Hospital in Požega and by the Ethics Review Committee of the Medical Faculty of the University of Zagreb. Informed parental consent was obtained in all cases.