Neurodevelopmental Disorders and Delays in Preterm Children

Introduction: Preterm Birth and Its Global Burden

The World Health Organization defines a preterm birth as one that occurs before 37 weeks or 259 days of gestation (Beck, Wojdyla, Say, Betran et al., 2010). Worldwide, the majority of preterm births occur in Africa and Asia, but the highest percentages of preterm births — measured as a proportion of all births — occur in North America. Almost half of preterm births are idiopathic; 15–20% are due to medical decisions or are elective, which probably contributes to the higher percentage of preterm births in North America; and about 30% are due to the rupture of preterm membranes. Of all early neonatal death causes, preterm birth accounts for approximately 28% of deaths not attributable to some type of congenital malformation (Beck et al., 2010).

Low birth weight, sensory and motor problems, and cognitive difficulties are all associated with preterm births. Although preterm and low birth weight babies are born across all socioeconomic levels, rates are highest among impoverished mothers and especially among members of ethnic minority groups (Beck et al., 2010). The effects of preterm births are compounded by the difficulties caregivers face in helping their children attain normal levels of health and development. Often, the caregivers of preterm children live in less protective environments and have limited access to the medical and social support services and intervention programs aimed at reducing the negative long-term consequences of premature births (Beck et al., 2010; Saigal & Doyle, 2008).

Preterm births are exceptional among all adverse pregnancy outcomes because they are defined by a time span rather than being tied to any particular etiology or specific pathophysiology. If an infant is born preterm, the actual physical signs displayed are often inversely proportional to the child's gestational age, which is expected given that preterm development follows a fairly predictable timeline. Research has therefore left little doubt that a child's gestational age is the most significant factor influencing later outcomes associated with preterm births.

In the 1970s, prior to the widespread use of hospital-assisted ventilation for preterm infants, very few babies survived if born before 28 weeks of gestation. However, with the earlier and increasing use of assisted ventilation, antenatal corticosteroids, and pulmonary surfactant — as well as changing attitudes among parents and physicians regarding the use of intensive care for preterm infants — survival rates for very preterm infants, particularly those born before 28 weeks of gestation, improved markedly during the mid-1990s (Saigal & Doyle, 2008). Even though preterm births at 32–36 weeks of gestation are five times more frequent than births before 32 weeks, their public health effects are not well documented. In the United States in 2003, 12.3% of births were preterm — a concerning figure, as records since 1981 indicate a 31% rise in the U.S. preterm birth rate. Two-thirds of these births were late preterm births, defined as occurring between 34 and 36 weeks of gestation (Beck et al., 2010).

Depending on their gestational age, preterm infants are at risk for many different types of medical problems affecting multiple organ systems. Preterm children have significantly higher proportions of sensory deficits, cerebral palsy, learning disabilities, and other illnesses compared to children born at full term. The morbidity associated with preterm births often extends well into the child's later life, with profound physical and psychological effects on both child and family, and enormous economic costs for families and society. In 2005, estimates of the total costs to the United States attributable to complications of preterm births — including medical, educational, and estimated lost productivity — exceeded $26.2 billion (Beck et al., 2010).

Medical Issues Associated with Preterm Birth

When a baby is born before term, most of its organs are immature; however, the brain and the lungs appear to be especially susceptible to the consequences of premature birth. This inevitably results in high rates of long-term health and neurological issues for these children. Because of the increasing costs of providing neonatal intensive care and the growing social and economic burdens of disabilities associated with preterm births, there is an ongoing debate about whether the use of intensive care is justifiable for preterm infants at borderline viability. As survival rates increase, clinicians will find themselves increasingly exposed to preterm birth survivors. Physicians and other health care workers should therefore be aware of the evolving outcomes of preterm births, the long-term effects of associated disabilities, and the numerous health problems incurred by survivors, their families, and society (Saigal & Doyle, 2008).

Neurological problems associated with preterm birth are numerous and include developmental disability, developmental delays, apnea of prematurity, retinopathy of prematurity, cerebral palsy, hypoxic-ischemic encephalopathy, and intraventricular hemorrhage. This last complication — bleeding within the ventricles of the brain — has been known to affect as many as 25% of preterm babies and is especially problematic when the baby is born before the 32nd week of pregnancy (Saigal & Doyle, 2008). Babies can be resilient, and milder brain bleeds may not result in severe or lasting complications; however, more severe bleeds can cause irreparable brain damage or even death.

With respect to neurological issues in preterm infants, the thyroid gland, pituitary gland, and hypothalamus all begin their development early in gestation. Berbel, Navarro, Auso, Varea, et al. (2010) investigated the role of the thyroid gland in brain development. At approximately 10–12 weeks of gestation, thyroid hormone synthesis begins, and serum thyroid hormone levels progressively rise for the remainder of gestation. The hypothalamic-pituitary-thyroid axis, which deals with stress, hormone regulation, and other functions, becomes functional in the infant during the latter half of gestation; however, its development continues until nearly two months after birth in normal human infants. As a result, the developing infant requires thyroid hormones from the mother during its development in utero.

Thyroid hormones are extremely important regulators of the infant's brain development during both the fetal and neonatal periods. During these periods, these hormones control both neuronal and glial proliferation in specific brain regions and are important in regulating neural migration and neural differentiation. Neural differentiation also includes the development of neuronal connections and myelination, which are crucial to normal development. This differentiation takes place in very discrete developmental periods, or windows. Thus, the role of these thyroid hormones in coordinating the timing of specific developmental signals and events is critical, and even transient disruptions in thyroid hormone availability can have profound effects on the infant's brain development. Some research has linked the neurodevelopmental problems associated with preterm birth to a lack of maternal thyroid hormones, as the immature infant's thyroid gland cannot meet its own requirements.

Magnetic Resonance Imaging (MRI) can be useful in identifying structural abnormalities of the preterm infant's brain. However, in many developmentally delayed children MRI cannot detect any structural difficulties, and more sensitive methods must be used. For example, Filippi, Ulug, Deck, Zimmerman, and Heier (2002), in a seminal study, reported results using Proton MR Spectroscopy to detect differences in brain myelination between normal children and developmentally delayed children over the age of two who had normal MRI scans. Children under age two with delays did not yet demonstrate this difference. Consequently, preterm children may have subtle brain differences not readily observed by conventional assessment techniques, and the researchers suggested using different methods to investigate these etiologies.

While neurological issues are primarily responsible for the functional developmental delays in children, other complications can also affect the development of a preterm child. These problems include: cardiovascular complications; respiratory problems such as respiratory distress syndrome or chronic lung disease; a number of severe metabolic and gastrointestinal problems that can result in delayed growth; immune system problems such as susceptibility to infections or diseases like pneumonia; and hematologic complications (Saigal & Doyle, 2008).

Neurodevelopmental Sequelae: Cerebral Palsy and Mental Retardation

Cerebral palsy is a heterogeneous group of neurologically related disorders that can involve central nervous system functions as well as other functions such as learning, movement, vision, hearing, and cognitive speed (Saigal & Doyle, 2008). As a result, there are several variations of cerebral palsy, including dyskinetic (mixed muscle tone leading to difficulties with posture and movement), spastic (increased muscle tone leading to stiff and jerky movements), ataxic (poor coordination and low muscle tone leading to floppy movements), and mixed (two or more of the other types present). Across most studies, the incidence of cerebral palsy in preterm children is negatively related to weeks of gestation, although some studies indicate curvilinear trends (Saigal & Doyle, 2008).

Both the prevalence and severity of cerebral palsy in preterm infants generally vary depending on gestational age at birth. Saigal and Doyle (2008) report the results of Swedish studies indicating that rates of cerebral palsy were 14%, 19%, and 3% for infants born at 23–24, 25–26, and 27 weeks of gestation, respectively. A significant number of children born preterm develop cerebral palsy, and many of these children have moderate to severe motor disabilities. These disabilities obviously lead to delays in motor and even sensory development (Marlow, Wolke, Bracewell, & Samara, 2005; Saigal & Doyle, 2008).

Children with either moderate or severely disabling cerebral palsy are significantly more likely to display cognitive impairments compared to age-matched normal peers as well as children with other motor problems (Saigal & Doyle, 2008). Marlow, Wolke, Bracewell, and Samara (2005) performed a large and widely cited study of very early preterm infants at six years of age, comparing them to their full-term peers on several cognitive measures. Overall performance was significantly lower for children with cerebral palsy compared to children without neurological abnormalities. Moreover, the cognitive scores of very preterm children who later develop cerebral palsy are typically poorer than those of children born preterm at a more advanced gestational age. Forty-six percent of children born between 22 and 25 weeks of gestation had severe or moderate disabilities such as cerebral palsy, vision or hearing loss, and learning problems.

Mental retardation is not uncommon among preterm infants. Like cerebral palsy, there is an inverse relationship between weeks of gestation at birth and the prevalence and severity of mental retardation in preterm infants (Saigal & Doyle, 2008). Using the United States criteria for mental retardation (IQ < 70), Neubauer, Voss, and Kattner (2008) found a high proportion of mental retardation in a cohort of preterm infants treated at a neonatal intensive care unit and followed up to age ten. The researchers defined a major impairment as the presence of one or more of the following: cerebral palsy, intellectual disability, blindness, deafness, and/or intractable epilepsy. In a cohort of 135 children, 24 had major impairments as defined; of those 24 children, 19 (79%) had mental retardation. The researchers did not delineate the various IQ scores of this subset, so the range of mental impairment within the cohort remains unknown; however, they did report that children born at earlier gestational ages were more likely to have more severe deficits. Given the aforementioned discussion of the role of thyroid hormones in cerebral development, the finding of high levels of mental retardation in this group is not surprising.

References

Beck, S., Wojdyla, D., Say, L., Betran, A.P., Merialdi, M., Requejo, J.H., Rubens, C., Menon, R., & Van Look, P.F. (2010). The worldwide incidence of preterm birth: A systematic review of maternal mortality and morbidity. Bulletin of the World Health Organization, 88, 31–38.

Beck et al. note that prior to this research, there had been no data on the worldwide prevalence of preterm births, their etiologies, and mortality rates associated with them. The researchers performed an extensive search of published and unpublished literature to determine the rates, etiologies, and associated mortalities connected to preterm births. The data were drawn from two WHO worldwide surveys covering the years 1997–2002 and 2003–2007. The researchers were also able to estimate preterm birth rates from countries with little or no records using multiple regression analyses. Findings indicated that different rates and etiologies of preterm births occur in different countries. For instance, North American preterm birth rates were noted to be high due to high rates of multiple pregnancies and the increasing age of women giving birth — leading to more complications and Caesarean sections — whereas in Africa, intrauterine infection or lack of availability of drugs appeared to be responsible.

Berbel, P., Navarro, D., Auso, E., Varea, E., Rodriguez, A.E., Ballesta, J.J., Salinas, M., Flores, E., Faura, C.C., & Morreale de Escobar, G. (2010). Role of late maternal thyroid hormones in cerebral cortex development: An experimental model for human prematurity. Cerebral Cortex, 20(6), 1462–1475.

The authors studied the effects of hypothyroxinemia (decreased levels of serum thyroid hormones such as thyroxine and T4), a common finding among premature infants. This condition has been associated with many poor outcomes in preterm infants, including death, cerebral palsy, intraventricular hemorrhage, and periventricular leukomalacia. The authors discuss the role of the thyroid in child development and how a lack of these hormones in preterm infants can lead to the aforementioned disabilities. The study itself is an animal study in which maternal rats were thyroidectomized and the pups were nursed by surrogate mothers. The effects of a lack of thyroid hormones and of hormonal treatment were examined. Results suggested that treatment with thyroxine and other hormones may be beneficial for preterm infants.

Filippi, C.G., Ulug, A.M., Deck, M.D.F., Zimmerman, R.D., & Heier, L.A. (2002). Developmental delay in children: Assessment with proton MR spectroscopy. American Journal of Neuroradiology, 23, 882–888.

The researchers sought to establish a protocol for detecting possible structural brain differences in developmentally delayed children with otherwise normal MRI scans. Seven children over the age of two with developmental delays and seven children under the age of two with developmental delays — all with normal MRI scans — were compared to controls using Proton MR Spectroscopy. The older children displayed decreases in N-acetylaspartate/Creatine levels and increases in Choline/Creatine levels in the anterior and parieto-occipital subcortical white matter compared to the control group. These differences are believed to indicate slower myelination of these subcortical brain tracts. The younger group displayed no differences. The researchers suggested that more sensitive imaging methods should routinely be used to understand the etiology of developmental delays.

Johnson, S., Wolke, D., Hennessy, E.M., & Marlow, N. (2011). Educational outcomes in extremely preterm children: Neuropsychological correlates and predictors of attainment. Developmental Neuropsychology, 36(1), 74–95.

The researchers followed up on the participants from the Marlow, Wolke, Bracewell, and Samara (2005) study of extremely preterm infants, assessing them with the Wechsler Individual Achievement Test – II (WIAT-II) at 11 years of age. Measures of reading ability and mathematics were approximately one-half to one standard deviation below the comparison group. Overall composite scores were significantly lower than expected compared to the comparison group. These results indicate that preterm children without severe neurodevelopmental delays experience mild difficulties with overall academic abilities compared to full-term children. Multiple regression analyses identified several predictive neonatal and environmental variables.

Marlow, N., Hennessy, E.M., Bracewell, M.A., & Wolke, D. (2007). Motor and executive function at 6 years of age after extremely preterm birth. Pediatrics, 120, 793–804.

The researchers administered a battery of tests of executive functioning, visuo-spatial abilities, and fine motor control to a subset of subjects from the Marlow et al. (2005) study — specifically those without severe neurodevelopmental disorders such as cerebral palsy. The major assessment instruments came from the Developmental Neuropsychological Assessment (NEPSY). The preterm participants performed significantly poorer across all measures than the full-term comparison group; however, the magnitude of the differences was in the area of one standard deviation. Thus, while the preterm group performed below expectation, they were not clinically impaired. Moderating variables were also discussed.

Marlow, N., Wolke, D., Bracewell, M.A., & Samara, M. (2005). Neurologic and developmental disability at six years of age after extremely preterm birth. New England Journal of Medicine, 352, 9–19.

The researchers evaluated preterm children in mainstream schools using a clinical examination that included a comprehensive neuropsychological assessment. The preterm children were assessed at a median age of 30 months and again at six years of age. Assessment was also performed on 160 six-year-old children born at full term. Comparisons were made using standardized normative data and against the comparison group results. In general, the preterm children performed worse when comparisons were made to the comparison group than when compared to normative data. The cognitive and neurological impairments tended to be chronic and more predictive of later functioning than other measures such as motor functioning.

Neubauer, A-P., Voss, W., & Kattner, E. (2008). Outcome of extremely low birth weight survivors at school age: The influence of perinatal parameters on neurodevelopment. European Journal of Pediatrics, 167, 87–95.

The researchers followed a cohort of extremely low birth weight children treated at their neonatal intensive care unit, assessing them at three, six, nine, and twelve months and then annually up to age ten. The purpose of this study was to document the developmental changes in this group over the short and long term and to determine which difficulties were chronic and which waxed and waned over time. There was a high initial mortality rate for very preterm infants, and dropout rates were also high (related to higher birth weights), so that of 200 infants beginning the program, data were reported on 135. Among survivors, there were high rates of neurodevelopmental disabilities, and there was an inverse relationship between disability severity and both gestational age at birth and birth weight. Children with more severe neurological issues (n = 24) tended to remain relatively impaired, whereas children with less severe neurological problems demonstrated the most improvement over time.

Restiffe, A.P., & Gherpelli, J.L.D. (2006). Comparison of chronological and corrected ages in the gross motor assessment of low-risk preterm infants during the first year of life. Arquivos de Neuro-Psiquiatria, 64(2B), 418–425.

The researchers assessed 36 preterm infants for motor disabilities and development using the Alberta Infant Motor Scale (AIMS), a gross motor measure consisting of 58 items organized into four postures: prone, supine, sitting, and standing. The sample was without major neurological abnormalities (43 were originally assessed, but seven were not available at follow-up). The research was prompted by a debate in the literature over the use of corrected versus chronological age scores to evaluate preterm infants' developmental level. The researchers found that using chronological age to categorize the motor development of preterm infants without severe neurological disorders underestimates function during the first year of life. Moreover, preterm infant gross motor development appeared to mature according to the child's conceptional rather than chronological age.

Saigal, S., & Doyle, L.W. (2008). An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet, 371, 261–269.

The researchers performed an extensive search of articles published between 1990 and 2000 dealing with premature, preterm, and low birth weight infants. Data were compiled on mortality rates, survival rates, and functional outcomes related to both behavioral and physical performance as these children developed. The researchers specifically sought studies reporting long-term outcomes in geographically defined cohorts to avoid reporting bias. Relevant findings included long-term deficits in cognitive development, IQ, behavioral problems, and psychological issues in preterm infants as they matured, with severity of problems being inversely related to gestational age.

Weisglas-Kuperus, N., Hille, E.E., Duivenvoorden, H.H., Finken, M.J.J., Wit, J.M., van Buuren, S., Goudoever, J.B., & Verloove-Vanhorick, P.S. (2009). Intelligence of very preterm or very low birth weight infants in young adulthood. Archives of Disease in Childhood: Fetal and Neonatal Edition, 94(3), F196–F200.

These researchers examined the impact of premature birth and other factors on intelligence scores obtained in adulthood. Subjects from the POPS database in the Netherlands with a gestational age of less than 32 weeks were administered a standardized intelligence test at 19 years of age. While participants did not demonstrate the typical finding of overall lower IQ scores compared to those born at full term (mean IQ was 97.4, with slightly different scores for children above and below 32 weeks of gestation), there were interesting trends in the data. Multiple regression analysis indicated that parental education was a mediating factor in the cohort's IQ scores. Moreover, gestational age was positively related to IQ, and those born at 26 weeks of gestation displayed significantly lower IQ scores.