Peggy MacLean, Susanne Duvall & Jean Lowe
What is low birth weight?
Premature birth occurred in 14.9 million babies born in 2010, or in over 10% of the births worldwide and is defined as birth prior to 37 weeks (Blencowe et al., 2013). In 2013, 1.92 % preterm births were infants born fewer than 32 weeks gestation and 0.73% occurring prior to 28 weeks gestation (Rogers & Hintz, 2016).
Viability, which is typically considered to be between 22 and 24 weeks gestation, can differ depending on the location of birth (i.e., country) and neonatal services available in that location (Marlow, Bennett, Draper, Hennessy, Morgan, &
Costeloe, 2014). Over the last decade, survival rates of infants born preterm have increased substantially, particularly for children born earlier in gestation. For instance, survival rates of infants born at 23 weeks gestation have increased from 8% to 52% in Sweden in the most recent era (Fellman et al., 2010). Similarly, survival rates have increased to 63% survival in Japan (Ishi et al., 2013).
Diagnostic features
Given the increase in survival rates among infants born preterm, research in the past 50 years has focused on understanding the differing neurodevelopmental outcomes found within children born preterm. Studies examining neurodevelop - mental outcomes have characterized children based on gestational age or birth weight. Guidelines by the World Health Organization has provided classification of prematurity by gestational age as follows: very preterm before 32 weeks gestation, moderate preterm birth is between 32 and 33 weeks gestation and ‘late preterm birth between 34 and 36 weeks gestation’ (Putnick, Bornstein, Eryigit- Madzwamuse, & Wolke, 2016). Studies have also grouped infants based on birth weights, with birth weights of less than 2500 grams (approximately 5 pounds and
8 ounces) as ‘low birth weight,’ infants with birth weights less than 1500 grams as
‘very low birth weight (VLBW),’ and infants with birth weights less than 1000 grams as ‘extremely low birth weight (ELBW).’ Though studies differ in using gestational age or birth weight to classify infants, there is general consensus that outcomes differ with differing gestation and birth weights and risk of neuro - developmental difficulties increase as gestational ages and birth weight decreases (Stoll et al., 2010).
The risk associated with prematurity is largely due to the fact that infants born preterm are born before the end of the third trimester, a vulnerable period when brain growth is the greatest with a four-fold increase in brain size and during which the organization of the central nervous system is at a particularly vulnerable stage (Clouchout et al., 2012). As a result of this vulnerability, studies have focused on the impact of prematurity and its associated medical complications on neuro - developmental outcomes.
Studies examining neurodevelopmental outcomes within preterm population began by focusing on broad measures of functioning, such as intelligence. Although these studies found that children born preterm had significantly different IQ scores from their counterparts, their scores were only slightly lower, in the Borderline to Average range, once children with major disabilities were excluded (Aylward, 2002; Weindrich, Laucht, & Schmidt, 2003). As studies began focusing on more specific cognitive processes, such as Executive Functioning, our understanding of the impact of prematurity on cognitive skills deepened. For example, studies began demonstrating that even after matching on age and IQ, children born preterm show Executive Function weaknesses (Taylor & Clark, 2016).
Working Memory (WM) and related Executive Function (EF) deficits
With an increase in focus on specific neurodevelopmental outcomes, the role of Executive Functioning skills in preterm populations has gained particular interest. Executive Function has been hypothesized to be related to functional real-world life outcomes, in fact a longitudinal study by Moffitt and colleagues (2011) demon strated that childhood Executive Function predicts many adult outcomes including interaction with law enforcement, financial and physical health. Though Executive Functioning is conceptualized differently within the literature, most conceptualize it as an umbrella term that encompasses three core areas: Working Memory, inhibition and cognitive flexibility (Davidson, Amso, Anderson, &
Diamond, 2006). Working Memory refers to the ability to hold information in mind, which can range from simple concrete memories to complex representations and symbols. Within the realm of EF, Working Memory is related to the manipu lation of this information, as well as acting upon this information. Inhibition refers to acting by choice versus acting on impulse while cognitive flexibility refers to the ability to quickly and accurately change behavior. Other cognitive processes have also been associated with Executive Function: such as anticipation, goal selection, planning
and organization, initiation of a novel activity, self-regulation, mental flexibility, Working Memory and utilization of feedback (Anderson, 2002).
In typically developing populations some researchers argue that EF is a multidimensional concept as seen in adults (containing the facets of Working Memory, inhibition and flexible rule use) (Garon, Byron, & Smith, 2008 for review).
Empirical studies by other researchers argue that during the preschool period EF is an undifferentiated and unitary concept in children born preterm (Baron, Weiss, Litman, Ahronovich, & Baker, 2014) and full term (Hughes & Ensor, 2007; Wiebe, Espy, & Charak, 2008). Thus, literature regarding other aspects of Executive Function, not only Working Memory, may provide additional information and comprehensive understanding, especially in studies with younger populations. For example, in a sample of 3- to 4-year-olds significantly lower Executive Function was seen in the very low birth weight group across all measures of Executive Function, including: Reverse Categorization task (Working Memory and rule use), Dimensional Change Card Sort-Separated Dimensions task (DCCSS) (cognitive flexibility and Working Memory), Gift Delay Peek (inhibition) and Bear Dragon task (inhibition, cognitive flexibility and Working Memory) (Lowe, Erickson, MacLean, Duvall, Ohls & Duncan, 2014).
Although research has found that children born preterm are more vulnerable to Executive Functioning difficulties, findings have varied depending on what domain of Executive Function is studied. For example, research examining mental flexibility and inhibition within preterm populations, report inconsistent findings.
Some studies, for example, have shown impaired mental flexibility (e.g., Taylor, Minich, Bangert, Filpek, & Hack, 2004; Tideman, 2000) and poor inhibitory control (Böhm, Katz-Salamon, Smedler et al., 2002; Nosarti, Allin, Frangou, Rifkin, &
Murray, 2005) among children born preterm while others have not reported deficits in flexibility (Curtis, Lindeke, & Georgieff, 2002; Espy, Stalets, McDiarmid, Senn, Cwik, & Hamby, 2002) or inhibitory control deficits (e.g., Elgen, Lundervold, &
Sommerfelt, 2004).
Conversely, research examining Working Memory has consistently found deficits. Studies have consistently shown deficits in Working Memory in children born preterm, even after controlling for cognitive skills like IQ or crystalized verbal ability (Taylor & Clark, 2016; Vicari, Caravale, Carlesimo, Casadesi, & Allemand, 2004).
Preschoolers born LBW without major neurological deficits may have specific difficulty with spatial Working Memory when compared with full term children matched for chronological age and IQ (Vicari, Caravale, & Carlesimo, 2004). In fact, spatial Working Memory has been a robust domain of weakness in infants (Mooney, De Haan, Platten, Sanderson, Day, & Marlow, 2014; Woodward, Edgin, Thompson,
& Inder, 2005), school age (Fitzpatrick, Carter & Quigley, 2016) and adult (Tseng et al., 2017) preterm populations.
Auditory Working Memory, often assessed through recall of a string of digits that is recited forwards or backwards, has also been found to be reduced in chil- dren born low birth weight at school age (Aarnoudse-Moens, Smidts, Oosterlaan,
Duivenvoorden, & Weisglas-Kuperus, 2009; Mulder, Pitchford, & Marlow, 2010).
More recent research has hypothesized that Working Memory deficits may be related to underlying weaknesses in sustained attention and processing speed in these groups (Gorman, Barnes, Swank, Prasad, Cox, & Ewing-Cobbs, 2016). Working Memory deficits, in addition to processing speed differences, have been postulated to underlie academic achievement deficiencies in low birth weight populations (Mulder, Pitchford, & Marlow, 2010). In sum, deficits in Working Memory as well as other associated aspects of Executive Function have routinely been implicated in children born low birth weight.
Neurological profile
As previously discussed, infants born preterm are at an increased risk for poorer neurodevelopmental outcomes given that their birth occurs during a vulnerable period in brain growth and infants born preterm are also at a greater risk of experiencing medical complications that have been shown to further impact neuro - development (Taylor & Clark, 2016). For example, more extreme prematurity (ELBW (<1000 grams)), smaller gestational age and being born small for gestational age have been implicated in Executive Function deficits, including poorer Working Memory (Stoll et al., 2010). Additionally, different perinatal medical severity factors have also been found to be predictive of Executive Function deficits, with gestational age predicting difficulty with inhibition laden tasks and number of surgeries and maternal steroids predicting difficulties on Executive Function tasks with high inhibition, Working Memory and cognitive flexibility demands (Dimensional Change Card Sort-Separated) (Duvall, Erickson, MacLean, & Lowe, 2015).
Infants born preterm are also at higher risk of lung immaturity, a common complication found within prematurity. Lung immaturity and resultant respiratory distress syndrome continues to be the major cause of morbidity and mortality in low birth weight infants with respiratory support needed in approximately 60% of preterm children (Te Pas & Hooper, 2016). Studies that have examined the impact of lung immaturity and resultant hypoperfusion (poor oxygenation) have shown that these complications impact the still developing brain and lead to early oxygen deprivation (hypoxia/ischemia), which is hypothesized to underlie diffuse white matter injury in this group that can have far reaching consequences on brain development (Huang & Castillo, 2008). Specifically, diffuse white matter injury can negatively impact subsequent myelination, development of subcortical structures such as the basal ganglia and thalamus (Inder, Wang, Volpe, & Warfield, 2003), cerebellar growth (Shah et al., 2006), maturation of gray matter structures (Inder et al., 1999), subsequent development of white matter fiber tracks (Hüppi et al., 2001), and result in axonal damage and damage to immature oligodendrocytes (Volpe, 1997). White matter integrity is essential to prefrontal neural networks implicated in Executive Function and attention processes as well as efficient information processing and response speed (Filley, 2001).
Examination of neuroimaging in young children born low birth weight has provided some windows into the relationship between anatomy and early Working Memory specifically. One study conducted by Woodward and colleagues (2005) showed that MRI conducted at term was related to object Working Memory at age two (Woodward, Edgin, Thompson, & Inder, 2005). They found that Working Memory performance at age two was related to bilateral reductions in total tissue volumes in the dorsolateral prefrontal cortex, sensorimotor, parietooccipital and premotor areas (Woodward et al., 2005). In adults born very low birth weight, reduced hippocampal volume was found in conjunction with lower Working Memory performance (Aanes, Bjuland, Skranes, & Løhaugen, 2015). Additionally, larger third ventricles and smaller cerebral white matter, thalamus, hippocampus, cerebellum white matter, and anterior cingulate volume has been found in very low birth weight toddler compared to a full-term group (Lowe et al., 2012).
Additionally, as orbital frontal volume decreased, the early Working Memory scores (as measured by the A-not-B task) of children born very low birth weight increased.
The increased risk of perinatal brain injury associated with prematurity, for instance, has been shown to be particularly associated with Executive Function deficits (Young et al., 2016). Three specific kinds of brain injury have been found to be associated with preterm birth: intraventricular hemorrhage (IVH), cystic periventricular leukomalacia (PVL) and diffuse white matter abnormalities (Volpe, 2009). IVH and PVL have relatively low incidence rates (4% and 3%, respectively).
Diffuse white matter injury, on the other hand, has the highest incidence with 20% of infants born preterm displaying moderate to severe white matter abnormal - ities and another 51% displaying mild abnormalities (Inder, Wells, Mongridge, Spencer, & Volpe, 2003). Woodward and colleagues also demonstrated that white matter abnormalities were linked to cognitive and developmental outcomes, including Working Memory (Woodward, Clark, Boca, & Inder, 2012). Brain abnormalities on neonatal imaging (cranial ultrasounds or conventional MRI) such as indications of white matter abnormalities, periventricular leukomalacia, intraventricular hemorrhage, or ventricular enlargement have been associated with broad Executive Function weaknesses and Working Memory deficits in preterm populations (Thompson et al., 2014; Young et al., 2016).
Impact of Working Memory in prematurity on daily functioning and functional impairments
Research has also increasing highlighted the longer-term impact of Working Memory deficits on children’s everyday life. Most studies have focused on the impact of Working Memory deficits on academic functioning. Studies have focused specifically on the central role that Working Memory plays in mathematic skills. Working Memory skills, for example, has been used as a predictor of later mathematic skills time (Bull, Epsy, & Wiebe, 2008; Toll, Van der Ven, Kroesbergen, & Van Luit, 2011). Studies examining the link between Working Memory and mathematic skills have shown how components of Working Memory
relate to mathematic performance (Friso-van den Bos, Van der Ven, Kroesbergen,
& van Luit, 2013 for review). In a meta-analysis, Friso-van den Bos and colleagues (2013), for example, found that better performance on each component of Working Memory was associated with better mathematical performance with verbal updating showing the strongest relationship and inhibition and shifting showing the weakest association.
Research examining the impact of Working Memory difficulties has also explored the impact on social functioning. Studies have shown, for instance, that better Working Memory abilities facilitate children’s social development (Riggs, Jahromi, Razza, Dillworth-Bart, & Mueller, 2006). Studies examining this relationship highlight that the ability to process social information, an ability important to social functioning, is highly dependent on Working Memory capacities (de Wilde, Koot, & van Lier, 2016). Studies have shown, for example, that low Working Memory performance is associated with peer rejection. Monks and colleagues (2005), for example, showed that children with poorer Working Memory skills had more difficulty in novel situations.
Studies examining different components of Working Memory have found a relationship between Working Memory performance and social development. For example, in a sample of 1109 children followed over two academic years, starting in Kindergarten, de Wilde and colleagues (2016) found that visuospatial Working Memory performance was associated with children’s social relationships with both their peers and teachers. More specifically, poorer Working Memory performance was related to increases in teacher–child conflict and decreases in teacher–child warmth as well as decreases in likeability by peers. Similarly, McQuade and colleagues (2013) found that verbal Working Memory was also related to social relationships.
Some have argued that behavioral difficulties, particularly in the classroom, may be related to Working Memory capacities (e.g., Gathercole, Durling, Evans, Jeffcock, & Stone, 2008). Gathercole and colleagues, for example, examined the relationship between Working Memory and classroom inattentive behavior and found that children found to have poor Working Memory were impaired behavioral ratings of inattention (Alloway, Gathercole, Kirkwood, & Elliot, 2009;
Gathercole, et al., 2008). Jarrold and colleagues (2014) replicated these findings by finding that teacher ratings of inattentive/hyperactive/disruptive behavior in the classroom were related to Working Memory measure. Given these findings, many have argued that examining the relationship between classroom difficulties and Working Memory needs further study since it is possible that classroom behavioral difficulties may be secondary to more fundamental deficits in Working Memory ( Jarrold, Mackett, & Hall, 2014).
Research examining the functional impact of Working Memory deficits in preterm populations, however, has been more limited. Of the studies that have examined the impact of Working Memory deficits in preterm populations, most have focused on its impact on academic performance. Early Working Memory difficulties, for example, have been shown to predict academic and learning
difficulties in 6-year-old children born preterm (Wolke & Meyer, 1999). Similar findings have also been reported in children born very preterm, VLBW, and extremely low birth weight (Downie, Frisk, & Jakobson, 2005; Saavalainen et al., 2008). Mulder and colleagues (2010), for example, found that academic attainment differences between children born very preterm could be accounted for by children’s processing speed and Working Memory.
One area that has been explored, though not extensively, is the role of Working Memory in behavioral outcomes in children born preterm. It has been well documented that children born preterm are at a higher risk of behavioral difficulties compared to peers (Wong et al., 2014). Increased rates of attention-deficit/
hyperactivity disorder (ADHD), particularly inattentive type, have also been found within children born preterm (Wong et al., 2014).
Similar to studies with children born term, the relationship between behavioral difficulties and Working Memory has also been examined in preterm population, though again not extensively. In an attempt to further delineate the nature of behavioral difficulties found within preterm populations, some studies have explored what neurocognitive components may be involved. Similar to findings among children born term, Working Memory has also been implicated. Nadeau and colleagues (2001), for instance, found that teacher-rated measures of inattention were associated with Working Memory performance in children born very preterm (Nadeau, Boivin, Tessier, Lefebvre, & Robaey, 2001). In a middle school sample of children born very preterm, Mulder and colleagues (2011) also found that the elevated inattention behaviors rated by teachers in the very preterm group compared to the term group, were related to slow processing speed and poor Working Memory in that group.
Interventions
In the last years, research has focused increasingly on what intervention improves Executive Functioning skills more broadly and Working Memory skills, more specifically. Some of these interventions have included physical exercise, computer training and school interventions with most purported to improve Executive Function (Diamond & Ling, 2016 for review). Though most report effectiveness, their effects and generalizability appear to be variable with benefits diminishing once practice ends (for review, Diamond & Ling, 2016).
In low birth weight groups specifically, fewer intervention studies have been conducted. Recent studies have examined the impact of a computerized Working Memory training program (Cogmed JM program) in children born very low birth weight, with promising early results. In a group of 5- to 6-year-old children, for example, improvement in spatial Working Memory was seen in short-term (Grunewaldt, Løhaugen, Austeng, Brubakk, & Skranes, 2013; Lee, Pei, Andrew, Kerns, & Rasmussen, 2016) and longer-term intervals (7 months after a 5-week computerized training program) (Grunewaldt, Skranes, Brubakk, & Läghaugen, 2016). Additional randomized clinical trials of computerized adaptive Working
Memory training are in progress (Pascoe et al., 2013), which will more stringently examine this question. This will be important to understand the mechanisms at work as a recent study by de Jong (2014) found that the mentoring component to many CogMed programs may account for the benefits to a greater degree than the computerized games themselves. Further exploration regarding interventions for Working Memory and Executive Function in the very low birth weight group represent a promising future direction for research, especially since children who start further behind in Executive Function skills appear to benefit the most from a variety of Executive Function intervention (Diamond & Ling, 2016).
Current debates
A current debate within the field is related to prematurity including late preterm birth and its impacts on cognition, Executive Function and Working Memory.
Late preterm birth (34 to <37 weeks’ gestation) is associated with lower birth weights compared to infants born at full term (38–42 weeks gestational age controls) and this has been posited to be a risk factor for adverse effects (Brumbaugh, Hodel &
Thomas, 2014). In recent years more concern has emerged regarding the outcomes of children born ‘near term,’ previously this had been felt to be inconsequential with regard to mortality and morbidity (Baron et al., 2014). Greater risks for re- hospitalization, school struggles, and behavioral difficulties have been found in late preterm groups, which may implicate underlying Executive Function weaknesses.
With regard to Working Memory specifically, 4-year-old children born late preterm were found to have poorer performance on a verbal Working Memory task (digit span) than a full term control group (Brumbaugh et al., 2014). In contrast, in a sample of 3-year-olds, who were identified as complicated late preterm (NICU hospitalization), no differences were found in verbal Working Memory compared to the full term group (recall digits forward); although differences were found in other domains of Executive Function (verbal fluency) (Baron, Erickson, Ahronovich, Coulehan, Baker, & Litman, 2009). This is an important area of debate, as currently children born late preterm or with moderately lower birth weights are not routinely followed up with developmental screening despite the fact that early interruption of fetal brain maturation may put children born late preterm at greater risk for developmental sequelae.
References
Aarnoudse-Moens, C. S., Smidts, D. P., Oosterlaan, J., Duivenvoorden, H. J., & Weisglas- Kuperus, N. (2009). Executive Function in very preterm children at early school age.
Journal of Abnormal Child Psychology, 37(7), 981–993.
Aanes, S., Bjuland, K. J., Skranes, J., & Løhaugen, G. C. (2015). Memory function and hippocampal volumes in preterm born very-low-birth-weight (VLBW) young adults.
NeuroImage, 105, 76–83.
Alloway, T. P., Gathercole, S. E., Kirkwood, H., & Elliott, J. (2009). The cognitive and behavioral characteristics of children with low Working Memory. Child Development, 80(2), 606–621.