Extreme prematurity and attention impairment
Preterm infants are at increased risk for a wide range of developmental disorders,
including sensory, motor, cognitive, and other brain disorders (Lorenz et al., 1998;
Bhutta et al., 2002; Aarnoudse-Moens et al., 2009), and the risk is highest for those
infants born before 28 weeks gestation, i.e., extremely preterm or extremely low gestational
age infants (Wood et al., 2005; Serenius et al., 2013). As large cohorts of extremely
preterm infants have reached school age, the prevalence of brain dysfunctions that
affect academic success has been quantified, and antecedents and correlates of these
problems have been better characterized. The most prevalent of these is attention
deficit/hyperactivity disorder (ADHD) (Hack et al., 2009; Johnson et al., 2010).
Based on screening questionnaires, such as the Child Behavioral Checklist (Hille et
al., 2001) and the Strengths and Difficulties Questionnaire (Elgen et al., 2002; Samara
et al., 2008; Delobel-Ayoub et al., 2009), children born extremely preterm perform
worse than full term children on attention scales. Using Diagnostic and Statistical
Manual-based criteria, extremely preterm children have a risk of ADHD that is four
times that of full term controls (Johnson et al., 2010; Scott et al., 2012).
Some studies report an association of extreme prematurity with the inattention type
of ADHD but not the hyperactivity/impulsivity type (Hack et al., 2009; Johnson et
al., 2010; Johnson and Marlow, 2011), while others report associations with both types
of ADHD (Anderson et al., 2011; Scott et al., 2012). In one sample, inattentive behaviors
were explained by sequential memory problems, while hyperactive behaviors were explained
by global intellectual impairment (Nadeau et al., 2001). The attention impairment
among preterm infants affects a range of domains of attention including selective
attention, sustained attention, attention encoding, shifting attention, and divided
attention (Mulder et al., 2009; Anderson et al., 2011).
In the general population ADHD is associated with conduct disorder (Nock et al., 2006),
but this does not appear to be the case among preterm infants (Elgen et al., 2002;
Hack et al., 2009; Johnson et al., 2010; Scott et al., 2012). Extremely preterm infants
with ADHD are more likely to have cognitive impairment than those without ADHD, and
in one study there was no association between extreme prematurity and ADHD among infants
without cognitive impairment (Johnson et al., 2010). Impaired attention is a likely
contributor to extremely preterm children's increased risk of cognitive impairment
and behavioral problems (Weijer-Bergsma et al., 2008). Moderately preterm children
exhibit some developmental catch up in selective attention so that the difference
between these children and term children narrows with increasing age (Mulder et al.,
2009).
Risk factors for attention impairment among extremely preterm infants
Social disadvantage is more prevalent among mothers delivering prematurely (Paneth,
1995), and is a risk factor for attention problems during childhood among preterm
infants (Hack et al., 2009; Lindstrom et al., 2011; Scott et al., 2012). This variable
conveys information about a variety of factors including race, maternal psychosocial
stress, and mother's education (Adler et al., 2012). In unselected samples, maternal
smoking, which is associated with preterm delivery, has been associated with attention
impairment (Nomura et al., 2010).
The strong inherited contribution to ADHD (Thapar et al., 2012) appears to be less
important among preterm infants (Johnson and Marlow, 2011). Male sex, which is predictive
of more severe neonatal illness after preterm birth, is associated with the hyperactive
type of ADHD among extremely low birth weight children (Hack et al., 2009). Neonatal
illnesses which occur frequently after extremely preterm birth, such as necrotizing
enterocolitis and chronic lung disease, could explain the smaller contribution of
genetics in this group. In one extremely preterm cohort, necrotizing enterocolitis
was predictive of impaired selective attention but not other attention domains (Anderson
et al., 2011). At school age, children who had recovered from neonatal chronic lung
disease, as compared to preterm children without chronic lung disease, had more attention
problems, based on teacher's report (Gray et al., 2008). However, in two other cohorts
no neonatal factors were predictive of an attention problem (Hack et al., 2009; Johnson
et al., 2010). In another cohort of extremely preterm children, an Apgar score less
than 8 at 5 min was associated with a higher risk of using medication for ADHD (Lindstrom
et al., 2011).
Among very low birth weight infants, intraventricular hemorrhage (and presumably the
accompanying brain damage) (Indredavik et al., 2010) and subnormal head growth (Peterson
et al., 2006) are associated with attention problems. In a large prospective study,
white matter injury was associated with a 2.7-fold increase in the risk of ADHD at
6 years of age (Whitaker et al., 1997). Ultrasound is only modestly sensitive for
detection of white matter abnormalities (Maalouf et al., 2001; Inder et al., 2003;
Miller et al., 2003). More sensitive imaging techniques, using magnetic resonance
imaging (MRI) also have identified structural correlates of attention impairment.
Among adolescents who had very low birth weight, thinning of the corpus callosum and
reduced white matter volume were associated with attention deficit but were not associated
with hyperactivity (Indredavik et al., 2005). Diffuse tensor imaging, which identifies
disruption or disorganization of white matter tracts, indicates that reduced fractional
anisotropy of the external capsule and middle and superior fascicles is associated
with higher inattention scores on the ADHD Rating Scale IV (Skranes et al., 2007).
Inflammation and cerebral white matter damage in extremely preterm infant
Even when an infection is distant from the brain, maternal and neonatal infections
are associated with perinatal brain damage (Dammann and O'Shea, 2008). Administration
of endotoxin to a variety of immature experimental animals results in cerebral damage,
and the damage is mediated by inflammation-related molecules including cytokines,
chemokines, adhesion molecules, and matrix metalloproteinases (Wang et al., 2006).
A range of clinical disorders in humans has been associated with perinatal infection
and inflammation, including ultrasound-defined white matter injury, microcephaly,
cerebral palsy, cognitive impairment, behavioral dysfunctions, and psychiatric illness
(Hagberg et al., 2012).
Biomarkers of perinatal infection and inflammation include neutrophil infiltration
of the placenta (Holzman et al., 2007) and inflammation-related proteins in the amniotic
fluid and neonatal blood. Clinical initiators of inflammation include maternal infections
(McElrath et al., 2011), lung injury induced by mechanical ventilation (Bose et al.,
2013), necrotizing enterocolitis (Martin et al., 2013), and neonatal sepsis (Leviton
et al., 2012).
In a large cohort of extremely preterm infants, the ELGAN cohort, both clinical indicators
(McElrath et al., 2009; Martin et al., 2010) and biomarkers of inflammation (Leviton
et al., 2010) have been associated with perinatal brain damage and subsequent developmental
impairment at 2 years of age. In this cohort, persistent/recurrent elevations of seven
inflammation-related proteins, defined as an elevation on at least 2 days a week or
more apart in the first 2 weeks of life, are associated with a 2- to 3.9-fold increase
in the risk of an attention impairment identified at 2 years of age using the Child
Behavioral Checklist [manuscript under review].
Maternal or neonatal infections occur in a majority of pregnancies that result in
an extremely preterm birth, yet the prevalence of ADHD among the offspring is typically
less than 20%, suggesting that inflammation requires other factors, which could include
genetic susceptibility, to contribute to the occurrence of ADHD. In a genetically
isolated community with a high prevalence of ADHD, severe maternal respiratory infection
was associated with a 3.3-fold increase in risk, suggesting that genetic factors could
modify associations between inflammation and ADHD in humans (Pineda et al., 2007).
In a preclinical model, inflammation-induced attentional impairments and abnormalities
in dopamine neurons were more severe in mice genetically deficient in Nurr1, which
plays important roles in differentiation, migration, and survival of dopaminergic
neurons (Vuillermot et al., 2012).
Might interventions to reduce perinatal inflammation decrease the risk of attention
impairments among extremely preterm children?
Antenatal interventions
The consistent association of perinatal inflammation and brain disorders, including
attention impairment, suggests that immuno-modulatory interventions might decrease
the risk of attention problems in extremely preterm infants.
Antenatal treatment of the mother with glucocorticoids might modulate inflammation's
effects on the brain. For example, antenatal glucocorticoids decrease the risk of
cerebral palsy (Roberts and Dalziel, 2006). However, in two randomized clinical trials
of antenatal steroids, attention abilities were not improved, nor was the risk of
ADHD reduced, by this intervention (Dalziel et al., 2005; Crowther et al., 2007).
Maternal infection is a frequent initiator of preterm labor (Romero et al., 2007),
and often is accompanied by a fetal systemic inflammatory response (Gotsch et al.,
2007). However, antenatal antibiotic treatment of mothers with preterm labor, but
without overt infection, does not decrease the risk of attention problems in the offspring
(Kenyon et al., 2008a,b).
Antenatal treatment with magnesium sulfate reduces the risk of cerebral palsy in offspring
of mothers who develop preterm labor prior to 30 weeks gestation (Rouse, 2007). However,
the effect of this intervention on attention problems has not been reported (Doyle
et al., 2009).
Children of obese mothers are more likely than children of women with a pre-pregnancy
weight in the normal range to have a low Bayley Scales Mental Development Index at
age 2 years (Hinkle et al., 2012) and a lower reading score at kindergarten age (Hinkle
et al., 2013). Since maternal pre-pregnancy obesity is associated with later inflammation
in the offspring (Leibowitz et al., 2012), interventions that reduce maternal obesity
could reduce the risk of attention problems in the offspring.
Postnatal interventions
Postnatal strategies to decrease inflammation-related perinatal brain injury include
interventions to prevent initiators of inflammation and broader strategies to modulate
inflammation.
The three most obvious initiators of systemic inflammation are bacteremia (Leviton
et al., 2012), mechanical ventilation. (Bose et al., 2013), and necrotizing enterocolitis
(Martin et al., 2013). Our hope is that whatever reduces the occurrence of these three
major complications in the NICU will reduce the later occurrence of attention problems.
Broader strategies to modulate inflammation include those that shorten or minimize
the intensity of inflammation once initiated. For example, caffeine reduces the risk
of chronic lung disease, an inflammatory pulmonary condition, and decreases the risk
of neurodevelopmental impairment. Unfortunately, the effects of perinatal caffeine
on attention problems have not been reported (Schmidt et al., 2007).
Although postnatal steroids decrease lung inflammation (Halliday et al., 2009, 2010),
no evidence has been offered to date that attention abilities are improved by postnatal
steroids (Yeh et al., 2004). Similarly, human milk is associated with a reduced risk
of necrotizing enterocolitis (Sisk et al., 2007), but other than a small pilot randomized
trial of sphingomyelin-fortified human milk (Tanaka et al., 2013), evidence is lacking
of an effect of human milk on attention in extremely preterm infants.
Other potential approaches to broadly reduce systemic inflammation have been suggested
by preclinical studies. In animal models of perinatal brain injury which either directly
or indirectly involve inflammation, (Hagberg et al., 2002; Wang et al., 2006, 2009;
Thornton et al., 2012) injury can be attenuated by hypothermia (Fukuda et al., 2001;
Tomimatsu et al., 2001, 2003), melatonin (Robertson et al., 2013), pentoxifylline
(a methyl xanthine) (Dilek et al., 2013), and erythropoietin (Kumral et al., 2007).
Hypothermia is an effective neuroprotective agent in humans born near term (Jacobs
et al., 2013), and will be studied in preterm infants [ClinicalTrials.gov identifier:
NCT01793129]. Melatonin and erythropoietin also are being studied as neuroprotective
strategies for preterm infants [ClinicalTrials.gov identifier: NCT00649961 (melatonin)
and NCT01378273 (erythropoietin)]. As mentioned above, caffeine, a methyl xanthine,
appears to be neuroprotective in preterm infants although data about it effect on
attention is lacking.
In addition to acute interventions, strategies might be found for attenuating the
sustained disruption to brain development that persists months and perhaps years after
an initial insult to the immature brain. The mechanisms underlying sustained disruption
appear to include sustained inflammation as well as epigenetic changes, in which case
an extended window of opportunity for intervention might exist (Fleiss and Gressens,
2012).
Summary
Extremely preterm infants have an increased risk of attention problems and a better
understanding of the antecedents of these problems can lead to prevention strategies.
Perinatal systemic inflammation, an antecedent of structural and functional brain
disorders in extremely preterm infants, appears to be an antecedent of attention problems.
Interventions to prevent initiators of inflammation or modulate systemic inflammation
might decrease the risk of attention problems among children born extremely preterm.
Author contribution
T. Michael O'Shea wrote the initial draft of the paper. L. Corbin Downey and Karl
K. C. Kuban revised the paper. All authors approved the final version.