Extreme prematurity and attention deficit: epidemiology and prevention

Abstract

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). 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). 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). [...]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).

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.

Acknowledgments

The authors thank Dr. Alan Leviton for helpful critique of this paper. This work was supported by The National Institute of Neurological Disorders and Stroke (5U01NS040069-05 and 2R01NS040069-06A2).

References

Aarnoudse-Moens, C. S. H., Weisglas-Kuperus, N., van Goudoever, J. B., and Oosterlaan, J. (2009). Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics 124, 717–728. doi: 10.1542/peds.2008-2816

Adler, N., Bush, N. R., and Pantell, M. S. (2012). Rigor, vigor, and the study of health disparities. Proc. Natl. Acad. Sci. U.S.A. 109, 17154–17159. doi: 10.1073/pnas.1121399109

Anderson, P. J., De Luca, C. R., Hutchinson, E., Spencer-Smith, M. M., Roberts, G., and Doyle, L. W. (2011). Attention problems in a representative sample of extremely preterm/extremely low birth weight children. Dev. Neuropsychol. 36, 57–73. doi: 10.1080/87565641.2011.540538

Bhutta, A. T., Cleves, M. A., Casey, P. H., Cradock, M. M., and Anand, K. J. S. (2002). Cognitive and behavioral outcomes of school-aged children who were born preterm—a meta-analysis. JAMA 288, 728–737. doi: 10.1001/jama.288.6.728

Bose, C. L., Laughon, M. M., Allred, E. N., O'Shea, T. M., Van Marter, L. J., Ehrenkranz, R. A., et al. (2013). Systemic inflammation associated with mechanical ventilation among extremely preterm infants. Cytokine 61, 315–322. doi: 10.1016/j.cyto.2012.10.014

Crowther, C. A., Doyle, L. W., Haslam, R. R., Hiller, J. E., Harding, J. E., and Robinson, J. S. (2007). Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N. Engl. J. Med. 357, 1179–1189. doi: 10.1056/NEJMoa071152

Dalziel, S. R., Lim, V. K., Lambert, A., McCarthy, D., Parag, V., Rodgers, A., et al. (2005). Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial. Br. Med. J. 331, 665–668A. doi: 10.1136/bmj.38576.494363.E0

Dammann, O., and O'Shea, T. M. (2008). Cytokines and perinatal brain damage. Clin. Perinatol. 35, 643–663. doi: 10.1016/j.clp.2008.07.011

Delobel-Ayoub, M., Arnaud, C., White-Koning, M., Casper, C., Pierrat, V., Garel, M., et al. (2009). Behavioral problems and cognitive performance at 5 years of age after very preterm birth: the EPIPAGE study. Pediatrics 123, 1485–1492. doi: 10.1542/peds.2008-1216

Dilek, M., Kumral, A., Okyay, E., Ozbal, S., Tugyan, K., Tuzun, F., et al. (2013). Protective effects of pentoxifylline on lipopolysaccharide-induced white matter injury in a rat model of periventricular leukomalasia. J. Matern. Fetal. Neonatal. Med. doi: 10.3109/14767058.2013.798290. [Epub ahead of print].

Doyle, L. W., Crowther, C. A., Middleton, P., and Marret, S. (2009). Antenatal magnesium sulfate and neurologic outcome in preterm infants. Obstet. Gynecol. 113, 1327–1333.

Elgen, I., Sommerfelt, K., and Markestad, T. (2002). Population based, controlled study of behavioural problems and psychiatric disorders in low birthweight children at 11 years of age. Arch. Dis. Child. Fetal Neonatal Ed. 87, F128–F132. doi: 10.1136/fn.87.2.F128

Fleiss, B., and Gressens, P. (2012). Tertiary mechanisms of brain injury: a new hope for treatment of cerebral palsy. Lancet Neurol. 11, 556–566. doi: 10.1016/S1474-4422(12)70058-3

Fukuda, H., Tomimatsu, T., Watanabe, N., Mu, J. W., Kohzuki, M., Endo, M., et al. (2001). Post-ischemic hypothermia blocks caspase-3 activation in the newborn rat brain after hypoxia-ischemia. Brain Res. 910, 187–191. doi: 10.1016/S0006-8993(01)02659-2

Gotsch, F., Romero, R., Kusanovic, J. P., Mazaki-Tovi, S., Pineles, B. L., Erez, O., et al. (2007). The fetal inflammatory response syndrome. Clin. Obstet. Gynecol. 50, 652–683. doi: 10.1097/GRF.0b013e31811ebef6

Gray, P. H., O'Callaghan, M. J., and Poulsen, L. (2008). Behaviour and quality of life at school age of children who had bronchopulmonary dysplasia. Early Hum. Dev. 84, 1–8. doi: 10.1016/j.earlhumdev.2007.01.009

Hack, M., Taylor, H. G., Schluchter, M., Andreias, L., Drotar, D., and Klein, N. (2009). Behavioral outcomes of extremely low birth weight children at age 8 years. J. Dev. Behav. Pediatr. 30, 122–130. doi: 10.1097/DBP.0b013e31819e6a16

Hagberg, H., Gressens, P., and Mallard, C. (2012). Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann. Neurol. 71, 444–457. doi: 10.1002/ana.22620

Hagberg, H., Peebles, D., and Mallard, C. (2002). Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment. Retard. Dev. Disabil. Res. Rev. 8, 30–38. doi: 10.1002/mrdd.10007

Halliday, H. L., Ehrenkranz, R. A., and Doyle, L. W. (2009). Late (>7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst. Rev. 1:CD001145. doi: 10.1002/14651858.CD001145.pub2

Halliday, H. L., Ehrenkranz, R. A., and Doyle, L. W. (2010). Early (<8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst. Rev. 1:CD001146. doi: 10.1002/14651858.CD001146.pub3

Hille, E. T. M., den Ouden, A. L., Saigal, S., Wolke, D., Lambert, M., Whitaker, A., et al. (2001). Behavioural problems in children who weigh 1000 g or less at birth in four countries. Lancet 357, 1641–1643. doi: 10.1016/S0140-6736(00)04818-2

Hinkle, S. N., Schieve, L. A., Stein, A. D., Swan, D. W., Ramakrishnan, U., and Sharma, A. J. (2012). Associations between maternal prepregnancy body mass index and child neurodevelopment at 2 years of age. Int. J. Obes. 36, 1312–1319. doi: 10.1038/ijo.2012.143

Hinkle, S. N., Sharma, A. J., Kim, S. Y., and Schieve, L. A. (2013). Maternal pre-pregnancy weight status and associations with children's development and disabilities at kindergarten. Int. J. Obes. (Lond). doi: 10.1038/ijo.2013.128. [Epub ahead of print].

Holzman, C., Lin, X. M., Senagore, P., and Chung, H. (2007). Histologic chorioamnionitis and preterm delivery. Am. J. Epidemiol. 166, 786–794. doi: 10.1093/aje/kwm168

Inder, T. E., Anderson, N. J., Spencer, C., Wells, S., and Volpe, J. J. (2003). White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. Am. J. Neuroradiol. 24, 805–809.

Indredavik, M. S., Skranes, J. S., Vik, T., Heyerdahl, S., Romundstad, P., Myhr, G. E., et al. (2005). Low-birth-weight adolescents: psychiatric symptoms and cerebral MRI abnormalities. Pediatr. Neurol. 33, 259–266. doi: 10.1016/j.pediatrneurol.2005.05.002

Indredavik, M. S., Vik, T., Evensen, K. A. I., Skranes, J., Taraldsen, G., and Brubakk, A. M. (2010). Perinatal risk and psychiatric outcome in adolescents born preterm with very low birth weight or term small for gestational age. J. Dev. Behav. Pediatr. 31, 286–294. doi: 10.1097/DBP.0b013e3181d7b1d3

Jacobs, S. E., Berg, M., Hunt, R., Tarnow-Mordi, W. O., Inder, T. E., and Davis, P. G. (2013). Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst. Rev. 1:CD003311. doi: 10.1002/14651858.CD003311.pub3

Johnson, S., Hollis, C., Kochhar, P., Hennessy, E., Wolke, D., and Marlow, N. (2010). Psychiatric disorders in extremely preterm children: longitudinal finding at age 11 years in the EPICure study. J. Am. Acad. Child Adolesc. Psychiatry 49, 453–463. doi: 10.1016/j.jaac.2010.02.002

Johnson, S., and Marlow, N. (2011). Preterm birth and childhood psychiatric disorders. Pediatr. Res. 69, 11R–18R. doi: 10.1203/PDR.0b013e318212faa0

Kenyon, S., Pike, K., Jones, D. R., Brocklehurst, P., Marlow, N., Salt, A., et al. (2008a). Childhood outcomes after prescription of antibiotics to pregnant women with preterm rupture of the membranes: 7-year follow-up of the ORACLE I trial. Lancet 372, 1310–1318. doi: 10.1016/S0140-6736(08)61202-7

Kenyon, S., Pike, K., Jones, D. R., Brocklehurst, P., Marlow, N., Salt, A., et al. (2008b). Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet 372, 1319–1327. doi: 10.1016/S0140-6736(08)61203-9

Kumral, A., Baskin, H., Yesilirmak, D. C., Ergur, B. U., Aykan, S., Genc, S., et al. (2007). Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neonatology 92, 269–278. doi: 10.1159/000105493

Leibowitz, K. L., Moore, R. H., Ahima, R. S., Stunkard, A. J., Stallings, V. A., Berkowitz, R. I., et al. (2012). Maternal obesity associated with inflammation in their children. World J. Pediatr. 8, 76–79. doi: 10.1007/s12519-011-0292-6

Leviton, A., Hecht, J. L., Onderdonk, A. O., Kuban, K., O'Shea, T. M., Allred, E. N., et al. (2010). Microbiological and histologic characteristics of the extremely preterm infant's placenta predict white matter damage and later cerebral palsy. Pediatr. Res. 67, 95–101. doi: 10.1203/PDR.0b013e3181bf5fab

Leviton, A., O'Shea, T. M., Bednarek, F. J., Allred, E. N., Fichorova, R. N., and Dammann, O. (2012). Systemic responses of preterm newborns with presumed or documented bacteraemia. Acta Paediatr. 101, 355–359. doi: 10.1111/j.1651-2227.2011.02527.x

Lindstrom, K., Lindblad, F., and Hjern, A. (2011). Preterm birth and attention-deficit/hyperactivity disorder in schoolchildren. Pediatrics 127, 858–865. doi: 10.1542/peds.2010-1279

Lorenz, J. M., Wooliever, D. E., Jetton, J. R., and Paneth, N. (1998). A quantitative review of mortality and developmental disability in extremely premature newborns. Arch. Pediatr. Adolesc. Med. 152, 425–435. doi: 10.1001/archpedi.152.5.425

Maalouf, E. F., Duggan, P. J., Counsell, S. J., Rutherford, M. A., Cowan, F., Azzopardi, D., et al. (2001). Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants. Pediatrics 107, 719–727. doi: 10.1542/peds.107.4.719

Martin, C. R., Bellomy, M., Allred, E. N., Fichorova, R. N., and Leviton, A. (2013). Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns. Fetal Pediatr. Pathol. 32, 222–234. doi: 10.3109/15513815.2012.721477

Martin, C. R., Dammann, O., Allred, E. N., Patel, S., O'Shea, T. M., Kuban, K. C. K., et al. (2010). Neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia. J. Pediatr. 157, 751–756. doi: 10.1016/j.jpeds.2010.05.042

McElrath, T. F., Allred, E. N., Boggess, K. A., Kuban, K., O'Shea, T. M., Paneth, N., et al. (2009). Maternal antenatal complications and the risk of neonatal cerebral white matter damage and later cerebral palsy in children born at an extremely low gestational age. Am. J. Epidemiol. 170, 819–828. doi: 10.1093/aje/kwp206

McElrath, T. F., Fichorova, R. N., Allred, E. N., Hecht, J. L., Ismail, M., and Leviton, A. (2011). Blood protein profiles of infants differ by the pregnancy complication in infants born before the 28th week of gestation. Am. J. Obstet. Gynecol. 204, 418.e1–418.e12. doi: 10.1016/j.ajog.2010.12.010

Miller, S. P., Cozzio, C. C., Goldstein, R. B., Ferriero, D. M., Partridge, J. C., Vigneron, D. B., et al. (2003). Comparing the diagnosis of white matter injury in premature newborns with serial MR imaging and transfontanel ultrasonography findings. Am. J. Neuroradiol. 24, 1661–1669.

Mulder, H., Pitchford, N. J., Hagger, M. S., and Marlow, N. (2009). Development of executive function and attention in preterm children: a systematic review. Dev. Neuropsychol. 34, 393–421. doi: 10.1080/87565640902964524

Nadeau, L., Boivin, M., Tessier, R., Lefebvre, F., and Robaey, P. (2001). Mediators of behavioral problems in 7-year-old children born after 24 to 28 weeks of gestation. J. Dev. Behav. Pediatr. 22, 1–10. doi: 10.1097/00004703-200102000-00001

Nock, M. K., Kazdin, A. E., Hiripi, E., and Kessler, R. C. (2006). Prevalence, subtypes, and correlates of DSM-IV conduct disorder in the national comorbidity survey replication. Psychol. Med. 36, 699–710. doi: 10.1017/S0033291706007082

Nomura, Y., Marks, D. J., and Halperin, J. M. (2010). Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring. J. Nerv. Ment. Dis. 198, 672–678. doi: 10.1097/NMD.0b013e3181ef3489

Paneth, N. S. (1995). The problem of low-birth-weight. Future of Child. 5, 19–34. doi: 10.2307/1602505

Peterson, J., Taylor, H. G., Minich, N., Klein, N., and Hack, M. (2006). Subnormal head circumference in very low birth weight children: neonatal correlates and school-age consequences. Early Hum. Dev. 82, 325–334. doi: 10.1016/j.earlhumdev.2005.09.014

Pineda, D. A., Palacio, L. G., Puerta, I. C., Merchan, V., Arango, C. P., Galvis, A. Y., et al. (2007). Environmental influences that affect attention deficit/hyperactivity disorder—study of a genetic isolate. Eur. Child Adolesc. Psychiatry 16, 337–346. doi: 10.1007/s00787-007-0605-4

Roberts, D., and Dalziel, S. (2006). Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst. Rev. 1:CD004454. doi: 10.1002/14651858.CD004454.pub2

Robertson, N. J., Faulkner, S., Fleiss, B., Bainbridge, A., Andorka, C., Price, D., et al. (2013). Melatonin augments hypothermic neuroprotection in a perinatal asphyxia model. Brain 136, 90–105. doi: 10.1093/brain/aws285

Romero, R., Espinoza, J., Goncalves, L. F., Kusanovic, J. P., Friel, L., and Hassan, S. (2007). The role of inflammation and infection in preterm birth. Semin. Reprod. Med. 25, 21–39. doi: 10.1055/s-2006-956773

Rouse, D. (2007). A randomized controlled trial of magnesium sulfate for the prevention of cerebral palsy. Am. J. Obstet. Gynecol. 197, S2. doi: 10.1016/j.ajog.2007.10.002

Samara, M., Marlow, N., and Wolke, D. (2008). Pervasive behavior problems at 6 years of age in a total-population sample of children born at <= 25 weeks of gestation. Pediatrics 122, 562–573. doi: 10.1542/peds.2007-3231

Schmidt, B., Roberts, R. S., Davis, P., Doyle, L. W., Barrington, K. J., Ohlsson, A., et al. (2007). Long-term effects of caffeine therapy for apnea of prematurity. N. Engl. J Med. 357, 1893–1902. doi: 10.1056/NEJMoa073679

Scott, M. N., Taylor, H. G., Fristad, M. A., Klein, N., Espy, K. A., Minich, N., et al. (2012). Behavior disorders in extremely preterm/extremely low birth weight children in kindergarten. J.Dev. Behav. Pediatr. 33, 202–213. doi: 10.1097/DBP.0b013e3182475287

Serenius, F., Kallen, K., Blennow, M., Ewald, U., Fellman, V., Holmstrom, G., et al. (2013). Neurodevelopmental outcome in extremely preterm infants at 2.5 years after active perinatal care in Sweden. JAMA 309, 1810–1820. doi: 10.1001/jama.2013.3786

Sisk, P. M., Lovelady, C. A., Dillard, R. G., Gruber, K. J., and O'Shea, T. M. (2007). Early human milk feeding is associated with a lower risk of necrotizing enterocolitis in very low birth weight infants. J. Perinatol. 27, 428–433. doi: 10.1038/sj.jp.7211758

Skranes, J., Vangberg, T. R., Kulseng, S., Indredavik, M. S., Evensen, K. A. I., Martinussen, M., et al. (2007). Clinical findings and white matter abnormalities seen on diffusion tensor imaging in adolescents with very low birth weight. Brain 130, 654–666. doi: 10.1093/brain/awm001

Tanaka, K., Hosozawa, M., Kudo, N., Yoshikawa, N., Hisata, K., Shoji, H., et al. (2013). The pilot study: sphingomyelin-fortified milk has a positive association with the neurobehavioural development of very low birth weight infants during infancy, randomized control trial. Brain Dev. 35, 45–52. doi: 10.1016/j.braindev.2012.03.004

Thapar, A., Cooper, M., Jefferies, R., and Stergiakouli, E. (2012). What causes attention deficit hyperactivity disorder. Arch. Dis. Child. 97, 260–265. doi: 10.1136/archdischild-2011-300482

Thornton, C., Rousset, C. I., Kichev, A., Miyakuni, Y., Vontell, R., Baburamani, A. A., et al. (2012). Molecular mechanisms of neonatal brain injury. Neurol. Res. Int. 2012, 16. doi: 10.1155/2012/506320

Tomimatsu, T., Fukuda, H., Endo, M., Watanabe, N., Mu, J. W., Kohzuki, M., et al. (2001). Effects of hypothermia on neonatal hypoxic-ischemic brain injury in the rat: phosphorylation of Akt, activation of caspase-3-like protease. Neurosci. Lett. 312, 21–24. doi: 10.1016/S0304-3940(01)02178-4

Tomimatsu, T., Fukuda, H., Endoh, M., Mu, J., Kanagawa, T., Hosono, T., et al. (2003). Long-Term neuroprotective effects of hypothermia on neonatal hypoxic-ischemic brain injury in rats, assessed by auditory brainstem response. Pediatr. Res. 53, 57–61. doi: 10.1203/00006450-200301000-00012

Vuillermot, S., Joodmardi, E., Perlmann, T., Ogren, S. O., Feldon, J., and Meyer, U. (2012). Prenatal immune activation interacts with genetic nurr1 deficiency in the development of attentional impairments. J. Neurosci. 32, 436–451. doi: 10.1523/JNEUROSCI.4831-11.2012

Wang, X. Y., Hellgren, G., Lofqvist, C., Li, W. L., Hellstrom, A., Hagberg, H., et al. (2009). White Matter Damage After Chronic Subclinical Inflammation in Newborn Mice. J. Child Neurol. 24, 1171–1178. doi: 10.1177/0883073809338068

Wang, X. Y., Rousset, C. I., Hagberg, H., and Mallard, C. (2006). Lipopolysaccharide-induced inflammation and perinatal brain injury. Semin. Fetal Neonatal Med. 11, 343–353. doi: 10.1016/j.siny.2006.04.002

Weijer-Bergsma, E. V., Wijnroks, L., and Jongmans, M. J. (2008). Attention development in infants and preschool children born preterm: a review. Infant Behav. Dev. 31, 333–351. doi: 10.1016/j.infbeh.2007.12.003

Whitaker, A. H., Van Rossem, R., Feldman, J. F., Schonfeld, I. S., Pinto-Martin, J. A., Tore, C., et al. (1997). Psychiatric outcomes in low-birth-weight children at age 6 years: relation to neonatal cranial ultrasound abnormalities. Arch. Gen. Psychiatry 54, 847–856. doi: 10.1001/archpsyc.1997.01830210091012

Wood, N. S., Costeloe, K., Gibson, A. T., Hennessy, E. M., Marlow, N., and Wilkinson, A. R. (2005). The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth. Arch. Dis. Child. Fetal Neonatal Ed. 90, 134–140. doi: 10.1136/adc.2004.052407

Yeh, T. F., Lin, Y. J., Lin, H. C., Huang, C. C., Hsieh, W. S., Lin, C. H., et al. (2004). Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N. Engl. J. Med. 350, 1304–1313. doi: 10.1056/NEJMoa032089