Role of Intervention Strategies for At-risk Preterm Infants

Role of Intervention Strategies for At-risk Preterm Infants concurrent motor repertoire at 3 to 4 months post-term.9 When espite increased survival rates of preterm infants, the prevalence of developmental disabilities in preterm FMs are normal, a smooth, variable concurrent motor repersurvivors is still high.1 Although the rates of major toire is a marker for a normal outcome, and the risk for the dehandicaps have remained relatively constant in the last velopment of DCD is low (5%). When the concurrent motor decade, the prevalence of milder dysfunctions seems to be inrepertoire is monotonous, the risk for the development of creasing. Cognitive, behavioral, and mild DCD is approximately 30%.9 Although preSee related articles, diction of neurodevelopmental outcome at motor problems without major motor defip 359 and p 366 an early age is difficult, these and other neurocits are now the most dominant neurodevemotor tests show that the best prediction is achieved when some lopmental sequelae in children born preterm.2,3 These problems include learning disabilities, borderline to low IQ form of qualitative aspect of motor behavior is considered.6 In this issue of The Journal, Stephens et al 10 adds to our scores, attention-deficit, and specific neuropsychological defi3 knowledge of early prediction by means of neurobehavioral cits affecting visuomotor integration and executive function. These abnormalities occur in >50% of children born preterm assessment. They showed that their previously developed with very low birth weight (VLBW; < 1500 g) and often do neurobehavioral scale can help to predict poor motor outnot occur in isolation.2 The situation is further confounded come at 24 months of age. Originally, the Neonatal Intensive by the social, ethnic, and educational background of the parents Care Unit Network Neurobehavior Scales (NNNS) was dealso possibly influencing the prevalence of these disabilities. veloped to investigate the effects of cocaine exposure. The auIn early infancy, it is difficult to identify the individual inthors have now investigated the predictive value of the NNNS fant at highest risk for mild motor, cognitive, and behavioral for cerebral palsy at 12 to 36 months and low psychomotor problems. Models of pathogenesis include changes related to developmental index (PDI) at 24 months in a cohort of developmental disruptions and brain injury.2,4 Although nearly 400 preterm infants, born before 36 weeks gestation. global white matter damage revealed with ultrasound scanThe NNNS provides a comprehensive assessment of 3 dimenning and magnetic resonance imaging is quite common in sions of the newborn: neurologic integrity, behavioral funcchildren born preterm, and volumes of gray matter are also tioning, and stress behavior. Each dimension has a number diminished, clear associations of cognition with pathological of scores, from which 13 summary scores are calculated. Cechanges on neuroimaging have not been definitely demonrebral palsy and low PDI (<70) at 24 months were associated strated.5 Another method to identify infants at risk is some with 4 items from the NNNS administered at 4 weeks postform of neurobehavioral assessment at an early age.6 Of these, term: low quality of movement, high lethargy, low handling, the assessment of the quality of spontaneous general moveand hypotonia. In various combinations, these items contribments has emerged as a reliable and valid predictor of major uted 19% to the variance in cerebral palsy diagnosis and 26% motor deficits for the individual infant.7 This method is in low PDI. The authors conclude that the neurobehavioral based on visual Gestalt perception of the quality of general profile of under-arousal at 4 weeks post-term may predict movements in the preterm, term, and post-term periods, as poor motor outcome in preterm infants. This information long as 5 months post-term. The quality of so called fidgety about the risk of poor motor outcome was the addition to general movements (FMs), present between 9 and 20 weeks other predictors, such as chronic lung disease, intraventricupost-term and defined as continuous small movements of lar hemorrhage, and periventricular leukomalacia. moderate speed in all directions, is a particularly accurate The study by Stephens et al is part of a larger project and an marker for neurological outcome. Most infants (96%) with extension of previously published data. There are some limitanormal FMs have normal neurological outcomes, and ceretions, which the authors recognize. Approximately half the bral palsy develops in most infants (95%) in whom FMs infants had been exposed to intrauterine cocaine, and further are absent during this period.8 An early indicator with progprospective studies are needed to determine the predictive nostic value for the development of milder neurological defvalue for all preterm infants. However, the under-arousal at icits (eg, developmental coordination disorder [DCD]) is the 44 weeks as a risk factor for cerebral palsy and low PDI at follow-up is an interesting new finding. It is already known that monotonous movements (as opposed to variable and complex movements) at this age are related to cerebral palsy,8,9 DCD Developmental coordination disorder and the low quality of movements reported in this study may FM Fidgety general movement reflect brain damage. The under-arousal, low movement IBAIP Infant Behavioral Assessment and Intervention Program quality, and lethargy may also reflect the role motor activity NNNS Neonatal Intensive Care Unit Network Neurobehavior

D

PDI VLBW

Scales Psychomotor developmental index Very low birth weight

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has at this early age in normal development. Rapid brain development in the early post-term months is accompanied by equally rapid motor and psychological development. The infants’ exploration of their environment with several motor strategies, integrating and refining neural input and output, may lead to better neurological and cognitive development. The absence of such a variable motor repertoire at this particular age (eg, because of the under-arousal) might hamper the infants’ abilities to interact with the world around them, which leads to delayed or impaired development.11 This would imply that early intervention, aimed at stimulation of more variable motor strategies, may result in a better functional outcome. This brings us to another study in this issue of The Journal, about an early intervention program for VLBW infants.12 The authors conducted a multi-center randomized controlled trial of 176 infants to determine whether the Infant Behavioral Assessment and Intervention Program (IBAIP) improved development and behavior in VLBW infants at 24 months corrected age. The intervention group received 6 to 8 post-discharge interventions until 6 months corrected age. The intervention consisted of supporting the infants’ selfregulation and development and facilitating sensitive parent-infant interactions. The control infants received regular care. Unfortunately, more children in the intervention group were <28 weeks gestational age than in the control group, despite randomization. As a result, the authors had to adjust for differences in perinatal characteristics. They found an intervention effect of 6.4 points on the PDI at 24 months, favoring the intervention infants. Significant intervention effects on mental development and behavior were not found. The authors conclude that the IBAIP showed sustained motor improvement in VLBW infants until 2 years corrected age. This study adds to the growing literature on the effects of early developmental interventions in preterm infants. The authors found a positive effect on motor development, rather than on mental or behavioral development. Only subgroup analysis revealed that mental and motor outcomes improved in intervention infants with bronchopulmonary dysplasia and with combined biological and social risk factors. Early intervention programs may have positive effects, particularly on the cognitive development of preterm infants.13 The effect size is approximately 0.4 to 0.5 SD, thus 6 to 8 IQ points. These effects are mostly short-term, until the age of 3 years, and not seen anymore at school age. At any age, intervention has limited effects on motor outcomes,13 although specific developmental training in which parents learn how to promote infant development may produce a positive effect on motor development.14 It would be helpful to know which particular aspects of the IBAIP produced the marked improvement of motor development. In an earlier study, the authors described the IBAIP in more detail:15 ‘‘The intervention aims to enhance the infant’s social and environmental interactions without causing distress, which reinforces the infant’s motivation and autonomy to explore and learn from the information. The IBAIP builds on both the infant’s and parent’s strengths, seeking 348

Vol. 156, No. 3 opportunities instead of problems in behavior, enhancing mutually satisfying interaction and parental involvement.’’

From this description, one may hypothesize that parental involvement, stimulating a playful and interactive environment, and promotion of self-produced motor behavior play a key role. The children from families that combine several risk factors, including low education attainment of the parents, may benefit from this type of intervention.16 This was also the case in this study.12 There exists a large variety in early developmental intervention programs. Because of the resources required to provide early intervention, there is urgent need for further research on the identification of the children at highest risk and on the effects of early intervention throughout childhood. It will be fascinating to see whether these efforts would succeed in improving the motor, cognitive and behavioral outcome of the preterm children in the next decade. n Arend F Bos, MD, PhD Beatrix Children’s Hospital, Division of Neonatology University Medical Center Groningen University of Groningen, Groningen The Netherlands Reprint requests: Arend F Bos, Beatrix Children’s Hospital, Division of Neonatology, University Medical Center Groningen, University of Groningen Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: a.f.bos@bkk. umcg.nl.

References 1. Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008;371:261-9. 2. Aylward GP. Neurodevelopmental outcomes of infants born prematurely. J Dev Behav Pediatr 2005;26:427-40. 3. Johnson S. Cognitive and behavioural outcomes following very preterm birth. Sem Fetal Neonatal Med 2007;12:363-73. 4. Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 2009;8:110-24. 5. Hart AR, Whitby EW, Griffiths PD, Smith MF. Magnetic resonance imaging and developmental outcome following preterm birth: review of current evidence. Dev Med Child Neurol 2008;50:655-63. 6. Heineman KR, Hadders-Algra M. Evaluation of neuromotor function in infancy—a systematic review of available methods. J Dev Behav Pediatr 2008;29:315-23. 7. Einspieler C, Prechtl HFR. Prechtl’s assessment of general movements: a diagnostic tool for the functional assessment of the young nervous system. Ment Retard Dev Disabil Res Rev 2005;11:61-7. 8. Prechtl HFR, Einspieler C, Cioni G, Bos AF, Ferrari F, Sontheimer D. An early marker for neurological deficits after perinatal brain lesions. Lancet 1997;349:1361-3. 9. Bruggink JLM, Einspieler C, Butcher PR, van Braeckel KNJA, Prechtl HFR, Bos AF. The quality of the early motor repertoire in preterm infants predicts minor neurologic dysfunction at school age. J Pediatr 2008;153:32-9. 10. Stephens BE, Liu J, Lester B, LaGasse L, Shankaran S, Bada H, et al. Neurobehavioral assessment predicts motor outcome in preterm infants. J Pediatr 2010;156:366-70. 11. Butcher PR, Bos AF, van Braeckel KNJA, Einspieler C, Stremmelaar EF, Bouma JM. The quality of infants’ spontaneous movements: an early

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March 2010 predictor of intelligence and behavior at school age. J Child Psychol Psychiatry 2009;50:920-30. 12. Koldewijn K, van Wassenaer A, Wolf MJ, Meijssen D, Houtzager B, Beelen A, et al. An infant behavioral assessment and intervention program in very low birth weight infants: outcome at 24 months. J Pediatr 2010;156:359-65. 13. Orton J, Spittle A, Doyle L, Anderson P, Boyd R. Do early intervention programmes improve cognitive and motor outcomes for preterm infants after discharge? A systematic review. Dev Med Child Neurol 2009;51:851-9.

14. Blauw-Hospers CH, Hadders-Algra M. A systematic review of the effects of early intervention on motor development. Dev Med Child Neurol 2005;47:421-32. 15. Koldewijn K, Wolf MJ, van Wassenaer A, Meijssen D, van Sonderen L, van Baar A, et al. The Infant Behavioral Assessment and Intervention Program for very low birth weight infants at 6 months corrected age. J Pediatr 2009;154:33-8. 16. Bonnier C. Evaluation of early stimulation programs for enhancing brain development. Acta Paediatr 2008;97:853-8.

The Pulmonary Collectins and Respiratory Syncytial Virus: Is There a Clinical Link?

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ore than a decade of basic science research suggests even though the authors controlled for RSV exposure varithat the pulmonary collectins, surfactant protein A ables such as day care, tobacco exposure, and number of sib(SP-A) and D (SP-D), are critical components of lings, these studies were confounded by the numerous the lung innate immune system. Mouse models of collectin variables that contribute to the exposure and acquisition of deficiency indicate that SP-A and SP-D are required for norRSV infection (eg, hand-washing). In addition, it is difficult mal clearance of a variety of pulmonary to accept that the SP-D methionine 11 allele See related article, p 409 pathogens such as respiratory syncytial viis abnormal when it is present in 61% of the rus (RSV) and that if infection occurs in the absence of these population. At best, these studies can claim that these polyproteins, the lungs fill with host immune cells that release exmorphisms are associated with a risk of acquiring RSV infeccessive amounts of inflammatory cytokines, oxygen radicals, tion, but they do not address the severity of the clinical illness and metalloproteinases. Despite the considerable innate imresulting from the infection. Considering that most infants mune defects that are associated with SP-A or SP-D defiare infected with RSV during the first year of life and virtually ciency in animal models, we have yet to find susceptibility all infants are infected by their second birthday, predicting to pulmonary infection that is clearly caused by mutations which infants are at risk for RSV infection is not useful bein either of these genes. cause all infants are at risk.4 The clinically important and biologically relevant question is, once an infant is exposed Previous studies of genetic modifiers of RSV pathogenesis to RSV and the infectious process is set in motion, are distinct have focused on candidate genes involved in either viral polymorphisms in SP-A or SP-D associated with a worse activities (ie, attachment, fusion, replication, and clearance clinical outcome? of the virus) or the response of the host immune system.1 Because of the role of collectins in both RSV binding/clearIn this issue of The Journal, El Saleeby et al5 took a unique ance and the regulation of host defense cells, several groups approach to examining SP-A polymorphisms. Rather than have hypothesized that polymorphisms of the SP-A (SFTPA) comparing RSV-infected infants with healthy control infants, or SP-D (SFTPD) genes would be associated with increased their study population included only infants infected with susceptibility or resistance to RSV infection. To this point, RSV. Within this infected population, they examined the asthe Finnish group led by Mikko Hallman found that the sociations between polymorphisms within the surfactant SP-A2 allele 1A3 was present in 5% of infants infected with protein A2 gene and clinical markers of disease severity (hosRSV when compared with 0.5% of healthy control infants.2 pital admission, intensive care unit admission, need for meSpecifically, their analysis suggested that substitution of lychanical ventilation, and length of hospital stay greater than 4 sine for glutamine at position 223 (part of the SP-A binding days). Although their study design prohibited the analysis of domain) was overrepresented in RSV-infected patients, sugthe effect of SP-A on the early stages of RSV infection, it did gesting that this change in SP-A inhibited normal SP-A activallow the authors to eliminate the confounding variables of ity. Analysis of polymorphisms within the SP-D gene found RSV acquisition that severely limited previous studies. that 72% of infants infected with RSV had methionine at poWithin this population, homozygosity for the 1A0 allele was protective against hospitalization (OR = 0.15, CI: 0.05 sition 11, whereas this allele was found in only 61% of healthy to 0.47), whereas patients homozygous or heterozygous for control infants.3 Although these results are intriguing, both of these studies compared hospitalized infants infected with asparagine at amino acid position 9 were 2-fold more likely RSV with healthy uninfected control infants. Therefore, to need intensive care, mechanical ventilation, or hospitalization for longer than 4 days. RSV SP-A SP-D

Respiratory syncytial virus Surfactant protein A Surfactant protein D

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