Published online June 1, 2006
PEDIATRICS Vol. 117 No. 6 June 2006, pp. 1996-2005 (doi:10.1542/peds.2005-2310)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Delobel-Ayoub, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Delobel-Ayoub, M.
Related Collections
Right arrow Office Practice

Behavioral Outcome at 3 Years of Age in Very Preterm Infants: The EPIPAGE Study

Malika Delobel-Ayoub, MDa, Monique Kaminski, MsCa, Stéphane Marret, MD, PhDb, Antoine Burguet, MD, PhDc, Laetitia Marchand, MsCa, Sylvie N'Guyen, MD, PhDd, Jacqueline Matis, MDe, Gérard Thiriez, MDc, Jeanne Fresson, MD, PhDf, Catherine Arnaud, MD, PhDg, Martine Poher, MD, PhDh, Béatrice Larroque, MD, PhDa for the EPIPAGE Study Group

a Research Unit on Perinatal Health and Women's Health, Villejuif, France
b Hôpital Charles Nicolle, Rouen, France
c Hôpital St Jacques, Besançon, France
d Hôpital Mère Enfant, Nantes, France
e Hopital Hautepierre, Strasbourg, France
f Hopital Universitaire, Nancy, France
g Research Unit on Epidemiology and Public Health, Institut National de la Santé et de la Recherche Médicale U558, Toulouse, France
h Hopital de Calais, Calais, France


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. Our goal was to compare the prevalence of behavioral problems between very preterm children and term children at 3 years of age and examine the factors associated with behavioral problems in very preterm children.

METHODS. We conducted a prospective population-based cohort study: the EPIPAGE (Étude Epidémiologique sur les Petits Ages Gestationnels) study. All infants born between 22 and 32 weeks of gestation in 9 regions of France in 1997 were included and compared with a control group of infants born at term. Sociodemographic status, obstetric, and neonatal data were collected at birth and in the neonatal units. At 3 years of age, the behavioral problems of 1228 very preterm singleton children without major neurodisabilities, and 447 term children were studied using the Strengths and Difficulties Questionnaire completed by the parents.

RESULTS. Very preterm children were more likely than controls to have behavioral difficulties. Among very preterm children, several medical conditions were associated with a high total difficulty score: major neonatal cerebral lesions diagnosed by cranial ultrasonographic studies, hospitalization within the last year, poor health, and psychomotor delay. A high birth order and sociodemographic factors such as young maternal age and low educational level of the mother were also identified as risk factors for behavioral difficulties. The differences between very preterm children and controls remained significant after adjustment for sociodemographic characteristics, neonatal complications, and neurodevelopmental status, for a high total difficulties score, hyperactivity, conduct problems, and for peer problems. For emotional problems, the difference was at the limit of significance.

CONCLUSIONS. Very preterm children have a higher risk of behavioral problems at 3 years of age compared with term-born children. Health and neurodevelopmental status of the child were significantly associated with behavioral difficulties.

Key Words: very preterm children • behavior • preschool age

Abbreviations: EPIPAGE—Étude Epidémiologique sur les Petits Ages Gestationnels • SDQ—Strengths and Difficulties Questionnaire • CBCL—Child Behavior Checklist • OR—odds ratio • CI—confidence interval

Although advances in perinatal care, with increased use of antenatal steroid therapy, in utero transfer and surfactant therapy, have increased the chances of survival of very preterm infants, mortality and morbidity of these infants remain high.1 The consequences of immaturity are not only restricted to severe neurosensory disabilities such as cerebral palsy, hearing loss, and blindness. Even premature infants who have relatively uncomplicated neonatal courses are at risk for developmental delays in motor skills, lower cognitive performance, and learning difficulties.2–4 A meta-analysis has shown that preterm/low birth weight children have lower cognitive scores at school age compared with controls.5 Difficulties at school such as repeating a grade or attending special needs classes are more frequent among very low birth weight children.2,3

Studies into the behavioral problems of preterm children are less common. However, most data suggest that preterm infants have an increased risk of hyperactivity and attention deficit disorders.5–13 Some studies suggest an increased risk, compared with the general population, for conduct problems,7,14 emotional difficulties7,14,15 or poorer social competencies.13,16,17

The various methods used to assess behavioral problems make it difficult to compare the data from the published studies. Most of the studies have recruited children on the basis of birth weight and not gestational age, which results in an overrepresentation of children with intrauterine growth restriction, for whom the consequences may be different from those of immaturity.

Most of the studies were conducted on older children at school age, in part because of difficulties in measuring behavioral problems in preschool-aged children. Only a few studies have looked at behavior at 2 or 3 years of age, and then with only a small sample size, including also moderate preterm children.15,18–20

Children born prematurely may experience behavioral problems for several reasons. Complications of preterm birth may have long-term effects on the central nervous system and thus induce behavioral disorders as well as cognitive or neuromotor disabilities. A very preterm birth requires a long duration of hospitalization and separation from the parents, which may cause difficulties in the early parent-child interaction. The preterm birth also generates anxiety in the parents that modify the parental relationship with their child and may result in an overprotective attitude.21 Poor health during childhood may also be associated with behavioral difficulties.22

This study aims to investigate the behavioral problems of very preterm infants in a population-based cohort of infants without major disabilities. The first objective is to test the hypothesis that 3-year-old very preterm children are more likely to have behavioral problems than term children of the same age, and to identify which behavioral problems are involved. The second objective is to identify the main social and medical factors associated with behavioral difficulties in very preterm children.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
The EPIPAGE study (Étude Epidémiologique sur les Petits Ages Gestationnels) is a population-based cohort in which the principal aim was to assess the outcome of children born very preterm. This study included all births in 1997 occurring between 22 and 32 weeks' gestational age in the maternity wards of 9 French regions and a control group of infants born at 39 to 40 weeks' gestational age in 1997 in the same regions.23 After approval from the parents, the infants were enrolled in a longitudinal study and were surveyed annually, until 5 years of age, with postal questionnaires addressed to the parents.24

At hospital discharge, the follow-up was proposed to the parents of 2382 very preterm infants (all very preterm infants surviving at discharge, except in 2 regions where 1 of 2 infants born at 32 weeks' gestation was randomly selected) and 666 unmatched term controls. The follow-up was accepted for 2276 (96%) preterm and 557 (84%) controls. One term infant and 20 preterm infants died before 3 years of age.

At 3 years of age, a questionnaire was sent to the parents: 1880 answers were obtained for very preterm infants (79%) and 453 for term infants (68%). Because our study aimed to evaluate behavioral problems in very preterm infants without major disabilities, 63 children with disabilities such as blindness, deafness, or severe cerebral palsy at 3 years of age were excluded. Multiple births (593 children in the very preterm group and 6 children in the control group) were also excluded from the analysis because the assessment by parents of the behavior of their children could be different between multiples and singletons, and because there were too few multiple births in the control group to allow any comparison. Then 6 children were excluded from the very preterm group because they were >4 years old when the questionnaire was completed. The final sample included 1228 very preterm singletons and 447 term singletons; 82% of the parents filled the questionnaire when their child was between 35 and 37 months.

Data Collected
Data about pregnancy, delivery, and medical care of infants were extracted from medical charts in maternity and neonatal units. The gestational age was calculated as the number of completed weeks of amenorrhea and was the best obstetric estimate using the first prenatal ultrasound and the date of the last menstrual period. Small for gestational age was defined as a birth weight less than the 10th percentile for gender and gestational age in the EPIPAGE population. Cranial ultrasound scans were conducted in 98% of the very preterm infants and the results were classified into 4 categories25: (1) major lesions: periventricular leukomalacia or periventricular parenchymal hemorrhagic involvement; (2) moderate lesions: intraventricular hemorrhage with ventricular dilatation or isolated ventricular dilatation or echodensity lasting >14 days; (3) minor lesions: intraventricular hemorrhage without ventricular dilatation, germinal matrix layer hemorrhage; and (4) none of these abnormalities. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen at 36 weeks postmenstrual age.

Social characteristics of the family were obtained by interview of the mother in the maternity unit. We considered maternal age at birth (<25, 25–34, ≥35 years of age), birth order of the infant (1, 2 or 3, ≥4), maternal education (secondary school diploma or not), social class of the family (highest level of occupation of the parents or occupation of the mother if she lives alone, classified as low, middle, and high social class), marital status of the mother (mother living alone or not), and the mother's nationality (French or other). Information was missing for several women for these last 2 variables, and a "missing" category was added.

We included the French version of the Strengths and Difficulties Questionnaire (SDQ)26 for 3- to 4-year-old children in the questionnaire addressed to the parents when the children were 3 years old. The SDQ is a brief behavioral questionnaire easily completed by parents. It has been compared with the Rutter questionnaire and the Child Behavior Checklist (CBCL) and shows high correlations with them.26,27 It comprises 25 items divided into 5 scales of 5 items each, which survey 5 types of behavior: hyperactivity-inattention, conduct problems, emotional symptoms, peer problems, and prosocial behavior. For each item, parents can choose between 3 answers scored as 0 = not true, 1 = moderately true, and 2 = certainly true. Scores for all but the last behavior type are summed to provide a total difficulties score from 0 to 40. As suggested by the authors of the SDQ, scores for each scale were prorated if at least 3 items were completed. Cutoffs for high scores were suggested for the SDQ for 4- to 16-year-old children, but these could not be transposed to the SDQ for 3- to 4-year-old children used in our study. Therefore, we chose cutoffs on the basis of the distribution of the scores in our control group for each scale. Cutoffs were defined so that ~10% of the children in the control group were considered as having a behavioral problem (hyperactivity ≥7, conduct problems ≥7, emotional symptoms ≥5, peer problems ≥5, prosocial behavior ≤5, and total difficulties ≥18.5).

The questionnaire included questions about the health and development of the child at 3 years of age. We selected the following information: hospitalization of the child during the last year; neurodevelopmental delay of the child (if the child was not able to run, to make a sentence with 3 words, or to wash his or her hands); and the health of the child, judged by the parents as excellent, good, or poor.

Data Analysis
For each scale of the SDQ (total difficulties, hyperactivity, conduct problems, emotional symptoms, peer problems, and prosocial behavior), scores of behavioral problems were considered high when they were beyond cutoffs. We looked at the relation between each behavioral problem and the following factors: gender, medical condition at delivery and during the neonatal period, social characteristics of the family, medical and developmental status of children at 3 years of age.

We used multivariate analyses to identify the major risk factors for behavioral disorders in very preterm infants (results shown only for total difficulties). We selected for multivariate analyses as potential risk factors for a behavior problem variables that were related to the total difficulties at P < .2: gender, maternal age at birth, birth order, maternal level of education, marital status of the mother, gestational age, cerebral lesions at the cranial ultrasound scans, duration of the neonatal hospitalization, neurodevelopmental delay at 3 years, hospitalization during the last year, and health of the child assessed by parents at the age of 3. Because of the strong colinearity between social class and maternal education on the one hand and duration of intubation and duration of hospitalization on the other, only level of education and length of hospitalization were considered in the multivariate analysis. We compared behavioral problems between preterm and term infants after controlling for potential confounders; 3 models were used to identify which type of risk factors explained the difference between term and very preterm infants: model 1 included social characteristics, model 2 included the medical and developmental status of the child, and model 3 included all of these factors.

Weighting was applied to the data for all analyses to take into account the 2 regions that followed only 1 infant of 2 born at 32 weeks' gestation. All associations were quantified with weighted odds ratios (ORs) with 95% confidence intervals (CIs). Numbers given in the tables are those observed, but all percentages are weighted. For multivariate analyses, we used weighted logistic regression models. Analyses were performed with Stata 7.0 (Stata Corp, College Station, TX).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
For each behavioral type, high scores were significantly more frequent in the very preterm group compared with the term group (Table 1). The prevalence of high total difficulties was 20% in the preterm group and 9% in the control group. The differences between the 2 groups were significant for all behavioral types.


View this table:
[in this window]
[in a new window]
  		TABLE 1 High SDQ Scores in Very Preterm Infants and Term Infants

 
In the very preterm group, infants born between 24 and 28 weeks' gestation were more likely to have a high total difficulties score than those born in the 2 other classes of gestational age, although this was not statistically significant (Table 2). We saw the same trend for hyperactivity and the peer problems, and the relationship between gestational age and the prosocial behavior was significant. The gestational age was not associated with the age of the child when the parents filled the questionnaire. There was no relationship between gestational age and conduct problems or emotional symptoms.


View this table:
[in this window]
[in a new window]
  		TABLE 2 High SDQ Scores According to Gestational Age in Very Preterm Infants

 
A high total difficulties score was significantly more common in boys than in girls and for children of young mothers or mothers with a low social class (Table 3). The trend was the same for children whose mothers were living alone. For the medical condition of very preterm infants, a high total difficulties score was related to major cerebral lesions at ultrasound during the neonatal period. A high total difficulties score was also more common for children who were hospitalized for >13 weeks in the NICU and for children who were intubated for >10 days (Table 4). For the health and development of the children after hospital discharge, a high total difficulties score was more common in children who had been admitted to the hospital during the last year, in children with neurodevelopmental delay, and in children for whom health was judged poor by their parents.


View this table:
[in this window]
[in a new window]
  		TABLE 3 High Total Difficulties Score According to Social Characteristic of the Family Among Very Preterm Infants

 

View this table:
[in this window]
[in a new window]
  		TABLE 4 High Total Difficulties Score According to Medical Characteristics Among Very Preterm Infants

 
In a multivariate model looking for associations between social or medical factors and high total difficulties score among very preterm children, we found that a young maternal age at birth and a low level of education remained strongly related to a high total difficulties score (Table 5). A high birth order also seemed to be a risk factor for a high total difficulties score. The degree of immaturity was not significantly related to a high total difficulties score, although there was a higher risk for the 24- to 28-weeks group. Major cerebral lesions remained a risk factor for a high total difficulties score (OR: 2.4; CI: 1.1–5.2). Poor health at 3 years of age as assessed by parents as neurodevelopmental delay at 3 years of age and hospitalization during the last year were strongly related to a high total difficulties score.


View this table:
[in this window]
[in a new window]
  		TABLE 5 High Total Difficulties Score According to Social and Medical Characteristics (Logistic-Regression Model)

 
We compared the SDQ scores between very preterm and term infants (Table 6). For each scale, we conducted 4 logistic regressions. After adjustment for the social characteristics, the ORs decreased slightly for all SDQ scales except for conduct problems, but all remained highly significant. Adjustment for health and development characteristics of the child at 3 years of age led to a slight larger reduction of ORs. For prosocial behavior, the difference between very preterm and term infants became nonsignificant. Finally, after adjusting for all these variables, the excess of risk for all the behavioral difficulties decreased but remained significant except for emotional symptoms and prosocial behavior.


View this table:
[in this window]
[in a new window]
  		TABLE 6 Comparisons of Behavioral Outcome Between Very Preterm and Term Children After Adjustment for Major Risk Factors

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our large population-based cohort study has shown that behavioral difficulties were more common in very preterm infants at 3 years of age than that in term children. The differences between the very preterm and control groups remained significant for most of the behavioral difficulties after adjustment for social characteristics and for health and development of the children. In very preterm children, major white matter cerebral lesions, neurodevelopmental delay, poor health of the child as assessed by the parents, high birth order, and poor social conditions were factors associated with a high behavioral difficulties score.

The prospective design of our study and its size allowed us to investigate those characteristics of the family and the child at birth or at 3 years of age that were risk factors of behavior difficulties at 3 years of age. The inclusion of a control group, born at term and for whom the data collection followed exactly the same design, allowed comparison with the very preterm children.

We evaluated the behavioral difficulties of very preterm children at 3 years of age. Studies at such a young age have rarely been conducted. One recent study showed that among low birth weight children having behavior problems at 3 years of age, 50% still presented behavior disorders at 5 years of age.20

Our study had some limitations. There were some refusals or loss to follow-up. Preterm children whose parents did not answer the 3 years of age questionnaire did not differ from responders with regard to gestational age, small for gestational age, cerebral lesions, bronchopulmonary dysplasia, or duration of hospitalization in the NICU. In both preterm and control groups, nonresponders had a higher birth order, mothers were younger and more often of a low social level. These children may have been at increased risk of behavioral problems and, therefore, the rate of difficulties may have been underestimated. However, social characteristics of children lost to follow-up were the same in very preterm infants and term infants. Anxious or depressed mothers report higher rates of behavioral problems in their children, but we have no measure of the mothers' psychologic state.

The SDQ was chosen because inclusion of positive items and shortness of the questionnaire, which make it more acceptable to the parents than other similar questionnaires. However, parents of very preterm and term infants may assess the behavior of their child differently, but we do not know whether parents of very preterm infants would either minimize or overestimate behavioral difficulties and thus we cannot be sure that the results are not biased in one way or the other.

We first aimed to compare risk of behavioral disorders between very preterm and term children. Results in the literature are inconsistent. Some studies did not report an increased risk of behavioral problems among all very preterm children, but found that only very preterm children presenting other medical or social risk factors, in addition to immaturity, were at increased risk for behavioral disorders.18,19 However, a prospective follow-up study of very low birth weight children reported an increase in the risk of behavioral disorders, evaluated with the CBCL at 3 years of age, for total problem score, attention deficit disorders, and emotional problems.15 Another prospective study examined the prevalence of behavioral problems in preterm infants (<37 weeks' gestational age) at 3 years of age, also measured with the CBCL, and found a prevalence of behavior problems of ~20% compared with the 10% prevalence expected in the general population.20 Similar results were also found among school-aged children: in a meta-analysis, Bhutta et al5 reported a relative risk of 2.64 for attention deficit disorders in low birth weight children or children born preterm compared with control subjects. Although some studies described an increase in risk for only 1 type of disorder, the most frequent being attention deficit and hyperactivity disorders,2,8,28 we found an increased risk for preterm children for total difficulty, hyperactivity, conduct problems, and peer problems; for emotional symptoms, it was at the limit of significance. Our results were in agreement with other studies, which described an increased risk for externalizing behavior problems (such as hyperactivity or conduct disorders) and internalizing disorders (such as anxiety or depression).7,29,30

Our second aim was to identify which sociodemographic and health or development characteristics of very preterm children at birth or at 3 years of age were predictors of behavioral difficulties at 3 years of age. We found that sociodemographic conditions such as high birth order, young age and low educational level of the mother, or low social level of the family were risk factors for behavioral difficulties. Previous studies have found that the socioeconomic level and the quality of the home environment are related to behavioral disorders.12,31 It has been suggested that the quality of the environment may support the child in developing self-regulated behaviors such as maintaining attention or inhibiting impulsive responses.11 Some social characteristics such as a low family income, a low maternal education, or a young maternal age are also associated with behavioral disorders of children of all gestational ages.22

Among the very preterm infants, the degree of immaturity was not significantly associated with behavior difficulties, a result similar to other studies of preterm infants,32,33 but there was a trend to a higher difficulties score in the lowest gestational ages (24–28 weeks).

We found that major cerebral lesions in the vulnerable white matter of the preterm infants increased the risk of behavioral problems among very preterm infants without major disabilities, even after controlling for neurodevelopmental delay. Studies on behavioral disorders in relation to lesions of the white matter detected by ultrasonographic studies are uncommon and inconsistent. One study reported an association between cerebral lesions and behavioral disorders at 6 years of age after controlling for sociodemographic factors and excluding children with cognitive delay or cerebral palsy.29 However, a smaller study found no relation between ultrasound cerebral lesions and behavioral problems among low birth weight children without major disabilities at 5 years of age.33

The diffuse form of white matter injury, in part resulting from the injury of premyelinating oligodendrocytes, is better diagnosed by cerebral magnetic resonance imaging than ultrasounds. However, studies have not found a strong link between diffuse white matter injury diagnosed by magnetic resonance imaging and subsequent behavioral disorders.34,35 Moreover, despite the longstanding emphasis on the vulnerability of cerebral white matter among very premature infants, we have now more and more data, which strongly suggest that cortical gray matter is also damaged.36,37 Even recent data obtained with quantitative magnetic resonance imaging suggest that behavioral disorders do not correlate with conventional markers of perinatal white matter injury, but may be related to brain growth and/or alteration in the development of gray structures such as the caudate nuclei and hippocampus.35,38,39 Neuronal-axonal disturbance could underlie the most common type of neurologic sequelae in very preterm children, that is, abnormalities of cognition, attention, and behavior.36 The assessment of the quality of general movements in the postnatal period is a sensitive tool to evaluate brain function in young infants.40 In a study with high-risk children, mostly preterm, the mildly abnormal general movements in the first postnatal months were associated with attention deficit hyperactivity disorder and aggressive behavior in childhood.40

Weisglas-Kuperus et al15 suggested that cerebral lesions may have an indirect role on behavioral problems as a result of their consequences on the cognitive development of the child. Nadeau et al10 showed that among extremely preterm children, hyperactivity at 7 years of age was associated with a lower IQ, whereas sensitive/isolated behavior was associated with neuromotor disabilities. Although limited, our results at 3 years of age are consistent with studies describing a relationship between cognitive or neuromotor delay and behavioral disorders among school-aged children born preterm or with a low birth weight.2,8,14,16

Our results suggest also that, apart from major cerebral lesions at ultrasound, complications during the neonatal period are not a major risk factor for behavioral difficulties among very preterm infants free from severe disabilities. However, behavioral difficulties seem to be strongly related to the health of the child at 3 years of age. In our study, poor health as assessed by parents and recent hospitalizations were also strongly related to behavioral difficulties. This has also been described in studies of various behavioral disorders among school-aged children born with low birth weight.31 Chronic physical conditions have also been found to be a significant risk factor for behavioral problems among children and adolescents in the general population.22

After controlling for all the risk factors found in this study, the differences in the amount of behavioral difficulty between very preterm infants and term infants remained highly significant. The early deprivation of the mother/placenta environment could be deleterious for the brain growth and its organization, but understanding the underlying processes by which the very preterm child develops behavioral disorders has proved difficult. The various factors (sociodemographic conditions, cerebral lesions, neurodevelopmental outcome, and poor health) associated with behavioral problems confirm the results of other studies of the recent literature, which suggest that the long-term effects of a very preterm birth on the central nervous system may lead to behavioral difficulties, first through a direct link with cerebral white matter and/or gray matter damage, whether visible or not with current imaging techniques and, second, through the consequences of social difficulties, difficulties in child-parent interactions, or neurodevelopmental impairment.

It is important to know whether children born very prematurely are at risk of behavioral problems early in life to deal with and prevent the effects of these problems at school age. Despite the difficulties in diagnosing behavioral problems in preschool-aged children, studies on the predictive validity of early diagnosis showed a high stability for attention deficit disorders, hyperactivity, and oppositional disorders.41,42 Even if there is not yet total agreement on the treatment strategies for these children, there is some evidence in favor of early prevention, early detection, and early initiation of intervention.43–45 Intervention programs aimed at reducing behavioral symptoms in preterm children should elevate the parental understanding of their child to help them to adjust their expectations and demands to the child's abilities.30

Very preterm infants are at increased risk of behavioral difficulties early in their development. Such behavioral difficulties are more frequent in children with health problems or neurodevelopmental delay during childhood. The follow-up of these very preterm children at school age will allow us to follow the evolution of these difficulties. These present results should encourage the early detection of behavioral difficulties to reduce their consequences on the well-being and social adaptation of the children.


   ACKNOWLEDGMENTS
 
Funding for this study was obtained from Institut National de la Santé et de la Recherche Médicale (French National Institute of Health and Medical Research), Merck-Sharp, Dohme-Chibret, la Fondation de la Recherche Médicale (the Medical Research Foundation) and la Direction Générale de la Santé du Ministère des Affaires Sociales (the Directorate General for Health of the French Ministry for Social Affairs), the Programme Hospitalier de Recherche Clinique.

EPIPAGE Study Group members include: Institut National de la Santé et de la Recherche Médicale (INSERM) U149: B. Larroque (national coordinator), P.Y. Ancel, B. Blondel, G. Bréart, M. Dehan, M. Garel, M. Kaminski, F. Maillard, C. du Mazaubrun, P. Missy, F. Sehili, K. Supernant; Alsace: M. Durant, J. Matis, J. Messer, A. Treisser (Hôpital de Hautepierre, Strasbourg); Franche-Comté: A. Burguet, L. Abraham-Lerat, A. Menget, P. Roth, J.-P. Schaal, G. Thiriez (CHU St Jacques, Besançon); Haute-Normandie: C. Lévêque, S. Marret, L. Marpeau (Hôpital Charles Nicolle, Rouen); Languedoc-Roussillon: P. Boulot, J.-C. Picaud (Hôpital Arnaud de Villeneuve, Montpellier), A.-M. Donadio, B. Ledésert (ORS Montpellier); Lorraine: M. André, J.-L. Boutroy, J. Fresson, J.M. Hascoët (Maternité Régionale, Nancy); Midi-Pyrénées: C. Arnaud, S. Bourdet-Loubère, H. Grandjean (INSERM U558, Toulouse), M. Rolland (Hôpital des enfants, Toulouse); Nord-Pas-de-Calais: C. Leignel, P. Lequien, V. Pierrat, F. Puech, D. Subtil, P. Truffert (Hôpital Jeanne de Flandre, Lille); Pays de la Loire: G. Boog, V. Rouger-Bureau, J.-C. Rozé (Hôpital Mère-Enfants, Nantes); Paris-Petite-Couronne: P.-Y. Ancel, G. Bréart, M. Kaminski, C. du Mazaubrun (INSERM U149, Paris), M. Dehan, V. Zupan (Hôpital Antoine Béclère, Clamart), M. Vodovar, M. Voyer (Institut de Puériculture, Paris).


   FOOTNOTES
 
Accepted Dec 16, 2005.

Address correspondence to Béatrice Larroque, MD, PhD, Institut National de la Santé et de la Recherche Médicale U149, 16 Avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France. E-mail: larroque{at}vjf.inserm.fr

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990's. Early Hum Dev. 1999;53 :193 –218[CrossRef][ISI][Medline]
  2. McCormick MC, Gortmaker SL, Sobol AM. Very low birth weight children: Behavior problems and school difficulty in a national sample. J Pediatr. 1990;117 :687 –693[ISI][Medline]
  3. Horwood LJ, Mogridge N, Darlow BA. Cognitive, educational, and behavioural outcomes at 7 to 8 years in a national very low birthweight cohort. Arch Dis Child Fetal Neonatal Ed. 1998;79 :F12 –F20[Abstract/Free Full Text]
  4. Foulder-Hughes LA, Cooke RW. Motor, cognitive, and behavioural disorders in children born very preterm. Dev Med Child Neurol. 2003;45 :97 –103[ISI][Medline]
  5. Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: A meta-analysis. JAMA. 2002;288 :728 –737[Abstract/Free Full Text]
  6. Chapieski ML, Evankovich KD. Behavioral effects of prematurity. Semin Perinatol. 1997;21 :221 –239[CrossRef][ISI][Medline]
  7. Pharoah PO, Stevenson CJ, Cooke RW, Stevenson RC. Prevalence of behaviour disorders in low birthweight infants. Arch Dis Child. 1994;70 :271 –274[Abstract]
  8. Szatmari P, Saigal S, Rosenbaum P, Campbell D, King S. Psychiatric disorders at five years among children with birthweights less than 1000g: A regional perspective. Dev Med Child Neurol. 1990;32 :954 –962[ISI][Medline]
  9. Mick E, Biederman J, Prince J, Fischer MJ, Faraone SV. Impact of low birth weight on attention-deficit hyperactivity disorder. J Dev Behav Pediatr. 2002;23 :16 –22[ISI][Medline]
  10. Nadeau L, Boivin M, Tessier R, Lefebvre F, Robaey P. Mediators of behavioral problems in 7-year-old children born after 24 to 28 weeks of gestation. J Dev Behav Pediatr. 2001;22 :1 –10[ISI][Medline]
  11. Robson AL, Pederson DR. Predictors of individual differences in attention among low birth weight children. J Dev Behav Pediatr. 1997;18 :13 –21[CrossRef][ISI][Medline]
  12. Girouard PC, Baillargeon RH, Tremblay RE, Glorieux J, Lefebvre F, Robaey P. Developmental pathways leading to externalizing behaviors in 5 year olds born before 29 weeks of gestation. J Dev Behav Pediatr. 1998;19 :244 –253[ISI][Medline]
  13. Hoff B, Hansen BM, Munck H, Mortensen EL. Behavioral and social development of children born extremely premature: 5-year follow-up. Scand J Psychol. 2004;45 :285 –292[CrossRef][ISI][Medline]
  14. Sommerfelt K, Ellertsen B, Markestad T. Personality and behaviour in eight-year-old, non-handicapped children with birth weight under 1500 g. Acta Paediatr. 1993;82 :723 –728[ISI][Medline]
  15. Weisglas-Kuperus N, Koot HM, Baerts W, Fetter WP, Sauer PJ. Behaviour problems of very low-birthweight children. Dev Med Child Neurol. 1993;35 :406 –416[ISI][Medline]
  16. Ross G, Lipper EG, Auld PA. Social competence and behavior problems in premature children at school age. Pediatrics. 1990;86 :391 –397[Abstract/Free Full Text]
  17. Schothorst PF, van Engeland H. Long-term behavioral sequelae of prematurity. J Am Acad Child Adolesc Psychiatry. 1996;35 :175 –183[CrossRef][ISI][Medline]
  18. Oberklaid F, Sewell J, Sanson A, Prior M. Temperament and behavior of preterm infants: A six-year follow-up. Pediatrics. 1991;87 :854 –861[Abstract/Free Full Text]
  19. Stoelhorst GM, Martens SE, Rijken M, et al. Behaviour at 2 years of age in very preterm infants (gestational age <32 weeks). Acta Paediatr. 2003;92 :595 –601[ISI][Medline]
  20. Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors of clinically significant behavior problems in low birth weight children at 3, 5, and 8 years of age. Pediatrics. 2004;114 :736 –743[Abstract/Free Full Text]
  21. Bremond M, Blond MH, Chavet-Queru MS, et al. Medical and psychological status of one-year-old premature babies without severe disability: case-control prospective study [in French]. Arch Pediatr. 1999;6 :1163 –1171[CrossRef][ISI][Medline]
  22. Gortmaker SL, Walker DK, Weitzman M, Sobol AM. Chronic conditions, socioeconomic risks, and behavioral problems in children and adolescents. Pediatrics. 1990;85 :267 –276[Abstract/Free Full Text]
  23. Larroque B, Breart G, Kaminski M, et al. Survival of very preterm infants: Epipage, a population based cohort study. Arch Dis Child Fetal Neonatal Ed. 2004;89 :F139 –F144[Abstract/Free Full Text]
  24. Larroque B. EPIPAGE: Epidemiologic study of very premature infants. Protocol of the survey [in French]. Arch Pediatr. 2000;7(suppl 2) :339s –342s[CrossRef]
  25. Larroque B, Marret S, Ancel PY, et al. White matter damage and intraventricular hemorrhage in very preterm infants: the EPIPAGE study. J Pediatr. 2003;143 :477 –483[CrossRef][ISI][Medline]
  26. Goodman R. The Strengths and Difficulties Questionnaire: a research note. J Child Psychol Psychiatry. 1997;38 :581 –586[ISI][Medline]
  27. Goodman R, Scott S. Comparing the Strengths and Difficulties Questionnaire and the Child Behavior Checklist: is small beautiful? J Abnorm Child Psychol. 1999;27 :17 –24[CrossRef][ISI][Medline]
  28. Breslau N, Brown GG, DelDotto JE, et al. Psychiatric sequelae of low birth weight at 6 years of age. J Abnorm Child Psychol. 1996;24 :385 –400[CrossRef][ISI][Medline]
  29. Whitaker AH, Van Rossem R, Feldman JF, et al. Psychiatric outcomes in low-birth-weight children at age 6 years: Relation to neonatal cranial ultrasound abnormalities. Arch Gen Psychiatry. 1997;54 :847 –856[Abstract]
  30. Stjernqvist K, Svenningsen NW. Ten-year follow-up of children born before 29 gestational weeks: Health, cognitive development, behaviour and school achievement. Acta Paediatr. 1999;88 :557 –562[CrossRef][ISI][Medline]
  31. McCormick MC, Workman-Daniels K, Brooks-Gunn J. The behavioral and emotional well-being of school-age children with different birth weights. Pediatrics. 1996;97 :18 –25[Abstract/Free Full Text]
  32. Rijken M, Stoelhorst GM, Martens SE, et al. Mortality and neurologic, mental, and psychomotor development at 2 years in infants born less than 27 weeks' gestation: the Leiden follow-up project on prematurity. Pediatrics. 2003;112 :351 –358[Abstract/Free Full Text]
  33. Sommerfelt K, Troland K, Ellertsen B, Markestad T. Behavioral problems in low-birthweight preschoolers. Dev Med Child Neurol. 1996;38 :927 –940[ISI][Medline]
  34. Olsen P, Paakko E, Vainionpaa L, Pyhtinen J, Jarvelin MR. Magnetic resonance imaging of periventricular leukomalacia and its clinical correlation in children. Ann Neurol. 1997;41 :754 –761[CrossRef][ISI][Medline]
  35. Abernethy LJ, Palaniappan M, Cooke RW. Quantitative magnetic resonance imaging of the brain in survivors of very low birth weight. Arch Dis Child. 2002;87 :279 –283[Abstract/Free Full Text]
  36. Volpe JJ. Encephalopathy of prematurity includes neuronal abnormalities. Pediatrics. 2005;116 :221 –225[Free Full Text]
  37. Inder TE, Warfield SK, Wang H, Huppi PS, Volpe JJ. Abnormal cerebral structure is present at term in premature infants. Pediatrics. 2005;115 :286 –294[Abstract/Free Full Text]
  38. Abernethy LJ, Cooke RW, Foulder-Hughes L. Caudate and hippocampal volumes, intelligence, and motor impairment in 7-year-old children who were born preterm. Pediatr Res. 2004;55 :884 –893[CrossRef][ISI][Medline]
  39. Peterson BS, Vohr B, Staib LH, et al. Regional brain volume abnormalities and long-term cognitive outcome in preterm infants. JAMA. 2000;284 :1939 –1947[Abstract/Free Full Text]
  40. Hadders-Algra M, Groothuis AM. Quality of general movements in infancy is related to neurological dysfunction, ADHD, and aggressive behaviour. Dev Med Child Neurol. 1999;41 :381 –391[CrossRef][ISI][Medline]
  41. Lahey BB, Pelham WE, Loney J, et al. Three-year predictive validity of DSM-IV attention deficit hyperactivity disorder in children diagnosed at 4–6 years of age. Am J Psychiatry. 2004;161 :2014 –2020[Abstract/Free Full Text]
  42. Cantwell DP, Baker L. Stability and natural history of DSM-III childhood diagnoses. J Am Acad Child Adolesc Psychiatry. 1989;28 :691 –700[ISI][Medline]
  43. Blackman JA. Attention-deficit/hyperactivity disorder in preschoolers: does it exist and should we treat it? Pediatr Clin North Am. 1999;46 :1011 –1025[CrossRef][ISI][Medline]
  44. Als H, Gilkerson L, Duffy FH, et al. A three-center, randomized, controlled trial of individualized developmental care for very low birth weight preterm infants: medical, neurodevelopmental, parenting, and caregiving effects. J Dev Behav Pediatr. 2003;24 :399 –408[CrossRef][ISI][Medline]
  45. Rauh VA, Nurcombe B, Achenbach T, Howell C. The Mother-Infant Transaction Program: the content and implications of an intervention for the mothers of low-birthweight infants. Clin Perinatol. 1990;17 :31 –45[ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



This article has been cited by other articles:


Home page
 J. Clin. Endocrinol. Metab.Home page
A. Buske-Kirschbaum, S. Krieger, C. Wilkes, W. Rauh, S. Weiss, and D. H. Hellhammer
Hypothalamic-Pituitary-Adrenal Axis Function and the Cellular Immune Response in Former Preterm Children
J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3429 - 3435.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via ISI Web of Science (6)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Delobel-Ayoub, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Delobel-Ayoub, M.
Related Collections
Right arrow Office Practice