NEW RESEARCH Psychiatric Disorders in Extremely Preterm Children: Longitudinal Finding at Age 11 Years in the EPICure Study Samantha Johnson, Ph.D., CPsychol., Chris Hollis, Ph.D., MRCPsych., Puja Kochhar, Enid Hennessy, M.Sc., Dieter Wolke, Ph.D., Dipl-Psych, CPsychol., Neil Marlow, D.M., FMedSci. B.Sc., Objective: To investigate the prevalence and risk factors for psychiatric disorders in extremely preterm children. Method: All babies born ⬍26 weeks gestation in the United Kingdom and Ireland from March through December 1995 were recruited to the EPICure Study. Of 307 survivors at 11 years of age, 219 (71%) were assessed alongside 153 term-born classmates. Parents completed a structured psychiatric interview about their child, and teachers completed a corresponding questionnaire from which DSM-IV diagnoses were assigned for 219 (100%) extremely preterm children and 152 (99%) classmates. An IQ test and a physical evaluation were also administered. Longitudinal data were available for extremely preterm children. Results: Extremely preterm children were more than three times more likely to have a psychiatric disorder than classmates (23% vs. 9%; odds ratio [OR] ⫽ 3.2; 95% confidence interval [CI] ⫽ 1.7, 6.2). Risk was significantly increased for: attention-deficit/hyperactivity disorder (ADHD; 11.5% vs. 2.9%; OR ⫽ 4.3; CI ⫽ 1.5 to 13.0), with increased risk for ADHD inattentive subtype (OR ⫽ 10.5; CI ⫽ 1.4 to 81.1) but not ADHD combined subtype (OR ⫽ 2.1; CI ⫽ 0.5 to 7.9); emotional disorders (9.0% vs. 2.1%; OR ⫽ 4.6; CI ⫽ 1.3 to 15.9), with increased risk for anxiety disorders (OR ⫽ 3.5; CI ⫽ 1.0 to 12.4); and autism spectrum disorders (8.0% vs. 0%; p ⫽ .000). Psychiatric disorders were significantly associated with cognitive impairment (OR ⫽ 3.5; CI ⫽ 1.8 to 6.4). Parent-reported behavioral problems at 2.5 and 6 years were independent predictors of psychiatric disorders at 11 years. Conclusions: Extremely preterm children are at increased risk for ADHD, emotional disorders, and autism spectrum disorders at 11 years of age. The mechanism of association with psychiatric disorder may include both cognitive impairment and early traumatic experiences that have an impact on both child and parent. Early screening for cognitive and behavioral problems may identify those at greatest risk. J. Am. Acad. Child Adolesc. Psychiatry, 2010;49(5):453– 463. Key Words: extremely preterm, psychiatric disorders, risk factors, ADHD, autism T he sequelae of very preterm birth have been increasingly well documented since the 1990s, when significant improvements in neonatal intensive care were paralleled by an increase in survival rates for extremely preterm births.1 Population-based studies have shown that children born extremely preterm (⬍26 weeks) or with extremely low birth weight (ELBW; ⬍1,000 g) are at high risk for later cognitive, neuromotor, and sensory mor- This article is the subject of an editorial by Dr. Joan L. Luby on page 439. Supplemental material cited in this article is available online. bidity, which are present in up to 50% of extremely preterm survivors at 11 years of age.2-4 Although severe cerebral palsy, blindness, and deafness continue to pose threats, it is increasingly clear that cognitive impairments are the most prevalent disability, accounting for the vast majority of functional disability in this population at school age.4 There is also increasing evidence of a high prevalence of more subtle, neuropsychological impairments in this population, with studies documenting deficits in a range of visuo-spatial processes, sensorimotor skills, and attention and executive functions,5,6 with learning disabilities documented in up to 40% of extremely preterm survivors in middle childhood.7 Emerging studies have also JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 www.jaacap.org 453 JOHNSON et al. shown a significant excess of parent- and teacherreported behavioral and emotional problems in these children, with studies most consistently identifying greatest risks for problems in domains of attention, concentration, and social relationships with peers.8,9 Clinically significant behavioral problems, identified by both parent and teacher reports, have been found in up to 20% of extremely preterm children at 6 years of age, with attention-deficit/ hyperactivity disorder (ADHD) symptoms reported in up to 31% of survivors.10,11 The most recent reports have also identified an increased prevalence of social and communication difficulties and autism spectrum disorder (ASD) symptoms in this population.9,12,13 The vast majority of previous studies have used screening questionnaires to assess behavioral problems. Four studies that have used diagnostic psychiatric evaluations have reported 22% to 28% prevalence of clinical diagnoses in low-birthweight (⬍2,000 g)14,15 and very-lowbirthweight (⬍1,500 g) children at school age,16,17 with greatest risk for anxiety disorders and ADHD. Two studies also report a significantly increased prevalence of ASD of 1% to 2%.14,17 However, these studies included all children born with low birthweight who were thus far more gestationally mature. These populations are likely to be at considerably less risk than extremely preterm children, given the significant association of adverse neuro-cognitive outcomes with decreasing gestational age at birth.18,19 The high prevalence of neuro-morbidity in extremely preterm children4 makes it likely that psychiatric problems may also be increased despite continued improvements in care and in survival. To date, the prevalence of diagnosed psychiatric disorders in a contemporary population of extremely preterm survivors has not been systematically investigated. The objectives of this study were to investigate the prevalence, correlates, and precursors of psychiatric disorders in a whole population of extremely preterm children at 11 years of age. METHOD All babies born at ⬍26 weeks gestation and admitted for neonatal intensive care in the United Kingdom and Ireland from March through December 1995 (n ⫽ 811) were identified as part of the EPICure Study.20 Subsequent follow-up studies were conducted at 2.5, 6, and 11 years of age of all surviving infants, including singleton and multiple births. Parental consent was provided for formal assessments on 283 (92%) and 241 (78%) of 308 survivors at 2.5 years21 and 6 years of age,3 respectively. Most recently, of 307 survivors at 11 years of age, 11 (4%) moved abroad, and the parents of 77 (25%) did not provide consent. The remaining 219 (71%) children were assessed (median age: 10 years, 11 months; range: 121 to 145 months). Information relating to perinatal variables and neonatal course were mostly available for all extremely preterm children, and longitudinal data were available for 213 of 219 assessed at 2.5 years and for 202 of 219 who were also assessed at 6 years. At the 6-year follow-up, for each extremely preterm child attending mainstream school, a child born at term was selected randomly where possible from three classmates closest in age and of the same sex and ethnicity.3 At 11 years, where the preterm child was at a different school to the original 6-year classmate, or the original classmate declined to participate, a new classmate was selected where possible using the same methodology, resulting in 43 new comparison children.4,7 Thus 153 classmates for whom parental consent was obtained were assessed at 11 years (median: 10 years 11 months; range: 117 to 147 months). Classmates were not selected for extremely preterm children in special schools. There were no significant differences in age, sex, and ethnicity between extremely preterm children and classmates. Parents and children were given information sheets, and parents provided informed consent. Children were assessed by a pediatrician and psychologist at school. As school assessments were scheduled by a research manager, and as pediatricians and psychologists had no prior contact with participants, assessors were thus blind to children’s group allocation at the time of testing. To obtain behavioral data, parents and teachers completed questionnaires, and parents participated in a structured psychiatric interview regarding their child’s behavior. Transcripts obtained from parental assessments and teacher questionnaires were reviewed by two independent child and adolescent psychiatrists who had no prior knowledge of the child and were thus blind to study group allocation. The study was approved by the Southampton and South West Hampshire NHS Research Ethics Committee. Measures The Development And Well Being Assessment (DAWBA),22 a structured psychiatric evaluation regarding children’s development and behavior, was administered to parents via a telephone interview (92%) or parents participated in an online version (8%) from which information required for assigning ICD1023 and DSM-IV-TR24 diagnoses of childhood psychiatric disorders was obtained. The questions and items covered by the telephone and on-line DAWBA interview were identical. In previous validation studies, independent DAWBA reassessments of children at- JOURNAL 454 www.jaacap.org OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 PSYCHIATRIC DISORDERS IN PRETERM CHILDREN TABLE 1 Prevalence of DSM-IV Psychiatric Disorders in Extremely Preterm Children (n ⫽ 219) and Classmates (n ⫽ 152) at 11 Years of Age Extremely Preterm Children Classmates DSM-IV Diagnosis Any DSM-IV clinical diagnosis Any ADHD ADHD inattentive subtype ADHD combined type Any emotional disorder Separation anxiety Specific phobia Social phobia Posttraumatic stress disorder Generalized anxiety disorder Childhood emotional disorder NOS Major depression Any autism spectrum disorder Autistic disorder Atypical autism Any conduct disorder Oppositional defiant disorder Conduct disorder Tic disorder [152] [138] [138] [138] [143] [143] [143] [143] [143] [143] [143] [143] [143] [143] [143] [152] [152] [152] [143] n % 13 4 1 3 3 3 0 0 0 0 0 1 0 0 0 9 8 2 2 (8.6) (2.9) (0.7) (2.2) (2.1) (2.1) (0) (0) (0) (0) (0) (0.7) (0) (0) (0) (5.9) (5.3) (1.3) (1.4) [219] [183] [183] [183] [201] [201] [200] [200] [200] [201] [200] [200] [201] [201] [201] [219] [219] [219] [200] n % OR 95% CI p 51 21 13 8 18 5 3 1 1 4 1 3 16 13 3 12 11 1 2 (23.3) (11.5) (7.1) (4.4) (9.0) (2.5) (1.5) (0.5) (0.5) (2.0) (0.5) (1.5) (8.0) (6.5) (1.5) (5.5) (5.0) (0.5) (1.0) 3.2 4.3 10.5 2.1 4.6 1.2 — — — — — 2.2 — — — 0.9 1.0 0.3 0.7 (1.7–6.2) (1.5–13.0) (1.4–81.1) (0.5–7.9) (1.3–15.9) (0.3–5.1) — — — — — (0.2–21.0) — — — (0.4–2.2) (0.4–2.4) (0.0–3.8) (0.1–5.1) 0.000 0.005 0.005 0.362 0.011 1.000 0.269 1.000 1.000 0.144 1.000 0.643 0.000 0.001 0.269 1.000 1.000 0.570 1.000 Note: Diagnoses with no cases in either group: panic disorder; agorophobia; obsessive compulsive disorder; elective mutism; disinhibited attachment disorder of childhood; reactive attachment disorder; eating disorder; schizophrenia; manic episode; attention-deficit/hyperactivity disorder hyperactiveimpulsive subtype; Asperger’s syndrome. Odds ratios (OR) are unadjusted. p Values in boldface type denote significance at .05 level. Numbers in square brackets indicate denominators for complete data obtained for assigning using the Development and Wellbeing Assessment (DAWBA). For Attention-Deficit/Hyperactivity Disorder (ADHD) this required both complete parent and teacher data, for emotional disorders and autism spectrum disorders this required at least compete parent data, and for conduct disorders this required complete parent or teacher data. CI ⫽ confidence interval; NOS ⫽ not otherwise specified. tending mental health clinics have shown substantial agreement between clinic and DAWBA diagnosis, and rates of DAWBA diagnoses discriminate strikingly well between community and clinical samples.22 The inter-rater reliability (kappa) of the DAWBA is excellent with 0.86 for any disorder, 0.57 for internalizing disorders, and 0.98 for externalizing disorders.25 Supplemental information was provided by teachers who completed a corresponding questionnaire-based version of the DAWBA, an approach previously evaluated in a large community study.25 Multi-informant data were collated by study assessors (pediatricians and psychologist), and potential cases were identified using computer-generated scoring algorithms (www. dawba.com). Summary sheets and clinical transcripts (with any reference to birth status removed) were then reviewed by two child and adolescent psychiatrists (C.H. and P.K.) who had no prior knowledge of the children or their birth status and were therefore blind to group allocation, and who assigned DSM-IV and ICD-10 consensus diagnoses. In this report we refer primarily to psychiatric disorders defined using DSMIV-TR24 criteria (ICD-10 classifications,23 which were also assigned, are shown in Table S1, available online). Diagnostic classifications were assigned for the broad categories of ADHD, emotional, conduct, autism spectrum, and tic disorders. Table 1 summarizes DSM-IV sub-classification of these broad categories. The Kaufman-Assessment Battery for Children (KABC)26 was used to obtain IQ scores from which cognitive impairment (scores less than ⫺2SD) was defined using the distribution of classmate scores (impairment denoted by scores less than 82) to account for the secular drift in IQ over time.27-29 A standard clinical evaluation conducted by a pediatrician was used to identify serious functional neuro-sensory (neuromotor/hearing/visual) impairment. These were also combined with cognitive impairment classifications to yield a single classification for overall functional disability. These data have been reported previously.4 Parent reports of behavior problems were obtained at 2.5 years using the Child Behavior Checklist (CBCL),30 from which clinically significant internalizing and externalizing behavior problems were identified according to the scoring manual (⬎97th percentile). At 6 years, parents and teachers completed the JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 www.jaacap.org 455 JOHNSON et al. TABLE 2 Factors Independently Associated with Psychiatric Disorders in Extremely Preterm Children at 11 Years of Age Variable Adjusted OR Neonatal and outcome at 2.5 years (n ⴝ 194) Internalizing behavior problemsa Neonatal and outcomes at 2.5 and 6 years (n ⴝ 163) Pervasive attentional problemsb (at 6 years) Serious functional disability (at 6 years) Necrotizing enterocolitis Pervasive conduct problemsb (at 6 years) Internalizing behavior problemsa (at 2.5 years) 95% CI p 6.15 2.74–13.8 ⬍0.001 3.07 3.38 7.15 10.3 12.3 1.13–8.31 1.29–8.87 1.00–51 2.87–37.3 3.96–38.4 0.027 0.013 0.050 ⬍0.001 ⬍0.001 Note: Pervasive problems indicate congruence between parent and teacher reports of clinically significant problems in each domain. CI ⫽ confidence interval; OR ⫽ odds ratio. a Assessed with Child Behavior Checklist (CBCL) at 2.5 years; regression is for risk of clinically significant behavior problems. b Assessed with Strengths and Difficulties Questionnaire (SDQ) at 6 years. Strengths and Difficulties Questionnaire (SDQ)31 from which scores above the 90th percentile have been previously proposed to best identify children with clinically significant problems.31 The distribution of classmates scores were used to classify clinically significant difficulties in emotional, conduct, inattention/ hyperactivity, and peer problems and for total behavioral difficulties. Congruence between parent and teacher reports of clinically significant difficulties was used to classify pervasive problems in each domain. These data have been reported previously.10 Neonatal data were obtained at discharge from hospital for extremely preterm children. Parental socio-economic status (SES) at 11 years was classified into four categories using the UK National Statistics Socio-Economic Classification (I—Professional/Managerial; II—Intermediate; III—Routine/Manual; IV—Unemployed).32 Data Analysis Data were double-entered and verified. SPSS and Stata (S.J., E.H.) were used to compare rates of psychiatric diagnoses between extremely preterm children and classmates using two-tailed Fisher’s exact tests for dichotomous outcomes. Results are reported as odds ratios (OR) with 95% confidence intervals (CI). The risk of psychiatric diagnosis was further investigated excluding children with neurosensory and cognitive impairment. Adjusted OR were investigated with sex and SES (I/II vs. III/IV) as covariates using logistic regression. As adjustment for these variables had no significant effects, unadjusted OR are reported throughout. Neonatal and neurodevelopmental outcome variables at 2.5 and 6 years were used in univariate logistic regression to predict psychiatric diagnoses. A multivariate forward stepwise procedure was applied to identify independent factors associated with psychiatric diagnoses (adjusted OR) at three time points: neonatal, outcomes at 2.5 years, outcomes at 6 years. Multiple imputation was used to estimate the underlying prevalence of psychiatric disorders in extremely preterm children after accounting for the selective and increasing loss to follow up at 2.5, 6, and 11 years. Significant factors associated with a diagnosis of any psychiatric disorder and those significantly associated with the former factors were included in the model that used the “ice” command in stata1033 with 20 imputations. In addition to the variables in Table 2, others included were fetal heart rate ⬎100 beats/min at 5 minutes, oxygen at 36w, post menstrual age, male sex, prolonged rupture of the membranes, mother’s age, and externalizing behavior problems at 2.5 years. RESULTS Dropout Analyses Extremely preterm survivors not assessed at 11 years (n ⫽ 88) were more likely to be born at 25 weeks, to unemployed parents of nonwhite ethnic origin or to have more frequent cognitive impairment at 2.5 and 6 years of age than those assessed (n ⫽ 219)4 There were no significant differences in parent-rated behavior problem scores at 2.5 years between children assessed and not assessed at 11 years. Prevalence of Psychiatric Disorders DAWBA assessments were obtained for 219 (100%) extremely preterm children and 152 (99%) classmates (for one classmate, neither parent nor teacher completed the interview or questionnaire). Both parent and teacher data were obtained for 183 (84%) extremely preterm children and 138 (90%) classmates. JOURNAL 456 www.jaacap.org OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 PSYCHIATRIC DISORDERS IN PRETERM CHILDREN Extremely preterm children were more likely to have a psychiatric disorder (23.3%) than classmates (8.6%) (OR ⫽ 3.2, CI 1.7 to 6.2; Table 1). Overall, 87 (40%) extremely preterm children and 2 (1.3%) classmates had serious cognitive impairment, and 35 (16%) extremely preterm children had serious neuro-sensory impairment compared with none of the classmates. These outcomes have been published in detail elsewhere.4 Although there was no significant difference in the rate of disorders among extremely preterm children with and without neurosensory impairment (29% vs. 22%; OR ⫽ 1.4; CI ⫽ 0.6 to 3.1), children with cognitive impairment were significantly more likely to have a disorder (37% vs. 14%; OR ⫽ 3.5; CI ⫽ 1.8 to 6.4). The prevalence of psychiatric disorders in extremely preterm children remained significantly increased after excluding children with neurosensory impairment but not after excluding those with cognitive impairment (Table 3). Using multiple imputation to correct for selective loss to follow-up, the estimated proportion of all extremely preterm survivors with psychiatric disorders rose marginally from 23.3% to 25% (CI ⫽ 19.4% to 31.1%). Attention-Deficit/Hyperactivity Disorder Attention-deficit/hyperactivity Disorder (ADHD) was the most prevalent psychiatric disorder among extremely preterm children, who were 4.3 times more likely to have ADHD compared with classmates. The greatest risk was for ADHD inattentive subtype (ADHD-I; Table 1). Of the four classmates with ADHD, three (75%) had ADHD-combined subtype. In contrast, among the 21 extremely preterm children with ADHD, eight (38%) had ADHD combined subtype and 13 (62%) had ADHD-I. There was a nonsignificant trend toward increased prevalence of ADHD in boys compared with girls among both classmates (5.1% vs. 1.3%; OR ⫽ 4.2; CI ⫽ 0.4 to 41.2) and preterm children (16.5% vs. 7.1%; OR ⫽ 2.6; CI ⫽ 0.98 to 6.7). Children with cognitive impairment were five times more likely to have ADHD than those without (20.8% vs. 5.4%; OR ⫽ 4.6; CI ⫽ 1.7 to 12.5). After excluding children with cognitive impairment, the risk of ADHD in extremely preterm children was halved and no longer significant (Table 3). Emotional Disorder Extremely preterm children were four times more likely to have an emotional disorder than were classmates. All three classmates with emotional disorders had separation anxiety and were female. Extremely preterm children had a broader range of emotional disorders; of these, 14 of 18 children had anxiety disorders, the most common of which were separation anxiety and generalized anxiety disorder (Table 1). Anxiety disorders accounted for the significant excess of emotional disorders overall (anxiety disorders: OR ⫽ 3.5; CI ⫽ 1.0 to 12.4). Among extremely preterm children, there were no significant differences in rates of emotional disorders by sex, gestational age, neurosensory impairment, or cognitive impairment. The risk for emotional disorders was unaffected after excluding children with neurosensory impairment, and was only marginally lower after excluding cognitive impairment (Table 3). Autism Spectrum Disorder Overall, 16 (8%) extremely preterm children had autism spectrum disorder (ASD) compared with none of the classmates (Table 1). Of these, 13 (6.5%) had autistic disorder, and 3 (1.5%) atypical autism; none had Asperger’s disorder or other ASDs. Extremely preterm children with ASD were more likely to be male (OR ⫽ 3.9; CI ⫽ 1.2 to 12.4), to have cognitive impairment (OR ⫽ 3.7; CI ⫽ 1.2 to 11.1), and to have functional disability (4.2; 1.3 to 13.6) than were their preterm counterparts without ASD. Detailed analyses of correlates and risk factors for ASD in this population are published elsewhere.34 Oppositional Defiant Disorder and Conduct disorder Oppositional defiant disorder (ODD) and conduct disorder (CD) were not significantly increased in extremely preterm children compared with classmates (Table 1). Among extremely preterm children, ODD/CD was not significantly associated with sex, gestational age, or neurosensory or cognitive impairment. Comorbid Psychiatric Disorders Overall, 13 (5.9%) extremely preterm children and four (2.6%) classmates had comorbid psychiatric disorders. Among extremely preterm children, 38 (17.4%) had one disorder, nine children (4.1%) had two disorders, and four (1.9%) had more than two disorders. Among classmates, these proportions were nine (5.9%), two (1.3%) and two (1.3%) respec- JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 www.jaacap.org 457 www.jaacap.org JOHNSON et al. 458 TABLE 3 Prevalence of DSM-IV Psychiatric Disorders in Classmates (n ⫽ 152), Extremely Preterm Children Excluding Those with Neurosensory Impairment (n ⫽ 184), and Extremely Preterm Children Excluding Those with Either Neurosensory or Cognitive Impairment (n ⫽ 121) at 11 Years of Age Extremely Preterm Children Excluding Those with Neurosensory Impairment Classmatesa DSM-IV Diagnosis JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 Any DSM-IV clinical diagnosis Any ADHD diagnosis ADHD inattentive subtype ADHD combined type Any emotional disorder Separation anxiety Specific phobia Social phobia Posttraumatic stress disorder Generalized anxiety disorder Childhood emotional disorder NOS Major depression Any autism spectrum disorder Autistic disorder Atypical autism Any conduct disorder Oppositional defiant disorder Conduct disorder Tic disorder 152 138 138 138 143 143 143 143 143 143 143 143 143 143 143 152 152 152 143 n % 13 4 1 3 3 3 0 0 0 0 0 1 0 0 0 9 8 2 2 8.6 2.9 0.7 2.2 2.1 2.1 0 0 0 0 0 0.7 0 0 0 5.9 5.3 1.3 1.4 184 154 154 154 171 171 170 170 170 171 170 170 171 171 171 184 184 184 170 n % OR 95% CI p 41 18 11 7 15 3 3 1 1 4 1 2 11 8 3 10 9 1 2 22.3 11.7 7.1 4.5 8.8 1.8 1.8 0.6 0.6 2.3 0.6 1.2 6.4 4.7 1.8 5.4 4.9 0.5 1.2 3.1 4.4 10.5 2.1 4.5 0.8 — — — — — 1.7 — — — 0.9 0.9 0.4 0.8 1.6–6.0 1.5–13.4 1.3–82.7 0.5–8.5 1.3–15.8 0.2–4.2 — — — — — 0.2–18.8 — — — 0.4–2.3 0.3–2.5 0.0–4.6 0.1–6.0 .001 .006 .006 .343 .013 1.000 .253 1.000 1.000 .129 1.000 1.000 .001 .009 .254 1.000 1.000 .592 1.000 Extremely Preterm Children Excluding Those with Either Neurosensory or Cognitive Impairment 121 102 102 102 112 112 112 112 112 112 112 112 112 112 112 121 121 121 112 n % OR 95% CI p 16 6 3 3 7 1 1 1 0 2 1 1 4 4 0 3 3 0 1 13.2 5.9 2.9 2.9 6.3 0.9 0.9 0.9 0 1.8 0.9 0.9 3.6 3.6 0 2.5 2.5 0 0.9 1.6 2.1 4.1 1.3 3.1 0.4 — — — — — 1.3 — — — 0.4 0.5 — 0.6 0.7–3.5 0.6–7.5 0.4–39.9 0.3–6.8 0.8–12.1 0.04–4.0 — — — — — 0.1–20.4 — — — 0.1–1.5 0.1–1.7 — 0.1–7.0 .242 .333 .316 1.000 .113 .632 .443 .443 — .195 .443 1.000 .037 .037 — .236 .355 .504 1.000 Note: Cognitive impairment was classified as IQ scores less than ⫺2 SD using classmates as reference data (i.e., IQ ⬍ 82). Diagnoses with no cases in either group: panic disorder; agorophobia; posttraumatic stress disorder; obsessive compulsive disorder; elective mutism; disinhibited attachment disorder of childhood; reactive attachment disorder; eating disorder; schizophrenia; manic episode; attention deficit/hyperactivity disorder hyperactive-impulsive subtype; Asperger’s syndrome. p Values in boldface type denote significance at .05 level. ADHD ⫽ attention-deficit/hyperactivity disorder; CI ⫽ confidence interval; NOS ⫽ not otherwise specified; OR ⫽ odds ratio. a Classmates: n ⫽ 150 when children with serious cognitive impairment were excluded. These two children did not have disorders, and thus the prevalence remains the same as for the full group. PSYCHIATRIC DISORDERS IN PRETERM CHILDREN tively. Among children with psychiatric disorders, extremely preterm children were no more likely to have comorbid disorders than classmates (25.5% vs. 30.8%; p ⫽ .732). Of 21 extremely preterm children with ADHD, 10 (47%) had comorbid psychiatric disorder: five (24%) had an ASD, 4 (19%) had an emotional disorder, and 6 (29%) had ODD/ CD. Of four classmates with ADHD, all had a comorbid psychiatric disorder, of whom three (75%) had ODD/CD and one (25%) had an emotional disorder. Precursors of Psychiatric Diagnoses at 11 Years in Extremely Preterm Children None of the neonatal variables examined were significantly associated with psychiatric diagnoses on univariate analyses. However, the risk was marginally significant (p ⬍ .1) for boys and for children born through vaginal breech deliveries (Table 4). In contrast, developmental outcomes at 2.5 years were significantly associated with psychiatric diagnoses, the strongest association with parent-reported internalizing behavior problems. At 6 years, there were strong associations with pervasive conduct problems and overall behavioral difficulties, and moderate prediction by serious cognitive or functional disability, attention, and peer problems (Table 4). On multivariate analyses, no neonatal variables were independent predictors of psychiatric disorder at age 11 years; however male sex, breech delivery, and necrotizing enterocolitis (NEC) were marginally significant (p ⬍ .10). By 2.5 years, parent-reported internalizing behavior problems was the only significant independent variable, although male sex, NEC, and functional disability at 2.5 years were marginally associated with increased risk. At 6 years, NEC, functional disability, internalizing behavior problems at 2.5 years, and pervasive conduct and attention problems at 6 years had independent associations with psychiatric diagnoses (Table 2). Overall, parent-reported internalizing behavior problems at 2.5 years and pervasive conduct problems at 6 years were strong predictors of psychiatric diagnoses at 11 years. DISCUSSION This is the first investigation of the prevalence of psychiatric disorders in a whole population of extremely preterm children. The 23% prevalence and nearly threefold increased risk for psychiatric disorders observed is commensurate with the 22% to 28% prevalence and associated risk ratios reported in LBW/very LBW cohorts.14-17 Recent studies of extremely preterm/ELBW children have reported 29% to 40% prevalence of behavioral problems in middle childhood.9,10,14,35 However, these are based on symptom counts from screening questionnaires, and the rates of confirmed diagnoses that require impairment are typically lower, as found in the present study. The 23% prevalence reported may slightly underestimate the true prevalence, as multiple imputation used to account for selective dropout increased the prevalence of psychiatric disorders to 25% in the surviving population. Studies using behavioral screening measures8,9,10,35-37 and diagnostic evaluations14,16,17 increasingly point to an “extremely preterm phenotype” characterized by inattention and social and emotional problems, which is highlighted in the present results. Consistent with previous reports, the most frequent psychiatric disorder was ADHD for which the magnitude of risk was consistent with previous studies reporting odds ratios of 2 to 4 in other cohorts.11 We noted that this was attributable to the increased risk for ADHD inattentive subtype rather than ADHD combined subtype, and that ODD/CD was less strongly associated with ADHD in extremely preterm children than in classmates and in the general population.38 This has been noted previously,14,16,39,40 prompting authors to suggest that preterm survivors are more susceptible to cognitive impairments that are associated with ADHD-inattentive subtype (ADHD-I) and are relatively protected from developing conduct problems.39-41 It has also been suggested that ASD may be more closely associated with neuro-cognitive and environmental factors in this population. Although ASD is considered to have a largely genetic origin in the general population, autistic features are strongly associated with cognitive impairment12 and abnormal cerebral findings during the neonatal period13 and adolescence40 in extremely preterm children. We found that autism spectrum disorder was associated with extreme prematurity, which may be a marker for an environmental origin, or risk modifier, for ASD. The 8% prevalence of ASD observed in the present study was markedly higher than the 0.6% to 0.9% reported in the general population,38,42 but was expected, given recent reports of increased rates of ASD in LBW/very LBW co- JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 www.jaacap.org 459 JOHNSON et al. TABLE 4 Univariate Associations with Psychiatric Disorders in Extremely Preterm Children at 11 Years DSM-IV Psychiatric Diagnoses (N ⴝ 51) Neonatal n OR 95% CI p Male Gestational age (per week) Birthweight (per 100g) Head circumference (per cm) Singleton White ethnic origin Any antenatal steroids Preterm premature rupture of membranes Vaginal breech delivery Fetal heart rate ⬎100bpm @ 5mins Temperature ⬍35°C CRIB score (per point) Chorioamnionitis (suspected or proved) Abnormal cranial ultrasound scan Necrotizing Enterocolitis Any postnatal steroids for CLD Bronchopulmonary dysplasia (02 at 36 weeks) Any breast milk taken Duration of NICU admission (per week) Maternal age (per 10 years) Maternal education post-16 years Outcome at 2.5 years Serious cognitive impairmenta Serious functional disability Head circumference (per SDS) Internalizing behavior problemsb Externalizing behavior problemsb Outcome at 6 years Serious cognitive impairmentc Serious functional disability Head circumference (per SDS) Pervasive emotional problemsd Pervasive conduct problemsd Pervasive attentional problemsd Pervasive peer problemsd Pervasive total behavior problemsd 219 219 219 147 219 218 217 216 218 215 209 218 216 218 218 218 219 217 166 217 200 1.76 0.96 0.98 1.05 1.2 0.63 0.87 0.61 1.92 0.9 0.9 1.03 0.6 1.56 3.42 0.89 0.75 0.68 1.01 1.29 1.07 0.93–3.31 0.63–1.46 0.75–1.29 0.87–1.27 0.59–2.45 0.29–1.35 0.39–1.93 0.28–1.32 0.97–3.79 0.28–2.93 0.42–1.93 0.94–1.12 0.26–1.39 0.71–3.45 0.67–17.48 0.44–1.77 0.38–1.49 0.29–1.59 0.95–1.08 0.74–2.25 0.51–2.28 .081 .84 .90 .60 .61 .23 .73 .21 .061 .86 .79 .57 .23 .27 .14 .73 .42 .37 .67 .36 .85 194 213 211 194 194 2.79 2.34 0.79 6.15 3.56 1.18–6.58 1.22–4.51 0.63–0.98 2.74–13.81 1.45–8.75 .019 .011 .036 <.001 .006 202 202 201 167 166 170 167 165 3.39 3.09 0.78 1.72 8.37 3.47 3.4 5.14 1.73–6.63 1.58–6.04 0.61–1.00 0.68–4.34 3.00–23.35 1.62–7.42 1.56–7.39 2.20–12.01 <.001 .001 .052 .250 <.001 .001 .002 <.001 Note: Pervasive problems indicate congruence between parent and teacher reports of clinically significant problems in each domain. p Values in boldface type denote significance at .05 level. CI ⫽ confidence interval; CLD ⫽ chronic lung disease; CRIB ⫽ Clinical Risk Index for Babies; NICU ⫽ neonatal intensive care unit; OR ⫽ odds ratio; SDS ⫽ standard deviation score. a Bayley Scales of Infant Development 2nd Edition, Mental Development Index score ⫺2SD (scores ⬍70). b Assessed with Child Behavior Checklist (CBCL); regression is for risk of clinically significant behavior problems. c IQ ⫽ ⫺2 SD of classmates (scores ⬍82) using Kaufman-Assessment Battery for Children. d Assessed with Strengths and Difficulties Questionnaire (SDQ). horts14,17 and high positive screening rates in very preterm infants12,13 and adolescents.9 Emotional disorders were also significantly increased in extremely preterm children and, consistent with other studies, this resulted from an increased risk for anxiety disorders.16,17 Emotional disorders were not associated with physical (neu- rosensory) problems in extremely preterm children despite the association of emotional disorders with poor physical health in the general population,38 but the exclusion of children with cognitive impairment accounted for some of the significant excess of these disorders. Mechanisms underlying the association between extremely JOURNAL 460 www.jaacap.org OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 PSYCHIATRIC DISORDERS IN PRETERM CHILDREN preterm birth and anxiety disorder require further investigation and should take into account the impact of traumatic events on parental mental health and parent-child relationships.43,44 At first sight, the lack of significant associations with neurosensory impairment suggests that psychiatric disorders are not related to the type of focal brain injuries often associated with preterm birth. Such focal injuries are detectable by standard ultrasound imaging techniques used at the time of this study, and the risk factors for such injuries have hardly changed over the last two decades for very preterm children.45 However, the association of psychiatric disorders and other deficits (e.g., language, learning abilities) in very or extremely preterm children with cognitive impairment in this and other studies46,47 suggests that these disorders may result from global changes in functional architecture, brain anatomy, or connectivity that is evidenced in early MRI studies.48,49 These range from reduced brain volume, reduced cortical folding to punctate white matter lesions, decreased cortical complexity, and diffuse and excessive high signal intensity in MRI48-51 not easily detectable in ultrasound. These are not predicted by usual neonatal risk factors but may show up in functional deficits in early development. We did not find a relationship between psychiatric disorders and neonatal variables. Other studies, typically focused on specific psychopathology, have failed also to find a significant association with neonatal variables,9,14,16 whereas some report independent associations with neonatal ultrasound abnormalities.13,15 In the present study, parent-reported behavior problems at 2.5 years (i.e., early behavioral deficits) and 6 years were the strongest precursors of disorders at 11 years. However, the lack of significant associations with neonatal variables should be interpreted with caution because of low statistical power. Given the small number of clinical cases, the inclusion of more than five variables risks overfitting the model for multivariate analyses. A number of variables were marginally significant (p ⬍ .1) on both univariate and multivariate analyses, including male sex, vaginal breech delivery, and NEC, and significant associations were noted on univariate analyses for the majority of outcomes reflecting neuro-cognitive sequelae. Prevalence estimates were based on DSM-IV diagnostic criteria. When ICD-10 diagnostic criteria for hyperkinetic disorder were applied, no excess was found for extremely preterm children (Table S1, available online). ICD-10 classification of hyperkinetic disorder requires the presence of pervasive hyperactivity and impulsivity in addition to inattention; this significantly reduces the number of extremely preterm children meeting diagnostic criteria. The application of DSM-IV criteria thus has greater sensitivity for ADHDrelated behaviors given the inclusion of an ADHD-inattentive subtype classification. For this reason, we have reported rates of DSM-IV diagnoses and would advocate the use of these diagnostic criteria in future research with preterm populations. The strengths of this study include the use of diagnostic evaluations to classify psychiatric and behavioral disorders. The DAWBA has excellent reliability and validity,22,25 and was the principal measure of psychopathology in the British child and adolescent mental health surveys38 and other recent general population studies in the United Kingdom.52 The prevalence for psychiatric problems in the classmates were comparable to those reported in these UK population studies.38 Psychiatric data were collected for all children rather than for a subset identified as at risk, and diagnoses were made by consensus between two experienced clinical raters blind to birth status. Cognitive ability was assessed by psychologists using objective standardized tests, and neurosensory function was evaluated by experienced neurodevelopmental pediatricians. All study assessors were blind to group allocation. Limitations of the study include the use of different behavioral scales at age 2.5 years (CBCL) and 6 years (SDQ). However, comparisons between the CBCL and SDQ have indicated that both have similar sensitivity and specificity in detecting clinical caseness despite the SDQ being a much shorter instrument.53 For predictive purposes, we used the more reliable externalizing and internalizing clusters rather than specific subscales of the CBCL. Furthermore, we used the CBCL (⬎97th percentile) and SDQ (⬎90th percentile) recommended cut-off points to identify “clinical” risk cases in the regression analyses. A further limitation was the lack of psychiatric self-report at 11 years. Although this may have led to possible underreporting of emotional disorders (typically less sensitive to observer report), it is less likely to have affected detection of ADHD or ASD, which are typically assessed at this age by combination of parent and JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010 www.jaacap.org 461 JOHNSON et al. teacher report. Finally, as in most longitudinal studies,54,55 selective dropout of families with higher social risk and children with more cognitive problems occurred. However, using estimation functions, the “true” prevalence was only marginally underestimated in our study. Furthermore, recent empirical evidence and simulations indicate that the validity of regression models is only marginally affected even after selective dropout.52 In conclusion, almost one quarter of extremely preterm children had a psychiatric disorder at 11 years of age. The most frequent psychiatric conditions were ADHD (12%), emotional disorders (9%), and ASD (8%). Global cognitive impairment and early parentreported internalizing symptoms, likely to be the result of insult to normal brain development and the superimposed risk of acquired brain injury, mediate the risk of psychiatric disorder associated with extremely premature birth. These results have implications for research and clinical practice. Extremely preterm birth allows the study of white to gray matter brain development as it occurs using new neonatal imaging approaches.45 This may identify how key structures of the brain are altered and their association to the functional phenotype for extremely preterm children.56,57 Clinically, the findings suggest that much greater emphasis than that so far should be placed on early cognitive and psychological monitoring of extremely preterm children for emerging neuropsychiatric and emotional disorders. Routine cognitive and behavioral screening throughout the preschool period may help to facilitate early psychiatric referral and therefore be beneficial for extremely preterm children and their families. & Accepted February 4, 2010 Dr. Johnson is with the Institute for Women’s Health, University College London and the School of Clinical Sciences, University of Nottingham, UK; Drs. Hollis and Kochhar are with the Developmental Psychiatry Section, Division of Psychiatry, University of Nottingham, UK; Dr Hennessy is with Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK; Dr. Wolke is with the Health Sciences Research Institute, University of Warwick, UK; Dr. Marlow is with University College London, UK. This study was supported by the Medical Research Council (MRC), UK. We are indebted to the EPICure 1 Study Group, which includes pediatricians in 276 maternity units in the UK whose contribution was invaluable. We are also indebted to the many children and parents for their continued participation in the EPICure Study. Co-investigators were Neil Marlow (University of Nottingham; Chief Investigator), Kate Costeloe (Queen Mary University of London ), Enid Hennessy (Queen Mary University of London), Janet Stocks (University College London), and Elizabeth Draper (University of Leicester). Study assessors were Rebecca Trikic, Rebecca Smith, Samantha Johnson (Psychologists), Susan Thomas, Victoria Rowell, and Joseph Fawke (Pediatricians). Support for DAWBA data collection and analysis was provided by Professor Robert Goodman (Institute of Psychiatry, Kings College London). Disclosure: Drs. Johnson, Hollis, Kochhar, Hennessy, Wolke, and Marlow report no biomedical financial interests of potential conflicts of interest. Correspondence to: Prof. Chris Hollis, Developmental Psychiatry, South Block E Floor, Queen’s Medial Centre, Nottingham, NG7 2UH, UK; e-mail: chris.hollis@nottingham.ac.uk 0890-8567/10/©2010 American Academy of Child and Adolescent Psychiatry DOI: 10.1016/j.jaac.2010.02.002 REFERENCES 1. Wilson-Costello D, Friedman H, Minich N, Fanaroff AA, Hack M. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pediatrics. 2005;115:997-1003. 2. Hack M, Taylor HG, Drotar D, Schluchter M, Cartar L, Andreias L, et al. Chronic conditions, functional limitations, and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s. J Am Med Assoc. 2005;294:318-325. 3. Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med. 2005;352:9-19. 4. Johnson S, Fawke J, Hennessy E, Rowell V, Thomas S, Wolke D, et al. 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TABLE S1 Prevalence of ICD-10 Psychiatric Disorders in Extremely Preterm Children (n ⫽ 219) and Classmates (n ⫽ 152) Extremely Preterm Children Classmates ICD-10 Diagnosis Any ICD-10 clinical diagnosis Hyperkinetic disorder Emotional disorders Separation anxiety Phobic anxiety disorder Agorophobia Generalized anxiety disorder Other anxiety disorder Mild depressive episode Pervasive developmental disorders Childhood autism Atypical autism Conduct disorders Oppositional defiant disorder Unsocialized conduct disorder Tic disorder [152] [138] [143] [143] [143] [143] [143] [143] [143] [143] [143] [143] [152] [152] [152] [143] n % 13 3 3 3 0 0 0 0 1 0 0 0 9 8 1 2 (8.6) (2.2) (2.1) (2.1) (0) (0) (0) (0) (0.7) (0) (0) (0) (5.9) (5.3) (0.7) (1.4) [219] [183] [201] [201] [200] [200] [201] [200] [200] [201] [201] [201] [219] [219] [219] [200] n % OR 38 4 16 4 3 1 4 1 3 16 13 3 12 11 1 2 (17.4) (2.2) (8.0) (2.0) (1.5) (0.5) (2.0) (0.5) (1.5) (8.0) (6.5) (1.5) (5.5) (5.0) (0.5) (1.0) 2.2 1.0 4.0 0.9 — — — — 2.2 — — — 0.9 1.0 0.7 0.7 95% CI (1.2 (0.2 (1.2 (0.2 (0.2 (0.4 (0.4 (0.0 (0.1 to 4.4) to 4.6) to 14.1) to 4.3) — — — — to 21.0) — — — to 2.2) to 2.4) to 11.2) to 5.1) p .021 1.000 .029 1.000 .269 1.000 .144 1.000 .643 .000 .001 .269 1.000 1.000 1.000 1.000 Note: Diagnoses with no cases in either group: social anxiety disorder; panic disorder; posttraumatic stress disorder; obsessive compulsive disorder; moderate or severe depressive episode; elective mutism; disinhibited attachment disorder of childhood; reactive attachment disorder of childhood; conduct disorder confined to family context; socialized conduct disorder; eating disorder; manic episode; schizophrenia. Odds ratios are unadjusted. p Values in boldface type denote significance at .05 level. JOURNAL 463.e1 www.jaacap.org OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 49 NUMBER 5 MAY 2010