Functional somatic symptoms (FSS), defined as physical symptoms that cannot be ascribed to a well-defined physical disease,

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1 Infant Behaviors Are Predictive of Functional Somatic Symptoms at Ages 5-7 Years: Results from the Copenhagen Child Cohort CCC2000 Charlotte Ulrikka Rask, MD, PhD 1,2, Eva Ørnbøl, MSc 2, Else Marie Olsen, MD, PhD 3, Per Fink, MD, DmSci 2, and Anne Mette Skovgaard, MD, DmSci 4 Objective To investigate infancy predictors of impairing functional somatic symptoms (FSS) at child ages 5-7 years with a focus on problems with feeding, sleep, and tactile reactivity. Study design This study is part of a longitudinal birth cohort study, Copenhagen Child Cohort CCC2000. Child health, development, and functioning were assessed by community health nurses at 4 home visits from birth to age 10 months. FSS at ages 5-7 years were measured by the Soma Assessment Interview in 1327 children. Sociodemographic data and information on maternal psychiatric illness were obtained from the Danish National Registers. Results Multiple logistic regression analysis controlled for maternal psychiatric illness and annual household income revealed that combined infancy regulatory problems (ie, at least 2 of 3 problems of feeding, sleeping, or tactile reactivity during the first 10 months of living) predicted impairing FSS at 5-7 years (aor = 2.9, 95% CI: ). Maternal psychiatric illness during the child s first year of living was also associated with later child FSS (aor = 7.1, 95% CI: ). Conclusion Regulatory problems may be an early marker of disturbed sensory reactivity in young children, which together with maternal psychiatric problems, point to possible early risk mechanisms of impairing FSS in childhood. (J Pediatr 2013;162:335-42). Functional somatic symptoms (FSS), defined as physical symptoms that cannot be ascribed to a well-defined physical disease, affect 10%-30% of children and adolescents, and may include headaches, abdominal and musculoskeletal pain, fatigue, and dizziness. 1-4 The overall prevalence increases with age, and girls tend to report more FSS than boys. 1,2 Children with FSS often experience impairment in daily activities, perceive their health negatively, and are frequently seen in pediatric settings 3-5 ; 2%-4% of all pediatric visits are reportedly due to FSS. 6 This is not only costly, but may lead to induced morbidity due to overinvestigation and overtreatment. Research suggests that childhood FSS may continue over time 7 and be a precursor of functional somatic syndromes in adults, such as irritable bowel syndrome. 8 Identifying modifiable early childhood factors that contribute to FSS may improve outcomes. Models for FSS suggest a multifactorial etiology, 9 with child-related factors (biologic vulnerability and increased stress sensibility), 10 and family-related factors (mood disorders and FSS or somatization disorders in the family), 4 as well as parental overprotection. 11 Data on early child factors of FSS are limited, but 2 population-based cohort studies have investigated whether regulatory problems in infancy were predictive of functional symptoms later in childhood. 12,13 Regulatory problems include hyper-sensitivity to sensory and tactile stimuli and difficulty of self-regulation where infants with these problems are described as needing assistance to settle back to sleep once awoken, and may have particular problems when new ways of feeding are being introduced. 14 Of parental factors in infancy, parents anxiety has been found to predate later recurrent abdominal pain (RAP), 12 and maternal psychological distress to predict RAP in the children 13 years later. 15 Furthermore, socioeconomic factors have been suggested to play a role in the risk mechanisms of FSS. 1,16 Taken together, the findings point to early disturbed sensory reactivity as a marker of biological programming for later FSS in which parental, especially maternal, and social factors may be early mediators. This study aimed to investigate markers of early regulatory problems as predictors of childhood FSS. We hypothesized that: (1) impairing FSS at the ages 5-7 years would be associated with problems of regulation in infancy; and (2) the predictive power would be affected by psychosocial factors, specifically in the form of maternal psychiatric problems and family economic adversities. FSS RAP SAI Functional somatic symptoms Recurrent abdominal pain Soma Assessment Interview From the 1 Regional Center for Child and Adolescent Psychiatry, Aarhus University Hospital, Aarhus, Denmark; 2 Research Clinic for Functional Disorders and Psychosomatics, Aarhus University Hospital, Aarhus, Denmark; 3 Regional Center for Child and Adolescent Psychiatry, Copenhagen University Hospital, Bispebjerg, Denmark; and 4 Regional Center for Child and Adolescent Psychiatry, Copenhagen University Hospital, Glostrup, Denmark Funded by TrygFonden, the Pharmaceutical Fund, the Beatrice Surovel Haskell Fund for Child Mental Health Research of Copenhagen, Mrs C. Hermansen s Memorial Fund, Lily Bethine Lund s Fund, the Research Initiative of Aarhus University Hospital Clinical Institute (Aarhus University), the Research Fund of 2004, the Medical Association in Aarhus, the Pool for Psychiatric Research (Aarhus County), Dagmar Marshall s Fund, King Christian X Fund, the Fund of Research in Mental Disorders, Rosalie Petersen s Fund, the Research Fund of the Danish Medical Association, the Fund of Research in Public Health (Aarhus County) and the Augustinus Fund. The authors declare no conflicts of interest /$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved

2 THE JOURNAL OF PEDIATRICS Vol. 162, No. 2 Methods This study was part of the Copenhagen Child Cohort CCC2000, 17 counting all 6090 children born in a welldefined geographical area around Copenhagen, Denmark, in The cohort has been followed prospectively since birth. At the 5-7 years follow-up, a random sample of 3000 members of the cohort was assessed, of whom 2912 were eligible for inclusion in the present study. Nine had died and 79 were not contactable. Complete data on FSS were available for a total of 1327 children from the random sample (45.6% of the total eligible sample) who formed the final study sample. The study was approved by the Scientific Ethics Committee of Copenhagen County (KA-05103) and the Danish Data Protection Agency. All parents of participating children gave written informed consent. Measures and Constructs Data were obtained from 2 sources: (1) the Danish Medical Birth Register; and (2) community health nurses. In this program, health nurses with specific training in child assessment visit the same family regularly during the first year of life. Data from the health nurses assessments were prospectively recorded using a standardized procedure as part of 4 routine home visits conducted when the children were at the ages 1-5 weeks (visit 1), 2-3 months (visit 2), 4-6 months (visit 3), and 8-10 months (visit 4). Data recorded comprised the standardized information from the parents as well as the results and conclusions of the health nurse s observations and assessments of the child. The health nurse recorded whether each single variable was normal or not (for details of the standardized record see 17 ). Regarding the particular variables, overall development was recorded at each visit according to the health nurse s assessments of weight and length, psychomotor development, language/communication skills, and the emotional and social functioning of the child. An overall variable was constructed and scored according to the conclusion from the latest available visit. The variables of feeding and sleep were recorded after the health nurse s global judgment of the parent s information as well as her observations at each home visit. The variable of tactile reactivity was assessed by the nurse s direct observations of the child s reactions at home visit 1 and 2 (Table I). We constructed a common indicator variable of infancy regulatory problems on the basis of the 3 domains: feeding, sleep regulation, and tactile reactivity. Measures of feeding and sleep were only included from the second month of life (visit 2, 3, and 4) as most normally developing children first begin to establish a regular pattern of feeding and sleep at this age. The overall variable of no regulatory problems was defined as the child having neither feeding, sleeping, nor tactile problems. One problem was defined as either feeding or sleeping or tactile problems, whereas combined problems was defined as the combinations of 2 or more problems of feeding, sleep, and/or tactile reactivity (Table I). Maternal mental health problems were ascertained from 2 sources: (1) the health nurse s recording from the first visit 1-5 weeks after childbirth on whether the mother had expressed that she has had any psychological problems in the pre- and perinatal period (answer categories: yes/ no); and (2) register data on whether the mother had been diagnosed with a mental disorder at hospital during the child s first year of life. These data from the National Psychiatric Central Register comprise data on all psychiatric contacts with an International Classification of Diseases, 10th revision diagnosis of a mental disorder (F00-F99). 18 At each visit the nurses made assessments of several aspects of the mother-child relation based on the direct observation of the mother in interaction with the child. Hereby, a variable, based on the mother s expectations and handling of the child and the affective involvement and synchronicity and joy between mother and child, was recorded as within the normal range or not. 17 For this study, an overall variable for the mother-infant relationship was constructed and categorized as not normal if the health nurse had concluded so at one or more visits. Socioeconomic and demographic data, covering the period around the child s birth, were obtained from Danish National Registers. In this study, we used annual household income as the marker of socioeconomic level. 16 Outcome Variable FSS at 5-7 years were measured by the Soma Assessment Interview (SAI), a parent interview developed to investigate FSS in a general population study of young children. Detailed descriptions of the SAI and preliminary validation has been reported elsewhere. 3,19 In the SAI, structured questions are applied to determine whether the child has a known chronic physical disease and/or has experienced any of 20 separate physical symptoms during the past year. In the presence of possible unexplained symptoms, the parent s detailed verbal descriptions of these symptoms and their associated impairment are also recorded. Subsequently, clinical raters (ie, physicians) review all the data before the assessment of FSS, where only children with definite FSS are classified as cases. Assignment of impairing or nonimpairing FSS is based on answers to structured questions covering distress, interference with social life, the use of health services, and/or absence from school or day care. Included in this study was only impairing FSS defined as FSS with a medium or great amount of distress, and/or interference with social life, and/or at least 3 doctor visits and/or hospitalization, and/ or at least 7 days of absence from day care or school during the past year due to FSS. Statistical Analyses All analyses were performed using STATA v. 11 for windows (Stata Corp, College Station, Texas). c 2 Test was used to compare impairing FSS versus no or nonimpairing FSS with regard to different child, maternal, and social 336 Rask et al

3 February 2013 ORIGINAL ARTICLES Table I. Description and frequency of baseline variables in the study sample (n = 1327) Variables Frequency n (%) Description Source Child factors Sex 1327 (100) The child s sex Medical Birth Register Boy: 660 (49.7) Girl: 667 (50.3) Gestational age 1303 (98.2) Calculated from first day of last menstruation (Term: $37 wk, Preterm: <37 wk) Tactile reactivity 1199 (90.4) Whether the child shows pleasure being touched and/or can easily be comforted in the parents arms, problems at least at 1 visit Distribution n (%) Medical Birth Register Term: 1236 (94.9) Preterm: 67 (5.1) Health nurse records: visit 1 and 2 Feeding problems 1248 (94.0) Feeding problems at least at 1 visit Health nurse records: visit 2, 3, and 4 Sleeping problems 1251 (94.3) Sleeping problems at least at 1 visit Health nurse records: visit 2, 3, and 4 Infancy regulatory 1251 (94.3) Combined tactile reactivity-, feeding-, Constructed variable problems and/or sleeping problems made from the above Overall development 1254 (94.5) Final conclusion by the health nurse concerning overall somatic and mental development at the latest available visit Mother-child factors Mother-child relationship 1254 (94.5) Whether the mother-child relationship is abnormal as concluded by the health nurse at 1 or more visits Maternal factors Postnatal psychiatric illness 1327 (100) Mother having contact to psychiatric hospital because of a psychiatric disorder during the child s first year of living Pre/perinatal psychological problems 1234 (93.0) Maternal self-reported psychological problems during the pre- and perinatal period Social factors Social level of living area 1327 (100) Proxy social status of living area (municipality) of the family at time of birth* Annual household income 1316 (99.2) The sum of disposal household income in year 2000 and 2001 calculated for the entire cohort, dichotomized as the upper quartile versus the lower 3 quartiles Maternal education level 1263 (95.2) Mother s educational level at the time of birth (ISCED) 3 basic variables Health nurse records: visit 1, 2, 3, or 4 Health nurse records: visit 1, 2, 3, 4 Psychiatric Central Register Health nurse record: visit 1 Danish Central Civil Registration System Integrated Database for Labor Market Research Integrated Database for Labor Market Research No problem: 1184 (98.7) Problem: 15 (1.3) No problem: 1007 (80.7) Problem: 241 (19.3) No problem: 1024 (81.8) Problem: 227 (18.2) No problems: 853 (68.2) 1 Problem: 318 (25.4) Combined problems: 80 (6.4) Normal: 1181 (94.2) Not normal: 73 (5.8) Normal: 1174 (93.6) Not normal: 80 (6.4) No: 1314 (99.0) Yes: 13 (1.0) No: 1184 (96.0) Yes: 50 (4.0) High: 334 (25.2) Intermediate: 465 (35.0) Low: 528 (39.8) Upper: 424 (32.2) Lower: 892 (67.8) Primary (1-10 y): 182 (14.4) Secondary (10-14 y): 660 (52.3) Tertiary (15-19 y): 421 (33.3) Ethnicity 1323 (99.7) Number of parents born in Denmark Medical Birth Register 2: 1061 (80.2) 1: 157 (11.9) None: 105 (7.9) Parents living together 1323 (99.7) Whether parents were living together at the time of birth Medical Birth Register Yes: 1251 (94.6) No: 72 (5.4) ISCED, International Standard Classification of Education. *Preconstructed variable from the Authorities in the Capital Region, based on data from the Danish Central Civil Registration System concerning income level in the different areas. characteristics. According to our conceptual framework with a proximal, intermediate, and distal level of determinants for FSS, we then performed a series of multiple logistic regressions, sequentially adding child, maternal, and social factors. To avoid overfitting, there should be cases for each explanatory parameter. Therefore, with 58 cases with impairing FSS, only 1 factor from each level was included in these analyses. Thus, infancy regulatory problems were chosen as the main child factor, postnatal psychiatric illness as the maternal factor, and the annual household income as the social factor. Model I examined the crude association between infancy regulatory problems and impairing FSS at ages 5-7 years. In model II, maternal psychiatric illness was added, and in the model III all 3 factors were included. The results are shown as ORs, 95% CI, and P values (2-sided). For all analyses, statistical significance was set to P <.05. The outcome of impairing FSS was hampered with the amount of missing data, as only parents to 1327 out of 2912 eligible children performed the SAI, leaving 1585 children without clarification concerning impairing FSS. Details on attrition analyses have been given elsewhere 3 and revealed that nonparticipants had higher socioeconomic adversities than participants. A social gradient has been reported in the prevalence of FSS in children. Also, univariate analyses Infant Behaviors Are Predictive of Functional Somatic Symptoms at Ages 5-7 Years: Results from the Copenhagen Child Cohort CCC

4 THE JOURNAL OF PEDIATRICS Vol. 162, No. 2 in the present study showed regulatory problems to be associated with socioeconomic adversity (data not shown). This suggested that the missing values could be related to the observed variables in the study. Therefore, in order to proceed with multiple imputation to test the influence of possible selection bias on models I-III, we assumed that the missing data were missing at random. We used logistic imputation method on the outcome of impairing FSS based on the asymptotic approximation of the posterior predictive distribution of the missing data as implemented in STATA 11. We chose to make 50 completed datasets. The imputation model included all variables used in the sequentially adjusted models as well as a range of sociodemograhic variables associated with nonparticipation (eg, lower maternal education, parents not living together, non Danish ethnicity, families from less affluent areas, and preterm birth). Results The overall prevalence of any FSS was 23.2% (n = 308) with a higher prevalence among girls than boys (27.6 vs 18.8%, X 2 = 14.41, P <.0001). Impairing FSS were found in 4.4% (n = 58), and in this subgroup, there was no statistically significant sex difference. Pain complaints (ie, limb pain, headache, and/or stomach ache) were the most frequent types of FSS. Further details on the epidemiology of FSS in this sample have been described elsewhere. 3 Data from infancy (at least 1 routine health nurse visit) were available for 1254 (94.5%) of the children, and data on regulatory problems were available for 94.3% of these children. Register data on maternal psychiatric illness and annual household income during the child s first year of living were available in 100% and 99.2% of the children, respectively. Table I shows the distribution of the variables. Univariate Analyses Table II shows associations between impairing FSS and infancy regulatory problems, other child factors, maternal mental health problems, and socioeconomic demographic details of the family at the time of the child s birth. Associations of Infancy Regulatory Problems, Early Development, and FSS at Ages 5-7 Years. Combined infancy regulatory problems were significantly associated with impairing FSS at ages 5-7 years, whereas this association was not found for children with only 1 problem (Table II). No statistically significant association was found between developmental risk factors of the child (premature birth or overall delayed development) and later presence of impairing FSS. Maternal Mental Health Problems in Infancy and FSS at Ages 5-7 Years. The mothers reports to the health nurse of having psychological problems in the pre- and perinatal period were significantly associated with the mothers having a psychiatric disorder during the children s first year of life (P <.001) and mothers psychiatric illness the year post partum was significantly associated with the child having impairing FSS at the ages of 5-7 years (P =.001). A total of 13 mothers were diagnosed with an International Classification of Diseases, 10th revision mental disorder, the majority with affective disorders (depressive disorder: n = 8; bipolar disorder: n = 1) and anxiety disorders or severe adjustment reactions (n = 4). No mother was diagnosed as psychotic. No significant associations were found between maternal self-reported psychological problems and regulatory problems or later FSS in the child. Mother-Infant Relationship Problems and FSS at Ages 5-7 Years. Mother-infant relationship problems were significantly associated with contemporary regulatory problems of the child (P <.001) and with maternal psychiatric illness during the first postnatal year (P <.001). No significant association was found between relationship problems in infancy and impairing FSS at ages 5-7 years. Associations of Social Factors and FSS at Ages 5-7 Years. A trend, but no statistically significant association, was found between the indicator variables for socioeconomic adversities at the time of the child s birth and later impairing FSS (Table II). Multivariate Analyses Univariate analyses showed that both combined infancy regulatory problems and maternal psychiatric illness were significantly associated with impairing FSS at the ages 5-7 years. In the multivariate analyses, the sequential adjustment for the effects of potential confounding by maternal psychiatric illness and annual household income did not significantly change the predictive power of combined regulatory problems on later FSS, and maternal psychiatric illness also remained a predictor after the adjustment for annual household income (Table III). The size of the data set did not allow more thorough, sophisticated analyses (ie, examination of potential effect modification). However, repeating the analyses while excluding the 13 children with mothers with postnatal psychiatric illness entailed no significant change in the association between infant regulatory problems and later impairing FSS (crude OR = 2.6, 95% CI ). Analyses with multiple imputed data sets, which took attrition into account, did not change the results. When repeating the analyses on children with nonimpairing FSS, no significant associations with the included predictors could be found (data available on request). Discussion Children experiencing combined problems in the regulation of feeding, sleep, and/or tactile reactivity during infancy have a nearly 3-fold increased risk of impairing FSS at ages 5-7 years, whereas no significant associations were found regarding FSS without impairment. Thus, the differentiation between clinically-significant symptoms and the 338 Rask et al

5 February 2013 ORIGINAL ARTICLES Table II. Univariate analyses of impairing FSS and child, maternal, and social factors Predictor Impairing FSS (n = 58) No or nonimpairing FSS (n = 1269) n (%) n (%) Statistics Child factors Child sex Boys 28 (48.3) 632 (49.8) X 2 = 0.05, d.f.(1) Girls 30 (51.7) 637 (50.2) P =.820 Gestational age Term 54 (94.7) 1182 (94.9) c 2 < 0.01, d.f.(1) Preterm 3 (5.3) 64 (5.1) P =.966 Missing = 1 Missing = 23 Infancy regulatory problems No problems 31 (58.5) 822 (68.6) c 2 = 7.33, d.f.(2) 1 Problem 14 (26.4) 304 (25.4) P =.026 Combined problems 8 (15.1) 72 (6.0) Missing = 5 Missing = 71 Overall development Normal 50 (94.3) 1131 (94.2) c 2 < 0.01, d.f.(1) Not normal 3 (5.7) 70 (5.8) P =.959 Missing = 5 Missing = 68 Mother-child factors Mother-child relationship Normal 49 (92.5) 1125 (93.7) c 2 = 0.13, d.f.(1) Not normal 4 (7.5) 76 (6.3) P =.722 Missing = 5 Missing = 68 Maternal factors Postnatal psychiatric illness No 55 (94.8) 1259 (99.2) c 2 = 10.99, d.f.(1) Yes 3 (5.2) 10 (0.8) P =.001 Self-reported psychological problems No 49 (94.2) 1135 (96.0) c 2 = 0.41, d.f.(1) Yes 3 (5.8) 47 (4.0) P =.521 Missing = 6 Missing = 87 Social factors Social living area Low 25 (43.1) 503 (39.6) c 2 = 1.24, d.f.(2) Intermediate 22 (37.9) 443 (34.9) P =.538 High 11 (19.0) 323 (25.5) Annual household income Lower (1-3 quartiles) 45 (77.6) 847 (67.3) c 2 = 2.67, d.f.(1) Upper (4 quartiles) 13 (22.4) 411 (32.7) P = Missing = 11 Maternal education level (ISCED) Primary 8 (14.3) 174 (14.4) c 2 = 1.00, d.f.(2) Secondary 26 (46.4) 634 (52.5) P =.605 Tertiary 22 (39.3) 399 (33.1) Missing = 2 Missing = 62 Ethnicity 2 Danish parents 51 (87.9) 1010 (79.8) c 2 = 2.30, d.f.(2) 1 Danish parent 4 (6.9) 153 (12.1) P =.317 None 3 (5.2) 102 (8.1) - Missing = 4 Parents living together Yes 56 (96.6) 1195 (94.5) c 2 = 0.47, d.f.(1) No 2 (3.4) 70 (5.5) P = Missing = 4 d.f., degree of freedom. very common, nonimpairing symptoms that affect every child at one time or another seem to be important and suggest the relevance of including impairment criteria in studies of FSS. Our findings correspond to results from studies of associations between irregular feeding and sleeping and the later development of specific bothersome somatic complaints (ie, headache and RAP) at preschool or school age. 12,13 Possible mechanisms include the child s hypersensitivity to sensory stimuli 20,21 and an early programming of autonomic hyper-reactivity. 10 In accordance with this, we may hypothesize the early emergence of markers of dysregulation of the autonomic nervous system and the hypothalamic pituitary axis, as well as alternations in the central processing of sensory input as observed in adult patients with functional somatic syndromes. 9 Regulatory difficulties in infancy may also be regarded as a more global and unspecific risk factor for a broad range of health problems in the preschool years, including FSS. 22,23 Recent studies have specifically suggested that eating and sleep Infant Behaviors Are Predictive of Functional Somatic Symptoms at Ages 5-7 Years: Results from the Copenhagen Child Cohort CCC

6 THE JOURNAL OF PEDIATRICS Vol. 162, No. 2 Table III. Multivariate analyses: Logistic regression models of infancy regulatory problems on impairing FSS at the ages 5-7 years Model I (n = 1251) Child factor Model II (n = 1251) Adding maternal factor Model III (n = 1244) Adding social factor Factor OR (95% CI) OR (95% CI) OR (95% CI) Infancy regulatory problems 1 Problem 1.2 ( ) 1.2 ( ) 1.2 ( ) Combined problems 3.0 ( ) 3.0 ( ) 2.9 ( ) Maternal psychiatric illness Yes ( ) 7.1 ( ) Annual household income Lower (1-3 quartiles) ( ) problems during early childhood may be risk factors for mood and anxiety disorders later in life, 24 and FSS in children have consistently been shown to be associated with an increased risk of emotional symptoms and/or problems. 5 Taken together, the association of early regulatory problems and FSS may also reflect a particular and shared diathesis between FSS and emotional disorders. Having a mother being admitted to and diagnosed at a hospital with a psychiatric illness in the first year of the child s life was predictive for impairing FSS at the ages 5-7 years, whereas mental health problems reported to health nurses in the weeks around childbirth were not. The difference in risk can be explained by both severity and the timing of exposure to the child. Thus, mental health problems causing referral to a hospital in the first year after childbirth indicate more severe and longerlasting problems compared with complaints of psychological problems in the weeks around birth, which probably are dominated by more mild and temporary reactions. The finding is in accordance with the results from a study of children with RAP showing an increased risk in families with maternal anxiety, depression, and somatization. 25 Furthermore, our findings corroborate results from a study of Helgeland et al, who demonstrated that maternal anxiety and depression in early childhood predicted RAP in their offspring 13 years later, 15 andthestudybyramchandani et al who also found anxiety in parents to predate the onset of RAP in their children by several years in a doseresponse relationship. 12 There are conflicting reports on sex and FSS in this age group. Some report no prepuberty sex difference, 26 others report a higher frequency in females than in males, as also seen in adolescence and adulthood. 27 In our study, girls had a higher overall FSS prevalence than boys, whereas no significant sex difference was found in the subgroup of children with impairing FSS. These findings might indicate that the conflicting data presented in the current literature are influenced by the use of different case criteria. We found no robust evidence for associations between impairing FSS and socioeconomic adversities early in life, and controlling for annual household income in the multivariate analyses did not significantly change the predictive power of infancy regulatory problems and maternal psychiatric illness. Results from other studies of the impact of socioeconomic disadvantage on child FSS are contradictory, 1,28 and a recent Swedish study found economic stress, but not social class, to be associated with functional somatic complaints. 16 The main strength of the present study lies in its prospective data collection by heath professionals of core infancy variables in an unselected birth cohort, an outcome measure that covers the full range of FSS, and the use of register data on maternal psychiatric illness. Several limitations need to be highlighted. First, the small sample sizes, especially regarding the number of mothers with postnatal psychiatric illness and self-reported psychological problems, have implications for the reliability of the data and the possibility of examining a possible interaction between maternal psychiatric illness and infancy regulatory problems for the later development of impairing FSS. Also, due to the small case number, as well as the lack of specific data regarding, daily stressors, medications, and chronic physical conditions, we were unable to take into account several other putative covariates that may affect the development of FSS. Second, the psychometric properties of the data collection by health nurses have not been established. The study was embedded in an existing child health surveillance program where the validity of the health nurses assessments was sought, optimized by the use of a standardized record with guidelines contained in a manual. This posits a potential limitation regarding the quality of these data but also represents a strength of the study, namely that of a high participation rate in the data collection, which at this stage lies at 94.5%. Third, the construct of regulatory problems in infancy is rather new and has not yet become fully validated. We used a measure of combined regulatory problems that was inspired by the literature and studies of regulatory predictors in infancy, which most commonly have included feeding and sleep, but also persistent crying and variables of difficult temperament. 29,30 We included data on feeding and sleep together with data on the child s tactile reactivity because the last measure can be regarded as a marker of problems that may be included in a concept of difficult temperament or as a regulatory disorder of hypersensitivity. 14 Fourth, the case definition of FSS has to be discussed. Owing to the study design, a large general population study, it was not possible to include physical examination of the children in order to validate the classification of symptoms as functional. However, the case definition was sought validated by the measure, the SAI, which combines a highly 340 Rask et al

7 February 2013 ORIGINAL ARTICLES structured parent interview with a clinician review. Hereby, detailed symptom descriptions were obtained in case of the slightest doubt about the origin of the reported symptoms, which made it possible to take into account further valuable information supporting the diagnosis in the final assessment by the clinical raters. Only children assessed with definite FSS were classified as cases, which potentially reduced misclassification of symptoms because of medications, small accidents, or because of an underlying physical disease. Accordingly, the diagnostic validity of FSS in this study was optimized compared with the commonly used measures of FSS in epidemiologic research, which are based on parent and/or self-reported symptom checklists (for further details of the validity of the FSS assessment, see 3,19 ). Finally, a limitation of the study concerns the attrition of children of putatively higher risk of FSS, as participating children were more often of Danish ethnicity and had fewer socioeconomic adversities than nonparticipants (for details of attrition issues, see 3 ). This might lower the generalizability regarding less advantaged populations and reduce the power of the associations. However, additional analyses with imputed data sets did not imply that this was the case. This is one of the first steps in the prospective investigation of early predictors of impairing FSS in childhood. The findings point to infancy regulatory problems as early and probably unspecific markers of pathophysiological changes that could be associated with functional somatic syndromes later in life. Current knowledge suggests that the impact of parental regulation on early child regulatory problems heralds a developmental pathway where infant problems are exaggerated by parental problems and vice versa. If so, the risk mechanisms might imply that especially maternal psychopathology (eg, anxiety, depression) influences the child s capacity to self-regulate. In a developmental perspective, this may sustain or increase a physiological vulnerability for later FSS. The perspective of mapping the modifiable early risk mechanisms of FSS in children could have implications for treatment and prevention of FSS in early childhood. Parents of infants with regulatory problems could be taught to help their infants regulate their behavioral and physiological state, which could potentially reduce the risk of later development of impairing FSS. n Submitted for publication Dec 27, 2011; last revision received Jun 13, 2012; accepted Aug 2, References 1. Berntsson LT, Kohler L, Gustafsson JE. Psychosomatic complaints in schoolchildren: a Nordic comparison. Scand J Public Health 2001;29: Campo JV, Fritsch SL. Somatization in children and adolescents. 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