Abstract:

This study aimed to evaluate the medium-term effects that hospitalization in the first 48 months of life has on the development of psychiatric disorders at 6 and 11 years of age among individuals in a birth cohort in a middle-income country. We analyzed data from a 2004 birth cohort (N = 4,231) in the city of Pelotas, Rio Grande do Sul State, Brazil. The frequency of hospitalization was investigated at 12, 24 and 48 months of life. When the children were 6 and 11 years old, psychiatric disorders were investigated with the Development and Well-Being Assessment. We used logistic regression to adjust for potential confounders. The overall frequency of hospitalization during the first 48 months of life was 33.1% (95%CI: 31.4; 34.7). Among the hospitalized children 25.6% (95%CI: 24.1; 27.1), 4.7% (95%CI: 4.0; 5.5) and 2.8% (95%CI: 2.3; 3.5) were hospitalized 1, 2 or ≥ 3 times during this period, respectively. After adjustment for potential confounders, the chance of presenting any psychiatric disorder at 6 and 11 years of age was higher for the children who had been hospitalized during the first 48 months of life than for those who had not, with OR of 1.50 (95%CI: 1.19; 1.88) and 1.63 (95%CI: 1.28; 2.07), respectively. Our results support the hypothesis that hospitalization in the early stages of life has an effect on the subsequent mental health of children. Preventive measures are needed in order to minimize the negative experiences of children who are hospitalized during infancy.

Keywords:
Mental Disorders; Hospitalization; Cohort Studies

Resumo:

O estudo teve como objetivo avaliar os efeitos no médio prazo da hospitalização nos primeiros 48 meses sobre o desenvolvimento de transtornos psiquiátricos aos 6 e 11 anos de idade entre membros de uma coorte de nascimentos em um país de renda média. Analisamos os dados de uma coorte de nascimentos de 2004 (N = 4.231) na cidade de Pelotas, Rio Grande do Sul, Brasil. Foi investigada a frequência da hospitalização aos 12, 24 e 48 meses de vida. Quando as crianças tinham 6 e 11 anos de idade, os transtornos psiquiátricos foram investigados com o Development and Well-Being Assessment. Usamos a regressão logística para ajustar os potenciais fatores de confusão. A frequência global de hospitalização durante os primeiros 48 meses de vida foi 33,1% (IC95%: 31,4; 34,7). Entre as crianças que tinham sido hospitalizadas, 25,6% (IC95%: 24,1; 27,1), 4,7% (IC95%: 4,0; 5,5) e 2,8% (IC95%: 2,3; 3,5) foram internadas 1, 2 ou ≥ 3 vezes durante o período, respectivamente. Depois de ajustar para os potencias fatores de confusão, as chances de apresentar qualquer transtorno psiquiátrico aos 6 e 11 anos de idade foram mais altas em crianças que haviam sido hospitalizadas nos primeiros 48 meses de vida, com OR de 1,50 (IC95%: 1,19; 1,88) e 1,63 (IC95%: 1,28; 2,07), respectivamente. Nossos resultados corroboram a hipótese de que a hospitalização na primeira infância tem efeito sobre a saúde mental posterior. São necessárias medidas preventivas para minimizar as experiências negativas de crianças com história de hospitalização na infância.

Palavras-chave:
Transtornos Mentais; Hospitalização; Estudos de Coortes

Resumen:

Este estudio tuvo como meta evaluar los efectos a medio plazo que tiene una hospitalización durante los primeros 48 meses de vida en el desarrollo de trastornos psiquiátricos entre los 6 y 11 años de edad, con individuos en una cohorte de nacimientos en un país de renta media. Analizamos los datos de una cohorte de nacimientos de 2004 (N = 4.231) en la ciudad de Pelotas, Rio Grande do Sul, Brasil. Se investigó una frecuencia de hospitalización a los 12, 24 y 48 meses de vida. Cuando los niños tenían entre 6 y 11 años de edad, se investigaron los trastornos psiquiátricos con una evaluación sobre desarrollo y bienestar. Se usó regresión logística para ajustar potenciales factores de confusión. La frecuencia general de hospitalización durante los primeros 48 meses de vida fue de un 33,1% (95%CI: 31,4; 34,7). Entre los niños hospitalizados un 25,6% (95%CI: 24,1; 27,1), 4,7% (95%CI: 4,0; 5,5) y 2,8% (95%CI: 2,3; 3,5) estuvieron hospitalizados 1, 2 o ≥ 3 veces durante este período, respectivamente. Tras ajustar los factores de confusión, la oportunidad de presentar cualquier trastorno psiquiátrico entre los 6 y 11 años de edad fue mayor para los niños que habían sido hospitalizados durante los primeros 48 meses de vida, respecto a quienes no lo habían estado, con un OR de 1,50 (95%CI: 1,19; 1,88) y 1,63 (95%CI: 1,28; 2,07), respectivamente. Nuestros resultados avalan la hipótesis de que la hospitalización en estadios tempranos de la vida tuvo un efecto en la futura salud mental de los niños. Son necesarias medidas preventivas, con el fin de minimizar las experiencias negativas de los niños que habían sido hospitalizados durante la infancia.

Palabras-clave:
Trastornos Mentales; Hospitalización; Estudios de Cohortes

Introduction

Hospitalization is defined as being admitted to a hospital (for medical care or observation) and remaining there for at least 24 hours ¹1. Ministério da Saúde. Padronização da nomenclatura do censo hospitalar. 2ª Ed. Brasília: Ministério da Saúde; 2002.. It can be considered a stressful, traumatic event in the life of an individual, because it implies a rupture in family and social relations ²2. Barros L. As consequências psicológicas da hospitalização infantil: prevenção e controlo. Anál Psicol 1998; 1:11-28.^,33. Nagera H. Children's reactions to hospitalization and illness. Child Psychiatry Hum Dev 1978; 9:3-19.^,44. Mrazek DA. Effects of hospitalization on early child development. In: Emde R, Harmon RJ, editors. Continuities and discontinuities in development. Boston: Springer; 1984. p. 211-25.^,55. Lau BWK, Tse WWC. Psychological effects of physical ilness and hospitalization on the child and the family. Hong Kong Journal of Psychiatry 1993; 3:9-18.^,66. Bonn M. The effects of hospitalization on children: a review. Curationis 1994; 17:20-4.^,77. Coyne I. Children's experiences of hospitalization. J Child Health Care 2006; 10:326-36.^,88. Donato N. Estratégias de enfrentamento do estresse na hospitalização infantil: revisão bibliográfica [Monography]. Ribeirão Preto: Universidade de São Paulo; 2012.. This process is even more intense and marked in childhood, given that children have limited mechanisms to cope with stressful experiences. In children, the main sources of stress during hospitalization are maternal separation, the use of invasive procedures and routine changes ²2. Barros L. As consequências psicológicas da hospitalização infantil: prevenção e controlo. Anál Psicol 1998; 1:11-28.^,33. Nagera H. Children's reactions to hospitalization and illness. Child Psychiatry Hum Dev 1978; 9:3-19.^,44. Mrazek DA. Effects of hospitalization on early child development. In: Emde R, Harmon RJ, editors. Continuities and discontinuities in development. Boston: Springer; 1984. p. 211-25.^,55. Lau BWK, Tse WWC. Psychological effects of physical ilness and hospitalization on the child and the family. Hong Kong Journal of Psychiatry 1993; 3:9-18.^,66. Bonn M. The effects of hospitalization on children: a review. Curationis 1994; 17:20-4.^,77. Coyne I. Children's experiences of hospitalization. J Child Health Care 2006; 10:326-36.^,88. Donato N. Estratégias de enfrentamento do estresse na hospitalização infantil: revisão bibliográfica [Monography]. Ribeirão Preto: Universidade de São Paulo; 2012..

The first years of life are simultaneously a time of great opportunity and a time of great vulnerability for brain development. Crucial aspects of brain architecture begin to be formed before and immediately after birth, and many fundamental aspects of that architecture are established in the first years of life ⁹9. Grossman AW, Churchill JD, McKinney BC, Kodish IM, Otte SL, Greenough WT. Experience effects on brain development: possible contributions to psychopathology. J Child Psychol Psychiatry 2003; 44:33-63.^,1010. Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci 2004; 16:1412-25.. Stress in childhood can affect the structural and functional systems of the developing brain, making an individual more vulnerable to psychological problems ¹¹11. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011; 137:959-97.^,1212. Pollak SD. Mechanisms linking early experience and the emergence of emotions: illustrations from the Study of Maltreated Children. Curr Dir Psychol Sci 2008; 17:370-5.. There is evidence that long-term exposure to stress in general, as well as to specific environmental stresses during sensitive periods of development, produces structural and functional disturbances, leading to a wide variety of physical and mental deficits in the short, medium and long term ¹³13. Kun D, Ben-Shlomo Y. A life course approach to chronic disease epidemioloy. 2nd Ed. Oxford: Oxford University Press; 2004.^,1414. Frodl T, Reinhold E, Koutsouleris N, Reiser M, Meisenzahl EM. Interaction of childhood stress with hippocampus and prefrontal cortex volume reduction in major depression. J Psychiatr Res 2010; 44:799-807.^,1515. Shonkoff JP, Garner AS; Committee on Psychosocial Aspects of Child and Family Health; Committee on Early Childhood, Adoption, and Dependent Care; Section on Developmental and Behavioral Pediatrics. The lifelong effects of early childhood adversity and toxic stress. Pediatrics 2012; 129:e232-46..

The mental health of individuals is influenced by individual, behavioral, socioeconomic and environmental characteristics ¹⁶16. World Health Organization. Risks to mental health: an overview of vulnerabilities and risk factors. Geneva: World Health Organization; 2012.. In childhood and adolescence, mental disorders are associated with factors such as gender, age, skin color, birth weight, gestational age, parental education, family income, smoking and alcohol consumption during pregnancy, maternal mental health, chronic diseases, stressful and traumatic events, mother-child interaction, etc. ¹⁷17. Fleitlich B, Goodman R. Social factors associated with child mental health problems in Brazil: cross sectional survey. BMJ 2001; 323:599-600.^,1818. Petresco S, Anselmi L, Santos IS, Barros AJD, Fleitlich-Bilyk B, Barros FC, et al. Prevalence and comorbidity of psychiatric disorders among 6-year-old children: 2004 Pelotas Birth Cohort. Soc Psychiatry Psychiatr Epidemiol 2014; 49:975-83..

Globally, about 20% of children and adolescents suffer from some disabling mental illness; suicide is the third leading cause of death among adolescents and approximately half of all adult mental illnesses begin in adolescence ¹⁹19. Belfer ML. Child and adolescent mental disorders: the magnitude of the problem across the globe. J Child Psychol Psychiatry 2008; 49:226-36..

Between 1970 and 1999 various studies were conducted in high-income countries. Despite certain methodological limitations, such as insufficient sample sizes, high losses to follow-up and failure (in some studies) to adjust for confounding variables, they reported a greater likelihood of having behavioural problems or emotional problems during childhood and adolescence for children who had been hospitalized for prolonged periods (or on more than one occasion) in the first years of life than for those who had not, those in the former group also being found to perform more poorly in school ²⁰20. Douglas JW. Early hospital admissions and later disturbances of behaviour and learning. Dev Med Child Neurol 1975; 17:456-80.^,2121. Quinton D, Rutter M. Early hospital admissions and later disturbances of behaviour: an attempted replication of Douglas' findings. Dev Med Child Neurol 1976; 18:447-59.^,2222. Haslum MN. Length of preschool hospitalization, multiple admissions and later educational attainment and behaviour. Child Care Health Dev 1988; 14:275-91.^,2323. Fahrenfort JJ, Jacobs EA, Miedema S, Schweizer AT. Signs of emotional disturbance three years after early hospitalization. J Pediatr Psychol 1996; 21:353-66.^,2424. Youngblut JM, Brooten D. Alternate child care, history of hospitalization, and preschool child behavior. Nurs Res 1999; 48:29-34.^,2525. Simons B, Bradshaw J, Silva PA. Hospital admissions during the first five years of life: a report from the Dunedin Multidisciplinary Child Development Study. N Z Med J 1980; 91:144-7.^,2626. Shannon FT, Fergusson DM, Dimond ME. Early hospital admissions and subsequent behaviour problems in 6 year olds. Arch Dis Child 1984; 59:815-9.. Those studies also showed that hospitalized infants were typically separated from their families; remained bedridden and inactive; rarely received analgesia or anaesthesia; and had prolonged hospital stays. Such studies prompted changes in the practices related to the hospitalization of infants, the most important change being that mothers are now allowed to keep their babies with them day and night (a practice known as “rooming-in”) during the immediate post-partum period, as well as being allowed to be present throughout the hospitalization of the infant ²⁷27. Davies R. Marking the 50th anniversary of the Platt Report: from exclusion, to toleration and parental participation in the care of the hospitalized child. J Child Health Care 2010; 14:6-23..

In an extensive review of the literature, we identified no studies evaluating the medium- and long-term effects that hospitalization in the first years of life has on mental health now that practices related to the hospitalization of infants have been changed. Therefore, the objective of this study was to evaluate a birth cohort in terms of the medium-term effects that hospitalization during the first 48 months of life has on the development of psychiatric disorders by the ages of 6 and 11 years.

Methods

Participants

We studied a birth cohort comprising all live births occurring between January 1 and December 31, 2004, among mothers living in the urban area of Pelotas, Rio Grande do Sul State, Brazil. Live births were identified during daily visits to the maternity wards of the five municipal hospitals. Of a total of 4,287 births, 4,231 were live births and were included in the cohort. The mothers were interviewed within the first 24h after delivery (refusal rate of less than 1%). A structured questionnaire designed to collect information related to the family, mother and child, as well as to the pregnancy and the use of health care services, was administered by trained interviewers. The children in the cohort were evaluated in their homes at 3, 12, 24 and 48 months of age, with follow-up rates > 90%. The children, together with their mothers or legal guardians, were invited to the Federal University of Pelotas School of Medicine, where a dedicated clinic had been constructed, for additional follow-up assessments at 6 and 11 years of age, the attendance rates for which were 90.2% and 86.6%, respectively. Details of the study methodology can be found in previous publications ²⁸28. Santos IS, Barros AJ, Matijasevich A, Domingues MR, Barros FC, Victora CG. Cohort profile: the 2004 Pelotas Brazil Birth Cohort Study. Int J Epidemiol 2011; 40:1461-8.^,2929. Santos IS, Barros AJ, Matijasevich A, Zanini R, Cesar MAC, Camargo-Figuera FA, et al. Cohort profile update: 2004 Pelotas (Brazil) Birth Cohort Study. Body composition, mental health and genetic assessment at the 6 years follow-up. Int J Epidemiol 2014; 43:1437-a-f..

Study outcome

Psychiatric disorders at 6 and 11 years of age were identified with the Development and Well-Being Assessment (DAWBA^{) (30}30. Goodman R, Ford T, Richards H, Gatward R, Meltzer H. The Development and Well-Being Assessment: description and initial validation of an integrated assessment of child and adolescent psychopathology. J Child Psychol Psychiatry 2000; 41:645-55.. Designed for use in individuals 5-17 years of age, the DAWBA allows psychiatric diagnoses to be made in accordance with the criteria established in the DSM-IV ³¹31. American Psychological Associaton. Diagnostic and statistical manual of mental disorder DSM-IV. 4th Ed. Washington DC: American Psychological Associaton; 1994. and the 10^th revision of the International Classification of Diseases (ICD-10^{) (32}32. World Health Organization. The ICD-10 classification of mental and behavioral disorders: diagnostic criteria for research. Geneva: World Health Organization; 1993. the latter being used in this study. Trained psychologists that administered the DAWBA assessment to the mothers or legal guardians of the evaluated children were blind to the exposures of interest.

The following DAWBA sections were applied: separation anxiety disorder; specific phobia; social phobia; generalized anxiety disorder; post-traumatic stress disorder; panic disorder and agoraphobia; obsessive compulsive disorder; attention deficit hyperactivity disorder; oppositional defiant disorder; conduct disorder; eating disorders; and tic disorders. We analyzed three types of psychiatric outcome measures: any psychiatric disorder; externalizing disorders (including oppositional defiant disorder, conduct disorder and attention deficit hyperactivity disorder); and internalizing disorders (including anxiety and depression).

Main exposure

Hospitalization in the cohort was investigated at 3, 12, 24 and 48 months. The questions posed were as follows: (at 3 and 12 months) “Has (the child) been admitted to the hospital from birth until now?”; (at 24 months) “Has (the child) been admitted to the hospital since (his/her) first birthday?”; and (at 48 months) “Has (the child) been admitted to the hospital since (his/her) second birthday?”. By aggregating the information from each of those follow-up assessments, we constructed a dichotomous (yes/no) variable characterizing the occurrence of hospitalization at any point during the first 48 months of life. The hospitalizations that occurred after hospital discharge at birth were considered. We also analyzed frequency of hospitalizations during the first 48 months of life (0, 1, 2, and ≥ 3 times). The term hospitalization is used as a synonym for “hospitalizations during the first 48 months of life”.

Potential confounding factors

Information related to the characteristics of the mother and the children were collected in the perinatal period. Family income in the month prior to the interview was a variable that was collected continuously and analyzed in quintiles (the first quintile representing the poorest 20% of the population). Maternal level of education at the time of delivery was categorized as 0-4, 5-8, 9-11 or ≥ 12 years of schooling. Maternal age at the time of delivery was categorized as < 20, 20-34 or > 34 years. The mothers were also categorized, by parity, as nulliparous, primiparous or multiparous. Maternal marital status was analyzed as a dichotomous variable, as having a partner or not (single, widowed or divorced). The skin color of the mother was categorized as white or as black/brown, as observed by the interviewer. Mothers who responded in the affirmative to the question “During the pregnancy, did you feel depressed or nervous?” were classified as having had depression during the pregnancy. Maternal smoking and alcohol consumption during pregnancy were evaluated retrospectively at the time of delivery. Women who had smoked at least one cigarette a day in any trimester of the pregnancy were classified as having smoked regularly during the pregnancy. Alcohol consumption during pregnancy was defined as ingestion of any dose of alcohol during any trimester of the pregnancy. Planned pregnancy was analyzed as a dichotomous (yes/no) variable. The type of delivery was classified as vaginal or caesarean. Neonatal birth weight was measured by hospital staff using a scale (with a precision of 10g) that was calibrated regularly by the research team. Neonates weighing less than 2,500g were classified as low-birth-weight infants. Gestational age was based on the date of the last menstrual period whenever that was consistent with the body weight, body length and head circumference at birth, according to the normal curves of those parameters for sex and gestational age ³³33. Fenton TR. A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format. BMC Pediatr 2003; 3:13.. If the date of the last menstrual period was inconsistent with those parameters or was unknown, we adopted the estimated clinical maturity of the newborn in accordance with the method described by Dubowitz et al. ³⁴34. Dubowitz LM, Dubowitz V, Goldberg C. Clinical assessment of gestational age in the newborn infant. J Pediatr 1970; 77:1-10.. Neonates born before 37 weeks of gestational age were considered preterm infants. Admission of the infant to the neonatal intensive care unit was analyzed as a dichotomous (yes/no) variable.

Statistical analysis

The χ² test was used in order to compare the occurrence of hospitalization with the distribution of the characteristics of the mothers and infants. When appropriate, we performed the χ² test for linear trend. To evaluate the association between hospitalization and psychiatric disorders at 6 and 11 years of age, we used logistic regression analysis, calculating odds ratios (OR) and 95% confidence intervals (95%CI). Using multiple logistic regression, we assessed the association between any hospitalization and frequency of hospitalizations and psychiatric disorders (any, internalizing or externalizing disorders), adjusting for the characteristics of the mothers and infants. For each outcome measure, we constructed three models: the crude analysis (Model 1); the crude analysis adjusted for the characteristics of the mothers (Model 2); and the crude analysis adjusted for the characteristics of the mothers and for the characteristics of infants (Model 3). If the significance level was below 0.20, the variable remained in the model as a potential confounder for the next level.

Ethical aspects

At each follow-up assessment, the mother or legal guardian of each child gave written informed consent. The respondents were assured that the data would remain confidential, that their participation was voluntary and that they could leave the study at any time, without consequences for the child or family. Based on the child psychiatrist’s evaluation children who needed further assessment and advice were referred to local care services available in the city. The study was approved by the Ethics Research Committee of the Federal University of Pelotas School of Medicine.

Results

Of the 4,231 individuals who comprised the original cohort, information related to hospitalization and to the development of a psychiatric disorder at 6 or 11 years of age was available for 3,132 (74%). That lack of information was found to be associated with lower family income (p < 0.001), lower maternal levels of education (p = 0.028), prematurity (p < 0.001) and low birth weight (p = 0.024).

The frequency of hospitalization was 33.1% (95%CI: 31.4; 34.7). Among the hospitalized children 25.6% (95%CI: 24.1; 27.1), 4.7% (95%CI: 4.0; 5.5) and 2.8% (95%CI95: 2.3; 3.5) were hospitalized 1, 2 or ≥ 3 times during this period, respectively.

We found that a higher frequency of hospitalization was associated with lower family income, a lower level of maternal education and lower maternal age (χ² test for linear trend p < 0.001 for all^{) (}Table 1). Hospitalization was higher among the children of mothers who had no partner, who had black or brown skin colour or who reported being depressed or smoked during pregnancy, as well as being higher among the children of mothers who were multiparous than among those of mothers who were primiparous or nulliparous. Neither planned pregnancy nor consumption of alcohol during pregnancy was associated with hospitalization.

Table 2 shows hospitalization in relation to the characteristics of the infant. The frequency of hospitalization was higher among the infants who were male, as well as among those who had low birth weight, those who had been preterm infants and those who had been admitted to the neonatal intensive care unit after birth.

Psychiatric disorders, whether externalizing or internalizing, were more common among the children who had been hospitalized than among those who had not (Figure 1). At six years of age, a greater frequency of any psychiatric disorder was observed in hospitalized children than among those classed as non-hospitalized, 15.9% (95%CI: 13.8; 18.3) and 10.8% (95%CI: 9.5; 12.2), respectively. With regard to internalization and externalization disorders, the frequency was higher among children hospitalized compared to non-hospitalized children, but this difference was not statistically significant. At 11 years, both the frequency of any psychiatric disorder (15.4%, 95%CI: 13.2; 17.7, p < 0.001) and of externalizing disorders (6.6%, 95%CI: 5.1; 8.2%, p < 0.001) and internalization (7.5%, 95%CI: 6.0; 9.3, p < 0.001) was higher in the children who had been hospitalized compared to the non-hospitalized children.

Table 3 shows the crude and adjusted analyses of the association between hospitalization (yes/no) and the development of a psychiatric disorder by 6 and 11 years of age. In the crude analysis, the chance of having any psychiatric disorder at 6 and 11 years of age was higher among children who had been hospitalized than for those who had not. After adjustment for potential confounding factors, the effect size of the association was reduced but remained statistically significant. For the association between hospitalization and the development of an internalizing disorder by 6 or 11 years of age, adjusting for the characteristics of the mothers and infants did not substantially alter the effect size observed in the crude analysis. In the crude analysis, the chance of presenting an externalizing disorder at 6 and 11 years of age was 64% and 93% higher, respectively, for the children who had been hospitalized than for those who had not. After having been adjusted for the characteristics of the mothers and infants, the association between hospitalization and the development of an externalizing disorder at 6 years of age lost its significance, although the association with the development of an externalizing disorder at 11 years of age remained significant.

Table 4 shows the crude and adjusted analyses of the association between the frequency of hospitalization (0, 1, 2, ≥ 3 times) and the development of a psychiatric disorder at age 6 and 11. In the crude analysis was observed a dose-response relationship between the frequency of hospitalizations and the chance of having any psychiatric, internalizing or externalizing disorder at age 6, but not at age 11. At age 6, after adjustment for potential confounding factors, the odds of having any psychiatric disorder and internalizing disorder for children with ≥ 3 hospitalizations were two times higher than among those who never hospitalized. At age 11, children that hospitalized ≥ 3 times had higher odds of having any psychiatric disorder, internalizing and externalizing disorders than those that never hospitalized.

Discussion

The results of the present study suggest that children hospitalized in the first 48 months of life are more likely to develop any psychiatric disorder, internalizing and externalizing disorders at 6 and 11 years of age than are children who were not, even after the analyses have been adjusted for a variety of characteristics related to the mothers and infants. The chance of presenting any psychiatric disorder at age 6 and 11 among children with ≥ 3 hospitalizations was almost two-times higher than among those who never hospitalized.

Some of the main determinants associated with childhood hospitalization found in the literature such as males, prematurity, low birth weight, low family income, low maternal schooling, and smoking exposure were also observed in this study ³⁵35. Matijasevich A, Cesar JA, Santos IS, Barros AJD, Dode MASO, Barros FC, et al. Hospitalizations during infancy in three population-based studies in Southern Brazil: trends and differentials. Cad Saúde Pública 2008; 24 Suppl 3:S437-43.^,3636. Caetano JRM, Bordini IAS, Puccini RF, Peres CA. Fatores associados à internação hospitalar de crianças menores de cinco anos, São Paulo, SP. Rev Saúde Pública 2002; 36:285-91.^,3737. Botelho C, Correia AL, Silva AMC, Macedo AG, Silva COS. Fatores ambientais e hospitalizações em crianças menores de cinco anos com infecção respiratória aguda. Cad Saúde Pública 2003; 19:1771-80.^,3838. Macedo SEC, Menezes AMB, Albernaz E, Post P, Knorst M. Fatores de risco para internação por doença respiratória aguda em crianças até um ano de idade. Rev Saúde Pública 2007; 41:351-8.. Birth weight and gestational age have a great influence on the child’s health status in the first years of life and are inversely associated with the risk of infectious diseases and hospitalization ³⁵35. Matijasevich A, Cesar JA, Santos IS, Barros AJD, Dode MASO, Barros FC, et al. Hospitalizations during infancy in three population-based studies in Southern Brazil: trends and differentials. Cad Saúde Pública 2008; 24 Suppl 3:S437-43.^,3636. Caetano JRM, Bordini IAS, Puccini RF, Peres CA. Fatores associados à internação hospitalar de crianças menores de cinco anos, São Paulo, SP. Rev Saúde Pública 2002; 36:285-91.^,3737. Botelho C, Correia AL, Silva AMC, Macedo AG, Silva COS. Fatores ambientais e hospitalizações em crianças menores de cinco anos com infecção respiratória aguda. Cad Saúde Pública 2003; 19:1771-80.^,3838. Macedo SEC, Menezes AMB, Albernaz E, Post P, Knorst M. Fatores de risco para internação por doença respiratória aguda em crianças até um ano de idade. Rev Saúde Pública 2007; 41:351-8.. The study by Macedo et al. ³⁸38. Macedo SEC, Menezes AMB, Albernaz E, Post P, Knorst M. Fatores de risco para internação por doença respiratória aguda em crianças até um ano de idade. Rev Saúde Pública 2007; 41:351-8. evaluated the risk factors for hospitalization due to acute respiratory disease in children up to one year of age in the four hospitals in the city of Pelotas, found that the absence or low maternal schooling, previous history of wheezing and shortness of breath, use of beak, maternal smoke, age under six months and male sex were associated with the risk of hospitalization for acute respiratory disease.

Corroborating with the findings of this study Douglas et al. ²⁰20. Douglas JW. Early hospital admissions and later disturbances of behaviour and learning. Dev Med Child Neurol 1975; 17:456-80. reported that the incidence of troublesome behavior at 13-15 years of age was significantly higher among children who had been hospitalized (≥ 7 days or on multiple occasions) before 5 years of age than among those who had not (20.6% vs. 14.7%; p < 0.01). Quinton et al. ²¹21. Quinton D, Rutter M. Early hospital admissions and later disturbances of behaviour: an attempted replication of Douglas' findings. Dev Med Child Neurol 1976; 18:447-59. found that the occurrence of behavioral problems was found to be significantly more common among children who had previously been hospitalized for ≥ 4 days than among children who had not and emotional disorders were five times more common among the children who had experienced ≥ 2 hospitalizations in the first years of life than among those who had not. Haslum ²²22. Haslum MN. Length of preschool hospitalization, multiple admissions and later educational attainment and behaviour. Child Care Health Dev 1988; 14:275-91. reported that hospitalization before 5 years of age was associated with inattentive/hyperactive behavior, as evaluated by teachers, and with antisocial, inattentive/hyperactive behavior, as evaluated by the parents (p < 0.001 for both). The children who had been hospitalized on multiple occasions had significantly worse Rutter Children’s Behaviour Questionnaire (RCBQ) scores for antisocial behaviour than those who had been hospitalized only once (β = 0.13, p < 0.02), and that the association remained significant even after adjustment for social factors, family characteristics and the length of the hospital stay(s). Youngblut et al. ²⁴24. Youngblut JM, Brooten D. Alternate child care, history of hospitalization, and preschool child behavior. Nurs Res 1999; 48:29-34. evaluated the effects that age at admission and length of hospital stay had in children 3-5 years of age. The authors found that the length of hospital stay correlated only weakly with the scores on the various Child Behaviour Checklist (CBCL) subscales (anxious/depressed, somatic, withdrawn, aggressive and delinquent), whereas age at hospitalization correlated positively with aggressive behavior.

Our findings support the hypothesis that exposure to risk factors during critical periods of growth and development increases the susceptibility to developing mental disorders in later life ¹³13. Kun D, Ben-Shlomo Y. A life course approach to chronic disease epidemioloy. 2nd Ed. Oxford: Oxford University Press; 2004.. Psychiatric disorders are multifactorial conditions, the development of which is influenced by biological, genetic, social and environmental factors. Therefore, stressful situations in early life have the potential to cause physiological and metabolic changes that increase the risk of developing psychiatric disorders in later life ⁹9. Grossman AW, Churchill JD, McKinney BC, Kodish IM, Otte SL, Greenough WT. Experience effects on brain development: possible contributions to psychopathology. J Child Psychol Psychiatry 2003; 44:33-63.^,1010. Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci 2004; 16:1412-25.^,1111. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011; 137:959-97.. Brain circuits and hormonal systems are formed and activated in early life. When a child experiences a stressor, their body attempts to regulate stress by releasing hormones, which can be a useful compensatory mechanism, although prolonged or frequent responses to stress can increase the risk of physical and mental health problems ¹⁰10. Knudsen EI. Sensitive periods in the development of the brain and behavior. J Cogn Neurosci 2004; 16:1412-25.^,1111. Miller GE, Chen E, Parker KJ. Psychological stress in childhood and susceptibility to the chronic diseases of aging: moving toward a model of behavioral and biological mechanisms. Psychol Bull 2011; 137:959-97.. In addition, a dose-response pattern was observed in the association between number of hospitalizations and a child’s internalizing disorders after adjustment for potential confounding factors. A plausible explanation for this association would be based in the classical conditional theory, where a reflexive or automatic type of stimulus could acquire the capacity to evoke a response that was originally evoked by another stimulus. According to this theory, the child could associate the neutral stimulus (hospital) with an unconditioned stimulus (physical disease - which causes unpleasant feelings) increasing negative emotional responses (fear, anxiety, sadness) during and after hospitalization. The presence of a biological gradient (dose-response relationship), one of Hill’s criteria, may suggests a causal association. However, length of hospital stay, an important variable, was not available in the present study. Some investigations have shown that the longer the hospitalization, the greater the risk for behavioral/emotional problems among children ²⁰20. Douglas JW. Early hospital admissions and later disturbances of behaviour and learning. Dev Med Child Neurol 1975; 17:456-80.^,2121. Quinton D, Rutter M. Early hospital admissions and later disturbances of behaviour: an attempted replication of Douglas' findings. Dev Med Child Neurol 1976; 18:447-59.^,2222. Haslum MN. Length of preschool hospitalization, multiple admissions and later educational attainment and behaviour. Child Care Health Dev 1988; 14:275-91.^,2323. Fahrenfort JJ, Jacobs EA, Miedema S, Schweizer AT. Signs of emotional disturbance three years after early hospitalization. J Pediatr Psychol 1996; 21:353-66.^,2424. Youngblut JM, Brooten D. Alternate child care, history of hospitalization, and preschool child behavior. Nurs Res 1999; 48:29-34.^,2525. Simons B, Bradshaw J, Silva PA. Hospital admissions during the first five years of life: a report from the Dunedin Multidisciplinary Child Development Study. N Z Med J 1980; 91:144-7.^,2626. Shannon FT, Fergusson DM, Dimond ME. Early hospital admissions and subsequent behaviour problems in 6 year olds. Arch Dis Child 1984; 59:815-9.. Future studies should address not only hospitalization/number of hospitalizations during childhood but also length of hospital stay, trying to discriminate whether the greatest risk is found only among those individuals who had prolonged hospitalizations.

Among the positive aspects of this study is its prospective longitudinal design, which involved population-based monitoring with high follow-up rates. Because this was a longitudinal study, the temporality of the association between exposure and outcome was preserved. In addition, the possibility of a recall bias was reduced because the occurrence of the exposure was investigated at various time points (at 3, 12, 24 and 48 months). Another positive aspect is that psychiatric disorders were identified through the use of a validated instrument applied by psychologists who were trained and supervised, thus ensuring the quality of the data.

Our study has certain limitations. The information about the psychiatric problems of the children was obtained solely from the mothers or legal guardians. Follow-up losses (associated with low family income, lower maternal schooling, prematurity and low birth weight) may indicate the presence of selection bias on the study, probably underestimating the effect of the association found, since the frequency of hospitalization in families with these characteristics was higher. The information regarding maternal psychological distress and maternal habits such as alcohol intake and smoking during pregnancy was collected by means of a questionnaire without a more detailed investigation or use of validated and standardized instruments. This fact could have jeopardized the correct identification of exposed mothers and the impact of these exposures on the outcome. Finally, our data pertain to a single medium-sized city and therefore might not be representative of the population of Brazil as a whole.

In conclusion, our results support the hypothesis that hospitalization in the early stages of life has a subsequent effect on the mental health of children and adolescents. This is quite relevant, given that half of all mental health problems in adulthood begin in childhood or adolescence ³⁹39. Fergusson DM, Horwood LJ, Ridder EM. Show me the child at seven: the consequences of conduct problems in childhood for psychosocial functioning in adulthood. J Child Psychol Psychiatry 2005; 46:837-49.^,4040. Fergusson DM, Horwood LJ, Ridder EM. Conduct and attentional problems in childhood and adolescence and later substance use, abuse and dependence: results of a 25-year longitudinal study. Drug Alcohol Depend 2007; 88 Suppl 1:S14-26.^,4141. Richards M, Abbot R, Collis G, Hackett P, Matthew H, Jones P, et al. Childhood mental health and life chances in post-war Britain: insights from three national birth cohort studies. http://www.centreformentalhealth.org.uk/childhood-mental-health-and-life-chances(accessed on 02/Apr/2016).
http://www.centreformentalhealth.org.uk/... . Despite the improvements in hospital practices seen in the last decade, hospitals are far from being safe and appropriate environments for children. Preventive measures such as the practice of humanized care and the qualification of health services are needed in order to minimize the negative experiences of hospitalized children. Further studies, conducted in different socioeconomic contexts, are warranted in order to confirm the consistency of the association detected here.

Acknowledgments

This article was conducted with data from the Pelotas (Brazil) birth cohort study, conducted by the Graduate Program in Epidemiology of the Federal University of Pelotas, with the support of the Brazilian Association of Public Health (Abrasco). From 2009 to 2013, the 2004 birth cohort was funded by the Wellcome Trust. Previous phases of the study were funded by the World Health Organization, Program of Support to Nucleus of Excellence (PRONEX), Brazilian National Research Council (CNPq), Ministry of Health and Pastoral of the Child. The 11-year follow-up was also funded by the São Paulo Research Foundation (FAPESP; grant number 2014/13864-6).

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