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1 GESTATIONAL LENGTH, BIRTH WEIGHT AND LATER RISK FOR DEPRESSION Valentin Matei 1, Carmen Udrea 1 1 MD Psychiatrist, Clinical Hospital of Psychiatry Prof dr Al. Obregia, Bucharest. Contact Received April 14, 2011, Revised July 08, 2011, Accepted July 28, 2011.

2 Abstract: Background: There is already numerous data in literature suggesting an association between low birth weight, shorter gestational age and increased risk for later depression but the results of these studies are mixed. An association between these factors may be mediated by increased exposure to corticotrophin releasing hormone. Objective: The objective of this study is to assess correlations between low birth weight, shorter gestational age and later risk for depression in adulthood (at 26 years). Methods: This study builds on the 1970 British Cohort Study (BCS70). Data was collected at birth and age 26. Results: By using the chi-square method to compare the group of people with early gestational age with the group of people with normal gestational age, there is an increased risk for later depression in people with an early gestational age (p=0.047) with OR= The risk remains statistically significant (p=0.042) after controlling (logistic regression) for potential confounders (birth weight, parental socio-economic status and childhood cognitive functioning) with OR = There are statistical significant (p=0.002) differences between people who would later develop depression and people who did not, with the former having lower birth weight (t-test). However, after controlling using logistic regression for gestational length and the potential confounders, no statistically significant relationship between low birth weight and later depression was found. Conclusions: Shorter gestational age may represent a risk factor for later depression while low birth weight does not represent a risk. Key words: prenatal factors, depression. Rezumat: Introducere: Există deja date numeroase în literatură sugerând existenţa unei asocieri dintre greutatea mică la naştere, o perioadă mai scurtă a sarcinii şi creşterea riscului ulterior de depresie. Această asociere poate fi mediată prin creşterea expunerii fetale la hormonul eliberator de corticotropină. Rezultatele studiilor ce au cercetat aceste posibile asocieri sunt însă mixte. Obiectiv: Obiectivul studiului meu a fost de a cerceta dacă greutatea mai mică la naştere şi o perioadă gestaţională mai scurtă reprezintă factori de risc pentru apariţia depresiei în perioada adultă (26 ani). Metodă: Studiul meu a folosit datele obţinute în studiul de cohortă British Cohort Study 1970 (BCS70). Am analizat datele colectate la naştere şi la vârsta de 26 de ani. Rezultate: Grupul de persoane cu o perioadă gestaţională mai scurtă prezintă un risc de depresie statistic semnificativ (p=0.047) mai mare decât cei cu perioadă gestaţională normală (chi pătrat), OR=1.760.Riscul rămâne statistic semnificativ (p=0.042) după ce am controlat datele pentru alţi potenţiali factori de risc pentru depresie (greutatea la naştere, statutul socioeconomic al părinţilor, funcţionarea cognitivă în copilărie) cu ajutorul logistic regression, OR = Când am analizat datele cu ajutorul t test există diferenţe statistic semnificative (p=0.002) între cei care ulterior vor dezvolta depresie şi cei care nu vor dezvolta depresie, cei care vor dezvolta depresie fiind mai uşori la naştere. Însă după ce am analizat datele cu ajutorul logistic regression controlând datele pentru alţi potenţiali factori de risc pentru depresie nu mai există diferenţe semnificativ statistice între cele două grupuri. Concluzii: O perioadă gestaţională mai scurtă decît cea normală reprezintă un factor de risc pentru dezvoltatea depresiei în perioada adultă. Greutatea mai mică la naştere nu reprezintă însă factor de risc pentru apariţia ulterioară a depresiei. Cuvinte cheie: factori prenatali, depresie

3 INTRODUCTION Environmental factors during early-life may have a fundamental impact on the organism s later development, structure, function and lifespan. This hypothesis has long been recognized in many fields of life sciences. It has been interpreted as an evolutionarily advantageous ability to adjust an individual s metabolism and behaviour to environmental conditions that are likely to prevail during the individual s life. A review of studies on perinatal risk and later health problems suggests that exposure to stress in utero and/or early in life may increase vulnerability to subsequent normative stress and impair functions of the central nervous system (CNS) and hypothalamic pituitary adrenal (HPA) axis (1). It is hypothesized that these changes elevate the risk for both emotion regulation and physical health problems, particularly related to respiratory function (2) and cardiovascular reactivity (1). Animal studies show that chronic perinatal stress increases the risk for subsequent problems in physical health, affect and behaviour (3). Several aversive experiences in utero and in the neonatal period result in a sensitization of emotional and HPA axis responses to subsequent stress (4, 5). Human studies similarly suggest that stressful prenatal experiences, such as maternal smoking, preterm birth or low birth weight (LBW), may contribute to abnormalities in the endocrine system (6, 7). This pathway may be mediated by increased exposure to corticotrophin releasing hormone (CRH), because CRH is involved in the organization of the CNS during this sensitive period (8). Birth weight and gestational age do not represent all antenatal and perinatal predictors for a good gestational time, but may be considered proxies for a healthy gestational period and therefore may well represent a suitable start for studying gestational factors associated with the later risk of depression. There is already numerous data in the literature suggesting an association between birth weight, gestational age and later risk for depression. A relationship between lower birth weight and depression was found in a cohort of male study participants interviewed at age 68. (9) This was measured using the self-reported Geriatric Depression Scale and the Geriatric Mental State semi-structured interview. Data from this cohort does not include length of gestation, and thus it remains unclear whether this association is attributable to slower intrauterine growth or shorter length of gestation, or both. A potential role of slow intrauterine growth and lower birth rate in the manifestation of later depressive symptoms is supported by 2 studies. One included 26-year-old women (10) and the other both women and men aged 23, 33 and 42 (11). These studies measured symptoms using the self-reported Malaise Inventory. The correlation appeared however slightly weaker after adjusting for gestational length. Associations between gestational length and depression were not, however, reported in these studies. The influence of shorter gestational age was supported by a recent study in 1,371 members of the Helsinki Birth Cohort. This study showed an association between shorter gestational age and increased depressive symptoms as assessed by the Beck Depression Inventory (administered twice) and Center for Epidemiological Studies Depression Scale (12). The effect of low birth weight on depressive symptoms showed a threshold effect, being confined to people with a birth weight below 2,500 g. These findings suggest that mechanisms linking the early environment with later-life susceptibility to depressive symptoms may include mechanisms leading to shorter duration of gestation as well as those related to slower intrauterine growth.

4 The purpose of this paper is to study the connections between both duration of gestation and birth weight and the later risk at 26 years of age for depression in a cohort population British Cohort Study (BCS70). METHODS Subjects The data analysed in this paper originated from the cohort study British Cohort Study (BCS70). This study began in 1970 and originally enrolled new-born infants from England, Scotland and Wales between the 5 th and 7 th April 1970 (13, 14). This paper analysed the correlations between gestational age and birth weight and the presence or not of depression in the same individuals when they became young adults (26 years, in 1986). The British Cohort Study initially focused on the health status of new-borns but afterwards its purpose broadened to evaluate physical, educational and social development of the children enrolled. The members of the cohort were evaluated at birth (1970, N=16135), at 5 years (1975, N=13135), 10 years (1980, N=14875), 16 years (1986 N=11628), 26 years (1996, N= 9003), 30 years (2000, N = ) and 34 years (2004, N=9656). The purpose of 5 years evaluation was to assess children s health status and the educational and care system these children received. At birth the information was obtained from the nurse who overviewed the labour, from mothers and from the medical files. At age 5, data was obtained by a health visitor specifically trained for this study, from mothers (questionnaires and direct interview about socio-economic status, education, work and health status of children), children (cognitive tests), and from the children s medical files. At age 26 data was obtained by a 16 page postal questionnaire which included questions about: qualifications and skills; training; employment and earnings; unemployment and periods out of the labour market; relationships, marriage and children; housing and household; health and health-related behaviour and other. Table 1 shows the number of participants and sources of information in the BCS throughout the time frame of the research.

5 Year of evaluation 1970 (birth) 1975 (5 years) 1980 (10 years) 1986 (16 years) 1996 (26 years) Sources of Informatio n Nurses who overviewed the birth Mothers Medical files Parents Tests completed by participants Medical files Parents School Tests completed by participants Medical files Parents School Tests and interview completed by participants Medical files Questionnaire completed by participants Number Percent responders Table 1: Data about time course and information sources BCS 1970 Measure of depression At age 26, data on the severity of depressive symptoms was collected using The Malaise Inventory (15). An overall Malaise score for a cohort member is the sum across the individual variables, yielding a minimum score of 0 and a maximum of 24. A score of 8 or higher is the recommended cut-off for a depressive episode (16). This paper analyses the correlations between gestational age and birth weight at the moment of children birth (1970) and the presence or not of depression in the same children when they became young adults (26 years, in 1986). Measure of gestational age, and birth weight. Data was obtained from medical files of each newborn (1970). Statistical analysis. Two groups were created, the first one comprised of people considered as controls (overall Malaise score less or equal to 7), the second group were assumed to have depression (Malaise score of 8 or over). A further 2 groups were also created, the first one comprised of infants born at full term (37-41 weeks) or no more than 2 weeks later, and the second one comprised of children born earlier (less than 37 weeks) and therefore considered to have a shorter gestational age. The correlations between duration of gestation and the later risk of depression were initially analysed with chi-square and afterwards with logistic regression (controlling for birth weight of babies, cognitive functioning of babies at age 5 and socio-economic status of parents). Cognitive functioning in childhood (age 5) was evaluated with the English Picture Vocabulary Test (17) (EPVT). The English Picture Vocabulary Test (EPVT) is an adaptation by Brimer and Dunn of the American Peabody Picture Vocabulary Test. This represents a tool designed to estimate the vocabulary level (an excellent guide to the general mental ability of intact people and IQ) and was developed as a quick, easy-to-administer test of verbal

6 intelligence for use with children between the ages of two-and-a-half and 18 (theoretical range 0-60). The EPVT raw score is the total number of correct items occurring before the ceiling item (the final item achieved after the child made 5 consecutive mistakes). Parental educational level was used as a general indicator of parental socio-economic status. The correlations between the later risk of depression and birth weight were analysed with t-test using birth weight as a continuous variable. Then birth weight was categorised into 4 groups (group 1</=2500g, group 2= g, group= g and group 4 >3500 g). Logistic regression controlling for potentially confounders (gestational length, childhood cognitive functioning and parental SES) was used in the analysis. RESULTS Gestational age In the first group, (94.1%) of children were born at full term (37-41 weeks) or 2 weeks later (this last group comprised of 403 children considered to be born at full term)- this group is considered to have a normal gestational age. The second group (earlier gestational age - of less than 37 weeks) consisted of 744 children-5.9%. From the first group (normal gestational age) 7% (N=143) developed depression by age 26. From the second group (earlier gestational group) 11.7% (N=14) developed depression by age 26. Using chi-square to compare the risk of depression in the 2 groups, the risk of individuals that had a shorter gestational age developing depression by age 26 is significantly higher than for individuals with a normal gestation age (p=0.047): Odds ratio-or=1.760, Confidence Interval-CI 95%= Data are presented in graph % Depression 2 0 normal gestational length shorter gestational length Graph 1. Percentage of later depression in population with normal vs shorter gestational length.

7 From this data, shorter gestational length appears to be a risk factor for depression in adulthood. However, because shorter gestational length may also be associated with some other factors which could also be risk factors for later depression (such us: cognitive functioning, birth weight, parental socio-economic status), logistic regression controlling for the above variables was used. Earlier gestational age continued to represent a significant (p=0.042) risk factor for later development of depression after controlling for cognitive functioning in childhood, birth weight and parental socio-economic status. People with a shorter gestational time had an increased risk for developing depression in adulthood, with an OR =1.885 (CI 95%= ). Birth weight The mean birth weight for the entire group (N=12755) is 3747 g. The birth weight was initially analysed as a continuous variable and t test was used to compare the 2 groups (depressed versus non-depressed). The mean birth weight for the group later developing depression (N=949) was 3700 g. This was statistically significantly lower (p=0.002) than the mean birth weight (3765 g) of the second group (N=5199). The data was also analysed as a categorical variable in order to control for potential confounders. Four groups of birth weight were created: group 1</=2500g, group 2= g, group 3= g and group 4 >3500 g. Data is presented in table 2. Non-depressed age 26 N (%) Depressed Age 26 N ( %) Group (6.2) 69 (7.4) </=2500g Group (19.1) 218 (23.4) g Group (37.4) 331 (35.5) g Group (37.4) 315 (33.8) >3500 g Table 2. Number and proportion of depressed and non-depressed people in different birth weight groups Logistic regression was used to analyse the differences between the groups regarding the later risk of depression, using as a reference group the one with birth weight above 3500g. There was an increased risk for having depression in both group 1 (birth weight less than 2500 g) with OR=1.332 (CI 95%= ), p=0.05 and in group 2 (birth weight between g), with OR= (CI 95%= ) p=0.002 compared with the

8 reference group (birth weight greater than 3500g-group 4), but there were no differences between the third group (birth weight between g) with OR=1.052 (CI 95%= ), p=0.552 and the reference group. The analysis was then repeated and adjusted for potential confounders (duration of gestation, cognitive functioning in childhood and parental SES). Data is presented in table 3. OR (95% CI), unadjusted OR (95% CI), adjusted* Group ( ) p= ( ) p=0.347 Group ( ) p= ( ) p=0.876 Group ) p= ( ) p=0.814 Group 4 1 (reference group) 1 (reference group) Table 3. Risk of depression age 26 by birth weight groups, unadjusted and adjusted data *Data adjusted for length of gestation, childhood cognitive functioning and parental SES. After controlling for the above confounders, birth weight ceased to represent a statistically significant risk factor for depression (p value for trend =0.225), whilst duration of gestation continued to represent a risk factor for depression, p=0.042 with OR=1.885 and CI 95%= DISCUSSION Epidemiological findings, together with experimental work in animals, produced the concept of programming. This is a process whereby a stimulus or insult at a sensitive period of development has lasting or lifelong influence. In other words, one genotype may give rise to different phenotypes based on conditions during early development, which is referred to as developmental plasticity. The underlying causes of depression are incompletely understood. The importance of studying early origins of depression is highlighted by the developmental origin of health and disease hypothesis as well as by previous epidemiological studies. The literature data regarding the putative associations between low birth weight, shorter duration of gestation and a later risk of depression is far from being straightforward. Low birth weight has been found to be associated with self-reported depressive symptoms and clinical diagnosis of depression at varying ages (9, 10, 11). These findings are indeed in agreement with the developmental origins of health and disease hypothesis. However, challenging this hypothesis on depression, a recent study found no association between birth weight and psychiatric ward admission for depression in adult men (18). Gestational length has rarely been a focus in the previous studies either this information has not been available (9, 18) or it has been available but assigned the status of a covariable (10, 11). Gestational length was not associated with later risk for depression in Cheung s study (11). According to Raikkonen (12) the length of gestation, consistently predicted depressive symptoms later in life but birth weight showed nonlinear association with depression.

9 The results of my study show an increased risk of developing depression in people with a shorter gestational period, even after controlling for birth weight and other potential confounders (parental SES, childhood cognitive functioning). There was no evidence of an increased risk of depression in people with low birth weight after controlling for gestational length and other potential confounders (parental SES, childhood cognitive functioning). As we can see from the above examples, despite several studies supporting a link between low birth weight and/or shorter gestational time and later risk for depression this relationship is mixed. Body size at birth and gestational length may both have unique predictive powers and reflect foetal growth-related processes that are under different physiological controls. The results presented here add to this uncertainty, clearly suggesting the need for more work in order to better establish the association between low birth weight and/or gestational length and later risk of depression in order to disentangle the role of birth weight and gestational length as unique (or common) risk factors for adulthood depression. REFERENCES 1. Sanchez MM, Ladd CO, Plotsky PM. Early adverse experience as developmental risk factor for late psychopathology: evidence from rodent and primate models. Developmental Psychopathology 2001;13: Wamboldt MZ, Hewitt JK, Schmitz S et. al. Familial association between allergic disorders and depression in adult Finnish twins. American Journal of Medical Genetics (Neuropsychiatric Genetics) 2000;96: Ward AJ. Prenatal stress and childhood psychopathology. Child Psychiatry and Human Development 1991;22: Chuckley S. The neuroendocrinology of depression. British Medical Bulletin 1996; 52: Meaney MJ. Maternal care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annual Review of Neuroscience 2001;24: Wadhwa PD, Sandman CA, Garite TJ. The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system. Progress in Brain Research 2001;133: Heim C, Nemeroff CB. The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biological Psychiatry 2001;49: Sandman CA, Wadhwa PD, Chicz-DeMet A, et. al. Maternal corticotropin-releasing hormone and habituation in the human fetus. Developmental Psychobiology 1998; 34: Thompson C, Syddall H, Rodin I, Osmond C, Barker DJ. Birth weight and the risk of depressive disorder in late life. Br J Psychiatry 2001;179: Gale CR, Martyn CN. Birth weight and later risk of depression in a national birth cohort. Br J Psychiatry 2004;184: Cheung YB, Khoo KS, Karlberg J, Machin D. Association between psychological symptoms in adults and growth in early life: longitudinal follow-up study. BMJ 2002; 325: Raikkonen K, Pesonen AK, Kajantie E et al. Length of gestation and depressive symptoms at age 60 years. Br J Psychiatry 2007; 190: Butler NR, Golding J, Howlett BC. From Birth to Five: A Study of the Health and Behaviour of a National Cohort. Oxford: Pergamon, Bynner J, Butler N, Ferri E et al. The design and conduct of the surveys of the National Child Development Study and the 1970 British Cohort Study. In: CLS Cohort Studies Working Paper 1. London: Centre for Longitudinal Studies, Institute of Education, University of London, Rutter M, Tizard J, Whitmore K. Education, health and behaviour. London: Longman, Rodgers B, Pickles A, Power C et al. Validity of the Malaise Inventory in general population samples. Social Psychiatry and Psychiatric Epidemiology 1999; 34:

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