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Prenatal origins of hospitalization for personality disorders: The Helsinki Birth Cohort Study
Psychiatry Research 179 (2010) 226–230
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Prenatal origins of hospitalization for personality disorders: The Helsinki Birth Cohort Study Marius Lahti a,⁎, Katri Räikkönen a, Kristian Wahlbeck b,c, Kati Heinonen a, Tom Forsén b,d,e, Eero Kajantie b,f, Anu-Katriina Pesonen a,f, Clive Osmond g, David J.P. Barker h, Johan G. Eriksson b,e,i,j a
Department of Psychology, University of Helsinki, Helsinki, Finland National Institute for Health and Welfare, Helsinki, Finland Psychiatric Unit, Vaasa Central Hospital, Vaasa, Finland d Internal Medicine Unit; Vaasa Central Hospital, Vaasa, Finland e Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland f University of Helsinki, Hospital for Children and Adolescents, Helsinki, Finland g MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK h DOHaD Centre, University of Southampton, Southampton, UK i Vasa Central Hospital, Vaasa, Finland j Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland b c
a r t i c l e
i n f o
Article history: Received 19 January 2009 Received in revised form 3 July 2009 Accepted 27 August 2009 Keywords: Body size at birth Head circumference Head-to-length ratio Birth weight Dramatic personality disorder Placental area Fetal growth
a b s t r a c t Although a suboptimal prenatal environment has been linked with schizophrenia and depression, possible associations with personality disorders remain unclear. The aim of this study was to examine the associations of body size at birth and length of gestation with hospitalization for personality disorders in a cohort study of 6506 men and 5857 women born in Helsinki, Finland, between 1934 and 1944. International Classification of Diseases (-8, -9, -10) diagnoses of personality disorders were extracted from the national Finnish Hospital Discharge Register since 1969. 102 men and 80 women had been hospitalized due to any personality disorder. 41 men and 30 women had dramatic personality disorders. Among men, head circumference showed an inverse J-shaped, nonlinear association with hospitalization for personality disorders. Men with a small head circumference were at increased risk. Also in men, a smaller head-to-length ratio linearly predicted personality disorders. Among women, a smaller placental area predicted increased risk of hospitalization for dramatic personality disorders. Vulnerability to personality disorders may be programmed during fetal life. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction A suboptimal prenatal environment (Roseboom et al., 2006), particularly as reflected in prematurity (Lawlor et al., 2006), and in a small body size at birth (Barker, 2004; Barker et al., 2005), is independently associated with an increased risk for cardiovascular disease (Barker, 2004; Barker et al., 2005; Roseboom et al., 2006) and type 2 diabetes (Barker, 2004; Lawlor et al., 2006; Roseboom et al., 2006). Another line of evidence suggests that a suboptimal prenatal environment (Brown et al., 2000; St Clair et al., 2005), shorter length of gestation (Byrne et al., 2007; Räikkönen et al., 2007), and small body size at birth (Wahlbeck et al., 2001; Cannon et al., 2002; Nilsson et al., 2005; Räikkönen et al., 2008) may also predict the risks of schizophrenia (Wahlbeck et al., 2001; Cannon et al., 2002; Nilsson et al., 2005; St Clair et al., 2005; Byrne et al., 2007) and depression ⁎ Corresponding author. Department of Psychology, University of Helsinki, PO Box 9, FI 00014 University of Helsinki, Finland. Tel.: +358 9 19129541; fax: +358 9 19129521. E-mail address: marius.lahti@helsinki.fi (M. Lahti). 0165-1781/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2009.08.024
(Brown et al., 2000; Räikkönen et al., 2007, 2008). These findings are in line with the Developmental Origins of Health and Disease (DOHaD) hypothesis, which suggests that a suboptimal prenatal environment may permanently alter developing organ structures and function of biological systems placing an individual at increased risk for diseases in subsequent life (Barker, 2004). Personality disorders are severe mental disorders with an estimated point prevalence rate between 4.4% (Coid et al., 2006) and 9% (Samuels et al., 2002). These disorders are associated with an increased risk for cardiovascular disease (Pietrzak et al., 2007) and are predictive of allcause mortality and particularly of suicides (Neeleman, 2001). Elucidating the etiological pathways to personality disorders is thus important for public health purposes. Although the DOHaD hypothesis might also shed light on the etiology of personality disorders, not much is known about the role played by prenatal factors in the development of personality disorders. The Dutch Famine studies showed associations between prenatal famine exposure and the development of schizoid (Hoek et al., 1996) and antisocial (Neugebauer et al., 1999) personality disorders among men. In a recent study in Sweden, preterm boys born
M. Lahti et al. / Psychiatry Research 179 (2010) 226–230
small for gestational age were at increased risk of hospitalization for personality disorders (Monfils Gustafsson et al., 2009). However, neither prematurity nor being born small for gestational age by themselves exerted significant effects among either sex (Monfils Gustafsson et al., 2009). Another study found an effect of self-reported prematurity but no effect of self-reported birth weight on borderline personality disorder (Bandelow et al., 2005). Here we report the associations between birth weight, other anthropometric measurements, and length of gestation and hospitalization for personality disorders in 6506 men and 5857 women participating in the Helsinki Birth Cohort 1934–44 Study. 2. Methods 2.1. The sample The original study cohort comprised 13,345 subjects born singleton in Helsinki, Finland, at one of the two public maternity hospitals in the city. Of these, 241 subjects had either moved abroad or died before the start of Finnish Hospital Discharge Register (HDR) data collection in 1969. An additional 487 subjects had no data on socioeconomic position in childhood available, for 235 subjects gestational age could not be estimated, and 19 subjects had comorbid eccentric (cluster A) personality and schizophrenia spectrum psychotic disorders. In these 19 cases, the schizophrenia spectrum diagnosis was seen as the dominant feature. The abovementioned 982 subjects were excluded from the study. The cohort available for the analysis comprised 12,363 subjects (6506 men and 5857 women, 92.6% of the original cohort). The excluded participants were more often women (P = 0.003), shorter (P = 0.008), lighter (P = 0.03), and smaller in head circumference (P = 0.004) at birth but did not differ from the included participants in year of birth or in the prevalence of hospitalization for personality disorders. The Helsinki Birth Cohort Study has been approved by the Ethics Committee of the National Public Health Institute. 2.2. Neonatal and childhood characteristics Data on year of birth, weight, length, head circumference, placental weight, and placental diameter and the date of mother's last menstrual period were extracted from birth records. Ponderal index, a measure of thinness at birth, was calculated as weight divided by height3 (kg/m3) and head-to-length ratio was calculated to reflect the proportion of brain compared to trunk growth. Length of gestation was calculated by subtracting the date of mother's last menstrual period from the birth date of the child. Two measures of placental diameter (lesser, maximal) were recorded routinely in these maternity hospitals until 1970s. Assuming an elliptical surface, we estimated the surface area of the placenta as maximal x lesser diameter x π/4 (Roseboom et al., 1999). The size of the placental area reflects the spread of the placenta across the inner wall of the uterus. We extended our analyses from the more traditional anthropometry at birth to this indicator that has previously been associated with prenatal malnutrition (Roseboom et al., 1999). Socioeconomic position in childhood as reflected by the occupational status of the father [classified as manual workers (64.0%), lower middle class (23.5%), and upper middle class (12.5%)] was derived from school, child welfare clinic, and birth records (inferred from the last two, respectively, if data from school records was not available). 2.3. Definition of personality disorder and personality disorder clusters Diagnoses were extracted from the HDR carrying diagnosis of all hospitalizations in Finland between 1969 and 2005. The subjects were linked with the HDR using the personal identification number that has been allocated to each resident of Finland. The HDR covers all psychiatric and general hospitals in Finland and is a valid and reliable tool for research (Keskimäki and Aro, 1991). The validity of HDR diagnosis has not been studied with regard to personality disorders, but the HDR has shown good validity with regard to psychotic disorders in general (Perälä et al., 2007), and schizophrenia in particular (Mäkikyrö et al., 1998) in Finnish community samples. The former study showed that diagnoses based on the HDR are more reliable than those based on medical examination, interview- or questionnaire-based measures, when a combined bestestimate diagnosis was used as the validation criteria (Perälä et al., 2007). Diagnoses have been entered into the HDR according to the International Classification of Diseases, Eighth Revision (ICD-8) until 1986, according to ICD-9 using Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria until 1995, and according to ICD-10 since 1996. The validity of the ICD diagnostic criteria for personality disorders have been tested with regard to their reliability and to their concordance with the DSM diagnoses. Concerns have been raised about the reliability of some of the specific ICD personality disorder diagnoses (Bronisch and Mombour, 1994). However, studies on any personality disorder, our primary outcome, indicate acceptable rates of interrater and test–retest reliability for the diagnostic criteria that has been used in Finland (Bronisch and Mombour, 1994; Muhs and Ori, 1995). With regard to diagnostic concordance, for the ICD-10 and DSMIV diagnoses a concordance value of kappa 0.78 indicating high agreement was reported for any personality disorder as outcome (Starcevic et al., 1997). The ICD-9 version used in Finland and DSM-III-R had the same criteria for personality disorders.
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In the current study, the primary and subsidiary diagnoses of specific, unspecific, and mixed personality disorders were used as indexing personality disorder. We identified personality disorders from the HDR with the following diagnostic codes; 2955, 3010, and 3012–3019 (from ICD-8); 3010, 3012–3014, 3015A, 3016–3019 (from ICD-8 and ICD-9); F21, F60, and F61 (from ICD-10). More specifically, we identified eccentric personality disorders as schizoid (301.2 (ICD-8); 3012A (ICD-9); F60.1 (ICD10)), schizotypal (295.5 (ICD-8); 3012C (ICD -9), F21 (ICD-10)), and paranoid (301.0 (ICD -8,-9); F60.0 (ICD-10)) personality disorders; dramatic personality disorders as dissocial (antisocial) (301.7 (ICD-8, -9); F60.2 (ICD-10)), emotionally unstable (borderline) (301.3; 301.88 (ICD -8); 3018D (ICD-9); F60.3 (ICD-10)), narcissistic (301.8B (ICD -9)), and histrionic (301.5 (ICD-8); 3015A (ICD-9); F60.4 (ICD-10)) personality disorders; and fearful personality disorders as anankastic (obsessive– compulsive) (301.4 (ICD-8, -9); F60.5 (ICD-10)), avoidant (301.8C (ICD-9) F60.6 (ICD10)), and dependent (301.6 (ICD-8, -9); F60.7 (ICD-10)) personality disorders. Furthermore, we identified the diagnoses of schizophrenia, schizoaffective, and persistent delusional disorder (used as exclusion criteria when concurrent with eccentric personality disorders) with the ICD 8 and 9 codes 2950–2954, 2956–2959 and 297 and with ICD-10 codes F20, F22, F24 and F25. Although not in the international manuals, all physicians and psychiatrists in Finland were instructed to use the code 301.88 to index borderline personality disorder at time when the ICD8-codes were in use. The code 3018E was used for passive– aggressive personality disorder, which is no longer categorized as a specific personality disorder. Cases with a diagnosis of an unspecific or a mixed personality disorder (301.80 and 301.99 from ICD8; 301.8X and 3018E from ICD-9; and F60.8, F60.9, F61 from ICD-10) were included in the analysis concerning all personality disorders but excluded from the cluster-specific analyses (n = 78). Cases with such a diagnosis together with a cluster-specific diagnosis were included in the cluster groups. In contrast, subjects with diagnoses of two or three separate clusters were excluded from the cluster-specific analyses (n = 7). A total of 182 subjects (1.5% of the sample; 102 men and 80 women) had been hospitalized with a diagnosis of personality disorder. More specifically, 14 subjects (0.1%; 11 men and 3 women) had eccentric, 71 had dramatic (0.6%; 41 men and 30 women), and 12 had fearful personality disorders (0.1%; 4 men and 8 women). Because of the low number of subjects with eccentric and fearful personality disorders, clusterspecific analyses were restricted to dramatic personality disorders. 2.4. Statistical analysis T- and χ2 -tests and univariate analysis of variance were used to compare study variables according to sex, socioeconomic position in childhood, and/or year of birth. We used logistic regression analyses instead of Cox models (participants were young adults when the HDR data collection was started and the date indicated in the HDR might not have been their first hospital admission), to study the effects of weight and other anthropometric measurements at birth, and length of gestation on hospitalization for personality disorders and specifically for dramatic personality disorders. All associations were adjusted for sex, socioeconomic position in childhood, and year of birth, and weight and other anthropometric measurements at birth also for length of gestation. We also ran the analysis separately by sex. All neonatal characteristics were converted to z scores by sex (Royston, 1991). A z score represents the difference from the mean value for all the girls and all the boys participating in the Helsinki Birth Cohort 1934–44 study, and is expressed as standard deviations. Some studies have shown that the associations between body size at birth and psychopathology may be nonlinear (Cheung 2002; Gunnell et al., 2003). We also examined the potential nonlinearity of the effects. Nonlinear effects (squared terms) were tested in the presence of linear ones.
3. Results Table 1 presents the neonatal characteristics of the sample for men and women separately. Men differed from women in neonatal characteristics in the predicted direction. Socioeconomic position in childhood was not associated with weight or the other anthropometric Table 1 The neonatal characteristics of the sample. Men
Women
Neonatal characteristic
N
Mean (S.D.)
Birth weight (g) Length at birth (cm) Ponderal index (kg/m3) Head circumference (cm) Length of gestation (days) Head circumference/length-ratio (cm/cm) Placental weight (kg) Placental area (cm2)
6506 3469.3 (486.4) 6457 50.6 (1.9) 6457 26.7 (2.2) 6447 35.3 (1.5) 6506 278.9 (14.4) 6418 0.70 (0.03)
5857 3343.0 (459.1) 5803 49.9 (1.8) 5803 26.8 (2.2) 5796 34.7 (1.4) 5857 279.7 (13.7) 5757 0.69 (0.03)
6488 6464
5849 5833
0.65 (0.12) 261.7 (55.7)
N
Mean (S.D.)
0.64 (0.12) 258.8 (54.1)
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Fig. 1. The association between head circumference at birth and personality disorders in adulthood. The bars represent odds ratios for personality disorders for three groups defined by head-circumference z-scores: z < − 1; −1 ≤ z ≤ 1; and z > 1. The odds ratios are adjusted for sex, socioeconomic position of childhood, year of birth, and length of gestation. The error bars represent 95% confidence intervals.
measurements or with length of gestation (P-values ≥ 0.12). The number of participants hospitalized due to personality disorders or due to dramatic personality disorders did not differ by sex, socioeconomic position in childhood, or by year of birth (P-values≥ 0.07). 3.1. Neonatal characteristics and hospitalization for personality disorders and for dramatic personality disorders Analyses of nonlinear effects showed a significant, inverse J-shaped effect of head circumference at birth on hospitalization for personality disorders (P = 0.005). Participants with a smaller head circumference
(z < −1 S.D.) were at a 1.64-fold (95% confidence interval (CI)= 1.11 to 2.41, P = 0.01) risk of hospitalization for personality disorders compared with those with a medium size head circumference (−1 S.D. ≤z ≤ 1 S. D.) (Fig. 1). Those with a larger head circumference (z > 1 S.D.) did not differ in their risk from the ones with a medium size head circumference (Odds ratio (OR) for those with a larger head circumference = 1.14, 95% CI= 0.74–1.75, P = 0.55). The nonlinear pattern (P = 0.01 for nonlinearity) was more pronounced among men (Table 2). For those men with a smaller head circumference, the risk of hospitalization for personality disorders was 1.83-fold (95% CI = 1.06 to 3.14, P = 0.03) compared with those men with a medium size head circumference. Also among men, a smaller head-to-length ratio at birth showed a linear association with a 1.26-fold increased risk of hospitalization for personality disorders (Table 2). Of the predictors available, the surface area of the placenta was the only significant predictor of hospitalization for dramatic personality disorders. A smaller placental area (OR = 1.32, 95% CI = 1.03 to 1.69, P = 0.03) linearly predicted dramatic personality disorders. This effect was significant among women (P = 0.05) (Table 3). Weight, length, ponderal index, placental weight, and length of gestation were not significantly associated with hospitalization for personality disorders or for dramatic personality disorders.
4. Discussion We studied the effects of body size at birth and length of gestation on hospitalization for personality disorders in general and for dramatic personality disorders in particular. Men with a small head circumference at birth were at increased risk of hospitalization for personality disorders compared with men with a medium size head circumference. Also a small head-tolength ratio predicted an increased risk of personality disorders
Table 2 Neonatal characteristics and personality disorders: linear and curvilinear (quadratic) effects. Men Neonatal characteristic c
Birth weight Length at birthc Ponderal indexc Head circumferencec Length of gestationd Head circumference/length-ratioc Placental weightc Placental areac a b c d
Women a
Odds ratio (95% CI)
P linear
0.98 0.88 1.14 1.12 1.08 1.26 0.86 0.92
0.88 0.25 0.20 0.27 0.45 0.02 0.14 0.40
(0.79–1.22) (0.71–1.09) (0.93–1.40) (0.91–1.38) (0.89–1.31) (1.03–1.52) (0.71–1.05) (0.76–1.12)
b
P quadratic
Odds ratioa (95% CI)
p linearb
p quadratic
0.47 0.32 0.71 0.01 0.97 0.31 0.32 0.20
1.00 1.13 0.89 1.14 1.09 1.01 1.07 1.12
1.00 0.32 0.29 0.27 0.42 0.90 0.56 0.35
0.84 0.72 1.00 0.12 0.70 0.26 0.14 0.52
(0.79–1.27) (0.89–1.42) (0.71–1.11) (0.90–1.44) (0.88–1.36) (0.81–1.27) (0.85–1.35) (0.89–1.40)
Odds ratios and 95% confidence intervals (CIs) for each standard deviation (S.D.) unit decrease in these variables. The linear P-values are from analyses examining only linear effects and are not adjusted for the quadratic terms. Adjusted for gestational age, childhood SES, and year of birth. Adjusted for childhood SES and year of birth.
Table 3 Neonatal characteristics and dramatic personality disorders: linear and curvilinear (quadratic) effects. Men Neonatal characteristic c
Birth weight Length at birthc Ponderal indexc Head circumferencec Length of gestationd Head circumference/length -ratioc Placental weightc Placental areac a b c d
Women
Odds ratio (95% CI)a
P linearb
P quadratic
Odds ratioa (95% CI)
P linearb
P quadratic
1.10 1.04 1.11 1.25 1.14 1.23 0.97 1.21
0.59 0.81 0.52 0.17 0.36 0.18 0.83 0.25
0.71 0.84 0.57 0.57 0.49 0.19 0.90 0.86
1.00 1.09 0.88 1.17 1.09 1.09 1.13 1.48
0.99 0.66 0.50 0.43 0.65 0.62 0.52 0.048
0.06 0.053 0.30 0.48 0.17 0.83 0.29 0.53
(0.78–1.54) (0.75–1.45) (0.81–1.53) (0.91–1.72) (0.86–1.53) (0.91–1.67) (0.71–1.33) (0.88–1.67)
Odds ratios and 95% confidence intervals (CIs) for each S.D. unit decrease in these variables. The linear P-values are from analyses examining only linear effects and are not adjusted for the quadratic terms. Adjusted for gestational age, childhood SES, year of birth. Adjusted for childhood SES and year of birth.
(0.68–1.48) (0.74–1.60) (0.61–1.27) (0.80–1.71) (0.76–1.56) (0.76–1.57) (0.77–1.66) (1.00–2.18)
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among men. Hospitalization for dramatic personality disorders, by contrast, was associated with placental size among women, for whom a smaller placental area was associated with an increased risk. All these effects were independent of socioeconomic position in childhood, year of birth, and length of gestation. To our knowledge, this is the first study to show that a smaller head circumference and a smaller head-to-length ratio at birth predict an increased risk of hospitalization for personality disorders among men. Previously, similar findings have been found for schizophrenia (Nilsson et al., 2005), though a meta-analysis concluded the effect to be of borderline significance (Cannon et al., 2002). The specificity of the effect is thus of question and further studies should examine whether small head size at birth is a general predisposing factor for psychopathology or does it predispose specifically to personality disorders. Furthermore, links between small head circumference at 1 year of age and violent offending in adulthood have been described (Ikäheimo et al., 2007). Although we found effects of fetal brain growth on personality disorders in general, these previous findings show resemblance to ours as they suggest reduced brain growth either prenatally or during infancy in offenders, among whom personality disorders, especially antisocial, are highly prevalent (Elonheimo et al., 2007; Zoccali et al., 2008). We found no effect of birth weight, birth length, or length of gestation on hospitalization for personality disorders. Resembling these findings, in a recent Swedish study neither prematurity nor being born small for gestational age by themselves predicted hospitalization for personality disorders among either sex (Monfils Gustafsson et al., 2009). However, in preterm boys, those who were born small for gestational age were at significantly increased risk compared with appropriate for gestational age-sized controls. Whereas Monfils Gustafsson et al. (2009) examined the role of the lowest extremes of birth weight and length of gestation in personality disorders, we studied the effects of these factors across their whole range of variation. Furthermore, the two studies examined personality disorders at different ages. The diagnoses in our study were identified throughout the adulthood life course between the years 1969 and 2004 when the subjects of our cohort ranged between 24 and 70 years of age, whereas in the Swedish study the diagnoses were given between 12 and 21 years of age (Monfils Gustafsson et al., 2009). An earlier study found an effect of preterm birth on borderline personality disorder (Bandelow et al., 2005). However, the independence of this effect from confounders was not tested for and the study used indices dependent on the subjects' own recall (Bandelow et al., 2005). In line with the results of Monfils Gustafsson et al. (2009), we found no effects of prenatal factors on hospitalization for any personality disorder among women. However, we found that a smaller placental area was associated with an increased risk of hospitalization for dramatic personality disorders among women. To our knowledge, the size of the placental area has not previously been studied with regard to psychiatric disorders. Mechanisms underlying the associations between small head circumference and small head-to-length ratio and hospitalization for personality disorders remain unidentified. However, head circumference is strongly associated with brain volume (Lindley et al., 1999), and reduced brain size can be seen as reflecting attenuated fetal brain growth. The smaller head-to-length ratio indicates reduced brain growth also in comparison to trunk growth. A number of prenatal factors such as malnutrition (Stein et al., 2004) and maternal psychological distress (Seckl, 2008) induce alterations in brain growth. These factors are also associated with changes in HPA axis glucocorticoid functioning (Seckl, 2008), which is also associated with head circumference at birth (Power et al., 2006). Abnormalities in HPA axis functioning have been described in personality disorders (Rosmond et al.,
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1999). Prenatal programming of glucocorticoid functioning may thus be hypothesized as a possible neurobiological mechanism contributing to the association between reduced fetal brain growth and hospitalization for personality disorders. As an alternative explanation for our findings, genetic factors could influence fetal growth as well as predispose to personality disorders. Genetic effects have been shown on both head circumference at birth (Lunde et al., 2007) and on personality disorders of all clusters (Torgersen et al., 2000). However, a twin study on schizophrenia suggested that fetal growth effects are at least partially independent of genetic effects (Nilsson et al., 2005), arguing for a causal role of conditions during fetal life. Moreover, the mechanisms underlying the association between smaller placental area and hospitalization for dramatic personality disorders are largely unknown. Placental area correlated positively with body size at birth in our sample (data not shown), and a small placental area has previously been found in fetal growth restriction (Biswas and Ghosh, 2008). Hence, factors associated with fetal growth restriction might also underlie changes in the size of the placenta, and, indeed, a smaller placental area has been associated with malnutrition during pregnancy (Roseboom et al., 1999). Although a novel finding, the smaller placental area found in dramatic personality disorders calls for further research to confirm the finding and to study its specificity. The strengths of our study include the large sample of participants derived from a general population, the use of birth register data to index body size at birth, and the longitudinal study design. There are also limitations to our study. One of these is the small number of subjects identified with personality disorder. Only 1.5% of our subjects had received personality disorder diagnoses. The low number of patients might have led to sample-specific findings and the findings need to be confirmed in further studies. However, the percentage of subjects with personality disorders is comparable to another recent study where hospitalization for personality disorders was also the outcome (Monfils Gustafsson et al., 2009). We concentrated on the patient categories with a larger number of patients in order to detect meaningful associations, which led to an emphasis on dramatic and any personality disorder as the outcomes. We could not study the specific effects on eccentric and fearful personality disorders. This restricts the generalizability of our findings. More studies are needed to target the other disorder clusters and the more specific diagnostic groups. Our diagnoses were based on hospital records and not all people with personality disorders require hospitalization. This suggests that the patients in our study had severe disorders where hospitalization was required and our results may not be generalized to less severe personality disorders not in need of hospital treatment. Changes in diagnostic criteria over time might also have introduced some heterogeneity to the diagnostic groups. Furthermore, since ultrasound measurements were not available in 1934–44, we calculated length of gestation based on maternal self-reports of last menstruation date. Hence, these values contain some inaccuracy. However, body size at birth and length of gestation correlate as expected in our sample (data not shown). Besides, length of gestation was calculated similarly for each subject. It is thus unlikely that this inaccuracy would have influenced our main findings, which were independent of length of gestation. To conclude, the results of this large cohort study on the prenatal origins of hospitalization for personality disorders in adulthood suggest that reduced fetal brain growth predisposes men to personality disorders and a smaller placental area is associated specifically with hospitalization for dramatic personality disorders among women. Although the mechanisms underlying these associations remain largely unidentified, the findings highlight the importance of factors operating during prenatal development in the etiology of personality disorders.
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Acknowledgment This study was supported by grants from Emil Aaltonen Foundation, Helsinki University's Research Funds, the Academy of Finland, the British Heart Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Diabetes Research Foundation, the Finnish Medical Society (Duodecim), Finska Läkaresällskapet, the Päivikki and Sakari Sohlberg Foundation, the Juho Vainio Foundation, the Yrjö Jahnsson Foundation, the Signe and Ane Gyllenberg Foundation, and the Finnish Foundation for Pediatric Research. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Furthermore, the authors would like to thank the staff at National Institute for Health and Welfare and at University of Helsinki, Department of Psychology for their assistance with the article.
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Psychiatry Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p s yc h r e s
Prenatal origins of hospitalization for personality disorders: The Helsinki Birth Cohort Study Marius Lahti a,⁎, Katri Räikkönen a, Kristian Wahlbeck b,c, Kati Heinonen a, Tom Forsén b,d,e, Eero Kajantie b,f, Anu-Katriina Pesonen a,f, Clive Osmond g, David J.P. Barker h, Johan G. Eriksson b,e,i,j a
Department of Psychology, University of Helsinki, Helsinki, Finland National Institute for Health and Welfare, Helsinki, Finland Psychiatric Unit, Vaasa Central Hospital, Vaasa, Finland d Internal Medicine Unit; Vaasa Central Hospital, Vaasa, Finland e Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland f University of Helsinki, Hospital for Children and Adolescents, Helsinki, Finland g MRC Epidemiology Resource Centre, University of Southampton, Southampton, UK h DOHaD Centre, University of Southampton, Southampton, UK i Vasa Central Hospital, Vaasa, Finland j Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland b c
a r t i c l e
i n f o
Article history: Received 19 January 2009 Received in revised form 3 July 2009 Accepted 27 August 2009 Keywords: Body size at birth Head circumference Head-to-length ratio Birth weight Dramatic personality disorder Placental area Fetal growth
a b s t r a c t Although a suboptimal prenatal environment has been linked with schizophrenia and depression, possible associations with personality disorders remain unclear. The aim of this study was to examine the associations of body size at birth and length of gestation with hospitalization for personality disorders in a cohort study of 6506 men and 5857 women born in Helsinki, Finland, between 1934 and 1944. International Classification of Diseases (-8, -9, -10) diagnoses of personality disorders were extracted from the national Finnish Hospital Discharge Register since 1969. 102 men and 80 women had been hospitalized due to any personality disorder. 41 men and 30 women had dramatic personality disorders. Among men, head circumference showed an inverse J-shaped, nonlinear association with hospitalization for personality disorders. Men with a small head circumference were at increased risk. Also in men, a smaller head-to-length ratio linearly predicted personality disorders. Among women, a smaller placental area predicted increased risk of hospitalization for dramatic personality disorders. Vulnerability to personality disorders may be programmed during fetal life. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction A suboptimal prenatal environment (Roseboom et al., 2006), particularly as reflected in prematurity (Lawlor et al., 2006), and in a small body size at birth (Barker, 2004; Barker et al., 2005), is independently associated with an increased risk for cardiovascular disease (Barker, 2004; Barker et al., 2005; Roseboom et al., 2006) and type 2 diabetes (Barker, 2004; Lawlor et al., 2006; Roseboom et al., 2006). Another line of evidence suggests that a suboptimal prenatal environment (Brown et al., 2000; St Clair et al., 2005), shorter length of gestation (Byrne et al., 2007; Räikkönen et al., 2007), and small body size at birth (Wahlbeck et al., 2001; Cannon et al., 2002; Nilsson et al., 2005; Räikkönen et al., 2008) may also predict the risks of schizophrenia (Wahlbeck et al., 2001; Cannon et al., 2002; Nilsson et al., 2005; St Clair et al., 2005; Byrne et al., 2007) and depression ⁎ Corresponding author. Department of Psychology, University of Helsinki, PO Box 9, FI 00014 University of Helsinki, Finland. Tel.: +358 9 19129541; fax: +358 9 19129521. E-mail address: marius.lahti@helsinki.fi (M. Lahti). 0165-1781/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2009.08.024
(Brown et al., 2000; Räikkönen et al., 2007, 2008). These findings are in line with the Developmental Origins of Health and Disease (DOHaD) hypothesis, which suggests that a suboptimal prenatal environment may permanently alter developing organ structures and function of biological systems placing an individual at increased risk for diseases in subsequent life (Barker, 2004). Personality disorders are severe mental disorders with an estimated point prevalence rate between 4.4% (Coid et al., 2006) and 9% (Samuels et al., 2002). These disorders are associated with an increased risk for cardiovascular disease (Pietrzak et al., 2007) and are predictive of allcause mortality and particularly of suicides (Neeleman, 2001). Elucidating the etiological pathways to personality disorders is thus important for public health purposes. Although the DOHaD hypothesis might also shed light on the etiology of personality disorders, not much is known about the role played by prenatal factors in the development of personality disorders. The Dutch Famine studies showed associations between prenatal famine exposure and the development of schizoid (Hoek et al., 1996) and antisocial (Neugebauer et al., 1999) personality disorders among men. In a recent study in Sweden, preterm boys born
M. Lahti et al. / Psychiatry Research 179 (2010) 226–230
small for gestational age were at increased risk of hospitalization for personality disorders (Monfils Gustafsson et al., 2009). However, neither prematurity nor being born small for gestational age by themselves exerted significant effects among either sex (Monfils Gustafsson et al., 2009). Another study found an effect of self-reported prematurity but no effect of self-reported birth weight on borderline personality disorder (Bandelow et al., 2005). Here we report the associations between birth weight, other anthropometric measurements, and length of gestation and hospitalization for personality disorders in 6506 men and 5857 women participating in the Helsinki Birth Cohort 1934–44 Study. 2. Methods 2.1. The sample The original study cohort comprised 13,345 subjects born singleton in Helsinki, Finland, at one of the two public maternity hospitals in the city. Of these, 241 subjects had either moved abroad or died before the start of Finnish Hospital Discharge Register (HDR) data collection in 1969. An additional 487 subjects had no data on socioeconomic position in childhood available, for 235 subjects gestational age could not be estimated, and 19 subjects had comorbid eccentric (cluster A) personality and schizophrenia spectrum psychotic disorders. In these 19 cases, the schizophrenia spectrum diagnosis was seen as the dominant feature. The abovementioned 982 subjects were excluded from the study. The cohort available for the analysis comprised 12,363 subjects (6506 men and 5857 women, 92.6% of the original cohort). The excluded participants were more often women (P = 0.003), shorter (P = 0.008), lighter (P = 0.03), and smaller in head circumference (P = 0.004) at birth but did not differ from the included participants in year of birth or in the prevalence of hospitalization for personality disorders. The Helsinki Birth Cohort Study has been approved by the Ethics Committee of the National Public Health Institute. 2.2. Neonatal and childhood characteristics Data on year of birth, weight, length, head circumference, placental weight, and placental diameter and the date of mother's last menstrual period were extracted from birth records. Ponderal index, a measure of thinness at birth, was calculated as weight divided by height3 (kg/m3) and head-to-length ratio was calculated to reflect the proportion of brain compared to trunk growth. Length of gestation was calculated by subtracting the date of mother's last menstrual period from the birth date of the child. Two measures of placental diameter (lesser, maximal) were recorded routinely in these maternity hospitals until 1970s. Assuming an elliptical surface, we estimated the surface area of the placenta as maximal x lesser diameter x π/4 (Roseboom et al., 1999). The size of the placental area reflects the spread of the placenta across the inner wall of the uterus. We extended our analyses from the more traditional anthropometry at birth to this indicator that has previously been associated with prenatal malnutrition (Roseboom et al., 1999). Socioeconomic position in childhood as reflected by the occupational status of the father [classified as manual workers (64.0%), lower middle class (23.5%), and upper middle class (12.5%)] was derived from school, child welfare clinic, and birth records (inferred from the last two, respectively, if data from school records was not available). 2.3. Definition of personality disorder and personality disorder clusters Diagnoses were extracted from the HDR carrying diagnosis of all hospitalizations in Finland between 1969 and 2005. The subjects were linked with the HDR using the personal identification number that has been allocated to each resident of Finland. The HDR covers all psychiatric and general hospitals in Finland and is a valid and reliable tool for research (Keskimäki and Aro, 1991). The validity of HDR diagnosis has not been studied with regard to personality disorders, but the HDR has shown good validity with regard to psychotic disorders in general (Perälä et al., 2007), and schizophrenia in particular (Mäkikyrö et al., 1998) in Finnish community samples. The former study showed that diagnoses based on the HDR are more reliable than those based on medical examination, interview- or questionnaire-based measures, when a combined bestestimate diagnosis was used as the validation criteria (Perälä et al., 2007). Diagnoses have been entered into the HDR according to the International Classification of Diseases, Eighth Revision (ICD-8) until 1986, according to ICD-9 using Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria until 1995, and according to ICD-10 since 1996. The validity of the ICD diagnostic criteria for personality disorders have been tested with regard to their reliability and to their concordance with the DSM diagnoses. Concerns have been raised about the reliability of some of the specific ICD personality disorder diagnoses (Bronisch and Mombour, 1994). However, studies on any personality disorder, our primary outcome, indicate acceptable rates of interrater and test–retest reliability for the diagnostic criteria that has been used in Finland (Bronisch and Mombour, 1994; Muhs and Ori, 1995). With regard to diagnostic concordance, for the ICD-10 and DSMIV diagnoses a concordance value of kappa 0.78 indicating high agreement was reported for any personality disorder as outcome (Starcevic et al., 1997). The ICD-9 version used in Finland and DSM-III-R had the same criteria for personality disorders.
227
In the current study, the primary and subsidiary diagnoses of specific, unspecific, and mixed personality disorders were used as indexing personality disorder. We identified personality disorders from the HDR with the following diagnostic codes; 2955, 3010, and 3012–3019 (from ICD-8); 3010, 3012–3014, 3015A, 3016–3019 (from ICD-8 and ICD-9); F21, F60, and F61 (from ICD-10). More specifically, we identified eccentric personality disorders as schizoid (301.2 (ICD-8); 3012A (ICD-9); F60.1 (ICD10)), schizotypal (295.5 (ICD-8); 3012C (ICD -9), F21 (ICD-10)), and paranoid (301.0 (ICD -8,-9); F60.0 (ICD-10)) personality disorders; dramatic personality disorders as dissocial (antisocial) (301.7 (ICD-8, -9); F60.2 (ICD-10)), emotionally unstable (borderline) (301.3; 301.88 (ICD -8); 3018D (ICD-9); F60.3 (ICD-10)), narcissistic (301.8B (ICD -9)), and histrionic (301.5 (ICD-8); 3015A (ICD-9); F60.4 (ICD-10)) personality disorders; and fearful personality disorders as anankastic (obsessive– compulsive) (301.4 (ICD-8, -9); F60.5 (ICD-10)), avoidant (301.8C (ICD-9) F60.6 (ICD10)), and dependent (301.6 (ICD-8, -9); F60.7 (ICD-10)) personality disorders. Furthermore, we identified the diagnoses of schizophrenia, schizoaffective, and persistent delusional disorder (used as exclusion criteria when concurrent with eccentric personality disorders) with the ICD 8 and 9 codes 2950–2954, 2956–2959 and 297 and with ICD-10 codes F20, F22, F24 and F25. Although not in the international manuals, all physicians and psychiatrists in Finland were instructed to use the code 301.88 to index borderline personality disorder at time when the ICD8-codes were in use. The code 3018E was used for passive– aggressive personality disorder, which is no longer categorized as a specific personality disorder. Cases with a diagnosis of an unspecific or a mixed personality disorder (301.80 and 301.99 from ICD8; 301.8X and 3018E from ICD-9; and F60.8, F60.9, F61 from ICD-10) were included in the analysis concerning all personality disorders but excluded from the cluster-specific analyses (n = 78). Cases with such a diagnosis together with a cluster-specific diagnosis were included in the cluster groups. In contrast, subjects with diagnoses of two or three separate clusters were excluded from the cluster-specific analyses (n = 7). A total of 182 subjects (1.5% of the sample; 102 men and 80 women) had been hospitalized with a diagnosis of personality disorder. More specifically, 14 subjects (0.1%; 11 men and 3 women) had eccentric, 71 had dramatic (0.6%; 41 men and 30 women), and 12 had fearful personality disorders (0.1%; 4 men and 8 women). Because of the low number of subjects with eccentric and fearful personality disorders, clusterspecific analyses were restricted to dramatic personality disorders. 2.4. Statistical analysis T- and χ2 -tests and univariate analysis of variance were used to compare study variables according to sex, socioeconomic position in childhood, and/or year of birth. We used logistic regression analyses instead of Cox models (participants were young adults when the HDR data collection was started and the date indicated in the HDR might not have been their first hospital admission), to study the effects of weight and other anthropometric measurements at birth, and length of gestation on hospitalization for personality disorders and specifically for dramatic personality disorders. All associations were adjusted for sex, socioeconomic position in childhood, and year of birth, and weight and other anthropometric measurements at birth also for length of gestation. We also ran the analysis separately by sex. All neonatal characteristics were converted to z scores by sex (Royston, 1991). A z score represents the difference from the mean value for all the girls and all the boys participating in the Helsinki Birth Cohort 1934–44 study, and is expressed as standard deviations. Some studies have shown that the associations between body size at birth and psychopathology may be nonlinear (Cheung 2002; Gunnell et al., 2003). We also examined the potential nonlinearity of the effects. Nonlinear effects (squared terms) were tested in the presence of linear ones.
3. Results Table 1 presents the neonatal characteristics of the sample for men and women separately. Men differed from women in neonatal characteristics in the predicted direction. Socioeconomic position in childhood was not associated with weight or the other anthropometric Table 1 The neonatal characteristics of the sample. Men
Women
Neonatal characteristic
N
Mean (S.D.)
Birth weight (g) Length at birth (cm) Ponderal index (kg/m3) Head circumference (cm) Length of gestation (days) Head circumference/length-ratio (cm/cm) Placental weight (kg) Placental area (cm2)
6506 3469.3 (486.4) 6457 50.6 (1.9) 6457 26.7 (2.2) 6447 35.3 (1.5) 6506 278.9 (14.4) 6418 0.70 (0.03)
5857 3343.0 (459.1) 5803 49.9 (1.8) 5803 26.8 (2.2) 5796 34.7 (1.4) 5857 279.7 (13.7) 5757 0.69 (0.03)
6488 6464
5849 5833
0.65 (0.12) 261.7 (55.7)
N
Mean (S.D.)
0.64 (0.12) 258.8 (54.1)
228
M. Lahti et al. / Psychiatry Research 179 (2010) 226–230
Fig. 1. The association between head circumference at birth and personality disorders in adulthood. The bars represent odds ratios for personality disorders for three groups defined by head-circumference z-scores: z < − 1; −1 ≤ z ≤ 1; and z > 1. The odds ratios are adjusted for sex, socioeconomic position of childhood, year of birth, and length of gestation. The error bars represent 95% confidence intervals.
measurements or with length of gestation (P-values ≥ 0.12). The number of participants hospitalized due to personality disorders or due to dramatic personality disorders did not differ by sex, socioeconomic position in childhood, or by year of birth (P-values≥ 0.07). 3.1. Neonatal characteristics and hospitalization for personality disorders and for dramatic personality disorders Analyses of nonlinear effects showed a significant, inverse J-shaped effect of head circumference at birth on hospitalization for personality disorders (P = 0.005). Participants with a smaller head circumference
(z < −1 S.D.) were at a 1.64-fold (95% confidence interval (CI)= 1.11 to 2.41, P = 0.01) risk of hospitalization for personality disorders compared with those with a medium size head circumference (−1 S.D. ≤z ≤ 1 S. D.) (Fig. 1). Those with a larger head circumference (z > 1 S.D.) did not differ in their risk from the ones with a medium size head circumference (Odds ratio (OR) for those with a larger head circumference = 1.14, 95% CI= 0.74–1.75, P = 0.55). The nonlinear pattern (P = 0.01 for nonlinearity) was more pronounced among men (Table 2). For those men with a smaller head circumference, the risk of hospitalization for personality disorders was 1.83-fold (95% CI = 1.06 to 3.14, P = 0.03) compared with those men with a medium size head circumference. Also among men, a smaller head-to-length ratio at birth showed a linear association with a 1.26-fold increased risk of hospitalization for personality disorders (Table 2). Of the predictors available, the surface area of the placenta was the only significant predictor of hospitalization for dramatic personality disorders. A smaller placental area (OR = 1.32, 95% CI = 1.03 to 1.69, P = 0.03) linearly predicted dramatic personality disorders. This effect was significant among women (P = 0.05) (Table 3). Weight, length, ponderal index, placental weight, and length of gestation were not significantly associated with hospitalization for personality disorders or for dramatic personality disorders.
4. Discussion We studied the effects of body size at birth and length of gestation on hospitalization for personality disorders in general and for dramatic personality disorders in particular. Men with a small head circumference at birth were at increased risk of hospitalization for personality disorders compared with men with a medium size head circumference. Also a small head-tolength ratio predicted an increased risk of personality disorders
Table 2 Neonatal characteristics and personality disorders: linear and curvilinear (quadratic) effects. Men Neonatal characteristic c
Birth weight Length at birthc Ponderal indexc Head circumferencec Length of gestationd Head circumference/length-ratioc Placental weightc Placental areac a b c d
Women a
Odds ratio (95% CI)
P linear
0.98 0.88 1.14 1.12 1.08 1.26 0.86 0.92
0.88 0.25 0.20 0.27 0.45 0.02 0.14 0.40
(0.79–1.22) (0.71–1.09) (0.93–1.40) (0.91–1.38) (0.89–1.31) (1.03–1.52) (0.71–1.05) (0.76–1.12)
b
P quadratic
Odds ratioa (95% CI)
p linearb
p quadratic
0.47 0.32 0.71 0.01 0.97 0.31 0.32 0.20
1.00 1.13 0.89 1.14 1.09 1.01 1.07 1.12
1.00 0.32 0.29 0.27 0.42 0.90 0.56 0.35
0.84 0.72 1.00 0.12 0.70 0.26 0.14 0.52
(0.79–1.27) (0.89–1.42) (0.71–1.11) (0.90–1.44) (0.88–1.36) (0.81–1.27) (0.85–1.35) (0.89–1.40)
Odds ratios and 95% confidence intervals (CIs) for each standard deviation (S.D.) unit decrease in these variables. The linear P-values are from analyses examining only linear effects and are not adjusted for the quadratic terms. Adjusted for gestational age, childhood SES, and year of birth. Adjusted for childhood SES and year of birth.
Table 3 Neonatal characteristics and dramatic personality disorders: linear and curvilinear (quadratic) effects. Men Neonatal characteristic c
Birth weight Length at birthc Ponderal indexc Head circumferencec Length of gestationd Head circumference/length -ratioc Placental weightc Placental areac a b c d
Women
Odds ratio (95% CI)a
P linearb
P quadratic
Odds ratioa (95% CI)
P linearb
P quadratic
1.10 1.04 1.11 1.25 1.14 1.23 0.97 1.21
0.59 0.81 0.52 0.17 0.36 0.18 0.83 0.25
0.71 0.84 0.57 0.57 0.49 0.19 0.90 0.86
1.00 1.09 0.88 1.17 1.09 1.09 1.13 1.48
0.99 0.66 0.50 0.43 0.65 0.62 0.52 0.048
0.06 0.053 0.30 0.48 0.17 0.83 0.29 0.53
(0.78–1.54) (0.75–1.45) (0.81–1.53) (0.91–1.72) (0.86–1.53) (0.91–1.67) (0.71–1.33) (0.88–1.67)
Odds ratios and 95% confidence intervals (CIs) for each S.D. unit decrease in these variables. The linear P-values are from analyses examining only linear effects and are not adjusted for the quadratic terms. Adjusted for gestational age, childhood SES, year of birth. Adjusted for childhood SES and year of birth.
(0.68–1.48) (0.74–1.60) (0.61–1.27) (0.80–1.71) (0.76–1.56) (0.76–1.57) (0.77–1.66) (1.00–2.18)
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among men. Hospitalization for dramatic personality disorders, by contrast, was associated with placental size among women, for whom a smaller placental area was associated with an increased risk. All these effects were independent of socioeconomic position in childhood, year of birth, and length of gestation. To our knowledge, this is the first study to show that a smaller head circumference and a smaller head-to-length ratio at birth predict an increased risk of hospitalization for personality disorders among men. Previously, similar findings have been found for schizophrenia (Nilsson et al., 2005), though a meta-analysis concluded the effect to be of borderline significance (Cannon et al., 2002). The specificity of the effect is thus of question and further studies should examine whether small head size at birth is a general predisposing factor for psychopathology or does it predispose specifically to personality disorders. Furthermore, links between small head circumference at 1 year of age and violent offending in adulthood have been described (Ikäheimo et al., 2007). Although we found effects of fetal brain growth on personality disorders in general, these previous findings show resemblance to ours as they suggest reduced brain growth either prenatally or during infancy in offenders, among whom personality disorders, especially antisocial, are highly prevalent (Elonheimo et al., 2007; Zoccali et al., 2008). We found no effect of birth weight, birth length, or length of gestation on hospitalization for personality disorders. Resembling these findings, in a recent Swedish study neither prematurity nor being born small for gestational age by themselves predicted hospitalization for personality disorders among either sex (Monfils Gustafsson et al., 2009). However, in preterm boys, those who were born small for gestational age were at significantly increased risk compared with appropriate for gestational age-sized controls. Whereas Monfils Gustafsson et al. (2009) examined the role of the lowest extremes of birth weight and length of gestation in personality disorders, we studied the effects of these factors across their whole range of variation. Furthermore, the two studies examined personality disorders at different ages. The diagnoses in our study were identified throughout the adulthood life course between the years 1969 and 2004 when the subjects of our cohort ranged between 24 and 70 years of age, whereas in the Swedish study the diagnoses were given between 12 and 21 years of age (Monfils Gustafsson et al., 2009). An earlier study found an effect of preterm birth on borderline personality disorder (Bandelow et al., 2005). However, the independence of this effect from confounders was not tested for and the study used indices dependent on the subjects' own recall (Bandelow et al., 2005). In line with the results of Monfils Gustafsson et al. (2009), we found no effects of prenatal factors on hospitalization for any personality disorder among women. However, we found that a smaller placental area was associated with an increased risk of hospitalization for dramatic personality disorders among women. To our knowledge, the size of the placental area has not previously been studied with regard to psychiatric disorders. Mechanisms underlying the associations between small head circumference and small head-to-length ratio and hospitalization for personality disorders remain unidentified. However, head circumference is strongly associated with brain volume (Lindley et al., 1999), and reduced brain size can be seen as reflecting attenuated fetal brain growth. The smaller head-to-length ratio indicates reduced brain growth also in comparison to trunk growth. A number of prenatal factors such as malnutrition (Stein et al., 2004) and maternal psychological distress (Seckl, 2008) induce alterations in brain growth. These factors are also associated with changes in HPA axis glucocorticoid functioning (Seckl, 2008), which is also associated with head circumference at birth (Power et al., 2006). Abnormalities in HPA axis functioning have been described in personality disorders (Rosmond et al.,
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1999). Prenatal programming of glucocorticoid functioning may thus be hypothesized as a possible neurobiological mechanism contributing to the association between reduced fetal brain growth and hospitalization for personality disorders. As an alternative explanation for our findings, genetic factors could influence fetal growth as well as predispose to personality disorders. Genetic effects have been shown on both head circumference at birth (Lunde et al., 2007) and on personality disorders of all clusters (Torgersen et al., 2000). However, a twin study on schizophrenia suggested that fetal growth effects are at least partially independent of genetic effects (Nilsson et al., 2005), arguing for a causal role of conditions during fetal life. Moreover, the mechanisms underlying the association between smaller placental area and hospitalization for dramatic personality disorders are largely unknown. Placental area correlated positively with body size at birth in our sample (data not shown), and a small placental area has previously been found in fetal growth restriction (Biswas and Ghosh, 2008). Hence, factors associated with fetal growth restriction might also underlie changes in the size of the placenta, and, indeed, a smaller placental area has been associated with malnutrition during pregnancy (Roseboom et al., 1999). Although a novel finding, the smaller placental area found in dramatic personality disorders calls for further research to confirm the finding and to study its specificity. The strengths of our study include the large sample of participants derived from a general population, the use of birth register data to index body size at birth, and the longitudinal study design. There are also limitations to our study. One of these is the small number of subjects identified with personality disorder. Only 1.5% of our subjects had received personality disorder diagnoses. The low number of patients might have led to sample-specific findings and the findings need to be confirmed in further studies. However, the percentage of subjects with personality disorders is comparable to another recent study where hospitalization for personality disorders was also the outcome (Monfils Gustafsson et al., 2009). We concentrated on the patient categories with a larger number of patients in order to detect meaningful associations, which led to an emphasis on dramatic and any personality disorder as the outcomes. We could not study the specific effects on eccentric and fearful personality disorders. This restricts the generalizability of our findings. More studies are needed to target the other disorder clusters and the more specific diagnostic groups. Our diagnoses were based on hospital records and not all people with personality disorders require hospitalization. This suggests that the patients in our study had severe disorders where hospitalization was required and our results may not be generalized to less severe personality disorders not in need of hospital treatment. Changes in diagnostic criteria over time might also have introduced some heterogeneity to the diagnostic groups. Furthermore, since ultrasound measurements were not available in 1934–44, we calculated length of gestation based on maternal self-reports of last menstruation date. Hence, these values contain some inaccuracy. However, body size at birth and length of gestation correlate as expected in our sample (data not shown). Besides, length of gestation was calculated similarly for each subject. It is thus unlikely that this inaccuracy would have influenced our main findings, which were independent of length of gestation. To conclude, the results of this large cohort study on the prenatal origins of hospitalization for personality disorders in adulthood suggest that reduced fetal brain growth predisposes men to personality disorders and a smaller placental area is associated specifically with hospitalization for dramatic personality disorders among women. Although the mechanisms underlying these associations remain largely unidentified, the findings highlight the importance of factors operating during prenatal development in the etiology of personality disorders.
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Acknowledgment This study was supported by grants from Emil Aaltonen Foundation, Helsinki University's Research Funds, the Academy of Finland, the British Heart Foundation, the Finnish Foundation for Cardiovascular Research, the Finnish Diabetes Research Foundation, the Finnish Medical Society (Duodecim), Finska Läkaresällskapet, the Päivikki and Sakari Sohlberg Foundation, the Juho Vainio Foundation, the Yrjö Jahnsson Foundation, the Signe and Ane Gyllenberg Foundation, and the Finnish Foundation for Pediatric Research. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Furthermore, the authors would like to thank the staff at National Institute for Health and Welfare and at University of Helsinki, Department of Psychology for their assistance with the article.
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