Psychological Medicine (2015), 45, 985–999. doi:10.1017/S0033291714001998
© Cambridge University Press 2014
OR I G I N A L A R T I C L E
Late preterm birth, post-term birth, and abnormal fetal growth as risk factors for severe mental disorders from early to late adulthood M. Lahti1*, J. G. Eriksson2,3,4,5,6, K. Heinonen1, E. Kajantie2,7, J. Lahti1, K. Wahlbeck2,8, S. Tuovinen1, A.-K. Pesonen1, M. Mikkonen2, C. Osmond9, D. J. P. Barker† and K. Räikkönen1 1
Institute of Behavioural Sciences, University of Helsinki, Finland National Institute for Health and Welfare, Helsinki, Finland 3 Institute of Clinical Medicine, University of Helsinki, Finland 4 Vaasa Central Hospital, Vaasa, Finland 5 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland 6 Folkhälsan Research Centre, Helsinki, Finland 7 Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland 8 The Finnish Association for Mental Health, Helsinki, Finland 9 MRC Lifecourse Epidemiology Unit, University of Southampton, UK 2
Background. Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. Method. Of 12 597 Helsinki Birth Cohort Study participants, born 1934–1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. Results. Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. Conclusions. Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term. Received 16 October 2013; Revised 13 June 2014; Accepted 25 July 2014; First published online 5 September 2014 Key words: Anxiety disorders, gestational age, longitudinal cohort study, mental disorders, mood disorders, personality disorders, psychotic disorders, SGA and LGA birth, substance use disorders, suicides.
Introduction Several studies have shown that preterm birth predicts an increased risk of mental disorders in childhood, adolescence, and young adulthood (Abel et al. 2010; Loe et al. 2011; El Marroun et al. 2012; Fazel et al. 2012; Nosarti et al. 2012; D’Onofrio et al. 2013). This risk extends to different mental disorders across
* Address for correspondence: M. Lahti, Ph.D., Institute of Behavioural Sciences, University of Helsinki, Siltavuorenpenger 1 A, PO Box 9, FI 00014 University of Helsinki, Finland. (Email: marius.lahti@helsinki.fi) † Deceased.
diagnostic boundaries (Abel et al. 2010; Fazel et al. 2012; D’Onofrio et al. 2013). However, most of this evidence comes from studies comparing preterm individuals born at the lowest end of gestational age or birth weight distributions with individuals born at term and/or with normal weight. Nevertheless, late preterm births, defined as birth from 34 + 0 to 36 + 6 weeks+days of gestation, constitute over 70% of all preterm births (Davidoff et al. 2006; Moster et al. 2008). Only a few studies to date have assessed the longterm consequences of late prematurity on mental disorders. Previous evidence suggests that late preterm birth predicts an increased risk of any mental disorder and particularly of internalizing disorders in childhood
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(Talge et al. 2010; Rogers et al. 2013). Significant associations to attention deficit hyperactive disorder have also been reported (Linnet et al. 2006; Talge et al. 2010), but the findings are inconsistent (Rogers et al. 2013). In a study with a follow-up to young adulthood, individuals born late preterm had increased risks of schizophrenia and of disorders of psychological development, behaviour, and emotion (Moster et al. 2008). Another register study showed that a combined group of individuals born moderately (at 32 + 0 to 33 + 6 weeks+days of gestation) or late preterm had increased risks of any severe mental disorder, mood, non-affective psychotic, organic, and stress-related disorders, substance dependence, and of suicide and suicide attempts in adolescence and young adulthood (Lindström et al. 2009; Nosarti et al. 2012). However, to our knowledge, no previous study has offered a lifecourse perspective examining whether the possible effects of late preterm birth on mental disorders extend across adult ages from young to old adulthood. Some studies suggest that the increased risk for mental disorders associated with preterm birth may characterize especially those preterm individuals who were born small for gestational age [SGA; defined as birth size at 42 standard deviations (S.D.s) or below the 5th or 10th percentile of that predicted by their gestational age; Laursen et al. 2007; Räikkönen et al. 2008; Strang-Karlsson et al. 2008; Monfils Gustafsson et al. 2009]. In fact, previous studies have shown that at least until young adulthood, individuals born SGA are at increased risk of severe mental disorders independently of their gestational age (Abel et al. 2010; Niederkrotenthaler et al. 2012; Nosarti et al. 2012). However, we know of no studies that would have examined whether the effects of SGA birth on mental disorders persist from early to late adulthood. Finally, scarce evidence suggests that post-term (542 weeks of gestation; Lindström et al. 2005; El Marroun et al. 2012) and large for gestational age (LGA; 5+2 S.D.s or above 90th or 95th percentile; van Lieshout & Boyle, 2011) births may also predict increased risk of psychopathology in childhood and in adolescence. However, to our knowledge, no studies have systematically assessed the effects of post-term birth on mental health in adulthood. Moreover, for LGA birth, such studies are scarce, and the existing studies have yielded inconsistent findings (Moilanen et al. 2010; Keskinen et al. 2013). Hence, in the current study, we examine whether each of these prenatal risk factors contribute to the risks of mental disorders severe enough to lead to hospitalization or contribute to death from early to late adulthood. More specifically, our first study objective was to examine from a life-course perspective if individuals born late preterm differ from their term-born
counterparts in their risks of severe mental disorders across adult ages. As a second study question, we studied if the effects of SGA birth across the gestational age distribution, from late preterm to post-term birth, on mental disorders persist across adult ages. We also add to the literature by examining whether post-term or LGA births increase the risk of severe mental disorders in adulthood. Based on previous findings in younger cohorts, we hypothesized that late preterm and post-term births and SGA and LGA births each set forth predisposing effects on the risks of severe mental disorders.
Method The study sample Our study cohort was the Helsinki Birth Cohort Study (HBCS). The HBCS comprises 13 345 singleton live births [6975 men (52.3%) and 6370 women (47.7%)] at the two public maternity hospitals in Helsinki, Finland, between 1934 and 1944. The HBCS, described in detail elsewhere (Osmond et al. 2007), has been approved by the Ethics Committee of the National Public Health Institute. For the current study, we excluded all individuals with biologically implausible values for gestational age, both as absolute values and compared to their birth weight. Namely, we excluded individuals with gestational age below 26 weeks or above 44 weeks, and preterm individuals with disproportionally large birth weight for gestational age (> + 2 S.D.; Kajantie et al. 2010). These criteria led to the exclusion of 535 (4.0%) individuals. Furthermore, since we focused on late preterm births, and our study sample did not provide sufficient statistical power to study the risks of mental disorders among individuals born very or moderately preterm, we excluded 128 (1.0%) participants born before 34 weeks of gestation. From the current study, we also excluded 54 (0.4%) cohort members with missing or imprecise data in the Finnish Hospital Discharge Register (HDR) or the Causes of Death Register (CDR) or who had died with missing data on year of death or moved abroad with missing data on year of moving abroad, and 31 (0.2%) individuals who had been hospitalized for or who had died from injuries of undetermined intent. The current study sample thus comprised 12 597 individuals, 6563 (52.1%) men and 6034 (47.9%) women. Compared to the included participants, the excluded cohort members came more often from families where the father was a manual worker (63.4 v. 56.7%, p = 0.001) or where the mother was unmarried (7.4% v. 4.7%, p = 0.002). In comparison to the included participants, the excluded cohort members with
Risk factors for severe mental disorders across adulthood adequate data on gestational age were more often born SGA (7.0% v. 2.3%, p < 0.001), and the excluded cohort members with adequate diagnostic data had a higher risk of severe mood disorders [hazard ratio (HR) = 1.45, p = 0.01]. Gestational age and fetal growth We extracted data on the date of mothers’ last menstrual period and on infants’ date of birth and birth weight from hospital birth records. Gestational age was calculated by subtracting the date of birth from mothers’ self-reported date of last menstrual period. The participants were divided into three groups by their gestational age: late preterm (34–36 weeks), term (37–41 weeks), and post-term (42–43 weeks) birth. We defined SGA birth in sex-stratified models as birth weight at or below −2 S.D. of that predicted by gestational age, appropriate for gestational age (AGA) birth as birth weight between −2 and +2 S.D. of that predicted by gestational age, and LGA birth as birth weight at or above +2 S.D. that predicted by gestational age (Lee et al. 2003). Since there are no official growth charts available in Finland for 1934–1944, we defined these indices of fetal growth based on the distributions of birth weight and gestational age in our own study cohort. Diagnoses of mental disorders We identified the diagnoses of mental disorders from the HDR and CDR. Our diagnostic follow-up extended across 42 years of adult life, from 1969 to 2010. At the end of the follow-up, the participants were aged between 66 and 76 years. The HDR carries the primary and up to three subsidiary discharge diagnoses of all hospitalizations and the CDR carries the primary, underlying, and contributory causes of death for all deaths in Finland. Both registers have been in use since 1969 when a personal identification number was given to each Finnish citizen. In Finland, International Classification of Diseases, eighth revision (ICD-8) was in use in clinical practice between 1969 and 1986; ICD-9, the Diagnostic and Statistical Manual of Mental Disorders, Third Revision was used between 1987 and 1995; and ICD-10 has been in use since 1996. The HDR (Sund, 2012) and the CDR (Lahti & Penttilä, 2001) are valid and reliable research tools. Of mental disorders, the HDR diagnoses of schizophrenia (Pihlajamaa et al. 2008), bipolar disorder (Kieseppä et al. 2000), and any psychotic disorder (Perälä et al. 2007) each demonstrate high specificity levels. Also the validity of the HDR ICD-8 diagnoses of alcohol dependence and psychosis has gained research support (Poikolainen, 1983).
987
In addition to assessing the associations of late preterm, post-term, SGA, and LGA birth with severe mental disorders as one broad diagnostic category, we assessed associations to seven specific diagnostic categories; substance use, (non-affective) psychotic, mood, anxiety, and personality disorders and suicides and suicide attempts. The diagnostic codes corresponding to the different diagnostic categories are shown in Table 1, together with the number and the percentage of participants with each diagnosis and the median age at and the age range of first diagnosis. Between 1969 and 2010, there were 1660 participants (13.2%; 1058 men and 602 women) who had been hospitalized with a diagnosis of mental disorder as a hospital discharge diagnosis or had died with a diagnosis of severe mental disorder included in the death certificate. The median age at first diagnosis of any severe mental disorder was 43.4 years (range 19.0–76.6 years). Suicide is often under-diagnosed (Kapusta et al. 2011), and it is uncertain if the diagnoses of injuries of undetermined intent represent suicide in individual cases. Hence, to maximize the reliability of our suicide assessment and to minimize the amount of ‘false negative’ diagnosis, individuals with a diagnosis of injuries of undetermined intent or of poisonings of usually selfinflicted intent with no history of psychopathology were excluded from the study. We identified these exclusion diagnoses with the diagnostic codes E98 from ICD-8, E97 from ICD-9, and Y10–Y34, T39 and T42–T43 from ICD-10. Furthermore, for the analyses on the specific diagnostic categories, we excluded from the control outcome group all participants with other mental disorders. Thus, the comparison outcome group for all the analyses included 10 937 individuals (5505 men and 5432 women) with no diagnosis of severe mental disorder or of injuries of undetermined intent at any time point. On the other hand, all individuals with a particular diagnosis were included as ‘diagnostic cases’ for that diagnosis, independently of whether or not they had other types of comorbid psychopathology.
Confounders and covariates The potential confounders of the associations between the prenatal risk factors and mental disorders that were used in the analyses were sex, year of birth, socioeconomic position in childhood, and mothers’ marital status at childbirth. The latter two were used since they have frequently been associated with preterm birth and with fetal growth (Zeitlin et al. 2002; Blumenshine et al. 2010; El-Sayed et al. 2012) and with an increased risk of mental disorders (Mäkikyrö
988
Diagnostic codes
Prevalence (%)
Diagnostic category
ICD diagnostic codes
All subjects
Men
Women
Median age (in years) at first diagnosis (range)
Any mental disordera
ICD-8: 291, 295, 296–305, 306.4–306.5, 306.8, 306.98, 307; E95 ICD-9: 291–292, 295–298, 300–304, 305, 3071A, 3074, 3075A–3075B, 3078A, 3079X, 3090A, 3092C–3099X, 312; E95 ICD-10: F1–F6, R45.8, X60–X84; Y87.0 ICD-8: 291, 303–304 ICD-9: 291–292, 303–305 ICD-10: F10–F19 ICD-8: 295, 297, 298.10–299.99 ICD-9: 295, 297–298 ICD-10: F20–F29 ICD-8: 296, 298.00, 300.40, 300.41, 301.10 ICD-9: 296, 3004A, 3011D ICD-10: F30–F39 ICD-8: 300.00–300.30, 300.50–300.99, 305, 306.80, 307.99 ICD-9: 3000A–3003A, 3006A–3009X, 3078A, 309 ICD-10: F40–F48 ICD-8: 301.00, 301.20–301.99
1660 (13.2%)
1058 (16.1%)
602 (10.0%)
43.4 (19.0–76.6)
872 (6.9%)
694 (10.6%)
178 (2.9%)
45.9 (25.5–76.6)
331 (2.6%)
175 (2.7%)
156 (2.6%)
38.4 (19.0–73.6)
577 (4.6%)
283 (4.3%)
294 (4.9%)
48.0 (24.5–75.2)
318 (2.5%)
159 (2.4%)
159 (2.6%)
40.1 (25.6–71.0)
195 (1.5%)
109 (1.7%)
86 (1.4%)
41.3 (24.8–66.6)
126 (1.0%)
98 (1.5%)
28 (0.5%)
48.8 (29.0–70.5)
83 (0.7%)
39 (0.6%)
44 (0.7%)
38.4 (19.6–49.4)
Substance use disordersb (ICD-10: Mental and behavioural disorders due to psychoactive substance use) Psychotic disorders (ICD-10: Schizophrenia, schizotypal, and delusional disorders) Mood disorders [ICD-10: Mood (affective) disorders] Anxiety disorders (ICD-10: Neurotic, stress-related and somatoform disorders) Personality disorders (ICD-10: Specific and mixed personality disorders) Suicides (ICD-10: Intentional self-harm) Suicide attempts (ICD-8: Intentional self-harm)
ICD-9: 3010A, 3012A–3015A, 3016A–3018X ICD-10: F60–F61 ICD-8 & ICD-9: E95 ICD-10: R45.8, X60–X84; Y87.0 ICD-8: E95
HDR, Finnish Hospital Discharge Register; CDR, Cause of Death Register. The diagnoses (corresponding to codes F50–F59 or F62–F69 in ICD-10) were included in the ‘Any mental disorder’ category, but were not assessed as a separate category. b For the diagnoses of substance intoxifications (ICD-9; 305ICD-10: F1x.0, only the primary diagnoses from the HDR and the CDR were included in the diagnostic categories. All other diagnostic entities include primary and up to three subsidiary hospital discharge diagnoses, and primary, underlying and contributory causes of death. a
M. Lahti et al.
Table 1. International classification of disease diagnostic codes on mental disorders severe enough to warrant or contribute to hospital treatment (HDR) or to be the underlying, intermediate or contributing cause of death (CDR). The prevalence and percentage of subjects with each diagnosis, and median age at first diagnosis for each diagnostic category
Risk factors for severe mental disorders across adulthood
989
Table 2. Birth and sociodemographic characteristics of the study sample
Characteristic
All subjects N (%)
Men N (%)
Women N (%)
Gestation length 34–36 weeks 37–41 weeks 5 42 weeks
664 (6.2%) 10 712 (84.2%) 1221 (9.6%)
369 (5.6%) 5579 (85.0%) 615 (9.4%)
295 (4.9%) 5133 (85.1%) 606 (10.0%)
Birth weight adjusted for length of gestation SGA (4−2 S.D.) AGA (< − 2 to
© Cambridge University Press 2014
OR I G I N A L A R T I C L E
Late preterm birth, post-term birth, and abnormal fetal growth as risk factors for severe mental disorders from early to late adulthood M. Lahti1*, J. G. Eriksson2,3,4,5,6, K. Heinonen1, E. Kajantie2,7, J. Lahti1, K. Wahlbeck2,8, S. Tuovinen1, A.-K. Pesonen1, M. Mikkonen2, C. Osmond9, D. J. P. Barker† and K. Räikkönen1 1
Institute of Behavioural Sciences, University of Helsinki, Finland National Institute for Health and Welfare, Helsinki, Finland 3 Institute of Clinical Medicine, University of Helsinki, Finland 4 Vaasa Central Hospital, Vaasa, Finland 5 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland 6 Folkhälsan Research Centre, Helsinki, Finland 7 Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland 8 The Finnish Association for Mental Health, Helsinki, Finland 9 MRC Lifecourse Epidemiology Unit, University of Southampton, UK 2
Background. Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. Method. Of 12 597 Helsinki Birth Cohort Study participants, born 1934–1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. Results. Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. Conclusions. Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term. Received 16 October 2013; Revised 13 June 2014; Accepted 25 July 2014; First published online 5 September 2014 Key words: Anxiety disorders, gestational age, longitudinal cohort study, mental disorders, mood disorders, personality disorders, psychotic disorders, SGA and LGA birth, substance use disorders, suicides.
Introduction Several studies have shown that preterm birth predicts an increased risk of mental disorders in childhood, adolescence, and young adulthood (Abel et al. 2010; Loe et al. 2011; El Marroun et al. 2012; Fazel et al. 2012; Nosarti et al. 2012; D’Onofrio et al. 2013). This risk extends to different mental disorders across
* Address for correspondence: M. Lahti, Ph.D., Institute of Behavioural Sciences, University of Helsinki, Siltavuorenpenger 1 A, PO Box 9, FI 00014 University of Helsinki, Finland. (Email: marius.lahti@helsinki.fi) † Deceased.
diagnostic boundaries (Abel et al. 2010; Fazel et al. 2012; D’Onofrio et al. 2013). However, most of this evidence comes from studies comparing preterm individuals born at the lowest end of gestational age or birth weight distributions with individuals born at term and/or with normal weight. Nevertheless, late preterm births, defined as birth from 34 + 0 to 36 + 6 weeks+days of gestation, constitute over 70% of all preterm births (Davidoff et al. 2006; Moster et al. 2008). Only a few studies to date have assessed the longterm consequences of late prematurity on mental disorders. Previous evidence suggests that late preterm birth predicts an increased risk of any mental disorder and particularly of internalizing disorders in childhood
986
M. Lahti et al.
(Talge et al. 2010; Rogers et al. 2013). Significant associations to attention deficit hyperactive disorder have also been reported (Linnet et al. 2006; Talge et al. 2010), but the findings are inconsistent (Rogers et al. 2013). In a study with a follow-up to young adulthood, individuals born late preterm had increased risks of schizophrenia and of disorders of psychological development, behaviour, and emotion (Moster et al. 2008). Another register study showed that a combined group of individuals born moderately (at 32 + 0 to 33 + 6 weeks+days of gestation) or late preterm had increased risks of any severe mental disorder, mood, non-affective psychotic, organic, and stress-related disorders, substance dependence, and of suicide and suicide attempts in adolescence and young adulthood (Lindström et al. 2009; Nosarti et al. 2012). However, to our knowledge, no previous study has offered a lifecourse perspective examining whether the possible effects of late preterm birth on mental disorders extend across adult ages from young to old adulthood. Some studies suggest that the increased risk for mental disorders associated with preterm birth may characterize especially those preterm individuals who were born small for gestational age [SGA; defined as birth size at 42 standard deviations (S.D.s) or below the 5th or 10th percentile of that predicted by their gestational age; Laursen et al. 2007; Räikkönen et al. 2008; Strang-Karlsson et al. 2008; Monfils Gustafsson et al. 2009]. In fact, previous studies have shown that at least until young adulthood, individuals born SGA are at increased risk of severe mental disorders independently of their gestational age (Abel et al. 2010; Niederkrotenthaler et al. 2012; Nosarti et al. 2012). However, we know of no studies that would have examined whether the effects of SGA birth on mental disorders persist from early to late adulthood. Finally, scarce evidence suggests that post-term (542 weeks of gestation; Lindström et al. 2005; El Marroun et al. 2012) and large for gestational age (LGA; 5+2 S.D.s or above 90th or 95th percentile; van Lieshout & Boyle, 2011) births may also predict increased risk of psychopathology in childhood and in adolescence. However, to our knowledge, no studies have systematically assessed the effects of post-term birth on mental health in adulthood. Moreover, for LGA birth, such studies are scarce, and the existing studies have yielded inconsistent findings (Moilanen et al. 2010; Keskinen et al. 2013). Hence, in the current study, we examine whether each of these prenatal risk factors contribute to the risks of mental disorders severe enough to lead to hospitalization or contribute to death from early to late adulthood. More specifically, our first study objective was to examine from a life-course perspective if individuals born late preterm differ from their term-born
counterparts in their risks of severe mental disorders across adult ages. As a second study question, we studied if the effects of SGA birth across the gestational age distribution, from late preterm to post-term birth, on mental disorders persist across adult ages. We also add to the literature by examining whether post-term or LGA births increase the risk of severe mental disorders in adulthood. Based on previous findings in younger cohorts, we hypothesized that late preterm and post-term births and SGA and LGA births each set forth predisposing effects on the risks of severe mental disorders.
Method The study sample Our study cohort was the Helsinki Birth Cohort Study (HBCS). The HBCS comprises 13 345 singleton live births [6975 men (52.3%) and 6370 women (47.7%)] at the two public maternity hospitals in Helsinki, Finland, between 1934 and 1944. The HBCS, described in detail elsewhere (Osmond et al. 2007), has been approved by the Ethics Committee of the National Public Health Institute. For the current study, we excluded all individuals with biologically implausible values for gestational age, both as absolute values and compared to their birth weight. Namely, we excluded individuals with gestational age below 26 weeks or above 44 weeks, and preterm individuals with disproportionally large birth weight for gestational age (> + 2 S.D.; Kajantie et al. 2010). These criteria led to the exclusion of 535 (4.0%) individuals. Furthermore, since we focused on late preterm births, and our study sample did not provide sufficient statistical power to study the risks of mental disorders among individuals born very or moderately preterm, we excluded 128 (1.0%) participants born before 34 weeks of gestation. From the current study, we also excluded 54 (0.4%) cohort members with missing or imprecise data in the Finnish Hospital Discharge Register (HDR) or the Causes of Death Register (CDR) or who had died with missing data on year of death or moved abroad with missing data on year of moving abroad, and 31 (0.2%) individuals who had been hospitalized for or who had died from injuries of undetermined intent. The current study sample thus comprised 12 597 individuals, 6563 (52.1%) men and 6034 (47.9%) women. Compared to the included participants, the excluded cohort members came more often from families where the father was a manual worker (63.4 v. 56.7%, p = 0.001) or where the mother was unmarried (7.4% v. 4.7%, p = 0.002). In comparison to the included participants, the excluded cohort members with
Risk factors for severe mental disorders across adulthood adequate data on gestational age were more often born SGA (7.0% v. 2.3%, p < 0.001), and the excluded cohort members with adequate diagnostic data had a higher risk of severe mood disorders [hazard ratio (HR) = 1.45, p = 0.01]. Gestational age and fetal growth We extracted data on the date of mothers’ last menstrual period and on infants’ date of birth and birth weight from hospital birth records. Gestational age was calculated by subtracting the date of birth from mothers’ self-reported date of last menstrual period. The participants were divided into three groups by their gestational age: late preterm (34–36 weeks), term (37–41 weeks), and post-term (42–43 weeks) birth. We defined SGA birth in sex-stratified models as birth weight at or below −2 S.D. of that predicted by gestational age, appropriate for gestational age (AGA) birth as birth weight between −2 and +2 S.D. of that predicted by gestational age, and LGA birth as birth weight at or above +2 S.D. that predicted by gestational age (Lee et al. 2003). Since there are no official growth charts available in Finland for 1934–1944, we defined these indices of fetal growth based on the distributions of birth weight and gestational age in our own study cohort. Diagnoses of mental disorders We identified the diagnoses of mental disorders from the HDR and CDR. Our diagnostic follow-up extended across 42 years of adult life, from 1969 to 2010. At the end of the follow-up, the participants were aged between 66 and 76 years. The HDR carries the primary and up to three subsidiary discharge diagnoses of all hospitalizations and the CDR carries the primary, underlying, and contributory causes of death for all deaths in Finland. Both registers have been in use since 1969 when a personal identification number was given to each Finnish citizen. In Finland, International Classification of Diseases, eighth revision (ICD-8) was in use in clinical practice between 1969 and 1986; ICD-9, the Diagnostic and Statistical Manual of Mental Disorders, Third Revision was used between 1987 and 1995; and ICD-10 has been in use since 1996. The HDR (Sund, 2012) and the CDR (Lahti & Penttilä, 2001) are valid and reliable research tools. Of mental disorders, the HDR diagnoses of schizophrenia (Pihlajamaa et al. 2008), bipolar disorder (Kieseppä et al. 2000), and any psychotic disorder (Perälä et al. 2007) each demonstrate high specificity levels. Also the validity of the HDR ICD-8 diagnoses of alcohol dependence and psychosis has gained research support (Poikolainen, 1983).
987
In addition to assessing the associations of late preterm, post-term, SGA, and LGA birth with severe mental disorders as one broad diagnostic category, we assessed associations to seven specific diagnostic categories; substance use, (non-affective) psychotic, mood, anxiety, and personality disorders and suicides and suicide attempts. The diagnostic codes corresponding to the different diagnostic categories are shown in Table 1, together with the number and the percentage of participants with each diagnosis and the median age at and the age range of first diagnosis. Between 1969 and 2010, there were 1660 participants (13.2%; 1058 men and 602 women) who had been hospitalized with a diagnosis of mental disorder as a hospital discharge diagnosis or had died with a diagnosis of severe mental disorder included in the death certificate. The median age at first diagnosis of any severe mental disorder was 43.4 years (range 19.0–76.6 years). Suicide is often under-diagnosed (Kapusta et al. 2011), and it is uncertain if the diagnoses of injuries of undetermined intent represent suicide in individual cases. Hence, to maximize the reliability of our suicide assessment and to minimize the amount of ‘false negative’ diagnosis, individuals with a diagnosis of injuries of undetermined intent or of poisonings of usually selfinflicted intent with no history of psychopathology were excluded from the study. We identified these exclusion diagnoses with the diagnostic codes E98 from ICD-8, E97 from ICD-9, and Y10–Y34, T39 and T42–T43 from ICD-10. Furthermore, for the analyses on the specific diagnostic categories, we excluded from the control outcome group all participants with other mental disorders. Thus, the comparison outcome group for all the analyses included 10 937 individuals (5505 men and 5432 women) with no diagnosis of severe mental disorder or of injuries of undetermined intent at any time point. On the other hand, all individuals with a particular diagnosis were included as ‘diagnostic cases’ for that diagnosis, independently of whether or not they had other types of comorbid psychopathology.
Confounders and covariates The potential confounders of the associations between the prenatal risk factors and mental disorders that were used in the analyses were sex, year of birth, socioeconomic position in childhood, and mothers’ marital status at childbirth. The latter two were used since they have frequently been associated with preterm birth and with fetal growth (Zeitlin et al. 2002; Blumenshine et al. 2010; El-Sayed et al. 2012) and with an increased risk of mental disorders (Mäkikyrö
988
Diagnostic codes
Prevalence (%)
Diagnostic category
ICD diagnostic codes
All subjects
Men
Women
Median age (in years) at first diagnosis (range)
Any mental disordera
ICD-8: 291, 295, 296–305, 306.4–306.5, 306.8, 306.98, 307; E95 ICD-9: 291–292, 295–298, 300–304, 305, 3071A, 3074, 3075A–3075B, 3078A, 3079X, 3090A, 3092C–3099X, 312; E95 ICD-10: F1–F6, R45.8, X60–X84; Y87.0 ICD-8: 291, 303–304 ICD-9: 291–292, 303–305 ICD-10: F10–F19 ICD-8: 295, 297, 298.10–299.99 ICD-9: 295, 297–298 ICD-10: F20–F29 ICD-8: 296, 298.00, 300.40, 300.41, 301.10 ICD-9: 296, 3004A, 3011D ICD-10: F30–F39 ICD-8: 300.00–300.30, 300.50–300.99, 305, 306.80, 307.99 ICD-9: 3000A–3003A, 3006A–3009X, 3078A, 309 ICD-10: F40–F48 ICD-8: 301.00, 301.20–301.99
1660 (13.2%)
1058 (16.1%)
602 (10.0%)
43.4 (19.0–76.6)
872 (6.9%)
694 (10.6%)
178 (2.9%)
45.9 (25.5–76.6)
331 (2.6%)
175 (2.7%)
156 (2.6%)
38.4 (19.0–73.6)
577 (4.6%)
283 (4.3%)
294 (4.9%)
48.0 (24.5–75.2)
318 (2.5%)
159 (2.4%)
159 (2.6%)
40.1 (25.6–71.0)
195 (1.5%)
109 (1.7%)
86 (1.4%)
41.3 (24.8–66.6)
126 (1.0%)
98 (1.5%)
28 (0.5%)
48.8 (29.0–70.5)
83 (0.7%)
39 (0.6%)
44 (0.7%)
38.4 (19.6–49.4)
Substance use disordersb (ICD-10: Mental and behavioural disorders due to psychoactive substance use) Psychotic disorders (ICD-10: Schizophrenia, schizotypal, and delusional disorders) Mood disorders [ICD-10: Mood (affective) disorders] Anxiety disorders (ICD-10: Neurotic, stress-related and somatoform disorders) Personality disorders (ICD-10: Specific and mixed personality disorders) Suicides (ICD-10: Intentional self-harm) Suicide attempts (ICD-8: Intentional self-harm)
ICD-9: 3010A, 3012A–3015A, 3016A–3018X ICD-10: F60–F61 ICD-8 & ICD-9: E95 ICD-10: R45.8, X60–X84; Y87.0 ICD-8: E95
HDR, Finnish Hospital Discharge Register; CDR, Cause of Death Register. The diagnoses (corresponding to codes F50–F59 or F62–F69 in ICD-10) were included in the ‘Any mental disorder’ category, but were not assessed as a separate category. b For the diagnoses of substance intoxifications (ICD-9; 305ICD-10: F1x.0, only the primary diagnoses from the HDR and the CDR were included in the diagnostic categories. All other diagnostic entities include primary and up to three subsidiary hospital discharge diagnoses, and primary, underlying and contributory causes of death. a
M. Lahti et al.
Table 1. International classification of disease diagnostic codes on mental disorders severe enough to warrant or contribute to hospital treatment (HDR) or to be the underlying, intermediate or contributing cause of death (CDR). The prevalence and percentage of subjects with each diagnosis, and median age at first diagnosis for each diagnostic category
Risk factors for severe mental disorders across adulthood
989
Table 2. Birth and sociodemographic characteristics of the study sample
Characteristic
All subjects N (%)
Men N (%)
Women N (%)
Gestation length 34–36 weeks 37–41 weeks 5 42 weeks
664 (6.2%) 10 712 (84.2%) 1221 (9.6%)
369 (5.6%) 5579 (85.0%) 615 (9.4%)
295 (4.9%) 5133 (85.1%) 606 (10.0%)
Birth weight adjusted for length of gestation SGA (4−2 S.D.) AGA (< − 2 to
