Deviant intrauterine growth and risk of schizophrenia: A 34-year follow-up of the Northern Finland 1966 Birth Cohort

Schizophrenia Research 124 (2010) 223–230

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Schizophrenia 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 / s c h r e s

Deviant intrauterine growth and risk of schizophrenia: A 34-year follow-up of the Northern Finland 1966 Birth Cohort Kristiina Moilanen a,b,⁎, Jari Jokelainen c,d, Peter B. Jones e, Anna-Liisa Hartikainen f, Marjo-Riitta Järvelin c,g, Matti Isohanni a a

Department of Psychiatry, Institute of Clinical Medicine, University of Oulu, P.O. Box 5000, FIN-90014, Oulu, Finland Department of Psychiatry, University Hospital of Oulu, FIN-90029, Oulu Finland c Institute of Health Sciences, University of Oulu, FIN-90014, Oulu, Finland d Unit of General Practice, University Hospital of Oulu, FIN-90029, Finland e Department of Psychiatry, University of Cambridge, Box 189 Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK f Department of Obstetrics and Gynecology, University Hospital of Oulu, FIN-90029, Oulu, Finland g Division of Epidemiology and Biostatistics, School of Public Health, 156, Norfolk Place, St Mary's Campus, Imperial College London, UK b

a r t i c l e

i n f o

Article history: Received 7 February 2010 Received in revised form 5 September 2010 Accepted 8 September 2010 Available online 8 October 2010 Keywords: Schizophrenia Fetal growth Birth weight Birth length Cohort study

a b s t r a c t Background: Low birth weight conveys a modest risk for schizophrenia. The effects of high birth weight and deviant birth length are less clear. Methods: We linked perinatal data from 10,934 subjects from the Northern Finland 1966 Birth Cohort (n=12 058) to the Finnish Hospital Discharge Register where we identified 111 cases of DSM-III-R schizophrenia up to age 35 years. Adjusted odds ratios between the risk of schizophrenia and birth weight, birth length and ponderal index and the risk of schizophrenia were analyzed. Results: Both low (OR 2.5; 95% CI 1.2–5.1) and high birth weight (OR 2.4; 95% CI 1.1–4.9) increased the risk of later schizophrenia. In addition, short (OR 2.6; 95% CI 1.1–5.9) and long babies had an elevated risk of schizophrenia as adults (OR 1.8; 95% CI 1.0–3.5). A reverse J-shape curve described the associations between birth weight, length and schizophrenia. Conclusions: Deviant intrauterine growth of the fetus in either direction was associated with increased risk of schizophrenia. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Brain abnormalities in schizophrenia may begin during fetal development (Gilmore et al., 2001). As an index of intrauterine growth, birth weight may be considered an important indicator of fetal brain maturation. Several (Hultman et al., 1997; McNeil et al., 1993; Sacker et al., 1995) but not all studies (Jones et al., 1998; Kendell et al., 2000) have demonstrated that lower mean birth weight is associated with an increased risk of later

⁎ Corresponding author. Department of Psychiatry, Institute of Clinical Medicine, University of Oulu, P.O. Box 5000, FIN-90014 University of Oulu, Finland. Tel.: + 358 405851246. E-mail address: kristiina.moilanen@oulu.fi (K. Moilanen). 0920-9964/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2010.09.006

schizophrenia. In their meta-analysis Kunugi et al. (2001) concluded that it is not clear-cut whether mean birth weight is lower in schizophrenia cases than in control population. An excess of particularly low birth weight (b2500 g) in individuals who will develop schizophrenia is well replicated (Dalman et al., 1999; Hultman et al., 1999; Ichiki et al., 2000; Jones et al., 1998; Kunugi et al., 2001; Rifkin et al., 1994; Sacker et al., 1995; Smith et al., 2001). Kunugi et al. (2001) concluded that low birth weight is a modest but definite risk factor for schizophrenia; odds ratios ranged between 1.7 and 3.9 with a pooled effect of 2.6. A meta-analysis of published prospective, population-based studies (Cannon et al., 2002) reported a similar result (OR 1.67; 95% CI 1.22–2.29), with a more stringent definition of low birth weight (b2000 g) resulting in a higher risk (OR 3.9; 95% CI 1.4–10.8).

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There are four reports concerning the association of high birth weight with schizophrenia, two from Sweden (Hultman et al., 1997, 1999), one from Italy (Bersani et al., 2007) and our preliminary report from Finland (Moilanen et al., 2002). Hultman et al. (1997) showed that a disproportional birth weight for body length (1 SD heavy for length) was associated with an increased risk of schizophrenia (OR 4.42; 95% CI 1.97– 9.91). In their later study, high birth weight for gestational age was related to elevated risk of reactive psychosis among females, but not among males, although detailed data were not presented (Hultman et al., 1999). In the case–control study of Bersani et al. (2007) high birth weight (N4000 g) increased the risk of schizophrenia (OR 4.52; 95% CI 1.00–20.48). Gunnell et al. (2003) noted a reverse J-shape association between gestation-adjusted birth weight and schizophrenia among Swedish male conscripts born in 1974–1980. In their later study with a further 5 years of follow-up of the cohort of Swedish men and women born in 1974–1980, they found little evidence of an association between deviant birth weight and schizophrenia. However, the authors concluded that the study did not rule out a small increased risk among babies N4.0 kg (Gunnell et al., 2005). Studies of deviant birth length and schizophrenia provide conflicting results. In the study by Wahlbeck et al. (2001) a unit (cm) decrease in birth length was associated with increased risk of schizophrenia (OR 1.12 95% CI 1.03–1.22). In addition, Gunnell et al. (2005) found an inverse association between birth lengths with schizophrenia. Short babies were at increased risk, the risk halving per 10 cm increase in birth length (hazard ratio 0.53; 95% CI 0.31–0.89). On the other hand, studies by Hultman et al. (1999) and Dalman et al. (1999, 2001) and meta-analysis based on these studies showed no evidence of shortness at birth and increased risk of schizophrenia; pooled odds ratio 1.06; 95% CI 0.86–1.31 (Cannon et al., 2002). The current study addresses these issues by extending the earlier findings from the Northern Finland 1966 Birth Cohort that low birth weight (Jones et al., 1998) increases the risk of schizophrenia. Here, we report the risk of schizophrenia across the entire distribution of birth weight among both sexes, as well as the relation between birth length and schizophrenia. 2. Methods 2.1. Subjects The data are extracted from the Northern Finland 1966 Birth Cohort which is an unselected, population-based sample of 12,058 children born alive (Rantakallio, 1969). It covers 96.3% of all live births in the provinces of Oulu and Lapland in Finland with an estimated date of birth between January 1st 1966 and December 31st 1966. This general population birth cohort has been followed for more than 30 years (Järvelin et al., 2004). The present study is based on 10,934 individuals living in Finland at the age of 16 years who allowed the use of their data. Permission to gather data was obtained from the Ministry of Health and Social Affairs provided the permission to collect the data from hospital records and the entire study was approved by the Ethical Committee of the Northern Ostrobothnia Hospital District. All participants gave written informed consent.

2.2. Early growth variables Birth weight (±5 g) was available for 10,932 subjects and birth length (±1 cm) for 10,933. These were measured and recorded immediately after birth (Jones et al., 1998). Ponderal index (birth weight / birth length3) was used as a measurement of thinness and nutritional status. Gestational age was defined by the mother's last menstrual period and was missing for 366 subjects, 7 of whom suffered from schizophrenia in adulthood.

2.3. Adult psychiatric morbidity The Finnish Hospital Discharge Register (FHDR) was established in the early 1970s and records all admissions to hospitals and health centres in Finland. It includes dates of admission and discharge, the primary ICD diagnosis, up to three subsidiary diagnoses and a hospital identification code (Miettunen et al., in press). Subjects with schizophrenia were identified in following four phases and summarised in a flow chart (Fig. 1). First, we identified all cohort members over 16 years who appeared in the FHDR until the end of 1997 (age 31–32) with any diagnosis of mental disorder (i.e. ICD-8 290–309, ICD-9 290–316, and ICD-10 F00–F69, F99). Second, we retrieved and scrutinized their hospital case records and validated the diagnoses according to DSM-III-R criteria (Isohanni et al., 1997; Moilanen et al., 2003). Inter-rater reliability was good with a kappa value of 0.85 for schizophrenia. Third, we interviewed as many as possible of the subjects identified in this way as having a psychotic DSM-III-R-diagnosis. This took place during 1999– 2001 when they were 33–35 years old. We used the Structured Diagnostic Interview for DSM-III-R (SCID; Spitzer et al., 1989) supplemented by anamnestic information from hospital case notes (Tanskanen et al., 2005). Finally, we combined the cases of schizophrenia validated by the SCID with those who could not be interviewed because they had died, could not be traced or refused our invitation but had been assigned a DSM-III-R-diagnosis of schizophrenia. As shown in Fig. 1, the present study includes 111 subjects with DSM-III-R schizophrenia. All of them had appeared on the FHDR and had their case notes reviewed to establish this diagnosis, of which 61 had subsequently been interviewed with the SCID to confirm the diagnosis. The comparison group consisted of the remaining population who had either not appeared on the FHDR with a mental illness or who had psychiatric disorders other than schizophrenia (N = 10 823).

2.4. Confounding factors We considered as potential confounding factors sex and parental history of psychosis. Cohort members' mothers and fathers who appeared on the FHDR between 1972 and 2000 for any psychosis (i.e. ICD-8 290–299, ICD-9 290–299, and ICD-10 F 20–29) were identified. This parental history of psychosis was used as a proxy variable for genetic risk by dividing the study population into those with and without a positive parental history.

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Cohort members with a diagnosis of DSM-III-R psychos is by the end of year 1997 according to the Finnish Hospital Discharge Register, n = 160

4 subjects did not fulfill the criteria of psychosis were excluded: -developmental disorder (3) -schizotypal personality disorder (1)

45 subjects had a diagnosis of nonschizophrenic psychosis and were excluded: -schizophreniform psychosis (8) -schizoaffective disorder (7) -psychotic depression (11) -bipolar disorder with psychotic features (8) -delusional disorder (6) -brief reactive psychosis (1) -psychotic disorder NOS (4)

Study population: subjects with a diagnosis of DSM-III-R schizophrenia, by the end of year 1997, n = 111

10 subjects with schizophrenia had died by the end of year 2001

Subjects with schizophrenia who were invited to participate in the field survey 1999-2001, n = 101

26 refused to participate and 14 were not traced

Subjects with schizophrenia who participated in the field survey 1999-2001 and were interviewed by SCID, n = 61

Non-participants with schizophrenia of whose diagnosis is based on validation of hospital notes against DSM-III-R criteria, n = 50

Combined sample of 111 DSM-III-R schizophrenia cases by the of year 1997 up to age 35 years. Fig. 1. Case ascertainment, diagnostic validation and definition of the study population applied in the Northern Finland 1966 Birth Cohort Study.

2.5. Statistical methods Numbers and percentages show the distribution of birth weight categories (low b2500 g, normal 2500–4499 g, and high ≥4500 g), birth weight adjusted for gestational age (small b2 SD, mean, and large N2 SD), birth length (≤46, 47– 53,and ≥54 cm) and ponderal index (g/m3 as ≤5, 6–94,

and ≥95 centiles) by diagnostic outcome. We defined small or large size for gestational age as being 2 SD below or above the mean birth weight for each gestational week. We used logistic regression analysis to examine the association between birth weight and length and schizophrenia; unadjusted and adjusted odds ratios (OR) and their 95% confidence interval (95% CI) were presented. In addition,

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Fig. 2. Smoothed OR curves of schizophrenia by birth weight and length. The curves were constructed by using generalized additive regression models. The shaded areas indicate two standard errors above and below the estimate of the smooth.

generalized additive logistic regression (Hastie and Tibshirani, 1990) was used to provide a graphic representation of the association between birth weight and schizophrenia (Fig. 2). Some investigators have drawn attention to the decline in mean birth weight for gestational age especially before the 37th week of gestation (Carr-Hill and Pritchard, 1983) while others (Rantakallio et al., 1991) have attributed this difference to errors in gestational age assessment. It has been proposed that many women experience bleeding in early pregnancy which may be misinterpreted as the last menstrual period before pregnancy. This would mean that some term or nearly term infants are wrongly recorded as preterm, and these cases would increase the mean birth weights in the corresponding gestational weeks. When comparing gestational ages calculated from the last menstrual period with those based on ultrasound measurements, underestimation is much more common than

overestimation (Bennett et al., 1982; Campbell et al., 1985; Imoedemhe et al., 1985). Therefore, we also used the “corrected” birth weights for gestational age in the analyses using a non-parametric regression model presented by Oja et al. (1991). In this model it is assumed that the only possible errors in gestational assessment are −4 weeks (underestimation) and +4 weeks (overestimation). Insertion of these error possibilities into the model yielded the final non-parametric mixture model. This model was used to estimate error risk in gestational assessment and also assigned a posterior probability of having miscalculated gestational age. The observed gestational age was corrected by −4 weeks, +4 weeks or not at all, according to the highest posterior probability of possible errors. The statistical analyses and graphics were undertaken using the free software package R (R Development Core Team, 2006).

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3. Results

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for interaction between birth weight and gender or parental history for psychosis was significant (test for interaction between birth weight and gender, P = 0.98, test for interaction between birth weight and parental history for psychosis, P = 0.3). Fig. 2 illustrates a reverse J-shaped association between birth weight and risk of schizophrenia from the generalized additive regression model with birth weight and birth length as a continuous variable.

Table 1 shows early growth variables of the cases and noncases stratified by sex. Schizophrenia cases did not differ significantly from non-cases concerning mean weight, mean length or ponderal index at birth. Low and high birth weight was more common among schizophrenia cases compared to non-cases. A corresponding finding was seen related to birth length schizophrenia cases were more often short and long at birth than non-cases. A multivariate analysis (Table 2) showed the association between birth weight and schizophrenia. Both low and high birth weight approximately doubled the risk of the schizophrenia. A similar pattern was found between birth length and schizophrenia. Short newborns had almost a three-fold, and tall newborns had nearly a two-fold risk of schizophrenia. We found no evidence of an association between deviant ponderal index and schizophrenia. Sixteen of the 111 schizophrenia cases had a parent with a positive history of psychosis (14%); the corresponding number among the 10,823 non-cases was 95 (0.9%). Neither of the tests

4. Discussion We report three main findings: elevated risk of later schizophrenia among particularly long newborns; replications of findings regarding increased risk of schizophrenia among infants with low but also high birth weight; confirmation of an association between elevated risks of schizophrenia among short newborns. The first of these is completely novel. The strengths of our study were the general populationbased birth cohort sample, contemporary and precise recording of birth weight and length, reduced risk for selection bias,

Table 1 Growth characteristics at birth of the schizophrenic subjects and non-cases in the Northern Finland 1966 Birth Cohort. Predictors

Birth weight (g) Birth length (cm) Ponderal index (g/cm3)

Males

Females

All

Schizophrenia

Non-cases

Schizophrenia

Non-cases

Schizophrenia

Non-cases

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

3534 50.4 27.1

704 2.38 2.61

3558 50.7 27.4

538 1.96 4.36

3432 49.8 28.3

768 2.03 3.36

3424 49.9 27.7

509 1.89 5.00

3497 50.2 27.6

727 2.27 2.95

3493 50.3 27.5

529 1.96 4.68

N

%

N

%

N

%

N

%

N

%

N

%

Birth weight (g) b 2500 2500–4499 ≥ 4500 All

4 62 6 72

6 86 8

158 5126 232 5516

3 93 4

4 33 2 39

10 85 5

205 4997 103 5305

4 94 2

8 95 8 111

7 86 7

363 10,123 335 10,821

3 94 3

Gestational age (week) b 37 ≥ 37 All

6 60 66

9 91

457 4882 5339

9 91

3 35 38

8 92

442 4674 5116

9 91

9 95 104

9 91

899 9556 10,455

9 91

Birth weight for gestational age Small (b 2 SD) Mean Large (N 2 SD) All

2 59 5 66

3 89 8

71 5065 202 5338

1 95 4

2 35 1 38

5 92 3

128 4906 82 5116

2 96 2

4 94 6 104

4 90 6

199 9971 284 10,454

2 95 3

Birth weight for “corrected” gestational age Small (b 2 SD) Mean Large (N 2 SD)

1 59 6

2 89 9

59 5072 207

1 95 4

0 37 1

0 97 3

100 4930 86

2 96 2

1 96 7

1 92 7

159 10,002 293

1 96 3

Birth length (cm) ≤ 46 47–53 ≥ 54 or over All

7 54 10 71

10 76 14

206 4890 421 5517

4 88 8

5 33 1 39

13 84 3

310 4842 154 5306

6 91 3

12 87 11 110

11 79 10

516 9732 575 10,823

5 90 5

Ponderal index (g/m3, centiles) ≤5 6–94 ≥ 95 All

5 64 2 71

7 90 3

288 4983 246 5517

5 90 5

2 33 4 39

5 85 10

242 4769 295 5306

5 90 5

7 98 6 110

6 89 5

530 9752 541 10,823

5 90 5

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Table 2 Birth weight, weight for gestational age, weight for “corrected” gestational age (calculated by using a non-parametric mixture model to estimate error risk in gestational assessment), length and ponderal index at birth in relation to risk of later schizophrenia in offspring in the Northern Finland 1966 Birth Cohort. Unadjusted OR (95% CI) for schizophrenia

Adjusted OR (95% CI) for schizophrenia

2.3 (1.1–4.9) Reference 2.5 (1.2–5.3)

2.5 (1.2–5.1) Reference 2.4 (1.1–4.9)

Birth weight for gestational age (N = 104) Small (b 2 SD) 2.1 (0.8–5.9) Mean Reference Large (N 2 SD) 2.2 (1.0–5.2)

2.2 (0.8–6.1) Reference 2.1 (0.9–5.0)

Birth weight (N = 111) Low (b 2500 g) Normal (2500–4499 g) High (≥4500 g)

Birth weight for “corrected” gestational age (N = 104) Small (b 2 SD) 0.7 (0.1–4.7) 0.7 (0.1–4.2) Mean Reference Reference Large (N 2 SD) 2.5 (1.1–5.4) 2.3 (1.0–5.1) Birth length (N = 110) Short (≤ 46 cm) Normal (47–53 cm) Long (≥54 cm)

2.3 (1.0–5.4) Reference 2.1 (1.1–3.9)

2.6 (1.1–5.9) Reference 1.8 (1.0–3.5)

Ponderal index (N = 110) ≤ 5 centiles 6–94 centiles ≥ 95 centiles

1.3 (0.6–2.8) Reference 1.1(0.5–2.5)

1.3 (0.6–2.8) Reference 1.2 (0.5–2.6)

Adj = Adjusted for parental history of psychoses and sex.

minimal missing data, careful diagnostic validation and strict DSM-III-R criteria for schizophrenia. The study had reasonable statistical power for our primary analyses since we were able to take advantage of the whole cohort. However, the rarity of functional psychoses and small effect sizes means that Type II statistical errors are possible; rejection of the null-hypothesis is not self-evident and large effects are probably worth considering even when confidence limits include unity. In a population-based sample, a nonsignificant result does not prove the null-hypothesis, but it may reflect either small effect size or inadequate power (Kraemer et al., 2001). This was also the case in the interaction tests. The use of interaction terms is controversial and there is no simple relationship between interaction terms and true interactions in population (Greenland, 1989). The contemporary somatic measurements taken immediately after birth are a considerable strength. Timing of birth weight measurements, as well as inaccuracy and rounding, may introduce a major source of error. Due to “regression dilution” bias (Clarke et al., 1999), errors in birth weight estimates would tend to underestimate the true strength of the association with health outcome. In our study, the last menstrual period was recorded at the beginning of pregnancy, decreasing the risk of recall bias concerning gestational age. Our results were also of the same magnitude when we used the “corrected” gestational ages in the analyses. Potential confounders of the association between schizophrenia, birth weight and length were selected according to their theoretical importance. The risk for schizophrenia is

higher in men than in women (Aleman et al., 2003), hence the consideration of sex of the offspring in our analyses. We used parental history of hospital-treated psychosis as an indicator of familial and genetic risk. This definition includes limitations: we were able to start the register data collection in 1972 when the cohort members were about 6 and their parents at ages about 30–40 years old. We also included all parental functional psychoses, something that was reflected in their high prevalence: 14% of parents of probands with schizophrenia had experienced hospital-treated psychosis. Based on earlier studies, 1.3% of parents of such probands would, themselves, have DSM-III-R schizophrenia (Kendler et al., 1993), while 6% have schizophrenia with a broader definition (Gottesman and Shields, 1982). Data on psychosis in the siblings were not available. On the other hand, the genetic liability for schizophrenia appears to be dispersed amongst a broad range of diagnoses in relatives (Tienari et al., 2003), which supports our decision to include all parental psychoses. When extending follow-up by 8 years our earlier result of the association between low birth weight and increased risk of schizophrenia was repeated (Jones et al., 1998) in line with many other studies (Cannon et al., 2002; Gunnell et al., 2003; Hultman et al., 1999; Kunugi et al., 2001; Smith et al., 2001; Wahlbeck et al., 2001). However, Gunnell et al. (2005) could not replicate their previous findings of a positive association between low birth weight and schizophrenia when they extended their analysis to females and had a longer period of follow-up with almost ten times more cases of schizophrenia (adjusted odds ratio 1.02, 95% CI 0.61 to 1.71). Our findings agree with the previous results of Gunnell et al. (2003) and of Bersani et al. (2007) of high birth weight and increased risk of schizophrenia, but they defined high birth weight more broadly than we did in our study (N4000 g vs. N4500 g). In the recent study by Gunnell et al. (2005) the evidence for increased risk was weak. Both our study and that of Hultman et al. (1997) are not directly comparable due to differing definitions of disproportional birth weight; they used birth weight for body length while we used large for gestational age. However, Dalman et al. (1999, 2001) found no association between high birth weight (N4500 g) and elevated risk of schizophrenia in their two studies, first with 254 and then with 524 Swedish schizophrenia cases. In relation to birth length and the risk of schizophrenia some previous findings have failed to prove any association (Cannon et al., 2002). However, the results of Wahlbeck et al. (2001) and Gunnell et al. (2005) concur with our findings of an association between short at birth and elevated risk of schizophrenia. Similarly, Byrne et al. (2007) demonstrated a trend for short birth length and increased risk of schizophrenia. To the best of our knowledge, the association between tall at birth and increased risk of schizophrenia has not been reported previously. By analyzing birth weight and birth length as a continuous variable in the generalized additive logistic regression model, it further supported the notion that there is an additive increase of risk in schizophrenia when birth weight and birth length either decreased or increased from the mean. Analyzing birth weight and birth length and association of schizophrenia across the range of birth weights and birth lengths means that it is possible to define any possible association between deviant birth weight, length and raised risk of schizophrenia throughout the range of reported values.

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Family history of psychosis is not included in many studies assessing risk for schizophrenia and birth weight (Hultman et al., 1997, 1999; Wahlbeck et al., 2001), although Sacker et al. (1996) found an increased risk for low birth weight infants in their meta-analysis concerning mothers with schizophrenia. On the other hand, Thomas et al. (2001) found no effect of maternal psychosis on the association between low birth weight and risk for schizophrenia. Maternal history of psychosis as an independent factor strongly increased the risk of schizophrenia among offspring in the Swedish studies by Dalman et al. (1999, 2001) but had no effect on the association between birth weight and schizophrenia. These authors were able to adjust for psychotic illness only in mothers, not the recorded biological fathers. Our own findings are similar to those of Thomas et al. (2001) and Dalman et al. (1999, 2001): the interaction between parental history for psychosis and birth weight was not significant. Among individuals destined to develop schizophrenia low birth weight has been reported as predicting poorer premorbid functioning and an earlier onset age of illness (Rifkin et al., 1994; Smith et al., 2001). Insulin-like factors (IGF), in particular IGF-I, play an important role in human growth and human brain development (Le Roith, 1997) with low birth weight infants having lower levels of IGFs (Ong et al., 2000). It has been hypothesised that low levels of IGF-I may be the true risk modifying factor, increasing an individual's susceptibly to schizophrenia (Gunnell and Holly, 2004). Furthermore, exposure to any kind of stress during pregnancy exerts activation of the hypothalamic–pituitary–adrenal axis, leading to an increase in maternal levels of steroids. Stressinduced glucocorticoid secretion may have a programming role for prenatal development and it can impair brain growth. It is known that the increased level of steroids reduces neonatal birth weight (Gur et al., 2004) and may decrease brain cell proliferation (van den Hove et al., 2006) as well as impairing hippocampal neurogenesis (Sapolsky et al., 2000; Coe et al., 2003) that may lead to structural and functional impairments underlying the increased risk for psychosis. High birth weight of schizophrenia subjects has previously been associated with early illness onset (Smith et al., 2001). High birth weight can provoke some obstetric complications or respiratory difficulties during prolonged labor that lead to hypoxic/ischemic brain damage (Bersani et al., 2007) so increasing the risk of schizophrenia (Rosso et al., 2000; Nicodemus et al., 2008). Alteration of normal gene expression, associated with this risk may result from hypoxia. Fetal hypoxia as a stress factor mediates expression of some important molecular determinants of synaptic plasticity and cellular homeostasis, particularly brain-derived neurotrophic factor (BDNF) (Fumagalli et al., 2004) with the BDNF gene being a putative candidate gene for schizophrenia (Shoval and Weizman, 2005). There is certainly evidence that shortness at birth has consequences for later health. It has been associated with risk of low intellectual and psychological performance (Lundgren et al., 2004), developmental delay (Morris et al., 1998) and coronary heart disease risk among women (Forsen et al., 1999). In the general population tall infants have been found to have higher risk of perinatal death (Melve et al., 2000) and breast cancer patients with high birth length have double the risk of dying from the disease (Maehle et al., 2010). The mechanisms

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behind the link with schizophrenia remain obscure but, again, may involve the effects on neural development and function of growth promoting hormones such as IGF and growth hormone. Our study has shown that deviant birth weight and length are characteristics that predict schizophrenia to a modest degree. Further research involving larger cohorts with stored prenatal serum will enable the investigation of the role of hormones that control intrauterine growth and later brain maturation that may mediate the link with schizophrenia. Role of Funding Source The Academy of Finland, the Research Foundation of Orion Corporation, the Sigrid Juselius Foundation and the Stanley Medical Research Institution had no further role in the study design; in collection, analysis and interpretation of data; in writing the report; and in the decision to submit the paper for publication. Contributors Authors Hartikainen and Järvelin collected the obstetric and the followup data. Authors Moilanen, Jokelainen, Jones and Isohanni planed this study and conducted the literature searches. Author Jokelainen planned and performed the statistical analysis. All authors contributed to and have approved the final manuscript. Conflict of Interest All authors declare that they have no personal, financial, or other conflict of interest related to the contents of this manuscript. Acknowledgements This work was supported by grants from the Academy of Finland, the Research Foundation of Orion Corporation, the Sigrid Juselius Foundation and the Stanley Medical Research Institute. Earlier versions of this paper were presented at the XIth Biennial Winter Workshop on Schizophrenia, Davos, Switzerland 24 February–1 March 2002 and at the 2002 APA Annual Meeting in Philadelphia, Pennsylvania 18–23 May 2002.

References Aleman, A., Kahn, R.S., Selten, J.P., 2003. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch. Gen. Psychiatry 60, 565–571. Bennett, M.L., Little, G., Dewhurst, C.J., Chamberlain, G., 1982. Predictive value of ultrasound measurement in early pregnancy: a randomized controlled trial. Br. J. Obstet. Gynaecol. 89 (5), 338–341. Bersani, G., Manuali, G., Ramieri, L., Taddei, I., Bersani, I., Conforti, F., Cattaruzza, M.S., Osborn, J., Pancheri, P., 2007. The potential role of high or low birthweight as risk factor for adult schizophrenia. J. Perinat. Med. 35 (2), 159–161. Byrne, M., Agerbo, E., Bennedsen, B., Eaton, W.W., Mortensen, P.B., 2007. Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study. Schizophr. Res. 97, 51–59. Campbell, S., Warsof, S.L., Little, D., Cooper, D.J., 1985. Routine ultrasound screening for the prediction of gestational age. Obstet. Gynecol. 65 (5), 613–620. Cannon, M., Jones, P.B., Murray, R.M., 2002. Obstetric complications and schizophrenia: historical and meta-analytical review. Am. J. Psychiatry 159 (7), 1080–1092. Carr-Hill, R.A., Pritchard, C.W., 1983. Reviewing birth weight standards. Br. J. Obstet. Gynaecol. 90 (8), 718–725. Clarke, R., Shipley, M., Lewington, S., Youngman, L., Collins, R., Marmot, M., Peto, R., 1999. Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am. J. Epidemiol. 150 (4), 341–353. Coe, C.L., Kramer, M., Czeh, B., Gould, E., Reeves, A.J., Kirschbaum, C., Fuchs, E., 2003. Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys. Biol. Psychiatry 54, 1025–1034. Dalman, C., Allebeck, P., Gullberg, J., Grunewald, C., Köster, M., 1999. Obstetric complication and the risk of schizophrenia: a longitudinal study of a National Birth Cohort. Arch. Gen. Psychiatry 56 (3), 234–240. Dalman, C., Thomas, H.V., David, A.S., Gentz, J., Lewis, G., Allebeck, P., 2001. Signs of asphyxia at birth and risk of schizophrenia. Population-based case–control study. Br. J. Psychiatry 179, 403–408.

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K. Moilanen et al. / Schizophrenia Research 124 (2010) 223–230

Forsen, T., Eriksson, J.G., Tuomilehto, J., Osmond, C., Barker, D.J.P., 1999. Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. BMJ 319, 1403–1407. Fumagalli, F., Bedogni, F., Perez, J., Racagni, G., Riva, M., 2004. Corticostriatal brain-derived neurotrophic factor dysregualtion in adult rats following prenatal stress. Eur. J. Neurosci. 20, 1348–1354. Gilmore, J.H., van Tol, J.J., Streicher, H.L., Williamson, K., Cohen, S.B., Greenwood, R.S., Charles, C.H., Kliewer, M.A., Whitt, K.J., Silva, S.G., Hertzberg, B.S., Chescheir, N.C., 2001. Outcome in children with fetal mild ventriculomegaly: a case series. Schizophr. Res. 48, 219–226. Gottesman, I.I., Shields, J., 1982. Schizophrenia: The Epigenetic Puzzle, first ed. Cambridge University Press, United Kingdom. Greenland, S., 1989. Modeling and variable selection in epidemiological analysis. Am. J. Public Health 79 (3), 340–349. Gunnell, D., Holly, J.M.P., 2004. Do insulin-like growth factors underlie associations of birth complications, fetal and pre-adult growth with schizophrenia? Schizophr. Res. 67 (1–2), 309–311. Gunnell, D., Rasmussen, F., Fouskakis, D., Tynelius, P., Harrison, G., 2003. Patterns of fetal and childhood growth and the development of psychosis in young males: a cohort study. Am. J. Epidemiol. 158 (4), 291–300. Gunnell, D., Harrison, G., Whitley, E., Tynelius, P., Rasmussen, F., 2005. The association of fetal and childhood growth with risk schizophrenia. Cohort study of 720.00 Swedish men and women. Schizophr. Res. 79 (2–3), 313–322. Gur, C., Diav-Citrin, O., Shechtman, S., Arnon, J., Ornoy, A., 2004. Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod. Toxicol. 18, 93–101. Hastie, T., Tibshirani, R., 1990. Generalized Additive Models, second ed. Chapman & Hall, New York. Hultman, C.M., Ohman, A., Cnattingius, S., Wieselgren, I.M., Lindstrom, L.H., 1997. Prenatal and neonatal risk factors for schizophrenia. Br. J. Psychiatry 170, 128–133. Hultman, C.M., Sparen, P., Takei, N., Murray, R.M., Cnattingius, S., 1999. Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case–control study. BMJ 318, 421–426. Ichiki, M., Kunugi, H., Takei, N., Murray, R.M., Baba, H., Arai, H., Oshima, I., Okagami, K., Sato, T., Hirose, T., Nanko, S., 2000. Intra-uterine physical growth in schizophrenia: evidence confirming excess of premature birth. Psychol. Med. 30 (3), 597–604. Imoedemhe, D.A., Mitford, E., Chan, R., Djahanbakhch, O., 1985. An evaluation of routine early pregnancy ultrasonography. Acta Obstet. Gynecol. Scand. 64 (5), 427–431. Isohanni, M., Mäkikyrö, T., Moring, J., Räsänen, P., Hakko, H., Partanen, U., Koiranen, M., Jones, P., 1997. A comparison of clinical and research DSMIII-R diagnoses of schizophrenia in a Finnish National Birth Cohort. Clinical and research diagnoses of schizophrenia. Soc. Psychiatry Psychiatr. Epidemiol. 32 (5), 303–308. Järvelin, M.R., Sovio, U., King, V., Lauren, L., Baizhuang, X., McCarthy, M.I., Hartikainen, A.L., Laitinen, J., Zitting, P., Rantakallio, P., Elliott, P., 2004. Early life factors and blood pressure at age 31 years in the 1966 Northern Finland Birth Cohort. Hypertension 44, 838–846. Jones, P.B., Rantakallio, P., Hartikainen, A.L., Isohanni, M., Sipilä, P., 1998. Schizophrenia as a long-term outcome of pregnancy, delivery, and perinatal complications: a 28-year follow-up of the 1966 North Finland General Population Birth Cohort. Am. J. Psychiatry 155 (3), 355–364. Kendell, R.E., McInneny, K., Juszczak, E., Bain, M., 2000. Obstetric complications and schizophrenia. Two case–control studies based on structured obstetric records. Br. J. Psychiatry 176, 516–522. Kendler, K.S., McGuire, M., Gruenberg, A.M., O'Hare, A., Spellman, M., Walsh, D., 1993. The Roscommon family study. I. Methods, diagnosis of probands, and risk of schizophrenia in relatives. Arch. Gen. Psychiatry 50 (7), 527–540. Kraemer, H.C., Stice, E., Kadzin, A., Offord, D., Kupfer, D., 2001. How do risk factors work together? Mediators, moderators, and independent, overlapping and proxy risk factors. Am. J. Psychiatry 58 (6), 848–856. Kunugi, H., Nanko, S., Murray, R.M., 2001. Obstetric complications and schizophrenia: prenatal underdevelopment and subsequent neurodevelopmental impairment. Br. J. Psychiatry Suppl. 40, s25–s29. Le Roith, D., 1997. Insulin-like growth factors. N. Engl. J. Med. 336, 633–640. Lundgren, M., Cnattingius, S., Jonsson, B., Tuvemo, T., 2004. Intellectual performance in young adult males born small for gestational age. Growth Horm. IGF Res. 14, S7–S8. Maehle, B., Vatten, L.J., Tretli, S., 2010. Birth length and weight as predictors of breast cancer prognosis. BMC Cancer 10, 15. McNeil, T.F., Cantor-Graae, E., Nordstrom, L.G., Rosenlund, T., 1993. Head circumference in “preschizophrenic” and control neonates. Br. J. Psychiatry 162, 517–523. Melve, K.K., Gjessing, H.K., Skjærven, R., Øyen, N., 2000. Infants' length at birth: an independent effect on perinatal mortality. Acta Obstet. Gynecol. Scand. 79, 459–464.

Miettunen, J., Suvisaari, J., Haukka, J., Isohanni., M., in press. Use of Register Data for Psychiatric Epidemiology in the Nordic Countries, in: Tsuang, M., Tohen, M., Jones. P. (Eds.), Textbook in Psychiatric Epidemiology, 3 rd edition. Wiley-Blackwell. Moilanen, K., Jokelainen, J., Hartikainen, A.L., Järvelin, M.R., Jones, P.B., Isohanni, M., 2002. High birth weight for gestational age as a predictor of schizophrenia: a 31-year follow-up of the Northern Finland 1966 Birth Cohort. Schizophr. Res. 53, s244. Moilanen, K., Veijola, J., Läksy, K., Mäkikyrö, T., Miettunen, J., Kantojärvi, L., Kokkonen, P., Karvonen, J.T., Herva, A., Joukamaa, M., Järvelin, M.L., Jones, P.B., Isohanni, M., 2003. Reasons for the diagnostic discordance between clinicians and researchers in schizophrenia in the Northern Finland 1966 Birth Cohort. Soc. Psychiatry Psychiatr. Epidemiol. 38 (6), 305–310. Morris, S.S., Victoria, C.G., Barros, F.C., Halpern, R., Menezes, A.M.B., Cesar, J.A., Horta, B.L., Tomasi, E., 1998. Length and ponderal index at birth: associations with mortality, hospitalizations, development and postnatal growth in Brazilian infants. Int. J. Epidemiol. 27, 242–247. Nicodemus, K.K., Marenco, S., Batten, A.J., Vakkalanka, R., Egan, M.F., Straub, R.E., Weinberger, D.R., 2008. Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol. Psychiatry 13, 873–877. Oja, H., Koiranen, M., Rantakallio, P., 1991. Fitting mixture models to birth weight data: a case study. Biometrics 47 (3), 883–897. Ong, K., Kratzsch, J., Kiess, W., Costello, M., Scott, C., Dunger, D., 2000. Size at birth and cord blood levels of insulin, insulin-like growth factor 1 (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3 and the soluble IGF-II/ mannose-6-phosphate receptor in term human infants. The ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. J. Clin. Endocrinol. Metab. 85, 4266–4269. R Development Core Team, 2006. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Rantakallio, P., 1969. Groups at risk in low birth weight infants and perinatal mortality. Acta Paediatr. Scand. 193, 1–71. Rantakallio, P., Oja, H., Koiranen, M., 1991. Has the intrauterine weight-gain curve changed in shape? Paediatr. Perinat. Epidemiol. 5 (2), 201–210. Rifkin, L., Lewis, S., Jones, P., Toone, B., Murray, R., 1994. Low birth weight and schizophrenia. Br. J. Psychiatry 165, 357–362. Rosso, I.M., Cannon, T.D., Huttunen, T., Huttunen, M.O., Lönnqvist, J., Casperoni, T.L., 2000. Obstetric risk factors for early-onset schizophrenia in a Finnish Birth Cohort. Am. J. Psychiatry 157 (5), 801–807. Sacker, A., Done, D.J., Crow, T.J., Golding, J., 1995. Antecedents of schizophrenia and affective psychoses: obstetric complications. Br. J. Psychiatry 166, 734–741. Sacker, A., Done, D.J., Crow, T.J., 1996. Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case–control studies. Psychol. Med. 26, 279–288. Sapolsky, R.M., Romero, L.M., Munck, A.U., 2000. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr. Rev. 21, 55–89. Shoval, G., Weizman, A., 2005. The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia. Eur. Neuropsychopharmacol. 15 (3), 319–329. Smith, G.N., Flynn, S.W., McCarthy, N., Meistrich, B., Ehmann, T.S., MacEwan, G.W., Altman, S., Kopala, L.C., Honer, W.G., 2001. Low birthweight in schizophrenia: prematurity or poor feral growth? Schizophr. Res. 47, 177–184. Spitzer, R.I., Williams, J.B.W., Gibbon, M., First, B., 1989. Structural Diagnostic Interview for DSM-III-R. Structured Clinical Interview for DSM-III-RPatient Edition (SCID-P 9/1/89 Version). Biometrics Research Department, New York State Psychiatric Institute, New York, NY. Tanskanen, P., Veijola, J.M., Piippo, U.K., Haapea, M., Miettunen, J.A., Pyhtinen, J., Bullmore, E.T., Jones, P.B., Isohanni, M., 2005. Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 Birth Cohort. Schizophr. Res. 75, 283–294. Thomas, H.V., Dalman, C., David, A.S., Gentz, J., Lewis, G., Allebeck, P., 2001. Obstetric complications and risk of schizophrenia. Effect of gender, age at diagnosis and maternal history of psychosis. Br. J. Psychiatry 179, 409–414. Tienari, P., Wynne, L.C., Läksy, K., Moring, J., Nieminen, P., Sorri, A., Lahti, I., Wahlbeck, K.E., 2003. Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish adoptive family study of schizophrenia. Am. J. Psychiatry 160 (9), 1587–1594. Van den Hove, D.L., Steinbusch, H.W., Scheepens, A., van den Berg, W.D., Kooiman, L.-A., Boosten, B.J., Prickaerts, J., Blanco, C.E., 2006. Prenatal stress and neonatal rat brain development. Neuroscience 137 (1), 145–155. Wahlbeck, K., Forsen, T., Osmond, C., Barker, D.J., Eriksson, J.G., 2001. Association of schizophrenia with low maternal body mass index, small size at birth, and thinness during childhood. Arch. Gen. Psychiatry 58 (1), 48–52.