Deviant intrauterine growth and risk of schizophrenia: A 34-year follow-up of the Northern Finland 1966 Birth Cohort
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 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 (< 2500 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 (< 2000 g) resulting in a higher risk (OR 3.9; 95% CI 1.4–10.8).
There are four reports concerning the association of high birth weight with schizophrenia, two from Sweden (Hultman et al., 1997, Hultman et al., 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 (> 4000 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 > 4.0 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, Dalman et al., 1999, Dalman et al., 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.
Section snippets
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
Results
Table 1 shows early growth variables of the cases and non-cases 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
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 population-based birth cohort sample, contemporary and precise recording of birth weight and length,
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 follow-up 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 (60)
- et al.
Obstetric conditions and risk of first admission with schizophrenia: a Danish national register based study
Schizophr. Res.
(2007) - et al.
Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys
Biol. Psychiatry
(2003) - et al.
Outcome in children with fetal mild ventriculomegaly: a case series
Schizophr. Res.
(2001) - et al.
Do insulin-like growth factors underlie associations of birth complications, fetal and pre-adult growth with schizophrenia?
Schizophr. Res.
(2004) - et al.
Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study
Reprod. Toxicol.
(2004) - et al.
The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia
Eur. Neuropsychopharmacol.
(2005) - et al.
Low birthweight in schizophrenia: prematurity or poor feral growth?
Schizophr. Res.
(2001) - et al.
Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 Birth Cohort
Schizophr. Res.
(2005) - et al.
Prenatal stress and neonatal rat brain development
Neuroscience
(2006) - et al.
Sex differences in the risk of schizophrenia: evidence from meta-analysis
Arch. Gen. Psychiatry
(2003)
Predictive value of ultrasound measurement in early pregnancy: a randomized controlled trial
Br. J. Obstet. Gynaecol.
The potential role of high or low birthweight as risk factor for adult schizophrenia
J. Perinat. Med.
Routine ultrasound screening for the prediction of gestational age
Obstet. Gynecol.
Obstetric complications and schizophrenia: historical and meta-analytical review
Am. J. Psychiatry
Reviewing birth weight standards
Br. J. Obstet. Gynaecol.
Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies
Am. J. Epidemiol.
Obstetric complication and the risk of schizophrenia: a longitudinal study of a National Birth Cohort
Arch. Gen. Psychiatry
Signs of asphyxia at birth and risk of schizophrenia. Population-based case–control study
Br. J. Psychiatry
Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study
BMJ
Corticostriatal brain-derived neurotrophic factor dysregualtion in adult rats following prenatal stress
Eur. J. Neurosci.
Schizophrenia: The Epigenetic Puzzle
Modeling and variable selection in epidemiological analysis
Am. J. Public Health
Patterns of fetal and childhood growth and the development of psychosis in young males: a cohort study
Am. J. Epidemiol.
The association of fetal and childhood growth with risk schizophrenia. Cohort study of 720.00 Swedish men and women
Schizophr. Res.
Generalized Additive Models
Prenatal and neonatal risk factors for schizophrenia
Br. J. Psychiatry
Prenatal and perinatal risk factors for schizophrenia, affective psychosis, and reactive psychosis of early onset: case–control study
BMJ
Intra-uterine physical growth in schizophrenia: evidence confirming excess of premature birth
Psychol. Med.
An evaluation of routine early pregnancy ultrasonography
Acta Obstet. Gynecol. Scand.
A comparison of clinical and research DSM-III-R diagnoses of schizophrenia in a Finnish National Birth Cohort. Clinical and research diagnoses of schizophrenia
Soc. Psychiatry Psychiatr. Epidemiol.
Cited by (37)
Meta-analysis of comorbid diabetes and family history of diabetes in non-affective psychosis
2020, Schizophrenia ResearchCitation Excerpt :There is also evidence for a number of shared prenatal risk factors for schizophrenia and DM2. These include nulliparity (Dalman et al., 1999), maternal obesity and gestational diabetes (Cannon et al., 2002), preeclampsia (Cannon et al., 2002), exposure to prenatal famine/nutritional deficiency (Susser et al., 1996), low and high birth weight (Moilanen et al., 2010), and season of birth (Messias et al., 2004). Furthermore, the majority of offspring exposed to these risk factors do not develop schizophrenia, suggesting that an interaction between environmental factors and genetic vulnerability may mediate these associations in susceptible individuals.
Gestational length affects neurocognition in early-onset schizophrenia
2016, Psychiatry Research