In the first study, HBW (> 4000 g) was found to be associated with increased risk of schizophrenia. A statistically significant association between birth weight and PPDs other than schizophrenia was not detected, suggesting that individuals who later develop schizophrenia may be particularly sensitive to pre- and perinatal factors associated with birth weight. An association between LBW (< 2500 g) and schizophrenia was not detected, despite this being a widely replicated finding in the literature (Cannon et al. 2002a; Abel
et al., 2010; Byars et al., 2014). This discrepancy is proposed to reflect the
assumption that the risk factors associated with schizophrenia may be different among individuals presenting with elevated genetic liability for schizophrenia, in comparison to the risk factors operating in the general population (Keskinen et al., 2013). It is also possible that morbidity later in life, which has been commonly associated with LBW, has become more apparent in more recent cohorts due the decrease in mortality seen among LBW neonates in younger cohorts as a result of advances in obstetric and neonatal care (McCormick et al., 1985; Heinonen et al., 1988; Sipilä et al., 1994). The median year of the birth study sample was 1957 and thus, subjects comprising the study group were born during a period of major advancements in obstetric services in Finland. This is, for example, reflected in the number of births that took place in hospitals, which in Finland increased from 31.0% to 92.5% between the years 1940 and 1960 (Hemminki, 1983); during this period the infant mortality rate also decreased from 4% (1950-1951) to 0.5% (1991-1995) (The official statistics of Finland XI: 62, 1962; Hemminki, 1983; Piekkala et al., 1986; Pitkänen et al., 2000). The distribution of birth weight has also changed in the Finnish population, and the overall prevalence of HBW neonates in younger cohorts has increased (Kinnunen et al., 2003; Lahti-Koski et al., 2010).
The association between HBW and schizophrenia described in the present study in conjunction with elevated genetic loading for schizophrenia supports recent findings from the NFBC suggesting that HBW increases schizophrenia risk, particularly among subjects presenting with elevated genetic liability for schizophrenia (Keskinen et al., 2013). Interestingly, in the literature HBW has been found to associate with an increased risk of neurodevelopmental disorders, including ASDs in both the Swedish (Abel et al., 2013), and the Danish (Byars et al., 2014) populations. ASDs have been associated with elevated heritability estimates (80%) similar to that of schizophrenia (Sullivan
et al., 2012), supporting evidence suggesting that the interaction of genetic
predisposition and pre- and perinatal factors associated with HBW may influence neurodevelopment.
This study corroborates previous reports describing an association between HBW and increased schizophrenia risk (Hultman et al., 1997; Gunnell et al., 2003; Bersani et al., 2007; Moilanen et al., 2010). However, it was not possible to assess the direct causal factors underlying this association in the study sample. The causal mechanisms underlying the association between HBW and schizophrenia risk have not to date been investigated in the literature. One of the potential causal mechanisms underlying the association between HBW and schizophrenia could be pre- and perinatal hypoxia. HBW is associated with hypoxia-related obstetric complications, including prolonged labour, instrumental vaginal delivery, emergency Caesarean section, Apgar score <4 and increased admission to a neonatal special care unit (Jolly et al., 2003; Jastrow et al., 2010). There is evidence for an association between the overall severity of obstetric complications and increased ventricular enlargement in subjects with schizophrenia (Bersani et al., 2009), and hypoxic-ischaemia- related obstetric complications have been associated with an increased risk of developing a psychotic disorder (Zornberg et al., 2000). Some evidence suggests that subjects with genetic liability for schizophrenia, may be more susceptible to decreased foetal growth in connection with prenatal adversities such as pre-eclampsia, prenatal infection and hypoxia (Eide et al., 2013; Fineberg et al., 2013). An association between LBW and schizophrenia was not detected in this study sample, presenting with high genetic loading for schizophrenia, suggesting the pre- and perinatal factors associated with elevated genetic susceptibility may be different from those operating in the general population.
The association of perinatal hypoxia and genetic liability is a well replicated finding in relation to schizophrenia risk (Stefanis et al., 1999; Rosso et al., 2000; Cannon et al., 2002b; Van Erp et al., 2002; Schulze et al., 2003; Ebner
et al., 2008). It is possible that the influence of HBW on hypoxia-related
specialized obstetric and neonatal care was limited. Advances in obstetric care may have reduced the frequency and severity of HBW-associated hypoxia- related obstetric complications in younger cohorts (Henriksen, 2008; Koyanagi et al., 2013). It is also probable that the risk of hypoxia-related perinatal complications associated with the delivery of a large infant would have been elevated, particularly among subjects born at home relative to subjects born in a hospital setting.
Based on the primary finding of an association between HBW and schizophrenia, it was investigated whether this association was driven by maternal diabetes. Gestational diabetes, one of the strongest triggers of HBW (Wallace and McEwan, 2007), was not routinely diagnosed prior to the 1970s (Golden et al., 2009), thus information on maternal diabetes at the time of the interview was used a proxy for a possible history of gestational diabetes. This inference was justified based on findings demonstrating that women with gestational diabetes have been found to present with a 10-fold increased risk of developing T2DM (Shen et al., 2016). In the present study, maternal diabetes was found to increase schizophrenia risk among offspring. However, the association was found to be independent of birth weight. A statistically significant association between maternal diabetes and primary PPDs other than schizophrenia was not detected, suggesting that individuals who develop schizophrenia may be sensitive to factors related to impaired maternal glucose metabolism during pregnancy. The observation is in accordance with previous findings describing an association between maternal diabetes during pregnancy and increased schizophrenia risk among offspring (Cannon et al., 2002a). However, the meta-analysis by Cannon et al. (2002a) did not differentiate between types of diabetes (type 1, type 2 or gestational diabetes) and also did not specify whether impaired maternal glucose metabolism was present before pregnancy. In the current study, the precise nature and course of maternal diabetes in relation to pregnancy were also unknown. Offspring of diabetic mothers have been found to present with HBW, LBW and normal birth weight, depending on the severity of diabetes, the degree of diabetic control and the presence of other complicating factors (Ornoy, 2011). Maternal diabetes during pregnancy is most commonly associated with HBW. However, diabetes during pregnancy in combination with such complications as nefropathy is typically associated with LBW (Kendrick et al., 2015). Diabetes during pregnancy is associated with foetal hypoxia, immune system activation, oxidative stress, placental abnormalities, pre-eclampsia, lower Apgar scores and increased requirement of Caesarean section, factors also associated with increased schizophrenia risk (Kotlicka-Antczak et al., 2001; Cannon et al., 2002a; Van Lieshout and Voruganti, 2008; Reece et al., 2009; Benros et al.,
2011; Ornoy, 2011; Vambergue and Fajardy, 2011; Wadsack et al., 2012; Eide
independent of one another. Interestingly, T2DM has been found to be more prevalent among parents of individuals with psychotic disorders, suggestive of shared environmental and genetic risk factors underlying both disorders (Fernandez-Egea et al., 2008a, Fernandez- Egea et al., 2008b; Van Welie et
al., 2013; Miller et al., 2016). Interestingly, specific variants of the D2-receptor gene have recently been found to associate with elevated glucose levels among subjects with schizophrenia, strengthening the evidence for possible shared risk factors underlying glucose metabolism and psychiatric morbidity (Lawford et al., 2016).
Various autoimmune diseases, including systemic lupus erythematosus, Sjogren’s syndrome and rheumatoid arthritis, and some childhood leukaemias have been associated HBW (Simard et al., 2008; Caughey et al., 2009; Mandl
et al., 2009). The mechanisms underlying an association between HBW and
immunological disorders remain relatively unsubstantiated. One explanation has been suggested to relate to the effects of cortisol and prenatal dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis (Phillips et
al., 1998). Patients with rheumatoid arthritis have been proposed to present
with abnormally low levels of cortisol, which may associate with increased inflammation (Imrich and Rovensky, 2010).