Gestational length affects neurocognition in early-onset schizophrenia
Introduction
According to neurodevelopmental models, schizophrenia is the behavioral outcome of deviations in early neurodevelopment, including prenatal insults such as obstetric complications (OC) (Brown, 2006, Brown et al., 2005, Cannon et al., 2002). Several studies and meta-analyses indicate an association between OC and the later development of schizophrenia, and suggest three groups of complications; complications of pregnancy, abnormal fetal growth and development, and complications of delivery (Brown et al., 2011, Byrne et al., 2007, Cannon et al., 2002, Clarke et al., 2012).
While fetal hypoxia has strong support as a risk factor for schizophrenia (Clarke et al., 2012, Rosso et al., 2000), it has also been proposed to mediate the effects of other OC (Cannon et al., 2000, Clarke et al., 2012). Research also indicate an association between schizophrenia and prenatal exposure to infection (Brown, 2006, Brown et al., 2000, Brown et al., 2009, Mittal et al., 2008b), to inflammation (Cannon et al., 2014, Chaves et al., 2015), to stress (Holloway et al., 2013, Khashan et al., 2008, Malaspina et al., 2008, van Os and Selten, 1998) and to diabetes (Cannon et al., 2002, Van Lieshout and Voruganti, 2008). Though the results diverge, a few studies find a relationship between risk of schizophrenia and a low birth weight, especially below 2500 g (Abel et al., 2010, Gunnell et al., 2003, Hultman et al., 1999, Lahti et al., 2015), a low and high birth weight (Gunnell et al., 2003, Moilanen et al., 2010) and a low gestational age (Byrne et al., 2007, Geddes et al., 1999, Nosarti et al., 2012). However, the direct association between OC and schizophrenia has been debated, and cohort studies have mostly failed to confirm this effect (Rosso et al., 2000). In a Scottish population study by Kendell et al. (2000), there were no significant associations between OC and schizophrenia in one birth-cohort, while a caesarean section and long-lasting labor were more common in a later birth-cohort. Similar results were found in a Finnish study with no significant primary effect of OC on the risk of schizophrenia (Clarke et al., 2011).
A meta-analysis suggests that risk of schizophrenia associated with OC might be particularly important for those with a young age at symptom onset, indicating that it involves neurodevelopmental impairment (Verdoux et al., 1997). Recent studies support these findings; Preti et al. (2012) detect an associations between OC and earlier age of onset, while Rubio-Abadal et al. (2015) claim that lower birth weight and more OC determine an earlier onset-age. Because research indicates different results due to age of onset, several studies have examined young people with psychosis. A common cut-off point in early-onset schizophrenia (EOS) has been on symptom onset before 18 years of age, which includes about 5% of the schizophrenia population (Cannon et al., 1999, Frangou, 2013, Holmen et al., 2012, Juuhl-Langseth et al., 2014). EOS patients are especially interesting for research because they are in their adolescence, a period with extensive brain maturation and alterations in cognitive structures and functions (Juuhl-Langseth et al., 2014). Consequently, they provide unique neurodevelopmental data that may contribute to a better understanding of schizophrenia at all ages (Rapoport et al., 2012, Remschmidt, 2002). Nonetheless, most studies of OC and schizophrenia include all patients, thus; a majority with onset after 18 years of age (adult-onset schizophrenia (AOS) (Juuhl-Langseth et al., 2014, Oie et al., 2011)), implying that the findings from AOS studies could potentially be influenced by the small number of participants in the sample with EOS.
So far, little is known about the role of prenatal insults on EOS (Margari et al., 2011). One study reports no relationship between OC and EOS (Margari et al., 2011). In a populations with onset before 13 years of age, Matsumoto et al. (1999) detect an association between OC and psychosis, while Ordonez et al. (2005) find no such relationship. A number of studies use obstetric material collected from maternal recall, which may be unreliable (Kotlicka-Antczak et al., 2014, McIntosh et al., 2002). We have found only two studies on OC and early psychosis that have used information from birth registries in comparison to healthy controls (Cannon et al., 2000, Rosso et al., 2000). Both centered on hypoxia-associated OC, and found that these complications increased the odds of earlier onset of psychosis but not of later onset. The studies used median splits for age of onset, hence implying that the mean age in the early psychosis group was above 18 (27.1/21.5, respectively). Even so, the findings indicate that complications during pregnancy and birth may have a specific impact on early psychosis. Consequently, studies of the relationship between OC and EOS are of particular interest.
It has been suggested that cognitive dysfunction is a central feature of schizophrenia that often exists prior to symptoms, which reflects underlying abnormalities in brain neurodevelopment (Frangou, 2013, Rund, 2009, Rund et al., 2015, Seidman et al., 2006). Patients with EOS and AOS seem to have a similar cognitive profile (Holmen et al., 2010, Oie et al., 2011), but EOS is reckoned to be more severe with worse premorbid abnormalities, as well as worse long term symptomatic and functional outcomes (Frangou, 2013, Kumra and Charles Schulz, 2008). In understanding the course of the abnormal brain development in schizophrenia, some suggest an association between OC and cognitive impairment (Ellman et al., 2012, Freedman et al., 2013, Ochoa et al., 2013, Torniainen et al., 2013). Comprehending the manner in which OC and cognition coalesce may help clarify the pathway that underlies psychotic illness, which is essential for developing primary prevention strategies (Mittal et al., 2008a).
Earlier findings indicate that OC may have a specific impact on EOS (Cannon et al., 2000, Rosso et al., 2000), as well as on neurocognition (Ellman et al., 2012, Freedman et al., 2013, Ochoa et al., 2013, Torniainen et al., 2013). Still, we find no previous study that has examined the relationship between OC and cognition in EOS. So far, most research on OC and neurodevelopment have investigated AOS and single OC measures, such as hemoglobin levels during pregnancy (Ellman et al., 2012), maternal infections (Brown et al., 2009), maternal influenza (Ellman et al., 2009) or birth weight (Freedman et al., 2013, Torniainen et al., 2013).
There are reasons to believe that different OC would likely affect different areas of cognition. In one study, Brown et al. (2009) found that prenatal infections were associated with impaired executive function in schizophrenia. While previous research has identified strong associations between executive dysfunction and structural and functional deficits in the prefrontal cortex (Goldberg et al., 1990, Rusch et al., 2007), both deficits might be affected by gestational exposure to infections. Other research suggests that schizophrenia cases that have been exposed to influenza during gestation have a higher risk of impairments in verbal tasks (Ellman et al., 2009), whereas hypoxia-associated OC were found to be unrelated to language acquisition deficits in the premorbid period (Bearden et al., 2000). Interestingly, reductions in neurocognitive performance among those exposed to OC was less extensive in the healthy control group with the same labor-conditions (Ellman et al., 2012, Ellman et al., 2009, Freedman et al., 2013), which may indicate a greater effect of OC on neuropsychological development in schizophrenia. This underscores the importance of studies in which an assessment of healthy controls is included, as well as studies that aim to identify the magnitude of specific OC on specific domains of cognition in schizophrenia.
Ochoa et al. (2013) examined a wider range of OC in relation to cognitive functioning, and found that first episode schizophrenia (FES) patients with a higher level of “neurodevelopmental contribution” (including OC) had a significantly slower processing speed than that of other FES patients. Healthy controls were not evaluated. Even though Ochoa et al. (2013) did not consider OC separately, the findings supported an association between fetal development and cognition in schizophrenia.
The present study is the first to investigate a relationship between OC and cognitive deficits in EOS. Earlier results from our research group have found significant neurocognitive deterioration in EOS patients (Holmen et al., 2010, Juuhl-Langseth et al., 2014, Thormodsen et al., 2012), and an interesting question is whether there may be associations between OC and cognition in the same sample.
Due to previous research that indicates an association between OC and earlier age of symptom onset in schizophrenia; our first research hypothesis is that we expect to find a higher frequency of OC among EOS patients than among healthy controls. Furthermore, findings suggest an association between OC and cognitive dysfunction in schizophrenia. There are reasons to assume that different OC may affect different areas of cognition, such as executive functions and processing speed. Our second hypothesis is therefore that OC affect the overall cognition in EOS, but have a more profound impact on executive functions and processing speed.
Section snippets
Subjects
The patients were participants in the Early-onset Study (starting in 2005), a broader research project at the University of Oslo on early-onset psychotic disorders (Holmen et al., 2010, Juuhl-Langseth et al., 2014, Thormodsen et al., 2012). The patients were recruited from different inpatient and outpatient units in Oslo and the region of Eastern Norway, and were included if they were between 12 and 18 years of age and met the diagnosis criteria for a broad schizophrenia-spectrum disorder
Results
There were no statistically significant differences in frequency of OC between the EOS group and the healthy controls (Table 3). Some of the participants in the EOS group have the diagnosis of psychosis NOS. When the group of NOS (N=7) was excluded from the analyses, the results were unchanged.
As expected and previously reported (Holmen et al., 2010, Juuhl-Langseth et al., 2014, Thormodsen et al., 2012), the EOS group performed significantly worse than the HC in all cognitive domains, except in
Discussion
The present study is the first to examine a large number of obstetric complications in relation to neuropsychological functioning in early-onset schizophrenia. Contrary to our first hypothesis, we found no significant associations between OC and EOS in comparison to healthy controls. These results were sustained when we excluded the participants in the EOS group who had the diagnosis of Psychosis NOS, and when we pair-matched the samples on age and gender. Earlier research suggested an
Role of the funding source
This work was supported by the South-Eastern Norway Regional Health Authority (Grant numbers 2004-259 and 2006-186 to Dr. Rund). The funding source had no role in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
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