Elsevier

Psychiatry Research

Volume 244, 30 October 2016, Pages 78-85
Psychiatry Research

Gestational length affects neurocognition in early-onset schizophrenia

https://doi.org/10.1016/j.psychres.2016.07.017Get rights and content

Highlights

  • A shorter gestational length in EOS led to significant decreases in cognition.

  • Gestational length had a different impact on patients with EOS than controls.

  • A shorter gestational length did not increase the risk for developing EOS.

Abstract

Obstetric complications (OC) have been linked to an increased risk for schizophrenia in offspring, especially in early-onset schizophrenia (EOS). Extensive cognitive deficits occur in EOS, although no study has yet to investigate the relationship between OC and cognition in EOS. This study aims to examine the frequency of OC in EOS compared to controls, and also investigates the relationship between OC and neurocognitive dysfunction in the two groups. Nineteen EOS patients and 53 healthy controls were tested with the MATRICS Consensus Cognitive Battery (MCCB), and the cognitive measures were combined with OC data from the Norwegian Birth Registry. The results indicated no group differences in OC in EOS and healthy controls, but a shorter gestational length in the EOS group led to significant decreases in the overall neurocognitive composite score, and in processing speed. This suggests that the poorer neuropsychological performances commonly found in EOS may be partly attributable to the length of gestation. The worsened neurocognitive functioning did not appear among controls, so gestational length had a different impact on the two groups. Our findings indicated that a shorter gestational length did not increase the risk for developing EOS, but did significantly affect the cognitive difficulties in this group.

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.

References (91)

  • M. Juuhl-Langseth et al.

    Relative stability of neurocognitive deficits in early onset schizophrenia spectrum patients

    Schizophr. Res.

    (2014)
  • R.S. Keefe et al.

    Characteristics of the MATRICS Consensus Cognitive Battery in a 29-site antipsychotic schizophrenia clinical trial

    Schizophr. Res.

    (2011)
  • M. Kotlicka-Antczak et al.

    Obstetrical complications and Apgar score in subjects at risk of psychosis

    J. Psychiatr. Res

    (2014)
  • E.J. Lawrence et al.

    The very preterm brain in young adulthood: the neural correlates of verbal paired associate learning

    J. Pedia.

    (2010)
  • H. Matsumoto et al.

    Childhood-onset schizophrenia and obstetric complications: a case--control study

    Schizophr. Res

    (1999)
  • V.A. Mittal et al.

    Prenatal exposure to viral infection and conversion among adolescents at high-risk for psychotic disorders

    Schizophr. Res

    (2008)
  • K. Moilanen et al.

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

    Schizophr. Res.

    (2010)
  • C. Nosarti et al.

    Neural substrates of letter fluency processing in young adults who were born very preterm: alterations in frontal and striatal regions

    Neuroimage

    (2009)
  • S. Ochoa et al.

    Cognitive profiles of three clusters of patients with a first-episode psychosis

    Schizophr. Res

    (2013)
  • A.E. Ordonez et al.

    Lack of evidence for elevated obstetric complications in childhood onset schizophrenia

    Biol. Psychiatry

    (2005)
  • G. Pedersen et al.

    Generalizability studies of the Global Assessment of Functioning-Split version

    Compr. Psychiatry

    (2007)
  • J.A. Perianez et al.

    Trail Making Test in traumatic brain injury, schizophrenia, and normal ageing: sample comparisons and normative data

    Arch. Clin. Neuropsychol.

    (2007)
  • A. Preti et al.

    Obstetric complications in early psychosis: relation with family history of psychosis

    Psychiatry Res.

    (2012)
  • T.K. Rajji et al.

    Cognitive performance of individuals with schizophrenia across seven decades: a study using the MATRICS consensus cognitive battery

    Am. J. Geriatr. Psychiatry

    (2013)
  • E. Rubio-Abadal et al.

    Birth weight and obstetric complications determine age at onset in first episode of psychosis

    J. Psychiatr. Res.

    (2015)
  • N. Rusch et al.

    Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia

    Schizophr. Res.

    (2007)
  • C.A. Sandman et al.

    Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock

    Peptides

    (2006)
  • R. Thormodsen et al.

    Visual backward-masking performance in a longitudinal study of early onset schizophrenia

    Psychiatry Res.

    (2012)
  • K.M. Abel et al.

    Birth weight, schizophrenia, and adult mental disorder: is risk confined to the smallest babies?

    Arch. Gen. Psychiatry

    (2010)
  • C.E. Bearden et al.

    A prospective cohort study of childhood behavioral deviance and language abnormalities as predictors of adult schizophrenia

    Schizophr. Bull.

    (2000)
  • R.H.B. Benedict

    Brief Visuospatial Memory Test—Revised

    (1997)
  • J.R. Blair et al.

    Predicting premorbid IQ: a revision of the National Adult Reading Test

    Clin. Neuropsychol.

    (1989)
  • J. Brandt et al.

    The Hopkins Verbal Learning Test-Revised

    (2001)
  • A.S. Brown

    Prenatal infection as a risk factor for schizophrenia

    Schizophr. Bull.

    (2006)
  • A.S. Brown et al.

    Maternal exposure to toxoplasmosis and risk of schizophrenia in adult offspring

    Am. J. Psychiatry

    (2005)
  • A.S. Brown et al.

    Maternal exposure to respiratory infections and adult schizophrenia spectrum disorders: a prospective birth cohort study

    Schizophr. Bull.

    (2000)
  • A.S. Brown et al.

    Prenatal exposure to maternal infection and executive dysfunction in adult schizophrenia

    Am. J. Psychiatry

    (2009)
  • M. Cannon et al.

    Priming the brain for psychosis: maternal inflammation during fetal development and the risk of later psychiatric disorder

    Am. J. Psychiatry

    (2014)
  • M. Cannon et al.

    School performance in Finnish children and later development of schizophrenia: a population-based longitudinal study

    Arch. Gen. Psychiatry

    (1999)
  • M. Cannon et al.

    Obstetric complications and schizophrenia: historical and meta-analytic review

    Am. J. Psychiatry

    (2002)
  • T.D. Cannon et al.

    A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia

    Schizophr. Bull.

    (2000)
  • C. Chaves et al.

    The role of inflammation in schizophrenia: an overview

    Trends Psychiatry Psychother.

    (2015)
  • M.C. Clarke et al.

    The role of obstetric events in schizophrenia

    Schizophr. Bull.

    (2006)
  • M.C. Clarke et al.

    Increased risk of schizophrenia from additive interaction between infant motor developmental delay and obstetric complications: evidence from a population-based longitudinal study

    Am. J. Psychiatry

    (2011)
  • E.P. Davis et al.

    The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development

    Child. Dev.

    (2010)
  • View full text