Association of Birth Asphyxia With Regional White Matter Abnormalities Among Patients With Schizophrenia and Bipolar Disorders

Abstract

IMPORTANCE White matter (WM) abnormalities are commonly reported in psychiatric disorders.Whether peripartum insufficiencies in brain oxygenation, known as birth asphyxia, are associated with WM of patients with severe mental disorders is unclear.OBJECTIVE To examine the association between birth asphyxia and WM in adult patients with schizophrenia and bipolar disorders (BDs) compared with healthy adults. DESIGN, SETTING, AND PARTICIPANTSIn this case-control study, all individuals participating in the ongoing Thematically Organized Psychosis project were linked to the Medical Birth Registry of Norway (MBRN), where a subset of 271 patients (case group) and 529 healthy individuals (control group) had undergone diffusion-weighted imaging (DWI). Statistical analyses were performed from June 16, 2020, to March 9, 2021.EXPOSURES Birth asphyxia was defined based on measures from standardized reporting at birth in the MBRN. MAIN OUTCOMES AND MEASURES Associations between birth asphyxia and WM regions ofinterest diffusion metrics, ie, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), were compared between groups using analysis of covariance, adjusted for age, age squared, and sex. RESULTSOf the 850 adults included in the study, 271 were in the case group (140 [52%] female individuals; mean [SD] age, 28.64 [7.43] years) and 579 were in the control group (245 [42%] female individuals; mean [SD] age, 33.54 [8.31] years). Birth asphyxia measures were identified in 15% to 16% of participants, independent of group. The posterior limb of the internal capsule (PLIC) showed a significant diagnostic group × birth asphyxia interaction (F (1, 843) = 11.46; P = .001), reflecting a stronger association between birth asphyxia and FA in the case group than the control group. RD, but not AD, also displayed a significant diagnostic group × birth asphyxia interaction (F (1, 843) = 9.28; P = .002) in the PLIC, with higher values in patients with birth asphyxia and similar effect sizes as observed for FA. CONCLUSIONS AND RELEVANCEIn this case-control study, abnormalities in the PLIC of adult patients with birth asphyxia may suggest a greater susceptibility to hypoxia in patients with severe mental illness, which could lead to myelin damage or impeded brain development. Echoing recent early-stage schizophrenia studies, abnormalities of the PLIC are relevant to psychiatric disorders, as the PLIC contains important WM brain pathways associated with language, cognitive function, and sensory function, which are impaired in schizophrenia and BDs.

Prioritization of potential causative genes for schizophrenia in placenta

“…4e , Supplementary Data 48 , 54 ), consistent with data showing that both high and low birthweight represent a risk factor for schizophrenia 3 , 61 , 62 . Overall, these data suggest that an effect of placental genes on fetal growth may lead to very different neurodevelopmental trajectories, likely depending on the various factors that can be associated with birthweight, that is, birth asphyxia 63 , gestational diabetes, and other early life complications.…”

The impact of placental genetic risk for schizophrenia and birth asphyxia on brain development

“…Severe birth asphyxia is associated with increased risk of developing SZ (odds ratio = 4.4) (6). In both patients with SZ and controls, we have previously reported signi cantly more cases of several severe OCs co-occurring in the presence of birth asphyxia (> 73%) than when birth asphyxia had not been present (< 22%) (7), suggesting birth asphyxia might be a concomitant of complicated pregnancies (8, 9) and of placental pathology (10,11).…”

“…Participants were excluded if IQ<70, unable to give consent or not pro cient in a Scandinavian language. All MRI scans were assessed by a neuroradiologist using a graded scheme (7), and if pathology was detected, the participant was excluded from the study. Additional exclusion criteria for controls were current or previous psychiatric illness, substance use disorders or dependency within the last 6 months and if they or a rst-degree relative had a lifetime history of severe psychiatric disorder.…”

Errors in Methods and Table

“…In the Original Investigation titled “Association of Birth Asphyxia With Regional White Matter Abnormalities Among Patients With Schizophrenia and Bipolar Disorders,” published December 20, 2021, there were errors in the Statistical Analysis subsection of the Methods section and in Table 1. In the first paragraph of the Statistical Analysis, the second sentence should have read that post hoc, pairwise group comparisons were performed if there were significant group associations.…”

“…In the first paragraph of the Statistical Analysis, the second sentence should have read that post hoc, pairwise group comparisons were performed if there were significant group associations. In Table 1, a heading was incorrectly labeled “Main effect size”; it should have read “Group associations.” This article has been corrected …”