Long-term maternal recall of obstetric complications in schizophrenia research

Obstetric complications (OCs) are consistently implicated in the aetiology of schizophrenia. Information about OCs is often gathered retrospectively, from maternal interview. It has been suggested that mothers of people with schizophrenia may not be accurate in their recollection of obstetric events. We assessed the validity of long term maternal recall by comparing maternal ratings of OCs with those obtained from medical records in a sample of mothers of offspring affected and unaffected with psychotic illness. Obstetric records were retrieved for 30 subjects affected with psychosis and 40 of their unaffected relatives. The Lewis-Murray scale of OCs was completed by maternal interview for each subject blind to the obstetric records. There was substantial agreement between maternal recall and birth records for the summary score of “definite” OCs, birth weight, and most of the individual items rated, with the exception of antepartum haemorrhage. There were no significant differences in the validity of recall or in errors of commission by mothers for affected and unaffected offspring. These findings indicate that several complications of pregnancy and delivery are accurately recalled by mother's decades after they occurred. Furthermore, there is no indication that mothers are less accurate in recalling OCs for their affected offspring than their unaffected offspring. When comparing women with and without recall errors, we found those with recall errors to have significantly worse verbal memory than women without such errors. Assessing the cognition of participants in retrospective studies may allow future studies to increase the reliability of their data.     

Handedness and maternal smoking during pregnancy

Nonright-handedness (NRH) has been attributed to hypoxia-induced brain changes in the fetus and associated pregnancy and birth complications (PBCs). Maternal smoking during pregnancy is known to produce prenatal hypoxia for the fetus, which may result in low birth weight and other PBCs. It was hypothesized that maternal smoking during pregnancy results in a leftward shift of handedness in the offspring. This study compared the distribution of handedness in the offspring of mothers who did and did not smoke cigarettes during pregnancy. Information on maternal smoking, handedness, and PBCs was analyzed for 803 university students. There was a significant shift to the left in the distribution of handedness scores for the offspring of smoking mothers (N = 216), as compared to those of nonsmoking mothers (N = 587). Offspring of smoking mothers also reported significantly more PBCs. Results are consistent with the hypothesis that NRH is associated with pathological neurodevelopment.     

Risk for obstetric complications and schizophrenia

The goal of this study was to determine whether cases with schizophrenia or related disorders show a history of obstetric complications significantly more often than control subjects and, if so, whether the enhanced risk of a negative pregnancy outcome also extends to the non-schizophrenic offspring of cases. Data based on the obstetric birth case-notes of patients with diagnosed schizophrenia or related disorders were compared to those of normal 'healthy' control subjects; each case/control pair was individually matched by gender, time and parity of birth, maternal age and marital status. Forty-four case/control pairs born in Padova (Italy) between 1964 and 1978 were assessed for prenatal and perinatal complications, including abnormal gestational age or birthweight. No significant differences were observed between cases and control subjects in the general characteristics of birth; gestational age and birthweight in particular were strictly comparable between cases and control subjects. The schizophrenia spectrum patients (75%) were more likely than control subjects (59%) to have experienced at least one definite obstetric complication: odds ratio=2.07 (95% CI: 0.83-5. 15). Cases also suffered more complications per birth than control subjects (average 2:1). In particular, obstetric complications involving a clear damaging potential were seen significantly more often among cases than control subjects: 34% vs. 9%, Fisher's exact test, P=0.008 (odds ratio=5.17, 95% CI: 1.55-17.21). Moreover, severe obstetric complications were noted more often among males (n=13, 41%) than females (n=2, 15%). When any previous pregnancies of the mothers of patients were compared with those of the mothers of control subjects, mothers of cases were seen to have suffered unfavorable pregnancy outcomes significantly more often. In particular mothers of cases were seen to have had more miscarriages (OR=4.66), and pre-term births (OR=2.58) than control subects' mothers. Severe, brain-damaging obstetric complications would seem to be a possible antecedent to a diagnosis of schizophrenia or a related disorder in adulthood. Indeed, some early onset cases may be accounted for by prenatal brain lesions. This enhanced risk of negative pregnancy outcome may be under genetic control, contributing to the persistence of schizophrenia in the general population. The 'healthy' status of control subjects was ascertained indirectly, not by individual assessment of the subjects. The sample size limits the statistical power of calculations.     

母亲孕产期并发症与子代精神分裂症的关系

目的 探讨母亲孕产期并发症与子代精神分裂症的关系。方法 病例对照研究,单因素、多因素分析,并计算相对危险度和95％的可信限。结果 单因素分析显示,孕期并发症(OR=4.63,95％CI=1.27～20.66)、产期并发症(OR=3.29,95％CI=1.06～11.29)达到统计学意义。性别分层分析,男性患者的产科并发症发生率明显高于对照组。多因素分析,孕期营养差、孕期并发症与精神分裂症有密切的关系,OR(95％CI)分别为3.98(1.13～14.07)、4.93(1.44～16.86)。结论 精神分裂症的发生与孕产期环境因素密切相关,孕期、产期损伤者为精神分裂症的高危人群.     

Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications.

BACKGROUND: Hippocampal volume reduction has been repeatedly demonstrated in schizophrenia. The relative contribution of genetic and environmental factors to this is unclear. METHODS: To address this question, we compared volumetric measurements of the left and right hippocampus, obtained using stereological methods from brain MRI scans, from two groups of patients with schizophrenia as well as healthy controls (n = 26). Patients (n = 27) in the first group, had no family history of schizophrenia and had experienced severe pregnancy and birth complications (PBCs). The second group comprised of patients (n = 21) without a history of severe PBCs from families multiply affected with schizophrenia. RESULTS: Reduction of the left hippocampal volume was associated with the diagnosis of schizophrenia but was present only in patients with a history of severe PBCs; in this group the smaller hippocampal volume, the earlier the onset of psychosis. CONCLUSIONS: Our findings suggest that environmental factors, in this case severe PBCs, make a significant contribution to hippocampal abnormalities in schizophrenia.     

Revisiting the association between maternal smoking during pregnancy and ADHD

Objective

Studies examining the relationship between maternal smoking during pregnancy and the development of Attention Deficit Hyperactivity Disorder (ADHD) among offspring have yielded mixed results, with some studies suggesting a strong association and others finding no association. These studies have varied in quality of design and measures. The purpose of this study was to evaluate the association between maternal smoking during pregnancy and offspring ADHD, using detailed prospective smoking data and subsequent follow-up data from the Collaborative Perinatal Project (CPP).

Method

Maternal smoking status was collected throughout pregnancy during the original CPP study. Offspring were followed-up in early adulthood and questioned about ADHD symptoms and diagnosis. Logistic regression was used to model the association between maternal smoking during pregnancy and ADHD. Linear and logistic regression were used to examine clinical characteristics and remission rates associated with ADHD in relation to maternal smoking.

Results

No association was found between maternal smoking during pregnancy and offspring ADHD. Further, no differences in age of onset, number of symptoms, or likelihood of remission were found among ADHD subjects with and without a history of maternal smoking during pregnancy.

Conclusions

These findings do not support the hypothesis that maternal smoking during pregnancy is causally related to ADHD. Ongoing research should continue to strive to identify those environmental or genetic factors that may enhance the impact of maternal smoking on ADHD or that may be associated more clearly with the development and potential prevention of ADHD.     

Mean diffusivity: A biomarker for CSF-related disease and genetic liability effects in schizophrenia

Mean diffusivity (MD), the rotationally invariant magnitude of water diffusion that is greater in cerebrospinal fluid (CSF) and smaller in organized brain tissue, has been suggested to reflect schizophrenia-associated cortical atrophy. Regional changes, associations with CSF, and the effects of genetic predisposition towards schizophrenia, however, remain uncertain. Six-direction diffusion tensor imaging DTI and high-resolution structural images were obtained from 26 schizophrenia patients, 36 unaffected first-degree patient relatives, 20 control subjects and 32 control relatives (N = 114). Registration procedures aligned diffusion tensor imaging (DTI) data across imaging modalities. MD was averaged within lobar regions and the cingulate and superior temporal gyri. CSF volume and MD were highly correlated. Significant bilateral temporal, and superior temporal MD increases were observed in schizophrenia compared with unrelated control probands. First-degree relatives of schizophrenia probands showed larger MD measures compared with controls within bilateral superior temporal regions with CSF volume correction. Superior temporal lobe brain tissue deficits and proximal CSF enlargements are widely documented in schizophrenia. Larger MD indices in patients and their relatives may thus reflect similar pathophysiological mechanisms. However, persistence of regional MD effects after controlling for CSF volume, suggests that MD is a sensitive biological marker of disease and genetic liability, characterizing at least partially distinct aspects of brain structural integrity.     

The role of obstetric complications in the pathogenesis of schizophrenia

The article is a review of research data on the occurrence of pregnancy and delivery complications in schizophrenic patients and their possible contribution to developing schizophrenia in adolescence or adulthood. Many studies revealed that subjects who have a positive obstetric complications history are at higher risk of developing schizophrenia. Obstetric complications, especially those resulting in asphyxia, are often mentioned as possible environmental factors that can disturb the brain developmental processes, which can be responsible for developing schizophrenia in the future. Obstetric complications can act as an environmental pathogenic factor in some cases of schizophrenia (for example not genetically conditioned ones). They can also constitute an additional factor that, acting together with other (for example genetic factors, results in schizophrenia phenotype). There are still inconsistent data and many methodological problems concerning obstetric complications studies. The problem requires further investigation with improved and unified methodological procedures applied.     

Heart rate variability in preterm infants and maternal smoking during pregnancy

Objective  Tobacco smoke exposure increases the risk of premature birth and of dying of sudden infant death syndrome (SIDS). Prematurity significantly increases the risk of dying of SIDS, but mechanisms underlying this epidemiological finding are unclear. The cumulated effect of both prematurity and prenatal exposure to nicotine on autonomic heart rate control has not been studied. Methods  Using coarse-graining spectral analysis, we compared heart rate variability (HRV) indices of preterm newborns at 33–34 weeks post-conceptional age from smoking (n = 19) and non-smoking (n = 21) mothers. Assessment of tobacco exposure relied on maternal reports and newborns cotinine analysis. We observed how indicators of HRV depended on gestational age at birth. Results  At 33–34 weeks postconceptional age, the newborns from smoking mothers had lower HRV low frequency power normalised to the total spectral power (LF/TP) than the control group (median values: 8% vs. 15% respectively, p < 0.02). In the non-smoking group, RR-interval values and total HRV power were correlated with gestational age at birth, with a shorter RR and a lower total HRV power in lesser gestational ages (ρ = 0.67, p = 0.03, ρ = 0.71, p = 0.003 respectively). This correlation was not observed for RR values in the group with smoking mothers.     

The hippocampus in families with schizophrenia in relation to obstetric complications

BACKGROUND: Hippocampal volume reduction is a well replicated finding in schizophrenia. Evidence indicates a contribution of genetic and environmental factors, especially the influence of obstetric complications to this volume reduction. The aim of this study was to compare hippocampal volume of schizophrenic patients as well as and their relatives with control subjects and to quantify the additional contribution of obstetric complications. METHODS: T1 weighted MRI brain scans of 50 schizophrenic patients, 88 first-degree relatives and 53 healthy control subjects were used to perform volumetric measurements on the left and right hippocampus. A set of clinical measures including obstetric complications were recorded for all family members. RESULTS: Numerically our measurements revealed a hippocampal volume reduction in schizophrenic patients (left: - 14%, right: - 15%) and, although less pronounced, in their unaffected relatives (left: - 6%, right: - 10%). Noted differences in hippocampal volume between schizophrenic patients and controls were only significant for the left side. Hippocampal volumes of patients and their relatives with obstetric complications were reduced bilaterally. CONCLUSIONS: Hippocampal volume reduction is present in schizophrenic patients and their first-degree relatives, suggesting an influence of genetic factors.. In addition, however, obstetric complications have also been shown to play a major role.     

No effect of obstetric complications on basal ganglia volumes in schizophrenia

Background

Heterogeneous findings have been reported in studies of basal ganglia volumes in schizophrenia patients as compared to healthy controls. The basal ganglia contain dopamine receptors that are known to be involved in schizophrenia pathology and to be vulnerable to pre- and perinatal hypoxic insults. Altered volumes of other brain structures (e.g. hippocampus and lateral ventricles) have been reported in schizophrenia patients with a history of obstetric complications (OCs). This is the first study to explore if there is a relationship between OCs and basal ganglia volume in schizophrenia.

Methods

Thorough clinical investigation (including information on medication) of 54 schizophrenia patients and 54 healthy control subjects was undertaken. MR images were obtained on a 1.5 T scanner, and volumes of nucleus caudatus, globus pallidum, putamen, and nucleus accumbens were quantified automatically. Information on OCs was blindly collected from original birth records.

Results

Unadjusted estimates demonstrated a relationship between increasing number of OCs and larger volume of nucleus accumbens in schizophrenia patients and healthy controls. No statistically significant relationships were found between OCs and the basal ganglia volumes when controlled for intracranial volume, age, and multiple comparisons. There were no effects of typical versus atypical medication on the basal ganglia volumes. The patients with schizophrenia had larger globus pallidum volumes as compared to healthy controls, but there were no case–control differences for accumbens, putamen, or caudate volumes.

Conclusion

The present results do not support the hypothesis that OCs are related to alterations in basal ganglia volume in chronic schizophrenia.     

Influence of genetic loading,obstetric complications and premorbid adjustment on brain morphology in schizophrenia: a MRI study

Cerebrospinal fluid (CSF) space enlargement in schizophrenia is a prominent finding. This study was initiated to examine the influence of genetic loading, obstetric complications and premorbid adjustment on the extent of this enlargement. The sample of this MRI study consisted of 40 schizophrenic patients, 24 psychiatric and 40 healthy family members from 10 uniaffected and 19 multiple affected families with schizophrenia, such as 27 control subjects from non-affected families. The ventricle-to-brain-ratio (VBR), and the areas of the third ventricle, sylvian fissure, temporal horn and interhemispheric fissure at the slice where these structures reached their maximum were examined relatively to the corresponding total brain areas. The sum of CSF areas was calculated as a parameter for global atrophy. From MANCOVA adjusted for intervening variables the right VBR and the sum of CSF areas revealed significant differences between diagnostic groups. For these areas schizophrenic patients showed an increase compared to control subjects and family members with psychiatric disorder. Genetic loading influenced the interhemispheric fissure, enlarged in multiple affected compared to uniaffected families, and the temporal horn asymmetry, which was right sided (right > left) in control subjects and multiple affected families, but inverted in uniaffected families. Neonatal obstetric complications influenced only the size of the VBR, while premorbid adjustment predicted various CSF areas. In conclusion, schizophrenic subjects from multiple and uniaffected families showed a global atrophy, which was most pronounced in the VBR. Genetic loading seems to have an impact on frontal regions as the interhemispheric fissure and on the temporal horn. Received: 14 February 2002 / Accepted: 17 February 2003 Correspondence to Peter Falkai, MD     

The common genetic liability between schizophrenia and bipolar disorder: a review

Current psychiatric nosology, strongly influenced by Kraepelin's dichotomy, classifies schizophrenia and bipolar disorder as separate diagnostic categories. However, growing evidence indicates that the two disorders may be more closely related than was thought in the past. Bipolar disorder and schizophrenia display considerable overlap in epidemiologic features; no risk factor is known to be specific to either. Furthermore, family studies reveal familial co-aggregation of the two disorders, and twin studies suggest a significant overlap in the genes contributing to schizophrenia, schizoaffective disorder, and mania. Finally, despite the difficulties in the identification of convincing genetic loci for psychiatric disorders, there are at least four genomic regions in which linkage has been shown for both schizophrenia and bipolar disorder. Thus, recent evidence increasingly supports a dimensional approach in the understanding of the functional psychoses, and this is expected to have implications for etiologic research and future clinical treatment.     

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

Obstetric complications (OCs) may be a risk factor for developing schizophrenia. In a recent study of a meta-analysis, the odds ratio for the development of the disorder in adulthood associated with OCs has been reported to be about 2.0 (i.e., a two-fold increase in risk). However, little attention has been paid to the involvement of OCs in risk of the development of childhood-onset schizophrenia. Therefore, the authors examined the relationship between OCs and childhood-onset schizophrenia. Thirty-three children, aged 8-13 years (average 12.4 years), meeting the DSM-III-R criteria for schizophrenia, were compared with controls (children with anxiety disorder) matched for sex and age. Childhood-onset schizophrenics showed significantly greater scores in all of the three measures of OCs according to Parnas et al.'s scale compared with controls. Moreover, those individuals exposed to OCs were 3.5 times as likely to develop schizophrenia as were those without OCs. The risk association between OCs and the disorder was far greater for male than for female schizophrenics. Our results, together with those in previous studies showing the association between OCs and adult-onset schizophrenia, suggest that childhood- and adult-onset schizophrenia may, at least in part, share a common neuropathogenesis.     

Lack of evidence for elevated obstetric complications in childhood onset schizophrenia.

BACKGROUND: Pre-, peri-, and postnatal obstetric complications (OC) are reported to be more frequent in adult patients with schizophrenia and have been linked to both greater severity and to "earlier" age of onset (before either age 18 or 22) in studies of adult patients. We hypothesized that by extrapolation, patients with childhood-onset schizophrenia (COS), with very early onset and very severe illness, would have had more numerous or more salient OC compared with their healthy siblings. METHODS: We compared the obstetric records of 60 COS children and 48 healthy siblings using the Columbia Obstetrics Complication Scale, a comprehensive measurement scale consisting of 37 variables having included a separate scale for fetal hypoxia. RESULTS: Patients with COS did not have a higher incidence of OC than the healthy sibling control group with the exception of increased incidence of maternal vomiting. CONCLUSIONS: Obstetric complications, with the possible exception of maternal vomiting, are unlikely to play a major role in the etiopathogenesis of childhood-onset schizophrenia.     

Obstetric complications as antecedents of schizophrenia: Empirical effects of using different obstetric complication scales

The new McNeil-Sjöström Scale for obstetric complications (OCs), as well as scales of Lewis et al. (Schizophrenia: Scientific progress. Oxford University Press, 1989) and Parnas et al. (British Journal of Psychiatry, 140, 416–420, 1982), were applied to the OC histories of 70 singleton schizophrenics and 70 demographically-matched controls from the same hospital delivery series, using blindly assessed hospital pregnancy and birth record information. With the McNeil-Sjöström scale, schizophrenics were found to have significantly increased rates of OCs for the total reproduction, as well as for labor-delivery and the neonatal period but not for pregnancy. Significant increases in OCs in these schizophrenics were also found in scores produced by the Lewis et al. scale but not by the Parnas et al. scale. Further application of these three scales to OC data obtained through parental report for 23 monozygotic (MZ) twin pairs discordant and 10 pairs concordant for schizophrenia, as well as seven normal control MZ pairs, showed a significant difference in OC rates across the different twin pair groups, when assessed by the McNeil-Sjöström and Parnas et al. scales, but not by the Lewis et al. scale. The particular scoring system used in a study is thus of considerable importance not only for findings concerning OC histories of schizophrenics vs. controls, but also for the relationship between OCs and other presumed etiological factors in schizophrenia. Among the three scales, the McNeil-Sjöström scale provided the most sensitive assessment of OC history for schizophrenics.     

The effects of mild maternal stress during pregnancy on the behavior of rat pups

Mild maternal stress in the form of chronic daily subcutaneous injections of saline or the vehicle for diazepam to pregnant rats was shown to result in some long term, subtle but reliable, changes in the behavior of the offspring. The same vehicle given for the same period of time in the dam's drinking water, without injection had no effect on the development of later behavior of rat pups. Chronic prenatal injections of saline or vehicle for diazepam, used in many experiments as controls for the evaluation of drug effects were shown to have some long lasting behavioral effects in the offspring of the treated dams. The series of experiments reported here compared the offspring of saline or vehicle injected dams to those of uninjected dams on a variety of developmental measurements, an open field behaviour and on learning performance in a complex brightness discrimination maze.     

Cerebral cortical thickness and a history of obstetric complications in schizophrenia

Introduction

Magnetic resonance imaging (MRI) studies have demonstrated that patients with schizophrenia have thinner brain cortices compared with healthy control subjects. Neurodevelopment is vulnerable to obstetric complications (OCs) such as hypoxia and birth trauma, factors that are also related to increased risk of developing schizophrenia. With the hypothesis that OCs might explain the thinner cortices found in schizophrenia, we studied patients with schizophrenia and healthy controls subjects for association between number and severity of OCs and variation in cortical thickness.

Methods

MRI scans of 54 adults with schizophrenia or schizoaffective disorder and 54 healthy controls were acquired at Karolinska Institutet, Stockholm, Sweden. Measures of brain cortical thickness were obtained using automated computer processing (FreeSurfer). OCs were assessed from obstetric records and scored blindly according to the McNeil–Sjöström scale. At numerous cortical locations, putative effects of OCs on cortical thickness variation were tested for each trimester, for labour, for composite OC scores, severe OC scores, and hypoxia scores among patients and controls separately.

Results

Number and severity of OCs varied among both patient and control subjects but were not associated with cortical thickness in either of the groups. Patients demonstrated thinner brain cortices but there were no significant differences in number and severity of OC scores across groups.

Conclusion

In the present study, number and severity of obstetric complications were not associated with brain cortical thickness, in patients with schizophrenia or in healthy control subjects. The thinner brain cortices found in patients with schizophrenia were not explained by a history of OCs.