Kathryn M. Abel

Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events.

CONTEXT Most societies believe that a mothers psychological state can influence her unborn baby. Severe adverse life events during pregnancy have been consistently associated with an elevated risk of low birth weight and prematurity. Such events during the first trimester have also been associated with risk of congenital malformations. OBJECTIVE To assess the effect in offspring of antenatal maternal exposure to an objective measure of stress on risk of adverse neurodevelopment, specifically schizophrenia. We hypothesized that the strongest relationship would be to maternal exposures during the first trimester. DESIGN Population-based study. SETTING Denmark. PARTICIPANTS In a cohort of 1.38 million Danish births from 1973 to 1995, mothers were considered exposed if 1 (or more) of their close relatives died or was diagnosed with cancer, acute myocardial infarction, or stroke syndrome up to 6 months before conception or during pregnancy. Offspring were followed up from their 10th birthday until their death, migration, onset of schizophrenia, or June 30, 2005; admissions were identified by linkage to the Central Psychiatric Register. Main Outcome Measure Schizophrenia. RESULTS The risk of schizophrenia and related disorders was raised in offspring whose mothers were exposed to death of a relative during the first trimester (adjusted relative risk, 1.67 [95% confidence interval, 1.02-2.73]). Death of a relative during other trimesters or up to 6 months before pregnancy were not linked with a higher risk of schizophrenia. CONCLUSIONS Our population-based study suggests that severe stress to a mother during the first trimester may alter the risk of schizophrenia in offspring. This finding is consistent with ecological evidence from whole populations exposed to severe stressors and suggests that environment may influence neurodevelopment at the feto-placental-maternal interface.

Sex differences in schizophrenia

Evidence suggests sex differences in schizophrenia reflect differences in both neurodevelopmental processes and social effects on disease risk and course. Male:female incidence approximates 1.4:1 but at older onset women predominate. Prevalence differences appear smaller. Men have poorer premorbid adjustment and present with worse negative and less depressive symptoms than women, which may explain their worse medium term outcome according to a range of measures. Substance abuse is a predominantly male activity in this group, as elsewhere. Findings of sex differences in brain morphology are inconsistent but occur in areas that normally show sexual dimorphism, implying that the same factors are important drivers of sex differences in both normal neurodevelopmental processes and those associated with schizophrenia. There are sex differences in antipsychotic responses but sex-specific endocrine effects on illness and response to antipsychotics are potentially complex. Oestrogens role as an adjunctive medication is not yet clear due to methodological differences between the few randomized controlled trials. Services that are sensitive to differences in gender can better meet their patients’ specific needs and potentially improve outcome.

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

CONTEXT Studies linking birth weight and mental illness onset are inconclusive. They have primarily focused on the World Health Organization low birth weight threshold (2500 g) and schizophrenia. To our knowledge, low birth weight per se has not been conclusively linked with schizophrenia risk and specificity of the effect to birth weight below the standard threshold or to particular psychiatric diagnoses has not been demonstrated. OBJECTIVES To examine whether (1) low birth weight (<2500 g) is associated with increased risk for adult schizophrenia; (2) risk extends into the normal weight range; and (3) risk is confined to schizophrenia or linked to other adult mental illnesses. DESIGN Population-based cohort study. SETTING Sweden and Denmark. PARTICIPANTS Singleton live births in Sweden (1973-1984) and Denmark (1979-1986) (N = 1.49 million). Births were linked to comprehensive national registers of psychiatric treatment, with follow-up to December 31, 2002 (Sweden), or to June 30, 2005 (Denmark). There were 5445 cases of schizophrenia and 57 455 cases of any adult psychiatric disorder. MAIN OUTCOME MEASURE Crude and adjusted odds ratios for birth weight less than or more than 3500 to 3999 g in consecutive 500-g strata (from 500-1499 g to > or =4500 g) for schizophrenia, any psychiatric diagnoses, and specified psychiatric diagnoses. RESULTS Schizophrenia was associated with birth weight less than 2500 g. The association was not restricted to birth weight less than 2500 g and there was a significant linear trend of increasing odds ratios with decreasing birth weight across the birth weight range. This was mirrored for any psychiatric diagnosis and for each of the categories of psychiatric disorder. CONCLUSIONS Findings suggest there is an association between birth weight and adult mental disorder, but there is no indication this effect is specific to birth weight less than 2500 g or to schizophrenia. Future research should explore common disorder-specific mechanisms that may link birth weight to development of psychiatric disorder in adulthood.

Approaching the biology of human parental attachment: brain imaging, oxytocin and coordinated assessments of mothers and fathers.

Brain networks that govern parental response to infant signals have been studied with imaging techniques over the last 15 years. The complex interaction of thoughts and behaviors required for sensitive parenting enables the formation of each individuals first social bonds and critically shapes development. This review concentrates on magnetic resonance imaging experiments which directly examine the brain systems involved in parental responses to infant cues. First, we introduce themes in the literature on parental brain circuits studied to date. Next, we present a thorough chronological review of state-of-the-art fMRI studies that probe the parental brain with a range of baby audio and visual stimuli. We also highlight the putative role of oxytocin and effects of psychopathology, as well as the most recent work on the paternal brain. Taken together, a new model emerges in which we propose that cortico-limbic networks interact to support parental brain responses to infants. These include circuitry for arousal/salience/motivation/reward, reflexive/instrumental caring, emotion response/regulation and integrative/complex cognitive processing. Maternal sensitivity and the quality of caregiving behavior are likely determined by the responsiveness of these circuits during early parent-infant experiences. The function of these circuits is modifiable by current and early-life experiences, hormonal and other factors. Severe deviation from the range of normal function in these systems is particularly associated with (maternal) mental illnesses - commonly, depression and anxiety, but also schizophrenia and bipolar disorder. Finally, we discuss the limits and extent to which brain imaging may broaden our understanding of the parental brain given our current model. Developments in the understanding of the parental brain may have profound implications for long-term outcomes in families across risk, resilience and possible interventions. This article is part of a Special Issue entitled Oxytocin and Social Behav.

Low dose ketamine increases prepulse inhibition in healthy men.

The N-methyl-D-aspartate (NMDA) antagonist, ketamine, produces neurobehavioural symptoms that mimic aspects of schizophrenia. Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is decreased in chronically ill, medicated schizophrenic patients and in animals treated acutely with NMDA antagonists. We tested the hypothesis that ketamine would produce psychotic symptoms and reduce PPI in healthy humans. Twenty male volunteers received placebo and ketamine in a within-subject, double-blind, cross-over design with 0.23 mg/kg ketamine hydrochloride or saline as a loading dose, followed by 0.5 mg/kg ketamine or saline over 45 min. Prepulse to pulse intervals were 30 ms and 120 ms. The Brief Psychiatric Rating Scale (BPRS) and the Clinician Administered Dissociative States Scale (CADSS) were administered. Ketamine produced a significant increase in PPI and significantly reduced startle magnitude, but did not alter habituation. Ketamine produced significant increases in BPRS and CADSS scores, with symptoms mimicking the negative and disorganisation symptoms of psychosis. In contrast to effects in rodents, this low dose of ketamine produced an increase in PPI despite producing psychopathological symptoms consistent with the NMDA psychosis model. These findings suggest that the cognitive and PPI changes of NMDA antagonists are not consistently linked at a phenomenological or neurochemical level.

Reduced infant birthweight consequent upon maternal exposure to severe life events.

Objective: To investigate the association between maternal exposure to severe life events and fetal growth (birthweight and small for gestational age). Stress has been associated with adverse pregnancy outcome. Methods: Mothers of 1.38 million singleton live births in Denmark between January 1, 1979 and December 31, 2002 were linked to information on their spouses, parents, siblings, and older children. Exposure was defined as death or serious illness in a relative during pregnancy or in the 6 months before conception. Linear regression was used to examine the effect of exposure on birthweight. Log-linear binomial regression was used to assess the effect of exposure on small for gestational age. Results: Death of a relative during pregnancy or in the 6 months before conception reduced birthweight by 27 g (adjusted estimate −27 g, 95% Confidence Interval (CI) = −33, −22). There was a significant association between maternal exposure to death of a relative and risk of a baby weighing below the 10th percentile (adjusted relative risk (RR) = 1.17, 95% CI = 1.13, 1.22) and 5th percentile (adjusted RR = 1.22, 95% CI = 1.15, 1.29). Conclusions: Mothers exposed to severe life events before conception or during pregnancy have babies with significantly lower birthweight. If this association is causal, the potential mechanisms of stress-related effects on birthweight include changes in lifestyle due to the exposure and stress-related dysregulation of the hypothalamic-pituitary-adrenal axis during pregnancy. IUGR = intrauterine growth restriction; CVA = cerebrovascular accident; AMI = acute myocardial infarction; SGA = small for gestational age; VSGA = very small for gestational age; GHQ = general health questionnaire; SES = socioeconomic status.

Repeated testing of prepulse inhibition and habituation of the startle reflex: a study in healthy human controls.

The aim of this study was to examine the effect of repeated testing on prepulse inhibition (PPI) and habituation of the startle reflex. Fifteen healthy control subjects (eight males, mean age 30 years; seven females, mean age 29 years) were tested on three occasions across the same day separated by a minimum of 2 h. An acoustic probe of 40-msec bursts of 116 dB(A) white noise over a continuous background noise of 70 dB(A) was presented binaurally through headphones and the eye-blink component of the startle response was measured taking electromyographic recordings from the right orbicularis oculi. The test session was identical at each time point and consisted of two blocks of 12 randomly mixed trials of four pulse-alone, four 60-msec prepulse and four 120-msec prepulse trials enclosed by two blocks each of six pulse-alone trials. There was huge variation in individual response magnitude that was independent of subsequent PPI in both women and men. Women showed greater PPI in the second half of sessions with the 120-msec prepulse only; but PPI was not altered significantly in either group between sessions across the day. In general, there was good test-retest reliability of PPI especially within trial type. Normal reflex habituation occurred across sessions and this effect was preserved in sessions across the day. Latency of response was significantly reduced in a session by the 60-msec trial type compared to the 120-msec trial type, as previously reported. Our results suggest that measures of PPI and habituation of the startle response are appropriate and reliable for a within-subject, test-retest design.

Rates of preterm birth following antenatal maternal exposure to severe life events: a population-based cohort study

BACKGROUND Preterm birth and other pregnancy complications have been linked to maternal stress during pregnancy. We investigated the association between maternal exposure to severe life events and risk of preterm birth. METHODS Mothers of all singleton live births (n = 1.35 million births) in Denmark between 1 January 1979 and 31 December 2002 were linked to data on their children, parents, siblings and partners. We defined exposure as death or serious illness in close relatives in the first or second trimesters or in the 6 months before conception. Log-linear binomial regression was used to estimate the effect of exposure on preterm birth, very preterm birth and extremely preterm birth. RESULTS There were 58 626 (4.34%) preterm births (<37 weeks), 11 732 (0.87%) very preterm births and 3288 (0.24%) extremely preterm births in the study cohort. Severe life events in close relatives in the 6 months before conception increased the risk of preterm birth by 16% (relative risk, RR = 1.16, [95% CI: 1.08-1.23]). Severe life events in older children in the 6 months before conception increased the risk of preterm birth by 23% (RR = 1.23, [95% CI: 1.02-1.49]) and the risk of very preterm birth by 59% (RR = 1.59, [95% CI: 1.08-2.35]). CONCLUSIONS Our population-based cohort study suggests that maternal exposure to severe life events, particularly in the 6 months before pregnancy, may increase the risk of preterm and very preterm birth.

Offspring psychopathology following preconception, prenatal and postnatal maternal bereavement stress

BACKGROUND Preconception, prenatal and postnatal maternal stress is associated with increased offspring psychopathology, but findings are inconsistent and need replication. We estimated associations between maternal bereavement stress and offspring autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, suicide attempt and completed suicide. METHOD Using Swedish registers, we conducted the largest population-based study to date examining associations between stress exposure in 738,144 offspring born 1992-2000 for childhood outcomes and 2,155,221 offspring born 1973-1997 for adult outcomes with follow-up to 2009. Maternal stress was defined as death of a first-degree relative during (a) the 6 months before conception, (b) pregnancy or (c) the first two postnatal years. Cox proportional survival analyses were used to obtain hazard ratios (HRs) in unadjusted and adjusted analyses. RESULTS Marginal increased risk of bipolar disorder and schizophrenia following preconception bereavement stress was not significant. Third-trimester prenatal stress increased the risk of ASD [adjusted HR (aHR) 1.58, 95% confidence interval (CI) 1.15-2.17] and ADHD (aHR 1.31, 95% CI 1.04-1.66). First postnatal year stress increased the risk of offspring suicide attempt (aHR 1.13, 95% CI 1.02-1.25) and completed suicide (aHR 1.51, 95% CI 1.08-2.11). Bereavement stress during the second postnatal year increased the risk of ASD (aHR 1.30, 95% CI 1.09-1.55). CONCLUSIONS Further research is needed regarding associations between preconception stress and psychopathological outcomes. Prenatal bereavement stress increases the risk of offspring ASD and ADHD. Postnatal bereavement stress moderately increases the risk of offspring suicide attempt, completed suicide and ASD. Smaller previous studies may have overestimated associations between early stress and psychopathological outcomes.

What predicts poor mother-infant interaction in schizophrenia?

BACKGROUND Poor clinician-rated parenting outcome and observed interactive deficits in mothers with schizophrenia admitted to a psychiatric mother and baby unit (MBU) reflect continuing concerns over the parenting capacity of this group. However, little is known about whether interaction deficits are accounted for by severity of illness or adverse social circumstances typically experienced by these mothers. METHOD Thirty-eight women with severe perinatal illness (schizophrenia n=13; affective disorders n=25) and their infants were observed in play interaction a week prior to MBU discharge. Clinical and sociodemographic data were also obtained. RESULTS Mothers with schizophrenia and their infants were rated to have poorer interactive behaviour than the affective disorders group. Infant avoidance of the mother was associated with a lack of maternal sensitivity and responsiveness. The deficits in mother-infant interaction found in the schizophrenia group could not be accounted for by our measures of illness severity or factors relating to adverse social circumstances. CONCLUSIONS The results replicate and extend previous findings showing poor interactive behaviours in mothers with schizophrenia, their infants, and in the dyad, in a range of areas following clinical recovery. The findings suggest that factors other than illness duration, dose of medication, marital status and occupational status are explanatory for the interactive deficits associated with maternal schizophrenia. Parenting interventions that aim to improve maternal sensitivity need to be developed specifically for this group.