Severe bereavement stress during the prenatal and childhood periods and risk of psychosis in later life: population based cohort study

Comparison with previous studies

Our data are broadly consistent with the largest population study to date of bereavement stress,22 where effects on schizophrenia, non-affective psychosis, and bipolar disorder were not seen after prenatal exposure. But our data are inconsistent with other population studies from Scandinavia.16 20 21 Evidence for an association between antenatal stress and schizophrenia is relatively weak. Paternal loss in the first but not second and third trimesters was reported to increase the risk of all psychiatric disorders compared with loss of fathers in the first year of an offspring’s life,16 and to increase the risk of schizophrenia but only in those without a family history of psychiatric disorders.20 One of the Scandinavian studies21 also reported an excess risk of affective disorder, including bipolar disorder, after bereavement in the second trimester but not in the first or third trimesters, and only in men.

Most studies have generally not considered differences in risks associated with the stress of experiencing a death in a member of the nuclear family versus extended family, and none has detailed the effects of different causes of death, although some have considered the effect of parental suicide.30 In our study, risk estimates were higher after death in the nuclear family than after death of any extended family member. Risks for non-affective psychosis were marginally greater than for affective psychosis, but only after the death of any extended family member. The reverse was true after the death of a nuclear family member, although numbers were too small to examine the effects of prenatal exposure to deaths in the nuclear family alone. The dose-response relation we report, where risks were generally higher after deaths in closer family members, and the earlier in childhood that the deaths occurred, and greatest after suicide, provide support for parental loss in childhood being a marker of both higher familial and higher environmental vulnerability to psychiatric disorder. Suicide increases the risk of psychiatric disorders through both genetic24 31 32and environmental effects.32 33 34 35 36 Parental loss, in particular from suicide, may have different meanings and consequences for offspring at different developmental stages.32 34 A longstanding literature describes a range of poor short and longer term outcomes in children exposed early to parental loss. Higher risks were seen for exposure in younger ages after death in the nuclear family. We offer two non-mutually exclusive explanations. First, the higher risk could reflect a greater vulnerability of brain development in early childhood to adverse effects from children’s environment and care. Secondly, the higher risk may reflect a greater duration of exposure to adverse social effects associated with the death of a close family member. A recent population survey of mental health among 5-16 year olds suggests that bereaved children are about one and a half times more likely than other children to have a diagnosis of any mental disorder.36 Two Danish register studies29 30 describe suicide of a mother being associated with a particularly increased risk of admission with bipolar disorder as an adult, especially if death occurs before the child is 10 years of age.30 Death of a relative by causes other than suicide was not associated with such an increased risk.

Mechanisms of risk, and indeed resilience for children living in families bereaved through the loss of a child or parent, are likely to be complex31 35 37 and to include primarily social factors alongside individual differences in the resilience of the child or family involved. To date, studies have not been able to disentangle genetic susceptibility to mental illness or death in the nuclear family from social disadvantage and their interaction with bereavement in childhood. In this study, adjusting for most potential confounders, including indicators of socioeconomic status, such as receipt of welfare and parental education, made little difference to risk estimates. Only a family history of psychotic or other psychiatric illness materially reduced the risk estimates, especially from suicide, but also from death through injuries and accidents; it did not materially change estimates for deaths from other natural causes. Thus, the association is supported by genetic factors,25 26 34 but as increased risks were still associated with both suicides and death from injuries or accidents, they may only explain a minor part of the crude excess risk.

Strengths and limitations of this study

This study has several methodological strengths. We describe rigorously the associations between exposures to bereavement stress in the preconception and prenatal periods and during childhood and risk for later psychiatric morbidity in offspring using a precise measurement of severe psychological stress at the individual level, validated measures of psychopathological outcomes, and adjustment for important child, family, and parental confounders. Several limitations remain relevant and should be dealt with in future research. For example, the death of a relative causes a subjective level of stress that varies by individual and circumstance and may endure over a variable length of time. Using date of death to time exposure to stress, we assume the relevant period of stress is the date of the death. We also assume that death of a relative induces substantial stress, whereas family members may not always grieve when someone dies—for example, if death occurs in an elderly relative or follows long term illness when it may provide relief—a notion with some support from our data, as cause of death determined the extent of risk. However, in general we believe that loss of a first degree relative (a partner or child) is very likely to result in grief and the associated psychological stress. Bereaved mothers might also modify relevant aspects of their behaviour (for example, substance misuse) in response to the stress, which may influence the associations.37 38 We were unable to assess accurate estimates for exposure to bereavement stress in the nuclear family by antenatal trimester or sex because events were too rare. Social class and socioeconomic status are well known associations of severe mental illness, such as schizophrenia,38 39 and loss of a parent is well recognised to bring socioeconomic disadvantage to a family.35 36 Although we adjusted for social class at birth of the child, we do not have a longitudinal measure of social class to take account of the effects of a decline in social circumstances associated with bereavement in families. Similarly, loss of a child has been associated with marital breakdown,37 and some evidence suggests that the children of bereaved parents may be more likely to live in single parent households, with their attendant excess risks associated with social adversity.35 36 37 38 39 We chose to rank exposures by timing of exposure to delineate critical periods of developmental risk. Overall, less than 0.5% of cases were exposed more than once, and sensitivity analysis found that unranking exposure made little difference to the results (data available from authors on request). We have previously scrutinised the level of misclassification when using inpatient care for psychosis as an indicator of occurrence of psychosis. During the 1980s in Sweden, there were no mobile outreach teams for psychoses, nor any specialist outpatient units. Thus, most incident cases of psychoses were treated in inpatient care. This gradually changed during the 1990s, and by 2005, 25% of incident cases were treated in outpatient care.40 This proportion may have increased since then, but as the follow-up in this cohort was between 1973 and 2006, we believe that the misclassification is likely to be relatively small and of an acceptable magnitude.

Few studies have been able to look specifically at severe mental health outcomes of children growing up in bereaved families in a whole population, or to examine risk by cause of death. Our findings support previous studies of the sequelae of suicide29 30 32 33 34 but further suggest that those exposed to suicide early in childhood have the greatest excess risk of subsequent psychotic illness. Early postnatal development and neurodevelopment, especially in the prefrontal cortex,41 may be particularly susceptible to diminished parenting resources, sensitivity, or stimulation as a consequence of maternal or parental stress.42 43 However, these findings cannot be explained merely by confounding due to family psychiatric history, and the mechanisms of risk are likely to be complex.25 26 27 36 There is a pressing need to identify resilience factors in children in bereaved families to develop appropriate interventions.44 45 Future studies should examine factors associated with resilience as an outcome alongside risk.44

Potential implications of the study

In this population, the lack of effect of severe prenatal maternal bereavement stress on the risk of psychosis in offspring has several possible implications. Taken together, the accumulated evidence is predominantly negative and overall suggests no consistent effect on risk of psychosis. This does not rule out other potential effects of prenatal bereavement. If this is the case, it suggests that severe psychological stress in pregnancy may be related to the social, emotional, and cognitive development of offspring, but without any detectable effect on risk of psychosis. Similarly, it is unclear why our results for bereavement stress and psychosis risk differ from those of studies examining prenatal stress and some other neuropsychiatric outcomes in offspring, such as attention-deficit/hyperactivity disorder or depression.7 21 One possible explanation is that a more severe disorder, such as psychosis, involves either alternative pathways or additional risk pathways. Exposure to several additional risk factors may be less likely to occur in a population where maternal health is good. Thus, severe antenatal maternal psychological stress may be an insufficient exposure in the pathway to more severe neurodevelopmental abnormalities such as psychosis, while remaining sufficient for more common, less severe neurodevelopmental outcomes. However, it may simply be that non-psychotic outcomes share only some of the risk mechanisms, or different risk mechanisms, to psychosis.

We do not fully understand the mechanisms of risk and resilience in the human fetus, although the fetus may be relatively protected from fluctuations in some maternal environmental stressors43 through several fetoplacental mechanisms that protect the immature fetal brain against the effects of maternal stress. These include β hydroxysteroid hydrogenase, an enzyme that breaks down maternal plasma glucocorticoids; as pregnancy progresses, increasing levels of maternal corticotrophin releasing hormone binding protein binds to maternal corticotrophin releasing hormone and inactivates it; and by mid-pregnancy, responses by the maternal hypothalamic-pituitary axis are attenuated or blunted.43 We found that the strongest association for risk of psychosis occurred after death in the nuclear family in early childhood (birth to 3 years) and, as suggested, this may reflect greater vulnerability to abnormal brain developmental trajectories the earlier the exposure occurs. In addition, the earlier in childhood, the longer a child is likely to be exposed to disruptive social and family effects associated with, for example, parental loss. Although previous work on childhood trauma and psychosis has rarely included children as young as those included here (0-2.9 years), exposures such as neglect, abuse, and bullying are difficult to ascertain in preschool aged children. However, our results in middle childhood are consistent with increasing evidence that such trauma may be related to later risk of psychosis.46

Future directions

Exposure to death of a parent or sibling in childhood is associated with an excess risk of developing a psychotic illness later in life. This does not seem to be the case after prenatal maternal exposure to death in the family. Risk is particularly associated with exposure in early childhood, or if death were by suicide or injury or accident compared with other causes of death. These associations are explained to some extent by genetic factors but are also likely, in large part, to include complex combinations of factors, creating more or less risk and resilience to future stressors. Such complex mechanisms require further investigation, and future studies should consider the broader contexts of parental suicide and parental loss in non-western, ethnically diverse populations and during conflict. More detailed evidence from adequately powered cohorts is also required before appropriately timed and appropriately resourced interventions can be developed to protect vulnerable families and children.