Based on two large samples of Swedish children, we found some evidence of a weak association between maternal bereavement experienced from one year before pregnancy to child birth and childhood asthma among boys while not girls. The associations also tended to be stronger for loss of a child or loss due to a traumatic cause of death.
Given that asthma has a strong immunological component; it is tempting to speculate that the fetal immune system altered upon prenatal stress challenges may contribute to the etiopathogenesis of asthma. It is well established that the immune system in mammals begins to develop prenatally 
with thymus organogenesis and T cell development in the thymus as a milestone 
. It is hypothesized that prenatal stress, through HPA-axis activation and fetal programming 
, modulates the developing immune system with enhanced polarization towards Th2 phenotype. For instance, stress-induced alterations in maternal cortisol may influence fetal immunomodulation and Th2 cell predominance through a direct influence on cytokine production 
. Further, the development of regulatory T cells may be impaired 
and stress may impact the maturation process of dendritic cells, further predisposing to a Th2 phenotype 
. Although there is few data on humans, animal models showed that prenatal psychological stress increases the risk of chronic immune diseases including various allergies and vulnerability toward airway hyperresponsiveness 
. These effects are probably due to stress-induced altered activity of HPA-axis which has immunoregulatory effects on the expression of IgE during pregnancy 
. A recent study also showed that newborns to mothers that had experienced a stressful period during pregnancy exhibited different innate and adaptive immune response 
. Finally, altered neuroimmune responsiveness may also influence the expression of asthma by enhancing an individual's susceptibility to other environmental factors which may contribute to asthma risk independently 
The stronger impact of loss of a child or of a traumatic cause, compared to loss of other relatives or loss due to more natural causes, on childhood asthma seems to be in agreement with previous findings on maternal bereavement and other childhood diseases 
. The different results between boys and girls as shown in our data are intriguing. Although the possibility of chance finding could not be ruled out, gender specific association between maternal bereavement and childhood diseases have also been described earlier. For example, a positive association between maternal bereavement and attention-deficit/hyperactivity disorder was mainly among boys but not girls 
, whereas for type 1 diabetes mainly among girls but not boys 
. A gender specific association may also be plausible for asthma given that gender differences in asthma are well established - boys have a higher prevalence of wheezing and asthma than girls before puberty but the pattern shifts toward girls around and after puberty 
. Boys have also been described to have different asthma-related traits such as bronchial hyperresponsiveness, allergic sensitization, serum IgE levels and developmental cytokine response profiles from girls 
. There are also differential growth of lung/airway size and immunological profiles between boys and girls 
. With respect to the development of asthma, these gender differences could all potentially make boys more sensitive to the impact of stress hormones as compared to girls.
Strengths of our study include the nationwide population-based design in a unified health care environment, prospectively and independently collected information on exposure and potential confounders that preclude recall bias, and the ascertainment of asthma by applying predetermined asthma criteria to the Patient Register and Drug Prescription Register. Sweden offers free inpatient and outpatient medical care to all residents. The Patient Register covers inpatient and outpatient visits but not visits to general practitioners and therefore we included asthma medication use from the Drug Prescription Register as an additional asthma ascertainment strategy in the present analyses where all dispensed asthma medications (except for those used during hospitalization) are registered. By using these asthma ascertainment criteria, we believe that we were able to identify the vast majority of asthma cases that had come into notice of the health care system. Furthermore, we were also able to study both incident cases of asthma symptoms among younger children (at 1–4 years) and any asthma attack among children with likely established diagnosis (at 7–12 years). Defining asthma is difficult among young children and use of inhaled corticosteroids and montelukast is not greatly specific for asthma. However, we believe that we have captured the real asthma cases (e.g., through the Patient Register) or the relatively severer cases of other conditions (i.e., with at least two dispenses of these specific medications) that will quite likely develop as asthma later on given that frequent wheezing such as obstructive bronchitis or (viral) infections of the respiratory tract during the first few years of life is a strong risk factor for subsequent asthma symptoms 
. In our multivariable analysis, maternal age at delivery, smoking during pregnancy and BMI at the prenatal care registration were all shown to be associated with a higher risk of asthma (data not shown), which further supported the validity of our asthma definition.
One inherent limitation of the present study, as of other register-based studies, is potential residual confounding due to factors not recorded in the registers. For example, although bereavement, especially loss of a child, is the most severe stressful life event that one may encounter, pregnant women might experience a variety of other milder stressors which could theoretically lead to an under-estimated association in our study. We also lacked information on other maternal characteristics including diet, physical activity and health seeking behaviors that might be related to both the mother's perception of the bereavement and the child's probability of being identified as an asthma patient by the health care system. Further, although we adjusted for maternal characteristics in the analyses, changes in social and economic status of the family (or mothers) after child birth as a result of the bereavement which might result in different asthma risk of the children were not captured. For example, loss of a child due to death has been associated with a higher risk of hospitalization for psychiatric disorders among the parents especially mothers 
. It is possible that these health consequences may result in less successful career of the parents and less affluent living environment among the children. Our findings that maternal loss of a child and spouse appeared to be the strongest risk predictors for child asthma at 7–12 years, compared to maternal loss of a parent or sibling, agreed with this line of reasoning. On the other hand, this possibility was not backed up by the stronger impact of a traumatic bereavement compared to bereavement of a natural cause. If financial setback were a mediate for the studied association, bereavement of natural causes such as a chronic disease should be more influential given the care giving burden of the family in addition to the psychological stress. Finally, although with the large material, our study was still underpowered to examine the potential modifying effect of timing and relative type of loss on the studied association.
In brief conclusion, our study provided some evidence for a potential association between prenatal stress and a higher risk of childhood asthma, mainly among boys.