Xiaoqin Liu

Birth weight, gestational age, fetal growth and childhood asthma hospitalization

BackgroundChildhood asthma may have a fetal origin through fetal growth and development of the immunocompetence or respiratory organs.ObjectiveWe examined to which extent short gestational age, low birth weight and fetal growth restriction were associated with an increased risk of asthma hospitalization in childhood.MethodsWe undertook a cohort study based on several national registers in Denmark, Sweden and Finland. We included all live singleton born children in Denmark during 1979-2005 (N = 1,538,093), in Sweden during 1973-2004 (N = 3,067,670), and a 90% random sample of singleton children born in Finland during 1987-2004 (N = 1,050,744). The children were followed from three years of age to first hospitalization for asthma, emigration, death, their 18th birthday, or the end of study (the end of 2008 in Denmark, and the end of 2007 in Sweden or Finland), whichever came first. We computed the pseudo-values for each observation and used them in a generalized estimating equation to estimate relative risks (RR) for asthma hospitalization.ResultsA total of 131,783 children were hospitalized for asthma during follow-up. The risk for asthma hospitalization consistently increased with lower birth weight and shorter gestational age. A 1000-g decrease in birth weight corresponded to a RR of 1.17 (95% confidence interval (CI) 1.15-1.18). A one-week decrease in gestational age corresponded to a RR of 1.05 (95% CI 1.04-1.06). Small for gestational age was associated with an increased risk of asthma hospitalization in term but not in preterm born children.ConclusionsFetal growth and gestational age may play a direct or indirect causal role in the development of childhood asthma.

Antidepressant use during pregnancy and psychiatric disorders in offspring: Danish nationwide register based cohort study

Objective To investigate the association between in utero exposure to antidepressants and risk of psychiatric disorders. Design Population based cohort study. Setting Danish national registers. Participants 905 383 liveborn singletons born during 1998-2012 in Denmark and followed from birth until July 2014, death, emigration, or date of first psychiatric diagnosis, whichever came first. The children were followed for a maximum of 16.5 years and contributed 8.1×106 person years at risk. Exposures for observational studies Children were categorised into four groups according to maternal antidepressant use within two years before and during pregnancy: unexposed, antidepressant discontinuation (use before but not during pregnancy), antidepressant continuation (use both before and during pregnancy), and new user (use only during pregnancy). Main outcome measure First psychiatric diagnosis in children, defined as first day of inpatient or outpatient treatment for psychiatric disorders. Hazard ratios of psychiatric disorders were estimated using Cox regression models. Results Overall, psychiatric disorders were diagnosed in 32 400 children. The adjusted 15 year cumulative incidence of psychiatric disorders was 8.0% (95% confidence interval 7.9% to 8.2%) in the unexposed group, 11.5% (10.3% to 12.9%) in the antidepressant discontinuation group, 13.6% (11.3% to 16.3%) in the continuation group, and 14.5% (10.5% to 19.8%) in the new user group. The antidepressant continuation group had an increased risk of psychiatric disorders (hazard ratio 1.27, 1.17 to 1.38), compared with the discontinuation group. Conclusions In utero exposure to antidepressants was associated with increased risk of psychiatric disorders. The association may be attributable to the severity of underlying maternal disorders in combination with antidepressant exposure in utero. The findings suggest that focusing solely on a single psychiatric disorder among offspring in studies of in utero antidepressant exposure may be too restrictive.

Prenatal exposure to maternal stress following bereavement and cardiovascular disease: A nationwide population-based and sibling-matched cohort study

Aims Cardiovascular disease (CVD) is among the leading determinants of mortality and morbidity, and causation may begin in the early intrauterine environment. Prenatal exposures to glucocorticoids or stress are potential risk factors of CVD later in life, but empirical evidence from large population studies is lacking. We explored the association between prenatal stress due to maternal bereavement following the death of a relative and CVD in the exposed offspring. Methods and results This population-based study included 2,607,851 children born in Denmark (1970–2008). Of these participants, 73,708 (2.8%) had a CVD event during follow-up (up to 40 years). A total of 50,940 (2.0%) subjects born to mothers who lost a relative during pregnancy or the year before were categorized as exposed. Cox Proportional Hazards models were used to analyse the data. The overall hazard ratio (HR) (95% confidence interval) of having a CVD was 1.13 (1.06–1.20); the estimate was 1.24 (1.11–1.38) for heart disease and 1.27 (1.01–1.60) for hypertension. Additional sibling-matched analyses showed an overall attenuated association (1.08 (0.94–1.24)). Conclusion Our results suggested a modest association between prenatal stress and CVD, both in childhood and early adulthood, which could be of importance, especially at an older age when the individuals are followed over a long period.

Prenatal stress and childhood asthma in the offspring: role of age at onset

BACKGROUND Asthma is a heterogeneous disorder with different phenotypes, and age at onset may define part of them. Little is known about possible association between prenatal stress and asthma phenotypes according to age at onset. We aim to investigate whether there is an association between prenatal stress and asthma, and if so, whether such an association differs according to age at asthma onset. METHODS We carried out a cohort study based on several national registers in Denmark, including all live singletons born during 1996-2007 in Denmark (N = 750,058). We identified children born to mothers who lost a close relative (a child, partner/spouse, a parent or a sibling) 1 year prior to or during pregnancy as the bereaved group. Using Cox proportional hazards regression model, we evaluated the hazard ratios (HRs) for asthma in children of bereaved mothers, compared with children of non-bereaved mothers. RESULTS Prenatal stress following maternal bereavement was associated with a marginally increased risk of asthma events in children aged 0-3 years [HR = 1.04, 95% confidence interval (CI): 1.00-1.07], while unexpected bereavement was associated with a higher risk (HR = 1.13, 95% CI: 1.02-1.24). There was no association between prenatal bereavement and asthma in children aged 4-15 years (HR = 1.02, 95% CI: 0.96-1.09). CONCLUSIONS Prenatal stress is possibly associated with asthma events in children aged 0-3 years, but not with asthma in children aged 4-15 years irrespective of age at asthma onset.

Perinatal psychiatric episodes: a population-based study on treatment incidence and prevalence

Perinatal psychiatric episodes comprise various disorders and symptom severity, which are diagnosed and treated in multiple treatment settings. To date, no studies have quantified the incidence and prevalence of perinatal psychiatric episodes treated in primary and secondary care, which we aimed to do in the present study. We designed a descriptive prospective study and included information from Danish population registers to study first-time ever and recurrent psychiatric episodes during the perinatal period, including treatment at psychiatric facilities and general practitioners (GPs). This was done for all women who had records of one or more singleton births from 1998 until 2012. In total, we had information on 822 439 children born to 491 242 unique mothers. Results showed first-time psychiatric episodes treated at inpatient facilities were rare during pregnancy, but increased significantly shortly following childbirth (0.02 vs 0.25 per 1000 births). In comparison, first-time psychiatric episodes treated at outpatient facilities were more common, and showed little variation across pregnancy and postpartum. For every single birth resulting in postpartum episodes treated at inpatient psychiatric facilities, 2.5 births were followed by an episode treated at outpatient psychiatric facility and 12 births by GP-provided pharmacological treatment. We interpret our results the following way: treated severe and moderate psychiatric disorders have different risk patterns in relation to pregnancy and childbirth, which suggests differences in the underlying etiology. We further speculate varying treatment incidence and prevalence in pregnancy vs postpartum may indicate that the current Diagnostic and Statistical Manual of Mental Disorders-5 peripartum specifier not adequately describes at-risk periods across moderate and severe perinatal psychiatric episodes.

Maternal preeclampsia and childhood asthma in the offspring

Preeclampsia is a possible risk factor for childhood asthma in the offspring. Our aim was to find whether preeclampsia is associated with childhood asthma. We also aimed to study whether a possible association can be explained by factors shared by siblings.

Antidepressant Use During Pregnancy and Asthma in the Offspring

BACKGROUND AND OBJECTIVES: It has been suggested that maternal depression during pregnancy is associated with asthma in the offspring, but the role of medical treatment of depression is not known. Our goal was to examine whether prenatal antidepressant use increases the risk of asthma in the offspring. METHODS: A cohort study was performed among all live singletons born in Denmark between 1996 and 2007. Mothers who had a diagnosis of depressive disorder and/or who used antidepressants 1 year before or during the index pregnancy were identified. Using a Cox proportional hazards regression model, we estimated the hazard ratio (HR) for asthma in the offspring after antidepressant use during pregnancy. RESULTS: Of the 733 685 children identified, 84 683 had a diagnosis of asthma. A total of 21 371 children were exposed to prenatal maternal depression (ie, a diagnosis of depressive disorder or use of antidepressants 1 year before or during pregnancy). Prenatal maternal depression was associated with childhood asthma (HR: 1.25 [95% confidence interval (CI): 1.20–1.30]). Overall, 8895 children were exposed to antidepressants in utero. Compared with children born to mothers with prenatal depression and no antidepressant use during pregnancy, the HR for asthma after any antidepressant use during pregnancy was 1.00 (95% CI: 0.93–1.08). HRs after use of selective serotonin reuptake inhibitors only, newer antidepressants only, and older antidepressants only were 0.95 (95% CI: 0.88–1.03), 1.11 (95% CI: 0.89–1.39), and 1.26 (95% CI: 1.02–1.55), respectively. CONCLUSIONS: Antidepressant use during pregnancy generally did not increase the risk of asthma. Only use of older antidepressants was associated with an increased risk of asthma.

Psychological Stress and Hospitalization for Childhood Asthma-a Nationwide Cohort Study in Two Nordic Countries

Objective Exposures to psychological stress in early life may contribute to the development or exacerbation of asthma. We undertook a cohort study based on data from several population-based registers in Denmark and Sweden to examine whether bereavement in childhood led to increased asthma hospitalization. Methods All singleton children born in Denmark during 1977-2008 and in Sweden during 1973-2006 were included in the study (N=5,202,576). The children were followed from birth to the date of first asthma hospitalization, emigration, death, their 18th birthday, or the end of study (31 December 2007 in Sweden and 31 December 2008 in Denmark), whichever came first. All the children were assigned to the non-bereaved group until they lost a close relative (mother, father or a sibling), from when they were included in the bereaved group. We evaluated the hazard ratio (HR) of first hospitalization for asthma in bereaved children using Cox proportional hazards regression models, compared to those who were in the non-bereaved group. We also did a sub-analysis on the association between bereavement and first asthma medication. Results A total of 147,829 children were hospitalized for asthma. The overall adjusted HR of asthma hospitalization in bereaved children was 1.10 (95% confidence interval (CI): 1.04-1.16), compared to non-bereaved children. The risk of asthma hospitalization was increased in those who lost a close relative at age of 14-17 years (HR=1.54, 95% CI: 1.23-1.92), but not in younger age groups. The association between bereavement and asthma hospitalization did not change over time since bereavement. In the sub-analysis in singleton live births during 1996-2008 recorded in the DMBR, bereavement was associated with a lower use of asthma medication (HR=0.87, 95% CI: 0.80-0.95). Conclusions Our data suggests that psychological stress following bereavement in late adolescence is associated with an increased risk of asthma hospitalization or lowers the threshold for asthma hospitalization.

Depression and Anxiety in the Postpartum Period and Risk of Bipolar Disorder: A Danish Nationwide Register-Based Cohort Study

OBJECTIVE The first-onset affective episode requiring inpatient treatment in the postpartum period can be a marker of bipolar disorder, but it is unknown whether milder postpartum affective episodes are also indicators of underlying bipolarity. Therefore, we aimed to study whether women with a nonpsychotic postpartum affective episode treated with antidepressants have an increased risk of bipolar disorder. METHODS A register-based cohort study was conducted in Denmark of 122,622 parous women without psychiatric history who received a first-time antidepressant prescription during 1997-2012. We compared women with a first-time antidepressant prescription, which was our indicator of a first-onset affective disorder, within 1 year postpartum to women with a first-time antidepressant prescription outside the postpartum period. Our outcome was psychiatric contact for bipolar disorder (ICD-10 criteria) during follow-up, and we estimated hazard ratios using Cox regressions. RESULTS The risk of bipolar disorder among women with a postpartum affective episode was higher than that in women with an affective episode outside the postpartum period. The risk of bipolar disorder was 1.66 (95% CI, 1.12-2.48) for postpartum antidepressant monotherapy and 10.15 (95% CI, 7.13-14.46) for postpartum antidepressant therapy plus a subsequent prescription for anxiolytics when these therapies were compared to antidepressant monotherapy outside the postpartum period. CONCLUSIONS First-onset nonpsychotic postpartum affective disorder can be a marker of underlying bipolarity. Women who fill an antidepressant prescription following childbirth should be asked about hypomanic or manic symptoms and monitored long term. Clinically, when antidepressant monotherapy is ineffective or the individual woman experiences persistent and concerning symptoms, health professionals should consider a possible bipolar spectrum disorder.

Maternal asthma severity and control during pregnancy and risk of offspring asthma

Background: Severe and uncontrolled asthma during pregnancy has been linked to several unfavorable perinatal outcomes. However, current knowledge on the association between the severity and control of maternal asthma and offspring asthma is sparse. Objective: We sought to investigate the extent to which offspring asthma is influenced by maternal asthma severity and control during pregnancy. Methods: We performed a prospective population‐based cohort study. Using linkage of Danish national registers, we constructed a cohort of 675,379 singletons, of which 15,014 children were born to asthmatic mothers. Among them, 7,188 children were born to mothers with active asthma during pregnancy. We categorized mothers with active asthma into 4 groups based on dispensed antiasthma prescriptions and on use of medical services: mild controlled, mild uncontrolled, moderate‐to‐severe controlled, and moderate‐to‐severe uncontrolled asthma. The outcomes were offspring early‐onset transient, early‐onset persistent, and late‐onset asthma. We estimated prevalence ratios (PRs) of each phenotype of asthma using a log‐binomial model with 95% CIs. Results: Higher prevalence of early‐onset persistent asthma was observed among children of asthmatic mothers with mild uncontrolled (PR, 1.19; 95% CI, 1.05–1.35), moderate‐to‐severe controlled (PR, 1.33; 95% CI, 1.09–1.63), and moderate‐to‐severe uncontrolled asthma (PR, 1.37; 95% CI, 1.17–1.61) compared with those of mothers with mild controlled asthma. A borderline increased prevalence of early‐onset transient asthma was observed among children of mothers with uncontrolled asthma. Conclusion: Maternal uncontrolled asthma increases the risk of early‐onset persistent and transient asthma. If replicated, this could suggest that maintaining asthma control in pregnancy is an area for possible prevention of specific phenotypes of offspring asthma.