Association between doxycycline use and long-term functioning in patients with schizophrenia.

IMPORTANCE AND OBJECTIVE: The brain-penetrant tetracycline antibiotics, minocycline and doxycycline, have been proposed as potential candidate drugs for treatment of schizophrenia, based on preclinical studies and clinical trials. A potential long-term beneficial effect of these antibiotics for schizophrenia patients has not been investigated. This study was designed to determine if redemption of doxycycline prescription in schizophrenia is associated with decreased incidence of disability pension, a proxy for long-term functioning. DESIGN: We performed a population-based cohort study with data from schizophrenia patients available through the Danish registers. Survival analysis models with time-varying covariates were constructed to assess incidence rate ratios (IRR) of disability pension after exposure to doxycycline or a non-brain penetrant tetracycline, defined as at least one filled prescription. The analysis was adjusted for age, sex, calendar year, parental psychiatric status and educational level. RESULTS: We used data from 11,157 individuals with schizophrenia (4,945 female and 6,212 male; average age 22.4 years old, standard deviation (std) 4.50). 718 of these were exposed to brain-penetrant doxycycline, and 1,498 individuals redeemed a prescription of one or more of the non-brain-penetrant tetracyclines. The average years at risk per person in this cohort was 4.9, and 2,901 individuals received disability pension in the follow-up period. There was a significantly lower incidence rate of disability pension in schizophrenia patients who had redeemed doxycycline compared to patients who did not redeem a prescription of any tetracycline antibiotics (Incidence rate ratio (IRR) 0.68; 95 % CI 0.56, 0.83). There was also a significant lower rate of disability pension in schizophrenia patients who redeemed doxycycline compared to individuals who redeemed a prescription of one of the non-brain penetrant tetracycline antibiotics (IRR 0.69 95 % CI 0.55, 0.87). CONCLUSIONS: In this observational study, doxycycline exposure is associated with a reduced incidence of disability pension. These data support further studies on the potential long term neuroprotective effects of doxycycline and level of functioning in schizophrenia patients.

In utero exposure to ADHD medication and long-term offspring outcomes.

Attention Deficit Hyperactivity Disorder (ADHD) medication is increasingly being used during pregnancy. Concerns have been raised as to whether ADHD medication has long-term adverse effects on the offspring. The authors investigated whether in utero exposure to ADHD medication was associated with adverse long-term neurodevelopmental and growth outcomes in offspring. The population-based cohort study in the Danish national registers included 1,068,073 liveborn singletons from 1998 to 2015 followed until any developmental diagnosis, death, emigration, or December 31, 2018. Children of mothers who continued ADHD medication (methylphenidate, amphetamine, dexamphetamine, lisdexamphetamine, modafinil, atomoxetine, clonidine) during pregnancy and children of mothers who discontinued ADHD medication before pregnancy were compared using Cox regression. Main outcomes were neurodevelopmental psychiatric disorders, impairments in vision or hearing, epilepsy, seizures, or growth impairment during childhood or adolescence. In total, 898 children were exposed to ADHD medication during pregnancy compared to 1270 children whose mothers discontinued ADHD medication before pregnancy. After adjustment for demographic and psychiatric characteristics of the mother, no increased risk of any offspring developmental disorders was found combined (aHR 0.97, 95% CI 0.81 to 1.17) or for separate subcategories. Similarly, no increased risk was found for any sub-categories of outcomes in the negative control or sibling controlled analyses. Neurodevelopment and growth in offspring do not differ based on antenatal exposure to ADHD medication. These findings provide reassurance for women with ADHD who depend on ADHD medication for daily functioning and who consider continuing medication in pregnancy.

Medication and procedural abortions before 13 weeks gestation and risk of psychiatric disorders.

BACKGROUND: The proportion of abortions provided by medication in the United States and worldwide has increased greatly since the U.S. Food and Drug Administration approved mifepristone in 2000. While existing research has shown that abortion does not increase risk of mental health problems, no population-based study has examined specifically whether a procedural or medication abortion increases risk of mental health disorders. OBJECTIVE: This study examined whether mental health disorders increased in the shorter and longer-term after a medication or procedural abortion. STUDY DESIGN: Using Danish population registers' data, we conducted a prospective cohort study in which we included 72,424 females born in Denmark between 1980 and 2006, who were ages 12 to 38 during the study period and had a first first-trimester abortion before 13 weeks gestation in 2000 to 2018. Females with no previous psychiatric diagnoses were followed from 1 year before their abortion until their first psychiatric diagnosis, December 31, 2018, emigration from Demark, or death, whichever came first. Risk of any first psychiatric disorder was defined as a recorded psychiatric diagnosis at an in- or out-patient facility from the 1 year after to more than 5 years after a medication or procedural abortion relative to the year beforehand. Results were adjusted for calendar year, age, gestational age, partner status, prior mental and physical health, childbirth history, childhood environment, and parental mental health history. RESULTS: Females having medication (n=37,155) and procedural abortions (n=35,269) had the same risk of any first psychiatric diagnosis in the year after their abortion relative to the year before their abortion (medication abortion adjusted incidence rate ratio [MaIRR]=1.02, 95% confidence interval [CI]: 0.93-1.12; procedural abortion adjusted incidence rate ratio [PaIRR]=0.94, 95% CI: 0.86-1.02). Moreover, as more time from the abortion passed, the risk of a psychiatric diagnoses decreased relative to the year before their abortion for each abortion method (MaIRR 1-2 years after=0.89, 95% CI: 0.80-0.98; PaIRR 1-2 years after=0.81, 95% CI: 0.88-1.05; MaIRR 2-5 years after=0.77, 95% CI: 0.71-0.84; PaIRR 2-5 years after=0.72, 95% CI: 0.67-0.78; MaIRR 5+ years after=0.58, 95% CI: 0.53-0.63; PaIRR 5+ years after=0.54, 95% CI: 0.50-0.58). CONCLUSION: Because the risk of psychiatric diagnoses was the same in the year after relative to the year before a medication and procedural abortion and the risk did not increase as more time after the abortion increased, neither abortion method increased risk of mental health disorders in the shorter or longer-term.

Self-harm in pregnancy and the postnatal year: prevalence and risk factors.

BACKGROUND: Self-harm in pregnancy or the year after birth ('perinatal self-harm') is clinically important, yet prevalence rates, temporal trends and risk factors are unclear. METHODS: A cohort study of 679 881 mothers (1 172 191 pregnancies) was conducted using Danish population register data-linkage. Hospital treatment for self-harm during pregnancy and the postnatal period (12 months after live delivery) were primary outcomes. Prevalence rates 1997-2015, in women with and without psychiatric history, were calculated. Cox regression was used to identify risk factors. RESULTS: Prevalence rates of self-harm were, in pregnancy, 32.2 (95% CI 28.9-35.4)/100 000 deliveries and, postnatally, 63.3 (95% CI 58.8-67.9)/100 000 deliveries. Prevalence rates of perinatal self-harm in women without a psychiatric history remained stable but declined among women with a psychiatric history. Risk factors for perinatal self-harm: younger age, non-Danish birth, prior self-harm, psychiatric history and parental psychiatric history. Additional risk factors for postnatal self-harm: multiparity and preterm birth. Of psychiatric conditions, personality disorder was most strongly associated with pregnancy self-harm (aHR 3.15, 95% CI 1.68-5.89); psychosis was most strongly associated with postnatal self-harm (aHR 6.36, 95% CI 4.30-9.41). For psychiatric disorders, aHRs were higher postnatally, particularly for psychotic and mood disorders. CONCLUSIONS: Perinatal self-harm is more common in women with pre-existing psychiatric history and declined between 1997 and 2015, although not among women without pre-existing history. Our results suggest it may be a consequence of adversity and psychopathology, so preventative intervention research should consider both social and psychological determinants among women with and without psychiatric history.

Genetic liability to posttraumatic stress disorder and its association with postpartum depression.

BACKGROUND: Childbirth may be a traumatic experience and vulnerability to posttraumatic stress disorder (PTSD) may increase the risk of postpartum depression (PPD). We investigated whether genetic vulnerability to PTSD as measured by polygenic score (PGS) increases the risk of PPD and whether a predisposition to PTSD in PPD cases exceeds that of major depressive disorder (MDD) outside the postpartum period. METHODS: This case-control study included participants from the iPSYCH2015, a case-cohort of all singletons born in Denmark between 1981 and 2008. Restricting to women born between 1981 and 1997 and excluding women with a first diagnosis other than depression (N = 22 613), 333 were identified with PPD. For each PPD case, 999 representing the background population and 993 with MDD outside the postpartum were matched by calendar year at birth, cohort selection, and age. PTSD PGS was calculated from summary statistics from the Psychiatric Genomics Consortium with LDpred2-auto. Odds ratios (ORs) were estimated using conditional logistic regression adjusted for parental psychiatric history and country of origin, PGS for MDD and age at first birth, and the first 10 principal components. RESULTS: The PTSD PGS was significantly associated with PPD (OR 1.42, 95% CI 1.20-1.68 per standard deviation increase in PTSD PGS) compared to healthy female controls. Genetic PTSD vulnerability in PPD cases did not exceed that of matched female depression cases outside the postpartum period (OR 1.10, 95% CI 0.94-1.30 per standard deviation increase). CONCLUSIONS: Genetic vulnerability to PTSD increased the risk of PPD but did not differ between PPD cases and women with depression at other times.

Polygenic liability, stressful life events and risk for secondary-treated depression in early life: a nationwide register-based case-cohort study.

BACKGROUND: In this study, we examined the relationship between polygenic liability for depression and number of stressful life events (SLEs) as risk factors for early-onset depression treated in inpatient, outpatient or emergency room settings at psychiatric hospitals in Denmark. METHODS: Data were drawn from the iPSYCH2012 case-cohort sample, a population-based sample of individuals born in Denmark between 1981 and 2005. The sample included 18 532 individuals who were diagnosed with depression by a psychiatrist by age 31 years, and a comparison group of 20 184 individuals. Information on SLEs was obtained from nationwide registers and operationalized as a time-varying count variable. Hazard ratios and cumulative incidence rates were estimated using Cox regressions. RESULTS: Risk for depression increased by 35% with each standard deviation increase in polygenic liability (p < 0.0001), and 36% (p < 0.0001) with each additional SLE. There was a small interaction between polygenic liability and SLEs (ß = -0.04, p = 0.0009). The probability of being diagnosed with depression in a hospital-based setting between ages 15 and 31 years ranged from 1.5% among males in the lowest quartile of polygenic liability with 0 events by age 15, to 18.8% among females in the highest quartile of polygenic liability with 4+ events by age 15. CONCLUSIONS: These findings suggest that although there is minimal interaction between polygenic liability and SLEs as risk factors for hospital-treated depression, combining information on these two important risk factors could potentially be useful for identifying high-risk individuals.

Prenatal antidepressant exposure and the risk of decreased gestational age and lower birthweight: A polygenic score approach to investigate confounding by indication.

INTRODUCTION: Prenatal antidepressant exposure has been associated with lower gestational age and birthweight. Yet, unmeasured residual confounding may inflate this association. We explored if maternal genetic liability for major depression explains part of the association of antidepressant use in pregnancy with lower gestational age and birthweight. MATERIAL AND METHODS: We employed the maternal polygenic score (PGS) for major depression as a measure of genetic liability. We used generalised linear models to estimate the differences in gestational age and birthweight at each PGS quintile between children whose mothers continued antidepressant use during pregnancy (continuation group), children whose mothers discontinued antidepressant use during pregnancy (discontinuation group) and unexposed children. RESULTS: After adjusting for confounders, we found significant differences in birthweight between PGS quintiles in the continuation and unexposed group. Yet, this relationship was not linear. Furthermore, at the lowest and highest PGS quintiles, the continuation group had significantly reduced mean gestational ages (adjusted ß ranges: 1.7-4.5 days, p < 0.001-0.008) and lower mean birthweights (adjusted ß ranges: 58.6-165.4 g, p = 0.001-0.008) than the discontinuation and unexposed groups. CONCLUSION: We confirmed that antidepressant use in pregnancy was associated with small reductions in gestational age and birthweight but found that genetic liability for depression was not linearly associated with this risk. The causality of the observed associations could not be established due to the observational nature of the study. Residual confounding linked to the underlying disease was likely still present.

Identification of women at high risk of postpartum psychiatric episodes: A population-based study quantifying relative and absolute risks following exposure to selected risk factors and genetic liability.

BACKGROUND: We quantified relative and absolute risks of postpartum psychiatric episodes (PPE) following risk factors: Young age, past personal or family history of psychiatric disorders, and genetic liability. METHODS: We conducted a register-based study using the iPSYCH2012 case-cohort sample. Exposures were personal history of psychiatric episodes prior to childbirth, being a young mother (giving birth before the age of 21.5 years), having a family history of psychiatric disorders, and a high (highest quartile) polygenic score (PGS) for major depression. PPE was defined within 12 months postpartum by prescription of psychotropic medication or in- and outpatient contact to a psychiatric facility. We included primiparous women born 1981-1999, giving birth before January 1st, 2016. We conducted Cox regression to calculate hazard ratios (HRs) of PPE, absolute risks were calculated using cumulative incidence functions. RESULTS: We included 8174 primiparous women, and the estimated baseline PPE risk was 6.9% (95% CI 6.0%-7.8%, number of PPE cases: 2169). For young mothers with a personal and family history of psychiatric disorders, the absolute risk of PPE was 21.6% (95% CI 15.9%-27.8%). Adding information on high genetic liability to depression, the risk increased to 29.2% (95% CI 21.3%-38.4%) for PPE. CONCLUSIONS: Information on prior personal and family psychiatric episodes as well as age may assist in estimating a personalized risk of PPE. Furthermore, additional information on genetic liability could add even further to this risk assessment.

Psychiatric visits during the postpartum year in women with eating disorders who continue or discontinue antidepressant treatment in pregnancy.

OBJECTIVE: To determine the association between continued antidepressant use in pregnancy and postpartum psychiatric visits for eating (ED) or mood/anxiety disorders in women with preexisting ED. METHOD: Using Danish health registry data (1998-2015), we identified 3529 pregnancies in women with ED prepregnancy: (i) 564 with continued antidepressant use before and during pregnancy; (ii) 778 with discontinued antidepressants before pregnancy; (iii) 2137 unexposed. Outpatient and inpatient postpartum visits for an ED or a mood/anxiety disorder constituted the outcome measures. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) using Cox regression with inverse probability of treatment weighting, and performed stratified analyses by antidepressant prescription filling in the first 3 months postpartum. RESULTS: The weighted cumulative incidence for an ED visit at end of follow-up was 4.5% (continued) and 4.8% (discontinued). We found no association between continued antidepressant and postpartum ED visit, relative to discontinued (HR: 0.89, 95% CI: 0.52-1.52). The HR for postpartum mood/anxiety disorder visit was 1.27 (95% CI: 0.68-2.36) with continued antidepressants versus discontinued but decreased if more than two antidepressant prescriptions were refilled. Continued antidepressant use was associated with a 57% reduced likelihood of a postpartum ED visit versus discontinued use in pregnancies with antidepressant prescription refills in the early postpartum. CONCLUSION: Among women with preexisting ED, there was no association between continued antidepressant use during pregnancy and the likelihood of postpartum psychiatric visits, relative to discontinued antidepressants before pregnancy. Continuation of treatment into the early postpartum is associated with reduced likelihood of postpartum ED visit. PUBLIC SIGNIFICANCE: Based on data from the Danish registries, we identified 3529 pregnancies among women with preexisting eating disorders before pregnancy. Women with continued antidepressant treatment both before and during pregnancy did not have a lower probability of having postpartum psychiatric visits for an eating disorder or for mood/anxiety disorders (often coexisting with eating disorders), relative to those who discontinued antidepressants before pregnancy. Further continuation of antidepressant treatment into the early postpartum is associated with improved maternal postpartum outcomes. However, residual confounding by disease severity limits confidence in this conclusion.

Antidepressant discontinuation before or during pregnancy and risk of psychiatric emergency in Denmark: A population-based propensity score-matched cohort study.

BACKGROUND: Women prescribed antidepressants face the dilemma of whether or not to continue their treatment during pregnancy. Currently, limited evidence is available on the efficacy of continuing versus discontinuing antidepressant treatment during pregnancy to aid their decision. We aimed to estimate whether antidepressant discontinuation before or during pregnancy was associated with an increased risk of psychiatric emergency (ascertained by psychiatric admission or emergency room visit), a proxy measure of severe exacerbation of symptoms/mental health crisis. METHODS AND FINDINGS: We carried out a propensity score-matched cohort study of women who gave birth to live-born singletons between January 1, 1997 and June 30, 2016 in Denmark and who redeemed an antidepressant prescription in the 90 days before the pregnancy, identified by Anatomical Therapeutic Chemical (ATC) code N06A. We constructed 2 matched cohorts, matching each woman who discontinued antidepressants before pregnancy (N = 2,669) or during pregnancy (N = 5,467) to one who continued antidepressants based on propensity scores. Maternal characteristics and variables related to disease severity were used to generate the propensity scores in logistic regression models. We estimated hazard ratios (HRs) of psychiatric emergency in the perinatal period (pregnancy and 6 months postpartum) using stratified Cox regression. Psychiatric emergencies were observed in 76 women who discontinued antidepressants before pregnancy and 91 women who continued. There was no evidence of higher risk of psychiatric emergency among women who discontinued antidepressants before pregnancy (cumulative incidence: 2.9%, 95% confidence interval [CI]: 2.3% to 3.6% for discontinuation versus 3.4%, 95% CI: 2.8% to 4.2% for continuation; HR = 0.84, 95% CI: 0.61 to 1.16, p = 0.298). Overall, 202 women who discontinued antidepressants during pregnancy and 156 who continued had psychiatric emergencies (cumulative incidence: 5.0%, 95% CI: 4.2% to 5.9% versus 3.7%, 95% CI: 3.1% to 4.5%). Antidepressant discontinuation during pregnancy was associated with increased risk of psychiatric emergency (HR = 1.25, 95% CI: 1.00 to 1.55, p = 0.048). Study limitations include lack of information on indications for antidepressant treatment and reasons for discontinuing antidepressants. CONCLUSIONS: In this study, we found that discontinuing antidepressant medication during pregnancy (but not before) is associated with an apparent increased risk of psychiatric emergency compared to continuing treatment throughout pregnancy.

Who prescribes quetiapine in Denmark?

The second-generation antipsychotic quetiapine is commonly used off-label for its anxiolytic and hypnotic properties. However, quetiapine is associated with problematic side-effects. We used Danish Medicinal Product Statistics and a 20% random sample of the Danish population's prescription fills (2001-2020) to describe the utilization of quetiapine and proportion of various prescriber types (general practitioner [GP], specialist in private practice, hospital physician and other prescribers) both in connection to first-time and subsequent prescriptions. In 2020, 92% of all quetiapine was dispensed outside hospitals and the average daily dispensed quantity of quetiapine per user corresponded to 100 mg/user/d. A GP issued 53% of first-time prescriptions and 75% of subsequent prescriptions for quetiapine in 2020. The proportion of quetiapine prescriptions issued by GPs varied by age group-from 14% among 0-17-year-olds to 93% among the ≥80-year-olds. Future initiatives on the rational use of quetiapine and related drugs, especially among adults, should target GPs.

Antidepressant use during pregnancy and risk of adverse neonatal outcomes: A comprehensive investigation of previously identified associations.

OBJECTIVE: Prenatal antidepressant use is widespread. Observational studies have investigated the neonatal effects of prenatal antidepressant exposure with inconclusive results. We aimed to comprehensively investigate the associations between prenatal antidepressant exposure and the most commonly studied adverse neonatal outcomes: preterm birth, birthweight, poor neonatal adaptation, persistent pulmonary hypertension of the neonate (PPHN), neonatal admission and congenital malformations. METHODS: We included 45,590 singletons (born 1997-2015) whose mothers used antidepressants within one year before pregnancy. Children were categorised into two groups: continuation (antidepressant use before and during pregnancy) or discontinuation (antidepressant use before but not during pregnancy). We applied random-effects logistic and linear regressions, adjusting for covariates. RESULTS: After adjusting for confounders, prenatal antidepressant exposure was associated with a 2.3 day (95% CI -2.9; -2.0) decrease in gestational age and a 51 g (95% CI -62g; -41 g) decrease in birthweight. The continuation group was at increased risk for moderate-to-late preterm birth (32-37 weeks) (aOR = 1.43; 95%CI 1.33; 1.55), moderately low birthweight (1500-2499 g) (aOR = 1.28; 95%CI 1.17; 1.41), postnatal adaptation syndrome (aOR = 2.59; 95%CI 1.87; 3.59) and neonatal admission (aOR = 1.52; 95%CI 1.44; 1.60) compared to the discontinuation group. CONCLUSION: Prenatal antidepressant exposure was associated with small decreases in gestational age and birthweight, as well as higher risk for moderate-to-late preterm birth, moderately low birthweight, neonatal admission and postnatal adaptation syndrome. No differences in risk were found for PPHN, or congenital malformations. The causality of the observed associations cannot be established due to the potential for unmeasured residual confounding linked to the underlying disease.

Perinatal mental health: how nordic data sources have contributed to existing evidence and future avenues to explore.

PURPOSE: Perinatal mental health disorders affect a significant number of women with debilitating and potentially life-threatening consequences. Researchers in Nordic countries have access to high quality, population-based data sources and the possibility to link data, and are thus uniquely positioned to fill current evidence gaps. We aimed to review how Nordic studies have contributed to existing evidence on perinatal mental health. METHODS: We summarized examples of published evidence on perinatal mental health derived from large population-based longitudinal and register-based data from Denmark, Finland, Iceland, Norway and Sweden. RESULTS: Nordic datasets, such as the Danish National Birth Cohort, the FinnBrain Birth Cohort Study, the Icelandic SAGA cohort, the Norwegian MoBa and ABC studies, as well as the Swedish BASIC and Mom2B studies facilitate the study of prevalence of perinatal mental disorders, and further provide opportunity to prospectively test etiological hypotheses, yielding comprehensive suggestions about the underlying causal mechanisms. The large sample size, extensive follow-up, multiple measurement points, large geographic coverage, biological sampling and the possibility to link data to national registries renders them unique. The use of novel approaches, such as the digital phenotyping data in the novel application-based Mom2B cohort recording even voice qualities and digital phenotyping, or the Danish study design paralleling a natural experiment are considered strengths of such research. CONCLUSIONS: Nordic data sources have contributed substantially to the existing evidence, and can guide future work focused on the study of background, genetic and environmental factors to ultimately define vulnerable groups at risk for psychiatric disorders following childbirth.

Self-harm in women with postpartum mental disorders.

BACKGROUND: Women suffering from first onset postpartum mental disorders (PPMD) have a highly elevated risk of suicide. The current study aimed to: (1) describe the risk of self-harm among women with PPMD and (2) investigate the extent to which self-harm is associated with later suicide. METHODS: We conducted a register-based cohort study linking national Danish registers. This identified women with any recorded first inpatient or outpatient contact to a psychiatric facility within 90 days after giving birth to their first child. The main outcome of interest was defined as the first hospital-registered episode of self-harm. Our cohort consisted of 1 202 292 women representing 24 053 543 person-years at risk. RESULTS: Among 1554 women with severe first onset PPMD, 64 had a first-ever hospital record of self-harm. Women with PPMD had a hazard ratio (HR) for self-harm of 6.2 (95% CI 4.9-8.0), compared to mothers without mental disorders; but self-harm risk was lower in PPMD women compared to mothers with non-PPMD [HR: 10.1, (95% CI 9.6-10.5)] and childless women with mental disorders [HR: 9.3 (95% CI 8.9-9.7)]. Women with PPMD and records of self-harm had a significantly greater risk for later suicide compared with all other groups of women in the cohort. CONCLUSIONS: Women with PPMD had a high risk of self-harm, although lower than risks observed in other psychiatric patients. However, PPMD women who had self-harmed constituted a vulnerable group at significantly increased risk of later suicide.

Genetic liability to major depression and risk of childhood asthma.

OBJECTIVE: Major depression and asthma frequently co-occur, suggesting shared genetic vulnerability between these two disorders. We aimed to determine whether a higher genetic liability to major depression was associated with increased childhood asthma risk, and if so, whether such an association differed by sex of the child. METHODS: We conducted a population-based cohort study comprising 16,687 singletons born between 1991 and 2005 in Denmark. We calculated the polygenic risk score (PRS) for major depression as a measure of genetic liability based on the summary statistics from the Major Depressive Disorder Psychiatric Genomics Consortium collaboration. The outcome was incident asthma from age 5 to 15 years, identified from the Danish National Patient Registry and the Danish National Prescription Registry. Stratified Cox regression was used to analyze the data. RESULTS: Greater genetic liability to major depression was associated with an increased asthma risk with a hazard ratio (HR) of 1.06 (95% CI: 1.01-1.10) per standard deviation increase in PRS. Children in the highest major depression PRS quartile had a HR for asthma of 1.20 (95% CI: 1.06-1.36), compared with children in the lowest quartile. However, major depression PRS explained only 0.03% of asthma variance (Pseudo-R2). The HRs of asthma by major depression PRS did not differ between boys and girls. CONCLUSION: Our results suggest a shared genetic contribution to major depression and childhood asthma, and there is no evidence of a sex-specific difference in the association.

Parental asthma occurrence, exacerbations and risk of attention-deficit/hyperactivity disorder.

OBJECTIVE: To investigate whether intrauterine exposure to maternal asthma or asthma exacerbations increases the risk of attention-deficit/hyperactivity disorder (ADHD). METHODS: Using Danish register data, this cohort study comprised of 961,202 live singletons born in Denmark during 1997-2012. Children were followed to a maximum of 20.0 years from birth until the first of ADHD-diagnosis/prescription, emigration, death, or 31 December 2016. Cox regression models were used to evaluate the association between maternal or paternal asthma, asthma exacerbations and offspring ADHD. RESULTS: During 11.4 million person-years of follow-up, 27,780 (2.9%) children were identified as having ADHD. ADHD risk was increased among offspring born to asthmatic mothers (hazard ratio (HR) 1.41, 95% CI: 1.36-1.46) or asthmatic fathers (HR 1.13, 95% CI: 1.08-1.18). Antenatal antiasthma medication treatment did not increase offspring ADHD. However, higher risks were observed among offspring of mothers with asthma exacerbations compared with children of asthmatic mothers with no exacerbations: HR 1.12 (95% CI: 1.00-1.25) for pre-pregnancy exacerbations; 1.21 (95% CI: 1.00-1.47) for exacerbations during pregnancy; and 1.25 (95% CI: 1.08-1.44) for exacerbations after delivery. CONCLUSIONS: These results support theories regarding shared genetic and environmental risk factors having a role in the development of ADHD.

Childhood infections and schizophrenia: The impact of parental SES and mental illness, and childhood adversities.

Childhood infection has been proposed as an important etiologic factor for schizophrenia. However, it is unclear to what extent the association between childhood infection and schizophrenia is confounded by parental socioeconomic status and mental illness, and childhood adversity, and whether the association is explained by familial liability for infections. We used a historical, population-based cohort design, selecting all singletons born in Denmark between 1981 and 1998 (n = 882,813). We identified exposure to infection as having been hospitalized with an infection in the Danish national registers. Data from a range of population-based registers were used to construct a childhood adversity index. The index included the following adversities: family disruption, parental incarceration, parental chronic somatic disease, death of a parent, parent permanently outside of workforce, childhood abuse and placement in out-of-home care. We also assessed parental socioeconomic status and mental illness. Multiple admissions with infections during childhood increased the risk of schizophrenia with an Incidence Rate Ratio (IRR) of 1.28 (95% CI: 1.19-1.38) for 1 infection to an IRR of 1.43 (95% CI: 1.30-1.58) for 2-3 infections and an IRR of 1.95 (95% CI: 1.66-2.29) for ≥4 infections. Parental socioeconomic status and mental illness, and childhood adversities increased the odds of acquiring childhood infections and was associated with schizophrenia, but did not explain the results. Similarly did familial liability for infection increase the risk of schizophrenia, but did not explain the association between infection and schizophrenia. Parental mental health modified the association between childhood infection and schizophrenia (p-value 0.02), and we found no significant effect of childhood infection in those with propensity for psychotic disorders.

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.

Vascular Pathology and Trajectories of Late-Life Major Depressive Disorder in Secondary Psychiatric Care.

OBJECTIVE: To examine 5-year trajectories of psychiatrist-treated late-life major depressive disorder (MDD), and evaluate whether previous vascular pathology is associated with more severe trajectories of late-life MDD. METHODS: Data were obtained from nationally representative civil, psychiatric, hospital, and prescription registers in Denmark. The sample included 11,092 older adults (≥60 years) who received their first diagnosis of MDD in a psychiatric facility in Denmark between 2000 and 2007. Trajectories of inpatient or outpatient contact at psychiatric hospitals for MDD over the 5-year period following index MDD diagnosis were modeled using latent class growth analysis. Measures of vascular disease (stroke, heart disease, vascular dementia) and vascular risk factors (hypertension, diabetes) were defined based on medication prescriptions and hospital-based diagnoses. Other predictors included demographic characteristics and characteristics of the index MDD diagnosis. RESULTS: The final model included 4 trajectories with consistently low (66% of the sample), high decreasing (19%), consistently high (9%), and moderate fluctuating (6%) probabilities of contact at a psychiatric hospital for MDD during the 5-year period following the index MDD diagnosis. We found no significant associations between any form of vascular pathology and trajectory class membership. Relative to the consistently low class, older age, greater severity and >12 months of prior antidepressant medication use predicted membership in the other three classes. CONCLUSIONS: A notable proportion (34%) of individuals diagnosed with MDD in late-life require secondary psychiatric treatment for extended time periods. We did not find evidence that vascular pathology predicts hospital contact trajectories in secondary-treated late-life MDD.

Out-of-home placement to age 18 years in children exposed to a postpartum mental disorder.

OBJECTIVES: Little is known about risk of custody loss or out-of-home placement among children whose mothers experience postpartum mental disorders, and whether this risk differs from that of children whose mothers had earlier onset of their mental disorder. METHODS: National Danish registers comprising 1 868 467 births (1982-2012) were used to determine how the timing of maternal illness onset influences out-of-home placement risk up to age 18 years among children exposed to a maternal mental disorder. RESULTS: Compared to children unexposed to maternal mental illness, risk was higher for children exposed to a maternal mental disorder whose mothers had a first contact for a mental disorder in the 0-12 months of predelivery (8.17/1000 person-years; aIRR 4.56, 95% CI 4.08-5.09), the first 3 months postpartum (4.60/1000 person-years; 3.55, 2.95-4.26) and 4-12 months postpartum (6.49/1000 person-years; 3.93, 3.50-4.41). Risk was even higher for children exposed to a maternal mental disorder when illness onset was more than 1-year predelivery (9.11/1000 person-years; 5.48, 5.32-5.66). CONCLUSION: Risk of out-home placement in children exposed to mothers with a new-onset postpartum mental disorder is almost as high as in children whose mothers have long-standing illness. A better understanding of the trajectories of these mothers and children is warranted.