Katrine Holde’s research while affiliated with Aarhus University and other places

Background Involuntary treatment for patients with anorexia nervosa is common and lifesaving, but also highly intrusive. Understanding how morbidity patterns relate to involuntary treatment can help minimise its use. Aim We estimate the relative risk of involuntary treatment according to morbidity profiles in patients with anorexia nervosa. Method This register-based cohort study included all individuals diagnosed with anorexia nervosa (ICD-10: F50.0, F50.1) between 1 January 2000 and 31 December 2016 in Denmark. Individuals were grouped by prior morbidities using latent class analysis (LCA). Cox proportional hazards regression estimated the relative risk of first involuntary treatment (e.g. involuntary admission, detention, locked wards) after a diagnosis with anorexia nervosa, regardless of the associated diagnosis. The relative risk of involuntary treatment was estimated with latent classes and the number of morbidities as exposure. Results A total of 9892 individuals with anorexia nervosa were included (93.3% female), of which 821 (8.3%) individuals experienced at least one involuntary treatment event. The LCA produced six classes, with distinct morbidity profiles. The highest hazard ratio was observed for a group characterised by personality disorders, self-harm and substance misuse (hazard ratio 4.46, 95% CI: 3.43–5.79) followed by a high burden group with somatic and psychiatric disorders (hazard ratio 3.96, 95% CI: 2.81–5.59) and a group with developmental and behavioural disorders (hazard ratio 3.61, 95% CI: 2.54–5.11). The relative risk of involuntary treatment increased primarily with the number of psychiatric morbidities. Conclusions Specific morbidity groups are associated with highly elevated risk of involuntary treatment among patients with anorexia nervosa. Targeting preventive interventions to high-risk groups may help reduce the need for involuntary treatment.

Background We examined the incidence of cancer types among individuals with eating disorders (EDs). Methods A nationwide longitudinal study of 6,807,731 individuals born between 1940 and 2015 was conducted using the Danish National Registries. Cox models with ED diagnosis as exposure and cancer diagnoses as outcomes were used to estimate hazard ratios (HRs) and 95% CIs while adjusting for sex, birth year, and comorbidities. The primary analysis comprised ICD-8 and ICD-10 codes for anorexia nervosa (AN) and other ED (OED). The secondary analysis comprised ICD-10 codes and included AN, bulimia nervosa (BN), and eating disorders not otherwise specified (EDNOS). Results AN was associated with a reduced incidence of breast cancer while adjusting for sex and birth year (HR, 0.80; 95% CI, 0.66–0.97) and elevated incidence of respiratory (HR, 1.59; 95% CI, 1.24–2.04), cervical (HR, 1.45; 95% CI, 1.05–1.98), and esophageal (HR, 4.77; 95% CI, 2.82–8.06) cancers. OED was associated with an elevated incidence of respiratory (HR, 1.57; 95% CI, 1.20–2.06) and cervical (HR, 1.60; 95% CI, 1.20–2.14) cancers. ICD-10–only analyses confirmed the association of AN with reduced incidence of breast cancer and elevated incidence of respiratory and cervical cancers. BN was associated with reduced incidence of breast cancer in sensitivity analysis. EDNOS was associated with reduced incidence of breast cancer and elevated incidence of respiratory and cervical cancers. Conclusions All EDs were associated with a reduced incidence of breast cancer. All EDs except BN were associated with a higher incidence of respiratory and cervical cancers. AN was associated with a higher incidence of esophageal cancer.

Background More research is needed to understand psychopathology among parents of children with mental disorders in the years before and after the child is diagnosed. Here, we estimated the risk of mental disorders and psychotropic medication use in parents of children with versus without mental disorders and the temporal associations between child and parental psychopathology. Methods We conducted a population‐based matched cohort study using Danish register data. The study population included child–parent pairs of all children diagnosed with a mental disorder of interest (attention‐deficit/hyperactivity disorder, autism spectrum disorder, intellectual disability, anxiety disorder, mood disorder, eating disorder, substance use disorder, and schizophrenia spectrum disorder) by 18 years of age during the period 1999–2014 and a matched reference population. Each child with a diagnosis was matched to 10 children of the same sex and birth year who had not been diagnosed with the mental disorder of interest. For all parents, we estimated the yearly incidence proportion of parental mental disorders and prescriptions for psychotropic medications 4 years before and after the child's diagnosis. Results We observed a substantially increased risk of mental disorders and psychotropic medication use among parents of children with a mental disorder, compared to the reference population. On average, parents of children with a diagnosis had twice the odds of mood disorders, anxiety disorders, and prescriptions for anti‐depressants and anti‐psychotics. The incidence of mood and anxiety disorders peaked in the 1–2 years before and after the child's diagnosis. The incidence of parental prescriptions for psychotropic medications (particularly anti‐psychotics) peaked in the year the child was diagnosed and in the 3 years before the child's diagnosis for anti‐depressants and sleep medications. Conclusions This study demonstrates clear temporal associations between child and parental psychopathology, with parental psychopathology peaking in the years immediately before and after the child's diagnosis.

Objective We examined the risk of adverse neonatal outcomes among children born to mothers with anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS). Design Cohort study. Setting Population‐based using Danish national registers. Population We included 1 517 839 singletons born between 1991 and 2015 in Denmark. Methods For each ED subtype, we compared children born to mothers with a recent (≤ 2 years before conception and during pregnancy) or past (> 2 years before conception) diagnosis, with children born to mothers who had not been diagnosed with the ED of interest before the index delivery. Main Outcome Measures Using multinomial logistic regression, we estimated relative risk ratios (RRRs) and 95% confidence intervals (CIs) for gestational age, birthweight, weight‐for‐gestational age, low Apgar score, Caesarean section, congenital malformations and postpartum haemorrhage. Results Both recent and past AN were associated with increased risk of low birthweight (recent: RRR = 2.36 [95% CI = 1.76–3.18]; past: 1.22 [1.04–1.43]), small‐for‐gestational age (recent: 1.52 [1.01–2.26]; past: 1.37 [1.16–1.62]), and preterm birth (recent: 1.83 [1.37–2.45]; past: 1.17 [1.00–1.36]), with more pronounced risks in recent AN. Recent (but not past) BN was associated with increased risk of low Apgar score (1.44 [1.03–2.00]). Recent (but not past) EDNOS was associated with increased risk of SGA (1.53 [1.04–2.27]). Conclusions Children born to mothers with EDs have an increased risk of some adverse neonatal outcomes, with more pronounced risks in recent than past EDs. These results underscore the need for improved prevention of maternal EDs and enhanced monitoring throughout pregnancy to mitigate adverse outcomes.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981–2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD or ASD diagnosis. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44%–100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal half sibling with ASD had increased risk of AN compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk whereas a negative association was found between AN-PGS and ADHD. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and genetic associations between ASD-PGS and AN and between AN-PGS and ADHD were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Background Previous studies have indicated associations between maternal mental disorders and adverse birth outcomes; however, these studies mainly focus on certain types of mental disorders, rather than the whole spectrum. Aims We aimed to conduct a broad study examining all maternal mental disorder types and adverse neonatal outcomes which is needed to provide a more complete understanding of the associations. Method We included 1 132 757 liveborn singletons born between 1997 and 2015 in Denmark. We compared children of mothers with a past (>2 years prior to conception; n = 48 646), recent (2 years prior to conception and during pregnancy; n = 15 899) or persistent (both past and recent; n = 10 905) diagnosis of any mental disorder, with children of mothers with no mental disorder diagnosis before the index delivery ( n = 1 057 307). We also considered different types of mental disorders. We calculated odds ratios and 95% CIs of low birthweight, preterm birth, small for gestational age, low Apgar score, Caesarean delivery and neonatal death. Results Odds ratios for children exposed to past, recent and persistent maternal mental disorders suggested an increased risk for almost all adverse neonatal outcomes. Estimates were highest for children in the ‘persistent’ group for all outcomes, with the exception of the association between persistent maternal mental disorders and neonatal death (odds ratio 0.96, 0.62–1.48). Conclusions Our study provides evidence for increased risk of multiple adverse neonatal outcomes among children of mothers with mental disorders, highlighting the need for close monitoring and support for women with mental disorders.

Eating disorders (EDs) commonly co-occur with other psychiatric and neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD); however, the pattern of family history and genetic overlap among them requires clarification. This study investigated the diagnostic, familial, and genetic associations of EDs with ADHD and ASD. The nationwide population-based cohort study included all individuals born in Denmark, 1981–2008, linked to their siblings and cousins. Cox regression was used to estimate associations between EDs and ADHD or ASD, and mediation analysis was used to assess the effects of intermediate mood or anxiety disorders. Polygenic scores (PGSs) were used to investigate the genetic association between anorexia nervosa (AN) and ADHD or ASD. Significantly increased risk for any ED was observed following an ADHD [hazard ratio = 1.97, 95% confidence interval = 1.75–2.22] or ASD diagnosis [2.82, 2.48–3.19]. Mediation analysis suggested that intermediate mood or anxiety disorders could account for 44–100% of the association between ADHD or ASD and ED. Individuals with a full sibling or maternal halfsibling with ASD had increased risk of AN [1.54, 1.33–1.78; 1.45, 1.08–1.94] compared to those with siblings without ASD. A positive association was found between ASD-PGS and AN risk [1.06, 1.02–1.09]. In this study, positive phenotypic associations between EDs and ADHD or ASD, mediation by mood or anxiety disorder, and a genetic association between ASD-PGS and AN were observed. These findings could guide future research in the development of new treatments that can mitigate the development of EDs among individuals with ADHD or ASD.

Background Although several types of risk factors for anorexia nervosa (AN) have been identified, including birth-related factors, somatic, and psychosocial risk factors, their interplay with genetic susceptibility remains unclear. Genetic and epidemiological interplay in AN risk were examined using data from Danish nationwide registers. AN polygenic risk score (PRS) and risk factor associations, confounding from AN PRS and/or parental psychiatric history on the association between the risk factors and AN risk, and interactions between AN PRS and each level of target risk factor on AN risk were estimated. Methods Participants were individuals born in Denmark between 1981 and 2008 including nationwide-representative data from the iPSYCH2015, and Danish AN cases from the Anorexia Nervosa Genetics Initiative and Eating Disorder Genetics Initiative cohorts. A total of 7003 individuals with AN and 45 229 individuals without a registered AN diagnosis were included. We included 22 AN risk factors from Danish registers. Results Risk factors showing association with PRS for AN included urbanicity, parental ages, genitourinary tract infection, and parental socioeconomic factors. Risk factors showed the expected association to AN risk, and this association was only slightly attenuated when adjusted for parental history of psychiatric disorders or/and for the AN PRS. The interaction analyses revealed a differential effect of AN PRS according to the level of the following risk factors: sex, maternal age, genitourinary tract infection, C-section, parental socioeconomic factors and psychiatric history. Conclusions Our findings provide evidence for interactions between AN PRS and certain risk-factors, illustrating potential diverse risk pathways to AN diagnosis.

Objective: To examine sex differences in risk factors for anorexia nervosa (AN). Method: This population-based study involved 44,743 individuals (6,239 AN cases including 5,818 females and 421 males, and 38,504 controls including 18,818 females and 19,686 males) born in Denmark between May 1981 and December 2009. Follow-up began on the individual's sixth birthday and ended at AN diagnosis, emigration, death, or December 31, 2016, whichever occurred first. Exposures included socioeconomic status (SES), pregnancy, birth, and early childhood factors based on data from Danish registers, and psychiatric and metabolic polygenic risk scores (PRS) based on genetic data. Hazard ratios were estimated using weighted Cox proportional hazards models stratified by sex (assigned at birth), with AN diagnosis as the outcome. Results: The effects of early life exposures and PRS on AN risk were comparable between females and males. Although we observed some differences in the magnitude and direction of effects, there were no significant interactions between sex and SES, pregnancy, birth, or early childhood exposures. The effects of most PRS on AN risk were highly similar between the sexes. We observed significant sex-specific effects of parental psychiatric history and body mass index PRS, though these effects did not survive corrections for multiple comparisons. Conclusions: Risk factors for AN are comparable between females and males. Collaboration across countries with large registers is needed to further investigate sex-specific effects of genetic, biological, and environmental exposures on AN risk, including exposures in later childhood and adolescence as well as the additive effects of exposures. Public significance: Sex differences in the prevalence and clinical presentation of AN warrant examination of sex-specific risk factors. This population-based study indicates that the effects of polygenic risk and early life exposures on AN risk are comparable between females and males. Collaboration between countries with large registers is needed to further investigate sex-specific AN risk factors and improve early identification of AN.