Anne-Marie Nybo Andersen

When the COVID‐19 pandemic emerged, pregnant women were quickly identified as a high‐risk group. It became a priority to clarify any risks associated with COVID‐19 infection, and later vaccination, to pregnant women and their offspring. The Nordic registries constituted unique resources to quickly answer these questions. Our findings from the Nordic registries demonstrated that pregnant women with COVID‐19 face a higher risk of hospitalization compared to non‐pregnant women of reproductive age, and a higher risk of venous thromboembolism and stillbirth. However, the majority of studies proved no COVID‐19 associated risks of adverse pregnancy outcomes. We also provided reassuring evidence indicating no increased risk of miscarriage, stillbirth, congenital malformations, preterm birth, or other adverse neonatal outcomes in children born to mothers vaccinated against COVID‐19 during pregnancy. In this commentary, we highlight both opportunities and methodological challenges when using the Scandinavian health registries during an ongoing pandemic crisis.

The family environment in which children grow up is associated with the development of their behaviour. It has been proposed that changes in family dynamics, associated with a child being born preterm, can influence siblings’ health. We tested the hypothesis that term-born children (≤ 14 years of age) with younger preterm born siblings are at an increased risk of having higher internalising and externalising behaviour problems than term-born children with term-born siblings. We also compared scores with children without siblings. We used harmonised data from four European birth cohorts. We grouped 65,711 term-born children (49% girls) across the four cohorts as follows: risk group (with younger preterm born siblings; n = 427), reference group (with only term siblings; n = 12,371), and only-child group (without siblings; n = 52,913). We investigated whether the internalising and externalising z-standardised scores of the term-born children differ by group. The scores came from parent-completed Strengths and Difficulties Questionnaire or Child Behaviour Checklist. Scores of the risk and only-child groups were compared to the reference group. Analyses were conducted in three age groups: ≤ 4, 5–10 and 11–14 years of age. We conducted a two-stage individual participant data meta-analysis and found no evidence of differences in internalising or externalising scores between the risk and the reference groups within any of the age groups. In contrast, the internalising and externalising scores of the only-child participants were higher than the reference group (Internalising- ≤ 4 years: mean difference (MD)=0.06 [95%CI = 0.03,0.08]; 5–10 years: MD = 0.12 [-0.01,0.25]; 11–14 years: MD = 0.07 [0.03,0.12]; Externalising- ≤ 4 years: MD = 0.06 [0.03,0.08]; 5–10 years: MD = 0.10 [0.06,0.15]; 11–14 years: MD = 0.09 [-0.03,0.21]).We found no evidence supporting that having a younger sibling born preterm is a risk factor for increased internalising or externalising behaviour. However, we observed higher internalising and externalising scores in children without siblings compared to those with term-born siblings.

Background: Studies of factors influencing body mass index (BMI) mostly focus on hypothesized/established factors. We aimed to explore potential factors influencing BMI across childhood and adolescence using a hypothesis-free exposome-wide association study (ExWAS), with external replication and Mendelian randomization (MR). Methods: The ExWAS was done in the Avon Longitudinal Study of Parents and Children (ALSPAC) using univariable regressions to estimate prospective associations of 2,523 exposures with BMI in infancy (up to 12 months, N = 12 761), early-childhood (13–60 months, N = 12 138), middle-childhood (61 months to 12 years, N = 9,105) and adolescence (13–18 years, N = 7379). Associations passing Bonferroni correction were followed-up with confounder-adjusted regression in ALSPAC. Replication of confounder-adjusted associations were explored in eight independent cohorts and/or MR analyses in ALSPAC. Results: The ExWAS identified 8, 16, 66 and 82 exposures prospectively associated with BMI in infancy, early-childhood, middle-childhood, and adolescence, respectively. Of these, 8, 11, 42, and 26 remained associated following confounder adjustment. Replicated associations included maternal BMI, smoking and fat intake; only maternal smoking was supported by MR. Associations of more TV viewing time with higher BMI at one or more ages was supported by MR showing more time spent watching TV in early-childhood leads to higher BMI in middle-childhood. It was not possible to explore replication or MR for confounder-adjusted associations of offspring emotion, sociability, and peer problems with subsequent BMI. Conclusions: Our ExWAS suggests more TV viewing time in early-childhood increases BMI in mid-childhood. Novel potential effects of social, emotional and peer exposures in childhood need replication and assessment of causality.

Motivation: The validity of epidemiologic findings can be increased using triangulation, i.e. comparison of findings across contexts, and by having sufficiently large amounts of relevant data to analyse. However, access to data is often constrained by practical considerations and by ethico-legal and data governance restrictions. Gaining access to such data can be time-consuming due to the governance requirements associated with data access requests to institutions in different jurisdictions. Results: DataSHIELD is a software solution that enables remote analysis without the need for data transfer (federated analysis). DataSHIELD is a scientifically mature, open-source data access and analysis platform aligned with the ‘Five Safes’ framework, the international framework governing safe research access to data. It allows real-time analysis while mitigating disclosure risk through an active multi-layer system of disclosure-preventing mechanisms. This combination of real-time remote statistical analysis, disclosure prevention mechanisms, and federation capabilities makes DataSHIELD a solution for addressing many of the technical and regulatory challenges in performing the large-scale statistical analysis of health and biomedical data. This paper describes the key components that comprise the disclosure protection system of DataSHIELD. These broadly fall into three classes: (i) system protection elements, (ii) analysis protection elements, and (iii) governance protection elements. Availability and implementation: Information about the DataSHIELD software is available in https://datashield.org/ and https://github.com/datashield.

Background: Atopic diseases, obesity and neuropsychiatric disorders are lifestyle-related and environmental-related chronic inflammatory disorders, and the incidences have increased in the last years.Objective: To outline the design of the 18-year follow-up of the Copenhagen Prospective Study on Asthma in Childhood (COPSAC₂₀₀₀) birth cohort, where risk factors of atopic diseases, obesity and neuropsychiatric disorders are identified through extensive characterisation of the environment, along with deep clinical phenotyping and biosampling for omics profiling.Methods: COPSAC₂₀₀₀is a Danish prospective clinical birth cohort study of 411 children born to mothers with asthma who were enrolled at 1 month of age and closely followed at the COPSAC clinical research unit through childhood for the development of atopic diseases. At the 18-year follow-up visit, biomaterial (hair, blood, urine, faeces, throat, and skin swabs, nasal lining fluid and scraping, and hypopharyngeal aspirates) and extensive information on environmental exposures and risk behaviours were collected along with deep metabolic characterisation and multiorgan investigations including anthropometrics, heart, lungs, kidneys, intestines, bones, muscles and skin. Neuropsychiatric diagnoses were captured from medical records and registers accompanied by electronic questionnaires on behavioural traits and psychopathology.Results: A total of 370 (90%) of the 411 cohort participants completed the 18-year visit. Of these, 25.1% had asthma, 23.4% had a body mass index >25 kg/m²and 16.8% had a psychiatric diagnosis in childhood. A total of 68.7% drank alcohol monthly, and when drinking, 22.2% drank >10 units. Of the participants, 31.4% were currently smoking, and of these, 24.1% smoked daily. A total of 23.8% had tried taking drugs, and 19.7% reported having done self-destructive behaviour. The mean screen time per day was 6.0 hours.Conclusion: This huge dataset on health and habits, exposures, metabolism, multiorgan assessments and biosamples from COPSAC₂₀₀₀by age 18 provides a unique opportunity to explore risk factors and underlying mechanisms of atopic disease and other lifestyle-related, non-communicable diseases such as obesity and neuropsychiatric disorders, which are highly prevalent in the community and our cohort.

Context: The risk of gestational diabetes mellitus (GDM) differs between the Danish population and several migrant groups. However, it is unclear if the incidence and timing of type 2 diabetes mellitus (T2DM) following GDM vary similarly. Objective: This work aimed to investigate the incidence of T2DM according to migration background based on country/region of origin among women with a previous GDM diagnosis and to explore the role of time since GDM diagnosis on the association. Method: Using nationwide registry data, we followed women diagnosed with GDM in Denmark during 2004 to 2018 to December 31, 2020. Poisson regression models were used to estimate incidence rates (IRs) of T2DM according to country/region of origin, adjusted for age, education, and body mass index. Results: The study included 20 873 women with a GDM diagnosis, of whom 22.3% were of migrant background and 77.7% were Danish. The mean follow-up time was 7.3 years, and 10.9% were registered with T2DM during the study period. Generally, migrant women had higher IRs of T2DM compared to Danish women, with substantial variations in risk between migrant groups. Women from Pakistan and Sri Lanka had 3 to 4 times higher IRs compared to Danish women. The timing of T2DM onset also varied, with women from Sri Lanka and Pakistan having an earlier onset of T2DM compared to other migrant and Danish women. Conclusion: This study demonstrated that country/region of origin is an important risk factor for T2DM in women with GDM. These findings underscore the importance of prevention programs targeting women with GDM and a high-risk origin.

Background: The burden of respiratory tract infections (RTIs) is high in childhood. Several residential exposures may affect relative rates. Objectives: To determine risk of RTIs in children ages 11 and 12 by residential exposures. Methods: We included children in the Danish National Birth Cohort (DNBC) at ages 11 and 12. We estimated incidence risk ratios (IRR) and 95% confidence intervals (CI) for counts of RTIs within the last year by exposure to mold/dampness, gas stove usage, summer and winter candle-burning, fireplace usage, cats and dogs indoors, and farmhouse living. We also estimated IRR and 95% CI for RTIs for predicted scores of four extracted factors (‘owned house’, ‘mold and dampness’, ‘candles’, and ‘density’) from exploratory factor analyses (EFA). Results: We included 42 720 children with complete data. Mold/dampness was associated with all RTIs (common cold: IRR_adj 1.09[1.07, 1.12]; influenza: IRR_adj 1.10 [1.05, 1.15]; tonsillitis: IRR_adj 1.19 [1.10, 1.28]; conjunctivitis: IRR_adj 1.16 [1.02, 1.32]; and doctor-diagnosed pneumonia: IRR_adj 1.05 [0.90, 1.21]), as was the EFA factor ‘mold/dampness’ for several outcomes. Gas stove usage was associated with conjunctivitis (IRR_adj 1.25 [1.05, 1.49]) and with doctor-diagnosed pneumonia (IRR_adj 1.14 [0.93, 1.39]). Candle-burning during summer, but not winter, was associated with several RTIs, for tonsillitis in a dose-dependent fashion (increasing weekly frequencies vs. none: [IRR_adj 1.06 [0.98, 1.14], IRR_adj 1.16 [1.04, 1.30], IRR_adj 1.23 [1.06, 1.43], IRR_adj 1.29 [1.00, 1.67], and IRR_adj 1.41 [1.12, 1.78]). Conclusion: Residential exposures, in particular to mold and dampness and to a lesser degree to indoor combustion sources, are related to the occurrence of RTIs in children.