We investigated the association between SARS-CoV-2 infection and new-onset type 1 diabetes (T1D) in children and adolescents in a nationwide, matched cohort study. The hazard ratio of new-onset T1D within 6 months after SARS-CoV-2 infection was 1.22 (0.58–2.58). The risk of new-onset T1D in children and adolescents was not significantly increased after SARS-CoV-2 infection.

The incidence of type 1 diabetes (T1D) in children and adolescents has increased during the COVID-19 pandemic1 and an association between SARS-CoV-2 infection and T1D has been demonstrated.2,3 However, increasing rates of childhood T1D were also reported before the pandemic.4 Furthermore, the incidence and severity of diabetic ketoacidosis (DKA) increased during the pandemic.5 This study aimed to determine the association between SARS-CoV-2 infection and new-onset T1D and DKA at T1D onset in Danish children and adolescents.

METHOD
Study Design
The LongCOVIDKidsDK study is a national, matched cohort study including data from national registries. Previous results from this cohort include reports on COVID-19 symptoms.6,7

Setting
Treatment of children and adolescents with T1D in Denmark is centralized in tertiary referral hospitals. International Classification of Diseases, tenth edition codes for relevant diagnoses are available through The Danish National Patient Registry, a national registry with data from all Danish hospitals.8

A nationwide, free-of-charge SARS-CoV-2 test strategy was implemented in Denmark from May 2020 until March 2022. polymerase chain reaction tests were easily accessible except in the early months (January–April 2020) of the pandemic and did not require symptoms of SARS-CoV-2 infection. Up to 200,000 tests were carried out daily on the Danish population of 6 million individuals. However, children younger than 3 years were not tested to the same extent. SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test results are registered in The Danish National Microbiology Database (Miba), a database that covers all microbiology test results performed in Denmark. The predominant SARS-CoV-2 variants in the study period were the ancestral, Alpha (February–June 2021) and Delta (July 2021) variants.

Participants
The cohort consisted of all Danish children and adolescents 0–18 years old with a positive SARS-CoV-2 RT-PCR test between January 1, 2020 and July 12, 2021, and matched references without a positive test. References were matched by age and sex (1:4). Children and adolescents with positive SARS-CoV-2 RT-PCR test results were identified from Miba. References were identified through the Danish Civil Registration System and included children and adolescents with both negative and no SARS-CoV-2 RT-PCR tests.

Exclusion criteria were non-Danish residency and T1D diagnosis before the index date.

Variables and Data Sources
The index date was established as the date of the first positive SARS-CoV-2 RT-PCR test. For references the index date was their match’s index date. Follow-up was 6 months from the index date defined as the first date of T1D diagnosis.

Disposition to T1D was defined as prior thyroiditis and/or coeliac disease or at least 1 parent with T1D. International Classification of Diseases, tenth edition codes for T1D, DKA and autoimmune disease, including time of diagnoses, were obtained from the Danish National Patient Registry (Table, Supplemental Digital Content 1, https://links.lww.com/INF/F197). In Denmark the WHO diagnostic criteria for T1D are used.9

Socioeconomic status was determined by parents’ education (2020) and household income (2019) using the Danish Education Registry and Income Statistics Registry. Maternal citizenship was used as proxy for ethnicity. Data was obtained from the Danish Civil Registration System.8

Information on COVID-vaccination was obtained from the Danish Vaccine Registry which all medical doctors are required to report to.

Statistical Analyses
The hazard ratio (HR) of new-onset T1D following SARS-CoV-2 infection was investigated using Cox proportional hazards regression adjusted for age (continuous), sex, disposition to T1D and prior autoimmune comorbidity. Subgroup analyses were planned for the age groups 0–4-, 5–11- and 12–18-year-olds.

HR of DKA at T1D onset following SARS-CoV-2 infection was investigated by Cox regression adjusted for age and sex.

Children and adolescents with missing data were excluded. Results with less than 5 observations are not reported in accordance with Danish legislation.

All analyses were conducted using SAS 9.4.

Approvals
The study was approved by the Danish Data Protection Agency (P-2021-195) and registered at clinicaltrials.gov (NCT04786353). Registry data access was granted by The Danish Health Data Authority (FSEID 00005625). Ethics committee approvals are not required for registry-based studies in Denmark.