[Skip to Navigation]
Sign In
Table.  Study Population Characteristics in Children With or Without DKA at Time of Diagnosis
Study Population Characteristics in Children With or Without DKA at Time of Diagnosis
1.
Nakhla  M, Rahme  E, Simard  M, Larocque  I, Legault  L, Li  P.  Risk of ketoacidosis in children at the time of diabetes mellitus diagnosis by primary caregiver status: a population-based retrospective cohort study.   CMAJ. 2018;190(14):E416-E421. doi:10.1503/cmaj.170676 PubMedGoogle ScholarCrossref
2.
Dabelea  D, Rewers  A, Stafford  JM,  et al Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study.   Pediatrics. 2014;133(4):e938-e945. doi:10.1542/peds.2013-2795 PubMedGoogle ScholarCrossref
3.
TRIGR Study Group.  Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR).   Pediatr Diabetes. 2007;8(3):117-137. doi:10.1111/j.1399-5448.2007.00239.x PubMedGoogle ScholarCrossref
4.
Elding Larsson  H, Vehik  K, Bell  R,  et al.  Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up.   Diabetes Care. 2011;34(11):2347-2352. doi:10.2337/dc11-1026 PubMedGoogle ScholarCrossref
5.
Writing Group for the TRIGR Study Group, Knip  M, Åkerblom  HK,  et al.  Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial.   JAMA. 2018;319(1):38-48. doi:10.1001/jama.2017.19826 PubMedGoogle ScholarCrossref
6.
Wolfsdorf  JI, Glaser  N, Agus  M,  et al.  ISPAD clinical practice consensus guidelines 2018: diabetic ketoacidosis and the hyperglycemic hyperosmolar state.   Pediatr Diabetes. 2018;19(suppl 27):155-177. doi:10.1111/pedi.12701 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Research Letter
    January 25, 2021

    Diabetic Ketoacidosis at the Time of Diagnosis of Type 1 Diabetes in Children: Insights From TRIGR

    Author Affiliations
    • 1Department of Pediatrics, Montreal Children’s Hospital, McGill University, Montreal, Quebec, Canada
    • 2Division of Bioinformatics and Biostatistics Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa
    • 3Division of Endocrinology, UPMC Children’s Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania
    • 4Department of Pediatrics, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada
    • 5Linköping University Hospital, Linköping, Sweden
    • 6Division of Pediatrics, Department of Clinical and Experimental Medicine, Medical Faculty, Linköping University, Linköping, Sweden
    • 7University of Helsinki, Helsinki, Finland
    • 8Helsinki University Hospital, Helsinki, Finland
    JAMA Pediatr. 2021;175(5):518-520. doi:10.1001/jamapediatrics.2020.5512

    Type 1 diabetes (T1D) is one of the most common chronic diseases of childhood. If left untreated, diabetic ketoacidosis (DKA), a largely preventable life-threatening complication, will occur. Currently, 19% of Canadian children and 40% of US children will present with DKA at the time of diagnosis of T1D.1,2 Because symptoms of T1D exist before the onset of DKA, 1 risk factor for DKA is a delay in the diagnosis and treatment of T1D. Other risk factors include younger age (<5 years) and lower socioeconomic status (SES).1

    Several prospective studies, including the Trial to Reduce Insulin Dependent Diabetes Mellitus in the Genetically at Risk (TRIGR), have followed up children at increased genetic risk of T1D from birth.3,4 Within these research settings, there was an increased awareness of diabetes risk and symptoms provided by the research teams, likely leading to earlier diagnosis and a decreased DKA risk at diagnosis. In a longitudinal study of children at increased genetic risk of T1D (the Environmental Determinants of Diabetes in the Young [TEDDY] study), participants experienced significantly less DKA at the time of diagnosis when compared with patients with new-onset T1D reported in national diabetes registries.4

    The objectives of this cohort study were to assess (1) the risk of DKA at T1D diagnosis in children followed up in the prospective TRIGR study and (2) whether participation in TRIGR, in which parents are aware of their child’s increased risk of developing T1D, is associated with decreased SES and age disparities in DKA risk at the time of diagnosis.

    Methods

    The TRIGR study protocol and results of the main study have been previously published.3,5 Written informed consent was obtained from the families before enrollment. The TRIGR study was approved by the ethics committees of all participating centers (eAppendix in the Supplement) and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Diabetic ketoacidosis was identified by treating physicians and defined according to centers’ respective national diabetes guidelines (ketonemia combined with a pH < 7.30).6 We used t tests to compare continuous variables and the Pearson χ2 test for categorical variables. Two-sided P < .05 was considered statistically significant. All analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc).

    Results

    A total of 173 children were diagnosed with T1D, among whom 8 patients (4.6%; 95% CI, 2.0%-8.9%) presented in DKA at diagnosis. Compared with DKA rates in the general population (19%-40%; P < .001) and rates observed in the TEDDY study (13.1%; P < .001), TRIGR particpants had lower rates of DKA at T1D diagnosis. Half of the DKA presentations were in the US. Among the 32 US children diagnosed with T1D, 4 (12.5%) presented in DKA, compared with only 1 of 46 (2.2%) Canadian children. Compared with those without DKA, patients with DKA were more likely to have fewer antibodies (mean [SD] number of positive antibodies, 2.6 [1.7] vs 4.1 [1.2]; P < .001) and more likely to have reported weight loss (4 [50.0%] vs 27 [16.4%]; P = .03) and fatigue (5 [62.5%] vs 46 [27.9%]; P = .049) at diagnosis (Table). Age at diagnosis, SES (as measured by parental educational level), and HLA antigen risk category were not associated with DKA risk (Table).

    Discussion

    TRIGR participants had a reduced risk of DKA at T1D diagnosis compared with DKA rates in the general population (19%-40%; P < .001) and rates observed in the TEDDY study (13.1%; P < .001).4 All TRIGR participants had a family member with T1D, whereas the TEDDY participants were primarily from the general population and fewer had a first-degree relative with T1D.4 Socioeconomic status was not associated with DKA risk, which may be attributable to our small sample size or suggest that increased awareness lessened the SES disparities generally observed with DKA risk at diagnosis.

    With these small numbers, our results suggest regional disparities in DKA risk, necessitating future exploration of whether differences in health care availability and access are factors that underly our findings. As observed in the present study, younger age at diagnosis is known to be associated with DKA risk at T1D diagnosis. However, our results did not reach statistical significance in our small sample size. Our study has some limitations, including a small sample size; as such, statistically significant SES and age disparities in DKA risk were not observed. Although our DKA rates were low, presumably due to increased T1D awareness, further exploration is needed regarding why DKA episodes were not completely preventable in T1D longitudinal follow-up studies.

    Back to top
    Article Information

    Accepted for Publication: August 10, 2020.

    Published Online: January 25, 2021. doi:10.1001/jamapediatrics.2020.5512

    Corresponding Author: Meranda Nakhla, MD, MSc, Department of Pediatrics, Montreal Children’s Hospital, McGill University, 1001 Decarie St, Ste A04.6316, Montreal, QC H4A 3J1, Canada (meranda.nakhla@mcgill.ca).

    Author Contributions: Dr Cuthbertson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Nakhla, Becker, Ludvigsson, Legault.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Nakhla, Cuthbertson, Legault.

    Critical revision of the manuscript for important intellectual content: Nakhla, Becker, Pacaud, Ludvigsson, Knip, Legault.

    Statistical analysis: Cuthbertson.

    Obtained funding: Becker, Knip.

    Administrative, technical, or material support: Becker, Pacaud, Ludvigsson, Knip.

    Supervision: Nakhla, Legault.

    Conflict of Interest Disclosures: Dr Nakhla reported receiving the Chercheur-Boursier Clinicien Award from Fonds de Recherche du Québec–Santé and Ministère de la Santé et des Services Sociaux du Québec during the conduct of the study. Dr Legault reported receiving personal fees from Lilly and Dexcom for administrative board participation and grants to his institution from Merck, Sanofi, and Astra-Zeneca outside the submitted work. In addition, Dr Legault has a patent as co-owner of IP in the field of artificial pancreas. Dr Pacaud reported receiving grants from the Canadian Institutes of Health Research and the National Institute of Health during the conduct of the study. He also reported grants from Eli Lilly Canada, other fees from Novo Nordisk, and personal fees from Abbott Canada outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported by grants HD040364, HD042444, and HD051997 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Special Statutory Funding Program for Type 1 Diabetes Research administered by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International, the Commission of the European Communities (specific RTD programme “Quality of Life and Management of Living Resources,” contract No. QLK1-2002-00372 “Diabetes Prevention.”), and the European Foundation for the Study of Diabetes/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland (Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, decision No. 250114), Dutch Diabetes Research Foundation, and Finnish Diabetes Research Foundation. The study formulas were provided free of charge by Mead Johnson Nutrition.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or of the Commission of the European Communities or anticipate the Commission’s future policy in this area.

    Additional Contributions: We acknowledge the Trial to Reduce Insulin-Dependent Diabetes Mellitus in the Genetically at Risk staff at all clinical sites, the data management unit, laboratories, research institutes, and administrative centers. We thank all participating families for their commitment to the study.

    References
    1.
    Nakhla  M, Rahme  E, Simard  M, Larocque  I, Legault  L, Li  P.  Risk of ketoacidosis in children at the time of diabetes mellitus diagnosis by primary caregiver status: a population-based retrospective cohort study.   CMAJ. 2018;190(14):E416-E421. doi:10.1503/cmaj.170676 PubMedGoogle ScholarCrossref
    2.
    Dabelea  D, Rewers  A, Stafford  JM,  et al Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study.   Pediatrics. 2014;133(4):e938-e945. doi:10.1542/peds.2013-2795 PubMedGoogle ScholarCrossref
    3.
    TRIGR Study Group.  Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR).   Pediatr Diabetes. 2007;8(3):117-137. doi:10.1111/j.1399-5448.2007.00239.x PubMedGoogle ScholarCrossref
    4.
    Elding Larsson  H, Vehik  K, Bell  R,  et al.  Reduced prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in young children participating in longitudinal follow-up.   Diabetes Care. 2011;34(11):2347-2352. doi:10.2337/dc11-1026 PubMedGoogle ScholarCrossref
    5.
    Writing Group for the TRIGR Study Group, Knip  M, Åkerblom  HK,  et al.  Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial.   JAMA. 2018;319(1):38-48. doi:10.1001/jama.2017.19826 PubMedGoogle ScholarCrossref
    6.
    Wolfsdorf  JI, Glaser  N, Agus  M,  et al.  ISPAD clinical practice consensus guidelines 2018: diabetic ketoacidosis and the hyperglycemic hyperosmolar state.   Pediatr Diabetes. 2018;19(suppl 27):155-177. doi:10.1111/pedi.12701 PubMedGoogle ScholarCrossref
    ×