In this study we compared the prevalence of DKA in children participating in TEDDY and diagnosed with type 1 diabetes before the age of 5 years with national population-based registers. Our analyses demonstrate that TEDDY subjects diagnosed with type 1 diabetes before the age of 2 years experienced significantly less DKA at diagnosis (15%) when compared with new-onset patients reported in national diabetes registers from countries participating in TEDDY and the SEARCH study (35–50%). Similarly, TEDDY children diagnosed with type 1 diabetes before the age of 5 years experienced less DKA at onset when compared with children in the SEARCH study and the German DPV Registry, but not compared with children from the Finnish or Swedish registries. Although the relatively high proportion of TEDDY subjects who were first-degree relatives of type 1 diabetes patients may have confounded our analysis, DKA rates within the TEDDY cohort were similar among children recruited from the general population and those with a first-degree relative with type 1 diabetes, indicating that knowledge of diabetes risk and close longitudinal follow-up may be associated with reduced DKA risk regardless of family history.
Although our analysis is strengthened by the inclusion of data from a national incidence study and registries performed in each of the countries participating in TEDDY, we should note that children with incident diabetes from Colorado and Washington could have simultaneously been included in both the SEARCH and TEDDY databases, and the TEDDY participants in Sweden, Finland, and Germany could have been included in the national registries. While such an occurrence could have biased our data, the effect (given lower rates of DKA noted in TEDDY) would have been to mask the differences observed. As we were still able to document significant reductions in DKA when comparing TEDDY to SEARCH and the national registries, the effect of any potential bias was likely minimal. Unfortunately, we were unable to perform an analysis where participants in both TEDDY and a population-based study or registry were excluded.
Perhaps the most challenging issue related to inclusion of data from multiple national incidence registries was that of interpreting data with an appreciation of the different definitions of DKA used in each study (). The SEARCH study used a composite definition of DKA that includes standard cutoffs for pH and bicarbonate but also allows for nonbiochemical clinical documentation to account for DKA status. The Finnish and DPV registries used standard biochemical data, but excluded DKA in children with negative urine ketones, negative blood ketones, or lack of symptoms. Conversely, the Swedish registry relied entirely on biochemical data to document DKA status. For the purposes of this analysis, TEDDY defined DKA using both strict criteria (standard cutoffs for pH and bicarbonate) and broad criteria (allowing us to document DKA status on the basis of urine/blood ketones and clinician documentation).
When comparing overall DKA rates in TEDDY participants with children reported in the Swedish and Finnish registry, no significant differences were seen in children diagnosed before 5 years of age. However, rates of DKA in TEDDY participants aged <5 years were significantly lower when compared with children from the U.S. SEARCH study and the German registry. These observations are concordant with reports that countries with a high incidence of type 1 diabetes (Finland and Sweden) report reduced frequencies of DKA when compared with countries with lower incidence of type 1 diabetes. Decreased frequencies of DKA at onset of disease have been reported from Finland between 1982 and 2001, with a decrease from 22.4 to 15.2% in children 0–15 years of age and a decrease from 32.1 to 17.7% in children with onset before the age of 5 years (6
). That said, the rate of DKA in children <2 years of age at onset remained unacceptably high (39.1%) (6
). On the contrary, German data from the DPV register did not reveal reduced frequency of DKA in any age-group between 1995 and 2007 (8
). In a Swedish study, the incidence of DKA at onset of type 1 diabetes in children diagnosed from 2000 to 2004 was 16%, with no difference reported between age-groups. However, children <2 years of age were not specifically analyzed (15
The youngest children with new onset type 1 diabetes (<2 years of age) remain at high risk of DKA () (6
). More specifically, these young children are prone to severe DKA at onset. Of the children in TEDDY diagnosed with severe DKA (pH <7.10), all three were <2 years of age (8, 10, and 14 months, respectively). Although all three were antibody positive prior to diagnosis, we should note that because of the lag time from antibody testing to reporting of results, the parents of these children were likely not informed of the antibody status prior to the diagnosis. As such, rapid analysis and reporting of antibody status in high-risk children could further aid in reducing DKA rates.
Unfortunately, our analysis lacked the power to determine if participation in TEDDY reduced the risk of severe DKA in children <2 years of age. That said, the observation of reduction in overall DKA in the youngest patients with new-onset diabetes suggests that participation in a longitudinal natural history study with provision of updated autoantibody risk information, frequent follow-up, and scheduled laboratory evaluations (autoantibodies, HbA1c, glucose, and OGTT) to diagnose asymptomatic cases is associated with reduced DKA risk. Although potentially cost prohibitive outside the constraints of a research protocol, combined approaches to educate communities on signs and symptoms of DKA (as in the Parma, Italy experiments) and to provide genetic or antibody screening to further identify high-risk subjects may eventually be required to achieve the goal of entirely preventing DKA in children.
DKA is a serious condition with high morbidity and risk of developing cerebral edema (for a review see Levin [19
]). Children diagnosed with DKA are hospitalized and often treated in intensive care units. An early diagnosis of diabetes would therefore be directly beneficial to the child and indirectly beneficial to society through reduction of morbidity, mortality, and cost at onset of disease. Additionally, early diagnosis and aggressive management of diabetes may be beneficial in allowing for the presence of a larger functioning β-cell mass, easier metabolic control, and possible reductions in long-term complication risk (12
). Children diagnosed in an early stage of disease may also be eligible to participate in intervention trials aimed at protecting remaining β-cell mass.
In conclusion, intensive longitudinal follow-up and continuous education regarding diabetes risk, as provided in diabetes prediction studies such as TEDDY, may yield direct benefit to young children diagnosed with type 1 diabetes through early diagnosis and reduction of DKA risk. Ongoing efforts to reduce and eliminate DKA at diagnosis in young children are urgently needed.