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DOI:10.4158/EP-2019-0351
© 2019 AACE.

Original Article EP-2019-0351

FAMILY HISTORY OF DIABETES IS ASSOCIATED WITH INCREASED RISK OF RECURRENT

DIABETIC KETOACIDOSIS IN PEDIATRIC PATIENTS

Janaki D. Vakharia, MD1,2 ; Sungeeta Agrawal, MD 3; Janine Molino, PhD1,4;

Lisa Swartz Topor, MD, MMSc1,5.

Running title: Family history of diabetes and recurrent DKA

From: 1 The Warren Alpert Medical School of Brown University, Providence, RI; 2 Department
of Internal Medicine and Pediatrics, Rhode Island Hospital, Providence, RI; 3 Division of
Pediatric Endocrinology, Floating Hospital for Children at Tufts Medical Center, Boston, MA;
4Lifespan Biostatistics Core, Rhode Island Hospital, Providence, RI; 5Division of Pediatric
Endocrinology, Hasbro Children’s Hospital, Providence, RI

Corresponding Author: Lisa Swartz Topor, MD, MMSc

Pediatric Endocrinology
Rhode Island Hospital/The Warren Alpert Medical School of Brown University
593 Eddy Street
Providence, RI 02903
Email: lisa_swartz_topor@brown.edu

DOI:10.4158/EP-2019-0351
© 2019 AACE.
Abstract

OBJECTIVE:
To determine the relationship between family history of diabetes mellitus (DM) and diabetic
ketoacidosis (DKA) recurrence in youth with established Type 1 diabetes mellitus (T1D).
METHODS:
We performed a retrospective chart review of patients with DKA admitted to a pediatric hospital
between January 2009 and December 2014. We compared patients with recurrent (≥ 2 admissions) and
non-recurrent DKA (1 admission) and investigated patient level factors, including family history, that
may be associated with DKA recurrence in pediatric patients with established T1D.
RESULTS:
Of the 131 subjects in the study, 51 (39%) subjects were in the recurrence group. Age ≥ 15 years old,
public health insurance, and family history of T1D or T2D were associated with recurrent DKA
admissions in both univariable and multivariable analyses. Family history was associated with DKA
recurrence, with an incidence rate ratio of 1.5 (95% CI=1.0 to 2.3, p=0.03). The association was not
explained by type of familial diabetes, first degree relative status, or whether the family member lived
in the household.

CONCLUSIONS:
Recognition that a positive family history of DM may be associated with a higher risk for DKA recurrence
in patients with established T1D may allow for targeted education and focus on a previously unidentified
population at increased risk for DKA. Understanding the mechanism underlying the effect of family
history of diabetes on the rates of DKA in patients with established T1D may allow for improved
identification and education of patients who may be at risk for DKA recurrence.

Abbreviations:
DKA = Diabetic ketoacidosis; TID = Type 1 diabetes mellitus; T2D = Type 2 diabetes mellitus; ISPAD =
International Society of Pediatric and Adolescent Diabetes; EHR = Electronic health record; IRR =
Incidence rate ratios ; ED = Emergency department.

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© 2019 AACE.
Introduction

Diabetic ketoacidosis (DKA) is a severe and life threating complication of Type 1 diabetes mellitus (T1D)
associated with serious complications in youth, including cerebral edema, stroke, and pulmonary
edema(1). Additionally, admissions for DKA in youth lead to missed school attendance, are disruptive to
families, and are associated with high expenditure of health care costs and resources (2). DKA occurs in
9-37% of youth at the onset of diabetes diagnosis (3-6), with rates that vary based upon geographic
location, population, and prevalence of T1D. DKA continues to occur after T1D diagnosis, with an
incidence of 9.9% over a 12 month period as reported in the T1D Exchange registry (7). DKA recurrence,
although preventable, remains a common public health issue for youth with T1DM.

Given the risk of morbidity and mortality with DKA, identification of populations at high risk for
recurrent DKA is an essential first step in improving health outcomes in youth with T1DM. Female
gender and adolescent age are associated with higher rates of DKA compared to other populations (8-
10). DKA readmissions also are more common in individuals of minority races, in individuals with pubic
insurance, and in those diagnosed at younger ages (6, 8, 11-13). Psychiatric co-morbidities, including
depression and eating disorders, are also associated with poor glycemic control (14, 15) and recurrence
of DKA (8, 16, 17).

Many studies (18-20) have shown that DKA at the time of diagnosis of T1D occurs less frequently in
those with a family history of DM compared to those without a family history. Less is known about the
impact of family history on risk of DKA recurrence in pediatric patients with an established diagnosis of
T1D. Understanding factors associated with the risk of DKA is instrumental in reducing the incidence of
these events. We aimed to investigate patient level factors, including family history, that may be
associated with DKA recurrence in pediatric patients with established T1D. We hypothesized that a
positive family history of diabetes would be associated with lower risk of DKA recurrence in this
population.

Methods

Participants and Design

Patients were identified from a previously characterized cohort of youth with hyperglycemic
emergencies who were hospitalized between January 1, 2009 and December 31, 2014 (21). We included
children and adolescents ages 0 to 21 years, who: 1) were hospitalized at least once during the time
frame of the study; 2) met diagnostic criteria for DKA at the time of admission, as defined by the
International Society of Pediatric and Adolescent Diabetes (ISPAD) consensus guidelines (17); and 3) had
an established history of type 1 diabetes mellitus, based on clinical presentation, clinical course, or
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pancreatic autoantibody testing. In order to focus solely on patients with established diabetes, all
patients who presented with new onset diabetes during the five year study period were excluded. Thus,
if a patient presented with new onset diabetes at any point in the five year study, all DKA admissions,
initial and subsequent, were excluded. Data collection was truncated to the five year time frame of the
study, and therefore data on DKA admissions prior to or after the five year period were not collected.
The five year period of the study was selected to allow an adequate window of time to study DKA
occurrence based on the annual frequency of DKA admissions at our institution. Additionally, data
collection was limited by the transition to a new electronic health record (EHR), and the five year time
frame ensured complete data access. This study was approved by the Institutional Review Board of
Lifespan Corporation.

Dependent variables

We recorded the number of DKA admissions during the study time frame. For descriptive analyses,
patients were sorted into a “non-recurrence group”, which included patients with 1 DKA admission
during the study period or a “recurrence group”, which included patients with ≥ 2 DKA admissions
during the study period.

Independent variables

We collected information from the EHR about demographics, family history of diabetes, primary
language, and type of insurance (private or public). Patients were categorized based upon their age at
the first DKA admission during the study period. We distinguished early adolescents from the middle-
late adolescents and young adult groups, based on the World Health Organization’s definition of
adolescents (22), because the latter groups are reported to have the highest risk for DKA recurrence
(10). Race and ethnicity were recorded from the EHR as Hispanic, non-Hispanic black, non-Hispanic
white, Asian, multiracial, or other. Primary language spoken was recorded as English or non-English.
Family history of diabetes was obtained from the EHR and included type of DM, whether or not the
family member(s) with DM were first degree relatives to the patient, and if the family member(s) with
DM lived with the patient.

Statistical Methods

Data was imported into SAS version 9.4 (SAS Institute Inc., Cary, NC) for statistical analysis. Descriptive
statistics for patient characteristic variables were obtained for the study sample overall and by
recurrence of DKA. Frequencies and percentages were reported. Chi-square tests and Fisher exact tests
(when cell counts were < 5) were used to compare patient characteristics between the DKA recurrence
and non-recurrence groups. Univariable and multivariable Poisson regression models were used to
assess the impact of patient characteristics on the number of DKA admissions. Parsimonious
multivariable models were developed by including only those patient characteristic variables with
p<0.20 in univariable models as independent variables. Incidence rate ratios (IRR) along with their 95%
confidence intervals were reported. Only patients with complete patient characteristic data were
included in these analyses to maintain the same analytic sample across models (N=116). Secondary
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analyses were performed on the subset of patients with a known family history of DM to assess whether
type of family history, first degree relative with DM, or family member with DM living in household were
possible mechanisms for recurring DKA events. Univariable Poisson regression models were estimated
to assess the association of these more detailed family history variables with number of DKA admissions.
IRR along with their 95% confidence intervals were reported. For all analyses, a p-value <0.05 was used
to determine statistical significance.

Results

Participants

There were 270 patients who had 411 admissions with hyperglycemic emergencies over a 5-year period.
One hundred thirty-one patients met inclusion criteria with 51 patients in the recurrence group and 80
patients in the non-recurrence group. Three patients were excluded for an initial presentation with
hyperosmolar hyperglycemic syndrome and 136 patients were excluded for new onset diabetes
mellitus. Of these 136 patients, 125 patients had one admission for DKA during the time frame of the
study and 11 patients had two or more admissions. Table 1 summarizes the characteristics of the study
participants. Gender, age, race and ethnicity were similar between the recurrence and non-recurrence
groups. A positive family history of either type 1 or type 2 diabetes (T2D) occurred more often in the
recurrence group compared to the non-recurrence group (94% vs. 59%, p-value <0.0001).

Factors associated with DKA recurrence

Age at admission, health insurance, and family history of T1D or T2D were associated with recurrent
DKA admissions in both univariable and multivariable analyses (Table 2). In multivariable analyses,
patients ≥ 15 years old had 60% more DKA admissions than patients <15 years old (IRR=1.6, 95% CI=1.1
to 2.2, p=0.004) and patients with public health insurance had 50% more DKA admissions than patients
with private health insurance (IRR=1.5, 95% CI=1.2 to 2.0, p=0.002). In multivariable analyses, patients
with a family history of DM had 50% more DKA admissions compared to those without a family history
of DM (IRR=1.5, 95% CI=1.0 to 2.3, p=0.03). Race was associated with number of DKA admissions in
univariable analyses, with non-Hispanic black patients having 80% more DKA admissions than non-
Hispanic white patients (IRR=1.8, 95% CI=1.3 to 2.5), though this association was not maintained in
multivariable analyses.

Family history of diabetes and DKA recurrence

Of the 48 patients in the recurrence group with a positive family history of DM, a majority (77.8%) had
at least one family member with T2D, and half (51.1%) also had at least one family member with T1D. In
the non-recurrence group, 90% had at least one family member with T2D and 37.5% had at least one
family member with T1D. We did not find differences in percentages of family members with T1D or T2D
between the groups (Figure 1), and did not find any association between the different types of DM in
family members and the number of DKA admissions (Table 3). Neither the presence of first degree

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© 2019 AACE.
relatives with diabetes nor a shared household with family members with DM were associated with DKA
recurrence (Table 3).

Discussion

Preventing DKA, especially in patients with established T1D, is a global challenge that has yet to be
solved. In contrast to prior reports demonstrating that family history of DM leads to reduced risk of DKA
at time of DM diagnosis (18-20), we found that a positive family history of DM was associated with
increased risk of DKA recurrence in pediatric patients with established T1D. This association was not
explained by type of familial diabetes, whether family members were first degree relatives, or whether
family members with diabetes lived in the household. Youth with T1D who have family members with
diabetes may be a population warranting enhanced diabetes education and intensive follow-up aimed at
decreasing the risk of DKA.

Lebenthal and colleagues investigated familial (defined as 2 or more first degree relatives with T1D) and
sporadic cases of T1D and, similar to our results, found that DKA frequency was higher in the familial
compared to the sporadic group (23). Patients in the familial group also had poorer glycemic control
overall compared to the sporadic group. Mulvaney and colleagues described that family members with
poorly controlled diabetes may have a negative effect on adolescent self-management of diabetes, and
that parents with poorly controlled DM may have difficulty enforcing optimal self-management for their
children (24, 25). Furthermore, Pinhas-Hamiel and colleagues found that poor lifestyle and health habits
are shared amongst familes with diabetes (26), likely resulting in poorer control. Due to our
retrospective data collection, we were unable to measure family understanding of diabetes, and did not
have access to information about glycemic control of family members with diabetes. Further work is
needed to identify and address how familial experience with diabetes and shared environmental factors
impact pediatric T1D care, glycemic control, and DKA risk.

Several studies have reported HLA haplotypes that are associated with T1D (27-29), and suggest genetic
underpinnings that contribute to T1D and DKA risk. A study by Turtinen et al reported that sporadic
cases of T1D more often lacked major risk HLA haplotypes compared to familial cases, and that specific
risk haplotypes were more frequent in familial cases (30). Black et al studied 1,662 participants from the
SEARCH for Diabetes in Youth Study and found ethnic variations amongst the distribution of risk
haplotypes in pediatric patients. They also identified specific risk haplotypes that were associated with
DKA recurrence (31). Inheritance of these haplotypes amongst children and their families may
contribute to variation in disease manifestation and may be a factor in the increased DKA frequency
seen in our patients with a family history of T1D.

Family history and risk for disease exacerbation for other pediatric diseases have been described. A
retrospective case-control study by Jean et al studied predictors of hospital admission versus emergency
department (ED) discharge in 12,066 children between 5 and 18 years old diagnosed with asthma
exacerbation in the ED. They found that a family history of asthma was an independent risk factor for
asthma exacerbation admissions in pediatric patient (32). Gaspar et al found that a family history of

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maternal asthma was significantly and independently associated with hospital admissions for asthma in
pediatric patients (33). A database study of more than 3,000 adult and pediatric patients with
inflammatory bowel disease (IBD) investigated the differences between familial and sporadic IBD, and
found that individuals with familial IBD had higher cumulative disease relapse rates (34). These studies,
combined with our findings, highlight the importance of family history in understanding disease
presentation, and point to potential genetic and environmental factors that impact disease
manifestation.

Our study is limited by its retrospective design, lending itself to rely on the accuracy of information
inputted to the EHR and encountering missing data. However, we used best-practice guidelines (35) to
review the medical record in order to optimize data collection. Data collection was limited to the 5-year
time frame of the study, and data on DKA admissions prior to or after the 5 year period were not
collected for the patients included in the study. This methodology may have led to misclassifying
recurrence patients as non-recurrence patients, and may have led to an underestimation of the
associations between patient characteristics and DKA recurrence. However, the classification of patients
was done systematically and its effect should have been equally distributed. Our study was
underpowered to detect associations between DKA recurrence and several components of family
history status. Additionally, medical details about family members were not available in the EHR. Larger,
prospective studies are needed to explore these relationships. Lastly, our study included a single
academic institution in an urban setting, and our study results may not be generalizable to other
populations.

Given the morbidity and mortality of DKA, along with its socioeconomic impact, it is important to
identify factors to reduce the incidence of DKA. Recognition that a positive family history of DM is
associated with a higher risk for DKA recurrence in patients with established T1D may allow for targeted
education and focus on a previously unidentified population at increased risk for DKA. Understanding
the mechanism underlying the effect of family history of diabetes on the rates of DKA in patients with
established T1D may allow for improved identification and education of patients who may be at highest
risk for DKA recurrence.

Conclusion

Family history of diabetes was associated with increased frequency of DKA recurrence in pediatric
patients with established T1D at our institution. Factors such as the type of familial diabetes, first
degree relative status, or whether the family member lived in the household were not found to be
mechanisms for this association. Large, multicenter, prospective studies are needed to further
investigate the effects of familial diabetes on DKA risk, and to identify ways to mitigate risk for recurrent
DKA. Patients and their family members with diabetes may be another target for public health and
quality improvement initiatives aimed at optimizing care in youth with T1D.

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© 2019 AACE.
References

1. Bialo SR, Agrawal S, Boney CM, Quintos JB. Rare complications of pediatric diabetic ketoacidosis.

World journal of diabetes. 2015;6:167-174.

2. Shrestha SS, Zhang P, Barker L, Imperatore G. Medical expenditures associated with diabetes

acute complications in privately insured U.S. youth. Diabetes care. 2010;33:2617-2622.

3. Hekkala A, Knip M, Veijola R. Ketoacidosis at diagnosis of type 1 diabetes in children in northern

Finland: temporal changes over 20 years. Diabetes care. 2007;30:861-866.

4. Samuelsson U, Stenhammar L. Clinical characteristics at onset of Type 1 diabetes in children

diagnosed between 1977 and 2001 in the south-east region of Sweden. Diabetes research and clinical

practice. 2005;68:49-55.

5. Schober E, Rami B, Waldhoer T. Diabetic ketoacidosis at diagnosis in Austrian children in 1989-

2008: a population-based analysis. Diabetologia. 2010;53:1057-1061.

6. 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:e938-945.

7. Cengiz E, Xing D, Wong JC, et al. Severe hypoglycemia and diabetic ketoacidosis among youth

with type 1 diabetes in the T1D Exchange clinic registry. Pediatric diabetes. 2013;14:447-454.

8. Malik FS, Hall M, Mangione-Smith R, et al. Patient Characteristics Associated with Differences in

Admission Frequency for Diabetic Ketoacidosis in United States Children's Hospitals. The Journal of

pediatrics. 2016;171:104-110.

DOI:10.4158/EP-2019-0351
© 2019 AACE.
9. Fritsch M, Rosenbauer J, Schober E, Neu A, Placzek K, Holl RW. Predictors of diabetic

ketoacidosis in children and adolescents with type 1 diabetes. Experience from a large multicentre

database. Pediatric diabetes. 2011;12:307-312.

10. Rewers A, Klingensmith G, Davis C, et al. Presence of diabetic ketoacidosis at diagnosis of

diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics. 2008;121:e1258-1266.

11. Bradford AL, Crider CC, Xu X, Naqvi SH. Predictors of Recurrent Hospital Admission for Patients

Presenting With Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Journal of clinical

medicine research. 2017;9:35-39.

12. Randall L, Begovic J, Hudson M, et al. Recurrent diabetic ketoacidosis in inner-city minority

patients: behavioral, socioeconomic, and psychosocial factors. Diabetes care. 2011;34:1891-1896.

13. Rewers A. Current concepts and controversies in prevention and treatment of diabetic

ketoacidosis in children. Current diabetes reports. 2012;12:524-532.

14. Lawrence JM, Standiford DA, Loots B, et al. Prevalence and correlates of depressed mood among

youth with diabetes: the SEARCH for Diabetes in Youth study. Pediatrics. 2006;117:1348-1358.

15. La Greca AM, Swales T, Klemp S, Madigan S, Skyler J. Adolescents With Diabetes: Gender

Differences in Psychosocial Functioning and Glycemic Control. Children's Health Care. 1995;24:61-78.

16. Galler A, Bollow E, Meusers M, et al. Comparison of glycemic and metabolic control in youth

with type 1 diabetes with and without antipsychotic medication: analysis from the nationwide

German/Austrian Diabetes Survey (DPV). Diabetes care. 2015;38:1051-1057.

17. Wolfsdorf JI, Allgrove J, Craig ME, et al. ISPAD Clinical Practice Consensus Guidelines 2014.

Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatric diabetes. 2014;15 Suppl 20:154-

179.

DOI:10.4158/EP-2019-0351
© 2019 AACE.
18. Hekkala A, Ilonen J, Knip M, Veijola R. Family history of diabetes and distribution of class II HLA

genotypes in children with newly diagnosed type 1 diabetes: effect on diabetic ketoacidosis. European

journal of endocrinology. 2011;165:813-817.

19. Blanc N, Lucidarme N, Tubiana-Rufi N. [Factors associated with childhood diabetes manifesting

as ketoacidosis and its severity]. Archives de pediatrie : organe officiel de la Societe francaise de

pediatrie. 2003;10:320-325.

20. Gunn ER, Albert BB, Hofman PL, Cutfield WS, Gunn AJ, Jefferies CA. Pathways to reduce diabetic

ketoacidosis with new onset type 1 diabetes: Evidence from a regional pediatric diabetes center:

Auckland, New Zealand, 2010 to 2014. Pediatric diabetes. 2017;18:553-558.

21. Agrawal S, Baird GL, Quintos JB, et al. Pediatric Diabetic Ketoacidosis With Hyperosmolarity:

Clinical Characteristics and Outcomes. Endocrine practice : official journal of the American College of

Endocrinology and the American Association of Clinical Endocrinologists. 2018;24:726-732.

22. World Health O. Orientation programme on adolescent health for health care providers.

Geneva: World Health Organization, 2006.

23. Lebenthal Y, Shalitin S, Yackobovitch-Gavan M, Phillip M, Lazar L. Retrospective comparative

analysis of metabolic control and early complications in familial and sporadic type 1 diabetes patients.

Journal of diabetes and its complications. 2012;26:219-224.

24. Mulvaney SA, Schlundt DG, Mudasiru E, et al. Parent perceptions of caring for adolescents with

type 2 diabetes. Diabetes care. 2006;29:993-997.

25. Mulvaney SA, Mudasiru E, Schlundt DG, et al. Self-management in type 2 diabetes: the

adolescent perspective. The Diabetes educator. 2008;34:674-682.

26. Pinhas-Hamiel O, Standiford D, Hamiel D, Dolan LM, Cohen R, Zeitler PS. The type 2 family: a

setting for development and treatment of adolescent type 2 diabetes mellitus. Archives of pediatrics &

adolescent medicine. 1999;153:1063-1067.

DOI:10.4158/EP-2019-0351
© 2019 AACE.
27. Hermann R, Turpeinen H, Laine AP, et al. HLA DR-DQ-encoded genetic determinants of

childhood-onset type 1 diabetes in Finland: an analysis of 622 nuclear families. Tissue antigens.

2003;62:162-169.

28. Thomson G, Valdes AM, Noble JA, et al. Relative predispositional effects of HLA class II DRB1-

DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue antigens. 2007;70:110-127.

29. Erlich H, Valdes AM, Noble J, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes

risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57:1084-1092.

30. Turtinen M, Harkonen T, Parkkola A, Ilonen J, Knip M. Characteristics of familial type 1 diabetes:

effects of the relationship to the affected family member on phenotype and genotype at diagnosis.

Diabetologia. 2019.

31. Black MH, Lawrence JM, Pihoker C, et al. HLA-associated phenotypes in youth with autoimmune

diabetes. Pediatric diabetes. 2013;14:121-128.

32. Jean T, Yang SJ, Crawford WW, Takahashi SH, Sheikh J. Development of a pediatric asthma

predictive index for hospitalization. Annals of allergy, asthma & immunology : official publication of the

American College of Allergy, Asthma, & Immunology. 2019;122:283-288.

33. Gaspar AP, Morais-Almeida MA, Pires GC, et al. Risk factors for asthma admissions in children.

Allergy and asthma proceedings. 2002;23:295-301.

34. Banerjee R, Pal P, Hutfless S, Ganesh BG, Reddy DN. Familial aggregation of inflammatory bowel

disease in India: prevalence, risks and impact on disease behavior. Intestinal research. 2019.

35. Gilbert EH, Lowenstein SR, Koziol-McLain J, Barta DC, Steiner J. Chart reviews in emergency

medicine research: Where are the methods? Annals of emergency medicine. 1996;27:305-308.

DOI:10.4158/EP-2019-0351
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Figure 1 Legend: The figure shows the composition of family history within the recurrence and non-

recurrence groups of patients with at least one family member with type 1 or type 2 diabetes mellitus.

Data on diabetes type was missing for 3 patients in the recurrence group and 7 in the non-recurrence

group. The differences between the groups were not statistically significant (p=0.21). DKA = Diabetic

ketoacidosis

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