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Type 2 Diabetes Mellitus in Children
Prenatal and Early Infancy Risk Factors Among Native Canadians
T. Kue Young, MD, PhD;
Patricia J. Martens, MSc, PhD;
Shayne P. Taback, MD;
Elizabeth A. C. Sellers, MD;
Heather J. Dean, MD;
Mary Cheang, MMath;
Bertha Flett, RN
Arch Pediatr Adolesc Med. 2002;156:651-655.
ABSTRACT
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Background Type 2 diabetes mellitus is increasingly being observed among children
and youth, including the Native population of Canada. Only one study has investigated
prenatal and early infancy risk factors for the disease.
Methods A case-control study was conducted; 46 patients younger than 18 years
were recruited from the only clinical center for the treatment of diabetes
serving the province of Manitoba, and 92 age- and sex-matched controls were
recruited from a pediatric ambulatory clinic serving a large Native population
in Winnipeg, Manitoba. Information on exposure to prenatal and early infancy
risk factors was obtained through questionnaires administered by a Native
nurse-interviewer.
Results Multiple logistic regression modeling identified preexisting diabetes
(odds ratio [OR], 14.4; 95% confidence interval [CI], 2.86-72.5), gestational
diabetes (OR, 4.40; 95% CI, 1.38-14.1), and breastfeeding longer than 12 months
(OR, 0.24; 95% CI, 0.13-0.99) as significant independent predictors of diabetic
status. Other factors, such as low (<2500 g) and high (>4000 g) birth weight
and maternal obesity, were also associated with diabetes in our population,
but the elevated risks were not statistically significant.
Conclusion Breastfeeding reduces the risk of type 2 diabetes among Native Canadian
children and should be promoted as a potential intervention to control the
disease.
INTRODUCTION
AN EPIDEMIC of type 2 diabetes mellitus has progressed among many Native
North American populations during the past several decades, and it shows no
sign of abating.1 The onset of the disease
has shifted toward childhood and adolescence, and more cases are being recognized
because of increased awareness and intensified screening.2-4
Although type 2 diabetes in youth most commonly affects populations with a
high prevalence of type 2 diabetes among adults,5
such as the Pima Indians of the southwestern United States,6
it is increasingly being observed in other populations.7-8
Despite the young age of onset, the diabetes that is diagnosed among
Native Canadian children should be classified as type 2.9-10
These children are not dependent on insulin for long-term survival, and they
do not fit the classical autosomal dominant mode of inheritance of the so-called
maturity-onset diabetes of youth. Islet cell, glutamic acid decarboxylase,
and insulin antibodies are absent.11 Many patients
with diabetes are obese, in a population already marked by widespread obesity.12
The emerging pattern and burden of childhood type 2 diabetes has been
attributed to the increasing prevalence of obesity among Native North American
children,6, 13 which is a result
of changing lifestyles, especially diet and physical activity level, perhaps
interacting with a genetic predisposition. In a retrospective cohort study
among the Pima, maternal diabetes, low and high birth weight, and not breastfeeding
were implicated as specific risk factors for diabetes.14-15
Type 2 diabetes in children and adolescents is of serious concern because
of the increased duration of the disease and the appearance of microvascular
and macrovascular complications during young adulthood. This study seeks to
identify explanatory factors to which the child may have been exposed in the
intrauterine environment and during early infancy. Given the substantial variation
in genetic susceptibility, sociocultural environment, and lifestyle patterns
among Native populations in North America, results from the Pima study may
not be readily generalizable to other populations.
SUBJECTS AND METHODS
A case-control design was used, and selection was based on disease status
(cases with type 2 diabetes vs controls without diabetes). We included as
cases Native children with type 2 diabetes diagnosed before age 18 years who
were currently under the clinical care of 2 of us (H.J.D. and E.A.C.S.) at
the Diabetes Education Resource Centre for Children and Adolescents, Health
Sciences Centre, Winnipeg, Manitoba. It is the only provincial center for
the treatment of diabetes in children and receives referrals from across Manitoba
and adjacent northwestern Ontario. These patients were scheduled for regular
follow-up care at the center and were asked to participate by the project
nurse (B.F.). Patients were not specifically recalled for the study but were
interviewed after their regular appointments. No patients refused to participate
in the study. Population-based, prevalent cases were ascertained independent
of exposure to any of the risk factors of interest.
To be included in the study, all cases must have satisfied the diagnostic
criteria proposed by the American Diabetes Association,16
namely, that fasting plasma glucose must equal or exceed 126 mg/dL (7.0 mmol/L).
There were no exclusion criteria because characteristics such as the subject's
pregnancy status, level of glycemic control, frequency of health care contact,
coexisting complications, and treatment modality are not concerns when examining
prediagnosis exposure to risk factors.
Nondiabetic controls were matched to cases by sex and age within 5 years.
We selected controls from the active patient caseload of the Ambulatory Care
Clinic at Winnipeg Children's Hospital; the control-case ratio was 2:1. The
study nurse was stationed at the clinic 1 day a week and recruited Native
patients for interviews. Recruitment ceased after the required number of controls
in the various age-sex groups had been reached. Controls were selected independent
of exposure status. The clinic has a large Native clientele, most of whom
are residents of the inner-city area where the clinic is located. However,
these children have moved to Winnipeg from Indian reserves all across the
province, and many move back and forth frequently between their home reserves
and the city, which approximates the geographic diversity of the case series.
Information on potential risk factors was collected through questionnaires
administered during in-person interviews with the parents or caregivers of
the cases and controls. The study nurse, who is of Native ancestry, conducted
all interviews over a 12-month period from September 2000 through August 2001.
Maternal risk factors were history of diabetes prior to and during pregnancy,
prepregnancy height and weight, and alcohol intake, smoking, and diet during
pregnancy. Infant risk factors were birth weight and method of infant feeding.
Neither cases nor controls underwent clinical examination or laboratory tests
for this study. Many of the items on the questionnaire were tested for cultural
relevance in the province-wide Manitoba First Nations Regional Health Survey,
conducted in 1997.
One of us (P.J.M.) has conducted extensive research on breastfeeding
prevalence, duration, and determinants among Native women in Manitoba17-18 and developed survey instruments
that were adapted for use in the present study. The informants were asked
if the child was ever breastfed. Those who answered in the affirmative were
further queried regarding the duration of the breastfeeding, the age when
formula, evaporated milk, or other milk was started, and the age when solids
were started. From these questions, the durations of any breastfeeding and
exclusive breastfeeding were determined. Instead of conducting a full-fledged
dietary survey, we focused on the frequency of consumption of "traditional
foods," ie, foods derived from the land by hunting and fishing, as a measure
of the adoption of a nontraditional lifestyle. Respondents said that they
ate a traditional diet "daily," "several times per week," "several times per
month," "several times during the entire pregnancy," or none at all. The body
mass index (weight in kg/height in m2) was computed and categorized
according to the National Institutes of Health (Bethesda, Md) clinical guidelines.19
This study was approved by the Health Research Ethics Board of the University
of Manitoba, Winnipeg. Signed, informed consent was obtained from the parents
or guardians of all respondents.
We compared cases and controls with respect to the distribution of various
variables and computed unadjusted odds ratios (ORs) and their 95% confidence
intervals (CIs). To control for potential confounding beyond the matching
factors of age and sex, we conducted multivariate matched analysis using conditional
maximum likelihood estimation with the SAS program PROC PHREG (version 8.1;
SAS Institute Inc, Cary, NC).
RESULTS
A total of 46 cases and 92 controls were recruited and interviewed.
The mean age of the cases, 14.0 years (95% CI, 13.3-14.6), was slightly higher
than that of the controls, whose mean age was 12.7 years (95% CI, 12.1-13.3).
Cases and controls had exactly the same sex distribution (54% girls vs 46%
boys). We matched the ages of 56% of controls to within ±2 years of
the cases and 33% to within ±2 to ±3 years, with only 11% matched
to within ±3 to ±5 years.
Table 1 compares the distribution
of several variables of interest between cases and controls. In multivariate
analysis, an initial full model included all variables from Table 1. Table 2 presents
the adjusted ORs and 95% CIs for patients with diabetes and compares different
categories of risk factors, controlling for all other risk factors. After
backward stepwise elimination, only 3 statistically significant (P<.05) independent explanatory variables remained: preexisting diabetes
(OR, 14.4; 95% CI, 2.86-72.5), gestational diabetes (OR, 4.40; 95% CI, 1.38-14.1),
and some breastfeeding for 12 months or longer (OR, 0.24; 95% CI, 0.07-0.84).
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Table 1. Distribution of Selected Variables Among 46 Cases and 92 Controls*
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Table 2. Adjusted Odds Ratio (OR) for Subjects With Diabetes Mellitus*
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We repeated the analysis using a dichotomized variable for infant feeding:
some breastfeeding, less than 6 months vs 6 months or longer. The independent
predictors of diabetes status were the same: preexisting diabetes (OR, 12.6;
95% CI, 2.56-61.5), gestational diabetes (OR, 4.18; 95% CI, 1.30-13.4), and
some breastfeeding for 6 months or longer (OR, 0.36; 95% CI, 0.13-0.99). We
also used the duration of any breastfeeding, in months, as a continuous variable
(OR, 0.95; 95% CI, 0.91-0.995).
Body mass index as a continuous variable was not a significant independent
predictor (OR, 1.04; 95% CI, 0.97-1.13) when it substituted for body mass
index categories in the model. An interaction term (smoking during pregnancy
x body mass index) was also not significant (OR, 1.83; 95% CI, 0.73-4.61).
COMMENT
Among the risk factors identified in this study, the strongest is maternal
diabetes. This is of concern because both gestational diabetes and type 2
diabetes during pregnancy are prevalent in several Native Canadian populations.20-21 Maternal diabetes is associated with
various risk factors for diabetes among adults, such as higher serum triglycerides,
obesity, and fasting insulin.22 Maternal diabetes
is also a strong predictor of high birth weight in the newborn.20-21,23
Although a mother could transmit genetic susceptibility to her offspring,
it is more likely that maternal diabetes increases the risk of diabetes in
children by altering the intrauterine environment. The Pima study shows that
in families where children were born both before and after their mother was
diagnosed with diabetes, the risk of diabetes was almost 4-fold higher among
siblings born after the mother developed diabetes.24
About 40% of type 2 diabetes cases among 5- to 19-year-old Pima children can
be attributed to maternal diabetes during pregnancy.25
The protective effect of breastfeeding confirms the observations of
the Pima study.14-15 A study of
Australian 2-year-olds found that those who were exclusively breastfed had
lower plasma glucose levels and higher levels of long-chain polyunsaturated
fatty acids than those who were bottle-fed. Early changes in skeletal muscle
membrane phospholipid fatty acid saturation have been postulated to play a
role in the development of insulin resistance.26
Our data should assist in the broader campaign to promote breastfeeding in
the Native Canadian population, which has been on the decline in recent decades.18
Although maternal recall of infant feeding is subject to recall bias,
studies in several developing countries have indicated remarkable validity
and reliability,27-28 and asking
mothers to recall practices from many years earlier is common in breastfeeding
studies. The Pima study of breastfeeding and diabetes published in 199714 used breastfeeding data that were collected in 1978
for a study on childhood respiratory infections in which mothers recalled
infant feeding practices from as many as 18 years earlier.29
High birth weight (>4000 g) and low birth weight (<2500 g) were associated
with a 40% increase in risk of diabetes, although the increase was not statistically
significant. High birth weight is common among many Native groups in Canada,30 and its prevalence among nondiabetic controls may
have masked the effect.
In an experimental study, fetal alcohol exposure was linked to the development
of insulin resistance in adult laboratory rats.31
Our population-based study also showed a 75%-increased risk in a human population.
Although the magnitude of the association is too small, and statistically
nonsignificant, to link any diabetes prevention effort explicitly with alcohol
consumption during pregnancy, there are sufficient health risks associated
with this behavior to warrant its reduction, regardless of its etiologic role
in diabetes.
Accumulating evidence suggests an association between smoking and diabetes
among adults,32 but there is no evidence that
smoking during pregnancy increases the risk of diabetes in children, beyond
the effect of smoking in lowering birth weight. As with alcohol, there are
sufficient grounds for reducing smoking during pregnancy, even if there is
no detectable effect on diabetes.
This study used a case-control design. Although community controls are
generally preferred because they are representative of the source population
from which cases are generated, our cases originated from many communities
across the province, making individual community visits logistically costly
and inefficient. We decided to use clinic controls, who, unlike hospital controls,
do not suffer from severe illness and are more representative of the general
childhood population.
In the short time since the problem of type 2 diabetes in Native youth
has been recognized, the burden of illness is rapidly increasing, creating
considerable stress on the health care and social support systems. The associated
complications of blindness, renal failure, amputations, and cardiovascular
disease devastate individual patients, their families, and their communities.
Although the demand for treatment, care, and support for individuals diagnosed
with diabetes will increase, this demand can be reduced in the future if effective
prevention is implemented. A first step toward the design of a preventive
strategy is the identification of risk factors, preferably very early on in
the natural history of the disease.
Based on the results of this study, any prevention strategy should involve
screening for diabetes before and during pregnancy, promoting healthy lifestyles
during pregnancy, reducing maternal obesity, and promoting breastfeeding during
infancy. None of these measures require huge expenses, and all can be integrated
into existing health care services. None are harmful, and all are beneficial
in their own right. The association with type 2 diabetes in children will
give these issues an even higher profile and provide the incentive for health
care professionals and planners to incorporate them into routine health care
programs.
| What This Study Adds
The onset of type 2 diabetes, previously thought of as an adult disease,
is occurring at increasingly younger ages in diverse populations. To date,
only one study, among the Pima Indians, has reported on maternal and early
infancy risk factors. We conducted a case-control study on Native Canadian
children and identified maternal diabetes (both preexisting type 2 and gestational)
as a strong risk factor and prolonged breastfeeding as a strong protective
factor, with a child who was breastfed for more than 12 months having only
24% of the risk of diabetes compared with a bottle-fed child. This study suggests
that there are preventive strategies that can be incorporated in existing
prenatal and infant health care programs to address a new health threat.
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AUTHOR INFORMATION
Accepted for publication March 22, 2002.
This study is supported by a grant from the Canadian Diabetes Association,
Toronto, Ontario, and the Senior Scientist Award (Dr Young) and a grant from
the Canadian Institutes of Health Research, Ottawa, Ontario.
This study has been approved by the Health Research Ethics Board of
the University of Manitoba (December 14, 1999; renewed March 20, 2001) and
the Research Impact Committee of the Health Sciences Centre (February 10,
2000).
Corresponding author and reprints: T. Kue Young, MD, PhD, Department
of Community Health Sciences, University of Manitoba, 750 Bannatyne Ave, Winnipeg,
Manitoba, Canada R3E 0W3 (e-mail: tkyoung{at}ms.umanitoba.ca).
From the Departments of Community Health Sciences (Drs Young, Martens,
and Taback and Mss Cheang and Flett) and Pediatrics and Child Health (Drs
Taback, Sellers, and Dean), Faculty of Medicine, University of Manitoba and
the Health Sciences Centre, Winnipeg; and the Department of Public Health
Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario (Dr
Young).
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