Childhood obesity has contributed to an increased incidence of type 2 diabetes mellitus
and metabolic syndrome (MS) among children. Intrauterine exposure to diabetes and
size at birth are risk factors for type 2 diabetes mellitus, but their association
with MS in childhood has not been demonstrated. We examined the development of MS
among large-for-gestational-age (LGA) and appropriate-for-gestational age (AGA) children.
The major components of MS (obesity, hypertension, dyslipidemia, and glucose intolerance)
were evaluated in a longitudinal cohort study of children at age 6, 7, 9, and 11 years
who were LGA (n = 84) or AGA (n = 95) offspring of mothers with or without gestational
diabetes mellitus (GDM). The cohort consisted of 4 groups, ie, LGA offspring of control
mothers, LGA offspring of mothers with GDM, AGA offspring of control mothers, and
AGA offspring of mothers with GDM. Biometric and anthropometric measurements were
obtained at 6, 7, 9, and 11 years. Biochemical testing included measurements of postprandial
glucose and insulin levels and high-density lipoprotein (HDL) cholesterol levels at
6 and 7 years and of fasting glucose, insulin, triglyceride, and HDL cholesterol levels
at 9 and 11 years. We defined the components of MS as (1) obesity (BMI >85th percentile
for age), (2) diastolic or systolic blood pressure >95th percentile for age, (3) postprandial
glucose level >140 mg/dL or fasting glucose level >110 mg/dL, (4) triglyceride level
>95th percentile for age, and (5) HDL level <5th percentile for age.
There were no differences in baseline characteristics (gender, race, socioeconomic
status, and maternal weight gain during pregnancy) for the 4 groups except for birth
weight, but there was a trend toward a higher prevalence of maternal obesity before
pregnancy in the LGA/GDM group. Obesity (BMI >85th percentile) at 11 years was present
in 25% to 35% of the children, but rates were not different between LGA and AGA offspring.
There was a trend toward a higher incidence of insulin resistance, defined as a fasting
glucose/insulin ratio of <7, in the LGA/GDM group at 11 years. Analysis of insulin
resistance at 11 years in a multivariate logistic regression revealed that childhood
obesity and the combination of LGA status and maternal GDM were associated with insulin
resistance, with odds ratios of 4.3 (95% confidence interval [CI]: 1.5-11.9) and 10.4
(95% CI: 1.5-74.4), respectively. The prevalence at any time of > or =2 components
of MS was 50% for the LGA/GDM group, which was significantly higher than values for
the LGA/control group (29%), AGA/GDM group (21%), and AGA/control group (18%). The
prevalence of > or =3 components of MS at age 11 was 15% for the LGA/GDM group, compared
with 3.0% to 5.3% for the other groups. Cox regression analysis was performed to determine
the independent hazard (risk) of developing MS attributable to birth weight, gender,
maternal prepregnancy obesity, and GDM. For Cox analyses, we defined MS as > or =2
of the following 4 components: obesity, hypertension (systolic or diastolic), glucose
intolerance, and dyslipidemia (elevated triglyceride levels or low HDL levels). LGA
status and maternal obesity increased the risk of MS approximately twofold, with hazard
ratios of 2.19 (95% CI: 1.25-3.82) and 1.81 (95% CI: 1.03-3.19), respectively. GDM
and gender were not independently significant. To determine the cumulative hazard
of developing MS with time, we plotted the risk according to LGA or AGA category for
the control and GDM groups from 6 years to 11 years, with Cox regression analyses.
The risk of developing MS with time was not significantly different between LGA and
AGA offspring in the control group but was significantly different between LGA and
AGA offspring in the GDM group, with a 3.6-fold greater risk among LGA children by
11 years.
We showed that LGA offspring of diabetic mothers were at significant risk of developing
MS in childhood. The prevalence of MS in the other groups was similar to the prevalence
(4.8%) among white adolescents in the 1988-1994 National Health and Nutrition Examination
Survey. This effect of LGA with maternal GDM on childhood MS was previously demonstrated
for Pima Indian children but not the general population. We also found that children
exposed to maternal obesity were at increased risk of developing MS, which suggests
that obese mothers who do not fulfill the clinical criteria for GDM may still have
metabolic factors that affect fetal growth and postnatal outcomes. Children who are
LGA at birth and exposed to an intrauterine environment of either diabetes or maternal
obesity are at increased risk of developing MS. Given the increased obesity prevalence,
these findings have implications for perpetuating the cycle of obesity, insulin resistance,
and their consequences in subsequent generations.