Xinhua Chen, MD, adjunct assistant professor, Department of Obstetrics and Gynecology, UMDNJ-School of Osteopathic Medicine

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estational diabetes mellitus (GDM) is glucose intolerance that is first recognized during pregnancy. GDM is a serious health problem; it clearly increases the risk of perinatal morbidity and mortality in the mother and fetus while presaging a long-term risk of developing type 2 diabetes in the mother and metabolic disorders in offspring exposed to maternal diabetes. Approximately 9-30% of pregnant women have a positive glucose challenge test (a standard glucose screening test) without developing GDM. Whether these women have a lesser degree of glucose intolerance or other metabolic abnormalities, or will develop impaired glucose tolerance postpartum, is unclear. Much of our recent research has been focused on studying the influences of maternal glucose intolerance on pregnancy outcomes, the biomarkers for early prediction of overt GDM and mild hyperglycemia.

Camden Study
For nearly three decades the Camden study has examined the effects of maternal nutrition and growth during pregnancy in successive cohorts of healthy pregnant women who reside in one of the poorest cities in the continental United States. The study is directed by Dr. Theresa Scholl, a professor in the Department of Obstetrics and Gynecology at UMDNJ-School of Osteopathic Medicine, and has been continuously funded by the NIH. More than 4,000 pregnant women, who are primarily urban and members of low income minority groups, have been studied and a unique data base with biological samples has been assembled.

Maternal glucose intolerance and pregnancy outcome
The birth of a large-for-gestational age (LGA) newborn is a common complication of GDM. LGA is defined as a neonatal birth weight greater than the 90th percentile for gestational age and adjusted for ethnicity, parity and infant gender. LGA infants are at increased risk for operative delivery, near-term death and possible permanent plexus injuries as well as long term metabolic complications. The literature relating mild maternal hyperglycemia without GDM to risk of LGA is inconsistent. Our earlier data from Camden women without type 1 or type 2 diabetes, or gestational diabetes, showed that plasma glucose level was positively associated with infant birth weight. Maternal complications, including Cesarean section and clinical chorioamnionitis were increased 2-fold or more in women with glucose >130mg/dl during the 50 gram oral glucose challenge test. This raised the question of whether higher maternal glucose predisposes to, or is a marker for, placenta inflammation and infection. Our recent findings from a subsequent cohort confirmed that a positive glucose challenge test (>140mg/dl) without GDM was associated with a 3-fold increased risk of delivering an LGA infant, suggesting that a positive glucose challenge test may be an intermediate state between normal glucose homeostasis and GDM, which influences fetal overgrowth.

Insulin resistance and biomarkers for early glucose intolerance Oxidative stress
There are multiple metabolic defects in patients with GDM, including increased insulin resistance and impaired insulin secretion. Oxidative stress and chronic systemic inflammation induce insulin resistance. Whether oxidative stress is involved in progression to, or pathogenesis of, GDM remains controversial. We explored the relationship between the antioxidant enzyme glutathione peroxidase (GPx) and insulin resistance. We found that at 16 weeks’ gestation, GPx activity was positively associated with markers of insulin resistance (increased fasting insulin and the homeostasis model of assessment for insulin resistance). Thus, in pregnant women without diabetes, there may be a link between insulin resistance and antioxidant defenses.

We subsequently examined whether altered GPx activity was associated with increased risk of GDM. After controlling for known risk factors, women in the highest tertile of the increase in GPx activity (3rd trimester and entry to care) had a 4-fold risk of GDM. In addition, elevated isoprostane excretion, an indicator of oxidative damage to lipids, was associated with a 5-fold increase in risk of preeclampsia, a serious hypertensive complication related to insulin resistance. Collectively, these data suggest that increased oxidative stress is associated with insulin resistance which, in turn, is linked to both GDM and preeclampsia. Thus, maternal antioxidant and oxidant status may prognosticate serious complications of pregnancy.

Chronic inflammation
Inflammation is associated with obesity because adipocytes secrete proinflammatory cytokines. We found that elevated serum ferritin (>131pmol/l) measured early in gestation (week 16) was highly associated with maternal adiposity and increased risk of GDM. But, it was unclear whether this elevation reflected excess iron stores or inflammation. In a nested case-control study we observed that both high serum ferritin and high C-reactive protein (a biomarker of inflammation) predicted ~2-fold increased risk of GDM. Both became not statistically significant after the adjustment for pre-pregnant BMI. Thus, these observations suggested that the association between elevated serum ferritin and GDM was mediated by the maternal fat mass via a low grade inflammatory response.

Free fatty acids
Plasma free fatty acids (FFAs) are commonly elevated during late pregnancy. Camden women with moderately elevated FFAs (>432 mM) not only have a significantly increased risk of GDM (3-fold) but also of a positive glucose challenge test without GDM (2-fold). Preterm delivery is the leading cause of neonatal mortality in the United States. High FFAs are associated with a nearly 3-fold greater risk of spontaneous preterm delivery and infant admission to neonatal intensive care unit. These effects appear to be independent of other known risk factors for either GDM or preterm delivery. Thus, elevated FFAs may be related to increased risks of GDM, mild maternal glucose intolerance and adverse pregnancy outcome.

Summary
In summary, we have prospectively studied the association of maternal
glucose intolerance and adverse pregnancy outcome in successive cohorts of women from Camden. There is no information on whether mechanisms that underlie GDM also underlie a more common condition — mild maternal hyperglycemia without GDM. Since the public health implications of
preventing or delaying the development of type 2 diabetes and its precursor, gestational diabetes mellitus, are important, we intend to address this issue in our future research.

Xinhua Chen, MD, MSCE, is an adjunct assistant professor in the Department of Obstetrics and Gynecology at the UMDNJ-School of Osteopathic Medicine in Stratford. Her focus has been epidemiological and clinical research on type 2
diabetes, gestational diabetes and obesity. She joined the Camden study and Dr. Scholl in January 2000. She is the recipient of a grant from the NIH to study impaired maternal glucose challenge and maternal-fetal outcomes.