Maternal obesity and inflammation

Studies of inflammation and insulin resistance in pregnancy were performed in non-obese women.1317 Since obesity precipitates inflammatory responses, excessive free fatty acid release, and subsequent insulin-resistant states in non-pregnant individuals, it is reasonable to assume that inflammatory responses and insulin resistance would be enhanced in obese compared to lean pregnant women. Comparisons of metabolic adjustments in lean and obese pregnant women are limited, but the few studies done show that obese women rely more on fat oxidation as a source of energy in late pregnancy than do lean women.18,19

The increase in fat oxidation among the obese women was significantly correlated with serum leptin concentrations (r = 0.76, p <0.005).19,20 Longitudinal changes in insulin sensitivity were also compared among women with BMIs <25, between 25 and 30, and >30.21 Although 50 to 60% decreases in insulin sensitivity were noted in all groups from before conception through late pregnancy (p <0.0001), the obese subjects were significantly less insulin-sensitive or more insulin-resistant than the lean women (p <0.0001) and overweight women (p <0.004), particularly prior to conception or at 12 to 14 weeks of gestation.

We studied changes in insulin sensitivity in 8 lean women (body fat <30%) and 12 obese women (body fat >30%) followed from 12 to 34 weeks of gestation22 (Figure 6.2). Insulin sensitivity was estimated from serum glucose and insulin

FIGURE 6.2 Decline in insulin sensitivity in lean and obese pregnant women. Insulin sensitivity was estimated from post-oral glucose tolerance test serum glucose and insulin levels23 in 8 lean and 12 obese (body fat >30%) women at 12, 22, 28, and 34 weeks of gestation. The decline in insulin sensitivity was greater in obese than in lean women between 12 and 34 weeks, p <0.005.

FIGURE 6.2 Decline in insulin sensitivity in lean and obese pregnant women. Insulin sensitivity was estimated from post-oral glucose tolerance test serum glucose and insulin levels23 in 8 lean and 12 obese (body fat >30%) women at 12, 22, 28, and 34 weeks of gestation. The decline in insulin sensitivity was greater in obese than in lean women between 12 and 34 weeks, p <0.005.

concentrations following oral glucose tolerance tests.23 Insulin sensitivity declined by 34% in the non-obese group from 12 to 34 weeks and by 60% in the obese group; the change in the two groups did not achieve statistical significance (p = 0.09). Insulin sensitivity did not differ between the two groups at 12 weeks of gestation, but it was significantly lower in the obese than in the non-obese at 34 weeks (p <0.005), reflecting the larger drop in insulin sensitivity in obese compared to lean women during gestation.

Since these preliminary studies showed that insulin sensitivity was lower in obese than in non-obese pregnant women, we studied the relationship between BMI and maternal cytokine levels in 51 women at 28 weeks' gestation.24 At the beginning of the third trimester, the BMI values of these women averaged 32 ± 9 kg/m2; the range was 21 to 54 kg/m2. BMI correlated with C-reactive protein (CRP) levels (r = 0.53; p <0.001) and leptin (r = 0.79; p <0.001). The relationship with TNF-a was borderline (r = 0.26; p <0.07). Thus, obese pregnant women, like obese non-pregnant women, tend to have higher circulating levels of pro-inflammatory cytokines.

The women with higher BMIs in this study also had higher levels of fasting glucose (r = 0.53; p <0.001), fasting insulin (r = 0.62, p <0.001), and homeostasis model assessment (HOMA) — an estimate of insulin resistance calculated from the fasting glucose:insulin ratio — (r = 0.64, p <0.001). Serum adiponectin levels were negatively associated with BMI (r = -0.32, p = 0.02). Women with higher BMIs at the beginning of the third trimester of pregnancy showed higher circulating levels of inflammatory markers, hyperglycemia, hyperinsulinemia, hyper-leptinemia, hypoadiponectinemia, and insulin resistance. These findings are consistent with studies of pro-inflammatory cytokines, adipocyte hormones, and glucose tolerance in non-pregnant, obese women.7

In a study of 24 lean women (BMI = 22.1 kg/m2) and 23 obese women (BMI = 31.0 kg/m2), Ramsay and co-workers found that both CRP and leptin concentrations were about twice as high in the obese compared to lean women.25 The logs of CRP and of leptin were strongly related with the log of fasting insulin (CRP: r = 0.47, p <0.001; leptin: r = 0.74, p <0.001). Furthermore, a step-wise regression model showed that both leptin and BMI were independent predictors of insulin; together, they explained 57% of the insulin variability, suggesting that body fatness and adipocyte hormones work together to create a maternal insulin-resistant state in pregnancy.

Our studies and that of Ramsay25 are limited by the fact that they are cross-sectional in nature. Longitudinal, prospective data are needed to comprehensively evaluate the relationship of maternal obesity, inflammation, and glycemic control during pregnancy. Nevertheless, preliminary data demonstrate that obesity in pregnancy is associated with marked hyperinsulinemia (in advance of gestational diabetes) and inflammatory up-regulation. Such metabolic perturbations may not only contribute to GDM and other maternal complications such as pre-eclampsia but also affect placental function and fetal growth and development.

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