The committee found no studies that directly link GWG to activation of the maternal or fetal HPA axis. However, several animal studies have linked periconceptional undernutrition to accelerated maturation of fetal HPA axis resulting in preterm delivery (Bloomfield et al., 2003, 2004; Kumarasamy et al., 2005).

Again, the committee also found no studies directly linking GWG to amniochorionic-decidual or systemic inflammation. However, it is plausible that maternal undernutrition may increase the risk of preterm delivery by suppressing immune functions or increasing oxidative stress. Macro- or micronutrient deficiencies are known to adversely affect maternal immune functions. For example, iron-deficiency anemia can alter the proliferation of T- and B-cells, reduce the killing activity of phagocytes and neutrophils, and lower bactericidal and natural killer cell activity, thereby increasing maternal susceptibility to infections (Allen, 2001). Furthermore, protein and/or micronutrient deficiencies may impair cellular antioxidant capacities because proteins provide the amino acids needed for synthesis of antioxidant defense enzymes, such as glutathione and albumin (reactive oxygen species scavengers); and many micronutrients themselves are antioxidants. Increases in reactive oxygen species, such as oxidized low-density lipoprotein and F2-isoprostanes (lipid peroxidation products), may contribute to cellular toxicity, inflammation, vasoconstriction, platelet aggregation, vascular apoptosis, and endothelial cell dysfunction (Luo et al., 2006), which may also activate the pathway to preterm delivery involving uteroplacental thrombosis and intrauterine vascular lesions.

Summary of the Evidence on an Association Between GWG and Preterm Birth

In summary, there is strong evidence for a U-shaped association between lower GWG and preterm birth among normal weight and under-weight women, and moderate evidence for an association of higher GWG and preterm birth. The magnitude of the association is fairly strong, with relative risks on the order of two, but difficult to summarize because of variability in the definitions of higher and lower rates of weight gain. There is no empirical basis for suggesting modifiers of this relationship other than prepregnancy BMI, for which the data are clear in showing that associations of low GWG with preterm birth are stronger among underweight women.

The committee was unable to infer a causal relationship between GWG and preterm delivery based on available evidence. Although there are intriguing data linking macro- and/or micronutrient deficiencies to accelerated maturation of fetal HPA axis and altered immune functions and/or increased oxidative stress, suggesting that a direct causal relationship is biologically plausibility, important questions regarding timing, threshold, content, and interactions remain unanswered. These uncertainties about a



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