In a prospective study of pregnant women with type 1 diabetes, we demonstrated lower serum carotenoids, especially β-carotene, in affected versus unaffected women before PE onset. We also observed a high prevalence of vitamin D insufficiency, most frequently in women who developed PE. Relative to early pregnancy, there was also a downward trend in lipid-adjusted carotenoids and tocopherols in the third trimester, perhaps representing antioxidant reserve depletion. This decline occurred because total cholesterol and triglycerides increased by 1.5- and twofold, respectively, between visits 1 and 3 (not shown) in all groups. We have previously shown that pregnant women with type 1 diabetes are already “primed” for PE by having elevated levels of endoglin (16
), and in this setting, antioxidant depletion may trigger PE.
We identified significantly lower serum β-carotene, and by some analyses, lower α-carotene, in pregnant women with type 1 diabetes who subsequently developed PE versus those who did not. Our longitudinal data, particularly between-group differences in serum carotenoids (DM PE+ vs. DM PE−) in the third trimester, concur with existing cross-sectional studies, performed later in pregnancy in nondiabetic women, that show lower circulating carotenoids in PE (8
). β-Carotene also possesses pro-vitamin A activity (22
), and we postulate that the low β-carotene in the third trimester could be explained by increased endogenous antioxidant consumption due to elevated oxidative stress or increased conversion to vitamin A to compensate for low vitamin A levels. In our study, low vitamin A levels in women with type 1 diabetes in the first trimester are comparable to those previously reported (9
) and to levels in U.S. adult women (23
). Thus, although not statistically significant, decreasing vitamin A levels between the second and third trimesters in women with type 1 diabetes could promote PE.
Vitamin D deficiency, an increasingly prevalent condition in women of childbearing age (20
), has been associated with PE in a large prospective study (5
). We found that the majority of our participants, regardless of geographic location (which included sunny regions such as Oklahoma, South Carolina, and Australia), were vitamin D deficient. Levels did not differ between sites. We lack information on dietary intake or ultraviolet light exposure. The women with type 1 diabetes as a whole had lower levels than our nondiabetic reference group (data not shown). The reason is unclear. Occult celiac disease, which may cause vitamin D malabsorption, is prevalent (5–10%) in type 1 diabetes (24
) and could be contributory.
Links between vitamin D deficiency and PE are unclear. Hyppönen (6
) proposed an immune hypothesis, whereby local disruption of vitamin D status promotes loss of maternal–fetal immune tolerance and immune maladaptation. Although this is intriguing, it has yet to be established as a cause for PE in humans. Another possibility is diminished placental 1α-hydroxylase activity, which occurs in PE (25
) and lowers local and circulating 1,25(OH)2
In agreement with Williams et al. (10
), our study does not support a relationship between serum α- and γ-tocopherols and PE, although the decline in adjusted α-tocopherol levels throughout the pregnancy might have a permissive effect in women already predisposed. The mean first trimester serum α-tocopherol values (25–30 μmol/L) in the women with type 1 diabetes in our study were comparable to normal values in U.S. adults and above the threshold indicating vitamin E deficiency (<11.6 µmol/L) (23
Our study has several limitations. The findings merit confirmation in larger prospective studies involving diabetic and nondiabetic women. Furthermore, confounding due to certain group differences in this small cohort, although nonsignificant, cannot be excluded. More data regarding maternal diet, vitamin supplement use, and ultraviolet exposure would have been helpful to dissect cause and effect. Measures of other antioxidant vitamins and enzymes would be of interest. Fasting overnight is challenging for pregnant women with type 1 diabetes, and at each visit, a similar proportion from each diabetic group (range 2–6 of 23 or 24) attended nonfasting. However, our conclusions were not substantially affected by statistical adjustment for prandial status (as presented) or exclusion of nonfasting visits (data not shown).
We believe this is the first longitudinal study of the relationship between PE in pregnant women with type 1 diabetes and antecedent serum levels of carotenoids and vitamins A, D, and E. We found that women with type 1 diabetes who developed PE had lower antecedent serum α- and β-carotene concentrations than those who did not. Vitamin D insufficiency affected most women with type 1 diabetes, and levels tended to be lower in those who developed PE. Lipid-adjusted levels of many of the fat-soluble antioxidants declined during pregnancy. Our study sample, although small, represented women with type 1 diabetes from different geographic locations. Further studies are needed to define whether optimizing fat-soluble antioxidant and vitamin status throughout pregnancy can reduce the high incidence of PE in those with type 1 diabetes.