Results
Maternal characteristics: Table 1 shows the baseline clinical characteristics of all women. There were no significant differences in age, ethnicity, smoking, gravidity, parity, duration of T1DM, systolic and diastolic blood pressure, mean arterial pressure (MAP), total cholesterol, LDL-cholesterol, triacylglycerol, and gestational age per visit between DM+PE+ and DM+PE-. However, at the initial study visit, HbA1c, Body Mass Index (BMI) and total daily insulin dose were significantly higher in DM+PE+ than DM+PE-, and HDL-cholesterol was significantly lower. There were no significant differences between the two normotensive groups at V1, except as expected, HbA1c was higher in women with diabetes.
25(OH)D deficiency was not associated with subsequent PE in women with T1DM: Vitamin D insufficiency and deficiency are defined as <32 and <20 ng/mL, respectively.6As shown in Figure 1, a majority (97%) of all women fell below the ‘normal’ level of vitamin D throughout pregnancy. Women with T1DM were more likely to be 25(OH)D deficient (DM+PE+: 73%; DM+PE-: 65%) than non-diabetic women (22%) at the first visit (p=0.009); however there were no significant differences in any measure of 25(OH)D during pregnancy between the DM+PE+ and DM+PE- groups. Total 25(OH)D was lower in DM+PE- than in DM- groups at the beginning of pregnancy (V1, p=0.020; V2, p=0.034), but neither bioavailable nor free 25(OH)D differed by diabetes status at any visit.
Higher second and/or third trimester 1,25(OH)2D (total, bioavailable, free) are associated with subsequent PE in women with T1DM: As shown in Figure 2, in the DM+PE+ vs the DM+PE- group, total 1,25(OH)2D was higher at V2 (p=0.005), and bioavailable and free 1,25(OH)2D were higher at V2 and V3 (bioavailable: V2, p=0.005; V3, p=0.031; free: V2, p=0.007 & V3, p=0.009). In the DM+PE- vs. the DM- group, all measures of 1,25(OH)2D were lower at V2 (total, p=0.002; bioavailable, p=0.004; free, p=0.018). Total 1,25(OH)2D significantly increased as pregnancy advanced in DM+PE+ (p<0.001) and DM+PE- (p=0.007).
Using logistic regression, data were analysed without and with covariates to assess the effectiveness of 1,25(OH)2D as a biomarker of PE. At V2, without covariates and in women with T1DM only, every 1 pg/mL increase in total 1,25(OH)2D increased the odds of developing PE by 3% (OR: 1.03 (1.01-1.05), p=0.012), while every 1pg/mL increase in bioavailable 1,25(OH)2D increased the odds for PE by 28% (OR: 1.28 (1.06-1.54), p=0.010). Likewise, at V3, every 1 pg/mL increase in bioavailable 1,25(OH)2D increased the odds for PE by 18% (OR: 1.18 (1.00-1.39), p=0.047). Covariate analyses including BMI, HbA1c and total adiponectin did not affect significance.
Ratios of total, bioavailable, and free 1,25(OH)2D to corresponding 25(OH)D concentrations (Table 2): In the DM+PE+ vs the DM+PE- group, total, bioavailable and free 1,25(OH)2D/25(OH)D (product:substrate) ratios were all higher at V3 (all p<0.05). There were no significant differences in these ratios at any stage of pregnancy between the DM+PE- and DM- groups, and there were no significant changes over time in any of the groups. For women with T1DM only, at V3, for every unit increase in total 1,25(OH)2D/25(OH)D, the odds of developing PE increased by 17% (OR: 1.17 (1.01-1.35), p=0.037), however, this significance did not persist after covariate adjustment.
Lower VDBP and higher 1,25(OH)2D/VDBP ratio are associated with subsequent PE in women with T1DM: As summarized in Table 2, in the DM+PE+ vs the DM+PE- group, VDBP was lower at V3 (p=0.032), and total 1,25(OH)2D/VDBP and [1,25(OH)2D bound to VDBP]/VDBP were both higher at V2 & V3 (all p<0.01). Total 25(OH)D/VDBP and [‘25(OH)D bound to VDBP’]/VDBP did not differ between DM+PE+ and DM+PE- at any study visit. In the DM+PE- vs the DM- group, total 1,25(OH)2D/VDBP and [‘1,25(OH)2D bound to VDBP’]/VDBP were lower at V2 (p=0.025 and p=0.018 respectively). VDBP significantly increased throughout pregnancy in all groups (all p<0.001). For women with T1DM only, for every 1 mg/dL increase in VDBP at V3, the odds of developing PE decreased by 8% (OR: 0.92 (0.85-1.00), p<0.05). At V2, for every unit increase in total 1,25(OH)2D/VDBP, the odds of developing PE increased almost three-fold (OR: 2.71 (1.28-5.77), p=0.009). Likewise, at V3, for every unit increase in total 1,25(OH)2D/VDBP, the odds of developing PE increased similarly (OR: 2.53 (1.21-5.29), p=0.013). Consideration of covariates had no effect.