Optimal glycaemic control, pre-eclampsia and gestational hypertension in women with type 1 diabetes in the Diabetes and Pre-Eclampsia Intervention Trial

OBJECTIVE
To assess the relationship between glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS
Pregnancy outcome (pre-eclampsia or gestational hypertension) was assessed prospectively in 749 women from the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT). HbA1c (A1C) values were available up to 6 months before pregnancy (n = 542), at the first antenatal visit (median 9 weeks) (n = 721), at 26 weeks’ gestation (n = 592), and at 34 weeks’ gestation (n = 519) and were categorized as optimal (<6.1%: referent), good (6.1–6.9%), moderate (7.0–7.9%), and poor (=8.0%) glycemic control, respectively.

RESULTS
Pre-eclampsia and gestational hypertension developed in 17 and 11% of pregnancies, respectively. Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia (P < 0.05, respectively). In early pregnancy, A1C =8.0% was associated with a significantly increased risk of pre-eclampsia (odds ratio 3.68 [95% CI 1.17–11.6]) compared with optimal control. At 26 weeks’ gestation, A1C values =6.1% (good: 2.09 [1.03–4.21]; moderate: 3.20 [1.47–7.00]; and poor: 3.81 [1.30–11.1]) and at 34 weeks’ gestation A1C values =7.0% (moderate: 3.27 [1.31–8.20] and poor: 8.01 [2.04–31.5]) significantly increased the risk of pre-eclampsia compared with optimal control. The adjusted odds ratios for pre-eclampsia for each 1% decrement in A1C before pregnancy, at the first antenatal visit, at 26 weeks’ gestation, and at 34 weeks’ gestation were 0.88 (0.75–1.03), 0.75 (0.64–0.88), 0.57 (0.42–0.78), and 0.47 (0.31–0.70), respectively. Glycemic control was not significantly associated with gestational hypertension.

CONCLUSIONS
Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy. These data suggest that optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes.

The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes

OBJECTIVE To assess the association between circulating angiogenic and antiangiogenic factors in the second trimester and risk of preeclampsia in women with type 1 diabetes.

RESEARCH DESIGN AND METHODS Maternal plasma concentrations of placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin (sEng) were available at 26 weeks of gestation in 540 women with type 1 diabetes enrolled in the Diabetes and Preeclampsia Intervention Trial.

RESULTS Preeclampsia developed in 17% of pregnancies (n = 94). At 26 weeks of gestation, women in whom preeclampsia developed later had significantly lower PlGF (median [interquartile range]: 231 pg/mL [120–423] vs. 365 pg/mL [237–582]; P < 0.001), higher sFlt-1 (1,522 pg/mL [1,108–3,393] vs. 1,193 pg/mL [844–1,630] P < 0.001), and higher sEng (6.2 ng/mL [4.9–7.9] vs. 5.1 ng/mL[(4.3–6.2]; P < 0.001) compared with women who did not have preeclampsia. In addition, the ratio of PlGF to sEng was significantly lower (40 [17–71] vs. 71 [44–114]; P < 0.001) and the ratio of sFlt-1 to PlGF was significantly higher (6.3 [3.4–15.7] vs. 3.1 [1.8–5.8]; P < 0.001) in women who later developed preeclampsia. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to a logistic model containing established risk factors (area under the curve [AUC], 0.813) significantly improved the predictive value (AUC, 0.850 and 0.846, respectively; P < 0.01) and significantly improved reclassification according to the integrated discrimination improvement index (IDI) (IDI scores 0.086 and 0.065, respectively; P < 0.001).

CONCLUSIONS These data suggest that angiogenic and antiangiogenic factors measured during the second trimester are predictive of preeclampsia in women with type 1 diabetes. The addition of the ratio of PlGF to sEng or the ratio of sFlt-1 to PlGF to established clinical risk factors significantly improves the prediction of preeclampsia in women with type 1 diabetes.

Preeclampsia is characterized by the development of hypertension and new-onset proteinuria during the second half of pregnancy (1,2), leading to increased maternal morbidity and mortality (3). Women with type 1 diabetes are at increased risk for development of preeclampsia during pregnancy, with rates being two-times to four-times higher than that of the background maternity population (4,5). Small advances have come from preventive measures, such as low-dose aspirin in women at high risk (6); however, delivery remains the only effective intervention, and preeclampsia is responsible for up to 15% of preterm births and a consequent increase in infant mortality and morbidity (7).

Although the etiology of preeclampsia remains unclear, abnormal placental vascular remodeling and placental ischemia, together with maternal endothelial dysfunction, hemodynamic changes, and renal pathology, contribute to its pathogenesis (8). In addition, over the past decade accumulating evidence has suggested that an imbalance between angiogenic factors, such as placental growth factor (PlGF), and antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng), plays a key role in the pathogenesis of preeclampsia (8,9). In women at low risk (10–13) and women at high risk (14,15), concentrations of angiogenic and antiangiogenic factors are significantly different between women who later develop preeclampsia (lower PlGF, higher sFlt-1, and higher sEng levels) compared with women who do not.

Few studies have specifically focused on circulating angiogenic factors and risk of preeclampsia in women with diabetes, and the results have been conflicting. In a small study, higher sFlt-1 and lower PlGF were reported at the time of delivery in women with diabetes who developed preeclampsia (16). In a longitudinal prospective cohort of pregnant women with diabetes, Yu et al. (17) reported increased sFlt-1 and reduced PlGF in the early third trimester as potential predictors of preeclampsia in women with type 1 diabetes, but they did not show any difference in sEng levels in women with preeclampsia compared with women without preeclampsia. By contrast, Powers et al. (18) reported only increased sEng in the second trimester in women with pregestational diabetes who developed preeclampsia.

The aim of this study, which was significantly larger than the previous studies highlighted, was to assess the association between circulating angiogenic (PlGF) and antiangiogenic (sFlt-1 and sEng) factors and the risk of preeclampsia in women with type 1 diabetes. A further aim was to evaluate the added predictive ability and clinical usefulness of angiogenic factors and established risk factors for preeclampsia risk prediction in women with type 1 diabetes.

Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes

OBJECTIVE: To assess the relationship between second and third trimester glycemic control and adverse outcomes in pregnant women with type 1 diabetes, as uncertainty exists about optimum glycemic targets.

RESEARCH DESIGN AND METHODS: Pregnancy outcomes were assessed prospectively in 725 women with type 1 diabetes from the Diabetes and Pre-eclampsia Intervention Trial. HbA1c (A1C) values at 26 and 34 weeks' gestation were categorized into five groups, the lowest, <6.0% (42 mmol/mol), being the reference. Average pre- and postprandial results from an eight-point capillary glucose profile the previous day were categorized into five groups, the lowest (preprandial <5.0 mmol/L and postprandial <6.0 mmol/L) being the reference.

RESULTS: An A1C of 6.0-6.4% (42-47 mmol/mol) at 26 weeks' gestation was associated with a significantly increased risk of large for gestational age (LGA) (odds ratio 1.7 [95% CI 1.0-3.0]) and an A1C of 6.5-6.9% (48-52 mmol/mol) with a significantly increased risk of preterm delivery (odds ratio 2.5 [95% CI 1.3-4.8]), pre-eclampsia (4.3 [1.7-10.8]), need for a neonatal glucose infusion (2.9 [1.5-5.6]), and a composite adverse outcome (3.2 [1.3-8.0]). These risks increased progressively with increasing A1C. Results were similar at 34 weeks' gestation. Glucose data showed less consistent trends, although the risk of a composite adverse outcome increased with preprandial glucose levels between 6.0 and 6.9 mmol/L at 34 weeks (3.3 [1.3-8.0]).

CONCLUSIONS: LGA increased significantly with an A1C ≥6.0 (42 mmol/mol) at 26 and 34 weeks' gestation and with other adverse outcomes with an A1C ≥6.5% (48 mmol/mol). The data suggest that there is clinical utility in regular measurement of A1C during pregnancy.

Serum Fatty Acid Binding Protein 4 (FABP4) Predicts Pre-eclampsia in Women with Type 1 Diabetes

Objective: To examine the association between fatty acid binding protein 4 (FABP4) and pre-eclampsia risk in women with type 1 diabetes.
Reesearch Design and Methods: Serum FABP4 was measured in 710 women from the Diabetes and Pre-eclampsia Intervention Trial (DAPIT) in early pregnancy and in the second trimester (median 14 and 26 weeks gestation, respectively).
Results: FABP4 was significantly elevated in early pregnancy (geometric mean 15.8 ng/mL [interquartile range 11.6–21.4] vs. 12.7 ng/mL [interquartile range 9.6–17]; P < 0.001) and the second trimester (18.8 ng/mL [interquartile range 13.6–25.8] vs. 14.6 ng/mL [interquartile range 10.8–19.7]; P < 0.001) in women in whom pre-eclampsia later developed. Elevated second-trimester FABP4 level was independently associated with pre-eclampsia (odds ratio 2.87 [95% CI 1.24, 6.68], P = 0.03). The addition of FABP4 to established risk factors significantly improved net reclassification improvement at both time points and integrated discrimination improvement in the second trimester.
Conclusions: Increased second-trimester FABP4 independently predicted pre-eclampsia and significantly improved reclassification and discrimination. FABP4 shows potential as a novel biomarker for pre-eclampsia prediction in women with type 1 diabetes.