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.

Implementing Risk Management::A Study of Major Malaysian Corporations

This study presents findings from a series of interviews with Risk Managers and/or Chief Risk Officers from major Malaysian companies about the prerequisites for the effective implementation of Risk Management programmes. The interviews highlight the importance of a number of factors, including: a strong commitment from the Board of Directors and Management in general, a desire for an appropriate risk culture, the development of formal Risk Management frameworks and policies, a recognition of the importance of risk communication, the appointment of a Chief Risk Officer (CRO) and the development of a complementary system of internal audit.

Risk factors (excluding hormone therapy) for endometrial hyperplasia: a systematic review.

Objective: To conduct a systematic review of risk factors associated with the development of Endometrial Hyperplasia (EH).

Data sources: Ovid MEDLINE, EMBASE and Web of Science databases were searched from inception to 30 June 2015.

Study eligibility: Fifteen observational studies that reported on EH risk in relation to lifestyle factors (n=14), medical history (n=11), reproductive and menstrual history (n=9) and measures of socio-economic status (n=2) were identified. Pooled relative risk estimates and corresponding 95% confidence intervals (CI) were able to be derived for EH and Body Mass Index (BMI), smoking, diabetes and hypertension, using random effects models comparing high versus low categories.

Results: The pooled relative risk for EH when comparing women with the highest versus lowest BMI was 1.82 (95% CI 1.22–2.71; n=7 studies, I2=90.4%). No significant associations were observed for EH risk for smokers compared with non-smokers (RR 0.88, 95% CI 0.66-1.17; n=3, I2=0.0%), hypertensive versus normotensive women (RR 1.51, 95% CI 0.72–3.15; n=5 studies, I2=79.1%), or diabetic versus non-diabetic women (RR 1.77, 95% CI 0.79–3.96; n=5 studies, I2=31.8%) respectively although the number of included studies was limited. There were mixed reports on the relationship between age and risk of EH. Too few studies reported on other factors to reach any conclusions in relation to EH risk.

Conclusions: A high BMI was associated with an increased risk of EH, providing additional rationale for women to maintain a normal body weight. No significant associations were detected for other factors and EH risk, however relatively few studies have been conducted and few of the available studies adequately adjusted for relevant confounders. Therefore, further aetiological studies of endometrial hyperplasia are warranted.

Bereavement outcomes: a quantitative survey identifying risk factors in family carers bereaved through cancer.

Background: Enabling patients to die in their preferred place is important but achieving preferred place of death may increase the informal carer’s risk into bereavement. Aim: to determine risk factors of family carers bereaved through cancer in Northern Ireland. Design: These results form part of a larger QUALYCARE-NI study which used postal questionnaires to capture quantitative data on carer’s bereavement scores using the Texas Revised Inventory of Grief. Setting/participants: Participants were individuals who: registered the death of a person between 1st December 2011 and 31st May 2012; where cancer (defined by ICD10 codes C00-D48) was the primary cause; where the deceased was over 18 years of age and death occurred at home, hospice, nursing home or hospital in Northern Ireland. Participants were approached in confidence by the Demography and Methodology Branch of the Northern Ireland Statistics and Research Agency. Those wishing to decline participation were invited to return the reply slip. Non-responders received a second questionnaire six weeks after initial invitation. Results indicated that risk factors positively influencing bereavement outcomes included patients having no preference for place of death and carers remaining in employment pre or post bereavement. In contrast, patients dying in hospital, carers stopping work, being of lower socio-economic status and close kinship to the deceased negatively impacted on bereavement scores. Family carers should be adequately supported to continue in employment; priority should be given to assessing the financial needs of families from lower socio-economic areas; and bereavement support should focus on close relatives of the deceased.

Lifestyle Risk Factors for Serrated Colorectal Polyps: a Systematic Review and Meta-Analysis

Background & Aims: Certain subsets of colorectal serrated polyps (SP) have malignant potential. Weperformed a systematic review and meta-analysis to investigate the association between modifiablelifestyle factors and risk for SPs. 
Methods: We conducted a systematic search of Medline, Embase, and Web of Science, forobservational or interventional studies that contained the terms risk or risk factor, and serrated orhyperplastic, and polyps or adenomas, and colorectal (or synonymous terms), published by March2016. Titles and abstracts of identified articles were independently reviewed by at least 2 reviewers.Adjusted relative risks (RR) and 95% CIs were combined using random effects meta-analyses toassess the risk of SP, when possible. 
Results: We identified 43 studies of SP risk associated with 7 different lifestyle factors: smoking,alcohol, body fatness, diet, physical activity, medication and/or hormone replacement therapy.When we compared the highest and lowest categories of exposure, factors we found to significantlyincrease risk for SP included tobacco smoking (RR, 2.47; 95% CI, 2.12–2.87), alcohol intake (RR, 1.33;95% CI, 1.17–1.52), body mass index (RR, 1.40; 95% CI, 1.22–1.61), and high intake of fat or meat.Direct associations for smoking and alcohol, but not body fat, tended to be stronger for sessileserrated adenomas/polyps than hyperplastic polyps. In contrast, factors we found to significantlydecrease risks for SP included use of non-steroidal anti-inflammatory drugs (RR, 0.77; 95% CI, 0.65–0.92) or aspirin (RR, 0.81; 95% CI, 0.67–0.99), as well as high intake of folate, calcium, or fiber. Nosignificant associations were detected between SP risk and physical activity or hormone replacementtherapy. 
Conclusions: Several lifestyle factors, most notably smoking and alcohol, are associated with SP risk.These findings enhance our understanding of mechanisms of SP development and indicate that riskof serrated pathway colorectal neoplasms could be reduced with lifestyle changes.