Metformin use in pregnancy: promises and uncertainties

Metformin has been prescribed in pregnancy for over 40 years; for much of this time, use has been limited both in numbers and geographically, and the evidence base has been confined to observational studies. In early years, perceived safety concerns and lack of availability of the drug in many countries acted as a barrier to use. More recently, RCTs have begun to examine the role of metformin in pregnancy in much-needed detail. However, this evidence base has been interpreted differently in different countries, leading to very wide variation in its current application in pregnancy. In this short review, we will discuss the history of metformin in pregnancy and highlight some of the key clinical trials. We will then consider some of the remaining controversies associated with metformin use in pregnancy, most important of these being the potential for long-term ‘programming’ effects on the fetus as a result of metformin being able to cross the placenta. We will also consider clinical situations where metformin might be avoided. Finally, we will discuss some future directions for this drug as it reaches its sixtieth anniversary

Gestational diabetes mellitus- right person, right treatment, right time?

Background: Personalised treatment that is uniquely tailored to an individual’s phenotype has become a key goal of clinical and pharmaceutical development across many, particularly chronic, diseases. For type 2 diabetes, the importance of the underlying clinical heterogeneity of the condition is emphasised and a range of treatments are now available, with personalised approaches being developed. While a close connection between risk factors for type 2 diabetes and gestational diabetes has long been acknowledged, stratification of screening, treatment and obstetric intervention remains in its infancy. Conclusions: Although there have been major advances in our understanding of glucose tolerance in pregnancy and of the benefits of treatment of gestational diabetes, we argue that far more vigorous approaches are needed to enable development of companion diagnostics, and to ensure the efficacious and safe use of novel therapeutic agents and strategies to improve outcomes in this common condition

Carbohydrate intake and cardiometabolic risk factors in high BMI African American children.

The aim of this study was to evaluate the relationship between intakes of subgroups of energy-providing carbohydrate, and markers of cardiometabolic risk factors in high BMI African American (AA) children.A cross sectional analysis was performed on data from a sample of 9-11 year old children (n = 95) with BMI greater than the 85th percentile. Fasting hematological and biochemical values for selected markers of cardiometabolic risk factors were related to intakes of carbohydrates and sugars.After adjusting for gender, pubertal stage and waist circumference, multivariate regression analysis showed that higher intakes of carbohydrate (with fat and protein held constant) were associated with higher plasma concentrations of triglycerides (TG), VLDL-C, IDL-C, and worse insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR). After dividing carbohydrate into non-sugar versus sugar fractions, sugars were significantly related to higher TG, VLDL-C, IDL-C, lower adipocyte fatty acid insulin sensitivity (ISI-FFA), and was closely associated with increased HOMA-IR. Similar trends were observed for sugars classified as added sugars, and for sugars included in beverages. Further dividing sugar according to the food group from which it was consumed showed that consuming more sugar from the candy/soda food group was highly significantly associated with increased TG, VLDL-C, IDL-C and closely associated with increased HOMA-IR. Sugars consumed in all fruit-containing foods were significantly associated with lower ISI-FFA. Sugars consumed as fruit beverages was significantly associated with VLDL-C, IDL-C and ISI-FFA whereas sugars consumed as fresh, dried and preserved fruits did not show significant associations with these markers.Sugars consumed from in all dairy foods were significantly associated with higher TG, VLDL-C and IDL-C, and with significantly lower HDL-C and ISI-FFA. These effects were associated with sugars consumed in sweetened dairy products, but not with sugars consumed in unsweetened dairy products. This analysis suggests that increases in carbohydrate energy, especially in the form of sugar, may be detrimental to cardiometabolic health in high BMI children

Club Pr project

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Residual renal function assessment with cystatin C

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/Vurea but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/Vurea. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters. © 2010 IPNA

Maternal thyroid function and child educational attainment: prospective cohort study

Objective: To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. Design: Prospective cohort study. Setting: Avon Longitudinal Study of Parents and Children cohort in the UK. Participants: 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). Exposures: Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. Main outcome measures: Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. Results: No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. Conclusions: Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement

Euvolemia in hemodialysis patients: a potentially dangerous goal?

Dialysis patients have high mortality rate and the leading cause of death is cardiovascular disease. Uremic cardiomyopathy differs from that due to conventional atherosclerosis, where cardiovascular changes result in ineffective circulation and lead to tissue ischemia. Modern dialysis has significant limitations with fluid management probably the most challenging. Current evidence suggests that both volume overload and aggressive fluid removal can induce circulatory stress and multi-organ injury. Furthermore, we do not have accurate volume assessment tools. As a result, targeting euvolemia might result in more harm than benefit with conventional hemodialysis therapy. Therefore, it might be time to consider a degree of permissive over-hydration until we have better tools to both determine ideal weight and improve current renal replacement therapy so that the process of achieving it is not so fraught with the current dangers