The unexplored role of sedentary time and physical activity in glucose and lipid metabolism-related placental mRNAs in pregnant women who are obese: the DALI lifestyle randomised controlled trial.

OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.

Metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes.

AIMS: To describe the metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes. METHODS: We performed a post hoc analysis using data from the Vitamin D And Lifestyle Intervention for gestational diabetes prevention (DALI) trial conducted across nine European countries (2012-2014). In women with a BMI ≥29 kg/m2 , insulin resistance and secretion were estimated from the oral glucose tolerance test values performed before 20 weeks, using homeostatic model assessment of insulin resistance and Stumvoll first-phase indices, respectively. Women with early gestational diabetes, defined by the International Association of Diabetes and Pregnancy Study Groups criteria, were classified into three groups: GDM-R (above-median insulin resistance alone), GDM-S (below-median insulin secretion alone), and GDM-B (combination of both) and the few remaining women were excluded. RESULTS: Compared with women in the normal glucose tolerance group (n = 651), women in the GDM-R group (n = 143) had higher fasting and post-load glucose values and insulin levels, with a greater risk of having large-for-gestational age babies [adjusted odds ratio 3.30 (95% CI 1.50-7.50)] and caesarean section [adjusted odds ratio 2.30 (95% CI 1.20-4.40)]. Women in the GDM-S (n = 37) and GDM-B (n = 56) groups had comparable pregnancy outcomes with those in the normal glucose tolerance group. CONCLUSIONS: In overweight and obese women with early gestational diabetes, higher degree of insulin resistance alone was more likely to be associated with adverse pregnancy outcomes than lower insulin secretion alone or a combination of both.

Maternal glycaemic control and risk of neonatal hypoglycaemia in Type 1 diabetes pregnancy: a secondary analysis of the CONCEPTT trial.

AIMS: To examine the relationship between maternal glycaemic control and risk of neonatal hypoglycaemia using conventional and continuous glucose monitoring metrics in the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT) participants. METHODS: A secondary analysis of CONCEPTT involving 225 pregnant women and their liveborn infants. Antenatal glycaemia was assessed at 12, 24 and 34 weeks gestation. Intrapartum glycaemia was assessed by continuous glucose monitoring measures 24 hours prior to delivery. The primary outcome was neonatal hypoglycaemia defined as glucose concentration < 2.6 mmol/l and requiring intravenous dextrose. RESULTS: Neonatal hypoglycaemia occurred in 57/225 (25.3%) infants, 21 (15%) term and 36 (40%) preterm neonates. During the second and third trimesters, mothers of infants with neonatal hypoglycaemia had higher HbA1c [48 ± 7 (6.6 ± 0.6) vs. 45 ± 7 (6.2 ± 0.6); P = 0.0009 and 50 ± 7 (6.7 ± 0.6) vs. 46 ± 7 (6.3 ± 0.6); P = 0.0001] and lower continuous glucose monitoring time-in-range (46% vs. 53%; P = 0.004 and 60% vs. 66%; P = 0.03). Neonates with hypoglycaemia had higher cord blood C-peptide concentrations [1416 (834, 2757) vs. 662 (417, 1086) pmol/l; P < 0.00001], birthweight > 97.7th centile (63% vs. 34%; P < 0.0001) and skinfold thickness (P ≤ 0.02). Intrapartum continuous glucose monitoring was available for 33 participants, with no differences between mothers of neonates with and without hypoglycaemia. CONCLUSIONS: Modest increments in continuous glucose monitoring time-in-target (5-7% increase) during the second and third trimesters are associated with reduced risk for neonatal hypoglycaemia. While more intrapartum continuous glucose monitoring data are needed, the higher birthweight and skinfold measures associated with neonatal hypoglycaemia suggest that risk is related to fetal hyperinsulinemia preceding the immediate intrapartum period.

Glycemic control and maternal and fetal outcomes in pregnant women with type 1 diabetes according to the type of basal insulin.

OBJECTIVE: To examine the potential role of the type of basal insulin on glycemic control and maternal and foetal outcomes in pregnant women with type 1 diabetes (T1DM). STUDY DESIGN: Retrospective cohort study of pregnancies attended at 18 Spanish tertiary hospitals. INCLUSION CRITERIA: T1DM, singleton pregnancies, delivery between 2002-2010, and use of the same basal and prandial insulin from before pregnancy until delivery. RESULTS: A total of 1534 pregnancies were included. The basal insulin most commonly used was Neutral Protamine Hagedorn (NPH) (51.7%), followed by glargine (23.2%) and continuous subcutaneous insulin infusion (CSII) (21.1%). CSII users had longer diabetes duration. Multiple logistic regression analysis showed that CSII was independently associated with lower doses of insulin, higher glycated haemoglobin (HbA1c) in all trimesters, and higher rates of miscarriage, preterm birth and neonatal hypoglycemia. Glargine was related to a higher risk of preterm birth and a small-for-gestational age infant (SGA). The odds ratios (OR) of the associations between insulin type and clinical outcomes (from 0.642 to 4.894) have a relevant magnitude. CONCLUSIONS: In this observational study of pregnant women with T1DM, the type of basal insulin was independently associated with metabolic variables and foetal outcomes.

In women with gestational diabetes mellitus factors influencing growth have a larger effect on placental weight than on birth weight.

BACKGROUND AND AIMS: Excessive fetal and placental growth are very common in diabetic pregnancy. We aimed to analyze in women with gestational diabetes mellitus (GDM) the association with birth weight (BW), placental weight (PW) and placental-to-birth weight (PWBW) ratio of acknowledged BW predictors. MATERIAL AND METHODS: We performed a retrospective analysis of a prospective cohort database from a tertiary hospital. Inclusion criteria were singleton pregnancy, diagnosis of GDM, delivery between 1982 and 2011 and gestational age at birth ≥23 weeks. Multiple regression analysis was performed using as dependent variables BW, PW and PWBW ratio and as independent ones maternal characteristics at baseline, metabolic characteristics (GDM diagnosis, treatment, control), pregnancy-induced hypertension, gestational age at delivery and fetal sex. Two sensitivity analyses were performed. RESULTS: We evaluated 2547 women, PW being available in 85.3%. BW was 3260g (2976, 3575), PW 620g (540, 720) and PWBW ratio 19.27 (17.20, 21.47). Among the 24 analyzed variables, there was an important overlap among those associated with BW, PW and PWBW ratio. For most characteristics associated with both BW and PW, the magnitude of the association was greater for the latter, both when promoting growth (i.e. prepregnancy body mass index, 3h plasma glucose at diagnosis) and when restricting it (insulin treatment). CONCLUSION: We conclude that in women with GDM and singleton pregnancies, variables associated with BW, PW and PWBW ratio overlap. The latter is the result of disproportionate associations with BW and PW, usually larger with PW.

Smoking affects the oral glucose tolerance test profile and the relationship between glucose and HbA1c in gestational diabetes mellitus.

AIMS: Current smokers in the general population have a lower 2 h plasma glucose after an oral glucose tolerance test (OGTT) and a higher HbA1c than non-smokers, but the relationships between OGTT/HbA1c and smoking status have not been addressed in pregnancy. We analysed glycaemic measurements in women with gestational diabetes mellitus in relation to smoking status. METHODS: We performed a review of the prospectively collected database of the diabetes and pregnancy clinic. We included women with gestational diabetes mellitus and a singleton pregnancy who delivered between 1986 and 2006. Bivariate and multivariate analyses were used to evaluate patient characteristics in relation to smoking status. RESULTS: A total of 2361 women met the inclusion criteria: 556 (23.5%) were active smokers, 266 (11.3%) quit during pregnancy and 1539 (65.2%) were non-smokers. Most baseline characteristics were similar across groups. Diagnostic OGTT was performed at a gestational age of [median (25th, 75(th) centiles)] 29 weeks (26, 33). Women who smoked at the beginning of pregnancy had a higher 1-h plasma glucose than non-smokers [11.8 (11, 12.7), 11.6 (11, 12.6) and 11.5 (10.8, 12.5) mmol/l, for active smokers, those who quit during pregnancy and non-smokers, respectively, P < 0.001] and a lower 3-h plasma glucose [7.3 (5.9, 8.4), 7.6 (6.4, 8.7) and 8.0 (6.8, 9.0) mmol/l, respectively, P < 0.001]. HbA1c was higher in women who smoked at the beginning of pregnancy. Multiple regression analysis confirmed the independent association of smoking status with HbA1c and OGTT plasma glucose. CONCLUSIONS: In women with gestational diabetes mellitus who smoke at the beginning of pregnancy, the shape of the OGTT is consistent with accelerated glucose absorption, and HbA1c is higher than expected for glycaemic values.

Gestational diabetes mellitus in women with multiple pregnancies: is the metabolic abnormality milder?

OBJECTIVE: We aimed to compare maternal characteristics and dysglycemia after delivery in women with gestational diabetes mellitus (GDM) according to pregnancy being multiple (MP) or singleton (SP). The hypothesis was that women with GDM and MP would have a milder glycemic abnormality before and after pregnancy than those with SP. METHODS: We performed a cohort study of 2908 women giving birth between 1986 and 2009. Logistic regression was performed to discriminate between MP and SP after anamnestic pre-pregnancy characteristics. Kaplan-Meier and Cox regression analyses were performed to assess if MP was independently associated with both impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) and diabetes after delivery. RESULTS: Family history of diabetes was the only independent anamnestic pre-pregnancy characteristic discriminating MP versus SP, OR 2.04 (95% CI 1.12, 3.70, p 0.019). The median time to progress to IFG/IGT was 7.52 years in SP (95% CI 6.92, 8.13) and 7.41 in MP (95% CI 3.84, 10.98), ns and the progression to DM did not differ. In addition, MP was not associated to IFG/IGT or to DM in the Cox regression analysis. CONCLUSIONS: In this cohort of women with GDM, those with MP did not demonstrate a lesser degree of dysglycemia after controlling for other pregnancy characteristics and pregnancy-independent factors.

Associations of Body Mass Index (Maternal BMI) and Gestational Diabetes Mellitus with Neonatal and Maternal Pregnancy Outcomes in a Multicentre European Database (Diabetes and Pregnancy Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention).

Objective. Assess the impact of Gestational Diabetes Mellitus (GDM) and obesity on neonatal and maternal pregnancy outcomes. Methods. Cross-sectional data (3343 pregnancies) from seven European centres were included in a multilevel analysis of the association between GDM/obesity and caesarean section, macrosomia and neonatal morbidities. Results. Comparison of databases identified reporting differences between countries due to the inclusion of true population based samples or pregnancies from specialised tertiary centres, resulting in higher prevalences of GDM for some countries. The analysis showed that obesity and GDM were independent risk factors of perinatal complications. Only BMI had a dose-dependent effect on the risk of macrosomia and caesarean section. Both obesity (BMI > 30 kg/m(2)) and GDM were independent risk factors of neonatal morbidities. Conclusions. Obesity and GDM were independent risk factors of perinatal complications. The effect of the worldwide obesity and diabetes epidemic is extending to the next generation.

Gestational diabetes mellitus in Europe: prevalence, current screening practice and barriers to screening. A review.

BACKGROUND: Gestational diabetes mellitus is a potentially serious condition that affects many pregnancies and its prevalence is increasing. Evidence suggests early detection and treatment improves outcomes, but this is hampered by continued disagreement and inconsistency regarding many aspects of its diagnosis. METHODS: The Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention (DALI) research programme aims to promote pan-European standards in the detection and diagnosis of gestational diabetes and to develop effective preventive interventions. To provide an overview of the context within which the programme will be conducted and its findings interpreted, systematic searching and narrative synthesis have been used to identify and review the best available European evidence relating to the prevalence of gestational diabetes, current screening practices and barriers to screening. RESULTS: Prevalence is most often reported as 2-6% of pregnancies. Prevalence may be lower towards the Northern Atlantic seaboard of Europe and higher in the Southern Mediterranean seaboard. Screening practice and policy is inconsistent across Europe, hampered by lack of consensus on testing methods, diagnostic glycaemic thresholds and the value of routine screening. Poor clinician awareness of gestational diabetes, its diagnosis and local clinical guidelines further undermine detection of gestational diabetes. CONCLUSIONS: Europe-wide agreement on screening approaches and diagnostic standards for gestational diabetes could lead to better detection and treatment, improved outcomes for women and children and a strengthened evidence base. There is an urgent need for well-designed research that can inform decisions on best practice in gestational diabetes mellitus screening and diagnosis.

Poorer perinatal outcome in male newborns of women with pregestational diabetes mellitus.

AIMS: To assess perinatal outcome in women with pregestational diabetes mellitus according to the sex of the fetus. METHODS: A retrospective review of all singleton pregnancies of women with pregestational diabetes progressing to a gestational age of 22 weeks or more who attended the diabetes and pregnancy clinic from 1981 to 2006 (n=455). We compared maternal characteristics and perinatal outcomes (perinatal mortality, major congenital malformations, small and large for gestational age newborns, preterm birth and a composite of the former) according to the sex of the fetus. A logistic regression analysis was performed using the composite perinatal outcome as the dependent variable and all maternal variables and sex of fetus as potential predictors. RESULTS: Maternal characteristics did not differ in mothers of male and female newborns. In the whole cohort, the composite perinatal outcome was significantly higher in male fetuses; adjusted OR 1.61 (95% CI 1.04-2.50). CONCLUSIONS: In women with pregestational diabetes, perinatal outcome was poorer in male newborns despite similar maternal characteristics.

Insulin requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction.

AIMS/HYPOTHESIS: The aim of the study was to analyse the insulin requirements of women with type 1 diabetes mellitus throughout pregnancy. METHODS: We have examined the weekly mean blood glucose (mmol/l), insulin requirements (U kg(-1) day(-1)) and total insulin requirements (U/day) in 65 women with type 1 diabetes mellitus and tight metabolic control since before pregnancy (HbA(1c) < or =6.0%). RESULTS: Both insulin requirement and total insulin requirement displayed a peak in week 9, a nadir in week 16 and a second peak in week 37. For the change in insulin requirement (4.08% per week) and in total insulin requirement (5.19% per week), the sharpest slope was observed from week 16 to week 37. However, two changes of direction took place in the first 11 weeks and eight out of nine episodes of severe hypoglycaemia requiring treatment with glucagon or i.v. glucose took place in the first 16 weeks. CONCLUSIONS/INTERPRETATION: Pregnant women with type 1 diabetes mellitus and tight metabolic control since before pregnancy displayed changes in insulin requirement and total insulin requirement with successive changes of direction. The sharpest slope was observed between 16 and 37 weeks, but insulin requirements were more unstable in the first 16 weeks. This information could help patients and physicians to react to changes in glycaemic pattern in a prompt and adequate way.

Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis.

CONTEXT: Glycemic disturbance is usually less severe in pregnant women with type 2 than in those with type 1 diabetes mellitus (DM). Nevertheless, a worse perinatal outcome in women with type 2 DM has been reported in some studies. OBJECTIVE: Our objective was to review maternal and fetal outcomes in pregnant women with type 2 vs. type 1 DM. STUDY SELECTION: We conducted a systematic review of papers providing original data on pregnancy outcomes in both type 2 and type 1 DM (Medline search of the period January 1, 1987, to June 30, 2008). Two independent investigators considered papers for eligibility, and a third one solved discrepancies. DATA EXTRACTION: Metaanalysis tools were used to compare four main outcomes (major congenital malformations, stillbirth, and neonatal and perinatal mortality) and 15 secondary ones (five maternal, 10 fetal). Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were used to assess quality. DATA SYNTHESIS: Thirty-three studies qualified for inclusion of 3743 citations retrieved. Women with type 2 DM had lower glycated hemoglobin (HbA1c) at booking and throughout pregnancy but a higher risk of perinatal mortality [odds ratio (OR) 1.50, 95% confidence interval (CI) 1.15-1.96] without significant differences in the rates of major congenital malformations, stillbirth, and neonatal mortality. As to secondary outcomes, women with type 2 DM had less diabetic ketoacidosis (OR 0.09, 95% CI 0.02-0.34) and cesarean section (OR 0.80, 95% CI 0.59-0.94) without differences in other outcomes. CONCLUSIONS: Despite a milder glycemic disturbance, women with type 2 DM had no better perinatal outcomes than those with type 1, indicating that type 2 DM in pregnancy is a serious condition.

Maternal glucose tolerance status influences the risk of macrosomia in male but not in female fetuses.

OBJECTIVE: To elucidate whether the risk of macrosomia, large for gestational age (LGA) and small for gestational age (SGA) is influenced by maternal body mass index and glucose tolerance differently in male and female fetuses. METHODS: A population study was conducted in 16 general hospitals from the Spanish National Health Service that included 9270 consecutive women with singleton pregnancies and without a former diagnosis of diabetes mellitus who delivered 4793 male and 4477 female newborns. Logistic regression analyses were performed to predict the effect of body mass index (BMI) category and glucose tolerance on macrosomia, large for gestational age newborns (LGA) and small for gestational age newborns (SGA) Separate analyses according to foetal sex were carried out for each outcome. The results were adjusted for maternal age, gestational age and pregnancy-induced hypertension. RESULTS: There were significant differences between males and females in the percentage of infants who had macrosomia, LGA or SGA. Maternal BMI category was positively associated with the risk of macrosomia and LGA in both male and female newborns. In addition, there was a negative association between maternal BMI and SGA that only reached significance in males. In contrast, gestational diabetes was only a predictor of macrosomia exclusively in male fetuses (OR 1.67, 95% CI 1.12 to 2.49) CONCLUSIONS: There is sexual dimorphism in the risk of abnormal birth weight attributed to maternal glucose tolerance status. A closer surveillance of foetal growth might be warranted in pregnant women with abnormal glucose tolerance carrying a male fetus.

Long-lasting subclinical Addison's disease.

OBJECTIVE: To report a patient with autoimmune adrenal disease and increased ACTH with longstanding hyperpigmentation as an isolated symptom. METHODS: A 49-year-old woman requested a diagnostic work-up for hyperpigmentation initiated 9 years before, associated with increased ACTH. She was receiving replacement therapy for autoimmune hypothyroidism. Basal and dynamic tests of glucocorticoid axis, basal investigation of mineralocorticoid axis and measurement of organ specific autoantibodies were performed. RESULTS: Plasma ACTH (143 pmol/l; normal <13.2 pmol/l) and antibodies against 21-hydroxylase (115 UI/ml; normal <1) were remarkably high, thyroid peroxidase and parietal cell antibodies were positive at low titer and all additional tests were normal. CONCLUSION: Autoimmune adrenal disease can have a very long preclinical period even with high concomitant ACTH and specific antibody titers.

Body mass index has a greater impact on pregnancy outcomes than gestational hyperglycaemia.

AIMS/HYPOTHESIS: We evaluated diabetes-related pregnancy outcomes in a cohort of Spanish women in relation to their glucose tolerance status, prepregnancy BMI and other predictive variables. METHODS: The present paper is part of a prospective study to evaluate the impact of American Diabetes Association (2000) criteria in the Spanish population. A total of 9,270 pregnant women were studied and categorised as follows according to prepregnancy BMI quartiles and glucose tolerance status: (1) negative screenees; (2) false-positive screenees; (3) gestational diabetes mellitus (GDM) according to American Diabetes Association criteria only; and (4) GDM according to National Diabetes Data Group criteria (NDDG). We evaluated fetal macrosomia, Caesarean section and seven secondary outcomes as diabetes-related pregnancy outcomes. The population-attributable and population-prevented fractions of predictor variables were calculated after binary logistic regression analysis with multiple predictors. RESULTS: Both prepregnancy BMI and abnormal glucose tolerance categories were independent predictors of pregnancy outcomes. The upper quartile of BMI accounted for 23% of macrosomia, 9.4% of Caesarean section, 50% of pregnancy-induced hypertension and 17.6% of large-for-gestational-age newborns. In contrast, NDDG GDM accounted for 3.8% of macrosomia, 9.1% of pregnancy-induced hypertension and 3.4% of preterm births. CONCLUSIONS/INTERPRETATION: In terms of population impact, prepregnancy maternal BMI exhibits a much stronger influence than abnormal blood glucose tolerance on macrosomia, Caesarean section, pregnancy-induced hypertension and large-for-gestational-age newborns.