Metformin Versus Insulin for Gestational Diabetes: Cognitive and Neuropsychological Profiles of Children Aged 9 years.

OBJECTIVE: We compared cognitive profile and neuropsychological performance in 9-year-old offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). METHODS: A total of 172 children whose mothers were randomly assigned to receive either metformin or insulin for GDM were studied at the age of 9 years. Of these children, 127 were from Turku, Finland (63 metformin and 64 insulin), and 45 from Oulu, Finland (19 metformin and 26 insulin). Clinical and demographic background characteristics were obtained at enrolment, birth, and 9-year follow-up. Cognitive profiles were examined at age 9 years with the Wechsler Intelligence Scale for Children. Neuropsychological functions were examined with 2 subtests of the Developmental Neuropsychological Assessment test battery assessing comprehension of instructions and narrative memory, Trail Making Test assessing attention and with Behavioral Rating Inventory of Executive Functioning, including parent-rated and teacher-rated evaluations. Academic functioning was studied with reading fluency subtest of the Screening test for reading, writing, and calculus for first to sixth grades and information about educational support received at school reported by parents. RESULTS: The cognitive profiles, including indexes of verbal comprehension, perceptual reasoning, working memory, and processing speed, did not differ significantly between metformin-treated and insulin-treated groups. Significant differences were not found between the treatment groups in assessed neuropsychological functions, reading fluency, or received level of support at school. CONCLUSION: Cognitive and neuropsychological outcomes were similar in 9-year-old children whose mothers had either metformin or insulin treatment of GDM.

Prediction of pre-diabetes and type 2 diabetes nine years postpartum using serum metabolome in pregnant women with gestational diabetes requiring pharmacological treatment.

AIMS: We examined the association between serum metabolome in women with pharmacologically treated gestational diabetes (GDM) and measures of glucose metabolism 9 years postpartum. METHODS: Serum targeted metabolome, adiponectin, inflammatory markers, and insulin-like growth factor-binding protein-1 phosphoisoforms were analyzed at the time of diagnosing GDM. Glucose metabolism and insulin resistance were assessed at 9 years postpartum. Data from 119 subjects were available for analyses. Associations between baseline measures and future measures of glycemia were examined with univariate regressions and multivariate prediction models. This is a secondary analysis of a previous prospective trial (NCT02417090). RESULTS: Baseline serum markers were most strongly related to measures of insulin resistance at 9-years follow-up. In multivariate analyses combination of IDL cholesterol, early gestational weight gain and in oral glucose tolerance test fasting and 2-h glucose predicted development of disorders of glucose metabolism (pre-diabetes and/or type 2 diabetes) better than clinical predictors alone (ROC-AUC 0.75 vs. 0.65, p = 0.020). CONCLUSIONS: Serum metabolome in pregnancy in women with GDM is related to future glucose metabolism and insulin resistance. Compared to clinical variables alone metabolome might result in better prediction of future disorders of glucose metabolism and could facilitate personalized risk stratification for postpartum interventions and follow-up.

Metformin versus insulin for gestational diabetes: Adiposity variables and adipocytokines in offspring at age of 9 years.

AIMS: To compare body composition, visceral adiposity, adipocytokines, and low-grade inflammation markers in prepubertal offspring of mothers who were treated with metformin or insulin for gestational diabetes mellitus (GDM). METHODS: 172 offspring of 311 mothers randomized to receive metformin (n = 82) or insulin (n = 90) for GDMwere studied at 9 years of age (follow-up rate 55%). Measurements included anthropometrics, adipocytokines, markers of the low-grade inflammation, abdominal magnetic resonance imaging (MRI), magnetic liver spectrometry (MRS), and whole body dual-energy X-ray absorptiometry (DXA). RESULTS: Serum markers of low-grade inflammation, visceral adipose tissue volume, total fat percentage, and liver fat percentage were similar between the study groups. Serum adiponectin concentration was higher in children in the metformin group compared to insulin group (median 10.37 vs 9.50 µg/ml, p = 0.016). This difference between groups was observed in boys only (median 12.13 vs 7.50 µg/ml, p < 0.001). Leptin/adiponectin-ratio was lower in boys in the metformin group than in the insulin group (median 0.30 vs 0.75; p = 0.016). CONCLUSIONS: Maternal metformin treatment for GDM had no effects on adiposity, body composition, liver fat, or inflammation markers in prepubertal offspring compared to maternal insulin treatment but was associated with higher adiponectin concentration and lower leptin/adiponectin-ratio in boys.

Insulin Resistance Is Associated with an Unfavorable Serum Lipoprotein Lipid Profile in Women with Newly Diagnosed Gestational Diabetes.

BACKGROUND: Gestational diabetes (GDM) is associated with various degrees of insulin resistance-a feature related to increased risk of adverse perinatal outcomes. We aimed to determine the previously poorly investigated associations between maternal insulin resistance and serum fasting metabolome at the time of GDM diagnosis. METHODS: Serum lipoprotein and amino acid profile was analyzed in 300 subjects with newly diagnosed GDM using a validated nuclear magnetic resonance spectroscopy protocol. Associations between insulin resistance (homeostasis model assessment of insulin resistance, HOMA2-IR) and serum metabolites were examined with linear regression. RESULTS: We found insulin resistance to be associated with a distinct lipid pattern: increased concentration of VLDL triglycerides and phospholipids and total triglycerides. VLDL size was positively related and LDL and HDL sizes were inversely related to insulin resistance. Of fatty acids, increased total fatty acids, relative increase in saturated and monounsaturated fatty acids, and relative decrease in polyunsaturated and omega fatty acids were related to maternal insulin resistance. CONCLUSIONS: In newly diagnosed GDM, the association between maternal insulin resistance and serum lipoprotein profile was largely as described in type 2 diabetes. Lifestyle interventions aiming to decrease insulin resistance from early pregnancy could benefit pregnancy outcomes via more advantageous lipid metabolism.

Maternal obesity, gestational diabetes mellitus, and diet in association with neurodevelopment of 2-year-old children.

BACKGROUND: Maternal metabolic disturbances and diet may influence long-term infantile neurodevelopment. We investigated whether maternal gestational diabetes mellitus (GDM), obesity, and diet could affect the neurodevelopment of 2-year-old children. METHODS: Neurodevelopment of children (n = 243) born to mothers with overweight or obesity was assessed with the Bayley Scales of Infant and Toddler Development-Third Edition, and the Hammersmith Infant Neurological Examination. Maternal adiposity was determined by air displacement plethysmography, and GDM with an oral glucose tolerance test. Dietary assessment included diet quality and fish consumption questionnaires, and three-day food diaries, from which dietary inflammatory index (DII®) scores were computed. RESULTS: GDM was associated with weaker expressive language skills (adj.ß = -1.12, 95% CI = -2.10;-0.15), and higher maternal adiposity with weaker cognitive, language, and motor skills in children (adj.p < 0.05). Maternal good dietary quality (adj.ß = 0.87, 95% CI = 0.004;1.73) and higher fish consumption (adj.p = 0.02) were related to better expressive language skills. DII scores were not associated with children's neurodevelopment. CONCLUSIONS: Findings suggest that GDM and higher maternal adiposity may lead to weaker neurodevelopmental skills, although still within the mean normative range in this population of children. Good dietary quality and higher fish consumption during pregnancy could benefit a child's language development. IMPACT: Gestational diabetes mellitus and maternal higher adiposity may have unfavorable effects on a 2-year-old child's neurodevelopment. An overall good quality of diet and higher fish consumption during pregnancy may result in more favorable cognitive and language skills when the child is 2-year-old. Our findings reveal that women with overweight or obesity, a risk group for pregnancy complications, could benefit from dietary counseling to support their children's neurodevelopment.

Fish Oil And/Or Probiotics Intervention in Overweight/Obese Pregnant Women and Overweight Risk in 24-Month-Old Children.

OBJECTIVES: To evaluate whether a fish oil and/or probiotics intervention in pregnant women with overweight or obesity would influence the tendency of their 24-month-old children to become overweight and alter their body fat percentage. METHODS: Women (n = 439) were double-blindly randomized into 4 intervention groups: fish oil+placebo, probiotics+placebo, probiotics+fish oil, and placebo+placebo (fish oil: 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid, probiotics: Lacticaseibacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). The intervention lasted from early pregnancy until 6 months postpartum. Children's (n = 330) growth data (height, weight, head circumference), a secondary outcome of the trial, were evaluated at birth, 3, 6, 12, and 24 months of age and compared to Finnish growth charts. Body fat percentage was measured with air displacement plethysmography (24 months). Logistic regression and general linear models were used to analyze the data. RESULTS: Probiotics+placebo [weight-for-height% adj. Odds ratio (OR) = 0.36, 95% confidence interval (CI) = 0.14-0.95] and probiotics+fish oil [weight-for-age standard deviation score (SD-score) adj. OR = 0.22, 95% CI = 0.07-0.71] associated with lower overweight odds in 24-month-old children compared to placebo+placebo. Results remained essentially the same, when probiotics' main effect (combined probiotics+placebo and probiotics+fish oil) was estimated; that is, lower overweight odds (weight-for-height% adj. OR = 0.48, 95% CI = 0.25-0.95 and weight-for-age SD-score adj. OR = 0.42, 95% CI = 0.20-0.88) compared to non-probiotics. No fish oil main effect (combined fish oil+placebo and probiotics+fish oil) was seen. The intervention did not influence body fat percentage. CONCLUSIONS: The administration of probiotics solely and in combination with fish oil during pregnancy to women with overweight or obesity lowered the overweight odds of their 24-month-old children.

Comparison of glucose metabolism and anthropometry in women with previous gestational diabetes treated with metformin vs. insulin: 9-year follow-up of two randomized trials.

INTRODUCTION: The main aim was to study whether the long-term incidences of type 2 diabetes, pre-diabetes and metabolic syndrome differed between women who were treated with metformin or insulin for gestational diabetes. MATERIAL AND METHODS: This 9-year follow-up study of two open-label randomized trials compares metformin and insulin treatments of gestational diabetes. In all, 165 women, 88 previously treated with insulin and 77 treated with metformin in the index pregnancy, were included in the analyses. An oral glucose tolerance test was performed, and measures of anthropometry, glucose metabolism, serum lipids and inflammatory markers were compared between the treatment groups. Disorders of glucose metabolism (pre-diabetes and type 2 diabetes) at the 9-year follow-up was the primary outcome of this study. This study was registered at ClinicalTrials.gov: NCT02417090. RESULTS: The incidences of pre-diabetes and type 2 diabetes (40.3% vs. 46.6%, odds ratio [OR] 0.77, 95% CI 0.40-1.50, p = 0.51), type 2 diabetes (14.3% vs. 15.9%, OR 0.88, 95% CI 0.34-2.26, p = 0.94), pre-diabetes (26.0% vs. 30.7%, OR 0.79, 95% CI 0.38-1.65, p = 0.62), and metabolic syndrome (45.9% vs. 55.2%, OR 0.69, 95% CI 0.35-1.35, p = 0.31) were comparable between the metformin and insulin groups. Moreover, there were no evident differences in the individual measures of anthropometry, glucose metabolism including HOMA-insulin resistance, serum lipids or inflammatory markers between the two treatment groups. CONCLUSIONS: Treatment of gestational diabetes with metformin vs. insulin during pregnancy is unlikely to have diverging long-term effects on maternal anthropometry, glucose metabolism or serum lipids. From this perspective, both treatments may be considered in gestational diabetes.

Potential pathobionts in vaginal microbiota are affected by fish oil and/or probiotics intervention in overweight and obese pregnant women.

New means to stabilize the microbial balance during pregnancy could benefit maternal health. Our objectives were to investigate in overweight/obese pregnant women 1) the impact of long-chain polyunsaturated fatty acids (fish oil) and/or probiotics on the vaginal microbiota, 2) its relation to gestational diabetes mellitus (GDM) and 3) its interaction with vaginal active matrix metalloproteinase-8 (aMMP-8) and serum high sensitivity C-reactive protein (hsCRP) and phosphorylated insulin-like growth factor-binding protein-1 (phIGFBP-1), IGFBP-1 and aMMP-8. The women were allocated to fish oil + placebo, probiotics + placebo, fish oil + probiotics and placebo + placebo-groups, from early pregnancy onwards (fish oil: 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid; probiotics: Lacticaseibacillus rhamnosus HN001 (formerly Lactobacillus rhamnosus HN001) and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). Vaginal and serum samples (early pregnancy, n = 112; late pregnancy, n = 116), were analyzed for vaginal microbiota using 16S rRNA gene amplicon sequencing and vaginal aMMP-8 and serum hsCRP, aMMP-8, phIGFBP-1 and IGFBP-1 by immunoassays. GDM was diagnosed from a 2-h 75 g OGTT. ClinicalTrials.gov, NCT01922791. The intervention exerted effects on many low-abundant bacteria. Compared to the placebo-group, there was a lower abundance of potential pathobionts, namely Ureaplasma urealyticum in the fish oil-group, Ureaplasma, U. urealyticum and Prevotella disiens in the probiotics-group, Dialister invisus and Prevotella timonensis in the fish oil + probiotics-group. Moreover, probiotics decreased the abundance of a few potential pathobionts during pregnancy. Many bacteria were related to GDM. The vaginal aMMP-8 level correlated significantly with α-diversity and inversely with two Lactobacillus species. Dietary interventions, especially probiotics, may have beneficial effects on the vaginal microbiota during pregnancy.

A healthy dietary pattern with a low inflammatory potential reduces the risk of gestational diabetes mellitus.

PURPOSE: An optimal diet for lowering the risk of gestational diabetes mellitus (GDM) is still to be defined, but may comprise of nutrient intakes, dietary patterns, diet quality, and eating frequency. This study was designed to investigate the contribution of diet in developing GDM in a comprehensive way. METHODS: The dietary intake of overweight or obese women, a risk group for GDM (n = 351), was assessed using 3-day food diaries and diet quality questionnaires in early pregnancy. Eating frequency and nutrient intakes were calculated, and dietary patterns identified using principal component analysis. The inflammatory potential of the diet was determined by calculating the dietary inflammatory index (DII®) and energy-adjusted DII (E-DII™). GDM was diagnosed with an oral glucose tolerance test at 24-28 gestational weeks. RESULTS: Higher adherence to 'healthier dietary pattern' characterized by consumptions of vegetables and rye bread associated with a reduced risk of GDM (adjusted OR 0.27, 95% CI 0.11-0.70). Higher E-DII score, indicating pro-inflammatory diet, was associated with a 27% higher risk of GDM (adjusted OR 1.27; 95% CI 1.08-1.49) for each E-DII point. In the evaluation of nutrient intakes, total fat, saturated fatty acids (SFAs), and trans fatty acids were higher and fiber lower in women developing GDM compared to women not developing GDM (all p < 0.05). Intakes of total fat, SFAs, and trans fatty acids were also significant predictors for GDM (all p < 0.05). CONCLUSIONS: The results emphasize the importance of an overall healthy diet and limitation of foods with SFAs, and other nutrients with a high inflammatory potential in reducing the risk of GDM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922791, August 14, 2013.

Metformin versus insulin therapy for gestational diabetes: Effects on offspring anthropometrics and metabolism at the age of 9 years: A follow-up study of two open-label, randomized controlled trials.

AIMS: To compare anthropometrics, and lipid and glucose metabolism in the 9-year-old offspring of mothers treated with metformin or insulin for gestational diabetes mellitus (GDM). MATERIALS AND METHODS: This was a Finnish two-centre, 9-year follow-up study of two open-label, randomized controlled trials comparing the effects observed in the offspring of mothers who received metformin and insulin treatment for GDM. Measurements included anthropometrics, blood pressure, lipoproteins, and oral glucose tolerance tests. This study was registered with ClinicalTrials.gov, number NCT02417090. RESULTS: At the age of 9 years 172 children (55% of the original study cohort, 82 from the metformin and 90 from the insulin group) participated in the study. No differences were found between the 9-year-old offspring groups in anthropometric variables, including body mass index and waist-to-height ratio. The offspring in the metformin group had higher high-density lipoprotein (HDL) cholesterol concentrations (1.72 vs. 1.54 mmol/L; P = 0.039) but lower low-density lipoprotein cholesterol (2.39 vs. 2.58 mmol/L; P = 0.046) and apolipoprotein B concentrations (0.63 vs. 0.67 g/L; P = 0.043) than the offspring in the insulin group. The difference in HDL cholesterol concentration was found to be significant only in boys (P = 0.003). The 2-hour glucose value in the oral glucose tolerance test was 0.6-mmol/L lower in boys from the metformin group than in those from the insulin group (P = 0.015). CONCLUSIONS: Metformin treatment for GDM is associated with similar offspring growth and glucose metabolism but a more favourable lipid profile at the age of 9 years as compared to insulin treatment.

Cord serum metabolome and birth weight in patients with gestational diabetes treated with metformin, insulin, or diet alone.

INTRODUCTION: Recent research has demonstrated the benefits of metformin treatment in gestational diabetes (GDM) on short-term pregnancy outcomes (including excessive fetal growth and pre-eclampsia), but its effects on fetal metabolism remain mostly unknown. Our aim was to study the effects of metformin treatment compared with insulin or diet on the cord serum metabolome and also to assess how these metabolites are related to birth weight (BW) in pregnancies complicated by GDM. RESEARCH DESIGN AND METHODS: Cord serum samples were available from 113, 97, and 98 patients with GDM treated with diet, insulin, and metformin, respectively. A targeted metabolome was measured using nuclear magnetic resonance spectroscopy. The patients in the metformin and insulin groups had participated in a previous randomized trial (NCT01240785). RESULTS: Cord serum alanine was elevated in the metformin group (0.53 mmol/L) compared with the insulin (0.45 mmol/L, p<0.001) and the diet groups (0.46 mmol/L, p<0.0001). All other measured metabolites were similar between the groups. The triglyceride (TG)-to-phosphoglyceride ratio, average very low-density lipoprotein particle diameter, docosahexaenoic acid, omega-3 fatty acids (FAs), and ratios of omega-3 and monounsaturated FA to total FA were inversely related to BW. The omega-6-to-total-FA and omega-6-to-omega-3-FA ratios were positively related to BW. Cholesterol in very large and large high-density lipoprotein (HDL) was positively (p<0.01) associated with BW when adjusted for maternal prepregnancy body mass index, gestational weight gain, glycated hemoglobin, and mode of delivery. CONCLUSIONS: Metformin treatment in GDM leads to an increase in cord serum alanine. The possible long-term implications of elevated neonatal alanine in this context need to be evaluated in future studies. Although previous studies have shown that metformin increased maternal TG levels, the cord serum TG levels were not affected. Cord serum HDL cholesterol and several FA variables are related to the regulation of fetal growth in GDM. Moreover, these associations seem to be independent of maternal confounding factors. TRIAL REGISTRATION NUMBER: NCT01240785.

Metagenomics analysis of gut microbiota in response to diet intervention and gestational diabetes in overweight and obese women: a randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVE: Gut microbiota and diet are known to contribute to human metabolism. We investigated whether the metagenomic gut microbiota composition and function changes over pregnancy are related to gestational diabetes mellitus (GDM) and can be modified by dietary supplements, fish oil and/or probiotics. DESIGN: The gut microbiota of 270 overweight/obese women participating in a mother-infant clinical study were analysed with metagenomics approach in early (mean gestational weeks 13.9) and late (gestational weeks 35.2) pregnancy. GDM was diagnosed with a 2 hour 75 g oral glucose tolerance test. RESULTS: Unlike women with GDM, women without GDM manifested changes in relative abundance of bacterial species over the pregnancy, particularly those receiving the fish oil + probiotics combination. The specific bacterial species or function did not predict the onset of GDM nor did it differ according to GDM status, except for the higher abundance of Ruminococcus obeum in late pregnancy in the combination group in women with GDM compared with women without GDM. In the combination group, weak decreases over the pregnancy were observed in basic bacterial housekeeping functions. CONCLUSIONS: The specific gut microbiota species do not contribute to GDM in overweight/obese women. Nevertheless, the GDM status may disturb maternal gut microbiota flexibility and thus limit the capacity of women with GDM to respond to diet, as evidenced by alterations in gut microbiota observed only in women without GDM. These findings may be important when considering the metabolic complications during pregnancy, but further studies with larger populations are called for to verify the findings.

Weight gain and body composition during pregnancy: a randomised pilot trial with probiotics and/or fish oil.

We evaluated the effects of fish oil and/or probiotic supplementation in a randomised placebo-controlled intervention pilot trial on gestational weight gain (GWG) and body composition. Additionally, the influence of gestational diabetes (GDM) on GWG and body composition was assessed. We randomised 439 overweight women into intervention groups: fish oil + placebo, probiotics + placebo, fish oil + probiotics and placebo + placebo (fish oil: 1·9 g DHA and 0·22 g EPA and probiotics: Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). GDM was diagnosed with oral glucose tolerance test. Body composition was measured with air displacement plethysmography at randomisation (mean 13·9) and in late pregnancy (mean 35·2 gestational weeks). Intervention did not influence mean GWG or change in body fat mass/percentage (P > 0·17). Body composition in early pregnancy did not differ between the women who did or did not develop GDM (adjusted P > 0·23). Compared with the normoglycaemic women (n 278), women diagnosed with GDM (n 119) gained less weight (7·7 (sd 0·4) v. 9·3 (sd 0·4) kg, adjusted mean difference -1·66 (95 % CI -2·52, -0·80) and fat mass (0·4 (sd 0·4) v. 1·8 (sd 0·3) kg, adjusted mean difference -1·43 (95 % CI -2·19, -0·67) during the follow-up. In conclusion, adiposity of pregnant overweight women was not affected by supplementation with fish oil and/or probiotics, nor did it predict the development of GDM. However, adiposity was reduced in women with GDM compared with normoglycaemic women irrespective of the dietary intervention.

Serum lipids and their association with birth weight in metformin and insulin treated patients with gestational diabetes.

AIMS: To compare the effects of metformin and insulin treatment on maternal serum lipids in patients with gestational diabetes (GDM), and to analyse the associations between individual lipids and birth weight (BW). METHODS: This is a secondary analysis of a randomized trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum lipidome was measured at baseline (the time of diagnosis, mean 30 gestational weeks, gw) and at 36 gw using nuclear magnetic resonance spectroscopy. RESULTS: Total and VLDL triglycerides, and VLDL cholesterol increased from baseline to 36 gw in both treatment groups. The rise in triglycerides was greater in the metformin treated patients (p < 0.01). Baseline total and VLDL triglycerides, VLDL cholesterol, and apolipoprotein B to A-1 ratio (apoB/apoA-1) associated positively with BW, more strongly in the metformin group. Among patients in the highest baseline VLDL cholesterol or apoB/apoA-1 quartile, those treated with insulin had lower BWs than those treated with metformin (p < 0.03). CONCLUSION: Compared to insulin, metformin treatment of GDM led to higher maternal serum concentrations of triglyceride-rich lipoproteins. Especially triglycerides and cholesterol in VLDL were positively associated with BW. Women with high VLDL cholesterol or high apoB/apoA-1 may benefit from insulin treatment over metformin with respect to offspring BW.

Metformin and insulin treatment of gestational diabetes: effects on inflammatory markers and IGF-binding protein-1 - secondary analysis of a randomized controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized by disturbed glucose metabolism and activation of low-grade inflammation. We studied whether metformin treatment has favorable or unfavorable effects on inflammatory markers and insulin-like growth factor-binding protein 1 (IGFBP-1) in GDM patients compared with insulin, and whether these markers associate with major maternal or fetal clinical outcomes. METHODS: This is a secondary analysis of a previous randomized controlled trial comparing metformin (n = 110) and insulin (n = 107) treatment of GDM. Fasting serum samples were collected at the time of diagnosis (baseline, mean 30 gestational weeks [gw]) and at 36 gw. Inflammatory markers serum high-sensitivity CRP (hsCRP), interleukin-6 (IL-6), matrix metalloproteinase-8 (MMP-8) and glycoprotein acetylation (GlycA) as well as three IGFBP-1 phosphoisoform concentrations were determined. RESULTS: In the metformin and insulin groups combined, hsCRP decreased (p = 0.01), whereas IL-6 (p = 0.002), GlycA (p < 0.0001) and all IGFBP-1 phosphoisoforms (p < 0.0001) increased from baseline to 36 gw. GlycA (p = 0.02) and non-phosphorylated IGFBP-1 (p = 0.008) increased more in patients treated with metformin than those treated with insulin. Inflammatory markers did not clearly associate with pregnancy outcomes but non-phosphorylated IGFBP-1 was inversely associated with gestational weight gain. CONCLUSIONS: Metformin had beneficial effects on maternal serum IGFBP-1 concentrations compared to insulin, as increased IGFBP-1 related to lower total and late pregnancy maternal weight gain. GlycA increased more during metformin treatment compared to insulin. The significance of this observation needs to be more profoundly examined in further studies. There were no evident clinically relevant relations between inflammatory markers and pregnancy outcome measures. TRIAL REGISTRATION: The trial comparing metformin and insulin treatment was registered in ClinicalTrials.gov ( NCT01240785 ) November 3, 2010. Retrospectively registered.

Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps. METHODS AND ANALYSIS: MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD. ETHICS AND DISSEMINATION: All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.

Efficacy of Fish Oil and/or Probiotic Intervention on the Incidence of Gestational Diabetes Mellitus in an At-Risk Group of Overweight and Obese Women: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

OBJECTIVE: To assess whether the risk of gestational diabetes mellitus (GDM) may be lowered and glucose metabolism improved by daily administration of fish oil and/or probiotic supplements in overweight and obese pregnant women. RESEARCH DESIGN AND METHODS: We randomized in a double-blind manner 439 women (mean 13.9 ± 2.1 gestational weeks [gw]) into four intervention groups: fish oil + placebo, probiotics + placebo, fish oil + probiotics, and placebo + placebo. Fish oil (1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid) and probiotic supplements (Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each) were provided for daily consumption from randomization beyond delivery. Primary outcomes were the incidence of GDM diagnosed with oral glucose tolerance test targeted at 24-28 gw and the change in fasting glucose between randomization and late pregnancy (mean 35.2 ± 0.9 gw). Insulin concentration, insulin resistance HOMA2-IR index, and pregnancy outcomes were determined, as were adverse effects related to the intervention. Analyses were by intent to treat. RESULTS: No differences were found among the intervention groups in the maternal and neonatal pregnancy outcomes or side effects related to the intervention (P > 0.05). The proportion of women with GDM (94 of 377; fish oil + placebo, 23 of 96, 24.0%; probiotics + placebo, 25 of 99, 25.3%; fish oil + probiotics, 26 of 91, 28.6%; and placebo + placebo, 20 of 91, 22.0%) and the change in glucose, insulin, or HOMA2-IR (n = 364) did not differ among the intervention groups (P > 0.11 for all comparisons). CONCLUSIONS: An intervention with fish oil and/or probiotics during pregnancy seemed to be both safe and well tolerated but conferred no benefits in lowering the risk of GDM or improving glucose metabolism in overweight and obese women.

Body composition measurement by air displacement plethysmography in pregnancy: Comparison of predicted versus measured thoracic gas volume.

OBJECTIVES: Body composition measurements with air displacement plethysmography (ADP) define body volume, which must be corrected for thoracic gas volume (TGV). We hypothesized that physiologic changes owing to pregnancy could affect the accuracy of predicted TGV and introduce errors into body composition measurements. METHODS: We investigated the effect of measuring versus predicting TGV on the accuracy of body composition calculations measured with ADP in overweight and obese pregnant women. The fat and fat-free masses of 110 women were determined with ADP with predicted and measured TGV. RESULTS: Measured TGV decreased from early to late pregnancy (P = 0.0002). Compared with measured TGV, predicted TGV was 6.3% higher during early gestation and 12.6% higher during late gestation (both P ≤ 0.001). The use of predicted instead of measured TGV in body composition calculations resulted in an overestimation of fat mass by 0.8% during the early stage, and 2.6% during the late stage of pregnancy (both P ≤ 0.001). CONCLUSIONS: Measuring TGV increases the accuracy of body composition measurement by ADP in overweight and obese women, particularly during the late stage of pregnancy.

Dietary quality influences body composition in overweight and obese pregnant women.

BACKGROUND & AIMS: Excessive adiposity and gestational weight gain (GWG) have been linked with maternal and offspring morbidity. We investigated the relation of maternal diet, physical activity and GWG on body composition in overweight and obese pregnant women. METHODS: Fat mass (FM) and fat free mass (FFM) of 110 overweight and obese pregnant women were measured by air displacement plethysmography in early and late pregnancy (mean 13.5 and 35.3 gestational weeks). At the same time points, the quality of overall diet was assessed by validated index of diet quality (IDQ) questionnaire (score < 10/15 denotes poor dietary quality and score ≥ 10/15 denotes good dietary quality), nutrient intakes by 3-day food diaries, and physical activity by questionnaire. Weight gain between early and late pregnancy was compared to the gestational weight gain guidelines issued by Institute of Medicine. RESULTS: Of the women, 77% gained more weight than recommended; this was related to greater dietary fat consumption (80 ± 21 g/day vs. 67 ± 11 g/day, p = 0.010) and greater increase in FM (2.7 ± 3.0 kg vs. -1.0 ± 2.4 kg, p < 0.001) compared to women with ideal GWG. Dietary protein intake (g) correlated positively with FFM at both time points (early pregnancy: r = 0.31, p < 0.002, late pregnancy: r = 0.39, p < 0.001). Women with higher dietary quality index score had more FFM, compared to women with lower dietary quality (early pregnancy FFM: 48.8 ± 5.8 kg vs. 45.8 ± 4.7 kg, p = 0.004, late pregnancy FFM: 56.1 ± 6.4 kg vs. 53.4 ± 5.6 kg, p = 0.025). No correlations were detected between total energy intake or physical activity and FM or FFM at early or late pregnancy. CONCLUSIONS: Body composition changes from early to late pregnancy were related to the amount of weight gained and overall dietary quality during pregnancy. Higher dietary quality and protein intake were associated with greater FFM, while dietary fat intake was related to excess weight gain. Identification of these dietary determinants of body composition and weight offers new targets for dietary counseling of pregnant women and thus potential for ensuing health benefits through reduced adiposity.

Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin.

AIMS: We compared the effects of metformin and insulin treatments of gestational diabetes mellitus (GDM) on amino acid metabolism. METHODS: 217 pregnant women diagnosed with GDM were randomized to receive either metformin or insulin. 1H nuclear magnetic spectroscopy was used to determine serum concentrations of alanine, glutamine, glycine, isoleucine, leucine, valine, histidine, phenylalanine, tyrosine, glucose and lactate at the time of diagnosis and at 36 gestational weeks (gw). RESULTS: Majority of the amino acid concentrations increased from 30 to 36 gw. The rise in alanine (16% vs. 8%, p < 0.0001), isoleucine (11% vs. 5%, p = 0.035) and lactate (29% vs. 14% p = 0.015) was larger in the metformin group compared to insulin group. Baseline alanine, glycine, isoleucine, leucine, valine and tyrosine were positively related to slightly earlier delivery. Alanine at 36 gw was positively associated with birth weight and glutamine with gestational hypertension or preeclampsia. Lactate at 36 gw was not associated with any adverse outcome. CONCLUSIONS: Compared to insulin metformin caused a greater increase in serum alanine, isoleucine and lactate concentrations. Although the observed differences in the metabolic variables were relatively small and not outright concerning, additional studies and follow-up data are required to ensure the safety of metformin use in pregnancy. The trial was registered in Clinicaltrials.gov, NCT01240785; http://clinicaltrials.gov/ct2/show/NCT01240785.