Hemoglobin A1c Trajectories During Pregnancy and Adverse Outcomes in Women With Type 2 Diabetes: A Danish National Population-Based Cohort Study.

OBJECTIVE: To identify and characterize groups of pregnant women with type 2 diabetes with distinct hemoglobin A1c (HbA1c) trajectories across gestation and to examine the association with adverse obstetric and perinatal outcomes. RESEARCH DESIGN AND METHODS: This was a retrospective Danish national cohort study including all singleton pregnancies in women with type 2 diabetes, giving birth to a liveborn infant, between 2004 and 2019. HbA1c trajectories were identified using latent class linear mixed-model analysis. Associations with adverse outcomes were examined with logistic regression models. RESULTS: A total of 1,129 pregnancies were included. Three HbA1c trajectory groups were identified and named according to the glycemic control in early pregnancy (good, 59%; moderate, 32%; and poor, 9%). According to the model, all groups attained an estimated HbA1c <6.5% (48 mmol/mol) during pregnancy, with no differences between groups in the 3rd trimester. Women with poor glycemic control in early pregnancy had lower odds of having an infant with large for gestational age (LGA) birth weight (adjusted odds ratio [aOR] 0.57, 95% CI 0.40-0.83), and higher odds of having an infant with small for gestational age (SGA) birth weight (aOR 2.49, 95% CI 2.00-3.10) and congenital malformation (CM) (aOR 4.60 95% CI 3.39-6.26) compared with women with good glycemic control. There was no evidence of a difference in odds of preeclampsia, preterm birth, and caesarean section between groups. CONCLUSIONS: Women with poor glycemic control in early pregnancy have lower odds of having an infant with LGA birth weight, but higher odds of having an infant with SGA birth weight and CM.

Danish Diabetes Birth Registry 2: a study protocol of a national prospective cohort study to monitor outcomes of pregnancies of women with pre-existing diabetes.

INTRODUCTION: Despite technological developments and intensified care, pregnancies in women with pre-existing diabetes are still considered high-risk pregnancies. The rate of adverse outcomes in pregnancies affected by diabetes in Denmark is currently unknown, and there is a limited understanding of mechanisms contributing to this elevated risk. To address these gaps, the Danish Diabetes Birth Registry 2 (DDBR2) was established. The aims of this registry are to evaluate maternal and fetal-neonatal outcomes based on 5 years cohort data, and to identify pathophysiology and risk factors associated with short-term and long-term outcomes of pregnancies in women with pre-existing diabetes. METHODS AND ANALYSIS: The DDBR2 registry is a nationwide 5-year prospective cohort with an inclusion period from February 2023 to February 2028 of pregnancies in women with all types of pre-existing diabetes and includes registry, clinical and questionnaire data and biological samples of mother-partner-child trios. Eligible families (parents age ≥18 years and sufficient proficiency in Danish or English) can participate by either (1) basic level data obtained from medical records (mother and child) and questionnaires (partner) or (2) basic level data and additional data which includes questionnaires (mother and partner) and blood samples (all). The primary maternal outcome is Hemoglobin A1c (HbA1c) levels at the end of pregnancy and the primary offspring endpoint is the birth weight SD score. The DDBR2 registry will be complemented by genetic, epigenetic and metabolomic data as well as a biobank for future research, and the cohort will be followed through data from national databases to illuminate possible mechanisms that link maternal diabetes and other parental factors to a possible increased risk of adverse long-term child outcomes. ETHICS AND DISSEMINATION: Approval from the Ethical Committee is obtained (S-20220039). Findings will be sought published in international scientific journals and shared among the participating hospitals and policymakers. TRIAL REGISTRATION NUMBER: NCT05678543.

Body mass index z-scores in the first 2 years of life were associated with adverse metabolic and anthropometric outcomes at 3 years of age.

AIM: We investigated associations between body mass index (BMI) z-scores for children aged 0-2 years and the BMI z-scores, body fat percentage and metabolic risk factors at 3 years of age. METHODS: This was a secondary analysis of the Lifestyle in Pregnancy and Offspring randomised controlled trial, carried out at two university hospitals in Denmark. It comprised 149 mothers with BMI ≥30 kg/m2 who did or did not receive a lifestyle intervention during pregnancy and a reference group of 97 mothers with normal-weight, with follow-up of their 3-year-old offspring. The children in these three groups were pooled for the data analyses, due to similar characteristics between groups. The BMI z-scores were calculated at 5 weeks, 5 months and 1, 2 and 3 years, using Danish reference groups. Their anthropometrics and metabolic outcomes were examined at 3 years of age. RESULTS: BMI z-scores at 5 months to 2 years were associated with BMI z-scores and body fat percentage at 3 years of age and BMI z-scores were not associated with metabolic risk factors at 3 years. CONCLUSION: BMI z-scores from 5 weeks of age were associated with adverse anthropometric outcomes but not with metabolic risk factors at 3 years of age.

Regional divergence and time trends in the prevalence of gestational diabetes mellitus: a national Danish cohort study.

AIMS: To evaluate the prevalence and time trends of gestational diabetes mellitus (GDM) across the five regions of Denmark with uniform national guidelines for screening and diagnosing GDM. METHODS: This register-based national cohort study included 287,684 births from 2013 to 2017. Trends in GDM prevalence over time and differences between the five regions were evaluated. Crude and adjusted odd ratios (ORs) for GDM were calculated including potential confounding clinical risk factors as age, BMI, educational level, marital status, parity, country of origin and assisted reproduction. RESULTS: From 2013 to 2017, GDM prevalence in Denmark increased by 7% per year (OR 1.07, 95% CI 1.06-1.09, P < 0.001). GDM prevalence varied considerably between regions and ranged from 3.0 to 5.9% in 2017, corresponding to a maximal regional difference of 97%. In crude analyses, the risk of GDM in 2017 was significantly different in four of five regions compared to the remaining regions (OR ranging from 0.60 to 1.55), and these differences persisted after adjusting for confounding clinical risk factors (adjusted OR: 0.59-1.45). CONCLUSION: The prevalence of GDM increased over time in all Danish regions with substantial regional divergence. Up to a 97%, difference in GDM prevalence was observed between Danish regions, which was not explained by available clinical risk factors. This occurred despite national guidelines and raises the question of whether regional variations in screening efficacy, diagnostic procedures or inequality in clinical health care access may explain the observed differences.

Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes.

OBJECTIVE: Pregnant women with type-1 diabetes have an increased risk of preeclampsia with kidney injury and cardiovascular complications. Urine excretion of plasmin and soluble membrane attack complex (sC5b-9) is elevated in severe preeclampsia. We hypothesized a coupling between these events and that active plasmin promotes intratubular complement activation and membrane deposition. METHODS: Stored urine and plasma samples from pregnant women with type-1 diabetes (n = 88) collected at gestational weeks 12, 20, 28, 32, 36 and 38 were used. In the cohort, 14 women developed preeclampsia and were compared with 16 nonpreeclampsia controls. RESULTS: Urine C3dg and sC5b-9-associated C9 neoantigen/creatinine ratios increased and were significantly higher in women who developed preeclampsia. Plasma concentrations did not change with gestation. Urine plasmin(ogen) correlated to urine C3dg (r = 0.51, P < 0.001) and C9 neoantigen (r = 0.68, P < 0.001); urine albumin correlated to C3dg (r = 0.44, P < 0.001) and C9 (r = 0.59, P < 0.001). Membrane-associated C3dg and C9 neoantigen was detected in urinary extracellular vesicles from patients but not controls at 36 weeks. Receiver operating characteristic curves showed that C3dg and C9 neoantigen were inferior to albumin as predictive biomarkers for preeclampsia. CONCLUSION: In preeclampsia, urinary excretion of activated complement relates significantly to albuminuria and to plasmin(ogen) but not to activation in plasma. Intratubular complement activation in preeclampsia is a postfiltration event tightly related to proteinuria/plasminogenuria and a possible mechanistic link to cellular damage and kidney injury.

Roux-en-Y Gastric Bypass Increases Glycemic Excursions During Pregnancy and Postpartum: A Prospective Cohort Study.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) and pregnancy markedly alter glucose metabolism, but evidence on glucose metabolism in pregnancy after RYGB is limited. Thus, the aims of the Bariatric Surgery and Consequences for Mother and Baby in Pregnancy study were to investigate interstitial glucose (IG) profiles during pregnancy, risk factors associated with hypoglycemia, and the association between fetal growth and hypoglycemia in pregnant women previously treated with RYGB, compared with control participants. RESEARCH DESIGN AND METHODS: Twenty-three pregnant women with RYGB and 23 BMI- and parity-matched pregnant women (control group) were prospectively studied with continuous glucose monitoring in their first, second, and third trimesters, and 4 weeks postpartum. Time in range (TIR) was defined as time with an IG level of 3.5-7.8 mmol/L. RESULTS: Women with RYGB were 4 years (interquartile range [IQR] 0-7) older than control participants. Pregnancies occurred 30 months (IQR 15-98) after RYGB, which induced a reduction in BMI from 45 kg/m2 (IQR 42-54) presurgery to 32 kg/m2 (IQR 27-39) prepregnancy. Women with RYGB spent decreased TIR (87.3-89.5% vs. 93.3-96.1%; P < 0.01) owing to an approximately twofold increased time above range and increased time below range (TBR) throughout pregnancy and postpartum compared with control participants. Women with increased TBR had a longer surgery-to-conception interval, lower nadir weight, and greater weight loss after RYGB. Finally, women giving birth to small-for-gestational age neonates experienced slightly increased TBR. CONCLUSIONS: Women with RYGB were more exposed to hypoglycemia and hyperglycemia during pregnancy compared with control participants. Further research should investigate whether hypoglycemia during pregnancy in women with RYGB is associated with decreased fetal growth.

Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study).

BACKGROUND: Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease. METHODS: Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013. SETTING: Exploratory sub-study using data from the nationwide EPICOM study. PARTICIPANTS: Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code. MAIN OUTCOME MEASURES: This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples. RESULTS: We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM. Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX). CONCLUSIONS: These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.

Vitamin D3 Supplementation in Overweight/Obese Pregnant Women: No Effects on the Maternal or Fetal Lipid Profile and Body Fat Distribution-A Secondary Analysis of the Multicentric, Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

Vitamin D deficiency is a common finding in overweight/obese pregnant women and is associated with increased risk for adverse pregnancy outcome. Both maternal vitamin D deficiency and maternal obesity contribute to metabolic derangements in pregnancy. We aimed to assess the effects of vitamin D3 supplementation in pregnancy versus placebo on maternal and fetal lipids. Main inclusion criteria were: women <20 weeks' gestation, BMI ≥ 29 kg/m2. Eligible women (n = 154) were randomized to receive vitamin D3 (1600 IU/day) or placebo. Assessments were performed <20, 24−28 and 35−37 weeks and at birth. Linear regression models were used to assess effects of vitamin D on maternal and cord blood lipids. In the vitamin D group significantly higher total 25-OHD and 25-OHD3 levels were found in maternal and cord blood compared with placebo. Adjusted regression models did not reveal any differences in triglycerides, LDL-C, HDL-C, free fatty acids, ketone bodies or leptin between groups. Neonatal sum of skinfolds was comparable between the two groups, but correlated positively with cord blood 25-OH-D3 (r = 0.34, p = 0.012). Vitamin D supplementation in pregnancy increases maternal and cord blood vitamin D significantly resulting in high rates of vitamin D sufficiency. Maternal and cord blood lipid parameters were unaffected by Vitamin D3 supplementation.

Hypoglycemia in Pregnancies Following Gastric Bypass-a Systematic Review and Meta-analysis.

The aims of this systematic review were to identify the prevalence of hypoglycemia among pregnant women treated with gastric bypass, and risk factors of hypoglycemic events in pregnancy. We searched MEDLINE, EMBASE, Cochrane, and Scopus databases from inception to April 6, 2021. Six studies investigating glucose metabolism in pregnancy following gastric bypass were included (n = 330). As assessed by the oral glucose tolerance test and continuous glucose monitoring, 57.6% (95% CI [40.1, 75.1]) of women with gastric bypass were exposed to hypoglycemia during pregnancy. No studies performed the mixed meal test, and no studies reported on risk factors associated with hypoglycemia. Further studies are required to determine the magnitude of hypoglycemia in these women's everyday-life using continuous glucose monitoring and mixed meal test.

The impact of anti-hypertensive treatment on foetal growth and haemodynamics in pregnant women with pre-existing diabetes - An explorative study.

OBJECTIVES: To explore the impact of anti-hypertensive treatment of pregnancy-induced hypertension on foetal growth and hemodynamics in women with pre-existing diabetes. METHODS: A prospective cohort study of 247 consecutive pregnant women with pre-existing diabetes (152 type 1 diabetes; 95 type 2 diabetes), where tight anti-hypertensive treatment was initiated and intensified (mainly with methyldopa) when office blood pressure (BP) ≥135/85 mmHg and home BP ≥130/80 mmHg. Foetal growth was assessed by ultrasound at 27, 33 and 36 weeks and foetal hemodynamics were assessed by ultrasound Doppler before and 1-2 weeks after initiation of anti-hypertensive treatment. RESULTS: In 215 initially normotensive women, anti-hypertensive treatment for pregnancy-induced hypertensive disorders was initiated in 42 (20%), whilst 173 were left untreated. Chronic hypertension was present in 32 (13%). Anti-hypertensive treatment for pregnancy-induced hypertensive disorders was not associated with foetal growth deviation (linear mixed model, p = 0.681). At 27 weeks, mainly before initiation of anti-hypertensive treatment, the prevalence of small foetuses with an estimated foetal weight <10th percentile was 12% in women initiating anti-hypertensive treatment compared with 4% in untreated women (p = 0.054). These numbers were close to the prevalence of birth weight ≤10th percentile (small for gestational age (SGA)) (17% vs. 4%, p = 0.003). Pulsatility index in the umbilical and middle cerebral artery remained stable after the onset of anti-hypertensive treatment in a representative subgroup (n = 12, p = 0.941 and p = 0.799, respectively). CONCLUSION: There is no clear indication that antihypertensive treatment causes harm in this particular at-high-risk group of pregnant women with diabetes, such that a larger well-designed study to determine the value of tight antihypertensive control would be worthwhile.

Apolipoprotein D and transthyretin are reduced in female adolescent offspring of women with type 1 diabetes: The EPICOM study.

AIMS: Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex-specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and that these alterations are associated with lipid profile and indices of insulin sensitivity and secretion. METHODS: A prospective nationwide follow-up study (EPICOM) in a Danish population. Blood samples were assessed from offspring of women with T1D (index offspring, n = 267, 13-20 years), and matched control offspring (n = 290). Serum proteins were analysed using a 25-plex cardio-metabolic targeted proteomics assay, which includes 12 apolipoproteins and 13 transport and inflammatory proteins. RESULTS: Apolipoprotein D (ApoD) and transthyretin (TTR) were reduced in index females as compared to female controls (-8.1%, p < 0.001 and -6.1%, p = 0.006 respectively), but not in index males (2.2%, p = 0.476 and -2.4%, p = 0.731 respectively). Sex-dependent inverse associations between exposure to maternal T1D in utero and ApoD and TTR were significant after adjusting for age, BMI-SDS and Tanner stage (OR = 0.252 [95% CI 0.085, 0.745], p = 0.013 and OR = 0.149 [95% CI 0.040, 0.553], p = 0.004). ApoD correlated to indices of insulin sensitivity and secretion in a similar sex-specific pattern in crude and adjusted analyses. CONCLUSIONS: Low ApoD may be regarded as an early risk marker of metabolic syndrome. A possible link between ApoD and cardiovascular disease needs further investigation.

GAD65 autoantibodies and glucose tolerance in offspring born to women with and without type 1 diabetes (The EPICOM study).

The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab-positive if diagnosed with diabetes or pre-diabetes. This EPICOM study is a prospective follow-up study focussing on pregnancies complicated by maternal T1D. The EPICOM study includes offspring (n = 278) born to mothers with pre-gestational T1D between 1993 and 1999 and matched un-exposed controls (n = 303). Age at the time of follow-up was 16.7 years (13.0-20.4 years). GAD65aab was measured using the Glutamic Acid Decarboxylase Autoantibody RIA kit from RSR© . An Oral Glucose Tolerance Test (OGTT) was performed, and abnormal glucose tolerance was defined as having either diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). GAD65aab could be measured in 561 participants. Of these, 17 (3%) were positive for GAD65aab (≥25 U/ml) with 11 (4%) offspring being born to women with T1D and 6 (2%) controls. The difference in GAD65aab status was not statistically significant (p = .2). One was diagnosed with GAD65aab-negative diabetes during the study, 18 were diagnosed with IFG, and 44 with IGT. Overall, more were GAD65aab-positive if diagnosed with abnormal glucose tolerance (p = .03). We found no association between GAD65aab status and HOMA-IR, HOMA-IS, birthweight, mode of delivery or maternal BMI prior to pregnancy. Our study found no overall difference in GAD65 status between offspring born to women with T1D and their matched controls. However, among the participants diagnosed with pre-diabetes more were GAD65-positive.

Unchanged Prevalence of Preeclampsia After Implementation of Prophylactic Aspirin for All Pregnant Women With Preexisting Diabetes: A Prospective Cohort Study.

OBJECTIVE: To evaluate the prevalence of preeclampsia after implementation of prophylactic aspirin for all pregnant women with preexisting diabetes compared with the prevalence in a previous risk-based prophylaxis. RESEARCH DESIGN AND METHODS: A prospective observational cohort study of 410 consecutive pregnant women with preexisting diabetes categorized according to aspirin prophylaxis strategy, with the prevalence of preeclampsia as primary outcome. In total, 207 women were included after implementation of prophylactic aspirin for all pregnant women with preexisting diabetes in February 2018 (all-cohort). The 203 women included before this date, where aspirin prophylaxis was risk based and only prescribed to selected women (selected-cohort), were studied for comparison. RESULTS: Aspirin was prescribed at ∼10 gestational weeks for 88% (all-cohort) compared with 25% (selected-cohort). HbA1c, parity, chronic hypertension, home blood pressure, microalbuminuria/diabetic nephropathy, and smoking were similar in the two cohorts in early pregnancy. In the all-cohort, fewer women had type 2 diabetes (32% vs. 42%, respectively; P = 0.04) and BMI tended to be lower (P = 0.05). The prevalence of preeclampsia was similar (12% vs. 11%, P = 0.69) in the two cohorts, and this was also the case with stratification for diabetes type. Prevalence of preterm delivery <37 weeks (23% vs. 27%, P = 0.30), preterm preeclampsia (7% vs. 7%, P = 0.96), and infants large (40% vs. 32%, P = 0.07) and small (7% vs. 6%, P = 0.88) for gestational age was similar in the two cohorts. CONCLUSIONS: Implementation of prophylactic aspirin for all pregnant women with diabetes did not reduce the prevalence of preeclampsia compared with the previous risk-based prophylaxis in this cohort study.

The importance of maternal insulin resistance throughout pregnancy on neonatal adiposity.

BACKGROUND: Although previous studies evaluated the association of maternal health parameters with neonatal adiposity, little is known regarding the complexity of the relationships among different maternal health parameters throughout pregnancy and its impact on neonatal adiposity. OBJECTIVES: To evaluate the direct and indirect associations between maternal insulin resistance during pregnancy, in women with obesity, and neonatal adiposity. In addition, associations between maternal fasting glucose, triglycerides (TG), non-esterified fatty acids (NEFA), and neonatal adiposity were also assessed. METHODS: This is a longitudinal, secondary analysis of the DALI study, an international project conducted in nine European countries with pregnant women with obesity. Maternal insulin resistance (HOMA-IR), fasting glucose, TG, and NEFA were measured three times during pregnancy (<20, 24-28, and 35-37 weeks of gestation). Offspring neonatal adiposity was estimated by the sum of four skinfolds. Structural equation modelling was conducted to evaluate the direct and indirect relationships among the variables of interest. RESULTS: Data on 657 mother-infant pairs (50.7% boys) were analysed. Neonatal boys exhibited lower mean sum of skinfolds compared to girls (20.3 mm, 95% CI 19.7, 21.0 vs 21.5 mm, 95% CI 20.8, 22.2). In boys, maternal HOMA-IR at <20 weeks was directly associated with neonatal adiposity (ß = 0.35 mm, 95% CI 0.01, 0.70). In girls, maternal HOMA-IR at 24-28 weeks was only indirectly associated with neonatal adiposity, which implies that this association was mediated via maternal HOMA-IR, glucose, triglycerides, and NEFA during pregnancy (ß = 0.26 mm, 95% CI 0.08, 0.44). CONCLUSIONS: The timing of the role of maternal insulin resistance on neonatal adiposity depends on fetal sex. Although the association was time-dependent, maternal insulin resistance was associated with neonatal adiposity in both sexes.

Prevalence of anxiety and depression symptoms in pregnant women with type 2 diabetes and the impact on glycaemic control.

AIMS: To study the prevalence of anxiety and depression symptoms in pregnant women with type 2 diabetes compared with pregnant women without diabetes. Secondly, to explore whether anxiety and/or depression symptoms in early pregnancy have an impact on glycaemic control and gestational weight gain. METHODS: A prospective cohort study of 90 consecutive singleton pregnant women with type 2 diabetes and 88 singleton pregnant women without diabetes. All women completed the Hospital Anxiety and Depression Scale questionnaire in early and late pregnancy. A score ≥8 in the anxiety or the depression scale was used to define anxiety and/or depression symptoms. RESULTS: Anxiety and/or depression symptoms were present in 40% of women with type 2 diabetes and 7% of women without diabetes in early pregnancy (Relative Risk = 5.87 (95% Confidence Interval: 2.60-13.22)). The figures were similar in late pregnancy. In women with type 2 diabetes and anxiety and/or depression symptoms in early pregnancy, HbA1c (mean ± SD) was 52 ± 14 vs. 49 ± 11 mmol/mol (6.9 ± 1.2 vs. 6.6 ± 1.0%), p = 0.31 in early pregnancy and 43 ± 8 vs. 40 ± 4 mmol/mol (6.1 ± 0.7 vs. 5.8 ± 0.4%), p = 0.04 in late pregnancy compared with women without symptoms. Gestational weight gain was similar in both groups. CONCLUSIONS: In women with type 2 diabetes, 40% had anxiety and/or depression symptoms in early pregnancy. Women with these symptoms obtained less optimal glycaemic control in late pregnancy but similar gestational weight gain as the remaining women.

Impact of Lean Body Mass and Insulin Sensitivity on the IGF-1-Bone Mass Axis in Adolescence: the EPICOM Study.

CONTEXT: Insulin-like growth factor-1 (IGF-1) is involved in the growth of muscle and bone mass and contributes to glucose homeostasis. The offspring of mothers with diabetes during pregnancy have an increased risk of insulin resistance (IR). OBJECTIVE: We hypothesized that bone mass was decreased in the offspring of mothers with type 1 diabetes (T1D), and that the IGF-1-bone mass relationship would be negatively influenced by IR. DESIGN: Data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) study performed from 2012 to 2013 were included. SETTING: This work is a follow-up study of a nationwide register study. PATIENTS: A total of 278 adolescent index offspring whose mothers had T1D and 303 matched controls were studied. MAIN OUTCOME MEASURE: Bone mineral content (BMC) determined by a dual-energy x-ray absorptiometry scan and the interaction with IGF-1 and insulin sensitivity were measured. RESULTS: There was no difference in BMC, bone mineral density, height (SD score [SDS]), or BMC/height between index and control offspring. IGF-1 (SDS) did not differ between the groups but insulin-like growth factor-binding protein 3 (SDS) was higher in index boys compared to controls (B = .31 [95% CI, 0.06-0.57], P = .02). The statistical path analysis showed that IGF-1 predicted BMC/height (B = .24 [95% CI, 0.02-0.45], P = .03), but lean mass was a mediator of this. IGF-1 and the homeostatic model assessment of IR were positively associated (B = .75 [95% CI, 0.37-1.12], P < .001). There was no moderating effect of the interaction between IR and IGF-1 on lean mass in the entire cohort (B = .005 [95% CI, -0.03 to 0.04], P = .81) or when analyzing index cases and controls separately. CONCLUSION: We found that lean mass was an intermediary factor in the IGF-1-bone mass relationship in a large cohort of adolescents, and this relationship was not moderated by IR.

Performance of early pregnancy HbA1c for predicting gestational diabetes mellitus and adverse pregnancy outcomes in obese European women.

AIMS: To investigate the performance of early pregnancy HbA1c for predicting gestational diabetes mellitus (GDM) and adverse pregnancy outcomes in obese women. METHODS: Post hoc analysis using data from the Vitamin D And Lifestyle Intervention for GDM prevention trials conducted across 9 European countries (2012-2014). Pregnant women (BMI ≥ 29 kg/m2) underwent a baseline HbA1c and oral glucose tolerance tests at < 20 weeks, 24-28 weeks, and 35-37 weeks. Women with GDM were referred for treatment. RESULTS: Among the 869 women tested, the prevalence of GDM was 25.9% before 20 weeks, with a further 8.6% at 24-28 weeks. The areas under the curves for HbA1c at the two time points were 0.55 (0.50-0.59) and 0.54 (0.47-0.61), respectively. An early HbA1c ≥ 5.7% (39 mmol/mol) (N = 111) showed low sensitivity (18.2%) with 89.1% specificity for GDM before 20 weeks, at 24-28 weeks (sensitivity of 8.0% and specificity of 88.6% after excluding early GDM), and throughout gestation (sensitivity of 15.9% and specificity of 89.4%). The ≥ 5.7% (39 mmol/mol) threshold was significantly associated with concurrent GDM before 20 weeks (adjusted OR (aOR) 2.77(1.39-5.51)) and throughout gestation (aOR 1.72 (1.02-2.89)), but not adverse pregnancy outcomes. CONCLUSIONS: Early pregnancy HbA1c is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women.

Temporal relationships between maternal metabolic parameters with neonatal adiposity in women with obesity differ by neonatal sex: Secondary analysis of the DALI study.

OBJECTIVES: To investigate the importance of time in pregnancy and neonatal sex on the association between maternal metabolic parameters and neonatal sum of skinfolds. METHODS: This was a longitudinal, secondary analysis of the vitamin D and lifestyle intervention for gestational diabetes mellitus study, conducted in nine European countries during 2012 to 2015. Pregnant women with a pre-pregnancy body mass index (BMI) of ≥29 kg/m2 were invited to participate. We measured 14 maternal metabolic parameters at three times during pregnancy: <20 weeks, 24 to 28 weeks, and 35 to 37 weeks of gestation. The sum of four skinfolds assessed within 2 days after birth was the measure of neonatal adiposity. RESULTS: In total, 458 mother-infant pairs (50.2% female infants) were included. Insulin resistance (fasting insulin and HOMA-index of insulin resistance) in early pregnancy was an important predictor for boys' sum of skinfolds, in addition to fasting glucose and maternal adiposity (leptin, BMI and neck circumference) throughout pregnancy. In girls, maternal lipids (triglycerides and fatty acids) in the first half of pregnancy were important predictors of sum of skinfolds, as well as fasting glucose in the second half of pregnancy. CONCLUSIONS: Associations between maternal metabolic parameters and neonatal adiposity vary between different periods during pregnancy. This time-dependency is different between sexes, suggesting different growth strategies.

Vitamin D levels were significantly higher during and after lifestyle intervention in pregnancy: A randomized controlled trial.

INTRODUCTION: Vitamin D deficiency is common in pregnancy, especially in obese women. Lifestyle intervention could potentially result in higher levels of vitamin D. We therefore aimed to study the effect of lifestyle intervention during pregnancy on serum levels of 25-hydroxyvitamin D (25(OH)D). MATERIAL AND METHODS: A total of 360 obese women were randomized before gestational age 14 weeks to lifestyle intervention (diet and exercise) or routine clinical follow up (controls). Clinical outcomes and levels of 25(OH)D were determined three times: At gestational age 12-15 weeks (baseline), gestational age 28-30 weeks and 6 months postpartum. RESULTS: A total of 304 (84%) women completed the intervention study and 238 (66%) attended postpartum follow up. Vitamin D levels were similar in the two groups at baseline. At gestational age 28-30 weeks and 6 months postpartum, 25(OH)D levels were significantly higher in the intervention group than in controls (75.6 vs 66.8 nmol/L, P = 0.009) and (54.8 vs 43.1 nmol/L, P = 0.013), respectively. Concurrently, vitamin D deficiency (25-hydroxyvitamin D <50 nmol/L) was less frequent in the intervention group than in controls: 15 vs 25% (P = 0.038) at gestational age 28-30 and 45 vs 63% (P = 0.011) 6 months postpartum, respectively. CONCLUSIONS: Lifestyle intervention during pregnancy was associated with significantly increased vitamin D levels in late pregnancy and postpartum compared with controls.