Mean Glucose and Gestational Weight Gain as Predictors of Large-for-Gestational-Age Infants in Pregnant Women with Type 1 Diabetes Using Continuous Glucose Monitoring.

Aims/hypothesis: To compare glycemic metrics during pregnancy between women with type 1 diabetes (T1D) delivering large-for-gestational-age (LGA) and appropriate-for-gestational-age (AGA) infants, and to identify predictors of LGA infants. Materials and Methods: A cohort study including 111 women with T1D using intermittently scanned continuous glucose monitoring from conception until delivery. Average sensor-derived metrics: mean glucose, time in range in pregnancy (TIRp), time above range in pregnancy, time below range in pregnancy, and coefficient of variation throughout pregnancy and in pregnancy intervals of 0-10, 11-21, 22-33, and 34-37 weeks were compared between women delivering LGA and AGA infants. Predictors of LGA infants were sought for. Infant growth was followed until 3 months postdelivery. Results: In total, 53% (n = 59) delivered LGA infants. Mean glucose decreased during pregnancy in both groups, with women delivering LGA infants having a 0.4 mmol/L higher mean glucose from 11-33 weeks (P = 0.01) compared with women delivering AGA infants. Mean TIRp >70% was obtained from 34 weeks in women delivering LGA infants and from 22-33 weeks in women delivering AGA infants. Independent predictors for delivering LGA infants were mean glucose throughout pregnancy and gestational weight gain. At 3 months postdelivery, infant weight was higher in infants born LGA compared with infants born AGA (6360 g ± 784 and 5988 ± 894, P = 0.04). Conclusions/interpretations: Women with T1D delivering LGA infants achieved glycemic targets later than women delivering AGA infants. Mean glucose and gestational weight gain were independent predictors for delivering LGA infants. Infants born LGA remained larger postdelivery compared with infants born AGA.

The effect of exercise training and motivational counselling on physical activity behaviour and psychosocial factors in pregnant women: secondary analyses of the FitMum randomised controlled trial investigating prenatal physical activity.

BACKGROUND: A physically active lifestyle is beneficial during pregnancy. However, little is known about physical activity (PA) behaviour and psychosocial factors in women during and after pregnancy. This study examined exercise behavioural regulation, exercise self-efficacy, health-related quality of life, sickness absence and musculoskeletal pain in pregnant women offered either structured supervised exercise training, motivational counselling on PA, or standard prenatal care in the FitMum randomised controlled trial. METHODS: Two hundred and eighteen healthy inactive pregnant women were randomised to structured supervised exercise training (n = 87), motivational counselling on PA (n = 86) or standard prenatal care (n = 45). The women answered the Behavioural Regulation in Exercise Questionnaire-2 (BREQ-2), the Pregnancy Exercise Self-Efficacy Scale (P-ESES-DK) and the Short Form 36 Health Survey Questionnaire (SF-36) at baseline (gestational age (GA) of max 15 weeks), GA 28 and 34 weeks, and one year after delivery. Sickness absence and low back and/or pelvic girdle pain were likewise reported in questionnaires at baseline and GA 28 weeks. RESULTS: Participants offered structured supervised exercise training or motivational counselling on PA had higher autonomous motivation for exercise during pregnancy compared with participants receiving standard prenatal care (e.g., difference in intrinsic regulation at GA 28 weeks, structured supervised exercise training vs. standard prenatal care: mean difference in score 0.39 [0.16; 0.64], p < 0.001). Participants offered structured supervised exercise training also had higher exercise self-efficacy during pregnancy (e.g., GA 28 weeks, structured supervised exercise training vs. standard prenatal care: mean difference in score 6.97 [2.05; 12.02], p = 0.005). All participants reported high exercise self-efficacy at baseline and medium exercise self-efficacy during pregnancy and one year after delivery. No differences were found between groups in health-related quality of life, sickness absence or low back and/or pelvic girdle pain during pregnancy. No group differences were found one year after delivery. CONCLUSION: Structured supervised exercise training and motivational counselling on PA had important effects on autonomous exercise motivation during pregnancy. Exercise self-efficacy was also increased with structured supervised exercise training compared to standard prenatal care. No group differences in health-related quality of life, sickness absence, or pain were found during and after pregnancy. No effects were found one year post-delivery after intervention cessation. TRIAL REGISTRATION: The study was approved by the Danish National Committee on Health Research Ethics (#H-18011067) and the Danish Data Protection Agency (#P-2019-512). The study adheres to the principles of the Helsinki declaration. Written informed consent was obtained at inclusion.

Cardiovascular autonomic nervous function in children conceived by assisted reproductive technology with frozen or fresh embryo transfer.

As a result of epigenetic changes, children conceived by assisted reproduction may be at risk of premature cardiovascular aging with notably increased blood pressures. Their cardiovascular autonomic nervous function is unknown. Therefore, this study investigated the cardiovascular autonomic nervous function in 8-12-yr-old children (51% girls) conceived naturally (n = 33) or by assisted reproduction with frozen (n = 34) or fresh (n = 38) embryo transfer by evaluating heart rate variability, during rest; from provocation maneuvers; and from baroreflex function. Heart rate and blood pressure response to provocation maneuvers and baroreflex function were comparable between children conceived naturally or by assisted reproduction. The mean RR-interval and high-frequency component of heart rate variability were lower in children conceived by assisted reproduction than in children conceived naturally. Children conceived by fresh embryo transfer had ∼17% lower heart rate-corrected standard deviation of normal-to-normal R-R intervals; ∼22% lower heart rate-corrected square root of the mean of the squared difference between successive R-R intervals; and ∼37% higher low-frequency/high-frequency ratio than naturally conceived children. Children conceived by assisted reproduction still had lower heart rate variability and vagal modulation than naturally conceived children after adjustment for confounders. Thus, these results raise the possibility of sympathetic predominance in children conceived by assisted reproduction. Therefore, it is important to reproduce these results in larger and older cohorts as sympathetic predominance relates with cardiovascular and metabolic diseases.NEW & NOTEWORTHY We observed that children conceived by assisted reproductive technology (both frozen and fresh embryo transfer) had lowered heart rate variability during rest as compared with children conceived naturally. During physiological stress maneuvers, however, the cardiovascular autonomic nervous regulation was comparable between children conceived by assisted reproductive technologies and naturally. Our findings highlight the potential that lowered heart rate variability during rest in children conceived by assisted reproductive technologies may precede premature hypertension.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

AIM: We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). MATERIALS AND METHODS: Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. RESULTS: In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. CONCLUSIONS: Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

Faster-acting insulin aspart versus insulin aspart in the treatment of type 1 or type 2 diabetes during pregnancy and post-delivery (CopenFast): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Faster-acting insulin aspart (faster aspart) is considered safe for use during pregnancy and breastfeeding but has not been evaluated in this population. We aimed to evaluate the effect of faster aspart versus insulin aspart on fetal growth, in women with type 1 or type 2 diabetes during pregnancy and post-delivery. METHODS: This open-label, single-centre, superiority trial was conducted at Rigshospitalet, Copenhagen, Denmark. Participants aged 18 years or older with type 1 or type 2 diabetes were stratified by diabetes type and insulin treatment modality (multiple daily injections or insulin pump), randomly assigned 1:1 to faster aspart or insulin aspart, from 8 weeks and 0 days (8+0) of gestation to 13+6 weeks of gestation, and followed up until 3 months post-delivery. Primary outcome was infant birthweight SD score. Secondary outcomes included HbA1c as well as maternal and fetal outcomes in all participants during the trial. This trial is registered with ClinicalTrials.gov, NCT03770767. FINDINGS: Between Nov 11, 2019 and May 10, 2022, 109 participants were included in the faster aspart group and 107 in the insulin aspart group. Primary outcome data were available in 203 (94%) of 216 participants, and no participants discontinued treatment during the trial. Mean birthweight SD score was 1·0 (SD 1·4) in the faster aspart group versus 1·2 (1·3) in the insulin aspart group; estimated treatment difference -0·22 [-0·58 to 0·14]; p=0·23. At 33 weeks of gestation, mean HbA1c was 42 mmol/mol (SD 6 mmol/mol; 6·0% [SD 0·9%]) versus 43 mmol/mol (SD 7 mmol/mol; 6·1% [SD 1·2%]); estimated treatment difference -1·01 (-2·86 to 0·83), p=0·28. No additional safety issues were observed with faster aspart compared with insulin aspart. INTERPRETATION: Treatment with faster aspart resulted in similar fetal growth and HbA1c, relative to insulin aspart, in women with type 1 or type 2 diabetes. Faster aspart can be used in women with type 1 or type 2 diabetes during pregnancy and post-delivery with no additional safety issues. FUNDING: Novo Nordisk. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Counselling on physical activity in Danish antenatal care: A qualitative study of experiences from both the pregnant woman's and the care provider's perspective.

OBJECTIVES: Physical activity during pregnancy is beneficial to maternal and fetal health, but most pregnant women do not achieve the recommended level of physical activity. To investigate how antenatal care can promote physical activity during pregnancy, this study explores experiences of physical activity counselling from the perspectives of pregnant women and antenatal care providers. METHODS: In a qualitative design with an inductive approach individual semi-structured interviews with 19 pregnant women and seven antenatal care providers were performed and analyzed using thematic analysis. RESULTS: The themes "Experiencing inadequate counselling", "Benefiting from individualized guidance", and "Voicing a need for enhanced support" cover the perspectives from the participating pregnant women. They often experienced insufficient physical activity counselling that left them insecure about proper physical activity during pregnancy. The pregnant women desired individualized and concrete advice and early and continuous support. From antenatal care providers the themes "Providers' perceived barriers in counselling", "Balancing the act of counselling", and "Acknowledging potential for enhanced counselling" were identified. They perceived barriers towards counselling including time restraints, lack of interest, and doubts about certain physical activity during pregnancy but expressed trying to adjust the counselling to meet the woman's individual situation. They acknowledged that continuous support during pregnancy and updated knowledge and increased focus among providers might improve physical activity counselling. CONCLUSIONS: Pregnant women received scarce counselling on physical activity in antenatal care, while care providers described several barriers towards counselling on physical activity. Both pregnant women and antenatal care providers recognized opportunities for enhanced physical activity counselling.

Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake.

Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.

Effects of Two Physical Activity Interventions on Sleep and Sedentary Time in Pregnant Women.

Pregnancy is often associated with poor sleep and high sedentary time (SED). We investigated the effect of physical activity (PA) interventions on sleep and SED in pregnant women. A secondary analysis of a randomized controlled trial (n = 219) explored the effect of structured supervised exercise training (EXE) or motivational counseling on PA (MOT) compared to standard prenatal care (CON) on sleep and SED during pregnancy. Three times during pregnancy, sleep was determined by the Pittsburgh Sleep Quality Index (PSQI) and SED by the Pregnancy Physical Activity Questionnaire (PPAQ). Also, a wrist-worn consumer activity tracker measured sleep and SED continuously. Data from the activity tracker confirmed that sleep time decreases, and SED increases by approx. 30 and 24 min/day, respectively, from baseline (maximum gestational age (GA) week 15) to delivery. Compared to CON, the global PSQI score was better for EXE in GA week 28 (-0.8 [-1.5; -0.1], p = 0.031) and for both EXE and MOT in GA week 34 (-1 [-2; -0.5], p = 0.002; -1 [-2; -0.1], p = 0.026). In GA week 28, SED (h/day) from PPAQ was lower in EXE compared to both CON and MOT (-0.69 [-1; -0.0], p = 0.049; -0.6 [-1.0; -0.02], p = 0.042). In conclusion, PA interventions during pregnancy improved sleep quality and reduced SED.

Effects of prenatal exercise on gestational weight gain, obstetric and neonatal outcomes: FitMum randomized controlled trial.

BACKGROUND: To investigate the effects of two different exercise interventions during pregnancy on gestational weight gain (GWG) and obstetric and neonatal outcomes compared to standard care. Additionally, we aimed to improve standardization of GWG measurements by developing a model to estimate GWG for a standardized pregnancy period of 40 weeks and 0 days accounting for individual differences in gestational age (GA) at delivery. METHODS: In a randomized controlled trial we compared the effects of structured supervised exercise training (EXE) three times per week throughout pregnancy versus motivational counselling on physical activity (MOT) seven times during pregnancy with standard care (CON) on GWG and obstetric and neonatal outcomes. Uniquely, to estimate GWG for a standardized pregnancy period, we developed a novel model to predict GWG based on longitudinally observed body weights during pregnancy and at admission for delivery. Observed weights were fitted to a mixed effects model that was used to predict maternal body weight and estimate GWG at different gestational ages. Obstetric and neonatal outcomes, among them gestational diabetes mellitus (GDM) and birth weight, were obtained after delivery. GWG and the investigated obstetric and neonatal outcomes are secondary outcomes of the randomized controlled trial, which might be underpowered to detect intervention effects on these outcomes. RESULTS: From 2018-2020, 219 healthy, inactive pregnant women with median pre-pregnancy BMI of 24.1 (21.8-28.7) kg/m2 were included at median GA 12.9 (9.4-13.9) weeks and randomized to EXE (n = 87), MOT (n = 87) or CON (n = 45). In total 178 (81%) completed the study. GWG at GA 40 weeks and 0 days did not differ between groups (CON: 14.9 kg [95% CI, 13.6;16.1]; EXE: 15.7 kg [14.7;16.7]; MOT: 15.0 kg [13.6;16.4], p = 0.538), neither did obstetric nor neonatal outcomes. For example, there were no differences between groups in the proportions of participants developing GDM (CON: 6%, EXE: 7%, MOT: 7%, p = 1.000) or in birth weight (CON: 3630 (3024-3899), EXE: 3768 (3410-4069), MOT: 3665 (3266-3880), p = 0.083). CONCLUSIONS: Neither structured supervised exercise training nor motivational counselling on physical activity during pregnancy affected GWG or obstetric and neonatal outcomes compared to standard care. TRIAL REGISTRATION: ClinicalTrials.gov; NCT03679130; 20/09/2018.

Risk factors for and pregnancy outcomes after SARS-CoV-2 in pregnancy according to disease severity: A nationwide cohort study with validation of the SARS-CoV-2 diagnosis.

INTRODUCTION: We identified risk factors and outcomes associated with SARS-CoV-2 infection in pregnancy in a universally tested population according to disease severity and validated information on SARS-CoV-2 during pregnancy in national health registers in Denmark. MATERIAL AND METHODS: Cohort study using data from national registers and medical records including all pregnancies between March 1, 2020 and February 28, 2021. We compared women with a validated positive SARS-CoV-2 test during pregnancy with non-infected pregnant women. Risk factors and pregnancy outcomes were assessed by Poisson and Cox regression models and stratified according to disease severity defined by hospital admission status and admission reason (COVID-19 symptoms or other). Using medical record data on actual period of pregnancy, we calculated predictive values of the SARS-CoV-2 diagnosis in pregnancy in the registers. RESULTS: SARS-CoV-2 infection was detected in 1819 (1.6%) of 111 185 pregnancies. Asthma was associated with infection (relative risk [RR] 1.63, 95% confidence interval [CI] 1.28-2.07). Risk factors for severe COVID-19 disease requiring hospital admission were high body mass index (median ratio 1.06, 95% CI 1.04-1.09), asthma (RR 7.47, 95% CI 3.51-15.90) and gestational age at the time of infection (gestational age 28-36 vs < 22: RR 3.53, 95% CI 1.75-7.10). SARS-CoV-2-infected women more frequently had hypertensive disorders in pregnancy (adjusted hazard ratio [aHR] 1.31, 95% CI 1.04-1.64), early pregnancy loss (aHR 1.37, 95% CI 1.00-1.88), preterm delivery before gestational age 28 (aHR 2.31, 95% CI 1.01-5.26), iatrogenically preterm delivery before gestational age 37 (aHR 1.49, 95% CI 1.01-2.19) and small-for-gestational age children (aHR 1.28, 95% CI 1.05-1.54). The associations were stronger among women admitted to hospital for any reason. The validity of the SARS-CoV-2 diagnosis in relation to pregnancy in the registers compared with medical records showed a negative predictive value of 99.9 (95% CI 99.9-100.0) and a positive predictive value of 82.1 (95% CI 80.4-83.7). CONCLUSIONS: Women infected with SARS-CoV-2 during pregnancy were at increased risk of hypertensive disorders in pregnancy, early pregnancy loss, preterm delivery and having children small for gestational age. The validity of Danish national registers was acceptable for identification of SARS-CoV-2 infection during pregnancy.

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.

Physical activity in pregnancy: a mixed methods process evaluation of the FitMum randomised controlled trial interventions.

BACKGROUND: Physical activity (PA) at moderate intensity is recommended for healthy pregnant women. The three-arm FitMum randomised controlled trial showed that it was possible to increase PA level during pregnancy with structured supervised exercise training (EXE) compared to standard care. Motivational counselling on PA (MOT) did not increase PA. This process evaluation aims to understand the implementation and mechanisms of impact of EXE and MOT. METHODS: A mixed methods process evaluation was conducted using the UK Medical Research Council's process evaluation framework by assessing implementation (reach, fidelity, and dose) and mechanisms of impact of the two interventions provided to pregnant women in FitMum. Data was collected both quantitatively (n = 220) and qualitatively (n = 20). RESULTS: The FitMum trial reached educated pregnant women (80% having an educational level ≥ bachelor's degree) with high autonomy of everyday life. Most participants (58%) were recruited at their first-trimester ultrasonic scan. Reasons to participate were personal (91%) and altruistic (56%). The intervention dose was delivered as intended with high fidelity in the original physical intervention setup and in the altered online setup during the COVID-19 restrictions. A low dose received in EXE (1.3 [95% CI, 1.1; 1.5] sessions/week) was partly explained by the pre-scheduled EXE sessions favouring participants with a flexible everyday life and a supportive social network. Dose received in EXE increased during online intervention delivery. Participants in MOT received 5.2 [4.7; 5.7] of 7 sessions. Mechanisms of impact comprised a perception of intervention commitment among participants in EXE due to the scheduled EXE sessions, whereas participants in MOT considered themselves as PA self-determined. PA was considered as constrained activities in EXE and included in daily activities in MOT. CONCLUSION: The FitMum interventions was delivered with high fidelity. During COVID-19, the dose received in EXE increased compared to the previous physical setup. Mechanisms of impact as commitment, perception of empowerment and perception of PA as well as the paradox between prioritising PA and family and the need of a flexible everyday life need to be considered when offering pregnant women PA interventions. Future interventions should consider a combination of physical and online exercise training for pregnant women.

Effects of Structured Supervised Exercise Training or Motivational Counseling on Pregnant Women's Physical Activity Level: FitMum - Randomized Controlled Trial.

BACKGROUND: Physical activity (PA) during pregnancy is an effective and safe way to improve maternal health in uncomplicated pregnancies. However, compliance with PA recommendations remains low among pregnant women. OBJECTIVE: The purpose of this study was to evaluate the effects of offering structured supervised exercise training (EXE) or motivational counseling on PA (MOT) during pregnancy on moderate-to-vigorous intensity physical activity (MVPA) level. Additionally, complementary measures of PA using the Pregnancy Physical Activity Questionnaire (PPAQ) and gold standard doubly labeled water (DLW) technique were investigated. The hypotheses were that both EXE and MOT would increase MVPA in pregnancy compared with standard care (CON) and that EXE would be more effective than MOT. In addition, the association between MVPA and the number of sessions attended was explored. METHODS: A randomized controlled trial included 220 healthy, inactive pregnant women with a median gestational age of 12.9 (IQR 9.4-13.9) weeks. A total of 219 women were randomized to CON (45/219), EXE (87/219), or MOT (87/219). The primary outcome was MVPA (minutes per week) from randomization to the 29th gestational week obtained by a wrist-worn commercial activity tracker (Vivosport, Garmin International). PA was measured by the activity tracker throughout pregnancy, PPAQ, and DLW. The primary outcome analysis was performed as an analysis of covariance model adjusting for baseline PA. RESULTS: The average MVPA (minutes per week) from randomization to the 29th gestational week was 33 (95% CI 18 to 47) in CON, 50 (95% CI 39 to 60) in EXE, and 40 (95% CI 30 to 51) in MOT. When adjusted for baseline MVPA, participants in EXE performed 20 (95% CI 4 to 36) minutes per week more MVPA than participants in CON (P=.02). MOT was not more effective than CON; EXE and MOT also did not differ. MVPA was positively associated with the number of exercise sessions attended in EXE from randomization to delivery (P=.04). Attendance was higher for online (due to COVID-19 restrictions) compared with physical exercise training (P=.03). Adverse events and serious adverse events did not differ between groups. CONCLUSIONS: Offering EXE was more effective than CON to increase MVPA among pregnant women, whereas offering MOT was not. MVPA in the intervention groups did not reach the recommended level in pregnancy. Changing the intervention to online due to COVID-19 restrictions did not affect MVPA level but increased exercise participation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03679130; https://clinicaltrials.gov/ct2/show/NCT03679130. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2020-043671.

Aortic distensibility is equal in prepubertal girls and boys and increases with puberty in girls.

Windkessel function is governed by conductance artery compliance that is associated with cardiovascular disease in adults independently of other risk factors. Sex-related differences in conductance artery compliance partly explain the sex-related differences in risk of cardiovascular disease. Studies on sex-related differences in conductance artery function in prepubertal children are few and inconclusive. This study determined the conductance artery compliance and cardiac function by magnetic resonance imaging in 150 healthy children (75 girls) aged 7-10 yr. Any sex-related difference in conductance artery function was determined with correction for other potential predictors in multivariable linear regression models. Our data showed that ascending [crude mean difference 1.11 95% confidence interval (CI) (0.22; 2.01)] and descending [crude mean difference 1.10 95% CI (0.09; 1.91)] aortic distensibility were higher in girls, but differences disappeared after adjustment for pubertal status and other identified potential predictors. Systolic and diastolic blood pressure, cardiac output, left ventricle (LV) systolic function, and total peripheral resistance did not differ between the sexes. In girls, heart rate was 7 beats/min higher, whereas pulse pressure (by 2 mmHg), LV end-diastolic volume index (by 7 mL), and stroke volume (by 5 mL) were lower. LV peak filling rate indexed to LV end-diastolic volume was 0.5 s-1 higher in girls. In conclusion, prepubertal girls and boys have equal conductance artery function. Thus, the well-known sex difference in adult conductance artery function seems to develop after the onset of puberty with girls initially increasing aortic distensibility.NEW & NOTEWORTHY Although it has been suggested that sex differences in conductance artery function may exist early in childhood, this study demonstrates that the well-known, sex-related difference in conductance artery stiffness (hence Windkessel function) in adulthood is not established before puberty. Thus, healthy prepubertal girls and boys have comparable conductance artery compliance. In contrast to previous studies, our study suggests that pubertal girls develop a more distensible aorta than prepubertal children.

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.

Structured supervised exercise training or motivational counselling during pregnancy on physical activity level and health of mother and offspring: FitMum study protocol.

INTRODUCTION: A physically active lifestyle during pregnancy improves maternal and offspring health but can be difficult to follow. In Denmark, less than 40% of pregnant women meet physical activity (PA) recommendations. The FitMum study aims to explore strategies to increase PA during pregnancy among women with low PA and assess the health effects of PA. This paper presents the FitMum protocol, which evaluates the effects of structured supervised exercise training or motivational counselling supported by health technology during pregnancy on PA level and health of mother and offspring. METHODS AND ANALYSIS: A single-site three-arm randomised controlled trial that aims to recruit 220 healthy, pregnant women with gestational age (GA) no later than week 15 and whose PA level does not exceed one hour/week. Participants are randomised to one of three groups: structured supervised exercise training consisting of three weekly exercise sessions, motivational counselling supported by health technology or a control group receiving standard care. The interventions take place from randomisation until delivery. The primary outcome is min/week of moderate-to-vigorous intensity PA (MVPA) as determined by a commercial activity tracker, collected from randomisation until GA of 28 weeks and 0-6 days, and the secondary outcome is gestational weight gain (GWG). Additional outcomes are complementary measures of PA; clinical and psychological health parameters in participant, partner and offspring; analyses of blood, placenta and breastmilk samples; process evaluation of interventions; and personal understandings of PA. ETHICS AND DISSEMINATION: The study is approved by the Danish National Committee on Health Research Ethics (# H-18011067) and the Danish Data Protection Agency (# P-2019-512). Findings will be disseminated via peer-reviewed publications, at conferences, and to health professionals via science theatre performances. TRIAL REGISTRATION NUMBER: NCT03679130. PROTOCOL VERSION: This paper was written per the study protocol version 8 dated 28 August 2019.

Genome-wide association study of circulating levels of glucagon during an oral glucose tolerance test.

BACKGROUND: In order to explore the pathophysiology underlying type 2 diabetes we examined the impact of gene variants associated with type 2 diabetes on circulating levels of glucagon during an oral glucose tolerance test (OGTT). Furthermore, we performed a genome-wide association study (GWAS) aiming to identify novel genomic loci affecting plasma glucagon levels. METHODS: Plasma levels of glucagon were examined in samples obtained at three time points during an OGTT; 0, 30 and 120 min, in two separate cohorts with a total of up to 1899 individuals. Cross-sectional analyses were performed separately in the two cohorts and the results were combined in a meta-analysis. RESULTS: A known type 2 diabetes variant in EYA2 was significantly associated with higher plasma glucagon level at 30 min during the OGTT (Beta 0.145, SE 0.038, P = 1.2 × 10-4) corresponding to a 7.4% increase in plasma glucagon level per effect allele. In the GWAS, we identified a marker in the MARCH1 locus, which was genome-wide significantly associated with reduced suppression of glucagon during the first 30 min of the OGTT (Beta - 0.210, SE 0.037, P = 1.9 × 10-8), equivalent to 8.2% less suppression per effect allele. Nine additional independent markers, not previously associated with type 2 diabetes, showed suggestive associations with reduced glucagon suppression during the first 30 min of the OGTT (P < 1.0 × 10-5). CONCLUSIONS: A type 2 diabetes risk variant in the EYA2 locus was associated with higher plasma glucagon levels at 30 min. Ten additional variants were suggestively associated with reduced glucagon suppression without conferring increased type 2 diabetes risk.

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.

One Year's Treatment with the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Decreases Hepatic Fat Content in Women with Nonalcoholic Fatty Liver Disease and Prior Gestational Diabetes Mellitus in a Randomized, Placebo-Controlled Trial.

Prior gestational diabetes mellitus (pGDM) is associated with increased risk of nonalcoholic fatty liver disease (NAFLD). Treatment with glucagon-like peptide 1 (GLP-1) receptor agonists has shown beneficial effects in NAFLD patients. We evaluated the effect of the GLP-1 analogue liraglutide on NAFLD features in women with pGDM. Eighty-two overweight/obese, nondiabetic women with pGDM were included. We performed abdominal ultrasound, transient elastography with controlled attenuation parameter (CAP), and blood sampling at baseline and after 1 year. Thirty-seven women were randomized to liraglutide (1.8 mg once-daily) and 45 to placebo. Based on the ultrasound scan, 18 women (22%) had ultrasound-verified NAFLD at baseline and of these, 10 (56%) received liraglutide treatment. After 1 year, eight participants no longer had steatosis, four in each treatment group. The number of participants who developed NAFLD was similar in the two treatment groups; five in the liraglutide group and six in the placebo group (p = 0.74). Compared to placebo, liraglutide reduced the CAP-assessed intrahepatic fat content (-28 (-44;-11) vs. 2 (-13;18) dB/m, p < 0.01) and body weight (-4.7 (-6.4;-2.9) vs. -1.4 (-3;0.3) kg, p < 0.01). One-year's liraglutide treatment had no effect on the presence of ultrasound-diagnosed NAFLD in overweight/obese nondiabetic women with pGDM, but reduced body weight and steatosis assessed by transient elastography with CAP.