Introduction of a nationwide first-trimester anomaly scan in the Dutch national screening program.

BACKGROUND: A significant proportion of major fetal structural anomalies can be detected in the first trimester by ultrasound examination. However, the test performance of the first-trimester anomaly scan (FTAS) performed in a low-risk population as part of a nationwide prenatal screening program is unknown. Potential benefits of the FTAS include early detection of fetal anomalies, providing parents with more time for reproductive decision-making. OBJECTIVES: To investigate the uptake, test performance and time to a final prenatal diagnosis after referral. STUDY DESIGN: A nationwide implementation study was conducted in the Netherlands (November 2021-November 2022). The FTAS was performed between 12+3 and 14+3 weeks gestation by certified sonographers using a standard protocol. Women were referred to a tertiary care center if anomalies were suspected. Uptake, test performance and time to a final prenatal diagnosis (days between referral and date of final diagnosis/prognosis for reproductive decision-making) were determined. Test performance was calculated for first-trimester major congenital anomalies, such as anencephaly and holoprosencephaly and all diagnosed anomalies <24 weeks gestation. RESULTS: The FTAS uptake was 74.9% (129 704/173 129). In 1.0% (1 313/129 704), an anomaly was suspected, of which 54.9% (n=721) had abnormal findings on the detailed first-trimester diagnostic scan and 44.6% (n=586) showed normal results. In 0.5% (n=6), intra-uterine fetal death occurred. In the total group of 721 cases with abnormal findings, 332 structural anomalies, 117 genetic anomalies, 82 other findings (abnormal fetal biometry, sonomarkers, placental/umbilical cord anomaly, an-/oligohydramnios) and 189 cases with transient findings (defined as ultrasound findings which resolved <24 weeks gestation) were found, with one case having an unknown outcome. 0.9% (n=1164) of all cases with a normal FTAS were diagnosed with a fetal anomaly in the second trimester. Test performance included a sensitivity of 84.6% (126/149) for first-trimester major congenital anomalies and 31.6% (537/1701) for all types of anomalies. Specificity for all anomalies was 99.2% (98 055/98 830); positive predictive value 40.9% (537/1 312); negative predictive value 98.8% (98 055/99 219); positive likelihood ratio 40.3; negative likelihood ratio 0.7; false positive rate 0.8% (775/98 830) and false negative rate 68.4% (1 164/1 701). The median time to diagnosis for structural anomalies was 20 days (6-43 days; median GA 16+3), for genetic anomalies 17 days (8.5-27.5 days; median GA 15+6 weeks) and for first-trimester major congenital anomalies 9 days (5-22 days; median GA 14+6 weeks). CONCLUSIONS: The performance of a newly introduced nationwide FTAS in a low-risk population showed a high sensitivity for first-trimester major congenital anomalies and a lower sensitivity for all anomalies combined. The program was accompanied by a referral rate of 1.0%, of which 59.1% involved cases where anomalies were either not confirmed or resolved before 24 weeks gestation. Timing of diagnosis was around 16 weeks gestation for referred cases. To evaluate the balance between benefits and potential harm of the FTAS within a nationwide prenatal screening program, it is essential to assess the effectiveness of the program over time and to consider the perspectives of both women and their partners, as well as healthcare professionals.

Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant women-a secondary analysis of the DALI study.

BACKGROUND/OBJECTIVES: Obese pregnant women are at high risk of developing gestational diabetes mellitus (GDM), which might be reduced by sufficient physical activity (PA) and reduced sedentary time (ST). We assessed whether PA and ST are longitudinally associated with the glucose-insulin axis in obese pregnant women. SUBJECTS/METHODS: In this secondary analysis of the DALI (vitamin D And Lifestyle Intervention for gestational diabetes mellitus prevention) study, pregnant women, <20 weeks gestation, with a pre-pregnancy body mass index (BMI) ≥ 29 kg/m2, without GDM on entry were included. Time spent in moderate-to-vigorous PA (MVPA) and ST were measured objectively with accelerometers at <20 weeks, 24-28 weeks and 35-37 weeks of gestation. Fasting glucose (mmol/l) and insulin (mU/l), insulin resistance (HOMA-IR) and first-phase and second-phase insulin release (Stumvoll first and second phase) were assessed at the same time. Linear mixed regression models were used to calculate between-participant differences and within-participant changes over time. Analyses were adjusted for gestational age, randomisation, pre-pregnancy BMI, education and age. MVPA, Insulin, HOMA-IR and Stumvoll first and second phase were log-transformed for analyses due to skewness. RESULTS: 232 women were included in the analysis. Concerning differences between participants, more ST was associated with higher fasting glucose (Estimate: 0.008; 95% CI: 0.002, 0.014), fasting insulin (0.011; 0.002, 0.019), HOMA-IR (0.012; 0.004, 0.021) and Stumvoll first and second phase (0.008; 0.001, 0.014 and 0.007; 0.001, 0.014). Participants with more MVPA had lower Stumvoll first and second phase (-0.137; -0.210, -0.064 and -0.133; -0.202, -0.063). Concerning changes over time, an increase in ST during gestation was associated with elevated Stumvoll first and second phase (0.006; 0.000, 0.011). CONCLUSIONS: As the glucose-insulin axis is more strongly associated with ST than MVPA in our obese population, pregnant women could be advised to reduce ST in addition to increasing MVPA. Moreover, our findings suggest that behaviour change interventions aiming at GDM risk reduction should start in early or pre-pregnancy.

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.

A core outcome set for studies of gestational diabetes mellitus prevention and treatment.

AIMS/HYPOTHESIS: The aim of this systematic review was to develop core outcome sets (COSs) for trials evaluating interventions for the prevention or treatment of gestational diabetes mellitus (GDM). METHODS: We identified previously reported outcomes through a systematic review of the literature. These outcomes were presented to key stakeholders (including patient representatives, researchers and clinicians) for prioritisation using a three-round, e-Delphi study. A priori consensus criteria informed which outcomes were brought forward for discussion at a face-to-face consensus meeting where the COS was finalised. RESULTS: Our review identified 74 GDM prevention and 116 GDM treatment outcomes, which were presented to stakeholders in round 1 of the e-Delphi study. Round 1 was completed by 173 stakeholders, 70% (121/173) of whom went on to complete round 2; 84% (102/121) of round 2 responders completed round 3. Twenty-two GDM prevention outcomes and 30 GDM treatment outcomes were discussed at the consensus meeting. Owing to significant overlap between included prevention and treatment outcomes, consensus meeting stakeholders agreed to develop a single prevention/treatment COS. Fourteen outcomes were included in the final COS. These consisted of six maternal outcomes (GDM diagnosis, adherence to the intervention, hypertensive disorders of pregnancy, requirement and type of pharmacological therapy for hyperglycaemia, gestational weight gain and mode of birth) and eight neonatal outcomes (birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, neonatal hypoglycaemia, neonatal death and stillbirth). CONCLUSIONS/INTERPRETATION: This COS will enable future GDM prevention and treatment trials to measure similar outcomes that matter to stakeholders and facilitate comparison and combination of these studies. TRIAL REGISTRATION: This study was registered prospectively with the Core Outcome Measures in Effectiveness Trials (COMET) database: http://www.comet-initiative.org/studies/details/686/.

Follow-up at 1 year and beyond of women with gestational diabetes treated with insulin and/or oral glucose-lowering agents: a core outcome set using a Delphi survey.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is linked with a higher lifetime risk for the development of impaired fasting glucose, impaired glucose tolerance, type 2 diabetes, the metabolic syndrome, cardiovascular disease, postpartum depression and tumours. Despite this, there is no consistency in the long-term follow-up of women with a previous diagnosis of GDM. Further, the outcomes selected and reported in the research involving this population are heterogeneous and lack standardisation. This amplifies the risk of reporting bias and diminishes the likelihood of significant comparisons between studies. The aim of this study is to develop a core outcome set (COS) for RCTs and other studies evaluating the long-term follow-up at 1 year and beyond of women with previous GDM treated with insulin and/oral glucose-lowering agents. METHODS: The study consisted of three work packages: (1) a systematic review of the outcomes reported in previous RCTs of the follow-up at 1 year and beyond of women with GDM treated with insulin and/or oral glucose-lowering agents; (2) a three-round online Delphi survey with key stakeholders to prioritise these outcomes; and (3) a consensus meeting where the final COS was decided. RESULTS: Of 3344 abstracts identified and evaluated, 62 papers were retrieved and 25/62 papers were included in this review. A total of 121 outcomes were identified and included in the Delphi survey. Delphi round 1 was emailed to 835 participants and 288 (34.5%) responded. In round 2, 190 of 288 (65.9%) participants responded and in round 3, 165 of 190 (86.8%) participants responded. In total, nine outcomes were selected and agreed for inclusion in the final COS: assessment of glycaemic status; diagnosis of type 2 diabetes since the index pregnancy; number of pregnancies since the index pregnancy; number of pregnancies with a diagnosis of GDM since the index pregnancy; diagnosis of prediabetes since the index pregnancy; BMI; post-pregnancy weight retention; resting blood pressure; and breastfeeding. CONCLUSIONS/INTERPRETATION: This study identified a COS that will help bring consistency and uniformity to outcome selection and reporting in clinical trials and other studies involving the follow-up at 1 year and beyond of women diagnosed with GDM treated with insulin and/or oral glucose-lowering agents during pregnancy.

A reduction in sedentary behaviour in obese women during pregnancy reduces neonatal adiposity: the DALI randomised controlled trial.

AIMS/HYPOTHESIS: Offspring of obese women are at increased risk of features of the metabolic syndrome, including obesity and diabetes. Lifestyle intervention in pregnancy might reduce adverse effects of maternal obesity on neonatal adiposity. METHODS: In the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention (DALI) lifestyle trial, 436 women with a BMI ≥29 kg/m2 were randomly assigned to counselling on healthy eating (HE), physical activity (PA) or HE&PA, or to usual care (UC). In secondary analyses of the lifestyle trial, intervention effects on neonatal outcomes (head, abdominal, arm and leg circumferences and skinfold thicknesses, estimated fat mass, fat percentage, fat-free mass and cord blood leptin) were assessed using multilevel regression analyses. Mediation of intervention effects by lifestyle and gestational weight gain was assessed. RESULTS: Outcomes were available from 334 neonates. A reduction in sum of skinfolds (-1.8 mm; 95% CI -3.5, -0.2; p = 0.03), fat mass (-63 g; 95% CI -124, -2; p = 0.04), fat percentage (-1.2%; 95% CI -2.4%, -0.04%; p = 0.04) and leptin (-3.80 µg/l; 95% CI -7.15, -0.45; p = 0.03) was found in the HE&PA group, and reduced leptin in female neonates in the PA group (-5.79 µg/l; 95% CI -11.43, -0.14; p = 0.05) compared with UC. Reduced sedentary time, but not gestational weight gain, mediated intervention effects on leptin in both the HE&PA and PA groups. CONCLUSIONS/INTERPRETATION: The HE&PA intervention resulted in reduced adiposity in neonates. Reduced sedentary time seemed to drive the intervention effect on cord blood leptin. Implications for future adiposity and diabetes risk of the offspring need to be elucidated. TRIAL REGISTRATION: ISRCTN70595832.

Cost-effectiveness of healthy eating and/or physical activity promotion in pregnant women at increased risk of gestational diabetes mellitus: economic evaluation alongside the DALI study, a European multicenter randomized controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with perinatal health risks to both mother and offspring, and represents a large economic burden. The DALI study is a multicenter randomized controlled trial, undertaken to add to the knowledge base on the effectiveness of interventions for pregnant women at increased risk for GDM. The purpose of this study was to evaluate the cost-effectiveness of the healthy eating and/or physical activity promotion intervention compared to usual care among pregnant women at increased risk of GDM from a societal perspective. METHODS: An economic evaluation was performed alongside a European multicenter-randomized controlled trial. A total of 435 pregnant women at increased risk of GDM in primary and secondary care settings in nine European countries, were recruited and randomly allocated to a healthy eating and physical activity promotion intervention (HE + PA intervention), a healthy eating promotion intervention (HE intervention), or a physical activity promotion intervention (PA intervention). Main outcome measures were gestational weight gain, fasting glucose, insulin resistance (HOMA-IR), quality adjusted life years (QALYs), and societal costs. RESULTS: Between-group total cost and effect differences were not significant, besides significantly less gestational weight gain in the HE + PA group compared with the usual care group at 35-37 weeks (-2.3;95%CI:-3.7;-0.9). Cost-effectiveness acceptability curves indicated that the HE + PA intervention was the preferred intervention strategy. At 35-37 weeks, it depends on the decision-makers' willingness to pay per kilogram reduction in gestational weight gain whether the HE + PA intervention is cost-effective for gestational weight gain, whereas it was not cost-effective for fasting glucose and HOMA-IR. After delivery, the HE + PA intervention was cost-effective for QALYs, which was predominantly caused by a large reduction in delivery-related costs. CONCLUSIONS: Healthy eating and physical activity promotion was found to be the preferred strategy for limiting gestational weight gain. As this intervention was cost-effective for QALYs after delivery, this study lends support for broad implementation. TRIAL REGISTRATION: ISRCTN ISRCTN70595832 . Registered 2 December 2011.

A core outcome set for studies evaluating the effectiveness of prepregnancy care for women with pregestational diabetes.

AIMS/HYPOTHESIS: The aim of this study was to develop a core outcome set (COS) for trials and other studies evaluating the effectiveness of prepregnancy care for women with pregestational (pre-existing) diabetes mellitus. METHODS: A systematic literature review was completed to identify all outcomes reported in prior studies in this area. Key stakeholders then prioritised these outcomes using a Delphi study. The list of outcomes included in the final COS were finalised at a face-to-face consensus meeting. RESULTS: In total, 17 outcomes were selected and agreed on for inclusion in the final COS. These outcomes were grouped under three domains: measures of pregnancy preparation (n = 9), neonatal outcomes (n = 6) and maternal outcomes (n = 2). CONCLUSIONS/INTERPRETATION: This study identified a COS essential for studies evaluating prepregnancy care for women with pregestational diabetes. It is advocated that all trials and other non-randomised studies and audits in this area use this COS with the aim of improving transparency and the ability to compare and combine future studies with greater ease.

Epidemiology of gestational diabetes mellitus according to IADPSG/WHO 2013 criteria among obese pregnant women in Europe.

AIMS/HYPOTHESIS: Accurate prevalence estimates for gestational diabetes mellitus (GDM) among pregnant women in Europe are lacking owing to the use of a multitude of diagnostic criteria and screening strategies in both high-risk women and the general pregnant population. Our aims were to report important risk factors for GDM development and calculate the prevalence of GDM in a cohort of women with BMI ≥29 kg/m2 across 11 centres in Europe using the International Association of the Diabetes and Pregnancy Study Groups (IADPSG)/WHO 2013 diagnostic criteria. METHODS: Pregnant women (n = 1023, 86.3% European ethnicity) with a BMI ≥29.0 kg/m2 enrolled into the Vitamin D and Lifestyle Intervention for GDM Prevention (DALI) pilot, lifestyle and vitamin D studies of this pan-European multicentre trial, attended for an OGTT during pregnancy. Demographic, anthropometric and metabolic data were collected at enrolment and throughout pregnancy. GDM was diagnosed using IADPSG/WHO 2013 criteria. GDM treatment followed local policies. RESULTS: The number of women recruited per country ranged from 80 to 217, and the dropout rate was 7.1%. Overall, 39% of women developed GDM during pregnancy, with no significant differences in prevalence across countries. The prevalence of GDM was high (24%; 242/1023) in early pregnancy. Despite interventions used in the DALI study, a further 14% (94/672) had developed GDM when tested at mid gestation (24-28 weeks) and 13% (59/476) of the remaining cohort at late gestation (35-37 weeks). Demographics and lifestyle factors were similar at baseline between women with GDM and those who maintained normal glucose tolerance. Previous GDM (16.5% vs 7.9%, p = 0.002), congenital malformations (6.4% vs 3.3%, p = 0.045) and a baby with macrosomia (31.4% vs 17.9%, p = 0.001) were reported more frequently in those who developed GDM. Significant anthropometric and metabolic differences were already present in early pregnancy between women who developed GDM and those who did not. CONCLUSIONS/INTERPRETATION: The prevalence of GDM diagnosed by the IADPSG/WHO 2013 GDM criteria in European pregnant women with a BMI ≥29.0 kg/m2 is substantial, and poses a significant health burden to these pregnancies and to the future health of the mother and her offspring. Uniform criteria for GDM diagnosis, supported by robust evidence for the benefits of treatment, are urgently needed to guide modern GDM screening and treatment strategies.

Is a motivational interviewing based lifestyle intervention for obese pregnant women across Europe implemented as planned? Process evaluation of the DALI study.

BACKGROUND: Process evaluation is an essential part of designing and assessing complex interventions. The vitamin D and lifestyle intervention study (DALI) study is testing different strategies to prevent development of gestational diabetes mellitus among European obese pregnant women with a body mass index ≥29 kg/m2. The intervention includes guidance on physical activity and/or healthy eating by a lifestyle coach trained in motivational interviewing (MI). The aim of this study was to assess the process elements: reach, dose delivered, fidelity and satisfaction and to investigate whether these process elements were associated with changes in gestational weight gain (GWG). METHODS: Data on reach, dose delivered, fidelity, and satisfaction among 144 participants were collected. Weekly recruitment reports, notes from meetings, coach logs and evaluation questionnaires (n = 110) were consulted. Fidelity of eight (out of twelve) lifestyle coach practitioners was assessed by analysing audio recorded counselling sessions using the MI treatment integrity scale. Furthermore, associations between process elements and GWG were assessed with linear regression analyses. RESULTS: A total of 20% of the possible study population (reach) was included in this analysis. On average 4.0 (of the intended 5) face-to-face sessions were delivered. Mean MI fidelity almost reached 'expert opinion' threshold for the global scores, but was below 'beginning proficiency' for the behavioural counts. High variability in quality of MI between practitioners was identified. Participants were highly satisfied with the intervention, the lifestyle coach and the intervention materials. No significant associations were found between process elements and GWG. CONCLUSION: Overall, the intervention was well delivered and received by the study population, but did not comply with all the principles of MI. Ensuring audio recording of lifestyle sessions throughout the study would facilitate provision of individualized feedback to improve MI skills. A larger sample size is needed to confirm the lack of association between process elements and GWG. TRIAL REGISTRATION: ISRCTN registry: ISRCTN70595832 ; Registered 12 December 2011.

Correlates of poor mental health in early pregnancy in obese European women.

BACKGROUND: Depression during pregnancy is associated with higher maternal morbidity and mortality, and subsequent possible adverse effects on the cognitive, emotional and behavioral development of the child. The aim of the study was to identify maternal characteristics associated with poor mental health, in a group of overweight/obese pregnant women in nine European countries, and thus, to contribute to better recognition and intervention for maternal depression. METHODS: In this cross-sectional observational study, baseline data from early pregnancy (< 20 weeks) of the DALI (Vitamin D and Lifestyle Intervention for gestational diabetes mellitus prevention) study were analyzed. Maternal mental health was assessed with the World Health Organization Well-Being Index (WHO-5). Women were classified as having a low (WHO-5 ≤ 50) or high wellbeing. RESULTS: A total of 735 pregnant women were included. The prevalence of having a low wellbeing was 27.2%, 95% CI [24.0, 30.4]. Multivariate analysis showed independent associations between low wellbeing and European ethnicity, OR = .44, 95% CI [.25, .77], shift work, OR = 1.81, 95% CI [1.11, 2.93], insufficient sleep, OR = 3.30, 95% CI [1.96, 5.55], self-efficacy, OR = .95, 95% CI [.92, .98], social support, OR = .94, 95% CI [.90, .99], and pregnancy-related worries (socioeconomic: OR = 1.08, 95% CI [1.02, 1.15]; health: OR = 1.06, 95% CI [1.01, 1.11]; relationship: OR = 1.17, 95% CI [1.05, 1.31]). CONCLUSIONS: Mental health problems are common in European overweight/obese pregnant women. The identified correlates might help in early recognition and subsequent treatment of poor mental health problems during pregnancy. This is important to reduce the unfavorable effects of poor mental health on pregnancy outcomes. TRIAL REGISTRATION: ISRCTN70595832 , 02.12.2011.

Maternal obesity and breastfeeding intention, initiation, intensity and duration: a systematic review.

This systematic review investigates the relationship between maternal obesity and breastfeeding intention, initiation, intensity, duration and milk supply. A comprehensive search was performed through three major databases, including Medline, Cochrane Library and Cumulative Index For Nursing and Allied Health Literature, and by screening reference lists of the relevant publications. Selection criteria were: report of original research, studies on low-risk obese mothers and the comparison with normal weight mothers which met at least two of the following primary outcomes: breastfeeding intention; initiation; intensity; duration and/or milk supply. Furthermore, the included reports had to contain a clear definition of pre-pregnant obesity, use compensation mechanisms for potential confounding factors, have a prospective cohort design and had to have been published between 1997 and 2011 and in English, French or Dutch. Effects of obesity on breastfeeding intention, initiation, intensity, duration and milk supply were analysed, tabulated and summarised in this review. Studies have found that obese women are less likely to intend to breastfeed and that maternal obesity seems to be associated with a decreased initiation of breastfeeding, a shortened duration of breastfeeding, a less adequate milk supply and delayed onset of lactogenesis II, compared with their normal weight counterparts. This systematic review indicates therefore that maternal obesity is an adverse determinant for breastfeeding success.

Preconception maternal gastric bypass surgery and the impact on fetal growth parameters.

BACKGROUND: Bariatric surgery is increasingly performed in women of reproductive age. As bariatric surgery will result in postoperative rapid catabolic weight loss which potentially leads to fetal malnutrition and directly related impaired intra-uterine growth, it is advised to postpone pregnancy for at least 12-18 months after surgery. OBJECTIVES: To investigate the consequences of preconception gastric bypass surgery (pGB) on fetal growth parameters and maternal pregnancy outcome. SETTING: Maasstad Hospital, The Netherlands, general hospital and Erasmus Medical Center, The Netherlands, university hospital. METHODS: We included 97 pGB pregnancies (Maasstad hospital) and 440 non-bariatric pregnancies (Rotterdam Periconception cohort, Erasmus Medical Center). Longitudinal second and third trimester fetal growth parameters (head circumference, biparietal diameter, femur length, abdominal circumference, estimated fetal weight) were analyzed using linear mixed models, adjusting for covariates and possible confounders. Fetal growth and birthweight in pGB pregnancies were compared to non-bariatric pregnancies and Dutch reference curves. Maternal pregnancy outcome in the pGB group was compared to non-bariatric pregnancies. RESULTS: All fetal growth parameters of pGB pregnancies were significantly decreased at 20 weeks' gestation (P < .001) and throughout the remaining part of pregnancy (P < .05) compared with non-bariatric pregnancies (crude and adjusted models). In our cohort, gestational weight gain was not significantly associated with birthweight corrected for gestational age. Birthweight was significantly lower in pGB pregnancies (estimate -241 grams [95% CI, -342.7 to -140.0]) with a 2-fold increased risk of small-for-gestational-age (SGA) (adjusted odds ratio 2.053 [95% CI, 1.058 to 3.872]). Compared to the non-bariatric pregnancies, we found no significant differences in maternal pregnancy outcome. CONCLUSIONS: PGB is associated with overall reduced fetal growth trajectories and a 2-fold increased risk of SGA, without significant adverse consequences for maternal pregnancy outcome. We recommend close monitoring of fetal growth after pGB.

DALI: Vitamin D and lifestyle intervention for gestational diabetes mellitus (GDM) prevention: an European multicentre, randomised trial - study protocol.

BACKGROUND: Gestational diabetes mellitus (GDM) is an increasing problem world-wide. Lifestyle interventions and/or vitamin D supplementation might help prevent GDM in some women. METHODS/DESIGN: Pregnant women at risk of GDM (BMI ≥ 29 (kg/m(2))) from 9 European countries will be invited to participate and consent obtained before 19+6 weeks of gestation. After giving informed consent, women without GDM will be included (based on IADPSG criteria: fasting glucose<5.1 mmol; 1 hour glucose <10.0 mmol; 2 hour glucose <8.5 mmol) and randomized to one of the 8 intervention arms using a 2 × (2 × 2) factorial design: (1) healthy eating (HE), 2) physical activity (PA), 3) HE+PA, 4) control, 5) HE+PA+vitamin D, 6) HE+PA+placebo, 7) vitamin D alone, 8) placebo alone), pre-stratified for each site. In total, 880 women will be included with 110 women allocated to each arm. Between entry and 35 weeks of gestation, women allocated to a lifestyle intervention will receive 5 face-to-face, and 4 telephone coaching sessions, based on the principles of motivational interviewing. The lifestyle intervention includes a discussion about the risks of GDM, a weight gain target <5 kg and either 7 healthy eating 'messages' and/or 5 physical activity 'messages' depending on randomization. Fidelity is monitored by the use of a personal digital assistance (PDA) system. Participants randomized to the vitamin D intervention receive either 1600 IU vitamin D or placebo for daily intake until delivery. Data is collected at baseline measurement, at 24-28 weeks, 35-37 weeks of gestation and after delivery. Primary outcome measures are gestational weight gain, fasting glucose and insulin sensitivity, with a range of obstetric secondary outcome measures including birth weight. DISCUSSION: DALI is a unique Europe-wide randomised controlled trial, which will gain insight into preventive measures against the development of GDM in overweight and obese women. TRIAL REGISTRATION: ISRCTN70595832.

Fetal growth and developmental programming.

The environment in utero and in early neonatal life may induce a permanent response in the fetus and the newborn, leading to enhanced susceptibility to later diseases. This review concentrates on the role and mechanisms of events during the antenatal and immediate postnatal period resulting in later life diseases, concentrating on abnormal growth patterns of the fetus. Fetal overgrowth is related to exposure to a diabetic intra uterine environment, increasing the vulnerability to transgenerational obesity and hence an increased sensitivity to more diabetic mothers. This effect has been supported by animal data. Fetal growth restriction is complex due to malnutrition in utero, catch up growth due to a high caloric intake and low physical activity in later life. Metabolic changes and a transgenerational effect of intra uterine malnutrition has been supported by animal data. In recent years the discovery of alterations of the genome due to different influences during embryonic life, called epigenetics, has led to the phenomenon of fetal programming resulting in changing transgenerational metabolic effects.

The Impact of Preconception Gastric Bypass Surgery on Maternal Micronutrient Status before and during Pregnancy: A Retrospective Cohort Study in the Netherlands between 2009 and 2019.

Post-bariatric weight loss can cause iatrogenic malnutrition and micronutrient depletion. In this study, we evaluated the impact of gastric bypass surgery (GB) and multivitamin supplement use on maternal micronutrient status before and across pregnancy. A retrospective medical chart review of 197 singleton pregnancies after GB with a due date between 2009 and 2019 was performed at a bariatric expertise center in the Netherlands. Hemoglobin, calcium, iron status, folate, vitamin D, vitamin B12 and ferritin levels were determined before and after GB during standard follow-up and at all gestational trimesters and analyzed using linear mixed models. Patients were prescribed standard multivitamin supplements or multivitamins specifically developed for post-bariatric patients (FitForMe WLS Forte (FFM)). Overall, hemoglobin and calcium levels decreased after surgery and during pregnancy, whereas folate, vitamin D, and vitamin B12 levels increased, and iron levels remained stable. FFM use was associated with higher hemoglobin, folate, vitamin D, and ferritin levels. In conclusion, through adequate supplementation and follow-up, GB does not have to result in impaired micronutrient status. Supplements developed specifically for post-bariatric patients generally result in higher micronutrient values than regular multivitamins before and during pregnancy. These data emphasize the urgent need for nutritional counseling including dietary and multivitamin supplement advise for post-bariatric women contemplating and during pregnancy.

Effects of Peri-Conception and Pregnancy Glycemic Variability on Pregnancy and Perinatal Complications in Type 1 Diabetes: A Pilot Study.

BACKGROUND: Not much is known about the effects of glycemic variability (GV) during the pre- and periconception period on pregnancy/perinatal complications. GV could potentially contribute to identification of high-risk pregnancies in women with type 1 diabetes. METHODS: An explorative retrospective cohort study was conducted between January 2014 and May 2019. Glucose data were retrieved from electronic patient charts. Pre-/periconceptional GV and GV during all three trimesters was expressed as mean glucose, standard deviation (SD), Coefficient of Variation (CV), High Blood Glucose Index (HBGI), Low Blood Glucose Index (LBGI) and Average Daily Risk Range (ADRR). Maternal and neonatal complications were summarized using a composite total complication score. Binary logistic regression analyses were conducted to assess associations between the GV measures and a total complication score>3, a maternal complication score>1 and a neonatal complication score>1. RESULTS: Of 63 eligible women, 29 women (38 pregnancies) were included. Women in the group with a total complication score>3 had a significantly higher ADRR at conception (OR 1.1, CI 1.0-1.2, p=0.048). No statistically significant correlations between complication score and any other GV metric besides the ADRR were found. Although not significant, in the group with a complication score>3, odds ratios>1 were found for SD in trimester 1 (OR 1.6, CI 0.6-4.5, p=0.357) and trimester 2 (OR 1.8, CI 0.5-6.2, p=0.376). CONCLUSIONS: Presence of a positive association between GV and pregnancy and perinatal complications depends on which pregnancy period is assessed and the GV metrics that are used.

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.

Epidemiology and (Patho)Physiology of Folic Acid Supplement Use in Obese Women before and during Pregnancy.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.