Riviste scientifiche

by Victoria Hodgetts Morton, Sarah J. Stock

by Tie-Ning Zhang, Xin-Mei Huang, Xin-Yi Zhao, Wei Wang, Ri Wen, Shan-Yan Gao

Pre-gestational diabetes mellitus (PGDM) has been known to be a risk factor for congenital heart defects (CHDs) for decades. However, the associations between maternal PGDM and gestational diabetes mellitus (GDM) and the risk of specific types of CHDs and congenital anomalies (CAs) in other systems remain under debate. We aimed to investigate type-specific CAs in offspring of women with diabetes and to examine the extent to which types of maternal diabetes are associated with increased risk of CAs in offspring.

We searched PubMed and Embase from database inception to 15 October 2021 for population-based studies reporting on type-specific CAs in offspring born to women with PGDM (combined type 1 and 2) or GDM, with no limitation on language. Reviewers extracted data for relevant outcomes and performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. Risk of bias appraisal was performed using the Cochrane Risk of Bias Tool. This study was registered in PROSPERO (CRD42021229217). Primary outcomes were overall CAs and CHDs. Secondary outcomes were type-specific CAs. Overall, 59 population-based studies published from 1990 to 2021 with 80,437,056 participants met the inclusion criteria. Of the participants, 2,407,862 (3.0%) women had PGDM and 2,353,205 (2.9%) women had GDM. The meta-analyses showed increased risks of overall CAs/CHDs in offspring born to women with PGDM (for overall CAs, relative risk [RR] = 1.99, 95% CI 1.82 to 2.17, P < 0.001; for CHDs, RR = 3.46, 95% CI 2.77 to 4.32, P < 0.001) or GDM (for overall CAs, RR = 1.18, 95% CI 1.13 to 1.23, P < 0.001; for CHDs, RR = 1.50, 95% CI 1.38 to 1.64, P < 0.001). The results of the meta-regression analyses showed significant differences in RRs of CAs/CHDs in PGDM versus GDM (all P < 0.001). Of the 23 CA categories, excluding CHD-related categories, in offspring, maternal PGDM was associated with a significantly increased risk of CAs in 21 categories; the corresponding RRs ranged from 1.57 (for hypospadias, 95% CI 1.22 to 2.02) to 18.18 (for holoprosencephaly, 95% CI 4.03 to 82.06). Maternal GDM was associated with a small but significant increase in the risk of CAs in 9 categories; the corresponding RRs ranged from 1.14 (for limb reduction, 95% CI 1.06 to 1.23) to 5.70 (for heterotaxia, 95% CI 1.09 to 29.92). The main limitation of our analysis is that some high significant heterogeneity still persisted in both subgroup and sensitivity analyses.

In this study, we observed an increased rate of CAs in offspring of women with diabetes and noted the differences for PGDM versus GDM. The RRs of overall CAs and CHDs in offspring of women with PGDM were higher than those in offspring of women with GDM. Screening for diabetes in pregnant women may enable better glycemic control, and may enable identification of offspring at risk for CAs.

by Anadeijda J. E. M. C. Landman, Marjon A. de Boer, Laura Visser, Tobias A. J. Nijman, Marieke A. C. Hemels, Christiana N. Naaktgeboren, Marijke C. van der Weide, Ben W. Mol, Judith O. E. H. van Laar, Dimitri N. M. Papatsonis, Mireille N. Bekker, Joris van Drongelen, Mariëlle G. van Pampus, Marieke Sueters, David P. van der Ham, J. Marko Sikkema, Joost J. Zwart, Anjoke J. M. Huisjes, Marloes E. van Huizen, Gunilla Kleiverda, Janine Boon, Maureen T. M. Franssen, Wietske Hermes, Harry Visser, Christianne J. M. de Groot, Martijn A. Oudijk

Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth.

We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat.From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 ± SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p = 0.32). In women with ≥80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates.

In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth.

Dutch Trial Register (NL5553, NTR5675) https://www.trialregister.nl/trial/5553.

by Marissa G. Hall, Anna H. Grummon, Isabella C. A. Higgins, Allison J. Lazard, Carmen E. Prestemon, Mirian I. Avendaño-Galdamez, Lindsey Smith Taillie

Pictorial warnings on tobacco products are promising for motivating behavior change, but few studies have examined pictorial warnings for sugary drinks, especially in naturalistic environments. This study aimed to examine the impact of pictorial warnings on parents’ purchases of sugary drinks for their children in a naturalistic store laboratory.

Parents of children ages 2 to 12 (n = 325, 25% identifying as Black, 20% Hispanic) completed a shopping task in a naturalistic store laboratory in North Carolina. Participants were randomly assigned to a pictorial warnings arm (sugary drinks displayed pictorial health warnings about type 2 diabetes and heart damage) or a control arm (sugary drinks displayed a barcode label). Parents selected 1 beverage and 1 snack for their child, as well as 1 household good; one of these items was selected for them to purchase and take home. The primary outcome was whether parents purchased a sugary drink for their child. Secondary outcomes included reactions to the trial labels, attitudes toward sugary drinks, and intentions to serve their child sugary drinks. Pictorial warnings led to a 17-percentage point reduction in purchases of sugary drinks (95% CI for reduction: 7% to 27%), with 45% of parents in the control arm buying a sugary drink for their child compared to 28% in the pictorial warning arm (p = 0.002). The impact of pictorial warnings on purchases did not differ by any of the 13 participant characteristics examined (e.g., race/ethnicity, income, education, and age of child). Pictorial warnings also led to lower calories (kcal), purchased from sugary drinks (82 kcal in the control arm versus 52 kcal in the pictorial warnings arm, p = 0.003). Moreover, pictorial warnings led to lower intentions to serve sugary drinks to their child, feeling more in control of healthy eating decisions, greater thinking about the harms of sugary drinks, stronger negative emotional reactions, greater anticipated social interactions, lower perceived healthfulness of sugary drinks for their child, and greater injunctive norms to limit sugary drinks for their child (all p < 0.05). There was no evidence of difference between trial arms on noticing of the labels, appeal of sugary drinks, perceived amount of added sugar in sugary drinks, risk perceptions, or perceived tastiness of sugary drinks (all p > 0.05).

Pictorial warnings reduced parents’ purchases of sugary drinks for their children in this naturalistic trial. Warnings on sugary drinks are a promising policy approach to reduce sugary drink purchasing in the US.

The trial design, measures, power calculation, and analytic plan were registered before data collection at www.clinicaltrials.gov NCT04223687.

by Samvida S. Venkatesh, Teresa Ferreira, Stefania Benonisdottir, Nilufer Rahmioglu, Christian M. Becker, Ingrid Granne, Krina T. Zondervan, Michael V. Holmes, Cecilia M. Lindgren, Laura B. L. Wittemans

Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders.

Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02–1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06–2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06–1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08–1.23], P = 3.24 × 10−05), and pre-eclampsia (OR [95% CI] = 3.08 [1.98–4.79], P = 6.65 × 10−07). Increased waist circumference posed a higher genetic risk (ORs = 1.16–1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06–1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy.

We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment.