Placental lipids transfer is essential for optimal fetal development, and alterations of these mechanisms could lead to a higher risk of adverse birth outcomes. Low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), and scavenger receptor class B type 1 (SCARB1) genes are encoding lipoprotein receptors expressed in the placenta where they participate in cholesterol exchange from maternal to fetal circulation. The aim of this study was thus to investigate the association between maternal lipid changes occurring in pregnancy, placental DNA methylation (DNAm) variations at LDLR, LRP1, and SCARB1 gene loci, and newborn’s anthropometric profile at birth. Sixty-nine normoglycemic women were followed from the first trimester of pregnancy until delivery. Placental DNAm was quantified at 43 Cytosine-phosphate-Guanines (CpGs) at LDLR, LRP1, and SCARB1 gene loci using pyrosequencing: 4 CpGs were retained for further analysis. Maternal clinical data were collected at each trimester of pregnancy. Newborns’ data were collected from medical records. Statistical models included minimally newborn sex and gestational and maternal age. Maternal total cholesterol changes during pregnancy (ΔT3-T1) were correlated with DNAm variations at LDLR (r = −0.32, p = 0.01) and LRP1 (r = 0.34, p = 0.007). DNAm at these loci was also correlated with newborns’ cord blood triglyceride and leptin levels. Mediation analysis supports a causal relationship between maternal cholesterol changes, DNAm levels at LRP1 locus, and cord blood leptin concentration (pmediation = 0.02). These results suggest that LRP1 DNAm link maternal blood cholesterol changes in pregnancy and offspring adiposity at birth, which provide support for a better follow-up of blood lipids in pregnancy.

Preeclampsia (PE) is now recognised as a cardiovascular risk factor for women. Emerging evidence suggests that children exposed to PE in utero may also be at increased risk of cardiovascular disease (CVD) in later life. Individuals exposed to PE in utero have higher systolic and diastolic blood pressure and higher body mass index (BMI) compared to those not exposed to PE in utero. The aim of this review is to discuss the potential mechanisms driving the relationship between PE and offspring CVD. Exposure to an adverse intrauterine environment as a consequence of the pathophysiological changes that occur during a pregnancy complicated by PE is proposed as one mechanism that programs the fetus for future CVD risk. Consistent with this hypothesis, animal models of PE where progeny have been studied demonstrate causality for programming of offspring cardiovascular health by the preeclamptic environment. Shared alleles between mother and offspring, and shared lifestyle factors between mother and offspring provide alternate pathways explaining associations between PE and offspring CVD risk. In addition, adverse lifestyle habits can also act as second hits for those programmed for increased CVD risk. PE and CVD are both multifactorial diseases and, hence, identifying the relative contribution of PE to offspring risk for CVD is a very complex task. However, considering the emerging strong association between PE and CVD, those exposed to PE in utero may benefit from targeted primary CVD preventive strategies.

The thymus undergoes a critical period of growth and development early in gestation and, by mid-gestation, immature thymocytes are subject to positive and negative selection. Exposure to undernutrition during these periods may permanently affect phenotype. We measured thymulin concentrations, as a proxy for thymic size and function, in children (n = 290; aged 9–13 years) born to participants in a cluster-randomized trial of maternal vitamin A or β-carotene supplementation in rural Nepal (1994–1997). The geometric mean (95% confidence interval) thymulin concentration was 1.37 ng/ml (1.27, 1.47). A multivariate model of early-life exposures revealed a positive association with gestational age at delivery (β = 0.02; P = 0.05) and higher concentrations among children born to β-carotene-supplemented mothers (β = 0.19; P < 0.05). At ∼9–12 years of age, thymulin was positively associated with all anthropometric measures, with height retained in our multivariate model (β = 0.02; P < 0.001). There was significant seasonal variation: concentrations tended to be lower pre-monsoon (β = −0.13; P = 0.15), during the monsoon (β = −0.22; P = 0.04), and pre-harvest (β = −0.34; P = 0.01), relative to the post-harvest season. All early-life associations, except supplementation, were mediated in part by nutritional status at follow-up. Our findings underscore the known sensitivity of the thymus to nutrition, including potentially lasting effects of early nutritional exposures. The relevance of these findings to later disease risk remains to be explored, particularly given the role of thymulin in the neuroendocrine regulation of inflammation.

Systematic reviews and meta-analyses suggest that behaviour change interventions have modest effect sizes, struggle to demonstrate effect in the long term and that there is high heterogeneity between studies. Such interventions take huge effort to design and run for relatively small returns in terms of changes to behaviour.

So why do behaviour change interventions not work and how can we make them more effective? This article offers some ideas about what may underpin the failure of behaviour change interventions. We propose three main reasons that may explain why our current methods of conducting behaviour change interventions struggle to achieve the changes we expect: 1) our current model for testing the efficacy or effectiveness of interventions tends to a mean effect size. This ignores individual differences in response to interventions; 2) our interventions tend to assume that everyone values health in the way we do as health professionals; and 3) the great majority of our interventions focus on addressing cognitions as mechanisms of change. We appeal to people’s logic and rationality rather than recognising that much of what we do and how we behave, including our health behaviours, is governed as much by how we feel and how engaged we are emotionally as it is with what we plan and intend to do.

Drawing on our team’s experience of developing multiple interventions to promote and support health behaviour change with a variety of populations in different global contexts, this article explores strategies with potential to address these issues.

Non-pharmacological early weaning (NPEW) induces liver damage in male progeny at adulthood; however, pharmacological early weaning (PEW) does not cause this dysfunction. To elucidate this difference in liver dysfunction between these two models and determine the phenotype of female offspring, de novo lipogenesis, β-oxidation, very low-density lipoprotein (VLDL) export, and gluconeogenesis in both sexes were investigated in the adult Wistar rats that were weaned after a normal period of lactation (control group) or early weaned either by restriction of access to the dams’ teats (NPEW group) or by reduction of dams’ milk production with bromocriptine (PEW group). The offspring received standard diet from weaning to euthanasia (PN180). NPEW males had higher plasma triglycerides and TyG index, liver triglycerides, and cholesterol by de novo lipogenesis, which leads to intracellular lipids accumulation. As expected, hepatic morphology was preserved in PEW males, but they showed increased liver triglycerides. The only molecular difference between PEW and NPEW males was in acetyl-CoA carboxylase-1 (ACC-1) and stearoyl-CoA desaturase-1 (SCD-1), which were lower in PEW animals. Both early weaning (EW) females had no changes in liver cholesterol and triglyceride contents, and the hepatic cytoarchitecture was preserved. The expression of microsomal triglyceride transfer protein was increased in both the female EW groups, which could constitute a protective factor. The changes in hepatic lipid metabolism in EW offspring were less marked in females. EW impacted in the hepatic cytoarchitecture only in NPEW males, which showed higher ACC-1 and SCD-1 when compared to the PEW group. As these enzymes are lipogenic, it could explain a worsened liver function in NPEW males.

Whether maternal obesity and gestational weight gain (GWG) are associated with early-childhood development in low-income, urban, minority populations, and whether effects differ by child sex remain unknown. This study examined the impact of prepregnancy BMI and GWG on early childhood neurodevelopment in the Columbia Center for Children’s Environmental Health Mothers and Newborns study. Maternal prepregnancy weight was obtained by self-report, and GWG was assessed from participant medical charts. At child age 3 years, the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Intelligence were completed. Sex-stratified linear regression models assessed associations between prepregnancy BMI and pregnancy weight gain z-scores with child PDI and MDI scores, adjusting for covariates. Of 382 women, 48.2% were normal weight before pregnancy, 24.1% overweight, 23.0% obese, and 4.7% underweight. At 3 years, mean scores on the PDI and MDI were higher among girls compared to boys (PDI: 102.3 vs. 97.2, P = 0.0002; MDI: 92.8 vs. 88.3, P = 0.0001). In covariate-adjusted models, maternal obesity was markedly associated with lower PDI scores in boys [b = −7.81, 95% CI: (−13.08, −2.55), P = 0.004], but not girls. Maternal BMI was not associated with MDI in girls or boys, and GWG was not associated with PDI or MDI among either sex (all-P > 0.05). We found that prepregnancy obesity was associated with lower PDI scores at 3 years in boys, but not girls. The mechanisms underlying this sex-specific association remain unclear, but due to elevated obesity exposure in urban populations, further investigation is warranted.

Lower birth weight is associated with a risk of type 2 diabetes in adulthood. However, it is not clear whether this association is modified by physical activity. This study aimed to examine the association between birth weight and glycemic status and whether this association is mediated by moderate- and vigorous-intensity activity (MVPA) in Japanese women. The participants were 103 nondiabetic women (47.4 ± 10.8 years), who underwent health checkups in which data of glycated hemoglobin (HbA1c) were collected. Abdominal circumference (AC) was measured at the umbilical region. Birth weight was obtained from the Maternal and Child Health Handbook records or reported based on the participant’s or his/her mother’s recall. Time (min/day) spent in MVPA (≥3.0 metabolic equivalents) was objectively measured using a triaxial accelerometer (Actimarker EW4800). Birth weight was inversely correlated with HbA1c (r = −0.32, P < 0.01). Multiple linear regression analyses revealed that lower birth weight was associated with increased HbA1c (β = −0.22, P < 0.05) even after adjusting for age, state of menstruation, AC, and family history of diabetes. This association was little changed when MVPA was introduced as an independent variable in the model (β = −0.23, P < 0.05). These results suggest that lower birth weight may be associated with higher HbA1c levels before the onset of type 2 diabetes, irrespective of adulthood physical activity. Early-life development should be taken into account when considering the risk of diabetes in Japanese women, even if they are physically active.

Growth in the immediate postnatal period for extremely low birth weight (ELBW, birth weight < 1000 g) infants is an important topic in neonatal medicine. The goal is to ensure adequate postnatal growth and to minimize complications resulting from suboptimal growth. Past efforts have focused on postnatal nutrition as well as on minimizing comorbidities. It has not been systematically assessed whether antenatal factors play a role in postnatal growth. In this report, we conducted a retrospective study on 91 maternal–neonatal pairs. We prospectively collected maternal and neonatal demographic data, neonatal nutrition in the first 7 days of life and after enteral nutrition is fully established, comorbidity data, as well as weight data from birth to 50 weeks corrected gestational age. We developed a linear mixed-effects model to examine the role of placental insufficiency, as defined by fetal Doppler studies, in postnatal weight z-score trajectory over time in the ELBW population. We relied on Akaike Information Criterion (AIC) and Bayesian Information Criterion (BIC) for model selection. Interestingly, the selected model included a quadratic term of time and a placental insufficiency-by-time interaction term. In a covariate analysis, AIC and BIC both favored a model that included calories intake in the first 7 days of life and the total duration of antibiotics as fixed-effects, but not their interaction terms with time. Overall, we demonstrated for the first time that placental insufficiency, an antenatal factor, is a major determinant of postnatal weight trajectory in the ELBW population. Prospective studies are warranted to confirm our findings.

Little is known about the long-term effect of breastfeeding on dietary habits. We examined the association between breastfeeding duration and adherence to current dietary patterns of young women. This was a cross-sectional analysis of 587 healthy women aged ≤45 years, undergraduates or nutrition graduates. Maternal characteristics and breastfeeding duration [<6; 6–<12; ≥12 months (reference)] were recalled. Diet was assessed using a food frequency questionnaire and patterns were identified using factor analysis by principal component. Adherence to patterns was categorized in tertiles; the first (T1 = reference) was compared to T2 + T3 (moderate-to-high adherence). Logistic regression was performed considering the minimal sufficient adjustment recommended by the directed acyclic graph. Median age was 22 (interquartile range (IQR) 20; 27) years and body mass index (BMI) 22.2 (IQR 20.4; 25.0) kg/m2. The four dietary patterns identified (Processed, Prudent, Brazilian and Lacto-vegetarian) explained 27% of diet variance. Women breastfed for <6 months showed lower chance of moderate-to-high adherence to the Prudent pattern (odds ratio (OR) = 0.53, p = 0.04). Breastfeeding was not associated with the other patterns. Maternal pre-pregnancy BMI was directly associated with moderate-to-high adherence to the Processed pattern (OR = 2.01, p = 0.03) and inversely to the Prudent pattern (OR = 0.52, p = 0.02). Higher adherence to the Brazilian pattern was associated with proxies of low socioeconomic status and the Lacto-vegetarian pattern with the opposite. Confirmation in prospective studies of the association found in this study between breastfeeding with the Prudent pattern in adult offspring could suggest that early feeding practices influence long-term dietary habits, which could then affect the risk of nutrition-related diseases.

This commentary is an author response to Lu and Wang, regarding the manuscript entitled ‘Cardiovascular risk factors in offspring exposed to gestational diabetes mellitus in utero: Systematic review and meta-analysis’. We address their concern regarding duplication of studies in the meta-analysis and the quality of included studies.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) particularly among chronic consumers of added sugar-rich diets. However, the impact of early consumption of such diets on NAFLD onset and progression is unclear. Thus, this study sought to characterise metabolic factors involved in NAFLD progression in young mice fed with a high-sucrose diet (HSD). Male Swiss mice were fed HSD or regular chow (CTR) from weaning for up to 60 or 90 days. Obesity development, glucose homeostasis and serum biochemical parameters were determined at each time-point. At day 90, mice were euthanised and white adipose tissue (WAT) collected for lipolytic function assessment and liver for histology, gene expression and cytokines quantification. At day 60, HSD mice presented increased body mass, hypertriglyceridemia, peripheral insulin resistance (IR) and simple steatosis. Upon 90 days on diet, WAT from HSD mice displayed impaired insulin sensitivity, which coincided with increased fasting levels of glucose and free fatty acids (FFA), as well as NAFLD progression to NASH. Transcriptional levels of lipogenic genes, particularly stearoyl-CoA desaturase-1, were consistently increased, leading to hepatic leukocyte infiltration and pro-inflammatory cytokines spillover. Therefore, our dataset supports IR triggering in the WAT as a major factor for dysfunctional release of FFA towards portal circulation and consequent upregulation of lipogenic genes and hepatic inflammatory onset, which decisively concurred for NAFLD-to-NASH progression in young HSD-fed mice. Notwithstanding, this study forewarns against the early introduction of dietary sugars in infant diet, particularly following breastfeeding cessation.

Gestational diabetes mellitus (GDM) is a pregnancy complication that affects one in seven pregnancies. Emerging evidence demonstrates that children born of pregnancies complicated by GDM may be at increased risk of cardiovascular disease (CVD) in adulthood. Therefore, the aim of this study was to determine cardiovascular risk factors in offspring exposed to GDM in utero. PubMed, CINAHL, SCOPUS, and EMBASE databases were searched. Information was extracted on established CVD risk factors including blood pressure, lipids, blood glucose, fasting insulin, body mass index (BMI), and endothelial/microvascular function. The review protocol is registered in PROSPERO (CRD42018094983). Prospective and retrospective studies comparing offspring exposed to GDM compared to controls (non-GDM pregnancies) were considered. We included studies that defined GDM based on the International Association of Diabetes and Pregnancy Study Groups (IADPSG) definition, or prior definitions. The PRISMA guidelines were followed in conducting this systematic review. Methodological quality was assessed using the Newcastle–Ottawa Quality Assessment Scale. Study selection, data extraction, and quality assessment were done by two independent reviewers. The data were pooled using a random-effects model. Of 59 eligible studies, 24 were included in the meta-analysis. Offspring exposed to GDM had higher systolic blood pressure (mean difference (MD): 1.75 mmHg, 95% CI 0.57–2.94; eight studies, 7264 participants), BMI z-score (MD 0.11, 95% CI 0.02–0.20; nine studies, 8759 participants), and glucose (standard MD 0.43, 95% CI 0.08–0.77; 11 studies, 6423 participants) than control participants. In conclusion, offspring exposed to GDM have elevated systolic blood pressure, BMI, and glucose. Those exposed to GDM in utero may benefit from early childhood blood pressure measurements.

Although bariatric surgery is approved for a woman of child-bearing age with an interest in subsequent pregnancy, reports of in utero growth issues during pregnancy have garnered a closer look at the impact of maternal surgical weight loss on the pre- and postpartum periods. Offspring of dams having received vertical sleeve gastrectomy (VSG) are born small-for-gestational age and have increased risk for metabolic syndrome later in life. Here, we aimed to determine whether the postnatal catch-up growth trajectory of bariatric offspring may be affected by milk composition. Milk samples were collected at postnatal day 15/16 from dams having received VSG surgery and fed a high-fat diet (HFD) (H-VSG), Sham surgery and fed chow (C-Sham), or Sham surgery and fed HFD (H-Sham). Milk obtained from H-VSG dams had elevated glucose (P < 0.05) and significantly reduced triglyceride content (P < 0.01). Milk from H-Sham dams had the lowest amount of milk protein (P < 0.05). Fatty acid composition measured by fractionation was largely not affected by surgery but rather maternal diet. No difference was observed in milk leptin levels; however, insulin, adiponectin, and growth hormone levels were significantly increased in milk from H-VSG animals. H-Sham had the lowest level of immunoglobulin (Ig)A, whereas IgG was significantly reduced in H-VSG. Taken together, the quality of milk from H-VSG dams suggests that milk composition could be a factor in reducing the rate of growth during the lactation period.

The endocannabinoid system (ECS), modulated by metabolites of linoleic acid (LA), is important in regulating cardiovascular function. In pregnancy, LA is vital for foetal development. We investigated the effects of elevated LA in H9c2 cardiomyoblasts in vitro and of a high linoleic acid (HLA, 6.21%) or low linoleic acid (LLA, 1.44%) diet during pregnancy in maternal and offspring hearts. H9c2 cell viability was reduced following LA exposure at concentrations between 300 and 1000 µM. HLA diet decreased cannabinoid receptor type 2 (CB2) mRNA expression in foetal hearts from both sexes. However, HLA diet increased CB2 expression in maternal hearts. The mRNA expression of fatty acid amide hydrolase (FAAH) in foetal hearts was higher in females than in males irrespective of diet and N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) mRNA expression showed an interaction between diet and sex. Data indicate that a high LA diet alters cell viability and CB2 expression, potentially influencing cardiac function during pregnancy and development of the offspring’s heart.

The Developmental Origins of Health and Disease (DOHaD) states that intrauterine maternal environment influences postnatal life by programming offspring’s metabolism. Intrauterine milieu induced by exercise during pregnancy promotes long-lasting benefits to the offspring’s health and seems to offer some resistance against chronic diseases in adult life. Alzheimer’s disease is a public health concern with limited treatment options. In the present study, we assessed the potential of maternal exercise during pregnancy in long-term programming of young adult male rat offspring’s cerebellar metabolism in conferring neuroprotection against amyloid-β (Aβ) neurotoxicity. Female Wistar rats were submitted to a swimming protocol 1 week prior mating and throughout pregnancy (five sessions/a week lasting 30 min). Aβ oligomers were infused bilaterally in the brain ventricles of 60-day-old male offspring. Fourteen days after surgery, we measured parameters related to redox state, mitochondrial function, and the immunocontent of proteins related to synaptic function. We found that maternal exercise during pregnancy attenuated several parameters in the offspring’s male rat cerebellum, such as the reactive species rise, the increase of inducible nitric oxide synthase immunocontent and tau phosphorylation induced by Aβ oligomers, increased mitochondrial fission indicated by dynamin-related protein 1 (DRP1), and protein oxidation identified by carbonylation. Strikingly, we find that maternal exercise promotes changes in the rat offspring’s cerebellum that are still evident in young adult life. These favorable neurochemical changes in offspring’s cerebellum induced by maternal exercise may contribute to a protective phenotype against Aβ-induced neurotoxicity in young adult male rat offspring.

One of the most consumed pesticides in the world is glyphosate, the active ingredient in the herbicide ROUNDUP®. Studies demonstrate that glyphosate can act as an endocrine disruptor and that exposure to this substance at critical periods in the developmental period may program the fetus to induce reproductive damage in adulthood. Our hypothesis is that maternal exposure to glyphosate during pregnancy and lactation in mice will affect the development of male reproductive organs, impairing male fertility during adult life. Female mice consumed 0.5% glyphosate-ROUNDUP® in their drinking water [glyphosate-based herbicide (GBH) group] or filtered water [control (CTRL) group] from the fourth day of pregnancy until the end of the lactation period. Male F1 offspring were designated, according to their mother’s treatment, as CTRL-F1 and GBH-F1. Female mice that drank glyphosate displayed reduced body weight (BW) gain during gestation, but no alterations in litter size. Although GBH male F1 offspring did not exhibit modifications in BW, they demonstrated delayed testicular descent. Furthermore, at PND150, GBH-F1 mice presented a lower number of spermatozoa in the cauda epididymis and reduced epithelial height of the seminiferous epithelium. Notably, intratesticular testosterone concentrations were enhanced in GBH-F1 mice; we show that it is an effect associated with increased plasma and pituitary concentrations of luteinizing hormone. Therefore, data indicate that maternal exposure to glyphosate-ROUNDUP® during pregnancy and lactation may lead to decreased spermatogenesis and disruptions in hypothalamus–pituitary–testicular axis regulation in F1 offspring.

Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22–3.06; aOR2 = 2.05, 95% CI: 1.33–3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30–3.11; aOR2 = 2.51, 95% CI: 1.69–3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03–2.45; aOR2 = 1.99, 95% CI: 1.05–3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET.

Use of the herbicide atrazine (ATR) is banned in the European Union; yet, it is still widely used in the USA and Australia. ATR is known to alter testosterone and oestrogen production and thus reproductive characteristics in numerous species. In this proof of concept study, we examined the effect of ATR exposure, at a supra-environmental dose (5 mg/kg bw/day), beginning on E9.5 in utero, prior to sexual differentiation of the reproductive tissues, until 26 weeks of age, on the development of the mouse penis. Notably, this is the first study to specifically investigate whether ATR can affect penis characteristics. We show that ATR exposure, beginning in utero, causes a shortening (demasculinisation) of penis structures and increases the incidence of hypospadias in mice. These data indicate the need for further studies of ATR on human reproductive development and fertility, especially considering its continued and widespread use.