Evidence suggests that maternal prepregnancy body mass index (BMI) is associated with offspring cardiometabolic risk factors. This study was aimed at assessing the association of maternal prepregnancy BMI with offspring cardiometabolic risk factors in adolescence and adulthood. We also evaluated whether offspring BMI was a mediator in this association. The study included mother–offspring pairs from three Pelotas birth cohorts. Offspring cardiometabolic risk factors were collected in the last follow-up of each cohort [mean age (in years) 30.2, 22.6, 10.9]. Blood pressure was measured using an automatic device, cholesterol by using an enzymatic colorimetric method, and glucose from fingertip blood, using a portable glucose meter. In a pooled analysis of the cohorts, multiple linear regression was used to control for confounding. Mediation analysis was conducted using G-computation formula. In the adjusted model, mean systolic blood pressure of offspring from overweight and obese mothers was on average 1.25 (95% CI: 0.45; 2.05) and 2.13 (95% CI: 0.66; 3.59) mmHg higher than that of offspring from normal-weight mothers; for diastolic blood pressure, the means were 0.80 (95% CI: 0.26; 1.34) and 2.60 (95% CI: 1.62; 3.59) mmHg higher, respectively. Non-HDL cholesterol was positively associated with maternal BMI, whereas blood glucose was not associated. Mediation analyses showed that offspring BMI explained completely the association of maternal prepregnancy BMI with offspring systolic and diastolic blood pressure, and non-HDL cholesterol. Our findings suggest that maternal prepregnancy BMI is positively associated with offspring blood pressure, and blood lipids, and this association is explained by offspring BMI.

Cardiometabolic diseases exhibit changes in lipid biology, which is important as lipids have critical roles in membrane architecture, signalling, hormone synthesis, homoeostasis and metabolism. However, Developmental Origins of Health and Disease studies of cardiometabolic disease rarely include analysis of lipids. This short review highlights some examples of lipid pathology and then explores the technology available for analysing lipids, focussing on the need to develop imaging modalities for intracellular lipids. Analytical methods for studying interactions between the complex endocrine and intracellular signalling pathways that regulate lipid metabolism have been critical in expanding our understanding of how cardiometabolic diseases develop in association with obesity and dietary factors. Biochemical methods can be used to generate detailed lipid profiles to establish links between lifestyle factors and metabolic signalling pathways and determine how changes in specific lipid subtypes in plasma and homogenized tissue are associated with disease progression. New imaging modalities enable the specific visualization of intracellular lipid traffic and distribution in situ. These techniques provide a dynamic picture of the interactions between lipid storage, mobilization and signalling, which operate during normal cell function and are altered in many important diseases. The development of methods for imaging intracellular lipids can provide a dynamic real-time picture of how lipids are involved in complex signalling and other cell biology pathways; and how they ultimately regulate metabolic function/homoeostasis during early development. Some imaging modalities have the potential to be adapted for in vivo applications, and may enable the direct visualization of progression of pathogenesis of cardiometabolic disease after poor growth in early life.

Donor-conceived neonates have poorer birth outcomes, including low birth weight and preterm delivery that are associated with poorer long-term health in adulthood through the developmental origins of health and disease (DOHaD) theory. The aim of this study was to conduct the first investigation of the adult health outcomes of donor-conceived people. An online health survey was completed by 272 donor sperm-conceived adults and 877 spontaneously conceived adults from around the world. Donor and spontaneously conceived groups were matched for age, sex, height, smoking, alcohol consumption, exercise, own fertility and maternal smoking. Donor sperm-conceived adults had significantly higher reports of being diagnosed with type 1 diabetes (P = 0.031), thyroid disease (P = 0.031), acute bronchitis (P = 0.008), environmental allergies (P = 0.046), sleep apnoea (P = 0.037) and having ear tubes/grommets surgically implanted (P = 0.046). This is the first study to investigate the health outcomes of adult donor sperm-conceived people. Donor sperm-conceived adults self-reported elevated frequencies of various health conditions. The outcomes are consistent with birth defect data from donor sperm treatment and are consistent with the DOHaD linking perturbed early growth and chronic disease in adulthood.

Rat offspring born to dams fed a high multivitamin diet (HV) are shown to have increased risks of obesity and metabolic syndrome. We hypothesized that a low-vitamin postweaning diet would enhance these characteristics in offspring born to HV dams. During pregnancy, Wistar rats were fed the AIN-93G diet with or without a 10-fold increase in vitamin content. In Experiment 1, at weaning, males were fed the recommended diet (RV) or a diet with 1/3 the vitamin content (1/3 RV) for 12 weeks. In Experiment 2, males and females were fed the RV diet or 1/6 RV diet for 35 weeks. Body weight was measured on a weekly basis, food intake on a daily basis, and for 1 h after an overnight fast following glucose gavage at 6, 12 and 24 weeks. Blood glucose and insulin responses to an oral glucose load were measured at 30 weeks. Males from HV dams, compared with those from RV dams, gained more weight in Experiment 1 (+7%, P < 0.05) and Experiment 2 (+11%, P < 0.0001), along with higher glucose response (+33%, P < 0.05). The 1/6 RV pup diet led to lower weight gain in males (−16%, P < 0.0001) and females (−13%, P < 0.0005), and lower food intake in males (−9%, P < 0.01) independent of the gestational diet. Females on the 1/6 RV diet and from HV dams had higher 1 h food intake (+36%, P < 0.05) and lower insulin response (−25%, P < 0.05) compared with those from RV dams. Exposure of the offspring to low-vitamin diets did not amplify the expression of the metabolic syndrome observed in those born to dams fed an HV diet.

In this study, we investigate if children born following assisted reproduction technologies (ARTs) are at an increased risk for long-term ophthalmic complications. For this purpose, a population-based cohort analysis was conducted which included all deliveries between 1991 and 2014 at a single tertiary medical center. Offspring were classified relative to conception method as ART or spontaneous pregnancies. Offspring hospitalizations up to the age of 18 years involving ophthalmic morbidities were evaluated according to a predefined set of ICD-9 codes. A Kaplan–Meier survival curve was used to compare cumulative hospitalization rates in exposed (ART) and unexposed offspring (spontaneous), and a Cox proportional hazards model was used to control for potential confounders. A total of 243,682 deliveries were included in the study. In that, 1.8% of the deliveries (4364) were of mothers who underwent fertility treatments and 98.2% (239,318) were conceived spontaneously. Offspring born to mothers who underwent fertility treatments had a significantly higher hospitalization rate involving ophthalmic morbidity, as compared to spontaneously conceived offspring (1.2% vs. 1.0%, p = 0.04). The Kaplan–Meier survival curve pointed to a significantly higher cumulative incidence of ophthalmic morbidity following ART (log rank p = 0.02). Cox proportional hazards model was adjusted for maternal age, preterm delivery, maternal hypertensive disorders, diabetes, and mode of delivery which demonstrated ART as an independent risk factor for long-term pediatric ophthalmic morbidity (adjusted hazard ratio = 1.37, CI 1.04–1.80, p-value = 0.02). We concluded that ART is an independent risk factor for long-term ophthalmic morbidity of the offspring.

Adipose tissue (AT) dysfunction links obesity of any cause with cardiometabolic disease, but whether early-life nutritional deficiency can program adipocyte dysfunction independently of obesity is untested. In 3–5-month-old juvenile microswine offspring exposed to isocaloric perinatal maternal protein restriction (MPR) and exhibiting accelerated prepubertal fat accrual without obesity, we assessed markers of acquired obesity: adiponectin and tumor necrosis factor (TNF)-α messenger ribonucleic acid (mRNA) levels and adipocyte size in intra-abdominal (ABD-AT) and subcutaneous (SC-AT) adipose tissues. Plasma cortisol, leptin and insulin levels were measured in fetal, neonatal and juvenile offspring. In juvenile low-protein offspring (LPO), adipocyte size in ABD-AT was reduced 22% (P = 0.011 v. controls), whereas adipocyte size in SC-AT was increased in female LPO (P = 0.05) and normal in male LPO; yet, adiponectin mRNA in LPO was low in both sexes and in both depots (P < 0.001). Plasma leptin (P = 0.004) and cortisol (P < 0.05) were reduced only in neonatal LPO during MPR. In juveniles, correlations between % body fat and adiponectin mRNA, TNF-α mRNA or plasma leptin were significant in normal-protein offspring (NPO) but absent in LPO. Plasma glucose in juvenile LPO was increased in males but decreased in females (interaction, P = 0.023); plasma insulin levels and insulin sensitivity were unaffected. Findings support nutritional programming of adipocyte size and gene expression and subtly altered glucose homeostasis. Reduced adiponectin mRNA and adipokine dysregulation in juvenile LPO following accelerated growth occurred independently of obesity, adipocyte hypertrophy or inflammatory markers; thus, perinatal MPR and/or growth acceleration can alter adipocyte structure and disturb adipokine homeostasis in metabolically adverse patterns predictive of enhanced disease risk.

Research into associations between early life nutritional exposures and vulnerability to adult non-communicable disease (NCD) highlights the importance of maternal diet. A booklet outlining evidence-based dietary guidelines for the first 1000 days of life was first published in 2016 by early life nutrition experts for distribution to pregnant women in Australia and New Zealand. First-time New Zealand mothers’ (n=9) perceptions of the booklet and its relevance for the future health of their child were explored via semi-structured focus groups and interviews. Recruitment took place via social media channels and antenatal classes around Auckland. Three major themes were identified using thematic analysis: 1. A difference in the ways mothers related to the booklet depending on their apparent level of health literacy and communication preferences; 2. A tendency for women to outsource decision-making to nutrition ‘rules’, rather than interpreting information to suit personal circumstances; 3. Intense pressure to comply, resulting in feelings of shame or guilt when the ‘rules’ were not followed. In this study, first-time mums expressed feeling under pressure to ‘get it right’ and identified a desire for more support from healthcare providers and society. Nutrition education is essential; however, a booklet should provide a starting point for conversation rather than a stand-alone list of recommendations. Further exploration is needed to develop a resource that can be used by health professionals working alongside women and their partners to support healthy child development.

It was reported that high blood cholesterol levels increased the susceptibility to mitochondrial dysfunction. This study hypothesized that the gestational hypercholesterolemia (HC) could induce the mitochondrial dysfunction in term human placenta. The eligible pregnant women were recruited from Xuanwu Hospital in Beijing during their first prenatal visit (before their 10th week of pregnancy). In total, 19 pregnant women whose serum total cholesterol levels were higher than 7.25 mm at third trimester (measured at 36–38 weeks) were selected as gestational HC. Other 19 pregnant women with normal cholesterol level matched with age, pre-gestational body mass index, and the neonatal gender were included as the control group. Full-term placenta samples were collected. The mitochondrial DNA (mtDNA) copy number, messenger RNA (mRNA) expression of cytochrome c oxidase subunit I, adenosine triphosphate monophosphatase 6 (ATP6ase), citrate synthase, peroxisome proliferator-activated receptor-γ (PPARγ) co-activator 1α, PPARγ co-activator 1β and estrogen-related receptor-α, and the activity of mitochondrial respiratory chain enzyme complex were measured. Pregnancy outcomes were obtained by extraction from medical records and the labor ward register. The results showed that only placental mtDNA copy number and mRNA expression of ATP6ase were significantly decreased in HC group. No significant differences were detected of other measurements between the two groups. These findings indicated that gestational HC might not induce the damage of placental function seriously.

In addition to being associated with a higher risk of complications during pregnancy, twinning may also be a proxy for altered hormonal exposure for mothers and twin offspring, with implications for their health later in life. We compared maternal and fetal steroid hormone and insulin-like growth factor concentrations between singleton (n=62) and twin (n=41) pregnancies. Maternal concentrations of androgens, estrogens, insulin-like growth factor (IGF)-1, IGF-binding protein (BP)-3 and prolactin were quantified during the third trimester and at delivery, as well as in the fetal circulation at birth. Geometric means accounting for gestational age were calculated for hormone concentrations and compared between matched twin and singleton pregnancies. Most maternal hormone concentrations were modestly higher in twin than in singleton pregnancies in the third trimester (ranging from 8.3% for IGF-1 to 17.1% for estradiol) and at delivery (ranging from 11.1% for IGFBP-3 to 15.2% for estriol). Cord serum hormones were generally similar in twin and singleton pregnancies, except for IGFBP-3, which was 200% lower in twins. The modest differences in maternal hormones in late gestation seem unlikely to explain alterations in hormonally related disease risk in mothers of twins compared with singletons. The large deficit of IGFBP-3 in the fetal circulation of twins at birth may allow for sufficient concentrations of IGF-2 for growth and development in an environment of shared nutritional resources.

We investigated the influence of maternal yellow-pea fiber supplementation in obese pregnancies on offspring metabolic health in adulthood. Sixty newly-weaned female Sprague-Dawley rats were randomized to either a low-calorie control diet (CON) or high calorie obesogenic diet (HC) for 6-weeks. Obese animals were then fed either the HC diet alone or the HC diet supplemented with yellow-pea fiber (HC + FBR) for an additional 4-weeks prior to breeding and throughout gestation and lactation. On postnatal day (PND) 21, 1 male and 1 female offspring from each dam were weaned onto the CON diet until adulthood (PND 120) for metabolic phenotyping. Adult male, but not female, HC offspring demonstrated increased body weight and feed intake vs CON offspring, however no protection was offered by maternal FBR supplementation. HC male and female adult offspring demonstrated increased serum glucose and insulin resistance (HOMA-IR) compared with CON offspring. Maternal FBR supplementation improved glycemic control in male, but not female offspring. Compared with CON offspring, male offspring from HC dams demonstrated marked dyslipidemia (higher serum cholesterol, increased number of TG-rich lipoproteins, and smaller LDL particles) which was largely normalized in offspring from HC + FBR mothers. Male offspring born to obese mothers (HC) had higher hepatic TG, which tended to be lowered (p = 0.07) by maternal FBR supplementation.

Supplementation of a maternal high calorie diet with yellow-pea fiber in prepregnancy and throughout gestation and lactation protects male offspring from metabolic dysfunction in the absence of any change in body weight status in adulthood.

We previously demonstrated decreased placental perfusion, reduced amniotic fluid protein content, and increased pregnancy loss in a nonhuman primate model of gestational protein restriction. Here, our objective was to link these detrimental findings with a functional placental assessment. As blood flow is critical to maternal-fetal exchange, we hypothesized that a protein-restricted diet would impair placental taurine uptake. Pregnant rhesus macaques were maintained on either control chow (CON, n = 5), a 33% protein-restricted diet (PR33, n = 5), or a 50% PR diet (PR50, n = 5) prior to and throughout pregnancy. Animals were delivered on gestational day 135 (G135; term is G168). Taurine activity was determined in fresh placental villous explants. Taurine transporter (TauT) protein expression, placental growth factor (PLGF), and insulin-like growth factor (IGF)-1 and IGF-2 protein concentrations were measured, and histological assessment was performed. Fetal body weights and placental weights were comparable between all three groups at G135. Placental taurine uptake was decreased in PR33- and PR50-fed animals compared to CON, yet TauT expression was unchanged across groups. PLGF was significantly increased in PR50 vs. CON, with no change in IGF-1 or IGF-2 expression in placental homogenate from PR-fed animals. Accelerated villous maturation was observed in all PR50 cases, three of five PR33, and was absent in CON. We demonstrate conserved fetal growth, despite a decrease in placental taurine uptake. Increased expression of PLGF and expansion of the syncytiotrophoblast surface area in the severely protein-restricted animals suggest a compensatory mechanism by the placenta to maintain fetal growth.

Polyunsaturated fatty acids are critically important for newborn nutrition and in the trajectory of growth and developmental processes throughout early life. This systematic review (PROSPERO ID: CRD42023400059) critically analyzes literature pertaining to how omega-3 and omega-6 fatty acids in human milk are related to health outcomes in early life. Literature selected for the review were published between 2005 and 2020 and included assessments in healthy term children between 0 and 5 years of age. The studies reported the relation between human milk fatty acids docosahexaenoic acid (C22:6n-3, DHA), eicosapentaenoic acid (C20:5n-3, EPA), alpha-linolenic acid (C18:3n-3, ALA), arachidonic acid (C20:4n-6, AA), and linoleic acid (C18:2n-6, LA) with three domains of health outcomes: neurodevelopment, body composition, and allergy, skin & eczema. Results from the 21 studies consistently suggested better health outcomes across the three domains for infants consuming milk with higher concentrations of total n-3, DHA, EPA, and ALA. Negative health outcomes across the three domains were associated with higher levels of total n-6, AA, and LA in milk. N-3 and n-6 content of milk were related to neurodevelopmental, body composition, and allergy, skin & eczema outcomes with moderate certainty. Maternal diet impacting milk fatty acid content and fatty acid desaturase genotype modifying physiologic responses to fatty acid intake were prominent gaps identified in the review using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies and GRADE approach. This research study can inform baby nutrition product development, and fatty acid intake recommendations or dietary interventions for mothers and children.

Asymptomatic bacteriuria (ASB) is a well-acknowledged infectious entity during pregnancy; yet its long-term implications are not well investigated. The present study aimed to test the association between maternal ASB during pregnancy and long-term offspring infectious hospitalizations. A population-based cohort analysis was conducted, comparing the incidence of long-term infectious-related hospitalizations of offspring born to mothers who were diagnosed with ASB during pregnancy, and those who did not have ASB. The study was conducted at a tertiary medical center and included all singleton deliveries between the years 1991 and 2014. Infectious morbidities were based on a predefined set of International Classification of Disease-9 codes. A Kaplan−Meier survival curve compared cumulative infectious hospitalization incidence between the groups, and a Cox regression model was used to adjust for confounding variables. During the study period, 212,984 deliveries met inclusion criteria. Of them, 5378 (2.5%) were diagnosed with ASB. As compared to offspring of non-ASB mothers, total long-term infectious hospitalizations were significantly higher among children to mothers who were diagnosed with ASB (13.1% vs. 11.1%, OR = 1.2, 95% CI 1.11–1.30, P ≤ 0.001). Likewise, a Kaplan−Meier curve demonstrated higher cumulative incidence of infectious hospitalizations among children born to mothers with ASB (log rank, P = 0.006). In the Cox regression model, while controlling for maternal age, diabetes mellitus, ethnicity, hypertensive disorders, and gestational age, maternal ASB was noted as an independent risk factor for long-term infectious morbidity in the offspring (adjusted HR = 1.1, 95% CI 1.01–1.17, P = 0.042). ASB during pregnancy increases offspring susceptibility to long-term infectious hospitalizations.

The DOHaD research field has successfully associated adult non-communicable diseases with inadequate nutrition in early periods of life. More recently, different types of exposure have been linked with impaired developmental outcomes and later health consequences, such as cesarean section at delivery, air pollution and domestic violence during pregnancy. The aim of this work is to bring up this issue looking at the published evidence on these three highly prevalent hazards in Latin American countries.

Intrauterine undernutrition may lead to fetal vascular programming. We compared abdominal aortic intima-media thickness (aIMT) and aortic diameter (aD) between appropriate for gestational age (AGA) and growth-restricted fetuses (GRF). We recruited 136 singleton fetuses at 34–37 weeks of gestation from Fetal Medicine Unit of Aga Khan University Hospital, Karachi (January–November 2017). Subjects were classified as AGA (n = 102) and GRF (n = 34) using INTER-GROWTH 21st growth reference and standard ultrasound protocol. Their far- and near-wall aIMT and aD were compared after adjustment of maternal age, first-trimester body mass index, fetal gender, hypertension and hyperglycemia in pregnancy. As the severity of growth restriction increased in GRF, aIMT and aD showed an increasing and a decreasing trend, respectively. Both far- and near-wall aIMT in GRF [(adj. β = 0.082, 95% confidence interval [CI] 0.042–0.123) and (adj. β = 0.049, 95% CI 0.010–0.089)] were significantly greater with reference to AGA fetuses. GRF subgroup analysis into small for gestational age (SGA) fetuses and intrauterine growth restricted (IUGR) revealed highly significant difference between AGA and IUGR for far (0.142 mm, P-value < 0.001) and near-wall aIMT (0.115 mm, P-value < 0.001) and marginally significant aD difference (0.51 mm, P-value 0.05). These findings suggest that the extent of fetal aortic remodelling is influenced by the severity of growth restriction. Hence, the targeted interventions for the cardiovascular health promotion of IUGR and SGA born neonates are desirable during early childhood, particularly in set ups with high prevalence of low birth weight babies.

While metabolic disorders such as obesity and diabetes are costly and deadly to the current population, they are also extremely detrimental to the next generation. Much of the current literature focuses on the negative impact of poor maternal choices on offspring disease, while there is little work examining maternal behaviors that may improve offspring health. Research has shown that voluntary maternal exercise in mouse models improves metabolic function in offspring. In this study, we hypothesized that controlled maternal exercise in a mouse model will effect positive change on offspring obesity and glucose homeostasis. Female mice were separated into three groups: home cage, sedentary, and exercise. The sedentary home cage group was not removed from the home cage, while the sedentary wheel group was removed from the cage and placed in an immobile wheel apparatus. The exercise group was removed from the home cage and run on the same wheel apparatus but with the motor activated at 5–10 m/min for 1 h/d prior to and during pregnancy. Offspring were subjected to oral glucose tolerance testing and body composition analysis. There was no significant difference in offspring glucose tolerance or body composition as a consequence of the maternal exercise intervention compared to the sedentary wheel group. There were no marked negative consequences of the maternal controlled exercise intervention. Further research should clarify the potential advantages of the controlled exercise model and improve experimental techniques to facilitate translation of this research to human applications.

An appropriate foetal cardiovascular (CV) response to reduced substrate supply (e.g. oxygen or other nutrients) is vital for growth and development, and may impact on CV control. The prevailing nutritional environment and associated CV changes may influence subsequent CV responses to challenges during late gestation, for example, umbilical cord occlusion (UCO). We investigated the effect of low-circulating glucose on foetal CV control mechanisms and response to UCO. Under general anaesthesia, late gestation foetal sheep (n = 7, 119 days gestational age (dGA), term ∼147 days) were implanted with vascular catheters, a bladder catheter, electrocardiogram electrodes and an umbilical cord occluder. Mean arterial pressure (MAP), heart rate (HR) and kidney function were monitored during maternal saline (MSAL, 125dGA) and insulin (MINS, 126dGA) infusion, and foetal CV responses were assessed during incremental doses of angiotensin II, a 90-s total UCO, and administration of phenylephrine to assess baroreflex function. During MINS infusion, the decrease in maternal and foetal blood glucose was associated with a small but significant decrease in foetal HR and reduced foetal baroreflex sensitivity (P < 0.05). The increase in foetal MAP during a 90-s UCO was greater during hypoglycaemia (P < 0.05). The MAP response to angiotensin II was not affected by hypoglycaemia. Decreased foetal HR and baroreflex sensitivity and increased CV responsiveness to UCO during hypoglycaemia indicates altered CV homoestatic mechanisms. The combination of altered nutrition and a CV challenge, such as UCO, during late gestation may have a cumulative effect on foetal CV function.

This study examined the link between two biological markers of stress vulnerability at 22–26 years of age and telomere length at 30–35 among extremely low birth weight (ELBW; <1000 g) survivors and normal birth weight (NBW; >2500 g) control participants. Sixteen ELBW and 22 NBW participants provided baseline afternoon salivary cortisol samples and resting frontal electroencephalogram (EEG) alpha asymmetry data at 22–26 years. Buccal cells were assayed for telomere length at 30–35 years. Analyses controlled for sex, postnatal steroid exposure, childhood socioeconomic status, time of cortisol sample collection, and body mass index at 22–26 years. Salivary cortisol and frontal asymmetry at age 22–26 independently predicted telomere length at age 30–35, such that relatively higher cortisol and greater relative right frontal asymmetry at rest predicted telomere shortening among NBW controls, but not among ELBW survivors. However, similar associations were not noted in ELBW survivors, suggesting that ELBW survivors may have different mechanisms of stress coping as a result of their early-life exposures. These findings offer preliminary evidence in support of the role of stress in the genesis of cellular senescence at least among those born at NBW, but that these links may differ in those born preterm.

Embryonal rhabdomyosarcoma is one of the major defined histologic variants of rhabdomyosarcoma that is mainly reported in children. The histologic appearance of this neoplastic entity recapitulates normal myogenesis. The tumor cells variably exhibit the different cellular phases of myogenesis ranging from undifferentiated mesenchymal cells to elongated myoblasts, multinucleated myotubes and differentiated muscle fibers. The carefully orchestrated embryonic signaling pathways that are involved in myogenesis, conceivably also result in the genesis of rhabdomyosarcoma; albeit as a corollary to an imbalance. We have attempted to review the pathogenesis of embryonal rhabdomyosarcoma in an endeavor to understand better, how closely it is linked to normal myogenesis in terms of its molecular dynamics and histologic presentation.