The mechanisms linking maternal nutrition to fetal growth and programming of adult disease remain to be fully established. We review data on changes in placental transport in response to altered maternal nutrition, including compromized utero-placental blood flow. In human intrauterine growth restriction and in most animal models involving maternal undernutrition or restricted placental blood flow, the activity of placental transporters, in particular for amino acids, is decreased in late pregnancy. The effect of maternal overnutrition on placental transport remains largely unexplored. However, some, but not all, studies in women with diabetes giving birth to large babies indicate an upregulation of placental transporters for amino acids, glucose and fatty acids. These data support the concept that the placenta responds to maternal nutritional cues by altering placental function to match fetal growth to the ability of the maternal supply line to allocate resources to the fetus. On the other hand, some findings in humans and mice suggest that placental transporters are regulated in response to fetal demand signals. These observations are consistent with the idea that fetal signals regulate placental function to compensate for changes in nutrient availability. We propose that the placenta integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensors. Together, these signals regulate placental growth and nutrient transport to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.

The availability of clinically feasible infant body composition assessment can inform current questions regarding the developmental origins of chronic disease. A strategic approach will facilitate more rapid advancement in knowledge. The objective of this study was to summarize published evidence and ongoing research activity in infant body composition using the PEA POD® infant body composition system. All published studies using the PEA POD® were identified and grouped according to study population and question. All centers with PEA POD® units were invited to participate in an online survey regarding past, current and future PEA POD® use, and results were analyzed using descriptive statistics. The resulting information was used to identify gaps or limitations in existing knowledge, thus highlighting potential research priorities. Twenty-seven published articles were identified and grouped into six research themes. Although the number of infants studied is significant in some areas, interpretation of data is limited by methodological differences. Survey responses were received from 16 of ∼60 centers. Research themes echoed those identified from the published literature. Controlling for or reporting potential confounding variables is essential for understanding infant body composition data. Measurement of health outcome variables would be helpful in identifying associations.

Contemporary clinical practice for the care of the prematurely born babies has markedly improved their rates of survival so that most of these babies are expected to grow up to live a healthy functional life. Since the clinical follow-up is of short duration (years), only limited data are available to relate non-communicable diseases in adult life to events and interventions in the neonatal period. The major events that could have a programming effect include: (1) intrauterine growth restriction; (2) interruption of pregnancy with change in redox and reactive oxygen species (ROS) injury; (3) nutritional and pharmacological protocols for clinical care; and (4) nutritional care in the first 2 years resulting in accelerated weight gain. The available data are discussed in the context of perturbations in one carbon (methyl transfer) metabolism and its possible programming effects. Although direct evidence for genomic methylation is not available, clinical and experimental data on impact of redox and ROS, of low protein intake, excess methionine load and vitamin A, on methyl transfers are reviewed. The consequences of antenatal and postnatal administration of glucocorticoids are presented. Analysis of the correlates of insulin sensitivity at older age, suggests that premature birth is the major contributor, and is compounded by gain in weight during infancy. We speculate that premature interruption of pregnancy and neonatal interventions by affecting one carbon metabolism may cause programming effects on the immature baby. These can be additive to the effects of intrauterine environment (growth restriction) and are compounded by accelerated growth in early infancy.

Genetic variants in the FTO (fat mass- and obesity-associated) gene have the highest association of all obesity-associated genes. Its placental expression was shown to relate to birth weight, suggesting that it may participate in the control of fetal weight gain. To gain more insight into the implication of FTO in fetal growth, we measured its placental expression in samples including extremes of abnormal fetal growth, such as after intrauterine growth restriction (IUGR) or macrosomia in both rats and humans. In rats, fetal growth was modulated by maternal nutritional modifications. In humans, placental villi were collected from pathological pregnancies (i.e. with IUGR or fetal macrosomia). Placental FTO mRNA expression was reduced by IUGR but was not significantly affected by macrosomia in either rats or humans. Our data suggest that placental FTO may participate in interactions between the in utero environment and the control of fetal growth under IUGR conditions by modulating epigenetic processes.

The risk for many chronic diseases appears to be mediated in part by birth weight. Among Aboriginal Canadians, the prevalence of end-stage renal disease and cardiovascular disease risk is disproportionately high, largely because of elevated diabetes prevalence. The relationships between birth weight (and other potential risk factors) and diabetes, hypertension, proteinuria and overweight/obesity were explored in 1439 rural Albertans (Canada), of whom 67.3% were Aboriginal. At voluntary outreach screening programs, demographic and clinical data were measured and recalled birth weights recorded. Statistical modeling using logistic regression was used to evaluate the relationships. In the final adjusted models, associations remained for low birth weight and proteinuria [odds ratio (OR) 2.36; 95% CI 1.24–4.49], as well as for high birth weight and overweight/obesity (OR 1.58; 95% CI 1.00–2.53). These findings emphasize the need to strive for healthy pregnancies, with appropriate weight gains in these and other disadvantaged populations around the world.

Antenatal corticosteroids are used to augment fetal lung maturity in human pregnancy. Dexamethasone (DEX) is also used to treat congenital adrenal hyperplasia of the fetus in early pregnancy. We previously reported effects of synthetic corticosteroids given to sheep in early or late gestation on pregnancy length and fetal cortisol levels and glucocorticoids alter plasma insulin-like growth factor (IGF) and insulin-like growth factor binding protein (IGFBP) concentrations in late pregnancy and reduce fetal weight. The effects of administering DEX in early pregnancy on fetal organ weights and betamethasone (BET) given in late gestation on weights of fetal brain regions or organ development have not been reported. We hypothesized that BET or DEX administration at either stage of pregnancy would have deleterious effects on fetal development and associated hormones. In early pregnancy, DEX was administered as four injections at 12-hourly intervals over 48 h commencing at 40–42 days of gestation (dG). There was no consistent effect on fetal weight, or individual fetal organ weights, except in females at 7 months postnatal age. When BET was administered at 104, 111 and 118 dG, the previously reported reduction in total fetal weight was associated with significant reductions in weights of fetal brain, cerebellum, heart, kidney and liver. Fetal plasma insulin, leptin and triiodothyronine were also reduced at different times in fetal and postnatal life. We conclude that at the amounts given, the sheep fetus is sensitive to maternal administration of synthetic glucocorticoid in late gestation, with effects on growth and metabolic hormones that may persist into postnatal life.

Two pregnancy cohorts were used to investigate the association between single-nucleotide polymorphisms (SNPs) in genes within the insulin-like growth factor (IGF)-axis and antenatal and postnatal growth from birth to adolescence. Longitudinal analyses were conducted in the Raine pregnancy cohort (n = 1162) using repeated measures of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) from 18 to 38 weeks gestation and eight measures of postnatal height and weight (1–17 years). Replications of significant associations up to birth were undertaken in the Generation R Study (n = 2642). Of the SNPs within the IGF-axis genes, 40% (n = 58) were associated with measures of antenatal growth (P ⩽ 0.05). The majority of these SNPs were in receptors; IGF-1R (23%; n = 34) and IGF-2R (13%; n = 9). Fifteen SNPs were associated with antenatal growth (either AC or HC or FL) in Raine (P ⩽ 0.005): five of which remained significant after adjusting for multiple testing. Four of these replicated in Generation R. Associations were identified between 38% (n = 55) of the IGF-axis SNPs and postnatal height and weight; 21% in IGF-1R (n = 31) and 9% in IGF-2R (n = 13). Twenty-six SNPs were significantly associated with both antenatal and postnatal growth; 17 with discordant effects and nine with concordant effects. Genetic variants in the IGF-axis appear to play a significant role in antenatal and postnatal growth. Further replication and new analytic methods are required in order to better understand this key metabolic pathway integrating biologic knowledge about the interaction between IGF-axis components.

Undernutrition during critical or sensitive prenatal periods may ‘program’ the fetus for increased chronic disease and mortality in later life. Using birth cohorts that were or were not exposed to severe food shortage in Utah in the mid-19th century, this study examines how in utero exposure to undernutrition is associated with mortality after age 50. The Utah Population Database is used to identify 1392 prenatally exposed individuals and 29,022 individuals from subsequent, unexposed birth cohorts. Gompertz hazards with parametric frailty show that males born between April and June of the famine period (and hence exposed during critical periods in utero during the winter months) have higher mortality risks compared with post-famine cohorts. Alternative Cox non-proportional hazard models suggest that females born during the same period have higher initial mortality risks (starting at age 50) that decline over time creating a mortality crossover with unexposed women at approximately age 70, a result not found for men. An ancillary sibling analysis that uses shared frailty survival models to compare individuals with prenatal exposure to undernutrition to their younger (post-famine) same-sex siblings finds no significant differences in adult mortality for males but the pattern for females support the findings from the previous analysis. Although findings are sensitive to model choice, this study presents evidence that is consistent with an association between undernutrition in utero and adult mortality, shows that effects may be sensitive to the duration and gestational period of exposure, and illustrates the differential exposure effects between genders.

There is evidence that epigenetic changes occur early in breast carcinogenesis. We hypothesized that early-life exposures associated with breast cancer would be associated with epigenetic alterations in breast tumors. In particular, we examined DNA methylation patterns in breast tumors in association with several early-life exposures in a population-based case–control study. Promoter methylation of E-cadherin, p16 and RAR-β2 genes was assessed in archived tumor blocks from 803 cases with real-time methylation-specific PCR. Unconditional logistic regression was used for case–case comparisons of those with and without promoter methylation. We found no differences in the prevalence of DNA methylation of the individual genes by age at menarche, age at first live birth and weight at age 20. In case–case comparisons of premenopausal breast cancer, lower birth weight was associated with increased likelihood of E-cadherin promoter methylation (OR = 2.79, 95% CI, 1.15–6.82, for ⩽2.5 v. 2.6–2.9 kg); higher adult height with RAR-β2 methylation (OR = 3.34, 95% CI, 1.19–9.39, for ⩾1.65 v. <1.60 m); and not having been breastfed with p16 methylation (OR = 2.75, 95% CI, 1.14–6.62). Among postmenopausal breast cancers, birth order was associated with increased likelihood of p16 promoter methylation. Being other than first in the birth order was inversely associated with likelihood of ⩾1 of the three genes being methylated for premenopausal breast cancers, but positively associated with methylation in postmenopausal women. These results suggest that there may be alterations in methylation associated with early-life exposures that persist into adulthood and affect breast cancer risk.

Street drug use during pregnancy is detrimental to fetal development. Although the prevalence of wheeze is high in offspring of substance-abusing mothers, nothing is known about the role of street drug use during pregnancy in its development. We investigated the impact of maternal street drug use and distress during pregnancy on the development of wheeze and allergy in preschool children. Questionnaire data were accessed from the Community Perinatal Care trial of 791 mother–child pairs in Calgary, Alberta. Using logistic regression, the association between maternal substance use and distress during pregnancy, and wheeze and allergy at age 3 years was determined in boys and girls. After adjusting for alcohol use during pregnancy, pre- and postnatal tobacco use, preterm birth, duration of exclusive breastfeeding, daycare attendance and maternal socioeconomic status, maternal street drug use during pregnancy [odds ratio (OR): 5.02, 95% confidence interval (CI): 1.30–19.4] and severe maternal distress during pregnancy (OR: 5.79, 95% CI: 1.25–26.8) were associated with wheeze in girls. In boys, an independent association was found between severe distress during pregnancy (OR: 3.85, 95% CI: 1.11–13.3) and allergies, but there was no association with maternal street drug use. In conclusion, we found an association between maternal street drug use and wheeze in preschool girls that could not be accounted for by maternal distress, smoking or alcohol use during pregnancy. Prenatal programming effects of street drugs may explain this association.