Ontogeny and nutritional programming of the hepatic growth hormone-insulin-like growth factor-prolactin axis in the sheep.

The liver is an important metabolic and endocrine organ in the fetus, but the extent to which its hormone receptor sensitivity is developmentally regulated in early life is not fully established. Therefore, we examined developmental changes in mRNA abundance for the GH receptor (GHR) and prolactin receptor (PRLR) plus IGF-I and -II and their receptors. Fetal and postnatal sheep were sampled at either 80 or 140 d gestation, 1 or 30 d, or 6 months of age. The effect of maternal nutrient restriction between early gestation to midgestation (i.e. 28-80 d gestation, the time of early liver growth) on gene expression was also examined in the fetus and juvenile offspring. Gene expression for the GHR, PRLR, and IGF-I receptor increased through gestation peaking at birth, whereas IGF-I was maximal near to term. In contrast, IGF-II mRNA decreased between midgestation and late gestation to increase after birth, whereas IGF-II receptor remained unchanged. A substantial decline in mRNA abundance for GHR, PRLR, and IGF-I receptor then occurred up to 6 months. Maternal nutrient restriction reduced GHR and IGF-II receptor mRNA abundance in the fetus, but caused a precocious increase in the PRLR. Gene expression for IGF-I and -II were increased in juvenile offspring born to nutrient-restricted mothers. In conclusion, there are marked differences in the ontogeny and nutritional programming of specific hormones and their receptors involved in hepatic growth and development in the fetus. These could contribute to changes in liver function during adult life.

The association between hospitalisation for childhood head injury and academic performance: evidence from a population e-cohort study.

BACKGROUND: Childhood head injury has the potential for lifelong disability and burden. This study aimed to establish the association between admission to hospital for childhood head injury and early academic performance. METHODS: The Wales Electronic Cohort for Children (WECC) study is comprised of record-linked routinely collected data, on all children born or residing in Wales. Anonymous linking fields are used to link child and maternal health, environment and education records. Data from WECC were extracted for children born between September 1998 and August 2001. A Generalised Estimating Equation model, adjusted for clustering based on the maternal identifier as well as other key confounders, was used to establish the association between childhood head injury and performance on the Key Stage 1 (KS1) National Curriculum assessment administered to children aged 5-7 years. Head injury was defined as an emergency admission for >24 h for concussion, skull fracture or intracranial injury prior to KS1 assessment. RESULTS: Of the 101 892 eligible children, KS1 results were available for 90 661 (89%), and 290 had sustained a head injury. Children who sustained an intracranial injury demonstrated significantly lower adjusted odds of achieving a satisfactory KS1 result than children who had not been admitted to hospital for head injury (adjusted OR 0.46, 95% CI 0.30 to 0.72). CONCLUSIONS: The findings of this population e-cohort study quantify the impact of head injury on academic performance, highlighting the need for enhanced head injury prevention strategies. The results have implications for the care and rehabilitation of children admitted to hospital with head injury.

Gestational age, birth weight, and risk of respiratory hospital admission in childhood.

OBJECTIVE: To investigate the risk of emergency respiratory hospital admission during childhood associated with gestational age at birth and growth restriction in utero. METHODS: The study included a total population electronic birth cohort with anonymized record-linkage of multiple health and administrative data sets. Participants were 318,613 children born in Wales, United Kingdom, between May 1, 1998, and December 31, 2008. The main outcome measure was emergency respiratory hospital admissions. RESULTS: The rate of admission in the first year of life ranged from 41.5 per 100 child-years for infants born before 33 weeks' gestation to 9.8 per 100 child-years for infants born at 40 to 42 weeks' gestation. The risk of any emergency respiratory admission up to age 5 years increased as gestational age decreased to <40 weeks. Even at 39 weeks' gestation, there was an increased risk of emergency hospital admissions for respiratory conditions compared with infants born at 40 to 42 weeks (adjusted hazard ratio 1.10; 95% confidence interval 1.08-1.13). Small for gestational age (<10th centile for gestation and gender-specific birth weight) was independently associated with an increased risk of any emergency respiratory admission to hospital (adjusted hazard ratio 1.07; 95% confidence interval 1.04-1.10). CONCLUSIONS: The risk of emergency respiratory admission up to age 5 years decreased with each successive week in gestation up to 40 to 42 weeks. Although the magnitude of increased risk associated with moderate and late preterm births is small, the number of infants affected is large and therefore presents a significant impact on health care services.

Do children who move home and school frequently have poorer educational outcomes in their early years at school? An anonymised cohort study.

Frequent mobility has been linked to poorer educational attainment. We investigated the association between moving home and moving school frequently and the early childhood formal educational achievement. We carried out a cohort analysis of 121,422 children with anonymised linked records. Our exposure measures were: 1) the number of residential moves registered with a health care provider, and 2) number of school moves. Our outcome was the formal educational assessment at age 6-7. Binary regression modeling was used to examine residential moves within the three time periods: 0 - <1 year; 1 - <4 years and 4 - <6 years. School moves were examined from age 4 to age 6. We adjusted for demographics, residential moves at different times, school moves and birth related variables. Children who moved home frequently were more likely not to achieve in formal assessments compared with children not moving. Adjusted odds ratios were significant for 3 or more moves within the time period 1 -<4 years and for any number of residential moves within the time period 4-<6 years. There was a dose response relationship, with increased odds ratios with increased frequency of residential moves (2 or more moves at 4-<6 years, adjusted odds ratio 1.16 (1.03, 1.29). The most marked effect was seen with frequent school moves where 2 or more moves resulted in an adjusted odds ratio of 2.33 (1.82, 2.98). This is the first study to examine the relationship between residential and school moves in early childhood and the effect on educational attainment. Children experiencing frequent mobility may be disadvantaged and should be closely monitored. Additional educational support services should be afforded to children, particularly those who frequently change school, in order to help them achieve the expected educational standards.

Nutritional programming of the metabolic syndrome.

The primary markers of the metabolic syndrome are central obesity, insulin resistance and hypertension. In this review, we consider the effect of changes in maternal nutrition during critical windows in fetal development on an individual's subsequent predisposition to the metabolic syndrome. The fetal origins of obesity, cardiovascular disease and insulin resistance have been investigated in a wide range of epidemiological and animal studies; these investigations highlight adaptations made by the nutritionally manipulated fetus that aim to maintain energy homeostasis to ensure survival. One consequence of such developmental plasticity may be a long term re-setting of cellular energy homeostasis, most probably via epigenetic modification of genes involved in a number of key regulatory pathways. For example, reduced maternal-fetal nutrition during early gestation to midgestation affects adipose tissue development and adiposity of the fetus by setting an increased number of adipocyte precursor cells. Importantly, clinically relevant adaptations to nutritional challenges in utero may only manifest as primary components of the metabolic syndrome if followed by a period of accelerated growth early in the postnatal period and/or if offspring become obese.

Early developmental influences on hepatic organogenesis.

The liver is the largest of the body's organs, with the greatest number of functions, playing a central role in coordinating metabolic homeostasis, nutrient processing and detoxification. The fetal liver forms during early gestation in response to a sequential array of distinct biological events, regulated by intrinsically programmed mechanisms and extracellular signals which instruct hepatic cells to either proliferate, differentiate or undergo apoptosis. A vast number of genes are involved in the initiation and control of liver development, many of which are sensitive to nutritional and hormonal regulation in utero. Moreover, liver mass is influenced by the gestational environment. Therefore, during periods of hepatic cell proliferation and differentiation, the developing fetal liver is sensitive to damage from both internal and external sources including teratogens, infection and nutritional deficiencies. For example, fetuses exposed to decreased materno-fetal nutrition during late gestation have a reduced liver mass, and/or perturbed liver function, which includes increased plasma LDL cholesterol and fibrinogen concentrations. These occur in conjunction with other risk factors present in the early stages of cardiovascular disease i.e. decreased glucose tolerance and insulin insensitivity in later life. Taken together, these findings suggest that liver mass, and later function, are essentially set in utero during fetal development-a process that is ultimately regulated by the intrauterine environment.

Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep.

The liver is a major metabolic and endocrine organ in growing neonates, but the extent to which its hormone receptor (R) sensitivity is potentially determined by maternal parity and the mother's nutritional environment is unknown. This was therefore investigated by sampling livers from postnatal sheep born to nulliparous or multiparous mothers. Offspring were sampled 1 or 30 days after birth from mothers consuming either 100 or 50% [i.e., nutrient-restricted (NR) group] of total metabolizable energy requirements from 110 days gestation to term ( approximately 147 days). Regardless of maternal diet, offspring of nulliparous mothers were lighter at birth and had smaller livers. By 1 mo of age, they exhibited catch-up growth, an adaptation not seen when mothers were NR, but they retained their lighter livers. At both sampling ages, livers from offspring born to nulliparous mothers exhibited increased mRNA abundance for growth hormone (GH) receptor, IGF-IR, plus hepatocyte growth factor (HGF); and at day 1 only IGF-I, but not IGF-IIR mRNA was decreased. In addition, mRNA for IGF-II, the HGFR, c-Met, and Bax were persistently reduced in these offspring. Effects of parity were largely unaffected by maternal nutrient restriction. Maternal parity therefore has a substantial effect on liver size during postnatal development and its receptor population that is not dependent on maternal diet. First-born offspring appear to exhibit a resetting of the endocrine control of hepatic growth within the HGF and GH-IGF axis, which could have later consequences after their growth has caught up.

Ontogeny and nutritional manipulation of the hepatic prolactin-growth hormone-insulin-like growth factor axis in the ovine fetus and in neonate and juvenile sheep.

The somatotrophic axis is the main endocrine system regulating postnatal growth; however, prenatal growth is independent of growth hormone (GH). Fetal development relies on the coordinated actions of a range of hormones, including insulin-like growth factors (IGF), and prolactin (PRL), in the control of differentiation, growth and maturation. In the sheep the abundance peaks for liver IGF-II and PRL receptors occur during late gestation while that for IGF-I receptor occurs at birth. All receptors, with the exception of GH receptor subsequently decrease by age 6 months. It has been proposed that maternal undernutrition during gestation regulates the maturation of the fetal hypothalmic-pituitary-adrenal axis and endocrine sensitivity. Critically, the timing of the nutritional insult may affect the magnitude of reprogramming. Maternal malnutrition during early to mid-gestation (3.2-3.8 MJ/d (60% total metabolisable energy requirements) v. 8.7-9.9 MJ/d (150% total metabolisable energy requirements) between 28 and 80 d of gestation) had no effect on body or liver weight. Nutrient-restricted (NR) fetuses sampled at 80 d (mid-gestation) showed up-regulation of hepatic PRL receptor, but following refeeding the normal gestational rise in PRL and GH receptors did not occur. Hepatic IGF-II receptor was down regulated in NR fetuses at both mid- and late gestation. Conversely, 6-month-old offspring showed no difference in the abundance of either GH receptor or PRL receptor, while IGF-II mRNA was increased. Offspring of ewes malnourished during late gestation (9.1 MJ/d (60% total metabolisable energy requirements) v. 12.7 MJ/d (100% total metabolisable energy requirements) from 110 d of gestation to term) showed reduced abundance of hepatic GH and PRL receptor mRNA. In conclusion, maternal undernutrition during the various stages of gestation reprogrammed the PRL-GH-IGF axis. Nutritional regulation of cytokine receptors may contribute to altered liver function following the onset of GH-dependent growth, which may be important in regulating endocrine adaptations during subsequent periods of nutritional deprivation.