Early Life Growth Restriction Research Articles

The Effect of an Early Life Motor Skill Intervention on Physical Activity in Growth-Restricted Mice.

Early life growth restriction significantly increases the risk of adulthood physical inactivity and thereby chronic disease incidence. Improvements in motor skill acquisition could result in greater physical activity engagement in the growth-restricted population, thus reducing chronic disease risk. The purpose of this study was to implement an early life motor training intervention to improve physical activity engagement in control and growth-restricted mice. Mice were growth restricted in early life utilizing a validated nutritive model or remained fully nourished in early life as a control. All mice were tested throughout early life for various components of motor skill acquisition. On postnatal day 10, mice were randomly assigned to engage in an early life motor skill intervention daily until postnatal day 21 or remained as a sedentary control. All mice were given access to an in-cage running wheel from postnatal days 45-70. Growth-restricted group (PGR) mice had impaired trunk and postural control, coordination/vestibular development, and hindlimb strength in early life compared with control mice. There were no differences in wheel running behavior between the trained and sedentary mice, although control mice ran at a faster average speed compared with PGR mice. Control female mice ran more than PGR female mice during the week 2 dark cycle. Early life growth restriction reduced motor skill attainment throughout early life, which may be associated with reduced ability to engage in physical activity in adulthood. The early life motor skill intervention did not elicit changes in body weight or physical activity engagement in control or PGR mice, indicating that a more intense/different intervention specifically targeting skeletal muscle may be necessary to counteract the detrimental effects of early life growth restriction.

Low birth weight and reduced postnatal nutrition lead to cardiac dysfunction in piglets.

Heart disease is the leading cause of death in humans and evidence suggests early life growth-restriction increases heart disease risk in adulthood. Therefore, this study sought to investigate the effects of low birth weight (LBW) and postnatal restricted nutrition (RN) on cardiac function in neonatal pigs. We hypothesized that LBW and RN would reduce cardiac function in pigs but this effect would be reversed with refeeding. To investigate this hypothesis, pigs born weighing <1.5 kg were assigned LBW, and pigs born >1.5 kg were assigned normal birth weight (NBW). Half the LBW and NBW pigs underwent ~25% total nutrient restriction via intermittent suckling (assigned RN) for the first 4 wk post-farrowing. The other half of piglets were allowed unrestricted suckling access to the sow (assigned NN). At 28 d of age (weaning), pigs were weaned and provided ad libitum access to a standard diet. Echocardiographic, vascular ultrasound, and blood pressure (BP) measurements were performed on day 28 and again on day 56 to assess cardiovascular structure and function. A full factorial three-way ANOVA (NN vs. RN, LBW vs. NBW, male vs. female) was performed. Key findings include reduced diastolic BP (P = 0.0401) and passive ventricular filling (P = 0.0062) in RN pigs at 28 d but this was reversed after refeeding. LBW piglets have reduced cardiac output index (P = 0.0037) and diastolic and systolic wall thickness (P = 0.0293 and P = 0.0472) at 56 d. Therefore, cardiac dysfunction from RN is recovered with adequate refeeding while LBW programs irreversible cardiac dysfunction despite proper refeeding in neonatal pigs.

The Effect of Growth Restriction on the Gut Microbiome in Mice

INTRODUCTIONEarly life growth restriction increases susceptibility to non‐communicable adult‐onset diseases. However, there is minimal mechanistic rationale for elevated disease risk. The gut microbiome assists in regulating host physiological processes, with emerging evidence suggesting microbiome dysregulation leads to increased risk of chronic disease. Thus, the purpose of this investigation was to determine differences in the gut microbiome of growth restricted mice as compared to non‐restricted mice.METHODSA cross‐fostering, protein‐restricted (8% protein) nutritive model in FVB mice was used to induce growth restriction during gestation (GUN; N=10 male,15 female) or lactation from days 1–21 of life (PUN; N=11 male, 12 female) along with a control group (CON, 20% protein, N=12 male, 11 female). At 21 postnatal days of age (PN21) all mice were weaned to a non‐restricted diet (20% protein), isolating undernutrition to early life windows. Fecal samples were collected weekly across the lifespan (until PN80) to determine longitudinal programming effects of growth restriction on the gut microbiome. Cecum samples were collected at PN21 and PN80. Microbiome analysis of fecal and cecum samples were conducted by first extracting the DNA using Qiagen Powersoil DNA extraction kits and conducting PCR amplification of the bacterial 16S rRNA gene amplicon profiles through the Qiita bioinformatics platform. Phenotypic growth markers of all three diet groups (CON, GUN, PUN) were analyzed using repeated measures ANOVA. Metabolomics data on the same samples is currently being analyzed and will be integrated with the microbiome dataset.RESULTSThe fecal microbiome was strongly separated by treatment group using the Bray‐Curtis distance measure (PERMANOVA p = 0.001). A random forest machine learning classification validated this separation showing an overall out‐of‐bag error rate of 18.6% across the three groups in the whole dataset. The PUN group was distinctly separated from GUN and CON, with a group error rate of only 15.0%. Differences in the microbiome were not evident through analysis at the Phylum level (Firmicutes/Bacteroidetes ratio) but was instead driven by differential abundances of specific rare taxa. Bifidobacterium was significantly elevated in the PUN group (Kruskal‐Wallis test p=0.00017), beginning as early as PN21 and remaining elevated in the PUN group through the lifespan (PN80).CONCLUSIONSA protein‐restricted nutritive model induces strong imprinting on the structure of the murine microbiome. Changes in the PUN group are primarily driven by differences in low abundance taxa. Understanding the mechanisms that lead to the microbiome dysbiosis shown here could lead to the development of therapeutic interventions to limit the development of a stunted or immature gut microbiota.Support or Funding InformationMSU Department of Biochemistry and Molecular Biology; MSU Department of Kinesiology

Pediatric cardiovascular risk factors.

The dominant cause of mortality, morbidity and hospitalization worldwide is cardiac complications, and are the major public health problem in adult populations. The worldwide research is being focused on the idea that cardiovascular disease is an early life pathological state. Early unfavorable exposures, acting in different periods of fetal and early postnatal life, have been observed to be responsible for permanent editions in the cardiac system. This idea has been confirmed by preclinical experimental studies confirming the early life growth restriction leading to developmental adaptations in cardiovascular form and system. All these editions results in elevated susceptibility to cardiovascular disease. The present review article will put emphasis on these risk factors, which lead to the deadly cardiac pathology state in young infants.

Gestational Age and Birth Weight and the Risk of Childhood Type 1 Diabetes: A Population-Based Cohort and Sibling Design Study.

We investigated the effects of gestational age, birth weight, small for gestational age (SGA), and large for gestational age (LGA) on risk of childhood type 1 diabetes. We conducted a population-based cohort study of all singleton live births in Sweden between 1973 and 2009 and a sibling control study. Perinatal data were extracted from the Swedish Medical Birth Register. Children with type 1 diabetes diagnosis were identified from the Swedish National Patient Register. Log-linear Poisson regression and conditional logistic regression were used for data analysis. The study cohort consisted of 3,624,675 singleton live births (42,411,054 person-years). There were 13,944 type 1 diabetes cases during the study period. The sibling control study consisted of 11,403 children with type 1 diabetes and 17,920 siblings. Gestational age between 33 and 36 weeks (relative risk [RR] 1.18 [95% CI 1.09, 1.28) and 37 and 38 weeks (RR 1.12 [95% CI 1.07, 1.17]) was associated with type 1 diabetes in the cohort study and remained significant in the sibling control study. SGA (RR 0.83 [95% CI 0.75, 0.93]) and LGA (RR 1.14 [95% CI 1.04, 1.24]) were associated with type 1 diabetes in the cohort study. The SGA association remained unchanged in the sibling study, while the LGA association disappeared. Very low birth weight was associated with a reduced risk of type 1 diabetes. The findings suggest a small association between gestational age and type 1 diabetes that is not likely due to familial confounding factors. Gestational age and type 1 diabetes may be related to insulin resistance due to early life growth restriction or altered gut microbiota in preterm babies.

Accelerated age-related decline in renal and vascular function in female rats following early-life growth restriction.

Many studies report sexual dimorphism in the fetal programming of adult disease. We hypothesized that there would be differences in the age-related decline in renal function between male and female intrauterine growth-restricted rats. Early-life growth restriction was induced in rat offspring by administering a low-protein diet (LPD; 8.7% casein) to dams during pregnancy and lactation. Control dams were fed a normal-protein diet (NPD; 20% casein). Mean arterial pressure (MAP) and renal structure and function were assessed in 32- and 100-wk-old offspring. Mesenteric artery function was examined at 100 wk using myography. At 3 days of age, body weight was ∼24% lower (P < 0.0001) in LPD offspring; this difference was still apparent at 32 wk but not at 100 wk of age. MAP was not different between the male NPD and LPD groups at either age. However, MAP was greater in LPD females compared with NPD females at 100 wk of age (∼10 mmHg; P < 0.001). Glomerular filtration rate declined with age in the NPD male, LPD male and LPD female offspring (∼45%, all P < 0.05), but not in NPD female offspring. Mesenteric arteries in the aged LPD females had reduced sensitivity to nitric oxide donors compared with their NPD counterparts, suggesting that vascular dysfunction may contribute to the increased risk of disease in aged females. In conclusion, females growth-restricted in early life were no longer protected from an age-related decline in renal and arterial function, and this was associated with increased arterial pressure without evidence of renal structural damage.

When early life growth restriction in rats is followed by attenuated postnatal growth: effects on cardiac function in adulthood.

Epidemiological and experimental studies demonstrate that intrauterine growth restriction (IUGR) followed by accelerated postnatal growth leads to increased risk of developing cardiac disease in adulthood. The aim of this study was to examine the effect of early life growth restriction on cardiac structure and function in young adult rats. IUGR was induced in Wistar Kyoto dams through administration of a low protein diet (LPD; 8.7% casein) during pregnancy and lactation; controls received a normal protein diet (NPD; 20% casein). Cardiac function and structure were assessed in female NPD (n = 7) and LPD (n = 7) offspring at 18 weeks of age by echocardiography and pressure-volume techniques, and systolic blood pressure by tail-cuff sphygmomanometry. LPD offspring remained significantly smaller throughout life compared to controls. There were no differences in the levels of systolic blood pressure, left ventricular cardiac dimensions, heart rate, ejection fraction and fractional shortening of the cardiac muscle between the investigated groups. Aortic peak systolic velocity was significantly reduced in the LPD group (P = 0.02). Our findings support the idea that the programming of adult cardiovascular disease can be prevented or delayed in IUGR offspring when postnatal growth trajectory resembles that of in utero.

Thrifty metabolic programming in rats is induced by both maternal undernutrition and postnatal leptin treatment, but masked in the presence of both: implications for models of developmental programming

BackgroundMaternal undernutrition leads to an increased risk of metabolic disorders in offspring including obesity and insulin resistance, thought to be due to a programmed thrifty phenotype which is inappropriate for a subsequent richer nutritional environment. In a rat model, both male and female offspring of undernourished mothers are programmed to become obese, however postnatal leptin treatment gives discordant results between males and females. Leptin treatment is able to rescue the adverse programming effects in the female offspring of undernourished mothers, but not in their male offspring. Additionally, in these rats, postnatal leptin treatment of offspring from normally-nourished mothers programmes their male offspring to develop obesity in later life, while there is no comparable effect in their female offspring.ResultsWe show by microarray analysis of the female liver transcriptome that both maternal undernutrition and postnatal leptin treatment independently induce a similar thrifty transcriptional programme affecting carbohydrate metabolism, amino acid metabolism and oxidative stress genes. Paradoxically, however, the combination of both stimuli restores a more normal transcriptional environment. This demonstrates that “leptin reversal” is a global phenomenon affecting all genes involved in fetal programming by maternal undernourishment and leptin treatment. The thrifty transcriptional programme was associated with pro-inflammatory markers and downregulation of adaptive immune mediators, particularly MHC class I genes, suggesting a deficit in antigen presentation in these offspring.ConclusionsWe propose a revised model of developmental programming reconciling the male and female observations, in which there are two competing programmes which collectively drive liver transcription. The first element is a thrifty metabolic phenotype induced by early life growth restriction independently of leptin levels. The second is a homeostatic set point calibrated in response to postnatal leptin surge, which is able to over-ride the metabolic programme. This “calibration model” for the postnatal leptin surge, if applicable in humans, may have implications for understanding responses to catch-up growth in infants. Additionally, the identification of an antigen presentation deficit associated with metabolic thriftiness may relate to a previously observed correlation between birth season (a proxy for gestational undernutrition) and infectious disease mortality in rural African communities.

Evidence of altered biochemical composition in the hearts of adult intrauterine growth-restricted rats

Epidemiological studies clearly link intrauterine growth restriction with increased risk of cardiac disease in adulthood. The mechanisms leading to this increased risk are poorly understood; remodeling of the myocardium is implicated. The aim was to determine the effect of early life growth restriction on the biochemical composition of the left ventricular myocardium in adult rats. Wistar Kyoto dams were fed either a low protein diet (LPD; 8.7 % casein) or normal protein diet (NPD; 20 % casein) during pregnancy and lactation; from weaning, the offspring were fed normal rat chow. At 18 weeks of age, the biochemical composition of the hearts of NPD control (n = 9) and LPD intrauterine growth-restricted (n = 7) offspring was analyzed using Fourier Transform Infrared (FTIR) micro-spectroscopy. Body weights at postnatal day 4 were significantly lower and remained lower throughout the experimental period in the LPD offspring compared to controls. FTIR analysis of the infrared absorption spectra across the whole "fingerprint" region (1,800-950 cm(-1)) demonstrated wider variation in absorbance intensity in the LPD group compared to controls. In particular, there were marked differences detected in the protein (1,540 cm(-1)), lipid (1,455 and 1,388 cm(-1)), proteoglycan (1,228 cm(-1)) and carbohydrate (1,038 cm(-1)) bands, indicating increased lipid, proteoglycan and carbohydrate content in the growth-restricted myocardium. In conclusion, changes in the biochemical composition of the myocardium provide a likely mechanism for the increased vulnerability to cardiovascular disease in offspring that were growth restricted in early life.

Prevention of Malnutrition and Growth Failure in VLBW Infants

The growth of preterm infants remains poor and nearly all are significantly growth restricted by term gestational age. The primary cause is under nutrition. This is not an insignificant problem-as much as half of certain later life disorders, including obesity and diabetes, may result from early life growth restriction. Normal fetal growth at 24-30 weeks gestation requires up to 4 g/kg/day of protein. Most preterm infants also receive too little of certain essential fatty acids that are necessary for normal neural development. If not fed this amount of nutrition, the consequences for such infants are clear-later life short stature, reduced muscle mass, and smaller brains that do not allow normal cognitive development. The good news, though, is that there is potential for improved brain growth and intellectual development if preterm infants are fed diets that supply nutrients at the appropriate rates necessary for normal third trimester human fetal growth. Preterm infants fed higher rates TPN solutions with higher rates of amino acids, preterm formula with more protein and non-protein energy, or milk with nutrient supplements have measurably improved developmental and intellectual outcomes in early childhood. By adolescence, brain structural development and verbal IQ are directly related to the original amount of nutrient intake that preterm infants receive, particularly of protein, but also of balanced energy supply and essential fatty acids. Clearly, more consistent approaches to enhanced nutrition of preterm infants are necessary to prevent growth failure and promote normal development.

For debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure.

We review the progress in testing the thrifty phenotype hypothesis. Many human epidemiological studies both by ourselves and others have confirmed and extended the original observations on which the hypothesis was based. We are not aware of any contradictory findings and we emphasise the strength of the association between birth weight and the subsequent development of the metabolic syndrome. We have worked extensively experimentally to test the hypothesis in a rat model in which pregnant and/or lactating dams are fed a diet moderately restricted in proteins. The range of programming effects that we have discovered in this example of fetal and early postnatal growth restriction is listed and includes changes in hormone receptors, signalling molecules and regulatory enzymes. We have shown the model to develop diabetes, the metabolic syndrome and signs of premature renal failure. We summarise these and other similarities between the phenotype of this model and human Type 2 diabetes and the metabolic syndrome. The number of insults during early development which can lead to a similar outcome is discussed and the suggestion is made that the early life response to stress is limited in its flexibility with outcomes including ageing and decreased longevity. Our preliminary results indicate that some MODY genes could suggest pathways whereby the changes occur and that epigenetic changes during development are involved. We conclude that the way is now clear to discover early human markers of programming by early life growth restriction and to use these to devise strategies for the prevention of Type 2 diabetes.