Normal Birth Weight Individuals Research Articles

Increased liver fat associates with severe metabolic perturbations in low birth weight men.

Ectopic liver fat deposition, resulting from impaired subcutaneous adipose tissue expandability, may represent an age-dependent key feature linking low birth weight (LBW) with increased risk of type 2 diabetes (T2D). We examined whether presumably healthy early middle-aged, non-obese LBW subjects exhibit increased liver fat content, whether increased liver fat in LBW is associated with the severity of dysmetabolic traits and finally whether such associations may be confounded by genetic factors. Using 1H magnetic resonance spectroscopy, we measured hepatic fat content in 26 early middle-aged, non-obese LBW and 22 BMI-matched normal birth weight (NBW) males. Endogenous glucose production was measured by stable isotopes, and a range of plasma adipokine and gut hormone analytes were measured by multiplex ELISA. Genetic risk scores were calculated from genome-wide association study (GWAS) data for birth weight, height, T2D, plasma cholesterol and risk genotypes for non-alcoholic fatty liver disease (NAFLD). The LBW subjects had significantly increased hepatic fat content compared with NBW controls (P= 0.014), and 20% of LBW vs no controls had overt NAFLD. LBW subjects with NAFLD displayed widespread metabolic changes compared with NBW and LBW individuals without NAFLD, including hepatic insulin resistance, plasma adipokine and gut hormone perturbations as well as dyslipidemia. As an exception, plasma adiponectin levels were lower in LBW subjects both with and without NAFLD as compared to NBW controls. Genetic risk for selected differential traits did not differ between groups. Increased liver fat content including overt NAFLD may be on the critical path linking LBW with increased risk of developing T2D in a non-genetic manner.

Cognitive and motor outcomes in children born low birth weight: a systematic review and meta-analysis of studies from South Asia

BackgroundSouth Asia contributes substantially to global low birth weight population (i.e. those with birth weight < 2500 g). Synthesized evidence is lacking on magnitude of cognitive and motor deficits in low birth weight (LBW) children compared to those with normal birth weight (NBW) (i.e. birth weight ≥ 2500 g). The meta-analysis aimed to generate this essential evidence.MethodsLiterature search was performed using PubMed and Google Scholar. Original research articles from south Asia that compared cognitive and/or motor scores among LBW and NBW individuals were included. Weighted mean differences (WMD) and pooled relative risks (RR) were calculated. All analyses were done using STATA 14 software.ResultsNineteen articles (n = 5999) were included in the analysis. Children < 10 years of age born LBW had lower cognitive (WMD -4.56; 95% CI: -6.38, − 2.74) and motor scores (WMD -4.16; 95% CI: -5.42, − 2.89) compared to children with NBW. Within LBW children, those with birth weight < 2000 g had much lower cognitive (WMD -7.23, 95% CI; − 9.20, − 5.26) and motor scores (WMD -6.45, 95% CI; − 9.64, − 3.27).ConclusionsIn south Asia, children born LBW, especially with < 2000 g birth weight, have substantial cognitive and motor impairment compared to children with NBW. Early child development interventions should lay emphasis to children born LBW.

Cardiometabolic Health in Adults Born Premature With Extremely Low Birth Weight.

Young adults born with extreme prematurity have increased blood pressure and insulin resistance. This study documents their metabolic health as they enter their fourth decade of life. The study objective was to compare body composition, glycemia, lipid levels, and blood pressure in adults born with extremely low birth weight (ELBW) versus age- and sex- matched normal birth weight (NBW) control subjects and to examine related previous and current exposures. The study examines one of the oldest regionally representative cohorts of ELBW subjects (birth weight <1 kg) and NBW individuals born between 1977 and 1982. The primary outcome was dysglycemia (type 2 diabetes or prediabetes) based on results of a 75-g oral glucose tolerance test. Secondary outcomes include body composition, insulin resistance, fasting lipid profile, and blood pressure. Potential predictive factors included birth weight, maternal antenatal corticosteroid exposure, retinopathy of prematurity, growth parameters, and smoking history. Adults (mean age, 31.8 years) born ELBW (n = 100) had a higher percent body fat (P = .004) and lower lean mass for height (P = .018) but similar waist circumference (P = .54) and BMI (P = .61) compared with NBW control subjects. ELBW adults had a 4.0-fold (95% confidence interval, 1.53-10.66) increased risk of developing dysglycemia. Adults born ELBW also had higher systolic (P = .004) and diastolic (P = .02) blood pressures compared with NBW control subjects, but there were no differences in lipid profile. By their fourth decade, these adults born extremely premature had increased body fat, lower lean mass, and a 4-fold increased risk of developing dysglycemia.

ELBW survivors in early adulthood have higher hepatic, pancreatic and subcutaneous fat.

Premature birth in conjunction with extremely low birth weight (<1 kg, ELBW) is associated with insulin resistance and increased cardiometabolic health risk compared to birth at full term with normal birth weight (NBW). However, little is known regarding the biologic mediators of these effects. Abdominal and ectopic lipid accumulation is linked to insulin resistance and metabolic dysfunction, yet whether ELBW survivors are predisposed to aberrant lipid deposition in adulthood is unknown. We used magnetic resonance imaging in a cohort of 16 NBW and 29 ELBW participants to determine if ELBW survivors have differences in pancreatic, hepatic, subcutaneous and visceral fat distribution compared to NBW participants. ELBW individuals had a higher proportion of liver and pancreatic fat compared to NBW subjects (P < 0.05). Abdominal subcutaneous fat, but not visceral fat, area was higher in ELBW survivors compared to NBW individuals. In multivariate analyses, tissue fat measures were most highly related to BMI and sex, but not preterm birth. This work highlights that fat deposition is enhanced in adults born preterm and suggests that ectopic fat accretion driven by their relatively greater adiposity may contribute to the higher rates of metabolic dysfunction seen in ELBW survivors.

Metabolic and Transcriptional Changes in Cultured Muscle Stem Cells from Low Birth Weight Subjects.

Developmental programming of human muscle stem cells could in part explain why individuals born with low birth weight (LBW) have an increased risk of developing type 2 diabetes (T2D) later in life. We hypothesized that immature muscle stem cell functions including abnormal differentiation potential and metabolic function could link LBW with the risk of developing T2D. Design/Settings/Participants: We recruited 23 young men with LBW and 16 age-matched control subjects with normal birth weight. Biopsies were obtained from vastus lateralis, and muscle stem cells were isolated and cultured into fully differentiated myotubes. We studied glucose uptake, glucose transporters, insulin signaling, key transcriptional markers of myotube maturity, selected site-specific DNA methylation, and mitochondrial gene expression. We found reduced glucose uptake as well as decreased levels of glucose transporter-1 and -4 mRNA and of the Akt substrate of 160-kDa mRNA and protein in myotubes from LBW individuals compared with normal birth weight individuals. The myogenic differentiation markers, myogenin and myosin heavy chain 1 and 2, were decreased during late differentiation in LBW myotubes. Additionally, mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α and cytochrome c oxidase polypeptide 7A were reduced in LBW myotubes. Decreased gene expression was not explained by changes in DNA methylation levels. We demonstrate transcriptional and metabolic alterations in cultured primary satellite cells isolated from LBW individuals after several cell divisions, pointing toward a retained intrinsic defect conserved in these myotubes.

Vasomotor sympathetic outflow in the muscle metaboreflex in low birth weight young adults.

A growing body of evidence suggests that low birth weight (LBW) offspring are associated with long-term structural and functional changes in cardiovascular and neuroendocrine systems. We tested the hypothesis that muscle metaboreflex activation produces exaggerated responses in cardiac autonomic tone (represented by heart rate variability ratio) and cutaneous vascular sympathetic tone (represented by plethysmography pulse wave amplitude) in LBW compared to normal birth weight (NBW) young adults. We recruited 23 LBW (18 females and five males) and 23 NBW (14 females and nine males) University of Zimbabwe students with neonatal clinical cards as proof of birth weight at term. Resting electrocardiogram, pulse waves, and blood pressures were recorded. Participants then underwent a static/isometric handgrip exercise until fatigue and a post-exercise circulatory arrest period of 2 minutes. We observed (results mean ± standard deviation) a greater mean increase in heart rate variability ratio from baseline to exercise for LBW compared to NBW individuals (1.015±1.034 versus [vs] 0.119±0.789, respectively; P<0.05). We also observed a greater mean decrease in plethysmography pulse wave amplitude from baseline to exercise (−1.32±1.064 vs −0.735±0.63; P<0.05) and from baseline to post-exercise circulatory arrest (−0.932±0.998 vs −0.389±0.563; P<0.05) for LBW compared to NBW individuals. We conclude that LBW may be associated with an exaggerated sympathetic discharge in response to muscle metaboreflex.

Exercise-induced cardiac fatigue in low and normal birth weight young black adults

The objective of the study was to compare the change in diastolic function, E/A ratio, in response to prolonged exercise in low birth weight and normal birth weight individuals. Using a case-control study design, 23 students of the University of Zimbabwe College of Health Sciences who had neonatal clinic cards as proof of birth weight were recruited into the study. Measurements of diastolic function, E/A ratio, were obtained using an echocardiogram before and after 75 minutes of exercise. Among the cohort, seven had low birth weight - <2500 g, three female patients and four male patients - and 16 had normal birth weight - six female patients and 10 male patients). The mean age was 20.7±3.3 years. After prolonged exercise for 75 minutes of running on a treadmill, decreases in diastolic function, E/A ratio, were significantly greater in low birth weight than in normal birth weight individuals (0.48±0.27 versus 0.19±0.18 p<0.05, respectively). There was a significant association between low birth weight and exercise-induced cardiac fatigue (the χ2 test p<0.05, odds ratio 4.64, 95% confidence interval 1.19-18.1). We conclude that low birth weight is associated with exercise-induced diastolic dysfunction in young adults.

Impaired Leptin Gene Expression and Release in Cultured Preadipocytes Isolated From Individuals Born With Low Birth Weight

Low birth weight (LBW) is associated with increased risk of the development of type 2 diabetes (T2D). The appetite-regulating hormone leptin is released from mature adipocytes, and its production may be decreased in immature preadipocytes from LBW individuals. We recruited 14 men born with LBW and 13 controls born with normal birth weight (NBW). Biopsy samples were obtained from subcutaneous abdominal fat depots, and preadipocytes were isolated and cultured. Gene expression of leptin and selected differentiation markers were analyzed during preadipocyte differentiation, and cell culture media were collected to analyze leptin secretion. DNA methylation of CpG sites in the leptin promoter was measured using pyrosequencing. We found that differentiating preadipocytes from LBW individuals showed reduced leptin gene expression and a corresponding reduced leptin release compared with NBW individuals. Mean DNA methylation of the proximal LEP promoter was increased in LBW compared with NBW individuals. The notion of impaired adipocyte maturation in LBW individuals was supported by a lower mRNA expression of the differentiation markers; fatty acid binding protein 4, peroxisome proliferator-activated receptor γ, and GLUT4. Our findings are consistent with impaired preadipocyte maturation, contributing to an increased risk of the development of T2D in LBW subjects.

Physical inactivity affects skeletal muscle insulin signaling in a birth weight-dependent manner

AimsWe investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects. MethodsTwenty LBW and 20 normal birth weight (NBW) subjects were investigated using the euglycemic–hyperinsulinemic clamp with excision of skeletal muscle biopsies pre and post 9days of bed rest. Employing Western blotting, we investigated skeletal muscle Akt, AS160, GLUT4, and AMPK signaling. ResultsPeripheral insulin action was similar in the two groups and was decreased to the same extent post bed rest. Insulin and AMPK signaling was unaffected by bed rest in NBW individuals. LBW subjects showed decreased insulin-stimulated Akt phosphorylation and increased AMPK α1 and γ3 protein expression post bed rest. Insulin response of AS160 phosphorylation was lower in LBW subjects both pre and post bed rest. ConclusionsBed rest-induced insulin resistance is not explained by impaired muscle insulin or AMPK signaling in subjects with or without LBW. Lower muscle insulin signaling in LBW subjects post bed rest despite similar degree of insulin resistance as seen in controls may to some extent support the idea that LBW subjects are at higher risk of developing type 2 diabetes when being physically inactive.

Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight

The molecular mechanisms linking physical inactivity and muscle insulin resistance in humans have been suggested to include increased muscle inflammation, possibly associated with impaired oxidative metabolism. We employed a human bed rest study including 20 young males with normal birth weight (NBW) and 20 with low birth weight (LBW) and increased risk of diabetes. The subjects were studied before and after 9 days of bed rest using the euglycemic-hyperinsulinemic clamp and muscle biopsy excision. Muscle inflammatory status was assessed as nuclear factor-κB (NF-κB) activity and mRNA expression of the pro-inflammatory MCP1 (CCL2) and IL6 and the macrophage marker CD68. Furthermore, mRNA expression of genes central to oxidative phosphorylation (OXPHOS) was measured including ATP5O, COX7A1, NDUFB6, and UQCRB. At baseline, muscle inflammatory status was similar in NBW and LBW individuals. After bed rest, CD68 expression was increased in LBW (P=0.03) but not in NBW individuals. Furthermore, expression levels of all OXPHOS genes were reduced after bed rest in LBW (P ≤ 0.05) but not in NBW subjects and were negatively correlated with CD68 expression in LBW subjects (P ≤ 0.03 for all correlations). MCP1 expression and NF-κB activity were unaffected by bed rest, and IL6 expression was too low for accurate measurements. None of the inflammatory markers correlated with insulin sensitivity. Although LBW subjects exhibit disproportionately elevated CD68 mRNA expression suggesting macrophage infiltration and reduced OXPHOS gene expression when exposed to bed rest, our data altogether do not support the notion that bed rest-induced (9 days) insulin resistance is caused by increased muscle inflammation.

Effect of Milk Formula Protein Content on Intestinal Barrier Function in a Porcine Model of LBW Neonates

Our study aimed at investigating the impact of the level of protein in milk formula on intestinal structure, barrier function, and its nervous regulation in normal and LBW neonates using a porcine model. Normal birth weight (NBW) or LBW piglets were fed from d7 to d28 of age either with a high protein (HP) or with an adequate protein (AP) formula or stayed with their mother [mother fed (MF)]. The proximal jejunum and distal ileum were sampled at d28 for morphometry analysis and ex vivo permeability measurement in Ussing chambers. Formula feeding induced a trophic effect on the jejunum and ileum of both NBW and LBW piglets, which exhibited longer villi than MF animals, irrespective of the type of formula. In NBW piglets, intestinal permeability was not altered by formula feeding. On the contrary, LBW piglets fed with HP formula, but not AP, exhibited a greater ileal permeability than MF piglets. Feeding the HP formula also disturbed jejunal and ileal regulation of permeability by acetylcholine and vasoactive intestinal peptide (VIP) in LBW compared with MF LBW piglets. In conclusion, the level of protein in formulas did not modify intestinal structure and function in NBW individuals but dramatically modified intestinal barrier function physiology in LBW individuals.

Low Birth Weight and Respiratory Disease in Adulthood

The proportion of low and very low birth weight births is increasing. Infants and children with a history of low and very low birth weight have an increased risk of respiratory illnesses, but it is unknown if clinically significant disease persists into adulthood. To determine if a history of low birth weight is associated with hospitalization for respiratory illness in adulthood. This study was a population-based, case-control study. Cases were adults 18 to 27 years of age who were hospitalized for a respiratory illness from 1998 to 2007 within Washington State who could be linked to a Washington State birth certificate for the years 1980 to 1988. Four control subjects, frequency matched by birth year, were randomly selected from Washington State birth certificates for each case patient. Control subjects who died before age 18 were excluded. Two levels of exposure were identified: (1) very low birth weight (birth weight <1,500 g) and (2) moderately low birth weight (birth weight, 1,500-2,499 g). Normal birth weight individuals (2,500-4,000 g) were considered unexposed. Respiratory hospitalizations were defined using discharge diagnosis codes. Logistic regression was used to calculate the odds ratio for hospitalization comparing exposed and unexposed individuals. A total of 4,674 case patients and 18,445 control subjects were identified. The odds ratio for hospitalization for respiratory illness was 1.83 for very low birth weight (95% confidence interval, 1.28-2.62; P = 0.001) and 1.34 for moderately low birth weight (95% confidence interval, 1.17-1.53; P < 0.0005). This association remained after adjustment for birth year, sex, maternal age, race, residence, and marital status. Adults with a history of very low birth weight or moderately low birth weight were at increased risk of hospitalization for respiratory illness.

Comparison of Current Health, Functional Limitations, and Health Care Use of Young Adults Who Were Born With Extremely Low Birth Weight and Normal Birth Weight

The objective of this study was to compare the current health status, physical ability, functional limitations, and health care use of extremely low birth weight and normal birth weight young adults. A longitudinal study was conducted of a population-based cohort of 166 extremely low birth weight survivors (501-1000 g birth weight; 1977-1982 births) and a group of 145 sociodemographically comparable normal birth weight individuals. Current health status, history of illnesses, hospitalizations, use of health resources, and physical self-efficacy were assessed through questionnaires that were administered to the young adults by masked interviewers. Individuals completed the assessments at a mean age of 23 years. Neurosensory impairments were identified in 27% of extremely low birth weight and 2% of normal birth weight individuals. No differences were reported in the current health status for physical or mental summary scores. Extremely low birth weight young adults reported a higher prevalence of chronic health conditions in the past 6 months. A significantly higher proportion of extremely low birth weight individuals had functional limitations in seeing, hearing, and dexterity and experienced clumsiness and learning difficulties. Except for prescription glasses, medications for depression, and home-care services for extremely low birth weight individuals, there were no significant differences between groups in use of health care resources. Extremely low birth weight individuals had significantly weaker hand grip strength and lower scores for physical self-efficacy, perceived physical ability, and physical self-confidence. Extremely low birth weight young adults seem to enjoy similar current health status to their normal birth weight peers. However, they continue to have significantly poorer physical abilities and a higher prevalence of chronic health conditions and functional limitations. Contrary to expectations, they do not pose a significant burden to the health care system at young adulthood.

Trends in the prevalence of cerebral palsy in Northern Ireland, 1981–1997

We describe trends in the prevalence of cerebral palsy (CP) by birthweight group, and in the severity of motor impairments and presence of associated intellectual impairment, in Northern Ireland from 1981 to 1997 (n=909; 510 males, 399 females; total population 415,936 live births) using data from a population-based register of CP. Children with suspected CP or who died before 1 year of age and those with CP of postneonatal origin were excluded. Prevalence of CP was 2.2 per 1,000 live births without significant change over time. Among very-low-birthweight (<1,500 g) live births, prevalence was 44.5 per 1,000 (95% confidence interval 32.3-59.8) from 1994 to 1997, with evidence of a statistically significant decline in prevalence since the mid- to late 1980s accompanied by a decrease in the severity of motor impairment and likelihood of intellectual impairment. Among moderately-low-birthweight (1,500-2,499 g) children there was weaker evidence of a peak prevalence in the late 1980s. Prevalence among normal-birthweight infants did not change significantly, but outcome in terms of severity of motor impairment and intellectual impairment improved in the 1990s. Occurrence of bilateral spasticity from 1994 to 1997 was associated with greater severity and likelihood of intellectual impairment for normal-birthweight individuals than for low- or very-low-birthweight individuals.

Blood Pressure Among Very Low Birth Weight (&lt;1.5 kg) Young Adults

Our objective was to compare the blood pressure of 20-y-old very low birth weight (VLBW; <1.5 kg) individuals with that of normal birth weight (NBW) control individuals. The population included 195 VLBW (92 female and 103 male) and 208 NBW (107 female and 101 male) individuals who were born between 1977 and 1979. Independent effects of birth weight status (VLBW versus NBW) and within the VLBW cohort of intrauterine growth (birth weight z score) were examined via multiple regression analyses. VLBW individuals had a higher mean systolic blood pressure (SBP) than NBW control individuals (114 +/- 11 versus 112 +/- 13 mm Hg). SBP for VLBW female infants was 110 +/- 9 versus NBW 107 +/- 12 and for VLBW male individuals was 118 +/- 11 versus NBW 117 +/- 11 mm Hg. After adjustment for gender, race, and maternal education, the difference in SBP between VLBW and NBW individuals was 1.9 mm Hg but was 3.5 mm after also adjustment for later size (20-y weight and height z scores), which reflects catch-up growth. For female individuals, the difference in SBP between VLBW and NBW individuals was significant both unadjusted and adjusted for later size, whereas for male individuals, the difference was significant only after adjustment for later size. Intrauterine growth did not have a significant effect on SBP within the VLBW group, even after adjustment for later size. VLBW individuals, specifically female individuals, have a higher SBP than NBW control individuals. This is not explained by intrauterine growth failure.

Natural progress of blood glucose in full-term low-grade low-birthweight infants.

Although various authors have suggested the risk of hypoglycemia in practical medicine for low-birthweight infants is exaggerated, convincing evidence using recent definitions of hypoglycemia is not documented. To evaluate the risk of hypoglycemia in low grade low-birthweight infants (LGLBWI) (2100 g < birthweight < 2500 g) whose only abnormality is low-birthweight, whole blood glucose (BGw) was measured five times (0, 0.5, 1, and 4 h after birth and just before the first bottle feeding) in 49 LGLBWI and 38 normal birthweight infants. Whole blood glucose was not lower in LGLBWI with a gestational age of 38-40 weeks (GT38LGLBWI) than in normal birthweight individuals with a gestational age of 38-40 weeks at each of the five measuring times. No case of GT38LGLBWI, not even in small for gestational age infants, required treatment for hypoglycemia. The BGw was significantly lower in 37-week gestational age LGLBWI than in GT38LGLBWI at 0.5 h and 1 h after birth (P < 0.05). However, in all cases with low BGw value (below 30 mg/dL at 1 h after birth), BGw value increased naturally to the normal level 1.5 h after birth. No symptoms of hypoglycemia were observed. In the care of hypoglycemia in LGLBWI, attention should be paid first to gestational age, namely, tendency to prematurity. In this study, however, no hypoglycemia that required treatment was found among full-term normal LGLBWI, even those who were small for gestational age. Frequent blood glucose measurement for those infants is therefore unnecessary.