Intrauterine Growth Restriction Children Research Articles

Microbiota-indole 3-propionic acid-brain axis mediates abnormal synaptic pruning of hippocampal microglia and susceptibility to ASD in IUGR offspring

BackgroundAutism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear.ResultsWe found that the IUGR rat model induced by prenatal caffeine exposure (PCE) showed ASD-like symptoms, accompanied by altered gut microbiota and reduced production of indole 3-propionic acid (IPA), a microbiota-specific metabolite and a ligand of aryl hydrocarbon receptor (AHR). IUGR children also had a reduced serum IPA level consistent with the animal model. We demonstrated that the dysregulated IPA/AHR/NF-κB signaling caused by disturbed gut microbiota mediated the hippocampal microglia hyperactivation and neuronal synapse over-pruning in the PCE-induced IUGR rats. Moreover, postnatal IPA supplementation restored the ASD-like symptoms and the underlying hippocampal lesions in the IUGR rats.ConclusionsThis study suggests that the microbiota-IPA-brain axis regulates ASD susceptibility in PCE-induced IUGR offspring, and supplementation of microbiota-derived IPA might be a promising interventional strategy for ASD with a fetal origin.21xhjpDoyB4JmdH7kH-NGnVideo

Abstract P202: Changes In Cerebral Mitochondrial Function In Intrauterine Growth-Restricted Offspring Before The Development Of Hypertension And Cerebrovascular Dysfunction

Background: Preeclampsia (PE), new-onset gestational hypertension (HTN) affects 3-8% of all births in the USA. PE is the leading cause for intrauterine growth restriction (IUGR). IUGR children have increased risks of HTN and cerebrovascular disease (CVD) later in life. Prior studies in our lab show adult male IUGR rat offspring (OS) to develop HTN, CVD, and cerebral mitochondrial dysfunction (mtDys) at 17 weeks while female IUGR OS exhibit CVD. The role of mtDys in HTN is unknown and is the focus of our study. We hypothesize that IUGR OS will have mtDys prior to HTN. Methods: Our surgical PE animal model utilized the reduced-uterine-perfusion pressure (RUPP) surgery at GD 14. OS from NP served as controls (CON) while OS from RUPP mothers were IUGR. At 12 weeks, OS BP was measured alongside cerebral mtDys through mitochondrial fusion and fission, electron-transport chain (ETC) proteins, and respiration. Results: BP did not change between sexes or among IUGR and CON offspring. Male IUGR OS showed elevated mtRes (State 2: 199 ± 1.08 v. 76 ± 1.13 pmol/mg, p < .05; State 3: 555 ± 3.02 v. 245 ± 1.77 pmol/mg, p < .05; State 4: 346 ± 1.66 v. 85 ± 1.12 pmol/mg, p < .05). Female IUGR and CON OS had no changes in BP or mtRes. Male IUGR OS had increased mito-fusion proteins MFN-1 (176 ± 1.68 v. 100 ± .57 IU/protein/CON %, p < .05), MFN-2 (155 ± 1.36 v. 100 ± .74 IU/protein/CON %, p < .05) and OPA-1 (166 ± 1.99 v. 100 ± .73 IU/protein/CON %, p < .05). DRP-1 had no changes in males; females had no changes in fusion or fission. Male IUGR OS had changes in ETC proteins (CI: 8 ± 9.34 v. 100 ± .82 IU/protein/CON %, p < .05; CII: 23 ± .53 v. 100 ± .52 IU/protein/CON %, p < .05; CIII: 26 ± .23 v. 100 ± .41 IU/protein/CON %, p < .05), as did female IUGR OS (CI: 12 ± .24 v. 100 ± .86 IU/protein/CON %, p < .05; CII: 29 ± .39 v. 100 ± .61 IU/protein/CON %, p < .05; CIII: 39 ± .56 v. 100 ± .62 IU/protein/CON %, p < .05; CIV: 76 ± .74 v. 100 ± .73 IU/protein/CON %, p < .05) vs. CON OS. Summary: Male IUGR OS have elevated mtRes, changed ETC proteins, and fusion proteins that may lead to mtDys and HTN development. This study is clinically relevant because specific cerebral therapy for mtDys for IUGR OS may prevent HTN and CVD development. Future studies will examine changes in mtDys causing male HTN and protection from HTN in females.

Cardiovascular Dysfunction in Intrauterine Growth Restriction.

We highlight important new findings on cardiovascular dysfunction in intrauterine growth restriction. Intrauterine growth restriction (IUGR) is a multifactorial condition which negatively impacts neonatal growth during pregnancy and is associated with health problems during the lifespan. It affects 5-15% of all pregnancies in the USA and Europe with varying percentages in developing countries. Epidemiological studies have reported that IUGR is associated with the pathogenesis of hypertension, activation of the renin-angiotensin system (RAS), disruption in placental-mTORC and TGFβ signaling cascades, and endothelial dysfunction in IUGR fetuses, children, adolescents, and adults resulting in the development of cardiovascular diseases (CVD). Experimental studies are needed to investigate therapeutic measures to treat increased blood pressure (BP) and long-term CVD problems in people affected by IUGR. We outline the mechanisms mediating fetal programming of hypertension in developing CVD. We have reviewed findings from different experimental models focusing on recent studies that demonstrate CVD in IUGR.

Prenatal environment and developmental trajectories: the intrauterine growth restriction.

The prenatal environment is of fundamental importance for the fetus, as the fetus is particularly susceptible to environmental influences while in utero, and several prenatal adversities may constitute a risk factor for fetal growth and child development. Intrauterine growth restriction (IUGR) refers to a pregnancy complication involving the inadequate growth of the fetus in utero, with potential programming consequences on the children's brain-behavior development. In this narrative review we will discuss the most recent literature about IUGR children, including their development and their relationship with the prenatal and postnatal environment. In particular, as an attempt to an adaptive response to intrauterine changes, the brain development of IUGR fetuses follows abnormal developmental pathways, which likely has cascade effects on the future neurodevelopmental outcomes of the children. Cognitive and motor functions are in fact impaired, as well as IUGR children present, across studies, poor socio-emotional abilities and a greater risk for internalizing and externalizing behavior problems. The current work also highlights how the postnatal environment, and in particular parental care, has an important role in IUGR development, acting as a protective factor, or otherwise increasing their constitutional vulnerabilities. Overall, this narrative review has important implications for clinical practice, suggesting the need for long-term follow-up care with IUGR children and strategies supporting parent-child interactions as well.

Birth weight and catch up growth are associated with childhood impulsivity in two independent cohorts

Individuals born after intrauterine growth restriction (IUGR) are more impulsive towards palatable foods, but it is not clear 1) if IUGR-related impulsivity is specific for foods and solely based on response inhibition and 2) if the development of impulsivity is due to being born IUGR per se or to growing up fast in the first few years of life (catch up growth). Children were classified in the IUGR group if the birth weight ratio was below 0.85. Delta z score for BMI was used as a measure of catch up growth. In MAVAN (N = 274), impulsivity was measured by the Information Sampling Task from the Cambridge Neuropsychological Test Automated Battery (IST - CANTAB), and in GUSTO using the Sticker Delay Task (N = 327). There is a significant effect of interaction between being born IUGR and the magnitude of catch up growth on the reflection impulsivity from IST-CANTAB at 60 months, in which greater catch up growth associates with greater impulsivity in the IST fixed condition in IUGR children. The finding was reproduced in children from the GUSTO cohort using the Sticker Delay Task. We confirmed that catch up growth interacts with IUGR, having a major role in the development of impulsivity in the first years of life and influencing inhibitory control and decision making processes.

Macronutrient and fibre intake of young Spanish children with reference to their in utero growth status: Are they eating a healthy diet?

To compare macronutrient and fibre intake by pre-school children born with intra-uterine growth restriction (IUGR) or as appropriate for gestational age (AGA) and to compare their intake with paediatric nutritional recommendations for identification of potential areas of modification during early life. A parental 3-day dietary record was obtained for children of age 1-6 years, born at Hospital Clinic, Barcelona, Spain (2002-2007) with IUGR (n = 37) or AGA (n = 53). Mean nutrient intake (adjusted for body mass index), nutrient adequacy ratios (NAR) and percentage of energy intake (EI%) were compared. Macronutrient and fibre intake of the two groups did not differ significantly. However, IUGR children showed significantly higher than the recommended levels of protein EI% (18 (95% confidence interval (CI) 16-19)), NAR for saturated fatty acids (SFAs) (1.2 (95% CI 1.1-1.5)) and NAR for carbohydrate (1.4 (95% CI 1.2-1.6)) and significantly lower than the recommended levels of NAR for unsaturated fatty acids (UFAs) (0.6 (95% CI 0.5-0.8)) and for fibre (0.6 (95% CI 0.5-0.8)). Likewise, children born with AGA showed similar pattern compared to the recommended levels for protein EI% (17 (95% CI 16-18)), NAR for SFAs (1.3 (95% CI 1.2-1.4)), NAR for UFAs (0.6 (95% CI 0.5-0.7)) and NAR for fibre (0.8 (95% CI 0.7-0.9)). Spanish pre-school children consume proteins and SFAs in abundance and UFAs and fibre in moderation. Reinforcement of healthy eating is recommended for long-term health benefits, especially for at-risk children born with IUGR, whose consumption of carbohydrate is additionally greater than that recommended.

Fetal growth interacts with multilocus genetic score reflecting dopamine signaling capacity to predict spontaneous sugar intake in children

BackgroundWe have shown that intrauterine growth restriction (IUGR) leads to increased preference for palatable foods at different ages in both humans and rodents. In IUGR rodents, altered striatal dopamine signaling associates with a preference for palatable foods. ObjectivesOur aim was to investigate if a multilocus genetic score reflecting dopamine-signaling capacity is differently associated with spontaneous palatable food intake in children according to the fetal growth status. Methods192 four-year old children from a community sample from Montreal and Hamilton, Canada, were classified according to birth weight and administered a snack test meal containing regular as well as palatable foods. Intrauterine growth restriction was based on the birth weight ratio below 0.85; children were genotyped for polymorphisms associated with dopamine (DA) signaling, with the hypofunctional variants (TaqIA-A1 allele, DRD2-141C Ins/Ins, DRD4 7-repeat, DAT1-10-repeat, Met/Met-COMT) receiving the lowest scores, and a composite score was calculated reflecting the total number of the five genotypes. Macronutrient intake during the Snack Test was the outcome. ResultsAdjusting for z-score BMI at 48 months and sex, there was a significant interaction of the genetic profile and fetal growth on sugar intake [βˆ = −4.56, p = 0.04], showing a positive association between the genetic score and sugar intake in IUGR children, and no association in non-IUGR children. No significant interactions were seen in other macronutrients. ConclusionsVariations in a genetic score reflecting DA signaling are associated with differences in sugar intake only in IUGR children, suggesting that DA function is involved in this behavioral feature in these children. This may have important implications for obesity prevention in this population.

Structural Brain Network Reorganization and Social Cognition Related to Adverse Perinatal Condition from Infancy to Early Adolescence.

Adverse conditions during fetal life have been associated to both structural and functional changes in neurodevelopment from the neonatal period to adolescence. In this study, connectomics was used to assess the evolution of brain networks from infancy to early adolescence. Brain network reorganization over time in subjects who had suffered adverse perinatal conditions is characterized and related to neurodevelopment and cognition. Three cohorts of prematurely born infants and children (between 28 and 35 weeks of gestational age), including individuals with a birth weight appropriated for gestational age and with intrauterine growth restriction (IUGR), were evaluated at 1, 6, and 10 years of age, respectively. A common developmental trajectory of brain networks was identified in both control and IUGR groups: network efficiencies of the fractional anisotropy (FA)-weighted and normalized connectomes increase with age, which can be related to maturation and myelination of fiber connections while the number of connections decreases, which can be associated to an axonal pruning process and reorganization. Comparing subjects with or without IUGR, a similar pattern of network differences between groups was observed in the three developmental stages, mainly characterized by IUGR group having reduced brain network efficiencies in binary and FA-weighted connectomes and increased efficiencies in the connectome normalized by its total connection strength (FA). Associations between brain networks and neurobehavioral impairments were also evaluated showing a relationship between different network metrics and specific social cognition-related scores, as well as a higher risk of inattention/hyperactivity and/or executive functional disorders in IUGR children.

Differential effect of intrauterine growth restriction on childhood neurodevelopment: a systematic review.

Neurodevelopmental disorders are increasingly believed to originate from intrauterine growth restriction (IUGR). Current reviews exploring the neurodevelopmental effects of IUGR, however, are mostly based on birthweight, an inadequate proxy. We aimed to examine the association between IUGR documented in utero, and neurodevelopmental outcomes during childhood. Medline, CINAHL, PsycInfo and Scopus were searched for relevant studies published after 1970. The analysis included studies that identified IUGR in utero, with follow-up assessments between 1 month and 12 years of age. Data was extracted for cognitive, behavioural, language, motor, hearing, vision or sleep outcomes. Studies were summarised separately for children born at <35 and ≥35 weeks gestation. Of 28 876 titles identified, 38 were suitable for inclusion. IUGR children born ≥35 weeks gestation scored on average 0.5 SD lower than non-IUGR children across all neurodevelopmental assessments. IUGR children born <35 weeks of gestation scored approximately 0.7 SD lower than non-IUGR children across all neurodevelopmental assessments. IUGR children with evidence of fetal circulatory redistribution (preferential perfusion of the brain) had more severe neurodevelopmental impairments than those born IUGR alone. IUGR increases the risk of neurodevelopmental impairment during childhood differentially across domains. IUGR children born preterm or with evidence of fetal circulatory redistribution are more severely affected. IUGR is associated with an overall risk for neurodevelopmental delay in a range of neurodevelopmental domains.

Poor infant inhibitory control predicts food fussiness in childhood – A possible protective role of n-3 PUFAs for vulnerable children

Intrauterine growth restriction (IUGR) children are more impulsive towards a sweet reward and have altered feeding behavior in adulthood. We hypothesized that early life inhibitory control predicts feeding behaviors later on in childhood, and the consumption of n-3 PUFAs during infancy may protect IUGR children from developing problematic feeding behaviors. 156 children had information on the Early Childhood Behavior Questionnaire (ECBQ) at 18 months, Food Frequency Questionnaire at 48 months and Children׳s Eating Behavior Questionnaire (CEBQ) at 72 months. There was a significant negative correlation between inhibitory control at 18 months and food fussiness at 72 months. A GLM model predicting food fussiness at 72 months showed significant interaction between n-3 PUFAs, inhibitory control and IUGR, with higher intakes associated with decreased risk for fussiness in IUGR children with poor inhibitory control. Deficits in early inhibitory control predict later food fussiness, and higher intakes of n-3 PUFAs in infancy may protect IUGR children from developing such behavior later.

Early childhood neurodevelopment after intrauterine growth restriction: a systematic review.

Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse developmental outcomes in early childhood. The objective of this study was to carry out a systematic review of neurodevelopmental outcomes from 6 months to 3 years after IUGR. PubMed, Embase, PsycINFO, Maternity and Infant Care, and CINAHL databases were searched by using the search terms intrauterine, fetal, growth restriction, child development, neurodevelopment, early childhood, cognitive, motor, speech, language. Studies were eligible for inclusion if participants met specified criteria for growth restriction, follow-up was conducted within 6 months to 3 years, methods were adequately described, non-IUGR comparison groups were included, and full English text of the article was available. A specifically designed data extraction form was used. The methodological quality of included studies was assessed using well-documented quality-appraisal guidelines. Of 731 studies reviewed, 16 were included. Poorer neurodevelopmental outcomes after IUGR were described in 11. Ten found motor, 8 cognitive, and 7 language delays. Other delays included social development, attention, and adaptive behavior. Only 8 included abnormal Doppler parameters in their definitions of IUGR. Evidence suggests that children are at risk for poorer neurodevelopmental outcomes following IUGR from 6 months to 3 years of age. The heterogeneity of primary outcomes, assessment measures, adjustment for confounding variables, and definitions of IUGR limits synthesis and interpretation. Sample sizes in most studies were small, and some examined preterm IUGR children without including term IUGR or AGA comparison groups, limiting the value of extant studies.

Albuminuria and sodiuria in IUGR children

Objective: Intrauterine growth restriction (IUGR) is associated with hyperfiltration, glomerulosclerosis and albuminuria. Albuminuria may further lead to tubulointerstitial inflammation, fibrosis and tubular atrophy. The time at which this may occur is unknown. This study was designed to assess the relationship between glomerular and tubular damage in IUGR children.Methods: We enrolled 50 children, 25 IUGR, categorized by estimated fetal weight <10th percentile and umbilical artery pulsatility index >2 SD, and 25 appropriate for gestational age (AGA) controls at 18 months of age. We compared albuminuria among IUGR and AGA children, to assess the relationship between albuminuria and contemporary sodium and lysozyme excretion, as a measure of tubular damage.Results: The albumin-creatinine (mg/g) and sodium-creatinine (μM/L) ratios (3.12 and 441.3, versus 1.39 and 226.1 in AGA; p = 0.002 and p = 0.012, respectively) were significantly higher in the IUGR subjects compared with AGA children, and significantly correlated (rho = 0.593, p = 0.002). Conversely, urinary lysozyme was undetectable or in normal excretion range.Conclusions: Our results show glomerulosclerosis and albuminuria in IUGR children aged 18 months. Elevated sodium excretion in the absence of abnormal lysozymuria may represent a epiphenomenon of glomerulosclerosis and of albuminuria.

Structural Brain Connectivity in School-Age Preterm Infants Provides Evidence for Impaired Networks Relevant for Higher Order Cognitive Skills and Social Cognition.

Extreme prematurity and pregnancy conditions leading to intrauterine growth restriction (IUGR) affect thousands of newborns every year and increase their risk for poor higher order cognitive and social skills at school age. However, little is known about the brain structural basis of these disabilities. To compare the structural integrity of neural circuits between prematurely born controls and children born extreme preterm (EP) or with IUGR at school age, long-ranging and short-ranging connections were noninvasively mapped across cortical hemispheres by connection matrices derived from diffusion tensor tractography. Brain connectivity was modeled along fiber bundles connecting 83 brain regions by a weighted characterization of structural connectivity (SC). EP and IUGR subjects, when compared with controls, had decreased fractional anisotropy-weighted SC (FAw-SC) of cortico-basal ganglia-thalamo-cortical loop connections while cortico-cortical association connections showed both decreased and increased FAw-SC. FAw-SC strength of these connections was associated with poorer socio-cognitive performance in both EP and IUGR children.

Pre-eclampsia—An additional risk factor for cognitive impairment at school age after intrauterine growth restriction and very preterm birth

ObjectiveTo explore the possible influence of pre-eclampsia on cognitive outcome in children born very preterm after intrauterine growth restriction (IUGR) and abnormal umbilical artery blood flow. MethodsCognitive function was evaluated at 5–8years of age with Wechsler scales in 34 children born before 30gestationalweeks after IUGR (PT-IUGR) (11 children were exposed to maternal pre-eclampsia, 23 non-exposed) and in 34 children with no maternal pre-eclampsia and birth weight appropriate-for-gestational age (PT-AGA) matched for gestational age at birth, gender and age at examination. ResultsThe subjects in the PT-IUGR group exposed to maternal pre-eclampsia had lower mean verbal IQ (VIQ) (mean±SD 74±16) and lower full scale IQ (FSIQ) (70±19) in comparison with both the non-exposed PT-IUGR (VIQ 89±15; p=0.013; FSIQ 83±14, p=0.029), and, the PT-AGA group (VIQ 96±15, p<0.001; FSIQ 90±14, p=0.001). The differences remained significant after adjustment for known confounders. VIQ and FSIQ did not differ between the non-exposed IUGR and PT-AGA children. ConclusionFetal exposure to maternal pre-eclampsia seems to have an additional negative impact to that of IUGR on cognitive function in children born very preterm.

Fetal aortic wall thickness: a marker of hypertension in IUGR children?

Fetuses with intrauterine growth restriction (IUGR) have significant aortic intima-media thickening (aIMT), which suggests that preclinical atherosclerosis might predispose the infants to hypertension. However, the natural course of aIMT in babies with IUGR remains an open question.The study enrolled 77 pregnant women between January 2007 and August 2009. The fetuses were classified as AGA (appropriate for gestational age) or IUGR, if the estimated fetal weight was between the 10th and 90th percentile or below the 10th percentile (with umbilical artery pulsatility index (PI) >2s.d.), respectively. Anthropometric parameters and aIMT were detected in each IUGR and AGA fetus at a mean gestational age of 32 weeks. The follow-up was performed in 25 IUGR and 25 AGA infants at a mean postnatal age of 18 months; the previous measurements were repeated, and blood pressure measurements were taken. The maximum aIMT was significantly higher in the IUGR fetuses and infants compared with the AGA infants, both in utero (2.05±0.43 vs. 1.05±0.19 mm, P<0.001) and at the follow-up (2.3±0.8 vs. 1.06±0.18 mm, P<0.0001), the resulting values significantly correlated (P=0.018) with one another. The systolic blood pressure was significantly increased in the IUGR subjects (123±16 vs. 104±8.5 mm Hg, P<0.0004), and it correlated with the prenatal and postnatal aIMT values (P<0.0156 and P<0.0054, respectively). The aortic wall thickening progression in IUGR fetuses and infants differed from AGA, which may predispose the infants to hypertension early in life and cardiovascular risk later in life.

The neurocognitive outcome of IUGR children born to mothers with and without preeclampsia

Objective: To examine long-term behavioral and neurodevelopmental outcome of children born growth restricted and exposed to hypertension in utero at 9 years of age. Methods: Somatic growth and neurocognitive outcomes were evaluated at age 9–10 years of age in 42 children born with intra uterine growth restriction (IUGR) after pregnancies complicated by hypertensive disorder (17 with maternal preeclampsia and 25 after gestational hypertension). This study group was compared to a control group of 78 IUGR children born after normotensive pregnancy. Results: Only weight was found to be significantly lower in the hypertensive-IUGR group, versus the normotensive IUGR children. No significant differences were found in any of the neurocognitive parameters including IQ, school achievements, and neurodevelopmental score at age 9–10 years. Conclusion: IUGR is a well known risk factor for later cognitive difficulties but maternal hypertensive disorder does not seem to add significantly to this risk.

Factors Associated with Height Catch-Up and Catch-Down Growth Among Schoolchildren

In developed countries, children with intrauterine growth restriction (IUGR) or born preterm (PT) tend to achieve catch-up growth. There is little information about height catch-up in developing countries and about height catch-down in both developed and developing countries. We studied the effect of IUGR and PT birth on height catch-up and catch-down growth of children from two cohorts of liveborn singletons. Data from 1,463 children was collected at birth and at school age in Ribeirão Preto (RP), a more developed city, and in São Luís (SL), a less developed city. A change in z-score between schoolchild height z-score and birth length z-score≥0.67 was considered catch-up; a change in z-score≤−0.67 indicated catch-down growth. The explanatory variables were: appropriate weight for gestational age/PT birth in four categories: term children without IUGR (normal), IUGR only (term with IUGR), PT only (preterm without IUGR) and preterm with IUGR; infant's sex; maternal parity, age, schooling and marital status; occupation of family head; family income and neonatal ponderal index (PI). The risk ratio for catch-up and catch-down was estimated by multinomial logistic regression for each city. In RP, preterms without IUGR (RR = 4.13) and thin children (PI<10th percentile, RR = 14.39) had a higher risk of catch-down; catch-up was higher among terms with IUGR (RR = 5.53), preterms with IUGR (RR = 5.36) and children born to primiparous mothers (RR = 1.83). In SL, catch-down was higher among preterms without IUGR (RR = 5.19), girls (RR = 1.52) and children from low-income families (RR = 2.74); the lowest risk of catch-down (RR = 0.27) and the highest risk of catch-up (RR = 3.77) were observed among terms with IUGR. In both cities, terms with IUGR presented height catch-up growth whereas preterms with IUGR only had height catch-up growth in the more affluent setting. Preterms without IUGR presented height catch-down growth, suggesting that a better socioeconomic situation facilitates height catch-up and prevents height catch-down growth.

Update: Consequences of Abnormal Fetal Growth

Intrauterine growth restriction (IUGR) is prevalent worldwide and affects children and adults in multiple ways. These include predisposition to type 2 diabetes mellitus, the metabolic syndrome, cardiovascular disease, persistent reduction in stature, and possibly changes in the pattern of puberty. A review of recent literature confirms that the metabolic effects of being born small for gestational age are evident in the very young, persist with age, and are amplified by adiposity. Furthermore, the pattern of growth in the first few years of life has a significant bearing on a person's later health, with those that show increasing weight gain being at the greatest risk for future metabolic dysfunction. Treatment with exogenous human GH is used to improve height in children who remain short after being small for gestational age at birth, but the response of individuals remains variable and difficult to predict. The mechanisms involved in the metabolic programming of IUGR children are just beginning to be explored. It appears that IUGR leads to widespread changes in DNA methylation and that specific "epigenetic signatures" for IUGR are likely to be found in various fetal tissues. The challenge is to link such alterations with modifications in gene expression and ultimately the metabolic abnormalities of adulthood, and it represents one of the frontiers for research in the field.

Heart rate variability analysis of normal and growth restricted children

Intrauterine growth restriction (IUGR) has been associated with an increased risk of cardiovascular disease in later life. The regularity mechanism of cardiovascular system is under the control of autonomic nervous system (ANS). The non-optimal fetal growth may alter the development of the ANS and this appears to persist in later life. The aim of the present work is to analyse the synergic activity of the ANS in normal and growth restricted children. Heart rate variability analysis from 24 h ECG recordings of 70 children between 9 and 10 years old, normal and IUGR was performed using linear and non-linear time series analysis techniques. The HRV parameters showed no significant difference between normal and IUGR children. Low birth weight and its association with development of the cardiovascular system and its control have been extensively studied. In order to investigate the effect of low birth weight on HRV parameters, the IUGR children were further divided into two groups: IUGR-1 (birth weight<2.50 kg) and IUGR-2 (birth weight≥2.50 kg). The results demonstrated that most of the HRV measures showed significant differences between normal versus IUGR-1 as well as IUGR-1 versus IUGR-2 groups. The effect of gender on HRV measures was also examined and we noticed that girls had lower HRV than boys.

Intrauterine growth restriction is associated with persistent aortic wall thickening and glomerular proteinuria during infancy

Low birth weight, caused either by preterm birth or by intrauterine growth restriction, has recently been associated with increased rates of adult renal and cardiovascular disease. Since aortic intima–media thickening is a noninvasive marker of preclinical vascular disease, we compared abdominal aortic intima–media thickness among intrauterine growth restricted and equivalent gestational age fetuses in utero and at 18 months of age. The relationship between intrauterine growth restriction, fetal aortic thickening, and glomerular function during infancy was measured by enrolling 44 mothers with single-fetus pregnancies at 32 weeks gestation: 23 growth restricted and 21 of appropriate gestational age as controls. Abdominal aortic intima–media thickness was measured by ultrasound at enrollment and again at 18 months of age. Fetuses with intrauterine growth restriction had significantly higher abdominal aortic intima–media thickness compared with age controls when measured both in utero and at 18 months. At 18 months, the median urinary microalbumin and median albumin–creatinine ratio were significantly higher in those infants who experienced intrauterine growth restriction compared to the controls. Our results show that intrauterine growth restriction is associated with persistent aortic wall thickening and significantly higher microalbuminuria during infancy.