Cause Of Intrauterine Growth Restriction Research Articles

Regulation of fetal liver growth in a model of diet restriction in the pregnant rat.

Limited nutrient availability is a cause of intrauterine growth restriction (IUGR), a condition that has important implications for the well being of the offspring. Using the established IUGR model of maternal fasting in the rat, we investigated mechanisms that control gene expression and mRNA translation in late-gestation fetal liver. Maternal fasting for 48 h during the last one-third of gestation was associated with a 10-15% reduction in fetal body weight and a disproportionate one-third reduction in total fetal liver protein. The fetal liver transcriptome showed only subtle changes consistent with reduced cell proliferation and enhanced differentiation in IUGR. Effects on the transcriptome could not be attributed to specific transcription factors. We purified translating polysomes to profile the population of mRNAs undergoing active translation. Microarray analysis of the fetal liver translatome indicated a global reduction of translation. The only targeted effect was enhanced translation of mitochondrial ribosomal proteins in IUGR, consistent with enhanced mitochondrial biogenesis. There was no evidence for attenuated signaling through the mammalian target of rapamycin (mTOR). Western blot analysis showed no changes in fetal liver mTOR signaling. However, eukaryotic initiation factor 2α (eIF2α) phosphorylation was increased in livers from IUGR fetuses, consistent with a role in global translation control. Our data indicate that IUGR-associated changes in hepatic gene expression and mRNA translation likely involve a network of complex regulatory mechanisms, some of which are novel and distinct from those that mediate the response of the liver to nutrient restriction in the adult rat.

Intrauterine growth restriction: impact on cardiovascular development and function throughout infancy.

Intrauterine growth restriction (IUGR) refers to the situation where a fetus does not grow according to its genetic growth potential. One of the main causes of IUGR is uteroplacental vascular insufficiency. Under these circumstances of chronic oxygen and nutrient deprivation, the growth-restricted fetus often displays typical circulatory changes, which in part represent adaptations to the suboptimal intrauterine environment. These fetal adaptations aim to preserve oxygen and nutrient supply to vital organs such as the brain, the heart, and the adrenals. These prenatal circulatory adaptations are thought to lead to an altered development of the cardiovascular system and "program" the fetus for life long cardiovascular morbidities. In this review, we discuss the alterations to cardiovascular structure, function, and control that have been observed in growth-restricted fetuses, neonates, and infants following uteroplacental vascular insufficiency. We also discuss the current knowledge on early life surveillance and interventions to prevent progression into chronic disease.

When Feeding Difficulties Are due to Genetics: The Case of Familial Partial 9q Duplication.

Chromosomal abnormalities may cause growth failure before or since birth. 9q duplication is reported as a cause of intrauterine growth restriction, mild dysmporphism, and intellectual disabilities. We report a case of a maternally inherited 9q21.31q21.33 duplication causing prenatal and postnatal growth restriction with feeding refusal and mild facial dysmorphisms, prenatally diagnosed by single-nucleotide polymorphism array analysis. Hypothesis of the possible pathogenic mechanisms are discussed.

Small for gestational age births among South Indian women: temporal trend and risk factors from 1996 to 2010

BackgroundThe birth weight and gestational age at birth are two important variables that define neonatal morbidity and mortality. In developed countries, chronic maternal diseases like hypertension, diabetes mellitus, renal disease or collagen vascular disease is the most common cause of intrauterine growth restriction (IUGR). Maternal nutrition, pregnancy induced hypertension, chronic maternal infections, and other infections such as cytomegalovirus, parvovirus, rubella and malaria are the other causes of IUGR. The present study examines the secular trend of Small for Gestational Age (SGA) over 15 years and risk factors for SGA from a referral hospital in India.MethodsData from 1996 to 2010 was obtained from the labour room register. A rotational sampling scheme was used i.e. 12 months of the year were divided into 4 quarters. Taking into consideration all deliveries that met the inclusion criteria, babies whose birth weights were less than 10th percentile of the cut off values specific for gestational ages, were categorized as SGA. Only deliveries of live births that occurred between 22 and 42 weeks of pregnancy were considered in this study. Besides bivariate analyses, multivariable logistic regression analysis was done. Nagelkerke R2 statistics and Hosmer and Lemeshow chi-square statistics were used as goodness of fit statistics.ResultsBased on the data from 36,674 deliveries, the incidence of SGA was 11.4% in 1996 and 8.4% in 2010. Women who had multiple pregnancies had the higher odds of having SGA babies, 2.8 (2.3-3.3) times. The women with hypertensive disease had 1.8 (1.5-1.9) times higher odds of having SGA. Underweight women had 1.7 (1.3 - 2.1) times and anaemic mothers had 1.29 (1.01 - 1.6) times higher odds. The mothers who had cardiac disease were 1.4 (1.01 - 2.0) times at higher odds for SGA. In teenage pregnancies, the odds of SGA was 1.3 (1.1 - 1.5) times higher than mothers in the age group 20 to 35 years.ConclusionsThere is a significant reduction in the incidence of SGA by 26% over 15 years. The women with the above modifiable risk factors need to be identified early and provided with health education on optimal birth weight.

Restrição de Crescimento Intrauterino

Are called ferns small for gestational age (SGA) those who have the estimated weight percentile below 10. Intrauterine growth restriction (IUGR) is the leading cause of SGA fetuses and is associated with high rate of fetal and neonatal morbidity and mortality. Proper diagnosis and monitoring has an impact as a marker of assistance for the mother and the fetus. This review aims to assist the management of this serious condition, trying to assist in reducing the deleterious effects on the fetus and the neonate. Currently, in addition to the investment in neonatal treatment, has sought to invest in the early recognition of patients with higher risk of having fetuses with IUGR and in therapeutic ways to increase its prevention, thus decreasing its incidence and severity. The main causes of IUGR are: genetic changes, infections and placental insufficiency. Recognize these causes help in the decision of the appropriate time of childbirth. Of all, the placental insufficiency is the most common and which presents the greatest challenges because it is paradoxically the least lethal potential and at the same time the most kills in our midst. The appropriate management of pregnancies with IUGR caused by placental insufficiency imposes the necessity of the full knowledge of the sequence of the hemodynamic changes fetus-placental Doppler to, for the decision about the necessity and the appropriate time, depending on the gestational age (GA), to anticipate the birth with a view to damaging action that prematurity can sum these ferns, with unfavourable repercussions that may go beyond the perinatal period.

Chronic hypoxemia in late gestation decreases cardiomyocyte number but does not change expression of hypoxia-responsive genes.

BackgroundPlacental insufficiency is the leading cause of intrauterine growth restriction in the developed world and results in chronic hypoxemia in the fetus. Oxygen is essential for fetal heart development, but a hypoxemic environment in utero can permanently alter development of cardiomyocytes. The present study aimed to investigate the effect of placental restriction and chronic hypoxemia on total number of cardiomyocytes, cardiomyocyte apoptosis, total length of coronary capillaries, and expression of genes regulated by hypoxia.Methods and ResultsWe induced experimental placental restriction from conception, which resulted in fetal growth restriction and chronic hypoxemia. Fetal hearts in the placental restriction group had fewer cardiomyocytes, but interestingly, there was no difference in the percentage of apoptotic cardiomyocytes; the abundance of the transcription factor that mediates hypoxia‐induced apoptosis, p53; or expression of apoptotic genes Bax and Bcl2. Likewise, there was no difference in the abundance of autophagy regulator beclin 1 or expression of autophagic genes BECN1, BNIP3, LAMP1, and MAP1LC3B. Furthermore, fetuses exposed to normoxemia (control) or chronic hypoxemia (placental restriction) had similar mRNA expression of a suite of hypoxia‐inducible factor target genes, which are essential for angiogenesis (VEGF, Flt1, Ang1, Ang2, and Tie2), vasodilation (iNOS and Adm), and glycolysis (GLUT1 and GLUT3). In addition, there was no change in the expression of PKC‐ε, a cardioprotective gene with transcription regulated by hypoxia in a manner independent of hypoxia‐inducible factors. There was an increased capillary length density but no difference in the total length of capillaries in the hearts of the chronically hypoxemic fetuses.ConclusionThe lack of upregulation of hypoxia target genes in response to chronic hypoxemia in the fetal heart in late gestation may be due to a decrease in the number of cardiomyocytes (decreased oxygen demand) and the maintenance of the total length of capillaries. Consequently, these adaptive responses in the fetal heart may maintain a normal oxygen tension within the cardiomyocyte of the chronically hypoxemic fetus in late gestation.

Early protein malnutrition negatively impacts physical growth and neurological reflexes and evokes anxiety and depressive-like behaviors

Malnutrition is a worldwide problem affecting millions of unborn and young children during the most vulnerable stages of their development. In humans, poor maternal nutrition is a major cause of intrauterine growth restriction which is associated with an increased risk of perinatal mortality and long-term morbidity. In addition, intrauterine growth restriction correlates with neurodevelopmental delays and alterations of brain structure and neurochemistry. While there is no doubt that maternal malnutrition is a principal cause of perturbed development of the fetal brain and that all nutrients have certain influence on brain maturation, proteins appear to be the most critical for the development of neurological functions. In the present study we assessed male and female mouse offspring, born to dams protein restricted during pregnancy and lactation, in physical growth and neurobehavioral development and also in social interaction, motivation, anxiety and depressive behaviors. Moreover, we evaluate the impact of the low protein diet on dams in relation to their maternal care and anxiety-related behavior given that these clearly affect pups development. We observed that maternal protein restriction during pregnancy and lactation delayed the physical growth and neurodevelopment of the offspring in a sex-independent manner. In addition, maternal undernutrition negatively affected offspring's juvenile social play, motivation, exploratory activity and risk assessment behaviors. These findings show that protein restriction during critical periods of development detrimentally program progeny behavior.

Intrauterine Growth Restriction Caused by Underlying Congenital Cytomegalovirus Infection

Human cytomegalovirus (HCMV) is the major viral etiology of congenital infection and birth defects. Fetal transmission is high (30%-40%) in primary maternal infection, and symptomatic babies have permanent neurological, hearing, and vision defects. Recurrent infection is infrequently transmitted (2%) and largely asymptomatic. Congenital infection is also associated with intrauterine growth restriction (IUGR). To investigate possible underlying HCMV infection in cases of idiopathic IUGR, we studied maternal and cord sera and placentas from 19 pregnancies. Anti-HCMV antibodies, hypoxia-related factors, and cmvIL-10 were measured in sera. Placental biopsy specimens were examined for viral DNA, expression of infected cell proteins, and pathology. Among 7 IUGR cases, we identified 2 primary and 3 recurrent HCMV infections. Virus replicated in glandular epithelium and lymphatic endothelium in the decidua, cytotrophoblasts, and smooth muscle cells in blood vessels of floating villi and the chorion. Large fibrinoids with avascular villi, edema, and inflammation were significantly increased. Detection of viral proteins in the amniotic epithelium indicated transmission in 2 cases of IUGR with primary infection and 3 asymptomatic recurrent infections. Congenital HCMV infection impairs placental development and functions and should be considered as an underlying cause of IUGR, regardless of virus transmission to the fetus.

Effect of Maternal Smoking Cessation Before and During Early Pregnancy on Fetal and Childhood Growth

BackgroundMaternal smoking during pregnancy is a major cause of intrauterine growth restriction and childhood obesity, but only a few studies have examined the association of smoking cessation before and during pregnancy with fetal and childhood growth. We examined this association in a prospective cohort study in Japan.MethodsOur study included children born between 1991 and 2006 and their mothers. Using a questionnaire, maternal smoking status was recorded at pregnancy. The anthropometric data of the children were collected during a medical check-up at age 3 years. Multiple linear and logistic regression models were used for data analysis stratified by sex.ResultsIn total, 2663 mothers reported their smoking status during early pregnancy, and data were collected from 2230 (83.7%) children at age 3 years. Maternal smoking during pregnancy was associated with a significant reduction in birth weight (approximately 120–150 g). Body mass index at age 3 years was significantly higher among boys born to smoking mothers than among boys born to nonsmoking mothers. Maternal smoking during pregnancy was associated with overweight at age 3 years among boys (adjusted odds ratio, 2.4; 95% CI, 1.03–5.4). However, among women who stopped smoking in early pregnancy, there was no increase in the risks of a small for gestational age birth or childhood overweight at age 3 years.ConclusionsChildren born to mothers who stopped smoking before or during early pregnancy had appropriate fetal and childhood growth.

Associations of intrauterine growth restriction with placental pathological factors, maternal factors and fetal factors; clinicopathological findings of 257 Japanese cases.

Intrauterine growth restriction (IUGR) is the leading cause of fetal mortality and morbidity. As an etiology, each of placental findings, maternal factors and fetal factors has been reported to be associated with IUGR, although a comprehensive approach to examine all of these parameters as a cause of IUGR has not been reported. In the present study, therefore, we comprehensively examined the placental findings and maternal and fetal factors in the cases of IUGR (n=257, mean maternal age, 30 years; gestational weeks, 34 weeks) and normal growth pregnancies (n=258, mean maternal age, 30 years; gestational weeks, 33 weeks), and determined risk factors for IUGR. The prevalence of pregnancy hypertension (PHT) (19% vs. 8%, P<0.01), smoking habit (3% vs. 0.7%, P<0.05) and fetal anomaly (3.5% vs. 0.8%, P<0.05) were higher in IUGR cases than normal growth pregnancies. Pathologically, the prevalence of infarction (33% vs. 14%, P<0.05), fetal vessel thrombosis (22% vs. 6%, P<0.001) and chronic villitis (11% vs. 3%, P<0.001) were higher in IUGR cases than those in normal growth pregnancies. A multivariable regression analysis revealed that maternal factors (PHT), fetal factors (anomaly), and placental findings (infarction, fetal vessel thrombosis, and chronic villitis) are independently associated with increased risk of IUGR (all P<0.01).

W154 PLACENTAL GENE EXPRESSION OF BAX AND BCL-2 GENES; APOPTOSIS AS A POTENTIAL CAUSE OF INTRAUTERINE GROWTH RESTRICTION

International Journal of Gynecology & ObstetricsVolume 119, Issue S3 p. S755-S755 Poster presentations W154 PLACENTAL GENE EXPRESSION OF BAX AND BCL-2 GENES; APOPTOSIS AS A POTENTIAL CAUSE OF INTRAUTERINE GROWTH RESTRICTION B. Börzsönyi, B. BörzsönyiSearch for more papers by this authorC. Demendi, C. DemendiSearch for more papers by this authorZ. Nagy, Z. NagySearch for more papers by this authorA. Pajor, A. PajorSearch for more papers by this authorJ. Rigo, J. RigoSearch for more papers by this authorI. Szentpéteri, I. SzentpéteriSearch for more papers by this authorJ.G. Joó, J.G. JoóSearch for more papers by this author B. Börzsönyi, B. BörzsönyiSearch for more papers by this authorC. Demendi, C. DemendiSearch for more papers by this authorZ. Nagy, Z. NagySearch for more papers by this authorA. Pajor, A. PajorSearch for more papers by this authorJ. Rigo, J. RigoSearch for more papers by this authorI. Szentpéteri, I. SzentpéteriSearch for more papers by this authorJ.G. Joó, J.G. JoóSearch for more papers by this author First published: 22 October 2012 https://doi.org/10.1016/S0020-7292(12)61879-7AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume119, IssueS3Abstracts of XX FIGO World Congress of Gynecology and ObstetricsOctober 2012Pages S755-S755 RelatedInformation

Placental Restriction Reduces Insulin Sensitivity and Expression of Insulin Signaling and Glucose Transporter Genes in Skeletal Muscle, But Not Liver, in Young Sheep

Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (-43%, P < 0.001) and skeletal muscle expression of INSR (-36%), IRS1 (-28%), AKT2 (-44%), GLUT4 (-88%), GSK3α (-35%), and GYS1 (-31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.

Histopathological or clinical features do not predict the presence of high level tetraploidy as a form of confined placental mosaicism in pregnancies affected by otherwise idiopathic IUGR

<h3>Aims</h3> Confined placental mosaicism (CPM) is a risk factor for intrauterine growth restriction (IUGR). We investigated if we could identify pregnancies affected by high level tetraploidy (>22% of metaphases) as a form of CPM (TCPM) by clinical or placental histological features, within a larger group of pregnancies affected by IUGR of unknown origin. <h3>Methods</h3> Placentae from pregnancies affected by IUGR of unknown cause over a period of 28 months were karyotyped: 12 of 52 placentas showed TCPM. Maternal age, gravidity, parity, pre-pregnancy body mass index (BMI), and placental histology were compared between IUGR affected pregnancies with or without TCPM. Placentas with other karyotypic abnormalities were excluded from analysis. <h3>Results</h3> Parity, gravidity or maternal age showed no significant difference. IUGR without TCPM mothers tended to have a slightly but significantly higher BMI. Placental histology failed to show a significant difference with regard to the presence of abnormality or the type of parenchymal abnormality identified. <h3>Conclusion</h3> The presence of TCPM in IUGR cannot be predicted by either clinical or histological factors. Karyotyping of all placentas from pregnancies with apparently idiopathic IUGR may be advisable to identify this cause of IUGR.

Histopathological or clinical features do not predict the presence of high level tetraploidy as a form of confined placental mosaicism in pregnancies affected by otherwise idiopathic IUGR

Aims Confined placental mosaicism (CPM) is a risk factor for intrauterine growth restriction (IUGR). We investigated if we could identify pregnancies affected by high level tetraploidy (>22% of metaphases) as a form of CPM (TCPM) by clinical or placental histological features, within a larger group of pregnancies affected by IUGR of unknown origin. Methods Placentae from pregnancies affected by IUGR of unknown cause over a period of 28 months were karyotyped: 12 of 52 placentas showed TCPM. Maternal age, gravidity, parity, pre-pregnancy body mass index (BMI), and placental histology were compared between IUGR affected pregnancies with or without TCPM. Placentas with other karyotypic abnormalities were excluded from analysis. Results Parity, gravidity or maternal age showed no significant difference. IUGR without TCPM mothers tended to have a slightly but significantly higher BMI. Placental histology failed to show a significant difference with regard to the presence of abnormality or the type of parenchymal abnormality identified. Conclusion The presence of TCPM in IUGR cannot be predicted by either clinical or histological factors. Karyotyping of all placentas from pregnancies with apparently idiopathic IUGR may be advisable to identify this cause of IUGR.

Extrinsic factors influencing fetal deformations and intrauterine growth restriction.

The causes of intrauterine growth restriction (IUGR) are multifactorial with both intrinsic and extrinsic influences. While many studies focus on the intrinsic pathological causes, the possible long-term consequences resulting from extrinsic intrauterine physiological constraints merit additional consideration and further investigation. Infants with IUGR can exhibit early symmetric or late asymmetric growth abnormality patterns depending on the fetal stage of development, of which the latter is most common occurring in 70–80% of growth-restricted infants. Deformation is the consequence of extrinsic biomechanical factors interfering with normal growth, functioning, or positioning of the fetus in utero, typically arising during late gestation. Biomechanical forces play a critical role in the normal morphogenesis of most tissues. The magnitude and direction of force impact the form of the developing fetus, with a specific tissue response depending on its pliability and stage of development. Major uterine constraining factors include primigravida, small maternal size, uterine malformation, uterine fibromata, early pelvic engagement of the fetal head, aberrant fetal position, oligohydramnios, and multifetal gestation. Corrective mechanical forces similar to those that gave rise to the deformation to reshape the deformed structures are often used and should take advantage of the rapid postnatal growth to correct form.

The long and short of it: the role of telomeres in fetal origins of adult disease.

Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.

Intrauterine Growth Restriction and Developmental Programming of the Metabolic Syndrome: A Critical Appraisal

According to the "small baby syndrome hypothesis," low birthweight and intrauterine growth restriction (IUGR) occurring in westernized countries mainly through altered placental flow, have been linked to increased metabolic syndrome risk in later life. Independency and causal mechanisms of this phenomenological association are a matter of controversy. By means of epidemiological as well as experimental methods, using meta-analyses and different rodent models of pre- and/or neonatal malnutrition and altered placental flow (uterine artery ligation; Lig), we systematically addressed the phenomenon. Our data and systematic literature analysis revealed that neither epidemiological nor experimental evidence seems to exist linking prenatal underfeeding, low birthweight, IUGR, or decreased placental flow in rats (Lig-model) as independent risk factors to increased metabolic syndrome risk in later life. Rather, pre- and/or neonatal overfeeding, elevated birthweight, rapid neonatal weight gain, and especially increased adiposity during critical periods of perinatal life may increase long-term risks. Perinatally acquired microstructural and epigenomic alterations in regulatory systems of metabolism and body weight seem to be critical, leading to a cardiometabolic risk disposition throughout life. While experimental data in Lig-offspring seem to be considerably biased, prenatal stress and postnatal overfeeding/rapid neonatal weight gain might be causally linked to a long-term deleterious outcome in growth restricted newborns. From a clinical point of view, prevention of causes of IUGR, as well as avoidance of perinatal overnourishment, might be prophylactic approaches to avoid perinatal programming of cardiometabolic risks.

Hypoxic fetal programming of the sympathetic nervous system

The link between intra uterine growth restriction (IUGR) and increased risk of adult cardiovascular disease in the offspring is well established. Chronic hypoxia in utero (CHU) is a well established cause of IUGR, and using in vitro methods, has been shown to cause endothelial dysfunction and sympathetic hyperinnervation in the offspring. Our aim is to assess the impact of CHU upon sympathetic nerve activity. We have made direct recordings of MSNA from arteries supplying the Spinotrapezius muscle under Alfaxan anaesthesia in Normal (N, n=7) and CHU rats (n=6), discriminating single unit activity from multiunit recordings. Arterial blood pressure, measured from the femoral artery, was similar in N and CHU rats (N:123±3, CHU: 119±5, mmHg). All single units (N=17, CHU=26) had cardiac and respiratory rhythmicity. Mean firing rates were similar (N: 0.48±0.09, CHU: 0.52±0.1, Hz). Further analysis showed that high frequency doublets and triplets of activity (>20hz) were more common in CHU. This may suggest increased release of Neuropeptide Y from sympathetic varicosities, and hence, impact upon cardiovascular health. Recordings during baro- and chemoreceptor stimulation are under analysis.

Fetal Programming of Gene Expression in Growth-Restricted Rats Depends on the Cause of Low Birth Weight

Low birth weight and intrauterine growth restriction (IUGR) can be caused by numerous different conditions. In many experimental settings, however, these different causes are not accounted for. This study aimed at comparing the impact of two frequent causes of IUGR (low utero-placental blood flow vs. malnutrition) on fetal programming of gene expression. We studied offspring of dams treated by uterine artery ligation or sham operation compared with untreated controls and offspring of dams that were fed either a low protein or normal protein diet. After Cesarean section at term, placental and fetal hepatic expression of key "metabolic" and "vasoregulative" genes was investigated by quantitative RT-PCR. Ligation neonates showed IUGR, reduced expression of placental leptin, placental and hepatic IGF-I, hepatic inducible nitric oxide synthase, and increased expression of placental IGF binding protein 1, hepatic IGF-II receptor and erythropoietin (EPO). Low protein offspring also showed IUGR but increased expression of placental leptin; IGF-I; placental and hepatic inducible nitric oxide synthase; hepatic insulin, IGF-I, and IGF-II receptors; and reduced expression of placental IGF binding protein 1, IGF-II, leptin-receptor type A, placental and hepatic leptin receptor type B, and EPO. Expression was independent of sex, birth weight, fetal intrauterine position, and EPO expression. In conclusion, the impact of IUGR on fetal and placental gene expression depends on the cause of low birth weight. Therefore, morbidity after IUGR should be analyzed referring to its pathophysiological cause rather than referring to low birth weight itself. Fetal hypoxia as estimated by hepatic EPO expression does not seem to be a key regulator of transcriptional activity in our models.

Restricción de Crecimiento Intrauterino: Causas, Características Clínicas, y Evaluación de Factores Asociados a Policitemia Sintomática

ABSTRACT Intrauterine Growth Restriction: Causes, Clinical Characteristics, and Evaluation of Factors Associated with Symptomatic Polycythemia The incidence of newborns (NB) with intrauterine growth restriction (IUGR) in Latin America and the Carib-bean is 10%. Objectives: To determine the causes and characteristics of IUGR in children born at the Hospital Nacional in Paraguay from January 1999 to December 2001 and establish which factors are associated with symptomatic polycythemia. Materials and Methods: An observational and descriptive retrospective cohort study with nested case-controls including 259 NB with birth-weight below the 3d percentile. Results: 165 (64%) of NBs were premature, with a mean age of 33.1 ± 3.1 weeks. 220 NB (84.9%) showed symmetrical IUGR and 37 (14.2%) perinatal asphyxia. The most frequent causes of IUGR were maternal hypertension 87 (33.5%), adolescent mother 67 (25.9%), older mothers 44 (17%), twin pregnancy 34 (13%), and STORCH group infections 17 (6.5%). The dominant pathologies in NBs were hyperbilirubinemia 119 (47%), transitory tachypnea 76 (30%), hyaline membrane disease 49 (19%), nosocomial sepsis 43 (17%), and hypoglycaemia 14 (36%). Of the 195 NB with hematocrit (HCT), 53 (27%) developed polycythemia, and of those, 14 (26%) were symptomatic. Symptoms included hypoglycemia 6 (43%), weak suck 6 (43%), apneas 4 (18%), respira-tory distress and hypotonia 3 (21%). The NB with symptomatic polycythemia had mostly suffered asphyxia (OR = 2.92), had asymmetric IUGR (OR = 2.39), or been children of preeclamptic mothers (OR=1.73). NB with thrombocytopenia were least frequently symptomatic. No signi fi cant difference was shown in mean HCT between symptomatic and asymptomatic NB. Conclusions: The most common cause of IUGR was maternal arterial hypertension (AHT). More than half of NB with IUGR were premature, with the symmetrical form being more common. Factors associated with evolution of polycythemia were NB who were asphyxiated or with preeclamptic mothers.(