Neuronatin gene expression levels affect foetal growth and development by regulating glucose transport in porcine placenta.

Imprinted genes play important regulatory roles in the growth and development of placentas and foetuses during pregnancy. In a previous study, we found that the imprinted gene Neuronatin (NNAT) is involved in foetal development; NNAT expression was significantly lower in the placentas of piglets that died neonatally compared to the placentas of surviving piglets. However, the function and mechanism of NNAT in regulating porcine placental development is still unknown. In this study, we collected the placentas of high- and low-weight foetuses at gestational day (GD 65, 90), (n = 4-5 litters/GD) to investigate the role of NNAT in regulating foetal growth and development. We found that the mRNA and protein levels of NNAT were significantly higher in the placentas of high-weight than low-weight foetuses. We then overexpressed NNAT in porcine placental trophoblast cell lines (pTr2) and demonstrated that NNAT activated the PI3K-AKT pathway, and further promoted the expression of glucose transporter 1 (GLUT1) and increased cellular calcium ion levels, which improved glucose transport in placental trophoblast cells in vitro. To conclude, our study suggests that NNAT expression impacts porcine foetal development by regulating placental glucose transport.

In Utero Fetal Weight in Pigs Is Regulated by microRNAs and Their Target Genes.

Impaired skeletal muscle growth in utero can result in reduced birth weight and poor carcass quality in pigs. Recently, we showed the role of microRNAs (miRNAs) and their target genes in prenatal skeletal muscle development and pathogenesis of intrauterine growth restriction (IUGR). In this study, we performed an integrative miRNA-mRNA transcriptomic analysis in longissimus dorsi muscle (LDM) of pig fetuses at 63 days post conception (dpc) to identify miRNAs and genes correlated to fetal weight. We found 13 miRNAs in LDM significantly correlated to fetal weight, including miR-140, miR-186, miR-101, miR-15, miR-24, miR-29, miR-449, miR-27, miR-142, miR-99, miR-181, miR-199, and miR-210. The expression of these miRNAs decreased with an increase in fetal weight. We also identified 1315 genes significantly correlated to fetal weight at 63 dpc, of which 135 genes were negatively correlated as well as identified as potential targets of the above-listed 13 miRNAs. These miRNAs and their target genes enriched pathways and biological processes important for fetal growth, development, and metabolism. These results indicate that the transcriptomic profile of skeletal muscle can be used to predict fetal weight, and miRNAs correlated to fetal weight can serve as potential biomarkers of prenatal fetal health and growth.

Trans-ethnic meta-analysis of genome-wide association studies identifies maternal ITPR1 as a novel locus influencing fetal growth during sensitive periods in pregnancy.

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.

Race-ethnic differences in the associations of maternal lipid trait genetic risk scores with longitudinal fetal growth.

BACKGROUND: Fetal growth, an important predictor of cardiometabolic diseases in adults, is influenced by maternal and fetal genetic and environmental factors. OBJECTIVE: We investigated the association between maternal lipid genetic risk score (GRS) and fetal growth among 4 US racial-ethnic populations (Whites, Blacks, Hispanics, and Asians). METHODS: We extracted genotype data for 2008 pregnant women recruited in the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort with up to 6 standardized ultrasound examinations. GRS was calculated using 240 single-nucleotide polymorphisms previously associated with higher total cholesterol (GRSTChol), low-density lipoprotein cholesterol (GRSLDLc), and triglycerides (GRSTG) and lower high-density lipoprotein cholesterol (GRSHDLc). RESULTS: At 40 weeks' gestation, a unit increase in GRSTG was associated with 11.4 g higher fetal weight (95% confidence interval [CI] 2.8-20.0 g) among normal-weight Whites, 26.3 g (95% CI 6.0-46.6 g) among obese Blacks, and 30.8 g (95% CI 6.3-55.3 g) among obese Hispanics. Higher GRSHDLc was associated with increased fetal weight across 36 to 40 weeks among normal-weight Whites and across 13 to 20 weeks among normal-weight Asians, but with decreased fetal weight across 26 to 40 weeks among normal-weight Hispanics. Higher GRSTChol was suggestively associated with increased fetal weight in males and decreased in females. Associations remained consistent after adjustment for serum lipids. CONCLUSION: Associations between fetal weight and maternal lipid GRS appear to vary by maternal race-ethnic group, obesity status, and offspring sex. Genetic susceptibility to unfavorable lipid profiles contributes to fetal growth differences even among normal-weight women suggesting a potential future application in predicting aberrant fetal growth.

Maternal BMI-Increasing Genetic Risk Score and Fetal Weights among Diverse US Ethnic Groups.

OBJECTIVE: Associations between maternal genetic risk for obesity and fetal weight were examined at the end of the first (13 weeks 6 days), second (27 weeks 6 days), and third (40 weeks 0 days) trimesters of pregnancy among four race/ethnic groups in the US. METHODS: For 603 white, 591 black, 535 Hispanic, and 216 Asian women, maternal genetic risk score (GRS) was calculated as the sum of 189 BMI-increasing alleles and was categorized into high or low GRS. Associations between GRS (continuous and categorical) and estimated fetal weight were tested overall and stratified by prepregnancy BMI, gestational weight gain (GWG), and fetal sex. RESULTS: High GRS compared with low GRS was associated with increased fetal weight at the end of the second (ß: 22.7 g; 95% CI: 2.4-43.1; P = 0.03) and third trimesters (ß: 88.3 g; 95% CI: 9.0-167.6; P = 0.03) among Hispanic women. The effect of GRS was stronger among Hispanic women with normal prepregnancy weight, adequate first trimester GWG, or inadequate second trimester GWG (P < 0.05). Among Asian women, high GRS was associated with increased weight among male fetuses but decreased weight among female fetuses (P < 0.05). CONCLUSIONS: Maternal obesity genetic risk was associated with fetal weight with potential effect modifications by maternal prepregnancy BMI, GWG, and fetal sex.

Genetic and Environmental Influences on Fetal Growth Vary during Sensitive Periods in Pregnancy.

Aberrant fetal growth is associated with morbidities and mortality during childhood and adult life. Although genetic and environmental factors are known to influence in utero growth, their relative contributions over pregnancy is unknown. We estimated, across gestation, the genetic heritability, contribution of shared environment, and genetic correlations of fetal growth measures (abdominal circumference (AC), humerus length (HL), femur length (FL), and estimated fetal weight (EFW)) in a prospective cohort of dichorionic twin gestations recruited through the NICHD Fetal Growth Studies. Structural equation models were fit at the end of first trimester, during mid-gestation, late second trimester, and third trimester of pregnancy. The contribution of fetal genetics on fetal size increased with gestational age, peaking in late second trimester (AC = 53%, HL = 57%, FL = 72%, EFW = 71%; p < 0.05). In contrast, shared environment explained most of phenotypic variations in fetal growth in the first trimester (AC = 50%, HL = 54%, FL = 47%, EFW = 54%; p < 0.05), suggesting that the first trimester presents an intervention opportunity for a more optimal early fetal growth. Genetic correlations between growth traits (range 0.34-1.00; p < 0.05) were strongest at the end of first trimester and declined with gestation, suggesting that different fetal growth measures are more likely to be influenced by the same genes in early pregnancy.

Accuracy of Prenatal Ultrasound in Detecting Growth Abnormalities in Triplets: A Retrospective Cohort Study.

Significant management decisions in triplet pregnancies are made based mainly on ultrasound measurements of fetal growth, although there is a paucity of data examining the accuracy of fetal weight measurements in these gestations. To evaluate accuracy of prenatal ultrasound to diagnose growth abnormalities (intrauterine growth restriction, severe growth discordance) in triplet pregnancies, a retrospective cohort study of 78 triplet pregnancies (234 fetuses) delivered at a single tertiary hospital from January 2004 to May 2015 was performed. Growth percentiles from the last ultrasound were derived from estimated fetal weight using Hadlock's formula for each triplet. Growth discordance was calculated for each triplet set using the formula {(estimated fetal weight largest triplet - estimated fetal weight smallest)/estimated fetal weight largest}. These estimations were compared to birth weights. Sensitivity of ultrasound to predict ≥1 growth restricted fetus in a triplet set was 55.6% [95% CI 35.3, 74.5]; specificity was 100% [95% CI 93.0, 100]; positive predictive value (PPV) 100% [95% CI 74.7, 100]; negative predictive value (NPV) 81.0% [95% CI 73.2, 85.7%]. Sensitivity of ultrasound to detect fetal growth discordance >25% in a triplet set was 80.0% [95% CI 44.4, 97.5], specificity 94.1% [95% CI 85.6, 98.4]; PPV 66.7% [95% CI 42.4, 84.5]; NPV 97.0% [95% CI 90.2, 99.1]. Prenatal ultrasound currently remains the most reliable tool to screen for growth anomalies in triplet pregnancies; however, it appears to have less than ideal sensitivity, missing a number of cases of intra-uterine growth restriction and significant growth discordance.

Prenatal and postnatal findings in small-for-gestational-age fetuses without structural ultrasound anomalies at 18-24 weeks.

OBJECTIVE: To assess phenotypic and genotypic characteristics of small-for-gestational-age (SGA) fetuses without structural anomalies at 18-24 weeks' gestation. METHODS: This retrospective study included structurally normal singleton fetuses with an abdominal circumference ≤ 5th percentile on detailed ultrasound examination between 18 and 24 weeks' gestation. Cases were stratified according to the absence or presence of other abnormal ultrasound findings, such as abnormal amniotic fluid or soft markers. All patients were offered invasive prenatal testing with rapid aneuploidy detection by qualitative fluorescence polymerase chain reaction (QF-PCR) and, if normal, consecutive single nucleotide polymorphism (SNP) array was also offered. Detailed postnatal follow-up (≥ 5 months) was performed. In cases in which a syndromic phenotype became apparent within 5 months after birth and SNP array had not been performed prenatally, it was performed postnatally. RESULTS: A total of 211 pregnancies were eligible for inclusion. Of the 158 cases with isolated SGA on ultrasound, 36 opted for invasive prenatal testing. One case of trisomy 21 and one case of a submicroscopic abnormality (a susceptibility locus for neurodevelopmental disease) were detected. Postnatal follow-up showed a postnatal apparent syndromic phenotype in 10 cases. In one case this was due to trisomy 21 and the other nine (5.8%; 95% CI, 2.8-10.0%) cases had normal SNP array results. In 32/53 cases with SGA and associated ultrasound abnormalities, parents opted for invasive testing. One case of trisomy 21 and one of triploidy were found. In 11 cases a syndromic phenotype became apparent after birth. One was due to trisomy 21 and in one case a submicroscopic anomaly (a susceptibility locus) was found. The remaining syndromic cases (17.3%; 95% CI, 8.7-29.0%) had normal SNP array results. CONCLUSION: Testing for chromosomal anomalies should be offered in cases of SGA between 18 and 24 weeks' gestation. Whole chromosome anomalies occur in 1.3% (95% CI, 0.2-3.9%) of isolated SGA and 5.8% (95% CI, 1.5-14.0%) of associated SGA. In 0.6% (95% CI, 0.1-2.8%) and 1.9% (95% CI, 0.2-8.2%), respectively, SNP array detected a susceptibility locus for neurodevelopmental disease that would not be detected by karyotyping, QF-PCR or non-invasive prenatal testing. Therefore, and because the genetic causes of SGA are diverse, we suggest SNP array testing in cases of SGA. Thorough postnatal examination and follow-up of infants that presented with reduced fetal growth is important because chromosomally normal syndromic phenotypes occur frequently in SGA fetuses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal Therapy with Ad.VEGF-A165 Increases Fetal Weight at Term in a Guinea-Pig Model of Fetal Growth Restriction.

In a model of growth-restricted sheep pregnancy, it was previously demonstrated that transient uterine artery VEGF overexpression can improve fetal growth. This approach was tested in guinea-pig pregnancies, where placental physiology is more similar to humans. Fetal growth restriction (FGR) was attained through peri-conceptual nutrient restriction in virgin guinea pigs. Ad.VEGF-A165 or Ad.LacZ (1 × 1010vp) was applied at mid-gestation via laparotomy, delivered externally to the uterine circulation with thermosensitive gel. At short-term (3-8 days post surgery) or at term gestation, pups were weighed, and tissues were sampled for vector spread analysis, VEGF expression, and its downstream effects. Fetal weight at term was increased (88.01 ± 13.36 g; n = 26) in Ad.VEGF-A165-treated animals compared with Ad.LacZ-treated animals (85.52 ± 13.00 g; n = 19; p = 0.028). The brain, liver, and lung weight and crown rump length were significantly larger in short-term analyses, as well as VEGF expression in transduced tissues. At term, molecular analyses confirmed the presence of VEGF transgene in target tissues but not in fetal samples. Tissue histology analysis and blood biochemistry/hematological examination were comparable with controls. Uterine artery relaxation in Ad.VEGF-A165-treated dams was higher compared with Ad.LacZ-treated dams. Maternal uterine artery Ad.VEGF-A165 increases fetal growth velocity and term fetal weight in growth-restricted guinea-pig pregnancy.

Increased placental nutrient transport in a novel mouse model of maternal obesity with fetal overgrowth.

OBJECTIVE: To identify possible mechanisms linking obesity in pregnancy to increased fetal adiposity and growth, a unique mouse model of maternal obesity associated with fetal overgrowth was developed, and the hypothesis that maternal obesity causes up-regulation of placental nutrient transporter expression and activity was tested. METHODS: C57BL/6J female mice were fed a control (C) or a high-fat/high-sugar (HF/HS) pelleted diet supplemented by ad libitum access to sucrose (20%) solution, mated, and studied at embryonic day 18.5. RESULTS: HF/HS diet increased maternal fat mass by 2.2-fold (P < 0.01) and resulted in glucose intolerance with normal fasting glucose. Maternal circulating insulin, leptin, and cholesterol were increased (P < 0.05) whereas total and high-molecular-weight adiponectin was decreased (P < 0.05). HF/HS diet increased fetal weight (+18%, P = 0.0005). In trophoblast plasma membranes (TPM) isolated from placentas of HF/HS-fed animals, protein expression of glucose transporter (GLUT) 1 and 3, sodium-coupled neutral amino acid transporter (SNAT) 2, and large neutral amino acid transporter 1 (LAT1) was increased. TPM System A and L amino acid transporter activity was increased in the HF/HS group. CONCLUSIONS: Up-regulation of specific placental nutrient transporter isoforms may constitute a mechanism underlying fetal overgrowth in maternal obesity.

Serum MicroRNAs as Diagnostic Biomarkers for Macrosomia.

BACKGROUND: Macrosomia is defined as an infant's birth weight of more than 4000 g. Although microRNAs (miRNAs) have been implicated in the pathogenesis of various diseases, the associations between serum miRNAs and macrosomia have been rarely reported. METHODOLOGY: We used the Taqman Low Density Array followed by quantitative reverse transcriptase polymerase chain reaction assays to screen for miRNAs associated with macrosomia using serum samples collected 1 week before delivery. RESULTS: Profiling results showed that 1 miRNA was significantly upregulated and 10 miRNAs were significantly downregulated in serum samples of macrosomia (ΔΔCt > 3-fold). The expression levels of miR-21 were significantly decreased in macrosomia as compared to the controls in the third trimester. Receiver operating characteristic (ROC) curve analyses showed that the area under the ROC curve for miR-21 was 67.7% (sensitivity = 66.7% and specificity = 70.0%). CONCLUSIONS: miR-21 in maternal serum is differentially expressed between macrosomia and controls, and miR-21 could be used as a candidate biomarker to predict macrosomia.

[The influence of hyperleptinemia during pregnancy on fetal weight and obesity development in progeny mice with agouti yellow mutation].

Maternal obesity increases the risk of obesity in the offspring, and obesity is accompanied by an increase in blood leptin levels. Leptin can influence the progeny metabolism via its influence on fetal growth and, possibly, via its action on AgRP expression in placenta. The "yellow" mutation at the mouse agouti locus (A(y)) evokes obesity and increases blood leptin levels in pregnant mice. The aim was to examine the influence of A(y) mutation in pregnant mice on fetal weight, placental expression of AgRP gene and food intake and obesity development in progeny. A(y) pregnant females as compared to control ones had increased circulating leptin levels on days 13 and 18 of pregnancy. Both fetal weight and placental expression of AgRP gene were increased on day 13 of pregnancy and decreased on day 18 of pregnancy in A(y) females as compared to control ones. Both control (a/a) and obesity prone (A(y)/a) male young born to A(y) mothers had lowered body weight and enhanced food intake between 5 and 11 weeks of age as compared to male progeny of control mothers. The enhanced leptin levels during pregnancy in mice are associated with retardation of obesity development in obesity prone male offspring and with changes in fetal weight and AgRP gene expression in placenta.

Co-expression analysis of fetal weight-related genes in ovine skeletal muscle during mid and late fetal development stages.

BACKGROUND: Muscle development and lipid metabolism play important roles during fetal development stages. The commercial Texel sheep are more muscular than the indigenous Ujumqin sheep. RESULTS: We performed serial transcriptomics assays and systems biology analyses to investigate the dynamics of gene expression changes associated with fetal longissimus muscles during different fetal stages in two sheep breeds. Totally, we identified 1472 differentially expressed genes during various fetal stages using time-series expression analysis. A systems biology approach, weighted gene co-expression network analysis (WGCNA), was used to detect modules of correlated genes among these 1472 genes. Dramatically different gene modules were identified in four merged datasets, corresponding to the mid fetal stage in Texel and Ujumqin sheep, the late fetal stage in Texel and Ujumqin sheep, respectively. We further detected gene modules significantly correlated with fetal weight, and constructed networks and pathways using genes with high significances. In these gene modules, we identified genes like TADA3, LMNB1, TGF-ß3, EEF1A2, FGFR1, MYOZ1, and FBP2 correlated with fetal weight. CONCLUSION: Our study revealed the complex network characteristics involved in muscle development and lipid metabolism during fetal development stages. Diverse patterns of the network connections observed between breeds and fetal stages could involve some hub genes, which play central roles in fetal development, correlating with fetal weight. Our findings could provide potential valuable biomarkers for selection of body weight-related traits in sheep and other livestock.

Síndrome de MIDAS: diagnóstico posnatal tras detectar en el feto un retraso del crecimiento intrauterino / MIDAS syndrome: postnatal diagnosis after a detection of a foetus with intrauterine growth retardation

Presentamos un caso de diagnóstico prenatal de un feto afecto de trisomía parcial del cromosoma 6 y monosomía parcial del cromosoma X:46X der(X)t(X;6)(p22.3;21.1). Dicho desbalance proviene de una translocación balanceada detectada en el cariotipo materno: 46XX t(X:6)(p22.3;p21.1). El diagnóstico se hizo mediante cariotipo fetal en líquido amniótico tras detectar un retraso severo del crecimiento fetal (menor de un percentil 3), tras descartar otras causas como origen del retraso. El neonato presenta una facies dismórfica, acompañada de dificultades para la alimentación y retraso del crecimiento y psicomotor, descritos en otros casos de trisomía parcial del cromosoma 6. Además presenta microftalmia y esclerocórnea asociadas a la microdeleción del cromosoma X en la región Xp22.3. Estos signos característicos nos permitieron hacer el diagnóstico clínico de síndrome de MIDAS(AU)

We present a prenatal diagnosis of a foetus affected by partial trisomy 6 p and partial monosomy X, 46X der(X)t(X;6)(p22.3;21.1), resulting from a maternal balanced translocation: 46XX t(X:6)(p22.3;p21.1) The diagnosis was made by cytogenetic analysis of amniotic fluid, after intrauterine growth retardation was detected (<3rd centile). Other causes were investigated. The newborn has a dysmorphic face, feeding difficulties, and growth and mental retardation. These characteristic features appear to make partial trisomy 6 p a clinically recognisable syndrome. Microphthalmia and sclerocornea were also present, both associated with microdeletion of Xp22.3 region. These characteristic signs led to the clinical diagnosis of MIDAS syndrome(AU)

The effect of feeding a low iron diet prior to and during gestation on fetal and maternal iron homeostasis in two strains of rat.

BACKGROUND: Iron deficiency anaemia during pregnancy is a global problem, with short and long term consequences for maternal and child health. Animal models have demonstrated that the developing fetus is vulnerable to maternal iron restriction, impacting on postnatal metabolic and blood pressure regulation. Whilst long-term outcomes are similar across different models, the commonality in mechanistic events across models is unknown. This study examined the impact of iron deficiency on maternal and fetal iron homeostasis in two strains of rat. METHODS: Wistar (n=20) and Rowett Hooded Lister (RHL, n=19) rats were fed a control or low iron diet for 4 weeks prior to and during pregnancy. Tissues were collected at day 21 of gestation for analysis of iron content and mRNA/protein expression of regulatory proteins and transporters. RESULTS: A reduction in maternal liver iron content in response to the low iron diet was associated with upregulation of transferrin receptor expression and a reduction in hepcidin expression in the liver of both strains, which would be expected to promote increased iron absorption across the gut and increased turnover of iron in the liver. Placental expression of transferrin and DMT1+IRE were also upregulated, indicating adaptive responses to ensure availability of iron to the fetus. There were considerable differences in hepatic maternal and fetal iron content between strains. The higher quantity of iron present in livers from Wistar rats was not explained by differences in expression of intestinal iron transporters, and may instead reflect greater materno-fetal transfer in RHL rats as indicated by increased expression of placental iron transporters in this strain. CONCLUSIONS: Our findings demonstrate substantial differences in iron homeostasis between two strains of rat during pregnancy, with variable impact of iron deficiency on the fetus. Whilst common developmental processes and pathways have been observed across different models of nutrient restriction during pregnancy, this study demonstrates differences in maternal adaptation which may impact on the trajectory of the programmed response.

Maternal administration of the herbal medicine toki-shakuyaku-san promotes fetal growth and placental gene expression in normal mice.

Toki-shakuyaku-san (TSS), an herbal formula based on traditional Chinese medicine, is commonly used in obstetrics. To examine the effects of TSS on the normal mouse fetus and placenta, TSS was administered to normal pregnant mice and their placentas and fetuses were studied. First, the effects of maternal TSS treatment on implantation were investigated. Administration of TSS from gestation day 0.5 (G0.5) to G6.5 showed that litter size was not altered at embryonic day 11.5 (E11.5), but the number of resorbed fetuses was slightly decreased. Then, to investigate effects on fetal and placental growths after implantation, TSS was administered from G5.5. At E14.5, the body weight of fetuses from TSS-treated dams was significantly increased. Gene expression of insulin-like growth factor 2 (Igf2), one of the most important modulators of fetal growth, was significantly increased in the placentas and fetuses of TSS-treated dams. In addition, the expression of particular placental developmental genes and nutrient transporter genes was significantly increased in TSS-treated placentas. At E18.5, after longer-term administration of TSS, fetal and placental weights were not altered, but the expression of the placental developmental and nutrient transporter genes remained elevated compared with controls. These results suggest that maternal TSS treatment in normal mice enhances the expression of Igf2, placental developmental genes and nutrient transporter genes, resulting in increased fetal weight. No obvious changes were observed in the expression of these genes after longer-term maternal TSS treatment.

Tissue-specific and minor inter-individual variation in imprinting of IGF2R is a common feature of Bos taurus Concepti and not correlated with fetal weight.

The insulin-like growth factor 2 receptor (IGF2R) is essential for prenatal growth regulation and shows gene dosage effects on fetal weight that can be affected by in-vitro embryo culture. Imprinted maternal expression of murine Igf2r is well documented for all fetal tissues excluding brain, but polymorphic imprinting and biallelic expression were reported for IGF2R in human. These differences have been attributed to evolutionary changes correlated with specific reproductive strategies. However, data from species suitable for testing this hypothesis are lacking. The domestic cow (Bos taurus) carries a single conceptus with a similar gestation length as human. We identified 12 heterozygous concepti informative for imprinting studies among 68 Bos taurus fetuses at Day 80 of gestation (28% term) and found predominantly maternal IGF2R expression in all fetal tissues but brain, which escapes imprinting. Inter-individual variation in allelic expression bias, i.e. expression of the repressed paternal allele relative to the maternal allele, ranged from 4.6-8.9% in heart, 4.3-10.2% in kidney, 6.1-11.2% in liver, 4.6-15.8% in lung and 3.2-12.2% in skeletal muscle. Allelic bias for mesodermal tissues (heart, skeletal muscle) differed significantly (P<0.05) from endodermal tissues (liver, lung). The placenta showed partial imprinting with allelic bias of 22.9-34.7% and differed significantly (P<0.001) from all other tissues. Four informative fetuses were generated by in-vitro fertilization (IVF) with embryo culture and two individuals displayed fetal overgrowth. However, there was no evidence for changes in imprinting or DNA methylation after IVF, or correlations between allelic bias and fetal weight. In conclusion, imprinting of Bos taurus IGF2R is similar to mouse except in placenta, which could indicate an effect of reproductive strategy. Common minor inter-individual variation in allelic bias and absence of imprinting abnormalities in IVF fetuses suggest changes in IGF2R expression in overgrown fetuses could be modulated through other mechanisms than changes in imprinting.

El exceso y el bajo peso corporal al nacimiento en hijos de madres con diabetes / Excess and low body weight at birth in diabetic-mother infants

Introducción: el hijo de madre con diabetes (HMD) puede sufrir alteraciones durante el embarazo por la enfermedad materna. Cuando aparece en la segunda mitad de la gestación hablamos de fetopatía diabética, más frecuente en mujeres con descontrol metabólico y en la diabetes mellitus gestacional (DMG). La edad, paridad, obesidad, ganancia de peso durante el embarazo, grado de intolerancia a la glucosa, entre otros, pueden influir como determinantes del crecimiento fetal. Los autores se propusieron conocer la relación de estos factores con el peso del neonato. Objetivo: identificar factores modificables en las embarazadas con diabetes que permitan aumentar la frecuencia de recién nacidos de adecuado peso según edad gestacional. Métodos: se analizaron los resultados en 2 038 nacidos vivos hijos de madres con diabetes (350 diabéticas pregestacionales y 1 688 diabéticas gestacionales), durante 14 años. Resultados: la frecuencia de exceso de peso corporal neonatal resultó 11,83 porciento, se alcanzó su reducción, pero sin aumento del bajo peso. No existieron diferencias significativas en frecuencia de exceso de peso corporal entre las diabéticas pregestacionales y las gestacionales. El exceso de peso neonatal se relacionó con: multiparidad, exceso de peso materno pregestacional, ganancia de peso excesiva y grado de control metabólico durante el embarazo. El bajo peso se relacionó con: bajo peso materno pregestacional, enfermedad hipertensiva gravídica y lesión vascular materna a nivel glomerular. Conclusión: los recién nacidos con exceso o bajo peso para la edad gestacional se relacionaron con factores de riesgo diferentes

Introduction: the child of a diabetic mother (CDM) can suffer alterations during pregnancy by this maternal disease. When it appears in the second half of gestation, we talk of diabetic foetopathy, which is more frequent in women with uncontrolled metabolic and gestational diabetes mellitus (GDM). Age, parity, obesity, weight gain during pregnancy, degree of glucose intolerance, among others, can influence fetal growth determinants. The research sought to understand the relationship of these factors with birth weight. Objective: to identify modifiable factors, which increase the frequency of newborns with appropriate weight for gestational age in diabetic pregnant women. Methods: results are analyzed in 2 038 live births born from diabetic mothers (350 diabetic pre-gestational and diabetic gestational 1 688), during 14 years. Results: occurrence of excess neonatal weight was 11.83 percent, its reduction was achieved, but with no increase in weight. No significant differences were observed in the frequency of excess body weight among pre-gestational and gestational diabetic patients. Neonatal overweight is associated with parity, maternal pre- pregnancy overweight, excessive weight gain and degree of metabolic control during pregnancy. Underweight was associated with low maternal weight before pregnancy, gestational hypertensive disease and mother vascular glomerular injury. Conclusion: the excess or low weights in infants in relation with their gestational age were associated with different risk factors

El exceso y el bajo peso corporal al nacimiento en hijos de madres con diabetes / Excess and low body weight at birth in diabetic-mother infants

Introducción: el hijo de madre con diabetes (HMD) puede sufrir alteraciones durante el embarazo por la enfermedad materna. Cuando aparece en la segunda mitad de la gestación hablamos de fetopatía diabética, más frecuente en mujeres con descontrol metabólico y en la diabetes mellitus gestacional (DMG). La edad, paridad, obesidad, ganancia de peso durante el embarazo, grado de intolerancia a la glucosa, entre otros, pueden influir como determinantes del crecimiento fetal. Los autores se propusieron conocer la relación de estos factores con el peso del neonato. Objetivo: identificar factores modificables en las embarazadas con diabetes que permitan aumentar la frecuencia de recién nacidos de adecuado peso según edad gestacional. Métodos: se analizaron los resultados en 2 038 nacidos vivos hijos de madres con diabetes (350 diabéticas pregestacionales y 1 688 diabéticas gestacionales), durante 14 años. Resultados: la frecuencia de exceso de peso corporal neonatal resultó 11,83 porciento, se alcanzó su reducción, pero sin aumento del bajo peso. No existieron diferencias significativas en frecuencia de exceso de peso corporal entre las diabéticas pregestacionales y las gestacionales. El exceso de peso neonatal se relacionó con: multiparidad, exceso de peso materno pregestacional, ganancia de peso excesiva y grado de control metabólico durante el embarazo. El bajo peso se relacionó con: bajo peso materno pregestacional, enfermedad hipertensiva gravídica y lesión vascular materna a nivel glomerular. Conclusión: los recién nacidos con exceso o bajo peso para la edad gestacional se relacionaron con factores de riesgo diferentes(AU)

Introduction: the child of a diabetic mother (CDM) can suffer alterations during pregnancy by this maternal disease. When it appears in the second half of gestation, we talk of diabetic foetopathy, which is more frequent in women with uncontrolled metabolic and gestational diabetes mellitus (GDM). Age, parity, obesity, weight gain during pregnancy, degree of glucose intolerance, among others, can influence fetal growth determinants. The research sought to understand the relationship of these factors with birth weight. Objective: to identify modifiable factors, which increase the frequency of newborns with appropriate weight for gestational age in diabetic pregnant women. Methods: results are analyzed in 2 038 live births born from diabetic mothers (350 diabetic pre-gestational and diabetic gestational 1 688), during 14 years. Results: occurrence of excess neonatal weight was 11.83 percent, its reduction was achieved, but with no increase in weight. No significant differences were observed in the frequency of excess body weight among pre-gestational and gestational diabetic patients. Neonatal overweight is associated with parity, maternal pre- pregnancy overweight, excessive weight gain and degree of metabolic control during pregnancy. Underweight was associated with low maternal weight before pregnancy, gestational hypertensive disease and mother vascular glomerular injury. Conclusion: the excess or low weights in infants in relation with their gestational age were associated with different risk factors(AU)

Heritability estimates of body size in fetal life and early childhood.

BACKGROUND: The objective was to estimate the heritability for height and weight during fetal life and early childhood in two independent studies, one including parent and singleton offsprings and one of mono- and dizygotic twins. METHODS: This study was embedded in the Generation R Study (n = 3407, singletons) and the Netherlands Twin Register (n = 33694, twins). For the heritability estimates in Generation R, regression models as proposed by Galton were used. In the Twin Register we used genetic structural equation modelling. Parental height and weight were measured and fetal growth characteristics (femur length and estimated fetal weight) were measured by ultrasounds in 2(nd) and 3(rd) trimester (Generation R only). Height and weight were assessed at multiple time-points from birth to 36 months in both studies. RESULTS: Heritability estimates for length increased from 2(nd) to 3(rd) trimester from 13% to 28%. At birth, heritability estimates for length in singletons and twins were both 26% and 27%, respectively, and at 36 months, the estimates for height were 63% and 72%, respectively. Heritability estimates for fetal weight increased from 2(nd) to 3(rd) trimester from 17% to 27%. For birth weight, heritability estimates were 26% in singletons and 29% in twins. At 36 months, the estimate for twins was 71% and higher than for singletons (42%). CONCLUSIONS: Heritability estimates for height and weight increase from second trimester to infancy. This increase in heritability is observed in singletons and twins. Longer follow-up studies are needed to examine how the heritability develops in later childhood and puberty.