epidermal-growth-factor and Fetal-Growth-Retardation

Fetal growth requires the correct balance of nutrients, oxygen, and growth factors operating under the direction of a genetic plan modified by maternal factors. The classic hormones of postnatal growth play differing roles with alternative controls compared to those after birth. The study of conditions of abnormal fetal growth illuminates the mechanism of normal fetal growth. It is now apparent that abnormal birth weight leads to long-term consequences.

Topics: Embryonic and Fetal Development; Epidermal Growth Factor; Fetal Growth Retardation; Fibroblast Growth Factors; Growth Substances; Humans; Infant, Low Birth Weight; Infant, Newborn; Insulin; Oncogenes; Somatomedins

The fetal nutritional milieu may have important regulatory influences on fetal growth and maturation. Fetuses of diabetics exposed to excessive glucose in late gestation show delayed maturation, whereas, fetuses subjected to nutrient deprivation resulting from decreased uterine blood flow exhibit restricted growth and accelerated maturation. Under conditions of nutrient deficiency, restricted growth and accelerated maturation may be important adaptations mediated through hormonal and growth factor signalling.

Topics: Animals; Diabetes Mellitus, Experimental; Disease Models, Animal; Embryonic and Fetal Development; Epidermal Growth Factor; Female; Fetal Growth Retardation; Fetal Organ Maturity; Glucose; Humans; Lung; Placenta; Pregnancy; Pregnancy in Diabetics; Rats

Fetal growth is regulated by an interplay of genetic and environmental factors. Fetuses with growth restriction secondary to decreased nutritional supply exhibit maturation whereas hyperglycemic fetuses of diabetic mothers show delayed lung and placental maturation. Membranes from fetuses of diabetics have a decrease in epidermal-growth-factor (EGF) binding, whereas EGF binding is increased in lung and placenta of growth-restricted fetuses. These results suggest that the EGF receptor is responsive to altered nutritional states and may be important to substrate flow to the fetus.

Topics: Animals; Embryonic and Fetal Development; Epidermal Growth Factor; Female; Fetal Growth Retardation; Humans; Nutritional Status; Pregnancy; Pregnancy in Diabetics

The present experiment was conducted to study the effects of dietary epidermal growth factor (EGF) supplementation on the liver antioxidant capacity of piglets with intrauterine growth retardation (IUGR). The present study consists of two experiments. In experiment 1, six normal-birth-weight (NBW) and six IUGR newborn piglets were slaughtered within 2 to 4 h after birth to compare the effects of IUGR on the liver antioxidant capacity of newborn piglets. The results showed that compared with NBW piglets, IUGR piglets had a lower birth weight and liver relative weight; IUGR piglets had a higher serum malondialdehyde (MDA) level, liver MDA level and hydrogen peroxide (H2O2) level, and had a lower liver total antioxidant capacity (T-AOC) level and glutathione peroxidase (GSH-Px) activity; IUGR trended to increase serum alanine aminotransferase activity, aspartate aminotransferase activity, and H2O2 level, and trended to decrease liver total superoxide dismutase activity. In experiment 2, six NBW piglets, and 12 IUGR piglets weaned at 21 d of age were randomly divided into the NC group (NBW piglets fed with basal diet); IC group (IUGR piglets fed with basal diet), and IE group (IUGR piglets fed with basal diet plus 2 mg/kg EGF), and feeding for 14 d. Organ index, serum parameters, liver antioxidant capacity, and liver antioxidant-related genes expression were measured. The results showed that compared to the IC group, dietary EGF supplementation (IE group) significantly reduced serum malondialdehyde level and H2O2 level, and liver protein carbonyl (PC) level and 8-hydroxydeoxyguanosine level of piglets with IUGR; dietary EGF supplementation (IE group) significantly increased serum T-AOC level, liver T-AOC level and GSH-Px activity; dietary supplemented with EGF (IE group) enhanced liver Nrf2, NQO1, HO1, and GPX1 mRNA expression compared to IC group. Pearson's correlation analysis further showed that EGF can alleviate liver oxidative injury caused by IUGR and improve the performance of IUGR piglets. In conclusion, EGF exhibited potent protective effects on IUGR-induced liver oxidative injury, by activating the Nrf2 signaling pathway to mediate the expression of downstream antioxidant enzymes and phase II detoxification enzymes (NQO1 and HO1), thereby alleviating liver oxidative damage and promoting the growth performance of IUGR piglets.. The liver is an important metabolic and secretory organ in vertebrates, which plays an important role in the overall health of animals. Studies have shown that intrauterine growth retardation (IUGR) can cause liver injury in piglets, which is unfavorable to the growth and development of piglets. Epidermal growth factor (EGF) has antioxidant properties, but its effect on liver oxidative damage caused by IUGR remains uncertain. In the present study, we chose newborn piglets with low birth weight as the IUGR models to investigate whether IUGR could cause oxidative damage in the liver. Then, the diet supplemented with EGF was fed to IUGR piglets to study the effects of EGF supplementation on the liver antioxidant function of IUGR-weaned piglets. Results showed that IUGR caused serious damage to the liver of piglets, while dietary EGF supplementation could reverse the oxidative injury induced by IUGR to some extent. Therefore, this study confirmed that EGF has positive effects on the liver health of piglets with IUGR.

Topics: Animals; Antioxidants; Dietary Supplements; Epidermal Growth Factor; Female; Fetal Growth Retardation; Hydrogen Peroxide; Liver; Malondialdehyde; NF-E2-Related Factor 2; Swine; Swine Diseases

The growth and survival of the mammalian fetus is highly dependent on the placenta. Several research groups have demonstrated the involvement of different transforming growth factor-beta (TGFβ) superfamily members and their related receptors in placentation. Cripto is a member of the epidermal growth factor-Cripto1/FRL1/Cryptic protein family and plays a critical role in embryonic development, stem cell maintenance and tumor progression through TGFβ-dependent and independent pathways. Several studies have suggested that Cripto may also have a role in female reproduction and pregnancy maintenance, but its specific role remains elusive.. We used a conditional knockout mouse model in which Cripto is deleted from the uterus using a loxP-Cre system. Cripto cKO females were mated with wildtype males and dissections were performed at different timepoints during pregnancy for assessment of the number and size of the implantation sites, resorption sites, fetal weight and placental development. Histology, IF staining and quantitative PCR were employed to analyze the placentation process.. We found that loss of maternal Cripto results in defective placentation, decreased vascularization within the placental labyrinth and leads to intrauterine growth restriction and fetal death. We further demonstrated that components of the VEGF and Notch signaling pathways are downregulated in Cripto cKO decidua and placenta potentially contributing to defects in the development of the vasculature at maternal-fetal interface.. These findings demonstrate that maternal Cripto is involved in the maternal-fetal communications required for proper development of the placenta and placental vasculature.

Topics: Animals; Epidermal Growth Factor; Female; Fertility; Fetal Growth Retardation; Membrane Glycoproteins; Mice; Mice, Knockout; Neoplasm Proteins; Placenta; Placentation; Pregnancy; Trophoblasts; Uterus

In this study, we compared human placental gene expression patterns of epidermal growth factor (EGF) in pregnancies with intrauterine growth restriction (IUGR) vs. normal pregnancies as control.. Gene expression of EGF was determined from human placental samples collected from all pregnancies presenting with IUGR at our institution during the study period January 1, 2010-January 1, 2011. Multiple clinical variables were also assessed including maternal age, gestational weight gain, increase of BMI during pregnancy and fetal gender.. A total of 241 samples were obtained (101 in the IUGR pregnancy group, 140 in the normal pregnancy group). EGF was found to be underexpressed in the IUGR group compared to normal pregnancy (Ln2(α): -1.54; p<0.04). Within the IUGR group no fetal gender-dependent difference was seen in EGF gene expression (Ln2(α): 0.44; p<0.06). Similarly, no significant difference in EGF expression was noted in cases with more vs. less severe forms of IUGR (Ln2(α): -0.08; p=0.05). IUGR pregnancies were significantly more common in the maternal age group 35-44 years compared to other age groups. Gestational weight gain and gestational BMI increase were significantly lower in IUGR pregnancies compared to controls.. Placental expression of EGF was found to be reduced in IUGR pregnancies vs. normal pregnancies. This may partly explain the smaller placental size and placental dysfunction commonly seen with IUGR. An increased incidence of IUGR was observed with maternal age exceeding 35 years. The probability of IUGR correlated with lower gestational weight gain and lower BMI increase during pregnancy.

Topics: Adolescent; Adult; Case-Control Studies; Epidermal Growth Factor; Female; Fetal Growth Retardation; Gene Expression; Humans; Infant, Newborn; Male; Placenta; Pregnancy; Sex Characteristics; Young Adult

Birthweight predicts health later in life and is influenced by inherited factors. We investigated the association of the c.61G > A, and c.2566G > A polymorphisms in the epidermal growth factor (EGF) gene [GenBank NM_001963] with birthweight in three groups of healthy pregnant women, and in women with pregnancies affected by fetal growth restriction (FGR). Subjects comprised 171 Sinhalese women with normal pregnancies (Group A), 64 white Western European women with normal pregnancies (Group B), 101 white Western European women with normal pregnancies and their babies (Group C) and 107 women with pregnancies affected by FGR, their partners and their babies (Group D). Maternal EGF genotypes were associated with birthweight of healthy babies of women in Groups A (P = 0.03), B (P = 0.001) and C (P = 0.01). The association persisted following adjustment for confounding by gestational age, sex, maternal weight, parity and smoking habit. The trend from heaviest to lightest birthweights in all these groups was c.61AA > c.61GA > c.61GG and c.2566GG > c.2566GA > c.2566AA. The EGF haplotype associated with lower birthweight (c.61G, c.2566A) was transmitted at increased frequency from heterozygous parents to babies affected by FGR in Group D (P = 0.02). These findings support the hypothesis that growth factors expressed by the feto-maternal unit affect birthweight, and implicates polymorphism in the EGF gene in the aetiology of birthweight variability.

Topics: Adult; Birth Weight; Case-Control Studies; Epidermal Growth Factor; Europe; Female; Fetal Growth Retardation; Gene Frequency; Haplotypes; Humans; Polymorphism, Genetic; Pregnancy; Sri Lanka; White People

The aim of the study was to compare epidermal growth factor (EGF) concentration in 81 colostrum samples collected from mothers of newborns in the following growth categories: preterm appropriate for gestational age (AGA), preterm small for gestational age (SGA), and full term (FT).. Significantly higher concentrations of EGF were found in the colostrum of mothers who delivered premature AGA infants at less than 32 weeks of gestation compared with mothers who delivered premature SGA babies at the same gestational age.. We concluded that the maternal compensatory mechanism accelerating the development of immature breast-fed infants may be disturbed when gestation is complicated by intrauterine growth retardation.

Topics: Birth Weight; Colostrum; Epidermal Growth Factor; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Milk, Human; Pregnancy; Premature Birth; Term Birth

Intrauterine growth-retarded (IUGR) infants have impaired gastrointestinal function with feeding difficulties and predisposition to necrotizing enterocolitis. The rabbit provides a model of IUGR based on uterine position. Sodium/glucose cotransporter-1 (SGLT-1) is a membrane protein responsible for carbohydrate transport across the intestinal brush border membrane. Previous studies demonstrate increases in small intestinal (SI) nutrient uptake in response to amniotic fluid supplementation with epidermal growth factor (EGF). To determine whether SGLT-1 expression plays a role in the intestinal response to EGF supplementation, this IUGR rabbit model was evaluated.. Eight pregnant rabbits underwent placement of intraamniotic catheters into 2 normal (Nl) and 2 IUGR fetuses per mother on gestational day 24. Mini-osmotic pumps infused either EGF (300 microg/kg per day) or control solution forming 4 study groups (EGF-Nl vs Cont-Nl; EGF-IUGR vs Cont-IUGR). On gestational day 31, the fetal SI was harvested. Sodium/glucose cotransporter-1/glyceraldehyde-3-phosphate dehydrogenase messenger RNA (mRNA) densitometric band ratios were measured by reverse transcriptase polymerase chain reaction. Immunohistochemistry SGLT-1 staining was performed on middle SI. Statistical analysis was performed using the analysis of variance.. Sodium/glucose cotransporter-1 was expressed in the gastrointestinal tract throughout the last one third of gestation. There were no native differences in SGLT-1 mRNA expression between Nl and IUGR fetuses at term. Epidermal growth factor infusion did not significantly affect SI SGLT-1 mRNA expression in either Nl or IUGR fetuses vs controls (EGF-Nl = 1.94 vs Cont-Nl = 1.94, P = .98; EGF-IUGR = 1.77 vs Cont-IUGR = 1.85, P = .74). Immunohistochemistry revealed increased SGLT-1 SI protein expression in infused IUGR fetuses.. Increases in previously documented up-regulation in SI nutrient transport after EGF infusion are independent of SGLT-1 mRNA expression. Further studies are warranted investigating SGLT-1 protein expression, localization, and functional kinetics in response to amniotic fluid supplementation with EGF.

Topics: Amniotic Fluid; Animals; Carbohydrate Metabolism; Disease Models, Animal; Epidermal Growth Factor; Female; Fetal Growth Retardation; Gene Expression Profiling; Intestines; Microvilli; Pregnancy; Pregnancy, Animal; Rabbits; Sodium-Glucose Transporter 1; Up-Regulation

Intrauterine growth retardation (IUGR) infants have impaired gastrointestinal function with resultant feeding difficulties and predisposition to necrotizing enterocolitis. Supplemented amniotic fluid swallowed by the developing fetus is a potential prenatal treatment for IUGR. Rabbits have naturally occurring IUGR fetuses based on uterine position. To determine intestinal response to epidermal growth factor (EGF) infusion, this rabbit model of IUGR was studied.. Eight pregnant rabbits underwent placement of intraamniotic catheters into 2 normal and 2 IUGR fetuses per mother on gestational day 24 of a 31-day gestation. Miniosmotic pumps infused either EGF (about 300 microg/kg/d) or control solution forming 4 study groups (EGF-Favored [Fav] v. Cont-Fav; EGF-IUGR v. Cont-IUGR). On gestational day 31, the fetal gastrointestinal tracts were harvested for analysis. Intestinal epithelial cell proliferation was studied by 5-bromo-2-deoxyuridine (BrdU) incorporation, villus heights were measured, and EGF mRNA was measured by reverse transcriptase polymerase chain reaction (RT-PCR). Statistical analysis was performed using Students' t test.. Fetal survival rate was 87%. EGF-IUGR fetal weights were increased compared with Cont-IUGR fetuses. EGF infusion significantly increased IUGR fetal small intestinal villus height and BrdU-positive small intestinal (SI) crypt cells, all approaching Cont-Fav levels. EGF mRNA was expressed throughout the gastrointestinal tract.. Supplemental amniotic EGF normalizes fetal weight and intestinal proliferation in the IUGR fetal rabbit. The inclusion of EGF in supplemental amniotic feeding solutions is supported.

Topics: Amniotic Fluid; Animals; Birth Weight; Drug Evaluation, Preclinical; Epidermal Growth Factor; Female; Fetal Growth Retardation; Humans; Infusion Pumps, Implantable; Intestine, Small; Pregnancy; Rabbits; Recombinant Proteins; RNA, Messenger

Topics: Amniotic Fluid; Epidermal Growth Factor; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Pregnancy

Fetal intrauterine growth retardation (IUGR) is one of the most common obstetric problems, with a frequency of 12% in Mexico. In the past, investigations have focused on extrinsic causes of IUGR. More recent studies have examined the intrinsic factors that cause fetal intrauterine growth. Maintenance of fetal growth has been attributed to insulin-like growth factor (IGF), epidermal growth factor (EGF) and transforming growth factor beta (TGF-beta). The objective of this study was to assess the levels of these growth factors during pregnancy and to determine whether or not low concentrations are associated with IUGR.. Nine women whose pregnancies were complicated by IUGR and a group of nine women whose pregnancies exhibited normal fetal intrauterine growth were studied. IUGR was determined by sonography and confirmed by weight at birth. Venous blood samples were taken from both groups of pregnant women at the end of each trimester. Enzyme-linked immunosorbent assays, immunoradiometric assays and radioimmunoassays were used to process samples, and the results were analysed by anova.. IGF-I levels increased in both groups during pregnancy, but the increase was lower (p < 0.001) in the IUGR group throughout pregnancy and at delivery. EGF did not show any significant changes during pregnancy. Blood TGF-beta levels varied only during the first trimester of pregnancy. The differences were not statistically significant. However, TGF-beta concentrations were higher in the pregnancies with IUGR. Women in the IUGR group were smaller than in the control group (p < 0.05), and, using the covariance test (p < 0.05), this was found to be correlated with IGF-I levels but not with EGF or TGF-beta levels.. Changes in fetal weight might be explained by the different concentrations of IGF. The structural homology between IGF-1 and insulin could mean that the presence of higher levels of IGF would result in a increased energetic metabolism that could contribute to fetal growth. EGF levels were not related to IUGR, and TGF-beta levels increased only during the first 3 months in the IUGR group. This observation correlates with the in vitro action of TGF-beta as a negative factor of growth, but as a positive support for sustaining early pregnancy. Our data illustrates that low height represents an increased risk factor for IUGR. These data also correlate with the studies involving extrinsic factors.

Topics: Adult; Body Weight; Embryonic and Fetal Development; Epidermal Growth Factor; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Mexico; Pregnancy; Pregnancy Trimester, First; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Socioeconomic Factors; Transforming Growth Factor beta

We investigated the physiological role of epidermal growth factor (EGF) in fetal growth in mice in which midgestational sialoadenectomy induced maternal EGF deficiency. Sialoadenectomy decreased the fetal weight significantly, indicating that maternal EGF deficiency caused intrauterine growth retardation. The weight of the fetal liver in the sialoadenectomized mice was reduced in proportion to the decrease in body weight (82.7+/-10.2 vs. 70.9+/-10.9 mg), whereas the brain weight was not reduced. Sialoadenectomy significantly decreased the glucose concentration in fetal plasma (86.0+/-13.0 vs. 63.0+/-11.8 mg/dl) without affecting the maternal plasma level of glucose. Transplacental transfer of 3H-2-deoxyglucose was significantly decreased by sialoadenectomy (5.17+/-1.25 vs. 2.94+/-1.02%), but transfer of 14C-aminoisobutyric acid was not affected. Northern blot analysis and in situ hybridization of glucose transporter isoform GLUT1 and GLUT3 messenger RNAs (mRNAs) in placenta revealed that sialoadenectomy significantly reduced the expression of GLUT3 mRNA without affecting GLUT1 mRNA levels. Administration of anti-EGF antiserum enhanced the effects of EGF deficiency, which were almost completely corrected by EGF supplementation. These results indicate that EGF plays an important role in fetal growth by regulating the transplacental supply of glucose via GLUT3 expression in the placenta.

Topics: Aminoisobutyric Acids; Animals; Blood Glucose; Deoxyglucose; Epidermal Growth Factor; Female; Fetal Blood; Fetal Growth Retardation; Fetus; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 3; Hypoglycemia; Mice; Mice, Inbred C3H; Monosaccharide Transport Proteins; Nerve Tissue Proteins; Placenta; Pregnancy; Pregnancy, Animal; Tissue Distribution

Epidermal growth factor (EGF), an angiogenic and mitogenic peptide, is known to be essential for normal fetal development in mice. Hypothetically, low maternal urine EGF levels might be associated with intrauterine growth restriction (IUGR) or pre-eclampsia (PE). We carried out a prospective study of 1009 consecutive women whose urine was sampled in early pregnancy (at a median of 13 weeks of gestation) between January and November 1993. Thirty women gave birth to IUGR babies and 24 developed PE. The study was designed as a nested case-control study with two matched controls for each case. EGF and human chorionic gonadotrophin (HCG) levels were measured and expressed in ng EGF/mg creatinine and IU HCG/mg creatinine. Logistic regression analysis was made with EGF or HCG levels as explanatory variables. Urinary EGF levels were significantly lower in the IUGR subgroup than in their controls, but no such difference was found between the PE subgroup and their controls. In the series as a whole, smokers were found to have lower EGF and HCG levels than non-smokers. In addition, correlation was found to exist between EGF and HCG levels (Spearman's rho 0.35; P<0.001). We conclude that a relative deficiency of EGF in early pregnancy might be one of the pathophysiological mechanisms of IUGR. However, the EGF level was an insufficiently discriminative variable to be of use for screening purposes.

Topics: Adult; Case-Control Studies; Chorionic Gonadotropin; Epidermal Growth Factor; Female; Fetal Growth Retardation; Humans; Logistic Models; Pre-Eclampsia; Pregnancy; Prospective Studies

To evaluate the significance of epidermal growth factor (EGF) in the development of fetal growth retardation (IUGR).. EGF concentrations in amniotic fluid, maternal and fetal blood from 86 pregnant women in the third-trimester were determined by radioimmunoassay (RIA). These subjects were divided into control, large-for gestational age (LGA) group and IUGR group according to neonatal birth weights. EGF concentrations in blood samples taken from umbilical vein and artery of 11 controls were also analyzed.. No significant differences of EGF concentrations existed in amniotic fluid, maternal and fetal blood between control and LGA group (P > 0.2 for all). Compared to the control, EGF concentration of IUGR group in amniotic fluid decreased but those in maternal and fetal blood increased significantly (P < 0.05 for all). EGF concentration of cord serum in IUGR group was significantly higher than that in LGA group (P < 0.05), but no differences of EGF levels in amniotic fluid and maternal blood existed between the two groups (P > 0.05, for all). EGF in blood samples taken from umbilical vein and artery were at the same level (P > 0.1).. EGF in amniotic fluid, maternal and fetal blood may originate from different sources, and EGF may play a role in the development of IUGR.

Topics: Adult; Amniotic Fluid; Epidermal Growth Factor; Female; Fetal Blood; Fetal Growth Retardation; Humans; Infant, Newborn; Pregnancy; Pregnancy Trimester, Third

Placental pathology in preeclampsia (PE) and intrauterine growth retardation (IUGR) is associated with alterations of the placental epidermal growth factor receptor (EGFR). It is encoded by a single gene, which gives rise to two different full-length transcripts and one putative truncated transcript in the placenta. The aim was to investigate if the placental mRNA expression pattern of EGFR differs between women with PE and/or IUGR and normal pregnancies. Tissue samples from placentas were obtained immediately after delivery. Total nucleic acids were prepared and mRNA levels of EGFR transcripts were measured by a solution hybridization technique. In the group with IUGR the placental mRNA expression of the two full-length transcripts was found to be significantly lower than in placentas from normal pregnancy, whereas the expression of the truncated transcript was higher. The groups with PE or PE with IUGR had a significantly higher mRNA expression of the truncated transcript, while there were no significant differences in the mRNA expression of the two full-length transcripts. These findings are consistent with an important role for EGFR in the regulation of placental and fetal growth.

Topics: Biopsy; Epidermal Growth Factor; Female; Fetal Growth Retardation; Gene Expression Regulation, Developmental; Gestational Age; Humans; Nucleic Acid Hybridization; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; RNA Probes; RNA, Messenger; Scintillation Counting

Epidermal growth factor (EGF) in urine was measured at 4-week intervals in 83 women referred for suspected intrauterine growth retardation (IUGR); 138 women with normal singleton pregnancies and newborns of normal weight served as controls. Of the 83 women, 30 delivered babies with weight below the 10th percentile after week 37. During pregnancy these women had shown significantly lower EGF levels than women who delivered normal-weight babies. However, due to the wide distribution of individual EGF data, no clear clinical cut-off point between normal and IUGR values could be established.

Topics: Epidermal Growth Factor; Female; Fetal Growth Retardation; Gestational Age; Humans; Pregnancy; Pregnancy Complications; Probability; Risk Factors

To investigate the relationship of epidermal growth factor (EGF) and its receptor (EGFR) with fetal birth weight.. Using enzyme linked immunoabsorbent assay (ELISA) method the EGF concentrations of materal sera, cord blood sera and amniotic fluids were determined in 40 cases with IUGR, 40 cases with term normal birth weight, 25 cases with fetal macrosomias and 15 cases with normal non-pregnant women. Simultaneously using the immunohistochemical method EGFR in placentas and fetal membrance was determined in all groups of pregnancy.. The EGF levels in normal non-pregnant women were lower than that in all groups of pregnancy. The EGF concentrations of materal sera, cord blood sera and amniotic fluid in IUGR group were lower than that in normal birth weight group. EGF levels were no difference between fetal macrosomias group and normal birth weight group. There is a positive correlation between the fetal birth weight and EGF concentrations in maternal sera, cord blood sera and amniotic fluids. In IUGR group the number of EGFR in placent and fetal membrane was less than that in normal birth weight group. In macrosomia group placental EGFR number was more than that in normal birth weight group.. EGF and its receptor levels are related with IUGR, EGF concentrations in maternal sera and amniotic fluids in the third trimester may be a valuable index for assessing the fetal growth.

Topics: Adult; Amniotic Fluid; Birth Weight; Epidermal Growth Factor; ErbB Receptors; Female; Fetal Blood; Fetal Growth Retardation; Fetal Macrosomia; Humans; Pregnancy

We studied human placental microvillous EGF receptor (EGFR) and its relationship with maternal and placental features in 14 cases of intrauterine growth retardation. Placental EGFR phosphorylation was significantly decreased or absent in 12 cases of small for gestational age neonates, as shown by SDS-PAGE, autoradiography, and scanning analysis. Specific [125I]EGF binding and Scatchard plots of the binding data showed a decreased number of EGFR in 6 of the 12 cases, with a mean maximal binding capacity of 1.09 +/- 0.32 pmol/mg for high affinity sites (mean control value = 2.30 +/- 0.23 pmol/mg). Most of the hypertensive women and smokers belonged to this subgroup. In three of the remaining six cases of small gestational age placentas with low EGFR phosphorylation, there was no maternal pathology or significant parenchymatous placental lesions. Five showed a 175-kD EGFR species when probed by [125I]EGF cross-linking and Western blotting with RK2 and C-Term, two polyclonal anti-EGFR antibodies, suggesting abnormal transduction of the EGF-induced signal. The sixth placenta yielded a single 145-kD EGFR band consistent with an abnormal EGFR structure; Western blot analysis showed no immunoreactive band. In conclusion, maternal and placental pathologies in intrauterine growth retardation are associated with various alterations of placental EGFR, pointing out the importance of EGFR ligands in the regulatory pathway of placental and fetal growth.

Topics: Binding Sites; Epidermal Growth Factor; ErbB Receptors; Female; Fetal Growth Retardation; Humans; Phosphorylation; Placenta; Pregnancy

The study of a possible alteration of epidermal growth factor receptor in placental membranes of smokers was performed.. We investigated the binding capacity and the autophosphorylation of epidermal growth factor receptor in membranes of 33 term placentas from smokers and nonsmokers with appropriate-for-gestational-age or small-for-gestational-age babies.. The binding capacity of epidermal growth factor receptor was similar in the four subgroups of placental membranes. In contrast, epidermal growth factor receptor autophosphorylation was impaired in the membranes from smokers relative to those from nonsmokers. This decrease was significant (p < 0.001) in the membranes from smokers with small-for-gestational-age babies. Insulin receptor phosphorylation was similar in the four groups.. Intrauterine growth retardation in women who smoke is associated with an alteration of placental epidermal growth factor receptor bioactivity and suggests that the regulatory role of epidermal growth factor in placental growth and differentiation is defective in this setting.

Topics: Epidermal Growth Factor; ErbB Receptors; Female; Fetal Growth Retardation; Humans; Membranes; Phosphorylation; Placenta; Pregnancy; Smoking

As fetal swallowing is documented in utero, supplementation of the ingested amniotic fluid with nutrients or hormones has been postulated as a potential prenatal treatment for intrauterine growth retardation (IUGR). To study the effect of epidermal growth factor (EGF) on the developing fetal small intestine, 12 pregnant rabbits underwent operation on day 24 of a normal 31-day gestation. Bilateral ovarian end fetuses underwent catheterization of their respective amniotic cavities with attachment to a miniosmotic pump. Study fetuses received recombinant human EGF at approximately 300 micrograms/kg/d for 1 week; controls received carrier solution only at an equivalent rate. On gestational day 31, fetuses were delivered by cesarean section and somatic measurements were recorded. The small intestine was harvested and proximal, middle, and distal regions were analyzed for lactase and maltase enzyme activity. Additionally, the uptake of radiolabeled glucose and proline was measured by a standard everted mucosal sleeve technique for each segment. Results were analyzed by Student's paired t test and reported as mean +/- SEM. Nine fetal pairs survived (75%). Small intestinal (SI) length was increased in EGF fetuses (54.8 +/- 1.9 cm) versus control (50.4 +/- 2.7 cm) (P = .02). Lactase activity, reported as UE/g protein, was significantly increased in the proximal segments in the EGF-infused fetuses; maltase was significantly increased in both the proximal and middle segments (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amnion; Animals; Biological Transport; Disaccharidases; Drug Evaluation, Preclinical; Epidermal Growth Factor; Female; Fetal Growth Retardation; Glucose; Humans; Infusion Pumps, Implantable; Intestine, Small; Pregnancy; Proline; Rabbits; Recombinant Proteins

The plasma concentration of epidermal growth factor (EGF) in female mice increases during pregnancy. Sialoadenectomy (surgical removal of the submandibular glands) on day 13 of gestation attenuates the rise in plasma EGF and significantly reduces the percent of live pups on day 19 of pregnancy to 80% compared with 95% for the control animals. EGF replacement therapy given to the sialoadenectomized mice successfully prevented this reduction in the percent of live pups on day 19. The average weight of the live fetuses from sialoadenectomized mothers was significantly lower than those from the control mothers, i.e., 1.00 +/- 0.14 (SD) g vs. 1.13 +/- 0.07 g. The administration of anti-EGF antiserum to the sialoadenectomized mice further affected fetal viability; only 70% of the pups were alive on day 19, with a mean weight of 0.93 +/- 0.15 g. The mean weight of the fetal body and that of the liver caused by sialoadenectomy were similarly reduced, but the brain was not affected, which shows that the growth retardation was asymmetrical. These findings suggest that EGF plays a physiological role in fetal growth and that EGF deficiency may be a cause of asymmetrical intrauterine growth retardation, which might be due to uteroplacental dysfunction.

Topics: Animals; Birth Weight; Epidermal Growth Factor; Female; Fetal Death; Fetal Growth Retardation; Immunization, Passive; Mice; Mice, Inbred C3H; Organ Size; Pregnancy; Submandibular Gland

Epidermal growth factor (EGF) concentrations in urine and plasma samples collected from pregnant women and neonates were measured by RIA. The EGF concentration of the first voided urine was higher in appropriate-for-date (AFD) neonates (33.9 +/- 23.0 ng/mg creatinine) than in those with intrauterine growth retardation (IUGR; 23.5 +/- 7.7 ng/mg creatinine, p less than 0.05) and heavy-for-date (19.8 +/- 5.2 ng/mg creatinine, p less than 0.05) neonates. The urinary EGF concentration of pregnant women showed no marked changes throughout pregnancy. Urinary EGF concentrations of women with AFD fetuses (45.9 +/- 31.2 ng/mg creatinine) did not differ significantly from those of women with diabetes (39.9 +/- 26.8 ng/mg creatinine) or women with multiple fetuses (44.6 +/- 30.6 ng/mg creatinine). However, women with IUGR fetuses showed lower urinary EGF concentrations (13.8 +/- 7.4 ng/mg creatinine, p less than 0.05) than women with AFD fetuses. Maternal and fetal platelet-poor plasma EGF concentrations at delivery were lower in the IUGR group (mother: 2.62 +/- 0.38 ng/ml, fetus: 2.16 +/- 0.07 ng/ml, respectively, p less than 0.05 and p less than 0.005) than in the AFD group (mother: 3.34 +/- 0.64 ng/ml, fetus: 3.24 +/- 0.93 ng/ml). In the IUGR group, the EGF concentration in fetal blood was always lower than that in maternal blood (p less than 0.05), although the AFD groups showed no such difference. These data suggest that EGF levels are closely related to fetal growth.

Topics: Birth Weight; Epidermal Growth Factor; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Osmolar Concentration; Pregnancy

Fetal growth retardation is associated with abnormal umbilical flow velocity. We have begun a systematic study of growth factors and their relationship to this specific pattern of growth retardation. Using a specific double-antibody epidermal growth factor (EGF) 125I-radioimmunoassay, we studied urinary EGF in normal pregnancy from 5 to 42 weeks of gestation, and amniotic fluid EGF from 18 to 24 weeks. EGF levels increased from early pregnancy until 21-28 weeks, when they declined to a level at term similar to non-pregnant controls and first-trimester pregnancy levels. There was no significant difference in urinary EGF levels between women delivering appropriate-for-gestational-age (AGA) infants, and those delivering small-for-gestational-age infants (SGA). We conclude that the urinary EGF is not different in the SGA pregnancy from normal pregnancy.

Topics: Amniotic Fluid; Creatinine; Epidermal Growth Factor; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Infant, Small for Gestational Age; Placenta; Pregnancy; Ultrasonography; Umbilical Arteries

Epidermal growth factor (EGF) attenuates growth when administered to rats less than 2 wk of age but lacks growth-retarding properties when given to older animals. Because the insulin-like growth factors (IGF) are postulated to be important regulators of somatic growth during the perinatal period, we examined the effect of exogenous EGF on serum and tissue concentrations of IGF-I and hepatic expression of mRNA for IGF-I and IGF-II. A single injection of EGF (500 ng/g body wt) produced a significant (P less than 0.01) decline in serum IGF-I concentration within 4 h in newborn rat pups [controls, 46.2 +/- 9.1 (SD) ng/ml; EGF treated, 29.4 +/- 4.0 ng/ml] but was ineffective in 2-wk-old animals (control IGF-I, 72.8 +/- 15.1 vs. 64.0 +/- 13.7 ng/ml). When the EGF was given on days 0-3 of life, circulating IGF-I concentrations were suppressed further (control, 61.4 +/- 8.6; EGF treated, 32.5 +/- 8.6 ng/ml). Despite the change in circulating IGF-I levels in the newborn rats, the amount of IGF-I extractable from liver and kidney of growth-retarded animals was not significantly different from control. Likewise, IGF-I and IGF-II mRNA expression in liver, as assessed by blot hybridization, was unchanged by the EGF treatment. The rapid decline in IGF-I concentration after EGF administration, coupled with the restriction of this phenomenon the first 2 wk of extrauterine life, implies that changes in IGF-I are involved in the pathogenesis of EGF-induced growth retardation.

Topics: Animals; Animals, Newborn; Epidermal Growth Factor; Female; Fetal Growth Retardation; Insulin-Like Growth Factor I; Pregnancy; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values; RNA, Messenger

We measured the amounts of epidermal growth factor receptor (EGFR) in plasma membranes from human placentas at term delivery in three groups: appropriate for gestational age (AGA), intrauterine growth-retarded (IUGR), and diabetes mellitus-complicated (DM) pregnancies. At the same time, EGFR mRNA levels were examined in three groups by dot and Northern blot analyses. Binding studies were performed using 125I-labeled human EGF as a ligand, and two classes (high and low) of binding sites were found in all specimens. Although dissociation constants (Kd) were not significantly different among three groups, the number of binding sites was significantly decreased in IUGR and DM placentas compared to that in the AGA group. Total cellular RNA was isolated from a part of the placentas used for binding studies using the guanidinium CsCl method, denatured, and dot blotted onto nitrocellulose filter. Poly(A)+ RNA was selected from the total RNA, electrophoresed in 1% agarose gel, and transferred onto nitrocellulose filters. Then, hybridization with 32P-labeled pE7 (a cDNA of EGFR), autoradiography, and densitometry were performed. The amounts of mRNA hybridized with pE7 were reduced in IUGR and DM placentas compared to that in the AGA group. The molecular sizes of EGFR mRNA were 10 and 5.6 kilobases in all three groups. These results suggest possible physiological actions of EGF on adequate feto-placental growth and development in human pregnancy.

Topics: Diabetes Mellitus; Epidermal Growth Factor; ErbB Receptors; Female; Fetal Growth Retardation; Humans; Placenta; Pregnancy; Pregnancy Complications; Pregnancy in Diabetics; Reference Values; RNA, Messenger

To investigate the role of epidermal growth factor (EGF) in feto-placental development, we measured the urinary and amniotic fluid EGF levels throughout pregnancy. Thirty urinary samples of non-pregnant women, 85 of normal pregnant women, 21 of women with toxemic pregnancy, 17 of postpartum women and 30 of newborns, and 55 amniotic fluid samples of pregnant women with a variety of conditions necessitating amniotomy and amniocentesis at 25-39 weeks of gestation were collected. EGF concentrations were measured by double-antibody radioimmunoassay. Urinary EGF levels of pregnant women reached their peak (24.6 +/- 6.7 ng/mg creatinine) at 19-22 gestational weeks; after that, they slightly decreased. Although there is no significant difference between the urinary EGF levels of non-pregnant women (19.0 +/- 5.1) and those of pregnant women (18.1 +/- 3.2), the EGF levels of toxemic women (12.2 +/- 1.5) were lower than those of normal pregnant women. The levels in puerperium women were similar to those found during pregnancy. However, the neonates had higher urinary EGF concentrations than those in pregnant women. On the other hand, EGF levels in amniotic fluid were higher according to gestational weeks and the levels of intrauterine growth retardation (IUGR) cases lower compared with normal pregnancy. Furthermore, EGF concentrations in amniotic fluid have a significant correlation with the creatinine levels in amniotic fluid. These data suggest that EGF plays an important role in fetoplacental development and it is possible that the measurement of amniotic fluid EGF might become available for the clinical assessment of fetal maturation.

Topics: Amniotic Fluid; Embryonic and Fetal Development; Epidermal Growth Factor; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Pregnancy

To examine the relationship between nutrient supply and fetal and placental growth, we examined epidermal growth factor (EGF) binding to membranes prepared from placentas of growth-restricted fetal rats. Intrauterine growth retardation was accomplished by unilateral ligation of the uterine artery; fetal rats on the contralateral uterine horn served as controls. Fetal growth restriction was accompanied by decreased placental wt at 19 and 20 day's gestation and significantly decreased placental glycogen content at 20 and 21 days, 30% and 15%, respectively. Placental DNA content and protein/DNA ratios were similar in the growth-restricted and control groups. Specific binding of 125I-EGF was increased in growth-restricted placentas at 19 and 20 days' gestation by 32% and 16%, respectively. 125I-EGF binding at 20-21 days increased linearly with the extent of placental growth restriction. Competitive binding experiments yielded linear Scatchard plots with an increased receptor density in growth-restricted placenta at 19 and 20 days' gestation, 74% and 60%, respectively. Binding affinities for the EGF receptor were similar in the two groups. The increased binding of EGF to membranes prepared from growth-restricted fetal rats may serve to enhance nutrient uptake under conditions of decreased uterine blood flow.

Topics: Animals; Epidermal Growth Factor; Female; Fetal Growth Retardation; Placenta; Pregnancy; Rats; Rats, Inbred Strains

Human epidermal growth factor (EGF) concentrations were measured by a specific solid phase RIA in random urine samples collected throughout the menstrual cycle of normal menstruating women (n = 8), women with tubal sterilization (n = 6), women taking a low dose oral contraceptive (n = 5), and women throughout pregnancy (n = 52) and delivery (n = 35). There were no differences in EGF concentrations between the proliferative and secretory phases of the menstrual cycle (P greater than 0.05). Normal menstruating women had higher urinary EGF concentrations [mean +/- SE, 37.2 +/- 6.0 micrograms/g creatinine (4.23 +/- 0.68 ng/mumol)] than women with tubal sterilization [32.7 +/- 4.0 (3.71 +/- 0.45)] or women taking a low dose oral contraceptive [19.5 +/- 6.0 (2.21 +/- 0.68)], but the differences were not significant (P greater than 0.05). During pregnancy, urinary EGF concentrations increased linearly from 6-20 weeks gestation (r = 0.76; P less than 0.001), then declined toward term (r = -0.71; P less than 0.001). EGF concentrations in early pregnancy (less than 12 weeks) or at term did not differ significantly from those in normal menstruating women (P greater than 0.05). For women delivering normal, appropriate for gestational age (AGA) infants, there was no correlation between urinary EGF concentrations and fetal weight or sex (P greater than 0.05). Urinary EGF concentrations in women delivering normal AGA infants [52.7 +/- 2.5 (5.98 +/- 0.28); n = 16] did not differ significantly (P greater than 0.05) from those in women with class A/B diabetes [41.9 +/- 2.8 (4.76 +/- 0.31); n = 6] or women delivering twins [45.6 +/- 2.6 (5.18 +/- 0.29); n = 8] with a greater fetoplacental mass. However, women delivering an intrauterine growth-retarded fetus with decreased fetoplacental mass had lower urinary EGF concentrations (24.9 +/- 2.2 (2.83 +/- 0.25); n = 5] than women with normal AGA infants (P less than 0.01). The significance of the rise in the urinary EGF concentration late in the second trimester and lower urinary EGF concentrations in women delivering intrauterine growth-retarded infants is not known, but may reflect an important physiological role for EGF in fetal-maternal hormonal interaction and development.

Topics: Adolescent; Adult; Contraceptive Devices, Female; Contraceptives, Oral; Epidermal Growth Factor; Female; Fetal Growth Retardation; Humans; Labor, Obstetric; Menstrual Cycle; Pregnancy; Sterilization, Tubal; Twins

Specific binding of 125I-human epidermal growth factor (hEGF) to homogenates of term human placentas and fetal membranes from normal and appropriate for gestational age (N = 20), intrauterine growth retarded (N = 9), twin (N = 11), White class A/B diabetic (N = 12), and large for gestational age (N = 13) pregnancies was measured. In all pregnancy states, placentas bound approximately four times more 125I-hEGF than did fetal membranes (P less than 0.001). There was no significant difference in 125I-hEGF binding to fetal membranes from the various pregnancy states (P greater than 0.05). 125I-hEGF specific binding to placentas from intrauterine growth retarded or twin pregnancies was significantly greater compared with placentas from normal and appropriate for gestational age pregnancies (P less than 0.05). The binding to placentas from pregnancies complicated by White class A/B diabetes or large for gestational age infants, on the other hand, was not significantly different from that to placentas from normal and appropriate for gestational age pregnancies. 125I-hEGF specific binding did not differ between placentas from intrauterine growth retarded or twin pregnancies (P greater than 0.05). Placental and fetal membrane 125I-hEGF binding did not vary with fetal sex, maternal race, placental weight, or gestational age between 37 to 42 weeks (P greater than 0.05). Placental but not fetal membrane 125I-hEGF binding increased with increasing infant weight when appropriate for gestational age and large for gestational age infants were included (P less than 0.05, r = 0.38, N = 32) but not for intrauterine growth retarded, appropriate for gestational age, or large for gestational age infants alone.

Topics: Embryonic and Fetal Development; Epidermal Growth Factor; Extraembryonic Membranes; Female; Fetal Growth Retardation; Gestational Age; Humans; Placenta; Pregnancy; Pregnancy in Diabetics; Pregnancy, Multiple; Twins