Relationship between nutritionally-mediated placental growth restriction and fetal growth, body composition and endocrine status during late gestation in adolescent sheep

The aim was to investigate the consequences of nutritionally-mediated placental growth restriction on fetal organ growth, conformation, body composition and endocrine status during late gestation. Embryos recovered from superovulated adult ewes inseminated by a single sire were transferred in singleton to the uterus of peripubertal adolescent recipients. Post-transfer, adolescent dams were offered a high (H) or moderate (M) level of a complete diet to promote rapid or moderate maternal growth rates, respectively (n=7 per group). After day 100 of gestation the feed intake of the M dams was adjusted weekly to maintain body condition score. Liveweight gain during the first 100 days of gestation was 301+/-24 and 90+/-4.6 g/day for the H and M groups, respectively. Maternal plasma concentrations of insulin, IGF-I and urea were significantly higher and non-esterified fatty acid concentrations significantly lower in H compared with M dams prior to slaughter on day 128 of gestation. At this stage of gestation, total placentome weight was 50 per cent lower in H compared with M groups (P< 0.001) and was associated with a 37 per cent reduction in fetal weight (P< 0.01). All variables of fetal conformation and absolute fetal organ weights, with the exception of the adrenal glands, were lower (P< 0. 05) in the fetuses from H intake dams. However, relative fetal organ weights expressed as g/kg fetal body weight, with the exception of the gut, were not influenced by maternal dietary intake. Furthermore, fetal weight but not maternal nutritional group were predictive of individual organ weight for all organs dissected. Together these results imply that growth restriction in the fetuses derived from H intake dams was largely symmetrical. Fetal plasma concentrations of insulin, IGF-I and glucose were attenuated (P< 0.05) in fetuses from H compared with M groups. The lower fetal body weight in the former group was associated with a reduction in absolute but not relative crude protein (P< 0.01) and fat content (P< 0.05). Total fetal liver glycogen content but not concentration was (P< 0.05) reduced in H versus M groups. The lower mass of both the placenta and fetal liver was due to a reduction in cell number rather than an alteration in cell size. Thus, over-nourishing adolescent sheep is associated with a major restriction in placental growth which mediates a gradual slowing of fetal growth during the final third of pregnancy.     

The effects of an obesogenic diet during pregnancy on fetal growth and placental gene expression are gestation dependent

Exposure to overnutrition in utero may increase offspring cardiometabolic disease risk. A mouse model of maternal exposure to an obesogenic diet (DIO) was used to determine effects on fetal and placental weight and gene expression in mid- and late gestation. DIO altered placental gene expression in mid-gestation without differences in fetal or placental weights. Weight gain was attenuated in DIO dams in late gestation and male pup weight was reduced, however there were no persistent changes in placental gene expression. Differences in maternal weight gain and/or specific dietary components may impact on fetal and placental growth and later disease risk.     

Periconceptional alcohol consumption causes fetal growth restriction and increases glycogen accumulation in the late gestation rat placenta

Introduction

Alcohol consumption is a common social practice among women of childbearing age. With 50% of pregnancies being unplanned, many embryos are exposed to alcohol prior to pregnancy recognition and formation of the placenta. The effects of periconceptional (PC) alcohol exposure on the placenta are unknown.

Methods

Sprague-Dawley rats were exposed to alcohol (12.5% v/v ad libitum) from 4 days prior to 4 days after conception and effects on placental growth, morphology and gene/protein expression examined at embryonic day (E) 20.

Results

PC ethanol (EtOH)-exposed fetuses were growth restricted and their placental/body weight ratio and placental cross-sectional area were increased. This was associated with an increase in cross-sectional area of the junctional zone and glycogen cells, especially in PC EtOH-exposed placentas from female fetuses. Junctional Glut1 and Igf2 mRNA levels were increased. Labyrinth Igf1 mRNA levels were decreased in placentas from both sexes, but protein IGF1R levels were decreased in placentas from male fetuses only. Labyrinth mRNA levels of Slc38a2 were decreased and Vegfa were increased in placentas following PC EtOH-exposure but only placentas from female fetuses exhibited increased Kdr expression. Augmented expression of the protective enzyme 11βHsd2 was found in PC EtOH-exposed labyrinth.

Discussion

These observations are consistent with a stress response, apparent well beyond the period of EtOH-exposure and demonstrate that PC EtOH alters placental development in a sex specific manner.

Conclusion

Public awareness should be increased to educate women about how excessive drinking even before falling pregnant may impact on placental development and fetal health.     

Maternal,placental and fetal exposure to bisphenol A in women with and without preeclampsia

Objectives: We aimed to investigate potential association between the exposure of bisphenol A (BPA) and preeclampsia. Methods: Concentrations of BPA were assessed in 58 pregnancies including 35 normotensive and 23 preeclamptic women, using a highly sensitive gas chromatography–mass spectrometry (GC-MS) method. Results: BPA was detected in maternal blood, fetal blood and placental tissue; and actual concentrations of BPA were determined. Interestingly, significant accumulation of BPA in the placentas of women with preeclampsia compared to normotensive women has been shown. Conclusions: This is the first study to highlight a significant correlation between preeclampsia and a high accumulation of BPA in the placenta.     

Clustering and classical analysis of clinical and placental phenotypes in fetal growth restriction and constitutional fetal smallness

This study aims to determine whether placental examination can be used to distinguish between pathologic fetal growth restriction (FGR) and constitutional fetal smallness. Data were extracted from a clinicoplacental database of high risk pregnancies during the period 1994–2013. These data were used to compare the 590 consecutive cases having birth weights below the 10th percentile with the 5201 remaining cases having gestational ages ≥20 weeks. The authors analyzed 20 clinical and 46 placental phenotypes using classical statistics, clustering analysis, and multidimensional scaling. Of the low-birth-weight babies, the following types of cases were compared:

• •246 cases with the clinical risk factors most discriminative for FGR were compared with 344 cases without these risk factors (gestational hypertension or severe preeclampsia, maternal substance abuse and/or smoking, oligohydramnios, and abnormal umbilical artery Dopplers), and
• •196 early-onset cases were compared with 394 late-onset cases.

Four categories of placental phenotypes (those with features of poor uteroplacental perfusion, postuterine placental pathology, chronic inflammation, and a mixed category) better defined the presumably true FGR than did the clinical phenotypes. Maternal smoking and oligohydramnios were associated with fewer abnormal placental phenotypes than were maternal hypertensive diseases and abnormal Dopplers. Early-onset cases of fetal smallness clustered with placental features of poor uteroplacental perfusion, whereas late onset cases did not. Placental examination helps to retrospectively distinguish constitutionally small fetuses from those that are pathologically growth restricted. The latter correlate best with the clinical risk for FGR and with early-onset FGR. This correlation may have prognostic significance for the child and for future pregnancies, since hypoxic placental lesions can occur without clinical risk factors but with a tendency to recur in future pregnancies.     

妊娠高血压综合征患者胎盘血管内皮生长因子的表达及其意义

目的　探讨胎盘血管内皮生长因子 (VEGF)在妊娠高血压综合征 (妊高征 )患者中的表达及其与胎盘血管网络构建、胎盘重量及新生儿体重的关系。方法　采用蛋白免疫印迹技术测定 2 5例正常妊娠妇女 (正常妊娠组 )及 2 5例妊高征患者 (妊高征组 )的胎盘组织中VEGF的表达。采用免疫组织化学法 ,用抗F8因子抗体标记两组孕妇胎盘中的血管密度。两组孕妇分娩后 ,测量新生儿身长、体重 ,并胎盘称重。结果　 (1)妊高征组和正常妊娠组孕妇胎盘VEGF积分吸光度值分别为2 4793± 6 5 79、4190 3± 110 0 9;胎盘血管密度分别为 (6 1± 11)和 (78± 11)个 / 40 0×视野。两组比较 ,差异均有极显著性 (P <0 0 1) ,且与妊高征患者病情严重程度相关。 (2 )妊高征组胎盘重量 [(4 6 0±5 9)g]较正常妊娠组 [(5 73± 99)g]显著下降 (P <0 0 1)。 (3)妊高征组新生儿体重为 (3176± 5 0 3)g,较正常妊娠组的 (34 6 8± 493)g显著下降 (P <0 0 5 ) ;而新生儿身长在两组间比较 ,差异无显著性(P >0 0 5 )。(4 )正常妊娠组中 ,胎盘VEGF的表达与血管密度、胎盘重量和新生儿体重的相关系数分别为 0 82 3、0 6 71、0 888;妊高征组分别为 0 90 5、0 85 9、0 732 ,两者均呈显著正相关 (P <0 0 1)。而VEGF表达与新生儿身长不相关     

Notch1蛋白在正常妊娠早中晚期胎盘绒毛中的表达变化及其意义

目的:检测Notch1蛋白在正常妊娠早、中、晚期胎盘绒毛中的表达水平变化,探讨Notch1在胎盘形成中的作用及意义。方法:采用免疫组织化学SP法、Real-timePCR、Western blot分别检测20例正常早期绒毛组织、15例中期妊娠和20例晚期妊娠胎盘组织中Notch1 mRNA及蛋白的表达水平。结果:Notch1蛋白在正常早、中、晚期妊娠过程中均有不同程度的表达,随着妊娠的进展其表达水平呈下调趋势,但无统计学差异(P>0.05)。正常早期绒毛组织中Notch1 mRNA的表达水平显著高于妊娠中、晚期胎盘组织(P<0.05)。结论:Notch1蛋白可能参与正常妊娠早期绒毛的分化及胎盘的形成过程,有利于维持妊娠的正常发展。     

胎儿生长受限孕妇的胎盘GLUT1表达与血清皮质醇的关系

目的探讨胎盘葡萄糖转运蛋白(glucose transporter,GLUT)的表达在胎儿生长受限(fetal growth restriction,FGR)发生发展中的作用及其与孕妇血清皮质醇(cortisol,CORT)水平的相关性.方法用免疫组织化学法检测20例FGR孕妇(FGR组)及24例正常妊娠孕妇(对照组)胎盘GLUT1的表达.利用放射免疫分析法测定两组孕妇产前血清CORT水平.同时测量新生儿出生体重和胎盘重量.结果FGR胎盘GLUT1表达水平(149.8±8.2)较对照组(155.9±6.5)明显降低(P＜0.05),胎盘合体滋养层基底膜面GLUT1的表达水平(135.3±4.2)较对照组(153.9±8.5)明显降低(P＜0.01).胎盘GLUT1表达水平与孕妇血清CORT水平呈负相关(r=-0.803,P＜0.01).结论胎盘组织中,特别是基底膜面的GLUT1表达水平下降可能是FGR的病因之一,CORT可能通过抑制胎盘GLUT1的表达,参与FGR的发病过程.     

The effect of a reversible period of adverse intrauterine conditions during late gestation on fetal and placental weight and placentome distribution in sheep

Adverse intrauterine conditions occurring during early to mid-gestation or throughout the whole of gestation influence placental weight and the distribution of placentome types in sheep. However, no study to date has investigated the effect of a reversible period of adverse intrauterine conditions during late gestation upon fetal and placental weight and placentome distribution in sheep. Twenty-two sheep fetuses were chronically instrumented with an inflatable cord occluder, amniotic and vascular catheters and with a Transonic flow probe around an umbilical artery. At 125 days (term isca.145 days) the occluder was inflated to reduce umbilical blood flow by ca.30 per cent for 3d in 12 fetuses (umbilical cord compressed, UCC). The occluder was then deflated and umbilical blood flow allowed to return to baseline. The remaining 10 fetuses acted as sham-operated controls in which the occluder remained deflated at all times. At 135-137dGA ewes were humanely killed and tissues collected, weighed and placentomes classified. A reduction in umbilical blood flow by approximately 30 per cent from baseline for 3 days in UCC fetuses led to mild fetal asphyxia throughout the period of cord-compression. After deflation of the occluder cuff, umbilical blood flow returned to a level that was significantly greater than that measured during baseline. Umbilical cord compression had no effect on fetal body weight but significantly increased fetal adrenal weight relative to body weight. While the total number of placentomes was not altered by cord-compression, total placentome weight and the total weight of C/D-type placentomes were both reduced in UCC relative to control placentae. In addition, the mean weight of placentomes, and of C/D-type placentomes specifically, was significantly lower in UCC relative to control placentae. When expressed as a percentage of the total number of placentomes in the placenta, there was a significantly lower percentage of C/D-type placentomes in UCC relative to control placentae. In addition, there was a significant relationship between the total number of placentomes and the percentage C/D-type placentomes in control, but not UCC, placentae. The data suggest that a temporary, reversible period of adverse intrauterine conditions occurring late in gestation in sheep has persisting effects upon the placenta, mean placentome weight and placentome distribution.     

Review: The role of multiple placental glucocorticoid receptor isoforms in adapting to the maternal environment and regulating fetal growth

The physiological mechanisms that confer different outcomes in morbidity and mortality of the fetus exposed to stressful environments may be driven by significant differences in the expression and function of the placental glucocorticoid receptor (GR). The recent discovery that the placenta contains at least 8 different isoforms of the GR raises questions about the regulation and physiological relevance of the many GR variants expressed in the placenta. The current data also highlights that individual differences in glucocorticoid sensitivity, variations in the effect of different complications of pregnancy on birth outcomes and sex differences in the response to stress, may all be dependent on a specific GR isoform expression profile. This review will investigate the current state of knowledge of GR isoforms in the placenta and discuss the potential role of these multiple isoforms in regulating glucocorticoid sensitivity.     

Maternal growth restriction and stress exposure in rats differentially alters expression of components of the placental glucocorticoid barrier and nutrient transporters

The placenta plays a major role in the development of fetal growth restriction, which affects 10% of pregnancies and contributes to chronic adult disease risk. We have reported that female rats born small develop cardiometabolic dysfunction only during pregnancy. The physiological tests performed during pregnancy induced a maternal stress response as indicated by increased maternal corticosterone concentrations. This stress effected placental growth compared to females who were unhandled during pregnancy. Maternal stress and growth restriction independently program F2 offspring metabolic dysfunction. This study investigated the effects of maternal stress and growth restriction on placental and fetal metabolic parameters that may contribute to F2 offspring metabolic disease. Maternal growth restriction reduced F2 fetal weight whilst maternal stress reduced placental weight. Stressed mothers had reduced insulin and increased glucose concentrations, changes that were reflected in the fetus. Fetal β-cell number was reduced by maternal growth restriction, but was increased by stress exposure. Maternal growth restriction reduced placental Slc2a1, Igf2, Slc38a2 and Nr3c1 gene expression. Maternal stress decreased the expression of Slc2a1, Igf2, Slc38a2, Nr3c1, Slc2a3, Slc2a4, Nr3c2, Hsd11b2, Crhr1 and Ogt. Maternal birth weight effects on fetal weight were likely due to changes in placental nutrient transporter and Igf2 expression. On the contrary, maternal stress induced a systemic effect by altering maternal metabolic parameters, placental gene expression and fetal glucose and insulin concentrations. This study highlights the importance of informing pregnant women on effective ways to cope with stress during pregnancy to prevent adverse long-term disease outcomes in their children.     

Increased placental angiogenesis in late and early onset pre-eclampsia is associated with differential activation of vascular endothelial growth factor receptor 2

Introduction

Placentas from both early-onset (EOPE) and late-onset pre-eclampsia (LOPE) exhibit signs of underperfusion, which in turn, may be associated with altered angiogenesis. Tyrosine 951 (Y951) and Y1175 phosphorylation of the vascular endothelial growth factor receptor 2 (VEGFR2) induced by VEGF triggers the angiogenesis process. Endothelial markers such as CD31 and CD34 have been used for estimating angiogenic processes in several tissues, including placenta. We asked whether vascular density in placental villi was related to Y951/Y1175 phosphorylation of VEGFR2 in LOPE or EOPE.

Methods

We obtained placental samples from women with normal pregnancies (n = 22), LOPE (n = 13), EOPE (n = 15) and preterm deliveries (n = 10). Slices from placental tissue were used for CD31 immunostaining. We estimated the expression of CD31, CD34, VEGF, and VEGFR2 by western blot and quantitative PCR. Y951 phosphorylation of VEGFR2 was estimated by western blot, whereas Y1175 phosphorylation was analyzed by ELISA.

Results

Vessel density in terminal villi and CD31 and CD34 protein abundance were increased in LOPE and EOPE compared to normal pregnancy. However, mRNA levels for CD31 and CD34 were lower in LOPE than in normal pregnancy and VEGF mRNA was higher in EOPE. VEGFR2 protein concentration was not different among the studied groups. Y951 and Y1175 phosphorylation of VEGFR2 was higher in LOPE than in the normotensive group, but only Y951 exhibited greater phosphorylation in EOPE compared to normal pregnancy.

Discussion

Changes in vessel formation in the pre-eclamptic placenta are controversial. Our study suggests a pro-angiogenic state in both LOPE and EOPE. These changes are however, associated with differential expression of endothelial markers and VEGFR2 activation.

Conclusion

There is evidence of increased placental angiogenesis in LOPE and EOPE that is associated with differential activation of VEGFR2.     

Predominance of L-dopa in fetal plasma and the amniotic fluid during late gestation in the rat

The purpose of this study was to reevaluate catecholamine distribution in fetal and maternal compartments during late gestation in the rat. Fetal and maternal plasma and amniotic fluid were collected from anesthetized rats on consecutive days from day 17 to day 22, the day of parturition. The fluid was analyzed for dihydroxyphenylalanine (L-dopa), dopamine, norepinephrine, and epinephrine by radioenzymatic assays. Amniotic fluid volume was determined by a direct weighing method. L-Dopa concentrations constituted approximately 50% of total fetal plasma catecholamines and were significantly higher in fetal than in maternal circulation. Dopamine concentrations in fetal plasma were tenfold lower than those of L-dopa but were also significantly higher in fetal than in maternal plasma; norepinephrine levels were similar in both. Maternal plasma epinephrine levels remained relatively constant, whereas fetal epinephrine levels increased fiftyfold from day 17 to day 22. L-Dopa concentrations in the amniotic fluid were tenfold higher than those of dopamine, and the concentrations of both increased markedly during the last 2 days of gestation. However, this apparent rise could be attributed to the concomitant fivefold reduction in the amniotic fluid volume observed at this time. It is concluded that L-dopa is the predominant catecholamine in both the fetal plasma and the amniotic fluid during late gestation in the rat. At the present time, neither the source nor the possible physiologic functions of L-dopa during fetal life are known.     

Effect of dexamethasone on pulmonary and renal angiotensin-converting enzyme concentration in fetal sheep during late gestation

OBJECTIVES: The effect of dexamethasone on tissue angiotensin-converting enzyme (ACE) was investigated in fetal sheep. STUDY DESIGN: Pulmonary and renal ACE concentrations were measured in 16 sheep fetuses at between 127 and 131 days of gestation (term 145+/-2 days): 6 were untreated, whereas 10 were chronically catheterized and infused intravenously with either saline solution (0.9%, n=4) or dexamethasone (45-60 microg. kg(-1). d(-1), n=6) for the previous 2 days. The dexamethasone dose increased plasma dexamethasone to around one fifth of that measured in newborn human infants delivered after maternal dexamethasone treatment. RESULTS: Over the period of infusion, arterial blood pressure increased significantly in the dexamethasone (+6.8+/-1.5 mm Hg, P<.05) but not saline-treated fetuses (+1.6+/-0.6 mm Hg). At delivery, pulmonary ACE in the dexamethasone-infused fetuses (1.24+/-0.26 nmoles hippurate. min(-1). mg protein(-1)) was significantly greater than in the control fetuses (0.50+/-0.07 nmoles. min(-1). mg protein(-1), P<.005); renal ACE was unchanged by dexamethasone treatment. Overall, pulmonary ACE and blood pressure were correlated on the last day of infusion (r=0.70, P<.05). CONCLUSION: The rise in pulmonary ACE seen in dexamethasone-treated sheep fetuses may contribute, in part, to the glucocorticoid-induced increase in blood pressure.     

妊娠肝内胆汁淤积症孕妇胎儿总胆酸水平对胎儿胰腺内分泌功能及胎儿生长发育的影响

目的 探讨妊娠肝内胆汁淤积症(ICP)孕妇的胎儿总胆酸水平与胎儿胰腺内分泌功能变化的关系及其对胎儿生长发育的影响.方法 选择2007年3月至2008年2月在中南大学湘雅二医院妇产科行剖宫产分娩的30例单胎ICP孕妇为ICP组,同期行剖宫产分娩的30例正常单胎孕妇为对照组.采用放射免疫法测定两组新生儿脐动脉血中胰岛素、胰高糖素水平;循环酶法测定总胆酸水平;氧化酶-过氧化物法测定血糖水平.并测量两组新生儿出生体重、身长,计算肥胖指数(PI).结果 (1)ICP组新生儿脐动脉血中胰岛素水平为(9.0±3.3)mU/L、胰岛素/胰高糖素比值为0.048±0.028,分别低于对照组的(10.1±3.7)mU/L及0.050±0.020,差异有统计学意义(P<0.05);ICP组新生儿脐动脉血中总胆酸水平为(10.3±3.8)μmol/L、胰高糖素水平为(235±57)ns/L,分别高于对照组的(4.1±1.3)μmol/L及(205±34)ng/L,差异有统计学意义(P<0.05);ICP组新生儿脐动脉血中血糖水平为(3.4±1.1)mmol/L,对照组为(3.6±1.2)mmol/L,两组比较,差异无统计学意义(P>0.05).(2)ICP组新生儿出生体重及身长分别为(3163±478)g及(46.5±2.3)cm,对照组分别为(3498±393)g及(49.3±1.9)cm,两组分别比较,差异均有统计学意义(P<0.01);ICP组新生儿PI(3.13±0.23)明显高于对照组(2.92±0.29),差异有统计学意义(P<0.01).(3)ICP组新生儿总胆酸水平分别与胰岛素、胰高糖素水平及胰岛素/胰高糖素比值呈直线关系,且随着总胆酸水平的升高,胰岛素水平及胰岛素/胰高糖素比值均降低,胰高糖素水平升高(P<0.01);ICP组新生儿脐动脉血中胰岛素水平及胰岛素/胰高糖素比值分别与出生体重、身长呈正相关,与PI呈负相关(P均<0.01);而胰高糖素水平与出生体重、身长呈负相关,与PI呈正相关(P均<0.01).结论 ICP孕妇的胎儿存在胰岛素分泌不足,胰高糖素分泌增多,胰岛素/胰高糖素比值下降的情况,其变化与脐动脉血总胆酸水平密切相关;胎儿胰腺内分泌功能变化可能影响胎儿的生长发育.     

The effects of unilateral ovariectomy during pregnancy on placental and fetal growth in mice

A comparison between placental weight and number of fetuses in normal mice and those in mice unilaterally ovariectomized on the sixth day of pregnancy, revealed a relative hypertrophy of the placentae of the latter group, with a predominance of the effect in litter sizes of five or less. The weights of the fetuses in the unilaterally ovariectomized group were not significantly different from those of the controls, thus affording no evidence of a causal connection between fetal weight and gross placental weight.     

Application of non-invasive prenatal testing in late gestation in a pregnancy associated with intrauterine growth restriction and trisomy 22 confined placental mosaicism

Objective

We present the application of non-invasive prenatal testing (NIPT) in late gestation in a pregnancy associated with intrauterine growth restriction (IUGR) and trisomy 22 confined placental mosaicism (CPM).