RESUMO
Context: Maternal glucose levels and body mass index (BMI) are determinants of fetal overgrowth, but their relation to fetal glucose consumption is not well characterized in human pregnancy. Objectives: To quantify uteroplacental glucose uptake and the allocation of glucose between the placenta and fetus and to identify factors that affect fetal glucose consumption. Design: Human in vivo study in term pregnancies. Setting: Oslo University Hospital, Norway. Participants: One hundred seventy-nine healthy women with elective cesarean section. Interventions: Uterine and umbilical blood flow was determined using Doppler ultrasonography. Glucose and insulin were measured in the maternal radial artery and uterine vein and the umbilical artery and vein. In a subcohort (n = 33), GLUT1 expression was determined in isolated syncytiotrophoblast basal and microvillous plasma membranes. Main Outcome Measures: Uteroplacental glucose uptake and placental and fetal glucose consumption quantified by the Fick principle. Results: Median (Q1, Q3) uteroplacental glucose uptake was 117.1 (59.1, 224.9) µmolâ min-1, and fetal and placental glucose consumptions were 28.9 (15.4, 41.8) µmolâ min-1â kg fetus-1 and 51.4 (-65.8, 185.4) µmolâ min-1â kg placenta-1, respectively. Fetal glucose consumption correlated with birth weight (ρ: 0.34; P < 0.001) and maternal-fetal glucose gradient (ρ: 0.60; P < 0.001), but not with maternal BMI or uteroplacental glucose uptake. Uteroplacental glucose uptake was correlated to placental glucose consumption (ρ: 0.77; P < 0.001). Fetal and placental glucose consumptions were inversely correlated (ρ: -0.47; P < 0.001), but neither was correlated with placental GLUT1 expression. Conclusion: These findings suggest that fetal glucose consumption is balanced against the placental needs for glucose and that placental glucose consumption is a key modulator of maternal-fetal glucose transfer in women.
Assuntos
Peso ao Nascer , Glicemia/metabolismo , Feto/metabolismo , Troca Materno-Fetal , Placenta/metabolismo , Adulto , Glicemia/análise , Índice de Massa Corporal , Feminino , Feto/irrigação sanguínea , Transportador de Glucose Tipo 1/análise , Transportador de Glucose Tipo 1/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Placenta/irrigação sanguínea , Circulação Placentária , Gravidez , Útero/irrigação sanguínea , Útero/metabolismoRESUMO
The human placenta is highly inaccessible for research while still in utero. The current understanding of human placental physiology in vivo is therefore largely based on animal studies, despite the high diversity among species in placental anatomy, hemodynamics and duration of the pregnancy. The vast majority of human placenta studies are ex vivo perfusion studies or in vitro trophoblast studies. Although in vitro studies and animal models are essential, extrapolation of the results from such studies to the human placenta in vivo is uncertain. We aimed to study human placenta physiology in vivo at term, and present a detailed protocol of the method. Exploiting the intraabdominal access to the uterine vein just before the uterine incision during planned cesarean section, we collect blood samples from the incoming and outgoing vessels on the maternal and fetal sides of the placenta. When combining concentration measurements from blood samples with volume blood flow measurements, we are able to quantify placental and fetal uptake and release of any compound. Furthermore, placental tissue samples from the same mother-fetus pairs can provide measurements of transporter density and activity and other aspects of placental functions in vivo. Through this integrative use of the 4-vessel sampling method we are able to test some of the current concepts of placental nutrient transfer and metabolism in vivo, both in normal and pathological pregnancies. Furthermore, this method enables the identification of substances secreted by the placenta to the maternal circulation, which could be an important contribution to the search for biomarkers of placenta dysfunction.
Assuntos
Coleta de Amostras Sanguíneas/métodos , Placenta/fisiologia , Transporte Biológico , Coleta de Amostras Sanguíneas/instrumentação , Feminino , Sangue Fetal , Humanos , Recém-Nascido , Placenta/irrigação sanguínea , Placenta/diagnóstico por imagem , Gravidez , Ultrassonografia Doppler/métodos , Ultrassonografia Pré-Natal/métodos , Veias Umbilicais/irrigação sanguínea , Artéria Uterina/diagnóstico por imagem , Útero/irrigação sanguínea , Útero/fisiologiaRESUMO
BACKGROUND: Preeclampsia is characterized by maternal endothelial dysfunction, which underlies a highly diverse clinical presentation. The pathophysiologic condition remains to be unraveled fully, but interplay between factors that are released from the placenta and maternal vascular vulnerability is likely. An imbalance in circulating angiogenic factors is a prominent feature of preeclampsia; placental growth factor and soluble Fms-like tyrosine kinase 1 have been implemented as biomarkers of placental function and preeclampsia. Their test accuracies are limited in a clinical setting, which urges better insight into their production and removal. Current data suggest that placental growth factor and soluble Fms-like tyrosine kinase 1 are released from the placenta. Both the circulating levels and the placental expression are altered in preeclamptic pregnancies. However, in vivo placental release has not been determined in human pregnancies. Moreover, there is evidence that extra-placental tissues might contribute to the circulating levels placental growth factor and soluble Fms-like tyrosine kinase 1 in normal and preeclamptic pregnancies. OBJECTIVES: We aimed to study the in vivo placental release of placental growth factor and soluble Fms-like tyrosine kinase 1 by determining the uteroplacental arteriovenous differences in human pregnancies. Further, we investigated whether this release was altered in early-onset preeclampsia compared with control subjects and whether there was a release of placental growth factor and soluble Fms-like tyrosine kinase 1 from maternal systemic endothelium. STUDY DESIGN: We conducted a case-control study at Oslo University Hospital and included 23 women with preeclampsia (diagnosis <34 weeks) and 20 control subjects. During cesarean delivery, we sampled blood from 3 vessels simultaneously (uterine vein, radial artery, and antecubital vein). We determined concentrations of placental growth factor and soluble Fms-like tyrosine kinase 1 and calculated the arteriovenous differences. A possible net placental and extra-placental release was evaluated with the use of a Wilcoxon signed rank test. Differences between groups were compared by a Mann-Whitney U-test. RESULTS: The median gestational age at delivery was 33.4 weeks (Q1, 28.3; Q3, 34.4 weeks) in the preeclamptic group and 39.3 weeks (Q1, 39.0; Q3, 39.6 weeks) in the control subjects. Women with preeclampsia had lower plasma concentrations of placental growth factor and higher concentrations of soluble Fms-like tyrosine kinase 1 compared with control subjects (P<.001). There were significant uteroplacental arteriovenous differences of soluble Fms-like tyrosine kinase 1 in preeclampsia (P<.001), but not in the control subjects. The uteroplacental arteriovenous differences of placental growth factor were significant in both groups (P<.001). Despite lower concentrations of plasma placental growth factor in women with preeclampsia, the arteriovenous differences were not significantly different from normal pregnancies (P=.53), even when we corrected for placental weight (P=.79). We found no placental growth factor or soluble Fms-like tyrosine kinase 1 concentration differences between the radial artery and the antecubital vein. CONCLUSION: Our findings are consistent with a net release of soluble Fms-like tyrosine kinase 1 from the placenta in early-onset preeclampsia. This study demonstrated a placental release of placental growth factor to the maternal circulation but could not demonstrate that this release was impaired in the preeclamptic group. We could not find evidence of systemic endothelial release of placental growth factor and soluble Fms-like tyrosine kinase 1 by analyzing the arteriovenous differences in the forearm. This study contributes to the pathophysiologic understanding of preeclampsia by the use of the clinical setting to test current concepts in vivo and underscores that studies of in vivo degradation rates of placentally released compounds are needed.
Assuntos
Fator de Crescimento Placentário/sangue , Pré-Eclâmpsia/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Braço/irrigação sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Placenta/metabolismo , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Artéria Radial , Útero/irrigação sanguínea , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , VeiasRESUMO
UNLABELLED: In the nonpregnant population, there is extensive evidence of a systemic low-grade inflammatory status in relation to excess adipose tissue. Less is known about the relation during pregnancy. OBJECTIVE: Our main objective was therefore to explore the effect of pregnancy on adiposity-related systemic inflammation. DESIGN AND METHODS: This study is a longitudinal cohort study of 240 pregnant women of Scandinavian heritage at Oslo University hospital-Rikshospitalet, Norway from 2002 to 2005. The inflammatory markers (C-reactive protein [CRP], Interleukin-6 [IL-6], monocyte chemoattractant protein 1 [MCP-1], IL1-Ra, tumor necrosis factor receptor II, and IL-10) were measured at four timepoints during pregnancy and analyzed by enzyme immuno-assay. The women were categorized based on BMI at inclusion (BMI <25, 25-30, and >30 kg/m(2)). Data were analyzed by Friedman-test, Wilcoxon signed rank test, or Kruskal-Wallis test as appropriate. RESULTS: Maternal adiposity was associated with significantly higher circulatory levels of several inflammatory markers (CRP, MCP-1, IL-6, and IL-1Ra). However, this proinflammatory upregulation was not evident toward the end of pregnancy, as levels of CRP, MCP-1, and IL-6 were not any longer significantly different between the BMI categories. CONCLUSIONS: Although normal pregnancy exhibits proinflammatory features, this does not seem to have additive or synergistic effects on the inflammation associated with adiposity. On the contrary, we found that the BMI-dependent increase in proinflammatory markers was not evident at the end of pregnancy.