Polycyclic aromatic hydrocarbons (PAHs) may explain the paradoxical effects of cigarette use on preeclampsia (PE).

Tobacco smoking and use of snus (smokeless tobacco) are associated with adverse effects on pregnancy and neonatal outcomes. Nicotine is considered a key toxicant involved in effects caused by both smoking and snus, while pyrolysis products including polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke represents the constituents most unequally divided between these two groups of tobacco products. The aim of this review was: i) to compare the impact, in terms of relative effect estimates, of cigarette smoking and use of Swedish snus on pregnancy outcomes using similar non-tobacco user controls, and ii) to examine whether exposure to PAHs from smoking could explain possible differences in impact on pregnancy outcomes. We systematically searched MEDLINE, Embase, PsycInfo, Web of Science and the Cochrane Database of Systematic Reviews up to October 2021 and identified studies reporting risks for adverse pregnancy and neonatal outcomes associated with snus use and with smoking relative to pregnant women with no use of tobacco. Both snus use and smoking were associated with increased risk of stillbirth, preterm birth, and oral cleft malformation, with comparable point estimates. These effects were likely due to comparable nicotine exposure. We also found striking differences. While both smoking and snus increased the risk of having small for gestational age (SGA) infants, risk from maternal smoking was markedly higher as was the reduction in birthweight. In contrast, the risk of preeclampsia (PE) was markedly lower in smokers than in controls, while snus use was associated with a slightly increased risk. We suggest that PAHs acting via AhR may explain the stronger effects of tobacco smoking on SGA and also to the apparent protective effect of cigarette smoking on PE. Possible mechanisms involved include: i) disrupted endocrine control of fetal development as well as placental development and function, and ii) stress adaption and immune suppression in placenta and mother.

Uteroplacental Glucose Uptake and Fetal Glucose Consumption: A Quantitative Study in Human Pregnancies.

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) µmol⋅min-1, and fetal and placental glucose consumptions were 28.9 (15.4, 41.8) µmol⋅min-1⋅kg fetus-1 and 51.4 (-65.8, 185.4) µmol⋅min-1⋅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.

The 4-vessel Sampling Approach to Integrative Studies of Human Placental Physiology In Vivo.

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.

Transplacental nutrient transfer in the human in vivo determined by 4 vessel sampling.

BACKGROUND: The intrauterine environment and especially the fetal nutritional conditions affect lifelong health. There are few human in vivo studies on fetal nutrition. The importance to test experimentally based concepts of fetal nutrition in a human in vivo setting is becoming increasingly apparent. A way of testing nutrient transfer in human is 4-vessel sampling, which implies blood sampling from artery and vein on both sides of the placenta. Here we give a brief review of the studies using the 4-vessel sampling method. METHOD: We performed systematic searches in Ovid MEDLINE and EMBASE (Ovid) from 1946 to May 2016. The following search terms were used to identify eligible articles: [placenta] AND [glucose/blood glucose] OR [amino acids] OR [lipids] OR [cholesterol] OR [nutrient] AND [blood sample] OR [biological transport] OR [transport/transfer/exchange] OR [maternal-fetal exchange] AND [humans]. RESULTS: The search retrieved 623 studies. After abstract scanning 25 full text articles were evaluated and seven articles describing 4-vessel sampling were identified. The studies had from 14 to 77 participants and reported placental transfer of different nutrients (glucose, lactate, amino acids and arachidonic acid). CONCLUSION: Few studies have used 4 vessel sampling to study placental nutrient transfer in human pregnancies. Overall these studies indicate that the transfer of nutrients between the mother and the fetus is highly "dynamic," i.e. most nutrients may pass either way on both the maternal and fetal sides of the placenta. Furthermore, the concept that the placenta is a metabolically highly active organ affecting transfer of glucose, amino acids and lipids, fits the human in vivo data. The 4-vessel method can provide essential information on the transfer between the mother, placenta and fetus of virtually any compound.

In vivo uteroplacental release of placental growth factor and soluble Fms-like tyrosine kinase-1 in normal and preeclamptic pregnancies.

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.

Placental glucose transfer: a human in vivo study.

OBJECTIVES: The placental transfer of nutrients is influenced by maternal metabolic state, placenta function and fetal demands. Human in vivo studies of this interplay are scarce and challenging. We aimed to establish a method to study placental nutrient transfer in humans. Focusing on glucose, we tested a hypothesis that maternal glucose concentrations and uteroplacental arterio-venous difference (reflecting maternal supply) determines the fetal venous-arterial glucose difference (reflecting fetal consumption). METHODS: Cross-sectional in vivo study of 40 healthy women with uncomplicated term pregnancies undergoing planned caesarean section. Glucose and insulin were measured in plasma from maternal and fetal sides of the placenta, at the incoming (radial artery and umbilical vein) and outgoing vessels (uterine vein and umbilical artery). RESULTS: There were significant mean (SD) uteroplacental arterio-venous 0.29 (0.23) mmol/L and fetal venous-arterial 0.38 (0.31) mmol/L glucose differences. The transplacental maternal-fetal glucose gradient was 1.22 (0.42) mmol/L. The maternal arterial glucose concentration was correlated to the fetal venous glucose concentration (r = 0.86, p<0.001), but not to the fetal venous-arterial glucose difference. The uteroplacental arterio-venous glucose difference was neither correlated to the level of glucose in the umbilical vein, nor fetal venous-arterial glucose difference. The maternal-fetal gradient was correlated to fetal venous-arterial glucose difference (r = 0.8, p<0.001) and the glucose concentration in the umbilical artery (r = -0.45, p = 0.004). Glucose and insulin concentrations were correlated in the mother (r = 0.52, p = 0.001), but not significantly in the fetus. We found no significant correlation between maternal and fetal insulin values. CONCLUSIONS: We did not find a relation between indicators of maternal glucose supply and the fetal venous-arterial glucose difference. Our findings indicate that the maternal-fetal glucose gradient is significantly influenced by the fetal venous-arterial difference and not merely dependent on maternal glucose concentration or the arterio-venous difference on the maternal side of the placenta.