Endothelial cell apoptosis is induced by fetal plasma from pregnancy with umbilical placental vascular disease

OBJECTIVE: Vascular disease in the umbilical placental circulation that is detected by umbilical artery Doppler study is associated with adverse fetal outcome. Endothelial cell activation and platelet consumption are features of this pathologic condition. We postulated that this was due to the local release of factors that cause endothelial cell injury and that these would spill into the fetal circulation. To test this hypothesis, we examined for the presence in fetal plasma of factors that induced endothelial cell apoptosis in pregnancies that were complicated by umbilical placental vascular disease. STUDY DESIGN: Isolated and cultured human umbilical vein endothelial cells were exposed to fetal plasma from the 3 fetal groups: normal pregnancy (n = 32 patients), pregnancy with umbilical placental vascular disease that was identified by an abnormal umbilical artery Doppler study (n = 38 patients), and pregnancy with maternal preeclampsia and normal umbilical artery Doppler study (n = 16 patients). Early apoptosis can be recognized by a loss of plasma membrane asymmetry with membrane uptake of annexin V. This was measured with annexin V and propidium iodide staining by fluorescent-activated cell scanning. Cells that underwent early apoptosis stained positive for annexin V and negative for propidium iodide (in contrast with cells that underwent necrosis). Cytosolic proteolytic activity was also measured. The lysates from endothelial cells that were stimulated by fetal plasma from umbilical placental vascular disease were tested for caspase-3 and caspase-8 activities by a fluorescent assay with spectrofluorophotometry. RESULTS: The percentage of endothelial cells that underwent apoptosis was significantly higher (P <.05) when stimulated with fetal plasma from pregnancies with umbilical placental vascular disease (17.71% +/- 1.31%) than with fetal plasma from normal pregnancies (9.76% +/- 0.87%). In the presence of maternal preeclampsia with normal umbilical artery Doppler study, the percent of apoptotic cells (11.31% +/- 1.59%) was similar to that of the normal group. In the group with abnormal umbilical artery Doppler study, there was no difference between pregnancies with preeclampsia (n = 17 pregnancies) and without preeclampsia (n = 21 pregnancies). The protease activity of caspase-3 was significantly enhanced in the group with umbilical placental vascular disease compared with normal pregnancy (0.79 +/- 0.06 vs 0.45 +/- 0.08 microMol/L). However, no difference in caspase-8 activity was detected (0.66 +/- 0.05 vs 0.56 +/- 0.05 microMol/L). CONCLUSION: Endothelial cell apoptosis is a feature of umbilical placental vascular disease. Our study demonstrates the presence of factors in the fetal plasma that caused endothelial cells to undergo early apoptosis. This increased apoptosis was only seen in the presence of placental vascular disease and was independent of the presence or absence of maternal preeclampsia. Our results indicate that programmed endothelial cell death occurs in the fetal circulation as a part of the injury that is associated with the development of umbilical placental vascular disease. The caspase-3, rather than caspase-8, signal transduction pathway appears to be involved in the mediation of endothelial cell apoptosis that was detected in our study.     

The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation.

OBJECTIVES: The soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1), an antagonist to vascular endothelial growth factor and placental growth factor, has been implicated in the pathophysiology of preeclampsia. Preeclampsia and pregnancy complicated with small for gestational age (SGA) fetuses share some pathophysiologic derangements, such as failure of physiologic transformation of the spiral arteries, endothelial cell dysfunction, and leukocyte activation. The objectives of this study were to: (1) determine whether plasma concentrations of sVEGFR-1 in mothers with SGA fetuses without preeclampsia at the time of diagnosis are different from those in patients with preeclampsia or normal pregnant women, and (2) examine the relationship between plasma concentrations of sVEGFR-1 and Doppler velocimetry in uterine and umbilical arteries in patients with preeclampsia and those with SGA. STUDY DESIGN: A cross-sectional study was conducted to determine the concentrations of the soluble form of VEGFR-1 in plasma obtained from normal pregnant women (n = 135), women with SGA fetuses (n = 53), and patients with preeclampsia (n = 112). Patients with SGA fetuses and those with preeclampsia were sub-classified according to the results of uterine and umbilical artery Doppler velocimetry examinations. Plasma concentrations of sVEGFR-1 were determined by an ELISA. Since these concentrations change with gestational age, differences among various subgroups were statistically estimated with the delta value, defined as the difference between the observed and expected plasma sVEGFR-1 concentration. The expected values were derived from regression analysis of plasma sVEGFR-1 concentrations in normal pregnancy. Regression analysis and univariate and multivariate analysis were employed. RESULTS: (1) Mothers with SGA fetuses had a mean plasma concentration of sVEGFR-1 higher than normal pregnant women (p < 0.001), but lower than patients with preeclampsia (p < 0.001). (2) Among patients with SGA fetuses, only those with abnormal uterine artery Doppler velocimetry had a mean plasma sVEGFR-1 concentration significantly higher than normal pregnant women (p < 0.001). (3) Among mothers with SGA fetuses in whom Doppler velocimetry was performed (n = 41), those with abnormalities in both the uterine and umbilical artery velocimetry had the highest mean delta of sVEGFR-1 plasma concentration (mean +/- standard deviation (SD): 0.69 +/- 0.29). Conversely, patients who had normal Doppler velocimetry in both uterine and umbilical arteries had the lowest mean delta (mean +/- SD: 0.09 +/- 0.29) of sVEGFR-1 plasma concentrations (ANOVA; p < 0.001). (4) Among patients with preeclampsia in whom Doppler velocimetry was performed (n = 69), those with abnormalities in both the uterine and umbilical artery velocimetry had the highest mean delta sVEGFR-1 plasma concentration (mean +/- SD: 1.01 +/- 0.22) among all groups classified (ANOVA; p < 0.001). (5) Among patients with SGA and those with preeclampsia, there was a relationship (Chi-square for trend p < 0.001 for both) between the severity of Doppler velocimetry abnormalities and the proportion of patients who had high delta sVEGFR-1 plasma concentrations (defined as a concentration two standard deviations (2SD) above the mean delta of normal pregnant women). (6) Multiple regression analysis suggested that the diagnostic category (e.g., SGA or preeclampsia), Doppler abnormalities, and gestational age at blood sampling were associated with an increase in plasma sVEGFR-1 concentrations (p < 0.001). CONCLUSIONS: These observations provide support for the participation of the soluble receptor of vascular endothelial growth factor in the pathophysiology of SGA with abnormal uterine artery Doppler velocimetry and preeclampsia. An excess of sVEGFR-1 is released into the maternal circulation of patients with preeclampsia and those with SGA fetuses, as abnormalities of impedance to blood flow involve uterine and umbilical circulation.     

A hypothesis for preeclampsia: adenosine and inducible nitric oxide synthase in human placental microvascular endothelium

Preeclampsia is a human syndrome characterized by elevated maternal blood pressure and proteinuria. It is the main cause of maternal morbidity and mortality, and fetal metabolic disturbances in developed and developing countries. Fetal complications in preeclampsia have been related with lower placental blood flow. The placenta lacks of innervation, thus vascular tone regulation depends on endothelial release of vasoactive molecules such as adenosine and nitric oxide (NO). Information about NO synthesis and its action in the feto-placental vasculature in preeclamptic pregnancies is controversial mainly due to the use of different methodological approaches, severity of the disease and cell type that had been analyzed. A high plasma level of adenosine has been reported in umbilical vein from preeclampsia compared with normal pregnancies. Since this nucleoside is mainly involved in the regulation of vascular tone and angiogenesis, perhaps through the modulation of potassium channels, it is suggested that it would be involved in the maintenance of normal feto-placental function. In this review we hypothesize a potential adenosine-mediated, NO-dependent mechanism accounting for the feto-placental reduced blood flow exhibited in preeclampsia. We summarize the potential mechanisms involved in the modulation of inducible NO synthase expression and activity in preeclampsia, emphasizing metabolic alterations in the placenta microvascular endothelial function. The involvement of adenosine, nucleoside membrane transporters and adenosine receptors, nuclear factor kappa B (NF-kappaB), potassium channels and angiogenesis, are also discussed regarding abnormal endothelial function in preeclampsia.     

Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies

OBJECTIVES: To evaluate whether intrauterine growth restriction (IUGR) as seen in preeclampsia is associated with high levels of fetal DNA in maternal circulation, and whether fetal DNA is related to altered uterine and/or umbilical artery Doppler velocimetry. METHODS: Fetal DNA quantification was performed by real-time PCR on SRY sequences in 64 male-bearing pregnant women with IUGR and/or preeclampsia and 89 controls. RESULTS: Fetal DNA content was significantly elevated in IUGR pregnancies similar to preeclampsia and correlated with altered umbilical Doppler velocimetry, while no correlation was found with uterine Doppler status. CONCLUSION: Increased fetal DNA levels in maternal plasma may be a sign of placental or fetal pathology even in the presence of normal uterine Doppler velocimetry, allowing a more precise diagnostic evaluation. The finding that elevated fetal DNA in IUGR pregnancies correlates with abnormal umbilical Doppler velocimetry suggests that fetal DNA release is associated more with fetal chronic hypoxia than with fetal size.     

Placental expression of nitric oxide synthase during HELLP syndrome: the correlation with maternal-fetal Doppler velocimetry

BACKGROUND: To correlate Doppler waveform of the uterine and umbilical vessels to placental nitric oxide synthase (NOS) expression in pregnant women with HELLP (hemolysis, elevated liver enzymes, low platelets count) syndrome. METHODS: mRNA expression of inducible NOS (iNOS) and endothelial NOS (eNOS) was assessed, after cesarean section, in placental samples from 10 women affected by HELLP syndrome and 10 controls. Pulsatility indices on Doppler waveform analysis from uterine and umbilical arteries were measured. RESULTS: iNOS expression was significantly lower in placenta from women with HELLP syndrome than controls. When comparing the results with Doppler flow measurements, we found a negative correlation between umbilical pulsatility index and eNOS expression (r = -0.91) and a positive correlation with iNOS expression (r = 0.86). CONCLUSIONS: The reduced iNOS expression in women with HELLP syndrome may indicate the extreme placental dysfunction that is unable to compensate for the endothelial derangement and related hypertension in spite of trying to improve fetoplacental perfusion and the delivery of nutrients to the fetus.     

Placental Doppler velocimetry in gestational diabetes mellitus

OBJECTIVE: To evaluate if maternal glucose level and growth of the fetus were related to placental vascular impedance in pregnancy complicated by gestational diabetes mellitus. MATERIAL AND METHODS: A retrospective study of 146 gestational diabetic women of which 117 needed insulin therapy. Glycosylated hemoglobin (HbA1c) was evaluated as well as umbilical and uterine artery Doppler velocimetry. The results were related to adverse outcome of pregnancy including newborn birthweight. RESULTS: Abnormal umbilical artery blood flow velocity was seen in 5% of the cases and abnormal uterine artery flow in 16%. Uterine and umbilical artery vascular impedance was significantly lower in macrosomic newborns. There was a poor correlation between HbA1c, vascular impedance and birthweight. There were 11 cases that developed preeclampsia, all having abnormal uterine artery Doppler and two abnormal umbilical artery Doppler. CONCLUSION: Uterine and umbilical artery vascular impedance in pregnancies complicated by gestational diabetes is related to birthweight and placental weight, but not to maternal HbA1c levels. Placental Doppler ultrasound does not seem to be of clinical value for fetal surveillance in these pregnancies unless the pregnancy is complicated by preeclampsia and/or intrauterine fetal growth restriction.     

Asymmetric dimethylarginine,an endogenous inhibitor of nitric oxide synthase,in maternal and fetal circulation

Pronounced dilation of the maternal vasculature occurs during normal pregnancy. Likewise, low resistance characterizes the fetoplacental circulation. Nitric oxide released by endothelial cells is a potent vasodilator known to be a key modulator of both maternal and fetal vascular tone. However, the mechanisms underlying the maternal circulatory adaptations and the low resistance of the fetal circulation remain unknown. The aim of the present study was to compare levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, in the maternal and fetal circulations.High performance liquid chromatography was used to measure asymmetric ADMA in the maternal and umbilical venous plasma.Plasma ADMA levels during the first trimester were 0.29 +/- 0.05, the third trimester before term 0.29 +/- 0.05, and at term 0.32 +/- 0.05 nmol/mL, which were significantly (P <.05) lower than the levels measured in nonpregnant women (0.41 +/- 0.06 nmol/mL). By contrast, ADMA levels in umbilical venous plasma averaged 1.02 +/- 0.18 nmol/mL, significantly (P <.005) higher than maternal levels. Unlike ADMA, levels of plasma L-arginine, the nitric oxide precursor, did not significantly differ among nonpregnant and pregnant women and the fetus.During pregnancy, maternal hemodynamics are modulated, at least in part, by a reduction in ADMA. Conversely, the low resistance to umbilical blood flow is maintained despite substantially higher fetal ADMA levels. Thus, the predominant mechanisms regulating the maternal and fetal circulation apparently differ.     

Reductions of vascular endothelial growth factor and placental growth factor concentrations in severe preeclampsia

OBJECTIVE: The aim of this study was to determine whether plasma concentrations of vascular endothelial growth factor and placental growth factor are altered in women with severe preeclampsia. STUDY DESIGN: We performed a case-control study to compare plasma concentrations of vascular endothelial growth factor and placental growth factor between women with severe preeclampsia and normotensive women admitted for delivery. Twenty-one women with severe preeclampsia were matched for gestational age and ethnicity with 21 normotensive women. Vascular endothelial growth factor and placental growth factor concentrations were measured with a specific antigen-capture enzyme-linked immunosorbent assay. RESULTS: Women with severe preeclampsia demonstrated significantly lower plasma concentrations of both vascular endothelial growth factor (6.36 +/- 3.96 pg/mL vs 18.65 +/- 5.98 pg/mL; P <.0001) and placental growth factor (138 +/- 119 pg/mL vs 531 +/- 340 pg/mL; P <.0001) than did women with normotensive pregnancy. Logistic regression analysis showed an independent association between plasma vascular endothelial growth factor concentration and plasma placental growth factor concentration and preeclampsia. CONCLUSION: Patients with severe preeclampsia had decreased maternal serum concentrations of both vascular endothelial growth factor and placental growth factor.     

Elevated circulating homocyst(e)ine levels in placental vascular disease and associated pre-eclampsia

We examined the hypothesis that hyperhomocyst(e)inaemia in the maternal or fetal circulation is associated with placental vascular disease with either the maternal syndrome of pre-eclampsia and/or fetal syndrome of growth restriction. Maternal plasma homocyst(e)ine levels were significantly higher in pregnancies complicated by pre-eclampsia, pregnancies with evidence of umbilical placental vascular disease, and pregnancies with both complications compared with the normal pregnancy group. In the fetal circulation mean plasma homocyst(e)ine concentration was significantly higher in the pre-eclampsia group compared with the normal group. The results suggest that hyperhomocyst(e)inaemia may be a risk marker for placental vascular disease and maternal pre-eclampsia. The elevated fetal plasma homocyst(e)ine concentrations, found only in the group of pregnancies with pre-eclampsia in the absence of umbilical placental vascular disease, may be due to an effect of placental vascular disease on homocyst(e)ine transfer from the maternal to fetal circulation.     

Altered mRNA expression of ecNOS and iNOS in myometrium and placenta from women with preeclampsia

Objective: Preeclampsia is a syndrome involving dysfunction of vascular endothelium and imbalance between endothelium derived constricting and relaxing factors. Recent evidence suggests that endothelium-derived nitric oxide (NO) plays a role in the regulation of vascular resistance during normal pregnancy and preeclampsia. NO is a potent vasodilator and is generated by the catalytic action of nitric oxide synthases ecNOS and iNOS in myometrium and placenta. Methods: In this study mRNA expressions of ecNOS and iNOS were compared in myometrium and placenta. Biopsies were collected from women with preeclampsia (n=8) and normal pregnancies (n=12). ecNOS and iNOS mRNA levels were determined using RT-PCR and expressed as arbitrary units after correction for control GAPDH gene mRNA levels. Results: The mRNA expression of ecNOS was significantly higher in both myometrium (p<0.05) and placenta (p<0.05) from women with preeclampsia compared to that in normal pregnancies, while the iNOS mRNA level was not altered in myometrium and lower in placenta (p<0.05) from women with preeclampsia. Conclusions: The higher ecNOS mRNA expression might be a compensatory response to an impaired vasodilatation in the uteroplacental circulation during preeclampsia. Whether the similar and reduced levels of iNOS mRNA expression in myometrium and placenta, respectively, in women with preeclampsia is of importance remains to be further evaluated. Received: 30 October 2000 / Accepted: 30 October 2000     

Role of arginase-2 and eNOS in the differential vascular reactivity and hypoxia-induced endothelial response in umbilical arteries and veins

The main vasodilator in the placenta is nitric oxide (NO), which is synthesized by endothelial NO synthase (eNOS). Arginase-2 competes with eNOS for l-arginine, and its activity has been related with vascular dysfunction. Recently, we showed that hypoxia induces arginase-2, and decreases eNOS activity in human umbilical vein endothelial cells (HUVEC). However there is evidence that vascular responses to hypoxia are not similar throughout the placental vascular tree. We studied whether arginase-2 plays a role controlling vascular tone in human umbilical vessels, and the changes in the expression of arginase-2 and eNOS proteins by hypoxia in endothelial cells from umbilical arteries (HUAEC) and veins (HUVEC). In isolated umbilical vessels the presence of eNOS and arginase-2 was determined in the endothelium, and the NO-dependent vasoactive responses in the presence and absence of S-(2-boronoethyl)-L-cysteine (BEC, arginase inhibitor) were studied. Additionally, HUAEC and HUVEC were exposed (0-24 h) to hypoxia (2% O2) or normoxia (5% O2), and protein levels of eNOS (total and phosphorylated at serine-1177) and arginase-2 were determined. In umbilical arteries and veins arginase-2 and eNOS were detected mainly at the endothelium. BEC induced a higher concentration-dependent relaxation in umbilical arteries than veins, and these responses were NOS-dependent. In HUAEC exposed to hypoxia there were no changes in eNOS and arginase-2 levels, however there was a significant increase of p-eNOS. In contrast, HUVEC showed an increase in arginase-2 and a reduction of p-eNOS in response to hypoxia. These results show that arginases have a vascular role in placental vessels counteracting the NOS-dependent relaxation, which is differentially regulated in placental artery and vein endothelial cells.     

Angiopoietin-2: A Promising Indicator for the Occurrence of Severe Preeclampsia

Background. The known connection between placental hypoxia and the development of preeclampsia suggests that angiogenic factors in the placenta would be changed and affect the maternal and/or umbilical cord plasma levels in patients with preeclampsia. Objective. The aim of this study was to determine the difference and correlation of placental mRNA expression and maternal/umbilical cord plasma concentrations of vascular endothelial growth factor A (VEGF-A), angiopoietin-1, and angiopoietin-2 between women with severe preeclampsia and normal pregnancies. Methods. Sixteen patients with severe preeclampsia and 29 normotensive pregnant women were studied. The placental mRNA expression was assessed using real-time quantitative RT-PCR analysis. Maternal/umbilical cord plasma levels were measured using an enzyme-linked immunoassay. Nonparametric methods were applied for statistical analysis. Results. Placental mRNA expression of angiopoietin-2 was significantly increased in patients with severe preeclampsia (p < 0.001). The maternal plasma angiopoietin-2 protein level was also significantly increased in women with severe preeclampsia (p < 0.05) and showed a positive correlation with the placental mRNA expression of angiopoietin-2 (r = 0.54, p < 0.005). For VEGF-A and angiopoietin-1, there were no significant differences between the two groups. A maternal plasma angiopoietin-2 concentration of 8.4 ng/mL had a sensitivity of 63% and a specificity of 83% for predicting severe preeclampsia. Conclusion. Placental angiopoietin-2 mRNA expression was increased and correlated with the maternal plasma angiopoietin-2 protein concentration in women with severe preeclampsia. This suggests that the plasma angiopoietin-2 protein level may be a candidate marker for severe preeclampsia.     

Doppler analysis and placental nitric oxide synthase expression during fetal growth restriction

Objective. To assess placental nitric oxide (NO) metabolism related to changes in the uteroplacental circulation during fetal growth restriction (FGR).

Methods. The resistance index (RI) from the uterine arteries and pulsatility index (PI) from the umbilical artery were determined by Doppler analysis in 15 patients with FGR and 12 healthy controls, before elective cesarean section. Inducible (iNOS) and endothelial (eNOS) NO synthase expression were measured in placental samples. Immunohistochemistry was performed for iNOS location in the placenta.

Results. During FGR, we observed a significant elevation of iNOS when compared with controls. Conversely, eNOS did not differ between the two groups. A negative correlation with eNOS (r = ?0.85) and a positive correlation with iNOS (r = 0.91) was found correlating to umbilical PI. The iNOS proteins were reduced in syncytiotrophoblast cells and increased in endothelium in the FGR group compared to the controls.

Conclusions. During FGR, placental iNOS expression is significantly increased; this increase possibly represents an adaptive physiological mechanism for overcoming a fetoplacental circulation deficiency.     

妊娠肝内胆汁淤积症患者脐带血管病变及血管活性物质的表达与胎儿窘迫发生的关系

目的 探讨妊娠肝内胆汁淤积症(ICP)患者脐带血管病理改变、脐带血管活性物质表达的变化与胎儿窘迫发生的关系.方法 应用HE染色法制片,光镜下观察25例ICP伴有胎儿窘迫(ICP窘迫组)、25例ICP不伴胎儿窘迫(ICP对照组)以及27例正常妊娠妇女(正常妊娠组)新生儿脐带血管病理改变;应用免疫组化辣根过氧化物酶-生物素标记(SABC)法测定内皮型一氧化氮合酶(eNOS)、诱导型一氧化氮合酶(iNOS)及内皮素1(ET-1)蛋白在各组脐静脉内皮细胞中的表达量,以平均吸光度(A)值表示;应用循环酶法测定脐静脉血总胆酸水平并进行相关性分析.结果 (1)脐静脉血总胆酸水平:ICP窘迫组为(19.0±2.3)μmol/L,ICP对照组为(9.0±1.7)μmol/L,正常妊娠组为(4.4±1.5)μmol/L,各组分别比较,差异均有统计学意义(P＜0.05).(2)脐静脉病理改变:ICP患者脐静脉内皮细胞单层扁平结构丧失,细胞向管腔耸立,梭形排列,细胞排列不均甚至脱落.ICP窘迫组患者脐静脉内皮细胞出现此病理改变的发生率(92%,23/25)明显高于ICP对照组(68%,17/25),差异有统计学意义(P＜0.05).(3)脐静脉内皮细胞中eNOS蛋白表达量:ICP窘迫组为0.09±0.06,ICP对照组为0.21±0.08,正常妊娠组为0.47±0.07,各组分别比较,差异均有统计学意义(P＜0.05).脐静脉内皮细胞中iNOS蛋白表达量:ICP窘迫组为0.20±0.04,ICP对照组为0.21±0.05,正常妊娠组为0.26±0.04,两ICP组分别与正常妊娠组比较,差异均有统计学意义(P＜0.01,P＜0.05);而ICP窘迫组与ICP对照组间比较,差异无统计学意义(P＞0.05).(4)脐静脉内皮细胞中ET-1蛋白表达量:ICP窘迫组为0.49±0.08,ICP对照组为0.32±0.07,正常妊娠组为0.14±0.06,两ICP组分别与正常妊娠组比较,差异均有统计学意义(P＜0.01,P＜0.05).(5)脐静脉血总胆酸水平与其病理改变的关系:脐静脉血总胆酸水平升高是脐静脉病理改变的危险因素;且与脐血管内皮细胞eNOS、iNOS的蛋白表达量呈负相关关系(r1=-0.88、r2=-0.45,P＜0.01);与脐血管内皮细胞ET-1蛋白的表达量呈正相关关系(r3=0.79,P＜0.01).结论 ICP患者脐静脉血高胆酸状态可能损伤脐静脉内皮细胞,且与其eNOS、iNOS蛋白表达下调、ET-1蛋白表达上调有关,脐静脉的这些改变可能与ICP患者胎儿窘迫的发生有关.     

Association of umbilical placental vascular disease with fetal acute inflammatory cytokine responses

OBJECTIVE: We examined the hypothesis that fetal proinflammatory cytokine release is a feature of placental vascular disease causing fetal compromise. We measured the concentrations of fetal proinflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interleukin-8 (IL-8) in the presence of vascular disease in the umbilical placental villous circulation. Vascular disease was identified by high-resistance umbilical artery Doppler flow velocity waveform studies. METHODS: We measured levels of the inflammatory cytokines IL-6 and TNF-alpha and the chemokine IL-8 in fetal blood. Blood was collected from the umbilical vein at delivery, and serum was stored at -70C until assayed using chemiluminescent and enzyme-linked immunosorbent assay methods. We studied 36 normal pregnancies delivered by elective cesarean at term and 50 pregnancies with a high-resistance umbilical artery Doppler flow velocity waveform pattern indicative of fetal placental vascular disease delivered by elective cesarean because of potential fetal compromise. RESULTS: In the presence of umbilical placental vascular disease there were significantly higher levels of IL-6 (median 5.3 pg/mL, P <.05) and IL-8 (median 26.5 pg/mL, P <.01) compared with normal pregnancies (median value of IL-6 and IL-8 were below assay threshold). There was no difference for TNF-alpha, with the median results undetectable in both groups.CONCLUSION: We found higher concentrations of IL-6 and IL-8 in the fetal circulation in the presence of umbilical placental vascular disease.