Tacrolimus concentrations after renal transplantation in a mother-neonate dyad: Maternal, neonatal and breast milk measurements.

WHAT IS KNOWN AND OBJECTIVE: We aim to add to the few reports on tacrolimus concentrations in breast milk and in maternal, umbilical vein and neonatal blood after maternal renal transplantation. CASE SUMMARY: In a 30-year-old pregnant woman, the tacrolimus concentration at delivery was the same in maternal, umbilical vein and neonatal blood. The breast milk/maternal blood tacrolimus ratio ranged from 0.40 to 0.64. WHAT IS NEW AND CONCLUSION: The maternal and neonatal blood tacrolimus concentrations at birth are equivalent; thus, one must assume that maternal tacrolimus concentrations directly affect the foetus and/or neonate. Tacrolimus is not detectable in the neonate 3 weeks after birth, suggesting that there is minimal transfer through breast milk.

Plasma amino acid pools in the umbilical cord artery show lower 15N natural isotope abundance relative to the maternal venous pools.

15N natural isotope abundance (NIA) is systematically higher in infants' hair than in that of their mothers at birth. This study aimed to investigate this difference in plasma pools. We compared 15N NIA values for plasma amino acid (AA) pools (free + protein-bound) in the umbilical cord artery (UCA) and vein (UCV) and in the maternal vein (MV) at birth. This preliminary study included 7 mother-infant dyads. Whole plasma was treated (HCl) to hydrolyze protein. Following derivatization, AAs were separated using gas chromatography and compound-specific 15N NIA values were measured on-line using an isotope ratio monitoring mass spectrometer. 15N NIA plasma AA pools in the UCA and UCV were highly correlated to the MV, r 2 > 0.89 and r 2 > 0.88 (both P < 10-4) respectively. The full model found a significant effect of sampling compartment (P = 0.02) and AA type (P < 0.0001) on 15N NIA plasma AA values. 15N NIA plasma AA was 0.74 ‰ higher (P = 0.01) in the MV than in the UCA. This study indicates that a decrease in 15N NIA for plasma AA pools occurs in the fetal-placental unit. Trial registration: ClinicalTrials.gov identifier: NCT00607061.

Antenatal Therapy for Fetal Supraventricular Tachyarrhythmias: Multicenter Trial.

BACKGROUND: Standardized treatment of fetal tachyarrhythmia has not been established. OBJECTIVES: This study sought to evaluate the safety and efficacy of protocol-defined transplacental treatment for fetal supraventricular tachycardia (SVT) and atrial flutter (AFL). METHODS: In this multicenter, single-arm trial, protocol-defined transplacental treatment using digoxin, sotalol, and flecainide was performed for singleton pregnancies from 22 to <37 weeks of gestation with sustained fetal SVT or AFL ≥180 beats/min. The primary endpoint was resolution of fetal tachyarrhythmia. Secondary endpoints were fetal death, pre-term birth, and neonatal arrhythmia. Adverse events (AEs) were also assessed. RESULTS: A total of 50 patients were enrolled at 15 institutions in Japan from 2010 to 2017; short ventriculoatrial (VA) SVT (n = 17), long VA SVT (n = 4), and AFL (n = 29). One patient with AFL was excluded because of withdrawal of consent. Fetal tachyarrhythmia resolved in 89.8% (44 of 49) of cases overall and in 75.0% (3 of 4) of cases of fetal hydrops. Pre-term births occurred in 20.4% (10 of 49) of patients. Maternal AEs were observed in 78.0% (39 of 50) of patients. Serious AEs occurred in 1 mother and 4 fetuses, thus resulting in discontinuation of protocol treatment in 4 patients. Two fetal deaths occurred, mainly caused by heart failure. Neonatal tachyarrhythmia was observed in 31.9% (15 of 47) of neonates within 2 weeks after birth. CONCLUSIONS: Protocol-defined transplacental treatment for fetal SVT and AFL was effective and tolerable in 90% of patients. However, it should be kept in mind that serious AEs may take place in fetuses and that tachyarrhythmias may recur within the first 2 weeks after birth.

Promoter methylation changes and vascular dysfunction in pre-eclamptic umbilical vein.

BACKGROUND: Hypertension is one of primary clinical presentations of pre-eclampsia. The occurrence and progress of hypertension are closely related to vascular dysfunction. However, information is limited regarding the pathological changes of vascular functions in pre-eclamptic fetuses. Human umbilical cord vein was used to investigate the influence of pre-eclampsia on fetal blood vessels in this study. RESULTS: The present study found that the vasoconstriction responses to arginine vasopressin (AVP) and oxytocin (OXT) were attenuated in the pre-eclamptic umbilical vein as compared to in normal pregnancy, which was related to the downregulated AVP receptor 1a (AVPR1a), OXT receptor (OXTR), and protein kinase C isoform ß (PKCß), owing to the deactivated gene transcription, respectively. The deactivated AVPR1a, OXTR, and PKCB gene transcription were respectively linked with an increased DNA methylation within the gene promoter. CONCLUSIONS: To the best of our knowledge, this study first revealed that a hyper-methylation in gene promoter, leading to relatively reduced patterns of AVPR1a, OXTR, and PKCB expressions, which was responsible for the decreased sensitivity to AVP and OXT in the umbilical vein under conditions of pre-eclampsia. The data offered new and important information for further understanding the pathological features caused by pre-eclampsia in the fetal vascular system, as well as roles of epigenetic-mediated gene expression in umbilical vascular dysfunction.

Higher Cord Blood Levels of Fatty Acids in Pregnant Women With Type 1 Diabetes Mellitus.

Context: Type 1 diabetes mellitus (T1DM) is associated with a disturbance of carbohydrate and lipid metabolism. Objective: To determine whether T1DM alters maternal and neonatal fatty acid (FA) levels. Design: Observational study. Setting: Academic hospital. Patients: Sixty pregnant women (30 women with T1DM with good glycemic control and 30 healthy women) were included in the study. Maternal blood, umbilical vein, and artery blood samples were collected immediately upon delivery. Following lipid extraction, the FA profiles of the total FA pool of maternal serum and umbilical vein and artery serum were determined by gas chromatography. Results: Total FA concentration in maternal serum did not differ between the study groups; it was significantly higher in umbilical vein serum of the T1DM group compared with that in the control group [median (interquartile range)]: T1DM 2126.2 (1446.4 to 3181.3) and control 1073.8 (657.5 to 2226.0; P < 0.001), and in umbilical artery vein serum: T1DM 1805.7 (1393.1 to 2125.0) and control 990.0 (643.3 to 1668.0; P < 0.001). Composition of FAs in umbilical vein serum showed significantly higher concentrations of saturated, monounsaturated, and polyunsaturated FAs (SFAs, MUFAs, and PUFAs, respectively) in the T1DM group than compared with those in the control group (P = 0.001). Furthermore, cord blood levels of leptin (P < 0.001), C-peptide (P < 0.001), and insulin resistance (P = 0.015) were higher in the T1DM group compared with controls. Conclusion: The neonates born to mothers with T1DM had higher concentrations of total FAs, SFAs and MUFAs, as well as PUFAs, compared with control newborns.

The effects of varying frequency and duration of mechanical stimulation on a tissue-engineered tendon construct.

Decellularized, discarded human tissues, such as the human umbilical vein, have been widely utilized for tissue engineering applications, including tendon grafts. When recellularized, such natural scaffolds are cultured in 3D dynamic culture environments (bioreactor systems). For tendon tissue-engineered grafts, such systems often employ oscillatory mechanical stimulation in the form uniaxial tensile strain. The three main parameters of such stimulation are frequency, duration, and force. In this study we investigated the effects of changing the duration (0.5, 1, and 2 h/day) and frequency (0.5, 1, 2 cycles/min) of stimulation of a human umbilical vein seeded with mesenchymal stem cells cultured for up to 7 days. Strain of the construct was held constant at 2%. The highest proliferation rates were observed in the 0.5 h/day duration and 1 cycle/min frequency (203% increase) with a close second being 1 h/day and 1 cycle/min frequency (170% increase). Static cultures along with a 2 cycles/min frequency and a 2 h/day duration of stretching did not increase cellular proliferation significantly. Extracellular matrix quality and alignment of the construct fibers had a direct relation to cellularity and those groups with the highest cellularity improved the most. Gene expression indicated cellular activity consistent with tendon-like tissue remodeling. In addition, scleraxis, tenascin-C, and tenomodulin were upregulated in certain groups after 7 days, with osteoblast, chondrocyte, and adipocyte phenotypes depressed. The stimulation parameters investigated in this study indicated that slower frequencies and shorter durations were best for construct quality in early stage cultures.

Identification of Antiangiogenic Potential and Cellular Mechanisms of Napyradiomycin A1 Isolated from the Marine-Derived Streptomyces sp. YP127.

Angiogenesis is the process of new blood vessel formation. Excessive angiogenesis is a critical factor in the progression of cancer, macular degeneration, and other chronic inflammatory diseases. When investigating the effects of crude extracts of cultured marine microorganisms, an extract of the cultured Streptomyces sp. YP127 strain was found to inhibit human umbilical vein endothelial cell (HUVEC) tube formation. Bioassay-guided fractionation and spectroscopic data analyses led to the identification of napyradiomycin A1 (1) as an antiangiogenic component of the extract. Compound 1 inhibited HUVEC tube formation in a concentration-dependent manner. It inhibited endothelial cell proliferation but did not affect human dermal fibroblast proliferation. Compound 1 also suppressed migration and invasion of vascular endothelial cells. In addition, compound 1 suppressed vascular endothelial cadherin expression and increased the permeability of the endothelial cell membrane. These results suggested that compound 1 modulates cell permeability and inhibits the angiogenesis of endothelial cells.

Neonatal fatty acid status and cardiometabolic health at 9years.

BACKGROUND: Long chain polyunsaturated fatty acid (LCPUFA) status is associated with risk of cardiovascular diseases in adulthood. We previously demonstrated no effect of LCPUFA supplementation after birth on BP and anthropometrics. Little is known about the association between fatty acid status at birth and cardiometabolic health at older ages. AIM: To evaluate associations between docosahexaenoic acid (DHA) and arachidonic acid (AA) levels in the umbilical cord and blood pressure (BP) and anthropometrics at 9years. STUDY DESIGN: Observational follow-up study. Multivariable analyses were carried out to adjust for potential confounders. SUBJECTS: 229 children who took part in a randomized controlled trial (RCT) on the effects of LCPUFA formula supplementation. OUTCOME MEASURES: BP was chosen as primary outcome; heart rate and anthropometrics as secondary outcomes. RESULTS: AA levels in the wall of the umbilical vein and artery were negatively associated with diastolic BP (B: vein -0.831, 95% CI: -1.578; -0.083, p=0.030; artery: -0.605, 95% CI: -1.200; -0.010, p=0.046). AA was not associated with systolic BP; DHA not with diastolic nor systolic BP. The AA:DHA ratio in the umbilical vein was negatively associated with diastolic BP (B: -1.738, 95% CI: -3.141; -0.335, p=0.015). Heart rate and anthropometrics were not associated with neonatal LCPUFA status. CONCLUSIONS: Higher AA levels and a higher AA:DHA ratio at birth are associated with lower diastolic BP at age 9. This suggests that the effect of LCPUFAs at early age is different from that in adults, where DHA is regarded anti-adipogenic and AA as adipogenic.

Pharmacokinetics and placental transfer of magnesium sulfate in pregnant women.

BACKGROUND: Magnesium sulfate is one of the most commonly prescribed intravenous medications in obstetrics. Despite its widespread use, there are limited data about magnesium pharmacokinetics, and magnesium is prescribed empirically without dose adjustment for different indications. OBJECTIVE: The aim of this study was to characterize the pharmacokinetics and placental transfer of magnesium sulfate in pregnant women and to determine key covariates that impact the pharmacokinetics. STUDY DESIGN: This is a prospective pharmacokinetic cohort study of pregnant women who were prescribed magnesium sulfate for preeclampsia, preterm labor, or extreme prematurity. Women received a 4-g loading dose and 2 g/h maintenance dose as clinically indicated. Maternal blood samples were obtained before and at multiple time points during and after magnesium administration. Cord blood also was sampled at delivery. A population pharmacokinetic approach that used a nonlinear mixed-effects modeling was used to characterize magnesium disposition. RESULTS: Pharmacokinetic profiles of 111 pregnant women were analyzed. Magnesium clearance was 3.98 L/h in preeclamptic women and 5.88 L/h non-preeclamptic women. Steady-state concentration of magnesium was 7.2 mg/dL in preeclamptic women compared with 5.1 mg/dL in non-preeclamptic women. Maternal weight significantly impacted time to steady state. The ratio of the mean umbilical vein magnesium level to the mean maternal serum magnesium level at the time of delivery was 0.94 ± 0.15. CONCLUSIONS: The study accurately characterizes the pharmacokinetics of magnesium administered to pregnant women. Preeclamptic status and maternal weight significantly impact serum magnesium levels. This pharmacokinetic model could be applied to larger cohorts to help tailor magnesium treatment and account for these covariates.

[Proteolytic activity of fetoplacental complex in norm and pathology].

The activity of angiotensin converting enzyme (ACE), carboxypeptidase N (CPN), and leucine aminopeptidase (LAP) has been investigated in the fetoplacental complex (FPC) in normal and placental insufficiency (FPI). ACE and LAP activities were significantly higher in the placental tissue than in maternal serum and umbilical vein serum. CPN activity was significantly lower in umbilical vein serum as compared to that of women in childbirth. Probably, the studied enzymes are involved in formation of reduced sensitivity of FPC of blood vessels during physiological pregnancy. In cases of placental insufficiency a significant increase of LAP activity was found in the placental tissue and umbilical vein serum. In addition, the pathological course of pregnancy caused a significant increase of CPN activity in serum of pregnant women in comparison to the norm. The obtained data suggest that during FPI proteolytic enzymes participate in the formation of compensatoty-adaptive reactions in the FPC. Results of this study are interesting in context of development of methods for prevention and correction of metabolic disorders in pathologies of pregnancy.

Human cytomegalovirus infection induces leukotriene B4 and 5-lipoxygenase expression in human placentae and umbilical vein endothelial cells.

INTRODUCTION: Human cytomegalovirus (HCMV) can cause congenital infection with risk of neurological disability. Maternal-fetal transmission is associated with placental inflammation. 5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of Leukotrienes (LTs), which are proinflammatory mediators. This study investigated the effect of HCMV infection on 5-LO expression and Leukotriene-B4 (LTB4) induction in human placentae and umbilical vein endothelial cells (HUVEC). METHODS: Seven placentae from fetuses with congenital HCMV infection and brain damage and six controls were stained with HCMV-immediate-early-antigen (HCMV-IEA) and 5-LO by immunohistochemistry. 5-hydroxyeicosatetraenoic acid (5-HETE) and LTB4 were measured in culture supernatant from ex vivo HCMV-infected placental histocultures by liquid chromatography. In vitro, HCMV infected HUVEC cells were analyzed for 5-LO mRNA and protein expression by real time PCR and immunofluorescence staining. RESULTS: HCMV-IEA was abundant in all HCMV infected placentae but absent in control placentae. 5-LO expression was higher in endothelial and smooth muscle cells of HCMV-infected placentae, compared to control placentae. HCMV infection induced an up-regulation of LTB4 in ex vivo placental explants with higher levels of LTB4 at 72 h compared to controls (p = 0.002). In vitro, 5-LO transcript and protein expression were significantly induced in HCMV-infected HUVEC, compared to the control cultures (p = 0.036). CONCLUSION: The presence of HCMV coincided with high 5-LO expression in cells of in vivo HCMV infected placentae. HCMV induced up-regulation of 5-LO in both ex vivo HCMV-infected placental explants and HUVEC. HCMV induced LT-biosynthesis in congenitally infected placentae may have a role in pathogenesis of congenital HCMV disease.

Maternal, umbilical arterial and umbilical venous 25-hydroxyvitamin D and adipocytokine concentrations in pregnancies with and without gestational diabetes.

OBJECTIVE: Gestational diabetes mellitus (GDM) has been associated with inflammation as well as Vitamin D insufficiency. While Vitamin D has anti-inflammatory properties, relationships between Vitamin D and inflammatory markers remain unexplored in GDM. Therefore, this case--control study investigated adipocytokine and Vitamin D [25(OH)D] concentrations and correlations in GDM and control women, as well as their neonates. DESIGN/PARTICIPANTS/MEASUREMENTS: seventy-three women participated: 36 GDM and 37 controls. Maternal samples were drawn at 31 weeks. Umbilical arterial and venous samples were collected at birth. 25(OH)D and adipocytokine concentrations were compared for GDM vs control maternal, umbilical arterial and venous samples. Correlations were explored between biochemical results, maternal and neonatal demographics. RESULTS: Compared with age- and weight-matched control participants, GDM women had significantly lower concentrations of 25(OH)D (77·3 ± 24·3 vs 93·2 ± 19·2 nm/l; P = 0·009); adiponectin (17·5 ± 11·8 vs 34·1 ± 20·3 µg/ml, P < 0·001); resistin (25·4 ± 9·1 vs 31·9 ± 12·1 ng/ml, P = 0·045); and plasminogen activator inhibitor-1 (PAI-1) 13·9 ± 10·0 vs 21·0 ± 12·6 ng/ml, P = 0·038), while delivering 1 week earlier (38·2 ± 1·2 vs 39·5 ± 0·9 weeks, P < 0·001). GDM maternal 25(OH)D concentrations positively correlated with PAI-1, IL-8 and TNF-α concentrations. Umbilical 25(OH)D concentrations were not significantly different in GDM vs control offspring, whereas adiponectin, resistin and PAI-1 concentrations were significantly lower in GDM offspring. CONCLUSIONS: GDM women had lower 25(OH)D concentrations than controls, while neonatal umbilical concentrations of 25(OH)D did not differ. GDM maternal and GDM offspring had lower adiponectin, resistin and PAI-1 concentrations compared with controls. Results suggest that both GDM women and their offspring demonstrate abnormal adipocytokine patterns.

Intermittent absent end diastolic velocity of the umbilical artery: antenatal and neonatal characteristics and indications for delivery.

OBJECTIVE: To check whether there is a difference in indications for delivery, antepartum and neonatal characteristics in intermittent absent end diastolic velocity (iAEDV) compared to persistent absent or reversed end diastolic velocity (pA/REDV). METHODS: A retrospective study of 109 patients with iAEDV or pA/REDV from 19 to 39 weeks. The delivery indication was classified as maternal or fetal. The primary antepartum and maternal characteristics were age, parity, AMA, chronic hypertension, PEC, thrombophilia, lupus, diabetes, smoker, placenta previa, gestational age (GA) at diagnosis of IUGR and/or SGA, GA at diagnosis of elevated S/D, iAEDV or pA/REDV, GA at delivery, minimal/absent variability day of delivery, BPP ≤ 6 prior to delivery. The primary neonatal outcomes were birth weight, arterial cord pH, neonatal demise, necrotizing enterocolitis, intraventricular hemorrhage and length of stay in the NICU. RESULTS: Fetuses with iAEDV were diagnosed with an elevated S/D at a later GA (29.6 vs. 27.5 weeks, p < 0.03), delivered at a later GA (31.6 vs. 29.7 weeks, p < 0.01), had a higher birth weight (1336.6 vs. 933 g, p < 0.0004), were more likely to be delivered for maternal indications (42.9% vs. 20.27%, p < 0.01), had a higher cord arterial pH (7.28 vs. 7.21, p < 0.002) and were less likely to have an arterial pH at birth <7.2 (0% vs. 34.1%, p < 0.002). CONCLUSIONS: Although fetuses with iAEDV have an improved antenatal course as compared with pA/REDV, indications for delivery are more likely to be maternal and adverse outcome is common.

Association between umbilical cord artery pCO2 and the Apgar score; elevated levels of pCO2 may be beneficial for neonatal vitality after moderate acidemia.

OBJECTIVE: To determine the association between 5-min Apgar score and umbilical cord artery carbon dioxide tension (pCO2). DESIGN: Observational study. SETTING: European hospital labor wards. POPULATION: Data from 36,432 newborns ≥36 gestational weeks were obtained from three sources: two trials of monitoring with fetal electrocardiogram (the Swedish randomized controlled trial and the European Union Fetal ECG trial) and Mölndal Hospital data. After validation of the acid-base values, 25,806 5-min Apgar scores were available for analysis. METHODS: Validation of the umbilical cord acid-base values was performed to obtain reliable data. 5-min Apgar score was regressed against cord artery pCO2 in a polynomial multilevel model. MAIN OUTCOME MEASURES: Five-min Apgar score, umbilical cord pCO2, pH, and base deficit. RESULTS: Overall, a higher cord artery pCO2 was found to be associated with lower 5-min Apgar scores. However, among newborns with moderate acidemia, lower umbilical cord artery pCO2 (≤median pCO2 for the specific cord artery pH) was associated with lower 5-min Apgar scores, with a relative risk of 2.0 (95% confidence interval: 1.4-2.8) for 5-min Apgar scores 0-6. CONCLUSIONS: Metabolic acidosis affects the newborn's vitality more than respiratory acidosis. In addition, elevated levels of pCO2 may be beneficial for fetuses with moderate acidemia, and thus cord artery pCO2 is a factor that should be considered when assessing the compromised newborn.

Arachidonic and docosahexaenoic acid in the blood of a mother and umbilical vein in diabetic pregnant women.

OBJECTIVE: The aim of the study was to determine the total concentration of fatty acids (FAs) in the maternal vein serum and in the umbilical vein serum in pregnant women suffering from Type 1 diabetes compared to healthy women. Additional goal was to determine the percentages of arachidonic (AA) and docosahexaenoic acid (DHA) in comparison to the total concentration of FAs. METHODS: The study included 63 pregnant women, 32 suffering from Type 1 diabetes and 31 healthy pregnant women. Extraction of total lipids was performed using gas chromatography. RESULTS: There was statistically significant difference in the total FAs concentration in the maternal vein serum and the umbilical vein serum between the two groups. There was a statistically significant higher concentration of total FAs in the maternal and umbilical vein serum of the diabetic group. Higher AA and DHA concentrations were found in the maternal vein serum compared to an umbilical vein serum of the diabetic group. CONCLUSION: No difference was found in AA and DHA percentages in the maternal or in the umbilical vein serum of diabetic pregnant women. Despite of T1DM, a good metabolic control leads to insignificant changes in the AA and DHA levels in diabetic pregnancy.

Selection of a high-affinity WW domain against the extracellular region of VEGF receptor isoform-2 from a combinatorial library using CIS display.

WW domains are small ß-sheet motifs that are involved in intracellular signalling through the recognition of proline-rich or phosphorylated linear peptide sequences. Here, we describe modification of this motif to provide a framework for engineering the side chains exposed on its concave surface. This non-natural scaffold incorporates an additional tryptophan, has a shorter loop 1 and supports modification of 25% of the natural protein to form a novel affinity reagent. We demonstrate the utility of this structure by selecting a high-affinity binder to the extracellular region of human vascular endothelial growth factor receptor isoform 2 (VEGFR-2) from a library of modifications, using a cell-free molecular display platform, CIS display. The isolate has low nanomolar affinity to VEGFR-2 and inhibits binding of human VEGF to its receptor with nanomolar activity. The structure is amenable to cyclisation to improve its proteolytic stability and has advantages over larger protein scaffolds in that it can be synthesised chemically to high yields offering potential for therapeutic and non-therapeutic applications.

Feto-placental nitric oxide, asymmetric dimethylarginine and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in severe preeclampsia.

OBJECTIVE: To measure plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA) and vascular endothelial growth factor (VEGF) levels and VEGF gene polymorphisms in fetal circulation in severe preeclampsia. METHODS: Cord vessels of singleton gestations complicated with severe preeclampsia 36 weeks or more (n = 31) and controls were sampled upon delivery for analyte measuring. Additionally, DNA was extracted from umbilical vein whole blood to determine the frequency of VEGF gene single nucleotide polymorphisms (SNPs): -2578 A/C, -1498 C/T, -1154 A/G, -634 C/G and +936 C/T. Coefficient correlations between analyte levels and placental and neonatal weight were calculated. RESULTS: NO plasma levels in umbilical vessels (artery and vein) were significantly higher in preeclampsia cases as compared to controls (4.67 ± 3.0 vs. 0.82 ± 0.90; 4.46 ± 3.0 vs. 0.82 ± 0.99 mmol/L, respectively, p = 0.0001 both). ADMA levels displayed a similar increased trend in both fetal vessels, but this did not reach statistical significance (2.57 ± 1.03 vs. 2.34 ± 0.57; 2.74 ± 0.94 vs. 2.42 ± 0.59 mmol/L, respectively, p > 0.05). VEGF was significantly lower in artery but not in vein in preeclampsia cases (200.48 ± 225.62 vs. 338.61 ± 287.03 pg/mL, p = 0.04). A significant positive correlation was found between NO and ADMA levels (artery and vein) among preeclampsia cases. Overall, the frequency of the studied VEGF gene SNPs did not differ among pre-eclamptic cases and controls; nevertheless, a significant trend toward lower umbilical vein VEGF levels was observed in pre-eclampsia cases in the presence of -2578 CC and -1154 AG genotypes. CONCLUSION: Near term gestations complicated with severe preeclampsia presented higher NO levels in fetal circulation, which correlated to ADMA and lower artery VEGF values. More research is warranted to confirm that selected VEGF SNPs may be associated with lower umbilical vein VEGF.

Interleukin-33 in the human placenta.

OBJECTIVE: Interleukin-33 (IL-33) is the newest member of the IL-1 cytokine family, a group of key regulators of inflammation. The purpose of this study was to determine whether IL-33 is expressed in the human placenta and to investigate its expression in the context of acute and chronic chorioamnionitis. METHODS: Placental tissues were obtained from five groups of patients: 1) normal pregnancy at term without labor (n = 10); 2) normal pregnancy at term in labor (n = 10); 3) preterm labor without inflammation (n = 10); 4) preterm labor with acute chorioamnionitis and funisitis (n = 10); and 5) preterm labor with chronic chorioamnionitis (n = 10). Immunostaining was performed to determine IL-33 protein expression patterns in the placental disk, chorioamniotic membranes, and umbilical cord. mRNA expression of IL-33 and its receptor IL1RL1 (ST2) was measured in primary amnion epithelial and mesenchymal cells (AECs and AMCs, n = 4) and human umbilical vein endothelial cells (HUVECs, n = 4) treated with IL-1ß (1 and 10 ng/ml) and CXCL10 (0.5 and 1 or 5 ng/ml). RESULTS: 1) Nuclear IL-33 expression was found in endothelial and smooth muscle cells in the placenta, chorioamniotic membranes, and umbilical cord; 2) IL-33 was detected in the nucleus of CD14+ macrophages in the chorioamniotic membranes, chorionic plate, and umbilical cord, and in the cytoplasm of myofibroblasts in the Wharton's jelly; 3) acute (but not chronic) chorioamnionitis was associated with the presence of IL-33+ macrophages in the chorioamniotic membranes and umbilical cord; 4) expression of IL-33 or IL1RL1 (ST2) mRNA in AECs was undetectable; 5) IL-33 mRNA expression increased in AMCs and HUVECs after IL-1ß treatment but did not change with CXCL10 treatment; and 6) IL1RL1 (ST2) expression decreased in AMCs and increased in HUVECs after IL-1ß but not CXCL10 treatment. CONCLUSIONS: IL-33 is expressed in the nucleus of placental endothelial cells, CD14+ macrophages, and myofibroblasts in the Wharton's jelly. IL-1ß can induce the expression of IL-33 and its receptor. Protein expression of IL-33 is detectable in macrophages of the chorioamniotic membranes in acute (but not chronic) chorioamnionitis.

Fetal venous Doppler in pregnancies with placental dysfunction and correlation with pH at birth.

OBJECTIVES: To determine the correlation between ph at birth and venous Doppler parameters in pregnancies with placental dysfunction. METHODS: This was a prospective cohort study of 58 pregnancies with the diagnosis of placental dysfunction between 26 and 34 weeks of gestation. Inclusion criteria were singleton pregnancies, abnormal umbilical artery (UA) Doppler, fetal growth restriction diagnosed by estimated fetal weight <10th centile for gestational age, intact membranes, and absence of fetal congenital abnormalities. The Doppler measurements were the following: UA pulsatility index (PI), ductus venosus (DV) pulsatility index for veins (PIV), intra-abdominal umbilical vein (UV) time-averaged maximum velocity (TAMxV) and blood flow and left portal vein (LPV) time-averaged maximum velocity (TAMxV) and blood flow. All Doppler parameters were transformed into z-scores (SD values from the mean) according to normative references. RESULTS: The UA pH at birth showed a negative significant correlation with the DV-PIV (p = 0.004) and the DV-PIV z-score (p = 0.004), while LPV TAMxV (p = 0.004), LPV TAMxV z-score (p = 0.002), LPV blood flow (p = 0.01), LPV blood flow normalized (p = 0.04) and UV blood flow (p = 0.04) positively correlated with pH at birth. Multiple regression analysis was performed and the DV-PIV z-score was the variable that independently correlated with pH at birth (p = 0.002). CONCLUSIONS: the present results suggest that changes in fetal venous blood flow, mainly DV and LPV are useful in the management of cases with early onset placental insufficiency and that venous Doppler parameters correlate with pH at birth.