Correlation between intrapartum CTG findings and interleukin-6 levels in the umbilical cord arterial blood: A prospective cohort study.

OBJECTIVE: to investigate the correlation between the intrapartum CardioTocoGraphic (CTG) findings "suggestive of fetal inflammation" ("SOFI") and the interleukin (IL)-6 level in the umbilical arterial blood. STUDY DESIGN: prospective cohort study conducted at a tertiary maternity unit and including 447 neonates born at term. METHODS: IL-6 levels were systematically measured at birth from a sample of blood taken from the umbilical artery. The intrapartum CTG traces were retrospectively reviewed by two experts who were blinded to the postnatal umbilical arterial IL-6 values as well as to the neonatal outcomes. The CTG traces were classified into "suggestive of fetal inflammation (SOFI)" and "no evidence of fetal inflammation (NEFI) according to the principles of physiologic interpretation the CTG traces. The CTG was classified as "SOFI" if there was a persistent fetal heart rate (FHR) increase > 10 % compared with the observed baseline FHR observed at the admission or at the onset of labor without any preceding repetitive decelerations. The occurrence of Composite Adverse Outcome (CAO) was defined as Neonatal Intensive Care Unit (NICU) or Special Care Baby Unit (SCBU) admission due to one or more of the following: metabolic acidaemia, Apgar score at 5 min ≤ 7, need of neonatal resuscitation, respiratory distress, tachypnoea/polypnea, jaundice requiring phototherapy, hypotension, body temperature instability, poor perinatal adaptation, suspected or confirmed early neonatal sepsis. MAIN OUTCOME MEASURES: To compare the umbilical IL-6 values between the cases with intrapartum CTG traces classified as "SOFI" and those classified as "NEFI"; to assess the correlation of umbilical IL-6 values with the neonatal outcome. RESULTS: 43 (9.6 %) CTG traces were categorized as "SOFI"; IL-6 levels were significantly higher in this group compared with the "NEFI" group (82.0[43.4-325.0] pg/ml vs. 14.5[6.8-32.6] pg/mL; p <.001). The mean FHR baseline assessed 1 h before delivery and the total labor length showed an independent and direct association with the IL-6 levels in the umbilical arterial blood (p <.001 and p = 0.005, respectively). CAO occurred in 33(7.4 %) cases; IL-6 yielded a good prediction of the occurrence of the CAO with an AUC of 0.72 (95 % CI 0.61-0.81). CONCLUSION: Intrapartum CTG findings classified as "SOFI" are associated with higher levels of IL-6 in the umbilical arterial blood.

Ultrasound parameters of early pregnancy and Doppler indices of blood vessels in the placenta and umbilical cord throughout the pregnancy period in sheep.

BACKGROUND: Ultrasonography is one of the most important techniques that enable the detection and monitoring of pregnancy. One such study using this technique is the assessment of the hemodynamics of fetal and umbilical blood vessels. However, there is little data on blood flow in the placentomes, which is the basic structural unit of the sheep's placenta. Therefore, the aim of this study was to determine the Doppler parameters in the arterial vessels of the caruncles, cotyledons and the umbilical cord as well as measuring venous flow rates during the entire gestation period of the sheep. Additionally, the usefulness of various other ultrasound parameters in the early diagnosis of pregnancy in sheep was analyzed. RESULTS: Most of the Doppler parameters in umbilical, cotyledonary and caruncular arteries were significantly correlated with the day of pregnancy (p < 0.01). In the early stages of pregnancy, the peak systolic velocity (PSV), regardless of the location of the artery, was significantly lower than that in the later stages of pregnancy (p < 0.01). PSV was also found to be significantly higher in the umbilical artery than in the cotyledonary and caruncular arteries (p < 0.01). Until the 50th day of pregnancy, the end diastolic velocity (EDV) was not found in the umbilical and cotyledonary arteries. EDV was significantly higher in the caruncular arteries than in the cotyledonary and umbilical arteries (p < 0.01). The resistance index (RI) and pulsatility index (PI) in the early stages of pregnancy were found to be significantly higher than that in the later stages of pregnancy (p < 0.01). The RI and PI were significantly lower in the caruncular arteries than in the arteries of the cotyledons and umbilical cord (p < 0.01). In the umbilical vein, all Doppler parameters were observed to be significantly higher than those in the placentomal veins (p < 0.01 or p < 0.05). Using transrectal ultrasound, pregnancy was detected between 20 and 28 days after mating. The ovaries were observed to have corpora lutea, the diameter of which was fairly consistent from the 17th to the 56th day of pregnancy. CONCLUSIONS: It has been demonstrated that both the location of the arterial vessel in the placental-umbilical circulation and the gestational age have a significant impact on hemodynamic parameters. The results also provide new insights about the blood flow in caruncular and cotyledonary arteries, which could contribute to a more holistic understanding of hemodynamic changes in the placentas of sheep. Analyzing haemodynamic parameters in the umbilical and placental veins are preliminary studies in sheep, but it could inspire further research in this field. Furthermore, the research conducted confirms the practicality and convenience of transrectal ultrasonography in the early diagnosis of pregnancy in sheep and also indicates that the identification and imaging of the corpus luteum using B-mode ultrasonography can be a very early and simple method of confirming effective mating in sheep.

Tokishakuyakusan ameliorates lowered body temperature after immersion in cold water through the early recovery of blood flow in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: 'Cold feeling' is a subjective feeling of unusual coldness that aggravates fatigue, stiffness, and other symptoms, thereby reducing quality of life. Tokishakuyakusan (TSS) is a Kampo medicine reported to improve cold feeling and is used to treat symptoms aggravated by cold feeling. However, the mechanism of action of TSS is unclear. Cold feeling may involve reduced blood flow and subsequent inhibition of heat transport. Therefore, elucidating the effects of TSS on blood flow is one of the most important research topics for clarifying the mechanism of action of TSS. AIM OF THE STUDY: We aimed to evaluate the effect of TSS on recovery from lowered body temperature by the immersion of rats in cold water and to clarify the involvement of blood flow in the action of TSS. MATERIALS AND METHODS: After female Wistar rats underwent 9 days of low room temperature stress loading (i.e. room temperature of 18 °C), they were subjected to immersion in cold water (15 °C) for 15 min. Body surface temperature, rectal temperature, and plantar temperature were measured before and after immersion in cold water. Blood flow was measured before and after immersion in cold water without low room temperature stress loading. TSS (0.5 g/kg or 1 g/kg) or the vehicle (i.e. distilled water) was orally administered once daily for 10 days for the measurement of body temperature or once 30 min before immersion in cold water for the measurement of blood flow. In addition, we examined the effect of TSS on calcitonin gene-related peptide (CGRP) release from dorsal root ganglion (DRG) cells, the effect of TSS ingredients on transient receptor potential (TRP) channels, and the effect of TSS ingredients on the membrane potential of vascular smooth muscle cells and evaluated the mechanism of the effects of TSS on blood flow. RESULTS: Body temperature and blood flow decreased after immersion in cold water and then recovered over time. A comparison of body temperature at each timepoint or area under the curve showed that TSS (1 g/kg) accelerated the recovery of body surface temperature, rectal temperature, and blood flow. TSS significantly increased CGRP release from DRG cells, which disappeared after pretreatment with HC-030031 (a transient receptor potential ankyrin 1 [TRPA1] antagonist). The effects of seven TSS ingredients on TRP channels were examined. The agonistic effect on TRPA1 was observed for atractylodin, atractylodin carboxylic acid and levistolide A. Among the TSS ingredients, atractylodin carboxylic acid had significant hyperpolarising effects. CONCLUSIONS: The mechanism by which TSS accelerates the recovery of lowered body temperature in rats after immersion in cold water may involve the acceleration of the recovery of lowered blood flow. Increased CGRP release from DRG cells by TSS, TRPA1 activation by TSS ingredients, and membrane potential changes in vascular smooth muscle cells caused by TSS ingredients are part of the mechanism of action of TSS. These findings may partly contribute to the interpretation of the beneficial effects of TSS on cold feeling.

Antibody against Na/K-ATPase Inhibitor Lowers Blood Pressure and Increases Vascular Fli1 in Experimental Preeclampsia.

BACKGROUND: Previous studies implicated cardiotonic steroids, including Na/K-ATPase inhibitor marinobufagenin (MBG), in the pathogenesis of preeclampsia (PE). We demonstrated that MBG induces fibrosis via mechanism involving inhibition of Fli1, a nuclear transcription factor and a negative regulator of collagen-1 synthesis. We hypothesized that PE blockade of increased MBG with antibody would lessen the fibrosis of umbilical arteries and lower the blood pressure in rats with PE. METHODS: We tested 36 pregnant Sprague-Dawley rats in which 12 were made hypertensive by 1.8% Na supplementation (days 6-19 of gestation), 12 pregnant rats served controls. At day 19, PE rats received one intraperitoneal injection of polyclonal anti-MBG-4 antibody (0.5 ug/ml) for 4 hours. RESULTS: PE was associated with higher blood pressure (117 ± 2 vs. 107 ± 2 mm Hg; P < 0.01), plasma MBG levels (1.54 ± 0.34 vs. 0.49 ± 0.11 nmol/L; P < 0.01), protein excretion (26 vs. 12 mg/24 hours), sFlt-1 (3-fold), decrease in Fli1 (7-fold) and increase in collagen-1 in aorta (4-fold) vs. control rats (all P < 0.01). In 12 rats treated with polyclonal anti-MBG-4 antibody blood pressure dropped (93 ± 3 mm Hg) and Fli1 was decreased much less (2-fold; P < 0.01 vs. nontreated rats). CONCLUSIONS: These results demonstrate that in experimental PE elevated MBG level is implicated in umbilical fibrosis via suppression of Fli1.

Addition of sildenafil citrate for treatment of severe intrauterine growth restriction: a double blind randomized placebo controlled trial.

Background: Severe intrauterine growth restriction complicates approximately 0.4% of the pregnancies. It increases the risk of perinatal morbidity and mortality.Subjects and methods: A double blind placebo controlled trial was conducted in Beni Suef University hospitals during 2017. It included 46 pregnant women with severe intrauterine growth restriction. Women were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20 mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Primary outcomes included improvement in umbilical and middle cerebral arteries pulsatility indices and abdominal circumference.Results: Umbilical and middle cerebral arteries Doppler indices showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = .001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value = .001).Conclusions: Sildenafil citrate may improve uteroplacental and fetal cerebral perfusion in pregnancies complicated by severe intrauterine growth restriction. It also improves abdominal circumference growth velocity. A wide scale randomized trials are needed for evaluation of neonatal and long term morbidity and mortality outcomes of pregnancies treated by sildenafil citrate.

Reference ranges for Doppler indices of umbilical and fetal middle cerebral arteries and cerebroplacental ratio: systematic review.

OBJECTIVE: To assess studies reporting reference ranges for umbilical artery (UA) and fetal middle cerebral artery (MCA) Doppler indices and cerebroplacental ratio (CPR), using a set of predefined methodological quality criteria for study design, statistical analysis and reporting methods. METHODS: This was a systematic review of observational studies in which the primary aim was to create reference ranges for UA and MCA Doppler indices and CPR in fetuses of singleton gestations. A search for relevant articles was performed in MEDLINE, EMBASE, CINAHL, Web of Science (from inception to 31 December 2016) and references of the retrieved articles. Two authors independently selected studies, assessed the risk of bias and extracted the data. Studies were scored against a predefined set of independently agreed methodological criteria and an overall quality score was assigned to each study. Linear multiple regression analysis assessing the association between quality scores and study characteristics was performed. RESULTS: Thirty-eight studies met the inclusion criteria. The highest potential for bias was noted in the following fields: 'ultrasound quality control measures', in which only two studies demonstrated a comprehensive quality-control strategy; 'number of measurements taken for each Doppler variable', which was apparent in only three studies; 'sonographer experience', in which no study on CPR reported clearly the experience or training of the sonographers, while only three studies on UA Doppler and four on MCA Doppler did; and 'blinding of measurements', in which only one study, on UA Doppler, reported that sonographers were blinded to the measurement recorded during the examination. Sample size estimations were present in only seven studies. No predictors of quality were found on multiple regression analysis. Reference ranges varied significantly with important clinical implications for what is considered normal or abnormal, even when restricting the analysis to the highest scoring studies. CONCLUSIONS: There is considerable methodological heterogeneity in studies reporting reference ranges for UA and MCA Doppler indices and CPR, and the resulting references have important implications for clinical practice. There is a need for the standardization of methodologies for Doppler velocimetry and for the development of reference standards, which can be correctly interpreted and applied in clinical practice. We propose a set of recommendations for this purpose. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Intervalos de referencia para los índices Doppler de la arterias umbilical y cerebral media del feto y la relación cerebroplacentaria: una revisión sistemática OBJETIVO: Evaluar los estudios que informan sobre intervalos de referencia para los índices Doppler y la relación cerebroplacentaria (RCP) de la arteria umbilical (AU) y la arteria cerebral media (ACM) del feto, mediante un conjunto de criterios de calidad metodológica predefinidos para el diseño del estudio, el análisis estadístico y los métodos de notificación. MÉTODOS: Esta fue una revisión sistemática de estudios observacionales en los que el objetivo principal fue crear intervalos de referencia para los índices Doppler de la AU y la ACM y la RCP de fetos de gestaciones con feto único. Se realizó una búsqueda de artículos relevantes en MEDLINE, EMBASE, CINAHL, Web of Science (desde el inicio hasta el 31 de diciembre de 2016) y en las referencias de los artículos recuperados. Dos autores, de forma independiente, seleccionaron los estudios, evaluaron el riesgo de sesgo y extrajeron los datos. Los estudios se calificaron según un conjunto predefinido de criterios metodológicos acordados de forma independiente y se asignó una puntuación de calidad global a cada estudio. Se realizó un análisis de regresión múltiple lineal para evaluar la asociación entre las puntuaciones de calidad y las características del estudio. RESULTADOS: Un total de 38 estudios cumplieron los criterios de inclusión. El mayor potencial de sesgo se observó en los siguientes casos: 'medidas de control de calidad del ultrasonido', donde sólo dos estudios demostraron una estrategia integral de control de calidad; 'número de mediciones tomadas para cada variable Doppler', que solo fue aparente en tres estudios; 'experiencia del ecografista', puesto que ningún estudio sobre la RCP informó claramente sobre la experiencia o la formación de los ecografistas, y tan solo lo hicieron tres estudios sobre el Doppler de la AU y cuatro sobre el Doppler de la ACM; y 'mediciones a ciegas', donde tan sólo un estudio sobre el Doppler de la AU comunicó que los ecografistas no tuvieron acceso a la medición registrada durante el estudio. Las estimaciones del tamaño de la muestra sólo se comunicaron en siete estudios. No se encontraron predictores de calidad en el análisis de regresión múltiple. Los intervalos de referencia variaron significativamente con implicaciones clínicas importantes para lo que se considera normal o anómalo, incluso cuando se restringió el análisis a los estudios con mayor puntuación. CONCLUSIONES: Existe una heterogeneidad metodológica considerable en los estudios que informan sobre los intervalos de referencia para los índices Doppler de la AU y la ACM y la RCP, y las referencias resultantes tienen implicaciones importantes para la práctica clínica. Es necesario estandarizar las metodologías de la velocimetría Doppler y desarrollar estándares de referencia que puedan ser interpretados y aplicados correctamente en la práctica clínica. Se propone una serie de recomendaciones para este fin.

Risk Factors for the Development of Refeeding Syndrome-Like Hypophosphatemia in Very Low Birth Weight Infants.

BACKGROUND: Refeeding syndrome is characterized by metabolic disturbance including hypophosphatemia and hypokalemia upon reinstitution of nutrition in severely malnourished patients. OBJECTIVE: The present study sought to identify the risk factors for the development of refeeding syndrome-like metabolic disturbance in very low birth weight infants. METHODS: The correlations of severe hypophosphatemia with the serum levels of potassium and ionized calcium, daily calorie and phosphate intake, and umbilical cord blood flow on ultrasonography were analyzed in 49 very low birth weight infants. RESULTS: Fifteen infants (36%) presented with hypophosphatemia during the first postnatal week. Hypophosphatemia was significantly associated with birth weight z score (odds ratio, 1.60; 95% confidence interval, 1.04-2.47; p = 0.034) and umbilical artery resistance index (odds ratio, 7.72E-04; 95% confidence interval, 1.14E-06-0.523; p = 0.031). Multiple regression analysis revealed that umbilical artery resistance index was independently associated with hypophosphatemia. CONCLUSIONS: Umbilical artery resistance index may serve as a useful marker for future development of refeeding syndrome-like hypophosphatemia in very low birth weight infants. Close monitoring of serum phosphorus and potassium levels and early intervention are important for the management of very low birth weight infants with intrauterine growth restriction due to placental dysfunction.

Estimation of neonatal outcome artery pH value according to CTG interpretation of the last 60 min before delivery: a retrospective study. Can the outcome pH value be predicted?

PURPOSE: The aim of this study was to analyze whether the umbilical artery pH value can be estimated throughout CTG assessment 60 min prior to delivery and if the estimated umbilical artery pH value correlates with the actual one. This includes analysis of correlation between CTG trace classification and actual umbilical artery pH value. Intra-and interobserver agreement and the impact of professional experience on visual analysis of fetal heart rate tracing were evaluated. METHODS: This was a retrospective study. 300 CTG records of the last 60 min before delivery were picked randomly from the computer database with the following inclusion criteria; singleton pregnancy >37 weeks, no fetal anomalies, vaginal delivery either spontaneous or instrumental-assisted. Five obstetricians and two midwives of different professional experience classified 300 CTG traces according to the FIGO criteria and estimated the postnatal umbilical artery pH. RESULTS: The results showed a significant difference (p < 0.05) in estimated and actual pH value, independent of professional experience. Analysis and correlation of CTG assessment and actual umbilical artery pH value showed significantly (p < 0.05) diverging results. Intra- and interobserver variability was high. Intraobserver variability was significantly higher for the resident (p = 0.001). No significant differences were detected regarding interobserver variability. CONCLUSION: An estimation of the pH value and consequently of neonatal outcome on the basis of a present CTG seems to be difficult. Therefore, not only CTG training but also clinical experience and the collaboration and consultation within the whole team is important.

Interaction between the effects of the selective estrogen modulator femarelle and a vitamin D analog in human umbilical artery vascular smooth muscle cells.

To further investigate the interaction between vitamin D system and estrogen-mimetic compounds in the human vasculature we studied the effect of the "less- calcemic" analog of 1,25(OH)2D3 (1,25D); JK 1624F2-2 (JKF) in the presence of selective estrogen modulator femarelle (F), the phytoestrogen daidzein (D) and estradiol-17b (E2) on 3[H] thymidine incorporation (DNA synthesis) and creatine kinase specific activity (CK) in human umbilical artery vascular smooth muscle cells (VSMC). F, D and E2, stimulated DNA synthesis at low concentrations, and inhibited it at high concentrations. All estrogen-related compounds increased CK dose- dependently. Daily treatment with JKF (1nM for 3days) resulted in decreased DNA synthesis, increased CK and up- regulation of the stimulation of DNA synthesis by low estrogen-related hormones whereas D- and E2- mediated inhibition of cell proliferation was abolished by JKF. In contrast, inhibition of cell proliferation by F could not be blocked by JKF. JKF also up-regulated the stimulatory effects on CK by F, E2 and D. VSMC expressed Estrogen Receptor (ER)a and ERb mRNA at a relative ratio of 2.7:1.0, respectively. JKF pretreatment increased ERa (∼50%) and decreased ERb (∼25%) expression. E2 did not affect ERs whereas both D and F up-regulated ERb (∼100%) and ERa (∼50%). Additionally, JKF increased the intracellular competitive binding of F (from ∼70 to ∼310%), of D (from ∼60 to ∼250%) and of E2 from (from∼70 to ∼320%). F reciprocally modulated the vitamin D system by up-regulating VDR- and 25 hydroxyy vitamin D 1-a hydroxylase (1OHase) mRNA expression (∼120%). F also stimulated 1OHase activity as indicated by an increase in the production of 1, 25D (∼250%). A similar increase was elicited by D (∼90%) but not by E2. In conclusion, F has unique effects on human VSMC in that it can sustain inhibition of cell growth even in the presence of the vitamin D analog JKF. That JKF increases ER expression and F increased the endogenous production of 1, 25D and VDR expression offer new opportunities to modulate VSMC growth. Whether or not these mutual effects of F and JKF can be exploited to promote vascular health, particularly in estrogen-deficient states (e.g., menopause) is under investigation.

Nifedipine increases fetoplacental perfusion.

AIM: Our aim is to evaluate the effect of nifedipine on fetoplacental hemodynamic parameters. METHODS: A retrospective study was conducted at a tertiary center with 30 patients for whom nifedipine treatment was used as a tocolytic therapy for preterm labor. Initiation of this treatment was at 31.6±2.5 weeks of gestation. We combined the pulse Doppler imaging parameters with grayscale imaging via the Bernoulli theorem, which is called the "continuity equation", to get the fetoplacental perfusion (FPP). Evaluated parameters were the resistance index (RI), the pulsatility index (PI), systole/diastole ratios (S/D), the velocity-time integral of the umbilical artery (VTI), the radius of the umbilical artery, the peak systolic velocity and the mean pressure gradient in the umbilical artery. From these parameters, the FPP was acquired. RESULTS: We found that the RI, the PI and the S/D ratio did not change after treatment with nifedipine. The mean pressure gradient, the VTI and the peak systolic velocity increased after treatment with nifedipine. Nifedipine increases FPP from 166±73.81 beat.cm3/min to 220±83.3 beat.cm3/min. DISCUSSION: Although nifedipine had no effect on the PI, the RI or the S/D, it increased the mean pressure gradient, the VTI and FPP.