Quality assessment of fetal middle cerebral and umbilical artery Doppler images using an objective scale within an international randomized controlled trial.

OBJECTIVES: To determine the quality of Doppler images of the fetal middle cerebral artery (MCA) and umbilical artery (UA) using an objective scale, and to determine the reliability of this scale, within a multicenter randomized controlled trial (Revealed versus concealed criteria for placental insufficiency in unselected obstetric population in late pregnancy (Ratio37)). METHODS: The Ratio37 trial is an ongoing randomized, open-label, multicenter controlled study of women with a low-risk pregnancy recruited at 20 weeks. Doppler measurements of the fetal MCA and UA were performed at 37 weeks. Twenty patients from each of the six participating centers were selected randomly, with two images evaluated per patient (one each for the MCA and UA). The quality of a total of 240 images was evaluated by six experts, scored on an objective scale of six items. Inter- and intrarater reliability was assessed using the Fleiss-modified kappa statistic for ordinal scales. RESULTS: On average, 89.2% of MCA images and 85.0% of UA images were rated as being of perfect (score of 6) or almost perfect (score of 5) quality. Kappa values for intrarater reliability of quality assessment were 0.90 (95% CI, 0.88-0.92) and 0.90 (95% CI, 0.88-0.93) for the MCA and UA, respectively. The corresponding inter-rater reliability values were 0.85 (95% CI, 0.81-0.89) and 0.84 (95% CI, 0.80-0.89), respectively. CONCLUSION: The quality of MCA and UA Doppler ultrasound images can be evaluated reliably using an objective scale. Over 85% of images, which were obtained by operators from a broad range of clinical practices within a multicenter study, were rated as being of perfect or almost perfect quality. Intra- and inter-rater reliability of quality assessment was very good. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

A putative role for telocytes in placental barrier impairment during preeclampsia.

Preeclampsia (PE) is a major health problem occurring in pregnant women and the principal cause of maternal morbidity and perinatal mortality. It is characterized by alteration of the extravilli trophoblast cell migration toward the endometrial spiral arteries with a concomitant reduction in maternal blood flow in the placenta. This result in a state of ischemia-hypoxia which triggers an oxidative stress stage with production of reactive oxygen species. A cascade of cellular and molecular events leads then to endothelial dysfunction, transduction pathway signal disruption and induction of apoptosis and necrosis mechanisms and therefore a significant reduction in the amount of nutrients required for normal fetal development. Placental anchoring chorionic and stem villi present a skeleton of myofibroblasts arranged in parallel disposition to its longitudinal axis. The intraplacental blood volume is controlled by the contraction/relaxation of these myofibroblasts, promoting the delivery of nutrients and metabolites to the fetus. Recently, a new mesodermal originated cell type has been described in the villous stroma, the so named "telocytes". These cells are strategically located between the smooth muscle cells of the blood vessel wall and the myofibroblasts, and it is reasonable to hypothesize that they may play a pacemaker role, as in the intestine. This study provide new information supporting the notion that the occurrence of oxidative stress in PE is not only related to endothelial dysfunction and apoptosis of the trophoblast cells, but also involves telocytes and its putative role in the regulation of fetal blood flow and the intra-placental blood volume. Some ideas aimed at dilucidating the relationship between placental failure and the behavior of telocytes in pathological organs in adulthood, are also discussed.

Role of the glucose tolerance test as a predictor of preeclampsia.

OBJECTIVE: To determine whether oral glucose tolerance tests (OGTT) play a role as predictors of preeclampsia (PET) in pregnant women. METHODS: A retrospective case-control study was conducted in 2,002 singleton pregnancies that had a uterine artery (UtA) Doppler at 22-25 weeks and an OGTT. The UtA Doppler and OGTT were adjusted based on maternal characteristics, and the results were expressed as multiples of the expected normal median and compared between groups. Logistic regression analysis was used to determine whether maternal characteristics, OGTT, and UtA Doppler significantly contribute to the prediction of early- (<34 weeks), intermediate- (34-37 weeks), or late-onset (>37 weeks) PET. The performance of the screening was determined by ROC curves. RESULTS: Women who developed PET were characterized by an older maternal age, an increased body mass index, and an altered UtA Doppler. The group with intermediate-onset PET was the only one associated with higher 2-hour OGTT levels compared to controls. Combined models were developed via logistic regression analysis using maternal characteristics, UtA Doppler, and OGTT to predict PET. These combined models were able to detect around 74, 42, and 21% of women who later developed early-, intermediate-, or late-onset PET, respectively, with only a 5% false-positive rate. CONCLUSIONS: This study shows that the combination of maternal characteristics, second-trimester UtA Doppler, and OGTT is a predictor of the development of PET in healthy pregnant women.

Is there a role for cervical assessment and uterine artery Doppler in the first trimester of pregnancy as a screening test for spontaneous preterm delivery?

OBJECTIVE: To evaluate the role of cervical length (CL) and uterine artery pulsatility index (UtA-PI) at 11+0 to 13+6 weeks as predictors of spontaneous preterm delivery (sPTD) in a Chilean population. METHODS: This was a prospective study of asymptomatic women with singleton pregnancies attending for a nuchal translucency scan at 11+0 to 13+6 weeks' gestation and who underwent a transvaginal scan for evaluation of CL and UtA-PI. Exclusion criteria were fetal and pregnancy complications (other than sPTD) and iatrogenic delivery at<34 weeks. Measurements of CL and UtA-PI were adjusted for fetal crown-rump length and maternal characteristics and expressed as multiples of the median (MoM) of the unaffected group. Prediction of sPTD using maternal and pregnancy characteristics was studied using logistic regression analysis. RESULTS: A total of 3480 women were recruited into the study and, after application of exclusion criteria, 3310 were included in the analysis. The rate of sPTD at<34 weeks was 0.9% (n=31). A previous PTD had occurred in 7.4% of parous women. Patients with sPTD in the index pregnancy were characterized by a significantly higher prevalence of previous PTD (12.9% vs 3.7%, P<0.05). No significant difference was found in either CL or UtA-PI between pregnancies with and without subsequent sPTD. Logistic regression analysis showed that smoking and previous PTD were significantly associated with sPTD at<34 weeks. The combination of these characteristics provided a detection rate of 26% with a false-positive rate of 8%. CONCLUSIONS: Neither UtA-PI nor CL during the first trimester was shown to be a useful predictor of early sPTD. However, a combined model that includes smoking and previous PTD predicts approximately one-quarter of those women destined to deliver at<34 weeks, with a false-positive rate of 8%.

Prediction of early and late pre-eclampsia from maternal characteristics, uterine artery Doppler and markers of vasculogenesis during first trimester of pregnancy.

OBJECTIVE: To develop a predictive model for pre-eclampsia using clinical, biochemical and ultrasound markers during the first trimester of pregnancy. METHODS: This was a nested case-control study within a pre-eclampsia screening project that involved 5367 asymptomatic pregnant women undergoing routine transvaginal uterine artery (UtA) Doppler at 11 + 0 to 13 + 6 weeks. Following exclusions, there were 70 pregnant women who later developed pre-eclampsia and 289 control patients enrolled during the first trimester who had serum or plasma samples taken at enrolment available for the purposes of this study. Of these, 17 pregnancies were diagnosed with early-onset (delivery < 34 weeks) pre-eclampsia and 53 with late-onset (delivery ≥ 34 weeks) pre-eclampsia. The lowest, highest and mean of left and right UtA pulsatility indices (PI) were calculated. Blood samples were stored at -84 °C until biochemical analysis for markers of vasculogenesis was performed. The distributions of the lowest UtA-PI and the biochemical markers were adjusted for maternal characteristics, expressed as multiples of the median (MoM), and compared between groups. Logistic regression analysis was used to evaluate if any variable was significantly associated with pre-eclampsia. RESULTS: Pregnancies that later developed pre-eclampsia were associated with higher maternal prepregnancy body mass index. An increased lowest UtA-PI was significantly associated with both early- and late-onset disease. Placental growth factor (PlGF) MoM was significantly reduced in women who later developed early- or late-onset pre-eclampsia compared with controls (median (interquartile range), 0.69 (0.33-1.46) and 1.10 (0.39-1.56), respectively, vs 1.19 (0.65-1.84), P < 0.05). Different combined models were generated by logistic regression analysis, and the detection rate with a fixed 10% false-positive rate was 47% and 29% for early- and late-onset pre-eclampsia, respectively. CONCLUSION: Pregnancies that later developed early or late pre-eclampsia were characterized by impaired placentation and an anti-angiogenic state during the first trimester of pregnancy. Regression models which include maternal characteristics, UtA Doppler and PlGF can apparently predict approximately half of pregnancies that will be complicated by early-onset pre-eclampsia. We believe more research in several areas is needed to aid in the creation of a better and more population-specific screening test for pre-eclampsia during the first trimester of pregnancy.

VEGF in the muscular layer of placental blood vessels: immuno-expression in preeclampsia and intrauterine growth restriction and its association with the antioxidant status.

The pathophysiology of preeclampsia (PE), a disorder occurring in 5% of all pregnancies, remains largely unknown, but early placental hypoxia and oxidative stress are known to be involved in the mechanism of the syndrome. Maternal plasma and placental tissue samples were collected from PE, intrauterine growth restriction (IUGR), and normotensive pregnant patients. The immunohistochemical expression of vascular endothelial growth factor (VEGF), malondialdehyde (MDA) production and the activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase GSH-Px) were determined in the placental tissue. F2-isoprostane concentration and the ferric reducing ability of plasma (FRAP) were determined in maternal plasma. We found that the PE and IUGR groups showed a higher expression of VEGF in the muscular layer of fetal chorionic vessels. In addition, increased plasma F2 isoprostane levels and a significant reduction of FRAP in the plasma of PE women, as well as a lower activity of SOD in PE placentas and a higher activity of GSH-Px in IUGR placentas were found. Additionally, lower PlGF and higher sFlt1 levels were observed in the maternal plasma of PE and IUGR than control. We concluded that in a hypoxic environment, the placenta expresses VEGF in the muscular layer of fetal vessels. The development of PE could be related to the increased expression of VEGF, with decreased placental SOD activity and a decrease of both plasma F2-isoprostane and FRAP levels. In turn, the development of IUGR could be related to the association of decreased plasma FRAP levels and increased placental GSH-Px activity.

Pregnancy outcome and fibrinolytic, endothelial and coagulation markers in women undergoing uterine artery Doppler screening at 23 weeks.

BACKGROUND: Pre-eclampsia (PET) and/or fetal growth restriction (FGR) remain a major cause of maternal and fetal morbidity and mortality. In pregnancy, fibrinolysis is controlled by the maternal endothelium and placenta, both of which are central to the pathogenesis of PET/FGR. Clinically, uterine artery Doppler screening at 23 weeks is used to predict PET/FGR. An abnormal uterine artery Doppler finding is defined as early diastolic bilateral uterine artery notching (BN) in the waveform. However, about 50% of mothers with BN do not develop PET/FGR. OBJECTIVES: We investigated fibrinolytic changes and uterine artery Doppler findings in the second trimester, and related them to pregnancy outcome; in particular assessing whether fibrinolytic markers could discriminate between normal and abnormal outcome in mothers with BN. PATIENTS/METHODS: Plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), plasminogen activator inhibitor-2 (PAI-2), plasmin-alpha(2) antiplasmin (PAP), D-dimers and markers of endothelial dysfunction were measured with Doppler ultrasound at 23 weeks. RESULTS: Those with BN had decreased PAP and D-dimer levels, and raised PAI-1 and thrombomodulin levels. Mothers with BN and PET/FGR had significantly increased t-PA levels and reduced PAI-2 levels. CONCLUSIONS: BN at 23 weeks of gestation is associated with increased PAI-1 levels. Within the BN group, mothers who developed PET/FGR had increased t-PA levels and decreased PAI-2 levels, although there was no net change in fibrinolysis as measured by D-dimer levels. No single fibrinolytic marker is helpful in determining pregnancy outcome in those with BN, but t-PA and PAI-2 are worthy of study in a multifactorial algorithm.

Fetal arterial and venous Doppler pulsatility index and time averaged velocity ranges.

OBJECTIVES: The aim of this study was to determine the fetal arterial and venous Doppler pulsatility index and time averaged velocity ranges for women undergoing third trimester ultrasound. METHODS: One hundred and seventy-two women with singleton pregnancy and clinical indication underwent biometry and fetal Doppler assessment at 23 to 41 weeks. Umbilical artery, middle cerebral artery, thoracic aorta and ductus venosus pulsatility index and time averaged velocity measurements were performed and corrected statistically based on the distribution of estimated fetal weight at the time of the scan. RESULTS: The tables and figures of the several vessels published in this study are broadly comparable to other publications and unlike others, are adjusted for the estimated fetal weight distribution. CONCLUSIONS: We present the values of the commonly measured Doppler indices in fetuses with normal growth at the time of scan. The ranges, therefore, have potential utility in the setting where referrals to a fetal assessment unit are made.

Screening for trisomy 21 during the routine second-trimester ultrasound examination in an unselected Chilean population.

OBJECTIVE: To evaluate the performance of a detailed ultrasound examination during the second trimester as a screening test for Down syndrome in an unselected Chilean population. METHODS: This was part of an ongoing longitudinal study. Included were 3071 women with singleton pregnancies who underwent routine ultrasound examination between 21 + 0 and 25 + 6 gestational weeks as a screening test for chromosomal abnormalities and major congenital structural defects, and who were diagnosed as having trisomy 21 or being chromosomally normal. Maternal age, and eight soft markers and cardiac defects associated with Down syndrome were evaluated as a screening test using logistic regression analysis. RESULTS: The incidence of Down syndrome was 0.6%, and the mean maternal age was 29.4 +/- 6.2 years. At least one of four soft markers (absent nasal bone, nuchal edema, short femur, echogenic foci) and/or cardiac defects was present in 77.8% of Down syndrome fetuses and in 3.1% of normal fetuses. Furthermore, with a false-positive rate of 1%, the detection rate using the combined model of ultrasound markers and maternal age was 72.2%. CONCLUSIONS: Second-trimester ultrasound markers are able to detect over 70% of Down syndrome fetuses with only a 1% false-positive rate.