Brian Trudinger

Flow velocity waveforms in the maternal uteroplacental and fetal umbilical placental circulations

A simple continuous-wave Doppler ultrasound system was used to record arterial flow velocity time waveforms from branches of the maternal uterine artery in the placental bed and the fetal umbilical arteries. The systolic-diastolic ratio of flow velocities was measured as an index of peripheral resistance. In normal pregnancy both circulations exhibit high diastolic flow velocities caused by low resistance. The study group consisted of 172 pregnancies with high fetal risk of which 53 resulted in delivery of a small-for-gestational age infant. The last study-to-delivery interval was less than 10 days. In the small-for-gestational age fetuses in whom both umbilical and uterine studies were normal there was good fetal outcome (19 cases). Neonatal morbidity occurred among those with abnormal umbilical studies with low diastolic flow velocities, indicating high resistance. Of these studies there were two subgroups. An abnormal uterine study (13 cases) indicated a primary maternal uteroplacental lesion and a normal study (21 cases) a primary fetal lesion. In cases of severe maternal hypertension, abnormal uterine artery waveforms were associated with abnormal umbilical artery waveforms.

Genotype dependent and cigarette specific effects on endothelial nitric oxide synthase gene expression and enzyme activity

We explored the interactive effects of endothelial nitric oxide synthase (eNOS) genotypes and cigarette smoking on protein levels and enzyme activity in 33 postpartum placentas. Whilst the eNOS protein levels were lower in the rare allele (0.48±0.11, n=9 vs. 1.05±0.10, n=24, P<0.01), the eNOS enzyme activity was about 7‐fold higher in the rare allele (4556.2±255.4 vs. 621.8±180.5 cpm/mg/min, P<0.01). Smokers had lower eNOS protein levels (1.07±0.09 vs. 0.50±0.19, P<0.05) in both alleles. It reduced the eNOS activities only in the rare allele (non‐smokers: 6143.8±251.2, n=5, smokers: 2968.5±259.4, n=4, 52% reduction, P<0.01). We conclude that associations between eNOS polymorphism and protein levels and enzyme activities are modifiable by smoking, the effects of smoking are dependent on the eNOS genotypes.

Doppler ultrasound waveform indices: A/B ratio, pulsatility index and Pourcelot ratio

Summary. Three different indices, the A/B ratio, the pulsatility index (PI) and the Pourcelot ratio (PR), are in common use for quantitative analysis of umbilical artery Doppler ultrasound waveforms. A detailed examination of the similarities and differences between these indices, together with the expected errors for each, was undertaken to enable informed comparisons and choices to be made. The indices were calculated from 133 last trimester recordings using an objective and very reliable computer analysis technique. The PI is more difficult to calculate than the other two quantities and the extra computation does not provide any extra information. The A/B ratio appears the simplest index to use but the values are not normally distributed. With the PR a normal distribution of values can be assumed. A theoretical consideration of errors showed that none of the indices is intrinsically less error prone for last trimester waveforms overall. The errors in the A/B ratio increase as the value of the index increase, whereas the converse holds for the PI and PR.

Low-dose aspirin therapy improves fetal weight in umbilical placental insufficiency

A randomized, placebo-controlled, double-blind trial was carried out to evaluate the fetal benefits of low-dose aspirin (150 mg/day) as a treatment of placental insufficiency during the last trimester of pregnancy. Forty-six women referred for study because there was concern about fetal welfare were found to have an elevated umbilical artery wave form systolic/diastolic ratio. Mothers with severe hypertension were excluded because fetal condition would not necessarily be the dominant determinant of obstetric decision making. A distinction was made between a high systolic/diastolic ratio (greater than 95th but less than 99.95th percentile) and an extreme systolic/diastolic ratio (greater than 99.95th percentile). There were 34 patients in the high ratio group and 12 in the extreme group. Aspirin therapy was associated with an increase in birth weight (mean difference 526 gm [p less than 0.02]), head circumference (1.7 cm [p less than 0.025]), and placental weight (136 gm [p less than 0.02]) in those patients with a high initial umbilical artery systolic/diastolic ratio. For the 12 women with an extreme initial systolic/diastolic ratio, aspirin therapy did not result in a significantly different pregnancy outcome.

ISUOG Practice Guidelines : use of Doppler ultrasonography in obstetrics

The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) is a scientific organization that encourages sound clinical practice, teaching and research related to diagnostic imaging in women’s healthcare. The ISUOG Clinical Standards Committee (CSC) has a remit to develop Practice Guidelines and Consensus Statements as educational recommendations that provide healthcare practitioners with a consensus-based approach for diagnostic imaging. They are intended to reflect what is considered by ISUOG to be the best practice at the time at which they are issued. Although ISUOG has made every effort to ensure that Guidelines are accurate when issued, neither the Society nor any of its employees or members accepts any liability for the consequences of any inaccurate or misleading data, opinions or statements issued by the CSC. They are not intended to establish a legal standard of care because interpretation of the evidence that underpins the Guidelines may be influenced by individual circumstances and available resources. Approved Guidelines can be distributed freely with the permission of ISUOG (info@isuog.org).

Doppler waveform pulsatility index and resistance, pressure and flow in the umbilical placental circulation: An investigation using a mathematical model

A mathematical model of the umbilical placental circulation was used to examine the effect of different physiological variables on the pulsatility index (PI) of the umbilical artery Doppler waveform. The variables include the umbilical and placental resistances, the volume flow rate and the pressure. In the model the branching structure of the placental villous tree is considered in detail, while each arterial branch is itself represented simply using a resistor and a capacitor. Placental vascular disease is modelled as obliteration of a fraction of the terminal branches of the tree. The model umbilical artery PI depends on the ratio of the placental resistance to the umbilical artery resistance. The PI increases with vascular disease, but the rate of increase is not uniform. Initially, the placental resistance and the PI increase very slowly with vessel obliteration. Once the level of vessel obliteration has reached a large enough value--typically between 60% and 90% obliteration--the PI begins to rise sharply. A larger placental vascular bed can accommodate a greater level of vessel obliteration before this rapid PI rise begins. The umbilical artery PI also depends on the pulsatility of the input (aortic bifurcation) pressure waveform, but blood pressure variations in the physically attainable range cannot account for the very high PI values associated with fetal compromise. Physically attainable pressure waveform changes would, however, enable the fetus with substantial placental vascular disease to maintain umbilical volume flow rate, and at the same time exhibit a raised umbilical artery PI value.

Umbilical artery velocity waveforms: normal reference values for A/B ratio and Pourcelot ratio

Summary. Normal reference values for the umbilical artery Pourcelot ratio and A/B ratio are reported. Thirty‐five normal patients were studied serially from 20 weeks to term. The A/B ratio centilcs were corrected for non‐normality of the underlying distribution by transforming from the Pourcelot ratio values. The correction needed was small during the last trimester, but larger for second trimester data. Of the 35 patients 24 were nulliparous and there was a slight tendency for the waveform indices to be higher in the nulliparae, but the numbers in this study were too small to be conclusive about the effect of parity.

Doppler umbilical and uterine flow waveforms in severe pregnancy hypertension

Summary. Doppler studies of the umbilical and uteroplacental bed arterial flow velocity waveforms were performed in a series of women suffering from severe proteinuric pregnancy hypertension. Ninety‐five women were studied and the mean interval between the last study and delivery was 1–4 days. An abnormally elevated umbilical artery systolic:diastolic (AB) ratio was present in 61 (64%) of the women. All 10 perinatal deaths were associated with pregnancies with an abnormal umbilical artery AB ratio. An elevated umbilical artery AB ratio was significantly associated with small‐for‐gestation and neonatal morbidity. Infants associated with extremely high umbilical artery AB ratios (≥ 99th centile) spent twice as long in the neonatal nursery as those with a lower value. There was no relation between the duration of hypertension and the umbilical study result. The uteroplacental bed artery flow velocity waveform did not correlate with fetal or neonatal mortality or morbidity. Patients with abnormal uteroplacental AB ratios also had abnormal umbilical artery AB ratios. We conclude that an abnormal fetal umbilical artery Doppler flow velocity waveform correlates with adverse fetal outcome in severe proteinuric pregnancy hypertension and suggest that the associated placental lesion may precede the maternal hypertension.

A proinflammatory cytokine response is present in the fetal placental vasculature in placental insufficiency

OBJECTIVE Vascular disease in the umbilical placental circulation is associated with fetal growth restriction and adverse outcome. It may be identified antenatally by the study of umbilical artery Doppler flow velocity waveforms. The cause of this vascular disease is unknown. We have previously provided indirect evidence for endothelial cell activation and a proinflammatory cytokine response. Recently, a family of inhibitors of cytokine signaling has been identified, referred to as the suppressors of cytokine signaling (SOCS). Activation of SOCS occurs when cytokines are produced in stimulated cells. We tested the hypothesis that endothelial cell activation was present in umbilical placental vascular disease and was associated with production of proinflammatory cytokines and members of the family of SOCS. STUDY DESIGN Placentas were collected at delivery and microvascular endothelial cells were isolated. We studied 13 normal pregnancies and 10 with umbilical placental vascular disease identified by an abnormal umbilical artery Doppler study. Placental pieces were digested with collagenase and purified by adherence to Dynabeads coated with monoclonal antibody against CD31. The RNA was extracted from isolated endothelial cells. The messenger RNA expression of cytokine production (interleukin-6 and interleukin-8) and the members of SOCS family (CIS, SOCS1, SOCS2, and SOCS3) were assessed by use of semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS In the microcirculation of the placenta, endothelial cell expression of interleukin-6 messenger RNA (2.50+/-0.60 vs 1.25+/-0.26) and interleukin-8 messenger RNA (2.83+/-0.55 vs 1.58+/-0.27) was up-regulated in umbilical placental vascular disease in comparison to normal pregnancy. The endothelial cell mRNA expression of SOCS2 (3.36+/-0.77 vs 1.76+/-0.29) and SOCS3 (2.77+/-0.60 vs 1.48+/-0.26) was enhanced in placental vascular disease. There was no significant difference in expression of CIS and SOCS1 in microvessel endothelial cells. CONCLUSION We have demonstrated that microvessel endothelium of the fetal placental vasculature produces both the proinflammatory cytokines (interleukin-6 and interleukin-8) and members of SOCS family (SOCS2 and SOCS3) in umbilical placental vascular disease. This cytokine production may play a key role in the interaction of endothelial cells of the placenta villi with neighboring cells. The up-regulation of SOCS2 and SOCS3 indicates these are the major negative regulators in umbilical placental microvessel endothelial cell activation pathways. By its occurrence, this also confirms the presence of a proinflammatory cytokine response.

Changes of Resistance to Activated Protein C in The Course of Pregnancy and Prevalence of Factor V Mutation

Summary: The purpose of this study was to examine the changes in activated protein C (APC) anticoagulant activity during pregnancy and determine whether changes in APC could contribute to thrombosis in the placental bed in preeclampsia. We measured APC anticoagulant activity in 150 women with a normal pregnancy and 50 women with preeclampsia. There was a significant reduction in the mean APC sensitivity ratio (APC‐SR) during pregnancy (p<0.001). APC resistance in preeclampsia was significantly higher than in normal pregnancy (p<0.01). Amongst women with APC resistance the presence of the factor V Leiden mutation was significantly higher in the preeclampsia group than in the normal pregnancy group (p<0.01). It seems that both factor V Leiden mutation and APC resistance may be associated with the development of preeclampsia. These results suggest that APC resistance may be an important mechanism underlying placental bed pathology in pregnancy and may be associated with an increased tendency to develop preeclampsia in some women. Assay of APC resistance and factor V Leiden mutation should be performed in women with preeclampsia.