Elsevier Trophoblast Research Award Lecture: Searching for an early pregnancy 3-D morphometric ultrasound marker to predict fetal growth restriction.

Fetal growth restriction (FGR) is a major cause of perinatal morbidity and mortality, even in term babies. An effective screening test to identify pregnancies at risk of FGR, leading to increased antenatal surveillance with timely delivery, could decrease perinatal mortality and morbidity. Placental volume, measured with commercially available packages and a novel, semi-automated technique, has been shown to predict small for gestational age babies. Placental morphology measured in 2-D in the second trimester and ex-vivo post delivery, correlates with FGR. This has also been investigated using 2-D estimates of diameter and site of cord insertion obtained using the Virtual Organ Computer-aided AnaLysis (VOCAL) software. Data is presented describing a pilot study of a novel 3-D method for defining compactness of placental shape. We prospectively recruited women with a singleton pregnancy and BMI of <35. A 3-D ultrasound scan was performed between 11 and 13 + 6 weeks' gestation. The placental volume, total placental surface area and the area of the utero-placental interface were calculated using our validated technique. From these we generated dimensionless indices including sphericity (ψ), standardised placental volume (sPlaV) and standardised functional area (sFA) using Buckingham π theorem. The marker for FGR used was small for gestational age, defined as <10th customised birth weight centile (cSGA). Regression analysis examined which of the morphometric indices were independent predictors of cSGA. Data were collected for 143 women, 20 had cSGA babies. Only sPlaV and sFA were significantly correlated to birth weight (p < 0.001). Regression demonstrated all dimensionless indices were inter-dependent co-factors. ROC curves showed no advantage for using sFA over the simpler sPlaV. The generated placental indices are not independent of placental volume this early in gestation. It is hoped that another placental ultrasound marker based on vascularity can improve the prediction of FGR offered by a model based on placental volume.

Developmental changes in spiral artery blood flow in the human placenta observed with colour Doppler ultrasonography.

OBJECTIVES: Our current knowledge of the physiological dilatation of spiral arteries in pregnancy, is based on histology. Real-time ultrasound visualisation of these changes may aid understanding of abnormal placentation. This study aimed to investigate if changes in the spiral artery blood flow can be followed 'in vivo' and explore the novel phenomenon of the larger 'mega-jets'. METHODS: Colour Doppler ultrasonography was used to identify the most prominent jets at blood from the spiral artery into the intervillous space. Their velocity, width and length were recorded seven set time points during pregnancy. RESULTS: Fifty two uncomplicated, term normotensive pregnancies were studied. Width and length of the jets' Doppler signals increased with gestation, the velocity decreased. The length of the jets shows a bi-modal frequency distribution. The width of the signals of longer ('mega') jets was significantly greater (p = 0.001) than that of the jets (mean 4.3 mm (3.1-5.9) versus 3.8 mm (1.8-5.8) respectively) at 34 weeks. However, there was no significant difference in the peak systolic velocity (p = 0.2). CONCLUSION: This study confirms that ultrasound can be used to study the gestation dependent changes in the haemodynamics of the placental basal plate predicted, but not proven, by histologic data. The bi-modal distribution of jet lengths suggests that mega-jets are a separate entity to 'normal' jets. That they are significantly wider than 'normal' jets and yet maintain the same velocity of blood flow suggests that they have a greater volume of blood flow. The mechanism for this is hypothesised and their apparent relationship with simple placental lakes discussed.

Inapplicability of fractional moving blood volume technique to standardize Virtual Organ Computer-aided AnaLysis indices for quantified three-dimensional power Doppler.

OBJECTIVE: To determine whether the technique of fractional moving blood volume (FMBV) is applicable to Virtual Organ Computer-aided AnaLysis II (VOCAL II™)-based indices to quantify three-dimensional power Doppler ultrasound (3D-PDU) by investigating the effect of gain level on the indices measured at a possible reference point for standardization. METHODS: Ten women with singleton pregnancy between 33+3 and 37+5 weeks' gestation were recruited. The optimal position for 3D acquisition of cord insertion into the placenta was identified and static 3D-PDU volumes were acquired using consistent machine configurations. Without moving the probe or the participant changing position, successive 3D volumes were stored at -3, -5, -7 and -9 dB and at the individualized sub-noise gain (SNG) level. Volumes were excluded if flash artifact was present, in which case all five volumes were reacquired. Using 4D View software, the cord insertion was magnified and the smallest sphere possible was used to measure vascularization index (VI), flow index (FI) and vascularization flow index (VFI). The associations between VOCAL indices and gain level were assessed using Pearson's correlation coefficient. RESULTS: VOCAL indices for cord insertion correlated poorly with gain level, whether fundamental or relative to SNG level (R(2) = 0.07 and 0.04, respectively). VI was consistently 100% and mean FI and VFI were 99.5 (SD, 0.57), with all values > 97 irrespective of gain level. CONCLUSIONS: Whilst previous work has shown that gain correlates well with placental tissue VOCAL indices, the correlation between gain level and VOCAL indices in an area of 100% vascularity at the cord insertion is poor. Regions of 100% vascularity appear to be artificially assigned a value approaching 100% for all VOCAL indices irrespective of gain level. This precludes using the technique of VOCAL indices from large vessels to standardize power Doppler measurements and the FMBV index is therefore not applicable to image analysis using VOCAL.

Influence of power Doppler gain setting on Virtual Organ Computer-aided AnaLysis indices in vivo: can use of the individual sub-noise gain level optimize information?

OBJECTIVES: To demonstrate the influence of gain setting on the calculated Virtual Organ Computer-aided AnaLysis (VOCAL(™)) three-dimensional (3D) indices and define a point, the sub-noise gain (SNG), at which maximum information is available without noise artifact. METHODS: Pregnant women were recruited at the time of their pregnancy-dating scan. Five identical static 3D power Doppler volumes of the placenta were acquired using identical machine settings apart from altering the power Doppler gain setting. The gain settings included the individualized SNG setting (determined by increasing gain until noise artifact was visible, then reducing it until the artifact just disappeared). The data were analyzed using VOCAL II. Vascularization index (VI), flow index (FI) and vascularization flow index (VFI) were calculated for the same sample at five different power Doppler gain levels. The relationship between the values calculated for the VOCAL indices and the gain value was explored using linear regression analysis. RESULTS: Results from 50 women were analyzed. The percentage difference in VI and VFI from that observed at the SNG level in each woman was significantly linearly related to the gain setting relative to that at the SNG point (VI: r(2) = 0.68, P < 0.0001; VFI: r(2) = 0.72, P < 0.0001), with the values produced for VI and VFI decreasing as the gain was turned down. There was a distinct 'turning point' at the SNG level with linear relationships above and below, but with significantly different gradients (P ≤ 0.001). This relationship was not demonstrated for FI. CONCLUSION: The SNG setting appears to represent each individual's optimum gain level. Using this may improve meaningful comparisons of VI and VFI between patients.

Measurement of spiral artery jets: general principles and differences observed in small-for-gestational-age pregnancies.

OBJECTIVE: To investigate whether the jets of blood from the mouths of the spiral arteries could be measured reliably, as well as their relationship with the uterine artery (UtA) and any differences in small-for-gestational-age (SGA) pregnancies. METHODS: Participants underwent serial ultrasound scans, from 11 weeks' gestation. Pulsatility index (PI) and resistance index (RI) of jets into the intervillous space (IVS) and UtA were recorded at every visit. Intra- and interobserver variability studies were performed. Customized birth weight centiles were calculated and SGA was defined as < 10(th) centile. Linear mixed model analysis was used to allow for the longitudinal nature of the data. RESULTS: Sixty-six women were recruited; 58 remained normotensive and delivered at term. Of these, six women delivered SGA newborns and 52 delivered appropriate-for-gestational-age newborns. All had pulsatile jets until 20 weeks' gestation. The PI and RI of the jets decreased with advancing gestation, following a trend similar to that of the UtAs. There was no correlation between the jets and UtA waveforms when gestational age was controlled for. For intraobserver variability the intraclass correlation coefficient was 0.9. The interobserver study showed no significant difference between the observers. Mixed model analysis demonstrated that PI and RI of jets were different in SGA pregnancies (P < 0.06). This difference was not seen for the UtAs (P = 0.8). CONCLUSION: This technique enables examination of characteristics of the jets of blood flowing from spiral arteries into the IVS. It is both precise and reproducible, with biologically plausible results. Further work is required to assess differences in pregnancies with adverse outcomes.