Reference ranges for uterine artery mean pulsatility index at 11 41 weeks of gestation

Ultrasound Obstet Gynecol 2008; 32: 128 132 Published online 6 May 2008 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/uog.5315 Reference ranges for uterine artery mean pulsatility index at 11 41 weeks of gestation O. GÓMEZ, F. FIGUERAS, S. FERNÁNDEZ, M. BENNASAR, J. M. MARTÍNEZ,B.PUERTO and E. GRATACÓS Fetal Growth and Pre-eclampsia Unit, Department of Maternal Fetal Medicine, ICGON, Hospital Clínic, University of Barcelona and Center for Biomedical Research on Rare Diseases (CIBERER), Barcelona, Spain KEYWORDS: Doppler ultrasonography parameters; pulsatility index; uterine arteries ABSTRACT Objectives To construct gestational age (GA)-based reference ranges for the uterine artery (UtA) mean pulsatility index (PI) at 11 41 weeks of pregnancy. Methods A prospective cross-sectional observational study was carried out of 20 consecutive singleton pregnancies for each completed gestational week at 11 41 weeks. UtAs were examined by color and pulsed Doppler imaging, and the mean PI, as well as the presence or absence of a bilateral protodiastolic notch, were recorded. Polynomials were fitted by means of leastsquare regression to estimate the relationship between the mean UtA-PI and GA. Results A total of 620 women were included. A seconddegree polynomial (Log e mean UtA-PI = 1.39 0.012 GA + GA 2 0.0000198, with GA measured in days), after a natural logarithmic transformation, was selected to model our data. There was a significant decrease in the mean UtA-PI between 11 weeks (mean PI, 1.79; 95 th centile, 2.70) and 34 weeks (mean PI, 0.70; 95 th centile, 0.99). It then became more stable up until 41 weeks (mean PI, 0.65; 95 th centile, 0.89). Conclusions The mean UtA-PI shows a progressive decrease until the late stages of pregnancy. Reference ranges for mean UtA-PI may have clinical value in screening for placenta-associated diseases in the early stages of pregnancy, and in evaluating patients with pregnancy-induced hypertension and/or small-forgestational age fetuses during the third trimester. Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Uterine artery (UtA) Doppler ultrasound examination has become a valuable method for indirectly assessing uteroplacental circulation from early gestation 1 and has been considered as a potential screening tool for the development of pre-eclampsia, fetal growth restriction, placental abruption and stillbirth 2 11. Another recent area of application is the prognostic value of UtA Doppler velocimetry in patients with pregnancyinduced hypertension and/or in small-for-gestational age (SGA) fetuses 12 16. The finding of an abnormal UtA Doppler pattern in these high-risk pregnancies strongly correlates with an adverse maternal and/or perinatal outcome 12 15,17,18. The clinical use of UtA Doppler ultrasound imaging requires the existence of reference values, but no such ranges exist despite the common use of UtA Doppler examination during pregnancy. Pulsatility index (PI) is currently the most commonly used index for the evaluation of UtA Doppler waveform patterns. However, previously published studies on UtA Doppler evaluation throughout pregnancy have used a variety of Doppler indices 3,5,6,10,12,14,15,17,19 22 or scoring systems 13,16,18. Gestational age (GA)-based reference ranges for the mean UtA-PI between 11 and 41 weeks of gestation have not been reported previously following validated methodological guidelines 23,24. The purpose of this study was to derive normative new GA-based reference ranges for the mean UtA-PI at 11 41 weeks of pregnancy in an appropriately selected population. METHODS A cross-sectional study was carried out of 20 consecutive singleton pregnancies for each completed gestational week at 11 41 weeks. Most of the women included in the study were undergoing routine scans at 11 14, 19 22 and 32 34 weeks. We also included early and late bookers, and healthy women participating in other Correspondence to: Dr O. Gómez, Department of Maternal Fetal Medicine, Institut Clinic de Ginecologia, Obstetricia i Neonatologia, Hospital Clínic, c/sabino de Arana 1, 08028 Barcelona, Spain (e-mail: ogomez@clinic.ub.es) Accepted: 18 January 2008 Copyright 2008 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

Reference ranges for uterine artery Doppler PI 129 research projects. Inclusion criteria were: GA determined before 22 weeks (crown rump length between 11 and 14 weeks 25, and biparietal diameter between 14 and 22 weeks 26 ); absence of risk factors for vascular disease, including pregestational diabetes, immune disease and renal disease; normal fetal growth (> 10 th and < 90 th centile on growth curves according to local standards) 27 ; absence of treatment with aspirin or heparin before enrollment; and normal umbilical artery Doppler pattern at the time of recruitment in pregnancies at > 24 weeks 28. Fetuses with chromosomal or structural abnormalities were excluded from the study. The research protocol was approved by the local ethics committee and all subjects gave their informed consent. UtA Doppler examinations were performed using an Aspen (Siemens Acuson Inc., Mountain View, CA, USA) or a Voluson 730 Pro (GE Healthcare Technologies, Milwaukee, WI, USA) ultrasound machine, both equipped with multifrequency transvaginal and transabdominal transducers. Examinations were carried out by a number of experienced observers. Data were entered into a computer database. In ultrasound examinations performed on pregnancies at 11 14 weeks a transvaginal transducer was used to obtain a sagittal section of the cervix. The probe was moved laterally until the paracervical vascular plexus was seen. Color Doppler imaging was used to identify the UtA at the level of the cervicocorporeal junction. Measurements were taken at this point before branching of the UtAs into the arcuate arteries. Pregnancies at 15 41 weeks were examined transabdominally. The probe was placed on the lower quadrant of the abdomen, angled medially, and again color Doppler imaging was used to identify the UtA at the apparent crossover with the external iliac artery. Measurements were taken approximately 1 cm distal to the crossover point. In all cases, once it had been ensured that the angle was less than 30, the pulsed Doppler gate was placed over the whole width of the vessel. Angle correction was then applied and the signal updated until three similar consecutive waveforms had been obtained. The PI of the left and right arteries was measured, and the mean PI was calculated (Figure 1). The presence or absence of a bilateral early protodiastolic notch was noted. A notch was defined as a persistent decrease in blood flow velocity in early diastole, below the diastolic peak velocity. Umbilical artery PI was measured using standard methodology 28. Statistical analysis We used the statistical method described by Royston and Wright to estimate reference intervals 23. In summary, polynomials were fitted by means of least-square regression to estimate the relationship between mean PI and GA. The best fitting model was selected on the basis of the residual SD. Z-scores (measurement mean/sd) were calculated for assessing model fit. Normal distribution of the Z-scores was checked with the Shapiro Francia W- test, and a natural logarithmic transformation of the data was used if appropriate. The SD was also modeled by GA Figure 1 Right (a) and left (b) uterine arteries (UtA) visualized by transabdominal color flow mapping and Doppler velocity waveforms at 38 weeks (mean UtA-PI, 0.64; absence of bilateral protodiastolic notch). from the scaled residuals. Equations of the polynomial regression curves were used to calculate the mean, and 5 th and 95 th centiles for each GA (centiles = estimated mean ± 1.645 SD). The adjusted correlation between mean UtA-PI and umbilical artery PI was calculated by means of multiple linear regression. Statistical procedures were performed using SPSS version 11.5 (SPSS Inc., Chicago, IL, USA). RESULTS The study population was recruited between January 2002 and December 2004 and comprised 620 women who met all of the inclusion criteria. Clinical characteristics and pregnancy outcomes of these women are shown in Table 1. The prevalence of bilateral notching was 46.3% (37/80 women) between 11 and 14 weeks, 16.5% (33/200 women) between 15 and 24 weeks, and 5% (17/340 women) between 25 and 41 weeks. The latter group included five cases between 25 and 28 weeks, four cases between 28 and 32 weeks, and eight cases between 32 and41weeks(figure2).

130 Gómez et al. Table 1 Demographic characteristics and pregnancy outcome of 620 women included in the study Variable Value Maternal age (years, mean ± SD) 30.2 ± 6.11 Ethnicity (%) White 85.3 Black 0.8 Other 15.9 Nulliparous (%) 63 Cigarette smoking > 5/day (%) 17.8 Pregnancy outcome GA at delivery (weeks, mean ± SD) 39.2 ± 2.05 Birth weight at delivery (g, mean ± SD) 3221 ± 513 Umbilical artery ph at delivery (mean ± SD) 7.24 ± 0.07 Umbilical vein ph at delivery (mean ± SD) 7.31 ± 0.06 Gestational hypertension (n (%)) 8 (1.29) Pre-eclampsia (n (%)) 8 (1.29) Birth weight at delivery < 10 th centile (n (%)) 57 (9.19) Preterm delivery (GA < 34 weeks) (n (%)) 16 (2.58) GA, gestational age. Mean PI 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 12 16 20 24 28 32 36 40 44 Gestational age (weeks) Figure 3 Scatterplot of the mean uterine artery pulsatility index (PI) measured by transvaginal ( ) and transabdominal ( ž) ultrasound examination vs. gestational age in our population. Estimated 5 th, 50 th and 95 th centiles are shown. Table 2 Reference intervals for mean uterine artery pulsatility index Presence/absence of notch (%) 100 80 60 40 20 0 11 14 15 19 20 24 25 28 29 32 33 41 Gestational age (weeks) Figure 2 Prevalence of bilateral notching ( ) or absence of notch ( ) throughout gestation. Transvaginal and transabdominal ultrasound examinations were performed on pregnancies at 11 14 weeks and 15 41 weeks, respectively. When adjusted for GA (by means of linear regression), a significant correlation was found between umbilical artery PI and mean UtA-PI (r = 0.32, P < 0.001). A second-degree polynomial, after natural logarithmic transformation, describing the relationship between mean UtA-PI and GA in days (Log e mean UtA-PI = 1.39 0.012 GA + GA 2 0.0000198) resulted in the lowest residual SD (0.256), and was therefore chosen to model our data. According to this model, mean UtA-PI shows a progressive decline from 11 to 34 weeks, and then remains stable until 41 weeks. The SD of log e mean UtA-PI was found to fit linearly with GA measured in days (SD Log e mean UtA-PI = 0.272 GA 0.000259). The Z-scores were normally distributed (Shapiro Francia W = 0.985, P = 0.1). Figure 3 shows a scatterplot of observed mean UtA-PI values against GA, along with calculated reference intervals, which are tabulated in Table 2. GA (weeks) 5 th centile 50 th centile 95 th centile 11 1.18 1.79 2.70 12 1.11 1.68 2.53 13 1.05 1.58 2.38 14 0.99 1.49 2.24 15 0.94 1.41 2.11 16 0.89 1.33 1.99 17 0.85 1.27 1.88 18 0.81 1.20 1.79 19 0.78 1.15 1.70 20 0.74 1.10 1.61 21 0.71 1.05 1.54 22 0.69 1.00 1.47 23 0.66 0.96 1.41 24 0.64 0.93 1.35 25 0.62 0.89 1.30 26 0.60 0.86 1.25 27 0.58 0.84 1.21 28 0.56 0.81 1.17 29 0.55 0.79 1.13 30 0.54 0.77 1.10 31 0.52 0.75 1.06 32 0.51 0.73 1.04 33 0.50 0.71 1.01 34 0.50 0.70 0.99 35 0.49 0.69 0.97 36 0.48 0.68 0.95 37 0.48 0.67 0.94 38 0.47 0.66 0.92 39 0.47 0.65 0.91 40 0.47 0.65 0.90 41 0.47 0.65 0.89 Transvaginal and transabdominal ultrasound examinations were performed on pregnancies at 11 14 weeks and 15 41 weeks, respectively. GA, gestational age. DISCUSSION This study describes new GA-based reference ranges of mean UtA-PI between 11 and 41 weeks of gestation in an

Reference ranges for uterine artery Doppler PI 131 appropriate large sample of pregnant women. Various Doppler indices 3,5,6,10,12,14,15,17,19 22, including some scoring systems 13,16,18, have been described for evaluation of the UtA velocity waveform during pregnancy. The PI and resistance index, alone or in combination with the presence of an early diastolic notch, have been the most commonly used indices. However, recent large studies on UtA Doppler imaging during pregnancy have uniformly used the PI 5,9,10. Consequently, we evaluated the distribution of UtA-PI measurements instead of the resistance index. The PI describes the shape of the velocity waveform much better, as it includes the area below the curve in the formula. Likewise and for this reason, the PI index indirectly informs about the presence or absence of a protodiastolic notch. Although a previous large study used the transabdominal route to perform the UtA Doppler examination at 11 14 weeks 5, we routinely use the transvaginal approach for the 11 14-week scan 1. It offers several advantages for UtA Doppler evaluation: the probe is located closer to the UtA, the angle of insonation is usually closer to 0 and the waveforms obtained have better definition. However, previous data have shown that UtA-PI values and prevalence of bilateral notching are significantly lower when recorded transabdominally 29,30. It is possible, therefore, that at least some of the decrease found in the mean UtA-PI and the prevalence of bilateral notching between the first and second trimesters might be due to the different routes used (Table 2 and Figure 2). We have followed stringent and validated methodological guidelines to construct these reference ranges 23,24. In particular, we did not exclude individuals on the basis of information that was not available at the time of measurement, such as birth weight, GA at delivery and perinatal outcome. A cross-sectional design was used as such studies are easier to perform and to combine with clinical practice. We included the same number of observations at each week of gestation (20 patients for each week between 11 and 41 weeks gestation). Finally, our data were collected by several operators, reflecting the measurements used in clinical practice and improving the external validity. The good interobserver reproducibility noted in a previous study by our group 31 suggests that mean UtA-PI is a reliable parameter in a clinical setting. UtA Doppler examination provides important information on the conversion process of spiral arteries into uteroplacental arteries. Reflecting the underlying process of placentation 1, the UtA resistance indices decline during the first half of pregnancy 3,6. However, there are few data regarding the normal UtA Doppler spectrum during the late second and third trimesters of gestation. This study confirms previous reports 22,32,33 suggesting that mean UtA-PI shows a significant and progressive decline with gestation. Our data also show that, together with the progressive fall in the mean UtA-PI, the prevalence of bilateral notching decreases with increasing GA. Interestingly, the decrease in mean UtA-PI continues throughout the third trimester until 34 weeks, although the prevalence of bilateral notch remains almost stable beyond 25 weeks of gestation. This might be explained by several factors. First, one could speculate that trophoblastic invasion proceeds slowly during the late second and third trimesters. Second, important maternal hemodynamic changes, such an increased cardiac output and reduced blood viscosity and peripheral resistance, also take place during late stages of pregnancy 34. Finally, there is a rise in the diameter of the UtA throughout gestation due to the increasing levels of estrogens, which have a vasodilatory effect 35. This study further demonstrates that late stages of pregnancy are characterized by very low impedance indices in the UtA Doppler examination. Aside from the factors discussed above, this may have been influenced by the fact that women with the highest PI values are more likely to deliver early. Early-onset and severe cases, which are characterized by the highest grade of placental ischemia and show the highest UtA resistance indices, will not contribute to the construction of reference ranges in the last stages of pregnancy. In summary, we have presented new mean UtA-PI charts derived from a cross-sectional study in a population of 620 women between 11 and 41 weeks of gestation. 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