Ultrasound Obstet. Gynecol. 10 (1997) 112-120 Reference resistance indices of the umbilical, fetal middle cerebral and uterine arteries at 24-42 weeks of gestation J. Kurmanavicius, I. Florio, J. Wisser, G. Hebisch, R. Zimmermann, R. Miiller, R. Huch and A. Huch Perinatal Research Unit, Department of Obstetrics, Zurich University Hospital, Switzerland Key words: DOPPLER, REFERENCE VALUES, RESISTANCE INDEX, PREGNANCY, UMBILICAL ARTERY, MIDDLE CEREBRAL, ARTERY, UTERINE ARTERIES. ABSTRACT The objective of this cross-sectional study was to construct new reference ranges for Doppler flow velocity waveform resistance indices for the fetal umbilical artery, middle cere- bral artery, placental and non-placental uterine arteries and the placentocerebral ratio in a large and minimally selected population attending a single clinic. Study design and data analysis adhered to a number of stringent and validated ‘methodological recommendations derived both from the recent literature and from a review of earlier publications in this field. The final database comprised initial routine Doppler velocimetry at 24-42 weeks’ gestation in 1675 pregnancies. Separate regression models were fitted to est- mate the mean and standard deviation at each gestational ‘age for each vessel. New charts, centile tables and regres- sion equations are presented for the resistance indices of the fetal umbilical artery, middle cerebral artery, placental and non-placental uterine arteries and the mean of both uterine arteries and for the placentocerebral ratio. INTRODUCTION ‘A number of investigators have reported reference ranges for fetal and uteroplacental Doppler flow velocity wave- forms, constructed from both longitudinal and cross- sectional data‘? and often called ‘normal’ ranges (a term best avoided as it implies incorrectly that all individuals within the range are clinically normal). Such reference ranges can be used to monitor fetomaternal Doppler values during pregnancy and/or to diagnose a specific circulatory abnormality; the latter application presumes information con the values associated with the abnormality concerned as well asin normal subjects. However, many of these reports have failed to state the purposes for which the reference ranges were developed. In addition, many have had methodological flaws, falling short of the ideal attributes of gestational age-related refer~ ence curve design, namely: smooth change with gestational age, good fit to the data at all ages and maximal mathe- ‘matical simplicity". Ocher common failings have included rnon-identification of the statistical method of analysis, a supernormal data set, inadequate account of the change in the variability of the measurement with gestation and failure to present scatter diagrams of the data with the fitted centiles superimposed™. In addition, many stu with a longitudinal design have analyzed the data as if they were cross-sectional, while the sample sizes used to compute the reference ranges (range 18-550 subjects) have generally been inadequate, accounting for the wide confi- dence intervals for the Sth and 95th centiles (in the rare cases in which these have been calculated)". In most studies the beginning and end of the reference ranges have contained significantly fewer observations than the middle part. For these reasons, the aim of the present study was to establish reference Doppler blood flow velocity waveform indices for fetoplacental vascular assessment following, stringent and validated methodological guidelines**, SUBJECTS AND METHODS ‘The study data were obtained from 2739 pregnant women, attending the Outpatient Department of the Obstetric Clinic at the University Hospital of Zurich. All the patients underwent Doppler ultrasonography at least once between 24 and 42 weeks of gestation. The database, constructed by means of the dedicated Perisono program", comprised over 7000 records. Pregnancies delivered in other hospitals, multiple pregnancies, pregnancies involving congenital malformations and pregnancies complicated by hyperten- sion, pre-eclampsia or severe maternal diabetes mellitus at Correspondence: Dr J. Kurmanavicius, Perinatal Research Unit, Departement fr 10, 8091 Zurich, Switerland ORIGINAL PAPER uuenheilkunde Universiatsspital Zurich, Frauenklinikstrasse Received 18-6-96 Revised 28-1-97 Accepted 28-2-97 54Resistance indices examination were excluded. Retrospective exclusion (on the grounds of small-for-dates birth weight, prematurity oF other events several weeks after the examination) was not practised. Only the first Doppler examination of each fetus was used for analysis. Some records from 27-30 weeks were excluded to achieve uniformity in the distribution of gestational age. The randomly selected exclusions were made with the statistical package SPSS 6.1 (SPSS Inc., USA). A residue of 1675 Doppler examinations was used for final analysis: mean gestational age at birth in this population was 38.6 + 2.4 (mean + SD) weeks, mean birth weight 3173+672g and mean umbilical artery pH 7.254 + 0.066. Gestational age was determined from the date of the last menstrual period and confirmed by measurement of first- trimester crown-rump length (CRL) and early second- trimester biparietal diameter (BPD). Gestational age was corrected to the ultrasound value if the difference between the two parameters exceeded 7 days. Examinations were carried out by several operators U.K., LE. J.W., G.H., R.Z., RLM.) using a 3.5-MHz trans- ducer (Acuson 128 XP1O, Acuson Inc., USA) under color Doppler control. The sample volume was 2-3 mm in width. A standard 5O-Hz high-pass filter was used. The spatial peak/temporal average intensity was consistently less than 50 mW/em?. The umbilical cord was investigated by color Doppler ultrasonography, and Doppler signals were recorded from the middle free-floating part of the umbilical artery. The blood flow velocity waveforms were recorded after the middle cerebral arteries were identified by color Doppler imaging at their origin from the internal carotid arteries, as displayed in the transverse section of the fetal head at the level of the cerebral peduncles. Recordings were always ‘made from the first third of the proximal middle cerebral artery. Both the fetal middle cerebral artery and umbilical artery were investigated under the minimal 045° insona- tion angle and measurements were made during general fetal inactivity and apnea. Uterine arteries were measured at the crossing with iliac vessels only during uterine relaxa- tion. Placental and non-placental vessels were measured separately and the mean of both sides was calculated. The signal was recorded for a minimum of five to eight cycles with blood flow velocity waveforms of equal shape and amplitude and satisfactory quality. One waveform was then analyzed and the resistance index (RI) calculated ‘manually with the use of electronic calipers. The placen- tocerebral ratio was calculated automatically by the Peri- sono program, which divided the umbilical artery RI by the middle cerebral artery RI. The data were analyzed with the use of statistical methods described by Royston’, Bland and Altman” and Altman", Reference ranges were constructed by regressing each index on gestational age. For each measurement, linear or polynomial regression models were fitted to the mean. The information about the standard deviation (SD) of the measurement is contained in the residuals around the fitted curve. According to Altman’, the parametric method of deriving a reference range is based on the assumption Kurmanavicius et al, that the residuals should have a normal distribution at each, gestational age and the absolute values of the residuals, should have a half normal distribution. The mean of a half standard normal distribution is V2/t. Thus, the mean of the absolute residuals multiplied by V2/r is an estimate of the SD of the residuals. Ifthe SD is not constant during gesta- tion (as with Doppler data), the values predicted from regressing the absolute residuals on gestational age multi- plied by v2/n will be the age-specific estimates of the SD. Since the residuals showed a skewed distribution, the data, were transformed to achieve a normal distribution accord- ing to the following recommendations by Royston’: (1) Umbilical artery RI: log(RI + 0.4); (2) Middle cerebral artery RI: not transformed; (3) Placentocerebral ratio (PCR): VPCR; (4) Non-placental uterine artery RI: log( RD); (5) Placental uterine artery RI: log(RI); (6) Mean RI of both uterine arteries: log(RD. Regression models were fitted separately to the mean and residuals as functions of gestational age for the trans- formed data. The 90% range (Sth and 95th centiles) was, obtained as mean + 1.645 multiplied by age-specific SDs. The reference ranges were obtained by back-transforma- tion of the calculated centile values. The 95% confidence intervals were calculated to evaluate the precision of the Sth and 95th centiles according to the method of Royston, All. statistical calculations were made in StatView 4.2 (Abacus Concepts, Inc., USA), SPSS 6.1 (SPSS. Inc., USA) and Excel 4.0 (Microsoft Corporation, USA) trun on a Power Macintosh 6100/66 computer (Apple Com- puter, Inc., USA). RESULTS Doppler measurements were obtained in 1675 pregnant women; due to unfavorable feral position, the middle cere- bral artery RI and umbilical artery RI could not be measured at the same examination in all cases. Table 1 gives the number of observations per artery per week of ‘gestation. In the case of the umbilical and uterine arteries, linear regression models were fitted to the mean and linear models to the SD. The 50th centile curve for the middle cerebral artery RI was calculated using fractional poly- rnomials with powers (0,0) and the SD was fitted to a linear model. The 95th centile was not calculated, because part of the observations had a maximum value of 1.0 or near 1.0, and the upper range could not be normalized. In the ease of the placentocerebral ratio, the mean and SD were both fitted using fractional polynomials. The powers of the mean of the placentocerebral ratio were 0.5 and 0.5, and the SD power was ~2. Figure 1 shows the diagnostic placentocerebral ratio plot, chosen because these data were the most difficult to normalize. The normal plot of SD scores did not deviate much from a straight line, thereby confirming the normal distribution of SD scores after data Ultrasound in Obstetrics and Gynecology 113 55Resistance indices ‘Table 1 Number of examinations of resistance indices Kurmanavicius et al. in umbilical artery, middle cerebral artery (MCA), uterine arteries and placentocerebral ratio (PCR) a diferent gestational weeks Gestational age Examinations (x) (weeks days) Untbilicalartery MCA POR Wien arteries Dom +6 55 4 4 8 Boas v6 9 es “a a 260026 +6 100 100 100 100 B02? +6 By 100 38 100 281028 +6 100 2 at 100 231029 +6 100 % % t00 301030 +6 ror 6 ss t00 Most r6 3 m4 a By 3ar0a2 06 102 i 5 100 3303346 100 101 100 100 Sioa too ° % 100 33t035 06 too 101 100 100 3610366 too 35 33 93 371037 +6 ° a %0 7 381038 36 a1 ” 3 7 3910396 a 8 3 30 s0ro40 26 % % 3 33 dea ” n % 33 oval 1663 1467 135 1632 4 Table2 Measured value (6) above and below the reference 3 - tangesin umbilial artery, middle cerebral artery, uterine arteries g 2 7 and placentocerebral ratio aes ‘< Sth centile _> 95th centile z Umbilical arcery 6a 44 5 Middle cerebral artery 5.0 Z-2 Placentocerebral ratio SA 39 3 Placenal retin stery 38 a8 es ——, —Nowplacemaluternearery 53, 63 ‘TOSS Mean toch ern aeres $2 6s Standard deviation score Figure 1 Normal plot of residuals fr Vplacentocerebral tio transformation. The proportion of observations falling between and outside the fitted centiles was calculated (Table 2). The regression equations are shown in Table 3. Figures 2-7 show the raw data for each measurement superimposed on the Sth, 50th and 95th centiles together with the 95% confidence intervals for the Sth and 95th centiles. Tables 4 and 5 show the estimated centiles at each week of gestation. DISCUSSION Fetal and uteroplacental blood flow velocity waveform indices have been studied by multiple investigators to des- cribe the physiological and pathological changes in the fetomaternal circulation during pregnancy. However, pub- lished reference ranges vary considerably. Our objective ‘was to overcome the numerous design and methodological flaws identified by Bland and Altman’? in previous studies. Choosing an appropriate sample with which to con- struct a reference range is crucial. It should be repre- sentative of the whole relevant population. In theory, a random sample should be taken of all pregnant women in the country; however, this is impossible in practice. We 114 Ultrasound in Obstetrics and Gynecology uscd data routinely collected in a single clinic. This may lead to a degree of unrepresentativeness, but to overcome this, only a single (the first) Doppler scan per pregnancy was used for analysis. Since Doppler scans are routinely performed in our clinic, there was no danger of including a large quantity of high-risk patients in our stady. The most difficult aspect of constructing a reference range concerns the exclusion criteria. In particular, it is desirable to have a general rule not to exclude individuals on the basis of information unavailable at the time of measurement”. Most studies have excluded preterm pregnancies and also ‘measurements relating to newborns weighing less than the 10th centile for gestational age'*”*'", However, birth weight and gestational age at delivery are unknown at examination at, say, 26 or 30 weeks. Consequently such exclusions create a supernormal sample. The use of an unselected series is more appropriate for tracking pregnan- cies over time, when there is no screening for a specific abnormality. We only made minimal exclusions: multiple pregnancies, intrauterine fetal death or maternal complica- tions at examination. To ascertain that we were not dealing with a high-risk sample, we confirmed that the frequency of fetal biometry values (particularly fetal abdominal 56Resistance indices Kurmanavicius et al. Table 3 Regression equations used to generate resistance index (RI) charts and tables in umbilical artery, middle cerebral artery, uterine arteries and placentocerebral ratio (PCR). W, gestational age in weeks; SQRT, square root; La, natural logarithm Regression equation Umbilical artery Sthcentile RI = 0.872 -0.0107°W Sth centile RI = 0.952 ~ 0.0098*W 9th centile RI = 1.034 ~ 0.0086*W Middle cerebral artery Sth centile SOth centile RI 95th centile not calculated Placentocerebral ratio Sch centile 0th centile 9th centile Placental uterine artery Sthentile RI = 0.274 + 0.00015*W SOch centile RI = 0.426 - 0.00094" 95th centile RI = 0.657 - 0.00297°W Non-placental uterine artery Stheentile RI =0.389 ~ 0.00173°W SOth centile RI = 0.546 ~ 0.00234" 95th centile RI = 0.767 - 0.00315*W Meant of both uterine arteries Sth centile 349 ~ 0.000847 W 0th centile 488 — 0.00163°W_ sth centile RU = (12.82 + 8.2045*Ln(W) ~ 1.2265*Ln(W)*Ln(W)) ~ 1.65*0.002242°W “12.82 + 8.2045*Ln(W) ~ 1.2265*La(W)*Ln(W) PCR = 6.5164 ~ 2.7392°SQRTIW) + 0.4881*SQRT(W)*Ln(W) PCR = 6.8931 ~ 2.9091 °SQRTIW) + 0.5246*SQRT(W)*Ln(W) PCR = 7.6995 ~ 3.3369°SQRTIW) + 0.6176*SQRT(W)*LniW) 1683 ~ 0,00288°W_ circumference) below the Sth centile at examination was, as expected, less than 5%. Mean birth weight was 3173 + 672 g, compared with that of the general Swiss population of 3260+ 1010g in 1985”. Unfortunately, there are no current epidemiological pregnancy data (at least not of mean birth weight and SD) available on the ‘Swiss population and 10-year-old data cannot be used for comparison. ‘Many of the published reference values were con structed using a longitudinal study design?34001222 Longitudinal studies were originally used to obtain data about within-subject changes over time. However, these studies do not appear to contain any analysis of within- subject changes in Doppler measurements: there is virtually no information on the number of scans per patient or on ‘whether each patient had the same number of scans. Roys ton” has estimated that a longitudinal study design re- quires more age-related scans than does a cross-sectional, design. Most studies reporting Doppler reference ranges have used small sample sizes, thereby accounting for the differences between the ranges concerned. The general rule states: the larger the sample size, the greater the precision of the resulting centles™. Because attention is concentrated on the tails of the distribution, several hundred observa- tions are necessary to get reasonable estimates of extreme centles*, Confidence intervals are commonly used to measure the precision of the estimates. However, many publications make no distinction between the reference range describing the berween-subject variation in a meas- ‘urement and the confidence interval indicating the range of, uncertainty of a statistical estimate. The 95% confidence intervals for the Sth and 95th centiles are evidence of the latter’s statistical variation and are closely related to sample size. For example, if our sample size was 200, the 95% confidence interval for the 95th centile would be £0.24 SD; corresponding figures for sample sizes of 1000, and 1667 would be £0.11 SD and +0.084 SD, respec tively. Yet this parameter was not calculated in any study except that by Sonesson and co-workers”, in which a small sample size resulted in wide 95% confidence bands. Bland and Altman® and Altman and Chitty have argued that reference centiles should change smoothly with gestation and be a good fit to the data. The regression ‘model must be as simple as possible. The scatter diagrams with the centiles superimposed in Figures 2-7 show a good, fit between the data and the regression models. Only a few publications provided smoothed reference curves!*#1721 or scatter diagrams of the data. Doppler data commonly show a positive skewness for umbilical and uterine artery Ris as well as for the placentocerebral ratio, meaning that the intervals between the 50th and 95th centiles must be larger than those between the SOth and Sth centiles. The riddle cerebral artery RI is negatively skewed and has larger intervals between the 50th and Sth centiles. We used different data transformations for the different vessels to achieve a normal distribution of residuals or at least reduce the skewness as much as possible. However, in one case it ‘was impossible to achieve a normal distribution of the upper values of the middle cerebral artery RI. [tis known, that only the Sch centile of the middle cerebral artery RI is Ultrasound in Obstetrics and Gynecology 115 57Resistance indices Kurmanavicius et al 1.00 0.90 0.80 0.70 0.60: 0.50: 0.40) Resistance index 0.30 0.20 0.10: 0.004 24 26 28 30 32 34 36 38 40 42 Gestational age (weeks) Figure 2 Raw data for umbilical artery resistance index with fitted Sth, SOch and 95th centiles together with 95% confidence intervals forthe Sth and 95¢h centiles 1.00) 0.90 0.80 0.70 0.60 0.50 0.40 Resistance index 0.30 0.20 0.10 0.00: 24 26 28 30 32 34 36 38 40 42 Gestational age (weeks) Figure 3 Raw data for middle cerebral artery resistance index with fitted Sth and SOth centiles together with 95% confidence intervals forthe Sth centile clinically important. Therefore, only the Sth centile was are inappropriate for reference ranges!" If adequate calculated. account is not taken of the change in measurement vari- common feature of age-related data is that both mean ability with gestation, a common error with serious con- and SD change with age. Methods assuming a constant SD sequences is that centiles are too far apart early in 116 Ultrasound in Obstetrics and Gynecology 58Resistance indices Kurmanavicius et al. 1.40 1.20 1.00 0.80 0.60 Placentocerebral ratio 0.40 0.20 0.00 4 26 28 30 32 34 36 38 40 a2 Gestational age (weeks) Figure 4 Raw data for the placentocerebral ratio with fitted Sth, SOth and 95th cenciles together with 95% confidence intervals for the Sth and 95th centiles 1.00 090 ‘i oso 0.70 0.60 0.50 Resistance index 0.30 0.20 0.00. 24 26 28 30 32 34 36 38 40 a2 Gestational age (weeks) Figure S Raw data for placental uterine artery resistance index with fited Sth, SO¢h and 95th centiles together with 95% confidence intervals for the Sth and 9Sth centiles pregnancy and too close later on®™°2", In our own fetal variation with increasing gestational age. Maternal (uterine Doppler study, as well as in fetal biometry generally", we artery) Doppler values, on the other hand, show less varia~ found no fetal measurement that did not show increasing tion with advancing gestational age. A small amount of Ultrasound in Obstetrics and Gynecology 117 °9Resistance indices Kurmanavicius et al 0.90 0.80 0.70 0.60 0.50 Resistance index 0.40 0.30 0.20 . 0.10 26 28 30 32 34 36 38 40 a2 Gestational age (weeks) Figure 6 Raw data for non-placental uterine artery cesistance index with fitted Sth, SOth and 95th centiles together with 95% confidence intervals forthe Sth and 95th centiles 1.00 0.30 0.380 070 0.60 0.50 0.40 Resistance index: 0.30 0.20 0.10 0.00. 24 26 28 30 32 34 36 38 40 a Gestational age (weeks) Figure 7 Raw data for the mean placental and non-placental uterine artery resistance index with fitted Sth, SOch and 95th centiles together with 95% confidence intervals forthe Sth and 95th centiles 118 Ultrasound in Obstetrics and Gynecology 60Resistance indices Kurmanavicius et al Table 4 Fitted esistance index (RI) centiles in the umbilical artery, middle cerebral artery and placentocerebral ratio Umbilical artery Middle cerebral artery Placemtocerebral ratio Week of = —— gestation Sth 50th 95th Sth 00h 9th Sth 50th 95th ry 0.61 O72 0.83 078 0.87 = 0.70 081 097 25 0.60 0.71 082 0.79 0.88 = 0.68 0.79 036 26 059 0.70 081 0.80 0.89 = 0.66 0.78 08s 7 058 0.69 0.80 0.80 0.30 = 0.64 0.76 094 28 07 068, 0.79 0.80 0.90 = 0.63 075 033 29 0.6 0.67 0.79 0.79 0.90 = 0.62 074 093 30 oss 0.6 0.78 0.79 0.90 = 0.60 073 093 31 04 065 0.77 0.78 089 = 0.60 073 093 32 0.83 0.64 0.76 0.76 0388 = 059 072 093 3 0.82 0.63 0.75 07s 0.87 = og on 0.94 34 ost 0.62 074 073 0.86 = 0.8 on 0.94 35 0.50 061 073 072 os = oss on 095 36 049 0.60 073 083 = 087 on 0.96 37 047 0.59 on ost = 07 on 097 38 046 0.58 o71 0.80 = 0.57 on 098 39 os 0.57 0.70 0.78 = 0.8 073 039 40 044 0.56 0.69 0.76 = 0.8 0.73 1.00 a 043, oss 0.68 0.73 = 088 0.74 1.02 a 0.42 0.54 0.67 0.56 71 = 0.59 0.75 1.03 Table S Fitted resistance index (RI) centile inthe uterine arceries Placental uterine artery Non-placental uterine artery ‘Mean of both arteries Week of gestation Sth 00h 95th Seb oth 95th 50h 95th 24 028 0.40 0.59 035 049 0.69 0.33 04s 061 25 028 0.40 oss 03s 049 0.69 0.33 04s 01 26 028 0.40 08 034 a9 0.69 0.33 04s 0.61 7 028 0.40 08 034 o4s 0.68 033 044 ot 28 028 040 037 034 4s 0.68 033 044 0.60 2» 028 0.40 037 034 048 0.68 032 044 0.60 30 028 0.40 07 034 oy 067 032 044 0.60 31 028 0.40 0.56 033 047 0.67 032 04a 0.59 32 028 0.40 056 03 0.47 0.67 032 04a 039 33 0.28 0.40, 0.56 03 047 0.66 032 043 039 34 028 039 0.56 033 0.47, 0.66 032 043 039 35 0.28 039 0s 0.33 0.46 0.66 032 043 oss 36 028 039 oss 033 0.46 0.65 032 043 08 37 028 039 oss 032 0.46 065 032 043 08 38 028 039 0.54 032 046 032 043 057 39 0.28 039 0.4 0332 os 032 042 037 40 0.28 039 0.54 032 os 0.32 042 087 4a 028 039 0.54 032 oas 0.64 031 042 0.56 a 0.28 039 033 032 os 063 031 0.42, 056 data in early and late pregnancy leads to the misinterpreta- tion of reference ranges in nearly all published fetal Doppler studies. A final point is that the data used to construct the reference range should reflect the measurements used in clinical practice. Usually only a single RI reading is taken from the fetal and uteroplacental vessels after six to cight uniform Doppler blood flow velocity waveforms have been obtained. Cycle-to-cycle variation in the um- bilical artery, middle cerebral artery and uterine arteries isslight", providing that appropriate conditions are taken into account. Our data were collected from measurements made by many operators, but the evidence suggests that interoperator variability was relatively low! A positive aspect of multioperator input is the prevention of bias due to the use of only one or two operators. In conclusion, we have presented new fetal and utero- placental Doppler centile charts derived from a cross- sectional study in an unprecedentedly large population of 1675 minimally selected pregnancies, designed to over- come many of the methodological flaws exemplified by earlier publications. ACKNOWLEDGEMENT ‘The authors would like to thank Professor Patrick Royston, (Department of Medical Statistics and Evaluation, Royal Postgraduate Medical School, London) for invaluable help in data evaluation. Ultrasound in Obstetrics and Gynecology 119 gyResistance indices REFERENCES 1. Gerson, A. G., Wallace, D. M., Stiller, R. J, Paul, D., Weiner, Sand Bolognese, R. J. (1987), Doppler evaluation of umbil cal venous and arterial blood flow in the second and third trimesters of normal pregnancy. Obstet. Gynecol, 70, 622-6 2. van Vuge, J. M., Ruissen, C. J, Hoogland, H.J-and de Haan, J. (1987). 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