Z-velocity Yields Low False Positive Rates in Screening for IUGR Independent of Gestational Age Adrian Mondry, Liu

Pengbo, Marie Loh, Max Mongelli

Abstract Background: Ultrasound scans provide the basis for detection of intrauterine growth restriction (IUGR) but often fail to distinguish IUGR from small for gestational age (SGA) fetuses. The present study introduces the concept of z-velocity, calculated as changes in z-scores over time, as an additional criterion in the diagnosis of IUGR. Methods: A computer program simulated 50,000 fetal abdominal circumference (FAC) scans based on published growth formulas. False positive rates (FPR) were calculated to determine optimal scan time and scan intervals. Using data from 325 pregnancies or an independent simulation of 32,000 FAC scans where real data did not allow statistically meaningful analysis, the two methods were compared using receiver operator characteristics (ROC). Results: Longer scan intervals generate lower FPR. A scan interval of three weeks with cut off point dz/ dt < -0.5 generates an optimal FPR of about 2%. ROC showed areas under the curve > 0.74 over the complete range of scan intervals. The positive predictive value of growth arrest as only diagnostic criterion, however, is too low to recommend it as exclusive or first diagnostic criterion. Discussion: Z- velocity may provide a viable addendum to 10th percentile as diagnostic criterion for IUGR by reducing FPR well below the published 16- 49%. It can be used to decide whether further diagnostic measures such as umbilical chord Doppler are called for in fetuses that fall below the 10th percentile. The diagnostic gain of combined diagnostic approaches can be calculated from large databases that include ponderal index as gold standard.

Introduction Birth weight lower than normal, commonly understood as below the 10th percentile, may be associated with increased morbidity and mortality, both in the perinatal period and in the later course of life1-3. Monitoring of intrauterine fetal growth by measuring standardized parameters of ultrasound morphometry allows the consulting physician to assess the potential risk of perinatal stress and to plan appropriate birth strategies2, and some causes for inadequate growth may be susceptible to treatment if recognized in

time4. Unfortunately, two commonly used terms in the process of decision making remain insufficiently defined and are often used synonymously: Small for Gestational Age (SGA) and Intrauterine Growth Restriction (IUGR). For the sake of clarity, in the following, SGA is defined as any fetus whose development parallels the normal growth curve, but is below the 10th percentile, while IUGR is attributed to any fetus whose growth departs from this parallel, even within the boundaries of the 10th percentile (see figure 1).

Figure 1: Comparison of SGA, IUGR and normal growth fetus by customized growth chart The potential for intervention necessitates a correct and early diagnosis of potentially low birth weight. Technically more demanding procedures such as umbilical Doppler scan can help differentiate between a constitutionally small fetus and one that is truly compromised. Convincing parents of the necessity to conduct supplementary diagnostic measures, however, may increase their level of anxiety which can have negative implications on the course of the pregnancy5,6. In view of this, the consultant obstetrician must carefully compromise between sensitivity and specificity of his initial suspicion. Given the narrow definition as defined above, the aim of this study is to describe a mathematical model for the diagnosis of IUGR based on growth velocity calculated from changes in z-scores per unit of time, discuss its limitations and translate it into practical recommendations. Materials and Methods Definition of terms and objective of the present study: The present study compares two methods for the diagnosis of intrauterine growth restriction (IUGR) based on fetal abdominal circumference (FAC) measurements. The first method is the classical method. Comparing individual fetus FAC scans to normalized growth charts, it uses as cutoff value for diagnosis of IUGR the lower 10th

percentile, i.e. if the FAC value for the fetus falls below the 10th percentile value for its corresponding gestational age, it is classified as IUGR. In this study, the 10th percentile cutoff values published by Chitty et al.7 were used. The second method proposed here uses growth velocity arrest, that is assessment of the fetuss growth rate calculated as z- velocity, as the factor for IUGR diagnosis. The z- velocity, dz/dt, is calculated as follows. ------------ (1) where Zscore(1) and Zscore(2) are the Z-scores calculated at the time of the first and the second ultrasound scan respectively, and scaninterval is the scan interval between the first and second ultrasound scan in weeks. The z-score gives the number of standard deviations that a measurement is from the mean. In this case, the measurement used is the fetal abdominal circumference (FAC). The formula for calculating Z-score for a given fetus i of gestational age j, denoted by Zscorei,j, is:
Zscorei , j = Observed _ FAC i , j Mean _ FAC j SD _ FAC j

------------ (2)

where Observed_FACi,j is the actual observed measured FAC value for fetus i of gestational age j while Mean_FAC and SD_FAC are the mean and standard deviation of simulated observed FAC measurements of gestational age j respectively. Theoretically, a normally growing fetus will have dz/dt values close to zero. IUGR can be diagnosed when dz/dt <0, as this is indicative of a lack of growth of the fetus. Here, the performance of the method is analyzed for various cut- off points between 1 and 0. The objective of the study is to answer the question whether the use of z- velocity instead or in addition to the classical 10th percentile method will improve the ultrasound based diagnosis of IUGR. Patients: Ultrasound scans from 325 British pregnancies identified as low risk for IUGR were used for assessment of the reliability of growth velocity arrest as diagnostic criterion for IUGR. After informed consent was obtained, each of the candidates underwent observations for different periods of time ranging from 14 to 105 days. The ultrasound measurements for the fetal abdominal circumference were taken every 1~6 weeks from 26 weeks of gestation onwards. All pregnancies led to singleton births. Table 1 and 2 summarized clinical characteristics of the maternal and infant data respectively. The patient cohort has been characterized more in detail previously8.

Mean: 26.74 SD: 4.81 Mean: 163.59 Height (cm) SD: 6.31 Mean: 66.48 Weight (kg) SD: 11.7 European: 93.8% Indo-Pakistani: 4.3% Ethnic Groups Afro-Caribbean: 1.2% Others: 0.6% Mean: 0.73 Parity SD: 0.91 Table 1: Maternal clinical characteristics Age (year)

Mean: 3406.09 SD: 552.55 Mean: 277.56 Delivery time (day) SD: 12.31 Table 2: Newborn clinical characteristics Birth Weight (g) Simulations: Two independent simulations of fetal abdominal circumference were computer generated as described below. The first simulation of 50,000 cases was used as a reference population, while the second simulation of 32,500 cases was used as samples to assess the efficiency of growth arrest calculated by z- score for the diagnosis of IUGR. To obtain the mean and standard deviation of simulated observed FAC measurements of gestational age j, a simulation consisting of 50,000 cases was performed. Using a published growth formula9 for British women and a fixed coefficient of variation of 5% for ultrasound error, computer software is used to generate a normal growth chart for FAC according to gestational age, then an error value is introduced to simulate observed values. A java program was written for the simulation, which runs on a Pentium IV PC. A random number generator was employed to produce a range of random numbers between 0 and 1. Normally distributed z values were then derived from these random numbers using a rational approximation for the standard distribution of Odeh and Evans10. Note that these are not the final z values used for the calculation of dz/dt. These derived z values are then used as the seed to generate the two ultrasound scan simulations. The computer first generates the true value of FAC at the initial scan according to Chittys formula7. The observed FAC value is then calculated based on the true value plus an error term, which is randomly allocated to the known ultrasound error for this

variable. For the simulation runs, a coefficient of variation for ultrasound error 5% was entered. For simplicity, a constant coefficient is chosen for all gestational ages. For comparison of the two diagnostic methods, Receiver Operating Characteristics (ROC) were calculated using data from a British population. The samples were 325 British pregnancies identified as low risk population for IUGR. With respect to sample size in ROC analysis, it has been suggested that meaningful qualitative conclusions can be drawn from ROC experiments performed with at least a total of about 100 observations11. Hence, the given data from real pregnancies allowed to perform ROC for the following combinations of gestational age and scan interval (Table 3) only. Gestational Age at First Scan (weeks) 26-28 Scan Interval (weeks) 6 3 29-31 6 3 32-34 4 5 35-37 3 Table 3: Combinations of Gestational Age and Scan Interval for which ROC was performed

In order to overcome the numerical limitations of the data from real pregnancies, an independent population of 32,500 cases was simulated to provide sufficient sample size for statistical analysis. Wherever mathematically meaningful, results from the analysis of data from real pregnancies was used, or analysis of simulated cases was compared to real data. All statistical analysis was done using SPSS 11.5 for Windows (SPSS Inc., Chicago, Il, USA). Results The simulated true FAC measurements and observed FAC measurements have a very similar mean value and standard deviation (table 4.) compared with the published data for British women12. GA (wk) 23 24 25 'Observed' fetal AC values Mean SD 178.66 11.03 189.40 11.63 199.77 12.28 'True' fetal AC values Mean SD 178.71 6.47 189.34 6.81 199.82 7.14 Reference values [A] Mean SD 190 10.2 206 12.7 214 11.8 Reference values [B] Mean SD 181.17 11.09 191.51 11.58 201.84 12.08

26 210.17 12.90 210.12 7.50 228 9.9 212.17 12.57 27 220.50 13.55 220.50 7.87 238 10.1 222.50 13.07 28 230.76 14.18 230.65 8.27 247 11.7 232.83 13.56 29 240.54 14.76 240.62 8.64 255 12.2 243.16 14.05 30 250.36 15.48 250.43 9.04 269 13.4 253.49 14.54 31 259.95 16.06 260.09 9.35 278 12.6 263.82 15.04 32 269.66 16.57 269.68 9.70 291 13.5 274.16 15.53 33 279.17 17.17 279.12 10.02 300 12.1 284.49 16.03 34 288.39 17.83 288.35 10.46 314 13.9 294.82 16.52 35 297.55 18.42 297.50 10.79 322 12.5 305.15 17.02 36 306.60 18.97 306.49 11.13 329 15.5 315.48 17.51 37 315.05 19.43 315.18 11.53 338 14.8 325.82 18.00 38 323.87 20.02 323.82 11.90 343 16.8 336.15 18.50 39 332.06 20.67 332.17 12.33 349 20.6 346.48 18.99 40 340.55 21.09 340.40 12.55 369 14.5 356.81 19.49 Table 4.: Simulated Observed and True FAC value compared to published measurements by [A] Larsen12 and [B] Chitty7. GA: gestational age. Wk: week. AC: abdominal circumference. SD: standard deviation Receiver operator characteristics were calculated comparing the growth velocity arrest method against the classical method. Due to restricted sample size of the pregnancies described in8, only the combinations shown in figure 2 could be calculated.

26-28wks; 6wks
1.0 .9 .8 .7 .6 .5 .4 .3

29-31wks; 3wks
1.0 .9 .8 .7 .6 .5 .4 .3

29-31wks; 6wks

32-34wks; 3wks

Sensitivity

.2 .1

Sensitivity
.1 .2 .3 .4 .5 .6 .7 .8 .9 1.0

.2 .1

0.0 0.0

0.0 0.0 .1 .2 .3 .4 .5 .6 .7 .8 .9 1.0

1 - Specificity

1 - Specificity

32-34wks; 4wks

32-34wks; 5wks

35-37wks; 3wks

1.0 .9 .8 .7 .6 .5 .4 .3

1.0 .9 .8 .7 .6 .5 .4 .3

1.0 .9 .8 .7 .6 .5 .4 .3

Sensitivity

Sensitivity

.2 .1

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Sensitivity
.1 .2 .3 .4 .5 .6 .7 .8 .9 1.0

.2 .1

0.0 0.0 .1 .2 .3 .4 .5 .6 .7 .8 .9 1.0

0.0 0.0

0.0 0.0 .1 .2 .3 .4 .5 .6 .7 .8 .9 1.0

1 - Specificity

1 - Specificity

1 - Specificity

Figure 2: ROC curves using data from 325 British pregnancies. The individual indices tell at what gestational age the first scan was performed, and the scan interval. The overall test performance of each measurement was assessed by examining the area under the ROC curve (AUC, table 5), which is considered the best discriminator of diagnostic performance11. In the present study, the area under the curve represents the probability that the growth velocity (dz/dt) value for a randomly chosen positive IUGR case will be less than the result for a randomly chosen negative IUGR case. Most of the AUC values were above 0.7 and had reasonably small standard errors. All the ROC yielded significances of less than 0.05 (except for gestational age 26-28 weeks and scan interval 6 weeks), which indicates a rejection of the null hypothesis of true AUC = 0.5 at 5% significance level. Gestational Age at Scan Interval AUC Standard 95% CI First Scan (weeks) (weeks) (significance) Error Lower Upper 26-28 6 0.675 (0.048) 0.083 0.512 0.839 29-31 3 0.730 (0.093) 0.099 0.536 0.925 6 0.715 (0.028) 0.088 0.543 0.887 32-34 3 0.705 (0.045) 0.082 0.545 0.865 4 0.755 (0.006) 0.074 0.610 0.899 5 0.876 (0.000) 0.050 0.778 0.974 35-37 3 0.801 (0.001) 0.060 0.684 0.919 Table 5: Area under the ROC curve (AUC) values for various gestational ages and scan intervals The corresponding false positive rates (FPR), that is the percentage of samples incorrectly identified as IUGR as described previously8,13, are summarized in table 6. Across all gestational age and scan intervals, as the dz/dt cutoff decreases from 0 to -1, FPR decreases from above 28% to around 1%. However, at the same time, true positive rates (TPR) also decrease from above 60% to below 4%. For further analysis, the median cutoff value of dz/dt = -0.5 was chosen as it maintains clinically acceptable FPR values of less than 2.2% across all gestational ages and scan intervals tested. Gestational Age at Scan Interval dz/dt cutoff

(weeks) 0 -0.25 -0.5 -0.75 -1 6 28.3 8.7 2.0 1.7 0.5 3 37.7 10.8 2.2 1.8 1.3 6 55.8 8.8 1.2 0.8 0.5 32-34 3 50.0 13.6 2.1 1.5 1.0 4 37.7 7.3 0.0 0.0 0.0 5 44.6 5.1 0.0 0.0 0.0 35-37 3 50.5 18.9 1.7 1.5 1.2 Table 6: False Positive Rates (FPR) values for identification of IUGR cases using zvelocity for diagnosis When the ROC computation is repeated using the much larger dataset of 32,000 simulated cases, the analysis can be carried out over the full range of gestational age and scan intervals as all cells are sufficient in number (table 7). Comparing growth velocity arrest against the classical method, all AUC values were at least 0.74 and with corresponding p-values of < 0.001. Standard error was also low at 0.003 across all combinations. AUC increases with larger scan interval and is generally independent of the gestational age.

First Scan (weeks) 26-28 29-31

Gestational Age (wk) 23 24 25 26 27 28 29

1 0.752 0.750 0.749 0.742 0.746 0.743 0.750

2 0.767 0.759 0.756 0.752 0.756 0.756 0.755

Scan Interval 3 4 0.767 0.777 0.768 0.775 0.764 0.773 0.763 0.770 0.760 0.767 0.761 0.771 0.759 0.768

5 0.792 0.787 0.787 0.783 0.776 0.774 0.778

6 0.799 0.789 0.785 0.788 0.786 0.781 0.783

30 0.743 0.754 0.752 0.761 0.773 0.780 31 0.747 0.754 0.759 0.767 0.771 0.776 32 0.742 0.751 0.757 0.764 0.770 0.772 33 0.748 0.750 0.758 0.760 0.767 0.772 34 0.747 0.752 0.759 0.760 0.766 0.770 35 0.741 0.758 0.757 0.762 0.768 0.768 36 0.747 0.747 0.757 0.759 0.762 0.770 37 0.743 0.751 0.759 0.764 0.766 NA 38 0.748 0.754 0.752 0.761 NA NA 39 0.748 0.750 0.754 NA NA NA 40 0.748 0.753 NA NA NA NA Table 7: Area under ROC curve (AUC) values using simulated data across gestational ages (23-40 wks) and scan intervals (1-6 wks) (NA: Time at 2nd scan is more than 42 weeks of gestation) Discussion A fetus is commonly considered as small for gestational age (SGA) if ultrasound measurements show an abdominal circumference and estimated birthweight below the 10th percentile14,15. Within the heterogenous group of SGA fetuses, 50- 70% are constitutionally small16. The lower the percentile cutoff point is set, however, the more likely a SGA fetus is not constitutionally small, but suffers from fetal growth restriction (IUGR), and the high incidence of truly IUGR fetuses is thought to explain the poor perinatal outcome of several studies examining SGA births17,18. Numerous studies (summary in15) show that lower than average birth weight may be associated with increased morbidity and mortality in later life. While it seems likely that genetic and environmental factors play a pivotal role19,20, estimates of lower birth weight during pregnancy may allow intervention on various levels. Interventions may address external social factors such as smoking, alcohol consumption and use of illicit drugs that contribute to pregnancy outcome21, or medical problems such as obstructed umbilical chord, thrombophilia, insufficient placental perfusion, and placenta previa. The potential for intervention obliges the consultant obstetrician to secure the diagnosis, and the particularly vulnerable psychological environment of pregnancy calls for an optimal balance of sensitivity and specificity in the decision- making process. Fetal abdominal circumference (FAC) and estimated fetal weight (EFW) are the most accurate diagnostic measurements to predict SGA. In high-risk women, FAC at less than the tenth percentile has sensitivities of 72.994.5% and specificities of 50.683.8% in the prediction of fetuses with birthweight at less than the tenth percentile. This allows to calculate false positive rates (FPR) of 16.2- 49.4%. The respective figures for EFW are sensitivities of 33.389.2% and specificities of 53.790.9%14, with FPR 9.1- 46.3%. A recent Cochrane collaboration review22 that examined routine late pregnancy (after week 24) ultrasound examinations with regards to altered perinatal outcome, however, found no conclusive benefit in maternal populations of unspecified or low risk. In low risk populations, it may be inferred that the FPR is relatively higher, as it has been postulated that in high risk populations, the high number of

In view of these findings, optimization of diagnostic procedures to increase specificity and sensitivity with the aim to reduce false positive diagnosis of IUGR as a trigger of anxiety seems a worthwhile endeavor. Monitoring of fetal growth velocity has been suggested as an alternative diagnostic criterion to the classical 10th percentile cutoff point before23, and is carried out routinely in late pregnancies with unclear gestational age24, but the efficiency of this approach is questionable25. This is to a large extent due to a high rate of false positive diagnoses. Using a mathematical model13 that assumed a coefficient of variation of 5% for error in ultrasonographic measurement (variability within and between observers) and a definition of IUGR as no apparent growth in abdominal circumference between two consecutive scans, false positive rates were shown to be high (12- 31% for scan intervals of one or two weeks started between week 28 and 38) and, as expected, they increased with shorter time intervals between scans and increasing gestational age. Accordingly, a cut- off point of 2 standard deviations was recommended25 for decision making whether additional diagnostic procedures such as umbilical Doppler scan should be initiated. This suggestion has met with critique26 as being too strict, thus reducing the sensitivity of the procedure, and the traditionally used 10th percentile cut off was recommended. As this is the generally accepted diagnostic criterion, the present study uses it for calculation of false positive rates as previously reported8,13. For clinical purposes, it would be ideal to assess the gain in diagnostic performance if zvelocity is used in addition to the classical 10th percentile method. Such a combination would necessarily result in a trade- off in sensitivity and specificity of the combined test relative to the individual component tests. This trade- off can be used as for deciding whether the combined test is advantageous over the individual tests27 on the basis of their likelihood ratios if sensitivity and specificity can be calculated for the individual tests by comparing them against a true- true gold standard. In the setting of the current study, comparison of diagnosis to ponderal index as absolute true/ gold standard was not possible: the data from real pregnancies8 did not include birth length, which could be used to calculate the ponderal index and thus distinguish better between SGA and IUGR pregnancies. The growth formula used for simulation did not account for birth length either, so that no birth lengths could be simulated that corresponded to the simulated FAC values. In fact, an adequate simulation seems not viable as the times of peak length velocity and peak weight velocity differ in utero, and therefore, it is generally assumed that alterations in the patterns of growth at different stages in gestation will lead to different anthropometric phenotypes at birth28. Even more disadvantageous for meaningful simulation of estimated birth length are recent findings in a small cohort of 44 Belgian women that length growth occurs in a gender- specific, pulsatile way in healthy fetus29. The use of simulation, however, is justified in order to allow for statistical meaningful numbers. The simulation is acceptably close to real pregnancies (table 4 and references7,12). While the analysis of z- velocity is novel to the present study, the simulation is based on a well established model13 that has been used for the assessment of growth velocity (but not z- velocity) in the diagnosis of IUGR25 and in highlighting the importance of customized growth charts for assessing normal growth8,26. Calculation of z- scores depends on a sizeable and customized reference database of

meaningful composition. Here, reference database and sample simulation were based on the same growth formula, so that a correct customization can be assumed. In practical application, the need to customize reference databases cannot be stressed enough8,26. As such, the use of simulation lies in highlighting probable results from real data and pointing out what information is needed not only to verify the prediction, but more importantly so answer the clinical want for more secure diagnosis of IUGR. In view of the findings presented here, the following diagnostic proceedings seem recommendable: In fetus smaller than 10th percentile found accidentally in a low risk pregnancy, a second scan after three weeks with calculation of z- velocity should be carried out to reduce the potential for false positive diagnosis of IUGR unless other clinical parameters indicate the need for more rapid diagnosis. The data from 325 real pregnancies can in this context be regarded to have the value of extended case descriptions. As such, however, it may have a value quite different from, but equal to that of a randomized, controlled study. Aronson recently discussed the value of medical anecdotes30; of the eight reasons listed there, the present study meets four: it generates a hypothesis (i.e., use of z- velocity reduces the rate of false positive diagnosis of IUGR and therefore rate of high- level interventions), it suggests a method of management (i.e., stepwise approach with regular scan and use of z- velocity in low risk cases where the fetal growth lies below the 10th percentile), it reminds and educates (i.e., of the benefit of early ultrasound, the importance of customized growth charts, and the lack of evidence for a benefit of ultrasound screens in low risk populations), and it hopes to stimulate a systematic review (i.e., the authors hope that the results will entice large scale data collectors such as national/ international obstetrics associations to design and carry out a prospective, randomized study). More often than not, observational studies give similar results to controlled randomized trials31,32, and critical appraisal of this notion leads to the conclusion that, while good controlled randomized trials do provide the highest level of evidence, a flexible approach may be taken "in which randomised controlled trials and observational studies have complementary roles. High quality observational studies may extend evidence over a wider population and are likely to be dominant in the identification of harms and when randomised controlled trials would be unethical or impractical"33. In view of this, only analysis of a very large database of real pregnancies that holds the required information (FAC, birth weight, birth length for this specific purpose) would allow to first calculate the ponderal index as a gold standard against which the individual and combined tests sensitivity and specificity could then be calculated and thus evaluated. If such data is available for retrospective analysis, the diagnostic benefit of sequential ultrasound with calculation of z- velocity compared to other diagnostic techniques can be calculated27, and definite practical recommendations can be made. Reference 1. 2. Kady MS, Gardosi J. Perinatal mortality and fetal growth restriction. Best Pract Res Clin Obstet Gynaecol 2004;18(3):397. Thornton JG, Hornbuckle J, Vail A, et al. Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial. Lancet 2004;364(9433):513.

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Over the years three terms associated with pathological intrauterine growth have come into common use, but are still not clearly defined in the sense that they are often used synonymously. These are Small for Gestational Age (SGA) and Intrauterine Growth Restriction (IUGR), the latter divided into symmetrical and asymmetrical IUGR. Looking at the distinctive association of various causes with different patterns of growth, it makes sense to clarify the terminology. From a physiological point of view, two forms of pathological growth can be distinguished: symmetrical and asymmetrical growth deficiency34. Symmetrical IUGR may indicate an early intrinsic insult impairing fetal growth, such as chromosomal abnormalities and congenital malformations, drugs or other chemical agents, or infection. Growth is symmetrically impaired because the insult happens at a time when fetal growth occurs primarily by cell division, and is very likely due to an early intrinsic insult, such as chromosomal aberrations and congenital malformations, chemical toxins including drugs, or infections. These suspicions usually arises from the maternal history and cannot be clarified any further by ultrasound alone but need other diagnostic measures, such as fetal karyotyping, serum examination for evidence of infection, clinical observation for signs of preecalmpsia, and evaluation of congenital and acquired thrombophilic disorders. Symmetric growth restriction usually occurs earlier in pregnancy, results more often in preterm labor than asymmetric growth restriction, and affected fetus have a higher neonatal morbidity rate and attain a lower mean birth weight than those with asymmetric growth restriction35. By contrast, asymmetric growth restriction is usually caused by extrinsic factors that result in inadequate supply for the fetal metabolism, most often due to maternal vascular disease and decreased placentar perfusion. Musculoskeleton and head circumference develop normally, whereas the abdominal circumference is decreased due to subnormal liver size and lack of subcutaneous fat. Asymmetric growth restriction usually occurs later in pregnancy, when fetal growth is usually due more to an increase in cell size than in cell number36. The growth pattern of SGA is much alike to the symmetrical type IUGR. Small for Gestational Age should be applied to fetus below the 10th percentile, which display normal anatomy and a normal growth pattern, i.e. parallel the normal growth curve at a fixed distance. If the fetus is somewhat small, but anatomically normal with an appropriate amniotic fluid volume and growth rate, the outcome will usually be a normal, constitutionally small neonate. If compared to a local, matched reference population, about 70% of fetus with an estimated birth weight below the 10th percentile will be constitutionally small16, and thus not be at increased risk.

Given this background, it makes sense to use the term SGA for all fetus below the 10th percentile, unless maternal history arouses suspicion of growth restriction, or any of the potential causes for symmetric growth restriction have been diagnosed. Under these circumstances, SGA becomes synonymous with the healthy, but constitutionally small fetus, while the term IUGR is reserved for those fetuses that have reason for or show signs of a pathological growth pattern. Mathematically, such a pathological growth pattern is best expressed by the z score, which represents the growth velocity. In the present simulation, when dz/dt is less than zero, the growth curve is no more parallel to the normal growth curve, which leads to IUGR diagnosis. Nevertheless, this review noted an awareness that repeated ultrasound examinations have a psychological impact on the mothers which at the time was insufficiently examined, and recommended that further studies focus on this topic. In developed societies with health care systems that provide if not mandate extensive antenatal monitoring, both parents and doctors often seem to perceive pregnancy as a manageable disease rather than a physiological state. The potential to use additional diagnostic measures may raise the anxiety level, which in consequence leads to increased health care use during pregnancy. The mothers perception of being at risk affects their psychosocial status37. Significant associations were found between depression and/or anxiety and increased nausea and vomiting, prolonged sick leave during pregnancy and increased number of visits to the obstetrician, specifically, visits related to fear of childbirth and those related to contractions. Planned cesarean delivery and epidural analgesia during labor were also significantly more common in women with antenatal depression and/or anxiety5. Maternal anxiety level was found to be associated with increased risk for preterm birth38. Whether the neonate is affected by maternal anxiety or mood disorders in general is controversial39,40, but it seems that maternal antenatal anxiety leads to emotional and behavioral problems in the children at four years of age41,42.